Pelvic Inflammatory Disease and the Risk of Ovarian Cancer and Borderline Ovarian Tumors

A Pooled Analysis of 13 Case-Control Studies

Christina B. Rasmussen; Susanne K. Kjaer; Vanna Albieri; Elisa V. Bandera; Jennifer A. Doherty; Estrid Høgdall; Penelope M. Webb; Susan J. Jordan; Mary Anne Rossing; Kristine G. Wicklund; Marc T. Goodman; Francesmary Modugno; Kirsten B. Moysich; Roberta B. Ness; Robert P. Edwards; Joellen M. Schildkraut; Andrew Berchuck; Sara H. Olson; Lambertus A. Kiemeney; Leon F. A. G. Massuger; Steven A. Narod; Catherine M. Phelan; Hoda Anton-Culver; Argyrios Ziogas; Anna H. Wu; Celeste L. Pearce; Harvey A. Risch; Allan Jensen

Disclosures

Am J Epidemiol. 2017;185(1):8-20. 

In This Article

Abstract and Introduction

Abstract

Inflammation has been implicated in ovarian carcinogenesis. However, studies investigating the association between pelvic inflammatory disease (PID) and ovarian cancer risk are few and inconsistent. We investigated the association between PID and the risk of epithelial ovarian cancer according to tumor behavior and histotype. We pooled data from 13 case-control studies, conducted between 1989 and 2009, from the Ovarian Cancer Association Consortium (OCAC), including 9,162 women with ovarian cancers, 2,354 women with borderline tumors, and 14,736 control participants. Study-specific odds ratios were estimated and subsequently combined into a pooled odds ratio using a random-effects model. A history of PID was associated with an increased risk of borderline tumors (pooled odds ratio (pOR) = 1.32, 95% confidence interval (CI): 1.10, 1.58). Women with at least 2 episodes of PID had a 2-fold increased risk of borderline tumors (pOR = 2.14, 95% CI: 1.08, 4.24). No association was observed between PID and ovarian cancer risk overall (pOR = 0.99, 95% CI: 0.83, 1.19); however, a statistically nonsignificantly increased risk of low-grade serous tumors (pOR = 1.48, 95% CI: 0.92, 2.38) was noted. In conclusion, PID was associated with an increased risk of borderline ovarian tumors, particularly among women who had had multiple episodes of PID. Although our results indicated a histotype-specific association with PID, the association of PID with ovarian cancer risk is still somewhat uncertain and requires further investigation.

Introduction

Ovarian cancer is the fifth most common cancer among women in developed countries, and it is the most fatal gynecological malignancy.[1] The etiology of ovarian cancer is still not fully clarified, although a number of risk factors have been identified. A reduced risk of ovarian cancer has been observed with increased parity,[2] use of oral contraceptives,[2] hysterectomy,[3] and tubal ligation,[3] whereas family history of ovarian or breast cancer,[2] use of hormone replacement therapy,[2] exposure to talc,[4] and a history of endometriosis[5] have been associated with increased risks.

The 2 dominant hypotheses to explain the development of ovarian cancer relate increased risk to a large number of lifetime ovulatory cycles (the incessant ovulation theory)[6] or exposure to high levels of gonadotropins (the gonadotropin theory).[7] However, inflammation has also been suggested as a potential biological mechanism that may underlie a number of epidemiologic associations not easily explained by either theory,[8,9] including talc exposure, endometriosis, tubal ligation, and hysterectomy. Furthermore, a link between pelvic inflammatory disease (PID) and the risk of ovarian cancer has been suggested, and this potential association may also be explained by the inflammation theory. PID is defined as an upper genital-tract infection and includes diagnoses of endometritis, salpingitis, pelvic peritonitis, and tubo-ovarian abscess caused by microorganisms ascending from the lower genital tract.[10] Approximately 800,000 women are treated for PID annually in the United States,[11] and it is estimated that 6%–20% of all women in the Western world are diagnosed with PID during their lifetimes.[12–14]

Epidemiologic studies investigating the association between PID and the risk of ovarian cancer and borderline ovarian tumors have been inconsistent, revealing increased risks in some studies[15–19] but not in all.[20–23] Moreover, most previous studies have had methodological problems, including limited statistical power due to small numbers of study subjects and/or a short follow-up period. Also, ovarian cancer is a heterogeneous disease consisting of different histotypes with different risk factor profiles.[24] However, few investigators have studied the role of PID separately for borderline tumors[15,18] or for the separate histotypes of ovarian cancer.[18,20]

To examine the association of PID with the risk of ovarian cancer, an international collaborative study was performed, using data from 13 case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). To our knowledge, this was the largest study of PID and ovarian cancer risk to date, thereby enabling a more robust estimation of risks among subgroups according to tumor behavior and histotype than has previously been possible.

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