Myoepithelial Tumors of Bone With EWSR1::PBX3 Fusion: A Spectrum From Benign to Malignant.

The EWSR1::PBX3 fusion gene, commonly associated with cutaneous syncytial myoepitheliomas, is also found in myoepithelial tumors (METs) of bone and soft tissue. These tumors typically demonstrate benign histology and favorable outcomes. This study examines 6 previously unreported intraosseous METs harboring the EWSR1::PBX3 fusion, focusing on their histopathologic characteristics, immunophenotype, clinical and radiographic profiles, and patient outcomes. The cohort comprised 5 men and 1 woman, aged 25 to 65 years (median age: 31 years), with tumors located in the proximal tibia (3 cases), distal radius (2 cases), and ilium (1 case) and sizes between 3.2 and 12.2 cm (median size: 3.9 cm). Imaging showed osteolytic lesions with varying degrees of cortical involvement and soft tissue extension in 3 cases. Histologically, 4 tumors showed mainly uniform oval-to-spindled cells in syncytial or fascicular arrangements within a collagenous matrix, displaying either bland nuclear features or mild atypia, and low to slightly elevated mitotic activity (≤1 per 10 high-power fields in 3 cases and 6 per 10 high-power fields in 1), classifying them as benign or atypical METs. In contrast, 2 tumors exhibited pronounced nuclear atypia with ovoid, spindled, epithelioid and round cells, hyperchromatic nuclei, inconspicuous nucleoli, increased N/C ratios, high mitotic rates (17 and 19 per 10 high-power fields), and extensive necrosis. Both tumors behaved aggressively-one patient underwent amputation after neoadjuvant chemotherapy and radiation, and the other died within 7 months with the disease still present. Immunohistochemically, the tumors consistently expressed epithelial membrane antigen and S100 but lacked keratin (AE1/AE3) expression. Our study demonstrated that bone METs with EWSR1::PBX3 fusions encompass a histologic continuum from benign to malignant, with benign/atypical METs mirroring their cutaneous analogs in morphology, and malignant variants distinguished by heterogeneous cytologic and architectural features, pronounced nuclear atypia, and high mitotic rates.

Superficial dedifferentiated liposarcoma: A clinicopathologic study.

INTRODUCTION: Dedifferentiation occurs in approximately 10% of atypical lipomatous tumors/well-differentiated liposarcomas (ALT/WDLPS), primarily in retroperitoneal or deep-seated tumors, conferring metastatic potential. Superficial dedifferentiated liposarcoma (sDDLPS) is rare, and its progression and natural history are poorly documented. METHODS: We performed a 15-year retrospective review of our pathology database to identify cases of DDLPS in the skin or subcutaneous tissue. Diagnosis of primary sDDLPS required evidence of non-lipogenic sarcoma in the skin or subcutis, with concurrent ALT/WDLPS and/or MDM2 amplification. RESULTS: We identified 14 cases of DDLPS involving skin or subcutis: 7 primary sDDLPS and 7 secondary lesions (3 from recurrent deep DDLPS and 4 from metastasis). Primary sDDLPS cases (4 females, 3 males; median age: 74) mainly presented as undifferentiated spindle cell or pleomorphic sarcoma. Tumor grades were grade 2 (5 cases) and grade 3 (2 cases), with three cases also showing grade 1 areas. MDM2 amplification was confirmed in 6 sDDLPSs for which FISH was successfully performed. Follow-up available for 6 sDDLPS patients showed 2 local recurrences, treated with re-excision and radiation therapy, with all disease-free at last follow-up (5-126 months). Of the 7 secondary cases, 2 had ongoing disease after multiple recurrences, 1 was disease-free, and all 4 with cutaneous metastasis died of disease (follow-up range: 24-263 months). CONCLUSION: These findings emphasize the importance of distinguishing between primary sDDLPS and secondary lesions due to their distinct prognoses. Metastasis or superficial extensions from deep DDLP correlate with a considerably worse prognosis than those originating in superficial tissues.

Myoepithelial carcinoma of the parotid gland with a novel CTCF::NCOA2 fusion.

We describe a case of a myoepithelial carcinoma of the superficial parotid gland in a 46-year-old male harboring a novel CTCF::NCOA2 gene fusion. To our knowledge, this novel gene fusion has not been described previously in myoepithelial carcinoma. A 46-year-old male patient presented with a mass involving the superficial left parotid gland with extension into the external auditory canal (EAC) and erosion of the conchal cartilage. Histologically, the neoplasm was composed of uniform spindled, epithelioid/ovoid cells arranged in cords and nests within hyalinized to myxoid stroma. On immunohistochemistry (IHC), the tumor cells demonstrated patchy and variable staining for low molecular weight cytokeratin (CAM5.2), pan-cytokeratin (OSCAR), and S-100. Overall, the morphological and immunohistochemical attributes supported a locally aggressive tumor of myoepithelial differentiation consistent with myoepithelial carcinoma. Molecular analysis using a custom 115-gene gene panel by targeted RNA sequencing, showed an in-frame CTCF::NCOA2 fusion. In addition to reporting this novel fusion in myoepithelial carcinoma, we also discuss relevant differential diagnosis, and provide a brief review of NCOA2 gene function in both normal and neoplastic contexts.

Urothelial Carcinoma: Divergent Differentiation and Morphologic Subtypes.

Urothelial carcinoma (UC) is known to encompass a wide spectrum of morphologic features and molecular alterations. Approximately 15% to 25% of invasive UC exhibits histomorphologic features in the form of "divergent differentiation" along other epithelial lineages, or different "subtypes" of urothelial or sarcomatoid differentiation. It is recommended that the percentage of divergent differentiation and or subtype(s) be reported whenever possible. Recent advances in molecular biology have led to a better understanding of the molecular underpinning of these morphologic variations. In this review, we highlight histologic characteristics of the divergent differentiation and subtypes recognized by the latest version of WHO classification, with updates on their molecular and clinical features.

Droplet Digital PCR (ddPCR) as a Novel Technology in Detecting CTNNB1 Mutations in Desmoid Fibromatosis.

Desmoid fibromatosis (DF) is a locally aggressive soft tissue neoplasm with frequent recurrences. DF is characterized by alterations in the Wnt/ß-catenin pathway, with the majority showing sporadic mutations in CTNNB1 , whereas others have germline mutations in APC . Immunohistochemical staining for ß-catenin is often difficult to interpret and can be negative in up to 30% of cases. Prior studies have shown that some DFs lacking nuclear expression of ß-catenin may carry activating CTNNB1 mutations. Droplet digital polymerase chain reaction (ddPCR) has been used effectively in detecting mutations in formalin-fixed, paraffin-embedded (FFPE) samples of various cancer types. In this study, we assess the diagnostic utility of ddPCR to detect CTNNB1 mutations in DF with ß-catenin expression on immunohistochemistry (IHC), as well as in diagnostically challenging cases. Of the 28 DFs with nuclear ß-catenin expression by IHC, 24 cases showed a CTNNB1 mutation by ddPCR using primers against the most common point mutations in CTNNB1 . The most frequent mutation was T41A (n=14; 50%), followed by S45F (n=8; 33%) and S45P (n=3;12%). We identified 8 additional (myo)fibroblastic lesions of uncertain classification, which were negative for nuclear ß-catenin expression by IHC. We detected CTNNB1 mutations in 3 unknown lesions, including S45F (n=2) and S45P (n=1). ddPCR is a sensitive, rapid and cost-efficient methodology to detect common CTNNB1 mutations in DF, especially in diagnostically challenging cases.

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review (Part 6): Correlation of PD-L1 Expression with the Status of Mismatch Repair System, BRCA, PTEN, and Other Genes.

Pembrolizumab (anti-PD-1) is allowed in selected metastatic castration-resistant prostate cancer (PC) patients showing microsatellite instability/mismatch repair system deficiency (MSI-H/dMMR). BRCA1/2 loss-of-function is linked to hereditary PCs and homologous recombination DNA-repair system deficiency: poly-ADP-ribose-polymerase inhibitors can be administered to BRCA-mutated PC patients. Recently, docetaxel-refractory metastatic castration-resistant PC patients with BRCA1/2 or ATM somatic mutations had higher response rates to pembrolizumab. PTEN regulates cell cycle/proliferation/apoptosis through pathways including the AKT/mTOR, which upregulates PD-L1 expression in PC. Our systematic literature review (PRISMA guidelines) investigated the potential correlations between PD-L1 and MMR/MSI/BRCA/PTEN statuses in PC, discussing few other relevant genes. Excluding selection biases, 74/677 (11%) PCs showed dMMR/MSI; 8/67 (12%) of dMMR/MSI cases were PD-L1+. dMMR-PCs included ductal (3%) and acinar (14%) PCs (all cases tested for MSI were acinar-PCs). In total, 15/39 (39%) PCs harbored BRCA1/2 aberrations: limited data are available for PD-L1 expression in these patients. 13/137 (10%) PTEN- PCs were PD-L1+; 10/29 (35%) PD-L1+ PCs showed PTEN negativity. SPOP mutations may increase PD-L1 levels, while the potential correlation between PD-L1 and ERG expression in PC should be clarified. Further research should verify how the efficacy of PD-1 inhibitors in metastatic castration-resistant PCs is related to dMMR/MSI, DNA-damage repair genes defects, or PD-L1 expression.

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 7: PD-L1 Expression in Liquid Biopsy.

Liquid biopsy is an accessible, non-invasive diagnostic tool for advanced prostate cancer (PC) patients, potentially representing a real-time monitoring test for tumor evolution and response to treatment through the analysis of circulating tumor cells (CTCs) and exosomes. We performed a systematic literature review (PRISMA guidelines) to describe the current knowledge about PD-L1 expression in liquid biopsies of PC patients: 101/159 (64%) cases revealed a variable number of PD-L1+ CTCs. Outcome correlations should be investigated in larger series. Nuclear PD-L1 expression by CTCs was occasionally associated with worse prognosis. Treatment (abiraterone, enzalutamide, radiotherapy, checkpoint-inhibitors) influenced PD-L1+ CTC levels. Discordance in PD-L1 status was detected between primary vs. metastatic PC tissue biopsies and CTCs vs. corresponding tumor tissues. PD-L1 is also released by PC cells through soluble exosomes, which could inhibit the T cell function, causing immune evasion. PD-L1+ PC-CTC monitoring and genomic profiling may better characterize the ongoing aggressive PC forms compared to PD-L1 evaluation on primary tumor biopsies/prostatectomy specimens (sometimes sampled a long time before recurrence/progression). Myeloid-derived suppressor cells and dendritic cells (DCs), which may have immune-suppressive effects in tumor microenvironment, have been found in PC patients circulation, sometimes expressing PD-L1. Occasionally, their levels correlated to clinical outcome. Enzalutamide-progressing castration-resistant PC patients revealed increased PD-1+ T cells and circulating PD-L1/2+ DCs.

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 2: Clinic-Pathologic Correlations.

Many studies have investigated the potential prognostic and predictive role of PD-L1 in prostatic carcinoma (PC). We performed a systematic literature review (PRISMA guidelines) to critically evaluate human tissue-based studies (immunohistochemistry, molecular analysis, etc.), experimental research (cell lines, mouse models), and clinical trials. Despite some controversial results and study limitations, PD-L1 expression by tumor cells may be related to clinic-pathologic features of adverse outcome, including advanced tumor stage (high pT, presence of lymph node, and distant metastases), positivity of surgical margins, high Grade Group, and castration resistance. Different PD-L1 positivity rates may be observed in matched primary PCs and various metastatic sites of the same patients. Over-fixation, type/duration of decalcification, and PD-L1 antibody clone may influence the immunohistochemical analysis of PD-L1 on bone metastases. PD-L1 seemed expressed more frequently by castration-resistant PCs (49%) as compared to hormone-sensitive PCs (17%). Some series found that PD-L1 positivity was associated with decreased time to castration resistance. Treatment with ipilimumab, cyclophosphamide/GVAX/degarelix, or degarelix alone may increase PD-L1 expression. Correlation of PD-L1 positivity with overall survival and outcomes related to tumor recurrence were rarely investigated; the few analyzed series produced conflicting results and sometimes showed limitations. Further studies are required. The testing and scoring of PD-L1 should be standardized.

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 1: Focus on Immunohistochemical Results with Discussion of Pre-Analytical and Interpretation Variables.

Immunotherapy targeting the PD-1-PD-L1 axis yielded good results in treating different immunologically ''hot'' tumors. A phase II study revealed good therapeutic activity of pembrolizumab in selected prostatic carcinoma (PC)-patients. We performed a systematic literature review (PRISMA guidelines), which analyzes the immunohistochemical expression of PD-L1 in human PC samples and highlights the pre-analytical and interpretation variables. Interestingly, 29% acinar PCs, 7% ductal PCs, and 46% neuroendocrine carcinomas/tumors were PD-L1+ on immunohistochemistry. Different scoring methods or cut-off criteria were applied on variable specimen-types, evaluating tumors showing different clinic-pathologic features. The positivity rate of different PD-L1 antibody clones in tumor cells ranged from 3% (SP142) to 50% (ABM4E54), excluding the single case tested for RM-320. The most tested clone was E1L3N, followed by 22C3 (most used for pembrolizumab eligibility), SP263, SP142, and 28-8, which gave the positivity rates of 35%, 11-41% (depending on different scoring systems), 6%, 3%, and 15%, respectively. Other clones were tested in <200 cases. The PD-L1 positivity rate was usually higher in tumors than benign tissues. It was higher in non-tissue microarray specimens (41-50% vs. 15%), as PC cells frequently showed heterogenous or focal PD-L1-staining. PD-L1 was expressed by immune or stromal cells in 12% and 69% cases, respectively. Tumor heterogeneity, inter-institutional preanalytics, and inter-observer interpretation variability may account for result biases.

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 4: Experimental Treatments in Pre-Clinical Studies (Cell Lines and Mouse Models).

In prostate cancer (PC), the PD-1/PD-L1 axis regulates various signaling pathways and it is influenced by extracellular factors. Pre-clinical experimental studies investigating the effects of various treatments (alone or combined) may discover how to overcome the immunotherapy-resistance in PC-patients. We performed a systematic literature review (PRISMA guidelines) to delineate the landscape of pre-clinical studies (including cell lines and mouse models) that tested treatments with effects on PD-L1 signaling in PC. NF-kB, MEK, JAK, or STAT inhibitors on human/mouse, primary/metastatic PC-cell lines variably down-modulated PD-L1-expression, reducing chemoresistance and tumor cell migration. If PC-cells were co-cultured with NK, CD8+ T-cells or CAR-T cells, the immune cell cytotoxicity increased when PD-L1 was downregulated (opposite effects for PD-L1 upregulation). In mouse models, radiotherapy, CDK4/6-inhibitors, and RB deletion induced PD-L1-upregulation, causing PC-immune-evasion. Epigenetic drugs may reduce PD-L1 expression. In some PC experimental models, blocking only the PD-1/PD-L1 pathway had limited efficacy in reducing the tumor growth. Anti-tumor effects could be increased by combining the PD-1/PD-L1 blockade with other approaches (inhibitors of tyrosine kinase, PI3K/mTOR or JAK/STAT3 pathways, p300/CBP; anti-RANKL and/or anti-CTLA-4 antibodies; cytokines; nitroxoline; DNA/cell vaccines; radiotherapy/Radium-223).

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 5: Epigenetic Regulation of PD-L1.

Epigenetic alterations (including DNA methylation or miRNAs) influence oncogene/oncosuppressor gene expression without changing the DNA sequence. Prostate cancer (PC) displays a complex genetic and epigenetic regulation of cell-growth pathways and tumor progression. We performed a systematic literature review (following PRISMA guidelines) focused on the epigenetic regulation of PD-L1 expression in PC. In PC cell lines, CpG island methylation of the CD274 promoter negatively regulated PD-L1 expression. Histone modifiers also influence the PD-L1 transcription rate: the deletion or silencing of the histone modifiers MLL3/MML1 can positively regulate PD-L1 expression. Epigenetic drugs (EDs) may be promising in reprogramming tumor cells, reversing epigenetic modifications, and cancer immune evasion. EDs promoting a chromatin-inactive transcriptional state (such as bromodomain or p300/CBP inhibitors) downregulated PD-L1, while EDs favoring a chromatin-active state (i.e., histone deacetylase inhibitors) increased PD-L1 expression. miRNAs can regulate PD-L1 at a post-transcriptional level. miR-195/miR-16 were negatively associated with PD-L1 expression and positively correlated to longer biochemical recurrence-free survival; they also enhanced the radiotherapy efficacy in PC cell lines. miR-197 and miR-200a-c positively correlated to PD-L1 mRNA levels and inversely correlated to the methylation of PD-L1 promoter in a large series. miR-570, miR-34a and miR-513 may also be involved in epigenetic regulation.

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 3: PD-L1, Intracellular Signaling Pathways and Tumor Microenvironment.

The tumor microenvironment (TME) includes immune (T, B, NK, dendritic), stromal, mesenchymal, endothelial, adipocytic cells, extracellular matrix, and cytokines/chemokines/soluble factors regulating various intracellular signaling pathways (ISP) in tumor cells. TME influences the survival/progression of prostate cancer (PC), enabling tumor cell immune-evasion also through the activation of the PD-1/PD-L1 axis. We have performed a systematic literature review according to the PRISMA guidelines, to investigate how the PD-1/PD-L1 pathway is influenced by TME and ISPs. Tumor immune-escape mechanisms include suppression/exhaustion of tumor infiltrating cytotoxic T lymphocytes, inhibition of tumor suppressive NK cells, increase in immune-suppressive immune cells (regulatory T, M2 macrophagic, myeloid-derived suppressor, dendritic, stromal, and adipocytic cells). IFN-γ (the most investigated factor), TGF-ß, TNF-α, IL-6, IL-17, IL-15, IL-27, complement factor C5a, and other soluble molecules secreted by TME components (and sometimes increased in patients' serum), as well as and hypoxia, influenced the regulation of PD-L1. Experimental studies using human and mouse PC cell lines (derived from either androgen-sensitive or androgen-resistant tumors) revealed that the intracellular ERK/MEK, Akt-mTOR, NF-kB, WNT and JAK/STAT pathways were involved in PD-L1 upregulation in PC. Blocking the PD-1/PD-L1 signaling by using immunotherapy drugs can prevent tumor immune-escape, increasing the anti-tumor activity of immune cells.

SMARCA4 (BRG1) and SMARCB1 (INI1) expression in TTF-1 negative neuroendocrine carcinomas including merkel cell carcinoma.

SMARCA4 and SMARCB1 loss of function has been implicated in many different tumors. The objective of this study was to investigate the loss of BRG1 and INI1 expression in TTF-1 negative neuroendocrine carcinomas to see if they are analogous to small-cell carcinoma of the ovary, hypercalcemic type. The potential role of these tumor suppressor genes in high-grade neuroendocrine carcinoma largely remains unknown. Cases of previously diagnosed Small cell carcinoma (SmCC), Large cell neuroendocrine carcinoma (LCNEC) and Merkel cell carcinoma (MCC) were selected. Immunohistochemical expression patterns for BRG1 and INI1 were interpreted as: intact, hybrid and complete loss of nuclear staining. SmCC and LCNEC cases were divided as TTF-1 positive and TTF-1 negative subsets. One case of TTF-1 negative SmCC (lung) showed loss of SMARCA4(BRG1) expression. Amongst TTF-1 negative LCNEC, one case (lung) showed complete loss of SMARCA4(BRG1) and partial loss of SMARCB1(INI1) and one case (lymph node) had hybrid expression of SMARCA4(BRG1) with intact SMARCB1(INI1) expression. All TTF-1 positive cases and all MCC cases showed intact expression of SMARCA4(BRG1) and SMARCB1(INI1). Our study highlights that SMARCA4(BRG1) is deficient in a subset of NEC. Inactivation of SMARCA4 in a subset of TTF-1 negative neuroendocrine carcinomas especially of pulmonary site can be further studied for their therapeutic response to targeted therapy e.g. EZH2 inhibitors. In addition, our study is the first to show that BRG1 and INI1 expression are intact in MCC and hence the biology of MCC might be completely exclusive of these two tumor suppressor genes.

Impact of margin status on survival after radical nephrectomy for renal cell carcinoma.

BACKGROUND: Data about the impact of surgical margin positivity on patient outcomes following radical nephrectomy (RN) for renal cell carcinoma (RCC) is limited. We evaluate the effect of positive surgical margins (PSMs) on relapse-free survival (RFS) and overall survival (OS.) METHODS: Clinicopathologic data of patients who underwent RN for RCC was analyzed based on margin status. χ2 and Student t test were used to compare groups. Cox regression analysis was used for the analysis. Kaplan-Meier method was used for survival curves. RESULTS: A total of 485 patients who underwent RN for RCC were analyzed. Most patients with T1/T2 stage had NSM. Most patients with T4 had PSM. T3 patients were split between the two groups. Analysis of the T3 group showed shorter RFS in the PSM group at 3 years (hazard ratio [HR]: 4.3, p = .01), and 5 years (HR: 4.3, p = .01.) OS analysis showed worse OS in PSM but not statistically significant. There was a significant association between PSM and laterality (p = .023) and histologic type (p = .025.) CONCLUSIONS: PSM was associated with shorter RFS after RN in T3 RCC patients. There was a trend towards worse OS in the PSM group, but it did not reach statistical significance. Laterality and histologic type were associated with surgical margin status.

Similarities and Differences in the 2019 ISUP and GUPS Recommendations on Prostate Cancer Grading: A Guide for Practicing Pathologists.

Contemporary subspecialization of practice in prostate pathology has seen a transition to complex, nuanced reporting, where a growing number of histopathologic parameters may signal differences in patient management. In this context, the International Society of Urological Pathology (ISUP) and the Genitourinary Pathology Society (GUPS) both published proceedings papers on the grading of prostate cancer in 2019. Overall, the 2 prostate cancer grading manuscripts reached many of the same conclusions and recommendations. Yet, each consensus was conducted somewhat differently, and in a couple of key areas, each reached different conclusions and recommendations. Herein, sourced from the experience and viewpoints of members of both societies, we provide the practicing pathologist a summary of the shared recommendations, and of the discordances. It is anticipated that these 2 documents will inform future iterations of recommendations and guidelines for reporting prostate cancer by organizations such as the College of American Pathologists, the Royal College of Pathologists, and the European Society of Pathology, which will promote best practices for their respective constituents. Our goal is to provide the practicing pathologist a useful catalog of the main points of both, allowing each practitioner to make informed decisions and understand any divergent opinions as may arise between observers for individual cases.

Primary round cell sarcomas of the urinary bladder with EWSR1 rearrangement: a multi-institutional study of thirteen cases with a review of the literature.

Primary Ewing sarcoma (ES) of the urinary bladder is a rare and aggressive small blue round cell malignant neoplasm associated primarily with translocation involving EWSR1 and FLI1 genes located in the 22nd and 11th chromosomes, respectively. To date, 18 cases have been published in the literature as single-case reports, based chiefly on CD99 positivity (17 patients). Molecular confirmation by fluorescence in situ hybridization was performed in 9 patients, and FLI1 immunohistochemical (IHC) analysis was not performed in any of these published cases. Herein, we present thirteen patients of more comprehensive primary round cell sarcomas of the urinary bladder with EWSR1 rearrangement. Clinicopathologic parameters including demographics; clinical presentation; histopathologic, IHC, and molecular profiles; and management and follow-up data of 13 patients with primary round cell sarcomas with EWSR1 rearrangement (Ewing family of tumor) of the urinary bladder were analyzed. The studied patients (n = 13) included 6 females and 7 males; their age ranged from 4 years to 81 years (median = 30 years). The most common clinical presentation was hematuria (n = 7), followed by hydronephrosis (n = 2, one with renal failure). The tumor size ranged from 2.9 cm to 15 cm in maximum dimension. Conventional ES architecture and histology was observed in 6 cases, and diverse histology was observed in 7 cases (adamantinomatous pattern [n = 1], alveolar pattern [n = 1], ganglioneuroblastoma-like pattern [n = 2], and small cell carcinoma-like pattern [n = 3]). All the tumors were muscle invasive (invasion into the muscularis propria). IHC analysis showed that all tumors expressed FLI1, CD99, and at least one neuroendocrine marker. Focal cytokeratin staining was positive in 2 patients, and RB1 was retained in all patients. EWSR1 rearrangement was seen in 12 of 12 tumors (in 12 patients) tested. A combined multimodal approach that included surgery with chemotherapy was instituted in all patients. Follow-up was available for 11 patients (ranging from 5 to 24 months). Six patients either died of disease (n = 3) or other causes (n = 3). Five patients were alive with metastases to the liver (n = 1), liver and lung (n = 2), liver and abdominal wall (n = 1), and kidney (n = 1). Based on our experience with the largest series to date and aggregate of the published data, ES/round cell sarcomas with EWSR1 rearrangement occurring in the bladder have bimodal age distribution with poor prognosis despite aggressive therapy. Owing to its rarity and age distribution, the differential diagnosis is wide and requires a systematic approach for ruling out key age-dependent differential diagnoses aided with molecular confirmation.

Peyronie disease: a clinicopathologic study of 71 cases with emphasis on histopathologic patterns and prevalent metaplastic ossification.

Peyronie disease (PD) is a benign, superficial fibromatosis involving the fascial structures of the penis, causing deformity, pain, and loss of function, for which there are few contemporary studies of the histopathology. We performed a multi-institutional review of 74 routine and consultation specimens submitted with clinical concern for PD. Of these, three non-PD lesions were identified and excluded (a myointimoma, a mammary-type myofibroblastoma, and fibrocalcific atherosclerosis). Of the 71 confirmed to be PD, the majority of patients were white (83%), with a median age of 55 years (range: 26-88). The dorsal aspect of the penis was the most common site involved (78%), followed by lateral (12%) and ventral (10%) aspects. The median degree of curvature was 70° (range: 20-360°). On review, three overall histologic patterns characterized the lesions resected: dense fibrotic plaque (61%), dense fibrotic plaque with focal or patchy metaplastic ossification (35%), and plaque composed predominantly of metaplastic ossification (4%). The fibrotic component was predominantly nodular (18%), hyalinized/lamellar (46%), or mixed (32%), excepting two cases consisting entirely of metaplastic bone. Chronic inflammation, when present, was most often focal and perivascular in distribution. In one case, an excision after collagenase treatment showed myxoid change and increased stromal cellularity. Overall, these findings define the range of PD histology, particularly emphasizing that the calcification noted clinically nearly always represents bona fide metaplastic ossification. Such context will be of value in evaluating specimens prospectively, in light of changing practices and the use of new technologies for treatment.

Genital verruciform xanthoma: lessons from a contemporary multi-institutional series.

AIMS: Verruciform xanthoma (VX) is an uncommon lesion, seen in the oral mucosa and rarely occurring at cutaneous genital sites. Reports of exceptional VX presentations dominate the literature; herein, we assess the clinical and histological features of a cohort of routine, consecutive cases. METHODS AND RESULTS: Clinicopathological features of genital VXs from four academic centres were reviewed. A cohort of 25 lesions from 24 patients (22 male, two female; median age = 62 years), occurred on the scrotum (84%), penis (8%) and perineum/vulva (8%). VX was never suspected clinically; considerations ranged from fibroepithelial polyps to squamous cell carcinoma. Classic diagnostic criteria were present at least focally in each lesion, including verrucous architecture, prominent wedge-shaped parakeratosis extending between exophytic epidermal projections and neutrophils in the stratum corneum. Xanthomatous cells were present in all cases, but scattered to rare in 24%. CONCLUSIONS: Consecutive genital VXs reliably exhibited classic histopathological features, although the essential finding of xanthomatous cells may be scarce. Our comparison to meta-analyses of published cases found relatively fewer penile and vulvar examples. Additionally, the median age was older than in published series, which have emphasised syndromic associations.

Pivarubicin Is More Effective Than Doxorubicin Against Triple-Negative Breast Cancer In Vivo.

Triple-negative breast cancer (TNBC) is unresponsive to antiestrogen and anti-HER2 therapies, requiring the use of cytotoxic drug combinations of anthracyclines, taxanes, cyclophosphamide, and platinum compounds. Multidrug therapies achieve pathological cure rates of only 2040%, a consequence of drug resistance and cumulative dose limitations necessitated by the reversible cardiotoxic effects of drug therapy. Safer and more effective treatments for TNBC are required to achieve durable therapeutic responses. This study describes the mechanistic analyses of the novel anthracycline, pivarubicin, and its in vivo efficacy against human primary TNBC. Pivarubicin directly activates PKCd, triggers rapid mitochondrial-dependent apoptosis, and circumvents resistance conferred by overexpression of P-glycoprotein, Bcl-2, Bcl-XL, and Bcr-Abl. As a consequence, pivarubicin is more cytotoxic than doxorubicin against MDA-MB-231, and SUM159 TNBC cell lines grown in both monolayer culture and tumorspheres. Comparative in vivo efficacy of pivarubicin and doxorubicin was performed in an orthotopic NSG mouse model implanted with MDA-MB-231 human TNBC cells and treated with the maximum tolerated doses (MTDs) of pivarubicin and doxorubicin. Tumor growth was monitored by digital caliper measurements and determination of endpoint tumor weight and volume. Endpoint cardiotoxicity was assessed histologically by identifying microvacuolization in ventricular cardiomyocytes. Primary tumors treated with multiple rounds of doxorubicin at MTD failed to inhibit tumor growth compared with vehicle-treated tumors. However, administration of a single MTD of pivarubicin produced significant inhibition of tumor growth and tumor regression relative to tumor volume prior to initiation of treatment. Histological analysis of hearts excised from drug- and vehicle-treated mice revealed that pivarubicin produced no evidence of myocardial damage at a therapeutic dose. These results support the development of pivarubicin as a safer and more effective replacement for doxorubicin against TNBC as well as other malignancies for which doxorubicin therapy is indicated.

Prevalence of Lymphoid Neoplasia in a Retrospective Analysis of Warthin Tumor: A Single Institution Experience.

Warthin tumor is one of the most common benign salivary gland tumors. Overt lymphoma is known to occur in the lymphoid stroma of Warthin tumor. In situ follicular neoplasia is difficult to identify in routine histologic examination of lymphoid tissue and has not been reported in association with Warthin tumor. Our objective is to determine the prevalence of overt malignant lymphoma and in situ follicular neoplasia in Warthin tumor. We conducted a retrospective histological evaluation of 89 sequential Warthin tumor cases with available slides and blocks from the years 2010-2019. Of these, 84 cases were subjected to immunohistochemical testing, while 5 cases had been previously worked up for the suspicion of lymphoma. We identified two additional cases of lymphoid neoplasia associated with Warthin tumor including small lymphocytic lymphoma/chronic lymphocytic leukemia (n = 1) and in situ follicular neoplasia (n = 1) in addition to previously reported case of follicular lymphoma included in this study. The prevalence rate of first-time detected lymphoid neoplasia in Warthin tumor is 3.4%. The prevalence rate of overt lymphoma is 2.2%, while the prevalence of in situ follicular neoplasia is 1.1%. We propose histologic criteria to identify small lymphocytic lymphoma and follicular lymphoma in Warthin tumor. These include a monotonous interfollicular expansion of small lymphocytes and germinal centers composed of a monotonous population of lymphocytes without polarity or tingible body macrophages respectively. It is very important for pathologists to perform a diligent morphological examination and perform immunohistochemistry in suspected cases to identify subtle involvement of Warthin tumor by lymphoma. In patients with involvement of Warthin tumor by in situ follicular neoplasia, concurrent lymphoma in the same tissue and other sites should be considered. Patients without overt lymphoma elsewhere likely have a low risk of progression to follicular lymphoma. The low prevalence of in situ follicular neoplasia in Warthin tumor, combined with the low rate of clinical progression to lymphoma, make routine screening of Warthin tumor for in situ follicular neoplasia unnecessary.