Tubal ligation and ovarian cancer risk in a large cohort: Substantial variation by histological type

Abstract

Histopathological and molecular studies suggest that different histological subtypes (histotypes) of ovarian cancer have different aetiologies. Few studies have been large enough to explore reliably the effect of tubal ligation (sterilization), which has been associated with a reduced overall risk of ovarian cancer, on different tumour histotypes. In a prospective study of 1.1 million UK women without prior cancer or bilateral oophorectomy, 8,035 ovarian cancers occurred during mean follow-up of 13.8 years. Using a Cox proportional hazards model, we estimated adjusted relative risks of ovarian cancer associated with tubal ligation. Overall, there was substantial heterogeneity in tumour risk associated with tubal ligation for the four main histotypes, serous, endometrioid, mucinous and clear cell (heterogeneity: p < 0.0001). For serous tumours, the most common histotype (n = 3,515), risks differed significantly between high-grade (RR: 0.77, 95% CI: 0.67-0.89) and low-grade tumours (RR: 1.13, 95% CI: 0.89-1.42); heterogeneity: p = 0.007. Relative risks were almost halved for endometrioid (n = 690, RR: 0.54, 95% CI: 0.43-0.69) and clear cell tumours (n = 401, RR: 0.55, 95% CI: 0.39-0.77), but there was no association between tubal ligation and mucinous tumours (n = 836, RR: 0.99, 95% CI: 0.84-1.18). For the main tumour histotypes we found little variation of risk by timing of tubal ligation. The significant differences by tumour histotype are unlikely to be due to confounding and are consistent with hypotheses that high-grade and low-grade serous tumours have different origins, and that some endometrioid and clear cell tumours might arise from cells and/or carcinogens travelling through the fallopian tubes.

Keywords: histological subtypes; histotype; ovarian cancer; sterilization; tubal ligation.

Figure 1

Relative risk of subtypes of ovarian cancer in women with versus without a history of tubal ligation. N = 1,132,914. Results show relative risks (hazard ratios) of ovarian cancer amongst women with a history of tubal ligation compared to women without a history of tubal ligation, by histological subtype. Analyses are adjusted for age, region, parity, family history of breast cancer, hysterectomy, use of the oral contraceptive pill and menopausal hormones, body mass index, smoking and socioeconomic status. Serous tumours have been split into low‐grade (serous borderline tumours and low‐grade serous carcinoma, here defined as grade 1) and high‐grade (serous carcinoma of grade ≥2). Endometrioid tumours have been split into low‐grade (here defined as grade 1–2) and high‐grade (grade 3); see main text for discussion of rationale for this. Note: The numbers of grade‐specific serous and endometrioid tumours do not sum to the total numbers of serous and endometrioid tumours, as information on tumour grade was missing for 1,475 serous carcinomas and 273 endometrioid carcinomas.

Figure 2

Relative risk of ovarian cancer in relation to the timing of tubal ligation (amongst parous women only). Results show relative risks (hazard ratios) of ovarian cancer by the timing of tubal ligation, with 95% group‐specific confidence intervals (95% g‐s CI). Each timing analysis was a separate model. For each analysis, we excluded nulliparous women, and sterilized women if their age at tubal ligation was unknown [993,166 women (6,744 cases) included in analyses]. For the analysis of tubal ligation at versus after the last birth, women with an unknown age at last birth were also excluded [967,166 women (6,556 cases) included in analyses]. Analyses are adjusted for age, region, parity, family history of breast cancer, hysterectomy, use of the oral contraceptive pill and menopausal hormones, body mass index, smoking and socioeconomic status. Heterogeneity tests are among women with a tubal ligation only.

Figure 3

Relative risk of ovarian cancer in women with versus without a history of tubal ligation, by subgroup. Results show the relative risks (hazard ratios) of ovarian cancer in women with versus without tubal ligation, by various other factors. The results for each subgroup are from separate models, restricted to women with no missing information on that variable, and thus total numbers of participants and cases will differ. Analyses are adjusted for age, region, parity, family history of breast cancer, hysterectomy, use of the oral contraceptive pill or menopausal hormones, body mass index, smoking and socioeconomic status, as appropriate.