Cancer Therapy Vol 3, page 243

Cancer Therapy Vol 3, 243-248, 2005

Update on cervical cancer

Review Article

Aaron C Han1,*, Maria Merzouk2, Richard Z Belch2

1

Department of Pathology,
Department of Gynecologic Oncology, The Reading Hospital Regional Cancer Center

__________________________________________________________________________________
*Correspondence: Aaron C Han, The Reading Hospital Regional Cancer Center, 6th Avenue and Spruce Street, West Reading, PA
19612; Phone: 610-988-8088; Fax: 610-988-5185; Email: HanA@ReadingHospital.org
Key words: cervical cancer, HPV biology, epidemiology and screening, Diagnosis
Abbreviations: carcinoma in situ, (CIS); computed axial tomography, (CT); Human papillomavirus, (HPV); lymphovascular space
involvement, (LVI); magnetic resonance imaging, (MRI); positron emission tomography-CT, (PET-CT); retinoblastoma, (Rb)
Received: 31 March 2005; Revised: 11 April 2005
Accepted: 12 April 2005; electronically published: April 2005

Summary
Cervical cancer is a significant cause of mortality worldwide in spite of recent advances with efficacious screening
methods. The role of human papillomavirus as the causative agent of cervical cancer is well established. In this
review, we examine the biology, epidemiology, diagnosis and treatment strategies for cervical cancer. We also
outline potential avenues for worldwide prevention of this disease, and potential therapeutic targets.

risk for neoplastic transformation (Baseman and Koutsky,

2005). It is widely accepted that with persistant infection,
and integration of the HPV genome into the host DNA is
the background in which carcinogenesis occurs (Ferenczy
and Franco, 2002). HPV proteins encoded by E6 and E7
genes interact with cellular proteins including p53 and Rb
gene, respectively, which regulate cell cycle, and
presumably this pathway is involved in cervical
carcinogenesis (Munger et al, 1992; Giarre et al, 2001).

I. Introduction
Cervical cancer continues to be a significant public
health problem. It is the second leading gynecologic
malignancy affecting women in the world (Platz and
Benda, 1995; Rohan et al, 2003). Cervical cancers are
predominately squamous cell carcinomas, with
approximately 20% of the cases are accounted for by
adenocarcinoma which appears to be increasing in
frequency. Human papillomavirus (HPV) is acknowledged
as the causative infectious agent in the vast majority of
cases of cervical cancer (Stoler, 2003). HPV infections
leads to precursor lesions, progressing to dysplasias and
frank carcinoma over time. There is often an orderly
progression to invasive cancer, and can occur
asymptomatically over a course of 10-20 years.

III. Cervical cancer epidemiology and

screening
Cervical cancer screening using the Papanicolaou
smear has effected marked impact on this disease,
reducing both the incidence and mortality of cervical
cancer (Foulks, 1998). In the United States for the period
1996 to 2000, the average annual age adjusted incidence
rate for cervical cancer was 8.7 per 100,000 women. This
incidence reaches a peak in white women at ages 45-49;
while it continues to increase beyond that age in black
women. Women older than 50 years of age have a higher
incidence than those younger (6.7 versus 13.9 per
100,000), with mortality rates also increasing with age,
being more than four fold higher in women over 50 years
of age. The age adjusted mortality rate from cervix cancer
in the United States was 3.0 per 100,000 women in the
period between 1996 and 2000. This is a significant
reduction compared to data from 1975 when mass

II. HPV biology

HPV is a DNA virus which is the causative agent of
cervical cancer (Stoler, 2003). This virus is sexually
transmitted. More than 80 types of HPV have been
identified. The majority of cervical cancers are associated
with types 16, 18, 31, 33, and 35. These are often referred
to as high risk HPV types, in contrast to others which are
more associated with warts, condyloma and low grade
cervical intraepithelial neoplasia (CIN). Of these HPV 16
is associated with about 50% of cases of cervical cancer.
HPV can infect and cause a acute transient infection, but
these frequently may clear and the patient would not be at
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screening was first widely adopted, at which time the age
adjusted incidence and mortality rate were 14.8 and 5.6
per 100,000 women respectively.
Socioeconomic status impacts on incidence, and
mortality in patients with cervical cancer (Singh et al,
2004; Wang et al, 2004). Lower social economic status
confers a 1.6 fold increase risk for developing carcinoma
in situ (CIS) when compared with those with higher
socioeconomic status. A two fold increase risk for cancer
was also correlated with limited accessibility to the
healthcare system. Social and economic pressures can also
indirectly affect the incidence of cervix cancer through
lifestyle and cultural factors, such as sexual behavior,
smoking and diet which are known risk factors. Parity,
oral contraceptive use, smoking and other concomitant
sexually transmitted disease appear to play a role in
cervical carcinogenesis (Castellsague et al, 2002). Dietary
factors as vitamin A, vitamin C, vitamin E, folic acid, as
well as the immune status are also linked to the disease
progression.

screening. Other presenting symptoms, such as urinary

dysfunction, pelvic pressure or pain, sciatic pain in
advanced disease may be present. Biopsies, whether
colposcopically directed or a visible gross lesion will
provide the tissue for histologic diagnosis. Endocervical
curettage, cervical conization and endometrial biopsy may
contribute to the diagnosis, especially in the absence of an
obvious lesion.
The extent of the disease at presentation remains the
most important prognostic factor (Pecorelli and Odicino,
2003). Clinical staging as defined by the 1994 FIGO
staging system for cervical carcinoma is useful (Table 1).
Cervical cancer continues to be a clinically staged disease,
as opposed to the surgical staging used in defining other
gynecologic malignancies. Survival is related to stage,
with 5-year survivals ranging from 99% (for early stage
IA) to 15% stage IV disease. The earliest of stage I disease
are based on histologic examination and microscopic
measurements of the depth of tumor invasion.
Other prognostic indicators used for treatment
planning include radiologic findings from computed
tomography (CT) and magnetic resonance imaging (MRI)
(Chiang and Quek, 2003). Because clinical staging
remains subjective, lesions may be understaged in up to
20-30% of cases, and these may correspond to nodal
involvement or parametrial spread. On the other hand,
overstaging can result from pelvic inflammatory disease

IV. Diagnosis
Abnormal bleeding presenting as post-coital
bleeding, intermenstrual or post-menopausal bleeding
remains the most common presenting symptoms of
cervical carcinoma (ACOG, 2002). Less than 10% of
cases are asymptomatic when detected by cervical
Table 1. The 1994 FIGO staging system for cervical carcinoma
Stage 0
Stage I

Stage II

Stage III

Stage IV

Carcinoma in situ, cervical intraepithelial neoplasia grade III

Carcinoma strictly confined to the cervix (extension to the corpus is disregarded)
IA
Invasive carcinoma that can be diagnosed only by microscopy. All macroscopically visible lesions
even with superficial invasion are allotted to be 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 be not more than 5.0 mm taken from the base of the
epithelium of the original tissue-superficial or glandular. The involvement of vascular spacesvenous or lymphatic-should 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 greater 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 greater than 4.0 cm
Cervical carcinoma that 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
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 that involves the lower third of the vagina, with no extension to the pelvic wall
IIIB
Extension to the pelvic wall and/or hydronephrosis or nonfunctioning kidney
The carcinoma has extended beyond the true pelvis, or biopsy proven involvement of the mucosa of the
bladder or rectum. A bullous edema, as such, does not permit a case to be allotted to stage IV.
IVA
Spread of the growth to adjacent organs
IVB
Spread to distant organs

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and other non-neoplastic pathology, which is estimated to
be as high as 20% in stage IIIB disease. The use of
positron emission tomography-CT (PET-CT) has been
shown in some studies to have a high specificity and
sensitivity in cervix cancer staging, approaching a positive
predicted value of 100% and a negative predicted value of
96% in patients with early stage disease (Kumar and
Alavi, 2004). This may be used more frequently in the
future for accurate staging in cases with equivocal clinical
findings especially in advanced disease to assess disease
extension.

cure rates (Greven et al, 1999). Prospective randomized

studies directly comparing surgery versus chemoradiation
have not been forthcoming. Chemoradiation is utilized in
conjunction with surgery for the treatment of bulky tumors
(greater than 4 cm) Radiation is utilized after radical
hysterectomy in high-risk patients with positive lymph
nodes, positive surgical margins of resection, or tumor
involving parametria (Kim et al, 2005). The role and
benefit for adjuvant chemotherapy after hysterectomy is
not yet defined.
Locally advanced cervical carcinoma (stage IIBIVA) is treated with chemoradiation for the most part
utilizing a platinum-based chemotherapy (Greven et al,
1999; ACOG 2002). External beam radiation and
brachytherapy provide tumoricidal management for
advanced cervical carcinoma. Neither surgery nor
chemoradiation are without their inherent risk of a major
complication. Perioperative complications associated with
surgery are rare; and late complications possibly include
lymphocyst formation, lymphedema, bowel and bladder
dysfunction. Although the risk of major complications
related to radiation therapy is low, the incidence increases
with time, and include fistulization, involving either bowel
or bladder, and small bowel obstruction. Thin body
habitus, a history of smoking, pre-radiation surgery and
pelvic infection are factors correlated with increased risk
of major complications.

V. Treatment and management

Superficially invasive cervix cancer carries an
excellent prognosis. Both depth of tumor invasion, and
degree of superficial tumor spread are related to the
probability of nodal metastases. The presence of
lymphovascular space involvement (LVI), although not in
the FIGO staging schema, also appears to imparts a more
significant risk of metastatic tumor spread (Graflun et al,
2004). In IA2 lesions, the risk of tumor recurrence is less
than 1% if there is no LVI. This risk increases to 17%
when LVI is noted by pathologic examination. Stromal
response, histologic grade and tumor histology have been
implicated as prognostic factors but the data pertaining to
these remain weak.
Microinvasive cervical carcinoma is often treated
with a simple extrafascial hysterectomy (Mota, 2003).
Early stage cancer, usually referring to stage IB1 (equal to
or less than 4 cm) and early stage IIA cancers can
potentially be cured with surgery (Lu and Burke, 2000).
Traditionally, the treatment of choice has been radical
hysterectomy or with radiation therapy, with comparable

VI. Pathology of cervical cancer

The vast majority of cervical cancers are epithelial tumors
with squamous cell carcinomas accounting for about 80%
of the primary tumors in the cervix (Figure 1, Platz and
Benda, 1999).

Figure 1. Invasive squamous carcinoma of the cervix with focal necrosis (H and E section).

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Cronje HS (2004) Screening for cervical cancer in developing
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Finegan MM, Han AC, Edelson MI and Rosenblum NG (2004)
p16 expression in squamous lesions of the female genital
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Tommasino M (2001) Induction of pRb degradation by the
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clinical outcome in early-stage cervical carcinomas. Int J
Gynecol Cancer 14, 896-902
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developments in the treatment of newly diagnosed cervical
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Han AC, Edelson MI, Peralta Soler A, Knudsen KA, LifschitzMercer B, Czernobilsky B, Rosenblum NG and Salazar H
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Klaes R, Benner A, Friedrich T, Ridder R, Herrington S, Jenkins
D, Kurman, RJ, Schmidt D, Stoler M and von Knebel
Doeberitz MK (2002) p16INK4A immunohistochemistry
improves interobserver agreement in the diagnosis of
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Klaes R, Friedrich T, Spitkovsky D, Ridder R, Rudy W, Petry U,
Dallenbach-Hellweg G, Schmidt D and von Knebel
Doeberitz M (2001) Overexpression of p16INK4A as a specific
marker for dysplastic and neoplastic epithelial cells of the
cervix uteri. Int J Cancer 92, 276-84.
Kumar R, Alavi A (2004) PET imaging in gynecologic
malignancies. Radiol Clin North Am 42, 1155-1167
Lee CM, Lee RJ, Hammond E, Tsodikov A, Dodson M,
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Rarely tumors of glandular origin and small cell

carcinomas are seen (Han et al, 2000; Zarka et al, 2003).
Squamous carcinomas may have varying degrees of
differentiation and amounts of keratin formation. In
addition to HPV infection, cervical cancers frequently
harbor other genetic alterations that herald other steps in
oncogenesis (Carico 2001; Klaes et al, 2001) These most
frequently include p16 and p53 (Keating et al, 2001;
Finegan et al, 2004). p16 has been shown to be expressed
in a large proportion of cervical squamous carcinomas
(approximately 70% or more). The regulation of this
tumor suppressor protein, presumably involves an HPV
dependent pathway (Sano et al, 1998, 2002). Current
studies are underway to examine the utility of p16 as an
adjunctive marker for cervical cancer screening (Lin et al,
2000; Bibbo et al, 2002; Klaes et al, 2002).
In addition our group has been interested in
examining the role of adhesion protein expression in
cancers of the cervix. We have seen the cell-cell adhesion
marker P-cadherin as a good marker for glandular tumors
of the cervix (Han et al, 2000), and often seen in
increasing frequency in dysplastic to frankly neoplastic
glandular tumors. In small cell cancers of the cervix, we
have shown that the neural adhesion protein N-cadherin
may be a tumor suppressor protein that is operative in the
development of these tumors (Zarka et al, 2003) Recent
studies on the oncogenetic profiles of cervical squamous
carcinoma has uncovered tumor heterogeneity, suggesting
that these tumors are not static, but undergo additional
mutations and expression or loss of oncogenes, probably
as a result of tumor clonal selection or tumor evolution
(manuscript in preparation)

VII. Summary
The last thirty years has seen dramatic change in the
incidence and mortality of cervical cancer in the United
States. This has been most dramatically affected by the
effective screening program associated with the pap
smear. Cervical cancer continues to be a significant
disease worldwide, and we are understanding more and
more of the tumor biology involved, and optimizing
current treatment approaches to the disease. Future studies
will hopefully uncover best practices for screening
strategies for developed and developing countries, as well
as preventative options (Lorincz, 1996; Cronje, 2004; Lee
et al, 2004; Suba, 2004) Since HPV is the cause of cervical
cancer in the majority of cases, research looking at
eradicating HPV infection, specifically through vaccine
trials is an area of significant interest, and holds much
promise (Wolf et al, 2003; Sterlinko and Banks, 2004).

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From left to right: Aaron Han, Maria Merzouk, Richard Belch

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