Chapter 093. Gynecologic Malignancies (Part 7) Patients with stage IV disease (outside the abdomen or invading the bladder or rectum) are treated palliatively with irradiation, surgery, and platinum-based chemotherapy. Progestational agents produce responses in ~10–20% of patients. Well-differentiated tumors respond most frequently, and response can be correlated with the level of progesterone receptor expression in the tumor. The commonly used progestational agents hydroxyprogesterone (Dilalutin), megestrol (Megace), and deoxyprogesterone (Provera) all produce similar response rates, and the antiestrogen tamoxifen (Nolvadex) produces responses in 10–25% of patients in a salvage setting. Chemotherapy is not very successful in advanced endometrial carcinoma. The most active single agents with consistent response rates of ≥20% include cisplatin, carboplatin, doxorubicin, epirubicin, and paclitaxel. Combinations of drugs with or without progestational agents have generally produced response rates similar to single agents. Cervix Cancer Incidence and Epidemiology Carcinoma of the cervix was once the most common cause of cancer death in women, but over the past 40 years, the mortality rate has decreased by 50% due to widespread screening with the Pap smear. In 2007, ~11,150 new cases of invasive cervix cancer occurred, and >50,000 cases of carcinoma in situ were detected. There were 3670 deaths from the disease, and of those patients, ~85% had never had a Pap smear. Worldwide, cervical cancer is the third commonest cancer diagnosed, and it remains the major gynecologic cancer in underdeveloped countries. It is more common in lower socioeconomic groups, in women with early initial sexual activity and/or multiple sexual partners, and in smokers. Etiology and Genetics Venereal transmission of human papilloma virus (HPV) has an important etiologic role. Over 66 types of HPVs have been isolated, and many are associated with genital warts. Those types commonly associated with cervical carcinoma are 16, 18, 31, 33, 52, and 58, but 70% of cases are caused by HPV-16 and -18. These, along with many other types, are also associated with cervical intraepithelial neoplasia (CIN). The protein product of HPV-16, the E7 protein, binds and inactivates the tumor-suppressor gene Rb, and the E6 protein of HPV-18 has sequence homology to the SV40 large T antigen and the capacity to bind and inactivate the tumor-suppressor gene p53. E6 and E7 are both necessary and sufficient to cause cell transformation in vitro. These binding and inactivation events may explain the carcinogenic effects of the viruses (Chap. 178). Screening and Prevention Vaccination against pathologic HPV appears to be an effective cervix cancer prevention strategy. Vaccines are made with inactivated virus-like particles that are noninfectious but highly immunogenic. The administration of a quadrivalent HPV vaccine against types 16, 18, 6, and 11 in a double-blind study of 2392 women completely prevented infection with the virus, and no cases of HPV-16–related CIN were seen in vaccinated women. This quadrivalent vaccine has been approved for use by the FDA for patients 9–26 years old and must be administered before HPV exposure to be effective. A second study with a bivalent vaccine (types 16 and 18) is underway. Both vaccines appear highly effective in preventing their particular HPV infections, and protection has persisted for at least 4.5 years after three injections over a 6-month period. Since not all oncogenic HPVs are targeted, patients will need to continue PAP smear surveillance. Uncomplicated HPV infection in the lower genital tract can progress to CIN. This lesion precedes invasive cervical carcinoma and is classified as low- grade squamous intraepithelial lesion (SIL), high-grade SIL, and carcinoma in situ. Carcinoma in situ demonstrates cytologic evidence of neoplasia without invasion through the basement membrane and can persist unchanged for 10–20 years, but most of these eventually progress to invasive carcinoma. The Pap smear is 90–95% accurate in detecting early lesions such as CIN but is less sensitive in detecting cancer when frankly invasive cancer or fungating masses are present. Inflammation, necrosis, and hemorrhage may produce false- positive smears, and colposcopic-directed biopsy is required when any lesion is visible on the cervix, regardless of Pap smear findings. The American Cancer Society recommends that women after onset of sexual activity, or >age 20, have two consecutive yearly smears. If negative, smears should be repeated every 3 years until age 65. The Pap smear can be reported as normal (includes benign, reactive, or reparative changes); atypical squamous cells of undetermined significance (ASCUS) or cannot exclude high-grade SIL (ASC-H); low- or high- grade CIN; or frankly malignant. Women with ASCUS, ASC-H, or low-grade CIN should have repeat smears in 3–6 months and be tested for HPV. Women with high-grade CIN or frankly malignant Pap smears should have colposcopic-directed cervical biopsy. Colposcopy is a technique using a binocular microscope and 3% acetic acid applied to the cervix in which abnormal areas appear white and can be biopsied directly. Cone biopsy is still required when endocervical tumor is suspected, colposcopy is inadequate, the biopsy shows microinvasive carcinoma, or when a discrepancy is noted between the Pap smear and the colposcopic findings. Cone biopsy alone is therapeutic for CIN in many patients, although a less radical electrocautery excision may be sufficient. Approximately 70% of invasive cervix cancers are squamous cell tumors, 20–25% are adenocarcinomas, and 2–5% are adenosquamous with epithelial and glandular structures. . Chapter 093. Gynecologic Malignancies (Part 7) Patients with stage IV disease (outside the abdomen or invading the. smear. Worldwide, cervical cancer is the third commonest cancer diagnosed, and it remains the major gynecologic cancer in underdeveloped countries. It is more common in lower socioeconomic groups,