Extragonadal germ cell tumors: A clinicopathologic study with emphasis on molecular features, clinical outcomes and associated secondary malignancies.

Extragonadal germ cell tumors (EGCTs) are rare, representing <5% of all germ cell tumors (GCTs). Whilst EGCTs share morphological and immunohistochemical features with their gonadal counterparts, they tend to be more aggressive and are frequently associated with secondary somatic malignancies. The aim of our study was to evaluate the clinical, morphological and immunohistochemical features, and to analyze tumors for chromosomal abnormalities of 12p, in addition to any novel genetic alterations, in a series of EGCTs. Seventy-seven EGCTs were included. Anterior mediastinum was the most common anatomic site, followed by central nervous system, retroperitoneum, sacroccygeal area, and neck. Whole genome SNP array identified isochromosome 12p in 26% of tumors. Additional cytogenetic abnormalities included the presence of gain of chr 21 in 37% of tumors. Somatic-type malignancies were identified in 8% of patients. Disease progression (metastasis and/or recurrence) was documented in 8 patients, most of whom died from their relapse. Three patients who died of disease had somatic-type malignancies. Mediastinal seminomas had a significantly better overall survival when compared to mediastinal non-seminomatous GCTs. Our study demonstrates that EGCTs share similar histologic features, but diverse clinical outcomes compared to their gonadal counterparts. Outcomes vary according to anatomic location and histologic subtypes. Our data corroborate that somatic-type malignancies are frequently encountered in mediastinal EGCTs and that their presence portends a poorer prognosis.

Diagnostic Approach to and Differential Diagnosis of Clear Cell and Glandular Lesions of the Lower Urinary Tract.

CONTEXT.­: A variety of glandular and clear cell lesions may be seen in the urinary bladder and/or urethra, ranging from benign to malignant primary and secondary tumors. Lesions with no malignant potential include reactive processes, such as nephrogenic metaplasia, and may show similar morphologic features as an infiltrative neoplasm, particularly in small biopsies. Similarly, ectopic tissues of Müllerian origin may be seen in the lower urinary tract, and their distinction from a true glandular neoplasm is essential to avoid overtreatment. A wide variety of primary and secondary malignant tumors exist with varying degrees of glandular and clear cell features. Therefore, surgical pathologists must be aware of the full scope of possible lesions to avoid misdiagnosis. OBJECTIVE.­: To provide a practical framework for approaching the diagnosis of clear cell and glandular lesions of the urinary bladder/urethra and prostate, highlighting the strengths and limitations of various diagnostic features and ancillary tests. DATA SOURCES.­: A review of the current literature was performed to obtain data regarding up-to-date diagnostic features and ancillary studies. CONCLUSIONS.­: In summary, distinct morphologic and immunohistochemical features and clinical and radiologic correlation are essential to establish an accurate diagnosis when such cases with glandular and clear features are encountered in the lower urinary tract.

Molecular characterization of large cell calcifying sertoli cell tumors: A multi-institutional study of 6 benign and 2 malignant tumors.

Large cell calcifying Sertoli cell tumors (LCCSCTs) are rare testicular tumors, representing <1 % of all testicular neoplasms. Almost 40 % of patients with LCCSCTs will present in the context of the inherited tumor predisposition syndrome, the Carney complex. While most LCCSCTs are benign, 10-20 % have malignant behavior. The aim of our study was to analyze LCCSCTs for novel molecular alterations in addition to PRKAR1A mutations and to identify potential drivers for malignant progression. Eight LCCSCTs diagnosed at two institutions were included. Two patients had the Carney complex confirmed on subsequent genetic testing, and two tumors had several adverse pathological findings. One patient presented with metastatic disease at the time of initial diagnosis. Targeted next-generation sequencing detected PRKAR1A alterations in all cases, with heterozygous PRKAR1A mutations in 5 tumors, germline Carney-complex-associated PRKAR1A mutation in 2 patients, and PRKAR1A fusion in 1 tumor. Additionally, sequencing the metastatic case identified CDKN1B and TERT promoter gene mutations. All tumors showed a low tumoral mutational burden and unremarkable copy number alterations except for frequent LOH of 17q24 encompassing the PRKAR1A locus. RNA expression analysis showed increased expression of several markers including novel PRUNE2, and usual markers like inhibin and calretinin. Our study showed that while LCCSCTs have been reported in the setting of cancer predisposition syndromes, the majority of these tumors occur sporadically. PRKAR1A alterations were present in all cases and appear to be the major driver in LCCSCTs. It remains to be determined whether malignant progression may be caused by additional driver mutations.

A rare entity: Ganglioneuroma of the prostate.

Ganglioneuromas are benign tumors arising from the neural crest. Histologically, they are composed of mature Schwann cells and ganglion cells admixed with fibrous tissue. While they frequently are seen in the abdomen and mediastinum, rare reports have highlighted their occurrences in the genitourinary system. The only prior reported prostatic ganglioneuroma arose in a patient with a history of neurofibromatosis type 1. In this report, we highlight the first reported prostatic ganglioneuroma without a known genetic linkage.

Conventional chondrosarcoma of the rib cage and sternum: clinicopathological and molecular analysis of 27 patients treated at a single institution.

Conventional chondrosarcoma of the chest wall is rare, accounting for 15% of cases. Our purpose was to document clinicopathological, imaging and outcome results from a novel set of chest wall chondrosarcomas, and to analyze for IDH mutations and novel molecular alterations. Gross and microscopic pathology, imaging and clinical charts were reviewed. Targeted next-generation sequencing was performed to identify somatic mutations and copy number alterations. The cohort consisted of 27 patients: 16 men and 11 women (mean age 51 years; range 23-76). Palpable mass was the most common presentation. Five were discovered incidentally. Among 20 tumors with complete imaging, 15 arose from a rib and 5 from the sternum. Seven rib tumors were central/intramedullary, 5 were periosteal, 2 were secondary peripheral chondrosarcomas, and one was indeterminate. Among sternal tumors, 4 were central/intramedullary and one was periosteal. Half the periosteal tumors arose from the costochondral junctional cartilage (CCJ). Periosteal chondrosarcomas were sometimes mistaken for extraskeletal masses on initial clinical or radiological examinations. Fifty-nine percent of all tumors were grade 1 and 41% were grade 2. None were dedifferentiated chondrosarcomas. Heterozygous IDH1 mutation was detected in one tumor and heterozygous RAD50 mutation in another. Local recurrence(s) happened in 41% and metastasis in 41%. Grade had strong association with local recurrence (25% grade 1 vs. 64% grade 2 [P = .0447]), metastatic recurrence (19% grade 1 vs. 73% grade 2 [P = .0058]), and survival. Although chest wall chondrosarcomas share morphologic and molecular features with other chondrosarcomas, there is a much higher incidence of periosteal chondrosarcomas. IDH mutant tumors are uncommon. Early diagnosis and margin-negative resection is treatment of choice since chondrosarcomas are chemo- and radioresistant.

Reprint of: de novo neuroendocrine features in prostate cancer.

Neuroendocrine tumors of the prostate are rare and encompass a group of entities that are classified based on a combination of morphological and immunohistochemical features. Despite the 2016 World Health Organization classification of prostatic neuroendocrine tumors, variants have been reported that do not fit well in the categorization scheme. While the majority of these tumors arise in the setting of castration-resistant prostate cancer (postandrogen deprivation therapy), de novo cases may occur. In this review, we highlight the most significant pathological and immunohistochemical features, emerging biomarkers, and molecular features of such tumors.

Extraskeletal Myxoid Chondrosarcoma: Retrospective Case Series Examining Prognostic Factors, Treatment Approaches, and Oncologic Outcomes.

OBJECTIVES: Extraskeletal myxoid chondrosarcoma (EMC) is an ultrarare soft tissue sarcoma, and a limited number of studies are published regarding its clinical course and efficacy of treatment. The goal of this retrospective case series is to explore patient characteristics, treatment approaches, and oncologic outcomes to help inform future EMC management. METHODS: All patients with a diagnosis of EMC seen at the University of Michigan Sarcoma Center between 1998 and 2021 were identified. A chart review was performed to analyze demographics, tumor characteristics, treatments, and outcomes. RESULTS: Forty-four patients with EMC were identified. The median follow-up was 49.8 months. The median age at diagnosis was 57 (range: 25 to 79), and 35 patients (80%) were male. Thirty-four patients (77%) had locoregional disease at diagnosis, and 26 patients (59%) ultimately developed metastatic disease. After locoregional curative-intent surgery, 15 patients had documented recurrence, of which 11 were metastatic (73%). Five-year overall survival was 79% for all patients, 86% for locoregional disease, and 58% for metastatic disease; for locoregional disease, 5-year disease-free and metastasis-free survival post-surgery were 43% and 53%, respectively; 1-year progression-free survival for metastatic disease from the start of first-line systemic therapy was 43%. Older age was the only factor statistically associated with improved prognosis, although perioperative radiotherapy, lower histologic grade, and negative margins also had directional associations with outcomes. CONCLUSIONS: The data in this patient series are generally consistent with published literature on EMC and demonstrate a high recurrence rate, high propensity for metastasis, and high rate of progression of metastatic disease on systemic therapy.

Molecular testing of soft tissue tumors.

BACKGROUND: The diagnosis of soft tissue tumors is challenging, especially when the evaluable material procured is limited. As a result, diagnostic ancillary testing is frequently needed. Moreover, there is a trend in soft tissue pathology toward increasing use of molecular results for tumor classification and prognostication. Hence, diagnosing newer tumor entities such as CIC-rearranged sarcoma explicitly requires molecular testing. Molecular testing can be accomplished by in situ hybridization, polymerase chain reaction, as well as next generation sequencing, and more recently such testing can even be accomplished leveraging an immunohistochemical proxy. CONCLUSION: This review evaluates the role of different molecular tests in characterizing soft tissue tumors belonging to various cytomorphologic categories that have been sampled by small biopsy and cytologic techniques.

Deciphering intratumor heterogeneity in clear cell renal cell carcinoma utilizing clinicopathologic and molecular platforms.

Clear cell renal cell carcinoma (CCRCC) is a common renal malignancy known for its lethality and chromosome 3p aberrancies associated with loss of VHL. It has been shown that additional prognostic molecular markers exist in other transcriptional modifiers such as BAP1 and SETD2. Molecular heterogeneity has been described between primary and metastatic sites as well as genetic diversity in spatial tumor analysis; however, morphologic and proteogenomic heterogeneity information is lacking. We assessed 77 nephrectomy specimens with a diagnosis of CCRCC for morphologic architectural patterns including nodular growth patterns and variations in WHO/ISUP grade. Evaluation of highly heterogeneous areas with immunohistochemical (IHC) staining for BAP1, UCHL1, SETD2, and CAIX was performed and correlated with morphologic and histology data. Ultimately, high variability in the morphologic and histological findings matched the complexity of the IHC findings. Alterations in expression of CAIX and UCHL1 correlated with alterations in transcriptional regulators BAP1 and SETD2 within the tumor. High-grade morphology, such as eosinophilia, were areas enriched for alteration of biomarker expression. This highly complex data set of morphologic and biomarker characteristics highlights the heterogeneity of morphology amongst high-grade CCRCC tumors.

De novo neuroendocrine features in prostate cancer.

Neuroendocrine tumors of the prostate are rare and encompass a group of entities that are classified based on a combination of morphological and immunohistochemical features. Despite the 2016 World Health Organization classification of prostatic neuroendocrine tumors, variants have been reported that do not fit well in the categorization scheme. While the majority of these tumors arise in the setting of castration-resistant prostate cancer (postandrogen deprivation therapy), de novo cases may occur. In this review, we highlight the most significant pathological and immunohistochemical features, emerging biomarkers, and molecular features of such tumors.

p53 null phenotype is a "positive result" in urothelial carcinoma in situ.

The concept of a "p53 null phenotype" (complete loss of staining) is well-recognized in the gynecologic pathology literature, implicitly reflecting that this staining pattern represents a TP53 mutation. However, in the genitourinary pathology literature, a p53 null phenotype has only been addressed regarding the prognosis of invasive urothelial carcinoma, and not as a diagnostic biomarker for urothelial carcinoma in situ (CIS). Herein, 25 cases of urothelial carcinoma in situ [diagnoses made on hematoxylin and eosin (H&E) stained sections] showing null pattern p53 staining were retrieved from 22 different patients (16 males and 6 females, age range 52-85 years; average 69.6 years), most commonly showing large cell pleomorphic pattern morphology. One representative tissue block per case was selected for next-generation DNA sequencing (NGS). All 21 cases (100%) passing quality control for NGS showed at least 1 TP53 mutation (majority nonsense or frameshift mutations), including 3 cases with 2 mutations and 3 cases with 3 mutations. Three patients with multiple available samples harbored 1 or more shared TP53 mutations at 2 different time points, indicating clonality of the temporally distinct lesions. Additionally, 2 patients had an additional unique TP53 mutation at a later time point, suggesting intratumoral heterogeneity and/or temporal clonal evolution. While urothelial CIS remains an H&E diagnosis in most cases, a p53 immunostain may be useful in a subset of challenging cases. This study demonstrates that a p53 null phenotype represents an aberrant result in urothelial CIS with supportive molecular analysis showing a previously unknown level of complexity for TP53 mutations among these noninvasive lesions. Adequate recognition of the p53 null phenotype as a "biologically supportive result", similar to strong and diffuse staining with p53, is important and may warrant a formal consensus statement for recommended p53 reporting (i.e., "wild type" versus "aberrant or mutant").

Large Cell Calcifying Sertoli Cell Tumor: A Clinicopathologic Study of 18 Cases With Comprehensive Review of the Literature and Reappraisal of Prognostic Features.

We present a series of 18 (8 clinically benign, 8 clinically ambiguous [ie, lacking sufficient follow-up to determine behavior], and 2 clinically malignant) large cell calcifying Sertoli cell tumors (LCCSCT) of the testis. The median patient age and size were 15.5 years and 1.9 cm for the benign tumors; 19 years and 1.6 cm for the ambiguous tumors; and 28.5 years and 2.3 cm for the malignant tumors. The most common presentation was a mass (n=12/18, 67%). Two patients (11%) had the Carney complex, and 2 had neurofibromatosis type 1. All tumors showed nodular growth with frequent lymphoid aggregates at the periphery. Within the nodules, there were nests and trabeculae of pale to eosinophilic epithelioid tumor cells with frequent cytoplasmic vacuolization interspersed with hypocellular, often myxoid stroma with conspicuous neutrophils. Spindled tumor cells were a minor component (<5%) in the clinically benign, ambiguous, and malignant tumors, except in 1 malignant tumor where they comprised 50% to 60% of the cellularity. Calcifications were noted in all but 2 benign tumors that were otherwise of typical appearance. Six tumors (3 in the clinically benign, 1 in the clinically ambiguous, and 2 in the malignant groups) were considered potentially malignant based on the presence of ≥1 adverse pathologic features previously recognized (see reference 1)-that is, size>4 cm, extratesticular growth, necrosis, significant atypia, vascular invasion, and >3 mitotic figures/10 HPFs. Of these, 3 tumors had ≥2 adverse features. One in a 7-year-old was clinically benign despite 5 "malignant" features; the remaining 2 in 27- and 30-year-olds, were clinically malignant, with both fulfilling previously suggested criteria for pathologically malignant tumors (age above 25 y and ≥2 adverse pathologic features). No clinically benign or ambiguous tumor met those same criteria. Of the adverse features, each of the 2 clinically malignant tumors showed tumor necrosis and lymphovascular invasion. All patients, except 1 with a clinically malignant tumor, were alive at a median follow-up of 33 months. In addition, in our literature review of 97 additional LCCSCTs, we identified 2 clinically malignant tumors in 42- and 45-year-old men that lacked any documented adverse pathologic criterion and 2 clinically malignant cases in patients with either the Carney complex or Peutz-Jeghers syndrome. In summary, our study and literature review support that all LCCSCTs in patients above 25 years old should be considered potentially malignant, and those in this age group with ≥2 adverse pathologic features warrant aggressive clinical management; furthermore, syndrome-associated cases are not uniformly benign. Tumor necrosis and lymphovascular invasion likely should receive greater adverse prognostic weight. LCCSCTs in young children may show benign outcomes despite several adverse pathologic features.

Ovarian cancer modulates the immunosuppressive function of CD11b+Gr1+ myeloid cells via glutamine metabolism.

OBJECTIVE: Immature CD11b + Gr1+ myeloid cells that acquire immunosuppressive capability, also known as myeloid-derived suppressor cells (MDSCs), are a heterogeneous population of cells that regulate immune responses. Our study's objective was to elucidate the role of ovarian cancer microenvironment in regulating the immunosuppressive function of CD11b+Gr1+ myeloid cells. METHODS: All studies were performed using the intraperitoneal ID8 syngeneic epithelial ovarian cancer mouse model. Myeloid cell depletion and immunotherapy were carried out using anti-Gr1 mAb, gemcitabine treatments, and/or anti-PD1 mAb. The treatment effect was assessed by a survival curve, in situ luciferase-guided imaging, and histopathologic evaluation. Adoptive transfer assays were carried out between congenic CD45.2 and CD45.1 mice. Immune surface and intracellular markers were assessed by flow cytometry. ELISA, western blot, and RT-PCR techniques were employed to assess the protein and RNA expression of various markers. Bone marrow-derived myeloid cells were used for ex-vivo studies. RESULTS: The depletion of Gr1+ immunosuppressive myeloid cells alone and in combination with anti-PD1 immunotherapy inhibited ovarian cancer growth. In addition to the adoptive transfer studies, these findings validate the role of immunosuppressive CD11b+Gr1+ myeloid cells in promoting ovarian cancer. Mechanistic investigations showed that ID8 tumor cells and their microenvironments produced recruitment and regulatory factors for immunosuppressive CD11b+Gr1+ myeloid cells. CD11b+Gr1+ myeloid cells primed by ID8 tumors showed increased immunosuppressive marker expression and acquired an energetic metabolic phenotype promoted primarily by increased oxidative phosphorylation fueled by glutamine. Inhibiting the glutamine metabolic pathway reduced the increased oxidative phosphorylation and decreased immunosuppressive markers' expression and function. Dihydrolipoamide succinyl transferase (DLST), a subunit of α-KGDC in the TCA cycle, was found to be the most significantly elevated gene in tumor-primed myeloid cells. The inhibition of DLST reduced oxidative phosphorylation, immunosuppressive marker expression and function in myeloid cells. CONCLUSION: Our study shows that the ovarian cancer microenvironment can regulate the metabolism and function of immunosuppressive CD11b + Gr1+ myeloid cells and modulate its immune microenvironment. Targeting glutamine metabolism via DLST in immunosuppressive myeloid cells decreased their activity, leading to a reduction in the immunosuppressive tumor microenvironment. Thus, targeting glutamine metabolism has the potential to enhance the success of immunotherapy in ovarian cancer.

De novo neuroendocrine transdifferentiation in primary prostate cancer-a phenotype associated with advanced clinico-pathologic features and aggressive outcome.

Neuroendocrine transdifferentiation of high-grade prostate cancer (PCA-NT) comprises a morphologic and immunophenotypic transition from conventional adenocarcinoma towards high-grade neuroendocrine/small cell carcinoma. This phenomenon is frequently observed post androgen deprivation and/or radiotherapy, but de novo instances are increasingly recognized. Herein, we report a series of de novo PCA-NT focusing on characteristic morphologic, immunophenotypic and clinical features. Treatment naïve PCA-NT were identified. IHC for PSA, NKX3.1, Chromogranin, Synaptophysin, Cyclin D1, RB and Ki67 were performed. Radiology, treatment and follow-up data were reviewed. Sixteen patients were included. Apart from focal areas of high-grade prostate cancer with acinar features (reminiscent of Grade Group 5 disease), extensive areas with sheets of cells with deep amphophilic/basophilic cytoplasm, enlarged, hyperchromatic nuclei with granular chromatin and inconspicuous to prominent nucleoli with high mitotic activity were identified. Immunohistochemistry showed patchy NKX3.1, patchy PSA, variable Synaptophysin and Chromogranin; RB and CyclinD1 showed loss of expression. Ki67 showed high proliferative index, in most cases. Adverse radiologic findings and metastases were documented in most cases. Two patients died of disease. De novo PCA-NT exhibits high-grade nuclei, high mitotic activity, reduced PSA expression with high Ki67 and functional inactivation of RB1 pathway, suggesting transition from androgen-driven to proliferation-driven phenotype. Most cases presented at advanced stage with adverse radiological findings, metastasis at time of diagnosis, and high mortality. In light of their prognostic and therapeutic implications, pathologists may need to maintain a sensitive threshold for performing immunostains-in particular, Ki67 and CyclinD1-when presented with such cases in their day to day clinical practice.

Characterization of SARS-CoV-2 and host entry factors distribution in a COVID-19 autopsy series.

Background: SARS-CoV-2 is a highly contagious virus that causes the disease COVID-19. We have recently reported that androgens regulate the expression of SARS-CoV-2 host entry factors ACE2 and TMPRSS2, and androgen receptor (AR) in lung epithelial cells. We also demonstrated that the transcriptional repression of the AR enhanceosome inhibited SARS-CoV-2 infection in vitro. Methods: To better understand the various sites of SARS-CoV-2 infection, and presence of host entry factors, we extensively characterized the tissue distribution and localization of SARS-CoV-2 virus, viral replication, and host entry factors in various anatomical sites sampled via autopsy. We applied RNA in-situ-hybridization (RNA-ISH), immunohistochemistry (IHC) and quantitative reverse transcription polymerase chain reaction (qRT-PCR) approaches. We also assessed histopathological changes in SARS-CoV-2 infected tissues. Results: We detect SARS-CoV-2 virus and viral replication in pulmonary tissues by RNA-ISH and IHC and a variety of non-pulmonary tissues including kidney, heart, liver, spleen, thyroid, lymph node, prostate, uterus, and colon by qRT-PCR. We observe heterogeneity in viral load and viral cytopathic effects among various organ systems, between individuals and within the same patient. In a patient with a history of kidney transplant and under immunosuppressant therapy, we observe an unusually high viral load in lung tissue by RNA-ISH, IHC and qRT-PCR. SARS-CoV-2 virus is also detected in this patent's kidney, liver and uterus. We find ACE2, TMPRSS2 and AR expression to overlap with the infection sites. Conclusions: This study portrays the impact of dispersed SARS-CoV-2 infection in diverse organ systems, thereby facilitating avenues for systematic therapeutic approaches.

Clinicopathological characterisation of renal cell carcinoma in young adults: a contemporary update and review of literature.

AIMS: Renal cell carcinomas are relatively rare in children and young adults. While well characterised in adults, the morphological and molecular characterisation of these tumours in young patients is relatively lacking. The objective of this study was to explore the spectrum of renal cell carcinoma (RCC) subtypes in children and young adults and to determine their clinico-pathological, immunohistochemical and molecular characteristics by evaluating a large retrospective cohort of renal cell carcinoma patients age 30 years or younger. METHODS AND RESULTS: Sixty-eight cases with confirmed diagnosis of renal cell carcinoma at age 30 years or younger were identified at our institution. Clear cell carcinoma accounted for the most common subtype seen in this age group. Translocation renal cell carcinoma and rare familial syndrome subtypes such as succinate dehydrogenase deficient renal cell carcinoma and tuberous sclerosis complex-associated renal cell carcinoma were found relatively more frequently in this cohort. Despite applying the 2016 WHO classification criteria, a high proportion of the tumours in our series remained unclassified. CONCLUSIONS: Our results suggest that renal cell carcinoma in children and young adults is a relatively rare disease that shares many histological similarities to renal cell carcinoma occurring in adults and yet demonstrate some unique clinical-pathological differences. Microphthalmia-associated transcription (MiT) family translocation RCC and rare familial syndrome subtypes are relatively more frequent in the paediatric and adolescent age groups than in adults. Clear cell RCC still accounted for the most common subtype seen in this age group. MiT family translocation RCC patients presented with advanced stage disease and had poor clinical outcomes. The large and heterogeneous subgroup of unclassified renal cell carcinoma contains phenotypically distinct tumours with further potential for future subcategories in the renal cell carcinoma classification.

Molecular classification of endometrial carcinoma applied to endometrial biopsy specimens: Towards early personalized patient management.

BACKGROUND: The current risk stratification systems used to guide management of endometrial cancer are based on irreproducible post surgical pathological information, hence the need for more reliable classification systems. Using microarray and sequencing technologies, TCGA recently identified four prognostically significant endometrial carcinoma subtypes, which subsequently proved reproducible using clinically applicable surrogate tests. Using these tests, we sought to determine the level of concordance between endometrial biopsies and subsequent hysterectomy specimens in assessing the molecular classification of endometrial carcinoma. MATERIALS AND METHODS: Fifty biopsies with corresponding hysterectomy specimens for endometrial carcinomas were collected. Additionally, 10 cases of biopsy proven atypical hyperplasia/EIN who were found to have endometrial carcinoma on resection were included. IHC for mismatch repair (MMR) proteins (MLH1, PMS2, MSH2 and MSH6) and P53 was performed. Microsatellite instability analysis was performed by PCR and Sanger sequencing was performed to detect mutations in exons 9 and 13 of the POLE gene. The level of concordance for tumor grade, histologic subtype, immunohistochemical and molecular profile in both specimens was determined using Cohen's kappa estimates. RESULTS: A high level of concordance was achieved for MMR-loss, MSI-high, P53-wild and abnormal types. In contrast, grade and histologic subtype showed only moderate levels of agreement. POLE gene mutation was detected in two patients. For both cases, mutations were detected only in resection specimens. When comparing atypical hyperplasia/EIN with subsequent hysterectomy tumor, the profile was identical to that of endometrial carcinoma. CONCLUSION: In our cohort of endometrial carcinoma, a high level of concordance was achieved between biopsy and hysterectomy specimens for MMR-loss, MSI-high, P53-wild and abnormal types, superior to that of grade and histologic subtype, providing earlier and more reliable prognostic information to inform management. Similar concordance could not be achieved for POLE mutation, given the low frequency of this mutation in our study.

Predictive Histologic Factors in Carcinosarcomas of the Uterus: A Multi-institutional Study.

Uterine carcinosarcomas are rare aggressive biphasic neoplasms. Because of its rarity, limited data are available on potential prognostic parameters. While several studies support that carcinomatous components predict outcomes, others do not. In this study, we evaluated the clinical and histopathologic features of 196 uterine carcinosarcomas to identify potential prognostic factors. Patients' ages ranged from 34 to 95 yr (median, 68 yr). Seventy-three (38%) patients experienced tumor recurrence during follow-up. Tumors ≥5 cm, outer half myometrial invasion, lymphovascular invasion, lymph node metastasis, advanced stage (International Federation of Gynecology and Obstetrics stages III-IV), sarcomatous component on recurrence, sarcoma dominance, and positive cytology were significantly associated with shorter disease-free interval (P<0.05). In addition, serous histology and rhabdomyoblastic differentiation was significantly associated with worse 3-yr overall survival. Our data supports that both carcinomatous and sarcomatous components play a role in tumor progression and survival of uterine carcinosarcoma patients, suggesting their equal importance in guiding management decisions.