AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• References

Background

Cervical cancer is the second 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. The incidence of invasive cervical cancer has declined steadily in the United States over the past few decades; however, it continues to rise in many developing countries. The change in the epidemiological trend in the United States has been attributed to mass screening with Papanicolaou tests.

Frequency

United States

In the United States, 11,150 new cases of cervical cancer are diagnosed each year. In addition, more than 50,000 cases of carcinoma in situ are diagnosed.

International

Internationally, 500,000 new cases are diagnosed each year.

Mortality/Morbidity

Of the 11,150 patients with cervical cancer, 3,670 will die from their disease each year in the United States. This represents 1.3% of all cancer deaths and 6.5% of deaths from gynecologic cancers.

Race

In the United States, cervical cancer is more common in Hispanic, African American, and Native American women than in white women.

Sex

Cervical cancer is found only in women.

Age

Cervical cancers usually affect women of middle age or older, but it may be diagnosed in any reproductive-aged woman.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• References

History

• Because women are screened routinely, the most common finding is an abnormal Papanicolaou test result.
• Clinically, the first symptom is abnormal vaginal bleeding, usually postcoital.
• Vaginal discomfort, malodorous discharge, and dysuria are not uncommon.
• The tumor grows by extending upward to the endometrial cavity, downward to the vagina, and laterally to the pelvic wall. It can invade the bladder and rectum directly.
• • Symptoms that can evolve, such as constipation, hematuria, fistula, and ureteral obstruction with or without hydroureter or hydronephrosis, reflect local organ involvement.
  • 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

• 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 examination findings often reveal pelvic metastasis.
• Leg edema suggests lymphatic/vascular obstruction from tumor.
• If the disease involves the liver, some patients develop hepatomegaly.
• Pulmonary metastasis usually is difficult to detect upon physical examination unless pleural effusion or bronchial obstruction becomes apparent.

Causes

Early epidemiological data demonstrated a direct causal relationship between cervical cancer and sexual activity. Major risk factors observed include sex at a young age, multiple sexual partners, promiscuous male partners, and history of sexually transmitted diseases. However, the search for a potential sexually transmitted carcinogen had been unsuccessful until breakthroughs in molecular biology enabled scientists to detect viral genome in cervical cells.

Strong evidence now implicates human papillomaviruses (HPVs) as prime suspects. HPV viral DNA has been detected in more than 90% of squamous intraepithelial lesions (SILs) and invasive cervical cancers compared to a consistently lower percentage in controls. Both animal data and molecular biologic evidence confirm the malignant transformation potential of papilloma virus–induced lesions. SILs are found predominantly in younger women, while invasive cancers are detected more often in women aged 10-15 years older, suggesting slow progression of cancer.

HPV infection occurs in a high percentage of sexually active women. Most of these infections clear spontaneously within months to a few years, and only a small proportion progress to cancer. This means that other crucial factors must be involved in the process of carcinogenesis.

Three main factors have been postulated to influence the progression of low-grade SILs to high-grade SILs. These include the type and duration of viral infection, with high-risk HPV type and persistent infection predicting a higher risk for progression; host conditions that compromise immunity, such as multiparity or poor nutritional status; and environmental factors such as smoking, oral contraceptive use, or vitamin deficiencies. In addition, various gynecologic factors, including age of menarche, age of first intercourse, and number of sexual partners, significantly increase the risk for cervical cancer.

• Human papillomavirus
• • HPV is 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, E7), which function as regulatory proteins, and 2 late open reading frame proteins (ie, L1, L2), which make up the viral capsid.
  • To date, 77 different genotypes of HPV have been identified and cloned, among which, types 6, 11, 16, 18, 26, 31, 33, 35, 39, 42, 43, 44, 45, 51, 52, 53, 54, 55, 56, 58, 59, 66, and 68 have the propensity to infect anogenital tissues.
  • The HPVs that infect the human cervix fall into 2 broad categories. The low-risk types consist of HPV 6b and 11, which are associated with low-grade SILs but are never found in invasive cancer. The high-risk types, mostly HPV 16 and 18, are found in 50-80% of SILs and in up to 90% of invasive cancers. Although less common, types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82 should also be considered carcinogenic.
  • The major difference between the 2 types is that after infection, the low-risk HPVs are maintained as extrachromosomal DNA episomes, while the high-risk HPV genome is found integrated into the host cellular DNA. The recombination event often leaves E6 and E7 directly coupled to the viral promoter and enhancer sequences, allowing their continued expression after integration. Because E7 binds and inactivates the Rb protein while E6 binds p53 and directs its degradation, the functional loss of both TP53 and the 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 human immunodeficiency virus (HIV) infection in the pathogenesis of cervical cancer is not fully understood. Studies have shown a higher prevalence of HPV in HIV-seropositive women than in seronegative women, and the HPV prevalence was directly proportional to the severity of immunosuppression as measured by CD4 counts.
  • Impaired lymphocyte function has been postulated to enhance latent or subclinical HPV activity, resulting in a higher rate of persistent infection.
  • Whether HIV has a synergistic effect on HPV infection, either by direct molecular interaction or through an indirect immunologic effect, remains unclear.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• References

Other Problems to be Considered

Cervicitis/infection, particularly granulomatous (rare)
Vaginal cancer
Metastatic cancer to cervix (rare)

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• References

Lab Studies

• A Papanicolaou test should be performed in every patient suggested to have a diagnosis of cervical cancer.
• The patient should be referred to a gynecologist for colposcopy, direct biopsies, and endocervical curettage.
• After the diagnosis is established, a complete blood cell count and serum chemistry for renal and hepatic functions should be ordered to look for abnormalities from possible metastatic disease.

Imaging Studies

• Once the diagnosis is established, imaging studies are performed for staging purposes.
• A routine chest radiograph should be obtained to help rule out pulmonary metastasis.
• CT scan of the abdomen and pelvis is performed to look for metastasis in the liver, lymph nodes, or other organs and to help rule out hydronephrosis/hydroureter.
• In patients with bulky primary tumor, barium enema studies can be used to evaluate extrinsic rectal compression from the cervical mass.
• The use of positron emission tomography (PET) scan is now recommended for patients with ³ stage IB2.

Other Tests

The International Federation of Gynecology and Obstetrics (FIGO) guidelines for staging are limited to colposcopy, biopsy, conization of cervix, cystoscopy, and proctosigmoidoscopy.

In the United States, more complex radiologic imaging, such as CT, MRI, and PET scans as well as surgical staging, are often done to guide therapeutic options.

Procedures

• In patients with bulky primary tumor, cystoscopy and proctoscopy should be performed to help rule out local invasion of the bladder and the colon.
• 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 frequently is recommended. Pretreatment surgical staging is the most accurate method to determine the extent of disease. However, little evidence suggests an improvement in overall survival with routine surgical staging. Therefore, pretreatment surgical staging should be individualized after a thorough nonsurgical workup, including fine-needle aspiration of lymph nodes, has failed to demonstrate metastatic disease.

Histologic Findings

Precancerous lesions of the cervix usually are detected via Papanicolaou test. The Papanicolaou test classification system has evolved over the years. In 1988, the National Cancer Institute (NCI) sponsored a workshop to standardize Papanicolaou test reporting. Currently, cervical cytology results are reported according to the 2001 Bethesda System.

Table 1. 2001 Bethesda System for Reporting Cervical Cytologic Diagnoses

General considerations

Complete evaluation should include Papanicolaou test with cytobrush and endocervical and endometrial samplings. If the smear result is suggestive of adenocarcinoma in situ, a cone biopsy should be performed. If the pathology still is unclear after the above workup, the patient should have dilatation and curettage.

Consideration should be given to obtaining ultrasound findings that adequately define the fallopian tubes and ovaries prior to defining uterine curettage to help identify primary malignancies of these organs.

Regarding invasive cervical cancer, the histology of cervical malignancy is predominantly of epithelial origin, with squamous cell carcinoma as the major group (85%). Less common histologies include adenocarcinoma, small cell carcinoma, melanoma, and lymphoma.

Staging

Two staging systems are frequently used in cervical cancer: FIGO, in collaboration with the World Health Organization (WHO), and the International Union Against Cancer (UICC). 

Table 2. Cervical Cancer Staging (primary tumor [T])

• NX: Regional lymph nodes cannot be assessed.
• N0: No regional lymph nodes metastasis.
• N1: Regional lymph nodes metastasis.

Table 3. AJCC Stage Grouping

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• References

Medical Care

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.

• Stage 0: Treatment options for stage 0 cancer include loop electrosurgical excision procedure (LEEP), laser therapy, conization, and cryotherapy.
• Stage IA: The treatment of choice for stage IA disease is surgery—total hysterectomy, radical hysterectomy, and conization are accepted procedures. Intracavitary radiation is an option for selected patients.
• Stage IB or IIA
• • For patients with stage IB or IIA disease, treatment options are either combined external beam radiation with brachytherapy or radical hysterectomy with bilateral pelvic lymphadenectomy.
  • Radical trachelectomy with pelvic lymph node dissection is appropriate for fertility preservation in stage IA2 and B1.
  • Most retrospective studies have shown equivalent survival rates for both procedures, although such studies usually are flawed due to patient selection bias and other compounding factors. However, a recent randomized study showed identical overall and disease-free survival rates.
  • Quality-of-life data, particularly in the psychosexual area, is relatively scant.
  • Postoperative radiation to the pelvis decreases the risk of local recurrence in patients with high-risk factors (positive pelvic nodes, positive surgical margins, and residual parametrial disease).
  • A recent 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 radiation.
• Stage IIB-IVA
• • For locally advanced cervical carcinoma (stages IIB, III, and IVA), radiation therapy was the treatment of choice for many years. However, the results from large randomized clinical trials demonstrated a dramatic improvement in survival with the combined use of chemotherapy and radiation.
  • For treatment with radiation alone, 5-year survival rates reportedly are 65-75%, 35-50%, and 15-20% for stages IIB, III, and IVA, respectively.
  • Radiation therapy begins with a course of external beam radiation to reduce tumor mass to enable subsequent intracavitary application. Brachytherapy is delivered using afterloading applicators that are placed in the uterine cavity and vagina.
  • The results of prospective, randomized, well-conducted studies of concurrent chemoradiation changed the standard of care in this group of patients.
  • In the Radiation Therapy Oncology Group trial, 403 patients with bulky IB and IIB-IVA cancers were randomized to either radiotherapy to a pelvic and paraaortic field or pelvic radiation with concurrent cisplatin and fluorouracil. Rates of both disease-free survival and overall survival were significantly higher in the group that received combination treatment.
  • Rose and associates conducted a Gynecologic Oncology Group (GOG) trial for patients with stage IIB, III, or IVA cancer, comparing the combination of radiation with 3 different chemotherapy regimens (cisplatin alone, cisplatin/5-fluorouracil/hydroxyurea, and hydroxyurea alone). Overall survival rates were significantly higher in the 2 groups that received cisplatin-containing regimens.¹
  • In another GOG trial, patients with bulky stage IB disease were randomized to either radiation alone or a combination of weekly cisplatin and radiation. All patients had adjuvant hysterectomy. Both disease-free survival and overall survival rates were significantly higher in the combined-therapy group at 4 years of follow-up.
  • Based on the aforementioned study results, using cisplatin-based chemotherapy in combination with radiation for patients with locally advanced cervical cancer represents the standard of care.
• Stage IVB and recurrent cancer
• • These patients are treated with chemotherapy. For many years, single agent cisplatin represented the standard of care. Recently, the combined use of cisplatin and topotecan was shown to significantly improve survival compared with single-agent cisplatin.
  • Palliative radiation is often used individually to control bleeding, pelvic pain, or urinary or partial large bowel obstructions from pelvic disease.
  • Total pelvic exenteration may be considered in patients with an isolated central pelvic recurrence.

Surgical Care

• Carcinoma in situ (stage 0) is treated with local ablative measures such as cryosurgery, laser ablation, and loop excision.
• • Hysterectomy should be reserved for patients with other gynecologic indications to justify the procedure.
  • After local treatment, these patients require lifelong surveillance.
• Palliative radiation often is used individually to control bleeding, pelvic pain, or urinary or partial large bowel obstructions from pelvic disease.
• Invasive procedures such as nephrostomy or diverting colostomy sometimes are performed in this group of patients to improve their quality of life.
• Special effort should be made to ensure comprehensive palliative care, including adequate pain control for these patients.
• The standard treatment for microinvasive disease (stage IA) is total hysterectomy.
• • 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 have a therapeutic conization with close follow-up, including cytology, colposcopy, and endocervical curettage.
  • Patients with medical comorbidities who are not surgical candidates can be successfully treated with radiation.

Consultations

• The treatment of cervical cancer frequently requires a multidisciplinary approach involving a gynecologic oncologist, radiation oncologist, and medical oncologist.

Diet

• Proper nutrition is important for patients with cervical cancer. Every attempt should be made to encourage and provide adequate oral food intake.
• Nutritional supplements such as Ensure or Boost are used when patients have had significant weight loss or cannot tolerate regular food due to nausea caused by radiation or chemotherapy.
• In patients with severe anorexia, appetite stimulants such as Megace 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.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• References

Chemotherapy should be administered in conjunction with radiation therapy to most patients with stage IB (high risk) to IVA. 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.

Drug Category: Chemotherapy agents

Inhibit cell growth and proliferation.

Drug Category: Vaccines

A human papillomavirus (HPV) vaccine is now available for prevention of HPV-associated dysplasias and neoplasias, including cervical cancer, genital warts (condyloma acuminata), and precancerous genital lesions. The immunization series should be completed in girls and young women aged 9-26 years.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• References

Deterrence/Prevention

• Screening of cervical cancer
• • For many years, the standard method for cervical cancer screening has been the Papanicolaou test. Retrospective data have shown that screening with a Papanicolaou test reduces the incidence rate of cervical cancer by 60-90% and the death rate by 90%.
  
  
  • The false-negative rate of a Papanicolaou test is 20%, which mostly results from sampling error. Physicians can reduce sampling error by ensuring adequate material is taken from both the endocervical canal and the ectocervix. Smears without endocervical or metaplastic cells must be repeated. Upon physical examination, suspicious or grossly abnormal cervical lesions should undergo biopsy regardless of cytologic findings.
  • Recently, new technologies have become available. Limited information is available regarding their sensitivity and specificity (compared with the conventional Papanicolaou test). Whether these new methods improve survival, compared with the conventional Papanicolaou test, is unknown.
  • Since its introduction more than 50 years ago, the use of the Papanicolaou test for cervical screening has reduced mortality by 70%. Nonetheless, the mortality rate in the United States has remained relatively constant during the last 25 years. One of the factors to explain this has been described as limitations of the traditional Papanicolaou test method itself.
  • The limitations of the conventional Papanicolaou test include limited sensitivity (51%) and a significant proportion of inadequate specimens. In addition, accurate interpretation of conventional Papanicolaou tests are often compromised by the presence of artifacts (such as blood, mucus, obscuring inflammation, scant cellular material, and air-drying artifact).
  • ThinPrep test: The ThinPrep test samples are collected the same way as the conventional Papanicolaou 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. Mucous and blood are removed in the process. The ThinPrep Papanicolaou test was approved in 1996 as an alternative to the traditional conventional smear.
  • HPV testing: The Hybrid Capture II HPV test was approved by the Food and Drug Administration (FDA) as a new approach for cervical cancer in 2003. This test is indicated for women aged 30 years and older, in conjunction with the Papanicolaou test. If both tests are negative, then the next Papanicolaou test can be delayed for 3 years.
  • The HPV test is also useful to interpret equivocal results from a Papanicolaou test. If a women has an ASCUS Papanicolaou test result and a positive HPV test, then additional work up with a colposcopy is indicated.
• Screening recommendations are as follows:
• • The American Cancer Society and US Preventive Services Task Force recommend that all women should begin screening for cervical cancer approximately 3 years after they begin to have vaginal intercourse, but no later than age 21.
  • Beginning at age 30, women who have had 3 normal consecutive Papanicolaou test results may get screening every 2-3 years. Women with high risk factors (DES exposure, HIV infection, or other immunodeficiencies) should continue yearly screening.
  • Another option for women aged 30 years and older is to get screened every 3 years with the conventional- or liquid-based Papanicolaou test plus HPV DNA test.
  • Women aged 70 years and older with 3 or more normal consecutive Papanicolaou test results and no abnormal Papanicolaou test results within the last 10 years may choose to stop having cervical cancer screening.
  • Women who have had a total hysterectomy may stop having cervical cancer screening. Exceptions are those who had a hysterectomy due to cervical carcinoma (or preinvasive changes) and women who had a hysterectomy without removal of the cervix.
• Prevention: Several measures are effective to prevent HPV infection and hence prevent cervical cancer.
• • Sexual abstinence
  • Barrier protection and/or spermicidal gels during sexual intercourse
  • Vaccination: Evidence suggests that HPV vaccines prevent HPV infection. A vaccine for HPV has been recently approved by the FDA.

Complications

• Complications from radiation alone
• • During the acute phase of pelvic radiation, the surrounding normal tissues such as the intestines, the bladder, and the perineum skin often are affected.
  • Acute adverse gastrointestinal effects include diarrhea, abdominal cramping, rectal discomfort, or bleeding. Diarrhea usually is controlled by either loperamide (Imodium) or atropine sulfate (Lomotil). Small, steroid-containing enemas are prescribed to alleviate symptoms from proctitis.
  • Cystourethritis also can occur, which leads to dysuria, frequency, and nocturia. Antispasmodics often are helpful for symptom relief.
  • Urine should be examined for possible infection. If urinary tract infection is diagnosed, therapy should be instituted without delay.
  • Proper skin hygiene should be maintained for the perineum, and topical lotion should be used in case erythema or desquamation occurs.
  • Late sequelae of radiation usually appear 1-4 years after treatment. The major sequelae include rectal or vaginal stenosis, small bowel obstruction, malabsorption, and chronic cystitis.
• Complications from surgery
• • The most frequent complication of radical hysterectomy is urinary dysfunction as a result of 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.

Prognosis

Prognosis of cervical cancer depends on disease stage. In general, the 5-year survival rate for stage I disease is higher than 90%, for stage II is 60-80%, for stage III is approximately 50%, and for stage IV disease is less than 30%.

Patient Education

• Cervical cancer is overrepresented among underserved and minority groups in the United States. It is imperative to increase awareness about the benefits of Papanicolaou test screening in these groups.
• For excellent patient education resources, visit eMedicine’s Cancer and Tumors Center, Women's Health Center, and Procedures Center. Also, see eMedicine’s patient education articles Cervical Cancer, Pap Smear, and Colposcopy.

ACKNOWLEDGMENTS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors Omid Hamid and Anthony El-Khoueiry to the development and writing of this article.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• References

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Article Last Updated: Dec 12, 2007