We found that 43% of tested women with primary fallopian tube carcinoma from our institution had germline BRCA mutations. BRCA2 mutations may play less of a role in hereditary tubal carcinogenesis than BRCA1 mutations. Only 1 patient in our cohort had a BRCA2 germline mutation. We attribute the higher incidence of BRCA mutations observed in our patients to our patient referral population with a high prevalence of Ashkenazi Jews and by extension, BRCA-related carcinomas. Additionally, our study population included patients with tubal carcinoma-in situ as well as patients of all religious backgrounds. In light of the reported more than 16% prevalence of BRCA mutations in patients with tubal carcinoma both from our institution and the larger, retrospective studies of Levine et al8 and Aziz et al,6 we concur with these authors’ recommendation that genetic testing is appropriate for all affected patients.26 Given that neither a family history of breast or ovary cancer nor a personal history of breast cancer accurately predicted BRCA mutation status in women with fallopian tube cancer, genetic testing is advised regardless of cancer history.
In our study, the distribution of the carcinomas did not differ between patients with BRCA-associated and sporadic fallopian tube cancer. Carcinoma typically involved the mid and distal segments of the fallopian tube, although 2 patients from each cohort had diffuse disease involving the entire length of fallopian tube. Two of the largest studies of tubal cancer patients with undetermined BRCA mutation status that evaluated the location of tubal disease failed to identify any cases of exclusively proximal tubal disease involving the cornua.28,29 The predominantly distal location of tubal cancer may reflect the anatomy of the fallopian tube, with a larger area of vulnerable epithelium in the ampullary and fimbriated rather than isthmic tubal segments. Careful pathologic assessment of the uterus, cervix, and ovaries is necessary to exclude the presence of synchronous gynecologic cancers, which have been reported to occur in 7–35% of patients with tubal carcinoma.22,30,31
The clinical significance of associated tubal atypia, hyperplasia, and dysplasia remains controversial. Tubal epithelial proliferations have been reported in up to 18% of routinely accessioned salpingectomy specimens.35–37 Although the pathogenesis of tubal cancer is not clear, it has been suggested that the model of epithelial cancer progression described in other malignancies may apply.38 The recent World Health Organization histologic classification of tubal carcinomas recognizes tubal carcinoma in situ as a specific diagnostic entity and studies of early “occult” tubal carcinomas in BRCA mutation carriers increasingly demonstrate foci of carcinoma in situ that transition to invasive carcinoma.29,34 Piek et al20 reported tubal dysplasia in 50% of 12 patients with a genetic predisposition to ovarian cancer who underwent prophylactic adnexectomy compared with none of 13 control patients whose fallopian tubes were removed for benign gynecologic disease. We found that tubal atypia, hyperplasia, or dysplasia occurred in the majority of BRCA-associated and sporadic tubal cancer patients and involved both tubes despite the unilateral primary location of the tubal carcinomas. Based upon these findings, we advise that any patient found to have occult tubal carcinoma in situ at the time of salpingo-oophorectomy should be counseled to undergo hysterectomy because of the potential for multifocal tubal neoplasia to completely evaluate all segments of the fallopian tubes.
As with other reports, the initial retrospective design of our study that examined patient survival suffered from selection bias by including only living cancer patients.12,40–43 We recognize the inherent bias of studying survival as an endpoint in a cohort of cancer survivors. We also recognize the limitation of incomplete BRCA sequencing in the study population and the high frequency of Ashkenazi Jewish women in our patient population. Although the BRCA screening techniques used in the study identify more than 90% of germline BRCA mutations in Jewish patients, a significant proportion of BRCA mutations in non-Jewish populations would not be detected. We have, therefore, amended the study to approach all newly diagnosed tubal cancer patients, and counsel them to have complete genetic evaluation and testing. Prospective multi-institutional studies with larger patient populations are necessary to validate our preliminary observations regarding the prevalence and characteristics of BRCA mutation–associated tubal carcinoma and to define the optimal prophylactic surgical procedure for BRCA mutation carriers to reduce their risk of tubal and ovarian carcinoma.
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