Risk of cervical cancer in women with a family history of breast and female genital tract neoplasms

The role of family history on the risk of cervical cancer has been investigated in an article including data from 2 studies, from Costa Rica and the Eastern United States (US).1 In the case-control study from Costa Rica, women with a family history of cervical cancer had a 2.4 times (95% confidence Interval [CI] 1.2–4.7) higher risk of developing cervical cancer or severe cervical dysplasia than women without affected first-degree relatives.1 In the case-control study from the Eastern US, the odds ratio (OR) in women with a family history of cervical cancer in first-degree relatives was 2.6 (95% CI 1.1–6.4) for squamous cell carcinoma (SCC) of the cervix and 1.3 (95% CI 0.4–3.9) for cervical adenocarcinoma.1 In the latter study, women with a family history of noncervical gynaecological malignancies had an OR of cervical SCC of 1.2 (95% CI 0.4–3.6), whereas the OR of cervical adenocarcinoma was 1.8 (95% CI 0.7–4.9).1 There is scant additional information on family history of cancer and risk of cervical cancer. In the Swedish Family-Cancer Database, having an affected daughter or mother doubled the risk of developing cervical cancer.2 The risk of developing cervical SCC was 2.0 (95% CI 1.5–2.5) in women with a mother diagnosed with the same cancer and 1.5 (95% CI 0.4–3.3) in women whose mother had had an adenocarcinoma of the cervix.3 We analysed the issue using data from an Italian case-control study. A hospital-based case-control study of invasive cervical cancer was conducted from 1981–1993 in the greater Milan area on 786 women (median age 53, range 17–79 years) with histologically confirmed invasive cervical cancer.4, 5 The histology was adenocarcinoma for 96 cases, SCC for 471 cases and unknown for 219 cases. We grouped cases with unknown histology with SCC because the latter represented the vast majority of cervical cancers in Italy.6 Controls were 917 women (median age 54, range 16–79 years) admitted to the same network of hospitals as cases for a wide spectrum of nongynaecological, nonneoplastic acute conditions unrelated to known or potential risk factors for cervical cancer. Among controls, 31% had traumatic conditions, 30% nontraumatic orthopedic disorders, 12% acute surgical conditions and 27% miscellaneous other illnesses. All interviews were conducted in hospital using a structured questionnaire including information on personal characteristics and habits.4, 5 Information on family history included number of sisters and if the mother or a sister had had a cancer of the breast, ovary, cervix uteri, corpus uteri or an unspecified uterine cancer. We estimated the OR of cervical cancer according to history of cancer at selected sites in first-degree relatives using unconditional multiple logistic regression models.7 We present ORs adjusted for age, education and lifetime number of sexual partners. Further adjustment for area of residence, smoking, parity, number of pap smears (excluding the one(s) leading to the diagnosis), oral contraceptive use and number of sisters did not substantially modify the ORs. Table I shows the ORs of cervical cancer in relation to history of selected cancers in first-degree relatives. A family history of breast or ovarian cancer was not associated with cervical cancer risk. Several women reporting a history of cancer of the uterus in the family were not able to specify whether the cancer was at the corpus or at the cervix uteri. The OR of SCC was 2.2 (95% CI 0.9–5.8) in women reporting a family history of cervical cancer, 0.8 (95% CI 0.3–2.0) in women reporting a family history of endometrial cancer, 2.5 (95% CI 1.0–5.9) for a family history of an unspecified uterine cancer, and 1.6 (95% CI 1.0–2.7) for a family history of any type of uterine cancer. No cervical adenocarcinoma case reported a family history of cervical cancer, whereas the OR of adenocarcinoma of the cervix were 2.9 (95% CI 0.9–9.2), 5.1 (95% CI 1.2–22) and 2.7 (95% CI 1.1–6.6) for a family history of endometrial, unspecified uterine and any uterine cancer, respectively. For all cervical cancers combined, the ORs were similar to those for SCC. After adjustment for additional potential confounders, the OR for all histologies combined became 0.9 (95% CI 0.6–1.5) for a family history of breast cancer, 1.6 (95% CI 0.5–5.2) for ovarian cancer, 1.9 (95% CI 0.7–5.1) for cervical cancer, 1.1 (95% CI 0.4–2.5) for endometrial cancer, 2.5 (95% CI 1.0–6.2) for an unspecified uterine cancer and 1.7 (95% CI 1.0–2.9) for any uterine cancer (not shown). Some limitations must be considered when interpreting the present findings. This study is based on information provided by the subjects, without any confirmation from other sources, and inaccuracies in reporting cancer in first-degree relatives must be taken into account.8 Several women, particularly cases, were not able to distinguish between cancer of the cervix and cancer of the corpus uteri in the relatives, and we also lacked information on age and other correlates of cancer risk in first-degree relatives. Furthermore, the power of the study was limited, in particular when adenocarcinoma was analysed separately. Moreover, the use of hospital controls has long been debated,7 since they may differ from the general population. However, we carefully excluded any admission diagnosis for controls potentially related to cervical cancer, and the similar hospital setting of interview in cases and controls may have improved comparability of medical data.9 In this study, the risk of cervical cancer overall was about 2-fold higher in women with a family history of cervical cancer, or of an unspecified cancer of the uterus, but not in women with a first-degree relative affected with breast, ovarian or endometrial cancer, in agreement with previous studies.1, 3 Of interest is the suggestion in the present study, as well as in the study from the Eastern US,1 that the risk of adenocarcinoma of the cervix is enhanced more by a family history of endometrial/gynaecologic noncervical cancers than by a family history of cervical cancer. Although the major determinant of both adenocarcinoma and SCC of the cervix is HPV infection, and the 2 histologic types appear to share several risk factors,10, 11 some differences have also been observed.11, 12, 13 Cervical adenocarcinoma, but not SCC, appears to share some risk factors with endometrial cancer too, such as obesity, hypertension and diabetes.12 In this study, the OR of adenocarcinoma of the cervix was 1.9 (95% CI 1.0–3.5) for women with a body mass index > 30 kg/m2 compared to women with a body mass index < 25 kg/m2. Since most endometrial cancers are adenocarcinomas, our data would suggest an inherited susceptibility to develop a specific histologic type of cancer. Although the data from the Swedish Family-Cancer Database lend some support to the hypothesis that in general inherited susceptibility may be histology specific, results were less convincing for cervical cancer, which were, however, based on small numbers.14 Since obesity, hypertension and diabetes also tend to aggregate in families, the association between adenocarcinoma of the cevix and endometrial cancer may be due, at least in part, to shared environmental exposure or genetic predisposition to these risk factors. Our study and the case-control study from the Eastern US1 included approximately 100 adenocarcinomas each, and consequently the confidence intervals were wide. Because of the small samples and of the limits in our data discussed above, the possibility that the observed differences between histologic types are due to chance or bias cannot be ruled out. In conclusion, our data confirm that cervical cancer aggregates in families and suggest that some differences may exist in familial predisposition to SCC and adenocarcinoma of the cervix. The authors thank Mrs. I. Garimoldi for editorial assistance. Yours sincerely, Eva Negri, Carlo La Vecchia, Cristina Bosetti, Silvia Franceschi, Fabio Parazzini