Clear Cell Adenocarcinoma of the Ovary Associated With In Utero Diethylstilbestrol Exposure: Case Report and Clinical Overview

Constantin A. Dasanu, MD, PhD; Thomas J. Herzog, MD


January 07, 2009


Clear cell adenocarcinomas of the vagina, cervix, endometrium, and ovaries show very similar histologic features. Apart from their morphologic similarities, clear cell carcinomas of the ovary and those of the lower genital tract have not been reported to have any common associations. Furthermore, Dickersin and coworkers[5] showed no difference between tumors in patients with confirmed histories of prenatal exposure to DES and those in patients who had no history of such exposure. No specific ultrastructural features could be identified as prognostic indices for these neoplasms.

We are aware that several other tumors and tumor-like lesions of the female genital tract may contain clear cells and may occasionally be misdiagnosed as clear cell adenocarcinomas. These conditions include microglandular hyperplasia, mesonephric hyperplasia, Arias-Stella change, smooth muscle tumors containing clear cells, metastatic renal cell carcinoma, steroid cell tumors, hepatomas, signet ring-cell stromal tumors, and various germ cell tumors.[6] Therefore, an experienced team of pathologists was consulted to review the pathologic specimen, and all of the above conditions were excluded.

In a recent study,[7] DES exposure in uterowas shown to be associated with an elevated risk for ovarian cancer. While preliminary, this finding supports continued monitoring of these patients for gynecologic cancer, as the population of women with a history of antenatal DES exposure is reaching into the fourth decade. However, none of the ovarian cancers described in that report have been shown to be of clear cell histology. Yet it could be concluded that, since clear cell cancers make up 5% to 10% of all malignant ovarian epithelial neoplasms, our case represents the normal distribution of this disease and the association is really between DES and epithelial ovarian cancer.

In contrast, another recent large epidemiologic study failed to demonstrate an increased cancer risk in DES-exposed daughters other than clear cell adenocarcinoma of the lower genital tract and breast cancer in older women.[8] This study showed the overall incidence of cancer rate ratios comparing exposed with unexposed women to be 1.32 (95% CI, 0.94-1.8). Breast cancer risk was elevated only among women older than 40 years (RR, 1.83; 95% CI, 1.1-3.2). The clear cell adenocarcinoma standardized incidence rate ratios among exposed women was nearly 40, and the estimated occurrence rate through age 39 was 1.6/1,000 women. Clear cell adenocarcinoma incidence decreased by more than 80% in women 25 years and older compared with those who were 20 to 24 years. Excluding clear cell adenocarcinoma and breast cancer, the overall risk ratio was 1.21 (95% CI, 0.74-2.0). DES was not associated with excess risks for either endometrial or ovarian cancer. These data suggest that the DES-associated increase in clear cell adenocarcinoma incidence remains elevated throughout the reproductive years.

With regard to the association between in utero DES exposure and breast cancer, there could be etiologic and developmental similarities between the increased risk for breast and ovarian cancers. In utero exposures may not act directly on the breast but may alter other physiologic pathways, such as hormone metabolism, that can affect risk later in life. Because the prenatally exposed population is still relatively young, follow-up to assess the overall carcinogenic impact of DES exposure seems warranted.

To our knowledge, this patient is the first clinical case featuring clear cell adenocarcinoma of the ovary that may be linked to DES exposure in utero. We would like to emphasize that clear cell adenocarcinoma of the vagina and cervix, not the ovary, were previously shown to be sites for tumors in female offspring exposed prenatally to DES. And since clear cell cancers can develop, not infrequently, in foci of endometriosis,[9] our patient's pathology specimen was carefully inspected for endometriosis and none was found. Moreover, evidence linking prenatal DES exposure with chronic ovarian inflammation, paraovarian cysts, and high-grade squamous neoplastic proliferation in the genital tract has been accumulating.[2,3,4]Although our patient is older than most patients in the Herbst cohort[1]anda sporadic case of clear cell carcinoma cannot be excluded with certainty, all of the above changes were present in our patient's pathology specimen. This further enhances our degree of suspicion on the causality between in utero DES exposure and the clear cell adenocarcinoma of the ovary in our patient.

In conclusion, our case of probable DES-induced transplacental carcinogenesis more than 4 four decades after exposure reinforces the need for continued routine gynecologic examinations in prenatally exposed individuals.


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