Managing endometriosis to prevent ovarian cancer

Endometriosis is a common condition, occurring in this country in 1 of 10 women of reproductive age. An association between endometriosis and subsequent ovarian carcinoma has been reported for decades, yet it is only recently that our knowledge has deepened enough to support more rational methods for preventing the malignancy.

Each year, approximately 22,000 new cases of ovarian cancer are diagnosed. The lifetime risk of developing this malignancy is low, but it is the deadliest of the gynecologic malignancies, with diagnosis usually made in advanced stages when prognosis is poor.

Dr. Farr Nezhat

Endometriosis shows some characteristics of malignancy, such as the development of local and distant foci, and attachment to and invasion of other tissues with subsequent damage to these tissues. Endometriosis also is characterized by recurrent, unregulated cell proliferation and estrogen-dependent growth.

Our attempts during the past 2 decades to detect ovarian carcinoma at the early stages through a combined screening modality involving transvaginal ultrasound and a test for the serum level of cancer antigen 125 have failed to provide any survival benefit or even any measurable reduction in morbidity. Today, early-stage ovarian carcinoma, which has a 5-year survival rate of more than 90%, is diagnosed in only a minority of women.

There is good news, however. In recent years our insight into the pathophysiology of ovarian cancer has deepened, providing us with a new paradigm for ovarian cancer pathogenesis that divides ovarian epithelial carcinoma into two distinct types with distinct molecular profiles – one which originates largely in the distal portion of the fallopian tube and the other which traces back to endometriosis.

This new paradigm strengthens and helps to explain the reported association between endometriosis and ovarian cancer. It also has important clinical implications for current practice. While we have much more to learn about the etiology of endometriosis and the causes of malignant transformation, our current knowledge provides a strong rationale for identification and close monitoring of some patients with endometriosis deemed at risk for ovarian cancer, risk-reducing medical management, earlier and more meticulous surgical treatment, and close monitoring.

By combining this new approach to endometriosis with consideration of salpingectomy after completion of childbearing, we have an unprecedented opportunity to reduce the incidence of epithelial ovarian cancer.

Dual pathogenesis

The majority of ovarian cancers are of epithelial origin and fall into four histologic categories: serous, endometrioid, clear cell, and mucinous. In recent years, we have gained a deeper understanding of the pathogenesis of ovarian carcinoma, with an array of epidemiologic, histologic, and molecular data showing us that epithelial ovarian cancers are also of two distinct types (Am J Obstet Gynecol. 2015 Sep;213[3]:262-7).

One of these types, a high-grade serous carcinoma, appears to arise in many cases in the epithelium of the fallopian tube. The other type of tumor is a low-grade carcinoma – particularly of the endometrioid and clear cell histologic subtypes – that originates largely from ovarian endometriotic lesions or from borderline serous tumors in the case of serous histology.

The majority of diagnosed stage 1 ovarian cancers are carcinomas of this low-grade type and not high-grade serous carcinomas. In a study of 76 consecutive stage 1 carcinomas, investigators found that ovarian endometriosis was present in 40 of the 76 cases. More than two-thirds of the 76 cases (71%) were nonserous cancers, and almost all of these cases were associated with endometriosis based on histologic examination (Fertil Steril. 2007 Oct;88[4]:906-10).

This study was among the first to show that the majority of stage 1 ovarian carcinomas are not high-grade serous carcinomas, but rather nonserous, primarily endometrioid and clear cell, cancers. The research demonstrated that endometriosis should be viewed as a potential precursor lesion to specific subtypes of ovarian cancer.

The malignant transformation of endometriosis was first suggested by Dr. J. A. Sampson in 1925, and a number of studies – in addition to the 2007 landmark study – have since described ovarian cancer arising from endometriosis, based on the frequent co-occurrence in surgical specimens.

Most recently, a study from the Ovarian Cancer Association Consortium (OCAC) found that women who reported a history of endometriosis had a significantly higher risk of developing ovarian cancer than the general population (odds ratio, 1.46).

Investigators of this critical study pooled data from 13 ovarian cancer case-control studies involving more than 13,226 controls and 7,911 women with invasive epithelial ovarian cancer – 818 (6.2%) and 738 (9.3%) of whom, respectively, reported a history of endometriosis. Specifically, they determined that self-reported endometriosis was associated with a 3.05-fold increased risk for clear cell invasive ovarian cancer and a 2.04-fold increased risk of endometrioid ovarian cancer.