Risk-Reducing Salpingo-Oophorectomy in BRCA Mutation Carriers: Role of Serial Sectioning in the Detection of Occult Malignancy

University of California, San Francisco, San Francisco, California, United States
Journal of Clinical Oncology (Impact Factor: 18.43). 02/2005; 23(1):127-32. DOI: 10.1200/JCO.2005.04.109
Source: PubMed


Women who carry deleterious mutations of BRCA1 or BRCA2 genes have up to a 54% lifetime risk of developing ovarian cancer. After childbearing, women at high risk increasingly choose bilateral risk-reducing salpingo-oophorectomy (RRSO). Two recent studies of BRCA mutation carriers reported occult malignancy in 2.5% of women undergoing RRSO. This study aimed to increase this detection rate using a protocol.
In 1996, the University of California San Francisco Gynecologic Oncology Program instituted a surgical-pathologic RRSO protocol that was composed of complete removal and serial sectioning of both ovaries and fallopian tubes, peritoneal and omental biopsies, and collection of peritoneal washings for cytology. We report the pathologic findings in 67 BRCA mutation carriers according to the degree of adherence to this protocol.
Of the 67 procedures, the protocol was followed completely or partially in 41 (61%). Seven occult malignancies were discovered, four in the fallopian tube and three in the ovaries. Six of these were microscopic, and all seven (17%) were found in specimens from complete or partial protocol procedures as opposed to standard procedures (P = .026). Other variables such as age, parity, BRCA1 or BRCA2 mutation, or type of surgery did not alter the strong effect of protocol procedure on the cancer detection rate.
A rigorous operative and pathologic protocol for RRSO increases the detection rate of occult ovarian malignancy in BRCA mutation carriers nearly seven-fold. If confirmed, this finding will alter postoperative management because additional staging, chemotherapy, and follow-up may be necessary in affected women.

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    • "During systematic histopathological examination of tissues from prophylactic adnexectomies for a genetic risk, the revelation of occult tubal cancer designed as STIC (about 10%, and between 50 and nearly 100% of these cases have exhibited involvement of the fimbriated end of the fallopian tube) gave rise to the postulate of a tubal origin for ovarian cancer, and encouraged comprehensive analysis of the tubes [18] [19]. Serous Tubal Intraepithelial Lesions (STILs) or Tubal Intraepithelial Lesions in Transition (TILT) described a spectrum of epithelial changes from normal appearing tubal epithelium to cytological atypia and tubal dysplasia, expressing p53 [3] [20]. "
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    ABSTRACT: Histopathological examination of material from prophylactic salpingo-oophorectomies performed in patients at genetic risk of ovarian cancer can reveal abnormalities interpreted as possible pre-cancerous “ovarian dysplasia” and tubal precursors lesions. We sought to study the morphological features and immunohistochemical expression patterns of neoplasia-associated markers in prophylactically removed ovaries and fallopian tubes (pBSO) in comparison with a group of serous tubal intraepithelial carcinoma (STIC) and non-cancerous controls.Study designMorphological features and immunohistochemical expression patterns of Ki-67 (for proliferation biomarker), p53 (key pathway of mullerian serous tumorogenesis), Bcl2 (anti-apoptotic), γH2AX (a double-strand breaks marker) and ALDH1 (a stem cell marker significantly associated with early-stage ovarian cancer) were blindly evaluated by two pathologists in 111 pBSO, 12 STICs and 116 non-cancerous salpingo-oophorectomies (control group) (nBSO).ResultsMorphological ovarian and tubal dysplasia scores were significantly higher in the pBSO than in controls (respectively, 8.8 vs 3.12, p < 0.0001, for ovaries and 6.54 vs 1.58, p < 0.0001 for tubes). Increased γH2AX expression was observed in the pBSO and STICs compared with the controls whereas expression patterns of Ki67, p53 and bcl2 were low to moderate in the pBSO group. STICs overexpressed Ki67 and p53 while bcl2 expression was low; Interestingly, ALDH1 expression was low in non dysplastic epithelium, high in dysplasia and constantly low in STICs.Conclusion The morphological and immunohistochemical profile of tubo-ovarian dysplasia and STICs might be consistent with progression toward neoplastic transformation in the Serous Carcinogenesis Sequence. These changes may be pre-malignant and could represent an important phase in early neoplasia. ALDH1 activation in pBSO samples and its extinction in STICs should be considered as a target for prevention.
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    • "Since PSC can originate as an occult mullerian neoplasm that commonly proliferates at other peritoneal sites (Colgan et al., 2001, 2002; Cass et al., 2005; Powell et al., 2005; Finch et al., 2006; Chand et al., 2007), the pathological (histology and staining) evaluation of PSC often does not identify the original tumor site and should be augmented with detailed analysis of the patient's clinical and family history and BRCA phenotype in order to assign the final diagnosis with reasonable medical certainty (Risch et al., 2001; Piek et al., 2004; Kindelberger et al., 2007; Gilks et al., 2008). BRCA-positive families are noted to have higher cancer rates affecting the colon, prostate, pancreas and peritoneum, as well as melanoma (Struewing et al., 1997; Frank, 2001; Paley et al., 2001; Al-Hussaini et al., 2004). "
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    • "These dysplastic and hyperplastic lesions resembled high grade serous carcinoma but without stromal invasion. These malignancies were found in the distal tube in 4–17% of females with BRCA mutations at the time of their risk-reducing surgery, 57% to 100% of which were located in the distal portion of the tubes [100] [101] [102] [103] [104]. "
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