In testicular germ cell tumors (TGCTs), staging is a major determinant of disease-specific outcomes and dictates clinical management. The 8th edition of the American Joint Committee on Cancer (AJCC) staging manual recommends that tumor deposits in the spermatic cord that are discontinuous with the primary tumor be considered pathologic stage M1 (clinical stage [CS] III). This recommendation is controversial because, if patients do not show other metastases, it results in upstaging from CS I to III. This is relevant because CSI patients are candidates for active surveillance, whereas chemotherapy represents the standard treatment of CSIII patients. In this study, we describe the clinicopathologic findings and disease outcomes of TGCT patients presenting with discontinuous cord involvement no other concurrent metastases (ie, otherwise CS I). A total of 19 patients were assessed: 16 nonseminomas and 3 seminomas. When the focus of discontinuous spermatic cord invasion was excluded from staging, 10 tumors were pT3, 8 were pT2, and 1 was pT1. Adjuvant chemotherapy was given to 15 patients, 10 of whom developed disease recurrence (8 of them showing metastases in the retroperitoneum). None of the 4 patients kept on active surveillance showed evidence of recurrence at last follow-up, which is incompatible with the natural history of untreated CS III TGCTs. If the focus of discontinuous cord involvement was excluded from staging, these 4 cases were all pT2. Our data support that discontinuous cord invasion should not be considered pM1, since this practice may result in overtreatment of patients that could be kept on surveillance. We suggest staging these tumors as pT3(disc), considering this finding a risk factor for recurrence.

Leiomyomas (LMs) represent the most frequent mesenchymal tumors of the urinary bladder. Despite their relative frequency, large clinicopathological studies are scarce, and their pathogenesis remains poorly understood. In this study, we performed a clinicopathological analysis of 35 bladder LMs and explored whether they share pathogenic mechanisms previously documented in uterine LMs. The tumors occurred in 18 women and 17 men, with a median age of 55 years (range: 20 to 78 y). Clinical data were available for 30 cases (85%). Most tumors were incidentally discovered (16/30, 53%), while the remaining patients presented predominantly with lower urinary tract symptoms. Ten patients had a prior history of cancer, and 3 women had a history of uterine LM. Tumor size, available in 12 cases, ranged from 6 to 66 mm (mean, 31 mm). Histologically, most tumors showed a uniform morphology, consisting of well-circumscribed nodules composed of bland smooth muscle cells without mitotic activity. Rare findings included extensive necrosis (3/35, 8%) and a pseudohyperplastic appearance (1/20, 5%). On immunohistochemistry, a subset of tumors, predominantly in females, expressed estrogen receptors (7/28, 25%), progesterone receptors (5/24, 21%), and androgen receptors (10/23, 43%). HMGA2 expression was observed in one case (1/27, 4%). Fumarate hydratase (FH) expression was retained in all tested tumors (n=31); 2SC expression was detected in 4 tumors (4/32; 12%), all with preserved FH and lacking distinctive histomorphological features of FH-deficient LMs. DNA sequencing of 2SC-positive tumors identified a pathogenic FH variant in one of the 4 analyzed cases at a low variant allele frequency. No other known pathogenic variants, including MED12 commonly seen in uterine LMs, were detected. Altogether, this study characterizes the clinicopathological features of large cohort of bladder LMs, highlighting unrecognized morphologic features, including cases with massive necrosis. Our findings suggest that bladder LMs differ pathogenetically from their uterine counterparts, with a more limited role for hormone receptor signaling and distinct genetic alterations.

So-called "somatic-type" malignancies (SMs) of germ cell tumor (GCT) origin resemble malignant neoplasms that arise from true somatic tissue. Except for enrichment in TP53 pathway alterations, the mutational profile of GCTs with SMs does not significantly differ from that of typical GCTs. Prior studies have suggested that copy number alterations (CNAs) of SMs may differ from those of conventional GCTs, but comparative genome-wide CNA analyses of paired components of GCTs with SMs have not been previously performed. The objective of this study was to compare CNAs in paired SMs and conventional components of individual GCTs. Twenty-two paired samples from 11 tumors were included in the study (6 metastases, 4 testicular primaries, and 1 mediastinal primary). Each paired sample represented synchronous conventional GCT and SM components from the same tumor, without pretreatment and post-treatment or primary-metastatic comparisons. The molecularly studied conventional GCT components included: teratoma (n=7), teratoma and yolk sac tumor (n=1), teratoma and seminoma (n=1), and seminoma (n=2). The SM components included: embryonic-type neuroectodermal tumor (ENT; n=3), rhabdomyosarcoma (RMS; n=2), ENT and RMS (n=1), unclassified sarcoma (n=2), nephroblastoma (n=1), carcinoma, NOS (n=1), and acinar cell carcinoma (n=1). In most tumors (8/11; 73%), CNA profiles of the paired samples were similar. In the remaining 3 tumors (3/11; 27%), the CNA profiles showed noticeable differences, with a higher number of CNAs in SM. Two of these were metastatic and the remaining was a mediastinal primary. No highly recurrent CNAs were identified in the SM components. The similar CNA profiles of paired SMs and conventional GCTs reinforces their common clonal origin. The differences observed in a subset likely reflect earlier divergent evolution of the SM subclones, with CNAs possibly underlying tumor progression.

Leiomyomas (LMs) represent the most frequent mesenchymal tumors of the urinary bladder. Despite their relative frequency, large clinicopathological studies are scarce, and their pathogenesis remains poorly understood. In this study, we performed a clinicopathological analysis of 35 bladder LMs and explored whether they share pathogenic mechanisms previously documented in uterine LMs. The tumors occurred in 18 women and 17 men, with a median age of 55 years (range: 20 to 78 y). Clinical data were available for 30 cases (85%). Most tumors were incidentally discovered (16/30, 53%), while the remaining patients presented predominantly with lower urinary tract symptoms. Ten patients had a prior history of cancer, and 3 women had a history of uterine LM. Tumor size, available in 12 cases, ranged from 6 to 66 mm (mean, 31 mm). Histologically, most tumors showed a uniform morphology, consisting of well-circumscribed nodules composed of bland smooth muscle cells without mitotic activity. Rare findings included extensive necrosis (3/35, 8%) and a pseudohyperplastic appearance (1/20, 5%). On immunohistochemistry, a subset of tumors, predominantly in females, expressed estrogen receptors (7/28, 25%), progesterone receptors (5/24, 21%), and androgen receptors (10/23, 43%). HMGA2 expression was observed in one case (1/27, 4%). Fumarate hydratase (FH) expression was retained in all tested tumors (n=31); 2SC expression was detected in 4 tumors (4/32; 12%), all with preserved FH and lacking distinctive histomorphological features of FH-deficient LMs. DNA sequencing of 2SC-positive tumors identified a pathogenic FH variant in one of the 4 analyzed cases at a low variant allele frequency. No other known pathogenic variants, including MED12 commonly seen in uterine LMs, were detected. Altogether, this study characterizes the clinicopathological features of large cohort of bladder LMs, highlighting unrecognized morphologic features, including cases with massive necrosis. Our findings suggest that bladder LMs differ pathogenetically from their uterine counterparts, with a more limited role for hormone receptor signaling and distinct genetic alterations.

AIMS:Germ cell neoplasia in situ (GCNIS) is the precursor of GCNIS-derived testicular germ cell tumours, including seminomas and non-seminomas. Most non-seminomas show mixed histology, often including components of seminoma. A small subset presents as pure non-seminomatous germ cell tumors. In these neoplasms, the absence of invasive seminoma. raises the possibility that reprogramming to non-seminoma may occur at an early in-situ stage (i.e., within the spermatogonial niche). This study examined GCNIS associated with pure embryonal carcinoma (EC) and postpubertal-type yolk sac tumour (YST) using immunohistochemistry for transcription factors characteristic of GCNIS/seminoma, EC, and YST phenotypes to determine if reprogramming to non-seminoma occurs within the spermatogonial niche. METHODS:GCNIS associated with pure testicular YST and EC was assessed using OCT4, FOXA2 (only YST), CD30 (only EC), SOX2 (only EC), SOX17, and NANOG immunohistochemistry. Adjacent foci of intratubular and invasive tumour were also evaluated, if present. RESULTS:Sixty-seven pure non-seminomas (63 EC, 4 YST) were evaluated. In all cases, GCNIS expressed OCT4, SOX17, and NANOG. GCNIS associated with EC was consistently negative for CD30 and SOX2, and GCNIS associated with YST was consistently negative for FOXA2. Adjacent invasive EC (62/67 cases) and intratubular EC (19/67) showed the classic EC immunophenotype: OCT4+/NANOG+/SOX17-/SOX2+/CD30+. Similarly, invasive YST adjacent to GCNIS was OCT4-/NANOG-/SOX17+/FOXA2+. CONCLUSIONS:Assessment of transcription factors involved in the induction and maintenance of EC and YST phenotypes suggests that, in pure non-seminomas, reprogramming occurs outside the spermatogonial niche.

Inflammatory and nested testicular sex cord tumor (INTSCT) is a recently recognized malignant testicular neoplasm characterized by distinctive morphologic, immunophenotypic, and molecular features, including frequent EWSR1::ATF1 gene fusions. Although prior series have established INTSCT as a distinct entity with aggressive behavior, its full clinicopathologic and molecular spectrum remains incompletely defined.Thirteen previously unreported INTSCT from multiple institutions were analyzed. Clinicopathologic features were reviewed, including clinical presentation, outcome, histologic findings, and immunophenotype. Molecular characterization was performed using RNA sequencing and/or fluorescence in situ hybridization (FISH) for EWSR1 and ATF1 rearrangements.Patients ranged from 22 to 71 years old (median 37). All presented with testicular masses. Among 8 patients with adequate follow-up, 7 developed metastases to retroperitoneal lymph nodes and 2 to lungs. Histologically, tumors consistently exhibited nested architecture, intratumoral and/or peritumoral inflammation, and thick collagenous stroma, with frequent cellular discohesion and vacuolated cytoplasm; one case showed a Leydig cell-like phenotype. Immunohistochemistry demonstrated high rates of inhibin-α, CD30, keratin, EMA, and SF1 expression, with absence of germ cell markers. Molecular studies revealed EWSR1::ATF1 fusion or EWSR1 rearrangement in 12 of 13 tumors.This multi-institutional series corroborates and expands prior observations, confirming INTSCT as a distinctive, aggressive malignant sex cord-stromal tumor with a highly recurrent EWSR1::ATF1 fusion. Awareness of its morphologic spectrum, including features mimicking Leydig cell tumor, is essential to avoid misdiagnosis and ensure appropriate clinical management.

Clear cell adenocarcinoma of the urinary tract (CCA-UT) is a rare, potentially aggressive tumor with very limited information regarding its clinicopathologic characteristics and molecular alterations. This study aimed to elucidate the clinicopathologic features and molecular landscape of one of the largest cohorts (35 cases) of this tumor, to identify genomic alterations and potential therapeutic targets. Seventy-nine percent of the patients were women, with a median age of 61 years. The urethra was the most common site (18; 51%), and all cases were ≥pT2 (pT2:15; pT3:11; pT4:8). Twenty-nine percent of the patients died of their disease on follow-up. On whole-exome sequencing, pathogenic/oncogenic alterations were identified in 91% (32/35) cases. These alterations, most frequently involved chromatin modifiers (66% cases), including ATRX , KMT2C , ARID1A , and ARID1B . Other frequently mutated genes included ATM , NF1 , and ERBB2 . Ninety-seven percent (34/35) of cases were microsatellite stable, and tumor mutational burden (TMB) was >10 mut/Mb in 9% (3/35) of cases. Five cases were homologous recombinant-deficient on ScarHRD analysis, and 3 cases showed BRCA mutations. Recurrent copy number loss events in Chr 1(p36.33-p35.3) were the most common copy number alterations (80%; n=28 cases). RNA-sequencing data analysis revealed numerous differentially expressed genes and enrichment of the epithelial-to-mesenchymal transition gene signature in individual samples. However, there was no statistical significance in the progression-free survival between cases with epithelial and mesenchymal phenotypes. CCA-UT are aggressive tumors with a heterogeneous molecular profile, underscoring the role of molecular analysis in identifying potential therapeutic options for the treatment of this pernicious tumor.

Aims Testicular sex cord-stromal tumours (TSCSTs) are rare neoplasms that arise from (or show differentiation to) elements derived from the sex cords or intertubular stroma. The current classification (World Health Organization, 2022) is based almost entirely on morphology, with many tumour types such as granulosa cell tumours being defined based on their resemblance to ovarian counterparts. Recent studies have uncovered new clinicopathological, molecular and biological nuances within this group of tumours, underscoring differences with ovarian homologues.Methods and results Considering the new data, a group of genitourinary pathology experts (Testicular Sex Cord-Stromal Tumour [TESST] group) has proposed a revised 'TESST classification' that incorporates the best available evidence. This classification is structured and hierarchical, composed of the following tiers: (1) group, (2) category, (3) entity and (4) histological pattern. 'Group' refers to the histological compartment a specific tumour belongs to (sex cords, stroma or both), whereas 'category' is defined by the phenotype of the tumour, taking non-neoplastic elements of the ovary and testis as a reference. The third tier, 'entity', refers to neoplasms with shared clinicopathological and/or molecular features that justify classifying them as distinct types. Lastly, 'histological patterns' are recurrent morphological variations within entities that are not linked to distinct clinicopathological or molecular features.Conclusions We propose a classification that will provide a framework to improve current clinical management and guide future research in the field.

To summarise the content and significance of the recently published second edition International Collaboration on Cancer Reporting (ICCR) histopathology dataset for testicular germ cell tumours, covering the Orchiectomy specimen dataset. We highlight key updates from the first editions, including alignment with the 5th edition World Health Organization (WHO) Classification, revised staging criteria, clarified core data elements versus non-core elements and the evidentiary basis underpinning these changes. A review of the ICCR 2nd edition dataset for Orchiectomy specimens of primary testicular tumours was performed, focusing on their development by an international expert committee using a consensus-based approach. Core (required) and non-core (recommended) data elements were identified along with the level of evidence supporting each, following National Health and Medical Research Council (NHMRC) criteria. Changes from the first edition were extracted by comparing dataset content and notes, informed by up-to-date literature through July 2024. The 2nd edition Orchiectomy dataset provides an integrated, harmonised framework for reporting testicular germ cell tumours. The dataset incorporates the WHO 5th Edition Classification of Urinary and Male Genital Tumours. Pathological staging criteria have been updated to align with the 8th edition Union for International Cancer Control (UICC)/American Joint Committee on Cancer (AJCC) tumour-node-metastasis (TNM) definitions. The second edition of this dataset includes changes to align the dataset with the WHO Classification of Tumours, Urinary and Male Genital Tumours, 5th edition, 2022. The ICCR dataset includes the 5th edition Corrigenda, July 2024. It was agreed that this dataset is not suitable for non-germ cell tumours, with the hope that a new dataset, especially for sex-cord stromal tumours, would be developed. The 2nd edition Orchiectomy dataset represents an authoritative, up-to-date standard for pathology reporting of primary testicular germ cell tumours. By incorporating the WHO 5th edition classifications, current TNM staging and the latest evidence on prognostic factors, this dataset facilitates uniform reporting and prognostication. The ICCR dataset underscores core data required for patient management decisions (e.g., adjuvant therapy in Stage I disease, post-chemotherapy management) while providing flexibility through non-core elements for additional useful information. Adoption of this internationally vetted dataset will enhance consistency, assist multidisciplinary treatment planning and align pathology reports with modern consensus guidelines and classifications. The dataset can be used in both high-resource and limited-resource settings without compromising the essential reporting standards.

Testicular adult granulosa cell tumors (AGCTs) are rare and show several clinical, pathological, and molecular differences with their ovarian counterparts. FOXL2 p.Cys134Trp, the ubiquitous molecular driver of ovarian AGCTs, is infrequent ( 7

Clear cell adenocarcinoma of the urinary tract (CCA-UT) is a rare, potentially aggressive tumor with very limited information regarding its clinicopathologic characteristics and molecular alterations. This study aimed to elucidate the clinicopathologic features and molecular landscape of one of the largest cohorts (35 cases) of this tumor, to identify genomic alterations and potential therapeutic targets. Seventy-nine percent of the patients were women, with a median age of 61 years. The urethra was the most common site (18; 51%), and all cases were ≥pT2 (pT2:15; pT3:11; pT4:8). Twenty-nine percent of the patients died of their disease on follow-up. On whole-exome sequencing, pathogenic/oncogenic alterations were identified in 91% (32/35) cases. These alterations, most frequently involved chromatin modifiers (66% cases), including ATRX , KMT2C , ARID1A , and ARID1B . Other frequently mutated genes included ATM , NF1 , and ERBB2 . Ninety-seven percent (34/35) of cases were microsatellite stable, and tumor mutational burden (TMB) was >10 mut/Mb in 9% (3/35) of cases. Five cases were homologous recombinant-deficient on ScarHRD analysis, and 3 cases showed BRCA mutations. Recurrent copy number loss events in Chr 1(p36.33-p35.3) were the most common copy number alterations (80%; n=28 cases). RNA-sequencing data analysis revealed numerous differentially expressed genes and enrichment of the epithelial-to-mesenchymal transition gene signature in individual samples. However, there was no statistical significance in the progression-free survival between cases with epithelial and mesenchymal phenotypes. CCA-UT are aggressive tumors with a heterogeneous molecular profile, underscoring the role of molecular analysis in identifying potential therapeutic options for the treatment of this pernicious tumor.

Accurate subtyping of renal cell carcinoma (RCC) remains a critical clinical challenge. Significant morphological overlap between histological variants leads to diagnostic uncertainty and suboptimal treatment decisions. This paper proposes a novel computer-aided diagnosis system that combines rotation-invariant texture analysis with hybrid deep learning for robust RCC classification. The framework introduces an optimized Local Binary Pattern (LBP) algorithm that captures rotation-invariant texture heterogeneity across circular neighborhoods at multiple scales. The algorithm generates discriminative feature maps that encode fine-to-coarse morphological patterns characteristic of RCC subtypes. These texture biomarkers are fused with RGB histopathology images to create enriched multi-channel inputs that preserve both chromatic and spatial information. Classification relies on a cascaded MobileNetV3–Transformer architecture. The CNN backbone hierarchically extracts local tissue patterns. The Transformer encoder then captures long-range spatial dependencies and global architectural context through self-attention mechanisms. The evaluation uses 298,071 patches from 383 whole-slide images that span six diagnostically challenging renal tumor subtypes. The system achieves a weighted F1-score of 91.20% at patch level and 94.90% at WSI level, with improvements of 3.75–6.30% over state-of-the-art models. External validation confirms robust generalization (TCGA-RCC: 91.83%; DHMC: 90.66%). These results highlight the potential of the proposed approach as a reliable diagnostic aid for precise RCC classification.

Accurate histopathological classification of renal cell carcinoma (RCC), along with its distinction from benign mimickers, is essential for precision oncology and optimal patient management. The morphological complexity and subtle differences among RCC tumors pose significant diagnostic challenges, often resulting in notable inter-observer variability. This paper presents a novel texture-informed hybrid deep learning framework that addresses these challenges by integrating a Rotation-Invariant Multi-Threshold Local Binary Pattern (RIMT-LBP) descriptor with a cascaded CNN-Transformer architecture for robust multiclass classification of renal cell neoplasms. The proposed RIMT-LBP descriptor is designed to capture multiscale tissue heterogeneity while maintaining robustness to orientation variability inherent in histopathological slides. Integrating this descriptor with the original images enriches the representation of RCC tumor features. Classification is performed using a proposed hybrid model that combines MobileNetV3Large for efficient local feature extraction and Transformer encoders for global contextual modeling. This hybrid architecture enables complementary analysis of both fine-grained cellular morphology and broader tissue architecture. The proposed model demonstrated strong whole slide image-level performance, achieving average weighted precision of 95.84%, recall of 95.36%, F1-score of 95.60%, and accuracy of 98.10%. Further analysis showed that the combined RGB+LBP approach (F1-score: 89.18%) outperformed both the RGB-only (F1-score: 84.44%) and LBP-only (F1-score: 80.31%) configurations at the patch level, confirming the complementary value of texture-informed features. Evaluation on two independent public datasets (TCGA-RCC and DHMC) confirmed the framework's consistent performance, with accuracies of 93.13% and 96.12%, respectively. These results highlight the clinical potential of integrating AI models for complementary analysis to improve RCC diagnostic accuracy.

BACKGROUND:Pagetoid involvement of the rete testis (RT) in seminoma is widely interpreted as spread of germ cell neoplasia in situ (GCNIS) rather than true invasion; however, this concept is based largely on morphologic observations. Assessment of isochromosome 12p [i(12p)], a hallmark of invasive germ cell tumors that is absent in GCNIS, was used to determine the nature of pagetoid RT involvement. METHODS:We retrospectively identified orchiectomy specimens with pure seminoma and pagetoid RT involvement from institutional archives. Isochromosome 12p status was assessed on formalin-fixed, paraffin-embedded tissues using fluorescence in situ hybridization (FISH) with a dual-color PKP2/D12Z3 probe. Pagetoid RT involvement, invasive seminoma, and intratubular seminoma (ITS) components were analyzed separately when present. RESULTS:Sixteen tumors were included, with successful FISH analysis in 15 (94%). Pagetoid RT involvement was evaluable in 14 cases and demonstrated i(12p) in only 1 (∼7%), while the remaining 13 were negative. In contrast, invasive seminoma showed i(12p) in 5/14 cases (∼36%). All seminoma components negative for i(12p) showed polysomy 12, suggesting that these are mutually exclusive alterations. Cases with discordant results contained i(12p)-positive seminoma and i(12p)-negative pagetoid RT involvement. Intratubular seminoma (ITS) was present in 6 tumors, being positive for i(12p) in 2 (∼33%). CONCLUSIONS:The absence of i(12p) in pagetoid RT involvement supports its interpretation as spread of GCNIS rather than invasive tumor. Rare detection of i(12p) in RT involvement suggest that, occasionally, this lesion may represent retrograde invasion by seminoma or, more likely, in-situ progression of GCNIS.

OBJECTIVE:Prior studies have reported the loss of α-smooth muscle actin (α-SMA) immunoreactivity in the inner circular layer of the muscularis propria in small bowel motility disorder cases, but this remains controversial with conflicting data. In this study, we aimed to characterize α-SMA immunoreactivity in the muscularis propria of the small intestine-specifically, jejunum-in patients with and without small bowel motility disorder. METHODS:A total of 28 transmural proximal jejunum biopsy specimens from adult patients with clinical impression of upper gastrointestinal dysmotility disorder and 64 control tissues were evaluated. The controls were full-thickness, longitudinal tissue sections from segmental resections performed due to gunshot wounds, multivisceral transplant donation, and tumors. Immunostaining for α-SMA was performed with appropriate controls to confirm the presence of immunoreactivity in the circular and longitudinal muscle layers of the muscularis propria in each sample and recorded as retained or diminished. RESULTS:In the small bowel motility disorder and control cases, 42.9% (12/28) and 70.3% (49/64) of the cases showed no or minimal α-SMA immunoreactivity in the inner circular layer with peripheral accentuation, respectively. CONCLUSIONS:Loss or diminished α-SMA immunoreactivity in the inner circular layer of the muscularis propria occurs with a similar frequency in cases with and without small bowel motility disorder and does not correlate with impairment of function.

Vasculogenic mesenchymal lesions (VMLs) are uncommon phenotypes of germ cell tumor (GCT) origin that are mostly found after chemotherapy of mediastinal yolk sac tumor (YST). These lesions typically lack expression of classical YST markers [α-fetoprotein (AFP) and glypican-3 (GPC3)]. FOXA2 and HNF1β are key inducers of the YST phenotype and co-operate to promote transcription of genes involved in YST development (AFP, GPC3, GATA3, among others). Immunohistochemical studies have shown that FOXA2 and HNF1β are more sensitive than AFP, GPC3, and GATA3 for conventional phenotypes of YST, whereas they are typically negative in sarcomatoid YST. In this study, assessment of VMLs showed that they do not express FOXA2 and HNF1β to a significant degree. These results suggest that the combined downregulation of FOXA2 and HNF1β may underlie the transformation of YST to “mesenchymal” phenotypes, with additional (still undefined) processes determining the final phenotype (sarcomatoid YST or VMLs).

Somatic‐type malignancies (SMs) arising in germ cell tumors (GCTs) are aggressive neoplasms resistant to systemic treatment. Most are diagnosed in metastatic sites after chemotherapy; however, they have also been well‐documented in primary testicular GCTs. Historically, SMs were thought to originate in components of teratoma that acquire molecular alterations equivalent to those that characterize their true somatic counterparts. However, recent studies have shown that SMs typically lack the hallmark molecular alterations seen in similar somatic tumors. Additionally, clinicopathologic and molecular data suggest that a subset may derive from yolk sac tumor (YST) rather than teratoma. In this study, we evaluated the relationship between conventional histological types of GCTs and SMs by comparing expression of microRNA (miR)‐371–373 and genomic methylation profiles. A total of 96 samples (including multiple paired conventional GCT–SM samples from individual tumors) were assessed for miR‐371–373 expression by RT‐qPCR and genomic DNA methylation using a clinically validated assay. Expression of miR‐371–373 was higher in conventional GCTs than in SMs (considered as a single category encompassing all histological subtypes). However, miR‐371–373 expression was heterogeneous among SMs, with significantly higher levels in sarcomatoid YST (SYST) and glandular neoplasms than in other SMs. Genomic DNA methylation analysis showed that SMs (considered as a single category) did not form a distinct cluster. Instead, they grouped into multiple clusters that did not show perfect correspondence with histology and often included conventional GCTs. Genome‐wide methylation assessment showed a higher abundance of hypermethylated regions in SMs than in conventional GCTs. Analysis of paired conventional GCT and ‘somatic‐type’ components that did not meet size criteria for SMs dissected from individual tumors demonstrated separation according to histology, suggesting that epigenetic processes play a role in the transition from conventional GCT to ‘somatic‐type’ phenotypes. Gene‐level and pathway‐level analyses identified MAPK/RAS signaling, mitosis/proliferation, differentiation towards neural tissue/neuroectoderm, epithelial‐to‐mesenchymal transition, and DNA repair as key differentially regulated processes in components with somatic‐type histology, suggesting mechanisms of progression from conventional to ‘somatic’ phenotypes in GCT. These results support the hypothesis that a subset of SMs derive from YST and suggest that some subtypes (such as SYST) may represent ‘intermediate’ phenotypes. Additionally, analysis of differentially methylated promoter regions in SM identified genes and biologic processess that may underlie 'somatic tranformation' in GCTs. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Osteoclast-rich undifferentiated carcinoma of the urinary tract, herein referred to as urothelial carcinoma with osteoclast-like giant cells (UCOGC), is an uncommon tumor currently classified under "poorly differentiated" urothelial carcinoma subtype composed of osteoclast-like giant cells intermixed with abundant mononuclear cells. Not infrequently, the mononuclear component exhibits eccentric nuclear localization reminiscent of plasmacytoid urothelial carcinoma. Given an index tumor where the mononuclear component of UCOGC showed prominent plasmacytoid histology and concomitant plasmacytoid urothelial carcinoma immunophenotype (aberrant loss of membranous E-cadherin with cytoplasmic p120 expression), herein we explore E-cadherin/p120 immunoreactivity in 14 UCOGC with sequencing performed on 4 tumors. Plasmacytoid histology in the mononuclear was identified in all 14 (100%) UCOGC, extent ranging from 20% to 70% (mean = 40%). In 13 of 14 UCOGCs, the mononuclear component showed loss of membranous E-cadherin while strong cytoplasmic p120 staining was present in all 14 tumors. Four UCOGCs also contained separate elements of plasmacytoid subtype urothelial carcinoma, all exhibiting aberrant loss of membranous E-cadherin with cytoplasmic p120 expression. NGS testing showed no evidence of E-cadherin mutations in 4 tested UCOGCs. Although both plasmacytoid UC and UCOGC are associated with poor outcomes, given the established clinicopathologic and molecular features of plasmacytoid urothelial carcinoma, it is prudent to avoid misclassifying UCOGC as plasmacytoid urothelial carcinoma based on the shared aberrant immunoprofile of the mononuclear (loss of membranous E-cadherin with cytoplasmic p120 expression). Recognition of the intimately admixed osteoclast-like giant cells characteristic of UCOGC (often overlooked when sparse and/or in a small biopsy setting) is key for accurate diagnosis.