Paul D. Stolley, and Joseph F. Fraumeni, Jr. Epidemiolog)' and ..... Lubin, J. H. A computer program for the analysis of matched case-control studies. Comput.
[CANCER RESEARCH 47, 1706-1711, March 15, 1987]
Epidemiology of Cervical Cancer by Cell Type Louise A. Brinimi,' Karen T. Tashima,2 Herman F. Lehman, Robert S. Levine, Katherine Mailin, David A. Savitz,3 Paul D. Stolley, and Joseph F. Fraumeni, Jr. Epidemiolog)' and Biostatistics Program, National Cancer Institute, Bethesda, Maryland 20892 [L. A. B., K. T. T., J. F. F.]; School of Public Health, university of Alabama at Birmingham, Birmingham, Alabama ÃŒS294[H. F. L.]; Papanicolaou Comprehensive Cancer Center, Miami, Florida 33136 [R. S L.]; Illinois Cancer Council, Comprehensive Cancer Center for the State of Illinois, Chicago, Illinois 60603 [K. M.]; School of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262 [D. A. S.J; and Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104 [P. D. S.]
ABSTRACT A multicenter case-control study of 481 invasive cervical cancer pa tients and 801 population controls enabled comparison of risk factors for squamous cell tumors (n = 418), adenosquamous cancers (n = 23), and adenocarcinomas (n = 40). The epidemiology of the squamous cell tumors resembled that found in other studies, with the major risk factors being absence of Pap smear screening (relative risk = 3.6 to 4.8 for those not screened within 5 yr), multiple sexual partners (relative risk = 2.9 for over ten partners), and history of genital infections or sores (relative risk = 2.3). Although based on small numbers, adenosquamous tumors ap peared to share some of these risk factors, notably number of sexual partners, years since last Pap smear, and level of education. Adenocar cinomas were not similarly affected, although sexual practices were marginally predictive. Obesity increased the risk of adenocarcinoma, but no other similarities to endometrial adenocarcinoma were observed. Smoking was a significant predictor of squamous cell tumors but did not affect adenocarcinomas. Extended use of oral contraceptives was a risk factor for all tumor types, especially adenocarcinoma, and a familial tendency to cervical cancer was also observed for all cell types.
INTRODUCTION The epidemiology of squamous cell carcinoma of the cervix has been widely investigated, with the effects of early age at first intercourse and multiple sexual partners suggesting vener eal transmission of an oncogenic agent. Little is known, how ever, about the rarer cervical cancers, notably adenocarcinomas, which comprise 4 to 10% of all cervical cancers (1-6). A similarity to endometrial cancer has been suggested by some investigators, but not tested by carefully designed epidemiológ ica! studies. Within the context of a large case-control study of invasive cancers of the cervix, we had the opportunity to evaluate differ ences in risk factors between squamous cell tumors and other histological types of cancer, including adenocarcinoma and tumors classified as mixed adenosquamous carcinoma. MATERIALS AND METHODS The methodology for this case-control study has been described in detail elsewhere (7). In brief, cases for study consisted of women, aged 20 to 74 yr, with invasive cervical cancer newly diagnosed during the period April 1982 to January 1984 at 24 hospitals in 5 study areas— Birmingham, Chicago, Denver, Miami, and Philadelphia. Two popu lation controls, identified through random digit dialing techniques, were individually chosen for each case, matching on telephone ex change, race, and 5-yr age group. After selecting a residential cluster matched on exchange for each case, telephone numbers were called, Received 8/4/86; revised 12/5/86; accepted 12/9/86. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1To whom requests for reprints should be addressed, at Environmental Epi demiology Branch. National Cancer Institute, Landow Building, Room 3C06, Bethesda, MD 20892. 2 Present address: Columbia College of Physicians and Surgeons, New York, NY 10032. 3 Present address: School of Public Health, University of North Carolina, Chapel Hill, NC 27514.
and enumeration of the female members of each household, age 20 to 69, was taken. Of 23,404 telephone numbers sampled, an enumeration, by age and race, of female members was obtained for 84.1 %, and 13,561 (57.9%) had eligible household members for control selection. Follow ing the selection of appropriately matched controls, a brief telephone interview was administered to ascertain histories of prior hospitalization. Approximately 25% of the initially selected controls were found to have had a hysterectomy (and thus not at risk for cervical cancer) and were replaced with other eligible controls. Trained interviewers conducted home interviews with both cases and controls. The majority (74%) of the cases were interviewed within 6 mo of diagnosis, while 35% were interviewed within 3 mo. Interviews lasted an average of 76 min and elicited detailed information on demographics, sexual behavior, marital and pregnancy history, men strual history and hygiene practices, contraceptive usage, medical his tory, smoking, diet, and family history of cancer. Interviews were completed for 481 of 658 eligible cases (73.1%) and for 801 of 1114 controls (71.9%). Refusal (9.7% of cases versus 21.9% of controls) was the major reason for nonresponse of study subjects. Other reasons included subjects having moved or being unlocatable (3.8% versus 3.4%), death (5.0% versus 0.5%), illness (2.1% versus 1.1%), and miscellaneous problems (1.7% versus 1.1%). In addition, it was not possible to obtain physican consent to interview 4.6% of the cases. Pathology information from hospital records enabled the cancers to be divided into three histological groups. A total of 418 cases were classified as squamous tumors, with 242 of these being designated as squamous, NOS.4 Other squamous tumors included 47 keratinizing types; 66 large cell, nonkeratinizing types; 2 small cell, nonkeratinizing types; 2 large cell carcinomas, NOS; 4 small cell carcinomas, NOS; 2 papi Ilomas; 38 microinvasive cancers; 13 carcinomas, NOS; and 1 carcinoma of undifferentiated type, NOS. Of the 40 adenocarcinoma cases, there were 28 adenocarcinomas, NOS; 6 papillary adenocarcinomas; 4 clear cell adenocarcinomas; 1 adenoid cystic carcinoma; and 1 mucinous adenocarcinoma. A total of 23 cases were characterized as adenosquamous carcinomas. The RR, as estimated by the odds ratio, was the measure of associ ation used for evaluating effects of exposures on the risk of cervical cancer. Unmatched logistic regression analyses comparing each case group to all controls were done to obtain maximum likelihood estimates of the odds ratios and 95% confidence intervals, while adjusting for confounding variables (8). Initially, effects of individual factors were assessed, adjusting only for age and race. Subsequently, all variables that showed evidence of univariate effects were entered into step-down logistic models to determine the major predictors for each tumor type. These analyses concentrated on comparisons of parameter estimates (odds ratios, logistic regression coefficients) rather than on levels of significance, since there was much more precision for the squamous cell tumors than for the other disease classifications. Because matching was used in the study design, analyses were also done comparing each case group to their matched controls, using both unmatched and matched (9) logistic analyses. No major discrepancies were observed between the matched and unmatched estimates apart from the antici pated loss in power. Unmatched estimates are thus presented.
RESULTS (Table 1) presents the demographic and socioeconomic dis tribution of the controls and the cases by histology. Although
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* The abbreviations used are: NOS, not otherwise specified; RR, relative risk.
EPIDEMIOLOGY
OF CERVICAL CANCER BY CELL TYPE
Table 2 Relative risks (adjusted for age and race) of invasive cervical cancers associated with sexual and reproductive factors AdenoAdenoSquamous cell carcinoma squamous (n418)19.627.524.628.246.8 = (n801)27.129.021.222.743.7 = (n 40)17.532.527.522.546.0 = (» 23)26.126.113.034.846.5 = carcinoma squamous cell Controls (n = 40) (n = 23) (n = 418) (n = 801) Age diagnosis'
