Microscopic and Early-Stage Ovarian Cancers in BRCA1/2 Mutation Carriers: Building a Model for Early BRCA-Associated Tumorigenesis

Discussion

The data reported here provide a view of the early natural history of ovarian and fallopian tube cancers in women with BRCA1/2 mutations, including differences between BRCA1 and BRCA2 mutation carriers. Although 76 women with BRCA1 mutations and 60 women with BRCA2 mutations underwent RRSO at MD Anderson, 6 cases of microscopic cancer were diagnosed in BRCA1 patients but no microscopic cancer cases were observed in BRCA2 patients. This is consistent with previous estimates of higher risk of ovarian cancer and earlier age of onset of ovarian cancer in BRCA1 mutation carriers than in BRCA2 mutation carriers (1, 23). Furthermore, while microscopic cancers were identified primarily in the fallopian tubes, they also occurred in the ovaries and peritoneal washings of BRCA1/2 mutation carriers. A review of microscopic cancers reported in the literature confirms our observation in BRCA1/2 mutation carriers and adds a case of an intracystic ovarian tumor. Our data also suggest that while many ovarian cancers actually originate from the fallopian tube, the ovary may be the preferred site for tumors to progress beyond the microscopic stage in BRCA1/2 mutation carriers.

With the data described here, we propose an updated model of the early stages of BRCA-associated ovarian cancer (Fig. 2), which expands the number of potential sites for ovarian cancer initiation. The fallopian tube epithelium, ovarian surface epithelium, ovarian cystic structures, and peritoneum may give rise to the early steps of carcinogenesis. Our single-institution experience and cases reported in the literature show that most “ovarian” cancers begin in the distal fallopian tube and fimbria. Some of these microscopic fallopian tube cancers progress and grow larger but remain confined to the tube, creating a primary tubal cancer (Fig. 2A). However, because of the close association between the fimbria and ovarian surface, fallopian tube tumor cells could also spread to the ovary. This tumor may appear confined to the ovarian surface (Fig. 2B), or due to the cyclic rupture, repair, and invaginations that occurs with ovulation, the tumor may be incorporated into the ovarian stroma, where it grows and expands (Fig. 2C). Alternatively, early carcinogenic changes may occur in the ovary (either on the surface or within cystic structures) where it quickly grows (Fig. 2D). In many cases, the ovary seems to provide a particularly rich environment to support tumor growth and most tumor mass is associated with the ovary. As the tumor grows larger, involving both the fallopian tube and the ovaries, it becomes difficult to identify whether the site of origin was ovaries or the fallopian tube. The observation of carcinoma in isolated peritoneal washings suggests that, less commonly, tumorigenesis might also begin in the peritoneum (not shown). However, additional cases with isolated positive peritoneal washings or cases of early peritoneal disease alone would be required to better address this issue. Furthermore, this study does not have sufficient cases to comment on other possible sequences of initiation or progression involving the peritoneum.

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Figure 2.

Possible pathways of BRCA-associated ovarian/fallopian tube cancer initiation and progression. A, some tumors begin in the fallopian tube and continue to grow larger, while remaining confined to the tube, creating a primary tubal cancer. However, because of the close association between the fimbria and ovarian surface, fallopian tube tumor cells could also spread to the ovary (B and C). B, cancer initiation occurs in the fallopian tube fimbria and a small number of cancer cells are deposited on to the ovarian surface, which provides a supportive environment for tumor growth. C, because of the cyclic rupture, repair, and invaginations that occurs with ovulation, cancer cells from the fimbria can be transferred into the ovarian stroma where it grows and expands. D, alternatively, early carcinogenic changes may occur within ovarian cysts where the tumor grows, again producing a dominant ovarian mass. As the tumor grows larger, involving both the fallopian tube and the ovaries, it becomes difficult to identify whether the site of origin was ovary or fallopian tube. OSE, ovarian surface epithelium.

The dominant size of ovarian masses observed in stage I and stage II ovarian/fallopian tube cancers in BRCA1/2 mutation carriers indicates that the ovary may be the preferred site for tumor growth. While early-stage cancers are rarely reported, our observation is also confirmed in a screening study by Lewin and colleagues (24). Three early-stage cancers were identified in BRCA1 mutation carriers (1 case at stage IA and 2 cases at stage IC). All 3 of these cancers were ovarian primaries. These observations imply that the ovarian microenvironment provides a permissive environment for tumor progression, regardless of the site of tumor initiation. We can hypothesize factors that may play a role (inflammation, hormonal changes, etc.), but detailed molecular studies will be required to better understand the contributions of the ovarian microenvironment during these early steps in tumorigenesis.

This updated model of ovarian cancer initiation and progression has implications for current clinical management strategies for BRCA mutation carriers. In recent years, a great deal of momentum has gathered behind the idea that the fallopian tube is the singular site of origin for ovarian cancer. However, our data indicate that caution should be exercised in allowing this hypothesis to impact clinical management. For example, because of the emphasis on the fallopian tube as the primary site of initiation, there has been discussion about the possibility of risk-reducing surgery to remove the fallopian tubes only. By leaving the ovaries, patients would avoid estrogen deprivation symptoms and perhaps be more likely to undergo surgery at a younger age. However, on the basis of this updated model of BRCA-associated ovarian carcinogenesis, salpingectomy may not be an effective preventive strategy. Initiated cells may have spread to the ovary at a very early point, resulting in a risk of carcinogenesis even if the tubes were removed. In addition, some BRCA-associated cancers may initiate in the ovaries or peritoneum and this cancer risk would be unaffected by salpingectomy alone. In both of these scenarios, the patient might have a false sense of protection against ovarian cancer. We propose that future, large-scale collaborative studies should evaluate the relationship between age at diagnosis of microscopic cancers and early-stage invasive cancers to determine whether there might be an age at which salpingectomy alone could be used as a temporizing risk-reducing strategy.

Several fundamental issues regarding ovarian cancer initiation and progression remain to be addressed. Future studies must address preneoplastic lesions that could be part of the continuum of BRCA-associated ovarian/fallopian tube carcinogenesis. For example, Crum and colleagues have proposed the “p53 signature” as an early lesion in the fallopian tube that precedes microscopic tumor development. The “p53 signature” is defined as 12 or more consecutive cells with strongly positive p53 nuclear staining within benign-appearing epithelium (25, 26). Further analysis of p53 signatures and continued efforts to identify additional precancerous lesions will be advanced through studying microscopic ovarian/fallopian tube cancers identified in BRCA mutation carriers. Studies are also necessary to evaluate the molecular implications of an updated model of ovarian cancer initiation and progression. For example, are the same early molecular events responsible for carcinogenesis in cancers that initiate in the ovary, fallopian tube, or peritoneum? Furthermore, are there common microenvironment contributions to carcinogenesis at these different sites? Bilateral microscopic cancers were diagnosed in several cases described here. This raises the question of whether metastasis occurs early in tumor development or whether this is an indication of multifocal initiation. Future studies must also determine whether all ovarian cancers proceed through a linear progression from early-stage to late-stage disease or perhaps some microscopic tubal carcinomas might bypass early-stage ovarian disease and progress directly to advanced stage disease. Addressing these basic issues in BRCA-associated ovarian tumorigenesis will be essential to creating improved in vitro and in vivo models to support development of prevention strategies for these high-risk patients.

It is important to note that this model is specific to BRCA-associated ovarian carcinogenesis; the relevance to sporadic ovarian cancer is unknown. Developing this type of model for sporadic ovarian cancer is problematic because microscopic cancers are rarely diagnosed in average-risk women and the intensive pathology review applied to BRCA1/2 mutation carriers is rarely performed in average-risk women. Because of the rarity of these cancers, large-scale collaborative studies will be invaluable to successfully creating a model of early events in sporadic ovarian cancer. While late-stage ovarian tumor tissues are readily available, it is difficult to extrapolate late-stage molecular findings to understand early molecular events.

In conclusion, our data suggest that the fallopian tube, ovary, and peritoneal surfaces may give rise to cancer initiation. Interestingly, most BRCA-associated early-stage cancers have a dominant ovarian mass, suggesting that the ovarian microenvironment should be further explored to better understand factors that support tumor progression. This updated model is important for an improved understanding of early events in BRCA-associated ovarian and fallopian tube carcinogenesis and may aid in identifying improved prevention strategies for women with BRCA1/2 mutations who delay or decline RRSO. By highlighting the many gaps in our basic knowledge of ovarian cancer, this study also emphasizes the need for a broad cooperative effort to continue to refine this data-driven model of early events in BRCA-associated ovarian carcinogenesis.