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Cervical cancer is usually a squamous cell carcinoma caused by human papillomavirus infection; less often, it is an adenocarcinoma. Cervical neoplasia is asymptomatic; the first symptom of early cervical cancer is usually irregular, often postcoital vaginal bleeding. Diagnosis is by a screening cervical Papanicolaou test and biopsy. Staging is clinical. Treatment usually involves surgical resection, or radiation therapy plus chemotherapy. If the cancer has widely metastasized, chemotherapy is often used alone.
Cervical cancer is the 3rd most common gynecologic cancer and the 8th most common cancer among women in the US. Mean age at diagnosis is about 50, but the cancer can occur as early as age 20.
Cervical cancer results from cervical intraepithelial neoplasia (CIN), which appears to be caused by infection with human papillomavirus (HPV) type 16, 18, 31, 33, 35, or 39. Risk factors for cervical cancer include
Other factors such as cigarette smoking and immunodeficiency also appear to contribute.
Pathology
CIN is graded as 1 (mild cervical dysplasia), 2 (moderate dysplasia), or 3 (severe dysplasia and carcinoma in situ). CIN 3 is unlikely to regress spontaneously; if untreated, it may, over months or years, penetrate the basement membrane, becoming invasive carcinoma.
About 80 to 85% of all cervical cancers are squamous cell carcinoma; most of the rest are adenocarcinomas. Sarcomas and small cell neuroendocrine tumors are rare.
Invasive cervical cancer usually spreads by direct extension into surrounding tissues or via the lymphatics to the pelvic and para-aortic lymph nodes. Hematogenous spread is possible but rare.
Symptoms and Signs
CIN is usually asymptomatic. Early cervical cancer can be asymptomatic. The first symptom is usually irregular vaginal bleeding, which is most often postcoital but may occur spontaneously between menses. Larger cancers are more likely to bleed spontaneously and may cause a foul-smelling vaginal discharge or pelvic pain. More widespread cancer may cause obstructive uropathy, back pain, and leg swelling due to venous or lymphatic obstruction; pelvic examination may detect an exophytic necrotic tumor in the cervix.
Diagnosis
Cervical cancer may be diagnosed during a routine gynecologic examination. It is considered in women with
CIN is usually evident on Pap tests, but about 50% of patients with cervical cancer have not had a Pap test for ≥ 10 yr. Patients at highest risk are the least likely to obtain regular preventive health care and to be tested regularly.
Reporting of cervical cytology results is standardized (see Table 6: Gynecologic Tumors: Bethesda Classification of Cervical Cytology* ). Further evaluation is indicated if atypical or cancerous cells are found, particularly in women at risk. If cytology does not show any obvious cancer, colposcopy (examination of the vagina and cervix with a magnifying lens) can be used to identify areas that require biopsy. Colposcopy-directed biopsy with endocervical curettage is usually diagnostic. If not, cone biopsy (conization) is required; a cone of tissue is removed using a loop electrical excision procedure (LEEP), laser, or cold knife.
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Table 6
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| Bethesda Classification of Cervical Cytology* |
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Category
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Specifics
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Comment
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Specimen type
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Conventional or thin-layer (liquid-based) Papanicolaou (Pap) test or another test
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Type of test is noted.
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Adequacy of the specimen
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Satisfactory for evaluation
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Any quality indicators (eg, endocervical or transformation zone component, partially obscuring blood; inflammation) are described.
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Evaluated but unsatisfactory
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Reason is specified.
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Rejected for evaluation
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Reason is specified.
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General categorization (optional)
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Negative for intraepithelial lesion or cancer
Epithelial cell abnormalities
Other abnormalities
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Findings are stated or described under Interpretation, below.
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Interpretation of negative (nonmalignant) abnormalities
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Organisms
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Possible findings include the following:
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Trichomonas vaginalis
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Fungi morphologically consistent with Candida sp
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Predominance of coccobacilli consistent with shift in vaginal flora suggesting bacterial vaginosis
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Bacteria morphologically consistent with Actinomyces sp
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Cellular changes associated with herpes simplex virus
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Other (reporting is optional)
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Possible findings include the following:
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Reactive cellular changes associated with inflammation, radiation, or IUD use
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Presence of glandular cells after hysterectomy
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Atrophy
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Interpretation of epithelial cell abnormalities
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Squamous cell
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Possible findings include the following:
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Atypical squamous cells of undetermined significance (ASC-US)
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Atypical squamous cells for which a high-grade lesion cannot be excluded (ASC-H)
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Low-grade squamous intraepithelial lesion encompassing HPV† infection or mild dysplasia (CIN 1)
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High-grade squamous intraepithelial lesion encompassing moderate (CIN 2) and severe dysplasia (CIN 3/CIS); whether the lesion has features suggesting invasion noted
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Squamous cell carcinoma
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Glandular cell
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Possible findings include the following:
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Atypical cells: Endocervical, endometrial, or glandular
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Atypical cells likely to be cancerous: Endocervical or glandular
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Adenocarcinoma in situ: Endocervical
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Adenocarcinoma: Endocervical, endometrial, extrauterine, or NOS
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Interpretation of other abnormalities
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Endometrial cells (in a woman > 40)
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Whether sample is negative for squamous intraepithelial lesion is specified.
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Other cancers
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———
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Type is specified.
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*Use of an automated device for scanning should be reported, as should other tests (eg, HPV) and their results.
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†Cellular changes of HPV infection—previously called koilocytosis, koilocytotic atypia, and condylomatous atypia—are included in the category of low-grade squamous intraepithelial lesion.
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CIN = cervical intraepithelial neoplasia; CIS = carcinoma in situ; HPV = human papillomavirus; IUD = intrauterine device; NOS = not otherwise specified.
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Adapted from the Bethesda System 2001, National Institutes of Health.
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Staging
Cancers are clinically staged based on biopsy, physical examination, and chest x-ray results (see Table 7: Gynecologic Tumors: Clinical Staging of Cervical Carcinoma*). If the stage is > IB1, CT or MRI of the abdomen and pelvis is typically done to identify metastases, although results are not used for staging. If MRI and CT are not available, cystoscopy, sigmoidoscopy, and IV urography, when clinically indicated, may be used for staging.
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Table 7
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| Clinical Staging of Cervical Carcinoma* |
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Stage
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Description
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0
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Carcinoma in situ (CIN 3), intraepithelial carcinoma
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I
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Carcinoma strictly confined to the cervix
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IA
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Preclinical carcinoma (diagnosed only by microscopy, with a depth of invasion < 5 mm from the surface)†
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IA1
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Measured invasion of stroma ≤ 3 mm in depth and ≤ 7 mm in width
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IA2
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Measured invasion of stroma > 3 mm and ≤ 5 mm in depth and ≤ 7 mm in width
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IB
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Clinically visible lesions confined to the cervix or preclinical lesions larger than those in stage IA2
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IB1
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Clinically visible lesions ≤ 4 cm
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IB2
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Clinically visible lesions > 4 cm
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II
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Extension beyond the cervix but not to the pelvic wall; involvement of the vagina but excluding the lower third
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IIA
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No obvious parametrial involvement
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IIB
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Obvious parametrial involvement
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III
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Extension to the pelvic wall, with rectal examination detecting no cancer-free space between the tumor and pelvic wall; involvement of the lower third of the vagina; all cases with hydronephrosis or with a nonfunctioning kidney secondary to the carcinoma
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IIIA
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Extension to lower third of the vagina but not to the pelvic wall
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IIIB
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Extension to the pelvic wall, hydronephrosis, or a nonfunctioning kidney
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IV
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Extension beyond the true pelvis or clinical involvement of the bladder or rectal mucosa (bullous edema does not signify stage IV)
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IVA
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Spread to adjacent pelvic organs
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IVB
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Spread to distant organs
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*Table is based on staging established by the International Federation of Gynecology and Obstetrics (FIGO) and American Joint Committee on Cancer (AJCC), 1995, 1996, 1997.
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†Depth of invasion should be measured from the base of the epithelium (surface or glandular) from which it originates. Vascular space involvement (venous or lymphatic) should not alter staging.
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The purpose of this staging system is to establish a large database for study; thus, the system uses worldwide uniform diagnostic criteria. The system excludes results of tests that are less likely to be available worldwide (eg, MRI) because most cases of cervical cancer occur in developing countries. Because such tests are not used, findings such as parametrial invasion and lymph node metastases are often missed, and thus understaging is possible.
When imaging tests suggest that pelvic or para-aortic lymph nodes are grossly enlarged (> 2 cm), surgical exploration, typically with a retroperitoneal approach, is occasionally indicated. Its sole purpose is to remove enlarged lymph nodes so that radiation therapy can be more precisely targeted and more effective.
Prognosis
In squamous cell carcinoma, distant metastases usually occur only when the cancer is advanced or recurrent. The 5-yr survival rates are as follows:
Nearly 80% of recurrences manifest within 2 yr. Adverse prognostic factors include lymph node involvement, large tumor size and volume, deep cervical stromal invasion, parametrial invasion, vascular space invasion, and nonsquamous histology.
Treatment
Treatment may include surgery, radiation therapy, and chemotherapy. If hysterectomy is indicated but patients cannot tolerate it, radiation therapy plus chemotherapy is used.
CIN and squamous cell carcinoma stage IA1
Cone biopsy with LEEP, laser, or cold knife is usually sufficient treatment. Hysterectomy is done for stage IA1 cancer if there are adverse prognostic factors (nonsquamous histology or lymphatic or vascular invasion). Radical hysterectomy is recommended by some experts; it includes bilateral pelvic lymphadenectomy and removal of all adjacent ligaments (eg, cardinal, uterosacral) and parametria and the upper 2 cm of the vagina. Hysterectomy can also be done if women no longer desire fertility. If there are no adverse prognostic factors, simple (extrafascial) hysterectomy is usually sufficient because risk of recurrence and lymph node metastasis is < 1%. Pelvic lymph node dissection is not indicated.
Stages IA2 to IIA
Treatment options include a radical hysterectomy and pelvic lymphadenectomy alone (stages IA2 to IB1) or a radical hysterectomy and pelvic lymphadenectomy with possible combined chemotherapy and pelvic radiation (stages IB2 to IIA). Chemotherapy is usually given concurrently. With either treatment, the 5-yr cure rates in stage IB or IIA are 85 to 90%. Surgery provides additional staging data and preserves the ovaries. If extracervical spread is noted during surgery, postoperative radiation therapy may prevent local recurrence.
In some patients who have early-stage cervical cancer and who wish to preserve fertility, a radical trachelectomy may be done. In this procedure, the cervix, parametria immediately adjacent to the cervix, upper 2 cm of the vagina, and pelvic lymph nodes are removed. The remaining uterus is reattached to the upper vagina, preserving the potential for fertility. Ideal candidates for this procedure are patients with the following:
Invasion of the upper cervix and lower uterine segment should be excluded by MRI. Rates of recurrence and death are similar to those after radical hysterectomy. If patients who have this procedure plan to have children, delivery must be cesarean.
Stages IIB to IVA
Radiation therapy plus chemotherapy (eg, cisplatin) is more suitable as primary therapy. Surgical staging should be considered to determine whether para-aortic lymph nodes are involved and thus whether extended-field radiation therapy is indicated; a retroperitoneal approach is used. Staging may be done via laparoscopy. External beam radiation therapy shrinks the central tumor and treats regional lymph nodes. This therapy is followed by brachytherapy (local radioactive implants, usually using cesium) to the cervix, which destroys the central tumor. Radiation therapy may cause acute complications (eg, radiation proctitis and cystitis) and, occasionally, late complications (eg, vaginal stenosis, intestinal obstruction, rectovaginal and vesicovaginal fistula formation).
Chemotherapy is usually given with radiation therapy, often to sensitize the tumor to radiation. Treatment is often ineffective for bulky and advanced-stage tumors.
Although stage IVA cancers are usually treated with radiation therapy initially, pelvic exenteration (excision of all pelvic organs) may be considered. If after radiation therapy, cancer remains but is confined to the central pelvis, exenteration is indicated and cures up to 50% of patients. The procedure may include a continent urostomy, low anterior rectal anastomosis without colostomy, omental carpet to close the pelvic floor (J-flap), and vaginal reconstruction with gracilis or rectus abdominis myocutaneous flaps.
Stage IVB and recurrent cancer
Chemotherapy is the primary treatment, but only 15 to 25% of patients respond to it and only briefly. Cisplatin is the most active drug and the current standard, but adding topotecan appears to improve overall response and survival. Combinations of paclitaxel, topotecan, gemcitabine, cisplatin, and vinorelbine are under study for treatment of recurrent squamous cell carcinoma. Paclitaxel is also used to treat recurrent or metastatic nonsquamous cancer. Metastases outside the radiation field appear to respond better to chemotherapy than does previously irradiated cancer or metastases in the pelvis.
Prevention
Pap tests
Routine cervical Pap tests are recommended yearly, starting when patients first begin having sexual intercourse or reach age 18. Pap test and HPV test can be done simultaneously. If both are normal or if 3 consecutive Pap tests are normal, some physicians test at 2- to 3-yr intervals. Testing continues until patients are age 65 to 70, have normal results for 10 yr, or have a hysterectomy. (See also cervical cancer screening guidelines.) Sexually active women are advised that condoms should be used during intercourse to prevent spread of HPV. HPV testing is the preferred method of follow-up evaluation for women ages 20 to30 with inconclusive Pap results such as ASCUS (atypical squamous cells of undetermined significance). If testing shows that the patient does not have HPV, a repeat Pap is recommended in 12 mo. If HPV is present, colposcopy should be done. Routine HPV testing plus a Pap test is recommended for women ≥ 30.
HPV vaccine
A newly developed vaccine (see Immunization: Human Papillomavirus) targets the 4 viral subtypes (HPV 6, 11, 16, and 18) most commonly associated with cervical intraepithelial lesions, genital warts, and cervical cancer. The vaccine aims to prevent cervical cancer but does not treat it. Three doses are given: the first dose is followed by one 2 mo and one 6 mo later. The vaccine is best given before sexual activity begins, but women who are sexually active should be vaccinated.
Last full review/revision November 2008 by David M. Gershenson, MD; Pedro T. Ramirez, MD
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