Human Pathology[JOURNAL]
Sun
200 papers
TRPS1 and GATA3 Expression in BRG1/SMARCA4-deficient Malignant Neoplasms.
Han J, Ding Y, Gan Q … +7 more , Sweeney K, Huang X, Hameed N, Weissferdt A, Wang Y, Peng Y, Sun H
Hum Pathol · 2026 Jul · PMID 42398545 · Publisher ↗
OBJECTIVES: SMARCA4/ BRG1-deficient malignant neoplasms are rare, high-grade tumors originating in sinonasal tract, thorax, gastrointestinal, and gynecological tracts, with breast-origin cases being underexplored. In thi...
OBJECTIVES: SMARCA4/ BRG1-deficient malignant neoplasms are rare, high-grade tumors originating in sinonasal tract, thorax, gastrointestinal, and gynecological tracts, with breast-origin cases being underexplored. In this study, we aimed to investigate the pathologic features of BRG1-deficient breast carcinoma. We also assessed the diagnostic utility of TRPS1 and GATA3 immunohistochemical staining in identifying BRG1-deficient breast carcinomas and distinguishing them from BRG1-deficient tumors of other primary sites. METHODS: To identify BRG1-deficient breast and non-breast cases, we detected BRG1 expression in 408 breast carcinomas using tissue microarrays. We also searched the institutional database for BRG1-deficient malignant neoplasms of both breast and non-breast origins diagnosed between 2021 and 2025. In total, we identified 22 cases from breast/axilla (n=5), thoracic (n=8), gastrointestinal (n=5), and gynecologic (n=4) sites. We then investigated the pathological features of BRG1-deficient breast carcinomas. We also assessed TRPS1 and GATA3 immunohistochemical staining in these BRG1-deficient tumors of different primary sites. RESULTS: Only 1 breast carcinoma showed BRG1 loss among the 408 cases in tissue microarray. BRG1-deficient breast carcinomas are high-grade tumors with primitive morphology. All the 5 cases had TRPS1 positivity, with 3 also positive for GATA3. In contrast, no tumors of the 17 BRG1-deficient thoracic, gastrointestinal, or gynecologic origins exhibited co-expression of TRPS1 and GATA3, only 4 cases expressed either TRPS1 or GATA3 (most weakly). CONCLUSIONS: This study confirmed that BRG1 loss is a rare event in breast carcinoma. Co-expression of TRPS1 and GATA3 is highly specific for breast origin in BRG1-deficient neoplasms. Combined use of these markers may aid in accurate tumor classification, particularly in metastatic or poorly differentiated presentations.
Clinicopathologic and Molecular Characteristics of Acral Melanomas Harboring RARA Fusions.
Abdelhammed MH, Yang RK, Lenskaya V … +2 more , Torres-Cabala CA, Cho WC
Hum Pathol · 2026 Jul · PMID 42398544 · Publisher ↗
Unlike in hematologic malignancies like acute promyelocytic leukemia (APL), the tumorigenic role of RARA fusions in solid tumors, including melanomas, remains largely unknown. Here, we present a comprehensive clinicopath...
Unlike in hematologic malignancies like acute promyelocytic leukemia (APL), the tumorigenic role of RARA fusions in solid tumors, including melanomas, remains largely unknown. Here, we present a comprehensive clinicopathologic and molecular analysis of two cutaneous melanomas harboring RARA fusions. Both melanomas were of the acral subtype, affecting the feet of adults (median age: 60.5 years) without sex predilection. At diagnosis, Breslow thickness ranged from 1.2 to 5.5 mm, ulceration was present in one case, and the median mitotic rate was 4/mm. Tumor cells exhibited variable cytomorphology, including spindled and epithelioid features, with occasional rhabdoid morphology. Molecular analysis revealed a consistently low tumor mutational burden (median: 4.5 mutations/Mb). One acral melanoma was triple wild-type (lacking mutations in BRAF, NRAS, and NF1) and showed no gene amplifications, but harbored a LOC107984974::RARA fusion. The other acral melanoma carried an NF1 loss-of-function mutation and multiple gene amplifications involving 11q13.3 (CCND1, FGF3, FGF4, FGF19), 11q13.5-q14.1 (PAK1), 12q15 (MDM2), and 6q24.3 (SHPRH), along with two RARA fusions: RARA::LRP5 and RARA::RNF169. Over a median follow-up of 23 months, one patient developed a distant metastasis involving the brain approximately 20 months after the initial diagnosis. At last follow-up, one patient was alive with disease, while the other remained alive without clinical or radiological evidence of recurrence. These findings expand the current understanding of the molecular landscape of acral melanomas and may provide insights into the potential utility of targeted therapies against RARA fusions in a subset of melanomas, analogous to their therapeutic role in APL.
Clinical Impact of Second Opinion Consultation in Bladder Biopsies and Transurethral Resection of Bladder Tumors.
Calagua C, Bhardwaj S, Cholan VO … +2 more , Hojabri M, Matoso A
Hum Pathol · 2026 Jul · PMID 42392277 · Publisher ↗
Accurate evaluation of bladder biopsies and transurethral resection of bladder tumors (TURBTs) is essential for appropriate clinical management, yet diagnostic variability remains a challenge. We evaluated a cohort of se...
Accurate evaluation of bladder biopsies and transurethral resection of bladder tumors (TURBTs) is essential for appropriate clinical management, yet diagnostic variability remains a challenge. We evaluated a cohort of second-opinion consultations (n=3,125) and institutional tissue reviews (n=754) of bladder biopsies and transurethral resection of tumors (TURBT) performed at our institution. The cohort included 3,879 consultations selected from 10,509 bladder specimens evaluated between January 2019 and December 2025. Original diagnoses were compared with consultation diagnoses. Overall, diagnostic discrepancies were common and frequently clinically significant. Tumor grade discrepancies were identified in 7% of patients (n=270), morphologic subtypes/variant discrepancies in 10.5% (n=407), and reclassification between benign and malignant diagnoses occurred in 12.2% of patients (malignant to benign: 6.5%, n=252; benign to malignant: 5.7%, n=223). Discrepancies in depth of invasion resulted in upstaging in 7.7% of tumors (n=299), including transitions from carcinoma in situ to lamina propria invasion and from lamina propria to muscularis propria invasion. Among flat lesions, approximately 12% of discrepancies involved the presence or absence of carcinoma in situ. Importantly, a subset of cases (2%) were reclassified as non-urothelial tumors (n=77), including prostatic origin (n=46), pure squamous cell carcinoma (n=10), inflammatory myofibroblastic tumor (n=4), villous adenoma (n=4), leiomyosarcoma (n=4), paraganglioma (n=3), ovarian tumors (n=3), and rare cases of angiosarcoma, breast and endometrial carcinoma (n=1 each). Following expert review, 30% were reclassified as high-risk lesions, while 10% were reclassified as low-risk. In conclusion, these findings support using subspecialty intra- or extra-departmental consultation in diagnostically challenging cases to and optimize patient management.
Prognostic relevance and molecular correlates of Claudin-1 expression in pancreatic neuroendocrine tumors.
Fattori A, Lu X, Baltzinger P … +9 more , Bachellier P, Addeo P, Imperiale A, Pessaux P, Kurtz JE, Goichot B, Baumert TF, Chenard MP, Malouf GG
Hum Pathol · 2026 Jun · PMID 42379528 · Publisher ↗
Pancreatic neuroendocrine tumors (pNETs) are biologically heterogeneous neoplasms with variable clinical outcomes. Current prognostic assessment relies largely on mitotic count and Ki-67 index, which may be affected by i...
Pancreatic neuroendocrine tumors (pNETs) are biologically heterogeneous neoplasms with variable clinical outcomes. Current prognostic assessment relies largely on mitotic count and Ki-67 index, which may be affected by intratumoral heterogeneity and sampling bias. Additional biomarkers are therefore needed to refine risk stratification and characterize aggressive disease biology. Here, we investigated the prognostic and biological significance of Claudin-1 (CLDN1), a tight junction protein implicated in epithelial tumor progression. CLDN1 expression was assessed by immunohistochemistry in 67 surgically resected pNETs using tissue microarrays. A data-driven cutoff (H-score >50) identified a CLDN1-high subset associated with significantly shorter disease-free survival (p = 0.009) and adverse clinicopathologic features. To define the molecular programs underlying CLDN1 overexpression, we performed RNA sequencing on 22 tumors matched for key clinical variables by propensity score matching. CLDN1-high tumors showed attenuation of endocrine lineage markers and enrichment of exocrine and fetal ductal transcriptional programs. Cell-of-origin deconvolution further revealed a shift from endocrine alpha/beta-cell identity toward ductal or acinar-like states. Transcriptomic clustering demonstrated partial convergence between CLDN1-high pNETs and pancreatic ductal adenocarcinoma profiles. In addition, CLDN1-high tumors exhibited activation of epithelial-mesenchymal transition, HIPPO signaling, and immune-related pathways, together with increased stromal and immune cell infiltration. Collectively, our findings identify CLDN1 as a marker of a biologically distinct and clinically aggressive pNET subset characterized by dedifferentiation, lineage plasticity, and tumor microenvironment remodeling, supporting further evaluation of CLDN1 as a candidate prognostic biomarker and potential therapeutic target in pNETs.
Mixed Phenotype Acute Leukemia: Lineage Assignment, Immunophenotypic Classification and Genetic Insights.
Leventaki V, Wang SA
Hum Pathol · 2026 Jun · PMID 42349662 · Publisher ↗
Mixed phenotype acute leukemia (MPAL) is a rare and biologically heterogeneous category characterized by discrete admixed populations of myeloid and lymphoid blasts (bilineal or mixed lineage) or with coexpression of lym...
Mixed phenotype acute leukemia (MPAL) is a rare and biologically heterogeneous category characterized by discrete admixed populations of myeloid and lymphoid blasts (bilineal or mixed lineage) or with coexpression of lymphoid and myeloid markers in a single blast population (biphenotypic or mixed phenotype). Despite advances in diagnostic criteria, MPAL remains a significant diagnostic and therapeutic challenge due to its immunophenotypic complexity and genetic diversity. Accurate classification relies heavily on multiparameter flow cytometry immunophenotyping, integrated with cytogenetic and molecular studies. The current World Health Organization classification and International Consensus Classification recognize specific genetic subtypes, including MPAL with t(9;22)(q34.1;q11.2)/BCR::ABL1 and MPAL with KMT2A rearrangement, reflecting the increasing importance of genomic profiling in disease characterization. Recent genomic studies have revealed additional recurrent alterations involving transcription factors, epigenetic regulators, signaling pathways, and lineage-specifying genes, including ZNF384 rearrangements, BCL11B alterations, mutations involving PHF6, WT1, FLT3, and RUNX1, and mutations affecting chromatin remodeling and cytokine signaling pathways. Importantly, distinct genetic lesions appear to correlate with specific immunophenotypic patterns, suggesting biologically meaningful disease subsets and providing insights into mechanisms of lineage plasticity and leukemogenesis. This review summarizes the current understanding of the immunophenotypic and genetic landscape of MPAL, emphasizing the integration of morphologic, immunophenotypic, cytogenetic, and molecular findings into diagnosis and subclassification.
Chronic myelomonocytic leukemia revisited: A comprehensive review with emphasis on the oligomonocytic subtype.
Loghavi S, Montalban-Bravo G
Hum Pathol · 2026 Jun · PMID 42335999 · Publisher ↗
Oligomonocytic chronic myelomonocytic leukemia (OM-CMML) is defined by an absolute monocyte count of 0.5-<1.0 × 10/L with relative monocytosis ≥10%. This entity was formally recognized in the 2022 WHO Classification of H...
Oligomonocytic chronic myelomonocytic leukemia (OM-CMML) is defined by an absolute monocyte count of 0.5-<1.0 × 10/L with relative monocytosis ≥10%. This entity was formally recognized in the 2022 WHO Classification of Haematolymphoid Tumours and the International Consensus Classification, representing a paradigm shift from prior thresholds requiring monocyte counts ≥1.0 × 10/L. This change in criteria captures a clinically and biologically meaningful disease state with independent prognostic significance and an almost 50% five-year cumulative incidence of progression to overt CMML. However, this change has also expanded the diagnostic boundaries of OM-CMML into territory previously classified as myelodysplastic syndromes (MDS). Accurate diagnosis requires integration of bone marrow morphology, flow cytometric monocyte subset partitioning, and genomic profiling. Cases harboring biallelic TET2 inactivation or TET2+SRSF2 co-mutation show the highest bone marrow monocyte burden, frequent classical monocyte (MO1; CD14+/CD16-) elevation, and highest progression risk representing biologically true OM-CMML, whereas SF3B1-mutated and biallelic TP53 mutated cases show MDS-directed biology and warrant reclassification. This review synthesizes current diagnostic frameworks, molecular heterogeneity, risk stratification approaches, and evolving classification proposals, thereby providing a practical guide for pathologists navigating OM-CMML in the modern genomic era.
Artificial intelligence-assisted screening for NTRK fusion-positive salivary gland tumors: A novel digital pathology workflow.
Onaga R, Sakashita S, Komura D … +5 more , Nakamura N, Tahara M, Ishii G, Ikeda T, Ishikawa S
Hum Pathol · 2026 Jun · PMID 42323990 · Publisher ↗
NTRK fusion is a promising therapeutic target for salivary gland cancer (SGC). However, the diagnostic complexity of the histological SGC subtype and low NTRK fusion-positive SGC incidence (5%), except for secretory carc...
NTRK fusion is a promising therapeutic target for salivary gland cancer (SGC). However, the diagnostic complexity of the histological SGC subtype and low NTRK fusion-positive SGC incidence (5%), except for secretory carcinoma (90%), limit targeted therapy. Despite recommended pan-TRK immunohistochemistry (IHC) screening, evaluation remains unstandardized. Artificial intelligence (AI) has now enabled the prediction of genetic and molecular information. We aimed to evaluate the usefulness of the AI model, a histopathological image retrieval system-Luigi-Oral-in detecting NTRK fusion-positive cases. All 273 primary salivary gland tumors surgically obtained between 2005 and 2023 were retrospectively and blindly assessed using fluorescence in situ hybridization (FISH) for ETV6 rearrangements, pan-TRK IHC (EPR17341), and differential diagnosis with Luigi-Oral for hematoxylin-eosin staining queries in December 2024 (https://luigi-pathology.com/). Luigi-Oral defined inclusion of secretory carcinoma among the top five diagnoses as positive differential indication. Overall, 273 salivary gland tumors were identified, including 104 benign and 169 malignant tumors, with 7 samples pathologically diagnosed as secretory carcinomas. FISH, pan-TRK IHC, and Luigi-Oral identified 7, 7, and 24 positive cases, respectively. All the FISH-positive cases were pathologically diagnosed as secretory carcinoma. Luigi-Oral exhibited a sensitivity, specificity, false-positive rate, and false-negative rate of 85.7%, 93.2%, 6.8%, and 14.3% for detecting FISH-positive cases, respectively. The false-positive rate was 13.3% in acinic cell carcinoma, histologically similar to secretory carcinoma. Luigi-Oral might be a useful alternative to IHC for screening NTRK fusion-positive rare SGC cases, and advances in digital pathology can facilitate implementation of an AI model in the NTRK screening workflow.
Evaluation of prognostic factors and outcomes in primary versus secondary myeloid sarcoma.
Kahlow CW, Germans S, Ramia de Cap M … +19 more , Bagg A, Du W, Hurwitz S, Arber DA, Hermina A, Fend F, Nann D, Chen W, Chen M, Cantu MD, Tam W, Bueso-Ramos CR, Kanagal-Shamanna R, Raess PW, Siddon A, George TI, Foucar K, Hasserjian RP, Weinberg OK
Hum Pathol · 2026 Jun · PMID 42320544 · Publisher ↗
Myeloid sarcoma (MS) is a rare extramedullary manifestation of myeloid neoplasia that may present as an isolated disease without concurrent bone marrow involvement, primary disease or secondary to an antecedent myeloid n...
Myeloid sarcoma (MS) is a rare extramedullary manifestation of myeloid neoplasia that may present as an isolated disease without concurrent bone marrow involvement, primary disease or secondary to an antecedent myeloid neoplasm. The molecular landscape and prognostic determinants of these groups remain incompletely defined. This multi-institutional retrospective cohort study of 145 histologically confirmed MS cases from multiple academic centers incorporates clinical, cytogenetic, and next-generation sequencing data to characterize disease biology and outcomes. Patients with primary MS (56.6% of cases) more often received stem cell transplant and achieved remission, while those with secondary disease (43.4%) were more likely to receive local irradiation and less likely to achieve remission. Isolated MS (20.7% of cases) demonstrated preserved peripheral blood counts and significantly lower mutational burden. Myelodysplasia-related (MR) mutations (44.5% of cases) were associated with higher mutational burden and increased cytogenetic abnormalities but did not influence outcomes. Secondary MS exhibited more frequent TET2 mutations, consistent with evolution from antecedent myeloid neoplasia. NPM1 mutations (52.6% of cases) were associated with skin involvement, higher remission/relapse rates, and frequent FLT3 co-mutation. Additional mutations, including ASXL1 and NRAS, were associated with distinct clinical features but not survival differences. Overall, this comprehensive study highlights clinical and molecular heterogeneity in MS. Outcomes appear to be influenced by an interplay of disease context, clonal architecture, and therapeutic strategy rather than individual mutations alone, underscoring the need for integrated molecular profiling and prospective studies to guide management. This study highlights that MS with MR mutations may follow different cellular pathways to evolution.
The Farooq, not the Lerner, grading system predicts disease-specific and overall survival in duodenal graft-versus-host disease.
Yang B, Youssef R, Saeed O … +1 more , González IA
Hum Pathol · 2026 Jun · PMID 42315014 · Publisher ↗
Histopathological evaluation of graft-versus-host disease (GVHD) is crucial in its diagnosis. In the upper gastrointestinal tract, the duodenum has been reported as the most affected site. However, studies characterizing...
Histopathological evaluation of graft-versus-host disease (GVHD) is crucial in its diagnosis. In the upper gastrointestinal tract, the duodenum has been reported as the most affected site. However, studies characterizing the features of duodenal GVHD (dGVHD) are sparse and no study to date have compared the utility of the traditionally use Lerner grading system and the recently proposed Farooq grading system. 130 cases were included with a median age of 40 years (range: 0.8-73) and 50.8% of the patients were men. The median follow-up time was 32 months (range: 0-185), 83.1% of patients received treatment for GVHD with a treatment response seen in 63.1%, and the overall mortality and GVHD-specific mortality within 6 months of biopsy was 48.1% and 10.4%, respectively. Apoptotic bodies, crypt dropout and ulceration were seen in 58.5%, 12.3% and 6.2% of the cases, respectively. In 50% of cases there were 1-6 apoptotic bodies in 10 continuous crypts and in 8.5% there were >6. No apoptotic bodies, crypt dropout or ulceration were seen in 53 cases (no histologic evidence of GVHD), for the remaining 77 cases a Lerner and Farooq grade was assigned. Utilizing the Lerner grade system cases were considered as grade 1 (46.2%), grade 2 (2.3%), grade 3 (4.6%) and grade 4 (6.2%); and using the Farooq grade cases were considered as indeterminate for GVHD (71.4%), low grade (18.2%), intermediate grade (6.5%) and high grade (2.3%). Treatment response was associated with Farooq grade (p = 0.003) but not with Lerner grade (p = 0.440). Only age and the Farooq grade were independently associated with overall survival (p = 0.004 and 0.005, respectively) and GVHD-specific survival (p = 0.013 and 0.026, respectively) within 6 months of biopsy. The Farooq grading system should be utilized over the Lerner system in dGVHD.
A report of thirteen non-conventional FLCN-mutated (renal) tumors (FMT) and a discussion of proposed diagnostic criteria, convergent FLCN/TFEB and FLCN/MITF E318K signaling, and FLCN immunohistochemistry.
Gupta S, Sterner RM, Hasumi H … +17 more , Jikuya R, Nakagawa H, Kryvenko ON, Jorda M, Torell NR, Stander Z, Colef RG, Tekin B, Whaley RD, Hernandez LH, Jimenez RE, Lucas PC, Kipp BR, Shen W, Erickson LA, Dasari S, Cheville JC
Hum Pathol · 2026 Jun · PMID 42315013 · Publisher ↗
BACKGROUND: Recent studies have demonstrated that FLCN-mutated tumors (FMT) represent a unique tumor type with dual FOXI1+ and L1CAM + cell populations. Low-grade, well-circumscribed eosinophilic tumors (conventional FMT...
BACKGROUND: Recent studies have demonstrated that FLCN-mutated tumors (FMT) represent a unique tumor type with dual FOXI1+ and L1CAM + cell populations. Low-grade, well-circumscribed eosinophilic tumors (conventional FMT, c-FMT) are typically indolent, whereas tumors exhibiting morphologic divergence from this pattern including tubulopapillary, microcystic, or tubulocystic architecture (non-conventional FMT, nc-FMT) may rarely demonstrate metastatic behavior. METHODS: Thirteen new nc-FMTs were evaluated using histologic review, immunohistochemistry, and a kidney cancer-specific next-generation sequencing (NGS) panel. Analysis for TFE3/TFEB rearrangements (by FISH/NGS) and chromosomal copy number changes were performed in a subset of cases. Combined findings from an overall cohort of 77 c-FMTs and 21 nc-FMTs across 35 patients have been reported. RESULTS: The most common morphologic pattern for nc-FMT was papillary/tubulopapillary (9/21, 43%), followed by microcystic (histiocyte-rich)/tubulocystic (7/21, 33%). GPNMB was an excellent immunohistochemistry screen showing diffuse positivity in all c-FMT (n = 34) and nc-FMT (n = 19), while L1CAM had less consistent expression in nc-FMT suggestive of a single cell population in some cases (H-score: 0, 3/20, 15%; H-score: 300, 4/20, 20%). Immunohistochemistry for FLCN failed to separate FMT (n = 23) from morphologic mimics (n = 13). Metastatic behavior was seen in 3/21 nc-FMT that had alterations of TFEB (amplification and gain, one case each) or an MITF p.E318K alteration (one case). CONCLUSIONS: Our cohort provides insight into the natural history of FMT and helps define the histopathologic and molecular features of nc-FMT. Rare metastatic nc-FMTs demonstrate potentially convergent FLCN/TFEB and FLCN/MITF signaling, a finding that warrants prospective validation and may enable improved prognostication of clinically aggressive tumors.
Histologic spectrum of BRCA-associated pancreatic ductal adenocarcinoma: A descriptive morphologic study.
Zabarsky-Shasha G, Raitses-Gurevich M, Stossel C … +4 more , Golan T, Schvimer M, Barshack I, Mayer C
Hum Pathol · 2026 Jun · PMID 42309195 · Publisher ↗
CONTEXT: Pancreatic ductal adenocarcinoma arising in carriers of germline BRCA1 or BRCA2 mutations represents a molecularly defined subgroup characterized by defective homologous recombination DNA repair, yet its histolo...
CONTEXT: Pancreatic ductal adenocarcinoma arising in carriers of germline BRCA1 or BRCA2 mutations represents a molecularly defined subgroup characterized by defective homologous recombination DNA repair, yet its histologic phenotype remains incompletely characterized. OBJECTIVE: To characterize the histologic spectrum of resected pancreatic ductal adenocarcinomas associated with germline BRCA mutations and to describe recurring morphologic features that may reflect underlying DNA-repair deficiency. DESIGN: A retrospective cohort study of surgically resected pancreatic ductal adenocarcinomas from patients with confirmed germline BRCA1 or BRCA2 mutations treated at a tertiary referral center. All hematoxylin-eosin-stained slides were jointly reviewed, and architectural, cytologic, stromal, and peritumoral features were assessed semiquantitatively. RESULTS: Thirty-two tumors with residual carcinoma were evaluable. Tumors demonstrated marked morphologic heterogeneity, including vacuolated morphology (21/32, 65.6%), clear-cell areas (12/32, 37.5%), large-duct pattern (8/32, 25.0%), and micropapillary growth (9/32, 28.1%). A high gland-to-stroma ratio was present in 21 of 32 cases (65.6%), accompanied by stromal hyalinization (23/32, 71.9%) and myxoid change (28/32, 87.5%). Marked nuclear pleomorphism (29/32, 90.6%) and loss of polarity (30/32, 93.8%) were common. Peritumoral lymphoid follicles were identified in 20 of 32 tumors (62.5%). CONCLUSIONS: BRCA-associated pancreatic ductal adenocarcinomas demonstrate recurrent morphologic patterns, including increased glandularity, stromal hyalinization, myxoid stromal change and architectural heterogeneity. These observations provide a framework for future comparative studies investigating morphologic correlates of homologous recombination deficiency in pancreatic cancer. Recognition of these patterns may support consideration of germline or somatic DNA-repair gene testing in appropriate clinical settings.
Pulmonary venoocclusive disease/pulmonary capillary hemangiomatosis: Inadequacy of clinico-radiologic features in diagnosis.
Hurst P, White D, Ryu JH … +3 more , Jenkins SM, Roden AC, Yi ES
Hum Pathol · 2026 Jun · PMID 42309194 · Publisher ↗
Pulmonary venoocclusive disease (PVOD)/pulmonary capillary hemangiomatosis (PCH) belongs to the WHO group 1 pulmonary hypertension (PH), labeled as pulmonary arterial hypertension (PAH), though it mainly involves pulmona...
Pulmonary venoocclusive disease (PVOD)/pulmonary capillary hemangiomatosis (PCH) belongs to the WHO group 1 pulmonary hypertension (PH), labeled as pulmonary arterial hypertension (PAH), though it mainly involves pulmonary veins, venules and capillaries. PVOD/PCH may occur as a pure form, with other types of PH, or with fibrotic interstitial lung diseases (ILDs). Recognition of PVOD/PCH is crucial as vasodilators used in PAH patients may cause severe pulmonary edema in PVOD/PCH patients. Since biopsy is relatively contraindicated in PAH given the high risk of complication, high resolution computed tomography (HRCT) plays an important role in the diagnosis of PVOD. Centrilobular ground-glass opacities (cGGO), interlobular septal thickening (IST) and mediastinal lymphadenopathy (mLAD) have been described as the triad of HRCT findings for PVOD/PCH but the sensitivity and specificity of this triad in different settings of PVOD/PCH have not been well characterized. In the present study, we compared the clinical and HRCT findings in different settings of PVOD/PCH. Cases of PVOD/PCH diagnosed with surgical lung biopsy, explant or autopsy were identified from the pathology archives (2003-2026) and categorized into 3 groups: pure PVOD/PCH (group 1, n = 14), PVOD/PCH with other types of PH (group 2, n = 3), and PVOD/PCH with fibrotic ILD (group 3, n = 6) after re-review of all slides to confirm the diagnosis. Clinical and radiologic findings were systematically evaluated and compared across these 3 groups. Mean ages at diagnosis were 51, 39, and 58 years in groups 1, 2, and 3, respectively. Median values for mean pulmonary arterial pressure were 51.0, 55.0, and 49.0 mmHg in groups 1, 2, and 3, respectively. There was no significant difference in sex or smoking status across the 3 groups. HRCT showed following results in groups 1, 2 and 3: cGGO in 57.1%, 66.7%, and 0% (p = 0.03); IST in 64.3%, 66.7% and 16.7%; mLAD in 85.7%, 66.7%, 83.3%. At least two of the three features of the triad of cGGO, IST, and mediastinal LAD were present in 10 of 14 (71.4%), 2 of 3 (66.7%), and 1 of 6 (16.7%) of group 1, 2 and 3 cases respectively. There was insufficient statistical power to detect potential trends in clinical and radiographic patterns across subgroups (with exception for cGGO), due to the small number of cases. Taken together, some PVOD/PCH cases in all groups of our cohort lacked the triad of HRCT findings and most patients were unsuspected of PVOD/PCH based on clinico-radiologic features. In conclusion, the role of pathologists would be highly important to raise the awareness of potential PVOD/PCH to pulmonologists given the therapeutic implications.
GPNMB immunohistochemistry distinguishes diagnostically challenging cases of lymphangioleiomyomatosis from other mesenchymal neoplasms presenting with cystic lung metastases.
Ji SF, Law ME, Dawley JC … +5 more , Manchen PJ, Butt YM, Smith ML, Tazelaar HD, Larsen BT
Hum Pathol · 2026 Jun · PMID 42269880 · Publisher ↗
Lymphangioleiomyomatosis (LAM) is a low-grade neoplasm in the family of perivascular epithelioid cell (PEComa) tumors with myomelanocytic differentiation. Metastatic LAM causes cystic lung disease, but diagnosis may be h...
Lymphangioleiomyomatosis (LAM) is a low-grade neoplasm in the family of perivascular epithelioid cell (PEComa) tumors with myomelanocytic differentiation. Metastatic LAM causes cystic lung disease, but diagnosis may be hampered by low tumor burden, limited expression of melanocytic markers, and pathologic mimics that can also cause cystic lung metastases. Glycoprotein non-metastatic melanoma protein B (GPNMB) is an emerging marker for PEComas, but its diagnostic utility in distinguishing LAM from pathologic mimics remains incompletely understood. Biopsies of cystic lung metastases were retrieved including LAM (n = 17), gynecologic metastasizing leiomyoma or low-grade leiomyosarcoma (n = 10), endometrial stromal sarcoma (n = 6), cellular fibrous histiocytoma/dermatofibroma (n = 3), angiosarcoma (n = 3), and non-LAM PEComa (n = 1). GPNMB immunohistochemistry was performed on each case, quantified, and compared to melan-A, HMB45, MiTF, and cathepsin K. All 17 LAM cases and one non-LAM PEComa expressed GPNMB, with most LAM cases showing expression in >75% of tumor cells. GPNMB also highlighted alveolar macrophages and two metastatic dermatofibromas, representing potential diagnostic pitfalls. Cathepsin K also diffusely highlighted LAM and the non-LAM PEComa. In contrast, expression of other melanocytic markers in LAM varied and was often absent or minimal. Our data show that GPNMB is highly expressed by LAM in the lung, with immunohistochemistry performance similar to cathepsin K but superior to traditional melanocytic markers. GPNMB may be useful to confirm diagnostically challenging cases of LAM and to exclude most non-PEComatous mimics presenting with cystic lung metastases, but metastatic dermatofibromas can be a diagnostic pitfall.
CAR-T cell therapy and its complications: Role of the pathologist in diagnosis.
Sarami I, Medeiros LJ
Hum Pathol · 2026 Jun · PMID 42264273 · Publisher ↗
CAR-T cell therapy has transformed the treatment of patients with hematologic malignancies but has also introduced a spectrum of post-therapy complications that frequently require histopathologic evaluation. While clinic...
CAR-T cell therapy has transformed the treatment of patients with hematologic malignancies but has also introduced a spectrum of post-therapy complications that frequently require histopathologic evaluation. While clinical toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are well characterized, the pathologist's role in interpreting post-CAR-T biopsy specimens remains underdefined and challenging. In this review, we focus on the histopathologic, immunophenotypic, and molecular features of post-CAR-T complications, including cytopenias, immune effector cell-associated syndromes, therapy-related myeloid neoplasms, secondary malignancies, and CAR-derived lymphoproliferations. We emphasize diagnostic pitfalls, differential diagnoses, and practical approaches to distinguishing reactive, inflammatory and neoplastic processes. Our aim in this review is to provide a pathology-centered framework to guide accurate diagnosis, prevent misclassification and support clinical decision-making in the evolving landscape of CAR-T therapy.
Multi-omics profiling identifies HMGA2 fusions as defining a distinct and prognostically favorable subtype of dedifferentiated liposarcoma with rhabdomyosarcomatous differentiation.
Zhang X, Shen X, Chen P … +14 more , Xian X, Qu C, Yang Y, Chen J, Chen J, Lu C, Chen X, Zhang Z, Li J, Wang Z, Ge M, Han T, Chen D, Hu W
Hum Pathol · 2026 Jun · PMID 42250699 · Publisher ↗
Dedifferentiated liposarcoma (DDLPS) with rhabdomyosarcomatous differentiation is associated with a poorer prognosis compared to other DDLPS subtypes. This highlights the importance of exploring its clinicopathological,...
Dedifferentiated liposarcoma (DDLPS) with rhabdomyosarcomatous differentiation is associated with a poorer prognosis compared to other DDLPS subtypes. This highlights the importance of exploring its clinicopathological, immune microenvironment, and molecular characteristics to inform personalized treatment strategies. In this study, we investigated five DDLPS patients with rhabdomyosarcomatous differentiation, summarizing their clinicopathological features, immune landscape through immunohistochemistry, and molecular alterations via next-generation sequencing (NGS) analysis, including both DNA and RNA sequencing. Additionally, we conducted a comparative analysis between the well-differentiated (WD) and dedifferentiated (DD) components within these tumors. Our findings identified recurrent HMGA2 fusions, including HMGA2-C12orf74, HMGA2-LPP, HMGA2-BASP1, HMGA2-NAV3, HMGA2-MYF6, and MYO10-HMGA2, which were mutually exclusive with MYC amplification. Notably, these HMGA2 fusions were associated with a more favorable prognosis, demonstrating a mean relapse-free time of 24.0 months, compared to only 2 months in patients without the fusion (P = 0.039). Chromosomal alterations were frequently observed, with 12q amplification being the most prevalent across all 10 tumor samples (5 DD and 5 WD components). Furthermore, DD components exhibited significantly higher levels of copy number variations (CNVs) than their WD counterparts (P = 0.01), with 15q loss exclusively detected in DD components (P < 0.01). In terms of the immune microenvironment, both DD and WD components showed significant infiltration of T cells and M2 macrophages. However, CD20 B cells were more abundant in WD components compared to DD components. Additionally, DD components harboring MYC amplification exhibited a more immunosuppressive state than those containing HMGA2 fusions, further underscoring the heterogeneity of these tumors. In conclusion, our multi-omics analysis identifies HMGA2 fusion as a promising diagnostic and prognostic biomarker for DDLPS with rhabdomyosarcomatous differentiation. The comprehensive molecular and immune landscape of this tumor subtype not only deepens our understanding of its pathophysiology but also provides critical insights for future precision medicine strategies.
Practical approaches to the diagnosis and differential diagnosis of T-lymphoblastic leukemia/lymphoma.
Wang WJ, Khoury JD, Fang H … +2 more , Medeiros LJ, Wang W
Hum Pathol · 2026 Jun · PMID 42248336 · Publisher ↗
T-lymphoblastic leukemia/lymphoma is a malignant neoplasm derived from T-cell precursors. These neoplasms can present initially as acute lymphoblastic leukemia (ALL) involving bone marrow or lymphoblastic lymphoma (LBL)...
T-lymphoblastic leukemia/lymphoma is a malignant neoplasm derived from T-cell precursors. These neoplasms can present initially as acute lymphoblastic leukemia (ALL) involving bone marrow or lymphoblastic lymphoma (LBL) involving lymph nodes, mediastinum or other extramedullary sites. Bone marrow and extramedullary tissue involvement frequently coexist. In this review, we begin with a short review of the clinical and morphologic features of ALL/LBL. We then focus on the immunophenotypic features of T-ALL/LBL. We delineate lineage-defining T-cell markers and immaturity-associated markers for the diagnosis and summarize immunophenotypic subtypes of T-ALL/LBL. Lastly, we discuss the differential diagnosis of T-ALL/LBL and address the challenges in distinguishing this neoplasm from acute undifferentiated leukemia, acute myeloid leukemia with minimal differentiation, mixed-phenotype acute leukemia, mature T-cell neoplasms, NK-cell neoplasms, T-lymphoblastic phase of chronic myeloid neoplasm, thymoma, indolent T-lymphoblastic proliferation, and blastic plasmacytoid dendritic cell neoplasm.
Contemporary approach to diagnosis and classification of acute myeloid leukemia.
Loneman DM, Nardi V, Hasserjian RP
Hum Pathol · 2026 Jun · PMID 42248335 · Publisher ↗
The term acute myeloid leukemia (AML) refers to a group of myeloid neoplasms characterized by maturation arrest, classically defined as ≥20% myeloblasts or myeloblast equivalents in the peripheral blood or bone marrow. I...
The term acute myeloid leukemia (AML) refers to a group of myeloid neoplasms characterized by maturation arrest, classically defined as ≥20% myeloblasts or myeloblast equivalents in the peripheral blood or bone marrow. In recent decades, a wealth of genetic information has reshaped our understanding of AML biology and enabled recognition of discrete molecular subgroups. However, questions remain, especially regarding which genetic lesions are class-defining and which are, at most, prognostic. These questions acquired particular salience with the advent of two classification systems, the 2022 International Consensus Classification and the WHO 5th Edition (WHO), replacing the prior WHO revised 4th Edition. While efforts are underway to unite current classification schemes, it is essential for pathologists to understand the rationale behind AML classification in the interest of patient care. Given the growing complexity in this area, this review aims to provide a practical guide for AML diagnosis and contemporary classification while highlighting areas of active inquiry which may inform future classification.
Metastatic malignant non-cervical gynecological tumors involving the genitourinary system: A contemporary clinicopathologic analysis of 27 patients.
Haw Y, Osunkoya AO
Hum Pathol · 2026 Jun · PMID 42242397 · Publisher ↗
INTRODUCTION: Metastatic non-cervical gynecological tumors involving the genitourinary system have not been well characterized. MATERIALS AND METHODS: A search was conducted through our urologic pathology and expert cons...
INTRODUCTION: Metastatic non-cervical gynecological tumors involving the genitourinary system have not been well characterized. MATERIALS AND METHODS: A search was conducted through our urologic pathology and expert consultation files of the senior author. Clinical data was extracted from electronic medical records. RESULTS: Twenty-seven patients were included in the study. Mean patient age was 60 years (range: 29-81 years). The most common site of origin was the ovary (19/27, 70%) with predominantly serous carcinomas. The second most common site was the endometrium (6/27, 22%), predominantly consisting of endometrioid adenocarcinoma (3/6, 50%). Other sites of origin included fallopian tube (2/27, 8%). The most common genitourinary system site of involvement was bladder (16/27, 59%). Other sites included peritoneum overlying the bladder (9/27, 33%), perivesical soft tissue (1/27, 4%), and perinephric soft tissue (1/27, 4%). The stages of the primary tumors in patients with resection specimens were originally categorized as pT2 in 3/25 (12%) and pT3 in 22/25 (88%). Nodal status in patients with lymph node excisions was pN1 in 9/10 (90%) and pN0 in 1/10 (10%). Follow-up data was available for 19/27 (70%) patients and 8/19 (42%) died of widespread metastatic disease, with a median survival of 48 months (range: 8-135 months). CONCLUSIONS: This is one of the largest studies to date of metastatic non-cervical gynecological tumors involving the genitourinary system. Our study demonstrates that these tumors most commonly arise from the ovary and endometrium, with the bladder representing the predominant genitourinary system site of secondary involvement. Pathologists need to be aware of potential diagnostic pitfalls associated with these tumors that may occasionally mimic primary bladder neoplasms with divergent differentiation.
Thymic hyperplasia with lymphoepithelial sialadenitis-like features A single-institution series of 21 new cases.
Weissferdt A, Medeiros LJ, Moran CA
Hum Pathol · 2026 Jun · PMID 42242396 · Publisher ↗
Thymic hyperplasia with lymphoepithelial sialadenitis-like features (TH-LESA) is a rare tumor-like condition of the thymus gland with less than 50 cases reported in the literature. Named after its resemblance to lymphoep...
Thymic hyperplasia with lymphoepithelial sialadenitis-like features (TH-LESA) is a rare tumor-like condition of the thymus gland with less than 50 cases reported in the literature. Named after its resemblance to lymphoepithelial sialadenitis (LESA) of the salivary glands, TH-LESA is a distinct form of thymic hyperplasia characterized by simultaneous epithelial and lymphoid hyperplasia. Recently, TH-LESA has been linked with autoimmune diseases (AID) and a potential for developing thymic lymphoma. We report 21 additional cases of surgically resected TH-LESA in 15 women and 6 men (mean age 53 years, range 29-74); most cases were identified incidentally. Eleven (52%) patients were African American, 7 (33%) were white and 1 (5%) was Asian; race was unknown for 2 patients. Five (24%) patients had a history of non-myasthenic AID, including systemic lupus erythematosus, Sjögren syndrome, and rheumatoid arthritis. Two (9.5%) patients developed lymphoma within the hyperplastic process: 1 extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) and 1 nodular sclerosis Hodgkin lymphoma (NSHL). Clinical follow-up revealed that 11 patients were alive 3 to 240 months postoperatively and 1 patient had died of cardiac disease; follow-up was unavailable for 9 patients. In this largest single-institution series to date, we confirm the reported association of TH-LESA with AID and lymphoma. Recognition of NSHL developing in TH-LESA expands the spectrum of lymphomas reported in association with this condition. Furthermore, TH-LESA appears to preferentially affect African American women, unlike patients with salivary gland LESA, perhaps providing an epidemiologic clue to its pathogenesis.
Clinicopathological significance of methylthioadenosine phosphorylase (MTAP) expression loss in hepatobiliary tumors.
Sasaki M, Sato Y, Nakanuma Y
Hum Pathol · 2026 Jun · PMID 42242395 · Publisher ↗
BACKGROUNDS: Expression loss of methylthioadenosine phosphorylase (MTAP), a tumor suppressor gene often co-deleted with CDKN2A/B, is a useful diagnostic marker of malignant tumors, such as mesothelioma, and a potential t...
BACKGROUNDS: Expression loss of methylthioadenosine phosphorylase (MTAP), a tumor suppressor gene often co-deleted with CDKN2A/B, is a useful diagnostic marker of malignant tumors, such as mesothelioma, and a potential therapeutic target. METHODS: We examined immunohistochemically a prevalence, clinicopathological significance and a usefulness as a diagnostic marker of MTAP expression loss in 35 hepatocellular carcinomas (HCCs), 43 small duct type intrahepatic cholangiocarcinomas (SD-iCCAs), 35 large duct type iCCAs (LD-iCCAs), 81 combined HCC-CCAs (cHCC-CCAs), 32 extrahepatic (ExH) CCAs, 29 intraductal papillary neoplasms (IPNBs) and 32 bile duct adenomas (BDAs). We also examined 52 bile duct biopsy samples (26 CCAs, 9 IPNBs, 17 non-neoplastic lesions) for MTAP expression loss. RESULTS: MTAP expression loss was detected in HCC, 20%; SD-iCCA, 21%; LD-iCCA, 35%; cHCC-CCA, 21%; ExH-CCA, 19%; IPNB, 7% (all with invasive carcinoma) and BDA, 0% (p < 0.01, BDA vs others; p < 0.05, IPNB vs LD-iCCA). cHCC-CCA and SD-iCCA with MTAP-loss were associated with less frequency of hepatitis C-related (p < 0.05) and less frequency of hTERT promoter mutations (p < 0.01). MTAP expression loss was significantly correlated to a deletion of p16 expression (p < 0.01). In bile duct biopsy samples, MTAP expression loss was detected in CCAs, 31%; IPNBs, 11%; non-neoplastic, 0%. The sensitivity and specificity were 30.7% and 100% for MTAP as a diagnostic marker. CONCLUSIONS: About 20% of hepatobiliary carcinomas showed MTAP expression loss, which may benefit from MTAP-directed therapies. MTAP expression loss may be a diagnostic marker for malignant hepatobiliary tumors. MTAP-deleted CCAs and cHCC-CCAs may represent a distinct group of hepatobiliary tumors.
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