Practice Essentials

Cervical cancer is the third most common malignancy in women worldwide, and it remains a leading
cause of cancer-related death for women in developing countries. In the United States, cervical
cancer is relatively uncommon.
Essential update: New cervical screening guidelines released by the ASCCP
In March 2013, the American Society for Colposcopy and Cervical Pathology (ASCCP) issued
updated cervical screening guidelines for managing women with abnormal cervical cancer screening
tests, and diagnosed cancer precursors. The Updated Consensus Guidelines for Managing Abnormal
Cervical Cancer Screening Tests and Cancer Precursors include [1, 2] :

Guidance for the management of discordant co-tests, in which results of either Pap smear or
HPV testing, but not both, are positive, with integration of co-testing into follow-up care. Colposcopy
and/or HPV DNA typing may be indicated in these cases.
A recommendation for a return to "routine" screening in women treated for cervical cancer.
The extension of management guidelines for adolescents under age 21 to women under age
25. The recommended workup varies according to findings of atypical squamous cells of
undetermined significance, or low-grade or high-grade squamous intraepithelial lesion, and may
include colposcopy.
Consideration of whether cervical intraepithelial neoplasia grade 1 (CIN1) on endocervical
canal curettage (ECC) should be treated as positive ECC or CIN1.
Guidance for the management of women with unsatisfactory cytologic findings and specimens
that are missing endocervical or transformation zone components. Colposcopy may be required for
women with positive HPV results or with repeated unsatisfactory cytologic findings.

Signs and symptoms

The most common finding in patients with cervical cancer is an abnormal Papanicolaou (Pap) test
result.
Physical symptoms of cervical cancer may include the following:

Abnormal vaginal bleeding

Vaginal discomfort
Malodorous discharge
Dysuria
See Clinical Presentation for more detail.

Diagnosis
Human papillomavirus (HPV) infection must be present for cervical cancer to occur. Complete
evaluation starts with Papanicolaou (Pap) testing.
Screening recommendations
Current screening recommendations for specific age groups, based on guidelines from the American
Cancer Society (ACS), the American Society for Colposcopy and Cervical Pathology (ASCCP), the
American Society for Clinical Pathology (ASCP), the US Preventive Services Task Force (USPSTF),
and the American College of Obstetricians and Gynecologists (ACOG), are as follows [3, 4, 5, 6] :

< 21 years: No screening recommended

21-29 years: Cytology (Pap smear) alone every 3 years
30-65 years: Human papillomavirus (HPV) and cytology cotesting every 5 years (preferred) or
cytology alone every 3 years (acceptable)

>65 years: No screening recommended if adequate prior screening has been negative and
high risk is not present
See Workup for more detail.

Management
Immunization

Evidence suggests that HPV vaccines prevent HPV infection. [7] The following 2 HPV vaccines are
approved by the FDA:

Gardasil (Merck, Whitehouse Station, NJ): This quadrivalent vaccine is approved for girls and
women 9-26 years of age to prevent cervical cancer (and also genital warts and anal cancer)
caused by HPV types 6, 11, 16, and 18; it is also approved for males 9-26 years of age [8]

Cervarix (GlaxoSmithKline, Research Triangle Park, NC): This bivalent vaccine is approved
for girls and women 9-25 years of age to prevent cervical cancer caused by HPV types 16 and 18 [9]
The Advisory Committee on Immunization Practices (ACIP) recommendations for vaccination are as
follows:

Routine vaccination of females aged 11-12 years of age with 3 doses of either HPV2 or HPV4
Routine vaccination with HPV4 for boys aged 11-12 years of age, as well as males aged 1321 years of age who have not been vaccinated previously

Vaccination with HPV4 in males aged 9-26 years of age for prevention of genital warts;
routine use not recommended
Stage-based treatment
The treatment of cervical cancer varies with the stage of the disease, as follows:

Stage 0: Carcinoma in situ (stage 0) is treated with local ablative or excisional measures such
as cryosurgery, laser ablation, and loop excision; surgical removal is preferred
Stage IA1: The treatment of choice for stage IA1 disease is surgery; total hysterectomy,
radical hysterectomy, and conization are accepted procedures
Stage IA2, IB, or IIA: Combined external beam radiation with brachytherapy and radical
hysterectomy with bilateral pelvic lymphadenectomy for patients with stage IB or IIA disease; radical
vaginal trachelectomy with pelvic lymph node dissection is appropriate for fertility preservation in
women with stage IA2 disease and those with stage IB1 disease whose lesions are 2 cm or smaller
Stage IIB, III, or IVA: Cisplatin-based chemotherapy with radiation is the standard of care [10]
Stage IVB and recurrent cancer: Individualized therapy is used on a palliative basis; radiation
therapy is used alone for control of bleeding and pain; systemic chemotherapy is used for
disseminated disease[10]
See Treatment and Medication for more detail.

Image library

Cervical carcinoma with adnexa.

Background
Cervical cancer is the third most common malignancy in women worldwide, and it remains a leading
cause of cancer-related death for women in developing countries. In the United States, cervical
cancer is relatively uncommon. (See Epidemiology.)
The incidence of invasive cervical cancer has declined steadily in the United States over the past few
decades; however, it remains at high levels in many developing countries. The change in the
epidemiologic trend in the United States has been attributed to mass screening with Papanicolaou
(Pap) tests, which permits detection and treatment of preinvasive disease.
Recognition of the etiologic role of human papillomavirus (HPV) infection in cervical cancer has led to
the recommendation of adding HPV testing to the screening regimen in women 30-65 years of age
(see Workup). However, women who have symptoms, abnormal screening test results, or a gross
lesion of the cervix are best evaluated with colposcopy and biopsy.

For further recommendations concerning cervical cancer evaluation and management of abnormal
Pap test results, and treatment of cervical intraepithelial neoplasia (CIN), see the American Society for
Colposcopy and Cervical Pathology (ASCCP) guidelines.[11] (See also Presentation and Workup.)
The treatment of cervical cancer varies with the stage of the disease. For early invasive cancer,
surgery is the treatment of choice. In more advanced cases, radiation combined with chemotherapy is
the current standard of care. In patients with disseminated disease, chemotherapy or radiation
provides symptom palliation. (See Treatment and Medication.)

Pathophysiology
Human papillomavirus (HPV) infection must be present for cervical cancer to occur. HPV infection
occurs in a high percentage of sexually active women. However, approximately 90% of HPV infections
clear on their own within months to a few years and with no sequelae, although cytology reports in the
2 years following infection may show a low-grade squamous intraepithelial lesion.
On average, only 5% of HPV infections will result in the development of CIN grade 2 or 3 lesions (the
recognized cervical cancer precursor) within 3 years of infection. Only 20% of CIN 3 lesions progress
to invasive cervical cancer within 5 years, and only 40% of CIN 3 lesions progress to invasive cervical
cancer with 30 years.
Because only a small proportion of HPV infections progress to cancer, other factors must be involved
in the process of carcinogenesis. The following factors have been postulated to influence the
development of CIN 3 lesions:

The type and duration of viral infection, with high-risk HPV type and persistent infection
predicting a higher risk for progression; low-risk HPV types do not cause cervical cancer

Host conditions that compromise immunity (eg, poor nutritional status, immunocompromise,
and HIV infection)

Environmental factors (eg, smoking and vitamin deficiencies)

Lack of access to routine cytology screening

In addition, various gynecologic factors significantly increase the risk of HPV infection. These include
early age of first intercourse and higher number of sexual partners.
Although use of oral contraceptives for 5 years or longer has been associated with an increased risk
of cervical cancer, the increased risk may reflect a higher risk for HPV infection among sexually active
women. However, a possible direct interaction between oral contraceptives and HPV infection has not
been disproved.[12]

Genetic susceptibility
Genetic susceptibility to cervical cancers caused by HPV infection has been identified via studies of
twins and other first-degree relatives, as well as genome-wide association studies. Women who have
an affected first-degree biologic relative have a 2-fold relative risk of developing a cervical tumor
compared with women who have a nonbiologic first-degree relative with a cervical tumor.[13, 14]Genetic
susceptibility accounts for fewer than 1% of cervical cancers.
Genetic changes in several classes of genes have been linked to cervical cancer. Tumor necrosis
factor (TNF) is involved in initiating the cell commitment to apoptosis, and the genes TNFa-8, TNFa572, TNFa-857, TNFa-863, and TNF G-308A have been associated with a higher incidence of
cervical cancer.[15, 16, 17, 18]Polymorphisms in another gene involved in apoptosis and gene repair, Tp53,
have been associated with an increased rate of HPV infection progressing to cervical cancer. [19, 20, 21, 22, 23]
Human leukocyte antigen (HLA) genes are involved in various ways. Some HLA gene anomalies are
associated with an increased risk of HPV infection progressing to cancer,[24, 25] others with a protective
effect.[26, 27] The chemokine receptor-2 (CCR2) gene on chromosome 3p21[28, 29] and the Fas gene on
chromosome 10q24.1[25, 30] may also influence genetic susceptibility to cervical cancer, perhaps by
disrupting the immune response to HPV. The CASP8 gene (also known as FLICE or MCH5) has a
polymorphism in the promoter region that has been associated with a decreased risk of cervical
cancer.[31]
Epigenetic modifications may also be involved in cervical cancer. Methylation is the best understood
and probably the most common mechanism of epigenetic DNA modeling in cancer. Aberrant DNA

methylation patterns have been associated with the development of cervical cancer and may harbor
important clues for developing treatment.[32, 33]

Human papillomavirus
HPV comprises a heterogeneous group of viruses that contain closed circular double-stranded DNA.
The viral genome encodes 6 early open reading frame proteins (ie, E1, E2, E3, E4, E6, and E7),
which function as regulatory proteins, and 2 late open reading frame proteins (ie, L1 and L2), which
make up the viral capsid.
To date, more than 115 different genotypes of HPV have been identified and cloned. A large
multinational cervical cancer study found that more than 90% of all cervical cancers worldwide are
caused by 8 HPV types: 16, 18, 31, 33, 35, 45, 52, and 58. Three types16, 18, and 45cause 94%
of cervical adenocarcinomas.[34] HVP type 16 may pose a risk of cancer that is an order of magnitude
higher than that posed by other high-risk HPV types. [35]
The World Health Organization (WHO) International Agency for Research on Cancer Monograph
Working Group has grouped HPV types of the mucosotropic alpha genus according to the evidence
supporting their association with cervical cancer (see Table 1, below). [35]
Table 1. Human Papillomavirus Types Associated With Cervical Cancer (Open Table in a new
window)
HPV Alpha Group

Types

Evidence for Cervical Cancer Causation

16

Most carcinogenic HPV type, known to cause cancer at several sites

18,31,33,35,39,45,51,52,56,58, 59

Sufficient evidence

2A

68

Limited evidence in humans and strong mechanistic evidence

2B

26,53,66,67,70,73,82

Limited evidence in humans

30,34,69,85,97

Classified by phylogenetic analogy to HPV types with sufficient or limited evidence in humans

6,11

Inadequate epidemiological evidence and absence of carcinogenic potential in mechanistic studies

HPV = human papillomavirus.

The HPVs that infect the human cervix fall into 2 broad risk categories. The low-risk types (eg, HPV 6
and 11) are associated with condylomata and a very small number of low-grade squamous epithelial
lesions (SILs) but are never found in invasive cancer. The high-risk types (eg, HPV 16) vary in
prevalence according to the cervical disease state.
Upon integration into the human genome, the linearization of high-risk HPV DNA places the E6 and
E7 genes in a position of enhanced replication. E7 binds and inactivates the Rb protein while E6 binds
p53 and directs its degradation, and the functional loss of the TP53 and RB genes leads to resistance
to apoptosis, causing uncensored cell growth after DNA damage. This ultimately results in
progression to malignancy.

Human immunodeficiency virus

The role of HIV infection in the pathogenesis of cervical cancer is not fully understood. However, HIV
infection is known to suppress the already low level of immune recognition of HPV infection, allowing
HPV to cause more damage than it would in immunocompetent women.
Cervical cancer is at least 5 times more common in HIV-infected women, and this increased
prevalence has remained essentially unchanged with the use of highly active antiretroviral therapy.
[36]
Studies have shown a higher prevalence of HPV infection in HIV-seropositive women than in
seronegative women, and the HPV prevalence was directly proportional to the severity of
immunosuppression as measured by CD4+ T-cell counts.

Etiology

With rare exceptions, cervical cancer results from genital infection with HPV, which is a known human
carcinogen.[37, 38, 39, 35, 40] Although HPV infections can be transmitted via nonsexual routes, the majority
result from sexual contact. Consequently, major risk factors identified in epidemiologic studies are as
follows:

Sex at a young age

Multiple sexual partners
Promiscuous male partners
History of sexually transmitted diseases
HIV infection is associated with a 5-fold increase in the risk of cervical cancer, presumably because of
an impaired immune response to HPV infection.[36]Exposure to diethylstilbestrol in utero has been
associated with an increased risk of CIN grade 2 or higher.[41]

Epidemiology
Cervical cancer is the third most common malignancy in women worldwide. The frequency varies
considerably between developed and developing countries, however: Cervical cancer is the second
most common cancer in developing countries, but only the tenth most common in developed
countries. Similarly, cervical cancer is the second most common cause of cancer-related deaths in
women in developing countries but is not even among the top 10 causes in developed countries. [42]
In the United States, cervical cancer is relatively uncommon. The incidence of invasive cervical
cancer has declined steadily in the US over the past few decades; for example, since 2004, rates
have decreased by 2.1% per year in women younger than 50 years and by 3.1% per year in women
50 years of age and older.[43] This trend has been attributed to mass screening with Pap tests.
[44]
Cervical cancer rates continue to rise in many developing countries, however.
The American Cancer Society (ACS) estimates that in the United States, 12,170 new cases of cervical
cancer will be diagnosed in 2012.[43] Internationally, more than 500,000 new cases are diagnosed each
year; rates vary widely, ranging from an annual incidence of 4.5 cases per 100,000 in Western Asia to
34.5 per 100,000 women in Eastern Africa.[45] In industrialized countries with well-established cytology
screening programs, the incidence of cervical cancer ranges from 4 to 10 per 100,000 women.
The incidence of CIN 2/3 disease in the US is about 150 per 100,000 women, with the peak incidence
around 800 per 100,000 women in the 25-29 year age group. The incidence of abnormal cytology
screens for all ages is an order of magnitude larger, at 7800 per 100,000 women.
Forouzanfar et al performed annual age-specific assessments of cervical cancer in 187 countries from
1980 to 2010. The global cervical cancer incidence increased from 378,000 cases per year in 1980 to
454,000 cases per year in 2010 (annual rate of increase, 0.6%). Cervical cancer death rates have
been decreasing, but the disease still accounted for 200,000 deaths in 2010; in developing countries,
46,000 of these women were aged 15-49 years, and 109,000 were aged 50 years or older.[46]

Age-related demographics
The Centers for Disease Control and Prevention (CDC) surveillance of screening-detected cancers
(colon and rectum, breast, and cervix) in the United States from 2004 to 2006 reported that the
incidence of late-stage cervical cancer was highest among women aged 50-79 years. [47] However,
cervical cancer may be diagnosed in any woman of reproductive age.
Indeed, rates of cervical adenocarcinoma have been increasing in women under 40 years of age.
[48]
These cases are less easily detected with Pap test screening, and survivorship is low because
cases tend to be detected at a late stage. Moreover, the HPV types causing adenocarcinoma are
different from the types causing squamous carcinoma. HPV 16, which is a stronger carcinogen than
other HPV types, has been found more frequently in younger women than in older ones. [49, 50]

Race-related demographics
Racial variation in cervical cancer rates per 100,000 women in the United States, according to
Surveillance Epidemiology and End Results (SEER) data from 2005-2009, was as follows:

Hispanic - 11.8
African American - 9.8

American Indian/Alaska Native - 8.1

White - 8.0
Asian/Pacific Islander - 7.2
Except for Asian/Pacific Islanders, women of other races have higher mortality from cervical cancers
than their white counterparts in the United States do. [51]Death rates from cervical cancer have been
highest among African Americans; however, death rates in African-American women decreased by
2.6% per year from 2004 to 2008 while remaining stable in white women. [43]

Prognosis
The prognosis in patients with cervical cancer depends on the disease stage. In general, the 5-year
survival rates are as follows:

Stage I - Greater than 90%

Stage II - 60-80%
Stage III - Approximately 50%
Stage IV - Less than 30%
The ACS estimates that 4220 women will die of cervical cancer in the United States in 2012. [43] This
represents 1.3% of all cancer deaths and 6.5% of deaths from gynecologic cancers.

Patient Education
Cervical cancer is overrepresented among underserved and minority groups in the United States. It is
imperative to increase awareness about the benefit of Pap test screening for preventing cervical
cancer among women in these groups. Education about the benefit of HPV vaccination is also
important but must be accompanied by the information that vaccination does not substitute for regular
screening.
A Cochrane review found that the best approach to encourage women to undergo cervical screening
involved invitations.[52] These may take any of the following forms:

Appointments (fixed or open)

Letters
Telephone calls
Verbal recommendations
Prompts
Follow-up letters
These findings relate to screening in developed countries, however, and their relevance to developing
countries is unclear. Further studies are required to determine the effectiveness of promising
interventions, such as revealing in an invitation letter the gender of the smear taker, using a health
promotion nurse, employing lay outreach health workers, and carrying out intensive attempts at
recruitment.
Proceed to Clinical Presentation
Because many women are screened routinely, the most common finding is an abnormal Papanicolaou
(Pap) test result. Typically, these patients are asymptomatic.
Clinically, the first symptom of cervical cancer is abnormal vaginal bleeding, usually postcoital. Vaginal
discomfort, malodorous discharge, and dysuria are not uncommon.
The tumor grows by extending along the epithelial surfaces, both squamous and glandular, upward to
the endometrial cavity, throughout the vaginal epithelium, and laterally to the pelvic wall. It can invade
the bladder and rectum directly, leading to constipation, hematuria, fistula, and ureteral obstruction,
with or without hydroureter or hydronephrosis. The triad of leg edema, pain, and hydronephrosis
suggests pelvic wall involvement. The common sites for distant metastasis include extrapelvic lymph
nodes, liver, lung, and bone.

Physical Examination

In patients with early-stage cervical cancer, physical examination findings can be relatively normal. As
the disease progresses, the cervix may become abnormal in appearance, with gross erosion, ulcer, or
mass. These abnormalities can extend to the vagina. Rectal examination may reveal an external
mass or gross blood from tumor erosion.
Bimanual pelvic examination findings often reveal pelvic or parametrial metastasis. If the disease
involves the liver, hepatomegaly may develop. Pulmonary metastasis usually is difficult to detect on
physical examination unless pleural effusion or bronchial obstruction becomes apparent. Leg edema
suggests lymphatic or vascular obstruction caused by tumor.
Previous

Diagnostic Considerations
In addition to the conditions listed in the differential diagnosis, other disorders to consider in a woman
with possible cervical cancer include the following:

Cervicitis/infection, particularly granulomatous (which is rare)

Primary melanoma and Paget disease
Vaginal cancer
Another rare possibility is that a primary cancer elsewhere in the body has metastasized to the cervix.

Differential Diagnoses

Cervicitis
Endometrial Carcinoma
Pelvic Inflammatory Disease
Vaginitis

Approach Considerations
Complete evaluation starts with Papanicolaou (Pap) testing. Positive results should prompt
colposcopy and biopsies with further workup of cervical intraepithelial neoplasia (CIN), including
excisional procedures. If pathologic evaluation after loop electrosurgical excision or conization
suggests invasive cancer with positive margins, the patient should be referred to a gynecologic
oncologist. Patients with suspicious or grossly abnormal cervical lesions on physical examination
should undergo biopsy regardless of the cytologic findings.
Once the diagnosis is established, a complete blood count (CBC) and serum chemistries for renal and
hepatic function should be ordered to look for abnormalities from possible metastatic disease, and
imaging studies should be performed for staging purposes. In the International Federation of
Gynecology and Obstetrics (Federation Internationale de Gynecologie et dObstetrique [FIGO])
guidelines for staging, procedures are limited to the following[53] :

Colposcopy
Biopsy
Conization of cervix
Cystoscopy
Proctosigmoidoscopy
Chest x-ray
Cystoscopy and proctoscopy should be performed in patients with a bulky primary tumor to help rule
out local invasion of the bladder and the colon. Barium enema studies can be used to evaluate
extrinsic rectal compression from the cervical mass.
In the United States, more complex radiologic imaging studies are often done to guide the choice of
therapeutic options. These may include computed tomography (CT), magnetic resonance imaging
(MRI), and positron-emission tomography (PET), as well as surgical staging. (See also Cervical
Cancer Imaging.)

reening Recommendations
The American Cancer Society (ACS), the American Society for Colposcopy and Cervical Pathology
(ASCCP), and the American Society for Clinical Pathology (ASCP) have issued joint guidelines for
cervical cancer screening.[5] In 2012, the US Preventive Services Task Force (USPSTF) issued
updated guidelines whose recommendations are consistent with those of the ACS, ASCCP, and
ASCP.[6] In November 2012, the American College of Obstetricians and Gynecologists (ACOG) issued
new screening guidelines that were also consistent with those of these groups. [3, 4]
Screening recommendations for specific patient age groups are as follows [3, 4, 5, 6]:

< 21 years No screening recommended

21-29 years Cytology (Pap smear) alone every 3 years
30-65 years Human papillomavirus (HPV) and cytology cotesting every 5 years (preferred)
or cytology alone every 3 years (acceptable)

> 65 years No screening recommended if adequate prior screening has been negative and
high risk is not present
The USPSTF cautions that positive screening results are more likely with HPV-based strategies than
with cytology alone and that some women may have persistently positive HPV results and require
prolonged surveillance with additional frequent testing. Similarly, women who would otherwise be
advised to end screening at age 65 years on the basis of previously normal cytology results may
undergo continued testing because of positive HPV test results. [6]
Current US guidelines advise against using HPV testing to screen for cervical cancer in women
younger than 30 years; the ACS advises that for screening in women 30-65 years of age, HPV testing
alone is not currently recommended for most clinical settings in the US. Annual screening is not
recommended at any age or with any method.
Women who have had a total hysterectomy may stop undergoing cervical cancer screening.
Exceptions are as follows:

Women who had a hysterectomy without removal of the cervix

Women who have had a CIN grade 2 or 3 lesion treated in the past 20 years
Women who have had cervical carcinoma at any time
Women in whom co-testing shows a negative Pap smear but a positive HPV test should have 12month follow-up cotesting. Women with atypical squamous cells of undetermined significance
(ASCUS) on Pap smear but a negative HPV test can be rescreened with cotesting in 5 years or with
cytology alone in 3 years.[5]

apanicolaou Testing
For many years, the Pap test has been the standard method for cervical cancer screening.
Retrospective data have shown that screening with a Pap test reduces the incidence of cervical
cancer by 60-90% and the death rate by 90%.
Because of false negatives, the best that a Pap test can do is to reduce the incidence of cervical
cancer to 2-3 per 100,000 women. False-negative tests mostly result from sampling error, which can
be reduced by ensuring that adequate material is taken from both the endocervical canal and the
ectocervix. Smears without endocervical or metaplastic cells should be repeated. (See Pap Smear.)
The limitations of the conventional Pap test include limited sensitivity (51%) and a significant
proportion of inadequate specimens. In addition, accurate interpretation of conventional Pap tests is
often compromised by the presence of artifacts (eg, blood, mucus, obscuring inflammation, scant
cellular material, or air-drying artifact).
Newer liquid-based Pap test technologies have become available. In a randomized, controlled trial
from the Netherlands that compared liquid-based and conventional cervical cytology, liquid-based

cytology reduced the proportion of unsatisfactory specimens from 1.1% to 0.3% and eliminated
obscuring blood, poor fixation, cytolysis, and insufficient spreading of cells as causes of unsatisfactory
results.[54]
With liquid-based cytology, however, older women (primarily those 55-60 years of age) were more
likely to have a sample called unsatisfactory. Nevertheless, 18-month follow-up showed that women
with unsatisfactory results by either method were not at higher risk for cervical abnormalities. [54]

ThinPrep Papanicolaou test

Test samples for the ThinPrep Pap test are collected the same way as those for the conventional Pap
test. However, the specimen is placed in a preservative solution rather than on a slide. An automated
processor prepares the sample and makes a uniform slide for review. Mucus and blood are removed
in the process. The ThinPrep Papanicolaou test was approved in 1996 by the US Food and Drug
Administration (FDA) as an alternative to the traditional conventional smear.
The Hybrid Capture II assay for HPV was approved by the FDA in 2003 as a new approach for
cervical cancer. This test is useful for interpreting equivocal results from a Pap test. If a woman has a
Pap test result showing ASCUS but a subsequent HPV test is negative, she can be rescreened with
Pap testing in 3 years; if the HPV test is positive, then additional workup with a colposcopy is
indicated.
The ACS guidelines favor using HPV testing with cytology in women aged 30 years and older. If both
tests are negative, then the next Pap test can be delayed for 5 years.

maging Studies for Metastasis

A routine chest radiograph is obtained to help rule out pulmonary metastasis. Chest radiography may
be considered optional for disease that is stage IB1 or lower.[10]
A CT scan of the abdomen and pelvis is performed to look for metastasis in the liver, lymph nodes, or
other organs (see the image below) and to help rule out hydronephrosis or hydroureter. MRI or
positron-emission tomography (PET) scanning is an alternative to CT scanning; in fact, PET scanning
is now recommended for patients with stage IB2 disease or higher.[10]

CT scan of cervical cell carcinoma demonstrates markedly enlarged lymph node

at left pelvic sidewall. This is consistent with pelvic lymph node metastasis, which is indicative of stage IIIB disease.
Cystic consistency is not unusual for metastatic cervical carcinoma. Primary tumor is well depicted as hypoattenuating
circumscribed mass. Cyst is present in anteriorly located left ovary.

Magnetic resonance whole-body diffusion-weighted imaging scanning has been used to distinguish
uterine cervical carcinoma from normal uterine cervix. This technique can also differentiate metastatic
nodes from benign nodes.[55] (See alsoCervical Cancer Imaging.)

Surgical Staging

Clinical staging protocols can fail to demonstrate pelvic and aortic lymph node involvement in 20-50%
and 6-30% of patients, respectively. For that reason, surgical staging sometimes is recommended.
Pretreatment surgical staging is the most accurate method of determining the extent of disease.
However, there is little evidence to suggest that routine surgical staging yields any significant
improvement in overall survival. Therefore, the decision whether to perform pretreatment surgical
staging should be made on an individual basis after a thorough nonsurgical workup, including fineneedle aspiration of lymph nodes, has failed to demonstrate metastatic disease.

istologic Findings
Precancerous lesions of the cervix usually are detected via a Pap test. The Pap test classification
system has evolved over the years. Standardized Pap test reporting emerged from a 1988 workshop
sponsored by the National Cancer Institute. Currently, cervical cytology results are reported according
to the 2001 Bethesda System.[56]

2001 Bethesda System for reporting cervical cytologic diagnoses

Specimen adequacy may be the single most important quality assurance component of the system.
Specimen classifications are as follows:

Satisfactory for evaluation (note presence/absence of endocervical/transformation zone

component)

Unsatisfactory for evaluation (specify reason)

Specimen rejected/not processed (specify reason)

Specimen processed and examined, but unsatisfactory for evaluation of epithelial abnormality
because of (specify reason)
General categorization (optional) is as follows:

Negative for intraepithelial lesion or malignancy

Epithelial cell abnormality
Other
Possible interpretations or results are as follows:
Negative for intraepithelial lesion or malignancy
Observed organisms (eg, Trichomonas, Candida, bacteria) and cellular changes consistent
with herpes simplex virus are reported
Reporting other nonneoplastic findings (ie, inflammation and atrophy) is optional
Epithelial cell abnormalities
Squamous cell
Atypical squamous cells (ASC)
ASCUS
ASC where a high-grade squamous intraepithelial lesion (HSIL) cannot be excluded (ASC-H)
Low-grade squamous intraepithelial lesion (LSIL)
Encompassing HPV, mild dysplasia, and CIN 1 (see the first image below)
HSIL
Encompassing moderate and severe dysplasia, carcinoma in situ, CIN 2, and CIN 3 (see the
second image below)
Squamous cell carcinoma (see the third image below)
Glandular cell
Atypical glandular cells (AGC) (specify endocervical, endometrial, or not otherwise specified)
AGC favoring neoplastic (specify endocervical or not otherwise specified)
Endocervical adenocarcinoma in situ (AIS)
Adenocarcinoma
Other (list not comprehensive)

Endometrial cells in a woman aged 40 years or older

intraepithelial neoplasia grade I.

Cervical

Cervical intraepithelial neoplasia grade III.

Squamous cell cervical carcinoma.

Automated review and ancillary testing are included as appropriate. Educational notes and
suggestions are optional.
The histology of cervical malignancy is predominantly that of squamous cell carcinoma, which
represents approximately 80% of cases, with adenocarcinomas representing almost 20%. Less
common histologies include small cell carcinoma, melanoma, and lymphoma.
There are 2 major staging systems that are frequently used in cervical cancer (see Table 2, below
and Cervical Cancer Staging):

The FIGO system, developed in collaboration with the World Health Organization (WHO) [53]
The TNM system, developed by the International Union Against Cancer (UICC) and the
American Joint Committee on Cancer (AJCC)[57]
Table 2. Cervical Cancer Staging: Primary Tumor (T) (Open Table in a new window)
TNM
Stage

FIGO
Stage

TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1

Cervical carcinoma confined to uterus (extension to corpus should be disregarded)

T1a

IA

Invasive carcinoma diagnosed only by microscopy. All macroscopically visible lesionseven with superficial invasionare T1b/1B.
Stromal invasion with a maximal depth of 5.0 mm measured from the base of the epithelium and a horizontal spread of 7.0 mm or less.
Vascular space involvement, venous or lymphatic, does not affect classification.

T1a1

IA1

Measured stromal invasion 3 mm or less in depth and 7 mm or less in lateral spread

T1a2

IA2

Measured stromal invasion more than 3 mm but not more than 5 mm with a horizontal spread 7 mm or less

T1b

IB

Clinically visible lesion confined to the cervix or microscopic lesion greater than IA2

T1b1

IB1

Clinically visible lesion 4 cm or less in greatest dimension

IB2

Clinically visible lesion more than 4 cm

T2

II

Cervical carcinoma extends beyond the cervix but not to the pelvic sidewall or to the lower third of vagina

T2a

IIA

Tumor without parametrial invasion

T2b

IIB

Tumor with parametrial invasion

T3

III

Tumor extends to the pelvic wall and/or involves the lower third of the vagina and/or causes hydronephrosis or nonfunctioning kidney

T3a

IIIA

Tumor involves lower third of vagina; no extension to pelvic sidewall

T3b

IIIB

Tumor extends to pelvic sidewall and/or causes hydronephrosis or nonfunctioning kidney

IV

Cervical carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the bladder mucosa or rectal mucosa. Bullous
edema does not qualify as a criteria for stage IV disease.

T4

IVA

Spread to mucosa of adjacent organs (bladder, rectum, or both)

M1

IVB

Distant metastasis

In the UICC/AJCC system, regional lymph node (N) involvementincluding paracervical, parametrial,
hypogastric (obturator), common, internal and external iliac, and presacral and sacral nodesis
graded as follows.

NX: Regional lymph nodes cannot be assessed

N0: No regional lymph node metastasis
N1: Regional lymph node metastasis
The T and N grades are combined with the grade for distant metastasis (M) to yield the staging for the
cancer (see Table 3, below).
Table 3. UICC/AJCC Staging for Cervical Cancer (Open Table in a new window)
Stage

Tumor

Node

Metastasis

Tis

N0

M0

IA1

T1a1

N0

M0

IA2

T1a2

N0

M0

IB1

T1b1

N0

M0

IIA

T2a

N0

M0

IIB

T2b

N0

M0

IIIA

T3a

N0

M0

IIIB

T1

N1

M0

T2

N1

M0

T3a

N1

M0

T3b

Any N

M0

IVA

T4

Any N

M0

IVB

Any T

Any N

M1

Approach Considerations
The treatment of cervical cancer varies with the stage of the disease (see Cervical Cancer Staging).
For early invasive cancer, surgery is the treatment of choice. In more advanced cases, radiation
combined with chemotherapy is the current standard of care. In patients with disseminated disease,
chemotherapy or radiation provides symptom palliation. (See also Cervical Cancer Treatment
Protocols.)
The treatment of cervical cancer frequently requires a multidisciplinary approach. Involvement of a
gynecologic oncologist, radiation oncologist, and medical oncologist may be necessary.

Stage-Based Therapy
Stage 0 cancer
Carcinoma in situ (stage 0) is treated with local ablative or excisional measures such as cryosurgery,
laser ablation, and loop excision. Surgical removal is preferred in that it allows further pathologic
evaluation to rule out microinvasive disease. After treatment, these patients require lifelong
surveillance.

Stage IA1 Cancer

The treatment of choice for stage IA1 disease is surgery. Total hysterectomy, radical hysterectomy,
and conization are accepted procedures. Lymph node dissection is not required if the depth of
invasion is less than 3 mm and no lymphovascular invasion is noted.
Selected patients with stage IA1 disease but no lymphovascular space invasion who desire to
maintain fertility may undergo therapeutic conization with close follow-up, including cytology,
colposcopy, and endocervical curettage. Patients with comorbid medical conditions who are not
surgical candidates can be successfully treated with radiation.
According to National Comprehensive Cancer Network (NCCN) guidelines, pelvic radiation therapy is
currently a category 1 recommendation for women with stage IA disease and negative lymph nodes
after surgery who have high-risk factors (eg, a large primary tumor, deep stromal invasion, or
lymphovascular space invasion).[10]

Stage IA2, IB, or IIA cancer

For patients with stage IB or IIA disease, there are 2 treatment options:

Combined external beam radiation with brachytherapy

Radical hysterectomy with bilateral pelvic lymphadenectomy
Radical vaginal trachelectomy with pelvic lymph node dissection is appropriate for fertility preservation
in women with stage IA2 disease and those with stage IB1 disease whose lesions are 2 cm or smaller.
[10]
The principal problems with pregnancy after trachelectomy are premature labor and the need to
undergo cesarean section for delivery.[58]
Most retrospective studies have shown equivalent survival rates for trachelectomy and hysterectomy,
though such studies usually are flawed because of patient selection bias and other compounding
factors. However, a 2008 study showed identical overall and disease-free survival rates for the 2
procedures.[59]
Current surgical guidelines for stage IA2 to IIA cervical cancers allow for minimally invasive
techniques, such as traditional laparoscopic and robotically assisted laparoscopic techniques, in the
surgical management of these tumors. Indeed, it has been shown that these less morbid procedures
are equally effective in achieving adequate surgical margins and lymph node dissection while
possessing the added advantage of shorter postoperative recovery times. [60, 61, 62]
An analysis of women from the Surveillance, Epidemiology, and End Results (SEER) database who
underwent radical hysterectomy with lymphadenectomy revealed that patients with node-negative

early-stage cervical cancer who underwent a more extensive lymphadenectomy had improved
survival.[63]Compared with patients who had fewer than 10 nodes removed, patients who had 21-30
nodes removed were 24% less likely to die of their tumors, and those who had more than 30 nodes
removed were 37% less likely to die.
Postoperative irradiation of the pelvis reduces the risk of local recurrence in patients with high-risk
factors (ie, positive pelvic nodes, positive surgical margins, and residual parametrial disease). [64] A
randomized trial showed that patients with parametrial involvement, positive pelvic nodes, or positive
surgical margins benefit from a postoperative combination of cisplatin-containing chemotherapy and
pelvic irradiation.[65]
Postoperative radiation therapy is also recommended in patients who have at least 2 intermediate risk
factors (including tumor size greater than 2 cm, deep stromal invasion, or lymphovascular space
invasion). For patients with IB2 or IIA cancer and tumors larger than 4 cm, radiation and
chemotherapy is selected in most cases. Risks are associated with combined therapy, but many of
these patients will meet either intermediate- or high-risk criteria after radical hysterectomy and
therefore are strong candidates for this approach.

Stage IIB, III, or IVA cancer

For locally advanced cervical carcinoma (stages IIB, III, and IVA), radiation therapy was the treatment
of choice for many years. Radiation therapy begins with a course of external beam radiation to reduce
tumor mass and thereby enable subsequent intracavitary application. Brachytherapy is delivered by
means of afterloading applicators that are placed in the uterine cavity and vagina.
Additionally, the results from large, well-conducted, prospective randomized clinical trials have
demonstrated a dramatic improvement in survival when chemotherapy is combined with radiation
therapy.[66, 67, 68] Consequently, the use of cisplatin-based chemotherapy in combination with radiation
has become the standard of care for primary management of patients with locally advanced cervical
cancer.[10]

Stage IVB and recurrent cancer

Individualized therapy is used on a palliative basis. Radiation therapy is used alone for control of
bleeding and pain, whereas systemic chemotherapy is used for disseminated disease. [10] For recurrent
disease, the choice of therapy is influenced by the treatments previously employed.
Treatment of pelvic recurrences after primary surgical management should include single-agent
chemotherapy and radiation, and treatment for recurrences elsewhere should include combination
chemotherapy.[69, 70, 71] For central pelvic recurrence after radiation therapy, modified radical
hysterectomy (if the recurrence is smaller than 2 cm) or pelvic exenteration should be undertaken. [72, 73]
For disease recurring after chemotherapy and radiation therapy, a disease-free interval of more than
16 months is considered to designate the tumor as platinum-sensitive. [74] The standard of care in these
cases is chemotherapy with a platinum-based doublet of paclitaxel and cisplatin. [70, 71, 75, 76]
The NCCN also recommends bevacizumab, docetaxel, gemcitabine, ifosfamide, 5-fluorouracil,
mitomycin, irinotecan, and topotecan as possible candidates for second-line therapy (category 2B
recommendation), as well as pemetrexed and vinorelbine (category 3 recommendation). In addition,
bevacizumab as single-agent therapy is also acceptable. [10]
In a recent analysis, by the National Cancer Institute (NCI), of the clinical trial Gynecologic Oncology
Group (GOG) 240, bevacizumab was found to extend survival by almost 4 months in patients with
advanced, recurrent, or persistent cervical cancer that had not responded to standard surgery or
radiotherapy.[77]
According to the NCI analysis of bevacizumab in cervical cancer patients, median survival was better
in women treated with chemotherapy plus bevacizumab, versus those treated with chemotherapy
alone. A total of 452 patients with pretreated metastatic, recurrent, or persistent cervical cancer were
enrolled in the GOG 240 study from 2009 to 2012. The patients received bevacizumab at a dosage of
15 mg/kg body weight, in conjunction with chemotherapy, 1 day every 3 weeks until disease
progression or unacceptable toxicity occurred.[77]

Recurrences arising in a previously irradiated field or after a disease-free interval of less than 16
months are less likely to respond to subsequent therapies. Consequently, patients with such
recurrences should be strongly encouraged to participate in clinical trials. Special efforts should be
made to ensure that they receive comprehensive palliative care, including adequate pain control.

Complications of Therapy
Radiation-related complications
During the acute phase of pelvic radiation therapy, the surrounding normal tissues (eg, intestines,
bladder, and perineal skin) often are affected. Acute adverse gastrointestinal (GI) effects include
diarrhea, abdominal cramping, rectal discomfort, and bleeding. Diarrhea can usually be controlled by
giving either loperamide or atropine sulfate. Small steroid-containing enemas are prescribed to
alleviate symptoms from proctitis.
Cystourethritis also can occur, leading to dysuria, frequency, and nocturia. Antispasmodics often are
helpful for symptom relief. Urine should be examined for possible infection. If urinary tract infection
(UTI) is diagnosed, therapy should be instituted without delay.
Proper skin hygiene should be maintained for the perineum. Topical lotion should be used if erythema
or desquamation occurs.
Late sequelae of radiation therapy usually appear 1-4 years after treatment. The major sequelae
include rectal or vaginal stenosis, small bowel obstruction, malabsorption, radiation enteritis,and
chronic cystitis.

Surgical complications
The most frequent complication of radical hysterectomy is urinary dysfunction resulting from partial
denervation of the detrusor muscle. Other complications include foreshortened vagina, ureterovaginal
fistula, hemorrhage, infection, bowel obstruction, stricture and fibrosis of the intestine or rectosigmoid
colon, and bladder and rectovaginal fistulas. Invasive procedures (eg, nephrostomy or diverting
colostomy) sometimes are performed in this group of patients to improve their quality of life.

Nutrition
Proper nutrition is important for patients with cervical cancer. Every attempt should be made to
encourage and provide adequate oral food intake.
Nutritional supplements (eg, Ensure [Abbott Nutrition, Columbus, OH] or Boost [Nestl HealthCare
Nutrition, Fremont, MI]) are used when patients have had significant weight loss or cannot tolerate
regular food because of nausea caused by radiation or chemotherapy. In patients with severe
anorexia, appetite stimulants such as megestrol can be prescribed.
For patients who are unable to tolerate any oral intake, percutaneous endoscopic gastrostomy tubes
are placed for nutritional supplementation. In patients with extensive bowel obstruction as a result of
metastatic cancer, hyperalimentation sometimes is used.

Prevention of Human Papillomavirus Infection

Human papillomavirus (HPV) infection is usually transmitted sexually, though rare cases have been
reported in virgins.[78] Condom use may not prevent transmission.[79, 78] A study in a mouse model by
Roberts et al found that a widely used vaginal spermicide, nonoxynol-9, greatly increased
susceptibility to HPV infection, whereas carrageenan, a polysaccharide present in some vaginal
lubricants, prevented infection.[80]
Evidence suggests that HPV vaccines prevent HPV infection. [7] PATRICIA (PApilloma TRIal against
Cancer In young Adults) found HPV 16/18 vaccine to be efficacious against cervical intraepithelial
neoplasia (CIN) grade 2 or 3 and adenocarcinoma in situ, irrespective of the HPV type in the lesion.
[81]
Cross-protective efficacy was demonstrated against 4 oncogenic HPV types not included in the
vaccine.[82] Use of an HPV 6/11/16/18 vaccine reduced the risk of any high-grade cervical lesions by
19.0% overall, irrespective of causal HPV type.[80]
The following 2 HPV vaccines are approved by the US Food and Drug Administration (FDA):

Gardasil (Merck, Whitehouse Station, NJ) This quadrivalent vaccine is approved for girls
and women 9 to 26 years of age to prevent cervical cancer (and also genital warts and anal cancer)
caused by HPV types 6, 11, 16, and 18; it is also approved for males 9 to 26 years of age [8]

Cervarix (GlaxoSmithKline, Research Triangle Park, NC) This bivalent vaccine is approved
for girls and women 9 through 25 years of age to prevent cervical cancer caused by HPV types 16
and 18[9]
The Advisory Committee on Immunization Practices (ACIP) recommends routine HPV vaccination of
girls aged 11-12 years with 3 doses of either HPV vaccine. The vaccination series can be started as
young as age 9 years. Catch-up vaccination is recommended for females aged 13-26 years who have
not been previously vaccinated or who have not completed the full series. [83]
The ACIP also recommends routine use of quadrivalent HPV vaccine in boys aged 11-12 years, as
well as in males aged 13-21 years who have not been vaccinated previously or who have not
completed the 3-dose series. Males aged 22-26 years may also be vaccinated. [84]
Screening for cervical cancer should continue in vaccinated women, following the same guidelines as
in unvaccinated women.[5] These vaccines do not provide complete protection against cervical cancer;
oncogenic HPV types other than 16 and 18 account for about 30% of cases, and cross-protection may
be only partial. In addition, not all vaccinated patients may mount an effective response to the
vaccine, particularly if they do not receive all 3 doses or if they get the doses at time intervals that are
not associated with efficacy.
Finally, the duration of protection with these vaccines has not yet been determined. The available
evidence suggests that immunity from infection with the HPV types covered by these vaccines will
persist for at least 6-8 years,[85] but continuing follow-up will be required to determine whether
revaccination will be necessary.
The safety of HPV vaccines is a deeply controversial topic. Follow-up of large patient populations who
participated in phase 3 clinical trials has documented that both FDA-approved HPV vaccines are
extremely safe. Articles in the popular media, however, have detailed cases of young women with
devastating illness attributed to the vaccines.
In postlicensure safety surveillance for the quadrivalent HPV vaccine, 6.2% of all reports to the
Vaccine Adverse Event Reporting System (VAERS) described serious adverse events, including
neurologic injury (eg, Guillain-Barr syndrome) and 32 reports of death. In comparison with other
vaccines, rates of most of these adverse events were no greater than the background rates, but there
was disproportional reporting of syncope and venous thromboembolic events. [86]

Medication Summary
Chemotherapy should be administered in conjunction with radiation therapy to most patients with
stage IB (high-risk) to stage IVA cervical cancer. Cisplatin is the agent used most commonly, although
5-fluorouracil also is used frequently. For patients with metastatic disease, cisplatin remains the most
active agent. Topotecan, ifosfamide, and paclitaxel also have significant activity in this setting. The
combination of topotecan and cisplatin improves overall survival. However, acute toxicities are also
increased.

Chemotherapy Agents, Alkylating

Class Summary
Alkylating chemotherapy agents inhibit cell growth and proliferation. They inhibit DNA synthesis
through the formation of DNA cross-links.
View full drug information

Cisplatin (Platinol)
Intrastrand cross-linking of DNA and inhibition of DNA precursors are among the proposed
mechanisms of action for cisplatin. This agent is used in combination with radiation therapy.
View full drug information

Ifosfamide (Ifex)

Ifosfamide forms DNA interstrand and intrastrand bonds that interfere with protein synthesis. Although
the US Food and Drug Administration (FDA) has approved this agent only for the treatment of
testicular cancer, it has several off-label indications, including treatment of cervical cancer.

Antineoplastics, Antimetabolite
Class Summary
Antimetabolite antineoplastic agents inhibit cell growth and proliferation. They interfere with DNA
synthesis by blocking the methylation of deoxyuridylic acid.
View full drug information

Fluorouracil (Adrucil)
Fluorouracil is a pyrimidine antimetabolite. Several mechanisms of action have been proposed,
including inhibition of thymidylate synthase and inhibition of RNA synthesis. This agent is also a
potent radiosensitizer.

Antineoplastics, Antimicrotubular
Class Summary
Antimicrotubular antineoplastic agents prevent cell growth and proliferation. They work by enhancing
tubulin dimers, stabilizing existing microtubules, and inhibiting their disassembly.
View full drug information

Paclitaxel (Taxol)
The mechanisms of action of paclitaxel are tubulin polymerization and microtubule stabilization. This
agent also participates in the breakage of chromosomes and modulation of immune response.

Antineoplastics, Topoisomerase Inhibitors

Class Summary
Topoisomerase-inhibiting antineoplastic agents prevent cell growth and proliferation. They work by
binding to topoisomerase and causing single-strand DNA breaks.
View full drug information

Topotecan (Hycamtin)
Topotecan inhibits topoisomerase I, inhibiting DNA replication. It acts in the S phase of the cell cycle.
Patients who have received prior chemotherapy should be given a lower dose initially.

Vaccines, Inactivated, Viral

Class Summary
Two human papillomavirus (HPV) vaccines are now available for prevention of HPV-associated
dysplasias and neoplasias, including cervical cancer, genital warts (condylomata acuminata), and
precancerous genital lesions. The immunization series should be completed in girls and young
women aged 9-26 years.[9] The duration of protection is not yet known, but follow-up to date has found
sustained immunogenicity and efficacy more than 8 years after vaccination.
View full drug information

Human papillomavirus vaccine, quadrivalent (Gardasil)

The quadrivalent recombinant HPV vaccine is indicated to prevent disorders secondary to infection
from HPV types 6, 11, 16, and 18, including cervical cancer, genital warts (condylomata acuminata),
and the following precancerous genital lesions:

Cervical adenocarcinoma in situ

Cervical intraepithelial neoplasia (CIN) grades 1, 2, and 3
Vulvar intraepithelial neoplasia grades 2 and 3
Vaginal intraepithelial neoplasia grades 2 and 3

The efficacy of the vaccine is mediated by humoral immune responses following the immunization
series.
View full drug information

Human papillomavirus vaccine, bivalent (Cervarix)

The bivalent recombinant HPV vaccine is prepared from the L1 protein of HPV types 16 and 18. It is
indicated for girls and women (ages 9-25 years) to prevent the following diseases caused by
oncogenic HPV types 16 and 18:

Cervical cancer
CIN grade 2 or higher
Cervical adenocarcinoma in situ
CIN grade 1
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