71 GYNECOLOGIC CANCER
Harrison’s Manual of Medicine
INCIDENCE AND EPIDEMIOLOGY Annually in the U.S., about 27,000 new cases are found and nearly 15,000 women die of ovarian cancer. Incidence begins to rise in the fifth decade, peaking in the eighth decade. Risk is increased in nulliparous women and reduced by pregnancy (risk decreased about 10% per pregnancy) and oral contraceptives. About 5% of cases are familial.
GENETICS Mutations in BRCA-1 predispose women to both breast and ovarian cancer. Cytogenetic analysis of epithelial ovarian cancers that are not familial often reveals complex karyotypic abnormalities including structural lesions on chromosomes 1 and 11 and loss of heterozygosity for loci on chromosomes 3q, 6q, 11q, 13q, and 17. C-myc, H-ras, K-ras, and HER2/neu are often mutated or overexpressed.
CLINICAL PRESENTATION Most pts present with abdominal pain, bloating, urinary symptoms, and weight gain indicative of disease spread beyond the true pelvis. Localized ovarian cancer is usually asymptomatic and detected on routine pelvic examination as a palpable nontender adnexal mass. Most ovarian masses detected incidentally in ovulating women are ovarian cysts that resolve over one to three menstrual cycles. Adnexal masses in postmenopausal women are more often pathologic and should be surgically removed. CA-125 serum levels are ³35 U/mL in 80–85% of women with ovarian cancer, but other conditions may also cause elevations. Screening is not effective outside of high-risk families.
PATHOLOGY Half of ovarian tumors are benign, one-third are malignant, and the rest are tumors of low malignant potential. These borderline lesions have cytologic features of malignancy but do not invade. Malignant epithelial tumors may be of five different types: serous (50%), mucinous (25%), endometrioid (15%), clear cell (5%), and Brenner tumors (1%, derived from urothelial or transitional epithelium). The remaining 4% of ovarian tumors are stromal or germ cell tumors, which are managed like testicular cancer in men (Chap. 70). Histologic grade is an important prognostic factor for the epithelial varieties.
STAGING Extent of disease is ascertained by a surgical procedure that permits visual and manual inspection of all peritoneal surfaces and the diaphragm. Total abdominal hysterectomy, bilateral salpingo-oopherectomy, partial omentectomy, pelvic and paraaortic lymph node sampling, and peritoneal washings should be performed. The staging system and its influence on survival is shown in Table 71-1.
Table 71-1 Staging and Survival in Gynecologic Malignancies
Pts with stage I disease, no residual tumor after surgery, and well- or moderately differentiated tumors need no further treatment after surgery and have a 5-year survival >95%. For stage II pts totally resected and stage I pts with poor histologic grade, adjuvant therapy with single-agent cisplatin, or cisplatin plus paclitaxel produces 5-year survival of 80%. Advanced-stage pts should receive paclitaxel, 175 mg/m2 by 3-h infusion, followed by carboplatin dosed to an area under the curve (AUC) of 7.5 every 3 or 4 weeks. Carboplatin dose is calculated by the Calvert formula: dose = target AUC × (glomerular filtration rate + 25). The complete response rate is about 55%, and median survival is 38 months.
INCIDENCE AND EPIDEMIOLOGY The most common gynecologic cancer, 34,000 cases are diagnosed in the U.S. and 6000 pts die annually. It is primarily a disease of postmenopausal women. Obesity, altered menstrual cycles, infertility, late menopause, and postmenopausal bleeding are commonly encountered in women with endometrial cancer. Women taking tamoxifen to prevent breast cancer recurrence and those taking estrogen replacement therapy are at a modestly increased risk. Peak incidence is in the sixth and seventh decades.
CLINICAL PRESENTATION Abnormal vaginal discharge (90%), abnormal vaginal bleeding (80%), and leukorrhea (10%) are the most common symptoms.
PATHOLOGY Endometrial cancers are adenocarcinomas in 75–80% of cases. The remaining cases include mucinous carcinoma; papillary serous carcinoma; and secretory, ciliate, and clear cell varieties. Prognosis depends on stage, histologic grade, and degree of myometrial invasion.
STAGING Total abdominal hysterectomy and bilateral salpingo-oopherectomy comprise both the staging procedure and the treatment of choice. The staging scheme and its influence on prognosis are shown in Table 71-1.
In women with poor histologic grade, deep myometrial invasion, or extensive involvement of the lower uterine segment or cervix, intracavitary or external beam radiation therapy is given. If cervical invasion is deep, preoperative radiation therapy may improve the resectability of the tumor. Stage III disease is managed with surgery and radiation therapy. Stage IV disease is usually treated palliatively. Progestational agents such as hydroxyprogesterone or megastrol and the antiestrogen tamoxifen may produce responses in 20% of pts. Doxorubicin, 60 mg/m2 IV day 1, and cisplatin, 50 mg/m2 IV day 1, every 3 weeks for 8 cycles produces a 45% response rate.
INCIDENCE AND EPIDEMIOLOGY In the U.S. about 16,000 cases of invasive cervical cancer are diagnosed each year and 50,000 cases of carcinoma in situ are detected by Pap smear. Cervical cancer kills 4900 women a year, 85% of whom never had a Pap smear. It is a major cause of disease in underdeveloped countries and is more common in lower socioeconomic groups, women with early sexual activity, multiple sexual partners, and in smokers. Human papilloma virus (HPV) types 16 and 18 are the major types associated with cervical cancer. The virus attacks the G1 checkpoint of the cell cycle; its E7 protein binds and inactivates Rb protein, and E6 induces the degradation of p53.
SCREENING Women should begin screening when they begin sexual activity or at age 20. After two consecutive negative annual Pap smears, the test should be repeated every 3 years. Abnormal smears dictate the need for a cervical biopsy, usually under colposcopy, with the cervix painted with 3% acetic acid, which shows abnormal areas as white patches. If there is evidence of carcinoma in situ, a cone biopsy is performed, which is therapeutic.
CLINICAL PRESENTATION Pts present with abnormal bleeding or postcoital spotting or menometrorrhagia or intermenstrual bleeding. Vaginal discharge, low back pain, and urinary symptoms may also be present.
STAGING Staging is clinical and consists of a pelvic exam under anesthesia with cystoscopy and proctoscopy. CXR, IV pyelography, and abdominal CT are used to search for metastases. The staging system and its influence on prognosis are shown in Table 71-1.
Carcinoma in situ is cured with cone biopsy. Stage I disease may be treated with radical hysterectomy or radiation therapy. Stages II–IV disease are usually treated with radiation therapy, often with both brachytherapy and teletherapy, or combined modality therapy. Pelvic exenteration is used uncommonly to control the disease, especially in the setting of centrally recurrent or persistent disease. Women with locally advanced (stage IIB to IVA) disease usually receive concurrent chemotherapy and radiation therapy. The role of chemotherapy is to act as a radiosensitizer. Hydroxyurea, 5-fluorouracil (5- FU), and cisplatin have all shown promising results given concurrently with radiation therapy. Cisplatin 75 mg/m2 IV over 4 h on day 1 and 5-FU 4 g given by 96-h infusion on days 1–5 of radiation therapy is a common regimen.
For a more detailed discussion, see Young RC: Gynecologic Malignancies, Chap. 97, p. 620, in HPIM-15.