R. J. Kurman

BACKGROUND: Epidemiologic studies have shown that the association of genital human papillomavirus (HPV) with cervical cancer is strong, independent of other risk factors, and consistent in several countries. There are more than 20 different cancer-associated HPV types, but little is known about their geographic variation. PURPOSE: Our aim was to determine whether the association between HPV infection and cervical cancer is consistent worldwide and to investigate geographic variation in the distribution of HPV types. METHODS: More than 1000 specimens from sequential patients with invasive cervical cancer were collected and stored frozen at 32 hospitals in 22 countries. Slides from all patients were submitted for central histologic review to confirm the diagnosis and to assess histologic characteristics. We used polymerase chain reaction-based assays capable of detecting more than 25 different HPV types. A generalized linear Poisson model was fitted to the data on viral type and geographic region to assess geographic heterogeneity. RESULTS: HPV DNA was detected in 93% of the tumors, with no significant variation in HPV positivity among countries. HPV 16 was present in 50% of the specimens, HPV 18 in 14%, HPV 45 in 8%, and HPV 31 in 5%. HPV 16 was the predominant type in all countries except Indonesia, where HPV 18 was more common. There was significant geographic variation in the prevalence of some less common virus types. A clustering of HPV 45 was apparent in western Africa, while HPV 39 and HPV 59 were almost entirely confined to Central and South America. In squamous cell tumors, HPV 16 predominated (51% of such specimens), but HPV 18 predominated in adenocarcinomas (56% of such tumors) and adenosquamous tumors (39% of such tumors). CONCLUSIONS: Our results confirm the role of genital HPVs, which are transmitted sexually, as the central etiologic factor in cervical cancer worldwide. They also suggest that most genital HPVs are associated with cancer, at least occasionally. IMPLICATION: The demonstration that more than 20 different genital HPV types are associated with cervical cancer has important implications for cervical cancer-prevention strategies that include the development of vaccines targeted to genital HPVs.

BACKGROUND: Experimental studies have provided strong evidence that human papillomavirus (HPV) is the long-sought venereal cause of cervical neoplasia, but the epidemiologic evidence has been inconsistent. PURPOSE: Given improvements in HPV testing that have revealed a strong link between sexual activity history and cervical HPV infection, we conducted a large case-control study of HPV and cervical intraepithelial neoplasia (CIN) to evaluate whether sexual behavior and the other established risk factors for CIN influence risk primarily via HPV infection. METHODS: We studied 500 women with CIN and 500 control subjects receiving cytologic screening at Kaiser Permanente, a large prepaid health plan, in Portland, Ore. The established epidemiologic risk factors for CIN were assessed by telephone interview. We performed HPV testing of cervicovaginal lavage specimens by gene amplification using polymerase chain reaction with a consensus primer to target the L1 gene region of HPV. Unconditional logistic regression analysis was used to estimate relative risk of CIN and to adjust the epidemiologic associations for HPV test results to demonstrate whether the associations were mediated by HPV. RESULTS: The case subjects demonstrated the typical epidemiologic profile of CIN: They had more sex partners, more cigarette smoking, earlier ages at first sexual intercourse, and lower socioeconomic status. Statistical adjustment for HPV infection substantially reduced the size of each of these case-control differences. Seventy-six percent of cases could be attributed to HPV infection; the results of cytologic review suggested that the true percentage was even higher. Once HPV infection was taken into account, an association of parity with risk of CIN was observed in both HPV-negative and HPV-positive women. CONCLUSION: The data show that the great majority of all grades of CIN can be attributed to HPV infection, particularly with the cancer-associated types of HPV. IMPLICATIONS: In light of this conclusion, the investigation of the natural history of HPV has preventive as well as etiologic importance.

Activating mutations in KRAS and in one of its downstream mediators, BRAF, have been identified in a variety of human cancers. To determine the role of mutations in BRAF and KRAS in ovarian carcinoma, we analyzed both genes for three common mutations (at codon 599 of BRAF and codons 12 and 13 of KRAS). Mutations in either codon 599 of BRAF or codons 12 and 13 of KRAS occurred in 15 of 22 (68%) invasive micropapillary serous carcinomas (MPSCs; low-grade tumors) and in 31 of 51 (61%) serous borderline tumors (precursor lesions to invasive MPSCs). None of the tumors contained a mutation in both BRAF and KRAS. In contrast, none of the 72 conventional aggressive high-grade serous carcinomas analyzed contained the BRAF codon 599 mutation or either of the two KRAS mutations. The apparent restriction of these BRAF and KRAS mutations to low-grade serous ovarian carcinoma and its precursors suggests that low-grade and high-grade ovarian serous carcinomas develop through independent pathways.

Determinants of genital human papillomavirus (HPV) persistence in 393 women initially cytologically normal were investigated by testing them for HPV DNA twice over a median interval of 14.9 months. At each visit, interview information was obtained and a cervicovaginal lavage sample was collected for polymerase chain reaction-based HPV testing. Twenty-six percent of the women were HPV-positive at the first sampling. Data on HPV type was available for 86 HPV-positive women (84%); 35 of these women (41%) had persistent type-specific HPV detection. Persistence decreased with time between samplings. Women aged > or = 30 years had a higher percentage of persistence (65%) than those < or = 24 years (32%, P = .02). The percentage of persistence was higher among women infected with HPV types known to be cancer-associated (45%) than among those infected with other types (24%, P = .11). These findings were independent of each other and of timing between samplings. Although based on a prevalent cohort, these results are concordant with previous suggestions that HPV infection is usually transient and that cervical cancer may arise from within the subset of women with persistent HPV infection.

OBJECTIVE: To determine the efficacy of conservative management of atypical hyperplasia and well-differentiated carcinoma of the endometrium in women under age 40. METHODS: Pathology records were searched to identify women under age 40 diagnosed with atypical hyperplasia or well-differentiated carcinoma of the endometrium between January 1990 and January 1996. All available biopsy, curettage, and hysterectomy specimens were reviewed. Follow-up was obtained from the patients' gynecologists. RESULTS: Sixty-seven records were identified. Atypical hyperplasia was found in 32 patients and well-differentiated carcinoma in 35 patients. Seven patients were excluded from analysis; four declined all treatment and follow-up, and three received no further treatment or tissue sampling from their physicians. Among 27 remaining patients with atypical hyperplasia, eight underwent hysterectomy, two were treated with ovulation induction, and 17 were treated with progestins, of whom 16 had regression of their lesions, and one had a persistent lesion. Among 33 women with well-differentiated carcinoma, 19 underwent hysterectomy, one was treated with bromocriptine, one was treated with oral contraceptives, and 12 were treated with progestins, of whom nine had regression of their lesions and three had persistent lesions. The median length of treatment required for a regression was 9 months. At a mean follow-up of 40 months, all patients were alive and well without evidence of progressive disease. Twenty-five women attempted to become pregnant, and five delivered healthy, full-term infants. CONCLUSION: Treatment of atypical hyperplasia and well-differentiated carcinoma of the endometrium with progestins appears to be a safe alternative to hysterectomy in women under age 40.