ACOG

PRACTICE
BULLETIN
CLINICAL MANAGEMENT GUIDELINES FOR
OBSTETRICIANGYNECOLOGISTS
NUMBER 35, MAY 2002
(Replaces Committee Opinion Number 242, October 2000)

This Practice Bulletin was

developed by the ACOG Committee on Practice Bulletins
Gynecology with the assistance
of Benjamin E. Greer, MD,
and Wui-Jin Koh, MD. The information is designed to aid
practitioners in making decisions about appropriate obstetric and gynecologic care. These
guidelines should not be construed as dictating an exclusive
course of treatment or procedure. Variations in practice may
be warranted based on the
needs of the individual patient,
resources, and limitations
unique to the institution or type
of practice.
Reaffirmed 2010

Diagnosis and Treatment

of Cervical Carcinomas
Invasive cervical carcinoma, once the most common reproductive-tract cancer
in the United States, has recently fallen to the rank of third most common.
Globally, cervical cancer is a major health problem, with a yearly incidence of
371,000 cases and an annual death rate of 190,000 (1). The International
Federation of Gynecology and Obstetrics (FIGO) recently revised its staging
criteria. In addition, new evidence has documented conclusively that survival
rates for women with cervical cancer improve when radiotherapy is combined
with cisplatin-based chemotherapy. This document will describe staging criteria and treatment for cervical carcinoma. For practical purposes, it will focus
on the squamous and adenocarcinoma histologies only.

Background
Prevalence
The American Cancer Society estimated that 12,900 new cases of cervical cancer would be diagnosed in the United States in 2001 and that 4,400 deaths from
cervical cancer would result (2). Cervical cancer comprises approximately 16%
of the estimated 80,300 cases of reproductive-tract cancers among women in
the United States. Seventy-eight percent of cases occur in developing countries
where cervical cancer is the second most frequent cause of cancer-related death
in women. The substantial decrease in incidence and mortality in developed
countries is thought to be a result of effective screening.

Risk Factors
Human papillomavirus is considered the most important factor contributing to the
development of cervical intraepithelial neoplasia and cervical cancer. Countries with
a high incidence of cervical cancer also have a high prevalence of human papillomavirus (1). Other epidemiologic risk factors associated with cervical intraepithelial

neoplasia and cervical cancer include history of sexual intercourse at an early age, multiple sexual partners, sexually
transmitted diseases (including chlamydia), and smoking (3).
Additional risk factors include a male partner or partners
who have had multiple sexual partners; previous history of
squamous dysplasias of the cervix, vagina, or vulva; and
immunosuppression, such as after organ transplantation or
patients with acquired immunodeficiency syndrome.

Diagnosis
The signs and symptoms of early cervical carcinoma
include watery vaginal discharge, intermittent spotting, and
postcoital bleeding. Often the symptoms go unrecognized
by the patient. Because of the accessibility of the cervix,
accurate diagnosis often can be made with cytologic screening, colposcopically directed biopsy, or biopsy of a gross or
palpable lesion (4). In cases of suspected microinvasion and
early-stage cervical carcinoma, cone biopsy of the cervix is
indicated to evaluate the possibility of invasion or to define
the depth and extent of microinvasion. Cold knife cone biopsy provides the most accurate evaluation of the margins.

Histology
The two major histologic types of invasive cervical carcinomas are squamous cell carcinomas and adenocarcinomas. Squamous cell carcinomas comprise 80% of cases,
and adenocarcinoma or adenosquamous carcinoma comprise approximately 15%. The remaining cases are made
up of various rare histologies, which may have very different biologic behavior.

Management
Early carcinomas of the cervix usually can be managed by
surgical techniques or radiation therapy. The more
advanced carcinomas require primary treatment with radiation therapy. Many changes in radiation therapy techniques have occurred in the past decade. These include
incorporation of higher energy external beam equipment,
improved field design to cover anatomic regions at risk,
increased use of tomographic imaging, recognition of the
adverse impact of prolonged treatment, increased familiarity with high-dose-rate brachytherapy, and, more recently,
the use of chemotherapy concurrent with radiation therapy.

Clinical Considerations and

Recommendations

How are patients with cervical carcinoma

categorized or staged?

Staging of gynecologic cancers attempts to define the

anatomic extent of a given cancer. This allows for scien-

tific comparison of treatment results from different centers or protocols. The three major staging systems are
those of FIGO, the American Joint Committee on Cancer,
and the International Union Against Cancer. Cancer registries approved by the American College of Surgeons
use the American Joint Committee on Cancers TNM
(tumor, nodes, metastasis) staging system. However, the
scientific literature reports gynecologic oncology statistics using the FIGO system. It is recommended that the
FIGO system be used to facilitate comparisons of international data.
Staging of invasive cervical cancer with the FIGO
system is achieved by clinical evaluation. Other gynecologic cancers are staged surgically. The current FIGO
nomenclature for cancer of the cervix was first adopted in
1994 (5) (see box, Carcinoma of the Cervix Uteri: FIGO
Nomenclature).
Careful clinical examination should be performed on
all patients. Examinations should be conducted by experienced examiners and may be performed under anesthesia.
Pretreatment evaluation of women with cervical carcinoma
often can be helpful if provided by an obstetriciangynecologist with advanced surgical training, experience, and
demonstrated competence, such as a gynecologic oncologist. The procedure may be scheduled to occur at the same
time the patient is undergoing another procedure requiring
anesthesia. Once established, the clinical stage must not be
revised because of subsequent findings, even if the cancer
recurs. The box, Guidelines for Clinical Staging of
Invasive Cervical Carcinoma, identifies key points in staging disease. These guidelines are made up of examinations
generally available throughout the world. Strict adherence
to the rules for staging provides the framework for making
valid scientific comparison of results.
Various optional examinations, such as ultrasonography, computed tomography (CT), magnetic resonance
imaging (MRI), lymphangiography, laparoscopy, and fineneedle aspiration, are valuable for treatment planning.
Surgical findings provide extremely accurate information
about the extent of disease and will guide treatment plans
but will not change the results of clinical staging. The
occasional hysterectomy specimen with unsuspected
extensive invasive cervical carcinoma cannot change the
previously documented clinical stage.
While not required as part of FIGO staging procedures, in the United States, various radiologic tests are
frequently undertaken to help define the extent of tumor
growth and guide therapy decisions, especially in
patients with locally advanced disease (ie, stage IIb or
more advanced). Computed tomography of the abdomen
and pelvis is the most widely used imaging study. Early
evaluation of the efficacy of CT scans in detecting
paraaortic adenopathy noted a very high specificity

ACOG Practice Bulletin No. 35

Carcinoma of the Cervix Uteri: FIGO Nomenclature

Stage 0 Carcinoma in situ, cervical intraepithelial neoplasia Grade III
Stage I The carcinoma is strictly confined to the cervix (extension to the corpus would be disregarded).
Ia
Invasive carcinoma that can be diagnosed only by microscopy. All macroscopically visible lesionseven with
superficial invasionare allotted to Stage Ib carcinomas. Invasion is limited to a measured stromal invasion with a
maximal depth of 5.0 mm and a horizontal extension of not more than 7.0 mm. Depth of invasion should not be
more than 5.0 mm taken from the base of the epithelium of the original tissuesuperficial or glandular.
The involvement of vascular spacesvenous or lymphaticshould not change the stage allotment.
Ia1 Measured stromal invasion of not more than 3.0 mm in depth and extension of not more than 7.0 mm
Ia2 Measured stromal invasion of more than 3.0 mm and not more than 5.0 mm with an extension of not
more than 7.0 mm
Ib
Clinically visible lesions limited to the cervix uteri or preclinical cancers greater than Stage Ia
Ib1 Clinically visible lesions not more than 4.0 cm
Ib2 Clinically visible lesions more than 4.0 cm
Stage II Cervical carcinoma invades beyond the uterus, but not to the pelvic wall or to the lower third of the vagina
IIa
No obvious parametrial involvement
IIb
Obvious parametrial involvement
Stage III The carcinoma has extended to the pelvic wall. On rectal examination, there is no cancer-free space between
the tumor and the pelvic wall. The tumor involves the lower third of the vagina. All cases with hydronephrosis
or nonfunctioning kidney are included, unless they are known to be due to other causes.
IIIa Tumor involves lower third of the vagina, with no extension to the pelvic wall
IIIb Extension to the pelvic wall or hydronephrosis or nonfunctioning kidney
Stage IV The carcinoma has extended beyond the true pelvis, or has involved (biopsy proved) the mucosa of the bladder
or rectum. Bullous edema, as such, does not permit a case to be allotted to Stage IV.
IVa Spread of the growth to adjacent organs (bladder or rectum or both)
IVb Spread to distant organs
Benedet JL, Odicino F, Maisonneuve P, Beller U, Creasman WT, Heintz AP, et al. Carcinoma of the cervix uteri. J Epidemiol Biostat 2001;6:743

(96%) but low sensitivity (34%) (6). However, with technologic advancements leading to increased imaging resolution, accuracy of CT scanning has improved (7).
Recent experience has suggested MRI is as accurate as
CT in assessing nodal involvement and provides better
definition of the extent of local tumors within the pelvis
(7). Some investigators have advocated the use of lymphangiography as the standard for noninvasive assessment of retroperitoneal adenopathy, but a recent review
has shown that contemporary CT and MRI results are as
accurate as lymphangiography and are preferable given
that more information is provided on local tumor
infiltration (7). Early experience with a new imaging
modality, positron emission tomography (PET), shows
considerable promise in further increasing the accuracy
of noninvasive radiologic staging. The sensitivity of
PET has been reported to be 75%, and the specificity
92% (8).

ACOG Practice Bulletin No. 35

Guidelines for Clinical Staging of Invasive

Cervical Carcinoma
Examinations should include inspection, palpation,
colposcopy, endocervical curettage, hysteroscopy,
cystoscopy, proctoscopy, intravenous pyelography,
and X-ray examination of lungs and skeleton.
Conization of the cervix is considered a clinical
examination.
Suspected bladder or rectal involvement should be
confirmed histologically.
If there is a question about the most appropriate
stage, the earlier stage should be assigned.
Data from Benedet JL, Odicino F, Maisonneuve P, Beller U, Creasman WT,
Heintz AP, et al. Carcinoma of the cervix uteri. J Epidemiol Biostat
2001;6:743

How is stage Ib1 carcinoma distinguished

from stage Ib2?

Is surgical evaluation of cervical carcinoma

appropriate?

As discussed earlier, the results of surgical evaluation

should not influence the stage determined by using the
FIGO clinical staging system. However, it is well recognized that the presence of lymph node metastasis is the
most important adverse predictor of survival. Although

In 1994, FIGO revised its staging criteria, subdividing

stage Ib carcinoma of the cervix into stage Ib1 (4 cm in
diameter) and stage Ib2 (>4 cm diameter). When the
tumor is confined to the cervix, the size of the primary
tumor has been shown to have a significant impact on
survival rates in stage Ib cervical cancer, regardless of
primary treatment modality (9, 10). A large, prospective
Gynecologic Oncology Group surgicalpathologic study
demonstrated that in stage Ib carcinoma of the cervix,
tumor size of 3 cm or more was an independent adverse
prognostic factor for decreased disease-free survival (11).
Other independent risk factors in this study were capillary-space involvement and depth of cervical stromal
invasion. A large study of patients treated by radiation
therapy or radiation therapy followed by hysterectomy
demonstrated significantly better survival rates for
patients with stage Ib tumors of less than 4 cm in diameter than for those with tumors greater than 4 cm (12).
Another study demonstrated the effect of tumor size on
outcomes in patients treated with radiation therapy alone
(ie, without surgery or chemotherapy). Five-year diseasefree survival rates for women with stage Ib cancer were
100% for lesions less than 1 cm in diameter, 93% for
those 11.9 cm, 98% for those 22.9 cm, 83% for those
33.9 cm, and 76% for lesions of 4 cm or more (13).
Retrospective analysis has evaluated patients who
had radical hysterectomies and lymph node dissections
for stage Ib1 and Ib2 cancers of the cervix (14). Patients
with stage Ib2 disease had a significantly worse 5-year
survival rate (72.8%) when compared with those who had
stage Ib1 tumors (90%). Also, in this study, in 38.7% of
cases of stage Ib1 disease and 72.9% of cases of stage Ib2
disease patients received postoperative radiation therapy
for high-risk indications such as positive lymph nodes,
parametrial disease, positive surgical margins, and deep
stromal invasion involving the outer third of the cervix.
The high percentage of postoperative radiation required
in patients with stage Ib2 disease suggests that primary
radiation should be considered for these patients and may
be supplemented by surgical or radiologic evaluation to
assess retroperitoneal nodal status.

surgical evaluation of cervical cancer remains controversial, it is the best method of assessing nodal involvement.
Retroperitoneal surgical lymph node dissection of the
pelvic and paraaortic lymph nodes provides important
information about treatment planning and prognosis.
Patients with positive lymph nodes can have radiation
fields modified appropriately to cover areas at risk.
Resection of positive lymph nodes is thought to provide
therapeutic benefit (15, 16). Therefore, surgical evaluation allows individualization of therapy and may result in
better clinical outcomes.

How is microinvasive cervical cancer diagnosed and treated?

The concept of microinvasive carcinoma of the cervix as

a distinct clinical entity was introduced by Mestwerdt in
1947 (17). The premise for this specific diagnosis was to
define a subset of patients with early carcinomas of the
cervix who had a favorable prognosis. It is important to
remember these lesions are defined microscopically and
cannot be visualized on gross inspection. The appropriate
definition of this entity has been debated for more than
50 years. The main issues affecting the definition are the
maximum depth of stromal invasion, the significance of
lymphatic-vascular space invasion, tumor volume, and
confluence of the invasion pattern as related to the frequency of pelvic node metastasis, vaginal recurrence, and
ultimate survival. These prognostic factors are important
determinants of treatment necessary for the best survival
with the lowest morbidity and, in certain circumstances,
may influence decisions regarding preservation of the
uterus for future pregnancy.
The definition of microinvasive carcinoma of the
cervix was modified by FIGO seven times between 1961
and 1994, indicating a lack of universal consensus. This
section will focus on the rationale for the 1994 definitions and the treatment options based on the best available scientific data.
During the 1970s, the concept of volumetric measurements for early small cancers, rather than just unidimensional consideration of penetration depth, was
being developed. Estimation of volume is most accurate
by using the three largest diameters of the lesions. The
rigorous technique for volumetric assessment requires
examining up to 100 sections per cone specimen. This
labor-intensive process was not well accepted. Bidimensional planar measurements were recommended
without testing. In 1988, FIGO changed the definition of
stage Ia2 tumor to include a specified maximal depth of
invasion of 5 mm and a maximal horizontal spread of
7 mm. This was based on the presumption that the overall volume of the microcarcinoma should not exceed

ACOG Practice Bulletin No. 35

ACOG Practice Bulletin No. 35

7.8% rate of nodal metastasis and a death rate of 2.4%.

One study that included only lesions of less than 5 mm
depth found nodal metastasis when the lateral spread was
greater than 7 mm (23).
According to the FIGO criteria, patients with stage
Ia1 carcinoma could be treated with simple hysterectomy
without nodal dissection or conization in selected cases.
Those patients with invasion greater than 3 mm and no
greater than 5 mm (stage Ia2) should undergo radical
hysterectomy and pelvic lymphadenectomy (4, 22).
Although lymphatic-vascular invasion should not
alter the FIGO stage, it is an important factor in treatment
decisions. The risk of recurrence with lymphatic-vascular
involvement is 3.1% if the extent of invasion is 3 mm or
less and 15.7% if it is greater than 3 mm and no greater
than 5 mm (22). Therefore, the presence of lymphaticvascular invasion would suggest the need for more radical treatment to obtain the optimal outcome. Evaluation
in consultation with an obstetriciangynecologist with
advanced surgical training, experience, and demonstrated
competence, such as a gynecologic oncologist, often
helps to determine the extent of surgery needed and the
optimal use of adjunctive therapy.
Preservation of fertility has become increasingly
important as more women are delaying having families.
A treatment dilemma arises for women with cervical carcinoma who have not started or completed childbearing
but desire the option to become pregnant. For both ethical and medicallegal reasons, patients who opt for conservative management should fully understand the risks
involved. Recent reports have described the use of radical trachelectomy with or without lymph node dissection
(24, 25). This procedure should be considered experimental and may be carried out best in consultation with
an obstetriciangynecologist with advanced surgical
training, experience, and demonstrated competence, such
as a gynecologic oncologist.
Treatment of microinvasive squamous carcinoma of
the cervix deserves careful attention to details and individualization of therapy based on histologic evaluation.
The concept of microinvasive adenocarcinoma has not
been generally accepted.

350 mm3. One study concluded that a microcarcinoma

with a tumor volume of less than 500 mm3 generally was
not associated with metastasis (18).
The 1988 FIGO definition of 5 mm of depth for
stage Ia2 was in conflict with the Society of Gynecologic
Oncologists definition of 3 mm or less for microinvasive
disease, which had been used in the United States since
1974. In 1994, FIGO modified its definition of stage Ia1
to 3 mm or less of invasion. Currently, stage Ia1 is
defined as a depth of invasion no greater than 3 mm and
no wider than 7 mm, and stage Ia2 is defined as a depth
of invasion greater than 3 mm but no greater than 5 mm
and no wider than 7 mm. Lymphatic-vascular invasion
should not alter the stage.
Despite this background and these definitions, diagnosis of microinvasive squamous carcinoma of the cervix is
difficult. The FIGO staging guidelines presume the diagnosis will be made with a cone biopsy. Cold knife cone
biopsies may be more accurate than loop electrosurgical
excision procedure (LEEP) cones, because the margins are
very important. Cautery artifact, loss of tissue, and thermal
destruction account for the inaccuracy of information provided by LEEP specimens. In the United States, patients
with abnormal Pap test results undergo colposcopy and
biopsy for diagnosis. Colposcopic biopsies usually are performed before conization. The biopsy removes part of the
lesion and, therefore, alters the apparent depth of invasion
as seen on the cone specimen (19). Another potential problem in evaluation involves the accepted techniques of
pathologic study. After initial fixation in formalin, cone
biopsy specimens are divided into quadrants and step-sectioned. Maximal extent of horizontal spread could be
underestimated by this procedure. In addition, there are difficulties in interpretation of the histology by pathologists.
In two large studies that employed pathology re-review of
cases initially diagnosed as microinvasive cervical carcinomas, 4050% of the cases were excluded because they did
not meet the criteria for microinvasion (20, 21). In
2040%, no invasion was thought to be present, and in
67%, the depth of invasion was greater than 5 mm.
Understanding the concepts behind definition and
diagnosis of microinvasive carcinoma of the cervix is
important to understanding the biology and behavior of
the disease. A comprehensive review of the current literature found that nodal metastasis is the most consistent
and strongest predictor of survival for patients with early
invasive cervical cancers (22). There is a relationship
between depth of invasion and nodal metastasis.
Minimally invasive lesionsthose with invasion up
to 3 mmhave a lymph node metastatic risk rate of 1.2%
and a death rate of less than 1%. However, lesions greater
than 3 mm and no greater than 5 mm of invasion have a

How is early-stage (IbIIa) carcinoma treated?

Both treatment strategies for stage Ib and early-stage IIa

invasive carcinoma include 1) a primary surgical approach
with radical hysterectomy and pelvic lymphadenectomy or
2) primary radiation therapy with external beam radiation
and either high-dose-rate or low-dose-rate brachytherapy.
A review of collective observational experiences reported
in the literature demonstrates a 5-year survival rate of
8792% using either approach (26).

What is the role of adjuvant therapy following

primary surgery in early-stage carcinoma?

The identification of various pathologic risk factors, such

as lymph node metastases, following primary surgical
management of early-stage cervical cancer portends a
higher rate of relapse and decreased survival rates (28).
Historically, attempts to improve outcome mainly
focused on the role of adjuvant pelvic radiation therapy,

with inconsistent results. More careful analysis of patterns of failure following radical hysterectomy has led to
better stratification of patients into risk groups and incorporated testing of systemic chemotherapy agents in those
considered at high risk of distant failure (28).
Two randomized clinical trials have greatly
advanced our understanding of the role of postoperative
therapy in cervical cancer (29, 30). Patients with histologically documented extracervical diseasespecifically
those with pelvic nodal involvement, positive margins, or
parametrial extensionare treated with concurrent
pelvic radiation therapy and cisplatin-based chemotherapy. The use of combined adjuvant chemotherapy
and radiation therapy in these high-risk patients following primary surgery significantly improves relapse-free
survival and overall survival rates when compared with
radiation therapy alone (29).
Following radical hysterectomy, a subset of nodenegative patients who have a constellation of primary risk
factors (large tumors, depth of stromal infiltration, and
lymphovascular space involvement) may be defined as
having intermediate risk for relapse. For these patients,
adjuvant pelvic radiation therapy provides clear therapeutic benefit, with significantly improved relapse-free
survival rates when compared with those who had no further therapy. However, observation of improvement in
overall survival favoring patients who had radiation therapy awaits further statistical confirmation following maturation of the data (30).

Until recently, there have been no prospective randomized studies comparing surgery and radiation therapy. An Italian randomized trial provides information
about primary surgery and radiation therapy but does not
include the addition of concurrent or neoadjuvant
chemotherapy (27). This study compared radical hysterectomy and primary radiotherapy with adjuvant radiation therapy in high-risk surgically treated patients.
Stratification for stage Ib and Ib2 was included.
Pathologic findings indicated identical 5-year overall and
disease-free survival rates in the radiation therapy group
and the surgical group with tailored postoperative radiation therapy. Severe morbidity occurred in 28% of patients
in the surgery and postoperative radiation therapy group
and in 12% of patients in the radiation therapyonly
group (P = 0.0004). In this study, adjuvant radiation therapy after primary surgery was used in 54% of patients
with tumors measuring 4 cm or less and in 84% of
patients with tumor diameters greater than 4 cm.
Significant prognostic factors included tumor diameter,
positive lymphangiography, and adenocarcinoma histology as identified on univariate and multivariate analyses.
Although the two modalities were found to be similarly effective in the randomized trials, the rate and types
of complications differ. The preference of treatment
depends on the situation, the physicians input, and the
patients age, health, and tumor characteristics.
Those who favor radical surgery point out that it
leaves the vagina in more functional condition, while
radiation therapy results in a reduction in length, caliber,
and lubrication of the vagina. In premenopausal women,
ovarian function can be preserved with surgery. The surgical approach also provides the opportunity for pelvic
and abdominal exploration and provides better clinical
and pathologic information with which to individualize
treatment. Surgery may be preferred over radiation therapy in women who have diverticular disease, tuboovarian
abscess, or appendiceal abscess; have had prior radiation
therapy; have congenital pelvic located kidney; or are
psychotic or noncompliant. Proponents of radiation therapy advocate primary radiation to avoid surgical morbidity or mortality, risk of blood loss and transfusion, and
excessive anesthesia time.

How is late-stage carcinoma (IIb or later)

treated?

Historically, primary radiation therapy has been used to

treat patients with bulky or locally advanced cervical cancer. The approach generally consists of external beam
radiation to achieve primary tumor reduction and provide
coverage to the parametria and regional nodes at risk,
supplemented by brachytherapy to increase radiation
dose delivery to the central residual tumor. Earlier
attempts to improve outcome results from primary radiation therapy by the addition of agents such as hydroxyurea or hypoxic cell sensitizers met with mixed success.
Results from five randomized trials on cervical cancer have established the role of concurrent cisplatinbased chemotherapy and radiation therapy for high-risk
or locally advanced disease (29, 3134). The various
studies had different eligibility criteria, but in total
included a broad spectrum of clinical presentations: 1)
patients with locally advanced tumors for whom
chemoradiation represented primary therapy (three studies [31, 32, 34]); 2) bulky early-stage cancers in which
chemoradiation was delivered prior to adjuvant hysterec-

ACOG Practice Bulletin No. 35

tomy (one study [33]); and 3) postradical hysterectomy

cases with high-risk pathologic factors (positive lymph
nodes, positive parametria, positive margins) for whom
adjuvant chemoradiation was given (one study [29]). In
each of the five studies, a statistically significant survival
advantage was observed among patients who received
radiation therapy with a concurrent cisplatin-based regimen when compared with those who received radiation
alone or radiation combined with hydroxyurea. The dramatic 3050% reduction in the relative risk of death in
the five trials prompted a rare clinical announcement
from the National Cancer Institute stating that strong
consideration should be given to the incorporation of
concurrent cisplatin-based chemotherapy with radiation
therapy in women who require radiation therapy for
treatment of cervical cancer (35).
The five reported studies used cisplatin administered either weekly as a single agent or in combination
with infusion 5-fluorouracil every 34 weeks (29,
3134). Although the optimal cisplatin-based chemotherapeutic regimen has not yet been fully defined, many
are choosing to use weekly cisplatin because of its ease
of delivery and favorable toxicity profile (36). However,
it is clear that the previously controversial use of hydroxyurea can be abandoned. Furthermore, it should be
remembered that the advantages of chemoradiation are
obtained only in the setting of concurrent therapy.
Neoadjuvant chemotherapy prior to radiation therapy
has shown no benefit and has even been detrimental in
some cases.
The cumulative results from the recently reported
randomized trials represent a major advance in the management of women with cervical cancer and have established a new paradigm for therapy. At present, women
with locally advanced cervical cancer in North America
should receive cisplatin-based chemotherapy concurrent
with radiation therapy.

Should squamous cell cancer and adenocarcinoma be treated differently?

ACOG Practice Bulletin No. 35

Underlying this question is the continuing debate regarding the independent prognostic implications of adenocarcinoma versus squamous cell histologies in cervical
cancer, especially in early-stage disease. Two large
reviews reflect the ongoing controversy. In an analysis of
813 patients with stage Ib cervical cancer entered into a
Gynecologic Oncology Group surgicalpathologic
study, excluding patients with positive paraaortic nodes
or gross extracervical disease, three specific cell types
were identified (645 squamous cell, 104 adenocarcinoma, and 64 adenosquamous). No significant differences
were found among the cell types with regard to the

patients age at presentation, performance status, pelvic

nodal metastases, depth of cervical invasion, uterine
extension, surgical margins, or parametrial infiltration.
Relapse-free survival rates were similar for all three histologies, but adenosquamous cell was associated with a
small, statistically significant reduction in overall survival, even after adjusting for associated pathologic risk
factors (37). In contrast, a retrospective review of 1,767
stage Ib cervical cancer patients who were clinically
staged and treated with primary radiation therapy identified adenocarcinoma histology (including adenosquamous cell types) as an independent risk factor for disease
recurrence and death, with distant metastases the primary site of failure (38, 39).
Despite the ongoing discussion regarding cell type
and prognosis, there is no evidence to support differences in treatment of invasive squamous cell cancer versus adenocarcinoma of the cervix. The only exception to
this is the management of microinvasive disease, where
guidelines have been developed for more conservative
management of patients with FIGO stage Ia1 squamous
cell cancer, corresponding with the Society of
Gynecologic Oncologists working definition for minimally invasive tumors discussed previously. It should be
emphasized that no definition for microinvasive adenocarcinoma of the cervix has been agreed upon; therefore,
treatment algorithms for such patients remain undefined.
For patients with frankly invasive disease, regardless of squamous cell or adenocarcinoma histology, the
primary options for treatment are radical hysterectomy
with lymphadenectomy or definitive radiation therapy.
In patients undergoing primary surgery who have positive nodes, positive margins, or parametrial infiltration,
adjuvant radiation concurrent with cisplatin-based
chemotherapy is indicated on the basis of positive results
from a randomized trial (29). In this trial, the addition of
chemotherapy to radiation appeared to overcome the
worse prognosis associated with adenocarcinoma cell
components, when compared with patients receiving
adjuvant radiation therapy only (29). For more advanced
disease in which primary radiation therapy is recommended, the addition of concurrent cisplatin-based
chemotherapy provides clear therapeutic benefit (35).

How should patients be monitored over the

long term?

Surveillance after primary therapy for invasive carcinoma of the cervix is universally recommended.
Approximately 35% of patients will have persistent or
recurrent disease. The main goal of surveillance is early
detection of recurrent disease so that patients can be
offered potentially curative salvage therapy. The average

1-year survival for patients with recurrent cervical cancer is 1020% (39, 40). Surveillance schedules should
take into account the risk of recurrence, which is highest
in the first 2 years following treatment (41). The potential benefit of salvage therapy depends on the stage of
disease, type of treatment, and location of recurrence (ie,
local, regional, or distant). In general, radical radiation
therapy is used for recurrent cervical cancer after primary hysterectomy, while salvage surgery is required for
those who relapse after primary radiation therapy. In
selected patients with centralized pelvic recurrences, salvage may be achieved in about 50% of cases (42).
Few studies have specifically addressed the efficacy
of routine surveillance follow-up after definitive cervical
cancer therapy in asymptomatic and disease-free
patients, as opposed to symptom-based reassessment.
Schedules for posttherapy surveillance vary by practitioner and institution, although a common approach
includes examinations and Pap tests every 34 months
for the first 3 years, decreasing to twice yearly in the
fourth and fifth years (4).
Investigators recently attempted to develop an optimal surveillance program based on outcome analysis
following primary therapy for stage-Ib cervical cancer
(43). Detection of asymptomatic recurrences, whether
locally in the pelvis or with isolated pulmonary metastases, led to significantly better salvage options and survival when compared with detection only in patients
presenting with symptomatic recurrences. The authors
concluded this subset of patients may benefit from careful posttherapy surveillance and proposed a schedule
involving thrice-yearly follow-up visits for the first 2
years, and twice-yearly visits subsequently to year 5,
with Pap tests and chest X-rays on a yearly basis.
Posttreatment follow-up also is beneficial for reasons other than the diagnosis of recurrence. The psychologic support and reassurance of continued contact with
the treating team is vitally important. Annual health
maintenance visits for mammography, blood pressure,
and evaluation of other medical problems are important.
Many of these patients undergo bilateral salpingooophorectomy or radiation therapy, and hormone
replacement therapy should be considered in such
patients. Cervical adenocarcinoma is not a contraindication to hormone replacement therapy.

How should patients with invasive cancer

diagnosed during pregnancy be treated?

Between 2.7% and 3.5% of cases of cervical cancer

occur in pregnant women (44). The diagnosis of invasive
carcinoma during pregnancy presents a therapeutic
dilemma. Fortunately, cervical cancer rarely causes

maternal mortality (45). The survival rate of patients

with stage I cervical cancer is excellent regardless of the
time of diagnosis during pregnancy, with recent reported
survival rates of 85% and 95% (46, 47). The overall survival rate for women who were pregnant and had invasive cervical cancer is 80% (48).
This clinical problem requires attention to the health
of the woman as well as the safety of the fetus. The
appropriate treatment is influenced by ethical concerns,
cultural and religious issues, and whether the patient
wishes to continue the pregnancy after being informed of
the potential risks and benefits of treatment. Optimal
counseling and therapy require an interdisciplinary
approach.
Therapeutic recommendations for a patient with
invasive cervical carcinoma are individualized according
to the patients presenting stage, lesion size, and desire to
continue the pregnancy. Pregnant women are 3.1 times
more likely than nonpregnant women to have diagnosed
Stage I disease, probably because of regular examinations (48). A summary of the current literature confirmed
that most patients with cervical cancer diagnosed during
pregnancy have stage I cancer (49). Seventy-six percent
have stage Ib, and 78% have squamous cell histology.
Pregnancy offers an ideal opportunity for cervical
cytologic screening. Figure 1 provides a general algorithm for the evaluation of abnormal cervical cytology in
pregnancy (50). A pregnant patient with carcinoma in
situ and microinvasive squamous carcinoma of 3 mm or
less can deliver vaginally and be reevaluated and treated
at 6 weeks postpartum.
Pregnant patients with invasive carcinoma of the
cervix may choose early termination or choose to continue the pregnancy. Those who have a mature fetus at the
time of diagnosis also may wish to delay treatment. If the
patient opts to continue the pregnancy, predelivery
assessment of fetal lung maturity by amniotic fluid analysis should be strongly considered, taking into account the
availability of neonatal support to optimize fetal outcome
and to avoid the potentially severe complications of prematurity, both in the neonatal period and in long-term
development (5154). Even those patients with earlystage disease should be aware that delaying treatment
carries an undefined, but likely small, risk of disease progression. However, delaying treatment to optimize fetal
maturity provides a major, quantifiable benefit for the
infant. All of the studies reporting outcome when treatment is intentionally delayed to optimize fetal outcome
suggest no measurable increased maternal risk (49). The
studies included 77 patients with early-stage cervical cancers who opted to delay treatment for 140 weeks. The
recurrence rate was 5% (4 of 77), which is similar to that
in nonpregnant patients.

ACOG Practice Bulletin No. 35

Abnormal cervical cytology

Colposcopy
Directed biopsy
No endocervical curettage

Cervical intraepithelial neoplasia

Microinvasive
squamous
carcinoma

Invasive carcinoma

Malignant
cytology
suggesting
invasion

Diagnostic
conization or
wedge biopsy
of cervix

Appropriate
therapy

Abnormal
cytology
without
suggesting
invasion

Papanicolaou test
and colposcopy
every 8 weeks

Microinvasion
3 mm

Anticipate vaginal delivery

Invasive
carcinoma

Figure 1. Evaluation of the

patient with abnormal cytology
during pregnancy. (Hannigan
EV. Cervical cancer in pregnancy.
Clin Obstet Gynecol 1990;33:
837845)

Appropriate
therapy

Reevaluate 6 weeks postpartum

The mode of delivery for those patients who choose

to delay treatment to allow fetal maturation remains controversial. Patients with small-volume, early-stage
lesions may be candidates for vaginal delivery. Whether
vaginal delivery promotes disease progression is not
clear. If possible, the patient should give birth by cesarean delivery at the time of planned radical surgery, and
vaginal delivery should be reserved for those patients
with preinvasive disease or stage Ia invasive disease with
planned postpartum fertility-sparing therapy. Intuitively,
it is prudent not to attempt vaginal delivery of women
with large or friable tumors, given the risk of obstructing
the progress of labor or the risk of bleeding with potentially life-threatening hemorrhage that might require
emergency hysterectomy under less than optimal circumstances.
The available literature includes reports of 10 cases
of implantation of malignancy at the episiotomy site
(5557). Posttreatment follow-up should include inspection and palpation of the episiotomy site. Treatment of
recurrent disease in the episiotomy consists of excision
followed by radiation.
For early-stage cervical cancer during pregnancy,
radical surgery and radiation therapy offer similar cure
rates. Radical hysterectomy with lymphadenectomy for
stage Ia2 to IIa cervical cancer during pregnancy has
demonstrated low associated morbidity, high survival

ACOG Practice Bulletin No. 35

rates, and an opportunity for preservation of ovarian function (49). Gestational edema and more pronounced cleavage planes facilitate the dissection.
When radical cesarean hysterectomy is performed, a
classical uterine incision is preferred. Bilateral ovariopexy is a reasonable consideration at the time of surgery
in the event that adjuvant radiation might be indicated
for patients with high-risk histopathologic features.
Results of a casecontrol study comparing radical surgery outcomes in pregnant and nonpregnant patients
demonstrated a higher blood loss in pregnant patients,
but this did not translate into a significant increase in
blood transfusion, operative morbidity, or major complication rates (58). Survival was 97% in the pregnant
patients and 90% in the controls, with mean follow-up
over 140 months.
Most pregnant patients who are candidates for radical surgery will benefit from surgery rather than radiation therapy, given the advantage of ovarian preservation
and the avoidance of radiation-associated vaginal fibrosis. Pregnant patients with stage IIb or more advanced
invasive cervical cancer and patients either not medically fit or not interested in primary surgical treatment
should undergo definitive radiation therapy. Patients
with advanced disease who elect to delay treatment
should have documented fetal pulmonary maturity prior
to classic cesarean delivery and should start their radia-

The following recommendations are based on

good and consistent scientific evidence (Level A):

For stage Ib and selected IIa carcinomas of the

cervix, either radical hysterectomy and lymph node
dissection or radiation therapy with cisplatin-based
chemotherapy should be considered. Adjuvant radiation therapy may be required in those treated surgically, based on pathologic risk factors, especially in
those with stage Ib2 carcinoma.

Stage IIb and greater should be treated with external-beam and brachytherapy radiation and concurrent cisplatin-based chemotherapy.

The following recommendations are based on limited or inconsistent scientific evidence (Level B):

10

For stage Ia1 microinvasive squamous carcinoma of

the cervix, treatment with conization of the cervix or
simple extrafascial hysterectomy may be considered.
Stage Ia2 invasive squamous carcinoma of the
cervix should be treated with radical hysterectomy
with lymph node dissection or radiation therapy,
depending on clinical circumstances.
Stage Ib1 should be distinguished from stage Ib2
carcinoma of the cervix because the distinction predicts nodal involvement and overall survival and
may, therefore, affect treatment and outcome.
Patients with squamous cell cancers and those with
adenocarcinomas should be managed similarly,
except for those with microinvasive disease. Criteria
for microinvasive adenocarcinomas have not been
established.

Following treatment for cervical carcinoma, patients

should be monitored regularly, for example, with
thrice-yearly follow-up examinations for the first 2
years and twice-yearly visits subsequently to year 5,
with Pap tests annually and chest X-rays annually
for up to 5 years.

Summary

The following recommendations are based primarily on expert opinion and consensus (Level C):

tion therapy postdelivery following uterine involution.

Pelvic and paraaortic lymph node dissection can be performed at the time of cesarean delivery to aid treatment
planning.
Planning radiation treatment for pregnant patients
with cervical cancer requires careful adaptation to adjust
for the anatomic distortion created by the gravid state.
Patients opting for primary radiation therapy with the
intent of pregnancy termination should begin with external-beam therapy. It is common for the pregnancy to
abort spontaneously when the woman is irradiated with
less than 4,000 cGy of external-beam radiation. In one
series, however, 27% of 45 patients did not abort and
required subsequent surgical uterine evacuation (58).

Treatment for pregnant patients with invasive carcinoma of the cervix should be individualized on the
basis of evaluation of maternal and fetal risks.

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The MEDLINE database, the Cochrane Library, and

ACOGs own internal resources and documents were used
to conduct a literature search to locate relevant articles published between January 1985 and December 2000. Priority
was given to articles reporting results of original research,
although review articles and commentaries also were consulted. Abstracts of research presented at symposia and
scientific conferences were not considered adequate for inclusion in this document. Guidelines published by organizations or institutions such as the National Institutes of
Health and the American College of Obstetricians and
Gynecologists were reviewed, and additional studies were
located by reviewing bibliographies of identified articles.
When reliable research was not available, expert opinions
from obstetriciangynecologists were used.
Studies were reviewed and evaluated for quality according
to the method outlined by the U.S. Preventive Services Task
Force:

Copyright May 2002 by the American College of Obstetricians and Gynecologists. All rights reserved. No part of this
publication may be reproduced, stored in a retrieval system, or
transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without prior
written permission from the publisher.
Requests for authorization to make photocopies should be
directed to Copyright Clearance Center, 222 Rosewood Drive,
Danvers, MA 01923, (978) 750-8400.
ISSN 1099-3630
The American College of Obstetricians and Gynecologists
409 12th Street, SW, PO Box 96920
Washington, DC 20090-6920
Diagnosis and treatment of cervical carcinomas. ACOG Practice
Bulletin No. 35. American College of Obstetricians and Gynecologists.
Obstet Gynecol 2002;99:855-867

Evidence obtained from at least one properly designed randomized controlled trial.
II-1 Evidence obtained from well-designed controlled
trials without randomization.
II-2 Evidence obtained from well-designed cohort or
casecontrol analytic studies, preferably from more
than one center or research group.
II-3 Evidence obtained from multiple time series with or
without the intervention. Dramatic results in uncontrolled experiments also could be regarded as this
type of evidence.
III Opinions of respected authorities, based on clinical
experience, descriptive studies, or reports of expert
committees.
Based on the highest level of evidence found in the data,
recommendations are provided and graded according to the
following categories:
Level ARecommendations are based on good and consistent scientific evidence.
Level BRecommendations are based on limited or inconsistent scientific evidence.
Level CRecommendations are based primarily on consensus and expert opinion.

ACOG Practice Bulletin No. 35

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