Cervical cancer accounts for about 20% of all gynecologic cancers. This cancer is largely preventable through screening and treatment of premalignant lesions. However, there were about 12,800 new cases and 4,200 deaths related to cervical cancer in 1999. More than 50,000 new cases of cervical carcinoma in situ are diagnosed each year. The incidence is 8 to 10 cases per 100,000 women per year. Average age of onset is 45 to 55, but there is a wide variation in the ages of those afflicted.
Several epidemiologic risk factors have been identified. Advanced age increases risk twofold. Black, Hispanic, and Native American women have a two- to threefold elevation in risk. A risk about three times that of the general female population is found in women of low socioeconomic status, multiparas, those engaging in sexual activity at a young age or with multiple partners, and chronic smokers. Women with a history of sexually transmitted disease (especially herpes or genital warts) are 2 to 10 times more likely to develop cervical cancer. Lack of regular Pap screening increases risk two- to sixfold. Immunosuppressed patients have a higher risk of cervical carcinoma. Dietary deficiency of ascorbic acid and carotene has been reported to augment the development of cervical neoplasia, although this is less well documented than the other risk factors. Screening is vital for diagnosis and treatment of cervical cancer in its earliest phases.
Pathogenesis of cervical cancer has received immense scrutiny in recent years. Molecular analysis has demonstrated that the etiology of cervical cancer in older women is similar to younger women. Human papillomavirus is regarded as the vector that confers susceptibility to neoplastic conversion or that directly incites transmutation to a malignant phenotype in some infected epithelial cells. Neoplastic tranformation usually originates at the squamocolumnar junction of the cervix. Varying degrees of cervical intraepithelial neoplasia (CIN) exist; these are graded from 1 to 3 on the basis of increasing severity of the lesion. Carcinoma in situ designates the condition in which all epithelial layers consist of neoplastic cells that are abutting the basement membrane, poised for invasion through this delimitation. It usually takes 10 to 20 years for intraepithelial neoplasia to progress to invasive disease. Most tumors (80%-90%) exhibit squamous histology; adenocarcinoma is the other predominant category. Other morphologies are rare.
Women with early invasive cervix cancer may have a cervix that appears normal to the naked eye, or they may have a small, ulcerated lesion that may seem to represent a benign inflammatory process. In such cases, cervical smears may be particularly effective in detecting preinvasive or early-stage disease. Most of these women are asymptomatic. On the other hand, patients with advanced cancer often experience symptoms. The most common abnormality is irregular vaginal bleeding. Postcoital spotting has long been considered a warning sign, but metrorrhagia or menorrhagia may occur as well. Some patients have a serosanguinous or yellow vaginal discharge that frequently is malodorous. Another symptom attributable to advanced cervical cancer is pain in the lower abdomen, pelvis, or back. Hematuria or rectal bleeding may occur if bladder or rectal invasion exists.
Invasive cancers display two primary modes of extension: local spread and metastasis via lymphatic and hematogenous routes. Cervical cancer may exhibit an ulcerative or exophytic appearance. Local expansion usually involves extension to the endocervix or vaginal fornices, followed by progressive infiltration of parametrial tissues, uterine corpus, bladder, or rectum. Lymphatic dissemination typically occurs in a stepwise progression. Pelvic nodes become involved before common iliac and para-aortic lymph node chains. Hematogenous spread may give rise to distant implants of cancer in lungs, bones, liver parenchyma, or other tissue. In general, the likelihood of metastasis rises with increasing size and expanse of tumor. Spread to the pelvic nodes is present in 15%, 30%, or 47%, respectively, for tumors confined to the cervix, in the parametrium, or involving the pelvic sidewall. The corresponding para-aortic nodal involvement for these situations is 6%, 16%, or 29%.
Cervical cancer is evaluated using a clinical staging system that is shown in Table 37.3. A pelvic examination should include a through evaluation of the cervix, vagina, parametria, and pelvic sidewalls. Extrapelvic regions that should receive extra attention include the abdomen, chest, and supraclavicular lymph nodes. Chest x-ray and intravenous urography are allowable radiographic techniques (under the clinical staging guidelines) for documenting the extent of tumor spread. Cystoscopy and proctoscopy are also permitted. General or conduction anesthesia is often employed to facilitate pelvic examination, procurement of biopsies, and cystoscopic and proctoscopic evaluations. Other studies that are sometimes helpful for diagnosis and treatment planning include lymphangiography, computed tomography (CT) scan, CT-directed lymph node aspiration, magnetic resonance imaging (MRI), positive emission tomograghy (PET) scan, blood count, serum chemistry profile, and urinalysis.
Treatment for cervical carcinoma may include surgery, radiotherapy and chemotherapy. The most commonly utilized modality is radiotherapy, which ideally employs one or both of two techniques. (1) Teletherapy, or external beam application, is directed to cervical, parametrial, and pelvic nodal regions (Figure 37.4A). The field may be extended superiorly if there is suspected or documented involvement of the common iliac or para-aortic nodes. (2) Brachytherapy, or intracavitary treatment, is commonly done with intrauterine placement of cesium over a time period calculated to deliver a standard dose (Figure 37.4B). The advantage of this technique is that extremely high doses of radiation can be applied to the tumor with less penetration of surrounding normal tissue. Recently, the utility of radiotherapy with concurrent cisplatin-based chemotherapy has been evaluated in several randomized trials. Patients with locally advanced (stage IIB-IVA) and bulky stage IB2 cervical cancers who were treated with combined radiation and chemotherapy had significantly improved progression-free and overall survival rates. Of the chemotherapy regimens available, single-agent cisplatin was shown to be just as efficacious as cisplatin/fluorouracil and better than regimens containing hydoxyurea.
Surgical strategies vary according to the extent of the lesion. Cervical conization or simple hysterectomy (abdominal or vaginal) may effectively treat carcinoma in situ and microinvasive cervical cancers. A radical hysterectomy involves removal of the uterus along with parametrial and paravaginal tissues; this is a treatment option for patients with Stage IA2-IIA disease. The upper portion of the vagina and the pelvic and para-aortic lymph nodes are excised as well (Figure 37.5).In premenopausal women, ovaries are not removed unless other indications necessitate their removal; however, in the postmenopausal patient a bilateral salpingo-oophorectomy is routinely performed.
The decision of whether to use surgery or RT for early-stage disease turns on several issues. Patients who are frail or have serious comorbidities may be poor surgical candidates. Recovery from surgery and most of its potential complications occurs within a narrow time frame, whereas radiation has both acute and chronic effects. Radiation-induced fibrosis is a lifetime process that is set in motion by the endarteritis provoked by RT. Ovarian function is obliterated by RT unless the ovaries have been positioned out of the pelvis. Sexual function is usually better preserved in women who have had surgery, as radiotherapy leads to agglutination of the vaginal tissues.
Advanced age has traditionally been considered a relative contraindication to radical pelvic surgery. The belief that such procedures in the elderly yield unacceptable morbidity has led to treatment of many older cervical cancer patients with radiotherapy rather than radical hysterectomy. Three retrospective studies have shown that, in properly selected older women, application of radical hysterectomy with modern surgical and postoperative care leads to complication rates comparable to those of younger women. Thus, radical hysterectomy should not be withheld as a treatment option for older patients who are otherwise good surgical candidates.
Choice of therapy is based on the clinical stage. Patients with stage IA1 cervical cancer may be treated by simple hysterectomy or, in selected cases, with conization. Women with stage IA2 cancer are treated the same as those with stage IB disease if there is more than 3 mm of invasion or lymphocapillary space involvement. Stage IB and stage IIA cancer is treated similarly; cure rates are comparable regardless whether radical hysterectomy or RT is employed. Cervical carcinoma of stages IIB, III, or IVA should be treated with radiation therapy. If ureteral obstruction is present, urinary diversion via nephrostomy or insertion of ureteral stents may be necessary to preserve renal function. Palliative RT may be used in individuals with stage IVB disease to control pain and bleeding from the pelvic tumor. Chemotherapy with agents such as cisplatin, 5-fluorouracil, bleomycin, vincristine, and ifosfamide is often given in hopes that some therapeutic benefit may be derived in cases of metastatic disease. "Cures," however, are unlikely with currently available chemotherapy.
Exenteration is an ultraradical procedure that is typically used for treatment of central tumor recurrence or persistence after radiotherapy. This procedure entails removal of pelvic organs, including the bladder and rectosigmoid colon. Exenteration obviously leads to disfigurement and has profound psychologic impact on the patient. Significant potential for morbidity attends this procedure. Therefore, this technique is reserved for patients who are medically fit to undergo an extended procedure and in whom there is a substantial prospect for cure.
Five-year survival figures are given in Table 37.4. These data highlight the importance of early detection and treatment of this cancer. Influence of age on treatment and survival related to cervical cancer has been examined. Five-year survival decreases as age increases; this holds true both for global comparison of age groups and for relationships within stage. Interestingly, a study from Japan has demonstrated that, when matched with respect to depth of invasion, patients over 60 had a lower incidence of lymph node metastases than their younger counterparts. Despite the lower frequency of lymphatic involvement, the older women still demonstrated a worse prognostic trend. Another study found that overall survival in women 85 years and older was only 23.8%. The 5-year survival rates for women 85years and older were 37.5% for stage II and 22.2% for stage III. There were no stage I or stage IV survivors. Survival is worse in older women, in part because cervical cancer is diagnosed at more advanced stages in this age group.
Interval evaluation of the cervical cancer patient after therapy is imperative. Recurrent cervical cancer detected at its earliest stages might be successfully treated with surgery, radiation, chemotherapy, or a combination of the three. Thirty-five percent of patients with invasive cervical cancer will have persistent or recurrent disease following treatment. The patient should be seen every 3 months for follow-up for 2 years, then visits should be at the discretion of the practitioner. In addition to focused history and physical examination, a Pap smear should be done. Chest x-rays, intravenous urograms, and CT scans may be ordered if circumstances dictate.
Recurrent cervical cancer carries a poor prognosis. Seventy-five percent of recurrences occur in the first 2 years after treatment; by the 5-year milestone, 90% of recurrences have developed. Fewer than 15% of patients with recurrent disease survive 1 year, and 5-year survival is less than 5%. Pain control is an extremely important aspect of caring for women with relapses. Therapeutic approaches include RT if the primary treatment was surgical. Cure is sometimes possible for patients with central recurrence following RT if they are candidates for pelvic exenteration. Palliative chemotherapy may be administered.
Death occurs by several mechanisms in cervical cancer patients. Extension of the tumor to the pelvic sidewall may cause ureteral obstruction and uremia. If the patient has received all available treatment for her cancer, usually no attempt is made at placing ureteral stents or percutaneous nephrostomies because uremic coma is not an unpleasant means of death in these women, who would otherwise often experience severe pain. Hemorrhage from the tumor bed or from erosion into pelvic vessels may lead to exsanguination and death. Hypercoagulability may precipitate Pulmonary embolism. Sepsis occurs in many of these women and can be fatal if not promptly recognized. Physical external compression of the rectosigmoid colon may cause large bowel obstruction and the attendant consequences. Radiation enteritis, cystitis, and pelvic fibrosis may all contribute to or directly induce the patient's demise.
Hormone replacement is not contraindicated in women with cervical cancer. Estrogen therapy may be especially important for maintenance of healthy vaginal tissue following castration or RT. To prevent endometrial hyperplasia or carcinoma, a progestin should be added to the estrogen if the uterus remains intact. Because many women treated for carcinoma of the cervix are relatively young, hormonal therapy affords the same advantages that would otherwise apply if they did not have cancer.