Konsensus FIGO 2016

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Volume 131 Supplement 2 October 2015 ISSN 0020-7292
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International Journal of Gynecology & Obstetrics Vol. 131 (2015) S75 S172
GYNECOLOGY
OBSTETRICS
International Journal of
FIGO Cancer Report 2015

Guest Editors: Lynette Denny, Michael Quinn
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GYNECOLOGY
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CONTENTS
Volume 131, Supplement 2, October 2015
EDITORIAL
L. Denny, M. Quinn
South Africa, Australia
S75
CANCER STAGING AND CLINICAL GUIDELINES

N.F. Hacker, P.J. Eifel,
J. van der Velden
Australia, USA, The Netherlands
Cancer of the vulva
S76
N.F. Hacker, P.J. Eifel,

J. van der Velden
Australia, USA, The Netherlands
Cancer of the vagina
S84
A. Bermudez, N. Bhatla, E. Leung

Argentina, India, Canada
Cancer of the cervix uteri
S88
F. Amant, M.R. Mirza, M. Koskas,

C.L. Creutzberg
Belgium, Denmark, France,
The Netherlands
Cancer of the corpus uteri
S96
J. Prat, 'N. Mbatani

Spain, South Africa
Uterine sarcomas
S105
J.S. Berek, C. Crum, M. Friedlander

USA, Australia
Cancer of the ovary, fallopian tube, and peritoneum
S111
H.Y.S. Ngan, M.J. Seckl,

R.S. Berkowitz, Y. Xiang,
F. Golfier, P.K. Sekharan,
J.R. Lurain
China, UK, USA, France, India
Update on the diagnosis and management of gestational trophoblastic

disease
S123
P.S. Binder, J. Prat, D.G. Mutch

USA, Spain
The future role of molecular staging in gynecologic cancer
S127
PATHOLOGY
J. Prat
Spain
Pathology of cancers of the female genital tract
S132
CANCER THERAPY
E.. Lundqvist, K. Fujiwara,
M. Seoud
Sweden, Japan, Lebanon
Principles of chemotherapy
S146
M. Seoud, E.. Lundqvist,

K. Fujiwara
Lebanon, Sweden, Japan
Targeted therapy in gynecologic cancers: Ready for prime time?
S150
S.K. Shrivastava, U. Mahantshetty,

K. Narayan
India, Australia
Principles of radiation therapy in low-resource and well-developed

settings, with particular reference to cervical cancer
S153
PATIENT CARE
S.V. Carr
Australia
Psychosexual health in gynecological cancer
S159
K. Weare
Australia
Rehabilitation after gynecological cancer treatment
S164
S.M. Kibel, J.M. Cain

South Africa, USA
Palliative care in gynecological cancer
S167
International Journal of Gynecology and Obstetrics 131 (2015) S75
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics

journal homepage: www.elsevier.com/locate/ijgo
EDITORIAL
The FIGO Gynecologic Oncology Committee is pleased to present the

second edition of the FIGO Cancer Report. Historically the report was
published at each FIGO World Congress as the Annual Report, going
as far back as 1937, and was composed of survival data from various
institutions around the world. Since 2009 the process of collating
international incidence and survival data stopped and a new Committee
was formed. This Committee initiated the current format of the FIGO
Cancer Report and its rst edition was presented at the FIGO Congress
held in Rome, Italy, in October 2012. The Committee has since
established collaboration with the Catalan Institute of Oncology to
resurrect the data collection program. This process is now at an
advanced stage and a detailed situational analysis of institutions able
to provide care to women with gynecological cancers is being conducted as we write this editorial in May 2015. Once the situational analysis is
complete the intention is to select 20 or so institutions in low- and
middle-income countries to collect incidence, stage, treatment, and
survival data. This will give us a global picture of the multiple inequities
in cancer care internationally and enable more targeted intervention by
organizations such as FIGO.
It is our intention to ensure that this, the second edition of the FIGO
Cancer Report, is disseminated as widely as possible internationally, and
therefore the chapters are available online with Open Access. We are
also developing a mobile App of the different criteria for FIGO staging,
which will ensure that those with smart phones will have instant access.
The chapters contained in the report have either been updated or are
new chapters. The new chapters include trophoblastic disease, targeted
therapies for gynecological cancer, rehabilitation after treatment for
gynecological cancer, psychosexual health in gynecological cancers,
palliative care in gynecological cancer, and the future role of molecular
staging in gynecological cancer. These six new chapters are added
to nine others that include the new staging for ovary, fallopian tube,
and peritoneum. Each chapter presents the site specic staging, the
rationale behind staging, as well as internationally accepted evidencebased guidelines. All chapters are fully referenced and the quality of
the evidence for intervention is graded.
The current FIGO Gynecologic Oncology Committee members are:
Lynette Denny (Chair), Gynecologic Oncologist, South Africa
Michael Quinn (Co-Chair), Gynecologic Oncologist, Australia
Sergio Pecorelli (Immediate Past Chair), Gynecologic Oncologist, Italy
Adriana Bermudez, Gynecologic Oncologist, Argentina
Joanna Cain, Gynecologic Oncologist, USA
Keiichi Fujiwara, Gynecologic Oncologist, Japan
Neville Hacker, Gynecologic Oncologist, Australia
Elisabeth vall Lundqvist, Medical Oncologist, Sweden
Jaime Prat, Pathologist, Spain
Shyam Shrivastava, Radiation Oncologist, India
The Committee composition is likely to change during the 2015 FIGO
World Congress when the report will be released, as members leave the
committee after serving a six-year term. The composition of the new
Committee will be announced by the incoming President of FIGO.
Lynette Denny
Groote Schuur Hospital/University of Cape Town, Cape Town, South Africa
E-mail address: lynette.denny@uct.ac.za.
Michael Quinn
Royal Womens Hospital and University of Melbourne, Melbourne, Australia
http://dx.doi.org/10.1016/j.ijgo.2015.06.024
0020-7292/ 2015 Published by Elsevier Ireland Ltd. on behalf of International Federation of Gynecology and Obstetrics. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
International Journal of Gynecology and Obstetrics 131 (2015) S76S83

FIGO CANCER REPORT 2015
Cancer of the vulva

Neville F. Hacker a, Patricia J. Eifel b, Jacobus van der Velden c
a
b
c
Gynecologic Oncology Cancer Centre, Royal Hospital for Women, Randwick, Australia
Department of Radiation Oncology, M.D. Anderson Cancer Center, Houston, TX, USA
Department of Gynecology, Academic Medical Center, Amsterdam, The Netherlands
1. Staging
1.1. Anatomy
1.1.1. Primary site
Cases should be classied as carcinoma of the vulva when the primary site of growth is in the vulva. Any lesion that involves both the vagina
and vulva (i.e. crosses the hymenal ring) should be classied as a carcinoma of the vulva. Tumors that present in the vulva as secondary
growths, from either a genital or extragenital site, should be excluded.
Malignant melanoma should be reported separately. There must be
histologic conrmation of the cancer.
1.1.2. Nodal stations
The inguinal and femoral nodes are the rst sites of regional spread.
1.1.3. Metastatic sites
Patients who have extrapelvic metastases or who have involvement
of pelvic lymph nodes (external, hypogastric, obturator, and common
iliac) are classied as having stage IVB disease.
1.2. Surgical staging classication
The staging system for vulvar cancer has been based on surgical ndings since 1988. The nal diagnosis is dependent upon thorough histopathologic evaluation of the operative specimen (vulva and lymph
nodes). Various modications have been made over time, with a subdivision of Stage I added in 1994. The FIGO staging of vulvar carcinoma
was last changed in 2009 by the FIGO Committee on Gynecologic
Oncology [1], to give better prognostic discrimination between stages
(Table 1). Table 2 compares the FIGO staging with the Union of International Cancer Control TNM classication.
1.2.1. Histopathologic types
Approximately 80% of cases are squamous cell carcinomas, and many
cases, particularly in younger women, are HPV related. Melanomas are
the second most common cancer seen in cancer centers, although
community-based studies have reported basal cell carcinomas to be the
second most common vulvar cancer [2]. The histopathologic types are:
squamous cell carcinoma
melanoma
verrucous carcinoma
Pagets disease of vulva
adenocarcinoma, not otherwise specied (NOS)
basal cell carcinoma, NOS
Bartholins gland carcinoma.
1.2.2. Histopathologic grades (G)
GX: Grade cannot be assessed

G1: Well differentiated
G2: Moderately differentiated
G3: Poorly or undifferentiated.
2. Introduction
Carcinoma of the vulva is an uncommon tumor, representing about
4% of gynecologic malignancies. Because of the relatively small experience of individual institutions, randomized trials of therapeutic approaches are uncommon, and most studies are based on retrospective
clinicopathologic reviews [3].
It is predominantly a disease of postmenopausal women, with the
age-specic incidence increasing with increasing age. Although the
external location of the vulva should encourage early presentation,
vulvar cancers are often advanced at the time of diagnosis.
Most squamous carcinomas occur on the labia majora, but the labia
minora, clitoris, and perineum may also be primary sites.
Vulvar intraepithelial neoplasia (VIN), a precursor lesion in some
cases, tends to occur in younger women and may be associated with
similar lesions of the cervix and vagina. A new classication of squamous VIN was introduced by the International Society for the Study of
Vulvovaginal Disease (ISSVD) in 2004 [4]. The term VIN 1 is no longer
used, and VIN 2 and 3 are simply called VIN. There are two types of
VIN: (1) VIN, usual type (warty, basaloid, and mixed), which is HPVrelated in most cases; and (2) VIN, differentiated type, which is seen
particularly in older women, and is often associated with lichen
sclerosus and/or squamous hyperplasia. The incidence of VIN, usual
type, and the incidence of invasive vulvar cancer in premenopausal
women should both decrease signicantly with increasing use of
HPV vaccination.
N.F. Hacker et al. / International Journal of Gynecology and Obstetrics 131 (2015) S76S83
vulvar dystrophy. Bleeding or discharge is an occasional presenting

symptom, and patients with advanced disease may present with a
lump in the groin caused by metastases to groin lymph nodes.
Table 1
FIGO staging of carcinoma of the vulva.
FIGO
Stage
S77
Description
Tumor conned to the vulva

Lesions 2 cm in size, conned to the vulva or perineum and with stromal
invasion 1.0 mma, no nodal metastasis
IB
Lesions N 2 cm in size or with stromal invasion N 1.0 mma, conned to the
vulva or perineum, with negative nodes
II
Tumor of any size with extension to adjacent perineal structures (lower
third of urethra, lower third of vagina, anus) with negative nodes
III
Tumor of any size with or without extension to adjacent perineal
structures (lower third of urethra, lower third of vagina, anus) with
positive inguinofemoral nodes
IIIA (i) With 1 lymph node metastasis (5 mm), or
(ii) With 12 lymph node metastasis(es) (b5 mm)
IIIB (i) With 2 or more lymph node metastases (5 m), or
(ii) With 3 or more lymph node metastases (b5 mm)
IIIC With positive nodes with extracapsular spread.
IV
Tumor invades other regional (upper 2/3 urethra, upper 2/3 vagina), or
distant structures
IVA Tumor invades any of the following:
(i) upper urethral and/or vaginal mucosa, bladder mucosa, rectal mucosa,
or xed to pelvic bone, or
(ii) xed or ulcerated inguinofemoral lymph nodes
IVB Any distant metastasis including pelvic lymph nodes
IA
a
The depth of invasion is dened as the measurement of the tumor from the epithelial
stromal junction of the adjacent most supercial dermal papilla to the deepest point of
invasion.
Treatment of vulvar cancer used to be primarily surgical, but radiation therapy and, to a lesser extent, chemotherapy have been progressively integrated into the treatment protocol over the past 30 years.
Therefore, management has evolved into an individualized multidisciplinary approach, and patients should be referred centrally to a gynecological cancer center where all relevant expertise is available [5,6]. Level
of Evidence B
3. Screening
There is no screening procedure for vulvar cancer. However, patients
with a past history of cervical or vaginal cancer should have inspection
of the vulva, with or without colposcopic examination, as part of their
regular follow-up. Patients with lichen sclerosus or a past history of
VIN should also be kept under regular surveillance, and taught to undertake regular self-examination with a mirror.
4. Squamous cell carcinoma
4.2. Diagnosis
If the disease appears to be entirely intraepithelial, initial assessment
should consist of multiple biopsies to exclude an invasive focus. A 3 or
4 mm Keyes biopsy instrument is ideal for this purpose. Patients with
multifocal lesions should have biopsies taken from several lesions.
If there appears to be invasive cancer present, a wedge or Keyes biopsy under local anesthesia in the ofce is usually sufcient to conrm
the diagnosis. The biopsy should include some underlying stroma.
For small tumors, it is preferable not to excise the entire lesion at the
time of biopsy because this makes it more difcult to plan the subsequent denitive resection.
If the lesion is 2 cm or less in diameter and depth of stromal invasion is less than or equal to 1 mm on the initial biopsy, radical local
excision of the lesion must be undertaken to allow serial sectioning to
properly assess the depth of invasion. If there is still no focus found
with a depth of invasion greater than 1 mm, this excision will also be
the denitive treatment [3].
4.3. Investigations
(1) Cervical cytology, if applicable.
(2) Colposcopy of the cervix and vagina because of the common association with other squamous intraepithelial lesions.
(3) For large lesions, a CT or MRI scan of the pelvis and groins is helpful to detect any enlarged lymph nodes in the groins or pelvis,
erosion into underlying bony structures, or other evidence of
metastatic disease.
(4) Routine full blood count, biochemical prole, and chest
X-ray preoperatively.
4.4. Clinical practice guidelines

The clinical ndings should be recorded on a staging diagram
(e.g. Fig. 1). The ndings according to the staging delineated in
Tables 1 and 2 are usually listed on the reverse side of the diagram.
4.1. Presenting symptoms

4.5. Treatment
Vulvar cancer may be asymptomatic, but most patients present with
a vulvar lump or ulcer, which may or may not be painful. There is often a
long-standing history of pruritus, which may be due to associated
Table 2
Cancer of the vulva: FIGO staging compared with TNM classication.
FIGO Stage
I
IA
IB
II
IIIA
IIIB
IIIC
IVA
IVB
Union for International Cancer Control (UICC)

T (tumor)
N (lymph nodes)
M (metastasis)
T1
T1a
T1b
T2/T3
T1, T2, T3
T1, T2, T3
T1, T2, T3
T4
Any T
N0
N0
N0
N0
N1a, N1b
N2a, N2b
N2c
N0N2
N3
M0
M0
M0
M0
M0
M0
M0
M0
M0
4.5.1. Treatment of vulvar intraepithelial neoplasia

Various treatment modalities are available for treating intraepithelial
lesions of the vulva [7,8]. Once the diagnosis has been established, supercial local excision of the vulvar epithelium with a 0.51.0-cm margin is
considered adequate for lesions of the lateral aspect of the vulva. Lesions
involving the labia minora may also be treated by local excision but may
respond favorably to laser vaporization. Laser is also appropriate for
clitoral and perianal lesions. Laser treatment of the hair-bearing skin of
the vulva will usually produce depigmentation and destruction of hair
follicles, with subsequent loss of hair growth. Large lesions may be
treated with a skinning vulvectomy and split-thickness skin graft. Level
of Evidence C
Two randomized controlled trials have shown promising results
with the topical immune response modier, imiquimod, with complete
response rates of 3581% reported [9,10]. Long-term follow-up of patients in one of the studies showed good sustained benet, although
the number of patients in the study was small [9]. Level of Evidence A
S78
Fig. 1. Vulvar staging diagram.
4.5.2. Invasive vulvar cancer

Management of vulvar cancer must be individualized. There is no
standard operation and the emphasis should be on performing the
most conservative operation consistent with cure of the disease [3].
In considering surgical treatment options, it is necessary to consider
independently the most appropriate management of:
(1) The primary lesion.
(2) The groin lymph nodes.
In cases of locally advanced disease, treatment options for each site
should be considered independently and then in the context of the overall management of the patient, in order to select a treatment that will optimize the likelihood of cure and minimize treatment-related morbidity.
4.5.3. Microinvasive vulvar cancer (Stage IA)

Stage IA carcinoma of the vulva is dened as a single lesion measuring 2 cm or less in diameter with a depth of invasion of 1.0 mm or less,
the depth being measured from the epithelialstromal junction of the
most adjacent supercial dermal papilla to the deepest point of invasion. Lesions of this extent should be managed with radical local
excision. Groin dissection is not necessary for lesions of this type

[11,12]. Level of Evidence C
4.5.4. Early vulvar cancer
Tumors conned to the vulva without suspicious lymph nodes, as
determined by clinical examination, with or without ultrasonic or radiological assessment, may be considered early.
4.5.4.1. Management of the primary lesion (Fig. 2). To decrease psychosexual morbidity, a more conservative operation than radical
vulvectomy usually is indicated. The procedure may be called a radical
local excision, and for localized lesions, this operation is as effective as
radical vulvectomy in preventing local recurrence [3,1317].
Surgical removal should achieve lateral margins of at least 1 cm, and
the deep margin should be the inferior fascia of the urogenital diaphragm, which is co-planar with the fascia lata and the fascia over the
pubic symphysis [13,1618].
If the lesion is close to the urethra, the distal 1 cm of the urethra may
be resected without jeopardizing urinary continence.
If there is associated VIN, this should be supercially excised to control symptoms, to exclude other areas of supercial invasion, and to
S79
4.5.4.3. Groin dissection. It is recommended that both inguinal and femoral nodes be removed, as inguinal node dissection alone is associated
with a higher incidence of groin recurrence [27]. Level of Evidence A
The femoral nodes are situated medial to the femoral vein within the
fossa ovalis. There is no need to remove the fascia lata to dissect the
femoral nodes [28]. Groin dissection may be safely performed through
a triple incision approach, and this should improve primary healing
compared with an en bloc resection of the vulva and groins [29]. Level
of Evidence C
An en bloc approach may still be useful for clitoral or periclitoral
lesions. To avoid skin necrosis, all subcutaneous tissue above the supercial fascia must be preserved.
Groin dissection (with postoperative radiation for patients with
positive groin nodes) was found to be superior to groin irradiation in
one small randomized trial [30]. Pretreatment imaging that might
have detected grossly enlarged nodes was not performed in that early
trial and the radiation technique used was considered inadequate
to cover the at-risk inguinofemoral nodes [31]. Retrospective clinical
reviews have suggested that radiation alone can control microscopic
disease in the groins if adequate coverage of the inguinofemoral nodes
is conrmed [32,33].
Fig. 2. Management of early vulvar cancer. * If there is associated VIN or lichen sclerosis,
these areas may be supercially excised.
prevent subsequent progression to invasive cancer. This is especially

true for differentiated VIN. Level of Evidence C
4.5.4.2. Management of groin lymph nodes. Recurrence in the groin

carries a very high mortality; therefore, appropriate groin treatment
is the single most important factor in reducing mortality from early
vulvar cancer [3].
All patients with FIGO stage 1B or stage II lesions should have at least
an ipsilateral inguinofemoral lymphadenectomy. Level of Evidence C
The incidence of positive contralateral nodes in patients with small
lateral lesions and negative ipsilateral nodes is less than 1%, so unilateral
groin dissection is appropriate for such lesions [3].
Bilateral groin dissection should be performed for midline tumors,
and for those involving the anterior labia minora [19]. Large lateral
tumors should probably also have bilateral dissection, and denitely if
the ipsilateral nodes are positive [19].
Sentinel node excision is being increasingly practiced in many
centers following the European multicenter observational study on sentinel node detection [20]. This procedure detects nodal metastasis in
most patients with regional spread of disease, and is associated with a
lower rate of lymphedema than complete lymphadenectomy. The
study, (GROINSS-V), involved 403 women with a unifocal tumor conned to the vulva less than 4 cm in diameter, stromal invasion more
than 1 mm, and clinically negative lymph nodes [20]. Sentinel nodes
were identied using blue dye and radiolabelled technetium. Lymphadenectomy was omitted in sentinel node negative women. Groin recurrences occurred in 2.3% of patients, with a median follow-up of 35
months. Overall disease-specic survival was 97% after 3 years and morbidity was substantially reduced. Higher false-negative rates have been
reported in other studies [2123].
Owing to the small but denite false-negative rate with sentinel
node biopsy, and the high risk of death if groin recurrence occurs,
some patients, properly informed of the risks and benets, will elect
to have a full groin dissection, despite the greater complication rate
[2426]. Level of Evidence B
4.5.4.4. Management of patients with positive groin nodes. The Gynecologic Oncology Group demonstrated superior results for pelvic and inguinal
radiation compared with pelvic node dissection for patients who had an
inguinal lymph node dissection with ndings of grossly positive or more
than one positive node [34]. Level of Evidence A. A recent retrospective,
multicenter German study also reported improved survival for patients
with positive groin nodes who received adjuvant radiotherapy directed
at the groins (positive/negative other elds) [35].
Several studies have emphasized the prognostic signicance of the
morphology of positive groin nodes, particularly the size of the metastasis and the presence or absence of extracapsular spread [3638].
Patients with one small lymph node metastasis do not appear to
benet from adjuvant radiation therapy; several series suggest that
their prognosis is good after inguinofemoral lymphadenectomy alone
[3739], but the number of patients in most series is too small to draw
denitive conclusions. A multicenter Dutch study of 75 patients with
vulvar cancer and one positive lymph node of all sizes reported that
adjuvant radiation was only benecial if extracapsular spread was
present [40].
Reasonable indications for bilateral pelvic and groin irradiation in
patients with positive groin nodes would be:
The presence of extracapsular spread.
Two or more positive groin nodes. Level of Evidence B
An ongoing international prospective observational trial (GROINSS-V
II) is investigating the efcacy of groin radiation, without inguinofemoral
lymphadenectomy, for patients with a single positive sentinel lymph
node 2 mm or less in diameter. Pending the results of this study, all
patients who have had a sentinel lymph node biopsy and are found
to have one or more positive nodes should be treated with a full
inguinofemoral lymph node dissection, followed by radiotherapy to
the groins and pelvis if indicated.
4.5.4.5. Radiation elds and doses. In most cases, elds should include the
inguinofemoral, external iliac, and internal iliac lymph nodes. The upper
border may be extended if there is extensive inguinal involvement or
suspicion of pelvic node metastasis.
One of a variety of radiation techniques can be selected, depending
on the patients body habitus and extent of disease. Treatments should
always be based on three-dimensional planning using high-quality CT
or MRI images.
Combined photon and electron techniques are often used to treat
the regional nodes, without overdosing the femoral heads. Care must
be taken to completely include both the supercial and deep inguinal
S80
lymph nodes. In thin patients, care must be taken to avoid underdosage of

supercial inguinal nodes by high-energy photon beams. If electron beams
are used, the energy must be sufcient to cover the femoral nodes. In recent
years, some clinicians have begun to use intensity-modulated radiation
therapy (IMRT) or other inverse-planned, computer-controlled delivery
techniques to treat vulvar cancer. Although these techniques can reduce
acute radiation effects in skin and soft tissue, the treatment planning
and delivery are complex, and the opportunity for unanticipated
underdosage of the target is substantial, suggesting that these cases may
be best treated by clinicians who have considerable specialized expertise.
The dose of radiation is determined by the initial extent of regional
disease and any known residual. After a groin dissection with microscopic
inguinal metastases, 50 Gy in 1.82.0 Gy fractions is usually sufcient.
If there are multiple positive nodes or if there is evidence of
extracapsular extension, doses up to 60 Gy may be given to a reduced
volume. Gross residual disease usually requires 6070 Gy to achieve a
high probability of regional disease control.
The effectiveness of concurrent chemotherapy in the treatment of
groin and pelvic lymph nodes is unknown.
4.5.5. Advanced vulvar cancer
Patients with primary tumors extending beyond the vulva, or bulky
positive groin nodes are considered to have advanced vulvar cancer. For
such patients, multimodality treatment planning is particularly important.
4.5.5.1. Management of groin lymph nodes. It is desirable to determine the
status of the groin nodes prior to planning the overall treatment [3].
Pelvic CT or MRI should be part of the patients initial workup. These
studies are particularly helpful in suggesting the extent of inguinal or
pelvic lymphadenopathy (Fig. 3). Pelvic MRI can also provide useful
information about the anatomical extent of the primary lesion, but is
not mandatory.
If there are no suspicious nodes in the groin on CT scan, bilateral
inguinofemoral lymphadenectomy may be performed. If nal histologic
assessment reveals positive nodes, adjuvant radiation to the groin and
pelvis should follow the guidelines given for early stage disease. If the
nodes are negative, groin and pelvic radiation may be eliminated.
Alternatively, primary chemoradiation therapy may be used to treat
the primary tumor as well as the groin and pelvic nodes if surgery is
deemed inappropriate for the individual patient [32,33].
Fig. 3. Management of clinically suspicious groin nodes.
If nodes are clinically positive, a complete lymphadenectomy should

be avoided because full groin dissection together with postoperative
groin irradiation may result in severe lymphedema. Only enlarged
nodes from the groin and pelvis should be removed if feasible, and the
patient given postoperative groin and pelvic radiation [41]. Level of
Evidence C
If there are ulcerated or xed groin nodes, they should be resected if
not inltrating muscle or femoral vessels, as determined by imaging
studies. If nodes are not felt to be resectable, they should be biopsied
to conrm the diagnosis then treated with primary radiation, with or
without chemotherapy. If appropriate, the nodes may be resected following radiation if there has been an incomplete response (Fig. 4)
[42]. Level of Evidence C
4.5.5.2. Management of the primary tumor (Fig. 5). If it is possible to resect
the primary lesion with clear surgical margins and without sphincter
damage leading to urinary or fecal incontinence, primary surgical excision is usually the preferred treatment. It usually follows dissection of
the groins, although this is not mandatory.
If primary surgery would result in the need for a bowel or urinary
stoma, it is preferable to employ primary radiation therapy, sometimes followed by a more limited resection of the residual tumor or
tumor bed [43,44].
Chemoradiation has been used extensively for large lesions if surgical resection would damage central structures (anus, urethra); durable
complete responses without the need for post-treatment surgery have
been well described [4549].
The groin nodes and pelvis may need to be included in the treatment
eld depending on the status of the groin nodes, as determined initially.
Treatment with neoadjuvant cisplatin and 5-uorouracil, or other
drug combinations, has been reported in small retrospective studies to
be effective for preservation of the anal sphincter and/or urethra in
patients with advanced vulvar cancer [50,51]. This approach deserves
further clinical research.
4.5.5.3. Radiation protocol. If the groin nodes are positive and meet the
requirements described earlier for adjuvant radiation, the initial radiation treatment elds should include the pelvis, inguinal nodes, and primary site, which are treated to a total dose of at least 50 Gy. Care must
be taken to adequately cover the inguinal nodes.
Some clinicians prefer to treat in an open-leg position but care must
be taken to apply bolus to the vulva to avoid underdosage of potentially
involved skin regions.
Areas of gross disease or particularly high risk are usually boosted
either with appositional elds of electrons selected to provide an adequate dose to the surface and at depth, or with conformal external
beam therapy. Gross vulvar disease probably requires 6070 Gy to
achieve local control, although investigators are currently exploring
Fig. 4. Management of clinically obvious groin nodes.
S81
vulvar melanomas [5759]. Primary lesions should be treated by radical

local excision, with margins around the lesion of at least 1 cm. Level of
Evidence C
The role of node dissection is also controversial, but the Intergroup
Surgical Melanoma Program has conducted a prospective, multiinstitutional randomized trial of elective node dissection versus observation for intermediate thickness cutaneous melanomas (14 mm)
[60]. There were 740 patients entered into the trial, and elective node
dissection resulted in a signicantly better survival for patients
60 years of age or younger, patients with tumors 12 mm thick, and
patients without tumor ulceration.
5.2. Bartholins gland cancer
Fig. 5. Management of advanced primary tumor. Treatment should usually follow dissection of the groins. Groin and pelvic radiation should follow standard indications.
a wide variety of chemoradiation schedules, and the relationship between dose and local control remains somewhat uncertain. Level of
Evidence C
4.5.5.4. Close surgical margins. Most recurrences from vulvar cancer
occur on the vulva. Rouzier et al. [52] described two types of local recurrences, those at the primary site and those at a remote site. In an analysis
of patients with vulvar cancer from the Royal Hospital for Women in
Sydney [13], primary site recurrences occurred with a median diseasefree interval of 21 months, and were associated with a histological margin of 8 mm or less, as previously reported [16 18]. Remote site recurrences occurred with a median disease-free interval of 69 months, and
were more commonly associated with lichen sclerosus. Although
some recent papers have not found an association between margin distance and local recurrence, these papers have not distinguished primary
from remote site recurrences [53,54].
Postoperative radiation is of benet for patients with close surgical
margins (less than 5 mm), if the margins cannot be re-excised [55]. A recent study of 205 patients with vulvar cancer from Boston reported that
the highest risk of vulvar recurrence was associated with margins of
5 mm or less (P = 0.002), and that patients who received a dose of
more than or equal to 56 Gy had a lower risk of relapse than those
who received less than or equal to 50.4 Gy (P b 0.05) [56].
In some cases, the positive margin may be boosted with brachytherapy, although this technique requires experience to avoid an excessive
risk of necrosis. Alternatively, the operative bed may be treated with
an appositional electron eld or in some cases, carefully planned conformal external beam irradiation. Level of Evidence C
5. Special situations
5.1. Vulvar melanoma
Vulvar melanoma is the second most common neoplasm of the
vulva. The majority of lesions involve the clitoris or labia minora. The
Clark or Breslow modications to the micro staging system should be
used for the staging of vulvar melanoma rather than the more common
TNM/FIGO system. These systems measure the depth of invasion in
terms of the descriptive histology of the skin.
Any pigmented lesion on the vulva should be excised for diagnosis
unless it has been known to be present and unchanged for some years.
In line with trends toward more conservative surgery for cutaneous
melanomas, there is a trend toward more conservative resection of
Cancers arising in the Bartholins gland may be either transitional or

squamous types, arising from the duct, or an adenocarcinoma from the
gland itself. Adenoid cystic and adenosquamous variants have also been
reported. Adenocarcinomas of the vulva occur, on average, approximately a decade earlier than invasive squamous cancers. Frequently,
diagnosis is made after resection of what was thought to be a persisting
Bartholins cyst.
The standard approach for Bartholins gland carcinomas has been
radical vulvectomy and bilateral groin dissection. However, ipsilateral
groin dissection and radical hemi-vulvectomy may be equally effective
for early lesions [61]. Because these lesions are deep in the ischiorectal
fossa, surgical margins are more likely to be close, particularly for
bulky lesions, and postoperative radiation to the vulva may decrease
the likelihood of local recurrence [61]. Level of Evidence C
If the ipsilateral groin nodes are positive, bilateral groin and pelvic
radiation may decrease regional recurrence.
For adenoid cystic lesions, radical local excision alone is the treatment of choice, with adjuvant local radiation recommended for positive
margins or perineural invasion [62]. Level of Evidence C
5.3. Pagets Disease
This is predominantly an intraepithelial lesion, but on occasion it
may be associated with an underlying invasive adenocarcinoma. It is
usually of primary cutaneous origin from the vulva, but may be secondary to an anorectal, urothelial, or noncutaneous genital tract carcinoma
(e.g. endocervical or endometrial) [63].
The disease occurs predominantly in the menopausal or postmenopausal population. Most patients will present with vulvar discomfort
and itching and on examination, an eczematoid, weeping lesion is
often seen. Diagnosis is usually conrmed by biopsy, which will generally differentiate an intraepithelial from an invasive lesion [3,64].
Intraepithelial Pagets disease requires supercial local excision. It is
difcult to obtain clear margins with this disease, as often the underlying histologic change will extend far beyond the macroscopic lesion.
More recently, there has been a move to perform less radical resection
for intraepithelial lesions, with re-excision at a later date should lesions
become symptomatic or clinically visible [65]. Lesions that involve or
extend into the urethra or anus can be particularly difcult to manage,
and may require laser therapy.
If there is an underlying adenocarcinoma, the invasive component
should be treated by radical local excision with margins of at least
1 cm. At least an ipsilateral inguinofemoral lymphadenectomy should
be performed for unilateral lesions, with adjuvant radiation following
the same indications as for squamous carcinomas [66]. Level of
Evidence C
6. Pathology
The surgical specimen should be correctly orientated and photographed. Photographs should be used to indicate the origin of tissue
blocks. The size of the specimen should be measured and the
S82
dimensions of any visible tumor measured. The macroscopic tumor-free

surgical margins should be measured. Sections are taken through the
tumor to measure tumor depth. Sections should be taken from urethral,
anal, and vaginal resection margins.
Lymph nodes should be carefully dissected out and the site from
which they are removed recorded. A full cross-section of each lymph
node should be embedded.
The following histological points should be noted:
(a) Tumor type: keratinizing, basaloid, bowenoid.
(b) Depth of invasion: measured from the epithelialstromal junction of the adjacent dermal papilla to the deepest point of invasion by the tumor.
(c) Tumor grade.
(d) Histological measurement of tumor-free margins and statement
as to whether the tumor is completely excised.
(e) Presence or absence of perineural or vascular space invasion.
(f) Nature of the adjacent nonmalignant squamous epithelium: VIN,
lichen sclerosus, squamous hyperplasia, HPV-associated changes.
(g) Sites and number of nodes examined and number of positive
nodes. Presence or absence of extracapsular extension.
Conict of interest
The authors declare that they have no conicts of interest.
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Cancer of the vagina

Neville F. Hacker a, Patricia J. Eifel b, Jacobus van der Velden c
a
b
c
Gynecologic Oncology Cancer Centre, Royal Hospital for Women, Randwick, Australia
Department of Radiation Oncology, M.D. Anderson Cancer Center, Houston, TX, USA
Department of Gynecology, Academic Medical Center, Amsterdam, The Netherlands
1. Staging
A description of the staging classication for primary vaginal carcinoma is detailed in Table 1.
Table 1
FIGO staging of cancer of the vagina.
FIGO Stage
Description
I
II
The carcinoma is limited to the vaginal wall

The carcinoma has involved the sub-vaginal tissue but has not
extended to the pelvic wall
The carcinoma has extended to the pelvic wall
The carcinoma has extended beyond the true pelvis or has
involved the mucosa of the bladder or rectum; bullous edema
as such does not permit a case to be allotted to Stage IV
Tumor invades bladder and/or rectal mucosa and/or direct
extension beyond the true pelvis
Spread to distant organs
III
IV
IVA
IVB

The most common sites of distant spread include the lungs, liver, and
bony skeleton. The rules for staging are similar to those for carcinoma of
the cervix.
1.1.4. Histopathologic types

Approximately 90% of primary vaginal cancers are squamous
cell carcinomas. Primary adenocarcinomas of the vagina occur, but
are rare.
GX: Grade cannot be assessed.

G1: Well differentiated.
G2: Moderately differentiated.
1.1. Anatomy
2. Introduction
1.1.1. Primary site

The vagina extends from the hymenal ring upward to the uterine
cervix. Cases should be classied as carcinoma of the vagina when the
primary site of the growth is in the vagina. Tumors present in the vagina
as secondary growths from either genital or extra-genital sites should
be excluded. A growth that has extended to the portio of the cervix
and reached the area of the external os should always be allotted to
carcinoma of the cervix. A growth limited to the urethra should be
classied as carcinoma of the urethra. A tumor involving the vulva
should be classied as carcinoma of the vulva. There should be histologic
verication of the disease.
Carcinomas of the vagina constitute only about 2% of malignant

neoplasms of the female genital tract [1]. The vagina, however, can
be a common site of metastatic gynecological cancer, by either
direct extension of cervical or vulvar tumors, or through lymphatic or
vascular deposits, as seen in endometrial cancer and gestational trophoblastic disease, respectively. Metastatic or direct extension of nongynecologic tumors to the vagina can also occur from the urinary
bladder, urethra, periurethral glands, rectum, and rarely the breast,
lung, or other sites.
Up to 30% of patients with primary vaginal carcinoma have a history
of in situ or invasive cervical cancer treated at least 5 years earlier
[24]. (It is arbitrarily assumed that an invasive squamous cell carcinoma occurring in the vagina more than 5 years after an invasive squamous cell carcinoma of the cervix is a new primary cancer.) Some
vaginal cancers are preceded by vaginal intraepithelial neoplasia
(VAIN), although the true malignant potential of VAIN is not known
[5,6]. Prior pelvic radiation has also been considered a possible cause
of vaginal cancer [7,8].
Most vaginal cancers occur in postmenopausal or elderly women [1].
When occurring in younger patients, the disease seems to be etiologically related to cervical neoplasia, and thus HPV dependent [9].

The upper two-thirds of the vagina is drained by lymphatics to the
pelvic nodes, with the lymphatics paralleling the course of the uterine
artery and the vaginal artery to the obturator, hypogastric (internal
iliac), and external iliac nodes. The distal third of the vagina drains to
the inguinal-femoral nodes. Some lesions, particularly those involving
the posterior vaginal wall, may drain via pararectal lymphatic channels
to presacral nodes.
3. Screening
Routine screening for vaginal cancer following hysterectomy for
benign disease is not recommended because these women are at extremely low risk of developing vaginal cancer. Women with a history
of cervical intraepithelial or invasive neoplasia are at increased risk,
but regular cytologic screening gives a low yield. The introduction of primary HPV testing will allow the screening interval to be increased,
which may make it cost-effective in this group of patients [10].
4. Vaginal intraepithelial neoplasia (VAIN)
For patients with an abnormal pap smear and no gross abnormality,
vaginal colposcopy and use of Lugols iodine to stain the vagina are
necessary. Biopsy of colposcopically abnormal areas is necessary,
usually under anesthesia. Excisional biopsy is useful for lesions involving the vaginal vault, where occult carcinoma may be found in up to
28% of patients with VAIN [11].
Treatment of VAIN must be individualized. Numerous treatments,
ranging from local surgical excision or ablation through to intracavitary
radiotherapy, have been used. Selection of the appropriate treatment is
usually based on a careful study of several factors, including the general
medical condition of the patient, the histology of the lesion, the location
and extent of the disease, as well as the experience and expertise of
the treating medical team. The proximity of the urethra, bladder,
and rectum to the vaginal epithelium is an important factor to be
considered. Damage or injury to these structures can occur with possible stula formation, particularly when the patient has had prior pelvic
radiation therapy.
Laser vaporization with a carbon dioxide laser is an effective
treatment for VAIN [12]. This technique generally requires local or
general anesthesia.
The use of topical 5-uorouracil (5-FU) is a relatively simple ambulatory treatment, which does not require anesthesia or complicated
equipment [13]. This approach may be especially valuable for patients
with widespread or multifocal disease, which would require an extensive surgical procedure. Adverse effects are usually minimal, as long as
it is not used more than twice a week.
Imiquimod 5% cream might represent an alternative method of
management in young, HPV-positive women with multifocal highgrade lesions (VAIN 2/3) [14].
Excisional procedures, either with electrosurgical loops or a scalpel
excision, have also been used to treat VAIN. Surgical excision is particularly appropriate for vault lesions [15]. Total vaginectomy and splitthickness skin grafting may be occasionally necessary to treat extensive
lesions that involve virtually the entire length of the vaginal tube and
where other conservative methods have been unsuccessful. Level of
Evidence C
5. Invasive carcinoma
Most patients present with painless vaginal bleeding and
discharge, and denitive diagnosis can usually be made by biopsy
of a gross lesion detected on speculum examination. This can
often be done in the ofce, but may be facilitated by examination
under anesthesia.
5.1. Treatment
Whenever possible, patients should be referred to tertiary referral
units because of the rarity of these lesions and the limited experience
of most practitioners with the specialized techniques used to treat
these cancers effectively. All treatment must be individualized, and
will vary depending on the stage of disease and the site of vaginal involvement. Whenever possible, an effort should be made to maintain
a functional vagina, although the combination of tumor destruction
S85
and treatment effects may cause narrowing or shortening of the vagina,

particularly in elderly women.
5.1.1. Surgery
Surgery has a limited role because of the close proximity of the bladder and rectum, but may be useful in the following situations [1,16,17]:
(1) In patients with Stage I disease involving the upper posterior vagina
If the uterus is still in situ, radical hysterectomy, upper
vaginectomy to achieve clearance of at least 1 cm, and pelvic
lymphadenectomy may be performed. If hysterectomy has
been performed previously, radical upper vaginectomy and pelvic lymphadenectomy may be appropriate.
(2) In young patients who require radiation therapy
Pretreatment laparotomy or laparoscopy may allow ovarian
transposition, or in selected cases, surgical staging and resection
of any bulky positive lymph nodes.
(3) In selected patients with Stage IVA disease, particularly if a
rectovaginal or vesicovaginal stula is present
Primary pelvic exenteration may be a suitable treatment option
for selected patients, either combined with pelvic lymphadenectomy or preoperative radiation [2]. Bilateral groin dissection
should be considered in such patients if the lower third of the vagina is involved.
(4) In patients with a central recurrence after radiation therapy
Surgery will usually necessitate some type of pelvic exenteration
in such patients. Level of Evidence C
5.1.2. Radiation therapy
Radiation therapy is the treatment of choice for most patients
with vaginal cancer, and usually requires careful integration of external
beam irradiation and intracavitary or interstitial brachytherapy.
External beam and brachytherapy techniques may vary widely,
depending on the precise location of the tumor and its relationship to
critical structures.
Although some authors have advocated treatment with brachytherapy alone for small Stage I (or even Stage II) cancers [1821], a combination of external beam irradiation and brachytherapy probably
reduces the risk of localregional recurrence in such cases. For larger
lesions, treatment is started with approximately 4550 Gy external
radiation to reduce the primary tumor volume and to treat the pelvic
nodes. This is then supplemented with brachytherapy or external beam
boosts to gross disease in the primary site and involved lymph nodes.
There is evidence for improved local control when the dose to the
primary tumor exceeds 70 Gy [19,21]. This is most easily achieved
using brachytherapy if the entire tumor volume can be treated to the
necessary dose without exceeding normal tissue tolerance. Although
brachytherapy is preferred whenever possible, highly conformal external beam boosts may achieve more homogeneous coverage of tumor in
selected patients who have massive tumors, or intimate association of
tumor with critical structures, for example the rectovaginal septum.
If the distal one-third of the vagina is involved, the groin nodes
should be treated. Level of Evidence C
There has been limited reported experience with chemoradiation
for vaginal cancer [2022]. A recent National Cancer Data Base study
of 13 689 patients diagnosed with vaginal cancer from 19982011
reported that the use of chemoradiation increased from 20.8% to
59.1% over that period [23]. The median overall survival was longer in
patients receiving chemoradiation compared with radiation alone
(56.2 vs 41.2 months), and use of chemoradiation was an independent
prognostic factor for improved survival. Level of Evidence C
5.2. Prognosis
Although the reported overall ve-year survival for vaginal cancer is
only about 52% [1], reports from major centers have indicated ve-year
S86
survival rates comparable to cervical cancer [1820]. A study of 193

patients from the M.D. Anderson Cancer Center in Houston reported
ve-year disease-specic survival rates of 85% for 50 patients with
Stage I disease, 78% for 97 patients with Stage II, and 58% for 46 patients
with Stages IIIIVA [22].
Conict of interest
6. Special situation
[1] Hacker NF. Vaginal Cancer. In: Berek JS, Hacker NF, editors. Berek and Hackers
Gynecologic Oncology. 6th ed. Philadelphia: Lippincott Williams and Wilkins;
2015. p. 60824.
[2] Eddy GL, Marks RD, Miller 3rd MC, Underwood Jr PB. Primary invasive vaginal
carcinoma. Am J Obstet Gynecol 1991;165(2):2928.
[3] Peters 3rd WA, Kumar NB, Morley GW. Carcinoma of the vagina. Factors inuencing
treatment outcome. Cancer 1989;55(4):8927.
[4] Rubin SC, Young J, Mikuta JJ. Squamous carcinoma of the vagina: treatment,
complications, and long-term follow-up. Gynecol Oncol 1985;20(3):34653.
[5] Lenehan PM, Meff F, Lickrish GM. Vaginal intraepithelial neoplasia: biologic aspects
and management. Obstet Gynecol 1986;68(3):3337.
[6] Rome RM, England PG. Management of vaginal intraepithelial neoplasia: a
series of 132 cases with long term follow-up. Int J Gynecol Cancer 2000;10(5):
38290.
[7] Pride GL, Buchler DA. Carcinoma of vagina 10 or more years following pelvic
irradiation therapy. Am J Obstet Gynecol 1977;127(5):5138.
[8] Hellman K, Lundell M, Silfversward C, Nilsson B, Hellstrom AC, Frankendal B. Clinical
and histopathological factors related to prognosis in primary squamous cell
carcinoma of the vagina. Int J Gynecol Cancer 2006;16(3):120111.
[9] Hellman K, Silfversward C, Nilsson B, Hellstrom AC, Frankendal B, Pettersson
F. Primary carcinoma of the vagina: factors inuencing the age at diagnosis.
The Radiumhemmet series 195696. Int J Gynecol Cancer 2004;14(3):
491501.
[10] Orr JM, Barnett JC, Leath 3rd CA. Incidence of subsequent abnormal cytology in
cervical cancer patients completing ve-years of post treatment surveillance
without evidence of recurrence. Gynecol Oncol 2011;122(3):5014.
[11] Hoffman MS, DeCesare SL, Roberts WS, Fiorica JV, Finan MA, Cavanagh D. Upper
vaginectomy for in situ and occult, supercially invasive carcinoma of the vagina.
Am J Obstet Gynecol 1992;166(1 Pt 1):303.
[12] Yalcin OT, Rutherford TJ, Chambers SK, Chambers JT, Schwartz PE. Vaginal
intraepithelial neoplasia: treatment by carbon dioxide laser and risk factors for
failure. Eur J Obstet Gynecol Reprod Biol 2003;106(1):648.
[13] Krebs HB. Prophylactic topical 5-uorouracil following treatment of human
papillomavirus-associated lesions of the vulva and vagina. Obstet Gynecol 1986;
68(6):83741.
[14] Haidopoulos D, Diakomanolis E, Rodolakis A, Voulgaris Z, Vlachos G, Intsaklis A. Can
local application of imiquimod cream be an alternative mode of therapy for patients
with high-grade intraepithelial lesions of the vagina. Int J Gynecol Cancer 2005;
15(5):898902.
[15] Indermaur MD, Martino MA, Fiorica JV, Roberts WS, Hoffman MS. Upper
vaginectomy for the treatment of vaginal intraepithelial neoplasia. Am J Obstet
Gynecol 2005;193(2):57781.
[16] Tjalma WA, Monaghan JM, de Barros Lopes A, Naik R, Nordin AJ, Weyler JJ. The role
of surgery in invasive squamous carcinoma of the vagina. Gynecol Oncol 2001;
81(3):3605.
[17] Ling B, Gao Z, Sun M, Sun F, Zhang A, Zhao W, et al. Laparoscopic radical hysterectomy with vaginectomy and reconstruction of vagina in patients with stage 1 primary
vaginal cancer. Gynecol Oncol 2008;109(1):926.
[18] Chyle V, Zagars GK, Wheeler JA, Wharton JT, Delclos L. Denitive radiotherapy for
carcinoma of the vagina: outcome and prognostic factors. Int J Radiat Oncol Biol
Phys 1996;35(5):891905.
[19] Perez CA, Grigsby PW, Garipagaoglu M, Mutch DG, Lockett MA. Factors affecting
long-term outcome of irradiation in carcinoma of the vagina. Int J Radiat Oncol
Biol Phys 1999;44(1):3745.
[20] Kirkbride P, Fyles A, Rawlings GA, Manchul L, Levin W, Murphy KJ, et al. Carcinoma
of the vagina: experience at the Princess Margaret Hospital (19741989). Gynecol
Oncol 1995;56(3):43543.
[21] Dalrymple JL, Russell AH, Lee SW, Scudder SA, Leiserowitz GS, Kinney WK, et al.
Chemoradiation for primary invasive squamous carcinoma of the vagina. Int J
Gynecol Cancer 2004;14(1):1107.
[22] Frank SJ, Jhingran A, Levenback C, Eifel PJ. Denitive radiation therapy for squamous cell carcinoma of the vagina. Int J Radiat Oncol Biol Phys 2005;62(1):
13847.
[23] Rajagopalan MS, Xu KM, Lin JF, Sukumvanich P, Krivak TC, Beriwal S.
Adoption and impact of concurrent chemoradiation therapy for vaginal cancer:
A National Cancer Data Base (NCDB) study. Gynecol Oncol 2014;135(3):
495502.
[24] Frank SJ, Deavers MT, Jhingran A, Bodurka DC, Eifel PJ. Primary adenocarcinoma of
the vagina not associated with diethylstilbestrol (DES) exposure. Gynecol Oncol
2007;105(2):4704.
[25] Herbst AL, Scully RE. Adenocarcinoma of the vagina in adolescence. A report of 7
cases including 6 clear-cell carcinomas (so-called mesonephromas). Cancer 1970;
25(4):74551.
[26] Reid GC, Schmidt RW, Roberts JA, Hopkins MP, Barrett RJ, Morley GW. Primary
melanoma of the vagina: a clinicopathologic analysis. Obstet Gynecol 1989;74(2):
1909.
[27] Kirschner AN, Kidd EA, Dewees T, Perkins SM. Treatment approach and outcomes of
vaginal melanoma. Int J Gynecol Cancer 2013;23(8):14849.
6.1. Adenocarcinoma
Approximately 10% of primary vaginal carcinomas are adenocarcinomas, and they may arise in areas of vaginal adenosis in diethylstilbestrol (DES) exposed patients, in Wolfan rest elements, periurethral
glands, or foci of endometriosis. DES-related clear cell carcinomas of
the vagina occurred mainly in young women, but as the DES-exposed
cohort is now over 50 years of age, DES-related tumors are now rare.
In a series of 26 patients with non-DES-related vaginal adenocarcinomas reported from the M.D. Anderson Cancer Center in 2007, the median age was 54 years [24].
6.1.1. Treatment
In general, adenocarcinomas are treated in a similar manner to squamous lesions, although greater emphasis should be placed on combined
modality therapy, even for small tumors, because of the greater propensity for local and distant recurrence [24].
6.1.2. Prognosis
Prognosis for DES-related clear cell carcinomas of the vagina is
generally good, with an overall survival of 78% [25]. Survival for nonDES-related adenocarcinomas is signicantly worse than for squamous
cancers. A recent study of 26 such patients from the M.D. Anderson
Cancer Center reported an overall ve-year survival of only 34%, with
a higher rate of both local recurrences and distant metastases [24].
6.2. Vaginal melanoma
Malignant melanomas of the vagina are rare, and almost all cases
occur in white women [26,27]. They most commonly occur in the distal
vagina, particularly on the anterior vaginal wall [26,28].
Most are deeply invasive and radical surgery has been the mainstay
of treatment, often involving some type of pelvic exenteration. Recently,
more conservative local excisions have been used, with comparable survival rates reported [2529]. This is usually combined with postoperative radiation. Overall ve-year survival is about 15% [27]. Level of
Evidence C
6.3. Sarcoma botryoides
Sarcoma botryoides is a highly malignant tumor of the
rhabdomyoblasts. These neoplasms are found in infants and children
and usually present with discharge, bleeding, or a visible mass at
the introitus.
In the past, exenterative surgery was used for these lesions, but
survival was poor. More recently, conservative surgery has been used
in conjunction with preoperative or postoperative chemotherapy
and radiotherapy with signicantly improved survival. Most reported
chemotherapeutic experience has been with vincristine, actinomycin
D, and cyclophosphamide (VAC) [3032].
If the lesion is small and can be resected with organ preservation,
surgery should be the initial approach. For bulkier lesions, preoperative
chemotherapy or localized teletherapy or brachytherapy may be used.
Extended radiotherapy elds are not recommended, as they may
produce signicant developmental problems with the bony pelvis by
destroying or interfering with growth centers in these structures.
The authors declare that they have no conicts of interest.

References
[28] Miner TJ, Delgado R, Zeisler J, Busam, Alektiar K, Barakat R, et al. Primary
vaginal melanoma: a critical analysis of therapy. Ann Surg Oncol 2004;11(1):
349.
[29] Buchanan DJ, Schlaerth J, Kurosaki T. Primary vaginal melanoma: thirteen year
disease-free survival after wide local excision and review of recent literature. Am J
Obstet Gynecol 1998;178(6):117784.
[30] Magn N, Haie-Meder C. Brachytherapy for genital-tract rhabdomyosarcomas in
girls: technical aspects, reports, and perspectives. Lancet Oncol 2007;8(8):
7259.
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[31] Magn N, Oberlin O, Martelli H, Gerbaulet A, Chassagne D, Haie-Meder C. Vulval and

vaginal rhabdomyosarcoma in children: The Institute Gustave Roussy brachytherapy
experience with particular attention on long-term outcomes. Int J Gynecol Cancer
2006;16(Suppl. 3):610 (Abst 0038).
[32] Arndt CA, Donaldson SS, Anderson JR, Andrassy RJ, Laurie F, Link MP, et al. What
constitutes optimal therapy for patients with rhabdomyosarcoma of the female
genital tract. Cancer 2001;91(12):245468.

Cancer of the cervix uteri

Adriana Bermudez a, Neerja Bhatla b, Eric Leung c
a
b
c
Gynecologic Oncology Unit, Buenos Aires University Hospital, Buenos Aires, Argentina
Department of Obstetrics and Gynecology, All India Institute of Medical Sciences, New Delhi, India
Department of Radiation Oncology, Sunnybrook Health Sciences Center, Odette Cancer Centre, Toronto, Ontario, Canada
1. Introduction
Worldwide, cervical cancer is now the fourth most common female
malignancy in both incidence and mortality, following breast, colorectal,
and lung cancers, and results in approximately 527 600 new cases and
265 700 deaths annually [1]. It is the second most commonly diagnosed
cancer and third most common cause of cancer death among females in
low-resource countries. More than 85% of new cases are diagnosed in
economically disadvantaged people. Nearly 90% of cervical cancer
deaths occur in low-resource regions of the world.
The following examinations are permitted for the determination of

FIGO staging, as indicated by presenting characteristics (see sections
below): palpation, inspection, colposcopy, endocervical curettage, hysteroscopy, cystoscopy, proctoscopy, intravenous pyelography, ultrasound of the renal tract, and X-ray examination of the lungs and
skeleton. Blood tests should include full blood count, and renal and
liver functions. Syphilis and HIV serology need to be considered, based
on discussion with the patient about risk factors.
2.1. Initial assessment of microinvasive disease

1.1. Anatomy
The cervix is the lower aspect of the uterus. It is roughly cylindrical
in shape, projects through the superior-anterior vaginal wall, and
communicates with the vagina through the endocervical canal, which
terminates in the external os located at the top of the vagina. Cancer
of the cervix may originate from the mucosa of the surface of the cervix
or from within the canal. Carcinoma of the uterine cervix grows locally
and may extend in continuity to the uterus and paracervical tissues, and
pelvic organs.
Cervical cancer may spread to regional lymph nodes, and only later
metastasize hematogenously to distant structures. Studies on sentinel
lymph nodes show that the cervix is drained into the following rst
echelon nodal stations most commonly: external iliac (43%), obturator
(26%) and parametrial (21%), from where they drain to the common
iliac nodes. From the common iliac nodes, lymph drainage goes to the
para-aortic nodes. The most common sites of distant spread include
the para-aortic, mediastinal and supraclavicular nodes, the lungs, liver,
and skeleton.
The diagnosis of both Stage IA1 and IA2 should be based on microscopic examination of removed tissue, preferably a cone biopsy, which
must include the entire lesion. The depth of invasion should not be
greater than 5 mm taken from the base of the epithelium, either surface
or glandular, from which it originates. The second dimension, the horizontal spread, must not exceed 7 mm. Vascular space involvement,
either venous or lymphatic, should not alter the staging, but should be
specically recorded because it may affect treatment decisions. Macroscopically obvious lesions, and those with larger dimensions, should
be staged as IB. It is impossible to clinically determine if a cancer of
the cervix has extended to the corpus. Extension to the corpus should
therefore be disregarded for staging purposes.
The diagnosis of Stage IA1 or IA2 disease can only be made on the
basis of a cone biopsy with negative margins, or on a trachelectomy or
hysterectomy specimen. If the margins of the cone biopsy are positive
for cervical intraepithelial neoplasia (CIN) III or invasive cancer, a second cone biopsy should be performed or the patient treated as for
Stage IB1 disease [3].
2.2. Initial evaluation of grossly invasive disease

2. Staging
FIGO staging is based on clinical examination. The FIGO staging
guidelines were most recently updated in 2009 (Table 1) [2]. Stage 0
is no longer included in the FIGO 2009 staging.
A thorough pelvic examination is mandatory to provide information
for FIGO staging, and this rarely requires anesthesia. When there is
doubt as to which stage a particular cancer should be allocated, the earlier stage is mandatory.
Visible lesions require a biopsy to conrm a diagnosis of cervical

carcinoma. A patient with a growth apparently xed to the pelvic wall
by a short and indurated, but not nodular, parametrium should be
allotted to Stage IIB. Stage III should be dened for cases where the
parametrium is nodular to the pelvic wall or if the growth itself extends
to the pelvic wall. The presence of hydronephrosis or non-functioning
kidney(s) resulting from obstruction of the ureter(s) by cancer also permits a case to be allotted to Stage III.
A. Bermudez et al. / International Journal of Gynecology and Obstetrics 131 (2015) S88S95
S89
Table 1
Cancer of the cervix uteri.
Stage
Description
The carcinoma is strictly conned to the cervix (extension to the uterine corpus should be disregarded).
Invasive cancer identied only microscopically. (All gross lesions even with supercial invasion are Stage IB cancers.) Invasion is limited to
measured stromal invasion with a maximum depth of 5 mm and no wider than 7 mm.
Measured invasion of stroma 3 mm in depth and 7 mm width.
Measured invasion of stroma N 3 mm and b 5 mm in depth and 7 mm width.
Clinical lesions conned to the cervix, or preclinical lesions greater than stage IA.
Clinical lesions no greater than 4 cm in size.
Clinical lesions N 4 cm in size.
The carcinoma extends beyond the uterus, but has not extended onto the pelvic wall or to the lower third of vagina.
Involvement of up to the upper 2/3 of the vagina. No obvious parametrial involvement.
Clinically visible lesion 4 cm
Clinically visible lesion N 4 cm
Obvious parametrial involvement but not onto the pelvic sidewall.
The carcinoma has extended onto the pelvic sidewall. On rectal examination, there is no cancer free space between the tumor and pelvic sidewall.
The tumor involves the lower third of the vagina. All cases of hydronephrosis or non-functioning kidney should be included unless they are known
to be due to other causes.
Involvement of the lower vagina but no extension onto pelvic sidewall.
Extension onto the pelvic sidewall, or hydronephrosis/non-functioning kidney.
The carcinoma has extended beyond the true pelvis or has clinically involved the mucosa of the bladder and/or rectum.
Spread to adjacent pelvic organs.
Spread to distant organs.
IA
IA1
IA2
IB
IB1
IB2
II
IIA
IIA1
IIA2
IIB
III
IIIA
IIIB
IV
IVA
IVB
In cases of grossly invasive disease, a chest X-ray, and evaluation of

hydronephrosis (with renal ultrasound, intravenous pyelography, CT,
or MRI) are mandatory. The bladder and rectum are evaluated by cystoscopy and sigmoidoscopy only if the patient is clinically symptomatic.
Cystoscopy is also recommended in cases of endocervical growth with
a barrel-shaped surface and in cases where the growth has extended
to the anterior vaginal wall. Suspected bladder or rectal involvement
should be conrmed by biopsy and histologic evidence. The presence
of bullous edema, as such, should not permit a case to be allotted to
Stage IV.
Imaging evaluation may be of additional benet to clinical examination in practice areas where resources allow. Imaging may allow for
identication of additional prognostic factors and help direct selection
of therapy. MRI provides the best radiologic assessment of primary
tumors greater than 10 mm, but is not mandatory [48]. Level of
Evidence B
CT and/or MRI and/or positron emission tomography (PET) may
provide information on nodal status or systemic spread, but are not
mandatory. Compared with CT and MRI, PET-CT is a more accurate imaging method for detecting nodal metastasis that are greater than
10 mm [5,912]. Isolated and unexpected areas of PET enhancement
should be further investigated with tissue diagnosis, if possible, to conrm or exclude the presence of distant metastatic disease [11,13,14].
Level of Evidence B
Compared with radiologic evaluation, surgical node dissection is
more accurate for assessment of para-aortic nodal disease [15,16]. In patients with advanced disease, laparoscopic staging of para-aortic lymph
nodes may be considered to allow treatment according to extent of
disease [17]. No impact on survival has been demonstrated; however,
surgical exclusion of para-aortic lymph node involvement portends a
better prognosis than radiographic exclusion alone [18]. Level of
Evidence B
In a review of 22 articles that evaluated the safety and impact of pretreatment surgical para-aortic lymph node staging (PALNS), para-aortic
lymph node metastases were found in 18% (range, 8%42%) of
patients with cervical cancer Stage IB-IVA [19]. The mean complication
rate of PALNS was 9% (range, 4%24%), the most common complication
being lymphocysts. PET-CT appears to be the most accurate imaging
method, with false-negative results in 4%15% of cases. Positive paraaortic nodes have been identied in up to 35% of Stage IIB and 20% of
Stage III tumors [19]. Knowing the status of para-aortic nodes may provide prognostic information as well as guide the extent of adjuvant or
primary radiation. It is, however, controversial and is not recommended
as a routine practice, particularly in resource-restricted environments

and in women with advanced disease associated with constitutional
symptoms.
2.3. Pathologic staging
In cases treated by surgical procedures, the pathologists ndings in
the removed tissues can be the basis for accurate statements on the extent of disease. The ndings should not be allowed to change the clinical
staging, but should be recorded in the manner described for the pathologic staging of disease. The TNM nomenclature is appropriate for this
purpose [20]. Unlike FIGO staging criteria, TNM staging accounts for
node positivity; however, the FIGO and TNM classications are otherwise virtually identical in describing the anatomical extent of disease.
Clinical staging is essential to select and evaluate therapy, while the
pathological stage provides the most precise data from which to estimate prognosis and calculate end results.
Infrequently, hysterectomy may be carried out in the presence of unsuspected invasive cervical carcinoma. Such cases cannot be clinically
staged or included in therapeutic statistics, but it is desirable that they
be reported separately. If considered appropriate, some of these patients
may be offered repeat laparotomy with full parametrectomy and pelvic
lymphadenectomy to allow potentially curative surgery and/or determine the need for adjuvant chemoradiation [21].
Staging is determined at the time of the primary diagnosis and cannot be altered, even at recurrence. Only if the rules for clinical staging
are strictly observed is it possible to compare results among clinics
and by differing modes of therapy.
2.4. Histopathology
All tumors must be microscopically veried. Cases should be classied as carcinomas of the cervix if the primary growth is in the
cervix. All histologic types must be included. The histopathologic
types are:
Squamous cell carcinoma (keratinizing; non-keratinizing; verrucous).

Endometrioid adenocarcinoma.
Clear cell adenocarcinoma.
Adenosquamous carcinoma.
Adenoid cystic carcinoma.
Small cell carcinoma.
Undifferentiated carcinoma.
S90
Grading by any of several methods is encouraged, but is not a basis

for modifying the stage groupings. Histopathologic grades are as follows:

When surgery is the primary treatment, the histologic ndings permit the case to have pathologic staging, as described above. In this situation, the TNM nomenclature may be used.
3. Cervical cancer screening
Primary prevention of cervical cancer through HPV vaccination of
girls, and secondary prevention through the detection of cervical cancer
precursors by various screening methods and their appropriate
treatment, are both known to be effective preventive measures.
Details on cervical cancer screening can be accessed via the FIGO
website (www.go.org).
4. Management of cervical cancer
4.1. Microinvasion
4.1.1. Stage IA1
Conization is the treatment of choice for this stage. If the patient has
completed childbearing, hysterectomy (abdominal, vaginal, or laparoscopic) may be considered [22].
Follow-up with Pap smears every 3 months for 2 years, and
then every 6 months for a further 3 years should be performed. If
follow-up is normal at 5 years, the screening schedule may be completed according to the recommendations in each country [23,24]. Level of
Evidence C
4.1.2. Stage IA2
Since lymph nodes may be involved in this stage, lymphadenectomy
is necessary [25,26]. The recommended treatment is type 2 radical
hysterectomy (ligation of the uterine artery where it crosses the ureter,
although a vaginal cuff is not necessary) with pelvic lymphadenectomy.
If fertility is desired, options are: (1) cervical conization with extraperitoneal or laparoscopic pelvic lymphadenectomy; or (2) radical
abdominal, vaginal, or endoscopic trachelectomy with pelvic lymphadenectomy performed according to the surgical approach [27,28].
4.1.3. Post-treatment follow-up after microinvasive carcinoma
Follow-up with Pap smears every 3 months for 2 years, and
then every 6 months for a further 3 years should be performed. If
follow-up is normal at 5 years, the screening schedule may be completed according to the recommendations in each country [23,24]. Level of
Evidence C
4.2. Grossly invasive cervical carcinoma (FIGO Stage IBIVA)
Concurrent platinum-based chemoradiation is the most indicated
treatment for this stage although neoadjuvant chemotherapy may
play a role in selected settings [29]. The treatment approach should be
decided based on the availability of resources, and tumor- and
patient-related factors.
4.2.1. Surgical management
Surgical treatment may be indicated in Stage IB1IIA1 disease: modied radical or radical (abdominal or endoscopic) hysterectomy with
pelvic lymphadenectomy [3032]. Level of Evidence B
Primary pelvic exenteration may be considered for Stage IVA disease
without extension to the pelvic sidewall or extra-pelvic disease [3346].
Level of Evidence C
4.2.1.1. Sentinel lymph node assessment

Identication of sentinel lymph nodes can be performed with dual
labeling using blue dye and radiocolloid [4749]. These procedures
may be considered in early stage cervical cancer, Stage IA and IB1
[5052].
If lymphovascular space invasion is present, pelvic lymphadenectomy needs to be considered. Level of Evidence C
Sentinel lymph node assessment of pelvic lymph nodes should not
be utilized in advanced disease [53].
4.2.1.2. Trend to lesser surgery for small tumors
Stages IA2IB1 with tumor size of less than 2 cm, cervical stromal invasion of less than 50%, and node negative on MR/CT imaging have been
considered as low risk.
Simple hysterectomy or trachelectomy, with either pelvic lymphadenectomy or sentinel lymph node assessment, have been considered
as adequate surgical treatment for low-risk cases [54,55]. Level of
Evidence D
4.2.1.3. Adjuvant radiation/chemotherapy
The risk of recurrence after radical surgery is increased in the presence of positive nodes, positive parametria, or positive surgical margins.
Adjuvant concurrent chemoradiation (cisplatin with or without 5uorouracil) improves overall survival, progression-free survival, and
both local and distant recurrences compared with pelvic irradiation
alone in such patients [42]. Level of Evidence B
Risk of pelvic recurrence is also increased in those with uninvolved
nodes but with primary associated risk factors: tumor size greater
than 4 cm, capillary-like space (CLS) involvement, and outer one-third
invasion of the cervical stroma [43,44]. Adjuvant whole pelvic chemoirradiation reduces the local failure rate and improves progressionfree survival compared with patients treated with surgery alone [43].
Level of Evidence B
Adjuvant radiation therapy with and without chemotherapy
may be particularly benecial for patients with adenocarcinoma or
adenosquamous histology, given the relatively higher rates of distant
failure [42,43]. Level of Evidence C
Patients with positive common iliac or para-aortic nodes may be
treated by extended eld radiation [56,57], with or without chemotherapy. Level of Evidence C
Intensity modulated radiation therapy has been explored in the
postoperative setting. A prospective multi-institutional study has
shown acceptable toxicities with this approach and a randomized trial
(TIME-C) is underway comparing intensity-modulated radiation therapy (IMRT) with standard eld-based radiation therapy in postoperative
cervical and endometrial cancer [58,59]. Although there is currently
insufcient evidence at the present time to recommend IMRT as a standard of care, many centers have shifted to using this technique in postoperative cervical and endometrial cancer treatment.
4.2.2. Neoadjuvant chemotherapy and surgery
The theoretical rationale for the use of neoadjuvant chemotherapy
(NACT) includes the induction of tumor shrinkage to facilitate radical
excision, and a possible improvement in outcomes over surgery alone.
There is also a possibility of NACT sterilizing nodes and parametria,
thereby reducing risk factors for adjuvant therapy after surgery; however, the efcacy of neoadjuvant therapy in this situation is not known.
A meta-analysis of randomized trials of neoadjuvant platinumbased chemotherapy prior to denitive surgery shows that patients
treated with NACT have better survival outcomes than those treated
with primary radiation alone, given at a relatively low dose [60]. No randomized data compare the results of NACT followed by surgery with
concurrent chemoradiation. The European Organization for Research
and Treatment of Cancer is currently conducting a Phase 3 study comparing NACT and surgery with denitive chemoradiation in patients
with FIGO Stages IB2, IIA2, or IIB cervical cancers.
NACT followed by surgery is commonly used in some countries,

but its role is uncertain as a review of available literature suggests no
benet of NACT-surgery over upfront surgery plus adjuvant therapy
[61]. Optimal pathologic response, dened as persistent residual disease
with less than 3 mm of stromal invasion in the surgical specimen, is
the strongest predictor of freedom from local recurrence for patients
treated with NACT and surgery [62]. A chemotherapy regimen of
paclitaxel, ifosfamide, and cisplatin has higher response rates than
ifosfamide and cisplatin for Stage IB2, although not for Stage IIB [63]. A
statistically signicant effect on overall survival was not found, although
this study was insufciently powered for overall survival outcomes
[63]. Surgery after NACT should consist of radical hysterectomy and
pelvic lymphadenectomy.
Many patients randomized to NACT-surgery either were unable
to proceed with radical surgery after chemotherapy (40%) or required
additional adjuvant therapy after surgery (26%) [64]. NACT surgery
should be carefully considered in patients with larger tumors or adenocarcinoma histology owing to lower response rates. Stage IIB and higher
stages should be preferentially managed with denitive chemoradiation therapy.
NACT obscures the pathologic ndings at the time of surgery,
complicating evaluation of indications for adjuvant radiotherapy with
or without adjuvant chemotherapy. Indications for adjuvant therapy
after primary surgery [42,43] are often applied in the setting of NACT
surgery. Level of Evidence C
4.2.3. Primary radiation management
Chemoradiotherapy is the standard of care for patients with IB2,
IIA2, IIB, IIIA, IIIB, and IVA disease. Standard concurrent chemoradiation
therapy includes external radiation and intracavitary brachytherapy
[65,66]. Level of Evidence A
4.2.3.1. Radiation
Standard radiation treatment of cervical carcinoma is external pelvic
irradiation plus brachytherapy. Suggested doses of external beam radiation are 4550 Gy in 180200 cGy per fraction. Standard radiation
planning techniques are outlined in Table 2. A full description of radiation used in cervical cancer treatment is included in the radiation therapy chapter included in the FIGO Cancer Report 2015 (this Supplement)
[67].
4.2.3.2. Total treatment time
Timely completion of radiotherapy is essential for optimal outcomes.
In retrospective trial data, patients with radiotherapy treatment times
of greater than 910 weeks had signicantly higher rates of pelvic failure, compared with women completing treatment in less than 67
S91
weeks [68,69]. It is recommended that all external beam radiotherapy

and brachytherapy be completed within 56 days.
4.2.3.3. Addition of chemotherapy to radiation
Concurrent chemoradiation confers a signicant overall survival
benet compared with the same radiation alone, with a meta-analysis
of 13 trials showing a ve-year survival advantage of 6% (Hazard
Ratio: 0.81) [29]. Concurrent chemoradiotherapy also reduced local
and distant recurrence, and improved disease-free survival. Level of Evidence A
A once-weekly infusion of cisplatin (40 mg/m2 weekly with appropriate hydration) for 56 cycles, is a commonly used concurrent chemotherapy regimen, and is equally effective and less toxic than combined
cisplatin and 5-uorouracil in a 21-day schedule during external
beam therapy [65,70]. For patients who are unable to receive platinum
chemotherapy, 5uorouracil-based regimens are an acceptable alternative [29,71]. Data on the toxicity associated with concurrent chemotherapy and extended eld irradiation are limited [56,57].
Although randomized studies of chemoradiotherapy included patients with Stage IB2 and above, given the magnitude of the survival
benet, concurrent chemotherapy with a platinum-based regimen is
often recommended for any patient considered suitable for radical radiotherapy, if the patient is t enough.
Additional adjuvant chemotherapy after concurrent chemoradiotherapy is being explored in an international randomized controlled
trial (OUTBACK Trial) [72]. A single randomized study suggests possible
benet in progression-free and overall survival with additional chemotherapy, but with more severe toxicity [73]. At present there is insufcient evidence to recommend additional adjuvant chemotherapy as a
standard of care.
4.2.3.4. Resource-limited practices
Where available, brachytherapy constitutes an essential component
of radical radiotherapy or chemoradiotherapy. However, bulky tumors
may be curable with external beam radiation alone if brachytherapy
and/or chemotherapeutic agents are not readily available. Recognized
prognostic factors for probability of cure include lower stage, squamous
cell histology, and good performance status.
In situations where brachytherapy is not available, an external beam
boost is a reasonable option to achieve local control. A total radiation
dose of 5470 Gy can provide local control rates of 52%, with a median
time to recurrence of 2.3 years [74].
4.2.3.5. Post-treatment follow-up
A systematic review of 17 retrospective trials for follow-up of
women after treatment for cervical cancer found the median time to
recurrence after treatment ranged from 736 months after primary
Table 2
External beam radiotherapy technique for cervical cancer.
Radiation technique
Targets
Simulation
2D techniques
CT simulation
Tumor plus uterus, parametrial tissue, and uterosacral ligaments
Pelvic lymph nodes (internal iliac, external iliac, obturator, and presacral) and lower common iliac lymph nodes
Margin for microscopic spread of disease
Tumor determined by palpation and CT scan (if available) plus 2 cm margin
A-P elds
Lateral: 2 cm lateral to the bony margin of the pelvis
Superior: L4/L5 or L5/S1 vertebral interspace
Inferior: 2 cm below the obturator foramen (or 2 cm below lower extent of clinical tumor)
Lateral elds
Anterior: anterior to symphysis pubis, 2 cm anterior to tumor
Posterior: posterior to sacrum to include potential microscopic disease along the uterosacral ligament
In patients with positive common iliac or para-aortic nodes, extended eld radiation should be considered [56,57]
Irradiation should be given by an appropriate energy causing a uniform dose distribution (5% to + 7%) within the target volume
18 MV generally provides a homogeneous dose distribution in the target volume with 4-eld techniques. In resource-limited areas,
satisfactory pelvic radiation therapy can be achieved with lower energy linacs or cobalt units
Target volumes
Field borders
Energy
S92
treatment [75]. An optimal post-treatment follow-up strategy has not

been established and clinical practice is variable. Common recommendations include educating patients about potential symptoms, history
taking, and clinical examination at routine follow-up intervals to detect
treatment complications and psychosexual morbidity, as well as to assess for recurrent disease. Level of Evidence D
Commonly used tests include chest X-ray, ultrasound, CT scans, and
intravenous pyelography.
As isolated central recurrences are potentially curable, closer clinical
follow-up in the 23 years after treatment may be important. Routine
imaging is not indicated. Special circumstances, such as involved high
pelvic lymph nodes, may justify interval imaging of the abdomen to
assess for potentially curable progression of disease. In the systematic
review, asymptomatic recurrent disease was detected using physical
exam (29%71%), chest X-ray (20%47%), CT (0%34%), and vaginal
vault cytology (0%17%) [75]. Frequent vaginal vault cytology does
not signicantly improve the detection of early disease recurrence.
Patients should return to annual population-based screening after
5 years of disease-free survival [75].
4.3. Stage IVB/distant metastases
4.3.1. Systemic therapy
Presentation with distant metastatic disease is rare, reported in
about 2% of cases [76]. There has been no randomized comparison of
chemotherapy to best supportive care for Stage IVB cervical carcinoma.
Few studies have evaluated the impact of systemic therapy on palliative
and quality-of-life endpoints. There is some evidence that concurrent
chemoradiation may have better response than systemic chemotherapy
[77]. Overall and disease-free survivals of 69% and 57% respectively have
been reported in patients with positive para-aortic and supraclavicular
lymph nodes [78]. Level of evidence D
A management plan should consider that the median duration of
survival with distant metastatic disease is approximately 7 months.
Despite limited response rates, cisplatin has been the standard
chemotherapy used in the setting of distant metastatic disease [79,80].
Given low response rates to cisplatin alone after concurrent chemoradiation, recent evidence supports the use of platinum doublets over
cisplatin alone, although with very modest benets in response rates.
Cisplatin may be combined with taxanes, topotecan, 5-uorouracil,
gemcitabine, or vinorelbine [80]. Carboplatin-paclitaxel combination
has also been successful in these cases. In a recent study, the addition of bevacizumab in a dose of 15 mg per kg body weight to chemotherapy with a combination of either cisplatin-paclitaxel or topotecanpaclitaxel was evaluated [81]. Bevacizumab increased the overall
survival (17.0 months vs 13.3 months; hazard ratio for death, 0.71;
98% CI, 0.540.95; P = 0.004 in a one-sided test) and higher response
rates (48% vs 36%, P = 0.008). Bevacizumab, as compared with chemotherapy alone, was associated with an increased incidence of hypertension of grade 2 or higher (25% vs 2%), thromboembolic events of
grade 3 or higher (8% vs 1%), and gastrointestinal stulas of grade 3 or
higher (3% vs 0%).
Table 3
Eastern Cooperative Oncology Group (ECOG) performance status.
Grade ECOG
0
1
2
3
4
5
Fully active, able to carry on all pre-disease performance without restriction

Restricted in physically strenuous activity but ambulatory and able to
carry out work of a light or sedentary nature, e.g. light house work,
ofce work
Ambulatory and capable of all self-care but unable to carry out any work
activities. Up and about more than 50% of waking hours
Capable of only limited self-care, conned to bed or chair more than 50%
of waking hours
Completely disabled. Cannot carry on any self-care. Totally conned to bed
or chair
Dead
Palliative systemic therapy may be considered for patients with

an ECOG (Eastern Cooperative Oncology Group) performance status
of 02 (Table 3). Discussion of participation in clinical trials should
be considered, particularly for patients who have relapsed within
12 months [82].
4.3.2. Palliative radiation for localized symptoms
Local treatment with radiation therapy is indicated to sites of symptomatic involvement in patients with metastatic disease. Alleviation of
symptoms with palliative radiation can often be achieved for pain arising from enlarged para-aortic or supraclavicular nodes, skeletal metastases [83], and symptoms associated with cerebral metastases. In view
of the short life expectancy of patients with metastatic cervical cancer,
palliative radiotherapy should be given via larger fractions over shorter
periods of time than conventional radical courses of treatment. There
are no data to endorse specic dose/fractionation schemes for soft tissue
metastases; commonly used schedules include large single fractions,
20 Gy in ve fractions, and 30 Gy in 10 fractions.
4.3.3. Comprehensive palliative care
Patients with incurable cervical cancer may develop a range of
challenging symptoms and should be managed on an individual basis.
Common problems associated with advanced cervical cancer can
include: pain, ureteric obstruction causing renal failure, hemorrhage,
malodorous discharge, lymphedema, and stulas. Patients may benet
from a wide range of clinical services to manage these symptoms, as
well as psychosocial care and support for patients and their families. Access to oral morphine is improving within low-resource countries and is
an important aspect of palliative care.
4.4. Recurrent disease
Recurrences may be pelvic, para-aortic, distant, or a combination.
The risk of both pelvic and distant failure increases with the bulk of
disease [84,85]. The majority of recurrences occur within 3 years of
diagnosis, and the prognosis is poor, with most patients dying as a result
of uncontrolled disease [86]. Treatment decisions should be based on
the performance status of the patient, the site of recurrence and/or metastases, the extent of metastatic disease, and prior treatment [87].
For patients with extensive local disease or distant metastatic
disease, the intent of therapy is palliative, and best supportive care is
generally the recommended management. For patients with good performance status and limited metastatic disease, a trial of platinum
doublet systemic therapy may be justied, understanding the limited
benets with respect to response rate and progression-free survival
[79,81]. Local recurrence that is not salvageable with surgery or radiotherapy has a very poor response to systemic chemotherapy.
4.4.1. Local recurrence
Some patients with locally recurrent disease after denitive therapy
(surgery or radiotherapy) are potentially curable. Favorable prognostic
factors include an isolated central pelvic recurrence with no sidewall
disease, a long disease-free interval, and size of the recurrence less
than 3 cm in diameter [36,88].
Relapse in the pelvis following primary surgery may be treated by
either radical chemoradiation or pelvic exenteration. Radical irradiation
with or without concurrent chemotherapy) may result in ve-year
disease-free survival rates of 45%74% with isolated pelvic failure after
primary surgery [89,90]. The extent of recurrent disease and involvement of pelvic lymph nodes are prognostic factors for survival [91].
Level of Evidence C
The radiation dose and volume should be tailored to the extent of recurrent disease; 4550 Gy in 180 cGy fractions should be delivered to
areas likely to be involved with microscopic disease, and a boost dose
of up to 6466 Gy to the gross tumor volume using eld reductions.
Concurrent chemotherapy with either cisplatin and/or 5-uorouracil

may improve outcome [92].
Pelvic exenteration may be a feasible treatment option in selected
patients who have recurrence after radiation. Suitable candidates for exenteration after previous surgery or pelvic radiation are patients without evidence of intra-peritoneal or extra pelvic spread, and who have
a tumor-free space along the pelvic sidewall [3337]. Level of
Evidence C
Owing to the morbidity of exenteration, its use is conned to those
with curative potential, and requires careful patient selection regarding
the associated physical and psychological demands. Conrmation of
recurrence with a pathologic specimen obtained by biopsy is essential
prior to proceeding with exenteration. A PET/CT is the most sensitive
non-invasive test to determine any sites of distant disease, and if possible, should be performed prior to exenteration [13,93100]. Patient
assessment and counseling regarding the implications and ability to
manage stoma and ostomy sites must be addressed prior to surgery
[101]. Careful selection of patients may yield a ve-year survival with
pelvic exenteration in the order of 30%60% [33,34,36], and an operative
mortality of less than 10% [102].
4.4.2. Para-aortic nodal recurrence
After the pelvis, para-aortic lymph nodes are the next most common
site of recurrent disease. Possible long-term survival with radical-intent
radiotherapy or chemoradiotherapy can be achieved in approximately
30% of patients with isolated para-aortic nodal recurrence [103]. Patients with asymptomatic, low volume recurrences that occur greater
than 24 months from initial treatment have better outcomes [103].
Level of Evidence C
5. Special circumstances
5.1. Incidental cervical cancer
Invasive cervical cancer may be found during the pathological evaluation of the specimen of a simple hysterectomy for an apparently benign condition. Overall survival is lower in cases of tumor cut-through
leaving residual disease [104]. When this circumstance happens, a
PET/CT scan if available, or a pelvic and abdominal CT or MRI scan and
chest imaging should be performed, to assess the extent of disease.
The treatment proposal should be tailored based on the histologic
and the radiologic ndings. Pelvic radiation (with or without concurrent
chemotherapy) and vaginal brachytherapy should be considered
5.2. Cervical cancer during pregnancy
A multidisciplinary decision-making team with the involvement of
an obstetrician, neonatologist, psychologist, and spiritual advisor is recommended to make a tailored individual therapeutic proposal. All plans
should be discussed with the patient (and preferably her partner), and
her wishes must be respected.
In general, the management of cervical cancer in pregnant
women follows the same principles as in non-pregnant women.
Cases before 1620 weeks are treated without delay with either surgery or chemoradiation.
From the second trimester onward, surgery and chemotherapy can
be used in selected cases while preserving the pregnancy [107]. Level
of Evidence C
If the diagnosis is made after 20 weeks, treatment delay appears to
be an option for Stages IA2 and IB1, with no apparent impairment of
prognosis compared with non-pregnant controls [108110]. Treatment
consisting of classical cesarean delivery and radical hysterectomy is
often undertaken when a balance is reached between competing maternal and fetal health risks, usually not later than 34 weeks of pregnancy.
Level of Evidence C
S93
For more advanced disease, it is not known whether treatment delay

will affect survival. If a treatment delay is planned in women with locally advanced disease, neoadjuvant chemotherapy may be considered in
an attempt to prevent disease progression [111,112].
Conict of interest
Dr Bermudez has received a grant from Pzer for Consulting
Services. Dr Bhatla has received research funding through her institute
from MSD, GlaxoSmithKline, and Digene/Qiagen Inc. Dr Leung has no
conicts of interest.
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Cancer of the corpus uteri

Frdric Amant a, Mansoor Raza Mirza b, Martin Koskas c, Carien L. Creutzberg d
a
Division of Gynecologic Oncology, University Hospitals Gasthuisberg, Leuven, Belgium

Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
c
Division of Gynecologic Oncology, Bichat University Hospital, Paris, France
d
Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands
b
1. Staging
1.1. Anatomy
1.1.1. Primary site
The upper two-thirds of the uterus above the level of the internal
cervical os is called the corpus. The fallopian tubes enter at the upper lateral corners of a pear-shaped body. The portion of the muscular organ
that is above a line joining the tubo-uterine orices is often referred to
as the fundus.
The major lymphatic trunks are the utero-ovarian (infundibulopelvic), parametrial, and presacral, which drain into the hypogastric,
external iliac, common iliac, presacral, and para-aortic nodes. Although
a direct route of lymphatic spread from the corpus uteri to the paraaortic nodes through the infundibulopelvic ligament has been suggested from anatomical and sentinel lymph node studies, direct metastases to the para-aortic lymph nodes are uncommon.
The vagina and lungs are the common metastatic sites.
1.2. Rules for classication
The FIGO Committee on Gynecologic Oncology, following its
meeting in 1988, recommended that endometrial cancer be surgically
staged. There should be histologic verication of grading and extent of
the tumor.
1.3. Histopathology
1.3.1. Histopathologic types (according to World Health Organization/
International Society of Gynecological Pathology classication)
All tumors are to be microscopically veried.
The histopathologic types are:
Endometrioid carcinoma: adenocarcinoma; adenoacanthoma (adenocarcinoma with squamous metaplasia); and adenosquamous carcinoma (mixed adenocarcinoma and squamous cell carcinoma).
Mucinous adenocarcinoma.
Serous adenocarcinoma.
Clear cell adenocarcinoma.
Undifferentiated carcinoma.
Mixed carcinoma (carcinoma composed of more than one type, with
at least 10% of each component).
Endometrial cancers are usually classied in one of the following

two categories:
Type 1 (grade 1 and 2 endometrioid carcinoma) may arise from
complex atypical hyperplasia and is linked to unopposed estrogenic stimulation.
Type 2 includes grade 3 endometrioid tumors as well as tumors of nonendometrioid histology and develops from atrophic endometrium.

Cases of carcinoma of the corpus should be grouped with regard to

the degree of differentiation of the adenocarcinoma as follows:
G1: less than 5% of a nonsquamous or nonmorular solid growth pattern.
G2: 6%50% of a nonsquamous or nonmorular solid growth pattern.
G3: greater than 50% of a nonsquamous or nonmorular solid
growth pattern.
1.3.3. Pathologic grading notes
Notable nuclear atypia (pleomorphism and prominent nucleoli), inappropriate for the architectural grade, raises the grade of a grade 1 or
grade 2 tumor by 1.
In serous and clear cell adenocarcinomas, nuclear grading takes precedent. Most authors consider serous and clear cell carcinomas high
grade by denition.
Adenocarcinomas with squamous differentiation are graded according to the nuclear grade of the glandular component.
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F. Amant et al. / International Journal of Gynecology and Obstetrics 131 (2015) S96S104
1.4. FIGO staging classication

The current FIGO staging classication for cancer of the corpus uteri
is given in Table 1. Comparison of the stage groupings with the TNM
classication is given in Table 2.
1.4.1. Regional lymph nodes (N)
NX: Regional lymph nodes cannot be assessed.

N0: No regional lymph node metastasis.
N1: Regional lymph node metastasis to pelvic lymph nodes.
N2: Regional lymph node metastasis to para-aortic lymph nodes, with
or without positive pelvic lymph nodes.
1.4.2. Distant metastasis (M)

MX: Distant metastasis cannot be assessed.
M0: No distant metastasis.
M1: Distant metastasis (includes metastasis to inguinal lymph nodes
or intraperitoneal disease).
1.4.3. Rules related to staging

Corpus cancer is surgically staged, therefore procedures previously
used for determination of stage are no longer applicable (e.g. the ndings of fractional curettage to differentiate between Stage I and Stage II).
There may be a small number of patients with corpus cancer who
will be treated primarily with radiation therapy. In these cases, the clinical staging adopted by FIGO in 1971 would still apply, but designation
of that staging system should be noted.
Ideally, distance from tumor to serosa should be measured. The
presence of lymphovascular space invasion (LVSI) should also be reported in the pathological report of the hysterectomy specimen. A
LVSI-positive status has a signicantly worse prognosis, especially if extensive LVSI is found [1]. The distinction by LVSI status could be more
relevant than the distinction between Stages IA and IB for predicting
survival in Stage I endometrial cancer [2].
As a minimum, any enlarged or suspicious lymph nodes should
be removed in all patients. For high-risk patients (grade 3, deep
myometrial invasion, cervical extension, serous or clear cell histology),
complete pelvic lymphadenectomy and resection of any enlarged
para-aortic nodes is recommended.
Table 1
Cancer of the corpus uteri.
FIGO
Stage
Ia
IIa
IAa
IBa
IIIa
IIIAa
IIIBa
IIICa
IIIC1a
IIIC2a
IVa
IVAa
IVBa
a
Tumor conned to the corpus uteri

No or less than half myometrial invasion
Invasion equal to or more than half of the myometrium
Tumor invades cervical stroma, but does not extend beyond the
uterus b
Local and/or regional spread of the tumor
Tumor invades the serosa of the corpus uteri and/or adnexaec
Vaginal involvement and/ or parametrial involvementc
Metastases to pelvic and/or para-aortic lymph nodesc
Positive pelvic nodes
Positive para-aortic nodes with or without positive pelvic lymph nodes
Tumor invades bladder and/or bowel mucosa, and/or distant
metastases
Tumor invasion of bladder and/or bowel mucosa
Distant metastasis, including intra-abdominal metastases and/or
inguinal nodes)
Either G1, G2, or G3.

Endocervical glandular involvement only should be considered as Stage I and no longer as Stage II.
c
Positive cytology has to be reported separately without changing the stage.
b
Table 2
Cancer of the corpus uteri: FIGO staging compared with the TNM classication.a
FIGO Stage
I
IA
IB
II
III
IIIA
IIIB
IIIC1
IIIC2
IVA
IVB
a
Union for International Cancer Control (UICC)

T
(tumor)
N
(lymph nodes)
M
(metastasis)
T1
T1a
T1b
T2
T3
T3a
T3b
T1T3
T1T3
T4
Any T
N0
N0
N0
N0
N0N1
N0
N0
N1
N1
Any N
Any N
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M1
Carcinosarcomas should be staged as carcinoma.
2. Introduction
Worldwide, endometrial cancer is the sixth most common malignant disorder with approximately 290 000 new cases annually. The
incidence is higher in high-income countries (5.5%) compared with
low-income countries (4.2%), although specic mortality is higher in
the latter. The cumulative risk of endometrial cancer up to the age of
75 years has been estimated as 1.6% for high-income regions and 0.7%
for low-income countries [3]. This difference has been associated with
an epidemic of obesity and physical inactivity, two important risk factors, in high-income countries. Moreover, endometrial cancer patients
with obesity also tend to have a poorer outcome [4]. On the other
hand, physical activity and long-term use of continuous combined
estrogenprogestin therapy is associated with a reduced risk of endometrial cancer [4,5]. Obesity is associated with earlier age at diagnosis,
and with endometrioid-type endometrial cancers. Similar associations
were not observed with nonendometrioid cancers, consistent with different pathways of tumorigenesis [6].
In North America and Europe, endometrial cancer is the most
frequent cancer of the female genital tract and the fourth most common
site after breast, lung, and colorectal cancer [3]. The incidence is rising as
life expectancy increases. Furthermore, an estimated 23 700 European
women died of endometrial cancer in 2012, which is the eighth most
common cause of death from cancer in women [7]. Importantly, the
corrected corpus uteri cancer mortality rates showed a decrease in
most European Union member states among women born before
1940 [8].
In North America, it is the seventh most frequent cause of death,
with approximately 55 000 new cases and 10 000 estimated new deaths
each year [3]. The increase in endometrial cancer incidence rates
after 2002 may be related to the widespread decrease in estrogen
plus progestin menopausal hormone therapy use, which has been
reported to lower endometrial cancer risk in overweight and obese
women [9]. However, the main reasons underlying the increase in endometrial cancer incidence in high-income countries remain the
increasing prevalence of obesity in postmenopausal as well as the increased life expectancy.
Endometrioid adenocarcinoma progresses through a premalignant
phase of intraepithelial endometrial neoplasia in a large proportion of
cases [10]. Other forms such as serous and clear cell carcinoma arise as
a result of a sequence of genetic mutations. In serous endometrial cancer, the mutant p53 plays a pivotal role [11]. Endometrial cancer research has gained some momentum in recent years and now provides
better information for clinical practice. Its early presentation following
postmenopausal bleeding results in a generally good prognosis, but it
should be treated using evidence-based protocols, and where appropriate, by expert multidisciplinary teams.
The role of population screening for endometrial cancer remains low
[12], although certain high-risk groups such as those with Lynch type 2
S98
syndrome can undergo endometrial surveillance by biopsy, or transvaginal ultrasonography if post menopausal. Transvaginal ultrasound
is reasonably sensitive and specic but screening of asymptomatic
women has in general been recommended only for those with Lynch
syndrome [13].
Following presentation, ultrasound is an effective rst test with a
high negative predictive value when the endometrial thickness is less
than 5 mm. In one of the largest studies undertaken, there was a negative predictive value of 96% among 1168 women in whom the results of
transvaginal ultrasound were correlated with an endometrial biopsy
obtained by curettage [14]. When a biopsy is required, this can be obtained usually as an ofce procedure using a number of disposable instruments developed for this purpose. In certain cases, hysteroscopy
may be helpful, and with exible instruments can also be done without
recourse to general anesthesia. However, the biological role of cells that
are transtubally ushed during hysteroscopy remains uncertain. If cervical stenosis or patient tolerance does not permit an ofce procedure,
hysteroscopy and curettage under anesthesia may be necessary. Individuals whose pelvic examination is unsatisfactory may also be evaluated with transvaginal or abdominal ultrasound to rule out concomitant
adnexal pathology.
Following a histopathologic diagnosis of endometrial adenocarcinoma, the local extent of the tumor, and evidence of metastatic disease should be determined. In addition, the perioperative risk should
be assessed.
As a minimum, the pathology report from endometrial sampling
should indicate the tumor type and grade of the lesion. A chest X-ray,
full biochemistry (renal and liver function tests), and blood count are
routine. A serum CA125 may be of value in advanced disease for
follow-up. Evaluation for metastasis is indicated particularly in patients
with abnormal liver function tests, and clinical ndings such as
parametrial or vaginal tumor extension. In high-risk patients, imaging
of the abdomen and lymph nodes may help determine the surgical
approach. In certain situations, cystoscopy and/or proctoscopy/barium
enema may be helpful if direct extension to the bladder or rectum
is suspected.
3. Prognostic tumor characteristics for high-risk disease
The recommended histopathologic criteria for determining highrisk disease are:
Tumor grade 3 (poorly differentiated).

More than 50% of myometrial invasion.
Lymphovascular space invasion.
Non-endometrioid histology (serous, clear cell, undifferentiated,
small cell, anaplastic, etc.).
Cervical stromal involvement.
The most accurate means of assessing both depth of myometrial invasion and cervical involvement is MRI scanning and intraoperative
frozen section [1517]. CT and MRI are equivalent in terms of evaluating
nodal metastases, but neither is good enough to replace surgical lymph
node assessment, which provides histological conrmation [18,19]. The
role of PET-CT and PET-MRI is currently being investigated.
Nonsurgical staging for endometrial cancer, where extrauterine disease exists, is inherently inaccurate, particularly in respect to small
nodal involvement, intraperitoneal implants, and adnexal metastasis.
4. Surgical staging procedure for endometrial cancer
In 1988, the FIGO Cancer Committee changed the ofcial FIGO staging from clinical to surgical for endometrial cancer. Since that recommendation, considerable debate has ensued as to what constitutes an
internationally acceptable approach. A generally recommended protocol would be that the abdomen should be opened with a vertical
midline abdominal incision and peritoneal washings taken immediately

from the pelvis and abdomen, followed by careful exploration of the
intra-abdominal contents. The omentum, liver, peritoneal cul-de-sac,
and adnexal surfaces should be examined and palpated for any possible
metastases, followed by careful palpation for suspicious or enlarged
nodes in the aortic and pelvic areas. The standard surgical procedure
should be an extrafascial total hysterectomy with bilateral salpingooophorectomy. Adnexal removal is recommended even if the tubes
and ovaries appear normal, as they may contain micrometastases.
Vaginal cuff removal is not necessary, nor is there any benet from
excising parametrial tissue in the usual case. Where obvious cervical
stromal involvement is demonstrated preoperatively, a modied radical
hysterectomy has been historically performed. However, there is
consensus (ESMO-ESGO-ESTRO) that simple hysterectomy with freemargins together with pelvic lymphadenectomy can be sufcient.
There has also been considerable debate on the safety of endoscopic
surgery for the treatment of endometrial cancer. Recent studies have
demonstrated that laparoscopic removal of the uterus and adnexae
(in experienced hands) appears to be safe. Whereas there is no difference in terms of major complications between abdominal hysterectomy
and laparoscopically assisted vaginal hysterectomy (LAVH) or total laparoscopic hysterectomy (TLH), the laparoscopic approach is associated
with a signicantly decreased risk of major surgical adverse event, a
shorter hospital stay, less pain, and quicker resumption of daily activities [2022]. Since the oncological safety of the laparoscopic approach
has now been demonstrated in several randomized studies [23,24], hysterectomy and bilateral salpingo-oophorectomy should be performed
with laparoscopy in those patients with no contraindications to laparoscopy (e.g. large-volume uterus). This approach can be accompanied by a
laparoscopic lymphadenectomy, if surgical staging is to be undertaken.
Robotic surgery for the surgical management of the morbidly obese patient is an option only in experienced hands. In such cases, the surgical
management using robotics has been reported to be safe and have
less perioperative complications compared with open surgery [25].
Retrospective studies have suggested equivalent oncologic outcomes
compared with traditional laparoscopic surgery [26,27].
Although mandated through the staging system, lymphadenectomy
of the pelvic and para-aortic areas remains controversial. Selective node
sampling is of dubious value as a routine and complete lymphadenectomy should be reserved for cases with high-risk features. Many individuals with endometrial cancer are obese or elderly, with other medical
problems, and clinical judgment is required to determine if additional
surgery is warranted. Any deeply invasive tumor or radiological suggestion of positive nodes is an indication for retroperitoneal lymph
node evaluation, with removal of any enlarged or suspicious nodes.
Documentation of positive nodes identies a high-risk population and
helps to tailor adjuvant treatment, since patients with Stage III disease
appear to benet from chemotherapy [28].
Indications for aortic node sampling would include suspicious aortic
or common iliac nodes, grossly positive adnexae, grossly positive pelvic
nodes, and high-grade tumors showing full thickness myometrial invasion. Patients with clear cell, papillary serous, or carcinosarcoma histologic subtypes are also candidates for aortic node sampling.
5. Who should perform the surgery?
Low-risk tumors will have positive nodes in less than 5% of cases
(well differentiated and b1/2 myometrial invasion) and do not require
full surgical staging. These women can be safely operated on by a general gynecologist, but those at greater risk of extrauterine disease, who
may require lymphadenectomy, should be referred to a gynecological
oncologist since care provided by gynecologic oncologists has been associated with better survival in high-risk cancers [29]. Moreover, primary management by gynecologic oncologists has been suggested to result
in an efcient use of health care resources and minimization of the potential morbidity associated with adjuvant radiation [30].
This triaging of women can be done most effectively by a thorough

preoperative assessment, paying particular attention to the pathology
and to radiological features. Triaging for lymphadenectomy is also possible during surgery. Intraoperative assessment mainly involves assessment of myometrial invasion [15,17,27]. Grading on frozen section is
possible, though suboptimal compared with preoperative grading [17].
6. When should surgery be performed?
The effect of waiting time for surgical staging on survival outcome of
endometrial cancer is controversial. A recent population-based study
concluded that a longer waiting time for surgical staging was associated
with worse survival outcomes in uterine cancer [31]. However, when
focusing on type I endometrial cancer only, the waiting time for surgical
staging was not associated with decreased survival outcome, presumably due to its excellent prognosis anyway [32].
7. Is lymphadenectomy therapeutic?
Although required for accurate staging, a therapeutic benet for
lymphadenectomy is controversial. Historically, one casecontrol
study suggested that it may be therapeutic [33] and another showed a
good prognosis even in node-positive women [34]. Another retrospective study showed a survival benet of complete lymphadenectomy
for patients with grade 3 tumors [35]. In the UK, the MRC ASTEC trial,
however, which randomized 1400 women undergoing surgery for presumed Stage I endometrial cancer to pelvic lymphadenectomy or no
lymphadenectomy, showed no therapeutic benet [36]. An Italian randomized trial of pelvic (and in 30% para-aortic) lymphadenectomy
versus no lymphadenectomy in 540 women also did not show any difference in rates of relapse or survival [37]. Both studies have been criticized because of a limited effort with respect to the extent of dissection
and lymph node evaluation, because of the high proportion of low-risk
patients, and because no direct decision on adjuvant therapy based on
lymphadenectomy was part of the protocols. Lymphadenectomy is primarily used for staging and should be considered in women with highrisk factors [38]. Although a direct survival benet of lymphadenectomy
has not been documented, the procedure identies node-positive
patients that may benet from adjuvant treatment. An international
trial of the role of lymphadenectomy to direct adjuvant therapy
for high-risk endometrial cancer (STATEC) is planned. The ongoing
ENGOT-EN2-DGCG/EORCT 55102 trial aims to answer this question by
comparing survival in patients with Stage I grade 3 endometrioid endometrial cancer, Stage I and II type 2 endometrial cancer or Stage II
endometrioid endometrial cancer and without metastatic node after
randomization for adjuvant chemotherapy.
In a retrospective study, para-aortic lymphadenectomy resulted
in an improved outcome in intermediate and high-risk patients
when compared with pelvic lymphadenectomy alone [39]. However,
adjuvant therapy was not comparable in the two groups. In patients
who underwent both pelvic and para-aortic lymphadenectomy, 77% received chemotherapy whereas this was given to only 45% of patients
who underwent pelvic lymphadenectomy alone. This study suggests
both pelvic and para-aortic lymphadenectomy are benecial in comparison with patients who undergo pelvic lymphadenectomy alone, but it
does not imply that extensive lymphadenectomy improves survival in
comparison with no lymphadenectomy.
8. Adjuvant treatment
Risk factors are used to determine the indication for adjuvant
radiation therapy, as the majority of patients are at low risk of recurrence. Low-risk disease (Stage I, grade 1 or 2 with no or supercial
myometrial invasion) does not require adjuvant radiation therapy,
as demonstrated in a Danish cohort study of low-risk women, with
96% ve-year survival after surgery alone [40]. A seminal Norwegian
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trial [41], which included 621 women treated after surgery with
vaginal brachytherapy, indicated that overall survival was not improved
by additional external beam radiation therapy (EBRT), although it did
reduce the risk of pelvic recurrence. Three large randomized trials of
pelvic radiation therapy versus no further treatment after surgery
have determined the role of radiation therapy based on risk factors,
and have led to reduced indications for adjuvant radiation therapy:
the PORTEC trial [42], the US GOG#99 trial [43], and the UK MRC
ASTEC trial [44]. All of these trials reported a signicant reduction
in the rates of vaginal and pelvic recurrence with EBRT, but without survival benet. EBRT added to the risk of long-term morbidity.
PORTEC and ASTEC trials had similar recurrence and survival rates
without lymphadenectomy, compared with GOG#99 that included patients with documented node-negative disease. PORTEC-1 showed
that most pelvic relapses were located in the vaginal vault (75%), and
that salvage rates were high in women who had not had previous radiation therapy [45].
The PORTEC-2 trial randomized 427 women with highintermediate
risk factors to EBRT or vaginal brachytherapy alone [46]. This trial
showed that vaginal brachytherapy had excellent vaginal control rates
(b2% at 5 years for both EBRT and vaginal brachytherapy groups),
with minimal adverse effects and signicantly better quality of life.
Quality of life of patients in the brachytherapy group remained the
same as those of an age-matched normal population [47]. Vaginal
brachytherapy has replaced EBRT as standard adjuvant treatment for
patients with highintermediate risk factors.
That omission of any EBRT or vaginal brachytherapy for
(high)intermediate risk disease increases recurrence rates (22%
for intermediate risk disease, of which 15% locoregional) but without
a difference in survival has been conrmed by a Danish population
study [48]. A patient preference study showed that patients
preferences are biased to a treatment preventing relapse [49].
The seminal NSGO-9501 trial investigated the use of both EBRT
and adjuvant platinum-based chemotherapy compared with EBRT
alone for patients with risk factors (grade 3 or deep invasion or adverse
histologies). This trial was published in a pooled analysis with the Italian
ILIADE trial [50]. While trials comparing adjuvant EBRT alone with
adjuvant cisplatin-based chemotherapy alone have not shown any difference in overall or relapse-free survival [51,52], the pooled NSGOEC9501/EORTC55991 and ILIADE trial analysis reported a signicant
9% improvement in progression-free survival (69% vs 78% at 5 years;
Hazard Ratio [HR] 0.63) with the addition of chemotherapy to EBRT,
and a trend for a 7% improvement in ve-year overall survival (75% vs
82%; HR 0.69, P = 0.07).
Ongoing and recently completed trials are currently investigating
the roles of EBRT or chemotherapy alone or combined EBRT and
chemotherapy for patients with high-risk or advanced stage disease
(GOG#249, GOG#258, PORTEC-3, Danish/EORTC trials). First results of
the randomised GOG-249 trial (601 patients with Stage I II endometrial cancer with high intermediate or high-risk factors, comparing
vaginal brachytherapy plus three cycles of carboplatin-paclitaxel
with pelvic EBRT) showed no differences in relapse-free survival (84%
vs 82%) or overall survival (92% vs 93%) between the arms at a median
follow-up of 24 months [53]. About 50% of the trial population had
grade 12 disease with a baseline ve-year survival of 86% 91%. In
the PORTEC-3 trial, patients with high-risk Stage I II or with Stage
III endometrial cancer were randomized to pelvic EBRT alone or EBRT
with two cycles of cisplatin followed by four cycles of carboplatin and
paclitaxel. PORTEC-3 completed accrual (686 patients enrolled) in late
2013 and results are expected in 2016. In the ongoing ENGOT-EN2DGCG-trial patients with node-negative endometrial cancer with
high-risk features are randomized to adjuvant chemotherapy (six cycles
of carboplatin-paclitaxel) or observation, with or without brachytherapy in both arms. These trials will answer many of the questions regarding optimal use and optimal schedules of adjuvant therapy for women
with high-risk endometrial cancer.
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In summary, adjuvant radiation therapy is not indicated for patients

with grade 12 tumors and no more than 50% myometrial invasion,
or for those with only a single risk factor. For patients with high
intermediate risk factors (at least two of the factors: age N60 years,
deep myometrial invasion, grade 3, serous or clear cell histology,
LVSI), vaginal brachytherapy alone is preferable to EBRT, providing excellent vaginal control without impacting on quality of life. In patients
with higher-risk disease (3 or more risk factors, Stages II and III), the
role of adjuvant chemotherapy, with or without radiation therapy, is
currently being investigated.
9. Progestogen therapy
This has been widely prescribed in the past, but a meta-analysis of
six randomized trials involving a total of 3339 women has shown no
survival benet for adjuvant progestogen therapy in endometrial cancer
[54]. A subsequently published randomized trial of 1012 women also
failed to demonstrate any survival benet [55].
10. Stage II
10.1. Occult Stage II disease
Patients with clinically occult Stage II disease are generally managed
in a similar way to patients with Stage I disease.
10.2. Clinical overt Stage II disease
Historically, radical hysterectomy, bilateral salpingo-oophorectomy,
bilateral pelvic lymphadenectomy, and selective aortic node dissection
can be used as primary treatment for clinically overt cervical involvement. However, this strategy is poorly supported by the medical literature. Results from one of the rare retrospective studies could not nd
any survival benet from radical hysterectomy for patients with
suspected gross cervical involvement in comparison with simple or
modied radical hysterectomy [56]. Since radical hysterectomy increases the risk of adverse events, surgical treatment in patients with
suspected gross cervical involvement deserves further prospective evaluation. Preoperative MRI scanning is advisable to exclude bladder involvement and ensure local resectability. Studies indicate excellent
results for this approach, with no benet from the addition of radiation
for patients with negative nodes [57,58]. Adjuvant radiotherapy is usually reserved for patients with involved nodes and/or close or involved
surgical margins.
However, neoadjuvant therapy followed by a less extensive simple
hysterectomy can represent an alternative.
The need for adjuvant radiotherapy has not been studied in a randomized trial, but a SEER study reported improved survival for patients
with Stage II endometrial cancer when adjuvant radiotherapy was used
after radical and simple hysterectomy [59,60].
If surgery is not considered feasible because of tumor extension, full
pelvic radiotherapy and intracavitary brachytherapy, as in cervical
cancer, may be employed.
11. Stage III
Most patients with Stage III endometrial cancer are managed by
complete surgical resection of all metastatic disease, followed by postoperative EBRT and/or chemotherapy. The randomized GOG#122 trial
included patients with Stages III and IV disease and residual tumor up
to 2 cm, and compared whole abdominal radiation with intensive
adjuvant chemotherapy (eight cycles of doxorubicin and cisplatin). It
showed a survival benet for chemotherapy (42% vs 53% estimated
ve-year survival), although event rates were high in both arms [28].
Adjuvant platin-based chemotherapy (more recently, carboplatin
and paclitaxel) is increasingly used to reduce the risk of metastases.
Retrospective studies have shown substantial pelvic recurrence rates

when EBRT was omitted when using chemotherapy [61,62], and current
ongoing trials are investigating the roles of chemotherapy, and combinations of chemotherapy and radiation therapy.
A recent meta-analysis including four multicenter randomized controlled trials involving 1269 women with primary FIGO Stage III/IV endometrial cancer who received primary cytoreductive surgery showed
that chemotherapy increases survival time after primary surgery by approximately 25% relative to radiotherapy [63]. Two trials, evaluating
620 women, mainly Stage III compared adjuvant chemotherapy with
adjuvant radiotherapy [52,64], one trial evaluating 552 women mainly
Stage III compared two chemotherapy regimens (cisplatin/doxorubicin/
paclitaxel versus cisplatin/doxorubicin treatment) in women who had
all undergone adjuvant radiotherapy (GOG 184) [65], and one trial contributed no data [51].
Overall and progression-free survivals were longer with adjuvant
chemotherapy compared with adjuvant radiotherapy [63]. In subgroup
analyses, the effects on survival in favor of chemotherapy were not
different for Stage III and IV, or Stage IIIA and IIIC. This evidence was
of moderate quality. Data from one trial showed that women receiving
adjuvant chemotherapy were more likely to experience hematological
and neurological adverse events and alopecia, and more likely to
discontinue treatment, than those receiving adjuvant radiotherapy
[63]. There was no statistically signicant difference in treatmentrelated deaths between the chemotherapy and radiotherapy treatment
arms [63]. There was no clear difference in progression free survival between intervention groups in the one trial that compared cisplatin/
doxorubicin/paclitaxel versus cisplatin/doxorubicin [65].
A large trial evaluating adjuvant chemotherapy alone (six cycles
of carboplatin-paclitaxel) compared with chemotherapy during and
after radiation therapy (same schedule as used in PORTEC-3) for Stage
III IV endometrial cancer (GOG 0258) has recently completed accrual
(804 patients) and results are expected in 2016.
Patients with presumed Stage III disease because of adnexal involvement should have full surgical staging and expert pathologic examination of the specimen, as primary tumors of both the ovary and the
endometrium may be present. Management should be individualized,
and based on the stage of each tumor.
Patients with clinical Stage III endometrial carcinoma that is not
felt to be resectable by virtue of vaginal or parametrial extension are
best treated primarily by pelvic irradiation, with or without chemotherapy [66]. Once therapy has been completed, exploratory laparotomy
should be considered for those patients whose disease now appears to
be resectable.
12. Stage IV
Patients with Stage IV disease based on intraperitoneal spread
benet from cytoreductive surgery only if there is no residual tumor
[67]. Neoadjuvant chemotherapy is an option, particularly if ascites is
present, and/or postoperative morbidity is considered likely [68]. After
surgery, platinum-based chemotherapy should be considered, based
on the GOG#122 trial cited above [28].
Patients with evidence of extra-abdominal metastases are usually
managed with systemic platinum-based chemotherapy, or hormonal
therapy if grade 1 and/or receptor positive. Combination chemotherapy
is the treatment of choice in advanced-stage disease as well as in relapsed disease. The combinations of doxorubicin, cisplatin, and paclitaxel (TAP) [69] and carboplatin and paclitaxel have been shown to be
most effective. The former is much more toxic.
Doxorubicin monotherapy versus doxorubicincisplatin doublet has
been investigated in two randomized trials [70,71]. Both documented
superiority of the combination chemotherapy in terms of progressionfree and overall survival, with manageable toxicity. Doxorubicin
cisplatin doublet versus doxorubicincisplatinpaclitaxel triplet was
tested in a phase III randomized trial [69]. The triplet regimen resulted
in a signicantly superior progression-free survival, though this regimen proved to be too toxic, with treatment-related deaths despite the
use of growth factors.
Carboplatinpaclitaxel doublet was tested in several phase II studies
in advanced-stage or relapsed disease, demonstrating a response rate
of 65%75% and progression-free survival of about 14 months [7274].
The interim results of the GOG-0209 trial, a noninferiority trial
comparing the combination of doxorubicin, cisplatin, and paclitaxel
(TAP) and G-CSF versus carboplatin and paclitaxel shows that
carboplatin and paclitaxel is not inferior to TAP [75]. The better tolerability prole of carboplatinpaclitaxel has lent credence to the use of
carboplatin and paclitaxel as the standard for adjuvant treatment in
Stage III and IV disease.
Pelvic radiotherapy in Stage IV disease may be used to provide local
tumor control and/or to treat symptoms such as vaginal bleeding or
pain from a local tumor mass, or leg edema due to lymph node involvement. Palliation of brain or bone metastases can be effectively obtained
with short courses (15 fractions) of radiotherapy.
13. Targeted therapy
While surgery, radiotherapy, and cytotoxic therapy have improved
outcomes for patients with endometrial cancer, insights into pathogenesis of cancer have led to the development of drugs targeting molecular
pathways vital to cancer cell survival including angiogenesis, DNA repair, and apoptosis. The tumor suppressor gene PTEN (phosphate and
tensin homolog detected on chromosome 10) is important for normal
cellular function. Mutations in PTEN result in decreased apoptosis and
are found in up to 83% of endometrioid carcinomas of the uterus [76].
Decreased transcription due to the mutation leads to decreased phosphatidylinositol 3-kinase (PI3K) inhibition, increased activity of Akt,
and uncontrolled function of mTOR. Elevated activity of mTOR is seen
in a vast majority of endometrial cancers [77]. The mammalian target
of rapamycin (mTOR) is a kinase that regulates cell growth and apoptosis [78]. Temsirolimus, deforolimus, and everolimus are mTOR inhibitors that have been tested as single agents in phase II studies. They
have been found to promote stable disease in 44% of patients with metastatic or recurrent cancer of the endometrium [79,80].
Development of a new blood supply (angiogenesis) is essential to
the development and maintenance of any tissue [81,82]. Diffusion of
nutrients over small distances is sufcient for cellular function, but in
order for tumor growth to exceed 1 mm3 in volume, new vessels must
be recruited [82]. Tumor cells generate angiogenic factors that promote
new vessel formation and recruit supporting cells. The vessel density
and circulating tumor levels of many proangiogenic proteins such as
vascular endothelial growth factor (VEGF) and platelet-derived growth
factor (PDGF) are poor prognostic factors for many solid tumors, including endometrial carcinoma [82]. VEGF is one of the best characterized
angiogenesis mediators [83,84]. Increased production of VEGF as well
as other growth factors is frequently observed in regions of hypoxia or
inammation and in the presence of activated oncogenes or downregulated tumor suppressor genes [85,86]. Overexpression of VEGF
results in increased endothelial cell proliferation, decreased apoptosis,
and increased fenestration of endothelial cells [8587]. VEGF overexpression has been shown to be associated with a poor prognosis in
most gynecologic malignancies including endometrial cancer [87]. The
role of drugs inhibiting angiogenesis pathways, such as bevacizumab
and tyrosine kinase inhibitors, is being studied in endometrial cancer.
In the rst phase II trial evaluating the activity and tolerability of
single-agent bevacizumab in 52 recurrent or persistent endometrial
cancers [88], seven patients (13.5%) had clinical responses and 21
(40.4%) had stable disease for 6 months.
Bevacizumab was added to adjuvant paclitaxel and carboplatin in a
phase II trial in patients with measurable disease [89]. Fourteen of the
15 patients were progression free at 6 months. A combination of
temsirolimus and bevacizumab showed a 24% response at the cost of
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signicant toxicity [90]. These rst studies of bevacizumab in advanced

and recurrent endometrial cancer need to be conrmed in another
much larger phase II trial (GOG 86P).
Concerning tyrosine kinase inhibitors, a phase II trial evaluated the
efcacy and safety of getinib in 26 patients with persistent/recurrent
endometrial cancer [91]. This treatment regimen was tolerable but
lacked sufcient efcacy to warrant further evaluation in this setting.
A phase II placebo-controlled randomized trial of chemotherapy plus
nintedanib (ENGOT-EN1) is to be initiated in Europe.
The phosphoinositol-3 kinase (PI3K) pathway is frequently dysregulated in endometrial cancer. Hormonal manipulation leads to response
in some patients, but resistance derived from PI3K pathway activation
has been documented. In a recent phase II trial of everolimus and
letrozole in women with recurrent disease, a clinical benet rate of
40% and objective response rate of 32% was documented [92].
Dysregulation of the cell cycle is one of the dened hallmarks of cancer. The cyclin-dependent kinases (CDKs) have a crucial role in the regulation of the G1/S transition. Palbociclib is a reversible oral inhibitor of
CDK4/6 with acceptable toxicity prole. A phase II randomized trial of
letrozole with and without palbociclib is being initiated in Europe.
Various groups have studied the use of HER2/neu-targeted therapies
in patients with aggressive endometrial cancer subtypes [93]. However,
a phase II study evaluating the efcacy of trastuzumab alone for advanced or recurrent HER2-positive endometrial carcinoma reported
no major tumor responses among the 34 women nally enrolled [94].
A randomized phase II evaluation of carboplatin/paclitaxel with and
without trastuzumab in HER2/neu + patients with advance/recurrent
uterine serous papillary carcinoma is currently recruiting participants.
14. Special considerations
14.1. Diagnosis post hysterectomy
Diagnosis of endometrial carcinoma post hysterectomy can present
some management problems, particularly if the adnexae have not
been removed. This situation most often arises following vaginal hysterectomy for pelvic prolapse. Recommendations for further postoperative
therapy are based on known risk factors for extrauterine disease related
to the histologic grade and depth of myometrial invasion. Individuals
with grade 3 lesions, deep myometrial invasion, or LVSI are candidates
for additional surgery to remove the adnexae, or adjuvant external
beam pelvic radiation therapy. Patients with a grade 1 or 2 lesion with
minimal myometrial invasion and no LVSI involvement generally require no further therapy.
14.2. Medically inoperable patients
Morbid obesity and severe cardiopulmonary disease are the general
reasons a patient with endometrial carcinoma may be thought to be
medically inoperable. Uterine brachytherapy can achieve cure rates in
excess of 70% and may be combined with external beam radiotherapy
in the presence of prognostic factors suggesting a high risk of involved
nodes. Primary radiation therapy for clinical Stage I and II endometrial
adenocarcinoma provides disease control, with fewer than 16% of surviving patients experiencing recurrence [95].
For patients with a well-differentiated lesion, contraindications to
general anesthesia, and who are unsuitable for radiotherapy, highdose progestins may be used.
14.3. Diagnosis in young women
The diagnosis of endometrial carcinoma during the reproductive
years should be made with caution, since this malignancy is uncommon
in women under 35 years, and grade 1 endometrial carcinoma may be
confused with severe atypical hyperplasia. In these women, consideration should be given to an estrogen-related underlying condition
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such as a granulosa cell tumor, polycystic ovaries, or obesity. Progestins

such as megestrol acetate (160 mg/day) or medroxyprogesterone acetate (500 mg/day) may be appropriate in these situations if preservation
of fertility is desired. The safety of such an approach has been reported
in a large number of studies, for grade 1 endometrial adenocarcinoma
and atypical hyperplasia only [96]. Equivocal lesions should be examined by an experienced pathologist. Although the literature describes
successful outcomes, fatal recurrences of endometrial cancer after a
conservative approach have been reported, and hysterectomy should
be recommended after childbearing has been completed.
Ovarian preservation, in patients with grade 1 intramucosal endometrial adenocarcinoma, was not associated with an increase in
cancer-related mortality in the largest sample available [97].
15. Follow-up
The conventional reasons for follow-up of treated cancer patients
involve providing reassurance, diagnosing early recurrence, and
collecting data. One prospective [98] and several retrospective studies
[99101] internationally have addressed follow-up. Overall, about 75%
of recurrences were symptomatic and 25% asymptomatic, and neither
recurrence-free nor overall survival were improved in asymptomatic
cases compared with those detected at clinical presentation. Most
(65%85%) recurrences were diagnosed within 3 years of primary treatment, and 40% of recurrences were local. The use of routine follow-up
Pap smears and chest X-rays is not cost-effective. In nonirradiated patients, a strong case can be made for regular follow-up to detect vaginal
recurrence at the earliest opportunity, given the high salvage rate following radiotherapy [102].
Two systematic reviews [103,104] documented evidence for the
utility of follow-up examinations, and concluded that follow-up should
be practical and directed by symptoms and pelvic examination, and that
frequency of follow-up visits may be reduced in low-risk patients. Given
the low risk of recurrence, vaginal cytology can be omitted, resulting in
reduced healthcare costs [105]. It appears that visual inspection is sufcient, since positive cytology is merely diagnosed in cases of symptomatic recurrence [100,106,107].
Patient counseling and follow-up should also acknowledge that
these patients are at risk of second cancers following their primary
endometrial cancer. The estimated incidence rate of Lynch syndrome
in an unselected endometrial cancer population is 3% 6% [108].
Routine pathologic screening of mismatch repair deciencies in the endometrial cancer specimen, similar to colorectal cancer, has been advocated [109]. A recent study showed that survivors of endometrial cancer
have a three-fold increased risk of a second cancer compared with a
matched population, mainly due to lifestyle factors and genetic susceptibility [110].
16. Recurrence
Localized recurrences are managed preferentially by surgery, irradiation, or a combination of the two, depending on the primary therapy.
Screening for distant metastases should be performed before deciding
on curative treatment. With an increasing number of patients managed
by surgery alone, radiotherapy provides an effective salvage treatment
in cases of vaginal or central pelvic recurrence. A combination of EBRT
and brachytherapy, preferably image guided, is usually required. Large
recurrences should be evaluated for excision, followed by radiotherapy.
Additional chemotherapy is being evaluated in an ongoing GOG trial.
Extended surgery may be justied, especially in patients who have
had prior radiation therapy. The results of pelvic exenteration in properly selected cases are similar to those obtained in cervical cancer.
Patients with non-localized recurrent tumors may be candidates for
progestin therapy (medroxyprogesterone acetate 50100 mg three
times a day or megestrol acetate 80 mg 23 times a day). The progestin
therapy is continued as long as the disease is static or in remission.
Maximum clinical response may not be apparent for 3 or more months

after initiating therapy. Platinum-based chemotherapy (cisplatinum
and doxorubicin, or carboplatin and paclitaxel) has been recommended
for patients with advanced or recurrent disease, not amenable to cure
by surgery and/or radiotherapy [28,72]. Targeted therapies are being investigated in several ongoing trials.
17. Recommendations for practice
(1) Preoperatively, a denitive tissue diagnosis must be obtained.
This helps to determine the surgical approach, and to differentiate tumors at low and high risk of lymph node metastasis.
Imaging can be useful to determine depth of myometrial
invasion, cervical involvement, and lymph node enlargement.
Level of Evidence C
(2) Lymphadenectomy in clinical Stage I endometrial cancer has no
impact on overall or relapse-free survival. Level of Evidence A.
Outside clinical trials, lymphadenectomy should be performed
for staging only in high-risk cases. There is little evidence to support a therapeutic benet, but it should be used to select women
with positive nodes for adjuvant therapy. Level of Evidence C
(3) Adjuvant radiotherapy for women with Stage I endometrial cancer with low, intermediate, or highintermediate risk features
has no impact on survival, although it reduces the rate of pelvic
recurrence. Level of Evidence A. Vaginal brachytherapy effectively reduces the risk of vaginal relapse in patients with risk factors. Level of Evidence A. External beam radiotherapy should be
considered in patients with positive nodes or advanced stage disease to ensure pelvic control. Level of Evidence B
(4) The addition of adjuvant chemotherapy to radiotherapy in patients with high-risk factors improves progression-free survival,
but an overall survival benet is unproven. Level of Evidence A
(5) Adjuvant chemotherapy for patients with early stage, high-risk
disease should only be considered within clinical trials.
(6) Chemotherapy is superior to whole abdominal radiation for patients with Stage III disease and abdominal disease with residual
nodules less than 2 cm diameter. Level of Evidence A
(7) Targeted therapy in endometrial cancer should only be considered within clinical trials.
(8) There is no evidence to support the use of adjuvant hormonal
therapy (progestogen). Level of Evidence A
(9) Patients with high-risk and advanced stage endometrial
cancer should be managed where possible by a gynecological
oncologist, working within a multidisciplinary team. Level of
Evidence A
(10) Patients with endometrial cancer are frequently old and frail, and
this should be taken into account when prescribing adjuvant
therapy. Professional consensus
Conict of interest
The authors have no conicts of interest to declare.
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Uterine sarcomas
Jaime Prat a, 'Nomonde Mbatani b
a
b
Department of Pathology, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain
Department of Obstetrics and Gynecology, Groote Schuur Hospital/University of Cape Town, Cape Town, South Africa
1. Introduction
2.1. Clinical features
Uterine sarcomas account for approximately 1% of all female genital

tract malignancies and 3%7% of all uterine cancers [1]. Their rarity and
histopathological diversity have contributed to the lack of consensus on
risk factors for poor outcome and optimal treatment [2].
Histologically, uterine sarcomas were classied initially into
carcinosarcomas (malignant mesodermal mixed tumors), accounting
for 50% of cases, leiomyosarcomas (30%), endometrial stromal sarcomas
(15%), and undifferentiated sarcomas (5%). Subsequently, carcinosarcoma has been reclassied, largely based on its spreading pattern,
as a dedifferentiated or metaplastic form of endometrial carcinoma.
However, as it behaves more aggressively than the usual type of
endometrial carcinoma, carcinosarcoma is still included in most
retrospective studies of uterine sarcomas, as well as in the separate
section of mixed epithelial and mesenchymal tumors of the 2014
WHO classication [3].
Tumor stage is the single most important prognostic factor. In the
past, uterine sarcomas were staged using a staging system proposed
in 1988 for endometrial carcinoma. This has not proven satisfactory
and, in 2009, a new FIGO staging system was developed for uterine
sarcomas (Table 1) [4]. The new staging system has two divisions, one
for leiomyosarcoma and endometrial stromal sarcoma (ESS), and one
for adenosarcoma. Carcinosarcoma is still staged using the endometrial
carcinoma staging system [4].
Prolonged use of tamoxifen, a uterine estrogen receptor agonist, is
associated with a three times risk of sarcoma development [5]. There
have been reported cases of radiation-induced sarcomas occurring
long after treatment for other cancers [6].
Neither preoperative imaging with ultrasonography nor PET scans
are capable of differentiating between benign or malignant smooth
muscle masses. The use of diffusion weighted magnetic resonance
imaging (DWI) for tumor location and characterization has been
suggested, but is yet to be validated.
Patients with carcinosarcomas and adenosarcomas tend to be much
older than patients with other sarcomas.
After excluding carcinosarcoma, leiomyosarcoma has become the

most common subtype of uterine sarcoma even though it accounts for
only 1%2% of uterine malignancies [2]. Approximately 1 in every 800
smooth muscle tumors of the uterus is a leiomyosarcoma [2]. It occurs
in women over 40 years of age who usually present with abnormal
vaginal bleeding (56%), a palpable pelvic mass (54%), and/or pelvic
pain (22%) [2]. Signs and symptoms resemble those of the far more
common leiomyoma and preoperative distinction between the two tumors may be difcult. Malignancy should be suspected by the presence
of tumor growth in postmenopausal women who are not using
hormonal replacement therapy, although it is rare for a leiomyosarcoma
to present as a rapidly growing tumor.
2. Leiomyosarcomas
Leiomyosarcomas are considered true sarcomas.
2.2. Pathological features

Leiomyosarcomas are either single masses or, when associated with
leiomyomas, the largest mass. They are typically voluminous tumors
with a mean diameter of 10 cm (only 25% of cases measure less than
5 cm). The cut surface is typically soft, bulging, eshy, necrotic, hemorrhagic, and lacks the prominent whorled appearance of leiomyomas.
The histopathologic diagnosis of leiomyosarcoma is usually straightforward as most clinically malignant smooth muscle tumors of the uterus
exhibit the constellation of hypercellularity, severe nuclear atypia,
and high mitotic rate generally exceeding 15 mitotic gures per 10
high-power-elds (MF/10 HPF) (Fig. 1) [3]. Moreover, one or more
supportive clinicopathologic features such as peri- or postmenopausal
age, extrauterine extension, large size (over 10 cm), inltrating border,
necrosis, and atypical mitotic gures are frequently present. However,
epithelioid and myxoid leiomyosarcomas are two rare variants that
may be difcult to recognize microscopically as their pathologic features
differ from those of ordinary spindle cell leiomyosarcomas. In both
tumor types nuclear atypia is usually mild and the mitotic rate often
less than 3 MF/10 HPF [3]. Necrosis may be absent in epithelioid
leiomyosarcomas and myxoid leiomyosarcomas are often hypocellular.
In the absence of severe cytologic atypia and high mitotic activity, both
tumors are diagnosed as sarcomas based on their inltrative borders.
The minimal pathological criteria for the diagnosis of leiomyosarcoma
are more problematic and, in such cases, the differential diagnosis
S106
J. Prat, 'N. Mbatani / International Journal of Gynecology and Obstetrics 131 (2015) S105S110
Table 1
FIGO staging for uterine sarcomas.
Stage
Denition
Leiomyosarcomas and endometrial stromal sarcomas

I
Tumor limited to uterus
IA
Less than 5 cm
IB
More than 5 cm
II
Tumor extends beyond the uterus, within the pelvis
IIA
Adnexal involvement
IIB
Involvement of other pelvic tissues
III
Tumor invades abdominal tissues (not just protruding into the abdomen).
IIIA
One site
IIIB
More than one site
IIIC
Metastasis to pelvic and/or para-aortic lymph nodes
IV IVA
Tumor invades bladder and/or rectum
IVB
Distant metastasis
Adenosarcomas
I
Tumor limited to uterus
IA
Tumor limited to endometrium/endocervix with no myometrial invasion
IB
Less than or equal to half myometrial invasion
IC
More than half myometrial invasion
II
Tumor extends to the pelvis
IIA
Adnexal involvement
IIB
Tumor extends to extrauterine pelvic tissue
III
Tumor invades abdominal tissues (not just protruding into the abdomen).
IIIA
One site
IIIB
More than one site
IIIC
Metastasis to pelvic and/or para-aortic lymph nodes
IV IVA
Tumor invades bladder and/or rectum
IVB
Distant metastasis
Carcinosarcomas
Carcinosarcomas should be staged as carcinomas of the endometrium.
Note: Simultaneous tumors of the uterine corpus and ovary/pelvis in association with
ovarian/pelvic endometriosis should be classied as independent primary tumors.
includes, not only benign smooth muscle tumors that exhibit variant
histologic features and unusual growth patterns (Boxes 1 and 2), but
also atypical smooth muscle tumors (so-called smooth muscle tumors
of uncertain malignant potential [STUMPs]) (Box 3). Application of
the WHO diagnostic criteria [3] has allowed distinguishing these
unusual histologic variants of leiomyoma frequently misdiagnosed as
well-differentiated or low-grade leiomyosarcomas in the past. In a
population-based study of uterine sarcomas from Norway [7], of 356
tumors classied initially as leiomyosarcomas, the diagnosis was
conrmed in only 259 (73%) cases, whereas 97 (27%) were excluded
on review and reclassied, according to WHO criteria, as leiomyomas
or leiomyoma variants
2.3. Immunohistochemistry and molecular biology

Leiomyosarcomas usually express smooth muscle markers such as
desmin, h-caldesmon, smooth muscle actin, and histone deacetylase 8
(HDCA8). However, epithelioid and myxoid leiomyosarcomas may
show lesser degrees of immunoreaction for these markers [3]. Also,
leiomyosarcomas are often immunoreactive for CD10 (mainly considered a marker of endometrial stromal differentiation) and epithelial
markers including keratin and EMA (the latter being more frequently
positive in the epithelioid variant) [3]. Conventional leiomyosarcomas
express estrogen receptors, progesterone receptors, and androgen
receptors in 30%40% of cases. Whereas a variable proportion of uterine leiomyosarcomas has been reported as being immunoreactive for
c-KIT, no c-KIT mutations have been identied [3].
The levels of Ki67 are higher in uterine leiomyosarcomas compared
with benign smooth muscle tumors. Overexpression of p16 has been
described in uterine leiomyosarcomas and may prove to be a useful adjunct immunomarker for distinguishing between benign and malignant
uterine smooth muscle tumors [8].
Fig. 1. Leiomyosarcoma.
The vast majority of uterine leiomyosarcomas are sporadic. Patients

with germline mutations in fumarate hydratase are believed to be at increased risk for developing uterine leiomyosarcomas as well as uterine
leiomyomas [9]. The oncogenic mechanisms underlying the development of uterine leiomyosarcomas remain elusive. Overall, uterine
leiomyosarcoma is a genetically unstable tumor that demonstrates
complex structural chromosomal abnormalities and highly disturbed
gene regulation, which likely reects the end-state of accumulation of
multiple genetic defects.
2.4. Prognosis
Leiomyosarcomas diagnosed according to the WHO criteria [3] are
associated with poor prognosis even when conned to the uterus at
the time of diagnosis [7,10]. Recurrence rate ranges from 53% to 71%
[11,12]. First recurrences occur in the lungs in 40% of patients and in
the pelvis in only 13% [13]. Overall ve-year survival rate ranges from
15% to 25% with a median survival of only 10 months in one study
[14]. In the Norwegian series, 148 patients with leiomyosarcomas limited to the uterus had a ve-year survival of 51% at Stage I and 25% at
Stage II (by the 1988 FIGO staging classication). All patients with
tumor spread outside the pelvis died within 5 years [7].
Box 1
Leiomyoma variants that may mimic malignancy.
Mitotically active leiomyoma

Cellular leiomyoma
Hemorrhagic leiomyoma and hormone-induced changes
Leiomyoma with bizarre nuclei (atypical leiomyoma)
Myxoid leiomyoma
Epithelioid leiomyoma
Leiomyoma with massive lymphoid infiltration
Box 2
Smooth muscle proliferations with unusual
growth patterns.
Disseminated peritoneal leiomyomatosis

Benign metastasizing leiomyoma
Intravenous leiomyomatosis
Lymphangioleiomyomatosis
Box 3
Atypical smooth muscle tumors (so-called smooth muscle tumors of
uncertain malignant potential [STUMP]).
Tumor cell necrosis in a typical leiomyoma
Necrosis of uncertain type with 10 MF/10 HPFs, or marked
diffuse atypia
Marked diffuse or focal atypia with borderline mitotic counts
Necrosis difficult to classify
There has been no consistency among various studies regarding

correlation between survival and patient age, clinical stage, tumor
size, type of border (pushing versus inltrative), presence or absence
of necrosis, mitotic rate, degree of nuclear pleomorphism, and vascular
invasion [3]. However, one study [15], found tumor size to be a major
prognostic parameter: 5 of 8 patients with tumors less than 5 cm in diameter survived, whereas all patients with tumors greater than 5 cm in
diameter died. In a series of 208 uterine leiomyosarcomas [2], the only
other parameters predictive of prognosis were tumor grade and stage.
In the report from Norway [7], including 245 leiomyosarcomas conned
to the uterus, tumor size and mitotic index were signicant prognostic
factors and allowed for separation of patients into three risk groups
with marked differences in prognosis.
Ancillary parameters including p53, p16, Ki 67, and Bcl-2 have been
used in leiomyosarcomas to try to predict outcome [10]. It is not clear
whether they act independently of stage. However, a recent study
revealed that the combination of tumor size, mitotic index, Ki67, and
Bcl-2 protein expression allows two groups of leiomyosarcomas to be
distinguished, with different survival: tumors greater than or equal
to10 cm in diameter, with greater than or equal to 20 MF/10 HPF, greater than or equal to10% immunoreactive nuclei for Ki67, and negative for
Bcl-2 had worse prognosis than smaller leiomyosarcomas with less than
or equal to 20 MF/10 HPF, less than or equal to10% immunoreactive
nuclei for Ki67, and positive or negative for Bcl-2 [15].
2.5. Treatment
Treatment of leiomyosarcomas includes total abdominal hysterectomy and debulking of the tumor if present outside the uterus. Removal of
the ovaries and lymph node dissection remain controversial as metastases to these organs occur in only a small percentage of cases and are
frequently associated with intra-abdominal disease [2]. Ovarian preservation may be considered in premenopausal patients with early-stage
leiomyosarcomas [2]. Lymph node metastases have been identied in
6.6% and 11% in two series of patients with leiomyosarcoma who
underwent lymphadenectomy [2,16]. In the rst series, the ve-year
disease-specic survival rate was 26% in patients who had positive
lymph nodes compared with 64.2% in patients who had negative
lymph nodes (P b 0.001) [16]. The inuence of adjuvant therapy on survival is uncertain. Radiotherapy may be useful in controlling local recurrences and chemotherapy with doxorubicin or docetaxel/gemcitabine is
now used for advanced or recurrent disease with response rates ranging
from 27% to 36% [17]. Some tumors may respond to hormonal treatment
[18]. Targeted therapies such as trabectedin have been investigated as
treatment in advanced stage or metastatic leiomyosarcoma with some
appreciable disease control [19].
classify a smooth muscle tumor into a specic category when possible

[3]. Most tumors classied as atypical smooth muscle tumors
(STUMP) have been associated with favorable prognosis and, in these
cases, only follow-up of the patients is recommended.
4. Endometrial stromal tumors
Endometrial stromal tumors account for less than 1% of all uterine
tumors [1]; nevertheless, they represent the second most common
category of mesenchymal uterine tumors. They are predominantly or
exclusively intramural neoplasms and are divided into benign and malignant based on the type of tumor margin: well-circumscribed tumors
are benign stromal nodules, whereas those exhibiting myometrial
invasion and permeation of myometrial lymphovascular spaces are sarcomas [3]. Endometrial sarcomas are further classied by the latest
WHO classication, based on resemblance to (or lack of) proliferativetype endometrial stroma, into the following three main categories:
(1) low-grade endometrial stromal sarcoma; (2) high-grade endometrial stromal sarcoma; and (3) undifferentiated endometrial sarcoma [3].
4.1. Low-grade endometrial stromal sarcoma
Low-grade endometrial stromal sarcomas frequently occur in
women between 40 and 55 years of age and more than 50% of patients
are premenopausal [19]. Some cases have been reported in women with
ovarian polycystic disease, and after estrogen use or tamoxifen therapy
[19]. Patients commonly present with abnormal uterine bleeding, pelvic
pain, and dysmenorrhea, but as many as 25% are asymptomatic [15]. At
presentation, extrauterine pelvic extension, most commonly involving
the ovary, is found in up to one-third of patients [19,20].
Microscopically, endometrial stromal sarcomas consist of welldifferentiated endometrial stromal cells exhibiting only mild nuclear
atypia and characteristically invade the lymphovascular spaces of the
myometrium (Fig. 2). Tumor cell necrosis is rarely seen.
The tumor cells are strongly immunoreactive for CD10, usually
positive for smooth-muscle actin and less frequently for desmin (30%),
but they are negative for h-caldesmon and HDAC8. Estrogen receptors
(only alpha isoform), progesterone receptors, androgen receptors, and
WT-1 are typically positive. Nuclear beta-catenin expression has been
shown in up to 40% of low-grade endometrial stromal sarcomas. The
most common cytogenetic abnormality of low-grade endometrial stromal sarcomas is a recurrent translocation involving chromosomes 7 and
17 t(7;17)(p15;q21)], which results in a fusion between JAZF1 and
SUZ12 (formerly designated as JJAZ1) [21]. The fusion can be detected
by uorescence in situ hybridization as well as by reverse transcriptase
polymerase chain reaction.
3. Atypical smooth muscle tumors (smooth muscle tumors of

uncertain malignant potential) (STUMP)
Uterine smooth muscle tumors that show some worrisome histological features (i.e. necrosis, nuclear atypia, or mitoses), but do not
meet all diagnostic criteria for leiomyosarcoma, fall into the category
of atypical smooth muscle tumors (STUMP) (Box 2) [3]. This diagnosis,
however, should be used sparingly and every effort should be made to
S107
Fig. 2. Low-grade endometrial stromal sarcoma.
S108
Low-grade endometrial stromal sarcomas are indolent tumors with

a favorable prognosis [19]. Tumor behavior is characterized by late
recurrences even in patients with Stage I disease; thus, long-term
follow-up is required. About one-third of patients develop recurrences,
most commonly in the pelvis and abdomen, and less frequently in the
lungs and vagina [19]. Stage of the tumor is the most signicant prognostic factor. Surgical stage higher than Stage I is a univariate predictor
of unfavorable outcome. Five-year survival for patients with Stages I and
II tumors is 90% compared with 50% for Stages III and IV [22].
Treatment of low-grade endometrial stromal sarcomas is largely surgical in the form of hysterectomy and bilateral salpingo-oophorectomy.
The tumors are often sensitive to hormones and it has been shown that
patients retaining their ovaries have a much higher risk of recurrence
(up to 100%) [23]. Lymph node dissection does not seem to have a
role in the treatment of these tumors. Patients may also receive adjuvant radiation or hormonal treatment with progestational agents or
aromatase inhibitors. Hormone replacement therapy is discouraged.
4.2. High-grade endometrial stromal sarcoma
These rare tumors have features that are intermediate between lowgrade endometrial stromal sarcomas and undifferentiated sarcomas
[24]. Patients range in age from 2867 years (mean 50 years) and usually present with abnormal vaginal bleeding, an enlarged uterus, or a
pelvic mass [25].
The tumors may appear as intracavitary polypoid or mural masses.
They range in size up to 9 cm (median 7.5 cm) and often show extrauterine extension at the time of diagnosis. The cut surface is eshy
with extensive areas of necrosis and hemorrhage. Microscopically,
they consist predominantly of high-grade round-cells that are sometimes associated with a low-grade spindle cell component that is most
commonly bromyxoid [25]. Mitotic activity is striking and typically
greater than 10 per 10 HPF. Necrosis is usually present. Rarely, areas of
conventional low-grade endometrial stromal sarcoma are seen. Highgrade endometrial stromal sarcomas are CD10, estrogen receptor, and
progesterone receptor negative but show strong diffuse cyclin D1 immunoreactivity (N 70% nuclei). They are also typically c-Kit positive but
DOG1 negative. High-grade endometrial stromal sarcoma typically harbors the YWHAE-FAM22 genetic fusion as a result of t(10;17) (q22;p13).
These tumors appear to have a prognosis that is intermediate, between low-grade endometrial stromal sarcomas and undifferentiated
uterine sarcomas [25]. Compared with low-grade endometrial stromal
sarcomas, patients with high-grade endometrial stromal sarcomas
have earlier and more frequent recurrences (often b1 year) and are
more likely to die of disease. Advanced or recurrent tumors (10;17)
should be treated aggressively with a combination of radiation and
chemotherapy as they do not respond to conventional treatment for
low-grade endometrial stromal sarcomas [25].
5. Adenosarcoma
Mllerian adenosarcoma is a mixed tumor of low malignant potential
that shows an intimate admixture of benign glandular epithelium and
low-grade sarcoma, usually of endometrial stromal type. It represents
between 5% and 10% of all uterine sarcomas. The tumor occurs mainly
in the uterus of postmenopausal women (average 58 years) but also in
adolescents and young adults (30%) [27]. Most adenosarcomas arise
from the endometrium, including the lower uterine segment, but rare
tumors develop in the endocervix (5%10% of cases) and in extrauterine
locations [28].
Adenosarcomas are polypoid tumors of approximately 56 cm
in maximum diameter (range, 120 cm) that typically ll and
distend the uterine cavity. Adenosarcomas with sarcomatous
overgrowth tend to be larger with a eshy, hemorrhagic, and necrotic cut surface. They invade the myometrium more often than
conventional adenosarcomas.
Microscopically, the stroma typically concentrates around the
glands forming periglandular cuffs (Fig. 3). Well-differentiated tumors
may exhibit only mild nuclear atypia and very few or no mitoses in
the stromal component. However, the presence of hypercellular
periglandular cuffs helps to distinguish adenosarcoma from its rarer benign counterpart, the adenobroma [28]. Heterologous mesenchymal
elements, usually rhabdomyosarcoma, are found in 10%15% of cases.
Vaginal or pelvic recurrence occurs in approximately 25%30% of
cases at 5 years and is associated almost exclusively with myometrial
invasion and sarcomatous overgrowth [27,28]. Myometrial invasion is
found in approximately 15% of cases, but deep invasion in only 5% [27,
28]. Sarcomatous overgrowth, dened as the presence of pure sarcoma,
usually of high-grade and without a glandular component, occupying at
least 25% of the tumor, has been reported in 8% to 54% of uterine
adenosarcomas [27,28].
Whereas immunoreactions for cell proliferation markers (Ki-67
and P53) are stronger in adenosarcomas with sarcomatous overgrowth
than in typical adenosarcomas, the expression of markers of cell differentiation (CD10 and PR) is higher in typical adenosarcomas than in
adenosarcomas with sarcomatous overgrowth [28].
Except when associated with myometrial invasion or sarcomatous
overgrowth, the prognosis of adenosarcoma is far more favorable
than that of carcinosarcoma; however, about 25% of patients with
adenosarcoma ultimately die of their disease [27]. Recurrences are
usually composed exclusively of mesenchymal elements. Distant
metastases, which occur in 5% of cases, are almost always composed
of pure sarcoma (70%). The treatment of choice is total abdominal
hysterectomy with bilateral salpingo-oophorectomy.
4.3. Undifferentiated endometrial sarcoma

This tumor is rare. Patients are typically postmenopausal (mean age
is 60 years) and have postmenopausal bleeding or signs/symptoms
secondary to extra-uterine spread [26]. Approximately 60% of patients
present with high-stage disease (Stage III/IV). The diagnosis of undifferentiated endometrial sarcoma is applied to tumors that exhibit
myometrial invasion, severe nuclear pleomorphism, high mitotic activity and/or tumor cell necrosis, and lack smooth muscle or endometrial
stromal differentiation [3]. The histological appearance of this tumor is
more like the mesenchymal elements of a carcinosarcoma than a typical
endometrial stromal tumor. It is variably CD10 positive and typically
estrogen receptor and progesterone weakly positive or negative.
Undifferentiated endometrial sarcomas are highly aggressive tumors
that are associated with a very poor prognosis (less than 2 years survival) [26]. Patients should be treated by hysterectomy and bilateral
salpingo-oophorectomy and adjuvant radiation and/or chemotherapy.
Fig. 3. Adenosarcoma.
6. Carcinosarcoma
Carcinosarcoma, also referred to as malignant mllerian mixed
tumor, is a biphasic neoplasm composed of distinctive and separate,
but admixed, malignant-appearing epithelial and mesenchymal
elements (Fig. 4). The mean age of patients with carcinosarcoma is in
the seventh decade, but the age range spans from the fourth through
the ninth decades [29]. The disease usually presents like other endometrial cancers with vaginal bleeding. Another typical presentation of
carcinosarcoma is in the form of a polypoid mass that protrudes through
the cervical os.
The epithelial component is serous, or high-grade carcinoma not
otherwise specied, in about two-thirds of cases, and endometrioid
carcinoma in approximately one-third [29]. In a recent study, 10% of
the carcinomatous components were FIGO grade 1, 10% grade 2, and
80% grade 3 [29]. The homologous components of carcinosarcoma
are usually spindle cell sarcoma without obvious differentiation;
many resemble brosarcomas or pleomorphic sarcomas. Almost all
are high-grade sarcomas. The most common heterologous elements
are malignant cartilage or skeletal muscle constituting something
that resembles either pleomorphic rhabdomyosarcoma or embryonal
rhabdomyosarcoma [1].
Carcinosarcomas are highly aggressive tumorsfar more aggressive
than usual endometrial carcinomas. The overall ve-year survival for
patients with carcinosarcoma is around 30% and for those with Stage I
disease (conned to the uterus) it is approximately 50% [1,6,30,31].
This is in contrast with other high-grade endometrial cancers for
which ve-year survival in Stage I disease is approximately 80% or
higher [32,33]. This has led to toxic treatment protocols that usually
include ifosfamide and cisplatin along with whole pelvic irradiation.
In carcinosarcomas, there is general agreement that surgical stage is
the most important prognostic indicator regardless of how the patient
was staged. A recent study found that the presence of heterologous
elements is a poor prognostic factor in patients with FIGO Stage I tumors
[29]. Other factors proposed include the histologic grade of the
carcinomatous and sarcomatous elements, the percentage of tumor
with sarcomatous differentiation, depth of myometrial invasion, and
presence of lymphovascular invasion [1,6,30,31].
6.1. Treatment of carcinosarcomas
Primary surgery for early disease includes a hysterectomy, bilateral
salpingo-oophorectomy, and pelvic node dissection as the tumor spread
pattern is similar to high-grade endometrial carcinomas. Omentectomy
is also advocated by some. Complete cytoreduction should be the aim of
surgery, as this may be associated with an overall survival benet.
Fig. 4. Carcinosarcoma.
S109
Combination chemotherapy seems to result in fewer recurrences

than whole body irradiation [34]. Patients with carcinosarcomas,
however, tend to be elderly with co-morbidities. The ideal agents
still need to be established. The results of the Gynecologic Oncology
Group 261 study, which aims to compare ifosfamide/paclitaxel versus
carboplatin/paclitaxel combinations in patients with advanced stage
or recurrent carcinosarcoma, are awaited. Radiotherapy is only able to
control pelvic disease [35].
6.2. Follow-up of sarcomas
Follow-up should be determined by risk of recurrence. As metastasis
to the lungs is common, efforts must be made to rule these out
remembering that early lesions tend to be asymptomatic but resectable.
Low-grade sarcoma patients may be followed for local relapse every 4
6 months for the rst 35 years, then yearly. High-grade tumors can be
followed-up every 34 months for the rst 23 years, twice a year for
the next 23 years, and then annually.
Conict of interest
The authors have no conict of interest.
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Cancer of the ovary, fallopian tube, and peritoneum

Jonathan S. Berek a, Christopher Crum b, Michael Friedlander c
a
b
c
Stanford Womens Cancer Center, Stanford Cancer Institute, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA
Brigham and Womens Hospital, Harvard Medical School, Boston, MA, USA
Royal Hospital for Women, Randwick, Sydney, Australia
1. Introduction
1.1. Primary sites: ovarian, fallopian tube, and peritoneal cancer
In 2014, the Gynecologic Oncology Committee of FIGO revised the
staging to incorporate ovarian, fallopian tube, and peritoneal cancer in
the same system. Changing the staging system required extensive
international consultation. The primary site (i.e. ovary, fallopian tube,
or peritoneum) is designated, where possible. When it is not possible
to clearly delineate the primary site, these should be listed as undesignated [1,2].
It has been presumed that fallopian tube malignancies were rare [2].
However, histologic, molecular, and genetic evidence shows that from
40% 60% of tumors that were classied as high-grade serous carcinomas of the ovary or peritoneum may have originated in the mbrial end
of the fallopian tube [38]. Therefore, the incidence of fallopian tube
cancers may have been substantially underestimated. These new data
support the view that high-grade serous ovarian, fallopian tube, and
peritoneal cancers should be considered collectively, and that the convention of designating malignancies as having an ovarian origin should
no longer be used, unless that is clearly the origination site. It has been
suggested that extrauterine tumors of serous histology arising in the
ovary, fallopian tube, or peritoneum might be described collectively as
Mllerian carcinomas [1,2] or pelvic serous carcinomas [9]. The latter tumor designation is controversial because some peritoneal tumors
might arise in extrapelvic peritoneum. Therefore, the simple term serous carcinoma" is preferred, and most of these are high-grade serous
carcinomas (HGSC).
Although there has been no formal staging for peritoneal cancers,
the FIGO staging system is used with the understanding that it is not
possible to have a Stage I peritoneal cancer.
1.1.1. Primary site
Ovarian epithelial tumors may arise within endometriosis or cortical
inclusions of Mllerian epithelium, likely a form of endosalpingiosis.
These include low-grade endometrioid carcinomas, clear cell carcinomas, borderline and low-grade serous carcinomas, and mucinous carcinomas. These tumors are thought to evolve slowly from lower-grade
precursor conditions (endometriotic cysts, cystadenomas, etc.) and are
classied as type I tumors [5]. Fallopian tube carcinomas arise in the
distal fallopian tube and the majority of these are high-grade serous
carcinomas. These are thought to evolve rapidly from more obscure
precursors and are designated as type II tumors [5,6]. This latter group
encompasses high-grade endometrioid carcinomas and carcinosarcomas. All of these high-grade carcinomas are nearly always associated
with mutations in the TP53 gene [5].
1.1.2. Lymphatic and lymph node drainage
The lymphatic drainage of the ovaries and fallopian tubes is via the
utero-ovarian, infundibulopelvic, and round ligament pathways and
an external iliac accessory route into the following regional lymph
nodes: external iliac, common iliac, hypogastric, lateral sacral, paraaortic lymph nodes and, occasionally, to the inguinal nodes [1,1012].
The peritoneal surfaces can drain through the diaphragmatic lymphatics
and thence to the major venous vessels above the diaphragm.
1.1.3. Other metastatic sites
The peritoneum, including the omentum and pelvic and abdominal
viscera, is the most common site for dissemination of ovarian and
fallopian tube cancers. This includes the diaphragmatic and liver
surfaces. Pleural involvement is also seen. Other extraperitoneal or
extrapleural sites are relatively uncommon, but can occur [1,1012].
After systematic pathologic analysis has excluded a tubal or ovarian
site of origin, malignancies that appear to arise primarily on the peritoneum have an identical spread pattern, and frequently may involve the
ovaries and fallopian tubes secondarily. These peritoneal tumors are
thought to arise in endosalpingiosis.
1.2. Classication rules
Although CT scans can delineate the intra-abdominal spread of
disease to a certain extent, ovarian, fallopian tube, and peritoneal cancers should be staged surgically. Operative ndings determine the precise histologic diagnosis, stage, and therefore the prognosis, of the
patient [1,9,10,1214].
In selected patients with advanced-stage disease, it may be appropriate to initiate chemotherapy prior to surgical intervention, and in these
cases, there should be histological or cytological conrmation of the diagnosis prior to starting neoadjuvant chemotherapy (see 5.2.2. below).
Chest radiograms may serve as a screen for pleural effusions. As
distant metastases are infrequent, there is no requirement for other radiological evaluation unless symptomatic. Serum CA125 levels may be
useful in determining response to chemotherapy, but they do not contribute to staging.
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J.S. Berek et al. / International Journal of Gynecology and Obstetrics 131 (2015) S111S122
1.2.1. Fallopian tube involvement

Fallopian tube involvement can be divided into three categories. In
the rst, an obvious intraluminal and grossly apparent fallopian tube
mass is seen with tubal intraepithelial carcinoma (carcinoma in situ)
that is presumed to have arisen in the fallopian tube. These cases should
be staged surgically with a histological conrmation of disease. Tumor
extension into the submucosa or muscularis and to and beyond the
serosa can therefore be dened. These features, together with the
laterality and the presence or absence of ascites, should all be taken
into consideration [1,3,6,7].
In the second scenario, a widespread serous carcinoma is associated
with a tubal intraepithelial carcinoma. A visible mass in the endosalpinx
may not be seen but the histologic ndings should be noted in the pathology report since they may indicate a fallopian tube primary. Tumors
obliterating both fallopian tube and ovary may belong to this group but
whether a presumptive assignment of a tubal origin can be made in
such cases is controversial given that tubal intraepithelial carcinoma
cannot be conrmed.
In the third scenariothe risk-reducing salpingo-oophorectomy
tubal intraepithelial carcinoma may be the only nding. It should be reported as originating in the fallopian tube and managed accordingly.
The majority of early serous cancers detected are found in the fallopian
tube, irrespective of genetic risk [15,16].
1.2.2. FIGO staging
The updated, revised FIGO staging system combines the classication for ovarian, fallopian tube, and peritoneum cancer. It is based
on ndings made mainly through surgical exploration (as outlined
above). Table 1 presents the 2014 FIGO staging classication for cancer
of the ovary, fallopian tube, and peritoneum. The equivalents within the
Union for International Cancer Control (UICC) TNM classication are
presented in Table 2.
In addition to these changes, several other modications of the
former staging system have been made to better prospectively capture
the data. Stage IC is now divided into three categories, IC1 (surgical
spill), IC2 (capsule ruptured before surgery or tumor on ovarian or
fallopian tube surface), and IC3 (malignant cells in the ascites or peritoneal washings). Stage IIC has been eliminated. The updated staging
includes a revision of the Stage IIIC based on spread to the retroperitoneal lymph nodes alone without intraperitoneal dissemination, because
an analysis of these patients indicates that their survival is signicantly
better than those who have intraperitoneal dissemination [17]. This category is now subdivided into IIIA1(i) (metastasis 10 mm in greatest
dimension), and IIIA1(ii) (metastasis N10 mm in greatest dimension).
Stage IIIA2 is now microscopic extrapelvic peritoneal involvement
with or without positive retroperitoneal lymph node metastasis. The
wording of Stage IIIB has been modied to reect the lymph node status. Stage IVB now includes metastases to the inguinal lymph nodes.
1.2.2.1. Regional lymph nodes (N)
NX: Regional lymph nodes cannot be assessed.
N0: No regional lymph node metastasis.
N1: Regional lymph node metastasis.
1.2.2.2. Distant metastasis (M)
MX: Distant metastasis cannot be assessed.
M0: No distant metastasis.
M1: Distant metastasis (excluding peritoneal metastasis).
1.3. Histopathologic classication
The majority of cases of ovarian cancer are of epithelial origin. FIGO
endorses the WHO histological typing of epithelial ovarian tumors. It is
Table 1
FIGO staging classication for cancer of the ovary, fallopian tube, and peritoneum.
Stage I: Tumor conned to ovaries or fallopian tube(s)
T1-N0-M0
IA: Tumor limited to 1 ovary (capsule intact) or fallopian tube; no tumor on
ovarian or fallopian tube surface; no malignant cells in the ascites or peritoneal
washings
T1a-N0-M0
IB: Tumor limited to both ovaries (capsules intact) or fallopian tubes; no tumor on
ovarian or fallopian tube surface; no malignant cells in the ascites or peritoneal
washings
T1b-N0-M0
IC: Tumor limited to 1 or both ovaries or fallopian tubes, with any of the following:
IC1: Surgical spill
T1c1-N0-M0
IC2: Capsule ruptured before surgery or tumor on ovarian or fallopian tube
surface
T1c2-N0-M0
IC3: Malignant cells in the ascites or peritoneal washings
T1c3-N0-M0
Stage II: Tumor involves 1 or both ovaries or fallopian tubes with pelvic
extension (below pelvic brim) or peritoneal cancer
T2-N0-M0
IIA: Extension and/or implants on uterus and/or fallopian tubes and/or ovaries
T2a-N0-M0
IIB: Extension to other pelvic intraperitoneal tissues
T2b-N0-M0
Stage III: Tumor involves 1 or both ovaries or fallopian tubes, or peritoneal
cancer, with cytologically or histologically conrmed spread to the
peritoneum outside the pelvis and/or metastasis to the retroperitoneal
lymph nodes
T1/T2-N1-M0
IIIA1: Positive retroperitoneal lymph nodes only (cytologically or histologically
proven):
IIIA1(i) Metastasis up to 10 mm in greatest dimension
IIIA1(ii) Metastasis more than 10 mm in greatest dimension
IIIA2: Microscopic extrapelvic (above the pelvic brim) peritoneal involvement
with or without positive retroperitoneal lymph nodes
T3a2-N0/N1-M0
IIIB: Macroscopic peritoneal metastasis beyond the pelvis up to 2 cm in greatest
dimension, with or without metastasis to the retroperitoneal lymph nodes
T3b-N0/N1-M0
IIIC: Macroscopic peritoneal metastasis beyond the pelvis more than 2 cm in
greatest dimension, with or without metastasis to the retroperitoneal lymph
nodes (includes extension of tumor to capsule of liver and spleen without
parenchymal involvement of either organ)
T3c-N0/N1-M0
Stage IV: Distant metastasis excluding peritoneal metastases
Stage IVA: Pleural effusion with positive cytology
Stage IVB: Parenchymal metastases and metastases to extra-abdominal organs
(including inguinal lymph nodes and lymph nodes outside of the abdominal
cavity)
Any T, any N, M1
recommended that all ovarian epithelial tumors be subdivided according to the classication given below [18].
The histologic classication of ovarian, fallopian tube, and peritoneal
neoplasia is as follows:
Serous tumors.
Mucinous tumors.
Endometrioid tumors.
Clear cell tumors.
Brenner tumors.
Undifferentiated carcinomas (this group of malignant tumors is of epithelial structure, but they are too poorly differentiated to be placed in
any other group).
Mixed epithelial tumors (these tumors are composed of two or more
of the ve major cell types of common epithelial tumors. The types are
usually specied).
Cases with high-grade serous carcinoma in which the ovaries and
fallopian tubes appear to be incidentally involved and not the primary
origin can be labeled as peritoneal carcinoma or serous carcinoma of
undesignated site, at the discretion of the pathologist.
Table 2
Cancer of the ovary, fallopian tube and peritoneum: FIGO staging (2014) compared with
TNM classication.a
FIGO
UICC
(Designate primary: Tov, Tft, Tp, or Tx) T

Stage
IA
IB
IC
IIA
IIB
IIIA
IIIB
IIIC
IV
Regional nodes (N)
Nx
N0
N1
Distant metastasis (M)
Mx
M0
M1
T1a
T1b
T1c
T2a
T2b
T3a
T3a
T3b
T3b
T3c
T3c
Any T
N0
N0
N0
N0
N0
N0
N1
N0
N1
N01
N1
Any N
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M1
Regional lymph nodes cannot be assessed

No regional lymph node metastasis
Regional lymph node metastasis
Distant metastasis cannot be assessed
No distant metastasis
Distant metastasis (excluding peritoneal
metastasis)
Notes:
1. The primary sitethat is, ovary, fallopian tube, or peritoneumshould be designated
where possible. In some cases, it may not be possible to clearly delineate the primary
site, and these should be listed as undesignated.
2. The histologic type should be recorded.
3. The staging includes a revision of the Stage III patients and allotment to Stage IIIA1 is
based on spread to the retroperitoneal lymph nodes without intraperitoneal dissemination, because an analysis of these patients indicates that their survival is signicantly
better than those who have intraperitoneal dissemination.
4. Involvement of retroperitoneal lymph nodes must be proven cytologically or histologically.
5. Extension of tumor from omentum to spleen or liver (Stage IIIC) should be differentiated
from isolated parenchymal splenic or liver metastases (Stage IVB).
a
Reproduced with permission from Berek et al. [1], p.482.
Epithelial tumors of the ovary and fallopian tube are further

subclassied by histologic grading, which can be correlated with prognosis. This grading system does not apply to nonepithelial tumors
[19]. Two grading systems are applied. For non-serous carcinomas
(most endometrioid and mucinous), grading is identical to that used
in the uterus, based on architecture with a one-step upgrade if there is
prominent nuclear atypia, as follows:

G3: Poorly differentiated.
Serous carcinomas are the most common in both the ovary and
tube. More than 90% of fallopian tube carcinomas are serous or highgrade endometrioid adenocarcinoma. Other cell types have been
reported, but are rare [1,2,24]. Serous carcinomas are graded in a twograde system betting their biology. High-grade serous carcinomas,
including both classic-appearing and those with SET features (solid,
endometrioid-like, and transitional) carry a high frequency of mutations in TP53 [2022]. Low-grade serous carcinomas are often associated
with borderline or atypical proliferative serous tumors, often contain
mutations in BRAF and KRAS and contain wild-type TPp53. Most moderately differentiated serous carcinomas carry mutations in TP53 and
should be combined with the high-grade tumors [19,2123].
Nonepithelial cancers, although uncommon, are extremely important. These include granulosa cell tumors, germ cell tumors, sarcomas, and lymphomas. They are discussed below as separate entities.
S113
Metastatic neoplasms to the ovary, such as tumors arising in the lower

reproductive tract sites (cervix or uterine carcinomas) and gastrointestinal tract (signet ring cell [Krukenberg] carcinomas, low grade
appendiceal or pancreaticobiliary mucinous tumors and other neoplasms) are graded and staged in accordance with their respective
sites of origin [1,2].
2. Epidemiology
Malignant tumors of the ovaries occur at all ages with variation in
histological subtype by age. For example, in women younger than
20 years of age, germ cell tumors predominate, while borderline tumors
typically occur in women in their 30s and 40s10 or more years younger than in women with invasive epithelial ovarian cancers, which
mostly occur after the age of 50 years.
The lifetime risk of a woman in the USA developing ovarian cancer is
approximately 1 in 70. Approximately 23% of gynecologic cancers are
ovarian in origin, but 47% of all deaths from cancer of the female genital
tract occur in women with ovarian cancer. Overall, epithelial ovarian
cancer accounts for 4% of all new cancer diagnoses in women and 5%
of all cancer-related deaths [1,2,25].
The overall incidence of epithelial tumors varies from 917 per
100 000 and is highest in industrialized countries, with the exception
of Japan [26]. However, this incidence rate increases proportionately
with age. The largest number of patients with epithelial ovarian cancer
is found in the 6064 years age group.
Established risk factors for epithelial ovarian tumors include reproductive risk factors. Women who have never had children are twice as
likely to develop this disease. First pregnancy at an early age, early menopause, and the use of oral contraceptives have been associated with
lower risks of ovarian cancer [27]. The relationship of these variables
to fallopian tube cancer is unclear.
As noted above, it has been previously presumed that fallopian tube
malignancies were rare; however, this has been challenged by evidence
to show that many tumors that were classied as serous carcinomas of
the ovary or peritoneal cancers appear to have their origin in the
fallopian tube [37]. When the origin is uncertain, the convention of
designating all serous cancers, as originating in the ovary should no longer be used and the term undesignated origin may be applied at the
discretion of the pathologist [18].
2.1. Genetics
Hereditary factors are implicated in approximately 10% of ovarian,
fallopian tube, and peritoneal cancers. Mutations that have been identied include [2832]:
(1) Inherited pathologenic mutations in the BRCA1 and the BRCA2
genes. Women who carry germline mutations in BRCA1 and
BRCA2 have a substantially increased risk of ovarian, tubal, and
peritoneal cancerabout 20%50% with BRCA1 and 10%20%
with BRCA2 [2932]. Typically these cancers occur at an earlier
age than sporadic cancers, particularly in BRCA1 mutation carriers, with a median age of diagnosis in the mid-40s.
(2) Inherited mutations in the mismatch repair genes associated
with Type II Lynch Syndrome. Women carrying these mutations
have an increased risk of a number of cancers including colon,
endometrial, and ovarian cancer. Typically, the ovarian cancers
that occur are endometrioid or clear cell histologically and are
usually Stage I.
(3) Inherited mutation in ARID1 is associated with clear cell and
endometrioid carcinomas [33].
Patients with a strong family history of epithelial ovarian, fallopian tube, or peritoneal cancers, particularly if there is a documented
germline mutation, are advised to have a risk-reducing bilateral
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salpingo-oophorectomy after appropriate counseling and at the completion of childbearing. All women who are suspected of carrying a
BRCA germline mutation, based on family history or young age of diagnosis and a high-grade serous or high-grade endometrioid cancer,
should be offered genetic testing. BRCA mutations may also occur in
women without a family history of breast/ovarian cancer, and genetic
testing should be considered in patients from ethnic groups where
there is a high incidence of founder mutations (e.g. Ashkenazi Jewish
ancestry), and in women with high-grade serous cancers under the
age of 70 years [2630]. Australian guidelines [34] suggest that all
women with epithelial ovarian cancer diagnosed under the age of 70
should be considered for BRCA mutation testing independent of family
history and histological subtype. In contrast, the Society of Gynecologic
Oncology (SGO) recommends that all women diagnosed with ovarian,
fallopian tube, or peritoneal carcinoma, regardless of age or family history, should receive genetic counseling and be offered genetic testing
[35]. Women whose family history suggests Lynch II syndrome should
undergo appropriate genetic counseling and testing.
3. Screening
To date, there are no documented effective screening methods that
reduce the mortality of ovarian, fallopian tube, or peritoneal cancers.
Studies using CA125, ultrasonography of the pelvis, and pelvic examination do not have an acceptable level of sensitivity and specicity, but trials are in progress in women in the general population and those in the
high-risk population. Women at increased genetic risk should be encouraged to consider risk-reducing bilateral salpingo-oophorectomy,
as this is the most effective way to reduce mortality in this population
of women [36,37]. An ACOG bulletin has recommended that opportunistic (at the time of a clinically indicated hysterectomy) bilateral
salpingectomy be considered in women not at genetic risk who wish
to retain their ovaries as a way to reduce their risk of later developing
high-grade serous carcinomas [38].
Prior to surgery a chest radiograph should be taken to screen for a

pleural effusion and a CT scan of the abdomen and pelvis should be performed to delineate the extent of intra-abdominal disease. However, in
the absence of extra-abdominopelvic disease, radiological scanning
does not replace surgical staging with laparotomy. Tumor markers including CA125, and carcinoembryonic antigen (CEA) should be considered [1]. With a high CA125 level, the most common diagnosis would be
epithelial ovarian, fallopian tube, or peritoneal cancer.
A gastric or colonic primary with metastases to the ovaries may
mimic ovarian cancer, and if the CEA is elevated, this should be considered. A current mammogram should be considered as patients are
frequently in the age group where breast cancer is prevalent. A colonoscopy is indicated when symptoms suggest possible bowel cancer [1].
The following factors point to the presence of a malignancy, and are
useful in the clinical assessment of masses:
Age of the patient (young for germ cell, older for epithelial
malignancies).
Bilaterality.
Tumor xation clinically.
Ascites.
Ultrasonographically complex, especially if solid areas.
CT nding of metastatic nodules.
Elevated tumor markers.
5. Primary surgery
In general, the prognosis of epithelial ovarian, fallopian, and peritoneal malignancies is independently affected by the following [1,44,45]:
Stage of the cancer at diagnosis.
Histological type and grade.
Maximum diameter of residual disease after cytoreductive surgery.
5.1. Staging laparotomy
4. Diagnosis
Patients with epithelial ovarian cancers conned to the ovary or
fallopian tube at initial diagnosis have a very good prognosis [3942].
The symptoms are often very insidious and the duration of symptoms
not very different between patients with early stage or advanced stage
disease [13,14]. This may reect the different biological behavior of
the various histological subtypes; for example, grade 1 serous, clear
cell, mucinous, and endometrioid cancers are commonly early stage at
presentation, whereas high-grade serous cancers are most often Stage
III because of early dissemination by a more aggressive cancer. Tumor
markers such as human gonadotropin (hCG) and alpha-fetoprotein
(AFP) are mandatory to exclude germ cell tumors in younger patients
with a pelvic mass or suspicious enlargement of an ovary.
Approximately two-thirds of all epithelial ovarian cancers are
Stage III or Stage IV at diagnosis. Presenting symptoms include vague
abdominal pain or discomfort, menstrual irregularities, and dyspepsia
and other mild digestive disturbances, which may have been present
for only a few weeks [13,14,43]. As the disease progresses, abdominal
distention and discomfort from ascites generally worsen, and may be
associated with respiratory symptoms from increased intra-abdominal
pressure or from the transudation of uid into the pleural cavities. Abnormal vaginal bleeding is an uncommon symptom.
Fallopian tube and peritoneal cancers likely present the same as
ovarian cancer. Past analyses have been biased because many fallopian
tube cancers have been presumed to arise in the ovaries.
A detailed medical history must be taken to ascertain possible risk
factors, history of other cancers, and history of cancer in the family.
Then a complete physical examination, including general, breast, pelvic,
and rectal examination, must be performed [1].
A thorough staging laparotomy is an important part of early

management. If the preoperative suspicion is malignancy, a laparotomy should be performed. If there is no visible or palpable evidence
of metastasis, the following should be performed for adequate staging
[1,10,11,13,14]:
Careful evaluation of all peritoneal surfaces.
Retrieval of any peritoneal uid or ascites. If there is none, washings of
the peritoneal cavity should be performed.
Infracolic omentectomy.
Selective lymphadenectomy of the pelvic and para-aortic lymph
nodes, at least ipsilateral if the malignancy is unilateral.
Biopsy or resection of any suspicious lesions, masses, or adhesions.
Random peritoneal biopsies of normal surfaces, including from the
undersurface of the right hemidiaphragm, bladder reection, cul-desac, right and left paracolic recesses, and both pelvic sidewalls.
Total abdominal hysterectomy and bilateral salpingo-oophorectomy
in most cases.
Appendectomy for mucinous tumors.
Upon entering the abdominopelvic cavity, the peritoneal uid
should be sent for cytology. In the absence of ascites, irrigation should
be performed and washings sent for cytology.
The laparotomy should proceed with a detailed examination of the
contents, including all the peritoneal surfaces. In addition to all the suspicious sites, biopsies from the peritoneal reection of the bladder, the
posterior cul-de-sac, both paracolic gutters, subdiaphragmatic surfaces,
and both pelvic sidewalls should be taken. The primary tumor, if limited
to the ovary, should be examined to look for capsular rupture. All
obvious sites of tumor must be removed wherever possible in addition

to total hysterectomy and bilateral salpingo-oophorectomy. The omentum, pelvic, and para-aortic lymph nodes should be removed for histological examination.
In younger women, fertility may be an issue. In these patients, conservative surgery, with preservation of the uterus and contralateral
ovary, should be considered after informed consent [40].
Clinical judgment is important in the approach to a pelvic mass in
the young, reproductive-aged woman. If the suspicion is strong for
malignancy, open laparotomy is generally indicated. Laparoscopy may
be more appropriate if the suspicion is more for benign disease, where
tumor markers (including hCG and AFP) are normal. A biopsy of any
suspicious lesion can be performed and frozen section obtained in
order to proceed expeditiously with denitive surgery.
Ovaries and fallopian tubes should be evaluated as thoroughly as
possible to establish the site of origin. If visible, the entire tube, particularly the distal portion, should be submitted for pathology and examined using the SEE-FIM protocol [32]. Ovaries should be scrutinized for
coexisting endometriotic cysts, adenobromas, or other benign conditions that could serve as a nidus of tumor development.
5.2. Cytoreductive (debulking) surgery for advanced stage disease
5.2.1. Primary debulking
At least two-thirds of patients with ovarian cancer present with
Stage III or IV disease. This may affect the performance status and tness
for surgery. However, the most important prognostic indicator in
patients with advanced stage ovarian cancer is the volume of residual
disease after surgical debulking. Therefore, patients whose medical
condition permits should generally undergo a primary laparotomy
with total abdominal hysterectomy, bilateral salpingo-oophorectomy,
omentectomy, and maximal attempt at optimal cytoreduction [1,
4446]. This may necessitate bowel resection, and occasionally, partial
or complete resection of other organs. Systematic pelvic and paraaortic lymphadenectomy of non-enlarged nodes does not improve
overall survival, when compared with removal of bulky nodes only,
although there is a modest improvement in progression-free survival
[47]. Level of Evidence A
5.2.2. Interval debulking
In selected patients with cytologically proven Stage IIIC and IV
disease who may not be good surgical candidates, 23 cycles of neoadjuvant chemotherapy may be given initially, followed by interval surgical cytoreduction and additional chemotherapy [48]. This is particularly
useful in patients with a large pleural effusion and/or gross ascites. In selected patients whose primary cytoreduction is considered suboptimal,
particularly if a gynecologic oncologist did not perform the initial operation, interval debulking may be considered after 23 cycles of systemic
chemotherapy [1,48,49]. Pathologic assessment for residual tumor following neoadjuvant therapy will enable an estimate of residual disease,
with modest predictive value in terms of survival [50].
6. Chemotherapy
6.1. Chemotherapy for early stage cancer
The prognosis of patients with adequately staged tumors with Stage
IA and Stage IB grade 12 epithelial cancers of the ovary is very good;
adjuvant chemotherapy does not provide additional benets and is
not indicated. For higher-grade tumors and for patients with Stage IC
disease, adjuvant platinum-based chemotherapy is given to most patients, although there has been debate about the absolute survival benet in women with Stage IA and IB cancers who have had thorough
surgical staging [39]. All patients with Stage II disease should receive
adjuvant chemotherapy. The optimal number of cycles in patients
with Stage I disease has not been denitively established, but typically
S115
between 3 and 6 cycles are administered. The Gynecologic Oncology

Group (GOG) 157 study suggested that 3 cycles of carboplatin and
paclitaxel was equivalent to 6 cycles, but in subgroup analysis, 6 cycles
appeared superior in patients with high-grade serous cancers [46].
There is no evidence to support adjuvant therapy for carcinoma in
situ of the fallopian tube and it is not recommended [1,2,41]. Level of
Evidence A
6.2. Chemotherapy for advanced stage ovarian cancer
Patients who have had primary cytoreduction should receive chemotherapy following surgery [1,51] (Table 3). The accepted standard
is 6 cycles of platinum-based combination chemotherapy, with a platinum (carboplatin or cisplatin) and a taxane (paclitaxel or docetaxel)
[5256]. Docetaxel may be considered in selected patients as it has
less neurotoxicity, but it is more myelosuppressive than paclitaxel
[52]. One relatively small study reported that maintenance chemotherapy with monthly paclitaxel increased disease-free interval but not
overall survival [57]. The role of maintenance chemotherapy is uncertain, is not standard practice, and is being investigated in clinical trials.
Although intraperitoneal chemotherapy has been shown to be
associated with improved progression-free survival and overall survival
in selected patients with optimally debulked Stage III ovarian cancer, it
is not widely used outside the USA because of concerns regarding increased toxicity and catheter-related problems, and the benets are
still debated [5862]. The GOG 172 trial compared intravenous paclitaxel plus cisplatin with intravenous paclitaxel plus intraperitoneal
cisplatin and paclitaxel in patients with Stage III ovarian or peritoneal
carcinoma, with no residual disease greater than 1 cm in diameter
[60]. Only 42% of patients in the intraperitoneal group completed
6 cycles of the assigned therapy, but the intraperitoneal group had
an improvement in progression-free survival of 5.5 months (23.8 vs
18.3 months; P = 0.05) and an improvement in overall survival of
15.9 months (65.6 vs 49.7 months; P = 0.03). Further studies of intraperitoneal therapy are ongoing. Level of Evidence A
Combination chemotherapy with either intravenous carboplatin and
paclitaxel or intraperitoneal cisplatin and paclitaxel (using the GOG 172
protocol) are the standard treatment options for patients with advanced
disease, with evidence to support the addition of bevacizumab in selected patients. The advantages and disadvantages of the intravenous versus intraperitoneal routes of administration of these drugs should be
discussed with the patient. Intraperitoneal chemotherapy is applicable
only to patients with advanced disease who have had optimal debulking
and have less than 1 cm residual disease. It should be used only in centers that have experience with intraperitoneal chemotherapy.
The recommended doses and schedule for intravenous chemotherapy are: carboplatin (starting dose AUC 56), and paclitaxel
(175 mg/m2), every 3 weeks for 6 cycles [47], or the dose-dense regimen of carboplatin AUC 6 every 3 weeks for 6 cycles and weekly paclitaxel 80 mg/m2 [62]. The Japanese GOG (JGOG) reported the ndings of
the latter regimen and showed improved progression-free survival and
overall survival [63]. This regimen is being compared with standard
every 3 weeks intravenous and intraperitoneal regimens in several
clinical trials. An Italian trial (MITO-7) investigated a different schedule
of weekly carboplatin (AUC 2 mg/mL per min) plus weekly paclitaxel
(60 mg/m2) compared with carboplatin (AUC 6 mg/mL per min, administered every 3 weeks) and paclitaxel (175 mg/m2) [64]. The weekly
regimen did not signicantly improve progression-free survival compared with the conventional regimen (18.8 months vs 16.5 months;
P = 0.18), but was associated with better quality of life and fewer
toxic effects. Other ongoing studies, including the ICON 8 trial and the
GOG 262 trial are assessing dose-dense chemotherapy, and will help
answer the important question regarding the role of dose dense
chemotherapy in a white population.
The recommended doses and schedule for intraperitoneal chemotherapy are paclitaxel 135 mg/m2 intravenously on day one, followed
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Table 3
Chemotherapy for advanced epithelial ovarian cancer: recommended regimens.a
Drugs
Standard regimens
Dose
Carboplatin
AUC = 56
Paclitaxel
175 mg/m2
Carboplatin
AUC = 5-6
Paclitaxel
80 mg/m2
Carboplatin
AUC = 5
Docetaxel
75 mg/m2
Cisplatin
75 mg/m2
Paclitaxel
135 mg/m2
Carboplatin (single agent) b
AUC = 5
AUC, area under the curve dose by Calvert formula (287).
Administration (h)
Interval
No. of treatments
Every 3 weeks
68 cycles
6 cycles
18 weeks
6 cycles
Every 3 weeks
Every week
Every week
Every 3 weeks
Every 3 weeks
Every 3 weeks
6 cycles, as tolerated
6 cycles
Abbreviation: AUC, area under the curve dose by the methods of Calvert et al. [65] and Nagao et al. [66].
a
Reproduced with permission from Berek et al. [1], p.510.
b
In patients who are elderly, frail, or poor performance status.
by cisplatin 100 mg/m2 intraperitoneally on day two, followed by

paclitaxel 60 mg/m2 intraperitoneally on day eight, every 3 weeks for
6 cycles, as tolerated [5860]. Many centers modify the dose of cisplatin
to 75 mg/m2 rather than 100 mg/m2 that was used in GOG 172 to reduce
toxicity. Others substitute carboplatin (AUC 56) for cisplatin in the
regimen. The impact on outcome of these pragmatic modications is
unknown, but intraperitoneal carboplatin is being evaluated in JGOGand NRG-sponsored clinical trials.
Bevacizumab 7.515 mg/kg every 3 weeks may be added to these
regimens [67,68]. Two studies have reported a modest, but statistically
signicant increase in progression-free survival in patients receiving
maintenance bevacizumab following carboplatin, paclitaxel, and
concurrent bevacizumab [67,68]. There is no evidence as yet to demonstrate an overall survival benet, but a subgroup analysis of the International Collaboration on Ovarian Neoplasms 7 (ICON7) trial found that
there was an improved median survival (30.3 vs 39.4 months) in patients with suboptimal Stage III and Stage IV [67]. The role, optimal
dose, timing (primary vs recurrent disease), and duration of treatment
of bevacizumab are still controversial.
In patients who may not tolerate combination chemotherapy
because of medical comorbidities or advanced age, single-agent,
intravenously administered carboplatin (AUC 56) can be given.
In patients who have a signicant hypersensitivity reaction to paclitaxel, an alternative active drug can be substituted (e.g. docetaxel or
nanoparticle paclitaxel). Carboplatin hypersensitivity is very uncommon in the rst-line setting, but is seen in some patients with recurrent
disease who have multiple lines of platinum-based chemotherapy.
In the case of carboplatin hypersensitivity, desensitization could be
attempted, depending on the severity of the reaction, or alternatively
cisplatin (5075 mg/m2) may be an option but there still may be a
risk of a severe allergic reaction.
The treatment of all patients with advanced stage disease is
approached in a similar manner, with dose modications based on the
toxicity of therapy. Care should be taken when considering combination
chemotherapy in patients with a very poor performance status or with
compromised renal function.
7. Secondary surgery
7.1. Second-look laparotomy
A second-look laparotomy (or laparoscopy) was previously performed in patients who have no clinical evidence of disease after completion of rst-line chemotherapy to determine response to treatment.
Although of prognostic value, it has not been shown to inuence
survival, and is no longer recommended as part of the standard of care
7.2. Secondary cytoreduction

Secondary cytoreduction may be dened as an attempt at cytoreductive surgery at some stage following completion of rst-line chemotherapy. Retrospective studies suggest that patients benet if all
macroscopic disease can be removed, which usually means patients
with a solitary recurrence. Patients with a disease-free interval longer
than 1224 months and those with only 12 sites of disease appear to
derive most benet [70,71]. The role of secondary cytoreductive surgery
is being evaluated in randomized clinical trials. Level of Evidence C
8. Follow-up for malignant epithelial tumors
There is no evidence to show that intensive clinical monitoring during follow-up after completion of primary surgery and chemotherapy
with early initiation of chemotherapy in asymptomatic women with recurrent disease improves overall survival or quality of life. In asymptomatic patients with CA125 progression and small volume disease or
no radiological evidence of recurrence, it is appropriate to delay starting
chemotherapy. However, there may be a subset of patients who are
suitable for secondary debulking surgery at the time of recurrence.
The objectives of follow-up include:
Assessment of response to the treatment.
Early recognition and prompt management of treatment-related
complications, including provision of psychological support.
Early detection of symptoms or signs of recurrent disease.
Collection of data regarding the efcacy of any treatment and the
complications associated with those treatments in patients treated
in clinical trials.
Promotion of healthy behavior, including screening for breast cancer
in patients with early stage disease, and screening for cervical cancer
in patients having conservative surgery.
There are no evidence-based guidelines regarding the appropriate follow-up schedule. During the rst year following treatment,
patients are seen every 3 months with a gradual increase in intervals
to every 46 months after 2 years and then annually after the fth
year. At each follow-up, the patient should have her history retaken,
including any change in family history of cancers and attention to
any symptoms that could suggest recurrence; a physical and pelvic
examinationshould be performed. This is an opportunity to refer appropriate patients for genetic testing if it was not done at diagnosis or
during treatment. The CA125 has traditionally been checked at regular
intervals, but there has been debate regarding the clinical benet of
using CA125 progression alone as a trigger for initiating second-line
chemotherapy. A large MRC OV05-EORTC 55955 study showed that
treating asymptomatic patients with recurrent ovarian cancer with
chemotherapy on the basis of CA125 progression alone did not improve

survival and early treatment in asymptomatic patients had a negative
impact on quality of life [72]. This study has generated considerable debate regarding the use of CA125 for follow-up, but most agree that it is
reasonable not to immediately initiate treatment unless there is a clear
clinical indication to do so. The timing of treatment should be based on
symptoms as well as clinical and radiological ndings. Imaging tests
such as ultrasonography of the pelvis, CT, MRI, and/or positron emission
tomography (PET) scans should be performed only when the clinical
ndings or the tumor markers suggest possible recurrence.
There appears to be no benet to initiating chemotherapy in an
asymptomatic patient with recurrent disease based only on rising
CA125 levels in the absence of clinical symptoms or radiological evidence of recurrence. In asymptomatic patients with small volume disease and no radiological evidence of recurrence, close observation is a
reasonable option, as well as entry into an appropriate clinical trial or
tamoxifen may be considered.
A Cochrane database systematic review of tamoxifen in unselected
women with recurrent ovarian cancer reported a 10% objective response and a 32% disease stabilization rate [73]. The patients treated
were very heterogeneous and included asymptomatic patients with rising CA125 levels, and symptomatic patients with chemotherapyresistant disease who had been heavily pretreated and had a poor
performance status. GOG 198 compared tamoxifen and thalidomide in
women with recurrent FIGO Stage III or IV epithelial ovarian, tubal, or
peritoneal cancer who had completed rst-line chemotherapy, and
who subsequently had Gynecologic Cancer InterGroup (GCIG) documented CA125 progression. The study reported that women who received thalidomide had a 31% increased risk of disease progression
(hazard ratio, 1.31), compared with those who were given tamoxifen
[74]. The median progression-free survival was 3.2 months in the thalidomide group versus 4.5 months in the tamoxifen group. This suggests
that tamoxifen may have a role in selected patients with a rising CA125
level, and the relationship between estrogen receptor positivity and
benet of tamoxifen in this patient population is being evaluated in
current studies.
9. Chemotherapy for recurrent epithelial malignancies
The majority of patients who present with advanced epithelial
cancers of the ovary/fallopian tube/peritoneum will relapse with a median time to recurrence of 16 months. Patients with recurrent ovarian
cancer constitute a heterogeneous group with a variable prognosis,
and a variable response to further treatment. The most widely used clinical surrogate for predicting response to subsequent chemotherapy and
prognosis has been the progression-free interval or the platinum-free
interval, which is dened as the time from cessation of primary
platinum-based chemotherapy to disease recurrence or progression
[75,76]. This has been useful to dene specic patient populations, but
it has a number of limitations and depends on how patients are followed. In particular, it depends on how recurrence is detected and dened.
Patients with a treatment-free interval of less than 6 months are classied as platinum resistant and generally treated with nonplatinumbased chemotherapy, while those with a treatment-free interval of
more than 6 months are considered to be platinum sensitive and commonly treated with platinum-based chemotherapy. Patients who progress while on treatment or within 4 weeks of stopping chemotherapy
are classied as platinum refractory [75,76].
There have been modications to these denitions, and time to
progression or recurrence rather than treatment-free interval or
platinum-free interval has been used to dene specic patient populations. There has been signicant change in practice over the last
20 years and patients have been routinely followed with regular
CA125 testing after completion of chemotherapy. For example, the
platinum-resistant subgroup may include asymptomatic patients
with CA125 progression alone at 3 months post chemotherapy or
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radiological evidence of recurrence as well as those who are symptomatic with clinical recurrence. The 4th Ovarian Cancer Consensus
Conference reached agreement that distinct patient populations should
be based on the interval from last platinum therapy and the time to
progression. The progression-free interval is dened from the last date
of platinum dose until progressive disease is documented [75,76].
For patients whose disease is considered platinum-sensitive, the
ICON 4 study showed advantage in terms of overall survival and
progression-free survival for a combination of carboplatin and paclitaxel
versus single-agent carboplatin [77]. Level of Evidence A
For patients with neurotoxicity, gemcitabine [78] or liposomal
doxorubicin [79] may be substituted for the paclitaxel. Level of
Evidence A
There is evidence that the addition of bevacizumab to the regimen of
carboplatin and gemcitabine improves progression-free survival
compared with carboplatin and gemcitabine in platinum-sensitive
disease [80].
For patients with denite platinum-resistant disease, enrollment on
available clinical trials or treatment with nonplatinum chemotherapy
should be considered. There are a number of chemotherapy options
including liposomal doxorubicin [81], topotecan [81], etoposide [82,
83], and gemcitabine [84,85]. The reported response rates are low,
about 10%, with a median time to progression of 34 months and a
median survival of 912 months. Over the last 5 years there have been
a number of trials carried out with new agents in patients with
platinum-resistant ovarian cancer, including epothilones, trabectedin
[86] and permetrexed [87] with no signicant increase in response
rates or progression-free survival. No new cytotoxic agent has been
approved to treat recurrent ovarian cancer for many years. The role
of angiogenesis inhibitors in platinum-resistant ovarian cancer is
discussed below.
The optimal management of a patient with platinum-resistant or refractory disease is complex and requires a careful assessment of the patients performance status, symptoms, and extent of disease. Attention
to symptom control and good palliative care is an essential component
of management.
With very few exceptions, recurrent disease is not curable and
the aim of treatment is to maintain quality of life and palliate symptoms particularly in patients with platinum resistant ovarian cancer [88]. There are many potential treatment options, including
chemotherapy, angiogenesis inhibitors, radiation therapy, or surgery
in selected patients and inclusion in clinical trials [71]. There is a subset
of patients who may benet from secondary surgical debulking,
but they constitute a minority. The role of secondary surgical debulking
is being addressed in prospective randomized clinical trials. Level of
Evidence C
An extensive review of targeted therapies can be found in the
chemotherapy chapter included in the FIGO Cancer Report 2015 (this
Supplement) [89].
10. Management of epithelial tumors of low malignant potential
(borderline tumors)
Compared with invasive epithelial cancers, borderline tumors tend
to affect a younger population and constitute 15% of all epithelial tumors
of the ovary [90]. Nearly 75% of these are Stage I at the time of diagnosis.
The following can be said for these tumors [91]:
The diagnosis must be based on the pathology of the primary tumor.
Extensive sectioning of the tumor is necessary to rule out invasive cancer.
The prognosis of these tumors is extremely good, with a 10-year survival of about 95%.
Invasive cancers that arise in borderline tumors are often indolent and
generally have a low response to platinum-based chemotherapy.
Spontaneous regression of peritoneal implants has been observed.
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Early stage, serous histology, and younger age at diagnosis are associated with a more favorable prognosis.
Although gross residual disease after primary laparotomy is associated with poorer prognosis, mortality from the disease remains low.
Those patients who have invasive implants in the omentum or other
distant sites are more likely to recur earlier, and although they are
commonly treated with cytotoxic chemotherapy the response rates
are low.
The causes of death include complications of disease (e.g. small
bowel obstruction) or complications of therapy, and only rarely malignant transformation. The mainstay of treatment is primary surgical
staging and cytoreduction. For patients with Stage I disease who want
to preserve fertility, conservative surgery with unilateral salpingooophorectomy can be considered after intraoperative inspection of
the contralateral ovary to exclude involvement [92]. For patients with
only one ovary, or bilateral cystic ovaries, a partial oophorectomy or
cystectomy can be considered for fertility preservation. For all other patients, total hysterectomy and bilateral salpingo-oophorectomy are recommended, with maximal cytoreduction if the disease is metastatic.
Patients with borderline tumors in all stages of disease should
be treated with surgery. A small percentage of patients with invasive
implants may benet from chemotherapy but the response to chemotherapy is unpredictable and generally much lower than that observed
in high-grade serous cancers. Uncommonly, some patients recur
early and have higher-grade invasive cancers and may benet from
chemotherapy [93].
In patients with late recurrence of the disease, secondary cytoreduction should be considered, and chemotherapy given only if invasive disease is present histologically.
Follow-up of patients with no evidence of disease is the same as for
those with malignant epithelial carcinomas, but at less frequent intervals. If the contralateral ovary has been retained, it should be followed
by transvaginal ultrasonography, at least on an annual basis [1,91,94].
Level of Evidence C
11. Management of granulosa cell tumors
Granulosa cell tumors account for about 70% of sex-cord stromal tumors and 3%5% of all ovarian neoplasms [2]. There are two types of
granulosa cell tumors: the juvenile and the adult types. Because of the
high estrogen production, the juvenile type typically presents with sexual precocity, while the adult type may present with postmenopausal
bleeding. The majority of patients are diagnosed with Stage I tumors.
The peak incidence is in the rst postmenopausal decade [2,95].
Granulosa cell tumors are generally indolent (i.e. with a tendency to
late recurrence). Stage at diagnosis is the most important prognostic
factor. Other prognostic factors include age at diagnosis, tumor size,
and histological features. If metastatic, adequate cytoreduction is the
mainstay of treatment. If the patient is young and the disease is conned
to one ovary, conservative surgery should be performed [96,97].
The infrequency of the disease, and its protracted course, has resulted in a lack of prospective studies. There is no evidence that adjuvant
chemotherapy or radiotherapy improves the results of surgery alone
for Stage I disease. The value of postoperative adjuvant chemotherapy
for higher-risk Stage I disease (tumor size N10 cm, capsule rupture,
high mitotic count) is uncertain, and has not been tested in randomized
studies. Platinum-based chemotherapy is used for patients with
advanced or recurrent disease, with an overall response rate of 63%
80% [9799].
Follow-up is clinical. For patients with elevated levels of inhibin B
and/or AMH at initial diagnosis of granulosa cell tumors, inhibin B and/
or AMH appear to be reliable markers during follow-up for early detection of residual or recurrent disease. There is no evidence-based preference for inhibin B or AMH as a tumor marker [100]. Serum inhibin is a
useful tumor marker in postmenopausal women. Level of Evidence C
12. Management of germ cell malignancies

This group of ovarian tumors consists of a variety of histologically
different subtypes that are all derived from the primitive germ cells of
the embryonic gonad. Malignant germ cell tumors represent a relatively
small proportion of all ovarian tumors. Prior to advances in chemotherapy, the prognosis for these aggressive tumors was poor. The use of
platinum-based chemotherapeutic regimes has made germ cell malignancies among the most highly curable cancers [95].
12.1. Presentation
The highest incidence of malignant germ cell tumors occurs in the
second and third decades of life. They are frequently diagnosed by nding a palpable abdominal mass in a young woman who complains of abdominal pain. The following are the symptoms of germ cell tumors in
order of frequency [95]:
Acute abdominal pain.

Chronic abdominal pain.
Asymptomatic abdominal mass.
Abnormal vaginal bleeding.
Abdominal distention.
12.2. Histological classication

The classication of germ cell tumors of the ovary is important to
determine prognosis and for treatment with chemotherapy. Germ cell
tumors are classied as follows [2,95]:
Dysgerminoma.
Embryonal carcinoma.
Polyembryoma.
Teratoma (immature; mature; mature with carcinoma [squamous
cell, carcinoid, neuroectodermal, malignant struma, etc.]).
Extraembryonal differentiation (choriocarcinoma; endodermal sinus
tumor [yolk sac tumor]).
12.3. Diagnosis, staging, and surgical management

Ovarian germ cell tumors are staged similarly to epithelial carcinomas, although the staging system used for male germ cell tumors is
probably more useful. The approach to treatment is based on the principles of management of metastatic germ cell tumors of the testis (i.e. low,
intermediate, and poor risk). Dysgerminoma is the equivalent of
seminoma in testicular cancer [101]. It is exquisitely sensitive to
platinum-based chemotherapy and is radiosensitive. The cure rate is
high irrespective of the stage. The other histological subtypes are equivalent to nonseminomatous testicular cancer. The aggressiveness of the
disease is dependent on the type, the most aggressive being endodermal sinus and choriocarcinoma, but with combination chemotherapy,
they are highly curable [102106].
As chemotherapy can cure the majority of patients, even with advanced disease, conservative surgery is standard in all stages of all
germ cell tumors. Conservative surgery means laparotomy with careful
examination and biopsy of all suspicious areas, with limited cytoreduction, thereby avoiding major morbidity. The uterus and the contralateral ovary should be left intact. Wedge biopsy of a normal ovary is
not recommended as it defeats the purpose of conservative therapy by
potentially causing infertility. Patients who receive conservative surgery
with the preservation of one ovary retain acceptable fertility rates despite adjuvant treatment with chemotherapy. There has been no report
of higher adverse obstetric outcome or long-term unfavorable sequelae
in the offspring [107110].
Secondary surgery is of no proven benet, except in those patients

whose tumor was not completely resected at the initial operation and
who had teratomatous elements in their primary tumor. Surgical resection of residual masses may be benecial in such patients, as there
may be mature teratomatous nodules that can continue to increase in
size [111].
12.4. Postoperative management and follow-up of dysgerminoma
Patients with Stage IA disease may be observed after surgery. A small
proportion of patients may recur, but they can be treated successfully at
the time of recurrence with a high rate of cure. Patients with disease beyond the ovary should receive adjuvant chemotherapy. Although radiation therapy is effective, ovarian failure makes it undesirable for patients
with an intact ovary. The long-term adverse effects are greater than
with chemotherapy and radiotherapy is now rarely used.
A follow-up surveillance regime for patients with Stage 1A
dysgerminoma is outlined in Table 4. This schedule is based on the experience managing seminomas in males and the reports by Patterson
et al. [112] and Dark et al. [113]. This pragmatic follow-up schedule
and has not been tested in randomized trials.
12.4.1. Chemotherapy for dysgerminoma
Dysgerminoma is extremely sensitive to chemotherapy, and treatment with chemotherapy cures the majority of patients, even with advanced disease [95,114]. The recommended chemotherapy regimen is
as follows:
Etoposide (E) 100 mg/m2 IV per day for 5 days every 3 weeks for
3 cycles.
Cisplatin (P) 20 mg/m2 IV per day for 5 days every 3 weeks for
3 cycles.
Bleomycin (B) 30 000 IU IV/IM on days 1/8/15 for 12 weeks (Optional)
(Note: bleomycin is dosed in International Units). If bleomycin is
omitted, then 4 cycles of EP are commonly used. Note that various
schedules of bleomycin have been used.
When there is bulky residual disease, it is common to give 34
courses of BEP chemotherapy [114]. Level of Evidence B
Table 4
Follow-up regime for Stage I germ cell malignancies.a
Regimen
Description
Surveillance
Baseline CT chest, abdomen, and pelvis, if not

performed preoperatively
Repeat CT or MRI, abdomen and pelvis at 3 months
after surgery
Repeat CT or MRI abdomen plus pelvis at 12 months
Pelvic ultrasound alternate visits (not when having
CT scan) for 2 years if non-dysgerminoma and for
3 years if dysgerminoma
Chest X-ray at alternate visits
Clinical examination
1 year
2nd year
3rd year
4th year
Years 510
Tumor marker follow-up
06 months
712 months
1224 months
2436 months
3648 months
48+ months
Monthly
2 monthly
3 monthly
4 monthly
6 monthly
Samples: serum AFP and hCG, LDH and CA 125
(regardless of initial value)
2 weekly
4 weekly
8 weekly
12 weekly
16 weekly
6 monthly until year 10
Abbreviations: AFP, alpha-fetoprotein; hCG, human chorionic gonadotropin; LDH, lactate

dehydrogenase.
a
Adapted from Patterson et al. [112].
S119
The optimal follow-up schedule has not been clinically investigated

in ovarian germ cancers and the frequency of visits and investigations is
controversial. Patients who have Stage I tumors and who are offered
surveillance need to be seen regularly and one option is to utilize the
follow-up regimen presented above [113]. Patients who have had chemotherapy have a lower risk of recurrence and the frequency of CT
scans can be reduced, which is similar to the approach for testicular
germ cell tumors [112]. Each follow-up visit should involve taking a
medical history, physical examination, and tumor marker determination. Although tumor markers are important, radiological imaging is
also pertinent, especially for patients whose tumor markers were not
raised at diagnosis. CT or MRI scans should be performed as clinically
indicated [113].
Patients who have not received chemotherapy should be followed
closely. Ninety percent of relapses in these patients occur within the
rst 2 years. At relapse, with few exceptions, these patients can be
successfully treated [113]. Level of Evidence D
12.5. Postoperative management and follow-up of non-dysgerminoma
germ cell malignancies
These tumors are highly curable with chemotherapy, even with advanced disease. Patients with Stage IA grade 12 immature teratoma
have a very good prognosis and should be only observed after primary
conservative surgery. It is controversial whether adjuvant chemotherapy adds any survival benet in this subgroup of patients. All other
patients with non-dysgerminomas, and higher-stage and higher-grade
immature teratomas should receive postoperative adjuvant chemotherapy [95].
The recommended chemotherapy regimen is etoposide 100 mg/m2
per day for 5 days with cisplatin 20 mg/m2 per day for 5 days, and
bleomycin at 30 000 IU IM/IV on days 1, 8, and 15 for a total of
12 weeks of treatment. For patients with good prognosis disease,
3 cycles of BEP are recommended, while patients with intermediate/
poor risk disease should receive 4 cycles of BEP [95].
Patients who relapse after BEP may still attain a durable remission with secondary chemotherapy regimens such as paclitaxel
ifosfamidecisplatin (TIP) [104]. High-dose chemotherapy and autologous marrow rescue may be considered in selected patients. These
patients should be managed in specialized units.
After chemotherapy, patients with metastatic immature teratomas
can sometimes have residual masses, which are composed entirely of
mature elements. These masses can grow, and should be resected
after the completion of chemotherapy. Level of Evidence B
All patients should have lactate dehydrogenase (LDH), alphafetoprotein (AFP), and human gonadotropin (beta hCG) blood tests
performed to monitor response to treatment. All patients treated with
chemotherapy should be followed-up with medical history, physical
examination, and appropriate tumor markers in the same way as
dysgerminomas. CT or MRI scans should be performed as clinically
indicated [93].
Relapses in patients usually occur within the rst 2 years after
diagnosis [95,104] Level of Evidence D
13. Sarcoma of the ovary
Ovarian sarcomas are rare and occur primarily in postmenopausal
patients [95,115]. Nevertheless, accurate diagnosis and differentiation
from other types of primary ovarian cancer are important, as the prognosis is generally poor.
There are two types of sarcoma. Malignant mixed Mllerian tumors
(MMMTs), the more common of the two, are biphasic tumors composed
of both carcinomatous and sarcomatous elements [115,116]. Most authors agree that most MMMTs are monoclonal in origin and should be
thought of and managed as a high-grade epithelial cancer. The sarcomatous component is derived from the carcinoma or from a stem cell that
S120
undergoes divergent differentiation. Thus, ovarian carcinosarcomas are

best regarded as metaplastic carcinomas.
Pure sarcomas are very rare and should be treated according to the
specic histological subtype. These rare sarcomas include brosarcomas, leiomyosarcomas, neurobrosarcomas, rhabdomyosarcomas,
chondrosarcomas, angiosarcomas, and liposarcomas. Their management is not discussed here.
Patients with early stage MMMTs have a better outcome than those
with advanced stage disease, but the overall prognosis is poor. They
should be managed similarly to high-grade pelvic serous cancers.
Their rarity prohibits any prospective randomized trials.
The principles of surgical management of ovarian MMMTS are the
same as for high-grade pelvic serous cancers [95]. Following surgery,
patients should receive platinum-based chemotherapy [95,113,114].
The follow-up schedule is as recommended for epithelial malignancies.
Level of Evidence C
Conict of interest
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Update on the diagnosis and management of gestational

trophoblastic disease
Hextan Y.S. Ngan a, Michael J. Seckl b, Ross S. Berkowitz c, Yang Xiang d, Franois Goler e,
P.K. Sekharan f, John R. Lurain g
a
Department of Obstetrics and Gynecology, University of Hong Kong, Queen Mary Hospital, Hong Kong, China
Departments of Histopathology and Medical Oncology, Charing Cross Trophoblastic Disease Center, Charing Cross campus of Imperial College London, London, UK
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
d
Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
e
Centre de Rfrence des Maladie Trophoblastiques, Hospices Civils de Lyon, Lyon, France
f
Department of Obstetrics and Gynecology, Institute of Maternal and Child Health, Medical College, Calicut, India
g
John I. Brewer Trophoblastic Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
b
c
1. Introduction
Gestational trophoblastic disease (GTD) is a group of uncommon conditions associated with abnormal pregnancy. Histologically, it includes the
benign partial and complete hydatidiform mole, invasive and metastatic
mole, as well as the malignant choriocarcinoma, placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT). Molar pregnancies may develop persistent elevated serum human chorionic
gonadotropin (hCG) levels after evacuation (complete mole 15%20%,
partial mole 0.1%5% [13]), with a chance of progression to choriocarcinoma that may require treatment. Together with the malignant forms of
GTD these are grouped under gestational trophoblastic neoplasia (GTN).
histological features are less marked in partial mole and fetal parts are
present, such as fetal cells [8]. Hydropic spontaneous abortion may
mimic the appearance of partial mole.
Cytogenetics can help to differentiate complete mole from partial
mole and hydropic spontaneous abortion. Typically, complete mole is
diploid and has 46,XX chromosomes with both Xs from paternal origin
whereas partial mole is triploid with maternal and paternal genetic
origin. Hydropic spontaneous abortion normally has 46,XX or XY from
both parents. Immunohistochemical staining of p57Kip2, which is an
imprinted gene, can help to show the presence of maternal genes and
enable complete mole to be excluded [8,9].
Rarely, invasive and metastatic moles can be diagnosed by removal
of the uterus or a metastatic lesion.
2. Epidemiology
Molar pregnancy is more common in some parts of Asia, with reported incidence rates as high as 2 per 1000 pregnancies [4,5] compared with
Europe and North American where the incidence is usually reported to
be less than 1 per 1000 pregnancies [6,7]. However, the incidence of
molar pregnancy seems to be decreasing in Asian countries, possibly related to improvements in the economy and diet as well as a decrease in
birth rates [4].
The incidence of choriocarcinoma is difcult to estimate because of
its rarity and trouble in clinically distinguishing postmolar choriocarcinoma from invasive mole owing to lack of histologic biopsy material.
Although choriocarcinoma has been reported to affect approximately
1 in 40 000 to 9 in 40 000 pregnancies [3], the incidence rates have
been declining. PSTT and ETT are rarer than choriocarcinoma.
3. Genetics and pathology
3.1. Molar pregnancy
Histologically, complete mole has orid cistern formation, trophoblastic proliferation, and absence of fetal parts. In contrast, such
3.2. Choriocarcinoma
Choriocarcinoma is a malignant tumor with absence of chorionic
villi, abnormal syncytiotrophoblast and cytotrophoblast, necrosis, and
hemorrhage. It may invade the uterus and surrounding organs and it
is common to have distant spread, particularly to the lung, but it may
also involve the liver, spleen, kidneys, bowels, and brain [8].
3.3. Placental site trophoblastic tumor

PSTT arises from the mononuclear intermediate trophoblast on the
maternal side of the placental bed invading the myometrium. It has
variable size and appearance, may be tan or yellowish with foci of necrosis, and on average is about 5 cm in size. Tumor cells have irregular
nuclear membranes, hyperchromatic nuclei, and dense eosinophilic to
amphophilic cytoplasm. Chorionic villi are absent. Tumor cells are strongly and extensively reactive to human placental lactogen (hPL) but only
focally reactive to hCG. It has to be differentiated from the benign
exaggerated placental site reaction where the Ki67 index is lower [8].
S124
H.Y.S. Ngan et al. / International Journal of Gynecology and Obstetrics 131 (2015) S123S126
3.4. Epithelioid trophoblastic tumor

ETT is a lesion of chorionic-type intermediate trophoblast. It usually
appears as a discrete, hemorrhagic, solid, and cystic lesion.
It may be found in the fundus, lower uterine segment, or endocervix,
or even the broad ligament. Histologically, islands of intermediate trophoblastic cells are surrounded by extensive necrosis and associated
with a hyaline-like matrix. The tumor is focally immunoreactive to
hPL, hCG, cytokeratin, and inhibin-alpha. It can be differentiated from
PSTT by positive p63 immunostaining. ETT may coexist with choriocarcinoma or PSTT [1012]. Emerging data indicate that atypical placental
site nodules (APSN) can co-exist and/or preceded ETT and PSTT,
suggesting that at least APSN cannot be regarded as benign [13].
4. Clinical presentation, investigations, and diagnosis

The most common presentation of a hydatidiform mole is abnormal
vaginal bleeding in pregnancy. With the advent of ultrasound assessment
of early pregnancy complications, molar pregnancy is usually diagnosed
during the rst trimester. Hence, the previous classical presentations of
hyperemesis gravidarum, hyperthyroidism, pre-eclampsia, pulmonary
trophoblastic embolization, and uterine size larger than dates are rarely
seen nowadays.
The typical snow storm appearance of complete mole may not be
seen in early rst trimester complete mole. Absence of fetal parts, cystic
appearance of the placenta, and deformed gestational sac may indicate
early molar pregnancy. Hence, some molar pregnancies are only diagnosed on histological examination after dilation and curettage for a
spontaneous abortion.
4.2. Gestational trophoblastic neoplasia

Postmolar GTN is usually diagnosed by hCG surveillance. Patients are
generally asymptomatic. At the 2000 FIGO Gynecology Oncology Committee meeting the denition of postmolar GTN based on hCG-level
changes, histology, and specic investigations was agreed upon
(Boxes 1 and 2) [14].
4.3. Human chorionic gonadotropin monitoring

For monitoring of GTN, an hCG assay that can detect all forms of hCG,
such as beta-hCG, core hCG, C-terminal hCG, nicked-free beta, beta core,
and preferably the hyperglycosylated forms, should be used; these are
different from those used for a routine pregnancy test. A persistent
low hCG level should be followed up, after exclusion of false positives
due to heterophile antibodies, as some may progress to GTN with rising
hCG level [15,16].
Box 1
FIGO criteria for diagnosis of postmolar gestational trophoblastic
neoplasia.
When the plateau of hCG lasts for four measurements over a
period of 3 weeks or longer; that is, days 1, 7, 14, 21.
When there is a rise in hCG for three consecutive weekly
measurements over at least a period of 2 weeks or more; days 1,
7, 14.
When the hCG level remains elevated for 6 months or more.
If there is a histologic diagnosis of choriocarcinoma.
Abbreviation: hCG, human chorionic gonadotropin.
Box 2
Tools for investigation of gestational trophoblastic neoplasia.
Chest X-ray is appropriate to diagnose lung metastases and it is
chest X-ray that is used for counting the number of lung
metastases to evaluate the risk score. Lung CT may be used.
Liver metastases may be diagnosed by ultrasound or CT
scanning.
Brain metastases may be diagnosed by MRI or CT scanning.
4.4. Gestational trophoblastic neoplasia after non-molar pregnancy

As only about 50% of GTN follows molar pregnancy, the rest can occur
after a spontaneous abortion, ectopic pregnancy, or a term pregnancy
where no hCG monitoring would be recommended. Therefore, clinical
presentations vary from abnormal vaginal bleeding; bleeding from metastatic sites in the abdomen, lung, or brain; pulmonary symptoms; and
neurological signs from spine or brain metastasis [3]. GTN should be considered in the differential diagnosis of patients with unusual presentations and serum hCG should be performed as part of the workup of
such patients.
5. Treatment
Suction evacuation of molar pregnancy should be carried out by an
experienced gynecologist, especially if the uterus is larger than
16 weeks gravid size and ideally under ultrasound guidance. The risk
of heavy bleeding can be reduced with use of oxytocics given after dilation and the onset of suction curettage. If there is no persistent bleeding,
second evacuation is usually not needed. Hysterectomy is rarely indicated unless there is a co-existing indication.
Follow-up with hCG monitoring is essential for early diagnosis of
postmolar GTN. Recent data show that GTN rarely occurs after the
hCG has spontaneously returned to normal and hence contraception
for only 6 months rather than 1 year is now recommended [3,17]. Termination of pregnancy is not indicated if accidental pregnancy occurs
during surveillance after the hCG level has returned to normal. Also,
data now show that it is safe to recommend oral contraceptives [18].
The risk of recurrence is low (0.6%2%) after one molar pregnancy,
although much increased after consecutive molar pregnancies [1921].
Mutations in NLRP7 and KHDC3L have been reported in women with recurrent molar pregnancy [2224].
5.2. Co-existing normal pregnancy with mole
Molar pregnancy rarely co-exists with a normal pregnancy. The diagnosis is usually made on ultrasound. Although there is a high risk of
spontaneous abortion, about 40% result in live births without signicantly increasing the risk of GTN [25]. Hence, in the absence of complications and normal genetic and ultrasound ndings, pregnancy can be
allowed to proceed.
Table 1
FIGO staging and classication for gestational trophoblastic neoplasia.
FIGO Stage
Description
I
II
Gestational trophoblastic tumors strictly conned to the uterine corpus

Gestational trophoblastic tumors extending to the adnexae or to the
vagina, but limited to the genital structures
Gestational trophoblastic tumors extending to the lungs, with or without
genital tract involvement
All other metastatic sites
III
IV
S125
Table 2
FIGO/WHO scoring system based on prognostic factors.
FIGO/WHO risk factor scoring with
FIGO staging
Age
Antecedent pregnancy
Interval from index pregnancy, months
Pretreatment hCG mIU/mL
Largest tumor size including uterus, cm
Site of metastases including uterus
Number of metastases identied
Previous failed chemotherapy
b40
Mole
b4
b103
lung
N40
Abortion
46
N103104
34
Spleen, kidney
14
Term
712
N104105
5
Gastrointestinal tract
58
Single drug
N12
N105
Brain, liver
N8
Two or more drugs
Notes: To stage and allot a risk factor score, a patients diagnosis is allocated to a Stage as represented by a Roman numeral I, II, III, or IV. This is then separated by a colon from the sum of all
the actual risk factor scores expressed in Arabic numerals e.g. Stage II:4, Stage IV:9. This Stage and score will be allotted for each patient.
5.3. Gestational trophoblastic neoplasia

Treatment of GTN is generally by chemotherapy. The best regimen to
use depends on stage and classication. In the 2000 FIGO staging and
classication (Tables 1 and 2), a risk score of 6 and below is classied
as low risk and above 6 is considered high risk.
5.3.1. Low-risk gestational trophoblastic neoplasia
Patients with low-risk GTN should be treated with one of the singleagent methotrexate or actinomycin D protocols listed in Box 3. The
Cochrane Review in 2012, including 513 patients in ve randomized
controlled trials, showed that actinomycin D (Act-D) appeared to be superior to methotrexate (MTX) (risk ratio [RR] 0.64; 95% condence interval, [CI] 0.540.76) [26]. Methotrexate was associated with
signicantly more treatment failure than actinomycin D (RR 3.81; 95%
CI, 1.648.86). A further trial is ongoing, comparing not only efcacy,
but toxicity and quality of life of pulsed actinomycin D and multiday
methotrexate regimens [27].
Chemotherapy should be changed to the alternative single agent if
there has been a good response to the rst agent but the hCG level plateaus above normal during treatment or if toxicity precludes an adequate
dose or frequency of treatment. If there is an inadequate response to the
initial single agent, a signicant elevation in hCG level, development of
metastasis, or resistance to sequential single-agent chemotherapy,
multi-agent chemotherapy as for high-risk disease should be initiated
[2]. Studies in the UK showed that if the hCG level is less than 100 IU/L
or 300 IU/L, change to single-agent Act-D gives a good response [2,28,
29]; otherwise, multiple agents need to be used.
After the hCG level has returned to normal, consolidation with 23
more cycles of chemotherapy will decrease the chance of recurrence.
The overall complete remission rate is close to 100% [2,30].
5.3.2. High-risk gestational trophoblastic neoplasia
Multiple agent chemotherapy regimens are used to treat high-risk
GTN. The most commonly used is EMA-CO (etoposide, methotrexate,
Box 3
Single-agent chemotherapy regimens for low-risk gestational trophoblastic neoplasia.
MTX-FA 8-day regimen (50 mg MTX intramuscularly on days
1,3,5,7 with folinic acid 15 mg orally 24 h after MTX on days
2,4,6,8); repeat every 2 weeks.
MTX 0.4 mg/kg (max. 25 mg) intravenously or intramuscularly
for 5 days every 2 weeks.
2
Actinomycin D pulse 1.25 mg/m intravenously every 2 weeks.
Actinomycin D 0.5 mg intravenously for 5 days every 2 weeks
2
Others: MTX 3050 mg/m intramuscularly weekly, MTX 300
mg/m2 infusion every 2 weeks, 5-fluorouracil, etoposide.
Abbreviations: MTX-FA, methotrexatefolinic acid.
actinomycin D, cyclophosphamide, vincristine) (Table 3), although the

Cochrane Database review [31] failed to conclude what combination
was best. The complete remission rate was approximately 85% and the
ve-year overall survival rate was 75%90%. However, patients with
liver and/or brain metastasis have poorer outcomes [3234].
5.3.3. Ultra high-risk gestational trophoblastic neoplasia and salvage

therapy
Among the high-risk group as dened by the FIGO staging and classication, a subgroup with a score greater than or equal to 12 as well as
patients with liver, brain, or extensive metastases did poorly when
treated with rst-line multiple agent chemotherapy [35].
For those with massive disease, starting with standard chemotherapy may cause severe marrow suppression leading to bleeding, septicemia, and even multiple organ failure. This may be avoided by starting
with a lower dose and a less intensive regimen, such as etoposide
100 mg/m2 and cisplatin 20 mg/m2 on days 1 and 2, repeated weekly
for 13 weeks, before starting the usual chemotherapy regimen [36].
For those patients with liver or brain metastases or a very high-risk
score, EP (etoposide and platinum)/EMA or another more intensive chemotherapy regimen (Table 4), rather than EMA, may yield a better response and outcome. Such regimens can also be used in treating
relapse or progressive disease while on rst-line chemotherapy. For
such high-risk patients, a longer consolidation with four cycles of chemotherapy should be considered.
In patients with brain metastases, an increase in the methotrexate
infusion to 1 g/m2 will help the drug cross the blood brain barrier and
intrathecal methotrexate 12.5 mg can be given at the time of CO when
EMA-CO is used. Some centers may give whole brain radiotherapy
3000 cGy in 200 cGy daily fractions concurrent with chemotherapy or
use stereotactic radiation to treat brain metastases.
Table 3
EMA-CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine)
chemotherapy.
Regimens
Regimen 1
Day 1
Etoposide
Actinomycin-D
Methotrexate
Day 2
Etoposide
Actinomycin-D
Folinic acid rescue
100 mg/m2 intravenous infusion over 30 minutes

0.5 mg intravenous bolus
100 mg/m2 intravenous bolus
200 mg/m2 intravenous infusion over 12 hours
100 mg/m2 intravenous infusion over 30 minutes
0.5 mg intravenous bolus
15 mg intramuscularly or orally every 12 hours for four doses
(starting 24 hours after beginning the methotrexate infusion)
Regimen 2
Day 8
Vincristine
1 mg/m2 intravenous bolus (maximum 2 mg)
Cyclophosphamide 600 mg/m2 intravenous infusion over 30 minutes
The two regimens alternate each week
S126
Table 4
Salvage chemotherapy.
EP-EMA (etoposide, cisplatin, etoposide, methotrexate and actinomycin-D)
TP/TE (paclitaxel, cisplatin/paclitaxel, etoposide)
MBE (methotrexate, bleomycin and etoposide)
VIP or ICE (etoposide, ifosfamide, and cisplatin or carboplatin)
BEP (bleomycin, etoposide and cisplatin)
FA (5-uorouracil, actinomycin-D)
FAEV (oxuridine, actinomycin-D, etoposide and vincristine)
High-dose chemotherapy with autologous bone marrow or stem cell transplant
5.4. Role of surgery

Surgery may have an important role in the management of GTN.
Hysterectomy can be considered in uncontrolled uterine bleeding,
although it can often be avoided with the use of uterine artery embolization. Laparotomy may be needed to stop bleeding in organs such as the
liver, gastrointestinal tract, kidneys, and spleen. Neurosurgery is needed
if there is bleeding into the brain or increased intracranial pressure. In
patients with an isolated drug-resistant tumor, removal of isolated cranial or pulmonary nodules or hysterectomy can improve survival.
5.5. Role of radiotherapy
Radiotherapy has a limited role in GTN, except in treatment of brain
metastasis, although its efcacy compared with intrathecal methotrexate is controversial [33,37].
5.6. PSTT/ETT
Both PSTT and ETT are less chemosensitive than choriocarcinoma.
Hysterectomy is the primary mode of treatment in most cases. However,
if fertility preservation is desired, especially in a localized lesion, conservative management such as uterine curettage, hysteroscopic resection,
and chemotherapy may be considered. Fertility preservation is not suitable in diffuse lesions. EP-EMA is the most commonly used chemotherapy. Interval from antecedent pregnancy of more than 48 months seems to
be the most signicant adverse prognostic factor.
5.7. Follow-up
After treatment of GTN, frequent monitoring of hCG for at least
12 months with reliable contraception is essential for surveillance
of relapse.
Future fertility, pregnancy, and offspring are not affected, although
psychosocial and sexual counseling may be needed for some patients.
Conict of interest
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The future role of molecular staging in gynecologic cancer

Pratibha S. Binder a, Jaime Prat b, David G. Mutch a
a
b
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, St Louis, MO, USA
Department of Pathology, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Spain
1. Introduction
A cancer staging system should be explicit, practical, and should provide information required to make important decisions about prognosis
and treatment. The rst FIGO staging nomenclatures for gynecologic
cancers were based solely on the anatomical extent of the disease
determined by physical examination and a few surgical parameters.
As surgical evaluation of some gynecologic cancers became feasible,
the FIGO staging system was revised to include surgical and histopathologic assessment of the tumor for most gynecologic cancers. Despite
modications in staging systems, the principles and purpose of cancer
staging remain the same (Box 1).
Identication of the cellular events leading to carcinogenesis provides additional information for comprehensive tumor classication
and prognostication. While genetic sequencing was expensive and
identifying driver mutations was laborious in the past, current technologies produce high-throughput data that makes methodical analysis of
DNA, RNA, and proteins achievable. Genetic and molecular studies can
be performed on blood and tumor samples obtained during the operative evaluation and treatment of cancer. A classication based on genomic and proteomic platforms is practical at this time, has minimal
morbidity, and could provide essential information regarding prognosis
and response to targeted therapies. The present article focuses on molecular discoveries that have been made in the last decade that should
be considered in future revisions of gynecologic cancer staging systems.
2. Ovarian cancer
2.1. Classication
Shih and Kurman [1] classied ovarian cancers into two types based
on genetic and histologic features. Type I is a heterogeneous group
including low-grade serous, endometrioid, clear-cell, and mucinous
carcinomas, which commonly arise from precursor lesions and are
typically slow growing. Type II includes high-grade serous cancers,
which usually present with advanced stage and metastasis at the time
of diagnosis and are associated with p53 mutations. Prat et al. [2] proposed a ve-subtype classication including high-grade serous
(HGSOv), low-grade serous (LGSOv), endometrioid (EOv), clear-cell
(CCOv), and mucinous (MOv) carcinomas. Each subtype has distinct
molecular events leading to carcinogenesis, therefore resulting in different precursor lesions, patterns of spread, prognosis, and response to
adjuvant therapy. Morphologic assessment is currently the mainstay

for subtype diagnosis, but immunohistochemical reactivity to Wilms
tumor protein (WT-1), estrogen receptor (ER), hepatocyte nuclear
factor (HNF) 1, cancer antigen 125 (CA-125), and Ki-67 (Table 1)
may be helpful [3]. Since research to detect aberrations in molecular
pathways is gaining popularity, characteristic genetic proles for each
subtype have also been determined (Table 1). Since there is overlap in
the histologic features and genetic proles of different ovarian cancer
subtypes, there is no clear consensus on which tests to routinely
perform for accurate diagnosis.
2.2. Homologous recombination repair pathway
Germline and somatic mutations in tumor suppressor genes BRCA1
and BRCA2 disrupt the cells ability to repair double strand breaks in
damaged DNA (homologous recombination). The BRCA pathway is
disabled in up to 50% of HGSOv. An assessment of 390 ovarian cancers
showed similar mutation rates in HGSOv and non-HGSOv of 13 genes
involved in homologous recombination DNA repair. The presence of a
mutation was associated with a longer overall survival and improved
response to platinum-based chemotherapy [4]. Poly (ADP-ribose) polymerase (PARP) inhibitors induce double strand DNA breaks that lead to
genomic instability and death in cells that lack homologous recombination repair genes. This treatment is therefore being used to target BRCA1
and BRCA2 mutated tumors [5]. Determination of BRCA status is
consequently valuable and satises the principles of cancer staging
since it classies patients into different prognostic groups and predicts
response to chemotherapy and targeted PARP inhibitors.
2.3. KRAS/MAPK pathway
The characteristic genetic alterations in the LGSOv subtype are
mutations in oncogenes KRAS and BRAF, leading to activation of the
mitogen-activated protein kinase (MAPK) pathway [3]. Although
LGSOv tend to be less aggressive, they are relatively non-responsive to
platinum-based chemotherapy. MEK inhibitors down-regulate key
enzymes in the MAPK pathway and therefore show promise in the
treatment of LGSOv and other tumors with MAPK pathway aberrations.
Pre-clinical research and multiple clinical trials have evaluated the use
of MEK inhibitors in ovarian and other gynecologic malignancies [6]. It
is important to identify cancers with MAPK pathway abnormalities as
S128
P.S. Binder et al. / International Journal of Gynecology and Obstetrics 131 (2015) S127S131
Box 1
The purpose of cancer staging.
To develop an accurate and universal terminology to describe
the extent of disease.
To characterize patients with cancer into different prognostic
groups and enable clinicians to counsel patients about treatment
options, morbidities, and mortality.
To allow meaningful comparisons of treatment efficacy and survival outcomes when comparing treatment strategies, institutions, or geographical areas as part of clinical trials and research.
these patients may benet from less toxic MEK inhibitors and other
targeted therapies.
2.4. Vascular endothelial growth factor
Angiogenesis is important and necessary for cancer growth and
metastasis. The presence of vascular endothelial growth factor (VEGF)
receptors and ligands has not been associated with prognosis or clinical
outcomes in ovarian cancer. However, bevacizumab, a monoclonal antibody that inactivates VEGF has been well studied and is important in the
treatment of primary and recurrent ovarian cancer. While the entire
cohort of patients treated with chemotherapy and bevacizumab for primary ovarian cancer only had a modest improvement in progressionfree survival compared with the patients treated with chemotherapy
alone, Gourley et al. [7] developed a 63-gene signature biomarker to
distinguish bevacizumab responders from non-responders. Preclinical
research has studied the benet of low-dose VEGFR2 antibodies in
modulating the tumor microenvironment to allow for an immunestimulatory phenotype with improved inltration of CD8+ T-cells [8].
Now low-dose bevacizumab is being evaluated in combination with
cancer vaccine therapies for breast and ovarian cancer. The search for
biomarkers to help guide treatment with antiangiogenesis drugs is ongoing [9]. Appropriate identication of patients that will benet from
this targeted therapy is vital to the safe and effective use of this expensive and potentially toxic therapy.
2.5. Cancer stem-cell markers
Despite high initial response rates to cytotoxic chemotherapy, the
recurrence rate for ovarian cancer remains high. The molecular features
of these cancers that lead to recurrence are not clearly understood, but
one theory is the presence of cancer stem cells in the original tumor.
Although cancer stem cells only represent a small proportion of the
tumor, they are resistant to chemotherapy and can grow rapidly, thereby repopulating tumors and leading to recurrence that is often resistant
to previous chemotherapy. The detection of sensitive markers for
ovarian cancer stem cells would have implications in predicting risk of
recurrence and prognosis. Cell surface receptors such as CD44, CD117,
Table 1
Immunohistochemistry reactivity and genetic mutation prole of ovarian cancer subtypes.
Subtype
IHC reactivity
Genetic mutation prole
HGSOv
P53+, WT-1+, ER+,

high Ki-67 index
P53-, WT-1+, ER+, low Ki-67 index
WT-1-, ER+
p53, BRCA1/2, aneuploidy
LGSOv
EOv
CCOv
MOv
HNF1+, WT-1-, ERCK7+, CK20+/, CEA+/,

CA19-9+/, CDX2+/
BRAF and KRAS mutations

ARID1A, CTNNB1, PTEN,
microsatellite instability
ARID1A, PIK3CA, PTEN, KRAS
KRAS, Her2
Abbreviations: HGSOv, high-grade serous ovarian cancer; LGSOv, low-grade serous ovarian cancer; EOv, endometrioid ovarian cancer; CCOv, clear-cell ovarian cancer; MOv,
mucinous ovarian cancer.
and CD133 are being evaluated as markers for ovarian cancer stemness
and as targets for therapeutics options against these chemo-resistant
cell types [10]. Identifying cancer stem cells could be very helpful in
predicting response to therapy and tumor behavior.
2.6. Genetic proling in ovarian cancer
The Cancer Genome Atlas (TCGA) research network performed
mRNA analysis on 489 HGSOv cancers and noted p53 mutations in
96% of cases [11]. While p53 is pivotal in HGSOv cancers, it is important
to note that not all p53 mutations are the same and further research
needs to be performed to determine the prognosis of different mutations in the p53 pathway. Anti-mutant p53 drugs are now available
and their ability to restore wild-type p53 properties to p53 mutant cancers is being studied [12]. In the future, determination of p53 mutation
and type should be fruitful in determining prognosis and possibly
response to anti-mutant p53 therapy. Results from the TCGA HGSOv cohort are also being used to develop genetic and promoter methylation
proles for chemotherapy responders versus non-responders [13].
Proling of large cohorts of ovarian cancers based on genomic and
proteomic platforms is still required to determine the prognostic ability
of different p53 mutations and other genes that are mutated at a lower
but signicant frequency.
3. Endometrial cancer
3.1. Classication
The rst description of endometrial cancer subtypes was by
Bokhman in 1983 [14]. He distinguished between type I and type II endometrial cancer based on patient phenotype, tumor histology, clinical
behavior, and survival rates. Today, pathologists assign a histologic
type to type I (low-grade endometrioid) and type II (high-grade
endometrioid, serous, clear cell, or carcinosarcoma) endometrial cancer
based on tumor morphology and a tumor grade (1: well differentiated;
2: moderately well differentiated; or 3: poorly differentiated), based on
glandular architecture and nuclear grade. Through genetic proling of
different histologic types, we now know that these tumors differ in
the early driver mutations that lead to carcinogenesis. The key mutations responsible for carcinogenesis are different in endometrioid endometrial cancers (EECs) and non-EECs (serous carcinomas and clear-cell
carcinomas [CCCs]) (Table 2), although there may be some overlap
in genetic proles since progression from endometrioid to nonendometrioid carcinoma may occur [15].
In addition to a high frequency of mutations in PTEN, CTNNB1, KRAS,
FGFR-2, ARID1A, and PIK3CA, EECs often express estrogen and progesterone receptors and have microsatellite instability. The presentation,
clinical behavior, and prognosis of EECs differ dependent on tumor
Table 2
Key mutations and useful biomarkers in the classication of endometrial cancer subtype.
Histologic type
Biomarker
Mechanism
Frequency
Endometrioid
PTEN
EGFR
KRAS
CTNNB1
FGFR2
MLH1
TP53
HER2/neu
PIK3CA
E-cadherin
EGFR
PIK3CA
PTEN
ARID1A
HNF1
Mutation/deletion
Overexpression
Mutation
Mutation
Mutation
Promoter methylation
Mutation/overexpression
Amplication/overexpression
Amplication
Loss of function
Overexpression
Mutation
Mutation
Mutation/loss of function
Overexpression
50%80%
40%45%
10%40%
10%45%
16%
20%
80%90%
30%40%
45%
40%90%
35%60%
Serous
Clear cell
grade. Catasus et al. [15] suggested that some high-grade EECs might
have signicant overlap with serous carcinomas. Whereas low-grade
EECs have a higher frequency of PTEN, KRAS, and CTNNB1 (beta-catenin)
mutations, high-grade EECs often have p53 and PIK3CA mutations [3,15].
Now we will discuss a few of the targetable pathways involved in endometrial carcinogenesis and associated targeted therapies (Table 3).
3.2. PTEN-PI3K-AKT-mTOR pathway
Mutations in the tumor suppressor gene PTEN and oncogene PIK3CA
lead to direct activation of the anti-apoptotic PI3K-AKT pathway. PTEN
mutations are more commonly seen in low-grade EECs, but loss of
PTEN protein expression can lead to up-regulation of the PI3K-AKT
pathway and inhibition of apoptosis, which is a poor prognostic maker
in EECs [15]. PIK3CA mutations are more common in high-grade EECs
and mixed histology endometrial cancers. PI3K/AKT/mTOR inhibitors
are being evaluated in pre-clinical and clinical trials [16]. While the
results of single therapy mTOR inhibitors in phase II trials have been
modest, there seems to be more potential when used in combination
with chemotherapy or other targeted inhibitors of angiogenesis or the
MAPK pathways. Unfortunately, the response to treatment with PI3K-,
AKT-, or mTOR-inhibitors does not correlate with PTEN mutations or
phosphorylated downstream targets (AKT, mTOR, S6). Therefore, we
must continue to search for biomarkers that predict response to these
targeted therapies.
3.3. KRAS-MAPK pathway
Mutated KRAS GTPase protein up-regulates the MAPK pathway
and can also bind the PIK3CA protein leading to activation of the PI3KAKT-mTOR pathway. KRAS mutations are mostly seen in EECS, rarely
in non-EECs, and are associated with longer disease-free survival [17].
Pre-clinical trials of MEK inhibitors as single therapy and in combination
with PI3K/AKT/mTOR inhibitors are promising and a clinical trial
evaluating the response of the MEK inhibitor trametinib alone or in
combination with an AKT inhibitor is underway.
3.4. Tyrosine kinase receptors
Tyrosine kinase receptors (TKRs) are a family of transmembrane glycoproteins that are usually activated by a variety of growth factors. The
important TKRs involved in endometrial carcinogenesis include HER2
(Erb-B2), EGFR (Erb-B1), FGFR2, and VEGFR.
Table 3
Targeted therapies in treatment of endometrial cancer.
Target
Drug
Research status
PI3K
AKT
mTOR
GDC-0941
GSK2141795
Temsirolimus
Everolimus
Ridaforolimus
AZD8055
GDC-0980
Trametinib
PD98059
PD0325901
Trastuzumab
Pertuzumab
Erlotinib
Getinib
Pertuzumab
Lapatinib
Ponatinib
PD173074
Bevacizumab
Brivanib
Nintedanib
Preclinical
Phase II active
Phase II completed
Phase II completed
Phase II completed
Preclinical
Preclinical
Phase II active
Preclinical
Preclinical
Phase II completed and active
Phase II completed
Phase II completed
Phase II completed
Phase II completed
Phase II completed
Phase I active
Preclinical
Phase II completed and active
Phase II completed
Phase II completed
PI3K/mTOR
MEK
HER2
EGFR
HER2/EGFR
FGFR2
VEGF
FGFR2/VEGF
S129
3.4.1. HER2
Overexpression of the HER2/neu protein is common in uterine
papillary serous cancers (UPSCs) and leads to cell proliferation, differentiation, and migration by activation of both the PI3K-AKT-mTOR and
MAPK pathways. HER2/neu RNA amplication and protein overexpression are ideal biomarkers as they predict survival and response to
chemotherapy as well as PI3K and mTOR inhibitors [18]. Trastuzumab
and pertuzumab are monoclonal antibodies against HER2 receptors
that are approved for the treatment of HER2-positive breast cancer.
They are currently being evaluated in the treatment of HER2-positive
UPSCs.
3.4.2. Epidermal growth factor receptor
Epidermal growth factor receptor (EGFR) overexpression is seen in
both EECs (low-grade and high-grade) and UPSCs [18]. EGFR activation
leads to the activation of many cellular pathways including PI3K-AKTmTOR and MAPK pathways. EGFR inhibitors getinib and erlotinib did
not improve survival in phase II trials of advanced endometrial cancer
and response rates were not associated with EGFR overexpression
[19]. Translational studies of the lapatinib (dual EGFR and HER
inhibitor) phase II trial identied one previous unreported EGFR mutation that was present and associated with objective tumor response in
one patient [20]. Further studies need to be performed to validate the
value of this mutation in predicting response to lapatinib.
3.4.3. FGFR2
Mutations in this oncogene are more common in low-grade EECs,
but it is associated with chemo-resistance and with poor progressionfree survival and overall survival [17]. Pre-clinical studies show that
the FGFR2 inhibitor PD173074 has a synergistic effect on apoptosis
when combined with cytotoxic chemotherapy [19]. In phase II clinical
trials, treatment of recurrent endometrial cancer with brivanib or
nintedanib resulted in a progression-free interval of at least 6 months
in 30% and 22% of patients, respectively [21,22].
3.4.4. Vascular endothelial growth factor
As with ovarian cancer, there is no clear consensus on whether VEGF
overexpression is associated with prognosis or response to angiogenesis
inhibitors in endometrial cancer. While bevacizumab alone had a modest response rate in recurrent endometrial cancer, the combination with
mTOR inhibitor temsirolimus improved response rates but was also
more toxic [23]. The efcacy and toxicity of bevacizumab with cytotoxic
chemotherapy for advanced endometrial cancer is being evaluated in
phase II trials. Since combination treatments can be expensive and
toxic, it is important to focus future research on biomarkers that predict
response to antiangiogenic drugs so that this treatment can be limited
to patients who would benet from treatment.
3.5. Genetic proling in endometrial cancer
The 2013 TCGA cooperative study on endometrial carcinoma has
expanded the dualistic clinicopathologic classication (types I and II)
to four molecular genetic categories: (1) POLE ultramutated; (2) microsatellite instability hypermutated, corresponding to type I; (3) copynumber low (CTNNB1 mutated); and (4) copy-number high (TP53 mutated), corresponding to type II [24]. Although categories 2 and 3
included mainly EECs and category 4 had predominantly serous
carcinomas, 25% of high-grade EECs showed a genetic prole similar
to serous carcinomas and were re-classied. Despite overlapping of
the molecular genetic ndings, there was some association between
separate categories and prognosis. The novel POLE ultramutated category consisted of 7% of tumors (type I and type II) and was characterized
by mutations in the gene POLE that is important for DNA replication
and repair. POLE mutations predicted favorable prognosis, particularly
in high-grade tumors. In another endometrial cancer cohort of 535
EECs, POLE mutations were found in 5.6% (70% were high-grade EEC)
S130
and were mutually exclusive of tumors with inherited microsatellite instability genotypes [25]. Therefore, classication as POLE ultramutated
provides information regarding prognosis and would preclude the
need for Lynch screening in these tumors.
Table 4
Important biomarkers and predictive ability in cervical cancer.
Predictive value
Biomarkers
Associated with prognosis
HIF-1
VEGF
SCC Ag
CEA
HR-HPV and type
HIF-1
EGFR
CD44v6
COX-2
HIF-2
4. Cervical cancer
Among gynecologic malignancies, cervical cancer has the highest incidence and mortality rate worldwide. Numerous biomarkers are under
investigation to predict progression of pre-invasive lesions to invasive
disease, as well as to predict prognosis and response to treatment of
invasive cervical cancer.
Associated with chemotherapy sensitivity
Associated with radiosensitivity
4.1. Proliferation markers

Proliferation markers such as p16, p53, and Ki-67 index are seen in
advanced stage and metastatic disease but they are not proven independent predictors of survival since almost all these patients will succumb
to their disease. However, the presence of p16 and Ki-67 by immunohistochemistry had a higher sensitivity and specicity in detecting clinically signicant pre-invasive lesions (CIN2, CIN3, and adenocarcinoma in
situ) than high-risk HPV testing [26]. IHC for p16 and Ki-67 may be
incorporated into cervical cancer screening to identify and treat preinvasive lesions that are likely to progress to invasive disease.
4.2. Biomarkers predicting advanced disease and prognosis
High expression of angiogenesis markers like HIF-1 and VEGF are
associated with poor prognosis in cervical cancer. HIF-1 expression
allows the proliferation and metastasis of cancer cells in an oxygenand nutrient-poor environment, and high IHC reactivity to HIF-1
predicts lower survival in cervical squamous cell carcinoma (SCC) and
adenocarcinomas. VEGF expression has been correlated to lymph node
metastasis and poor survival [27]. While most cervical cancers are positive for HRHPV, HPV-negative status was associated with an increased
risk of recurrence and death [28]. A high level of the serum biomarker
SCC antigen correlates with lymph node metastasis and advanced
disease visible by FDG-PET imaging and this information may guide
treatment strategies for individual patients [29].
4.3. Biomarkers predicting response to therapy
Hypoxic tumor environments prevent degradation of HIF-1 proteins and also increase resistance to chemotherapy and radiation [27].
Therefore HIF-1 expression may be a marker of resistance to primary
chemo-radiation therapy, but further research needs to be conducted
to validate this theory. In a systematic review, IHC reactivity to EGFR/
HER2 and COX-2 was associated with resistance to chemo- and/or
radiation-therapy [30]. Two large cohorts showed EGFR overexpression
and co-expression of EGFR and HER2 was associated with poor
progression-free survival and overall survival in patients treated with
primary chemoradiation therapy. COX-2 is associated with angiogenesis, inhibition of apoptosis, and resistance to radiation therapy. This
makes COX-2 an attractive target and preclinical studies already show
that COX-2 inhibition improves cervical cancer response to radiation.
4.4. Future of biomarkers in cervical cancer
Biomarkers such as high-risk HPV testing and IHC for p16 and Ki-67
index score have been tested in large cohorts and will soon be implemented in guidelines for screening and treating pre-invasive lesions.
Many biomarkers have shown promise in predicting the risk of
recurrence and response to chemo- and radiation-therapy (Table 4)
but they have not moved into clinical practice because of the lack of prospective data with large cohorts. Future research should be focused on
validating the prognostic values of candidate biomarkers including cell
cycle regulators (p16, p21, p27, cyclin A/D/E), receptor tyrosine kinases
(EGFR, HER2), metastatic or stem cell markers (CD44, cathepsin D), and
apoptotic markers (p53, Bcl-2, Bax) [30].
5. Vulvar cancer
Accurate evaluation of the prognostic potential of biomarkers in
vulvar cancer is difcult because most studies involve small case series.
Biomarkers evaluated in SCC of the cervix have also been evaluated in
small series of vulvar cancer. Similar to cervical SCC, biomarkers p16,
p21, VEGF, CD44, EGFR, and HER2 may correlate to clinical outcomes
in vulvar SCC [31]. High VEGF expression was associated with poor survival outcome in a series of 25 vulvar cancers, however multivariate
analysis was not performed owing to the small size of the cohort [32].
Clinical trials evaluating treatment of antiangiogenesis drugs and
other targeted therapies are also difcult owing to the low incidence
of disease.
Unlike cervical cancer, multiple small studies report conicting data
about the association of high-risk HPV and prognosis of vulvar cancers.
Most of the data does not show a signicant association between HPV
and prognosis, while another reports favorable clinical outcomes in
HPV positive vulvar cancers when compared with HPV-negative vulvar
cancers [31].
Matrix metalloproteinase 2 (MMP-2) is a protein biomarker present
in approximately 50% of vulvar cancers and the degree of IHC reactivity
is higher in invasive carcinomas when compared with pre-invasive precursor lesions [33]. IHC reactivity of MMP-2 was associated with shorter
survival after adjusting for tumor size, depth of invasion, and patient age
in a multivariate analysis of 75 vulvar cancers [34]. When MMP-2 expression exceeded 50%, there was a signicant reduction in ve-year
overall survival from 72.3% to 40%. Nafamostat mesilate is a synthetic inhibitor of MMP-2 that was evaluated in preclinical studies of SCC of the
vulva and the head and neck [35]. Nafamostat decreased proliferation
rates in vulvar cancer cell lines but it did not cause cell death and did
not reduce tumor burden in tumor-bearing mice.
6. Conclusion
Considerable progress has been made in the identication and validation of molecular markers for gynecologic cancers in the past decade.
However, this progress has not been accompanied by the introduction
of universal molecular marker testing in clinical practice. Genomic and
proteomic proling of large cohorts of gynecologic cancers will generate
a large amount of data regarding early mutation events in carcinogenesis. Now, expert committees need to be assembled to reach a consensus
on which biomarkers should be incorporated into classication and
staging of gynecologic cancers.
Conict of interest
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Pathology of cancers of the female genital tract

Jaime Prat
Department of Pathology, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Spain
1. Introduction
Pathology reports include not only histopathologic diagnoses but
also specic information relating to prognosis and treatment; thus, pathologists must have sufcient familiarity with the staging classication
and management of gynecological cancers to assure that their reports
communicate clinically relevant information. On the other hand, full
comprehension of the pathology report by the gynecological oncologist
requires familiarity with the terminology used in gynecological pathology as well as the techniques of gross examination. This chapter summarizes the pathological features of the most common gynecological
malignancies as well as an approach for processing gynecological
biopsies and surgical specimens.
2. Vulva
2.1. Malignant tumors and premalignant conditions
2.1.1. Squamous cell carcinoma
Carcinoma of the vulva accounts for 4% of all female genital cancers
and occurs mainly in women aged over 60 years. Squamous cell carcinoma is the most common type (86%). These tumors are divided into two
groups: keratinizing squamous cell carcinomas unrelated to HPV (N 70%
of cases), and warty and basaloid carcinomas, which are strongly
associated with high-risk HPV (b 25% of cases), mainly HPV16 [1,2].
Etiologic factors and precursor lesions: Keratinizing squamous
carcinomas frequently develop in older women (mean age, 76 years),
sometimes in the context of long-standing lichen sclerosus. The precursor lesion is referred to as differentiated vulvar intraepithelial neoplasia
(VIN) or VIN simplex (Fig. 1A), which carries a high risk of cancer development. In contrast, the less common HPV-associated warty and
basaloid carcinomas develop from a precursor lesion called undifferentiated or classic VIN (1B). HPV-associated VIN lesions have a low risk of
progression to invasive carcinomas (approximately 6%), except in older
or immunosuppressed women [1,2].
Pathology: VIN may be single or multiple, and macular, papular, or
plaque-like. Histologic grades are labeled VIN I, II, and III, corresponding
to mild, moderate, and severe dysplasia, respectively. However, grade
IIIwhich includes squamous cell carcinoma in situ [CIS]is by far the
most common.
Keratinizing squamous cell carcinomas usually follow differentiated
VIN (VIN simplex). Most tumors are exophytic but some may be ulcerative. Microscopically, the tumor is composed of invasive nests of
malignant squamous epithelium with central keratin pearls (Fig. 2).

The tumors grow slowly, extending to contiguous skin, vagina, and
rectum. They metastasize initially to supercial inguinal lymph nodes,
and then to deep inguinal, femoral, and pelvic lymph nodes [1,2].
Clinica features: The FIGO staging of vulvar cancer denes tumors of
any size limited to the vulva as Stage I carcinomas, tumors extending to
perineal structures (lower third) as Stage II, tumors with positive
inguinofemoral lymph nodes as Stage III, and tumors invading perineal
structures (upper third) or distant metastasis as Stage IV. Tumor grade
and number, size, and location of lymph node metastases determine
survival. Better-differentiated tumors have a better mean survival, approaching 90% if nodes are negative. Two thirds of women with inguinal
node metastases survive 5 years, but only one-fourth of those with pelvic node metastases live that long [3].
Prognosis correlates with stage of disease and lymph node status.
The number of inguinal lymph nodes with metastases is the most
important single factor. The prognosis of patients with vulvar cancer is
generally good, with an overall ve-year survival of 70% [1].
2.1.2. Verrucous carcinoma
Vulvar verrucous carcinoma is a distinct variety of squamous cell
carcinoma that manifests as a large fungating mass resembling a giant
condyloma acuminatum. HPV, usually type 6 or 11, is commonly identied. The tumor invades with broad tongues. Verrucous carcinomas
rarely metastasize. Wide local surgical excision is the treatment
of choice.
2.1.3. Basal cell carcinoma
Basal cell carcinomas of the vulva are identical to their counterparts
in the skin. They are not associated with HPV, rarely metastasize, and
are usually cured by surgical excision.
2.1.4. Malignant melanoma
Although uncommon, malignant melanoma is the second most
frequent cancer of the vulva (5%). It occurs in the sixth and seventh
decades but occasionally is found in younger women. It is highly aggressive, and the prognosis is poor. Management should be according to
guidelines for melanoma treatment elsewhere.
2.1.5. Extramammary Paget disease
The disorder usually occurs on the labia majora in older women. The
lesion is large, red, moist, and sharply demarcated. The origin of the
J. Prat / International Journal of Gynecology and Obstetrics 131 (2015) S132S145
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2.2.2. Wide local excision

In general, wide local excisions are performed for noninvasive
neoplasms such as VIN 3 or Paget disease of the vulva, as well as
supercially invasive (less than 1 mm) Stage I carcinomas. Orientation
is critical in these specimens. Describe and measure the lesions,
distances to resection margins, and the anatomic structures involved.
As intraepithelial lesions are often multifocal and difcult to discern
macroscopically, all surgical resection margins (peripheral and deep)
should be evaluated microscopically [1].
2.2.3. Simple (or total) vulvectomy
This includes the entire vulva and subcutaneous fat (dissection to
deep fascia). It is typically performed for noninvasive neoplasms that
widely involve the vulva. The resection margins must be thoroughly
evaluated [1].
Fig. 1. Vulvar intraepithelial neoplasia (VIN). (A) Well-differentiated (simplex) type. The
atypia is accentuated in the basal and parabasal layers. There is striking epithelial maturation in the supercial layers. (B) HPV-related undifferentiated (classic) VIN. Beneath a
hyperkeratotic surface the epithelial cells are atypical. There are numerous mitoses.
diagnostic cells (Paget cells) is controversial: they may arise in the

epidermis or epidermally derived adnexal structures.
Intraepidermal Paget disease may have been present for many years
and is often far more extensive throughout the epidermis than
preoperative biopsies indicate. Unlike Paget disease of the breast,
which is almost always associated with underlying duct carcinoma,
extramammary Paget disease is only rarely associated with carcinoma
of the skin adnexa. Invasion and metastases rarely occur, so treatment
usually requires only wide local excision or simple vulvectomy [1,2].
2.2. Gross description and processing of specimens
2.2.1. Excisional biopsies
Biopsies of the vulva should be handled like skin biopsies. Assess the
deep and lateral resection margins.
2.2.4. Radical vulvectomy

Radical vulvectomy consists of vulva excised to the deep fascia of the
thigh, the periosteum of the pubis, and the inferior fascia of the urogenital diaphragm. It is usually performed together with at least an inguinal
lymph node dissection, which may be included en bloc with the
vulvectomy. Total radical vulvectomies have largely been replaced in
favor of more limited excisions, but sufcient to completely excise the
primary tumor with a minimum 1 cm margin. The gross description
should include the size, location, depth of invasion, and all resection
margins, including perianal and vaginal margins. Depth of invasion
should be measured from the epithelialstromal junction of the adjacent dermal papilla to the deepest point of tumor invasion. Separate
lymph nodes into supercial and deep groups, and submit them entirely
for histologic examination [1].
3. Vagina
3.1. Malignant tumors of the vagina
Primary malignant tumors of the vagina are uncommon, constituting about 2% of all genital tract tumors. Most (80%) vaginal malignancies
represent metastatic spread. Tumors conned to the upper vagina are
usually treated by radical hysterectomy and vaginectomy. Squamous
cell carcinomas account for over 90% of primary vaginal malignancies.
Prognosis is related to the extent of spread of the tumor at the time of
its discovery. The ve-year survival rate for tumors conned to the
vagina (Stage I) is 80%, whereas it is only 20% for those with extensive
spread (Stages III/IV) [1].
3.1.1. Embryonal rhabdomyosarcoma (sarcoma botryoides)
Embryonal rhabdomyosarcoma occurs almost exclusively in girls
under 4 years old. It arises in the lamina propria of the vagina and
consists of primitive spindle rhabdomyoblasts, some of which show
cross-striations. Tumors less than 3 cm in greatest dimension tend to
be localized and may be cured by wide excision and chemotherapy.
Larger tumors have often spread to adjacent structures, regional
lymph nodes, or distant sites. Even in advanced cases, half of patients
survive with radical surgery and chemotherapy [1,2].
4. Cervix
4.1. Squamous cell neoplasia
Fig. 2. Keratinizing squamous cell carcinoma of vulva. Nests of neoplastic squamous cells,
some with keratin pearls, are evident.
Cytological screening in high-resource countries has decreased

cervical carcinoma by 50% to 85%; however, worldwide, cervical cancer
remains the second most common cancer in women.
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4.2. Cervical intraepithelial neoplasia

Cervical intraepithelial neoplasia (CIN) is a spectrum of intraepithelial changes that begins with minimal atypia and progresses
through stages of greater intraepithelial abnormalities to invasive
squamous cell carcinoma. The terms CIN, dysplasia, CIS, and squamous intraepithelial lesion (SIL) are commonly used interchangeably [1,2] (Fig. 3).
Epidemiology and molecular pathogenesis: HPV infection leads to
CIN and cervical cancer (Fig. 4). Low-grade CIN is a permissive infection
(i.e. HPV is episomal, freely replicates and thereby causes cell death).
Huge numbers of virus must accumulate in the cytoplasm before
being visible as a koilocyte (Fig. 3). In most cases of higher-grade CIN,
viral DNA integrates into the cell genome. Proteins encoded by E6 and
E7 genes of HPV 16 respectively bind and inactivate p53 and Rb proteins, thereby invalidating their tumor suppressor functions. After HPV
integrates into host DNA, copies of the whole virus do not accumulate
and koilocytes are absent in many cases of high-grade dysplasia and
all invasive cancers. Cells in high-grade CIN usually contain HPV types
16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. HPV types 16 and
18 are found in 70% of invasive cancers; the other high-risk types
account for another 25% [4].
Pathology: CIN is nearly always a disease of metaplastic squamous
epithelium in the transformation zone. The normal process by which
cervical squamous epithelium matures is disturbed in CIN, as evidenced
morphologically by changes in cellularity, differentiation, polarity, nuclear features, and mitotic activity. CIN 3 is synonymous with severe
dysplasia and CIS. The sequence of histologic changes from CIN 1 to
CIN 3 is shown in Fig. 3 [1,2].
Clinical features: The mean age at which women develop CIN is
2427 years for CIN 1 and CIN 2, and 3542 years for CIN 3. Based on
morphologic criteria, half of cases of CIN 1 regress, 10% progress to
CIN 3, and less than 2% become invasive cancer. The average time
Fig. 4. Role of HPV in the pathogenesis of cervical neoplasia.
for all grades of dysplasia to progress to CIS is about 10 years. At

least 20% of cases of CIN 3 progress to invasive carcinoma in that
time [1].
Fig. 3. Interrelations of naming systems in precursor cervical lesions. This chart integrates multiple aspects of the disease. It illustrates the changes in progressively more abnormal disease states
and provides translation terminology for the dysplasia/carcinoma in situ (CIS) system, cervical intraepithelial neoplasia (CIN) system, and The Bethesda system. The scheme also illustrates the
corresponding cytologic smear resulting from exfoliation of the most supercial cells as well as the equivalent histopathologic lesions (top). Abbreviation: SIL, squamous intraepithelial lesion.
When CIN is discovered, colposcopy, together with a Schiller test,

delineates the extent of the lesion and indicates areas to be biopsied.
Diagnostic endocervical curettage also helps to determine the extent
of endocervical involvement. Women with CIN 1 are usually followed
conservatively (i.e. repeated Pap smears plus close follow-up). Highgrade lesions are treated according to the extent of disease. LEEP (loop
electrosurgical excision procedure), cervical conization (removal of a
cone of tissue around the external os), laser ablation, electrocoagulation
diathermy, cryosurgery, and (rarely) hysterectomy may be done [1].
4.3. Microinvasive (supercially invasive) squamous cell carcinoma

This is the earliest stage (IA) of invasive cervical cancer. In this
setting, stromal invasion usually arises from overlying CIN (Fig. 5).
Staging of microinvasive disease is based on width and depth of invasion, dened as follows:
Invasion less than 3 mm (Stage IA1) or 5 mm (stage IA2) below the
basement membrane.
7-mm maximum lateral extension.
The earliest invasive changes (early stromal invasion or ESI)

appear as tiny irregular epithelial buds emanating from the base of
CIN 3 lesions. These small (b1 mm) tongues of neoplastic epithelial
cells do not affect the prognosis of CIN 3 lesions; hence, both can
be treated similarly with conservative surgery. In the 2009 FIGO
classication, ESI was excluded from Stage IA1. Some gynecologic oncologists further limit microinvasive carcinoma to tumors lacking
lymphovascular invasion (LVI). Stage IA2 tumors are associated with
lymph node metastases in about 8% of cases, whereas those that invade
less than or equal to 3 mm (stage IA1) have only a 1%2% risk of lymph
node metastases. Conization or simple hysterectomy generally cures
microinvasive cancers less than 3 mm deep [13].
The role of LVI as a prognostic indicator is more controversial than
that of the depth of invasion and lateral extent of tumor. The stroma
in which foci of invasion lie can retract during preparation of the tissue
sections for microscopic examination. A clear space can easily be
mistaken for LVI. Whereas some studies concluded that the presence
of tumor in lymphatic spaces was of no value by itself in predicting
which patients are likely to have lymph node metastases, other studies
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have reported that the presence of LVI is an important prognostic

indicator [1].
4.4. Invasive squamous cell carcinoma
Pathology: Early stages of cervical cancer are often poorly dened
lesions or nodular and exophytic masses. If the tumor is within the
endocervical canal, it can be an endophytic mass, which can inltrate
the stroma and cause diffuse cervical enlargement. Most tumors
are nonkeratinizing, with solid nests of large malignant squamous
cells and no more than individual cell keratinization. Most remaining
cancers show nests of keratinized cells in concentric whorls, so-called
keratin pearls.
Cervical cancer spreads by direct extension, through lymphatic
vessels and only rarely by the hematogenous route. Local extension
into surrounding tissues (parametrium) results in ureteral compression
(Stage IIIB); the corresponding clinical complications are hydroureter,
hydronephrosis, and renal failure secondary to ureteric obstructionthe
most common cause of death (50% of patients). Bladder and rectal
involvement (Stage IVA) may lead to stula formation. Metastases to
regional lymph nodes involve paracervical, hypogastric, and external
iliac nodes. Overall, tumor growth and spread are relatively slow,
since the average age for patients with CIN 3 is 3540 years; for stage
IA carcinoma, 43 years; and for stage IV, 57 years [13].
Clinical features: The Pap smear remains the most reliable screening test for detecting cervical cancer.
The clinical stage of cervical cancer is the best predictor of survival.
Overall ve-year survival is 60%, and by each stage it is: I, 90%; II, 75%;
III, 35%; and IV, 10%. About 15% of patients develop recurrences on the
vaginal wall, bladder, pelvis, or rectum within 2 years of therapy. Radical
hysterectomy is favored for localized tumors, especially in younger
women; radiation therapy, chemotherapy, or combinations of the two
are used for more advanced tumors [13].
4.5. Endocervical adenocarcinoma
This tumor makes up 20% of cervical cancers. The incidence of cervical adenocarcinoma has increased recently, with a mean age of 56 years
at presentation. Most tumors are of the endocervical cell (mucinous)
type. These tumors are often associated with adenocarcinoma in situ
and are frequently infected with HPV types 16 and 18 [1,2].
Adenocarcinoma in situ (AIS) generally arises in the squamocolumnar
junction and extends into the endocervical canal. Associated high-grade
squamous cell CIN occurs in 40% of cases of AIS. Invasive adenocarcinoma typically presents as a polypoid or papillary mass. Adenocarcinoma
of the endocervix spreads by local invasion and lymphatic metastases,
but overall survival is somewhat worse than for squamous carcinoma.
4.6.1. Punch biopsies
Biopsies are usually colposcopically directed. The best specimens are
at least several millimeters long with underlying stroma to a depth of
24 mm.
4.6.2. Endocervical curettage
Endocervical curettage is performed to evaluate the presence of
glandular neoplasms, cervical squamous neoplasia involving the
endocervical canal, or to determine whether endometrial carcinoma
has spread into the cervix.
Fig. 5. Microinvasive squamous cell carcinoma. The tumor invades 5 mm deep and 4 mm
wide. This tumor is stage IA2 according to FIGOs classication.
4.6.3. Cervical cone biopsy/excision and trachelectomy

Cone biopsy is the standard procedure performed for women with
high-grade CIN and glandular lesions (Fig. 6). The conventional cone biopsy is obtained using a scalpel (cold knife), but today it is often done
with laser or low-voltage, large-loop diathermy methods (LEEP).
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and (2) atypical hyperplasia/endometrial intraepithelial neoplasia

(EIN) [1,2].
5.1.1. Hyperplasia without atypia
This is an exaggerated proliferation of glands of irregular size and
shape with an increase in the gland-to-stroma ratio compared with
proliferative endometrium, but without signicant nuclear atypia. Risk
factors include obesity, polycystic ovarian disease, and diabetes. Hyperplasia without atypia is the result of unopposed estrogenic stimulation.
Patients have a three- to four-fold increased endometrial carcinoma
risk, rising to 10-fold after 10 years. Progression to endometrial carcinoma occurs in 1%3% of women with hyperplasia without atypia
Fig. 6. Cervical cone biopsy/excision. The craniocaudal length (A) and diameter (B) should
be measured; and both the radial (A) and endocervical (C) margins need to be assessed
(with differential inking). Use a stitch to designate 12 oclock, open cone and pin out to
x, and then block in the entire specimen sequentially (Figure reproduced with permission courtesy of BE Howitt and GL Mutter, Boston, MA, USA).
Trachelectomy may also be performed as a therapeutic procedure for

early-stage invasive carcinomas of the cervix. A trachelectomy is a
more extensive version of a cone excision, as the entire cervix is
removed, with or without a vaginal cuff.
The cone biopsy is a roughly cone-shaped excision of the uterine
cervix to include a portion of exocervix, external os with the entire
transformation zone, and endocervical canal with varying amounts of
deep tissue. The surgeon should note the 12 oclock position with a
black suture. For a trachelectomy specimen, the presence of a vaginal
cuff should be documented and measured.
Fixation for three hours before cutting is usually adequate. Serially
cut sections should be sequentially submitted. Submit the entire
specimen in a clockwise direction beginning at 1 oclock (Fig. 6). Both
the ectocervical and endocervical edges of the cone specimen need to
be assessed [1].
4.6.4. Hysterectomy for malignant cervical disease
Simple hysterectomy is performed for high-grade intraepithelial
neoplasms and many microinvasive cancers. Radical hysterectomy
(removal of paracervical soft tissue) is common for Stage I squamous
carcinomas and for some Stage 2A tumors.
For uteri removed for the treatment of CIN, amputate the cervix at
least 1.0 cm above the level of the external os and process in the way
that has been described above for a cone biopsy. Often, one section
from each quadrant may be sufcient. Each section should be full thickness to include the endocervical mucosa, squamocolumnar junction,
exocervix, and outer adventitia. Submit all of the parametrial tissue
since this represents the lateral and most signicant resection margin.
Separate and group lymph nodes as right and left, further by location
(internal iliac, external iliac, obturator, etc.) [1].
5. Corpus uteri
5.1. Endometrial hyperplasia
Endometrial hyperplasia forms a morphologic continuum of abnormal proliferation ranging from focal glandular crowding or simple
hyperplasia to well-differentiated adenocarcinoma.
Pathology: The 2014 WHO scheme distinguishes only two
categories of endometrial hyperplasia: (1) hyperplasia without atypia;
5.1.2. Atypical hyperplasia/endometrial intraepithelial neoplasia (EIN)

This lesion shows marked glandular crowding, often as back-to-back
glands, with little intervening stroma and cytologic atypia. Epithelial
cell nuclei are large and hyperchromatic with prominent nucleoli.
One-quarter to one-third of these women will be diagnosed with
endometrioid carcinoma at immediate hysterectomy or during the
rst year of follow-up. [2].
EIN refers to a monoclonal neoplastic growth of genetically altered
cells with greatly increased risk of becoming the endometrioid type of
endometrial adenocarcinoma. The main diagnostic criterion of EIN is
that gland area exceeds that of stroma (volume percentage stroma
b55%). Atypical hyperplasia/EIN contains many of the genetic changes
seen in endometrioid endometrial carcinoma, i.e. microsatellite instability, and PTEN, KRAS, and CTNNB1 (beta-catenin) mutation [1,2].
Clinical features: Hysterectomy is usually the therapy of choice if a
woman does not want more children. Women who want more children
or those with high operative risks may be treated with progestins.
5.2. Endometrial adenocarcinoma
Endometrial carcinoma is the sixth most frequent cancer diagnosed
in women globally with an age standardized incidence rate of 8.2 per
100 000. It is the fourth most common cancer in women in industrialized countries and the most common gynecologic cancer. Threequarters of women with endometrial cancer are postmenopausal. The
median age at diagnosis is 63 years [1,2].
Endometrial carcinoma is classied into two different types (Fig. 7
and Table 1). Type I tumors (Fig. 7A) (about 80%), endometrioid carcinomas, are often preceded by endometrial hyperplasia or EIN and are
associated with estrogenic stimulation. They occur mainly in pre- or
perimenopausal women and are associated with obesity, hyperlipidemia, anovulation, infertility, and late menopause. Typically, most
endometrioid carcinomas are conned to the uterus and follow a
favorable course. In contrast, type II tumors (Fig. 7B) (about 10%) are
nonendometrioid, largely serous carcinomas, arising occasionally in
endometrial polyps or from precancerous lesions in atrophic endometria (endometrial intraepithelial carcinoma). Type II tumors are not
associated with estrogen stimulation or hyperplasia, readily invade
myometrium and vascular spaces, and are highly lethal [1].
Endometrial cancer is the most common extracolonic cancer in
women with hereditary nonpolyposis colon cancer syndrome, a defect
in DNA mismatch repair that is also associated with ovarian cancers [5].
Molecular pathogenesis: A dualistic model of endometrial
carcinogenesis has been proposed. According to this model, normal
endometrial cells transform into endometrioid carcinoma through
replication errors, so-called microsatellite instability, and subsequent
accumulation of mutations in oncogenes and tumor suppressor genes.
For nonendometrioid carcinomas, alterations of p53 and loss of heterozygosity on several chromosomes drive malignant transformation [5].
Five main molecular alterations have been described in type I
endometrioid carcinomas: microsatellite instability (25%30% of the
cases); PTEN mutations (30%60%); PIK3CA mutations (26%39%);
ARID1A (20%); K-RAS mutations (10%30%); and CTNNB1 (-catenin)
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Fig. 7. Adenocarcinoma of the endometrium. (A) Endometrioid carcinoma. Polypoid tumor with only supercial myometrial invasion (left). Well-differentiated (grade 1) adenocarcinoma.
The neoplastic glands resemble normal endometrial glands (right). (B) Nonendometrioid carcinoma. Large hemorrhagic and necrotic tumor with deep myometrial invasion (left).
Nonendometrioid (serous) carcinoma exhibiting stratication of anaplastic tumor cells and abnormal mitoses (severe cytologic atypia) (right).
mutations with nuclear protein accumulation (25%38%). In contrast,

most type II nonendometrioid carcinomas have p53 mutations, Her-2/
neu amplication, and loss of heterozygosity on several chromosomes.
Nonendometrioid carcinomas may also derive from endometrioid carcinoma with microsatellite instability through tumor progression and
subsequent p53 mutations [5].
The Cancer Genome Atlas (TCGA) has conducted the most comprehensive genomic analysis of endometrial carcinomas reported to date
[6]. TCGA has expanded the dualistic classication of endometrial
carcinoma (types I and II) to four distinct molecular subgroups: (1) an
ultramutated POLE subgroup; (2) a hypermutated microsatellite unstable subgroup; (3) a copy-number low/microsatellite stable subgroup;
and (4) a copy-number high/serous-like subgroup. Even if overlapping
of the molecular genetic ndings makes it still difcult to separate
signicant prognostic categories, POLE mutations predict favorable
prognosis, particularly in high-grade tumors. On the other hand,
patients with endometrioid tumors that are serous-like at the molecular
level might benet from treatments that are typically used for serous
carcinomas [6].
Pathology:
Endometrioid adenocarcinoma of the endometrium: This type of endometrial cancer is composed entirely of glandular cells and is the most
common histologic variant (80%85%). The FIGO system divides this
tumor into three grades on the basis of the ratio of glandular to solid
elements, the latter signifying poorer differentiation. Less common
Table 1
Clinicopathologic features of endometrial carcinoma.
Type I: Endometrioid carcinoma Type II: Serous carcinoma
Age
Unopposed estrogen
Hyperplasia
precursor
Grade
Myometrial
invasion
Growth behavior
Genetic alterations
Pre- and perimenopausal

Present
Present
Postmenopausal
Absent
Absent
Low
Supercial
High
Deep
Stable
Microsatellite instability,
PTEN, PIK3CA, -catenin
Progressive
p53 mutations, loss
of heterozygosity
histologic variants include: endometrioid adenocarcinoma with

squamous differentiation and the mucinous and secretory types, both
associated with good prognosis [13].
Nonendometrioid endometrial carcinomas: They are aggressive as a
group, and histologic grading is not clinically useful, all cases being considered high grade.
Serous adenocarcinoma histologically resembles, and behaves like,
high-grade serous adenocarcinoma of the ovary (Fig. 8B). It often
shows transtubal spread to peritoneal surfaces. An intraepithelial
form has been termed serous endometrial intraepithelial carcinoma
(serous EIC), not to be confused with EIN, described earlier. Patients
with this type of tumor need to be staged and treated as if they had
ovarian cancer.
Clear cell adenocarcinoma is a tumor of older women. It contains large
cells with abundant cytoplasmic glycogen (clear cells) or cells with
bulbous nuclei that line glandular lumina (hobnail cells). Clear cell
carcinomas have a poor prognosis.
Carcinosarcoma (malignant mixed mesodermal tumor): In this highly
malignant tumor, pleomorphic epithelial cells intermingle with areas
showing mesenchymal differentiation. These mixed neoplasms are
derived from a common clone thought to be of epithelial origin.
Overall ve-year survival is 25% [1,2].
Clinical features: Unlike cervical cancer, endometrial cancer may

spread directly to para-aortic lymph nodes, thereby skipping pelvic
nodes. Patients with advanced cancers may also develop pulmonary
metastases (40% of cases with metastases).
Women with well-differentiated cancers conned to the endometrium are usually treated by simple hysterectomy. Postoperative
radiation is considered if: (1) the tumor is poorly differentiated or
nonendometrioid in type; (2) myometrium is deeply invaded; (3) the
cervix is involved; or (4) lymph nodes contain metastases.
Survival in endometrial carcinoma is related to multiple factors:
(1) stage, histotype and, for endometrioid tumors, grade; (2) age; and
(3) other risk factors, such as progesterone receptor activity, depth of
myometrial invasion, and extent of lymphovascular invasion [7].
Actuarial survival of all patients with endometrial cancer following
treatment is 80% after 2 years, decreasing to 65% after 10 years. Tumors
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Fig. 8. Leiomyosarcoma of the uterus. (A) A zone of coagulative tumor necrosis appears demarcated from the viable tumor. (B) The tumor shows considerable nuclear atypia and abundant
mitotic activity.
that have penetrated the myometrium or invaded lymphatics are more

likely to have spread beyond the uterus. Endometrial cancers involving
the cervix have a poorer prognosis. Spread outside the uterus entails the
worst outlook [3,7].
5.3. Endometrial sarcomas
Currently, endometrial sarcomas are classied into three categories:
(1) low-grade endometrial stromal sarcoma (LG-ESS); (2) high-grade
endometrial stromal sarcoma (HG-ESS); and (3) undifferentiated endometrial sarcoma (UES) [2]. LG-ESS represent less than 2% of uterine cancers. They may be polypoid or may diffusely invade the myometrium.
The tumor cells resemble endometrial stromal cells in the proliferative
phase. Nuclear atypia may be minimal to severe and mitotic activity
may be restrained. Expression of CD-10 and estrogen and progesterone
receptors help conrm the diagnosis. The most common cytogenetic abnormality of LG-ESS is a recurrent translocation involving chromosomes
7 and 17 t(7;17)(p15;q21), which results in a fusion between JAZF1 and
SUZ12 (formerly designated as JJAZ1) [1,2].
The recently re-established HG-ESS has features intermediate
between LG-ESS and undifferentiated sarcomas. It may appear as an
intracavitary polypoid or a mural mass. Microscopically, it consists
predominantly of high-grade round cells that are sometimes associated with a low-grade spindle cell component, usually bromyxoid.
Mitotic activity is very striking and typically more than 10 per 10
high-power elds (HPF). Necrosis is usually present. HG-ESS typically
harbors the YWHAE-FAM22 genetic fusion as a result of t(10;17)
(q22;p13) [1,2].
Higher-grade poorly differentiated sarcomas originating in the endometrium are designated as undifferentiated endometrial sarcoma [1,2].
Clinical features: Many years may elapse before LG-ESSs recur, and
metastases may occur even if the original tumor was conned to the
uterus at initial surgery. Recurrences usually involve the pelvis rst,
followed by lung metastases. Prolonged survival and even cure are feasible, despite metastases. By contrast, UES recur early, generally with
widespread metastases. Compared with patients with LG-ESS, those
with HG-ESS and undifferentiated endometrial sarcoma have earlier
and more frequent recurrences (often b 1 year) and are more likely to
die of disease. LG-ESS can be successfully treated with surgery and progestin therapy, with an expectation of 90% survival 10 years after
diagnosis [1,2].
myometrial invasion and sarcomatous overgrowth, eventually succumb

to local recurrence or metastatic spread [1,2].
5.5. Leiomyosarcoma
Leiomyosarcoma is a malignancy of smooth muscle origin whose incidence is only 1/1000 that of leiomyoma. It accounts for 2% of uterine malignancies. Its pathogenesis is uncertain. Women with leiomyosarcomas
are on average more than a decade older (age above 50 years) than
those with leiomyomas, and the malignant tumors are larger
(1015 cm vs 35 cm) [1,2].
Pathology: Leiomyosarcoma should be suspected if an apparent
leiomyoma is soft, shows areas of necrosis on gross examination, or
has irregular borders (invasion of adjacent myometrium). Mitotic
activity (10 or more mitoses per 10 HPFs), nuclear atypia, and geographical necrosis are the best diagnostic criteria (Fig. 8A and B).
Myxoid and epithelioid leiomyosarcomas may contain only ve mitoses
per 10 HPFs. Size is important as tumors less than 5 cm in diameter
almost never recur.
Most leiomyosarcomas are large and are advanced when detected.
They are usually fatal despite combinations of surgery, radiation therapy, and chemotherapy. Five-year survival is about 25% [1,2]. Almost all
leiomyosarcomas are high grade tumors and, usually, their diagnosis is
straightforward; however, a small fraction of uterine smooth muscle
tumors show atypical histologic features that are insufcient for the
diagnosis of malignancy or have an unpredictable clinical behavior.
These tumors have been designated as smooth muscle tumors of uncertain malignant potential (STUMP), but the term atypical smooth muscle
tumors, as introduced by the 2014 WHO classication of tumors [2],
seems preferable in view of their favorable behavior in most cases.
The latter term simply describes the morphologic ndings avoiding
the words uncertain and malignant, which create unnecessary concern for the patient.
In two recent studies of 41 and 16 cases of STUMP, only 3 (7%) and 2
(12%) patients developed recurrences, respectively [8,9]. Recurrence occurred, several years after hysterectomy, in the form of STUMP in
three cases and as leiomyosarcoma in the other two. All ve patients
were alive and disease free after prolonged follow-up. As indicated previously, when account is taken of mitotic count, myometrial invasion, nuclear atypia, tumor cell necrosis, size of tumor, and age of the patient,
tumors can be allocated to benign or malignant categories with greater
certainty and the term of uncertain malignancy can be avoided in
most cases.
5.4. Uterine adenosarcoma

Uterine (mllerian) adenosarcoma is a distinctive low-grade tumor
with benign glandular epithelium and malignant stroma. It should
be distinguished from carcinosarcoma, in which both epithelial
and stromal elements are malignant, and which is highly aggressive.
One-fourth of patients with adenosarcoma, particularly cases with
5.6.1. Endometrial biopsy

Tissue from an endometrial biopsy (curettage or outpatient
sampler) should be embedded in its entirety. A single hematoxylin
and eosin section is often sufcient for diagnostic purposes.
5.6.2. Malignant uterine disease

Evaluate all specimens with a preoperative diagnosis of malignancy
for residual tumor. If present, determine the maximum depth of
myometrial invasion and cervical involvement (mucosal or stromal).
The gross description must include the size, location, distribution
(focal or diffuse), and depth of myometrial invasion (Fig. 9). Sample
the uninvolved endometrium, including the lowermost margin of the
neoplasm (Fig. 10). At least one microscopic section should permit
measurement of the greatest depth of tumor invasion.
Lymphadenectomy may be included in the staging of endometrial
carcinoma. Careful dissection of lymphadenectomy specimens, with
submission of all possible lymph nodes is necessary [1]. One section
per node is adequate unless the size is too large.
6. Fallopian tube
Tumors of the fallopian tube are rare. Most primary malignancies
are adenocarcinomas, with peak incidence among women aged
5060 years. Recent observations suggest that some cases of highgrade serous carcinoma of the ovary (see below) may arise from the
mbriated end of the fallopian tube. Tubal carcinomas behave similarly
to ovarian carcinoma and frequently appear as a solid mass in the wall of
a grossly dilated tube, but may sometimes only be identied upon microscopic examination. The tumor is bilateral in 25% of cases. Prognosis
is poor, as the disease is almost always detected at advanced stage [1,2].
6.1. Risk-reducing salpingo-oophorectomy
An increasingly common indication for salpingectomy is prophylaxis
for patients who have BRCA1/2 mutations, a personal history of breast
cancer, or a strong family history of breast and/or tubo-ovarian cancer.
Typically the specimen is grossly unremarkable, however these
fallopian tubes, along with the corresponding ovaries, should be submitted entirely for histologic examination (Fig. 11) [1,2].
The protocol for sectioning and extensively examining the mbriated end (SEE-FIM protocol) was developed for processing risk-reducing
salpingo-oophorectomy specimens [10]. The entire tube is initially
xed for at least 4 h to prevent denuding of the mucosal epithelial
cells. Then, the mbriated end is amputated from the proximal tube
and sectioned longitudinally into multiple (at least four) sections and
the entire tube is submitted for histologic review.
Fig. 9. Endometrial carcinoma. Measurements of depth to which tumor invades. (A) Full
thickness of myometrial wall, measured from where endometrium adjacent to tumor is
normal (or hyperplasic). (B) Component of tumor exophytic and rising above imaginary
line drawn between adjacent normal endometrium. (C) Depth of invasion. (D) Tumorfree zone. (E) Width of tumor. A tumor is generally reported as measuring n x n x n and
C cm invasive into a wall A cm thick. Reproduced with permission from Mutter and
Prat [1].
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7. Ovary
7.1. Ovarian tumors
There are many types of ovarian tumors including benign, borderline, and malignant types. About two-thirds occur in women of reproductive age. Approximately 80% of ovarian tumors are benign. Almost
90% of malignant and borderline tumors are diagnosed after the age of
40 years [1,11].
Ovarian tumors are classied by the ovarian cell type of origin. Most
are common epithelial tumors (approximately 60%). Other important
groups are germ cell tumors (30%), sex cord/stromal tumors (8%), and
tumors metastatic to the ovary. Common epithelial tumors account for
about 90% of ovarian malignancies, high-grade serous adenocarcinoma
being the most common (70%).
Ovarian cancer is the second most frequent gynecologic malignancy
after endometrial cancer and carries a higher mortality rate than all
other female genital cancers combined. As it is difcult to detect early
in its evolution when it is still curable, over three-fourths of patients
already have extraovarian tumor spread to the pelvis or abdomen at
the time of diagnosis [1,11].
7.2. Epithelial tumors
Tumors of common epithelial origin can be broadly classied,
according to cell proliferation, degree of nuclear atypia, and presence
or absence of stromal invasion: (1) benign; (2) of borderline malignancy;
and (3) carcinoma.
Common epithelial neoplasms most commonly affect nulliparous
women and occur least frequently in women in whom ovulation has
been suppressed (e.g. by pregnancy or oral contraceptives). Whereas
the lifetime risk for developing ovarian cancer in the general population
is 1.6%, women with one rst-degree relative with ovarian cancer have a
5% risk. Also, women with a family history of ovarian carcinoma are at
greater risk for breast cancer and vice versa. Defects in repair genes
implicated in hereditary breast cancers, BRCA-1 and BRCA-2, are incriminated in familial ovarian cancers as well. As for endometrial carcinoma,
women with hereditary nonpolyposis colon cancer (HNPCC) are also at
greater risk for ovarian cancer [1,11].
Epithelial ovarian tumors are primarily classied according to cell
type into serous, mucinous, endometrioid, clear cell, transitional, and
squamous cell tumors [1,2,11]. However, none of these cells are found
in the normal ovary and their development has long been attributed
Fig. 10. Technique for sectioning the uterus. Sampling includes cervix (e.g. A, I); margins
adjacent and deep to a tumor (e.g. C, D); lower uterine segment and uppermost
endocervix (e.g. B, H)for example, to determine whether an endometrial cancer involves
the cervix, thus upstaging it; the wall for adenomyosis (e.g. D, F); and endometrium with
areas partially or totally seemingly free of tumor (e.g. C, G). Reproduced with permission
from Mutter and Prat [1].
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whereas endometrioid and clear cell carcinomas originate from ovarian

endometriosis [11].
7.3. Borderline tumors
Fig. 11. Sectioning and extensively examining the mbriated end (SEE-FIM protocol) for
cutting in a fallopian tube specimen. Cross-sections cut at approximately 3 mm intervals
of the length of the tube, and the mbriated end amputated and cut in the longitudinal
axis at 12 mm intervals (Figure reproduced with permission courtesy of BE Howitt and
GL Mutter, Boston, MA, USA).
to mllerian neometaplasia of the ovarian surface epithelium

(mesothelium). During embryonic life, the celomic cavity is lined by
mesothelium which also covers the gonadal ridge. The same mesothelial lining gives rise to mllerian ducts, from which the fallopian tubes,
uterus, and vagina arise (Fig. 12). Thus, the tumor cells would resemble
morphologically the epithelia of the fallopian tube, endometrium,
or endocervix [1,11]. Recently, it has been hypothesized that cytokeratin 7-positive embryonic/stem cells would give rise to immunophenotypically distinct neoplastic progeny [12], which would support
the old concept of mllerian neometaplasia. Besides the mesothelial
origin, there is now compelling evidence that a number of what have
been thought to be primary ovarian cancers actually originate in other
pelvic organs and involve the ovary secondarily. In fact, it has been
shown that some high-grade serous carcinomas arise from precursor
epithelial lesions in the distal mbriated end of the fallopian tube,
Borderline tumors show epithelial proliferation greater than that

seen in their benign counterparts and variable nuclear atypia; however,
in contrast to carcinomas, there is absence of stromal invasion, and their
prognosis is much better than that of carcinomas.
Serous borderline tumors generally occur in women aged
2050 years (average, 46 years). Serous tumors are more commonly
bilateral (34%) than mucinous ones (6%) or other types. The tumors
vary in size, although mucinous tumors may be gigantic. Serous borderline tumors have one or more cysts lined to varying extents by papillary
projections, ranging from ne and exuberant to grapelike clusters. These
structures show: (1) epithelial stratication; (2) moderate nuclear
atypia; and (3) mitotic activity. By denition, the presence of more than
focal microinvasion (i.e. discrete nests of epithelial cells b3 mm into the
ovarian stroma) identies a tumor as low-grade serous carcinoma
(LGSC), rather than a borderline tumor [1,2].
Despite the lack of ovarian stromal invasion, serous borderline
tumors, particularly those with exophytic growth, can implant on peritoneal surfaces (Fig. 13A) and, rarely (about 10% of peritoneal implants),
progress to LGSC and invade the underlying tissues (Fig. 13B). Histopathologically, invasive peritoneal implants and LGSC are identical lesions only distinguished by the timing of the disease and the volume
of the tumor. Whereas invasive implants are early supercial lesions
of microscopic or small macroscopic size (12 cm), LGSC frequently
presents as bulky disease (peritoneal carcinomatosis) [1,2,11].
Surgical cure occurs if the serous borderline tumor is conned to the
ovaries. Even if it has spread to the pelvis or abdomen, 90% of patients
are alive after 5 years. Although there is a signicant rate of late recurrence, the tumors rarely recur beyond 10 years. Late progression to
low-grade serous carcinoma has been reported in approximately 7% of
cases [1,2,7]. After fertility-sparing surgery, mucinous borderline
Fig. 12. Histogenesis of ovarian epithelial tumors.
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Fig. 13. Peritoneal implants of serous borderline tumor. (A) Noninvasive desmoplastic implant. The implant invaginates between adjacent lobules of omental fat. A few nests of tumor cells
are present within a loose broblastic stroma. (B) Invasive omental implant. The tumor glands and papillae appear disorderly distributed within a dense brous stroma and resemble a
low-grade serous carcinoma.
tumors may recur as carcinomas in the contralateral ovary; however,

such tumors should be considered independent primary tumors [13,14].
7.4. Malignant epithelial tumors (carcinomas)
Carcinomas of the ovary are most common in women aged
4060 years old, and are rare under the age of 35 years. Based on light
microscopy and molecular genetics, ovarian carcinomas are classied
into ve main subtypes, which, in descending order of frequency, are:
high-grade serous carcinomas (N70%), endometrioid carcinomas
(10%), clear cell carcinomas (10%), mucinous carcinomas (3%4%), and
low-grade serous carcinomas (b 5%) [11] (Table 2). These subtypes,
which account for 98% of ovarian carcinomas, can be reproducibly diagnosed and are inherently different diseases, as indicated by differences
in epidemiologic and genetic risk factors, precursor lesions, patterns of
spread, molecular events during oncogenesis, responses to chemotherapy, and outcomes. With progress toward subtype-specic management of ovarian cancer, accurate subtype assignment is becoming
increasingly important.
7.4.1. Serous adenocarcinomas
Molecular pathogenesis: Low-grade and high-grade serous carcinomas are fundamentally different tumors. Whereas low-grade tumors
are frequently associated with serous borderline tumors and have mutations of KRAS or BRAF oncogenes, high-grade serous carcinomas lack
ovarian precursor lesions and have a high frequency of mutations in
p53, but not in KRAS or BRAF. Interestingly, carcinomas arising in patients with germline BRCA1 or BRCA2 mutations (hereditary ovarian
cancers) are almost invariably the high-grade serous type and commonly have TP53 mutations.
Pathology: High-grade serous carcinomas (commonly called

cystadenocarcinomas) are the most common ovarian cancers and
most patients present with advanced stage disease (approximately
80%). Two-thirds of serous cancers with extraovarian spread are
bilateral. They are predominantly solid masses, usually with necrosis
and hemorrhage and typically show obvious stromal invasion. Most tumors have a high nuclear grade with highly cellular papillae and solid
areas (Fig. 14A). The mitotic rate is very high. Psammoma bodies are
often present [1,2,11].
Low-grade serous carcinomas show irregular stromal invasion by
small, tight nests of tumor cells within variable desmoplasia. The uniformity of the nuclei is the principal criterion for distinguishing low- and
high-grade serous carcinomas (Fig. 14B). Low-grade serous carcinomas
rarely progress to high-grade tumors [1,2,11].
7.4.2. Mucinous adenocarcinoma
Molecular pathogenesis: Mucinous ovarian tumors are
often heterogeneous. Benign, borderline, noninvasive, and invasive
carcinoma components may coexist within the same tumor. Such a
morphologic continuum suggests that tumor progression occurs from
cystadenoma and borderline tumor to noninvasive, microinvasive, and
invasive carcinomas. This hypothesis is supported by KRAS mutations
in mucinous tumors: 56% of cystadenomas and 85% of carcinomas
express mutated KRAS, with borderline tumors being intermediate
(Table 2) [1,11].
Pathology: Mucinous carcinomas are usually large, unilateral,
multilocular cystic masses containing mucinous uid. They often exhibit
papillary architecture (Fig. 14C). Since benign and malignant components may coexist within a single specimen, these tumors should be
sampled extensively. Mucinous tumors are bilateral in only 5% of the
cases; thus, nding bilateral or unilateral mucinous tumors smaller
Table 2
Main types of ovarian carcinoma.
High-grade serous
Low-grade serous
Mucinous
Endometrioid
Clear cell
Early or advanced
Serous borderline tumor
Early
Adenomaborderline
carcinoma sequence; teratoma
Early
Endometriosis,
adenobroma
Early
Endometriosis,
adenobroma
Genetic risk
Signicant molecular abnormalities
Advanced
Tubal metaplasia in inclusions
of ovarian surface epithelium
or fallopian tube
BRCA1/2
p53 and pRb pathways
?
BRAF or K-RAS
?
K-RAS
?
HNF-1
ARID1A
PIC3CA
Proliferation
Response to primary chemotherapy
Prognosis
High
80%
Poor
Low
26%28%
Favorable
Intermediate
15%
Favorable
HNPCC
PTEN,
-catenin,
ARID1A
PIK3CA
K-RAS
MI
Low
?
Favorable
Usual stage at diagnosis

Presumed tissue of origin/precursor
lesion
Low
15%
Intermediate
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Fig. 14. Representative examples of the ve main types of ovarian carcinoma, which together account for 98% of cases: (A) High-grade serous carcinoma; (B) Low-grade serous carcinoma;
(C) Mucinous carcinoma; (D) Endometrioid carcinoma; and (E) Clear cell carcinoma.
than 10 cm should raise suspicion of metastases from a mucinous

carcinoma elsewhere (e.g. gastrointestinal tract).
The category of mucinous borderline tumor with intraepithelial carcinoma is reserved for tumors that lack architectural features of invasive
carcinoma but, focally, show unequivocally malignant cells lining
glandular spaces. Mucinous borderline tumors with intraepithelial
carcinoma have a very low likelihood of recurrence [1,2,11].
Mucinous adenocarcinomas showing expansile or conuent glandular growth appear to have a more favorable prognosis than mucinous
carcinomas with destructive stromal invasion. The combination of
extensive inltrative stromal invasion, high nuclear grade, and tumor
rupture should be considered a strong predictor of recurrence for
Stage I mucinous adenocarcinomas [1,2,11].
Pseudomyxoma peritonei is a clinical condition of abundant gelatinous or mucinous ascites in the peritoneum, brous adhesions, and frequently mucinous tumors involving the ovaries. The appendix is also
involved by a similar mucinous tumor in 60% of the cases and appears
normal in the remaining 40%. Current data suggest that in most cases
the ovarian tumors are metastases from the appendiceal lesions [1,2].
7.4.3. Endometrioid adenocarcinoma
Endometrioid adenocarcinoma histologically resembles its uterine
counterpart (Fig. 14D), may have areas of squamous differentiation, and
is second only to serous adenocarcinoma in frequency. It accounts for

10% of all ovarian cancers. These tumors occur most commonly after
menopause. Up to half of these cancers are bilateral and, at diagnosis,
most tumors are either conned to the ovary or within the pelvis [1,2].
Molecular pathogenesis: Endometrioid carcinomas are thought to
arise by malignant transformation of endometriosis, and not from ovarian surface epithelium. The most common genetic abnormalities in sporadic endometrioid carcinoma of the ovary are somatic mutations of the
ARID1A, -catenin (CTNNB1), and PTEN genes and microsatellite instability. Endometrioid borderline tumors also have CTNNB1 (-catenin
gene) mutations (Table 2) [11].
Pathology: Although they may be cystic, most endometrioid
carcinomas are largely solid with areas of necrosis. These tumors are
graded like their uterine counterparts. Between 15% and 20% of patients
also harbor a uterine endometrioid carcinoma. Strong data suggest that
most of these cases arise independently, although some may be metastases from one or the other. This distinction has important prognostic
implications [1,2].
7.4.4. Clear cell adenocarcinoma
This enigmatic ovarian cancer is closely related to endometrioid
adenocarcinoma, and often occurs in association with endometriosis.
It constitutes 5%10% of all ovarian cancers usually occurring after
menopause. The most common genetic abnormalities are somatic

mutations of the ARID1A, PTEN, and PIK3CA genes [1,11].
Although patients typically present with Stage I or II disease, clear
cell carcinomas have a poor prognosis compared with other low-stage
ovarian carcinomas. Clear cell carcinomas of the ovary resemble their
counterparts in the vagina, cervix, and corpus; they show sheets or
tubules of malignant cells with clear cytoplasm (Fig. 14E).
Clinical features: By the time ovarian cancers are diagnosed, many
have metastasized to (i.e. implanted on) the surfaces of the pelvis, abdominal organs, or bladder. Ovarian tumors have a tendency to
implant in the peritoneal cavity on the diaphragm, paracolic gutters,
and omentum. Lymphatic spread is preferentially to para-aortic lymph
nodes near the origin of the renal arteries and to a lesser extent to
external iliac (pelvic) or inguinal lymph nodes [1,2].
Survival for patients with malignant ovarian tumors is generally
poor. The most important prognostic index is the surgical stage of the
tumor [15]. Overall, ve-year survival is only 35%. Prognostic indices
for epithelial tumors also include histologic type (grade) and the size
of the residual neoplasm.
Surgery, which removes the primary tumor, establishes the diagnosis, and determines the extent of spread, is the mainstay of therapy. The
peritoneal surfaces, omentum, liver, subdiaphragmatic recesses, and all
abdominal regions must be visualized, and as much metastatic tumor
removed as possible. Adjuvant chemotherapy is used to treat distant
occult sites of tumor spread.
7.5. Germ cell tumors
Tumors derived from germ cells make up one-fourth of ovarian
tumors. In adult women, ovarian germ cell tumors are virtually all
benign (mature cystic teratoma, dermoid cyst), but in children and
young adults, they are largely cancerous. In children, germ cell tumors
are the most common ovarian cancer (60%); they are extremely rare
after menopause. Rarely, germ cell tumors may arise from pre-existing
somatic neoplasms of the female genital tract. In these cases, the
teratoid tumors derive most likely from a pluripotent stem cell population of somatic neoplasms [1,2].
Neoplastic germ cells may differentiate along several lines producing:
Dysgerminomas are composed of neoplastic germ cells, similar to
oogonia of fetal ovaries.
Teratomas differentiate toward somatic (embryonic or adult) tissues.
Yolk sac tumors form extraembryonic endoderm and mesenchyme
and, less frequently, embryonic endodermal derivatives (intestine
and liver).
Choriocarcinomas feature cells similar to those covering the
placental villi.
Malignant germ cell tumors in women older than 40 years usually

result from transformation of one of the components of a benign cystic
teratoma. Malignant germ cell tumors tend to be highly aggressive;
however, with current chemotherapy, survival rates for many exceed
80% [1,2].
Recent stem cell research has provided several highly diagnostic
pluripotency markers, including transcription factors (SALL4, LIN28,
OCT3/4, and SOX2) and cytoplasmic/membranous proteins (glypican-3)
that are sequentially expressed in MGCTs according to their differentiation stage [1,2].
7.5.1. Dysgerminoma
Dysgerminoma is the ovarian counterpart of testicular seminoma,
and is composed of primordial germ cells. It accounts for less than 2%
of ovarian cancers in all women. Most patients are between 10 and
30 years. The tumors are bilateral in about 15% of cases.
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Pathology: Dysgerminomas are often large and rm and have a

bosselated external surface. The cut surface is soft and eshy. They
contain large nests of monotonously uniform tumor cells that have
clear glycogen-lled cytoplasm and irregularly attened central nuclei.
Fibrous septa containing lymphocytes traverse the tumor [1,2].
Dysgerminomas are treated surgically; 5-year survival for patients
with Stage I tumor approaches 100%. Because the tumor is highly
responsive to chemotherapy, even for higher-stage tumors ve-year
survival rates still exceed 80%.
7.5.2. Teratoma
Teratoma is a tumor of germ cell origin that differentiates toward somatic structures. Most teratomas contain tissues from at least two and
usually all three, embryonic layers. Immature teratomas contain
elements derived from the three germ layers. However, unlike mature
cystic teratomas, immature teratomas contain embryonal tissues.
These tumors account for 20% of malignant tumors in women under
the age of 20. Microscopically, they show multiple components such
as immature neural tissue (neuroepithelial rosettes and glia), glands,
and other structures found in mature cystic teratomas. Grading is
based on the amount of immature tissue present. Survival correlates
with tumor grade [1,2].
7.5.3. Yolk sac tumor
Yolk sac tumors are highly malignant neoplasms of women under
the age of 30 that histologically resemble the endoderm and mesenchyme of the primitive yolk sac (extra-embryonal) and embryonal
somatic tissues (intestine and liver). They are typically large, with extensive necrosis and hemorrhage. The most common histotype is the
reticular form. Schiller-Duval bodies are characteristic. They consist of
papillae that protrude into spaces lined by tumor cells, resembling the
glomerular spaces. The papillae are covered by a mantle of embryonal
cells and contain a brovascular core and a central blood vessel.
Yolk sac tumors secrete -fetoprotein which should be stained for in
all germ cell tumors. Detection of -fetoprotein in the blood is useful
for diagnosis and for monitoring the effectiveness of therapy. Once
uniformly fatal, ve-year survival with chemotherapy for Stage I yolk
sac tumors exceeds 80% [1,2].
7.5.4. Choriocarcinoma
Choriocarcinoma of the ovary is a rare tumor that mimics the
epithelial covering of placental villi, namely, cytotrophoblast and
syncytiotrophoblast. The pregnancy test is positive and the elevated
serum level of hCG may lead to ovarian stimulation and precocious
sexual development in young girls or menstrual abnormalities in older
patients. In women of reproductive age, however, it may also be a metastasis from an intrauterine gestational tumor. The tumor is unilateral,
solid, and widely hemorrhagic. Although highly aggressive, it responds
well to chemotherapy [1,2].
7.6. Sex cord/stromal tumors
These tumors represent 10% of ovarian tumors, vary from benign to
low-grade malignant, and may differentiate toward female (granulosa
and theca cells) or male (Sertoli and Leydig cells) structures [1,2].
7.7. Granulosa cell tumor
Granulosa cell tumors are the prototypical functional neoplasms of
the ovary associated with estrogen secretion. They should be considered
low-grade malignancies because of their potential for local spread and
the rare occurrence of distant metastases.
Most granulosa cell tumors occur after menopause (adult form) and
are unusual before puberty. A juvenile form occurs in children and
young women and has distinct clinical and pathologic features
(hyperestrinism and precocious puberty).
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Pathology: Adult-type granulosa cell tumors are large and focally

cystic to solid. The cut surface shows yellow areas, due to lipid-rich luteinized granulosa cells, white zones of stroma, and focal hemorrhages.
Random nuclear arrangement about a central degenerative space
(Call-Exner bodies) gives a characteristic follicular pattern. Tumor
cells secrete -inhibin, a protein that suppresses pituitary release of
follicle-stimulating hormone (FSH). Besides -inhibin, calretinin,
and FOXL2 are the most important positive immunoreactions [1,2].
Clinical features: Three-fourths of granulosa cell tumors secrete estrogens. Thus, endometrial hyperplasia is a common presenting sign.
Endometrial adenocarcinoma may develop if a functioning granulosa
cell tumor remains undetected. At diagnosis, 90% of granulosa cell tumors are within the ovary (Stage I). Over 90% of these patients survive
10 years. Tumors that have extended into the pelvis and lower abdomen
have a poorer prognosis. Late recurrence after surgical removal is not
uncommon after 510 years and is usually fatal [1,2].
7.11.2. Staging operations

Close cooperation between surgeon and pathologist is needed.
General guidelines for the surgeon include:
(1) Evaluate the ovarian mass to exclude metastasis from colon,
stomach, or elsewhere. Note penetration through capsule and
biopsy areas of adherence.
(2) Obtain ascitic uid or saline washings for cytology.
(3) Inspect all peritoneal surfaces. Prove that apparent implants are
malignant by frozen section, or submit multiple samples for permanent section, or both. Inspect the diaphragm, with biopsy of
visible lesions or scrapings for cytology.
(4) Conrm accuracy of apparent Stage I or II disease by generous
omental biopsy and sampling of pelvic and para-aortic nodes.
(5) After excision, mark the specimen indicating for the pathologist
the site of rupture and/or area(s) of adherence. Record residual
disease location and estimate extent.
7.8. Sertoli-Leydig cell tumors

Ovarian Sertoli-Leydig cell tumors are rare androgen-secreting
mesenchymal neoplasms of low malignant potential that resemble embryonic testis. Tumor cells typically secrete weak androgens (dehydroepiandrosterone). Sertoli-Leydig cell tumors occur at all ages but are
most common in young women of childbearing age. They vary from
well to poorly differentiated and some have heterologous elements
(e.g. mucinous glands and, rarely, even skeletal muscle and cartilage).
Nearly half of all patients with Sertoli-Leydig cell tumors exhibit
signs of virilization. Initial signs are often defeminization, manifested
as breast atrophy, amenorrhea, and loss of hip fat. Once the tumor is
removed, these signs disappear or at least lessen. Well-differentiated
tumors are virtually always cured by surgical resection, but poorly
differentiated ones may metastasize [1,2].
7.9. Steroid cell tumor
Steroid cell tumors of the ovary, also called lipid cell tumors, are
composed of cells that resemble lutein cells, Leydig cells, and adrenal
cortical cells. Most steroid cell tumors are hormonally active, usually
with androgenic manifestations.
Specimens submitted for pathologic examination are likely

to include:
Uterus with attached or separately submitted adnexa, preferably
delivered fresh to the pathologist immediately. Before xation, open
the uterine cavity, keeping in mind the possibility of a coexisting endometrial carcinoma or hyperplasia. Scrutinize the uterine serosal
surface for tumor deposits and section any adhesions to exclude
microscopic metastases (since these will raise the FIGO stage from
at least Stage I to at least Stage IIA).
Omentum. Slice nely, looking for tumor deposits and block these. If
none is found, sample any unusually rm areas. One to two blocks
should be sufcient. In over 20% of cases, the grossly normal omentum
will disclose microscopic foci of tumor.
Pelvic and/or para-aortic lymph nodes. Block all lymphoid tissue.
Peritoneal biopsies. These are often very small and should be
handled accordingly.
Peritoneal washings. The surgeon collects these by saline irrigation
from the left and right paracolic gutters, subdiaphragmatic region,
and pouch of Douglas. These uids should be processed by cytology
and cell block. Ascitic uid is treated similarly [1,15].
7.10. Tumors metastatic to the ovary

About 3% of cancers found in the ovaries arise elsewhere, mostly in
the large intestine, breast, endometrium, and stomach, in descending
order. These tumors vary from microscopic lesions to large masses.
Metastatic tumors large enough to cause symptoms originate most
often in the colon and may be estrogen secreting.
Krukenberg tumors are metastases to the ovary, composed of nests
of mucin-lled signet-ring cells in a cellular stroma derived from the
ovary. The stomach is the primary site in 75% of cases and most of the
rest are from the colon [1,2].
Bilateral ovarian involvement and multinodularity suggest a metastatic carcinoma, and both ovaries are grossly involved in 75% of cases.
7.11.1. Large cystic or neoplastic ovaries
Document whether the ovarian tumor is received intact or ruptured
and learn whether the rupture occurred intraoperatively. Many ovarian
tumors are cystic and all locules should be opened. Include the capsule
and tumor, and include tumor with adjacent normal parenchyma.
Generally, about one block per 2 cm of greatest tumor dimension will
sufce. Look for the fallopian tube, which may be incorporated in or
stretched over the tumor mass/cyst. It may contain coexistent neoplasia.
Germ cell tumors should be sampled extensively [1].
8. Gestational trophoblastic disease

The term gestational trophoblastic disease is a spectrum of disorders
with abnormal trophoblast proliferation and maturation, as well as
neoplasms derived from trophoblast.
8.1. Complete hydatidiform mole
Complete hydatidiform mole is a placenta with grossly swollen chorionic villi, resembling bunches of grapes, and showing varying degrees
of trophoblastic proliferation. Villi are enlarged, often exceeding 5 mm
in diameter.
Molecular pathogenesis and etiologic factors: Complete mole usually results from fertilization of an empty ovum that lacks functional
maternal DNA. Most commonly, a haploid (23,X) set of paternal chromosomes introduced by monospermy duplicates to 46,XX, but
dispermic 46,XX and 46,XY moles also occur. Moles characteristically
lack maternal chromosomes. Paternally imprinted genes, such as p57,
in which only the maternal allele is expressed, are not expressed in
villous trophoblasts of androgenetic-derived complete moles. Since
the embryo dies at a very early stage, before placental circulation has
developed, few chorionic villi develop blood vessels and fetal parts are
absent. Women with a prior hydatidiform mole have a 20-fold greater
risk of a subsequent molar pregnancy than the general population [1,2].
Pathology: Microscopically, many individual villi have cisternae.

Trophoblast is hyperplastic and composed of syncytiotrophoblast,
cytotrophoblast, and intermediate trophoblast. Considerable cellular
atypia is present.
Clinical features: Serum hCG levels are markedly elevated, and increase rapidly. Complications of complete mole include uterine hemorrhage, disseminated intravascular coagulation, uterine perforation, and
trophoblastic embolism. The most important complication is development of choriocarcinoma, which occurs in about 2% of patients.
Treatment consists of suction curettage of the uterus preferably
under ultrasound guidance and subsequent monitoring of serum
hCG levels. Up to 20% of patients require adjuvant chemotherapy
for persistent disease, but a 100% cure rate is expected even under
these circumstances.
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sheets of cells interspersed among myometrial cells. No chorionic villi

are seen. Placental site trophoblastic tumor is distinguished from
choriocarcinoma by its monomorphic (intermediate) trophoblastic proliferation, unlike the dimorphic pattern of trophoblast in choriocarcinoma. Most trophoblastic cells express human placental lactogen (hPL),
but a few express hCG [1,2].
Placental site trophoblastic tumor must be excised completely
(hysterectomy) to prevent local recurrence. It sometimes metastasizes and may be fatal. Large tumors and mitotic indices of more
than 5 mitoses/10 HPFs are associated with worse prognosis.
Conict of interest
The author has no conicts of interest to declare.
8.2. Invasive hydatidiform mole

The villi of a hydatidiform mole may only enter the supercial
myometrium or they may invade the uterus, and even the broad ligament. They tend to enter dilated venous channels of the myometrium
and one-third spread to distant sites, mostly the lungs. Uterine perforation is a major complication, but occurs in only a minority of cases [1,2].
8.3. Gestational choriocarcinoma
Choriocarcinoma occurs in 1 of 160 000 normal gestations, 1 of 15
000 spontaneous abortions, 1 of 5000 ectopic pregnancies, and 1 of 40
complete molar pregnancies. Unlike most other cancers, choriocarcinomas lack intrinsic tumor vasculature. Thus, the tumors are typically
necrotic and hemorrhagic and viable tumor is conned to the rim of
the neoplasm. There is a dimorphic population of cytotrophoblast and
syncytiotrophoblast, with varying degrees of intermediate trophoblast.
hCG is localized to the syncytiotrophoblastic element. By denition, tumors containing any villous structures, even if metastatic, are considered hydatidiform mole and not choriocarcinoma [1,2].
Choriocarcinoma invades mainly through venous sinuses in the
myometrium. It metastasizes widely via the bloodstream, especially to
lungs (over 90%), brain, gastrointestinal tract, liver, and vagina. With
current chemotherapy, recognition of risk factors (high hCG levels and
prolonged interval since antecedent pregnancy), and early treatment,
most patients are cured.
8.4. Placental site trophoblastic tumor
Placental site trophoblastic tumors are the least common trophoblastic tumors, and are mainly composed of intermediate trophoblastic
cells. Mononuclear and multinuclear trophoblast may be present as
References
[1] Mutter GL, Prat J, editors. Pathology of the Female Reproductive Tract. Third ed.
Edinburgh: Churchill Livingstone (Elsevier); 2014.
[2] Kurman RJ, Carcangiu ML, Herrington CS, Young RH, editors. WHO Classication of
Tumours of Female Reproductive Organs. Lyo: IARC; 2014.
[3] Mutch DG. The new FIGO staging system for cancers of the vulva, cervix,
endometrium and sarcomas. Gynecol Oncol 2009;115(3):3258.
[4] Stoler MH. Human papillomaviruses and cervical neoplasia: a model for carcinogenesis. Int J Gynecol Pathol 2000;19(1):1628.
[5] Matias-Guiu X, Prat J. Molecular pathology of endometrial carcinoma. Histopathology 2013;62(1):11123.
[6] The Cancer Genome Atlas Research Network, Kandoth C, Schultz N, Cherniack AD,
Akbani R, Liu Y, et al. Integrated genomic characterization of endometrial carcinoma.
Nature 2013;497(7447):6773.
[7] Prat J. Prognostic parameters of endometrial carcinoma. Hum Pathol 2004;35(6):
64962.
[8] Guntupalli SR, Ramirez PT, Anderson ML, Milam MR, Bodurka DC, Malpica A. Uterine
smooth muscle tumor of uncertain malignant potential: a retrospective analysis.
Gynecol Oncol 2009;113(3):3246.
[9] Ip PP, Cheung AN, Clement PB. Uterine smooth muscle tumors of uncertain
malignant potential (STUMP): a clinicopathologic analysis of 16 cases. Am J Surg
Pathol 2009;33(7):9921005.
[10] Medeiros F, Muto MG, Lee Y, Elvin JA, Callahan MJ, Feltmate C, et al. The tubal mbria
is a preferred site for early adenocarcinoma in women with familial ovarian cancer
syndrome. Am J Surg Pathol 2006;30(2):2306.
[11] Prat J. Ovarian carcinomas: ve distinct diseases with different origins, genetic alterations, and clinicopathological features. Virchows Arch 2012;460(3):23749.
[12] Crum CP, Herfs M, Ning G, Bijron JG, Howitt BE, Jimenez CA, et al. Through the glass
darkly: intraepithelial neoplasia, top-down differentiation, and the road to ovarian
cancer. J Pathol 2013;231(4):40212.
[13] Uzan C, Nikpayam M, Ribassin-Majed L, Gouy S, Bendifallah S, Cortez A, et al. Inuence of histological subtypes on the risk of an invasive recurrence in a large series of
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the ovary, fallopian tube, and peritoneum. Int J Gynecol Obstet 2014;124(1):15.

Principles of chemotherapy
Elisabeth vall Lundqvist a, Keiichi Fujiwara b, Muhieddine Seoud c
a
b
c
Department of Oncology and Department of Clinical and Experimental Medicine, Linkping University, Linkping, Sweden
Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka City, Japan
Department of Obstetrics and Gynecology, Gynecologic Oncology, American University of Beirut Medical Center, Beirut, Lebanon
1. Introduction
Chemotherapy plays a major role in the treatment of patients with
gynecological malignancies. In general, chemotherapy has a smaller
therapeutic window compared with drugs of other types; hence, the
potential for severe adverse effects associated with chemotherapy has
made appropriate patient and drug selection critical.
Before initiating treatment of any patient with a chemotherapeutic
agent, the following issues should be considered:
Tumor characteristics
The primary malignant diagnosis should be veried histologically.
Ideally, recurrent disease should be veried by cytology or preferably
histology; it is acknowledged that this is not always possible especially in ovarian cancer where the diagnosis of recurrent disease is usually
based on clinical examination, determination of tumor markers,
and imaging.
The extent of disease.
The likelihood of tumor response (e.g. type of cancer, rate of disease
progression, interval since last treatment).
Molecular biology if available.
Tumor markers if appropriate.
Patient characteristics
The patients age.

The patients general state of health (performance status).
Comorbidities (such as heart, liver, and kidney diseases).
Previous cancer treatments (response and adverse effects).
The patients psychosocial status.
Goals of treatment
Cure.
Tumor control to prolong survival.
Palliation of symptoms.
Chemotherapy should only be given to patients with a veried
malignant disease and specied type of cancer. Ideally, the rst relapse
should be veried with cytology or histology since other primary
tumors may develop. Gestational trophoblastic disease is an exception

where histological conrmation is not necessary prior to starting treatment. Before initiation of chemotherapy the goal of treatment should be
claried. If the treatment has a curative intention (e.g. ovarian germ cell
tumors or choriocarcinoma) even substantial adverse effects are acceptable if the probability of cure is high. When the goal of treatment is to
prolong survival, the balance of benet of treatment and adverse effects
should be carefully considered. When the goal of treatment is to reduce
the tumor burden to alleviate symptoms (palliative intention), treatment should be chosen so that the probability of severe adverse effects
is small. In these cases, the patient-reported adverse effects should
not be worse than the symptoms of disease. Chemotherapeutic agents
can be used in various protocols and routes, and can be used alone or
concurrent with radiotherapy or targeted therapy.
Physicians who treat patients with chemotherapy need to have
knowledge of tumor biology, cellular kinetics, pharmacodynamics,
kinetics, and drug resistance. Tumor cells use the same pattern for
cellular division and growth as normal cells and studies indicate that
cell division does not occur more rapidly in cancer than in normal
cells. The reason for the uncontrolled cell growth seems to be due to
loss of normal cell-cycle regulation and failure of programmed cell
death (apoptosis). The time it takes for a tumor mass to double its size
is referred to as the doubling time. Animal studies indicate that tumors
grow exponentially when they are very small, but the rate of cancer
growth slows as the tumor size increases (Gompertzian growth) [1].
There is limited information concerning the doubling time in human
tumors, but in general embryonal tumors have a short doubling time
(2040 days) while adenocarcinomas and squamous cell carcinomas
have relatively slower doubling times (50150 days).
Chemotherapeutic agents have several mechanisms of action and
affect cancer cells in a wide variety of ways. In general, cancer cells
that are actively moving through the different phases of the cell cycle
are highly chemosensitive, while cells in a resting state (G0) are
relatively insensitive. Tumors consisting of cancer cells that are rapidly
proliferating are therefore more responsive to chemotherapy. Patients
with slowly progressive disease can live many years but, in general,
their tumors are less sensitive to chemotherapy because the majority
of tumor cells at each treatment cycle are in a resting phase. According
to the log-kill principle, chemotherapeutic agents only kill a constant
fraction of cells rather than a specic number of cells [2]. A consequence
of this hypothesis is that the chemotherapy dose should not be reduced
in the case of a small tumor burden.
E.. Lundqvist et al. / International Journal of Gynecology and Obstetrics 131 (2015) S146S149
S147
2. Minimum requirements
3.1. Hypersensitivity reactions
2.1. Administration of chemotherapy
Most drug reactions are mild and appear during infusion in the form
of hot ushes, rash, and back pain. True allergic reactions are often more
severe (e.g. shortness of breath, edema, blood pressure changes) and
can even be life-threatening (anaphylaxis with cardiovascular collapse).
Drugs that are more often associated with hypersensitivity reactions in
the treatment of gynecological malignancies are platinum, liposomal
doxorubicin, and taxanes. Despite appropriate premedication, reactions
may occur during infusion with taxanes. These reactions tend to occur
during the rst cycles of treatment. Infusion reactions can often be treated by stopping the infusion and restarting at a slower rate. Hypersensitivity reactions associated with platinum agents occur more often
during later cycles or following re-exposure, and are more often severe.
Consider consultation with an allergist before rechallenge. Desensitization may be considered unless life-threatening reactions have occurred.
Preparation for a possible hypersensitivity reaction should be made
each time a patient is infused with chemotherapy. More specic guidelines are readily assessable, for example, the National Comprehensive
Cancer Network guidelines (www.nccn.org).
Health professionals who prescribe, administer, and/or supervise

the administration of chemotherapy should be qualied to administer
chemotherapy and have acquired skills to manage its adverse effects.
The administration of chemotherapy should comply with national
requirements concerning occupational safety and health.
Chemotherapy can be dangerous to professionals, patients, and next
of kin owing to its mutagenic, teratogenic, and carcinogenic capacity.
There is also a risk of direct skin irritation or damage in case of spill.
Preparation of the drugs must be performed in areas with special
ventilation systems and only by experienced onco-pharmacists.
Appropriate clothing including special gloves and gowns should be
worn when preparing and administrating the drugs. The right concentration and dilution in appropriate solutions (5% dextrose in water,
normal saline solution) and routes of administration (intravenous
push, or intravenous drip) and duration of infusion should be used.
Separate containers to dispose of the materials used when mixing
and giving the drugs are needed. The patient should be appropriately
monitored and all procedures documented in writing. At the facility
providing systemic chemotherapy medications, treatment of anaphylaxis should be immediately available and the staff should be trained
in cardiopulmonary resuscitation. Extravasation of a chemotherapeutic
agent acting as a vesicant (e.g. anthracyclines) can cause severe tissue
necrosis and calls for surgical intervention. Awareness of extravasation
and improved infusion techniques through a free-owing intravenous
line and careful monitoring are important preventive measures. A
clear algorithm for the use of the appropriate antidotes should be clearly
visible in the chemotherapy unit.
Adverse effects, weight, changes in performance status, and
appropriate laboratory tests should be assessed and documented before
each cycle. Quantication of adverse effects is usually done by
employing toxicity scales such as the National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI CTCAE) [3]. Adding
patient-reported outcome measures (PROM) may improve the accuracy
of the assessment [4]. Patient education concerning adverse effects
and their intervention should be regarded as part of treatment. Chemotherapy administration safety standards have been published by the
American Society of Clinical Oncology (ASCO)/Oncology Nursing
Society [5].
2.2. Minimum laboratory back-up requirements to administer chemotherapy

Immediate access to a laboratory facility is needed to receive reports
on at least a complete blood count (erythrocytes, leucocytes, platelets,
neutrophils), minimum liver function tests (alkaline phosphatase,
alanine transaminase, aspartate transaminase) and a creatinine
blood test.
3. Common adverse effects and how they are managed

Chemotherapy-induced adverse effects are most commonly caused
by damage of rapidly dividing normal cells, such as bone marrow cells,
cells lining the gastrointestinal and reproductive tracts, as well as cells
of hair follicles. Most chemotherapy drugs affect all these types of
cells, but to varying degrees depending on, for example, the drug,
dose, route of administration, and patient characteristics. Genetic variants of liver enzymes involved in drug metabolism probably account
for some of the observed inter-individual differences of adverse effects,
but have yet to reach clinical application. The sequence of giving certain
chemotherapeutic agents may affect their toxicities (such as the effect
of the combination of carboplatin and paclitaxel on thrombocytopenia).
3.2. Bone marrow/blood cells

The bone marrow is the most common site for chemotherapyinduced adverse effects. Neutropenia usually occurs 710 days after
treatment and during these periods there is an increased risk for infectious complications. The incidence of febrile neutropenia is relatively
low when using standard chemotherapy for gynecologic malignancies.
In general, there is no indication for the prophylactic use of granulocyte
colony-stimulating factors (G-CSFs). In case of treatment delays due to
neutropenia, the appropriate management should take the goal of the
treatment into account. To keep the course interval intact, dose reduction and/or the use of prophylactic G-CSFs may be appropriate. International guidelines for G-CSF administration are readily available [6,7].
The use of erythropoiesis-stimulating agents (ESAs) to treat
chemotherapy-induced anemia is debatable because of an increased
risk of thromboembolic events and the association with shorter survival. However, the mechanism behind the observed association between
ESAs and shorter survival in cancer patients is unclear. It is also
unknown whether all patients are at risk for being harmed. ASCO guidelines recommend that ESAs may be a treatment option for patients
undergoing myelosuppressive chemotherapy who have hemoglobin
levels less than 10 g/dL [8]. However, the potential harms and benets
of ESAs (e.g. decreased transfusions) need to be carefully discussed
with the patient, and compared with the potential harms (e.g. infections, immune-mediated adverse reactions) and benets (e.g. rapid
hemoglobin improvement) of blood transfusions.
The onset and recovery of thrombocytopenia is slightly later
compared with neutropenia. The sequence of giving certain chemotherapeutic agents may affect their toxicities (such as the effect of the
combination of carboplatin and paclitaxel on thrombocytopenia).
There is an increased risk of hemorrhagic complications when platelet
counts drop to less than 50 000/mm3 and there is a particularly
high risk of spontaneous bleeding once the platelet count is less than
10 000/mm3. Thrombocytopenia can be a challenging clinical problem
to treat. Platelet transfusions can provide temporary relief, but often
thrombocytopenia involves dose reductions or treatment delays.
3.3. Nausea and vomiting
Patients rate nausea/vomiting as one of the most distressing
adverse effects following chemotherapy. The incidence and severity of
chemotherapy-induced nausea/vomiting are affected by several factors,
including the specic chemotherapeutic agents used, as well as dosage,
schedule, and route of administration. The risk is increased among
women and patient-related factors such as age under 50 years; previous
S148
motion sickness and/or morning sickness during pregnancy; prior

chemotherapy emesis or anesthesia emesis; and anxiety. Alcoholism
decreases the risk of emesis. Chemotherapy-induced nausea/vomiting
is classied as acute or delayed. Acute-onset emesis usually occurs
within a few minutes to several hours and commonly resolves within
the rst 24 hours after drug administration. Delayed-onset emesis
develops more than 24 hours after chemotherapy administration and
generally peaks 4872 hours after administration. Depending on the
specic chemotherapy used, it can last for up to 7 days.
The goal of antiemetic therapy is to prevent nausea/vomiting;
therefore, antiemetic therapy should be initiated before chemotherapy
administration. The choice of antiemetic used is based on the emetogenic potential of the chemotherapy, prior experience with antiemetics, and patient risk factors. The emetogenicity of chemotherapy is
classied in four categories according to the percentage of patients not
receiving antiemetic prophylaxis who experience acute emesis: highly
emetogenic agents (90% risk of acute emesis); moderately emetogenic
agents (30%90% risk); low emetogenic agents (10%30% risk); and
minimal emetogenic agents (b10% risk). ASCO guidelines for the use
of antiemetics have recently been updated [9]. The key recommendation for patients receiving highly emetic chemotherapy regimens
is a 3-drug combination of neurokinin 1 (NK1) antagonist, serotonin
5-HT3 receptor antagonist, and dexamethasone. For moderate emetic
regimens, the recommendation is a 2-drug combination of palonosetron
and a corticosteroid. If palonosetron is not available, it may be substituted by a rst-generation 5-HT3 antagonist. A single 8-mg dose of
dexamethasone before chemotherapy is suggested for low emetogenic
chemotherapy agents and no routine prophylactic antiemetics are
recommended for minimal emetogenic agents. For patients receiving
combination chemotherapy, antiemetic treatment is chosen according
to the agent with the highest degree of emetic risk. Oral and intravenous
5-HT3 antagonists have equivalent efcacy when used at appropriate
doses. For selected patients unable to swallow, the transdermal route
may be of value. For patients with anticipatory emesis (occurring before
the patient receives chemotherapy), the most active antiemetic
regimens appropriate for the chemotherapy used should be chosen
initially. If anticipatory emesis occurs, behavioral therapy is suggested.
The incidence of anticipatory emesis varies between 18% and 57%, and
nausea is more common than vomiting.
Acupuncture point stimulation may be of some benet [10],
especially if modern antiemetic drugs are not available. In addition,
adjustment of eating habits, such as small frequent meals, may alleviate
nausea/vomiting. Other potential causes of emesis also need to be
considered, such as bowel obstruction, dyspepsia, brain metastasis,
electrolyte imbalance, and uremia.
Patients treated with chemotherapy may experience weight loss due
to loss of appetite, changes to sense of taste (e.g. metallic), sore mouth,
diarrhea, and constipation. Contributing factors may be pain, psychological factors, and poor performance status. Weight should be monitored
before each chemotherapy cycle. In case of weight loss exceeding
more than 10% for adults, appropriate investigation and directed therapy should be initiated and a dietary consultation is recommended.
3.4. Alopecia
Hair loss, or the fear of it, is one of the most troublesome adverse
effects of chemotherapy. Many chemotherapy agents do not induce
complete hair loss, but make the hair thin, fragile, and easily broken.
The effects usually begin within 23 weeks after initial chemotherapy,
but for taxanes, which often lead to complete alopecia, onset is quicker.
Hair grows back after treatment in almost all cases, and a full head is
seen after 36 months. During regrowth, the hair may have altered
color and structure. Proper pretreatment information about the risk of
hair loss, prescription of wigs when appropriate, and tips for headwear
and creation of new eyebrows and lashes may be helpful and provide
a feeling of control. There is some evidence that scalp cooling can
reduce hair loss during treatment with some chemotherapy agents

[11]. However, it should not be used if there is a high risk of cancer
cells surviving in the blood vessels of the scalp, such as certain hematological malignancies.
3.5. Peripheral neuropathy
Chemotherapy-induced peripheral neuropathy is a major doselimiting adverse effect of chemotherapy drugs commonly used in
gynecological malignancies, such as platinum and taxane. Peripheral
neuropathy typically occurs in 30%40% of patients and can begin
during or after the end of treatment. The symptoms, including pain,
numbness/tingling, sensory loss, and functional impairment, are often
only partially reversible and the neuronal damage can be permanent.
The risk of peripheral neuropathy is related to the chemotherapeutic
drug, cumulative dose, and the concomitant use of several neurotoxic
agents. The risk is also associated with patient characteristics such
as age and pre-existing neuropathy (e.g. alcohol, diabetes induced,
vitamin B12 deciency, and hypothyroidism). There is currently no
evidence-based pharmacological agent that can efciently prevent or
treat chemotherapy-induced peripheral neuropathy [12]. Therefore,
early detection of symptoms before they interfere with function and
activities of daily life is the best way to prevent the condition becoming
disabling. Dose modication, changing paclitaxel to, for example,
docetaxel, or even withdrawal of taxane may be necessary in platinumtaxane combination therapy. Patient needs include appropriate
shoes and awareness of potential hand and foot injuries due to
reduced neurosensitivity.
3.6. Sexual dysfunction, reproduction, and pregnancy
Sexual dysfunction is a common and distressing problem among
women treated for gynecological malignancies. The reason is multifactorial and includes decreased interest in sex and physical problems
such as dyspareunia and vaginal dryness. Although treatment-induced
sexual dysfunction is caused mainly by previous surgery and/or radiotherapy, chemotherapy can affect the vaginal mucosa leading to dryness
and supercial bleeding. In addition, vaginal infections such as fungus or
herpes may be reactivated. Sexual dysfunction needs to be actively
addressed and management may include lubricants, hormone replacement therapy, vaginal dilatators, and sexual counseling when appropriate. Patient education is important and should include information that
there is no medical reason for not engaging in sexual activity during the
chemotherapy treatment period.
The risk of chemotherapy-induced permanent ovarian insufciency
and infertility depends on patient age, drug dose, and specic
chemotherapeutic agent. The risk increases from 30 years of age and is
pronounced among women older than 40 years, especially after treatment with alkylating agents. Women younger than 30 years who
receive platinum-based chemotherapy will often have temporary
amenorrhea, but ovarian function commonly recovers. It is important
that patients use effective contraception during and up to one year
after completion of chemotherapy. Women who have not completed
childbearing and are at risk of infertility should discuss germ cell
preservation options with the medical team. The research eld within
female fertility preservation is rapidly changing, and no longer results
in a signicant delay in the initiation of cancer treatment.
Chemotherapy has potential mutagenic, teratogenic, and carcinogenic effects for the embryo depending on chemotherapy agent, dose,
and gestational stage. Gynecologic cancer during pregnancy is challenging and should be managed by a multidisciplinary team. Both the maternal prognosis and the risk for the fetus need to be taken into account.
Chemotherapy should be avoided during the rst trimester of gestation
but selective agents can be administered with reasonable safety during
the second and third trimester without an excessive increased risk for
the fetus [13,14]. A three-week period should be allowed between the
last chemotherapy dose and the expected date of delivery. Delivery

should be postponed preferably until 37 weeks or more of pregnancy.
However, long-term follow-up is limited and prospective studies are lacking. Breastfeeding should be avoided during chemotherapy treatment.
3.7. Other adverse effects
Some of the chemotherapy agents that are used to treat gynecological malignancies are recognized for their potential nephrotoxic effects.
These are cisplatin, ifosfamide, cyclophosphamide, and methotrexate.
Renal function should be monitored before every cycle and adequate
hydration given before and after treatment to maintain adequate
diuresis. Mannitol should be administered if indicated. Cognitive
impairment and fatigue are other more general adverse effects that
can affect women during and after chemotherapy.
Healthcare professionals should be educated and trained in
assessing and managing adverse effects. Patient and next of kin education about the acute and late adverse effects of chemotherapy should
be an integral part of cancer treatment. Cancer rehabilitation should
start at cancer diagnosis.
Conict of interest
M. Seoud received travel grants and honoraria from Roche for
presenting at conferences. E. Lundqvist received honoraria from
Roche, Boehringer-Ingelheim, and Merck Sharp & Dohme for presentations and from Astra Zeneca for participation on an advisory board.
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Targeted therapy in gynecologic cancers: Ready for prime time?

Muhieddine Seoud a, Elisabeth vall Lundqvist b, Keiichi Fujiwara c
a
b
c
Department of Obstetrics and Gynecology, Gynecologic Oncology, American University of Beirut Medical Center, Beirut, Lebanon
Department of Oncology and Department of Clinical and Experimental Medicine, Linkping University, Linkping, Sweden
Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Japan
1. Introduction: Unmet need

Each year, around 225 000 women are diagnosed with ovarian cancer and over 140 000 die [1]. Despite the recent advances in understanding the role of proper staging in early cases, maximal debulking efforts,
and new modes and route of adjuvant (including intraperitoneal and
dose-dense regimen), neoadjuvant, and palliative chemotherapeutic interventions, recurrences are inevitable and survival rates are still dismal
in the advanced stages.
Similarly, cervical cancer remains a major killer of women in lowresource countries and in women of low socioeconomic status in highresource countries. In 2012, 528 000 women were affected and
226 000 died of their disease [1]. Despite the recent advances in primary
prevention (HPV vaccination) and secondary prevention (screening by
cytology and/or HPV testing and subtyping), most women in lowresource countries have no access to either vaccination or screening,
and still present at a late stage.
Although early-stage and locally advanced cancers may be cured
with radical surgery, chemoradiotherapy, or both, these modalities are
scare in low-resource countries. Moreover, patients with metastatic
cancers and those with persistent or recurrent disease after platinumbased chemoradiotherapy have limited options [2,3]. In both of these
cancers, new forms of therapy are needed.
Increasing knowledge of the genetic basis for various cancers has led
to the development of new drugs that are tailored to these specic cancer pathways, while sparing normal cells and reducing the toxic adverse
effects of classical chemotherapy.
2. Ovarian cancer
New treatment options for women with advanced ovarian cancer include antiangiogenic drugs and poly (ADP-ribose) polymerase (PARP)
inhibitors. Others include vaccines and anti-PD-1/PD-L1 therapies.
2.1. Antiangiogenic therapies
Angiogenesis is the formation of new blood vessels from preexisting ones. A balance between pro- and antiangiogenic signaling
pathways is maintained so that angiogenesis is only switched on
when required for healing.
This pathway is governed by the vascular endothelial growth factor
receptors (VEGFRs). Three VEGFRs (VEGFR 1, 2, and 3) mediate the
effects of their ligands; these ligands comprise a family of growth factors, VEGF A through E, that induce proliferation and migration of endothelial cellsthe primary cell type involved in the formation of new
blood vessels.
In principle, once a tumor exceeds 1 mm in diameter it cannot receive adequate nutrients or oxygen from surrounding tissues by diffusion alone and it must then stimulate new blood vessel formation to
support further growth [4]. Tumor cells induce an angiogenic switch
in response to hypoxia and genetic alterations and produce angiogenic
growth factors that promote proangiogenic signaling pathways, such
as the VEGF pathway. The new blood vessels help the tumor grow and
provide potential routes for spread. VEGF signaling can be blocked at
several levels.
Targeted therapies differ from chemotherapy because they do not
induce direct cell kill but prolong time to progression. Objective
responses are therefore, in general, low, but progression-free survival
and overall survival can be prolonged anyway. In addition, since
targeted therapies affect disease-specic alterations and not normal tissues, they can be used as maintenance therapy.
In 2004, the US Food and Drug Administration (FDA) approved
bevacizumab, a monoclonal antibody targeting VEGF-A, for the rstline treatment of metastatic colorectal cancer in combination with
standard chemotherapy. More recently, the US Gynecologic Oncology
Group (GOG) 218 trial [5] and the European International Collaborative
Ovarian Neoplasm (ICON) 7 trial [6] investigated the addition of
bevacizumab to conventional chemotherapy in high-risk metastatic
ovarian cancer with maintenance bevacizumab following chemotherapy. The two trials showed a signicant benet on progression-free
survival and bevacizumab was approved by the European Medicines
Agency (EMA). The EMA also approved the use of bevacizumab in
platinum-sensitive recurrent ovarian cancer based on the OCEANS
trial [7], which showed doubling of the progression-free survival. In addition, the FDA and the EMA also approved the use of bevacizumab in
patients with recurrent, platinum-resistant ovarian cancer based on
the phase III AURELIA trial [8], which demonstrated that bevacizumab
with chemotherapy reduced the risk of disease progression by 52% compared with chemotherapy alone.
Currently, optimizing the use of bevacizumab is being investigated
in several trials, including the optimal duration (AGO-OVAR-17/
BOOST), and the optimal combination with dose-dense chemotherapy
(GOG 262, OCTAVIA), with intraperitoneal chemotherapy (GOG 252),
or with prior neoadjuvant chemotherapy (GOG 262, ROSiA). Because
M. Seoud et al. / International Journal of Gynecology and Obstetrics 131 (2015) S150S152
both the VEGF-dependent and Ang1/Ang2-Tie2-dependent angiogenesis pathways are active in ovarian cancer, other investigators are
assessing predictive tumor markers using either clinical characteristics
from the major trials or certain biological tumor markers, such as gene
immune signatures [9], histological subtypes such as the proliferative
and mesenchymal subgroups [10], and Ang 1 and Tie2 concentrations.
Other active angiogenic agents are also under investigation; for example, trebananib, which blocks Ang 1 and 2 by preventing their binding
to the Tie2 receptor differs from VEGF-targeted agents in terms of adverse effects, such as bowel perforation and hypertension. Its use was
associated with improvements in progression-free survival in patients
with recurrent epithelial ovarian cancer. However, other research involves targeting the VEGF-receptor signaling rather than its ligand.
Antiangiogenic therapy faces a number of barriers that limit its
potential. The clinical benet of these agents has been modest and
they are associated with high costs, which signicantly limit their use
in most low-resource countries, and signicant adverse effects such as
hypertension, thrombotic events, and bowel perforation. Moreover,
the role of angiogenesis in tumor development is clearly vastly more
complex than originally believed and the interaction between the
tumor, the vasculature, and the tumor microenvironment remains
poorly understood.
Other agents that have been investigated with variable responses
are pazopanib and cediranib. A phase II open-label study of pazopanib
(given 800 mg daily, orally) was conducted in 36 women with recurrent
ovarian cancer and an elevated CA125, who had previously had a complete CA125 response to platinum-based chemotherapy [11]. The authors reported that 11 (31%) women had a CA125 response, and
progression-free survival at 6 months was 17% (95% CI, 6%33%). A
phase II study of daily cediranib in 47 women with recurrent ovarian
cancer found the median progression-free survival was 5.2 months [12].
2.2. PARP inhibitors
PARP inhibitors rely on the sensitivity of cells containing a defect in
homologous recombination pathways to PARP inhibition (e.g. those
with BRCA mutations), which results in the death of target tumor cells
while sparing normal cells. Three ongoing studies are currently investigating this sensitivity: ARIEL, SOLO, and NOVA. Recently, both the FDA
and EMA approved olaparib, a PARP inhibitor, as a maintenance therapy
to prevent recurrence in platinum-sensitive ovarian cancer on the basis
of the phase III trial SOLO [13]. The manufacturer also submitted additional data supporting the use of olaparib in patients with BRCAmutated ovarian cancer who have already received three or more
chemotherapy treatments. Two other phase 3 trials are underway: the
SOLO2 trial is evaluating olaparib versus placebo as a maintenance
therapy; and the SOLO3 trial is evaluating olaparib compared with
standard chemotherapy for relapsed disease.
2.3. Other biologically active agents
Immunotherapy using anti-PD-1therapies (nivolumab) in relapsed
platinum-resistant ovarian cancer resulted in a dose-dependent response rate of 20%33% [14]. This can be used either with or without
an anti-CTLA-4 antibody (ipilimumab). Other research involves using
mTOR inhibitors, for clear cell cancers of the ovary and MEK inhibitors
for low-grade serous cancers [15,16].
3. Cervical cancer
Tumor neovascularization, as reected by an increased microvessel
density and strong immunostaining for the endothelial-cell marker
(CD31), is associated with an aggressive course in cervical cancer
[24]. Moreover, patients with high-grade cervical dysplasia and
invasive carcinoma have increased expression of VEGF and hypoxiainducible factor 1 (HIF-1) [17]. Invasion is noted when VEGF is
S151
up-regulated. On the one hand, oncogenic HPV subtypes enhance

HIF-1 protein production and VEGF expression, while on the other,
VEGF expression is diminished by silencing HPV E6 mRNA but not
when p53 is silenced, which means that E6 induces VEGF through a
p53-independent mechanism [18]. In addition, HIF-1 activity enhanced by E7 maps to its C-terminal and correlates with displacement
by E7 of the histone deacetylases HDAC1, HDAC4, and HDAC7 [19].
Recently, the FDA and EMA approved bevacizumab in combination
with paclitaxel plus either cisplatin or topotecan as a treatment for
patients with persistent, recurrent, or metastatic cervical cancer, based
on the extension of overall survival in the GOG 240 study [20].
Bevacizumab combined with chemotherapy increased overall survival
by 3.7 months, from 12.9 to 16.8 months, compared with chemotherapy
alone. Although this may be considered a small gain, it is hoped that
with the development of newer agents, quality overall survival may
be improved. Other VEGF and non-VEGF mediated compounds are
currently under investigation; for example, pazopanib (a tyrosine
kinase inhibitor that targets the VEGF receptor) and sorafenib (a
multikinase inhibitor) are two such agents [21]. However, data are lacking on vascular disrupting agents (e.g. vadimezan) and agents that
inhibit angiogenesis through non-VEGF-dependent pathways (e.g. the
Tie2angiopoietin-2 pathway). In addition, agents targeting nonangiogenic signal-transduction pathways including Wee1 checkpoint
inhibitors and Notch -secretase inhibitors may be promising.
4. Other gynecologic cancers
The role of biologically active agents is less studied in other gynecologic cancers. Unlike ovarian or cervical cancers, almost 90% of women
with endometrial cancer are treated by primary surgery with ve-year
survival rates of over 70% [22]. Even when endometrial cancer recurs,
it can be salvaged by a combination of surgery and radiotherapy. However, despite advances in radiotherapy, surgery, and chemotherapeutic
strategies, the prognosis of women with recurrent or advanced endometrial cancer is poor, with a median overall survival of approximately
710 months [2325].
There is a pressing need to improve current treatment strategies.
In endometrial cancer, the expression levels of VEGF correlate well
with prognosis [26]. In a phase II trial of single-agent bevacizumab in
recurrent endometrial cancer, 40.4% of patients had a progression-free
survival of at least 6 months [27]. Numerous other targeted agents
have been investigated with variable disappointing results in recurrent
and metastatic endometrial cancer. These included aibercept (VEGF
Trap-Eye) with a high-afnity binding to VEGF-A, VEGF-B, and placental growth factor [28,29]; thalidomide with antiangiogenesis effect
[30]; getinib and erlotinib, two tyrosine kinase inhibitors [31,32];
cetuximab, a monoclonal antibody against epidermal growth factor receptor (EGFR) [33]; trastuzumab and lapatinib, both EGFR type 2
(HER2)-related inhibitors that affect signal transduction [3436]; and
temsirolimus and ridaforolimus, which block the phosphoinositide 3kinase/AKT/mTOR pathway [37,38]. Other kinase inhibitors studied
are sunitinib, brivanib, sorafenib, and imatinib [39]. Other drugs target
epigenetic regulation of various cancer genes [40,41]. Epigenetic regulations may be particularly important in type I endometrial cancer.
The generally lower response rates of various targeted agents as
compared with standard chemotherapy (43.3%87%) [4144] may be
due to the multiplicity of carcinogenetic pathways and associated
genes. Thus suppression of a single molecule may not be enough. Resistance may be circumvented using combinations of molecular-targeted
drugs, and through the use of combination with current chemotherapeutic agents and/or hormonal therapy.
5. Conclusion
The role of targeted therapy in gynecological cancers, like in many
other cancers, remains elusive. The last decade has seen signicant
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M. Seoud et al. / International Journal of Gynecology and Obstetrics 131 (2015) S150S152
progress in dening the role of various genetic pathways and the use of
relevant agents. Few successes include the use of antiangiogenesis
agents and PARP inhibitors in ovarian cancer. The use of various clinical
and biochemical markers will help limit their use to those who will benet the most.
Conict of interest
M. Seoud received travel grants and honoraria from Roche for presenting at conferences. E. Lundqvist received honoraria from Roche,
Boehringer-Ingelheim, and Merck Sharp & Dohme for presentations
and from Astra Zeneca for participation on an advisory board.
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Principles of radiation therapy in low-resource and well-developed

settings, with particular reference to cervical cancer
Shyam Kishore Shrivastava a, Umesh Mahantshetty a, Kailash Narayan b
a
b
Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, India

Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Center, Melbourne, Australia
1. Introduction
Gynecological cancers are common in low-resource countries. Cervical cancer is one of the leading cancers in women in India and the fourth
most common cancer in women globally. Surgery with or without radiotherapy is commonly used to treat uterine, vulvovaginal, and early
cervical cancer. Radiotherapy plays an important role in the management of cervical cancer, where it is routinely used in radical/curative,
adjuvant, and palliative settings [1,2].
they express radiation injury at about 23 weeks following radiotherapy. Late responding tissues such as spinal cord, rectal wall, bladder, and
kidneys have a slow cell turnover. Radiation injury in these tissues is
expressed in months or years after radiotherapy, as the radiated cell
population slowly enters the active cell cycle phase. In summary, the radiation tolerance is relatively high for the cervix and vagina and low for
adjacent organs.
3. Radiation therapy in cervical cancer
2. Radiation treatment and doseresponse relationships
3.1. Radical radiation therapy for cervical cancer
The aim of radiation therapy is to achieve loco-regional control of

cancer while preserving normal tissue functions. Solid tumors have a
variable fraction of clonogenic cells that proliferate like any other normal tissues in the body. All clonogenic tumor cells must be eradicated
to achieve a cure. To improve the chances of cure, radiation doses may
have to be increased in proportion to the clonogens found in the
tumor. An increased radiation dose may also increase toxic and/or
acute reactions. The increased acute toxicity may be acceptable, provided it heals without any deleterious effects on the quality of life in surviving patients. Late radiation effects from pelvic radiotherapy may result
from damage to the rectosigmoid colon, bladder, small bowel, pelvic
and femoral bone, and bone marrow. The long-term effects of radiation
in these tissues can be minimized by using shrinking radiation elds,
appropriate shielding and, where possible, conformal radiation techniques giving differential doses to subclinical disease and gross disease
while sparing surrounding non tumor-containing normal tissues.
The standard of care for cervical cancers FIGO Stage Ib2 IIIb is
radical radiation therapy with or without concomitant cisplatin chemotherapy. Radical radiation therapy for cervical cancer consists of a combination of external beam radiotherapy (EBRT) to the pelvis covering the
uterus, cervix, parametria, and pelvic nodes. This is followed by brachytherapy to the primary tumor. The aim is to deliver a dose, equivalent
to 8085 Gy EQD2 (equivalent dose in 2 Gy per fraction) to point A.
The planned radical radiation/concomitant chemoradiation should be
completed within 8 weeks. Prolonging overall treatment time results in
poorer outcomes [3].
3.1.1. External radiation details
Using conventional fractionation, a dose of 4050.4 Gy in 1.8 or 2 Gy
fractions over a period of 46 weeks is recommended. Anterior-posterior
(AP-PA) portals or a four-eld box arrangement can be used. Shielding
corners of radiation elds helps in reducing the dose to the rectum, bladder, and small bowel, thereby reducing the toxicities.
2.1. Radiation tolerance doses

The tolerance of the cervix and uterus to radiation is usually more
than 200 Gy. With these doses, the rate of necrosis is less than 1%. The
upper vagina and distal vaginal mucosa can be treated up to140 Gy
and 100 Gy, respectively. Threshold doses reported for vesicovaginal stula and rectovaginal stula are 150 Gy and 8090 Gy, respectively.
However, these stulas can occur at much lower doses when the bladder base or rectovaginal septum has been grossly inltrated by tumor.
The radiation-induced adverse effects and their manifestations depend
on the type of tissues receiving radiation. Early responding tissues
such as the skin and intestinal mucosa have a high cell turnover and
3.1.2. Radiation planning

Either conventional uoroscopy-guided or computerized tomography (CT)-based planning can be used for EBRT. CT-based planning is increasingly used because of the wider availability of CT simulators in
many centers throughout the world. Fluoroscopy-guided conventional
planning is usually performed with the patient in the supine position.
Where a belly board is available, patients can be planned and treated
in the prone position. This helps to push the small bowel loops out of
the pelvis into the abdomen. Under uoroscopy guidance, bony landmarks are used to mark the portals. For the AP-PA two-eld technique,
the upper border of the pelvic treatment portal is located at the L45 or
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S.K. Shrivastava et al. / International Journal of Gynecology and Obstetrics 131 (2015) S153S158
L5S1 interspace. The lower extent of the pelvic eld is located at the
midpubis or inferior border of the obturator foramina or to a line
23 cm below the lowest vaginal disease level. Radio-opaque markers
may be placed in the vaginal cavity to identify the disease on the cervix
or vagina. The elds may be extended superiorly if microscopic or gross
metastatic disease is suspected in para-aortic nodes. The lateral borders
of the pelvic eld are placed at least 1.52.0 cm lateral to the pelvic brim
(bony pelvic sidewall). The lateral borders can be increased and corner
shielding reduced in obese patients to compensate for patient movement during treatment.
Using a four-eld technique results in lower radiation toxicities compared with two-eld AP-PA portals. In the four-eld technique (anteriorposterior and bilateral portals), the anterior border of the eld should be
1 cm anterior to the pubis to adequately cover the uterine fundus and the
anterior extent of the external iliac group of nodes with adequate margins. The posterior border should be at the S3 vertebra to include the
pre-sacral nodes located in front of the rst and second sacral vertebrae
and uterosacral ligaments. Customized blocks to shield the small bowel
region anterior-superiorly and the lower anorectal region on the lateral
elds are helpful in reducing late radiation toxicities in these tissues. Additionally, inguinal nodes should be included if the disease is extends into
or beyond the lower third of the vagina.
3.1.3. CT-based planning

A planning CT (slices 35 mm in thickness) of the abdomen and pelvis
using ducial skin markers with intravenous contrast is commonly used.
Intravenous contrast assists in differentiating between vessels and nodes.
Conformal planning with two elds AP-PA or a four-eld box technique
with blocks or multileaf collimators is planned after contouring various
structures and targets individually. Various conformal radiation techniques are used. These include the three-dimensional conformal radiation
technique (3D-CRT), intensity modulated radiation therapy (IMRT) with
or without image guidance (IGRT).
3.2. Brachytherapy
The ultimate in dose conformity and dose escalation for primary tumors of the cervix is achieved using brachytherapy. The use of brachytherapy results in organ sparing and improved therapeutic outcome in
terms of local control and reduced toxicities. In the recent past, IMRT/
SBRT boost have been tried in place of brachytherapy. The results of
such treatments have been signicantly inferior [4]. An accurately
placed brachytherapy application delivers high radiation doses to the
cervix, upper vagina, and medial parametria and relatively lower
doses to the rectum and bladder. Historically, brachytherapy was delivered with low dose rate (LDR) and medium dose rate (MDR) systems.
This is being progressively replaced with fractionated high dose rate
(HDR) systems. Randomized trials and meta-analysis comparing LDR
with HDR brachytherapy in cancer of the uterine cervix have shown
to be equally effective in terms of local control and survival [5,6]. Either
LDR or HDR brachytherapy can be used, taking into account the availability of equipment and other logistics of treatment delivery. HDR
brachytherapy can be performed as a day procedure in contrast to approximately 1520 hours of continuous LDR treatment. LDR treatment
requires an overnight hospital stay as an inpatient. Radiobiological considerations arising from using HDR radiation would require 35 applications of brachytherapy compared with 12 applications of LDR. There
are increasing reports of fewer complications and better local control
using HDR and this is becoming the preferred option [6].
Fractionated HDR brachytherapy treatment is started in the fth
week of external radiation preferably after obtaining optimum primary
tumor shrinkage. A dose of 7 Gy to point A per fraction and 35 fractions
depending on the EBRT doses and cumulative doses to the organs at risk
(bladder and rectum) is delivered.
3.2.1. Disease outcome with radical radiation alone

For early stage (IB IIA) cancer, local control rates of 75% and diseasefree survival of 60% 62% at 8 years have been reported. The disease outcome is better for small tumor sizes where both EBRT and brachytherapy
have been used. For advanced disease, the outcome is better for FIGO IIB
(65% 70% at 8 years) as compared with FIGO IIIB (40% at 8 years). Radical radiation therapy with conventional 2 Gy per fraction and higher total
doses with intracavitary brachytherapy without concomitant chemotherapy improves disease-free survival, which has been reported in a lowresource country setting [7]. The outcome improves with renement of
treatment protocols, a multimodality treatment approach, and with improved compliance to planned treatment [7].
3.3. Concurrent chemoradiation with cisplatin chemotherapy
Five randomized Phase III trials of radical radiotherapy alone versus
concurrent cisplatin-based chemotherapy and radiotherapy for the
treatment of cancer of the uterine cervix have shown the superiority of
concurrent chemoradiotherapy [2,811]. A further meta-analysis has
shown an absolute benet in overall survival and progression-free survival with chemoradiotherapy in patients with Stage IB2 IVA and
high-risk patients after hysterectomy [12,13]. While these trials vary
somewhat in terms of heterogeneity in data, stage of disease, suboptimal
doses of radiation, nonuniform usage of chemotherapeutic drugs, different schedules and doses of cisplatin, they all demonstrated a signicant
survival benet for concurrent chemoradiotherapy. The sole exception
was a Canadian trial that did not nd any survival benet of concurrent
weekly cisplatin over radiotherapy alone [14]. The major criticism of
the Canadian study was that nearly two-thirds of the patients who received chemoradiation had low hemoglobin, which was not corrected
during radiation and this may have had a negative impact on the therapeutic outcome [14]. Subsequently, an individual patient data-based
Cochrane meta-analysis suggested an estimated absolute survival benet of 10% (Stage IA to IIA), 7% (Stage IIB), and 3% (Stage III IVa) at
5 years. This analysis also showed a trend toward better outcome in patients receiving adjuvant chemotherapy following concomitant chemoradiation, which needs further evaluation [15].
While chemoradiation is regarded as the new standard of care for
women with cervical cancer, it is worth remembering that these results
were obtained in a trial setting in women from afuent countries who
had better nutritional or performance status and generally had normal
renal function compared with the majority of women from lower socioeconomic countries. Women from low-income countries generally
present with signicantly more advanced disease, poorer performance
status, and may not tolerate combination therapy as well as women in
better general health. Therefore, radical radiotherapy alone could be
considered for women with doubtful compliance or poor tolerance to
combined modality treatment, taking into account comorbid conditions
and social circumstances. Results of a large ongoing, randomized study
of chemoradiotherapy versus radiotherapy from India (NC00193791)
are awaited.
3.4. Management of vaginal vault cancers or local relapse after
primary surgery
Vault cancers in patients undergoing hysterectomy for presumed benign disease or subtotal hysterectomy for invasive cancers and relapse
following primary surgery may be treated either by radical radiation or
pelvic exenteration. Radical irradiation (with or without concurrent chemotherapy) may cure a substantial proportion of patients with isolated
pelvic failure after primary surgery. Radiation doses and volumes should
be tailored to the extent of disease. A dose of 4550.4 Gy in 1.82.0 Gy
fractionation should be delivered to microscopic disease followed by further boost to the gross tumor volume with brachytherapy or EBRT to a
total dose of 6466 Gy. The EBRT boost dose should be reduced if concurrent chemoradiotherapy is used. Use of an appropriate brachytherapy
boostespecially a perineal interstitial boostfor residual disease with

or without cisplatin chemotherapy results in a clinical outcome comparable with advanced cervical cancers [16]. Where synchronous pelvic
and distant recurrence is noted following primary radiotherapy for cervical cancer, a trial of chemotherapy for symptomatic control is indicated.
Cisplatin and sometimes carboplatin with paclitaxel is used. The expected median time to progression or death in such patients is 37 months. It
could be longer if disease is controlled in the radiated eld and recurrence is observed outside the previously treated volume.
3.5. Local recurrence after primary radiotherapy
The only potentially curative treatment of local failure after primary
irradiation is surgery provided the recurrence is limited to the cervix
and uterus. Pelvic exenteration is often required owing to postradiation
pelvic brosis or if clear resection margins between the bladder and rectum are not possible. Surgical salvage is contraindicated when in addition to central recurrence there is pelvic sidewall involvement or in
the presence of extrapelvic disease. The triad of unilateral leg edema,
sciatic pain, and ureteral obstruction is indicative of the extension of disease to the pelvic sidewall and signies unresectable disease. Salvage
surgery should only be undertaken in centers equipped with facilities
and expertise to manage complex surgery and its complications. The
prognosis of recurrent disease is better for patients with a disease-free
interval of greater than 6 months and with a recurrence 3 cm or less
in diameter located centrally. Following proper selection of patients,
the ve-year survival with pelvic exenteration is in the order of 30%
and in those suitable for hysterectomy it is 60%. Alternately, in a select
group of patients with local recurrence, salvage re-irradiation using
brachytherapy can be offered. The outcome with salvage re-irradiation
is better with a longer disease-free interval and if there are no late
toxicities from prior radiotherapy. This is achieved with higher
brachytherapy doses [17].
3.6. Systemic chemotherapy in Stage IVB or recurrent metastatic disease
Chemotherapy has a palliative role in patients with metastatic or
recurrent cervical cancer. There are a number of chemotherapeutic
agents with activity in metastatic or recurrent cervical cancer. Cisplatin is the most active cytotoxic agent, with a response rate of
20%30% and a median survival of 7 months. A combination of paclitaxel and carboplatin was superior to cisplatin alone in terms of response, progression-free survival, and sustained quality of life but
not overall survival [18]. In another Gynecologic Oncology Group
(GOG) study, the combination of topotecan and cisplatin was superior to cisplatin alone for response, progression-free survival, and
overall survival [19]. Therefore, selected patients with recurrent or
metastatic disease in good general condition could be offered one
of the combination regimens. For others, single agent cisplatin or
carboplatin and best supportive care continue to be appropriate
choices. Many biological agents have been tried in the treatment of
recurrent, persistent, or metastatic cervical cancer. In a recent randomized study, the use of bevacizumab in addition to chemotherapy
(paclitaxel plus carboplatin or topotecan plus paclitaxel) has shown
an improvement in median overall survival of 3.7 months [20].
Distant metastases should be treated with palliative intent using chemotherapy or radiotherapy or symptomatic and supportive care only.
Local treatment with radiation therapy is indicated to sites of symptomatic metastatic disease. The symptoms may arise from skeletal metastases, enlarged para-aortic or supra-clavicular nodes, or because of other
distant metastases. Occasionally, fully fractionated chemoradiotherapy
to isolated para-aortic nodal metastases can result in long-term survival
and should be attempted. In view of the shortened life expectancy of patients with metastatic cervical cancer, palliative radiotherapy should be
given using larger fractions over shorter periods than the duration of
conventional radical courses of treatment. Prospective evaluation of
S155
hypofractionated radiotherapy of advanced pelvic cancers was carried

out by the Radiation Therapy Oncology Group. A total dose of 44.40 Gy
was given in 12 fractions over three courses. Each course consisted of 4
fractions (QUAD SHOT) given twice a day over 2 days and repeated
after an interval of 4 weeks. The regimen was modied to 14 Gy in 4 fractions repeated two or three times, based on the patients general condition, giving a total dose of 42 Gy over 2 months. The moderate acute
effects are usually seen at around 10 days following the fourth fraction
and these usually heal by the time the patient returns for the subsequent
course. This regimen is better tolerated than 42 Gy given in 12 fractions
and given over 5 days a week, which produces higher and longer-lasting
acute effects on normal tissues for a similar tumor response [21].
4. Radiation treatment-related morbidity
Acute complications manifest during treatment, subacute complications occur at 36 months, and late effects manifest after
6 months of treatment.
4.1. Conventional radiation therapy with or without
concurrent chemotherapy
During pelvic radiotherapy, most patients experience mild to moderate fatigue and diarrhea, which respond to rest and antidiarrheal medications. Some women experience bladder irritation. These acute symptoms
are increased when combined with concurrent chemotherapy or extended eld radiation. Patients receiving concurrent chemotherapy may additionally have hematological and nephrotoxicity (cisplatin).
The late sequelae following radiation therapy commonly affect rectal, bladder, and small bowel function. These effects are radiation
dose-dependent and usually become evident on prolonged follow-up.
The reported grade III/IV late toxicities (requiring hospital admission
or intervention) range from 5% to 15%. In patients treated with imageguided brachytherapy, the incidence of such radiation effects has been
reduced to less than 3% [22].
Late rectal sequelae in the form of chronic tenesmus, telangiectasia
and profuse bleeding, rectal ulceration, and strictures have been reported (5%8%). These are usually seen during the 1836-month follow-up
period. The treatment options include steroid enemas, argon plasma coagulation, laser, or formalin application to the affected mucosa. Occasionally a diversion colostomy may be required.
Late bladder complications may manifest as hematuria, necrosis,
and rarely vesicovaginal or urethrovaginal stula. The incidence of
symptomatic grade III/IV late toxicities of the bladder after radical radiation is 4%8%. When other measures fail, hyperbaric oxygen therapy
(HBOT) may be tried for the treatment of hematuria. The use of HBOT
remains controversial however [23].
Late small bowel sequelae may manifest as chronic enteritis, subacute intestinal obstruction, perforation, and/or strictures. The incidence of symptomatic grade III/IV late toxicities of small bowel
following radical irradiation is 3%12%. These sequelae are higher in patients receiving adjuvant radiotherapy after radical surgery especially
with transperitoneal lymphadenectomies. This is due to the cumulative
and additive effects resulting from the combination of two major radical
treatment modalities [1].
Most patients treated with radical radiotherapy have telangiectasia
and brosis of the vagina, and signicant vaginal shortening resulting
in decreased sexual satisfaction and painful intercourse. These complications can be minimized by appropriate counseling and training in
the use of estrogen cream with vaginal cylinders at the time of radiotherapy. The weekly application of estrogen with a vaginal cylinder
should be continued in all women irrespective of their sexual status.
This is necessary to avoid thinning of vaginal mucosa thereby avoiding
vaginal spotting, which may be perceived by patients as a sign of recurrent cancer. Regular sexual activity is likely to enable some stretching of
S156
the vagina. During sexual intercourse, oil-based lubricants are advised

rather than water-based lubricants.
5. Modern radiation techniques
In the past two decades there has been rapid progress in radiation delivery techniques in parallel to advances in technology and imaging.
Newer EBRT techniques, such as IMRT, image-guided radiation therapy
(IGRT), and PET-CT guided radiation, have been utilized in the treatment
of cervical cancers. At present there is no conclusive evidence to support
their preferential use. These conformal EBRT techniques involve
contouring of the gross and subclinical disease volumes and normal organs/tissues requiring knowledge of the anatomy as seen on sectional
imaging (CT/MR/PET etc.). The radiation target includes gross tumor volume (GTV), which includes disease involving the cervix and extension to
the parametria, vaginal wall, uterus, and lymph nodes along with their
intervening lymphatics. The clinical target volume (CTV) includes the
entire cervix, uterus, and parametria up to the lateral pelvic wall and
upper 2 cm of the vagina below the lowermost gross involvement. The
planning target volume (PTV) includes appropriate margins over the
CTV. Consensus guidelines for nodal/lymphatic CTV contouring in cervical cancer have been published [24,25]. It should be remembered that
these terminologies and conventions are adopted through mutual agreements by various radiation oncology bodies and are not based on any
treatment results detailing dose response or patterns of failure studies.
Certainly, the contouring of normal tissue is important, as the conformal
mode of EBRT such as IMRT can achieve optimal sparing of normal tissues without compromising the doses to target. However, the day-today organ motion during the course of radiotherapy remains problematic. Specic normal tissues contoured are bladder, rectum, sigmoid, small
and large bowel, and bone marrow [22,26,27]. The potential advantages
of using newer EBRT techniques are as follows:
Limiting doses to normal tissues: This factor is of paramount importance and is going to be increasingly relevant in the future with the
practice of increasing doses to target volume [22,2628].
Dose escalation to the gross disease volume (primary and nodes) is
theoretically an important application of IMRT to any site. For cervical
cancer, brachytherapy excludes most of such need at the primary
tumor site. However, in locally advanced stages with inappropriate
geometry and size of residual disease not suited for brachytherapy,
IMRT could be used [29,30].
Concomitant boost application to special target regions can be
achieved using IMRT. These regions may include pelvic or paraaortic lymph nodes or the lateral one-third of the parametrium [22].
Radical treatments for para-aortic lymph nodes: Although FIGO staging does not change with identication of para-aortic lymph nodes
identied in imaging alone, the treatment should. Recently, several
authors have prescribed doses of 6066 Gy with concurrent chemotherapy and have demonstrated good local control and acceptable
toxicities [28,31,32]. However, the effect of such dose escalation on
long-term survival remains to be seen.
6. Advances in brachytherapy for cervical cancer

Historically, the brachytherapy systems formulated by the Manchester, Paris, and Stockholm groups were based on clinical experience.
These groups managed to deliver curative doses to the cervical tumor
in the absence of treatment planning systems. With the development
of various manuals, after-loaded applicators, and radium substitutes
such as Cs137, Co60, and Ir192, brachytherapy became safe and widely
available. High-dose-rate remote after-loading and advances in treatment planning systems have ensured well-dened protocols and
methods for brachytherapy dose analysis. Up until now, brachytherapy
was based on implant geometry (applicator and point-based) and
founded on theoretical concepts. Such a two-dimensional (2D) system

using orthogonal radiographs had major limitations. It lacked the information on the tumor volumes and organs at risk. Conventionally, point
doses are calculated for the rectum and bladder according to International Commission on Radiation Units and Measurements (ICRU) Report
38 recommendations [33]. The ICRU dose points do not represent the
dose received by the entire volume of the organs, and therefore the
doses to the organs at risk are not accurately known. This is evident
from the lack of signicant correlation between the point doses and incidence of toxicities, especially bladder and small bowel. In addition, the
extent of residual tumor cannot be seen in the radiographs. The position
of the applicator cannot be accurately assessed either within the uterus
or in relation to the surrounding tissues. Hence the dose gradient across
the tumor or the surrounding bowel cannot be ascertained.
Over the last two decades, various imaging modalities such as ultrasound, CT, MRI, and PET have been explored in an effort to delineate the
tumor volume to be targeted by EBRT and brachytherapy. Among the
imaging modalities, MRI is becoming increasingly popular for diagnosis
and treatment planning for EBRT and brachytherapy. Image-guided
brachytherapy (IGBT) has been possible mainly because of MRI, where
it is possible to image the residual tumor and normal tissues with the
brachytherapy applicator in treatment position. The Group Europen
de Curiethrapie and the European Society for Therapeutic Radiology
and Oncology (GEC-ESTRO) published guidelines for reporting and
practice of IGBT, including the concept of target, dose volume parameters, MR imaging protocols and quality assurance (GEC-ESTRO I-IV recommendations) [3437]. These have been widely accepted. According
to these recommendations, the target includes the gross tumor volume
seen asT2 bright areas in the cervix; the high-risk clinical target volume
(HR-CTV) consisting of the entire cervix and presumed disease extension at the time of brachytherapy (based on clinical and treatment planning MR image); and the intermediate-risk volume (IR-CTV), up to a
5 15-mm margin around HR-CTV to encompass the pre-treatment
disease at diagnosis [34]. GEC-ESTRO also recommends starting with
the standard method of dose prescription, either point A or the 60 Gy
reference volume, and then adjusting the loading pattern and dwell
times to ensure comprehensive target (HR-CTV) coverage while
limiting the dose to the organ at risk. Various dose volume parameters
related to target (D90, D100, D98, and V100) and organs at risk
(D0.1 cc, D1cc, D2cc) have been recommended [35]. There are no dose
volume constraints recommended. The doseresponse relationships
for various targets and constraints for organs at risk are evolving at
present (ongoing studies, Retro-EMBRACE and EMBRACE studies).
7. Current status of image-guided brachytherapy
A large series published from the Vienna group has reported the
clinical outcome of 156 patients treated with MR image-guided
adaptive brachytherapy combined with 3D conformal EBRT with or
without chemotherapy [38]. The results are promising, with excellent local control rates of 95% at 3 years in limited/favorable (Stage
IB/IIB) groups and 85% in large/poor response (Stage IIB/III/IV)
groups with acceptable treatment-related morbidity rates. Compared with their historical series, there is a relative reduction in pelvic recurrence by 65%70% and a reduction in major morbidity.
Similar mono-institutional series form other centers have been reported [39,40]. MR IGBT is being evaluated further in an ongoing
multicenter study involving several institutions in Europe, the USA,
and Asia (EMBRACE and Retro-EMBRACE).
However, the use of MR imaging for fractionated brachytherapy planning is not routinely practiced owing to the availability of MRI in radiotherapy set-ups, economical viability, etc. The use of alternate imaging
modalities such as CT scan, ultrasonography (transabdominal and
transrectal) for IGBT is being evaluated currently with promising results.
For low-income and resource-limited countries where cervical cancer is a major health problem, use of a simple, cost-effective imaging
modality like ultrasonography would result in wide applicability to

optimize cervical brachytherapy. Ultrasound-guided intracavitary
brachytherapy for cervical cancer has also been explored [41,42]. The
advantages of the universal availability of ultrasound, its costeffectiveness, advances in 3D and real-time ultrasound imaging, and
the small learning curve would make the application of this modality especially useful in low-resource countries. Recently, one of the largest
single institutional studies (292 patients) of ultrasound-guided and
MRI veried dosimetry of conformal brachytherapy of cervical cancer
reported their patterns of failure, late complications, and survival [43].
The conformal brachytherapy has markedly reduced long-term toxicities, usually associated with traditional brachytherapy for cervical cancer. However, the effects of such conformal radiotherapy on long-term
survival remain to be established.
Conict of interest
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Psychosexual health in gynecological cancer

Susan V. Carr
Royal Womens Hospital, Melbourne; and Department of Obstetrics and Gynecology, University of Melbourne, Melbourne, Australia
1. What is psychosexual health?

The literature surrounding psychosexual health and cancer patients
has primarily considered the functional aspects of the disease and its
treatment at the major expense of the emotional sequelae. Sexual
health is dened by WHO as: a state of physical, emotional, mental,
and social well-being in relation to sexuality; it is not merely the absence of disease, dysfunction or inrmity. Sexual health requires a positive and respectful approach to sexuality and sexual relationships, as
well as the possibility of having pleasurable and safe sexual experiences,
free of coercion, discrimination and violence [1].
A principle goal of WHO is to assist its member states in achieving the
highest attainable standard of health care for all, including sexual and reproductive health [2]. Global statistics show that the worlds female population is carrying an overwhelming burden of need in this area. Over 200
million women cannot access modern contraception, and millions of
women suffer rape, domestic violence, and sexual abuse, not only in the
context of wars and criminal activities, but also in their own homes [2].
Although the physical sequelae of these disasters can be treated, such
as treatment for sexually transmitted infections, the emotional impact
can frequently be hidden, ignored, or may not reveal its impact until
many years after the event.
Any illness or traumatic life event, past or present, can lead to sexual
problems in the lifetime of a woman, and gynecological cancer is no exception. It is the root cause or trigger for sexual difculties in at least 50%
of women affected [3]. In 2012, the estimated number of women living
with gynecological cancers was over three million, which means that
potentially 1.5 million gynecological cancer survivors could be affected
by an associated sexual difculty [4].
Within the context of gynecological cancer, many of these problems
can be alleviated if recognized and acknowledged early in the cancer
journey, therefore contributing dramatic improvements to a womans
overall well-being.
2. Prevalence of sexual problems in gynecological cancers
It is now estimated that half of the population of either sex will develop cancer at some time in their life. Globally, 40% 45% of women
will have a sexual problem at some stage, with the prevalence increasing with age [5]. Between 10% and 90% of women with any cancer will
have sexual problems [6] and over 50% of women with gynecological
cancer will have either temporary or persistent sexual difculties [3].
As diagnosis and treatments improve, the number of women surviving
cancer will increase, and survivorship issues including quality of life

have become increasingly important. Sexuality is a key component of
most subjective measurable quality of life indicators [7]. Sexual function
and enjoyment are important components of survivorship and should
not be ignored.
3. What problems are likely to be seen?

The most common sexual problems can be divided into two groups:
problems of function and/or problems of desire. There is, however, a
complex interplay of organic disorders with emotional and psychosocial
issues, and these divisions are merely articial. Formal denitions of female sexual dysfunction have been adopted, including the US classications in the Diagnostic and Statistical Manual of Mental Disorders [8],
although having a sexual difculty does not constitute having a mental
health disorder. Basson et al. [9] published a useful classication of the
problems. Such classications are useful for research purposes, but
may often be less helpful when treating women.
The predominant functional female sexual problem is pain on sexual
intercourse, or dyspareunia. Deep dyspareunia describes intracoital pelvic pain, and supercial dyspareunia is pain on vaginal entry. Either
could signify organic disease, and should be appropriately investigated.
If no pathology is demonstrated, and the pain persists, then an emotional cause must be considered and pursued.
Vaginismus, or involuntary spasm of the pubococcygeal and related
musculature, can prevent sexual intercourse taking place. Good history
taking can clarify whether there has been any penetration of the vagina,
not only penile, but by ngers, sex toys, or tampons. If not, this is diagnostic of primary vaginismus, and apart from close inspection of the
vulva and offer of gentle digital vaginal examination to determine the
extent of the vaginismus, no further clinical investigation is warranted.
Women with gynecological cancer are more likely to have secondary
vaginismus caused by pain experienced from the disease or its treatment, and fear of the pain occurring during sex [10].
Loss of libido or loss of sexual interest on the other hand is a problem
of desire. There are no physiological markers for loss of desire when its
origins are psychogenic, with psychosocial contributions, past and
present relationships, traumas, and emotional factors all inhibiting the
womans wish to be sexual. One of the key ways to determine the origins of the sexual difculty is to ask about the sexual and emotional relationship between the woman and her partner before the cancer
diagnosis. It should not be assumed that problems are all due to the
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S.V. Carr / International Journal of Gynecology and Obstetrics 131 (2015) S159S163
cancer, as long-standing relationship problems may be disclosed, and

need to be incorporated into any counselling.
The exception to this is the woman who suddenly becomes menopausal following cancer treatment, who had no problems with sex or
desire prior to her cancer therapy. Appropriate standard therapy for
her menopausal symptoms should be considered; however, the impact
of a cancer diagnosis will be life changing, and drug treatment of hormonal deprivation symptoms may not be sufcient without some psychological or counselling support, or may be contraindicated as in the
case of breast and endometrial cancer [11].
4. Sexual difculties arising from symptoms and treatments for
gynecological cancers
A diagnosis of gynecological cancer is overwhelming. While the instinctive professional response from clinicians is to ensure long-term
survival, sexual issues are important for quality of life and should be
considered in the decision-making process [12]. Sexual dysfunction is
one of the most common and distressing consequences of cancer treatment [13]. Many treatments are shown to have sexual impacts, both
positive and negative, and should be discussed fully with the woman
pre-treatment so that she can make an autonomous decision about
her care. Early offer of discussion of sexual issues in the cancer journey
can lead to better sexual outcomes.
4.1. Cervical cancer
Cervical cancer is the most common gynecological cancer worldwide. Cervical cancer survivors are at risk of sexual pain disorders, no
matter which modality of treatment is used. A small study of patients
who underwent radical vaginal trachelectomy for early stage cervical
cancer showed sexual dysfunction, including loss of libido, for up to
one year following treatment; however, by 12 months, sexual activity
had reached that of healthy women [14]. Following radical hysterectomy for locally advanced cervical cancer, there was no signicant difference in sexual activity and enjoyment between women with benign or
malignant disease; however, the cancer group had worse problems than
healthy controls with body image and vaginal functioning [15]. In
women with advanced cervical cancer given chemoradiotherapy, pain
during intercourse was in fact reduced after treatment [16]. This may
have been a result of the resolution of bleeding, discharge, and pelvic
pain. However, the anxiety surrounding cancer remains for many
women. Women surviving up to 15 years following cervical cancer
treatment showed poorer quality of life than healthy controls, and
those who had received radiotherapy were signicantly more affected
by sexual dysfunction than those who had surgery alone [17]. Despite
this however, orgasm may be unimpaired following radiation [18].
Many additional needs were expressed by women with cervical cancer;
however, sexuality and intimacy came to the fore as a predominant
issue for survivorship [19].
4.2. Ovarian cancer
It has been known for some time that the physical and emotional
impact of ovarian cancer can be devastating, leading to sexual as well
as global quality of life issues [20]. One study has shown a prevalence
of 63% for sexual difculties among women with a diagnosis of ovarian
cancer [3]. The effects of chemotherapy and surgery, combined with the
anxiety about survival can have a dramatic negative effect on the
womans libido, and even women who undertake risk-reducing
salpingo-oophorectomy can suffer sexual dysfunction [21]. Many of
these women are totally unprepared for the devastating effects of sudden menopause, with hot ushes, vaginal dryness, and loss of libido replacing a previously healthy sex life. This could be helped by more
realistic counselling before the procedure, and increased postoperative
emotional support.
4.3. Endometrial cancer

One study has shown that women who had surgery for endometrial
cancer had no differences in their own sexual experience postoperatively,
but compared with healthy controls, they had more sexual difculties
overall [22]. Women with Lynch syndrome who opt for preventive surgery tend to be happy overall with the surgery, but are often unprepared
for the physical adverse effects of menopause [23]. In contrast, Moldovan
et al. [24] has reported that, despite sometimes debilitating menopausal
symptoms, there were no signicant sexual difculties associated with
the procedure.
4.4. Vulvar cancer
Vulvectomy is a common treatment for vulvar malignancy. This is
increasingly affecting younger women, who are HIV positive. Women
with vulvar cancer can have many years of difculties with sex due to
often distressing vulvar symptoms and bleeding. Following treatment
they still suffer severe dyspareunia and body image distortion due to
the effects of treatment. Although a recent study showed no differences
in psychosocial and sexual functioning before and after vulvectomy, it
was acknowledged that women with vulvar malignancy have a high
risk for sexual problems compared with healthy controls [25]. Factors
associated with postoperative sexual difculties are increased age,
poor overall physical and mental health well-being, and extent of the
surgical excision [25]. This often elderly group of patients is usually
neglected from the psychosexual point of view.
5. Ethnic groups
The majority of the literature related to sexuality and cancer stems
from high-resource countries. Although most of these studies encompass all women, there is a lack of good published evidence on the treatment of the sexual sequelae of cancer in relation to ethnic minority
groups, within a majority culture [26]. Furthermore, data from lowand middle-income countries are scant. Much of the literature focuses
on sexual distress and activity in relation to HIV and AIDS which, of
course, is a global priority; however, this focus on infection transmission
should not take away from the emotional needs of the woman who suffers from gynecological cancer. Sexuality research around the globe
must be perceived and researched in terms of cultural, spiritual, ethnic,
and religious contexts.
6. Treatment strategies for sexual problems
6.1. Physical
Sexual problems in women with gynecological cancer may be associated with adverse effects of surgical, hormonal, and chemical treatments, as well as by the cancer itself. Fortunately, emotional, sexual,
and quality of life outcomes improve as less morbid, more minimally invasive surgical treatments for gynecological cancers develop [12].
Chemotherapy-induced ovarian failure in cancer patients is associated with all the possible symptoms of a sudden menopause, combined
with the emotional impact not only of the cancer, but loss of physical
well-being and fertility all at the same time.
Vaginal dryness can be a major problem to those women who wish to
have sex [27], and appropriate vaginal moisturizers and lubricants can
help. The issue of vaginal estrogen is still debated, but should be
discussed with the patient, weighing up the risk benet ratio for
each individual. Vaginal estrogen will, in most cases, alleviate the dryness, but there may be concerns about using hormones, especially in relation to breast cancer where the evidence is unclear. The scientic data,
however, support the safety of low dose vaginal estrogen therapy [28]. It
is not well understood that following a few weeks of vaginal estrogen,
the vagina thickens and cornies and estrogen is not absorbed as a result.
Newer treatments such as selective estrogen receptor modulators have

been used in place of vaginal estrogen in women without cancer [29],
and may prove good alternatives in the future [30]. There are nonhormonal vaginal moisturizers and lubricants to make sexual intercourse
more comfortable. Unfortunately, some commercial sexual lubricants
can be hyperosmolar and could cause epithelial disruption, facilitating
HIV transmission [31]. Simple lubricants such as olive oil or liquid glycerin have been used successfully in interventions to alleviate pain on intercourse due to vaginal dryness, combining their use with physiotherapy
and psychosexual counselling.
Treatments with pelvic external beam radiotherapy and/or with
brachytherapy may cause vaginal shortening, tightening, and lack of pliability. The use of vaginal dilators to overcome these complications is
widespread, despite lack of conclusive evidence, either for or against,
either with or without a coating of estrogen cream [32]. Unsurprisingly,
the intrusion of inserting a plastic (or sometimes glass) tube into a tender vagina after treatment is a task that may carry a deep psychological
and emotional impact [33], and will have resultant poor compliance.
Radiation oncologists agree that information about dilator use should
be given before treatment [34], and that sufcient patient information
and support are essential to improve compliance. Sensitivity to emotions and womens views and personal values in relation to sexuality
are essential supports to encouraging dilator use [35].
6.2. Emotional
Any of the above problems cannot fail to have an emotional impact on
the woman and on her partner. Many sexual difculties are automatically
blamed on the organic disruption caused by cancer and its treatments;
however, once any clearly indicated treatments have been given, in a sizable proportion of cases, the sexual difculty will remain unresolved.
Many sexual difculties are psychogenic, and no amount of skilled
clinical treatments will help if not linked closely to appropriate counselling, psychological, or psychosexual therapy. This form of intervention
will enable the woman to expose and reect on her sexual difculties,
in the context of her life and relationship not only since the cancer,
but beforehand. This is often a time when past problems, such as childhood abuse, or problems with her current partner will surface. Some
partners are disgusted by the physical impacts of cancer, and the relationship will suffer. On the other hand, some partners become more
supportive and the cancer leads to stronger relationships [36].
6.3. Psychosexual interventions
Classic psychosexual therapy, using brief, focused psychotherapeutic
techniques is the mainstay of treatment. It can be used with an individual or a couple, of any sexual orientation or cultural or religious background. This is a way of listening reectively to the patient, so that
they can gain their own insights into their sexual problem. The issue
of genital examination is considered if relevant, as it enables the
woman to connect with her genital area, and may trigger deep-seated
thoughts or anxieties that the woman had blocked emotionally. This,
of course, is a technique used only by clinicians who are qualied to examine the patient [37].
Clinical psychologists and counsellors trained in psychosexual work
also treat women with sexual problems. Globally, because the availability of trained personnel differs, many simple innovative treatment interventions have been tried. A brief intervention using a well-accepted
treatment, cognitive behavioral therapy (CBT), combined with sexual
health education had positive results on patients who had riskreducing salpingo-oophorectomy [21].
Psychosexual interventions work [38], and like all psychodynamic
interventions only require a trained counsellor and a means of allowing
access to the patient. The internet has enabled access to health care for
many people around the world who are not able to travel long and difcult land journeys to direct provision of health care. An online
S161
intervention with a professional moderator has proven acceptable to

gynecological cancer patients with a sexual difculty [39], and another
internet-based sexual difculties intervention with counselling sessions
proved more successful in improving sexuality issues than without a
counsellor; however, there was no difference between the two groups
in relation to emotional distress and quality of life [40]. Elsewhere, telephone interventions are being used, also with some success; however, it
is clear that the knowledge, skills, and training of the health professional
providing the intervention are relevant to the patient outcome.
Multidisciplinary care should form the backbone of treatment of
sexual difculties in women with gynecological cancer, incorporating
physical, psychoeducational, and psychosexual input. Team discussions,
including clinicians, psychosexual therapists, and physiotherapists are
well within the capabilities of many cancer centers, remembering that
the patient and her partner are the focal point and should always
be consulted.
7. Communication
It is impossible to diagnose and treat a sexual problem if one does
not acknowledge that it exists. Many studies in the past have identied
lack of willingness of doctors and nurses to discuss sex, but sadly recent
research has shown that not much has changed. For instance, in a cohort
sample of 1154 US obstetrician gynecologists, 60% did not ask patients about sexual problems [41]. Too often clinicians make value
judgements about their patients including whether sexuality is an important part of their lives. Such assumptions may include biases about
age, appearance, sexual preferences, and marital status of people who
have sex.
People with cancer and their partners have unmet sexual information
and support needs [42], often due to the unwillingness of healthcare professionals to discuss sexual issues, even though they recognize it may be
important to the patient.
There are many barriers to talking about sex, affecting both the patient and the clinician, such as cultural background, and age and gender
discrepancies between doctor and patient. There may be simple barriers,
such as lack of privacy in a consultation, as often cancer patients are accompanied by family or close friends. Patients often state that they feel it
is trivial to take up the doctors time with non-life-threatening issues
such as sex.
Clinicians often cite lack of training as a reason that they are uncomfortable talking about sex and poor provision of this training
has been noted [13]. Different models of communication skills
training have been used and those undertaking the training have
shown greater empathy and were more inclined to use open
questions [43]. This technique of speaking to the patient in an open
rather than interrogative manner can easily facilitate discussion of
intimate issues.
An even greater challenge in communication is the recognition that
individuals are sexual beings up to the end of life. To some women in the
palliative phase, sexual touch and closeness to their partner is of vital
importance. Sadly this is rarely recognized and addressed by palliative
care physicians [44].
8. Sexuality
It is important to remember that a minority of the female population
identies as lesbian, and that about 8% of the population is bisexual.
While this should make no difference to the quality of sexual health
care they receive, lesbians and bisexuals nd it difcult to disclose
their sexuality to clinicians, often inhibited by their cultural or religious
background, and fears of facing discrimination [45]. If the clinician asks
the patient at the outset if they have a sexual partner, and whether the
partner is male or female, it will greatly enhance the quality of the
doctor patient interaction. Lesbian partners in particular can be
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very supportive during the cancer journey, and should be given the opportunity to be present if the patient wishes.
9. Training
Despite the recognized need for treatment of sexual problems in
menopause and gynecological cancer, there is poor provision of specialist training to ensure that this important area of service provision is met
[46]. Undergraduate teaching is important, but it is only by recognizing
psychosexual medicine in formal gynecology or oncology training, as a
compulsory requirement of the course, that this situation will begin to
be addressed.
Innovative online programs [47] can make a major impact on global
training opportunities and give trainees around the world an opportunity to gain some skills and insight into treating sexual difculties in a
nonjudgmental way.
10. Psychosexual health care is a human right
Owing to the global prevalence of sexual problems associated
with gynecological cancer, it should be within every gynecologists
or oncologists duty of care to the patient to be aware of and have
some understanding of how to diagnose and facilitate treatment for
sexual problems in a nonjudgmental manner. This is true holistic
medicine, recognizing not only the cancer, but the woman behind
the symptoms, and requires awareness of the emotional, social, and
relationship aspects of the patients life. The ability of any person to
enjoy a sexual life free of coercion, shame, disease, or pain in a consensual manner is a fundamental element of the human rights of
women, and should be an unequivocally accepted as part of her gynecological cancer care.
To make a difference, even in the absence of expensive and sophisticated cancer treatments, just acknowledging, listening, and offering
support to the woman with sexual difculties related to cancer will ultimately have a major benet to her quality of life.
Conict of interest
The author has no conict of interest.
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Rehabilitation after gynecological cancer treatment

Katy Weare
Royal Womens Hospital, Melbourne, Australia
1. Introduction
The burden of disease and treatment effects from gynecological cancer can cause signicant distress in women as they begin to live longer
with a chronic disease. Even where there are good outcomes in terms of
cure, women have signicant rehabilitation requirements. Those
women entering the cancer survivor phase following treatment are likely to experience functional loss due to the physical and psychological effects of the disease, the treatment, and their personal processing of their
cancer experience.
Rehabilitation to mitigate the distress-causing symptoms is as
important a part of treatment as surgery, radiotherapy, or chemotherapy. For women with gynecological cancer we know that there is a complex interplay between the physiological and psychosocial symptoms,
which means that rehabilitation itself is often complex and requires
an integrative approach that treats the woman as a whole to achieve optimum success [1]. Rehabilitation is a key process within gynecological
cancer care that begins with sensitive and specic assessments to identify a womans functional level and the impairments that are impacting
upon it so that effective targeted interventions can be implemented [2].
The aim of rehabilitation is to assist a woman to achieve the best
possible level of function, to promote independence, and to adapt
themselves to a new normal [3,4]. In their 2013 qualitative study
interviewing women with gynecological and upper gastrointestinal
tract cancers, Sandsund et al. [3] found that nding a new normal was
an important aspect of their rehabilitation. This new state was attained
through a process of adjustment to the changes in themselves and
their relationships with others and the establishing new expectations
about their life as a cancer survivor. Within the eld of gynecological
cancer it is now recognized that measuring the success of treatment
by focusing on tumor response and survival is not sufcient and that
patient-reported outcomes that describe quality of life are clinically
meaningful [5].
2. Patient assessment
Increasing opportunities for rehabilitation to treat the complex
symptoms are now being recognized. Inevitably, though, these opportunities may be missed where poor communication and inadequate assessment of the woman following treatment occurs [6]. Outpatient
consultations can appear rushed, with women aware that the clinician
has limited time. In an environment where there is a focus on determining recurrence, symptoms may be missed, especially where they cause
embarrassmentsuch as sexual dysfunction, incontinence, or psychological distressand a patient may be reluctant to spontaneously report
their concern.
Gynecological cancer services that incorporate a screen and assessment tool within routine clinical practice allow women to identify and
communicate with their health provider the symptoms affecting their
well-being. Paul and Buschbacher [7] highlight the recommendation
in the Institute of Medicines report From Cancer Patient to Cancer
Survivor: Lost in Transition that assessment tools and screening instruments need to be systematically developed and evidence based. If they
are to be utilized in clinical practice, the tools also need to be practical,
and sensitive and specic to each patients cancer, symptoms, and functional needs. This creates the challenge that a tool developed to be sensitive and specic to the experience of women in one setting may not
necessarily meet the needs of women from another. For instance the
outcomes assessed by a tool designed in a high-resource country may
not be suitable to be used in a low-resource clinical setting.
The literature describes the development of a number of patient
outcome measures that have engaged women with gynecological
cancer to describe and prioritize their most concerning symptoms.
This engagement ensures that the measures are patient centered to
better detect the symptoms, grade the severity, and assist in determining the best rehabilitation interventions and if rehabilitation efforts
have been effective over time [5,6]. The QuESTGY assessment tool [8]
was developed in the UK for all gynecological cancer patients receiving
outpatient chemotherapy to reect actual clinical practice. It was developed by comparing issues raised by women in oncology consultations
and those issues in existing validated instruments. Subsequent interviews with women with gynecological cancer and cancer clinical
experts allowed the items to be prioritized. One important domain
that has an impact on quality of life and is amenable to rehabilitation efforts is sexual function. Interviews with clinicians conrmed their concerns about assessing sexual dysfunction; however, patient interviews
endorsed this as a signicant issue that should be included on assessment tools, albeit with a clear option for the recipient to leave blank if
desired [8].
The NFOSI-18 tool [5] was developed in the USA for use in clinical
practice and specically assesses patient-reported outcomes for
women with ovarian cancer. Again, the measures in this tool were
derived by a series of interviews with women with ovarian cancer and
oncology clinicians. Jensen et al. [5] promote that the NFOSI-18 tool is
likely to be more sensitive to identifying the physical, functional,
and psychosocial symptoms associated with ovarian cancer and the
K. Weare / International Journal of Gynecology and Obstetrics 131 (2015) S164S166
S165
treatment modalities, and better able to assess improvements in these

in response to rehabilitation interventions.
disappointed that their treatment was not over, which resulted in a negative attitude to the therapy.
3. Information needs
3.3. Tailored information
The continuous changes in symptoms as they transition through

treatments and disease progression can leave women distressed by
the uncertainty and unpredictability in their lives. A signicant strategy
within any rehabilitation program or intervention is to facilitate patients having a sense of control, which can prove a great coping mechanism and motivation to adhere to a rehabilitation intervention [9].
Information about what to expect, who they can contact, and resources
available to them is integral to self-management and regaining control
over their health [10,11]. The information they receive with regard to
their symptoms and the rehabilitation strategies to address them
needs to be consistent, timely, and tailored to the individual [12].
Bonner et al. [14] interviewed women to assess their perception of

vaginal dilator use and found that many women believed it would
have been benecial to receive a separate consultation with a nurse
about how to manage this therapy so that they were not overloaded
with information and would have an opportunity to discuss their particular concerns. Cullen et al. [13] stressed that the implementation of vaginal dilator therapy for a woman requires an understanding of her
relationship with her body and her sexuality in order to understand
her acceptance of it as therapy. A discussion that directly addresses
any embarrassment or emotional issues associated with the symptom
or the rehabilitation therapy can assist the woman to change her perceptions and values of the treatment; in the case of vaginal dilators
she may come to see it as part of her ongoing medical treatment rather
than as a sexual aid [13,14].
The intervention described by Schoeld et al. [9], to address the
psychosocial needs of women undergoing radiotherapy utilizing a
nurse-led tailored consultation together with peer support to deliver
information and self-care strategies to optimize their recovery, exemplies these principles. Nurses providing consultations to deliver an
evidence-based intervention receive training in key areas including
communication, psychosexual care and rehabilitation, patient education, and distress management. This intervention is to commence
prior to acute treatment to assist a patient to prepare for treatment,
but also to discuss vaginal health and psychosexual rehabilitation and
incorporating coaching and practice of self-care strategies. Subsequent
nurse-led consultations during and on completion of treatment consolidate this teaching and support the patient with further exploration of
the womans individual experience. The woman is provided with a documented survivorship care plan describing the diagnosis and treatment,
follow-up plan, and description of adverse effects and their management. A nal telephone consultation with the nurse two weeks after
completion of the treatment seeks to address the sense of abandonment
often described by women at this time. The nurse discusses with the patient their experience of utilizing self-care strategies including use of
vaginal dilators to promote optimal rehabilitation [9]. The effectiveness
of this program to deliver timely and tailored information, psychosocial
support through treatment, and engagement with vaginal dilator therapy is currently being studied in a randomized controlled trialthe
PeNTAGOn studycomparing it with usual care [9].
3.1. Consistency of information

Issues of consistency of information are often highlighted by authors
describing rehabilitation to prevent vaginal stenosis after pelvic radiotherapy [1214]. Miles and Johnson [15] in their 2014 update of a
Cochrane Review into vaginal dilator therapy concluded that there is
no reliable evidence supporting dilator therapy during radiotherapy
treatment, and while several observational studies of dilator therapy
after radiotherapy treatment suggest an association between frequent
dilator therapy and a reduction in self-reported stenosis, they acknowledge that there is no proof that a decrease in stenosis is an effect of the
dilator therapy. With no clear evidence as to the benet of a rehabilitation therapy, there is inevitably a range of recommendations and advice
given to patients [14].
Where advice is inconsistent a woman may struggle to motivate herself to comply with an intervention that she may perceive to be unpleasant. A number of clinical practice guidelines for vaginal dilator therapy
have been developed, which is important to ensure consistency of advice within an organization. Bakker et al. [12] in the development of a
guideline were motivated by the need to gain a consensus on recommendations for patients as to timing after completion of radiotherapy;
how to practice dilator therapy including duration, frequency, and size
of dilators; how information may be tailored to specic patient groups;
and nally who is most appropriate to deliver counselling and support
for this intervention [12].
3.2. Timing of information
4. Control and self-management

Many authors argue that it may be appropriate to deliver information about rehabilitation prior to acute treatments [13]. Juraskova
et al. [16] examined sexual adjustment following treatment for cervical
and endometrial cancer and argued that the advantage in raising issues
of sexuality and sexual dysfunction prior to commencement of treatment is that it lays the foundation for subsequent consultations and
ensures that the patient is not unprepared for symptoms impacting on
their sexuality and body image. In their interviews of women they
identied that women were better able to cope with planned treatment
procedures for which they had been prepared for compared with unexpected symptoms. They proposed that the patients coping was affected
by their sense of control that came from being aware and prepared for
an event [16].
Cullen et al. [13] interviewed women to understand their perspectives on vaginal dilator therapy and one of their care recommendations
was to introduce the vaginal dilator early on in treatment. Women revealed that if vaginal dilator therapy was mentioned prior to commencement of radiotherapy it was not discussed sufciently for
them to remember the plan for this rehabilitation therapy following
treatment. Those women who were unprepared for this next step felt
Rehabilitation interventions are designed to maximize the ability of

a woman to gain control and self-management over her health. Rehabilitation interventions should not just focus on what health-related
behavior is required, such as exercise, pelvic oor training, or vaginal dilator therapy, but also on the development of the womans ability to
self-manage. This sense of control can be extremely motivating, which
makes adherence to a rehabilitative regime much more likely. Donnelly
et al. [17] reported on womens experience of participating in a homebased physical activity intervention randomized controlled trial and
found that a patients own motivation was an important determinant
of their compliance with an exercise intervention. The design of
home-based interventions allows women from rural and regional locations to participate, and also gives the woman control of when and how
she engages in her own rehabilitation [17].
Motivation is fed by the ability to see the results of the intervention;
thus, it is important that measurable results that can be given to the patient are part of the design of a rehabilitation strategy. For a woman to
maintain long-term vaginal dilator therapy she can be motivated to continue if at consultation she feels that the examination is easier and the
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K. Weare / International Journal of Gynecology and Obstetrics 131 (2015) S164S166
clinician advises her about stenosis [14]. Those engaged in an exercise

program to improve their health, performance status, and symptoms
of fatigue may be motivated by objective measures of their improved
ability using pedometers and diarizing their progress [18]. Including
feedback into rehabilitation therapy can be reassuring of improvements
when it is positive and motivational for greater efforts or compliance
when the feedback shows that further improvement is possible. Of
course there are some for whom negative results can be demoralizing
and demotivating, therefore it is important that feedback is given sensitively with counselling and support available to the woman.
Peer support is also reported by many women as an effective component of rehabilitation therapies. The support and education provided
by the health professional can be enhanced by the provision of peer
support. For women with gynecological and upper gastrointestinal
tract cancer, Sandsund et al. [3] found that peer support offered these
women understanding and empathy that they appreciated on a practical and emotional level as it was sought by that individual at a time
when the participant was receptive to exchange or receive support
[3]. In their design of a rehabilitation intervention during and after radiotherapy, Schoeld et al. [9] used a multimodal design that incorporates nurse and peer-led support. In this intervention a peer contacts
women after they have had a consultation with the nurse before, during,
and on completion of radiotherapy and during the immediate recovery
period. The peers role is to provide psychosocial support allowing the
patient to describe their story and to assist them in normalizing this.
They are also trained to appropriately reinforce information about the
self-care strategies and to refer back to the nurse where required [9].
Signicant psychosocial distress is known to be experienced by
those living with cancer, but for women with gynecological cancer
there can be further impacts on their sexuality, body image, and social
relationships, which are compounded by issues of menopause, fertility,
bowel and bladder function, and sexual dysfunction. As women face an
anxious and uncertain future following treatment, the psychological impact of the disease and treatment may be more apparent in the survivorship phase [3].
Anxiety and lack of control play on each other, which affects the patients perception of the symptoms and capacity to adapt and nd a new
normal [3]. In their interviews with women with ovarian cancer, Jensen
et al. [5] identied that several psychosocial symptoms were prioritized,
including worry that their health would get worse, and their ability to
sleep well and to enjoy life. Increasingly this complexity is recognized
by looking at symptom clusters rather than at each symptom in isolation. Lopez et al. [19] took a qualitative approach using patient narratives over four time points to identify symptom clusters in women
with gynecological cancer. The most common symptom cluster was fatigue, sleep disturbance, pain, and depression [19].
Gynecological cancer rehabilitation has started to include interventions that target this symptom cluster by utilizing exercise to achieve
psychological and physical benets for women. Donnelly et al. [17], in
a follow-up to their randomized controlled trial testing the feasibility
and efcacy of a home-based physical activity behavioral change
intervention, interviewed participants to gain an understanding of
their experience. While the physical symptom of fatigue showed
improvement at least initially by participation in exercise, it was psychological improvement that was experienced by all participants.
Recognizing this, and in response to the participants suggestions for improvement to the program, the authors propose a multidimensional intervention that offers more than an exercise program but also includes
supportive care strategies that address healthy lifestyle, coping with uncertainty, and social support needs [17].
5. Conclusion
Rehabilitation following treatment for gynecological cancer helps
women adjust to their changed condition by effectively preventing or
mitigating the symptoms related to their cancer and its treatment

[20]. Strategies that ensure sensitive enquiry within clinical practice
into the physical, psychosocial, and functional symptoms that women
with gynecological cancer nd most distressing are an important rst
step in facilitating recovery. Preparing the patient with timely, consistent, and tailored information addresses their anxiety about the unknown and can support them to take control of their lives again. The
development of multidimensional rehabilitation interventions that are
exible both in how and when they are undertaken and that treat the
patient as a whole by integrating the physical, psychosocial, and behavioral aspects of the symptom experience is the future for gynecological
cancer rehabilitation.
Conict of interest
The author has no conicts of interest to declare.
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Palliative care in gynecological cancer

Shelley M. Kibel a, Joanna M. Cain b
a
b
St Lukes Hospice, Cape Town, South Africa

University of Massachusetts Medical School, Worcester, MA, USA
1. Introduction
2. Therapeutic relationship: The cornerstone of care
According to the WHO denition, Palliative care is an approach that

improves the quality of life of patients and their families facing the problems associated with life-threatening illness, through the prevention
and relief of suffering by means of early identication and treatment
of other problems, physical, psychosocial and spiritual [1]. In addition,
Palliative care is required from early in the disease course, can be delivered alongside potentially curative treatment, and continues to include
end-of-life or terminal care [2].
The WHO denition highlights fundamental principles. It afrms
life and regards dying as a normal process; and intends neither to hasten nor postpone death [1]. It also emphasizes impeccable assessment as essential for effective management.
Palliative care cannot be left solely to primary or palliative care physicians or to nurses. It needs to be actively embraced by all providers including oncologists and other specialists and integrated into all areas of
medical care [3,4]. Oncology follow-up visits are the ideal place to introduce the concept and every decision about treatment should take palliative or quality of life considerations into account. Giving up curative
treatment does not mean giving up hope or concern, nor does an attempt
at curative treatment mean that palliative care should not be offered.
Discussions about end-of-life care, refusal of care, and advance planning
have cultural dimensions that require great sensitivity and thought, but
opening these discussions is critical to the best end-of-life care [5].
Palliative care is an approach that embodies compassion [6]. It is not
dependent on sophisticated equipment, expensive buildings, or technology, and can be applied in any setting. It can easily be offered in
resource-poor settings as well as in countries with highly developed
healthcare services.
In practice this depends on a signicant shift in focus. Many societies
avoid and fear aging, death, and dying. Huge advances in medicine have
fed the belief that medicine can rescue everyone. Medicine has a responsibility to explore and address these fears as well as embrace and
advocate for the best of palliative care.
Some 80% of countries globally have low or very restricted access to
strong pain medications [7]. Although morphine is the gold standard
and the cheapest drug available, it is still illegal or unavailable in many
countries [7]. The African Palliative Care Association and others are
working actively to change this [8].
In addition to end-of-life issues, gynecological cancer presents many
long-term problems related to disease and treatment [9]. Both aspects
require a palliative focus.
People have a deep need to be seen and heard. This in itself is therapeutic. Very often it is not what was said but how it was said that is remembered. Good communication depends on sensitivity, authenticity,
and genuine human relationship [10]. Healthcare providers need to
convey that they care and that they will be there for their patients whatever path they take. Patients can fear being abandoned if cure is no longer a possibility, and providing the security of a continuing relationship
with their trusted caregiver is a key component.
Dealing with death and dying requires us to constantly confront our
own fears. Physicians can struggle to overcome not only their teaching,
which emphasizes rescuing and curing, but also their own fear of disability and dying. Caring for the dying invites us to look at our own
lives, values, attitudes, and beliefs to care compassionately for the
scope of needs our patients encounter on their cancer journey.
3. Ethical Issues
Ethical issues relate to both patients and context of care. Our
primary ethical responsibilities are to benet (benecence) and not
harm (non-malecence) while making sure patients understand and
can choose among options for their care (autonomy). In palliative care
the treatment goals are primarily ameliorating symptoms, alleviating
pain and suffering, and helping patients understand the disease course.
These become our ethical measures for success. Care of symptoms and
attention to quality of life are goals regardless of the curability of the
cancer [11], and have been shown to improve quality of life and
mood, and even lengthened survival in some studies [11].
Preserving patient autonomythe ability to make authentic decisions regarding their own health careis essential, though often
difcult. Societal, religious, and familial pressures on patients and caregivers have the potential to overwhelm decision making. The classic
example of family demanding everything be done to save their
mother, while the mother wants to have no resuscitative measures
with her terminal disease illustrates how this tension can present.
Women are at the center of families and often make choices that benet
the family before themselvesdenying themselves adequate pain or
other care because of cost or inconvenience to the family. Our role is
to advocate for the patients best interests, including encouragement
to ask for what she wants and needs.
Globally, lack of access to adequate pain control, palliative care options such as radiation, or advanced pain control techniques create
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ethical challenges related to context of care. Regulations that limit access to narcotic pain management at the end of life are harmful to
patients. Providers must advocate actively for policies and just allocation of essential medication and palliative care support in every resource setting [12].
4. Interdisciplinary team work
Palliative care emphasizes whole person medicine and it is impossible for one person to do this alone. Effective palliative care depends on
good teamwork. As an ideal, the basic care team should consist of a doctor, professional nurse, and social worker. The team can benet from a
dietician, occupational therapist, physiotherapist, massage therapist,
and creative artists, as well as a gynecologic oncologist, a radiation oncologist, a radiologist, an interventional radiologist, a pain specialist
from hospice services, and/or a palliative care physician [13]. In many
settings this is not possiblebut engaging cross-disciplinary health
providers provides different perspectives, ideas, and approaches that
can benet patient care. Incorporating spiritual care into the team
helps address not only the patients but their familys and even the
teams need to nd meaning in the process of care and dying and
transcend suffering.
Constant exposure to death and dying can rapidly lead to provider
burnout unless the load is shared. Teamwork can be challenging and requires good leadership and constant review. Well implemented it greatly improves quality of care, stress, and work satisfaction. Poor team
work can contribute to burnout. Five essentials are: trust, two-way
communication, respect, roles, and responsibility. Additional qualities
of good team work include positive leadership and management;
personal rewards, training, and development; skill mix; supportive
team; clarity of vision; and respecting and understanding roles [14].
5. Pain control
As with most incurable cancers, pain control is the dominant issue
and must be addressed. Judicious use of narcotics, radiation, and
nonnarcotic pain remedies is essential [12].
The goal of pain control needs to be discussed. For example: is the
goal to preserve normal function and ability to workand what is required for that? Is it to provide relief from neuropathic pain? Each situation requires a unique approach that will often be multimodal [15].
Understanding pain type, acuity, inciting and diminishing factors is
key to pain management. Prior drug interactions and physical, mental,
and contextual status should all be reviewed initially and on an ongoing
basis (Table 1).
The axiom of pain control is to treat different types of pain differently. Pain from cerebral swelling with brain metastases includes corticosteroids to reduce swelling and enhance function, as well as analgesic
medications. Pain from abdominal swelling can benet from massage
for back strain (due to abnormal posture), abdominal massage, or heat
as well as analgesia. Neuropathic pain may require early medication,
massage, and physical therapy to improve function. Treatment of
anxiety may reduce the need for analgesics.
When medication is required, the WHO pain ladder [16,17] remains
the standard, with non-narcotic therapies at its base. If the management
plan is not meeting pain needs, then reassessment of all elements is
requiredbefore adding narcotic medications. Successful pain control
depends on around the clock base relief, together with rapid acting
breakthrough medication for intermittent increases in pain or desire
to increase activity (Table 2). Finally, it is important to anticipate, assess,
and manage any adverse effects of medication, in particular, constipation, nausea, and vomiting
In places without access to narcotic medications, pain management
(particularly for end-of-life care or acute cancer pain) is exceptionally
difcult and a tragedy for the patient and her family. Maximal use of
all available medication, liberal use of additional means of comfort
Table 1
Key elements to review in planning a pain management strategy.
Elements to consider
What is the goal of pain management? Functional level, desired sensory levels,
time specic goals such as a specic event.
Priority among goals
What is the type of pain?
Neuropathic, tissue damage, pressure,
musculoskeletal, inammatory
Duration, level, and modifying factors Constant, occasional, related to
movement, morning, evening, etc. Use a
scale to measure level of pain
Prior management programs that
Heat, cool, massage, physical therapy,
have been effective
types of pain medicines
Reactions to pain or psychotropic
Allergies, nausea, constipation, depression,
medicines
other adverse effects
Overall health that may impact
Depression, anxiety, or other psychiatric
choices for pain management
conditions; addictions; renal and hepatic
function; cenral nervous system function;
respiratory distress; physical performance
status; nutritional status; skin status
Contextual modiers
Lack of insurance, nances, or limitations;
religious beliefs regarding suffering; lack
of care givers; safety of home setting
(massage, heat, physical therapy, positioning), as well as ongoing advocacy for rational narcotic access to prevent suffering, become essential
parts of treatment [18].
6. Other symptoms
Each disease has its own unique picture. Symptoms may be disease
or treatment related. Treatmentoften has serious lifelong side
effects, including cystitis, proctitis, intestinal strictures, stulas, vaginal
agglutination/sexual dysfunction, and chronic pain [9].
Table 2
Elements of a cancer pain strategy.
Strategy
Treat different types of pain differently.
Use multimodal approach and
combine as needed.
Give the medication at regular intervals

Use the least invasive form of
administration available
Adjust to comfort and individual goals
Make liberal use of additional

supportive care
Anticipate adverse effects and plan

for them
Anticipate changes in needs
Neuropathic pain: anticonvulsants,

antidepressants, gabapentinoids,
transcutaneous stimulation.
Acute inammation: corticosteroids.
Anxiety and depression: anxiolytics and
antidepressants.
Tissue damage pain (nociceptive): scale of
anti-inammatory to narcotic medications.
Bone metastases/brain metastases:
consider local radiation therapy.
If available, for localized pain, blocks and
indwelling epidural analgesia.
Provide a base level of pain control and
accommodate for breakthrough pain.
Oral, topical (patches and creams),
sublingual forms preferred over
subcutaneous or intravenous forms.
The patient is the best judge of whether
pain control is meeting her goals, and
individual tolerance and needs vary widely
Consider the role that massage, heat,
meditation, physical therapy, positioning,
and alternative therapies (aromatherapy,
music therapy, etc.) and spiritual care can
play to assist pain and anxiety control.
Constipation, somnolence, nausea can all
accompany pain control and planning
ahead can improve outcomes.
Use a pain scale and follow over time, as
needs will change both up and down with
treatment or progression of disease
General management principles [19] are:
Appropriate assessment
Explanation to patient and family at all stages
Correct reversible factors
Consider disease-specic palliative therapy
Non-pharmacological interventions
Appropriate rst line treatment
Adjuvant or second line treatment
Regular review with involvement of the interdisciplinary teamor
more experienced clinician; plus
Essential medication in palliative care (Table 3).
Eating is a fundamental human experience and feeding people is a

natural way of showing care and support. Many family members struggle to accept that the patient no longer wants to eat and this causes signicant distress. If aiding the appetite will improve the patients quality
of life or the patient has specic short-term goals, then progestins or
steroids to stimulate appetite may be considered.
6.2. Edema and ascites
Edema is common in late-stage gynecologic cancers owing to low
protein and lymphatic blockage, and is difcult to treat. Regular lymph
drainage massage and limb wrapping or support stockings/sleeves
may assist comfort.
Ascites may require repeated drainage or an indwelling catheter, although this must be balanced against the additional loss of protein and
increase in edema that result. High-dose spironolactone (100400 mg
per day) with furosemide may improve ascites.
6.3. Nausea and vomiting
Common causes are mechanical bowel obstruction, infection, metabolic disturbance (including hypercalcemia), renal failure, and occasionally cerebral metastases [9].
Bowel obstruction is a frequent occurrence, especially with ovarian
cancer, but few patients are amenable to surgical intervention and
must be chosen carefully after balancing patient preference, likelihood
of surgical success, prognosis, and risk factors. A simple colostomy
with progressive pelvic cervical cancer may give relief quickly without
Table 3
Essential medication for palliative care.a
Requirement
Use
Medication
Pain
General
Paracetamol, tramadol, codeine,

morphine (a WHO essential medicine),
fentanyl.
Ibuprofen, indomethacin.
Gabapentin (neuropathic pain).
Lorazepam, diazepam.
Zolpidem, midazolam, haloperidol.
Amitriptyline, citalopram.
Laxatives (senna, liquid parafn,
glycerin and dulcolax suppositories,
eet enema).
Immodium, codeine.
Metoclopramide, hyoscine
butylbromide, haloperidol, 5-HT3
antagonists, steroids, proton pump
inhibitors
Dexamethasone, prednisolone.
Spironolactone, furosemide.
Adrenalin, cyklokapron.
Neuro-psychiatric
Gastrointestinal
Diarrhea
Nausea/vomiting
Other
Inammation
Fluid/ascites
Bleeding
a long surgical recovery time. Given the multiple sites of obstruction,

particularly with progressive ovarian cancer, surgery is rarely used.
Nasogastric tubes are discouraged because they are uncomfortable,
but nasogastric or percutaneous gastric tubes may be helpful when
other approaches are not helping [20]. Antiemetics and medications to
reduce intestinal output are available for subcutaneous, rectal, oral/
lingual, and intravenous use, and continuous or around-the-clock use
is the most effective approach.
Often people cannot tolerate the idea of not being able to eat. Even
in the presence of total gastric outlet obstruction, many patients prefer
to eat a little and are prepared to tolerate vomiting rather than stop
eating completely.
6.4. Constipation, diarrhea, fecal incontinence
6.1. Loss of appetite and fatigue
Bone pain
Neuropathic pain
Anxiety
Insomnia/restlessness
Depression
Constipation
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For more details see the IAHPC List of Essential Medicines for Palliative Care [22].
Constipation, whether disease or medication induced, is a major

cause of discomfort and suffering. Pain medication may complicate
management, and a laxative regimen should always be provided along
with these medications, assuming there is no obstruction. Regular assessment and repeated education sessions are necessary.
Diarrhea may be a short- or long-term consequence of treatment,
and treatment should be focused on the etiology. For example, simple
lactose intolerance after radiation or long-term narcotic-based regimens to repress bowel motility have different solutions.
Fecal incontinence has a major impact on quality of life, and bowel
regimens or rarely surgical diversion can help. For the most part, local
attention to hygiene and skincare provides the best palliation for this
symptom from surgery, stulas, or disease.
6.5. Incontinence, urinary retention, urinary tract infection
Urinary incontinence may result from spinal cord compression, sacral plexus involvement, bladder inltration, or stulas. Skin protection
using barrier creams is essential. Urinary catheters, suprapubic catheter,
or nephrostomy are considerations. Each of these comes with increasing
complexity of management for the patient and caregivers and may
be unaffordable.
Urinary tract infection is common, with or without catheterization
and should be actively checked and treated.
6.6. Vaginal discharge and bleeding
Evaluation of a new discharge is always warranted as it may represent fungal or bladder infection, which can be treated. Discharge from
tumor growth, bleeding, or stula is very upsetting to the patient and
her caregivers. Collaboratively developing a plan for hygiene and providing a sense of control, particularly with vaginal bleeding, facilitates
management and opens the door to further discuss progression of disease and expectations.
Minor bleeding wounds may respond to topical adrenaline.
Cyklokapron (tranexamic acid), radiotherapy, or occasionally interventional radiology-based embolization, if available, may be useful to stop
bleeding. Direct pressure may also assist, for example a vaginal pack
and use of Monsel solution or other topical agents for cervical cancer
bleeding. Symptomatic anemia can be treated with blood transfusion
if resources allow and if the benets in terms of symptom relief and
quality of life are of reasonable and ethical duration.
Hemorrhage as the nal event is one that can traumatize all who
witness it. In patients where this is a possibility, family members and
healthcare providers should be prepared.
6.7. Shortness of breath
Air hunger and shortness of breath may result from anemia, infection, pleural effusion, lung metastases, or heart failure. Diuretics are
S170
seldom helpful except in heart failure. Fanning, morphine, and oxygen

bring symptomatic relief, as does anxiety control.
Pleural drainage and pleurodesis may be helpful for comfort and to
prevent recurrence of a pleural effusion if the condition of the patient
warrants this.
6.8. Deep vein thrombosis
Prevention is preferred with passive or active movement. Sequential
compression devices and anticoagulant therapy need to be considered
in the context of the patients prognosis, quality of life, and living
conditions, and balanced against the risk of bleeding.
6.9. Psycho-spiritual
Anxiety, depression, fear, denial, loss of body image, sexual frustration, and insomnia are almost always present to some degree and can
signicantly impact on physical symptoms. Treatment approaches are
both pharmacological and non-pharmacological.
Gynecological cancer strikes deep to the core of what it means to be
a woman. It is hidden, private, deep-seated, and may be associated with
deep shame. Additionally, women try to avoid causing distress to their
families and one of the greatest challenges to their identity can come
from being the one needing care rather than being the care giver.
Great sensitivity is needed in handling these women.
Existential fear in the face of death cannot be avoided and is part of
the human condition, but the more open the discussion and the more
active the personal support, the more ease the patient may feel in the
transition. Denial may need to be more actively confronted when it interferes with proactive planning for future care of the patient or minors.
Spiritual support, essential and integral to holistic care, must be individualized according to the patients religion, culture, and belief system.
It cannot be imposed or directed by the caregivers views.
7. Social considerations
Detailed social assessment of needs, preferably with a social worker
is imperative. Particular attention should be given to nancial needs,
needs of children, care, legal issues and wills, unresolved family conict,
and future planning. Social problems are often the main cause of
anxiety. Sometimes simple assistance, like a letter to an employer, is
all that is needed.
8. Palliative care emergencies
Detailed discussion is beyond the scope of this article and can be
found in the references [21]. Extremely rapid treatment is needed in
the case of hemorrhage, hypercalcemia, superior vena cava syndrome,
and spinal cord compression, but we must still weigh the potential benets and harms particularly with patients for whom survival is already
expected to be short.
9. Pressure and wound care
Good care can prevent skin pressure ulcers. The sacrum and heels
are vulnerable areas in bed-bound patients and need frequent evaluation. Simple movement on a regular basis will assure pressure relief
and enable local circulation. Sheepskin or other boots and pads also
improve circulation.
Wound healing can be assisted by multiple means. Keeping wounds
clean and dry is the basis of care. Continuous vacuum dressings have
signicantly improved time to wound closure for open wounds and
may also be helpful in managing discharge from malignant skin lesions
(cutaneous metastases) where no further therapy is planned.
10. End-of-life care

Cultural, religious, and spiritual views determine how patient and
family view the information that death is approaching. Good timing
and sensitivity are imperative. Each family unit is unique and there
are no blanket rules but clear, honest, compassionate communication
is needed. People vary in how much they need and want to know.
Usually the patient knows what is happening and may or may not
want more information. Generally family members welcome honest
communication and frequent updates are vital. Even in the late stages,
include the patient in the discussion and do not assume that lowered
level of consciousness means lack of awareness or feeling.
Comfort is the major factor determining treatment decisions.
Physical and psycho-spiritual needs must be assessed regularly and
unnecessary medication and intervention discontinued. Common endof-life symptoms are pain, nausea, vomiting, agitation, and respiratory
difculty. When oral medication is no longer possible, sublingual, rectal,
and subcutaneous administration are options. A restless patient may
have urinary retention, which can be relieved. Impeccable and gentle
nursing care is imperative with special attention to turning, wet linen,
diapers, bowel, skin, and mouth care.
Grief is expressed in myriad ways, some of which can be disturbing
to the patient or others around her. Challenges can arise when religious
or cultural taboos forbid the discussion of death as a possibility, let alone
a probability. Some groups see it as a sin to give up hope or even to think
negatively. These beliefs can present major challenges to appropriate
planning and management. Wherever possible provide information
about the dying process, what to do in the event of death and the availability of bereavement support.
11. Conclusion
If the principles of palliative care are understood they can be integrated into all levels of health care and all levels of healthcare training.
The principles are not complicated and once the concept is embraced,
shifting focus from curative to palliative should ideally become as simple as watching the sun rise and the sun set. Palliative care requires
both the art and science of medicine and is a pressing universal need.
Conict of interest
The authors have no conicts of interest.
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4

Volume 131 Supplement 2 October 2015 ISSN 0020-7292

FIGO Cancer Report 2015

Official publication of FIGO

International Journal of Gynecology & Obstetrics

Volume 131, Supplement 2

FIGO Cancer Report 2015

International Federation of Gynecology and

FIGO Chief Executive

International Editions and Collaborations

Dr Rohit V. Bhatt (rohit.v.bhatt@gmail.com)

The Secretariat of FIGO is at FIGO House, Suite 3,

R.M. Adanu (Ghana)

T.R.B. Johnson (USA)

FIGO Staging of Gynecologic

L. Denny (South Africa)

FIGO Cancer Report 2015

CANCER STAGING AND CLINICAL GUIDELINES

Cancer of the vulva

N.F. Hacker, P.J. Eifel,

Cancer of the vagina

A. Bermudez, N. Bhatla, E. Leung

Cancer of the cervix uteri

F. Amant, M.R. Mirza, M. Koskas,

Cancer of the corpus uteri

J. Prat, 'N. Mbatani

J.S. Berek, C. Crum, M. Friedlander

Cancer of the ovary, fallopian tube, and peritoneum

H.Y.S. Ngan, M.J. Seckl,

Update on the diagnosis and management of gestational trophoblastic

P.S. Binder, J. Prat, D.G. Mutch

The future role of molecular staging in gynecologic cancer

Pathology of cancers of the female genital tract

M. Seoud, E.. Lundqvist,

Targeted therapy in gynecologic cancers: Ready for prime time?

S.K. Shrivastava, U. Mahantshetty,

Principles of radiation therapy in low-resource and well-developed

Psychosexual health in gynecological cancer

Rehabilitation after gynecological cancer treatment

S.M. Kibel, J.M. Cain

Palliative care in gynecological cancer

International Journal of Gynecology and Obstetrics 131 (2015) S75

Contents lists available at ScienceDirect

International Journal of Gynecology and Obstetrics

FIGO Cancer Report 2015

The FIGO Gynecologic Oncology Committee is pleased to present the

International Journal of Gynecology and Obstetrics 131 (2015) S76S83

Contents lists available at ScienceDirect

International Journal of Gynecology and Obstetrics

FIGO CANCER REPORT 2015

Cancer of the vulva

1.2.2. Histopathologic grades (G)

GX: Grade cannot be assessed

vulvar dystrophy. Bleeding or discharge is an occasional presenting

Tumor conned to the vulva

4.4. Clinical practice guidelines

4.1. Presenting symptoms

Union for International Cancer Control (UICC)

4.5.1. Treatment of vulvar intraepithelial neoplasia

Fig. 1. Vulvar staging diagram.

4.5.2. Invasive vulvar cancer

4.5.3. Microinvasive vulvar cancer (Stage IA)

excision. Groin dissection is not necessary for lesions of this type