The epithelial ovarian carcinomas, which make up more than 85% of human ovarian cancer, arise in the ovarian surface epithelium (OSE). The etiology and early events in the progression of these carcinomas are among the least understood of all major human malignancies because there are no appropriate animal models, and because methods to culture OSE have become available only recently. The objective of this article is to review the cellular and molecular mechanisms that underlie the control of normal and neoplastic OSE cell growth, differentiation, and expression of indicators of neoplastic progression. We begin with a brief discussion of the development of OSE, from embryonic to the adult. The pathological and genetic changes of OSE during neoplastic progression are next summarized. The histological characteristics of OSE cells in culture are also described. Finally, the potential involvement of hormones, growth factors, and cytokines is discussed in terms of their contribution to our understanding of the physiology of normal OSE and ovarian cancer development.

/pdf/ovarian-surface-epithelium-biology-endocrinology-and-1ln38b94gz.pdf

Ovarian surface epithelium: biology, endocrinology, and pathology.

Ovarian cancer (OC) is the seventh most commonly diagnosed cancer among women in the world and the tenth most common in China. Epithelial OC is the most predominant pathologic subtype, with five major histotypes that differ in origination, pathogenesis, molecular alterations, risk factors, and prognosis. Genetic susceptibility is manifested by rare inherited mutations with high to moderate penetrance. Genome-wide association studies have additionally identified 29 common susceptibility alleles for OC, including 14 subtype-specific alleles. Several reproductive and hormonal factors may lower risk, including parity, oral contraceptive use, and lactation, while others such as older age at menopause and hormone replacement therapy confer increased risks. These associations differ by histotype, especially for mucinous OC, likely reflecting differences in etiology. Endometrioid and clear cell OC share a similar, unique pattern of associations with increased risks among women with endometriosis and decreased risks associated with tubal ligation. OC risks associated with other gynecological conditions and procedures, such as hysterectomy, pelvic inflammatory disease, and polycystic ovarian syndrome, are less clear. Other possible risk factors include environmental and lifestyle factors such as asbestos and talc powder exposures, and cigarette smoking. The epidemiology provides clues on etiology, primary prevention, early detection, and possibly even therapeutic strategies.

http://cancerbiomed.org/index.php/cocr/article/download/1004/1108

Epidemiology of ovarian cancer: a review.

ContextThe association between menopausal hormone replacement therapy and ovarian
cancer is unclear.ObjectiveTo determine whether hormone replacement therapy using estrogen only,
estrogen-progestin only, or both estrogen only and estrogen-progestin increases
ovarian cancer risk.DesignA 1979-1998 cohort study of former participants in the Breast Cancer
Detection Demonstration Project, a nationwide breast cancer screening program.SettingTwenty-nine US clinical centers.ParticipantsA total of 44 241 postmenopausal women (mean age at start of follow-up,
56.6 years).Main Outcome MeasureIncident ovarian cancer.ResultsWe identified 329 women who developed ovarian cancer during follow-up.
In time-dependent analyses adjusted for age, menopause type, and oral contraceptive
use, ever use of estrogen only was significantly associated with ovarian cancer
(rate ratio [RR], 1.6; 95% confidence interval [CI], 1.2-2.0). Increasing
duration of estrogen-only use was significantly associated with ovarian cancer:
RRs for 10 to 19 years and 20 or more years were 1.8 (95% CI, 1.1-3.0) and
3.2 (95% CI, 1.7-5.7), respectively (P value for
trend <.001), and we observed a 7% (95% CI, 2%-13%) increase in RR per
year of use. We observed significantly elevated RRs with increasing duration
of estrogen-only use across all strata of other ovarian cancer risk factors,
including women with hysterectomy. The RR for estrogen-progestin use after
prior estrogen-only use was 1.5 (95% CI, 0.91-2.4), but the RR for estrogen-progestin–only
use was 1.1 (95% CI, 0.64-1.7). The RRs for less than 2 years and 2 or more
years of estrogen-progestin–only use were 1.6 (95% CI, 0.78-3.3) and
0.80 (95% CI, 0.35-1.8), respectively, and there was no evidence of a duration
response (P value for trend = .30).ConclusionWomen who used estrogen-only replacement therapy, particularly for 10
or more years, were at significantly increased risk of ovarian cancer in this
study. Women who used short-term estrogen-progestin–only replacement
therapy were not at increased risk, but risk associated with short-term and
longer-term estrogen-progestin replacement therapy warrants further investigation.

https://jamanetwork.com/journals/jama/articlepdf/195119/joc20074.pdf

Menopausal hormone replacement therapy and risk of ovarian cancer.

Ovarian cancer is a commonly fatal disease for which prevention strategies have been limited, in part because of a lack of understanding of the underlying biology. This paper reviews the epidemiologic literature in the English language on risk factors and protective factors for ovarian cancer and proposes a novel hypothesis that a common mechanism underlying this disease is inflammation. Previous hypotheses about the causes of ovarian cancer have attributed risk to an excess number of lifetime ovulations or to elevations in steroid hormones. Inflammation may underlie ovulatory events because an inflammatory reaction is induced during the process of ovulation. Additional risk factors for ovarian cancer, including asbestos and talc exposure, endometriosis (i.e., ectopic implantation of uterine lining tissue), and pelvic inflammatory disease, cannot be directly linked to ovulation or to hormones but do cause local pelvic inflammation. On the other hand, tubal ligation and hysterectomy act as protective factors, perhaps by diminishing the likelihood that the ovarian epithelium will be exposed to environmental initiators of inflammation. Inflammation entails cell damage, oxidative stress, and elevations of cytokines and prostaglandins, all of which may be mutagenic. The possibility that inflammation is a pathophysiologic contributor to the development of ovarian cancer suggests a directed approach to future research

/pdf/possible-role-of-ovarian-epithelial-inflammation-in-ovarian-41m9986urn.pdf

Possible Role of Ovarian Epithelial Inflammation in Ovarian Cancer

ContextPostmenopausal estrogen use is associated with increased risk of endometrial
and breast cancer, 2 hormone-related cancers. The effect of postmenopausal
estrogen use on ovarian cancer is not established.ObjectivesTo examine the association between postmenopausal estrogen use and ovarian
cancer mortality and to determine whether the association differs according
to duration and recency of use.Design and SettingThe American Cancer Society's Cancer Prevention Study II, a prospective
US cohort study with mortality follow-up from 1982 to 1996.ParticipantsA total of 211 581 postmenopausal women who completed a baseline
questionnaire in 1982 and had no history of cancer, hysterectomy, or ovarian
surgery at enrollment.Main Outcome MeasureOvarian cancer mortality, compared among never users, users at baseline,
and former users as well as by total years of use of estrogen replacement
therapy (ERT).ResultsA total of 944 ovarian cancer deaths were recorded in 14 years of follow-up.
Women who were using ERT at baseline had higher death rates from ovarian cancer
than never users (rate ratio [RR], 1.51; 95% confidence interval [CI], 1.16-1.96).
Risk was slightly but not significantly increased among former estrogen users
(RR, 1.16; 95% CI, 0.99-1.37). Duration of use was associated with increased
risk in both baseline and former users. Baseline users with 10 or more years
of use had an RR of 2.20 (95% CI, 1.53-3.17), while former users with 10 or
more years of use had an RR of 1.59 (95% CI, 1.13-2.25). Annual age-adjusted
ovarian cancer death rates per 100 000 women were 64.4 for baseline users
with 10 or more years of use, 38.3 for former users with 10 or more years
of use, and 26.4 for never users. Among former users with 10 or more years
of use, risk decreased with time since last use reported at study entry (RR
for last use <15 years ago, 2.05; 95% CI, 1.29-3.25; RR for last use ≥15
years ago, 1.31; 95% CI, 0.79-2.17).ConclusionsIn this population, postmenopausal estrogen use for 10 or more years
was associated with increased risk of ovarian cancer mortality that persisted
up to 29 years after cessation of use.

https://jamanetwork.com/journals/jama/articlepdf/193665/joc01947.pdf

Pushkal P Garg

Papers

Hormone replacement therapy and the risk of epithelial ovarian carcinoma: a meta-analysis