Cervical cancer is the third most common gynecologic malignancy and the eighth most common malignancy among women in the USA. The mean age for developing cervical cancer is about 50 yr; however, it can affect women as young as 20. About 1% of all cervical cancers occur in pregnant or recently pregnant women.

Cervical cancer is essentially a sexually transmitted disease. Risk is inversely related to age at first intercourse and directly related to the lifetime number of sexual partners. Risk is also increased for sexual partners of men whose previous partners had cervical cancer.

Human papillomavirus (HPV) infection and the development of cervical neoplasia are strongly associated. HPV infection is linked to all grades of cervical intraepithelial neoplasia (CIN) and invasive cervical cancer. Infection with HPV types 16, 18, 31, 33, 35, and 39 increases the risk of neoplasia. However, other factors appear to contribute to malignant transformation. For example, cigarette smoking is associated with an increased risk of CIN and cervical cancer.

Pathology
Precursor cells (Cervical dysplasia, CIN) develop into invasive cervical cancer over a number of years. CIN grades I, II, and III correspond to mild, moderate, and severe Cervical dysplasia. CIN III, which includes severe dysplasia and carcinoma in situ, is unlikely to regress spontaneously and, if untreated, may eventually penetrate the basement membrane, becoming invasive carcinoma.
Squamous cell carcinoma accounts for 80 to 85% of all cervical cancers; adenocarcinomas account for most of the rest. Sarcomas and small cell neuroendocrine tumors are rare.

Invasive cervical cancer usually spreads by direct extension into surrounding tissues and the vagina or via the lymphatics to the pelvic and para-aortic lymph nodes drained by the cervix. Hematologic spread is possible.

Symptoms and Signs
CIN is usually asymptomatic and discovered because of an abnormal Pap smear. Patients with early-stage cervical cancer usually present with irregular vaginal bleeding, which is most often postcoital, but intermenstrual bleeding or menometrorrhagia may occur. Patients with larger cervical cancers or advanced-stage disease may present with foul-smelling vaginal discharge, abnormal vaginal bleeding, or pelvic pain. Obstructive uropathy, back pain, and leg swelling are manifestations of late-stage disease.

Diagnosis
More than 90% of early asymptomatic cases of CIN can be detected preclinically by cytologic examination of Pap smears obtained directly from the cervix. However, the false-negative rate is 15 to 40%, depending on the patient population and the laboratory. About 50% of patients with cervical cancer have never had a Pap smear or have not had one for >= 10 yr. The patients at higher risk for cervical neoplasia are the least likely to be tested regularly.

An abnormal Pap smear (ie, suggesting neoplasia, including dysplasia, CIN, carcinoma in situ, microinvasive carcinoma, or invasive carcinoma) requires further evaluation based on the descriptive diagnosis of the Pap smear and the patient’s risk factors (

see Table 241-3). The cellular classification system (I to V) is no longer used.

Suspicious cervical lesions should be biopsied directly. If there is no obvious invasive lesion, colposcopy can be used to identify areas that require biopsy and to localize the lesion. Colposcopy results can be clinically correlated (by assessing characteristic color changes, vascular patterns, and margins) with the results of the Pap smear. Colposcopy-directed biopsy usually provides enough clinical evidence for an accurate diagnosis. If colposcopic evaluation is unsatisfactory or inconclusive, a cervical conization biopsy is required, performed via a loop electrical excision procedure (LEEP), laser, or cold knife.

If cervical disease is invasive, staging is performed on the basis of the physical examination, with a metastatic survey including cystoscopy, sigmoidoscopy, IV pyelography, chest x-ray, and skeletal x-rays (

see Table 241-4). For early-stage disease (IB or less), chest x-ray is usually the only adjunctive test needed. CT or MRI of the abdomen and pelvis is optional; the results cannot be used to determine the clinical stage.

Prognosis and Treatment
Invasive squamous cell carcinoma usually remains localized or regional for a considerable time; distant metastases occur late. The 5-yr survival rates are 80 to 90% for stage I, 50 to 65% for stage II, 25 to 35% for stage III, and 0 to 15% for stage IV. 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 neuroendocrine histology.

For women with preinvasive cervical disease or microinvasive squamous cell carcinoma of the cervix, conization biopsy with LEEP, laser, or cold knife or cryotherapy is usually adequate treatment. Uncommonly, a hysterectomy is required to treat preinvasive cervical disease.

Because the tumor advances by direct spread or via lymphatics, treatment must include the regional nodes. Radiation therapy or surgery may be appropriate. Preserving surrounding normal tissues is also a goal.

Primary surgical treatment is reserved for patients with limited tumor spread. Patients with microinvasive disease (defined as tumor invading no more than 3 mm in depth from the basement membrane without vascular space invasion and with negative margins on cervical conization) may be treated with an extrafascial hysterectomy. The risk of recurrence and lymph node metastasis for these patients is < 1%. Pelvic lymph node dissection is not indicated.

Patients with stage IA2, IB, or IIA disease can be treated with radical hysterectomy, including bilateral pelvic lymph node dissection and removal of all adjacent ligaments (cardinal, uterosacral) and parametria, or with radiation therapy. The 5-yr cure rates for women with stage IB or IIA disease are 85 to 90% with either therapy. The advantages of surgery include a relatively short treatment time, provision of surgical staging data, preservation of ovaries in young women, and avoidance of vaginal stenosis and of late complications of radiation therapy. A major complication (eg, ureterovaginal or vesicovaginal fistula formation) occurs in < 1% of patients. If extracervical spread is noted during surgery, postoperative radiation may prevent local recurrence.

The advantages of radiation therapy are avoidance of the morbidity of major surgery, outpatient location, and suitability for poor surgical candidates. External beam radiation therapy shrinks the central tumor and treats the regional lymph nodes; this therapy is followed by brachytherapy (local radioactive applications, usually using cesium) to the cervix, which destroys the central primary tumor. Major acute complications include radiation proctitis and cystitis. Late complications, such as bowel obstruction and rectovaginal and vesicovaginal fistula formation, occasionally occur.

For patients with stage IIB, III, or IV disease, the treatment of choice is radiation therapy. Many advanced lesions require large doses. The failure rate for bulky and advanced-stage tumors within the pelvis is 40%, and the risk of pelvic and para-aortic lymph node metastasis and of distant metastasis is substantial. Using chemotherapy as a radiation sensitizer to control pelvic disease appears to improve survival. Before radiation therapy, surgical staging can be performed to assess the para-aortic lymph nodes, and extended-field radiation therapy can be delivered to this area if indicated.

If tumors are restricted to the pelvis and involve the rectum or bladder, exenteration (excision of all pelvic organs) may be considered. However, radiation therapy is usually tried first. Exenteration is the treatment of choice for recurrent or persistent cancer confined to the central pelvis after conventional radiation therapy. It cures up to 50% of patients. Recent refinements in this operation include a continent urostomy, low anterior rectal anastomosis without colostomy, omental carpet to close the pelvic floor, vaginal reconstruction with gracilis or rectus abdominis myocutaneous flaps, and improved perioperative care.

Patients with either metastatic disease beyond the regional lymph nodes or recurrent nonresectable disease are treated with systemic chemotherapy. Systemic chemotherapy is not considered curative. Distant metastases outside the radiation field appear to respond better to chemotherapy than does the previously irradiated central pelvic tumor. Cytotoxic drugs produce objective, short-lived regression in only 25 to 30% of patients. Cisplatin and ifosfamide are the most active.