Beth Crawford

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

PURPOSE 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. METHODS 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. RESULTS 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. CONCLUSION 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.

Risk-reducing salpingo-oophorectomy (RRSO) in BRCA mutation carriers: experience with a consecutive series of 111 patients using a standardized surgical-pathological protocol.

Background: Women carriers of BRCA mutations often have occult malignancy found at the time of risk-reducing bilateral salpingo-oophorectomy (RRSO). We report outcomes in 111 consecutive BRCA-positive women who had RRSO using a rigorous surgical-pathological protocol from 1996 to 2008. Method: We identified risk factors associated with finding an occult malignancy at RRSO with outcomes followed for a median of 61 months. Results: A total of 111 BRCA carriers elected RRSO, 10 patients [9.1%] had 14 sites of occult neoplasia. Two patients had invasive serous fallopian tube carcinoma (TSC) only, 1 patient had invasive serous ovarian carcinoma (OSC) only, 5 patients had tubal intraepithelial carcinoma (TIC) only, and 2 patients had multifocal lesions of the ovary (OSC) and TIC. Occult ovarian carcinomas were only detected in BRCA1 patients, and all BRCA2 carcinomas involved only the fallopian tube. The odds of finding occult carcinoma is 4 times greater (odds ratio, 4.3; 95% confidence interval, 1.06-20.7) in women older than 50 than in younger ones (P = 0.023). A history of invasive breast cancer was associated with a reduced risk of occult carcinoma (odds ratio, 0.2; 95% confidence interval, 0.05-0.85). In median follow-up of 5 years, recurrence rate after detection of an occult carcinoma was 10% and the risk for primary peritoneal carcinoma was less than 1%. Conclusion: A rigorous surgical protocol with meticulous pathologic review at RRSO yielded an overall detection rate of 9.1% for occult gynecological carcinoma in BRCA mutation carriers followed by a multidisciplinary team at a single institution. Primary peritoneal carcinoma after RRSO is rare.

Multistep Level Sections to Detect Occult Fallopian Tube Carcinoma in Risk-reducing Salpingo-oophorectomies From Women With BRCA Mutations: Implications for Defining an Optimal Specimen Dissection Protocol

Risk-reducing salpingo-oophorectomy (RRSO) significantly lowers the incidence of ovarian, tubal, peritoneal, and breast cancer in women who carry BRCA1 or BRCA2 germline mutations. A minority of RRSO specimens from these women will contain occult early-stage carcinoma. Most occult cancer is localized in the fallopian tube fimbriae and is as small as 1 mm in size. Pathologic detection is dependent on thoroughness of tissue examination. Recommended protocols to maximize tumor detection emphasize the role of thinly slicing the tubes and ovaries and embedding the entire specimen for microscopic examination. Additional multistep level sections of tubal fimbriae tissue blocks could theoretically increase detection of occult tubal carcinoma but the value of level sections has not been formally evaluated. This study tests the diagnostic utility of multistep level sections in RRSO specimens from 102 women with BRCA germline mutations. The original diagnoses were based on a single section from each block of thinly sliced (2 to 3 mm intervals) tissues of the entire RRSO specimen. Three multistep level sections were retrospectively obtained from each block containing tubal fimbriae. Clinically occult carcinoma ranging in size from 1 to 13 mm was initially detected in 11 of 102 women (5 in tubal fimbriae only, 1 in tubal isthmus only, 2 in fimbriae and ovary, and 3 in ovary only). Diagnoses in the original fimbrial slides and their level sections were concordant in all cases. All tubal cancers were detected in both the original sections and in the multistep level sections. None of the tubal carcinomas that were noninvasive on the original slides showed invasive growth on additional level sections. No tubal carcinoma was identified in the level sections of any case originally classified as benign. Clinical follow-up among women with benign RRSO findings revealed that 2 women subsequently developed peritoneal carcinomatosis at 22 and 62 months postoperatively. Retrospective exhaustive multistep level sectioning of all remaining tubal and ovarian blocks from both these women confirmed the original benign diagnosis in 1 woman but in the other woman, the deepest levels of 1 ovarian block revealed a single 1-mm nodule of cancer at the base of an ovarian surface epithelial invagination. This specimen was one of the first RRSO cases in our experience and on review of the original report, this ovary was not dissected into multiple slices along its short axis but was only bivalved along its long axis. We propose that there does not seem to be any diagnostic value in automatically performing multistep deeper level sections of RRSO specimens if the tissue is sectioned appropriately and if the specimen is sliced at intervals that are no more than 3 mm thick. Guidelines for evaluation of RRSO specimens should emphasize the use of an optimal dissection protocol and the importance of thin tissue slice intervals.

Uptake, Time Course, and Predictors of Risk-Reducing Surgeries in BRCA Carriers

INTRODUCTION AND AIMS For women who carry BRCA mutations, risk-reducing surgeries are an option to decrease breast and ovarian cancer risk. This study aims to determine the uptake, time course, and predictors of risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) in BRCA carriers. RESULTS In 272 female carriers, followed for a median of 3.7 years, 23% of those eligible chose RRM, and 51% percent chose RRSO. Among BRCA carriers who chose these procedures, median time to both RRM and RRSO was approximately 4 months after learning of BRCA-positive results. Predictors of RRM were as follows: age below 60 years (hazard ratio 1.8, p=0.04), prior breast cancer (hazard ratio 2.4, p=0.0004), and RRSO (hazard ratio 7.2, p<0.0001). Predictors of RRSO were as follows: age below 60 years (hazard ratio 3.6, p=0.006), prior breast cancer (hazard ratio 1.8, p=0.002), and RRM (hazard ratio 5.4, p<0.0001). CONCLUSIONS Many women who undergo BRCA testing use these results to make clinical decisions; those who choose risk-reducing surgeries typically do so within months of receiving BRCA-positive results. Predictors of risk-reducing surgery uptake include the following: age below 60 years, prior breast cancer, and utilization of another risk-reducing surgery. Future research directions include examining other preventive and screening options in BRCA carriers as well as studying motivations for choosing or declining risk-reducing surgeries.

Ductal Carcinoma In Situ in BRCA Mutation Carriers

PURPOSE The current literature suggests that ductal carcinoma in situ (DCIS) of the breast is infrequently diagnosed in patients with BRCA germline mutations. We studied women at high risk of hereditary breast cancer syndromes who underwent testing for BRCA1 and BRCA2 to estimate DCIS prevalence and incidence in known BRCA-positive women compared with high-risk women who were mutation negative. METHODS We analyzed breast event outcomes in a retrospective cohort of 129 BRCA-positive and 269 BRCA-negative women undergoing genetic testing for a BRCA mutation between September 1996 and December 2003 at University of California, San Francisco. We estimated the frequency of DCIS and invasive cancer and time to breast events from birth using a Cox proportional hazard model for competing risks. Histologic grade of DCIS was also compared between groups. RESULTS Among BRCA carriers, 48 (37%) had DCIS (with or without invasive cancer) compared with 92 noncarriers (34%). Univariate analysis showed that both DCIS and invasive cancer had an earlier onset in mutation carriers than in noncarriers, although on a per-woman basis, this difference was not statistically significant. High-grade DCIS was more common in BRCA1 mutation carriers than in patients without a mutation (P = .02). CONCLUSION DCIS is equally as prevalent in patients who carry deleterious BRCA mutations as in high familial-risk women who are noncarriers, but occurs at an earlier age. Our results argue for the consideration of DCIS as a criterion for BRCA risk assessments with appropriate weighting in prediction models such as BRCAPRO.

Early detection of high-grade tubal serous carcinoma in women at low risk for hereditary breast and ovarian cancer syndrome by systematic examination of fallopian tubes incidentally removed during benign surgery.

Early detection of sporadic pelvic serous carcinoma remains an elusive goal. In women at high risk for hereditary breast and ovarian cancer syndrome who undergo prophylactic salpingectomy, systematic pathologic examination of the fallopian tubes will detect occult tubal cancer, mostly in the fimbriae, of a minority of women. Such tubal cancers are the putative precursor to advanced-stage pelvic cancer. We hypothesized that early tubal cancer detection can also be accomplished in women at low risk using a similar approach. In this study, we performed complete and systematic examination of the fallopian tubes removed during surgery performed for benign indications. Among 522 women, 4 cases of serous tubal intraepithelial carcinoma (STIC) were identified. Three of these cases would have gone undetected using the current standard of care of sampling only a single random section of the tube. The fourth case was accompanied by occult ovarian carcinoma. The fimbriae contained STIC in 3 of the 4 cases and atypical mucosa in 1 case in which the STIC was in the nonfimbriated portion of the tube. The morphologic and immunohistochemical features (aberrant p53 and MIB-1) of these STICs were similar to those expected in high-risk women. All 4 patients with STIC underwent BRCA1 and BRCA2 gene testing; no germline mutations were identified in any patient. An additional 11 specimens contained atypical mucosal proliferations that fell short of morphologic and immunohistochemical criteria for STIC. Two of these 11 fulfilled criteria for a serous tubal intraepithelial lesion, and the remaining atypical proliferations exhibited normal p53 and MIB-1. For most specimens, the fimbriae could be completely submitted in 1 or 2 cassettes per tube. These results demonstrate that systematic examination of the tubal fimbriae can serve as a form of early detection of sporadic tubal cancer without incurring significant labor or cost. We propose that the tubal fimbriae should be completely examined in all patients undergoing benign surgery even if there are no clinical features to suggest risk for hereditary breast and ovarian cancer syndrome.

Performance of BRCA1/2 Mutation Prediction Models in Asian Americans

PURPOSE There are established differences in breast cancer epidemiology between Asian and white individuals, but little is known about hereditary breast cancer in Asian populations. Although increasing numbers of Asian individuals are clinically tested for BRCA1/2 mutations, it is not known whether computer models that predict mutations work accurately in Asian individuals. We compared the performance in Asian and white individuals of two widely used BRCA1/2 mutation prediction models, BRCAPRO and Myriad II. PATIENTS AND METHODS We evaluated BRCAPRO and Myriad II in 200 Asian individuals and a matched control group of 200 white individuals who were tested for BRCA1/2 mutations at four cancer genetics clinics, by comparing numbers of observed versus predicted mutation carriers and by evaluating area under the receiver operating characteristic curve (AUC) for each model. RESULTS BRCAPRO and Myriad II accurately predicted the number of white BRCA1/2 mutation carriers (25 observed v 24 predicted by BRCAPRO; 25 predicted by Myriad II, P > or = .69), but underpredicted Asian carriers by two-fold (49 observed v 25 predicted by BRCAPRO; 26 predicted by Myriad II; P < or = 3 x 10(-7)). For BRCAPRO, this racial difference reflects substantial underprediction of Asian BRCA2 mutation carriers (26 observed v 4 predicted; P = 1 x 10(-30)); for Myriad II, separate mutation predictions were not available. For both models, AUCs were nonsignificantly lower in Asian than white individuals, suggesting less accurate discrimination between Asian carriers and noncarriers. CONCLUSION Both BRCAPRO and Myriad II underestimated the proportion of BRCA1/2 mutation carriers, and discriminated carriers from noncarriers less well, in Asian compared with white individuals.

Transitional cell metaplasia of fallopian tube fimbriae: a potential mimic of early tubal carcinoma in risk reduction salpingo-oophorectomies from women With BRCA mutations.

Germline mutations in the hereditary breast/ovary carcinoma genes BRCA1 or BRCA2 confer increased lifetime risk for ovarian, fallopian tube, and primary peritoneal carcinoma. This risk can be minimized by prophylactic surgery. Risk-reducing salpingo-oophorectomy (RRSO) provides 2 potential benefits: long-term cancer risk reduction and immediate detection of occult early carcinoma, which frequently arises in the tubal fimbriae. Recognition of occult early tubal carcinoma is challenging because it is often microscopic in size and can be confined to the fimbrial epithelium without invasion. Transitional cell metaplasia is a benign epithelial alteration that is a common finding in the serosa of the tube but is underrecognized in the tubal fimbriae, where it may mimic tubal intraepithelial carcinoma. The aim of this study was to define the incidence, morphology, immunophenotype, and distribution of transitional cell metaplasia of the fimbriae in RRSO specimens from 96 women with BRCA germline mutations and to compare these features to those of tubal intraepithelial carcinoma in this cohort. RRSO specimens from an additional 30 women at increased risk for ovarian cancer based on strong family history were also studied, along with RRSO from 1 patient with Lynch syndrome, and 1 patient with PTEN mutation. Transitional cell metaplasia of the fimbriae was present in 26% of all RRSO specimens. It was commonly multifocal (67%), with involvement of the tip, edges, or base of the fimbrial plicae. Average size of a metaplastic focus was 1.3 mm (range: 0.1 to 10 mm). None of the metaplastic foci expressed p53 by immunohistochemistry nor was there increased staining for the proliferation marker MIB-1. Occult early carcinoma was detected in 6/128 RRSO specimens. Median tumor size was 2.7 mm (range: 1 to 11 mm). All expressed p53 and showed markedly increased MIB-1 staining. The key criteria distinguishing transitional cell metaplasia from tubal intraepithelial carcinoma were uniform cell size and shape, normal nucleus:cytoplasm ratios, lack of nuclear atypia, presence of nuclear grooves, lack of mitoses, and absence of p53 expression or increased staining for MIB-1. No particular clinical variables (BRCA 1 vs. BRCA 2 mutation, parity, personal history of breast cancer, prior abdomino-pelvic surgery, or intraoperative findings) or benign pathologic alterations in the RRSO specimens were associated with the presence of transitional cell metaplasia of the fimbriae. None of the patients with this finding developed peritoneal carcinoma during follow-up ranging from 1 month to 9 years. This study demonstrates that transitional cell metaplasia of the fimbriae is a common benign finding in RRSO specimens that should not be confused with the much less common finding of tubal intraepithelial carcinoma.

Association of tumor morphology with mismatch-repair protein status in older endometrial cancer patients: implications for universal versus selective screening strategies for Lynch syndrome.

Although there is consensus on the cost-effectiveness of a universal approach of screening all colorectal cancer patients for Lynch syndrome (LS) using mismatch-repair (MMR) protein immunohistochemistry (IHC) and/or microsatellite instability (MSI) testing, the question of universal versus selective screening of endometrial cancer patients remains to be resolved. We have prospectively implemented a selective screening algorithm for newly diagnosed endometrial cancer patients, triggered by patient age 50 years or younger, personal/family cancer pedigree that meets Bethesda guideline criteria, and/or presence of MMR-associated tumor morphology. Four-protein MMR IHC and MSI testing were performed if any of the criteria were met. This algorithm excluded screening of older patients without a cancer pedigree and whose tumors lacked MMR morphology. The aim of this study was to retrospectively determine whether these exclusion criteria missed any tumors with abnormal MMR. Among 273 consecutive patients with newly diagnosed endometrial cancers, 181 (66%) lacked criteria for screening. Retrospective MMR IHC confirmed intact MMR in 177 (97.8%) of these 181 unscreened patients, loss of MSH6 in 1 patient (0.5%), and loss of MSH1/PMS2 due to MLH1 promoter hypermethylation in 3 patients (1.7%). In comparison, 41% of patients fulfilling 1 or more criteria for screening had abnormal MMR IHC/MSI, mostly consisting of loss of MLH1/PMS2. MMR morphology contributed to detection of 92% of the abnormal MMR cases while cancer pedigree contributed to detection of the remainder. All of the abnormalities due to MSH2 and PMS2 were detected by the screening algorithm, but 1 of the 4 MSH6 cases was not. The latter finding is consistent with the literature that MSH6 endometrial cancers exhibit a phenotype different than those of the other MMR genes. We conclude that a genotype-specific approach to screening endometrial cancer for LS could consist of universal testing by MSH6 IHC and selective testing by MLH1, PMS2, and MSH2 IHC on the basis of age, cancer pedigree, and MMR morphology. Cost-effectiveness of this hybrid selective strategy deserves further study, particularly in comparison with a universal strategy. Further work to identify phenotypic features of endometrial cancers with methylated MLH1 that would allow them to be excluded from LS screening would also contribute to cost-effectiveness.

Ovarian pathology in risk-reducing salpingo-oophorectomies from women with BRCA mutations, emphasizing the differential diagnosis of occult primary and metastatic carcinoma.

Risk-reducing salpingo-oophorectomy (RRSO) is an effective prophylactic procedure for women with mutations in BRCA1 or BRCA2 genes, both of which confer an increased lifetime risk for ovarian, tubal, peritoneal, and breast cancer. In addition to lowering this risk, RRSO also offers the opportunity to detect occult early-stage fallopian tube or ovarian carcinoma. The differential diagnosis of occult tubal/ovarian cancer includes a spectrum of benign tubal and ovarian alterations and also occult metastatic breast cancer, although only rare cases of the latter have been reported in RRSO. Neoadjuvant breast cancer chemotherapy may contribute to diagnostic difficulty due to treatment-induced cytologic alterations. With the aim of elucidating features which may help with differential diagnosis, this study reports the incidence and pathologic features of benign ovarian alterations, benign ovarian tumors, and occult primary and metastatic malignancies in prophylactic oophorectomies from 108 women with a BRCA mutation and from 35 women with other strong risk factors for hereditary breast/ovarian carcinoma. We direct particular emphasis on morphologic features of primary ovarian lesions that may mimic occult metastatic breast cancer. We also evaluate histologic alterations due to neoadjuvant breast cancer chemotherapy in the ovary and fallopian tube of patients who received such treatment immediately preceding RRSO. Comparison is made to ovarian metastases of breast cancer in our hospital-based population of breast cancer patients, none of whom underwent RRSO. Overall, 69% of RRSO patients had a personal history of breast cancer. Neoadjuvant breast cancer chemotherapy was administered in 15%. Occult primary carcinoma occurred in 7 (6.5%) BRCA patients (5 in fallopian tube, 1 in fallopian tube and ovary, 1 in ovary). Ovarian metastasis of breast cancer occurred in 1 (1%) BRCA patient undergoing RRSO and in up to a similar proportion (0.8%) of the hospital-based population of breast cancer patients. The metastasis in the RRSO patient was clinically occult, unilateral, 0.2 cm, and demonstrated mild atypia without mitoses. Abundant foamy, vacuolated cytoplasm due to neoadjuvant chemotherapy exposure was notable. In contrast, ovarian metastases in the non-RRSO population were all clinically detected, bilateral, large, and exhibited well-developed malignant cytologic features. None of the normal cell types in the ovary or tube demonstrated any cytologic alterations in RRSO patients who received neoadjuvant chemotherapy. The main morphologic mimics of metastasis with superimposed chemotherapy-induced alterations in RRSO were stromal hyperthecosis (n=8), nodular hyperthecosis (n=2), adrenal rests (n=3), hilus cell nodules (n=43), and hilus cell hyperplasia (n=4). Occult primary ovarian carcinoma was reliably distinguished from ovarian metastases of breast cancer by WT-1+, p53+, mammaglobin−, GCDPF–immunoprofile. These results demonstrate that evaluation of RRSO specimens requires awareness of a spectrum of ovarian lesions which may mimic occult primary or metastatic carcinoma; awareness of the masquerading effects of neoadjuvant chemotherapy; and awareness of the potential morphologic differences between occult metastatic breast cancer in RRSO and non-RRSO specimens.