The unique metabolome of clear cell ovarian carcinoma.

Clear cell ovarian carcinoma (CCOC) is an aggressive malignancy affecting younger women. Despite ovarian cancer subtypes having diverse molecular and clinical characteristics, the mainstay of treatment for advanced stage disease remains cytotoxic chemotherapy. Late stage CCOC is resistant to conventional chemotherapy, which means a suboptimal outcome for patients affected. Despite detailed genomic, epigenomic, transcriptomic, and proteomic characterisation, subtype-specific treatment for CCOC has shown little progress. The unique glycogen accumulation defining CCOC suggests altered metabolic pathway activity and dependency. This study presents the first metabolomic landscape of ovarian cancer subtypes, including 42 CCOC, 20 high-grade serous and 21 endometrioid ovarian carcinomas, together comprising the three most common ovarian carcinoma subtypes. We describe a distinct metabolomic landscape of CCOC compared with other ovarian cancer subtypes, including alterations in energy utilisation and cysteine metabolism. In addition, we identify CCOC-specific alterations in metabolic pathways including serine biosynthesis and ROS-associated pathways that could serve as potential therapeutic targets. Our study provides the first in-depth study into the metabolome of ovarian cancers and a rich resource to support ongoing research efforts to identify subtype-specific therapeutic targets that could improve the dismal outcome for patients with this devastating malignancy. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

PRAME Immunohistochemistry for Distinguishing Vulvar and Vaginal Melanoma From Benign Melanocytic Nevi.

Vulvovaginal melanoma (VVM) is a rare but deadly disease, accounting for 5% of all vulvar malignancies, with a 5-yr survival rate of only 47% for all stages of the disease. VVM is a distinct subset of melanoma, with a unique genomic profile and underlying pathogenesis unassociated with sun exposure. Distinguishing these rare malignancies from very common pigmented lesions of the vulva and vagina is challenging as histologic features often overlap between entities. PReferentially expressed Antigen in MElanoma (PRAME) is a melanoma-associated protein, and immunohistochemistry (IHC) for PRAME distinguishes cutaneous, oral mucosal, and retinal melanoma from atypical nevi. Given the biological differences between VVM and cutaneous melanoma, the utility of PRAME IHC for the diagnosis of VVM is unknown. We accrued a cohort of 20 VVM and 21 benign vulvar melanocytic nevi. We found that nuclear PRAME IHC staining with 4+ intensity was present in 85% of the VVM and 0% of the nevi. With the assistance of PRAME IHC, we found evidence of close or positive margin involvement in 3 of 10 cases where margins were originally diagnosed as negative for melanoma in situ. Our study is the first to assess PRAME IHC in a cohort of VVM cases and provides confidence for using PRAME IHC to assist with diagnosis and margin assessment in this rare disease.

The implementation of community-based programs in Vietnam is promising in promoting health.

Background: Low-and middle-income countries mostly have ageing populations with many unmet economic, social, or health-related needs, Vietnam being an example. Community-based support in Vietnam, organized as Intergenerational Self-Help Clubs (ISHCs) based on the Older People Associations (OPA) model, can help to meet these needs by the provision of services for various aspects of life. This study aims to assess the implementation of the ISHCs and whether successful implementation is associated with more member-reported positive health. Methods: We used the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework to evaluate the implementation using multiple data sources: ISHC board surveys (n = 97), ISHC member surveys (n = 5,080 in 2019 and n = 5,555 in 2020), focus group discussions (6; n = 44), and interviews with members and board leaders (n = 4). Results: Reach ranged between 46 and 83% of ISHCs reaching target groups, with a majority of women and older people participating. Regarding Effectiveness, members indicated high satisfaction with the ISHCs. Adoption scores were high, with 74%-99% for healthcare and community support activities, and in 2019, higher adoption scores were associated with more members reporting good positive health. In 2020, reported positive health slightly decreased, probably due to the influence of the COVID-19 pandemic. A total of 61 ISHCs had consistent or improving Implementation from 2019 to 2020, and confidence in Maintenance was high. Conclusion: The implementation of the OPA model in Vietnam is promising regarding its promotion of health and may help to tackle the needs of an ageing population. This study further shows that the RE-AIM framework helps to assess community health promotion approaches.

Differentiated Exophytic Vulvar Intraepithelial Lesions: Case Reports and Review of Literature.

OBJECTIVES: The aims of this article were to describe 2 patients with a pathological diagnosis of differentiated exophytic vulvar intraepithelial lesion and to summarize the literature regarding this relatively new diagnosis. MATERIALS AND METHODS: The existing literature was searched on December 1, 2021, using the MEDLINE database (1966-2021), and all combinations of the following search terms were used: "differentiated exophytic vulvar intraepithelial lesion" and "differentiated vulvar intraepithelial neoplasia." RESULTS: Patients were postmenopausal and reported persistent vulvar itch associated with white hypertrophic plaques. Initial biopsies did not identify differentiated exophytic vulvar intraepithelial lesion. Invasive squamous cell carcinoma was found in both cases after surgical excision. CONCLUSIONS: Differentiated vulvar intraepithelial lesions and invasive squamous cell carcinoma should be considered in the differential diagnosis of vulvar itch associated with hypertrophic plaques in postmenopausal women. Excision of suspicious plaques is recommended for definitive diagnosis.

Performance of the pattern-based interpretation of p53 immunohistochemistry as a surrogate for TP53 mutations in vulvar squamous cell carcinoma.

AIMS: The most commonly mutated gene in vulvar squamous cell carcinoma (VSCC) is TP53 and its prognostic value, particularly in HPV-independent VSCC, is uncertain. In other tumours, p53 immunohistochemistry (IHC) is an excellent surrogate marker for TP53 mutations. In order to study this in VSCC, we assigned six p53 IHC patterns into two final classes: 'wild-type' or 'mutant'. We determined the performance and interobserver variability of this pattern-based p53 IHC approach. METHODS AND RESULTS: Two experienced gynaecological pathologists scored the predefined p53 IHC patterns of 59 VSCC, independently and blinded for molecular data. Agreement was calculated by Cohen's kappa. All disagreements regarding p53 IHC patterns were resolved by a consensus meeting. After DNA isolation, the presence of pathogenic TP53 variants was determined by next-generation sequencing (NGS). Sensitivity, specificity and accuracy of p53 IHC as a surrogate marker for TP53 mutation status were calculated. Initial p53 IHC pattern interpretation showed substantial agreement between both observers (k = 0.71, P < 0.001). After consensus, 18 cases (30.5%) were assigned a final p53 IHC class as TP53 wild-type and 41 cases (69.5%) as mutant. The accuracy between the p53 IHC class and TP53 mutation status, after the consensus meeting, was 96.6%. Moreover, the sensitivity and specificity were high 95.3% [95% confidence interval (CI) = 82.9-99.1% and 100% (95% CI = 75.9-100%)]. CONCLUSIONS: Pattern-based p53 IHC classification is highly reproducible among experienced gynaecological pathologists and accurately reflects TP53 mutations in VSCC. This approach to p53 IHC interpretation offers guidance and provides necessary clarity for resolving the proposed prognostic relevance of final p53 IHC class within HPV-independent VSCC.

Uterine Tumor Resembling Ovarian Sex Cord Tumor (UTROSCT): A Morphologic and Molecular Study of 26 Cases Confirms Recurrent NCOA1-3 Rearrangement.

Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare mesenchymal neoplasm, of uncertain biological potential, that was recently reported to exhibit recurrent gene fusions involving NCOA2-3. The purpose of this study was to, using a larger sample size, better characterize the histopathologic and molecular diversity of UTROSCT. Twenty-six cases of UTROSCT from 5 institutions were selected for further study. Fluorescence in situ hybridization for NCOA1, NCOA2, NCOA3, ESR1 and GREB1, and targeted RNA sequencing was performed on 17 and 8 UTROSCTs, respectively. Eight cases underwent massively parallel sequencing to detect single nucleotide variants (SNV), copy number variations, and structural variants using a targeted hybrid-capture based assay. NCOA1-3 rearrangement was identified in 81.8% (18/22) of cases. The most common fusion was ESR1-NCOA3, occurring in 40.9% (9/22). GREB1-NCOA1 (n=4), ESR1-NCOA2 (n=3), and GREB1-NCOA2 (n=1) rearrangements were also identified. No recurrent SNVs were identified and no tumor had SNVs in FOXL2, DICER1, STK11, or AKT1, which can be seen in ovarian sex cord-stromal tumors. Copy number variations were infrequent. Clinical follow-up was available for 11 cases with a mean follow-up interval of 94.4 (range, 1 to 319) months. Only one case had a recurrence 66 months after the initial diagnosis and this was the single case with a GREB1-NCOA2 fusion. This study reports the morphologic spectrum of UTROSCT and confirms the recently reported recurrent NCOA2-3 gene fusions, in addition to identifying novel rearrangements involving NCOA1 in these tumors.

Endometrial tumors with yolk sac tumor-like morphologic patterns or immunophenotypes: an expanded appraisal.

Uterine yolk sac tumors have gained increased recognition in recent years. The current study is a multi-faceted examination of yolk sac tumor-like phenotypes in endometrial tumors, based on an analysis of 3 groups of uterine tumors: Group 1: 9 endometrial tumors that had been classified as yolk sac tumor, or as having a yolk sac tumor component, were assessed with a 35-marker immunohistochemical panel, with the goal of defining their immunophenotypic spectrum; Group 2, comprised of 70 endometrial carcinomas of various histotypes, were analyzed for their expression of SALL4, Glypican-3, and AFP, to assess the specificity of these markers for yolk sac tumors relative to endometrial carcinomas; Group 3, comprised of 626 archived cases of endometrial carcinoma/carcinosarcoma, reviewed to define the frequency of yolk sac tumor-like morphology therein. Yolk sac tumor areas in the Group 1 cases were consistently immunoreactive for SALL4 and Glypican-3; variably positive for AFP (89%), Villin (89%), PLAP (78%), 34ßE12 (67%), CAM 5.2 (62.5%), EMA (56%), CD117 (50%), p16 (50%), CDX2 (44%), p53 (44% aberrant), MOC31 (37.5%), CK7 (33%), GATA3 (33%), CK5 (25%), and PAX8 (11%); and were negative for CD30, Napsin A, OCT4, estrogen, androgen, and progesterone receptors. 29 (41%) of the 70 group-2 cases expressed at least one of the 3 markers, and 96% of the positive cases was a high-grade histotype. Glypican-3, SALL4, and AFP were positive in 30, 20, and 2.8% of group-2 cases respectively; however, co-expression of any 2, or all 3 markers was uncommon (<9 and 1.4% of cases respectively). Potential yolk sac tumor-like morphology was identified in 5 (0.8%) of 626 group-3 cases, and three were ultimately deemed to be true yolk sac tumor phenotypes based on their morphologic and immunophenotypic similarity to the group 1 cases. These findings highlight the broad immunophenotypic spectrum of uterine yolk sac tumors, the potential pitfalls associated with using immunophenotypes alone to define yolk sac tumor differentiation in endometrial carcinoma, and the utility and limitations of morphologic assessment to identify yolk sac tumors at this site.

Novel PLAG1 Gene Rearrangement Distinguishes a Subset of Uterine Myxoid Leiomyosarcoma From Other Uterine Myxoid Mesenchymal Tumors.

Genetic alterations in uterine myxoid leiomyosarcoma are unknown. We investigate the clinicopathologic features of 19 uterine tumors previously diagnosed as myxoid leiomyosarcomas in which tumoral RNA was subjected to targeted RNA sequencing. PLAG1, BCOR, BCORL1, HMGA2, and ALK break-apart fluorescence in situ hybridization (FISH) and BCOR, PLAG1, and ALK immunohistochemistry were performed in cases which failed or lacked fusions by sequencing. The diagnosis of myxoid leiomyosarcoma was confirmed in 15 cases after exclusion of 4 tumors with BCOR and ALK rearrangements. These 15 patients presented at a median age of 50 years with stage I (3), II (2), III (2), and IV (1) tumors, respectively; stage was unknown in 7 cases. Tumor size ranged from 10 to 24 cm. Matrix was myxoid in all tumors and also eosinophilic in 2. Cells were spindled, epithelioid, and both in 10, 2, and 3 tumors and showed mild, moderate, and severe nuclear atypia in 3, 8, and 4 tumors, respectively. Mitotic index ranged from <1 to 14/10 HPF, while tumor necrosis was present in 6 (40%). Novel TRPS1-PLAG1 or RAD51B-PLAG1 fusions were detected by sequencing in 4 tumors, 3 of which were also confirmed by FISH. Diffuse PLAG1 expression was seen in 7 tumors, including 4 with PLAG1 rearrangement. No morphologic differences were seen among PLAG1 fusion-positive and fusion-negative tumors. No PLAG1, HMGA2, ALK, BCOR, or BCORL1 rearrangements were detected by FISH in 11 tumors. On the basis of sequencing and FISH results, PLAG1 rearrangements resulting in PLAG1 expression underpin ~25% of myxoid leiomyosarcomas and may serve as a useful diagnostic biomarker. Immunohistochemistry, targeted RNA sequencing, and/or FISH may distinguish myxoid leiomyosarcoma from its morphologic mimics.

Genomic profiling identifies GPC5 amplification in association with sarcomatous transformation in a subset of uterine carcinosarcomas.

Uterine carcinosarcoma, also known as Malignant Mixed Müllerian Tumour, is a high-grade biphasic neoplasm composed of sarcomatous elements thought to originate via transdifferentiation from high-grade endometrial carcinoma. To identify molecular factors contributing to the histogenesis of this tumour, we analyzed DNA extracted from matched carcinoma and sarcoma components from 12 cases of carcinosarcoma by a molecular inversion probe microarray to assess genomic copy number alterations (CNAs) and allelic imbalances. Widespread CNAs were identified in tumours with serous histology in the carcinoma component (9/12), while the remaining three cases with endometrioid carcinoma were near-diploid. Quantification of the extent of genomic aberrations revealed a significant increase in sarcoma relative to carcinoma in tumours with well-delineated histologic components. Focal amplification of 13q31.3 was identified in 6/12 profiled tumours, of which four harboured the aberration exclusively in the sarcoma component. This result was verified by fluorescence in situ hybridization against GPC5, the only gene situated within the minimal region of amplification. In a validation cohort composed of 97 carcinosarcomas and other uterine sarcomas, amplification of GPC5 (GPC5/CEP13 ratio ≥ 2.2) was identified in 11/97 (11.3%) cases (9/64 carcinosarcoma, 1/3 rhabdomyosarcoma, 1/21 leiomyosarcoma, 0/8 adenosarcoma, 0/1 undifferentiated endometrial sarcoma) and an additional 4 (2.8%) cases had low level gains (GPC5/CEP13 ratio ≥1.5 but <2.2). The functional relevance of Glypican-5, the gene product of GPC5, in regulating differentiation and lineage commitment was demonstrated in an endometrial carcinoma cell line in vitro. In conclusion, we identified GPC5 amplification as a molecular event mediating epithelial-mesenchymal transdifferentiation in a subset of uterine carcinosarcomas.

Hereditary Breast and Ovarian Cancer Syndrome: Moving Beyond BRCA1 and BRCA2.

The recent implementation of next generation sequencing and multigene platforms has expanded the spectrum of hereditary breast and ovarian cancer syndrome, beyond the traditional genes BRCA1 and BRCA2. A large number of other moderate penetrance genes have now been uncovered, which also play critical roles in repairing double stranded DNA breaks through the homologous recombination pathway. This review discusses the landmark discoveries of BRCA1 and BRCA2, the homologous repair pathway and new genes discovered in hereditary breast and ovarian cancer syndrome, as well as their clinicopathologic significance and implications for genetic testing. It also highlights the new role of PARP inhibitors in the context of synthetic lethality and prophylactic surgical options.

ZC3H7B-BCOR high-grade endometrial stromal sarcomas: a report of 17 cases of a newly defined entity.

High-grade endometrial stromal sarcoma likely encompasses underrecognized tumors harboring genetic abnormalities besides YWHAE-NUTM2 fusion. Triggered by three initial endometrial stromal sarcomas with ZC3H7B-BCOR fusion characterized by high-grade morphology and aggressive clinical behavior, we herein investigate the clinicopathologic features of this genetic subset by expanding the analysis to 17 such tumors. All of them occurred in adult women with a median age of 54 (range, 28-71) years. They were predominantly based in the endomyometrium and demonstrated tongue-like and/or pushing myometrial invasion. Most were uniformly cellular and displayed haphazard fascicles of spindle cells with mild to moderate nuclear atypia. Myxoid matrix was seen in 14 of 17 (82%) tumors, and collagen plaques were seen in 8 (47%). The mitotic index was ≥10 mitotic figures/10 high-power fields (HPFs) in 14 of 17 (82%) tumors with a median of 14.5 mitotic figures/10 HPFs. No foci of conventional or variant low-grade endometrial stromal sarcoma were seen. All tumors expressed CD10 with only limited or absent desmin, SMA and/or h-caldesmon staining. ER and PR expression in >5% of cells was seen in 4 of 12 (33%) tumors. Diffuse cyclin D1 and BCOR immunoreactivity was present in 7 of 8 (88%) and 7 of 14 (50%) tumors, respectively. Fluorescence in situ hybridization or targeted RNA sequencing confirmed ZC3H7B-BCOR fusion in all tumors, including four and two previously diagnosed as myxoid leiomyosarcoma and undifferentiated uterine sarcoma, respectively. Limited clinical data suggest that patients present at higher stage and have worse prognosis compared with published outcomes in low-grade endometrial stromal sarcoma. Tumors with ZC3H7B-BCOR fusion constitute a distinct group of endometrial stromal sarcomas with high-grade morphology that should be distinguished from other uterine mesenchymal neoplasms that may demonstrate myxoid morphology.

Undifferentiated Endometrial Carcinomas Show Frequent Loss of Core Switch/Sucrose Nonfermentable Complex Proteins.

Undifferentiated endometrial carcinoma is an aggressive type of endometrial carcinoma that typically presents with advanced stage disease and rapid clinical progression. In contrast to dedifferentiated endometrial carcinoma, undifferentiated carcinoma lacks a concurrent differentiated (typically low-grade endometrioid) carcinoma component, though the undifferentiated component of dedifferentiated carcinoma is similar histologically and immunophenotypically to pure undifferentiated carcinoma. We recently identified 3 mutually exclusive mechanisms of switch/sucrose nonfermentable (SWI/SNF) complex inactivation (BRG1 inactivation, INI1 inactivation or ARID1A/ARID1B co-inactivation) that are associated with histologic dedifferentiation in the majority of dedifferentiated endometrial carcinoma. In the current study, we aimed to determine by immunohistochemistry whether these patterns of SWI/SNF inactivation also occur in undifferentiated endometrial carcinomas. Of the 34 undifferentiated carcinomas examined, 17 (50%) exhibited SWI/SNF complex inactivation, with 11 tumors showing complete loss of both ARID1A and ARID1B, 5 showing complete loss of BRG1 and 1 showing complete loss of INI1. Ten of the remaining 17 undifferentiated carcinomas showed the following alterations: 5 tumors (15%) showed loss of ARID1A only with intact ARID1B, BRG1, and INI1 expression, 4 tumors (12%) showed mutated patterns of p53 staining with intact SWI/SNF protein expression, and 1 tumor (3%) harbored a POLE exonuclease domain mutation (P286R). SWI/SNF complex-inactivated tumors presented more frequently with extrauterine disease spread than those with intact expression (88% vs. 41%, respectively). In addition, patients with SWI/SNF complex-inactivated tumors had a significantly worse disease-specific survival (P=0.02). The findings here demonstrate frequent SWI/SNF complex inactivation in undifferentiated endometrial carcinomas, which has future implications regarding therapies that target chromatin remodelling and epigenetic control.

Clear cell and endometrioid carcinomas: are their differences attributable to distinct cells of origin?

Endometrial epithelium is the presumed tissue of origin for both eutopic and endometriosis-derived clear cell and endometrioid carcinomas. We had previously hypothesized that the morphological, biological and clinical differences between these carcinomas are due to histotype-specific mutations. Although some mutations and genomic landscape features are more likely to be found in one of these histotypes, we were not able to identify a single class of mutations that was exclusively present in one histotype and not the other. This lack of genomic differences led us to an alternative hypothesis that these cancers could arise from distinct cells of origin within endometrial tissue, and that it is the cellular context that accounts for their differences. In a proteomic screen, we identified cystathionine γ-lyase (CTH) as a marker for clear cell carcinoma, as it is expressed at high levels in clear cell carcinomas of the ovary and endometrium. In the current study, we analysed normal Müllerian tissues, and found that CTH is expressed in ciliated cells of endometrium (both eutopic endometrium and endometriosis) and fallopian tubes. We then demonstrated that other ciliated cell markers are expressed in clear cell carcinomas, whereas endometrial secretory cell markers are expressed in endometrioid carcinomas. The same differential staining of secretory and ciliated cells was demonstrable in a three-dimensional organoid culture system, in which stem cells were stimulated to differentiate into an admixture of secretory and ciliated cells. These data suggest that endometrioid carcinomas are derived from cells of the secretory cell lineage, whereas clear cell carcinomas are derived from, or have similarities to, cells of the ciliated cell lineage. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

miR-200c-driven Mesenchymal-To-Epithelial Transition is a Therapeutic Target in Uterine Carcinosarcomas.

Uterine carcinosarcomas (UCSs) are highly aggressive malignancies associated with poor prognoses and limited treatment options. These tumors are hypothesized to develop from the endometrial adenocarcinoma (EAC) through epithelial-mesenchymal transition (EMT). We test this long-standing hypothesis by depleting miR-200, a family of microRNAs critical for EMT, in EAC cell lines. Our data suggest that UCSs do not develop from EACs via EMT. Clinically more relevant, we show that miR-200 expression in UCS cells induces a robust mesenchymal-epithelial transition (MET). Using in vitro and murine xenograft models, we demonstrate decreased growth and aggressiveness of miR-200-overexpressing UCS cell lines. Whole transcriptome analysis confirmed changes consistent with an MET and also revealed changes in angiogenic genes expression. Finally, by treatment of UCS-xenografted mice with miR-200c incorporated in DOPC nanoliposomes, we demonstrate anti-tumor activities. These findings suggest that ectopic miR-200 expression using advanced microRNA therapeutics may be a potential treatment approach for patients with UCS.

BCOR is a robust diagnostic immunohistochemical marker of genetically diverse high-grade endometrial stromal sarcoma, including tumors exhibiting variant morphology.

Recognition of high-grade endometrial stromal sarcoma is important because of its aggressive clinical behavior. Morphologic features of YWHAE-NUTM2 high-grade endometrial stromal sarcoma may overlap with other uterine sarcoma types. BCOR immunoexpression was studied in these tumors and their morphologic mimics to assess its diagnostic utility. BCOR immunohistochemical staining was performed on archival tissue from 28 high-grade endometrial stromal sarcomas with classic morphology (20 YWHAE-NUTM2, 5 ZC3H7B-BCOR, 3 BCOR-ZC3H7B), 3 high-grade endometrial stromal sarcomas with unusual morphology and unknown gene rearrangement status, 66 low-grade endometrial stromal sarcomas, 21 endometrial stromal nodules, 38 uterine leiomyosarcomas, and 19 uterine leiomyomas. Intensity of nuclear staining and percentage of positive tumor cells were recorded. Strong diffuse nuclear BCOR staining (defined as >95% of tumor cells) was seen in the round cell component of all 20 (100%) classic YWHAE-NUTM2 high-grade endometrial stromal sarcomas and the 3 unusual high-grade endometrial stromal sarcomas which prompted FISH studies confirming YWHAE rearrangement in 2 tumors. Genomic PCR confirmed the presence of BCOR exon 16 internal tandem duplication in the third case. Diffuse BCOR staining was strong in three and weak in one BCOR-rearranged high-grade endometrial stromal sarcoma while absent in the remaining four BCOR-rearranged tumors. BCOR staining was weakly positive in <5% of tumor cells in 4 of 66 (6%) low-grade endometrial stromal sarcomas and 1 of 18 (6%) endometrial stromal nodules and weakly to moderately positive in <5-40% of tumor cells in 6 of 31 (19%) leiomyosarcomas. No BCOR staining was seen in the remaining low-grade endometrial stromal sarcomas, endometrial stromal nodules, leiomyosarcomas, or any of the leiomyomas. BCOR immunohistochemical staining is a highly sensitive marker for YWHAE-NUTM2 high-grade endometrial stromal sarcoma with both classic and unusual morphology and identifies a subset of high-grade endometrial stromal sarcoma with BCOR alterations, including BCOR rearrangement and internal tandem duplication.

Mediators of socioeconomic differences in adiposity among youth: a systematic review.

BACKGROUND: Youth with a low socioeconomic position in developed countries are at a disproportionately higher risk of being overweight or obese than their counterparts. Tackling these inequalities requires that the mechanisms behind them are well understood. OBJECTIVES: The aim of this review was to summarize existing evidence regarding the factors that mediate or contribute to the explanation of the relationship between socioeconomic position and adiposity among youth. METHODS AND RESULTS: A systematic literature search, conducted using the databases Medline, Embase, Web of Science and PsycINFO, yielded 28 eligible studies. These studies were of low to moderate methodological quality. The most consistent mediators of the association between socioeconomic position and adiposity identified in this review were as follows: consumption of sugar-sweetened beverages, television viewing, computer use, parental body mass index, breastfeeding duration, breakfast consumption, maternal smoking during pregnancy and infant feeding practices. The mediating role of physical activity as well as fruit and vegetable consumption was found to be indeterminate. Other potential mediators were explored in too few studies to make conclusions about their mediating role. CONCLUSION: The review found several modifiable factors that could be targeted as feasible in interventions aimed at reducing socioeconomic differences in overweight and obesity among youth.

Frequent Mismatch Repair Protein Deficiency in Mixed Endometrioid and Clear Cell Carcinoma of the Endometrium.

Mixed endometrioid and clear cell carcinoma of the endometrium refers to a scenario in which the tumor exhibits histologic features of both endometrioid and clear cell carcinoma. We observed a tendency for these tumors to occur in a mismatch repair (MMR) protein-deficient molecular background in a prior study that examined a small cohort of mixed-type endometrial carcinomas. The aim of this study was to determine the rate of MMR protein deficiency in a larger series of endometrial mixed endometrioid and clear cell carcinomas, through a retrospective survey of MLH1, PMS2, MSH2, and MSH6 expression in such tumors at 5 tertiary centers. A total of 41 cases were identified and 27 (66%) tumors demonstrated MMR protein deficiency with a comparable frequency across the contributing centers (ranging from 56% to 83%). Among the MMR protein-deficient cases, 59% showed concurrent MLH1 and PMS2 loss, 33% showed concurrent MSH2 and MSH6 loss, and 4% showed isolated PMS2 or MSH6 loss. Compared with a previously published series of 15 pure endometrial clear cell carcinomas, mixed endometrioid and clear cell carcinomas are associated with significantly better disease-specific survival (P=0.02). In summary, endometrial carcinomas with mixed endometrioid and clear cell histology are frequently MMR protein deficient. This finding has implications both for our understanding of its tumor biology and for the identification of patients with potential Lynch syndrome.

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.