Endometrial Cancers in BRCA1 or BRCA2 Germline Mutation Carriers: Assessment of Homologous Recombination DNA Repair Defects.

PURPOSE: Endometrial cancer (EC) is not considered a component of the hereditary breast and ovarian cancer syndrome but can arise in patients with germline BRCA1/2 (gBRCA1/2) mutations. Biallelic BRCA1/2 alterations are associated with genomic features of homologous recombination DNA repair deficiency (HRD) in cancer. We sought to determine if ECs in gBRCA1/2 mutation carriers harbor biallelic alterations and/or features of HRD. METHODS: Of 769 patients with EC who underwent germline panel testing, 10 pathogenic gBRCA1/2 mutation carriers were identified, and their tumor- and normal-derived DNA was subjected to massively parallel sequencing targeting at least 410 cancer-related genes. Three gBRCA1/2-associated ECs were identified in 232 ECs subjected to whole-exome sequencing by The Cancer Genome Atlas. Somatic mutations, copy number alterations, loss of heterozygosity, microsatellite instability (MSI), and genomic HRD features were assessed. RESULTS: Of the 13 patients included who had EC, eight harbored pathogenic gBRCA1 mutations and five harbored gBRCA2 mutations. Eight (100%) and two (40%) ECs harbored biallelic BRCA1 and BRCA2 alterations through loss of heterozygosity of the wild-type allele. All ECs harbored somatic TP53 mutations. One monoallelic/sporadic gBRCA2-associated EC had MLH1 promoter methylation and was MSI high. High large-scale state transition scores, a genomic feature of HRD, were found only in ECs with bi- but not monoallelic BRCA1/2 alterations. The Signature Multivariate Analysis HRD signature Sig3 was enriched in biallelic gBRCA1/2 ECs, and the three ECs from The Cancer Genome Atlas with BRCA1 biallelic alterations subjected to whole-exome sequencing displayed a dominant HRD-related mutational signature 3. CONCLUSION: A subset of gBRCA1/2-associated ECs harbor biallelic BRCA1/2 alterations and genomic features of HRD, which may benefit from homologous recombination-directed treatment regimens. ECs in BRCA2 mutation carriers might be sporadic and even MSI high, and may potentially benefit from immune-checkpoint inhibition.

Patterns of FIRST recurrence of stage IIIC1 endometrial cancer with no PARAAORTIC nodal assessment.

OBJECTIVE: To assess the rates and distribution of first recurrence in patients with FIGO stage IIIC1 endometrial cancer (EC) who did not undergo paraaortic dissection at surgical staging. METHODS: We retrospectively selected all (n = 207) stage IIIC1 patients treated at a single institution from 5/1993-1/2017. Sites of first recurrence were identified, disease-free (DFS) and overall survival (OS) calculated, multivariate logistic regression performed to identify factors associated with recurrence. RESULTS: Three-year DFS and OS were 66.5% and 85.7%, respectively. The most common histology was endometroid (64.2%). Three-year DFS was 81% (SE±3.8%) endometrioid vs. 39.5% (SE±6.6%) non-endometrioid (P < 0.001). Three-year OS was 96.9% (SE±1.8%) endometrioid vs. 65.6% (SE±6.7%) non-endometrioid (P < 0.001). Sixty-two (30.1%) patients recurred. Patterns of recurrence were: 14 (8.3%) multiple sites, 17 (8.2%) abdominal, 14 (6.8%) extra-abdominal, 17 (8.3%) isolated nodal (8 of these (3.9%) paraaortic). Patients with isolated tumor cells (ITCs) in lymph nodes only had 12/71 (17%) recurrence rate vs. 50/135 (37%) for patients with micro-/macrometastasis. On univariate analysis, grade (HR 4.67 95%CI 1.5-14.5, P = 0.008), histology (HR 4.9 95%CI 2.6-9.3, P < 0.001), myometrial invasion (HR 1.9 95%CI 1.04-3.5, P = 0.04), pelvic washing (HR 2.2 95%CI 1.1-4.5, P = 0.03), tumor volume in pelvic LNs (ITC vs. micro-/macrometastasis; HR 0.3 95%CI 0.2-0.7, P = 0.003) were associated with recurrence. On multivariate analysis, only histology was associated with recurrence (HR 7.88 95%CI 3.43-18.13, P < 0.001). CONCLUSIONS: Isolated paraaortic recurrence in stage IIIC1 EC is uncommon. Micro-/macrometastasis were associated with twice the recurrence rate compared to ITC. These data will help clinicians counsel patients with stage IIIC1 EC regarding paraaortic assessment.

Multicenter study comparing oncologic outcomes between two nodal assessment methods in patients with deeply invasive endometrioid endometrial carcinoma: A sentinel lymph node algorithm versus a comprehensive pelvic and paraaortic lymphadenectomy.

OBJECTIVES: To compare oncologic outcomes in the staging of deeply invasive endometrioid endometrial carcinoma (EEC) using a sentinel lymph node algorithm (SLN) versus pelvic and paraaortic lymphadenectomy to the renal veins (LND); to compare outcomes in node-negative cases. METHODS: At two institutions, patients with deeply invasive (≥50% myometrial invasion) EEC were identified. One institution used LND (2004-2008), the other SLN (2005-2013). FIGO stage IV cases were excluded. Clinical characteristics and follow-up data were recorded. RESULTS: 176 patients were identified (LND, 94; SLN, 82). SLN patients were younger (p = 0.003) and had more LVSI (p < 0.001). 9.8% in the SLN and 29.8% in the LND cohorts, respectively, received no adjuvant therapy (p < 0.001). There was no association between type of assessment and recurrence; adjusted hazard ratio (aHR; LND vs. SLN) 0.87 (95%CI 0.40, 1.89) PFS. After controlling for age and adjuvant therapy, there was no association between assessment method and OS (aHR 2.54; 95%CI 0.81, 7.91). The node-negative cohort demonstrated no association between survival and assessment method: aHR 0.69 (95%CI 0.23, 2.03) PFS, 0.81 (95%CI 0.16, 4.22) OS. In the node-negative cohort, neither adjuvant EBRT+/-IVRT (HR 1.63; 95%CI 0.18, 14.97) nor adjuvant chemotherapy+/-EBRT+/-IVRT (HR 0.49; 95%CI 0.11, 2.22) were associated with OS, compared to no adjuvant therapy or IVRT-only. CONCLUSION: Use of an SLN algorithm in deeply invasive EEC does not impair oncologic outcomes. Survival is excellent in node-negative cases, irrespective of assessment method. Adjuvant chemotherapy in node-negative patients does not appear to impact outcome.

Redefining stage I endometrial cancer: incorporating histology, a binary grading system, myometrial invasion, and lymph node assessment.

OBJECTIVE: We propose a new staging system for stage I endometrial cancer and compare its performance to the 1988 and 2009 International Federation of Gynecology and Obstetrics (FIGO) systems. METHODS: We analyzed patients with 1988 FIGO stage I endometrial cancer from January 1993 to August 2011. Low-grade carcinoma consisted of endometrioid grade 1 to grade 2 lesions. High-grade carcinoma consisted of endometrioid grade 3 or nonendometrioid carcinomas (serous, clear cell, and carcinosarcoma). The proposed system is as follows:IA. Low-grade carcinoma with less than half myometrial invasionIB. High-grade carcinoma with no myometrial invasionIC. Low-grade carcinoma with half or greater myometrial invasionID. High-grade carcinoma with any myometrial invasion RESULTS: Data from 1843 patients were analyzed. When patients were restaged with our proposed system, the 5-year overall survival significantly differed (P < 0.001): IA1, 96.7%; IA2, 92.2%; IB1, 92.2%; IB2, 76.4%; IC1, 83.9%; IC2, 78.6%; ID1, 81.1%; and ID2, 68.8%. The bootstrap-corrected concordance probability estimate for the proposed system was 0.627 (95% confidence interval, 0.590-0.664) and was superior to the concordance probability estimate of 0.530 (95% confidence interval, 0.516-0.544) for the 2009 FIGO system. CONCLUSIONS: By incorporating histological subtype, grade, myometrial invasion, and whether lymph nodes were removed, our proposed system for stage I endometrial cancer has a superior predictive ability over the 2009 FIGO staging system and provides a novel binary grading system (low-grade including endometrioid grade 1-2 lesions; high-grade carcinoma consisting of endometrioid grade 3 carcinomas and nonendometrioid carcinomas).

The impact of race and comorbidity on survival in endometrial cancer.

BACKGROUND: Poorer survival from endometrial cancer in blacks than in whites is well documented. The aims of this study were to determine whether diabetes, hypertension, or other conditions influence survival and whether accounting for these conditions reduces this racial disparity. METHODS: Using the SEER-Medicare database, we investigated the influence of diabetes, hypertension, and other comorbid conditions on survival in black and white women age ≥66 with endometrial cancer. We used Cox proportional hazards regression to evaluate the influence of comorbidities on survival for blacks and whites separately and to study survival differences between blacks and whites after adjustment for diabetes, hypertension, and other medical conditions, as well as for demographics, tumor characteristics, and treatment. RESULTS: In both racial subgroups, women with diabetes or other conditions had poorer overall survival, whereas hypertensive black women experienced better survival [HR, 0.74; 95% confidence interval (CI), 0.60-0.92]. For disease-specific survival, diabetes was associated with poorer survival in white women (HR, 1.19; 95% CI, 1.06-1.35) but not in blacks (HR, 0.97; 95% CI, 0.73-1.30); hypertension and other conditions were not significantly related to survival. After adjustment, black women had poorer survival than white women, with HRs of 1.16 (95% CI, 1.05-1.28) for overall and 1.27 (95% CI, 1.08-1.49) for disease-specific survival. CONCLUSIONS: Diabetes influences disease-specific survival in white women but not in blacks. The racial disparity in survival is not explained by the presence of other health conditions. IMPACT: Further research should focus on the unknown factors that lead to poorer survival in black women compared with whites.

Significant variation in the assessment of cervical involvement in endometrial carcinoma: an interobserver variation study.

The histologic assessment of cervical involvement in endometrial carcinoma may be problematic for a number of reasons, but an accurate evaluation of this is important for correct staging, dictating the need for adjuvant therapy, and prognostication. In this study, we assessed interobserver variation in the evaluation of cervical involvement in hysterectomy specimens of endometrial carcinoma among 6 specialist gynecologic pathologists. Seventy-six cases of endometrial carcinoma enriched for cases exhibiting some perceived issue in the assessment of cervical involvement were used. In all the cases, a single slide of the primary tumor in the uterine corpus and a single slide of the cervix were circulated among the 6 participants who filled in a proforma. On the basis of the responses, the tumors were staged according to the 1988 International Federation of Gynecology and Obstetrics (FIGO) staging system (I, IIA, IIB) and the 2009 FIGO staging system (I, II). Using the 1988 FIGO staging system, the unweighted and weighted κ values between individual observers ranged from 0.3115 to 0.6139 (average 0.4675) and from 0.3492 to 0.6533 (average 0.5065), respectively. The κ values between observers for the 2009 FIGO staging system ranged from 0.3481 to 0.6862 (average 0.4908). Although enriched for problematic cases, our study shows that there is at most a fair-to-good agreement among specialist gynecologic pathologists in the assessment of cervical involvement in endometrial carcinoma. Problematic factors include determination of the junction between the lower uterine segment and upper endocervix, the distinction between "floaters" and true cervical glandular involvement, the distinction between cervical glandular involvement and stromal involvement, and the distinction between cervical glandular involvement and reactive non-neoplastic lesions of the endocervical glands. There is a need for specialist pathology groups dealing with gynecologic cancers to develop and disseminate recommendations regarding the assessment of cervical involvement in endometrial carcinoma.

Immunohistochemistry as first-line screening for detecting colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome: a 2-antibody panel may be as predictive as a 4-antibody panel.

The utility of immunohistochemical detection of DNA mismatch repair proteins in screening colorectal cancer for hereditary nonpolyposis colorectal cancer (HNPCC) is being widely investigated. Currently, in both research and clinical settings, a 4-antibody panel that includes the 4 most commonly affected proteins (MLH1, MSH2, MSH6, and PMS2) is being used generally. On the basis of the biochemical properties of these proteins, we hypothesized that a 2-antibody panel, comprising MSH6 and PMS2, would be sufficient to detect abnormalities in all 4 proteins. We tested this hypothesis on a series of 232 colorectal carcinoma samples derived from 2 patient cohorts: (1) a prospectively accrued series of patients who were judged to carry a higher-than-average risk for HNPCC based on the revised Bethesda guidelines (n=190); and (2) a retrospective series of patients who were 40 years of age or younger (n=42). Immunohistochemical stains were regarded as negative (protein lost), when there was no nuclear labeling in tumor cells (with positive internal control). Overall, 70 of the 232 tumors demonstrated loss of at least one protein. The most common abnormality was concurrent loss of MLH1 and PMS2 (observed in 17% of the cases), followed by concurrent loss of MSH2 and MSH6 (6%). All MLH1 and MSH2-abnormal cases were also abnormal for PMS2 and MSH6, respectively, whereas 9 of 50 (18%) PMS2 and 6 of 20 (30%) MSH6-abnormal cases showed only isolated loss of PMS2 or MSH6 (with normal staining for MLH1 and MSH2). As such, our findings provide evidence that a 2-antibody panel (PMS2 and MSH6) is as effective as the current 4-antibody panel in detecting DNA mismatch repair protein abnormalities. Such a cost-effective approach carries significant implication, as immunohistochemistry is being widely used as first-line screening for HNPCC.

Ependymomas of the central nervous system and adult extra-axial ependymomas are morphologically and immunohistochemically distinct--a comparative study with assessment of ovarian carcinomas for expression of glial fibrillary acidic protein.

Extra-axial ependymomas are very rare but have been reported in the ovary, broad ligament, sacrococcygeal region, lung, and mediastinum. The histogenesis is obscure, and a thorough immunohistochemical analysis is lacking. We reviewed the morphologic and immunohistochemical features of 5 extra-axial ependymomas occurring in adults, 1 arising in an infantile sacrococcygeal teratoma, and a control group of 10 central nervous system (CNS) ependymomas in adults. All cases were evaluated for expression of epithelial membrane antigen, estrogen receptor (ER), progesterone receptor (PR), WT1, CD99, CK18, AE1:3, CAM 5.2, 34betaE12, CK7, CK20, synaptophysin, chromogranin, and glial fibrillary acidic protein (GFAP) using formalin-fixed, paraffin-embedded tissue. One hundred twelve ovarian carcinomas in 3 tissue microarrays were also studied with GFAP. The adult extra-axial cases demonstrated more architectural variability than the CNS cases. We observed that both the CNS and adult extra-axial ependymomas expressed GFAP diffusely, whereas only 9 stage III, high-grade ovarian serous papillary carcinomas stained with GFAP (2 strongly and diffusely and 7 exhibiting focally weak expression). There were significant immunophenotypic differences between adult extra-axial and CNS ependymomas, with extra-axial cases preferentially expressing 34betaE12 (60% vs. 0%), CK18 (100% vs. 20%), CAM 5.2 (60% vs. 10%), CK7 (80% vs. 10%), ER (100% vs. 10%), and PR (80% vs. 20%). Two spinal cord ependymomas expressed CK18, 1 expressed CK7, and 1 expressed CAM 5.2. CNS ependymomas more frequently expressed CD99 (100% vs. 20%). The following stains were not differentially expressed: epithelial membrane antigen (expressed in 2 of 15 cases, including both extra-axial and CNS ependymomas), synaptophysin (1/15), chromogranin (0/15), WT1 (8/15), AE1:3 (10/15), and CK20 (0/15). The ependymal elements of the sacrococcygeal tumor failed to express 34betaE12, CK18, CAM 5.2, and CK7, like most CNS ependymomas. The morphologic and immunophenotypic differences between extra-axial and CNS ependymomas suggest that they derive from distinct precursors and/or differentiate along distinct pathways. The differential diagnosis of extra-axial ependymomas is extensive, and GFAP expression in primary ovarian serous carcinomas, although rare, could theoretically contribute to diagnostic difficulties. ER and PR expression in extra-axial ependymomas may provide targets for hormonal therapy.