Increased Risk of Breast and Uterine Cancer Among Women With Ovarian Granulosa Cell Tumors

Discussion

In the largest cohort of patients with GCT to date, 4.14% had a personal history of breast cancer and 2.78% had a diagnosis of endometrial cancer. Our study thus provides further compelling evidence for an association between GCT and estrogen-related malignancies.

Several smaller studies prior to this population-based study have provided insight into the association between GCTs and breast and endometrial neoplasms. Historically, Evans et al. found a 5.5% incidence of breast cancer in 200 women with GCTs or theca cell tumors (9). Ohel et al. reported a 6.4% incidence of breast cancer among 172 patients diagnosed with GCT after a follow-up of 15-years, approximately 4 times higher than the incidence in the general population (10). An 11% incidence of endometrial pathology was also found among the 63 patients who had endometrial examination (10). Of note, this study did not differentiate between GCTs and theca cell tumor patients (10). Björkholm et al. analyzed the Swedish Cancer Registry and identified patients with GCT or theca-cell tumors diagnosed between 1958 and 1972. A total of 15 patients had a prior diagnosis of breast cancer, while four patients were concurrently diagnosed with breast cancer and GCT. The expected number of breast malignancies in that cohort was 10.3 with a calculated relative risk of 1.8 (95%CI=1.1, 2.9). Authors also found a four times increased risk of developing an endometrial carcinoma compared to the lifetime risk of the general population (12). In a more recent population-based study, Bryk et al. used the Finnish Cancer Registry to determine the incidence of new primary malignancies after GCTs, as well as the incidence of GCT following breast cancer. They identified 986 patients diagnosed between 1968 and 2013 and found breast cancer rate of 6.9%. An increased risk of developing breast cancer was only significant for malignancies diagnosed prior to the diagnosis of GCTs; they suggested that the lack of significance of developing breast cancer after a primary GCTs was due to the presence of surveillance bias. Interestingly, in this cohort the rate of uterine cancer was 2.5% lower than that previously reported, possibly due to the inclusion of a large number of women with a prior hysterectomy (7). Hammer et al., in a retrospective study, analysed 163 women diagnosed with a GCT between 1962 and 2003 at hospitals in Jutland, Denmark and found an increased risk of breast cancer (OR=3.3, 95%CI=1.6, 6.6) compared to the general population (8). Meisel et al. in a secondary analysis of the data of 118 patients that received chemotherapy for any stage GCT, found that 12 (10%) had a diagnosis of breast cancer prior to the diagnosis of GCT, an incidence that was 3.22 times higher than that expected based on the SEER rates (5). Van Meurs et al. analyzed a cohort of 1031 patients with GCT derived from the PALGA database of the Netherlands (11). For 614 patients, endometrial tissue was available for examination at the time of initial GCT diagnosis; 58 (5.9%) patients were found to have endometrial cancer (11). For 490 patients who did not undergo hysterectomy during the initial surgery for GCT, no increased risk of endometrial cancer was observed since only two (0.4%) patients were diagnosed with endometrial cancer after approximately 10 years of follow-up (11). Interestingly both patients had recurrent GCT at the time of endometrial cancer diagnosis (11).

The relationship between GCTs and estrogen-related malignancies could be explained physiologically through hyperestrogenism stimulating malignant breast tumor growth and endometrial hyperplasia. Interestingly, in Meisel et al.'s study (5), 100% (n=5) of the breast tumors identified in GCTs patients stained positive for estrogen receptor (ER) and progesterone receptor (PR). However, in the current study, 79.7% (47/59) and 61% (36/59) of tumors were estrogen and progesterone receptor positive respectively, comparable to the rate of hormone receptor positive breast cancer found in the general US population (13). Potentially, increased levels of estrogen in patients with GCT may regulate the differentiation of mammary stem cells located at niches in the basal epithelium contributing to breast cancer tumorigenesis (14). The associations with parity and obesity in patients also provide plausible hormonal similarities. However, a common yet unknown genetic susceptibility cannot be excluded as a causal etiology. For now, BRCA1 and BRCA2 genes, associated with breast cancer, are not known to be associated with GCTs and the pathognomic FOXL2 gene of GCTs is not known to be associated with breast cancer (2, 6). Therefore, metabolites of tamoxifen may contribute to the development of GCTs in breast cancer survivors (14).

The limitations of the present study include the lack of central pathology review and the loss during follow-up due to patient migration out of a SEER county. Our study is also limited by the inclusion of both previous, concomitant, and subsequent breast and uterine cancers, such that direct causal and temporal relationships cannot be drawn. However, even when excluding breast tumors diagnosed prior to GCT, patients had an increased risk of breast cancer compared to the general population. Use of tamoxifen for breast cancer could not be extrapolated from the data to measure the impact on risk. Moreover, certain confounding factors such as parity, BMI, use of hormone therapy and presence of premalignant breast lesions are not available in the SEER database. The strengths of the present data include the use of a multi-institutional racially diverse population-based database and the large sample size with a long follow-up.

Despite the limitations of our data, in this population-based study, an increased risk of uterine and breast malignancies was observed among women with ovarian GCTs. This information provides further evidence to a strong relationship between GCTs and the risk of developing breast or endometrial malignancies and could guide screening strategies and surgical planning of these patients in the future. We also suggest the creation of an international tumor registry of GCTs to further elucidate the optimal management of these patients. With greater numbers of patients, definitive analyses can be appropriately drawn to guide treatment and surveillance guidelines for these women. Patients diagnosed with GCT may benefit from earlier breast cancer screening and close follow-up.