The Malignant Potential of Ovarian Steroid Cell Tumors Revisited: A Multi-institutional Clinicopathologic Analysis of 115 Cases.

Steroid cell tumors (SCTs) of the ovary are rare and understudied, and as such, uncertainties remain about their malignant potential, as well as clinicopathologic predictors of patient outcome. Based on a multi-institutional cohort of cases, we present findings from the largest study of SCT reported to date. Clinicopathologic data were documented on 115 cases of SCT that were assembled from 17 institutions. The median patient age was 55 years (range: 9 to 84). When measured, preoperative androgen levels were elevated in 84.2% (48/57) of patients. A total of 111 (96.5%) cases were classified as stage I (103 stage IA; 2 stage IB; 6 stage IC). The stage distribution for the remaining 4 patients was as follows: stage II (n = 1), III (n = 3; 1 IIIA, 1 IIIB, 1 IIIC). The median tumor size was 3 cm (range: 0.2 to 22). Cytologic atypia, microscopic tumor necrosis, microscopic tumor hemorrhage, and a mitotic index of >1 mitotic figure/10 high-power fields were present in 52% (60/115), 9.6% (11/115), 37% (43/115), and 19% (22/115) of cases, respectively. Of 115 patients, 7 (6.1%) recurred postexcision, 4 (3.5%) ultimately died of disease, and 10 (8.7%) either recurred, died of disease, or were advanced stage at presentation. The median duration to recurrence postresection was 33 months (range: 23 to 180). Four of the 7 recurrences were stage IA at baseline. Tumor size >4 cm, International Federation of Gynecology and Obstetrics (FIGO) stage ≥IB, tumor necrosis, and tumor hemorrhage were each significantly associated with reduced recurrence-free survival in log-rank tests and univariable Cox models, with age older than 65 years being of marginal significance (hazard ratio [HR]: 5.4, 95% CI: 1.0-30.0, P = 0.05). Multivariable analyses suggested that FIGO stage ≥IB (HR: 27.5, 95% CI: 2.6-290.5), and age older than >65 years (HR: 21.8, 95% CI: 1.6-303.9) were the only parameters that were independently associated with recurrence. Cross-section analyses showed that tumor necrosis, tumor hemorrhage, and larger tumor size were significantly associated with a FIGO stage ≥IB status, which bolstered the conclusion that they are not independent predictors of recurrence. In summary, <10% of SCTs are clinically malignant, a substantially lower frequency than has previously been reported in the literature. Clinicopathologic predictors of patient outcomes that are prospectively applicable in practice could not be definitively established. Recurrences may occur many years (up to 15 y in this study) after primary resection, even in stage IA cases.

Selective breast/gynecologic pathology fellowship training in the United States: Experience of program directors.

Published data on combined breast and gynecologic [breast/gyn] surgical pathology fellowship training programs are limited. Our study aimed to survey the landscape of such fellowships in the United States (US), including specific information about their characteristics and the educational activities therein. Using web searches, we identified programs offering combined breast/gyn surgical pathology fellowship training. We developed a 26-item questionnaire asking program directors to report on the characteristics of their fellowship training structure. The search revealed 25 academic based programs offering one-year combined breast/gyn fellowship training, predominantly located (40 %) in the Northeast area. The following data was obtained: 44 % of the programs were accredited by the ACGME, 82 % required >19 weeks of breast and gyn service, and 69.6 % accepted the common application, 54.5 % of programs require completion of a research project for graduation. An annual average of 3000 breast and 3000 gyn cases appears to be the usual volume of cases. Interestingly, only 36 % of the program directors are graduates of a combined breast/gyn fellowship program. In conclusion, we present the most comprehensive and up-to-date census of combined breast/gyn pathology fellowships in the US. Our study provides valuable information on the current state of combined breast/gyn pathology fellowship training. The information will be helpful to current and prospective trainees, as well as program leaders.

Varying Phenotypes of Leydig Cell Hyperplasia of the Ovary: Two Case Reports.

Leydig cell hyperplasia (LCH) is a rare cause of hyperandrogenism that has been described only in case reports. The cases presented herein contrast the traditional presentation of LCH with an affected asymptomatic individual. The first case involves a 74-year-old woman presenting with symptomatic hyperandrogenism, whose symptoms resolved after bilateral salpingo-oophorectomy (BSO). The second patient presented with postmenopausal bleeding and an abdominal mass. Following total abdominal hysterectomy (TAH) and BSO, pathology showed ovarian LCH with concomitant endometrial cancer. The diagnosis of LCH is complex and requires careful investigation of many differential diagnoses. Incidentally discovered LCH may shed light on evolution and disease progression. Cases of LCH found in the setting of endometrial pathology may have implications on other states of testosterone excess.

Primary endometrial squamous cell carcinoma with synchronous early stage Fallopian adenocarcinoma: A case report and review of diagnostic and treatment considerations.

Background: Primary endometrial squamous cell carcinoma (PESCC) remains a rare sub-type of endometrial cancer. This case is especially unique due to the incidental finding of early stage Fallopian adenocarcinoma. This report adds to the literature of this rare condition and discuss it's etiology, clinical course, and treatment regimen.Case: 65 year old postmenopausal female presented with postmenopausal bleeding. Dilation and curettage revealed endometrial highly atypical squamous epithelial proliferation. Staging procedure showed FIGO stage IB squamous cell carcinoma of the endometrium, without evidence of cervical involvement. A small focus of incidental poorly differentiated FIGO stage IA adenocarcinoma of the left Fallopian tube was discovered. She underwent six cycles of Paclitaxel and Cisplatin, and has remained disease free for two years. Conclusion: Primary endometrial squamous cell carcinoma is poorly understood entity. Early diagnosis is critical due to the strong correlation between initial stage and survival. Biopsy of the cervix and endometrium should be considered in cases of abnormal uterine sampling. The case presented is a prototypical example of PESCC, both in presentation, pathology, and course. It is especially unique due to synchronous high grade Fallopian adenocarcinoma.

Combined BRCA2 and MAGEC3 Expression Predict Outcome in Advanced Ovarian Cancers.

Like BRCA2, MAGEC3 is an ovarian cancer predisposition gene that has been shown to have prognostic significance in ovarian cancer patients. Despite the clinical significance of each gene, no studies have been conducted to assess the clinical significance of their combined expression. We therefore sought to determine the relationship between MAGEC3 and BRCA2 expression in ovarian cancer and their association with patient characteristics and outcomes. Immunohistochemical staining was quantitated on tumor microarrays of human tumor samples obtained from 357 patients with epithelial ovarian cancer to ascertain BRCA2 expression levels. In conjunction with our previously published MAGEC3 expression data, we observed a weak inverse correlation of MAGEC3 with BRCA2 expression (r = −0.15; p < 0.05) in cases with full-length BRCA2. Patients with optimal cytoreduction, loss of MAGEC3, and detectable BRCA2 expression had better overall (median OS: 127.9 vs. 65.3 months, p = 0.035) and progression-free (median PFS: 85.3 vs. 18.8 months, p = 0.002) survival compared to patients that were BRCA2 expressors with MAGEC3 normal levels. Our results suggest that combined expression of MAGEC3 and BRCA2 serves as a better predictor of prognosis than each marker alone.

The Clinical Utility and Impact of Next Generation Sequencing in Gynecologic Cancers.

Next generation sequencing (NGS) has facilitated the identification of molecularly targeted therapies. However, clinical utility is an emerging challenge. Our objective was to identify the clinical utility of NGS testing in gynecologic cancers. A retrospective review of clinico-pathologic data was performed on 299 gynecological cancers where NGS testing had been performed to identify (1) recognition of actionable targets for therapy, (2) whether the therapy changed based on the findings, and (3) the impact on survival. High grade serous carcinoma was the most common tumor (52.5%). The number of genetic alterations ranged from 0 to 25 with a mean of 2.8/case. The most altered genes were TP53, PIK3CA, BRCA1 and BRCA2. Among 299 patients, 100 had actionable alterations (79 received a targeted treatment (Group1), 29 did not receive treatment (Group 2), and there were no actionable alterations in 199 (Group3). The death rate in groups 1, 2 and 3 was 54.4%, 42.8% and 50.2%, with an average survival of 18.6, 6.6 and 10.8 months, respectively (p = 0.002). In summary, NGS testing for gynecologic cancers detected 33.4% of actionable alterations with a high clinical action rate. Along with the high clinical utility of NGS, testing also seemed to improve survival for patients who received targeted treatment.

Grossly unremarkable cervix in endometrial carcinomas: lymphovascular space invasion and microcystic elongated and fragmented pattern may be associated with high incidence of cervical stromal involvement.

Accurate staging of endometrial carcinoma is crucial to optimize patients' care. A pivotal parameter that pathologists evaluate to guide staging is the presence of cervical stromal involvement. However, the standard protocol for adequate sampling of the cervix is lacking. A total of 71 grossly unremarkable cervices in hysterectomy specimens with endometrial carcinomas have been studied. Sixty-three (89.7%), five (7.0%), and three (4.2%) were FIGO stage I, II, and III, respectively. Of 71 (8.5%) cases, 6 cases had cervical stromal involvement, among which, 4 (67%) showed endometrioid carcinoma (EC), 1 case of serous carcinoma, and 1 carcinosarcoma. Microcystic elongated and fragmented (MELF) pattern was identified in 12 (16.9%) cases, among which 11 were EC. The presence of MELF pattern was associated with advanced age, deeper myometrial invasion, and advanced FIGO stage. Tumors with lower uterine segment involvement (5/6; 80%), lymphovascular space invasion (4/6; 67%), and MELF pattern (3/6; 50.0%) tended to have cervical stromal involvement. Thus, we provide evidence that the presence of these features in hysterectomy specimens from patients with endometrial carcinoma may warrant extended sampling of the cervix while submitting four representative sections (one section from each quadrant) seems adequate to evaluate for occult cervical stromal involvement in grossly unremarkable cervices in the absence of these features.

Diagnostic Utility and Significance of Performing Multistep Level Sections in Breast and Gynecologic Biopsy Specimens.

OBJECTIVES: The significance of performing multistep level sections, including preparation of unstained sections in breast and gynecologic biopsy specimens, has been studied. METHODS: Consecutive H&E-stained level sections of 785 atypical and malignant biopsy specimens were included. The diagnostic material was categorized into present, absent, increased in size, or depleted. If the multistep level sections helped in establishing the diagnosis after a nondiagnostic material or the tissue significantly increased in size, this was considered a positive impact. RESULTS: No effect and positive impact of performing multistep level sections were obtained in 84.8% and 15.2% by preparing a second level and 97.2% and 2.8% by preparing a third level, respectively. Eighteen (2.3%) of the diagnoses could have been missed without performing a second level, while 8 (1%) could have been missed without performing a third level. The intervening unstained sections were used in 27 of 785 (3.4%) of the cases. CONCLUSIONS: Staining two level sections with H&E significantly affected the diagnosis. However, preparing a third level did not improve the diagnosis. A universal protocol should be considered to standardize the handling of biopsy specimens among laboratories.

Primary adenocarcinomas of the vulva and related structures: An enigmatic and diverse group of tumors✰.

Approximately half of adenocarcinomas that involve the vulva are secondary, either through direct extension or metastases from elsewhere. Primary vulvar adenocarcinomas are rare and encompass a diverse array of neoplasms that are nominally classified based on the presumed tissue or organ of origin, the tumoral phenotype, or both. In this review, we summarize the clinicopathologic features of adenocarcinomas that originate from the vulva and related structures, including the terminal urethra. Adenocarcinomas of this region encompass lesions that are defined by their primary site (such as adenocarcinomas of the Bartholin gland, which by definition must be in the region of the Bartholin gland), histomorphology and immunophenotype (such as clear cell carcinoma and adenocarcinoma of intestinal [cloacogenic] type), or both (such as adenocarcinoma of skene gland origin, which is associated with that specific organ but which also displays a distinctive phenotype that is similar to the phenotype of high grade prostatic adenocarcinoma). Other types, such as mammary-type adenocarcinomas, are presumed to originate from the putative mammary-like glands of the vulva and display a spectrum of pathologic features that are similar to their mammary counterparts. Similarly, vulvar carcinomas of sweat gland origin are pathologically similar to their counterparts in the non-vulvar skin and include a variety of cutaneous adnexal-type malignancies such as apocrine adenocarcinoma and eccrine adenocarcinoma. Some tumors, such as adenoid cystic carcinoma, may represent a Bartholin gland adenocarcinoma, a carcinoma of sweat gland origin, or a carcinoma arising from extramammary Paget disease (EMPD), depending on the context. Invasive carcinomas of various types have been reported in 7-12.7% of EMPD, and these are likely the most common primary glandular malignancy of the vulva. Occasional vulvar adenocarcinomas have been reported to be HPV-associated, although this association has not been established for the broader group of vulvar adenocarcinomas. Rare adenocarcinomas are not classifiable by the aforementioned nosologic scheme, and are designated as vulvar adenocarcinoma NOS.

The clinical significance of metastatic breast carcinoma to intramammary lymph node.

The incidence of involved intramammary lymph node (intra-MLN) with breast carcinoma (BC) is rare. Its clinical significance and impact on the clinical decision making is unclear. A total of 113 BC cases with at least one positive intra-MLN were collected from 11 academic institutions. The inclusion criteria were subsequent axillary lymph node dissection, and the availability of information on T-stage, size of node metastasis, extranodal extension status, biomarkers status, and clinical follow-up. Stage 4 cases and/or neo-adjuvant treated patients were excluded. AJCC TN-stage was calculated twice, with and without intra-MLN. Five-year overall survival (OS) and relapse (local and/or distant)-free survival (RFS) were calculated and correlated with the clinicopathologic variables. Excluding intra-MLN, TN-stage correlated with OS (P = .016) but not with RFS (P = .19). However, when intra-MLN was included, TN-stage correlated with both OS (P < .001) and RFS (P = .016). In the multivariate analysis, when intra-MLN was excluded, only radiation therapy (RT) correlated with RFS (HR = 0.19, 95% CI: 0.054-0.66, P = .009). However, when intra-MLN was included in the TN-stage both RT (HR = 0.13, 95% CI: 0.04-0.45, P = .001) and TN-stage 3 (HR = 8.92, 95% CI: 1.47-54, P = .017) correlated with RFS. Tumor multifocality was the only variable correlated with OS when the intra-MLN involvement was excluded. When intra-MLN was included, multifocality became insignificant but TN-stage 3 correlated with OS (HR = 8.59, 95% CI: 1.06-69.71, P = .044). Positive intra-MLN is an independent factor in predicting both RFS and OS.

The Role of Castration-Resistant Bmi1+Sox2+ Cells in Driving Recurrence in Prostate Cancer.

BACKGROUND: Recurrence following androgen-deprivation therapy is associated with adverse clinical outcomes in prostate cancer, but the cellular origins and molecular mechanisms underlying this process are poorly defined. We previously identified a population of castration-resistant luminal progenitor cells expressing Bmi1 in the normal mouse prostate that can serve as a cancer cell-of-origin. Here, we investigate the potential of Bmi1-expressing tumor cells that survive castration to initiate recurrence in vivo. METHODS: We employed lineage retracing in Bmi1-CreER; R26R-confetti; Ptenf/f transgenic mice to mark and follow the fate of emerging recurrent tumor clones after castration. A tissue recombination strategy was used to rescue transgenic mouse prostates by regeneration as grafts in immunodeficient hosts. We also used a small molecule Bmi1 inhibitor, PTC-209, to directly test the role of Bmi1 in recurrence. RESULTS: Transgenic prostate tumors (n = 17) regressed upon castration but uniformly recurred within 3 months. Residual regressed tumor lesions exhibited a transient luminal-to-basal phenotypic switch and marked cellular heterogeneity. Additionally, in these lesions, a subpopulation of Bmi1-expressing castration-resistant tumor cells overexpressed the stem cell reprogramming factor Sox2 (mean [SD] = 41.1 [3.8]%, n = 10, P < .001). Bmi1+Sox2+ cells were quiescent (BrdU+Bmi1+Sox2+ at 3.4 [1.5]% vs BrdU+Bmi1+Sox2- at 18.8 [3.4]%, n = 10, P = .009), consistent with a cancer stem cell phenotype. By lineage retracing, we established that recurrence emerges from the Bmi1+ tumor cells in regressed tumors. Furthermore, treatment with the small molecule Bmi1 inhibitor PTC-209 reduced Bmi1+Sox2+ cells (6.1 [1.4]% PTC-209 vs 38.8 [2.3]% vehicle, n = 10, P < .001) and potently suppressed recurrence (retraced clone size = 2.6 [0.5] PTC-209 vs 15.7 [5.9] vehicle, n = 12, P = .04). CONCLUSIONS: These results illustrate the utility of lineage retracing to define the cellular origins of recurrent prostate cancer and identify Bmi1+Sox2+ cells as a source of recurrence that could be targeted therapeutically.

Subsequent breast and high grade serous carcinomas after risk-reducing salpingo-oophorectomy in BRCA mutation carriers and patients with history of breast cancer.

Risk-reducing salpingo-oophorectomy (RRSO) is a procedure to reduce the risk of adnexal cancer in BRCA mutation carriers and for hormonal manipulation in women with breast cancer (BC). The goal of the study is to report the frequency of subsequent BC and high-grade serous carcinoma (HGSC) following RRSO in BRCA1 and BRCA2 mutation carriers and in patients with personal history of BC with or without BRCA mutation. A series of 147 consecutive patients who received a RRSO were reviewed. Patient's age, clinical history, BC histotype, gene mutation data, incidence of post-RRSO BC and HGSC and time intervals were analyzed. The cases were followed for a mean of 49 months. Group 1 consists of 97 cases with pathogenic or likely pathogenic "deleterious" mutation BRCA1 (n = 49) or BRCA2 (n = 48). Group 2 consists of 50 cases with history of BC and no documented BRCA gene mutation. Prior to RRSO, 42 (43%) cases in group 1 had a history of BC and all cases in group 2 had a history of BC. There was no difference between the groups in the age at diagnosis for BC (Mean of 44 years). Following RRSO, 2/49 cases (4%) with BRCA1 mutation were found to have occult HGSC and none in BRCA2 cases. There were also 1 BC recurrence and 1 primary BC with BRCA1 mutation compared to 5 recurrent BC in Group 2 (10%). In conclusion, the risk of subsequent recurrent BC after RRSO appears to be higher (10%) in patients with history of BC with no BRCA mutation when compared to (2%) in BRCA mutation carriers.

Trends in High-Grade Cervical Cancer Precursors in the Human Papillomavirus Vaccine Era.

INTRODUCTION: The 2006 introduction of human papillomavirus vaccine targeted against genotypes 6, 11, 16, and 18 should result in decreased cervical dysplasia in vaccinated women. However, new cervical cancer guidelines to increase screening intervals complicate interpretation of trends. The hypothesis is that cervical dysplasia would decrease only in young vaccine-eligible women, and not older women. METHODS: The authors identified Davidson County, Tennessee, women aged 18-39 years with cervical intraepithelial neoplasia (CIN) grade 2 or greater and adenocarcinoma in situ, denoted as CIN2+, through pathology reports from laboratories serving this population. Biopsy specimens for human papillomavirus genotyping were collected. Trends in CIN2+ rates and associated human papillomavirus genotypes, 2008 through 2013, were examined. RESULTS: The authors identified 2,031 women with CIN2+. Rates of CIN2+ fell from 188.9 to 58.7 per 100,000 women aged 18-20 years (annual percentage change= -24.2, 95% CI= -41.4, -2.1) and from 495.6 to 332.4 per 100,000 women aged 21-24 years (annual percentage change= -10.2%, 95% CI= -16.3, -3.4). There was no significant change in CIN2+ rates for women aged 25-29 or 30-39 years. In biopsy specimens from 1,319 of 2,031 (65%) women, at least one human papillomavirus genotype was identified in 1,270 (96%). The prevalence of at least one of four vaccine human papillomavirus genotypes (6, 11, 16, and 18) declined from 59% in 2008 to 52% in 2013 (p=0.003). CONCLUSIONS: Diagnosis of CIN2+ decreased in women aged 18-24 years, but not in older women. Both changes in screening and human papillomavirus vaccination could have contributed to the decline of CIN2+ in young women.

Correlation between invasive mammary carcinoma grade and size in ultrasound-guided core needle biopsy and subsequent surgical excision.

The purpose of this study was to correlate the histologic grade, mitotic rate and size of invasive mammary carcinomas (IMC) on ultrasound (US) core needle biopsy (CNB) and the follow-up excision (FUE). The underestimation and overestimation of the grades by CNB were 11% and 8%. CNBs were more specific for grade 3 tumors. Tumors >10 mm by US examination showed greater concordance in grades. The size in the FUE was the best determinant of pT followed by US examination. The extent of IMC on CNB was larger than FUE in 8% resulting in pT upstaging in 3% of cases.

The role of skin ulceration in breast carcinoma staging and outcome.

Breast carcinoma with skin ulceration (SU) is considered a locally advanced disease. The purpose of the study is to investigate if SU is an independent adverse factor. Breast carcinoma patients with SU (n=111) were included in the study. A subset (n=38, study cohort) was matched with cases that had no SU (n=38, matched cohort); the survival analyses were compared between these groups. Then, cases (n=80) were staged independent from SU into stage I, II or III. Disease free survival (DFS) and overall survival (OS) were analyzed. Patients with larger tumors tended to present with distant metastases more often than patients with smaller tumors (P=.004). In the matched cases, the 5-year DFS probability was 53% for the study cohort and 58% for the matched cohort; and for OS 75% for the study cohort and 84% for the matched cohort with no statistical significant difference. However, there was a trend towards worse DFS for the patients whose tumors had SU. When the cases were staged based on tumor size and node status (I, II or III), the OS was statistically significant (P=.047) but not the DFS (P=.195). Relatively small tumors with SU had an extent of disease similar to that observed in patients with early stages disease. The survival analysis suggests that SU may not be an adverse factor. However, more cases are needed to further examine this finding.

Clear Cell Renal Cell Carcinoma Metastatic to the Gynecologic Tract: A Clinicopathologic Analysis of 17 Cases.

Clear cell renal cell carcinomas (CCRCC) rarely metastasizes to the gynecologic tract. In this study, we analyzed a multi-institutional data set to provide insights into the clinical, morphologic, and immunophenotypic features of this phenomenon. Seventeen metastatic CCRCC involving the gynecologic tract [ovary/fallopian tube (n=9), vulva (n=2), uterine corpus (n=3), cervix (n=2), uterine serosa (n=1)] were analyzed. Mean patient age was 62 yr (range: 45-79 yr). Most cases (15/17) presented as a recurrence 6 to 72 mo postnephrectomy, 1 case was concurrently diagnosed, and 1 case (a cervical metastasis) was diagnosed prenephrectomy. In 10 cases, metastases to other locations were identified within 6 wk of the gynecologic tract lesion. The adnexa were the most common site of metastases and the mean tumor size of adnexal metastases was 3.7 cm; in only 2 of 9 cases were metastases bilateral and only 1 had external surface nodules. The morphologic and immunohistochemical features of metastatic CCRCC were compared with those of 102 müllerian clear cell carcinomas (müllerian CCC: 49 endometrial, 53 ovarian). Although CCRCC and müllerian CCC displayed extensive morphologic overlap, a higher mitotic index and a higher frequency of an alveolar pattern were seen in CCRCC, whereas diffuse hobnail cells, hyaline globules, tubulocystic pattern, or any papillary pattern were more frequently seen in müllerian CCC. CA-IX, CD10, and renal cell carcinoma antigen were more frequently expressed in CCRCC than müllerian CCC, whereas Napsin-A, CK7, and p504S showed the reverse. PAX8 and HNF1ß did not significantly distinguish between the 2 groups. In summary, gynecologic tract metastases most often occur as a relapse of a previously resected CCRCC, and these relapses may occur many years postnephrectomy. Gynecologic tract metastases are often accompanied by concurrent metastases to other organs. The gross pathology of metastatic CCRCC in the ovary may potentially overlap with primary neoplasia. However, the expected morphology and immunophenotype of CCRCC are maintained in most gynecologic tract metastases. As such, although metastatic CCRCC and müllerian CCC may display significant overlap in pathologic features, several morphologic and immunophenotypic features are useful in their distinction.

Intraoperative Pathologic Consultation on Hysterectomy Specimens for Endometrial Cancer: An Assessment of the Accuracy of Frozen Sections, "Gross-Only" Evaluations, and Obtaining Random Sections of a Grossly "Normal" Endometrium.

OBJECTIVES: Pathologic intraoperative consultation (IOC) is a common approach for segregating the subset of patients with endometrial cancer who likely require a lymphadenectomy. METHODS: We evaluate factors related to the performance and value of IOC, including the accuracy of frozen sections, "gross-only examinations," and obtaining random sections when a gross lesion is not apparent. RESULTS: IOC was performed by gross examination only in 17 (8%) of 250 cases, the specificity and negative predictive value of which in diagnosing cancer were 100% and 85%, respectively. Among the 64 cases wherein a gross lesion was not apparent and random sections were examined, a final diagnosis of carcinoma was rendered in 20, of which only three (15%) had a diagnosable malignancy on the random section. The frozen-section/final diagnosis concordance was 80% for tumor grade. Determining the depth of myometrial invasion was problematic, with 36% underestimation and 2.6% overestimation. CONCLUSIONS: Obtaining random sections in the absence of a gross lesion has no significant benefit, and a negative result is likely to provide inaccurate data to the surgeon. Frozen-section analyses are a generally reliable tool to determine "low-risk" pathologic parameters that were evaluated herein when a gross lesion is present.

Atypical mucinous glandular proliferations in endometrial samplings: follow-up and other clinicopathological findings in 41 cases.

The 2014 World Health Organization classification calls for endometrial mucinous proliferations that display "confluent or cribriform architecture with even minimal atypia" in sampling specimens to be classified as carcinoma, and others whose features are not diagnostic of carcinoma to be categorized as atypical mucinous glandular proliferations (AMGPs). Herein, we evaluate follow-up findings in 41 cases that were classified as AMGP from our files. The average patient age was 46years (range, 37-59 years). Postbiopsy follow-up duration ranged from 15 to 109weeks (mean, 40 weeks). There was no follow-up resection in 12 patients (9 with repeat biopsies, all 9 with no clinical evidence of disease, mean follow-up of 43weeks), and 29 patients underwent a hysterectomy an average of 2.4months after the index biopsy. The distribution of pathologic findings in the uteri was as follows: no residual AMGP or carcinoma (5/29; 17%), AMGP (11/29; 38%), and adenocarcinoma (13/29; 45%). All adenocarcinomas were grade I and stage I, and histotypes were endometrioid (n=8), mucinous (n=3), and endometrioid with mucinous differentiation (n=2). Only 3 (23%) carcinomas were myoinvasive, of which 1 case, a mucinous carcinoma with a 40% endometrioid component, showed greater than 50% myometrial invasion. None of a wide array of morphologic features was significantly associated with a hysterectomy diagnosis of carcinoma (versus AMGP) on univariate analyses. In conclusion, our cohort of AMGP represents a biologically variable spectrum of lesions that includes mucinous hyperplastic proliferations as well as endometrioid and mucinous adenocarcinomas that are occasionally myoinvasive. Morphologic features that optimally stratified AMGP cases into clinically relevant subgroups were not identified.

Bmi1 marks distinct castration-resistant luminal progenitor cells competent for prostate regeneration and tumour initiation.

Identification of defined cell populations with stem/progenitor properties is key for understanding prostate development and tumorigenesis. Here we show that the polycomb repressor protein Bmi1 marks a population of castration-resistant luminal epithelial cells enriched in the mouse proximal prostate. We employ lineage tracing to show that these castration-resistant Bmi1-expressing cells (or CARBs) are capable of tissue regeneration and self-renewal. Notably, CARBs are distinct from the previously described luminal castration-resistant Nkx3.1-expressing cells (CARNs). CARBs can serve as a prostate cancer cell-of-origin upon Pten deletion, yielding luminal prostate tumours. Clonal analysis using the R26R-confetti allele indicates preferential tumour initiation from CARBs localized to the proximal prostate. These studies identify Bmi1 as a marker for a distinct population of castration-resistant luminal epithelial cells enriched in the proximal prostate that can serve as a cell of origin for prostate cancer.