Cervical Cancer

Practice Essentials

Cervical cancer (see the image below) 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.

View Image

Cervical carcinoma with adnexa.

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^{[1, 2, 3, 4]} :

• < 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

The 9-valent HPV vaccine (Gardasil 9 [9vHPV]) is available in the United States to decrease the risk of certain cancers and precancerous lesions in males and females. 9vHPV vaccine covers HPV subtypes 6, 11, 16, 18, 31, 33, 45, 52, and 58. Cervarix (2vHPV) and Gardasil (4vHPV) were discontinued in the United States in October 2016.

It is estimated that the 9vHPV vaccine can increase prevention of cervical high-grade squamous intraepithelial lesions in up to 90% of cases compared with the quadrivalent HPV vaccine.^[114]

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^[8]
• 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^[8]

See Treatment and Medication for more detail.

• References

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.^[9] (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.)

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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.^[10]

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.^{[11, 12]} 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, TNFa-572, TNFa-857, TNFa-863, and TNF G-308A have been associated with a higher incidence of cervical cancer.^{[13, 14, 15, 16]} 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.^{[17, 18, 19, 20, 21]}

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,^{[22, 23]} others with a protective effect.^{[24, 25]} The chemokine receptor-2 (CCR2) gene on chromosome 3p21^{[26, 27]} and the Fas gene on chromosome 10q24.1^{[23, 28]} 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.^[29]

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.^{[30, 31]}

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 types—16, 18, and 45—cause 94% of cervical adenocarcinomas.^[32] 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.^[33]

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).^[33]

Table 1. Human Papillomavirus Types Associated With Cervical Cancer

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See Table

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.^[34] 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.

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Etiology

With rare exceptions, cervical cancer results from genital infection with HPV, which is a known human carcinogen.^{[33, 35, 36, 37, 38]} 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.^[34] Exposure to diethylstilbestrol in utero has been associated with an increased risk of CIN grade 2 or higher.^[39]

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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.^[40]

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.^[41] This trend has been attributed to mass screening with Pap tests.^[42] Cervical cancer rates continue to rise in many developing countries, however.

The American Cancer Society (ACS) estimated that in the United States, 12,170 new cases of cervical cancer would be diagnosed in 2012.^[41] 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.^[43] 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.^[44]

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.^[45] 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.^[46] 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.^{[47, 48]}

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.^[49] 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.^[41]

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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 estimated that 4220 women would die of cervical cancer in the United States in 2012.^[41] This represents 1.3% of all cancer deaths and 6.5% of deaths from gynecologic cancers.

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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.^[50] 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.

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History

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.

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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.

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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 d’Obstetrique [FIGO]) guidelines for staging, procedures are limited to the following^[51] :

• 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.)

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Screening Recommendations

In 2014, the American College of Physicians (ACP) issued a new clinical guideline that does not recommend routine screening pelvic examinations in asymptomatic, nonpregnant adult women.^{[52, 53]} The expert panel cited not only a lack of strong evidence to support such screening but also the potential psychological/physical harms of false-positive results.^{[52, 53, 54]} Moreover, it noted that screening pelvic examinations have a low diagnostic accuracy for detecting ovarian cancer or bacterial vaginosis.^[52] The ACP recommends that screening examinations for cervical cancer should be limited to visual inspection of the cervix and to the use of cervical swabs for human papillomavirus.^[52]

Although the American College of Obstetricians and Gynecologists (ACOG) recommends routine annual pelvic examination in all women aged 21 years and older,^{[1, 2]} it recognizes that there are no data to support such examinations in low-risk asymptomatic patients.^{[53, 54]}

Previously, the American Cancer Society (ACS), the American Society for Colposcopy and Cervical Pathology (ASCCP), and the American Society for Clinical Pathology (ASCP) issued joint guidelines for cervical cancer screening.^[3] In 2012, the US Preventive Services Task Force (USPSTF) issued updated guidelines whose recommendations are consistent with those of the ACS, ASCCP, and ASCP.^[4]

Screening recommendations for specific patient age groups are as follows^{[1, 2, 3, 4]} :

• < 25 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

In January 2016, the ACOG issued screening guidelines following 2015 interim guidelines from the American Society for Colposcopy and Cervical Pathology and the Society of Gynecologic Oncology.^{[55, 2]}  The new guidelines are largely consistent with the above recommendations.^[2]

The USPSTF updated their draft recommendations in 2017 to recommend high-risk HPV testing alone every 5 years as an alternative to cytology screening alone every 3 years in women 30 years of age and older; cotesting is no longer recommended.^[56]  

In March 2013, the American Society for Colposcopy and Cervical Pathology (ASCCP) issued updated guidelines for managing women with abnormal cervical cancer screening results and diagnosed cancer precursors. The Updated Consensus Guidelines for Managing Abnormal Cervical Cancer Screening Tests and Cancer Precursors include the following^{[57, 58]} :

• Guidance for the management of discordant co-tests: If results of either Pap smear or HPV testing are positive, but not both, co-testing is integrated into follow-up care. Colposcopy, HPV DNA typing, or both may be indicated.
• Routine screening: A recommendation for a return to "routine" screening in women treated for cervical cancer is specified.
• Adolescent screening: Screening is no longer recommended for adolescents. Women aged 21-24 years are at low risk for invasive cervical cancer; however, they are at high risk for HPV exposure and associated lesions. The recommended workup varies according to findings of atypical squamous cells of undetermined significance or low-grade or high-grade squamous intraepithelial lesion; this may include colposcopy.
• Neoplasia guidance: The guidelines address 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.

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 12-month 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.^[3]

A study by Castle et al that included 990,013 women who had 1 or more HPV and cytology cotests in an 11-year period reported that five-year cervical intraepithelial neoplasia grade 3, adenocarcinoma in situ, and cervical cancer risks decreased after each successive negative co-test screening round (0.098%, 0.052%, and 0.035%).^[59]

The ACOG also issued the following recommendations on cervical cancer screening in HIV-positive women^{[1, 2]} :

• HIV-positive women younger than 30 yr can undergo cytology testing once every 3 yr instead of annually if they have had thre3 consecutive normal annual cytology tests; ACOG recommends against cotesting for women younger than 30 yr
• Women with HIV who are aged 30 yr or older can undergo either testing with cytology alone or cotesting; those with three consecutive normal annual cytology tests can then be screened annually, and those with one normal cotest result can also be screened annually
• ACOG recommends against starting screening before age 21 yr unless a woman is HIV-positive, regardless of the age of onset of sexual intercourse, as only 0.1% of cases of cervical cancer occur before age 20 yr, and evidence that screening is effective in this age group is lacking

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Papanicolaou 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.^[60]

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.^[60]

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.

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Human Papillomavirus Testing

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.

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Imaging 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.^[8]

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.^[8]

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CT scan of cervical cell carcinoma demonstrates markedly enlarged lymph node at left pelvic sidewall. This is consistent with pelvic lymph node metast....

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.^[61] (See also Cervical Cancer Imaging.)

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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 fine-needle aspiration of lymph nodes, has failed to demonstrate metastatic disease.

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Histologic 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.^[62]

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

  View Image

  Cervical intraepithelial neoplasia grade I.

  View Image

  Cervical intraepithelial neoplasia grade III.

  View Image

  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.

A study by Wang et al reported that atypical glandular cells found at cervical screening is associated with increased risk of cervical cancer for up to 15 years, particularly for cervical adenocarcinoma and women with atypical glandular cells at age 30-39.^[63]

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FIGO and TNM Staging

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)^[51]
• The TNM system, developed by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC)^[64]

Table 2. Cervical Cancer Staging: Primary Tumor (T)

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See Table

In the UICC/AJCC system, regional lymph node (N) involvement—including paracervical, parametrial, hypogastric (obturator), common, internal and external iliac, and presacral and sacral nodes—is 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

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See Table

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Approach Considerations

Intravaginal application of 5% 5-fluorouracil (5-FU) was found to be an effective treatment for cervical intraepithelial neoplasia (CIN) 2 in a prospective, nonblinded, randomized controlled study of 60 women.^{[65, 66]} At 6-month follow-up, disease regression was observed in 26 of 28 women (93%) who were treated with 5-FU and in 15 of 27 women (56%) in an observation-only group. Normal cervical biopsy, a normal Pap smear, and a negative human papillomavirus (HPV) test were seen in 14 of the 28 patients in the treatment group at 6-month follow-up, compared with 6 of the 17 patients in the observation group.^{[65, 66]} Topical 5-FU was well tolerated.

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.

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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).^[8]

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.^[8] The principal problems with pregnancy after trachelectomy are premature labor and the need to undergo cesarean section for delivery.^[67]

In a retrospective review of 62 patients with stage IB1 cervical carcinoma who underwent attempted radical trachelectomy and underwent preoperative magnetic resonance imaging (MRI), Lakhman et al found that pretrachelectomy MRI helped identify high-risk patients who were likely to need radical hysterectomy and helped confirm the absence of residual tumor after a cone biopsy with negative margins.^[68] A tumor size of 2 cm or larger and deep cervical stromal invasion on MRI were associated with an increased chance of radical hysterectomy.

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.^[69]

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.^{[70, 71, 72]}

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.^[73] 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).^[74] 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.^[75]

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.^{[76, 77, 78]} 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.^[8]

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.^[8] 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.^{[79, 80, 81]} For central pelvic recurrence after radiation therapy, modified radical hysterectomy (if the recurrence is smaller than 2 cm) or pelvic exenteration should be undertaken.^{[82, 83]}

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.^[84] The standard of care in these cases is chemotherapy with a platinum-based doublet of paclitaxel and cisplatin.^{[80, 81, 85, 86]}

The NCCN also recommends 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.^[8]

Treatment with bevacizumab plus cisplatin and paclitaxel or topotecan and paclitaxel was approved by the FDA in August 2014 for persistent, recurrent, or metastatic cervical cancer.^{[87, 88]} A statistically significant improvement in overall survival (OS) and an increase in the rate of tumor shrinkage was shown in women treated with bevacizumab plus chemotherapy compared with chemotherapy alone.^{[87, 89]} However, hypertension, thromboembolic events, and GI fistulas were higher in the bevacizumab group.^[89] Bevacizumab/paclitaxel/cisplatin or topotecan is considered a first-line regimen for recurrent or metastatic cervical cancer.^[8]

In a randomized study of 452 women with advanced cervical cancer (recurrent, persistent, or metastatic disease), Tewari et al reported that adding bevacizumab to combination chemotherapy prolonged survival in these women by about 3.7 months compared with chemotherapy alone (topotecan plus paclitaxel; cisplatin plus paclitaxel).^{[89, 90, 91, 92]} Because topotecan-paclitaxel was not superior to cisplatin-paclitaxel, the data from the groups treated with these combination regimens were combined.^{[89, 90]}

Median overall survival was 17.0 months with bevacizumab and chemotherapy, whereas it was 13.3 months with chemotherapy alone.^{[89, 90, 91, 92]} At a median follow-up of 20.8 months, 60% of the patients died.^[90] Progression-free survival was 8.2 months with bevacizumab plus chemotherapy but 5.9 months with chemotherapy alone. The response rate was 48% with bevacizumab and chemotherapy compared with 36% in the group receiving chemotherapy alone.^{[89, 90, 91, 92]} However, the addition bevacizumab also led to an increased incidence of adverse effects such as hypertension of grade 2 or higher (25% vs 2%), thromboembolic events of grade 3 or higher (8% vs 1%), and gastrointestinal fistulas of grade 3 or higher (3% vs 0%) compared with chemotherapy alone.^{[89, 90]}

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.

In June 2018, the FDA approved pembrolizumab for treatment of recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1 or greater) as determined by an FDA-approved test. Approval was based on the KEYNOTE-158 clinical trial (n=98). For the 77 patients whose tumors expressed PD-L1 with a CPS of 1 or greater, the ORR was 14.3%, with a CRR of 2.6% and partial response rate of 11.7%. Among the 11 responding patients, median duration of response was not yet reached (range, 4.1 to 18.6+ months) and 91% experienced a DOR of 6 months or longer. The median follow-up time was 11.7 months (range, 0.6 to 22.7 months).^[112]

• References

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.

• References

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 [Nestlé 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.

• References

Prevention of Human Papillomavirus Infection

Human papillomavirus (HPV) infection is usually transmitted sexually, though rare cases have been reported in virgins.^[93] Condom use may not prevent transmission.^{[93, 94]} 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.^[95]

Evidence suggests that HPV vaccines prevent HPV infection.^[5] 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.^[96] Cross-protective efficacy was demonstrated against 4 oncogenic HPV types not included in the vaccine.^[97] 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.^[95]

One HPV vaccine is available in the United States. A nine-valent HPV vaccine (Gardasil 9, 9vHPV) is indicated for females aged 9 through 45 years  to prevent cervical cancer (and also genital warts and anal cancer); in addition to coverage of HPV types 6, 11, 16, and 18, it covers HPV types 31, 33, 45, 52, and 58.^[98]  Other HPV vaccines (2vHPV [Cervarix], 4vHPV [Gardasil]) are no longer available in the United States. 

The 9vHPV vaccine is approved by the FDA for routine HPV vaccination of females and males aged 9 through 45 years.^[115] 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.^[99]  The 9vHPV vaccine may be offered as a 2-dose series for children and young adolescents aged 9-14 years.^[100]

In the Costa Rica Vaccine Trial, researchers documented durable antibody responses after 1 dose (as opposed to the standard 3 doses) of the bivalent human papillomavirus (HPV) 16/18 L1 viruslike particle vaccine Cervarix.^{[101, 102]} The investigators evaluated 78 women who received 1 dose of the vaccine, 192 who received 2 doses, and 120 who received all 3 doses. These women were compared with 113 women who did not receive vaccine but had antibodies against the viruses. All subjects in the 3 vaccine groups had antibodies against HPV 16 and 18 for as long as 4 years.^[102] Although antibody titers in women who received 1 dose were lower than those in women who received 3 doses, they remained stable over 4 years.

Screening for cervical cancer should continue in vaccinated women, following the same guidelines as in unvaccinated women.^[3] 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,^[103] 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 post licensure 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-Barré 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.^[104]

• References

Guidelines Summary

Guideline Contributor: Jori S Carter, MD, MS Assistant Professor, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Virginia Commonwealth University School of Medicine

Screening

Cervical cancer screening has traditionally used the Pap smear (conventional or liquid-based cytology). More recently, cytology has been supplemented by human papillomavirus (HPV) testing. Samples for these tests may be taken during a pelvic examination, along with visual inspection of the cervix, but the pelvic examination itself is not part of the screening process for cervical cancer.^[52]

Guidelines on cervical cancer screening have been issued by the following organizations:

• American Cancer Society (ACS)
• American Congress of Obstetrics and Gynecology (ACOG)
• American College of Physicians (ACP)
• American Society of Clinical Pathology (ASCP)
• American Society of Colposcopy and Cervical Pathology (ASCCP)
• U.S. Preventive Services Task Force (USPSTF)

In May 2012, the ACS, the ASCCP, and the ASCP issued joint guidelines for cervical cancer screening,^[3] followed shortly thereafter by updated guidelines from the USPSTF, whose recommendations are consistent with those of the ACS, ASCCP, and ASCP.^[4] In November 2012, ACOG issued new screening guidelines that were also consistent with the recommendations of these groups.^[2] In April 2015, the ACP issued best practice advice on cervical cancer screening in average-risk women; the recommendations were supported by ACOG and endorsed by ASCP. Screening recommendations for specific patient groups are as follows^{[3, 4, 2]} :

Table 1. Cervical Cancer Screening Recommendations

Table. 1

View Table

See Table

Although current guidelines advise against performing HPV testing in women younger than 30 years of age, and do not recommend HPV testing alone for primary cervical cancer screening, a growing body of evidence calls these recommendations into question. In April 2015, a panel of experts that included representatives from seven relevant organizations issued interim guidance that supports primary HPV testing as a reasonable technique for cervical cancer screening.^[105]

The USPSTF updated their draft recommendations in 2017 and 2018 to recommend high-risk HPV testing alone every 5 years as an alternative to cytology screening alone every 3 years in women 30 years of age and older; or cotesting every 5 years.^{[56, 113]}

ACOG guidelines for cervical cancer screening in HIV-positive women are as follows^[2] :

• HIV-positive women represent an exception to the recommendation against starting screening before age 21
• HIV-positive women younger than 30 yr can undergo cytology testing once every 3 yr instead of annually if they have had three consecutive normal annual cytology tests
• ACOG recommends against cotesting for women younger than 30 yr
• Women with HIV who are 30 yr of age or older can undergo either testing with cytology alone or cotesting with cytology and HPV testing; those with three consecutive normal annual cytology tests can then be screened annually, and those with one normal cotest result can also be screened annually

Management of Abnormal Screening Results

In 2013, both the American Society for Colposcopy and Cervical Pathology (ASCCP) and the American Congress of Obstetricians and Gynecologists (ACOG) released updated guidelines for managing women with abnormal cervical cancer screening results and diagnosed cancer precursors.

ASCCP and ACOG each provided detailed management algorithms for the following scenarios:^{[58, 106]}

• Women age 30 or older who are cytology negative but HPV positive
• Women with atypical squamous cells of undetermined significance (ASC-US) on cytology
• Women 21-24 years of age with either ASC-US or low-grade squamous intraepithelial lesion (LSIL)
• Women with LSIL
• Women 21-24 years of age with atypical squamous cells, cannot rule out high-grade SIL (ASC-H) and high-grade squamous intraepithelial lesion (HSIL)
• Women with HSIL
• Initial workup of patients with atypical glandular cells (AGC)
• Subsequent management of patients with AGC
• Women with no lesion or biopsy-confirmed grade 1 cervical intraepithelial neoplasia (CIN1) preceded by "lesser abnormalities"
• Women with no lesion or biopsy-confirmed CIN1 preceded by ASC-H or HSIL cytology
• Women 21-24 years of age with no lesion or biopsy-confirmed CIN1
• Young women with biopsy-confirmed grade 2 or 3 cervical intraepithelial neoplasia (CIN 2,3)
• Young women with biopsy-confirmed CIN 2,3 in special circumstances

ASCCP also provided management algorithms for the following scenarios^[58] :

• Women with unsatisfactory cytology
• Women with negative cytology but endocervical/transformation zone absent or insufficient
• Pregnant women with LSIL
• Women with atypical squamous cells; cannot exclude ASC-H
• Women diagnosed with adenocarcinoma in situ (AIS) during a diagnostic excisional procedure

The ASCCP consensus guidelines, which are also endorsed by the National Comprehensive Cancer Network (NCCN), include the following major recommendations^[58] :

• If either (but not both) Pap smear or HPV testing yields positive results, co-testing is integrated into follow-up care; colposcopy, HPV DNA typing, or both may be indicated
• Return to "routine" screening in women treated for cervical cancer
• Colposcopy may be required for women with positive HPV results or with repeated unsatisfactory cytological findings that are missing endocervical or transformation zone components

The ACOG recommendations fall into three categories: those based on consistent scientific evidence, those based on limited and/or inconsistent scientific evidence, and those primarily based on consensus and expert opinion. Major recommendations with consistent scientific evidence include the recommended screening outlined in Table 1, above, and the following^{[106, 2]} :

• For women with ASC-US, reflex HPV testing is preferred
• For women with HPV-positive ASC-US, whether identified on reflex HPV testing or co-testing, colposcopy is recommended
• For women with LSIL and no HPV test or a positive HPV test result, colposcopy is recommended
• For women with a histologic diagnosis of cervical intraepithelial neoplasia (CIN) 2, CIN 3, or CIN 2,3 and adequate colposcopic examination, both excision and ablation are acceptable treatment modalities, except in pregnant women and young women

The ACOG guidelines note that women with any of the following risk factors may require more frequent cervical cancer screening than is recommended in the routine screening guidelines, which were intended for average-risk women:

• HIV infection
• Immunocompromise (eg, solid organ transplant recipients)
• Exposure to diethylstilbestrol in utero
• Previous treatment for CIN 2, CIN 3, or cancer

Prevention

With rare exceptions, cervical cancer results from genital infection with HPV, which is a known human carcinogen. The U.S. Advisory Committee on Immunization Practices (ACIP) has issued the following recommendations for HPV vaccination^[107] :

• Routine vaccination of girls or boys aged 11-12 years with 2 or 3 doses of HPV9
• Previously unvaccinated females and males aged 13-26 years
• Children as young as 9 years may be vaccinated, particularly if there is a history of sexual abuse or assault
• Any man who has sex with a man and individuals with compromised immune systems (including people with HIV infection/AIDS), through age 26, if they were not fully vaccinated when they were younger

• References

Staging

In the International Federation of Gynecology and Obstetrics (Federation Internationale de Gynecologie et d’Obstetrique [FIGO]) guidelines for staging, procedures are limited to the following^[51] :

• Colposcopy
• Biopsy
• Conization of cervix
• Cystoscopy
• Proctosigmoidoscopy

The National Comprehensive Cancer Network (NCCN) guidelines include the addition of CT, MRI, combined PET-CT and surgical staging to guide treatment options. While the NCCN notes that cervical cytology and cervical biopsy generally results in an accurate diagnosis, cone biopsy (conization) is recommended if the cervical biopsy is inadequate to define invasiveness.^[116]

• References

Treatment

The European Society for Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN) have both released guidelines for the management of cervical cancer.^{[116, 108]}

In addition, the American Society for Clinical Oncology has released fertility preservation guidelines for adults with cancer. General recommendations include the following^[109] :

• The possibility of infertility should be addressed as early as possible before treatment starts
• Refer patients who express an interest in fertility preservation (and patients who are ambivalent) to reproductive specialists
• Answer basic questions about whether fertility preservation may have an impact on successful cancer treatment

Specific recommendations for treating women with cervical cancer include the following^[109] :

• Radical trachelectomy should be restricted to stage IA2 to IB cervical cancer with diameter < 2 cm and invasion < 10 mm
• Both embryo and oocyte cryopreservation should be offered as established fertility preservation methods
• Offer cryopreservation of unfertilized oocytes as an option for patients who do not have a male partner, do not wish to use donor sperm, or have religious or ethical objections to embryo freezing
• Ovarian transposition (oophoropexy) is an option when pelvic radiation therapy is performed; however, because of radiation scatter, ovaries are not always protected, and patients should be aware that this technique is not always successful

Early-stage (IA1) disease

ESMO and NCCN guidelines are in agreement that the treatment of choice for stage IA1 disease with no lymphovascular space invasion (LVSI) is fertility-sparing cone biopsy, or if preservation of fertility is not relevant, simple hysterectomy. For stage IA1 with LVSI, a cone biopsy or hysterectomy with lymphadenectomy is recommended; the NCCN recommends modified radical hysterectomy, while ESMO recommends extrafascial hysterectomy.^{[116, 108]}

According to the NCCN guidelines, postoperative pelvic radiation therapy (with or without concurrent cisplatin chemotherapy) is a category 1 recommendation for women with stage IA disease and negative lymph nodes after surgery who have high-risk cervical factors (eg, a large primary tumor, deep stromal invasion, and/or lymphovascular space invasion).^[116]

Stage IA2 disease

The NCCN and ESMO provide recommendations that include the following^{[116, 108]} :

• Fertility-sparing radical trachelectomy (NCCN) and pelvic lymph node dissection
• Cone biopsy followed by observation is acceptable, if the margins and lymph node dissection are negative
• For patients who do not desire fertility preservation, modified radical hysterectomy (NCCN) or extrafascial hysterectomy (ESMO) and bilateral pelvic lymph node dissection; ESMO recommends radical trachelectomy or radical hysterectomy with lymph node dissection when LVSI is present
• Pelvic radiation with brachytherapy (NCCN) or brachytherapy alone (ESMO) is recommended as an alternative option

Stage IB or IIA

According to NCCN guidelines, fertility-sparing radical trachelectomy and pelvic lymph node dissection is an option only for stage IB1 with tumors ≤2 cm. However, fertility-sparing treatment is not recommended for stage IB1 small-cell neuroendocrine histology and adenoma malignum.10 ESMO guidelines recommend either radical trachelectomy or conization with/without chemotherapy are offered as a fertility-preserving option to stage IB1 patients.^[55]

NCCN and ESMO non–fertility-sparing recommendations for stage IB or IIA are as follows^[108] :

• Radical hysterectomy and bilateral pelvic lymph node dissection: preferred for stages IB1 or IIA1; alternative treatment for stages IB2 or IIA2
• Concurrent chemoradiation is the preferred treatment for stages IB2 or IIA2
• Pelvic radiotherapy and brachytherapy with or without concurrent cisplatin-based chemotherapy is also acceptable for patients with stage IB1 or IIA1 disease

ESMO found no evidence that chemoradiation would be useful in patients with stages IB1 or IIA and tumors < 4 cm.^[108]

Advanced Disease

The NCCN acknowledges that traditionally, advanced disease included stages IIB-IVA; however, many oncologists now also include patients with IB2 and IIA2 in the advanced disease category. The NCCN advises that concomitant chemoradiation and brachytherapy is the standard of care. Radiation therapy is given in four to six cycles of 1.8-2 Gy, with one of the following cisplatin-based chemotherapy regimens^[116] :

• Cisplatin 40 mg/m² IV once weekly (not to exceed 70 mg/wk) or
• Cisplatin 50-75 mg/m² IV on day 1 plus 5-fluorouracil (5-FU) 1000 mg/m² continuous IV infusion on days 2-5 and days 30-33 (total dose 4000 mg/m² each course) or
• Cisplatin 50-75 mg/m² IV on day 1 plus 5-FU 1000 mg/m² continuous IV infusion over 24 h on days 1-4 (total dose 4000 mg/m² each cycle) every 3 wk for a total of three to four cycles

The ESMO guidelines provide similar recommendations.^[108]

In 2016, the American Society of Clinical Oncology (ASCO) issued its first clinical practice guideline on invasive cervical cancer. The guideline is "resource-stratified," and gives treatment recommendations that are tailored to the availability of healthcare resources in specific regions.^{[110, 111]} :

Some of the key recommendations are:

• In basic settings, where radiation therapy is not an option, extrafascial hysterectomy, either alone or after chemotherapy, can be an option for women with stage IA1 to IVA cervical cancer.
• Concurrent radiotherapy and chemotherapy is the standard of care in enhanced and maximal settings for women with stage IB to IVA disease. The addition of concurrent low-dose chemotherapy with radiotherapy is emphasized, but not at the cost of delaying radiation therapy if chemotherapy is not available.
• In limited-resource settings where brachytherapy is not available, extrafascial hysterectomy or a modification in patients who have residual tumor 2 to 3 months after concurrent chemoradiotherapy and additional boost is recommended.
• Patients with stage IV or recurrent cervical cancer in basic settings can receive single-agent chemotherapy (carboplatin or cisplatin).
• For patients who cannot be treated with curative intent, palliative radiotherapy should be used to relieve symptoms of pain and bleeding, if resources are available.
• In settings of scarce resources, single- or short-course radiotherapy regimens can used for retreatments, if feasible, for persistent or recurrent symptoms.
• If follow-up care is available, cone biopsy is recommended for women with stage 1A2 disease in basic-resource settings, and cone biopsy plus pelvic lymphadenectomy is recommended in limited settings. For patients in enhanced and maximal settings, radical trachelectomy is recommended for those with stage IB1 cervical cancer with tumor size up to 2 cm who desire fertility-sparing surgery.

Metastatic Disease

The NCCN and ESMO recommend cisplatin-based chemotherapy on a palliative basis.^{[116, 108]} The NCCN further recommends that radiation therapy may be considered for control of bleeding and pain. In addition, for second-line therapy, docetaxel, gemcitabine, ifosfamide, 5-fluorouracil, mitomycin, irinotecan, and topotecan may be considered (category 2B recommendation), as well as pemetrexed and vinorelbine (category 3 recommendation). Bevacizumab as single-agent therapy is also acceptable.^[116]

• References

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.

• References

Cisplatin (Platinol)

• Dosing, Interactions, etc.

Clinical Context:  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.

• References

Ifosfamide (Ifex)

• Dosing, Interactions, etc.

Clinical Context:  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.

• References

Class Summary

Alkylating chemotherapy agents inhibit cell growth and proliferation. They inhibit DNA synthesis through the formation of DNA cross-links.

• References

Fluorouracil (Adrucil)

• Dosing, Interactions, etc.

Clinical Context:  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.

• References

Class Summary

Antimetabolite antineoplastic agents inhibit cell growth and proliferation. They interfere with DNA synthesis by blocking the methylation of deoxyuridylic acid.

• References

Paclitaxel (Taxol)

• Dosing, Interactions, etc.

Clinical Context:  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.

• References

Class Summary

Antimicrotubular antineoplastic agents prevent cell growth and proliferation. They work by enhancing tubulin dimers, stabilizing existing microtubules, and inhibiting their disassembly.

• References

Topotecan (Hycamtin)

• Dosing, Interactions, etc.

Clinical Context:  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.

• References

Class Summary

Topoisomerase-inhibiting antineoplastic agents prevent cell growth and proliferation. They work by binding to topoisomerase and causing single-strand DNA breaks.

• References

Bevacizumab (Avastin)

• Dosing, Interactions, etc.

Clinical Context:  Bevacizumab is a recombinant humanized monoclonal antibody to VEGF. It blocks the angiogenic molecule VEGF, thereby inhibiting tumor angiogenesis and starving the tumor of blood and nutrients. It is indicated as part of a combination chemotherapy regimen for persistent, recurrent, or metastatic carcinoma of the cervix.

• References

Class Summary

Vascular endothelial growth factor (VEGF) is crucial to angiogenesis. VEGF inhibitors directly bind to the VEGF protein to disrupt angiogenesis.

• References

Pembrolizumab (Keytruda)

• Dosing, Interactions, etc.

Clinical Context:  Indicated for treatment of recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1 or greater) as determined by an FDA-approved test.

• References

Class Summary

Monoclonal antibodies that bind the programmed cell death-1 protein (PD-1) ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell proliferation and cytokine production.

• References

Human papillomavirus vaccine, nonavalent (Gardasil 9)

• Dosing, Interactions, etc.

Clinical Context:  Recombinant vaccine that targets 9 HPV types (6, 11, 16, 18, 31, 33, 45, 52, and 58). It is indicated for females aged 9 through 45 years to prevent cervical, vulvar, vaginal, and anal cancer. It is also indicated to prevent genital warts and dysplastic lesions (eg, cervical, vulvar, vaginal, anal). It is also indicated for males aged 9 through 45 years for prevention of neoplasias and dysplasias (eg, anal cancer).

• References

Human papillomavirus vaccine, bivalent (Cervarix)

• Dosing, Interactions, etc.

Clinical Context:  October 21, 2016: HPV bivalent vaccine discontinued in the United States.

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

• References

Class Summary

The 9-valent HPV vaccine is indicated for prevention of HPV-associated neoplasias and precancerous genital lesions. The 2-valent and 4-valent vaccines were discontinued from the US market in 2016.

Children and adolescents aged 15 years and younger need two, not three, doses of the HPV vaccine; this ACIP recommendation stems from the vaccine’s enhanced immunogenicity in preteens and adolescents aged 9-14 years. The schedule for older adolescents and young adults aged 15 through 45 years is three inoculations within 6 months.

• References