Grade and Estrogen Receptor Expression Identify a Subset of No Specific Molecular Profile Endometrial Carcinomas at a Very Low Risk of Disease-Specific Death.

Endometrial carcinoma (EC) can be divided into 4 prognostic molecular subtypes, and no specific molecular profile (NSMP) type is the most commonly occurring type (∼50%). Although described as having an intermediate to favorable prognosis, this subtype encompasses pathologically and molecularly diverse tumors. We aimed to identify factors associated with outcomes within the NSMP ECs that might be used to stratify prognosis and direct treatment. Clinicopathologic, immunohistochemical, and genetic features of a large series of NSMP EC were used to identify parameters that could identify the subset associated with a very favorable outcome (disease-specific death rate <5% at 5 years, termed low-risk NSMP). A total of 1110 NSMP ECs were profiled. In a univariate analysis, stage, grade, lymphovascular invasion, estrogen receptor (ER) and progesterone receptor (PR) expression, L1CAM overexpression, and mutations in PIK3CA were associated with disease-specific survival. Two critical features, grade and ER expression, identified a low-risk NSMP subset (grade 1-2, ER-positive [>1%], 84% of cases), which showed a 5-year disease-specific death rate of 1.6% across all stages and 1.4% within stage I. The remaining cases (high-risk NSMPs, grade 3, and/or ER-negative status) were responsible for most of the disease-specific deaths (disease-specific death rate at 5 years, 22.9%; hazard ratio compared with that of low-risk NSMPs: 16.3; 95% CI, 8.4-31.7). Within NSMP EC, the low-risk and high-risk categories were of prognostic significance independent of the stage on a multivariate analysis. Low-grade and ER-positive NSMP ECs are a homogeneous low-risk group associated with an exceptionally favorable prognosis in which de-escalation and/or endocrine therapy strategies can be applied. Grade 3 and/or ER-negative status identifies a high-risk NSMP subset, including rare high-grade histotypes (eg, clear cell, dedifferentiated, and mesonephric-like), responsible for most NSMP-related deaths. Subclassification of NSMPs allows for the category of low-risk EC molecular subtypes to be dramatically expanded because it now includes both POLEmut and the much more common low-risk NSMP EC.

Molecular subtype stratified outcomes according to adjuvant therapy in endometrial cancer.

OBJECTIVES: Recent data support the predictive implications of molecular subtype assignment in endometrial cancer (EC). Our objective was to retrospectively assess clinical outcomes according to adjuvant treatment received within EC molecular subtypes. METHODS: Clinical outcomes (disease-specific and progression-free survival DSS/PFS) of EC patients from a single institution and population-based cohorts that had undergone molecular classification were assessed with respect to adjuvant therapy received and 2016 ESMO risk group. RESULTS: 2472 ECs were assessed; 184 (7.4%) POLEmut, 638 (25.8%) MMRd, 1223 (49.5%) NSMP and 427 (17.3%) p53abn. N = 774 (34.6%) of the cohort were ESMO 2016 high risk and 109 (4.8%) were advanced or metastatic. In patients with MMRd EC, assessed across and within stage, there was no observed benefit in DSS or PFS with the addition of chemotherapy +/- radiation compared to radiation alone in ESMO high risk (p = 0.694) or ESMO high, advanced, metastatic risk groups combined (p = 0.852). In patients with p53abn EC, adjuvant chemotherapy given with radiation was associated with significantly longer DSS compared to radiation alone in ESMO high risk (p = 0.007) and ESMO high, advanced and metastatic risk groups combined (p = 0.015), even when restricted to stage I disease (p < 0.001) and when compared in serous vs. non-serous histotypes (p = 0.009). CONCLUSIONS: Adjuvant chemotherapy is associated with more favorable outcomes for patients with p53abn EC, including stage I disease and non-serous histotypes, but does not appear to add benefit within MMRd ECs for any stage of disease, consistent with PORTEC-3 molecular subanalysis. Prospective trials, assessing treatment efficacy within molecular subtype are needed, however these 'real-world' data should be considered when discussing adjuvant treatment with patients.

Variability in endometrial carcinoma pathology practice: opportunities for improvement with molecular classification.

We assessed the landscape of diagnostic pathology practice and how molecular classification could potentially impact management of patients with endometrial cancer by collecting patient samples, clinicopathologic data, and patient outcomes from EC patients diagnosed in 2016 at 10 Canadian tertiary cancer centers and 19 community hospitals. ProMisE molecular subtype (POLEmut, MMRd, p53abn, No Specific Molecular Profile (NSMP)) was assigned retrospectively. 1357 patients were fully evaluable including 85 POLEmut (6.3%), 380 MMRd (28.0%), 643 NSMP (47.4%), and 249 p53abn ECs (18.3%). Immunohistochemistry (IHC) for MMR proteins was undertaken at the time of primary diagnosis in 2016 in only 42% of the cohort (570/1357; range 3.5-95.4%/center). p53 IHC had only been performed in 21.1% of the cohort (286/1357; range 10.1-41.9%/center). Thus, based on the retrospective molecular subtype assignment, 54.7% (208/380) of MMRd EC had not been tested with MMR IHC (or MSI) and 48.2% (120/249) of p53abn ECs were not tested with p53 IHC in 2016. Molecular subtype diversity within histotypes was profound; most serous carcinomas were p53abn (91.4%), but only 129/249 (51.8%) p53abn EC were serous. Low-grade (Gr1-2) endometrioid carcinomas were mostly NSMP (589/954, 61.7%) but included all molecular subtypes, including p53abn (19/954, 2.0%). Molecular subtype was significantly associated with clinical outcomes (p < 0.001) even in patients with stage I disease (OS p = 0.006, DSS p < 0.001, PFS p < 0.001). Assessment of national pathologic practice in 2016 shows highly variable use of MMR and p53 IHC and demonstrates significant opportunities to improve and standardize biomarker reporting. Inconsistent, non-reflexive IHC resulted in missed opportunities for Hereditary Cancer Program referral and Lynch Syndrome diagnosis, and missed potential therapeutic implications (e.g., chemotherapy in p53abn EC, immune blockade for MMRd EC). Routine integration of molecular subtyping into practice can improve the consistency of EC pathology assessment and classification.

Endometrial carcinoma molecular subtype correlates with the presence of lymph node metastases.

BACKGROUND: The role of lymph node assessment/dissection (LND) in endometrial cancer (EC) has been debated for decades, with significant practice variation between centers. Molecular classification of EC provides prognostic information and can be accurately performed on preoperative endometrial biopsies. We assessed the association between molecular subtype and lymph node metastases (LNM) in order to determine if this tool could be used to stratify surgical decision making. METHODS: All EC patients undergoing primary staging surgery with planned complete pelvic +/- para-aortic LND from a single institution in the 2015 calendar year were identified, with clinicopathological and outcome data assessed in the context of retrospectively assigned molecular classification. RESULTS: 172 patients were included. Molecular classification of the total cohort showed 21 POLEmut (12.2%), 47 MMRd (27.3%), 74 NSMP (43.1%), and 30 p53abn (17.4%) ECs. Complete pelvic +/- para-aortic LND was performed in 171 of 172 patients, and LNM were found in 31/171 (18.1%). This included macrometastases (19/31), micrometastases (5/31), and isolated tumour cells (ITCs) (7/31). LNM were pelvic only in 83.9%, and pelvic plus para-aortic in 16.1%. There were no isolated para-aortic LNM. Molecular subtype was significantly associated with LNM (p = 0.004). There was a strong association between the presence of LNM and p53abn EC (nodal involvement in 44.8% of cases), with LNM detected in 14.2% of POLEmut, 14.9% of MMRd, and 10.8% of NSMP EC. On multivariate analysis, molecular subtype and preoperative CA 125 > 25 were significantly associated with LNM (p = 0.021 and p = 0.022 respectively) but preoperative grade and histotype were not (p = 0.24). CONCLUSION: EC molecular subtype is significantly associated with the presence of LNM. As molecular classification can be obtained on preoperative diagnostic specimens, this information can be used to guide surgical treatment planning and may reduce the cost and morbidity of unnecessary lymph node staging in EC care.

Variation in practice in endometrial cancer and potential for improved care and equity through molecular classification.

OBJECTIVES: We measured the variation in practice across all aspects of endometrial cancer (EC) management and assessed the potential impact of implementation of molecular classification. METHODS: Centers from across Canada provided representative tumor samples and clinical data, including preoperative workup, operative management, hereditary cancer program (HCP) referrals, adjuvant therapy, surveillance and outcomes, for all EC patients diagnosed in 2016. Tumors were classified into the four ProMisE molecular subtypes. RESULTS: A total of 1336 fully evaluable EC patients were identified from 10 tertiary cancer centers (TC; n = 1022) and 19 community centers (CC; n = 314). Variation of surgical practice across TCs was profound (14-100%) for lymphadenectomy (LND) (mean 57% Gr1/2, 82% Gr3) and omental sampling (20% Gr1/2, 79% Gr3). Preoperative CT scans were inconsistently obtained (mean 32% Gr1/2, 51% Gr3) and use of adjuvant chemo or chemoRT in high risk EC ranged from 0-55% and 64-100%, respectively. Molecular subtyping was performed retrospectively and identified 6% POLEmut, 28% MMRd, 48% NSMP and 18% p53abn ECs, and was significantly associated with survival. Within patients retrospectively diagnosed with MMRd EC only 22% had been referred to HCP. Of patients with p53abn EC, LND and omental sampling was not performed in 21% and 23% respectively, and 41% received no chemotherapy. Comparison of management in 2016 with current 2020 ESGO/ESTRO/ESP guidelines identified at least 26 and 95 patients that would have been directed to less or more adjuvant therapy, respectively (10% of cohort). CONCLUSION: Molecular classification has the potential to mitigate the profound variation in practice demonstrated in current EC care, enabling reproducible risk assessment, guiding treatment and reducing health care disparities.

Neuroendocrine Tumors of the Fallopian Tube: Report of a Case Series and Review of the Literature.

Primary neuroendocrine tumors of the fallopian tube are extremely rare with a few reported cases of high-grade neuroendocrine carcinoma and a single report of a carcinoid tumor arising in a teratoma. We report 4 cases of probable primary neuroendocrine tumors of the fallopian tube (2 carcinoid tumors/low-grade neuroendocrine tumors and 2 high-grade neuroendocrine carcinomas) in patients aged 49 to 71. These represent the first reported cases of primary tubal carcinoid tumor unassociated with a teratoma. We review the published literature regarding primary neuroendocrine tumors of the fallopian tube and speculate on the possible histogenesis of these neoplasms.

Canadian Consensus-based and Evidence-based Guidelines for Benign Endometrial Pathology Reporting in Biopsy Material.

Standardized terminology has proven benefits in cancer reporting; in contrast, reporting of benign diagnoses in endometrial biopsy currently lacks such standardization. Unification and update on the lexicon can provide the structure and consistency needed for optimal patient care and quality assurance purposes. The Special Interest Group in Gynecologic Pathology of the Canadian Association of Pathologists-Association Canadienne des Pathologistes (CAP-ACP) embarked in an initiative to address the current need for consensus terminology in benign endometrial biopsy pathology reporting. Nine members of the Special Interest Group developed a guideline for structured diagnosis of benign endometrial pathology through critical appraisal of the available peer-reviewed literature and joint discussions. The first version of the document was circulated for feedback to a group of professionals in akin fields, the CAP-ACP Executive Committee and the CAP-ACP general membership. The final 1-page document included 17 diagnostic terms comprising the most common benign endometrial entities, as well as explanatory notes for pathologists. The proposed terminology was implemented in the practice of 5 pathologists from the group, who applied the guideline to all benign endometrial biopsies over a 2-wk period. A total of 212 benign endometrial biopsies were evaluated in this implementation step; the recommended terminology adequately covered the diagnosis in 203 cases (95.8%). A list of terminology for benign endometrial biopsy reporting, based on expert consensus and critical appraisal of the available literature, is presented. On the basis of our results of implementation at multiple centers, the proposed guideline can successfully cover the large majority of diagnostic scenarios. The document has the potential to positively impact patient care, promote quality assurance, and facilitate research initiatives aimed at improving histopathologic assessment of benign endometrium.

The utility of sentinel lymph node mapping in the management of endometrial atypical hyperplasia.

OBJECTIVES: To determine the risk of endometrial cancer (EC) and lymph node involvement in patients with a preoperative diagnosis of "AH-only" versus "AH - cannot rule out carcinoma" and to study the value of SLN mapping. METHODS: We reviewed all patients with a preoperative diagnosis of atypical hyperplasia, who underwent primary surgery with SLN mapping followed by pelvic lymphadenectomy. Sensitivity and negative predictive value (NPV) of SLN and rates of endometrial cancer were calculated. RESULTS: Overall, 64/120 (53.3%) patients were found to have EC on final pathology: 58 stage IA, 3 IB, and 3 IIIC1. In patients with preoperative diagnosis of "AH", 44.3% (31/70) had EC on final pathology compared to 66% (33/50) in patients with "AH - cannot rule out cancer" (p=0.02). Overall, 3.3% of the patients (4/120) had lymph node involvement. In patients with EC with a pre-operative diagnosis of "AH", none had lymph node metastasis (0/31), compared to 12.1% (4/33) in patients with "AH - cannot rule out cancer" (p=0.06). Elevated preoperative CA125 levels (>25U/mL) were statistically associated with the risk of lymph node metastasis on final pathology (p=0.024). Unilateral and bilateral SLN detection occurred in 93.7% and 78.1% respectively. In patients with EC and bilateral SLN mapping, sensitivity and NPV were respectively 66.6% and 97.9%. There was one false negative (ITCs in non-SLN). CONCLUSION: Our data indicate that the risk of lymph node involvement in patients with a preoperative diagnosis of "AH-only" is null. Lymph node assessment could be omitted in those patients. Conversely this risk is significant in patients with "AH - cannot rule out cancer". SLN mapping could be a valuable staging procedure in these patients.

Tips and tricks to improve sentinel lymph node mapping with Indocyanin green in endometrial cancer.

OBJECTIVE: To determine the validity of sentinel lymph node (SLN) biopsy with ICG in endometrial cancer and to evaluate the factors associated with poor mapping or false negative. METHODS: We reviewed all patients who underwent primary surgery for endometrial carcinoma with SLN mapping using ICG followed by pelvic lymphadenectomy from February 2014 to December 2015. SLNs were ultrastaged on final pathology. Patients' demographics, surgical approach and histopathological factors were prospectively collected. Detection rate, sensitivity and negative predictive value (NPV) were calculated and univariate analysis was performed to evaluate factors associated with failed bilateral detection of SLNs. RESULTS: A total of 119 patients were included. The overall and bilateral detection rates were 93% and 74%. Sensitivity and NPV were 100% in patients with bilateral detection; 95% and 99% respectively in cases with at least unilateral detection. Advanced FIGO stage (III or IV) was the only factor related to failed bilateral detection (p = 0.01). In 14 hemi-pelvis, the specimen labelled as SLN did not contain nodal tissue on final pathology (only lymphatic channels), which represented 37% of the "failed detection" cases. One false negative occurred in a patient with an ipsilateral clinically suspicious enlarged lymph node. CONCLUSION: ICG is an excellent tracer for SLN mapping in endometrial cancer. Advanced FIGO stage correlated with failed bilateral detection (p = 0.01). Suspicious lymph nodes should be removed regardless of the mapping. Care should be taken to ensure that SLN specimen actually contains nodal tissue and not only swollen lymphatic channels, as this represents a significant cause of failed SLN mapping.

Isolated tumor cells identified by sentinel lymph node mapping in endometrial cancer: Does adjuvant treatment matter?

OBJECTIVE: To evaluate the outcome and the role of adjuvant treatment in the management of patients with endometrial cancer and isolated tumor cells (ITCs) identified by SLN mapping. METHODS: This single center study identified all patients undergoing hysterectomy, salpingo-oophorectomy, lymphadenectomy and SLN mapping for endometrial cancer between November 2010 and December 2015. Data was prospectively collected. Progression-free survival was analyzed according to the Kaplan-Meier method and compared using the log-rank test. RESULTS: A total of 519 patients were included. Overall, 85 patients (16.4%) were found to have SLN metastases of which 43 (51%) were macrometastasis, 11 (13%) micrometastasis (MM) and 31 (36%) ITC. Eleven (35%) of patients with ITCs received adjuvant chemotherapy±whole pelvic radiation therapy (WPRT), 10 (32%) received WPRT, and 10 (32%) received either no adjuvant treatment or vault brachytherapy (VBT) only. ITC patients received significantly less chemotherapy (p=0.0001) and WPRT (p=0.007) compared to patients with macrometastasis. Of note, ITC were not considered node positive in our study. With a median follow-up of 29months (range: 0-67), the progression free survival (PFS) at 3-years for the ITC patients was 95.5%, similar to node negative (87.6%) and micrometastasis patients (85.5%), but statistically better than patients with macrometastasis (58.5%) (p=0.0012). Only 1/31 patient with ITC recurred (IB, 7cm carcinosarcoma) despite adjuvant treatments. None of the ITC patients with endometrioid histology recurred (0/28) and none of the ITC patients who did not receive adjuvant treatment or VBT recurred (0/10). CONCLUSIONS: Patients with endometrial cancer found to have SLN ITCs have an excellent outcome. The use of adjuvant treatment should be tailored to uterine factors and histology and not solely based on the presence of ITCs. Patients with ITCs and otherwise low-risk uterine disease probably derive little benefit from receiving additional treatments. More studies are needed to confirm our results.

Predictors of non-sentinel lymph node (non-SLN) metastasis in patients with sentinel lymph node (SLN) metastasis in endometrial cancer.

OBJECTIVES: The aim of this study was to determine the risk of metastasis in the remaining non-SLNs when the SLN is positive and to identify the factors that can predict this risk. METHODS: We reviewed all patients who underwent primary surgery for endometrial carcinoma with lymphadenectomy and SLN mapping (November 2010-November 2013) in our center. SLNs were ultra-staged on final pathology. RESULTS: A total of 268 patients were included. Overall, 43/268 patients (16%) were found to have SLN metastasis: macro-metastasis in 24 patients, micro-metastasis in 7 and ITC in 12. Non-SLN metastases were found in 15 of the 43 patients (34.8%) with positive SLN. Size of the SLN metastasis was the only factor associated with an increased likelihood of non-SLN metastasis (p=0.005). When the size of the SLN metastasis was ≤2mm, the risk of having another positive lymph node was only 5%, conversely, when the size of the SLN metastasis was >2mm, the risk of having another positive lymph node was 60.8% (p<0.0001). Histologic type, grade, depth of myometrial invasion, LVSI, cervical stromal invasion and CA-125 were not predictive. CONCLUSION: When the SLN is positive, the risk of metastasis in the remaining non-SLNs was 34.8%. Size of the metastasis within the SLN was the only factor that could predict the risk of non-SLN metastasis; 2mm seems to be the cutoff size below which the risk of non-SLN metastasis is low.

Sentinel node mapping with indocyanine green and endoscopic near-infrared fluorescence imaging in endometrial cancer. A pilot study and review of the literature.

OBJECTIVES: Indocyanine green (ICG) with near-infrared (NIR) fluorescence imaging is a new tracer modality used for lymphatic mapping. We report our initial experience with ICG for SLN mapping in cervical and endometrial cancer using a new endoscopic fluorescence imaging system. METHODS: We reviewed all patients who underwent primary surgery for early-stage endometrial and cervical carcinoma with SLN mapping using fluorescence imaging followed by pelvic lymphadenectomy from February to July 2014. Intracervical injection of ICG at 3 and 9 o'clock was performed in all cases. SLNs were ultrastaged on final pathology. Sensitivity and specificity values were calculated. RESULTS: A total of 50 patients were included in the study (42 endometrial and 8 cervical cancers). The median age was 62 (24-88) and median BMI 29 (19-56). The median SLN count was 3.1 (0-7) and median lymph node count was 15 (2-37). The overall and bilateral detection rate was 96% (48/50) and 88% (44/50). Positive SLNs were identified in 22% of patients (11/50), including 8 isolated tumor cells (ITC), 2 micrometastasis and 1 macrometastasis. There was one side-specific false negative case. Sensitivity, specificity and NPV were 93.3%, 100% and 98.7% respectively per side. Paraaortic node dissection was performed in 22% of cases. Two had paraaortic node metastasis both in patients with positive pelvic SLN. There were no allergic reactions to the ICG. CONCLUSIONS: Based on our pilot experience, NIR fluorescence imaging with ICG is an excellent and safe tracer modality for SLN mapping with a very high overall (96%) and bilateral (88%) detection rate.

Is a More Comprehensive Surgery Necessary in Patients With Uterine Serous Carcinoma?

OBJECTIVE: Uterine serous carcinoma (USC) is an aggressive histologic subtype of endometrial cancer that shares similarities to serous ovarian cancer, with a propensity for spread to the upper abdomen, a high recurrence rate, and a poor prognosis. The aim of this study was to determine whether the traditional surgical staging procedure for endometrial cancer was adequate for USC or whether a more extensive surgery, similar to the staging procedure for ovarian cancer, needs to be performed. Specifically, the roles of omentectomy and sentinel lymph node (SLN) mapping were evaluated. METHODS: We retrospectively identified cases of presumed clinical stage I USC at our institution from April 2005 to March 2014. Medical records were reviewed for the following information: age at diagnosis, preoperative imaging, operative findings, surgical procedure, and final histology with definitive International Federation of Gynecology and Obstetrics stage. RESULTS: A total of 39 patients with presumed clinical stage I USC were identified. According to the final pathology report, the surgical stage was as follows: 17 stage IA (44%), 8 stage IB (20%), 3 stage II (8%), 2 stage IIIA (5%), 6 stage IIIC1 (15%), 1 IIIC2 (3%), and 2 stage IVB (5%). Therefore, 14 patients (36%) were surgically upstaged, but none of the patients had their clinical disease upstaged by virtue of finding microscopic metastatic disease in an otherwise normal-looking omentum. Sentinel lymph node mapping was performed in 19 patients (42%). Sensitivity and negative predictive value of SLN mapping were 100% when at least 1 SLN was identified. CONCLUSIONS: The detection of microscopic disease in radiologically and clinically normal-appearing omentum seems to be rare in USC. Sentinel lymph node mapping seems to be valuable in the serous subtype of endometrial cancer. A less extensive surgery may be possible in patients with USC as it seems to provide the same information as a more extensive surgery.

Simple vaginal trachelectomy in early-stage low-risk cervical cancer: a pilot study of 16 cases and review of the literature.

OBJECTIVE: This study aimed to evaluate the feasibility of simple vaginal trachelectomy and node assessment in patients with low-risk early-stage cervical cancer (<2 cm). METHODS: From May 2007 to November 2012, 16 women with low-risk small-volume cervical cancer underwent a simple vaginal trachelectomy preceded by laparoscopic sentinel node mapping plus or minus pelvic node dissection. Data were collected prospectively in a computerized database. Descriptive statistics and Kaplan-Meyer estimate were used for analysis. RESULTS: Patients' median age was 30 years and 12 (75%) were nulliparous. Six had a diagnostic cone, 6 had a loop electrocautery excision procedure, 3 had cervical biopsies, and 1 had polyp excision. All patients underwent a preoperative pelvic magnetic resonance imaging. Four patients had stage IA1 with lymph vascular space invasion (LSVI), 6 IA2, and 6 IB1. Ten (62.5%) had squamous lesions, 7 had adenocarcinoma. LVSI was present in 4 cases, suspicious in 2, and absent in 10. There were 2 surgical complications: a trocar site hematoma and a vaginal laceration. The median OR time was 150 minutes (range, 120-180 minutes) and median blood loss was 50 mL (range, 50-150 mL). On final pathology, lymph nodes were negative in all patients. Thirteen (81%) patients had either no residual disease (6) or residual dysplasia only (7) in the trachelectomy specimen. Margins were negative in all cases. With a median follow-up of 27 months (range, 1-65 months), there have been no recurrences. The recurrence-free survival at 24 months is 100%. Eight patients have conceived: 3 were term deliveries and 4 are ongoing. CONCLUSIONS: Simple trachelectomy and nodes seems to be a safe alternative in well-selected patients with early-stage low-risk cervical cancer. Our data will need to be confirmed in larger series.

Effectiveness of risk-reducing salpingo-oophorectomy in preventing ovarian cancer in a high-risk French Canadian population.

BACKGROUND: Women with germ line BRCA1 or BRCA2 mutations have a marked increased risk of breast and ovarian cancer compared with the general population, whereas risk-reducing salpingo-oophorectomy (RRSO) significantly lowers the incidence of these cancers. The objective of this study was to review the clinical and pathological characteristics of a French Canadian population undergoing RRSO. Surgical morbidity was also evaluated. MATERIALS AND METHODS: From December 1999 to December 2009, all women who underwent RRSO at our institution were identified. Medical records were retrospectively reviewed. Descriptive statistics, the Fischer exact test, and the Student t test were used for analysis. RESULTS: During the study period, RRSO was performed on 119 women. Mean age at surgery was 49 years (35-72 years), and 63 patients (53%) were premenopausal. Sixty-two women (52%) had a history of in situ or invasive breast cancer. BRCA1 and BRCA2 mutations were present in 34 patients (29%) and 42 patients (35%), respectively, whereas 43 patients (36%) were considered to have an increased risk of breast and ovarian cancer, despite a personal genetic test, which was either negative (n = 23) or unknown because the patient declined genetic testing (n = 20). Most patients with a uterus in place had a complementary hysterectomy (65%). Six complications occurred (3 hematomas, 2 cardiac arrhythmias, and 1 cystotomy). In one patient (0.8%), a high-grade stage II ovarian cancer was discovered at the time of surgery. Fallopian tube atypias were identified on final pathology in 8 cases (6.7%). After a median follow-up of 22 months, 4 women (3.4%) developed breast cancer and one woman (0.8%) developed peritoneal cancer. CONCLUSIONS: Risk-reducing salpingo-oophorectomy is highly effective in preventing ovarian, fallopian tube, and breast cancers in a high-risk French Canadian population; and the surgical morbidity is low.

Endometrial Gastric (Gastrointestinal)-type Mucinous Lesions: Report of a Series Illustrating the Spectrum of Benign and Malignant Lesions.

With the recent elucidation of gastric-type lesions in the female genital tract (especially in the cervix), occasional cases of endometrial adenocarcinoma displaying gastric (gastrointestinal) differentiation have been reported, but they are currently not recognized as a distinct pathologic entity. We report 9 cases of endometrial mucinous lesions which exhibit gastric (gastrointestinal)-type features by morphology and immunohistochemistry, including 4 adenocarcinomas and 5 benign mucinous lesions, in patients aged 32 to 85. The adenocarcinomas showed gastric-type morphology in all 4 cases and goblet cells in 1, with a component of benign gastric-type mucinous glands in 1 case. Immunohistochemically, the adenocarcinomas were positive for CK7 (4/4), CEA (4/4), MUC6 (3/3), PAX8 (3/4), CK20 (2/4), CDX2 (2/4), and estrogen receptor (1/4). They were negative for Napsin A (0/3), with mutation-type p53 staining in 2/4 cases, block-type p16 positivity in 1/4, and scattered chromogranin-positive cells in 1/2. Targeted next-generation sequencing revealed nonsense mutation in RB1 gene for the case with block-positive p16. Follow-up was available in all adenocarcinoma cases and indicated aggressive behavior; 2 patients were dead of disease at follow-up of 7 months to 3 years, 1 was alive with progression at 9 months, and 1 was alive without disease at 7 months. The benign mucinous lesions (including the benign component in 1 adenocarcinoma) exhibited gastric-type morphologic features in 5/6 cases, goblet cells in 5/6, and Paneth-like neuroendocrine cells in 1/6. These benign mucinous lesions were associated with an endometrial polyp in 5/6 cases. Cytologic atypia was present in 2/6 cases and a lobular architecture resembling cervical lobular endocervical glandular hyperplasia in 4/6. Immunohistochemically, the benign mucinous lesions were positive for CK7 (5/5), CDX2 (5/6), estrogen receptor (4/5), MUC6 (4/5), CK20 (3/5), PAX8 (3/5), and CEA (2/4), with scattered chromogranin-positive cells in 4/4 cases; in all cases tested Napsin A was negative, p53 was wild-type and p16 was negative. We propose the term "endometrial gastric (gastrointestinal)-type adenocarcinoma" for this distinctive group of rare aggressive endometrial carcinomas. We believe that benign or atypical gastric (gastrointestinal)-type mucinous lesions are putative precursors for these adenocarcinomas, comparable to recognized premalignant gastric-type lesions in the cervix and the vagina. Future recognition and reporting of these gastric-type endometrial mucinous lesions will help delineate their pathogenesis and clinical significance.

Indication and method of frozen section in vaginal radical trachelectomy.

Vaginal radical trachelectomy (VRT) is a fertility-sparing surgical technique used as an alternative to radical hysterectomy in early stage cervical carcinoma. With the advent of VRT, preoperative evaluation of the surgical margin has become imperative, because if the tumor is found within 5 mm of the endocervical margin, additional surgical resection is required. In a study published earlier from our center, we came to the conclusion that a frozen section should be conducted only when a cancerous lesion is grossly visible, and that it could be omitted in normal-looking specimens or VRT with nonspecific lesions. Since then, 53 VRT have been performed in our center, and frozen sections were conducted according to these recommendations. Fifteen VRT were grossly normal, 24 had a nonspecific lesion and 14 showed a grossly visible lesion. Final margins were satisfactory on all 15 grossly normal specimens. Of the 24 VRT with nonspecific lesions, 2 cases for which no frozen section was performed had unsatisfactory final margins (<5 mm). Of the 14 VRT with grossly visible lesions, 3 cases were inadequately evaluated by frozen section due to sampling errors, which led to unsatisfactory final margin assessment. These results confirm that a frozen section can be omitted on normal looking VRT specimens, but contrary to results published earlier, we recommend that a frozen section be performed on all VRT with nonspecific lesions. As for VRT with a grossly visible lesion, frozen section evaluation is still warranted, and we recommend increasing the sampling to improve the adequacy of frozen sections.

Proposed novel nomenclature of vulvar smooth muscle tumors; a case of Smooth Muscle Tumor of Uncertain Malignant Potential (STUMP) of the vulva.

•Clinical experience with smooth muscle tumors of the vulva is limited.•Some tumors present ambiguous histological features concerning for malignancy.•These include infiltration, mitotic activity, size, atypia and tumor cell necrosis.•A case of smooth muscle tumor of the vulva with cellular atypia is presented.•"Smooth Muscle Tumor of Uncertain Malignant Potential" of the vulva is advocated.

Interobserver Agreement in Endometrial Carcinoma Histotype Diagnosis Varies Depending on The Cancer Genome Atlas (TCGA)-based Molecular Subgroup.

The Cancer Genome Atlas recently identified a genomic-based molecular classification of endometrial carcinomas, with 4 molecular categories: (1) ultramutated (polymerase epsilon [POLE] mutated), (2) hypermutated (microsatellite instability), (3) copy number abnormalities-low, and (4) copy number abnormalities-high. Two studies have since proposed models to classify endometrial carcinomas into 4 molecular subgroups, modeled after The Cancer Genome Atlas, using simplified and more clinically applicable surrogate methodologies. In our study, 151 endometrial carcinomas were molecularly categorized using sequencing for the exonuclease domain mutations (EDM) of POLE, and immunohistochemistry for p53 and mismatch repair (MMR) proteins. This separated cases into 1 of 4 groups: (1) POLE EDM, (2) MMR-D, (3) p53 wildtype (p53 wt), or (4) p53 abnormal (p53 abn). Seven gynecologic pathologists were asked to assign each case to one of the following categories: grade 1 to 2 endometrioid carcinoma (EC), grade 3 EC, mucinous, serous carcinoma (SC), clear cell, dedifferentiated, carcinosarcoma, mixed, and other. Consensus diagnosis among all 7 pathologists was highest in the p53 wt group (37/41, 90%), lowest in the p53 abn group (14/36, 39%), and intermediate in the POLE EDM (22/34, 65%) and MMR-D groups (23/40, 58%). Although the majority of p53 wt endometrial carcinomas are grade 1 to 2 EC (sensitivity: 90%), fewer than half of grade 1 to 2 EC fell into the p53 wt category (positive predictive value: 42%). Pure SC almost always resided in the p53 abn group (positive predictive value: 96%), but it was insensitive as a marker of p53 abn (sensitivity 64%) and the reproducibility of diagnosing SC was suboptimal. The limitations in the precise histologic classification of endometrial carcinomas highlights the importance of an ancillary molecular-based classification scheme.