Although growing numbers of tubal carcinomas in carriers of BRCA1 and BRCA2 germline mutations have been reported, very little is known about the nature and frequency of their possible precursor lesions. The aim of this study is to investigate the occurrence of atypical proliferative tubal lesions in grossly normal fallopian tubes from 26 women with BRCA1 and BRCA2 germline mutations who underwent prophylactic salpingo-oophorectomy and whose ovaries were histologically negative for carcinoma. Fallopian tubes from 49 women who had undergone hysterectomy with salpingo-oophorectomy for uterine leiomyoma served as controls. In the 22 BRCA1-mutated women, there were two in situ carcinomas and two atypical hyperplasias of the tubal epithelium. The tubes of the BRCA2-mutated women and of the 49 control women did not show any atypical proliferation. The frequency of proliferative lesions of the tubal epithelium, including in situ carcinoma, appears to be increased in BRCA1 mutation carriers. Removal and thorough examination of the fallopian tubes at the time of surgical prophylaxis for ovarian cancer is therefore recommended.

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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.

Aims and background Women with BRCA1 or BRCA2 germline mutations have an elevated risk of developing breast and/or ovarian cancer. Because of the early onset of the disease, screening of this group of women should start at an earlier age than in the general population. The association of breast magnetic resonance imaging (BMRI) and ultrasonography (US) with mammography (MX) and clinical breast examination (CBE) in the regular surveillance of these individuals has been proposed and seems to improve the early detection of breast cancer. Methods Within a multicenter study started by the Istituto Superiore di Sanita (Rome), at the Istituto Nazionale Tumori of Milan (INT) we enrolled 116 women at high genetic risk for breast cancer; they were either BRCA1 or BRCA2 mutation carriers or had a strong family history of breast cancer. They underwent CBE, MX, US and BMRI once a year. Results Between June 2000 and April 2005, at INT 12 cancers were detected among the 116 screened individuals (10%). In this subgroup, 1 patient refused BMRI and in 2 cases US was not performed. With BMRI we found 11 cancers and 6 of them were detectable only by this technique. In these 6 cases, the size of the disease was less than 1 cm and MX was false negative due to irregularly nodular parenchyma in 4 cases and scar tissue or prosthesis in the other 2. US was not performed in 2 cases and was false negative in 4 cases. Three false positive results were found with BMRI: 1 case was considered suspect but related to hormonal influences; 1 case with the same pattern was sent for second-look US, which gave a negative result and BMRI review after 6 months showed normalization of the parenchyma; in the third case histology revealed the presence of adenosis. No false positive results were registered for MX. Conclusions The aim of secondary prevention is the detection of cancer at its earliest stage. BMRI screening in women with BRCA1 or BRCA2 mutations or at high familiar risk appears to be highly sensitive and may detect mammographically occult disease. The accuracy of MR imaging is higher than that of conventional imaging but the technique is flawed by a lower specificity. In order to avoid unnecessary biopsies we believe that the combination of BMRI and conventional imaging can be very useful in screening women with a high genetic risk of breast cancer, especially with second-look evaluation by means of US when BMRI yields the only positive diagnostic result. Second-look US has been demonstrated to be of critical importance both in recognizing false positive BMRI results and in guiding biopsies, when necessary.

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