Incidental Carcinomas in Prophylactic Specimens in BRCA1 and BRCA2 Germ-line Mutation Carriers, With Emphasis on Fallopian Tube Lesions

Abstract

The identification of germ-line mutations in 2 genes (BRCA1 and BRCA2) responsible for the majority of hereditary ovarian cancers has led an increasing number of women carriers of these mutations to undergo prophylactic oophorectomy (PO) to reduce their risk of subsequent ovarian carcinoma. A large number of unexpected, clinically occult neoplasms are thus being discovered. Up to December 2004, the Medical Genetics Service of the National Cancer Institute in Milan, Italy, has tested 756 probands from breast and/or ovarian cancer families for BRCA1 and BRCA2 germ-line mutations. Molecular screening of family members led to the identification of 344 female carriers of BRCA1 (239) or BRCA2 (105) germ-line mutations. Of the 186 potentially eligible women (37 of whom had tested positive for BRCA1 and 13 for BRCA2 mutation), 50 (26.8%) chose to undergo PO. Six clinically occult primary gynecologic malignancies (2 stage IIIC serous carcinomas of the ovary, 3 in situ serous carcinomas of the fallopian tube, and 1 stage IIB invasive serous carcinoma of the fallopian tube) and 1 occult ovarian metastasis from breast carcinoma were identified in the PO specimens of 7 women (all BRCA1 mutated). Four of the patients with occult primary gynecologic cancers are alive without disease 129, 87, 38, and 7 months after PO, respectively. One of the 2 patients with primary ovarian cancer and the single patient with tubal invasive carcinoma are alive with recurrent disease 83 and 20 months after PO, respectively. In addition, one of the patients whose PO specimen did not show any malignancy presented with stage IIIC tubal carcinoma 77 months after PO. The relatively high number of tubal neoplasms found at PO in this group of patients underlines the linkage between mutation and the risk of developing tubal cancer, and stresses the need to include removal of the entire tubes at the time of PO and of thoroughly evaluating the specimens at the microscopic level. The upstaging of all 3 invasive carcinomas after staging surgery, and the late recurrence and persistence of 2 of them despite treatment indicate that small size of the tumors should not preclude therapy.

Diagnostic usefulness of the Risk of Ovarian Malignancy Algorithm using the electrochemiluminescence immunoassay for HE4 and the chemiluminescence microparticle immunoassay for CA125

“…In some cases, occult ovarian cancers are detected following histopathological assessment of ovaries and fallopian tubes resected during surgery (37–39). The reported incidence of diagnosing occult ovarian cancer varies in the literature from 1.9% (36) to 16% (39). To date, no reports have been published regarding the usefulness of HE4 or ROMA in preoperative diagnosis aimed at possible detection of occult ovarian cancers in this group of patients.…”

Clinical Outcome of Isolated Serous Tubal Intraepithelial Carcinomas (STIC)

“…Nine main series, in some cases presented in more than one publication to allow for updates, provide clinical information about the 37 previously published cases of STIC (Table 2). 8,12,14,16–23 There are additional publications on frequency of STIC, which do not provide follow-up information and are not included in this discussion.…”

Mathematical models of breast and ovarian cancers

“…Data were collected from published studies of healthy germline BRCA1 and BRCA2 mutation carriers 25,63 , who had their ovaries and fallopian tubes removed prophylactically. In some of these women, unsuspected ovarian cancers were discovered upon surgery 61 . Brown and Palmer performed a Monte Carlo simulation of tumor life histories to fit an exponential in silico model for tumor growth using parameters derived from their meta-analysis, with separate growth rate parameters for early and advanced stage cancers.…”