Mod. Pathol. [JOURNAL]
Sun
200 papers
Low-Grade Myofibroblastic Sarcoma Represents an Epigenetically Distinct Myofibroblastic Tumor With USP6 Upregulation and Stable Genome.
Yeung MCF, Cheung HMH, Liu APY … +1 more , Shek TWH
Mod Pathol · 2026 Jun · PMID 41966275 · Publisher ↗
Low-grade myofibroblastic sarcoma (LGMS) is a rare, indolent mesenchymal neoplasm exhibiting myofibroblastic differentiation, with a propensity for local recurrence. The molecular basis of LGMS and its precise relationsh...
Low-grade myofibroblastic sarcoma (LGMS) is a rare, indolent mesenchymal neoplasm exhibiting myofibroblastic differentiation, with a propensity for local recurrence. The molecular basis of LGMS and its precise relationship with other histological mimics have remained largely undefined. To address this gap, we conducted the first comprehensive multiomics analysis of 6 LGMS cases, integrating whole-exome sequencing, RNA sequencing, and Illumina Methylation EPICv2 array profiling with comparative analysis against public sarcoma methylation cohorts and related fibroblastic tumors. Clinically, patients (median age 35.5 years) presented with small tumors (median size 1.45 cm), predominantly located in the head and neck, displaying classic histological features of diffusely infiltrative spindle cell fascicles with patchy mononuclear inflammation. Two of the 5 patients with follow-up developed local recurrence, and none metastasized (median follow-up duration 92.5 months). Genomically, all LGMS exhibited a low tumor mutational burden (median 2.31 mut/Mb) and a minimal fraction of genome altered, with TP53 and TSC2 deletions and NTRK1 and ERBB3 amplifications found in a subset of cases. No pathogenic fusions were detected. Transcriptomic profiling revealed a distinct signature featuring prominent USP6 overexpression and upregulation of inflammatory and immune-related genes, including CD274 (PD-L1), and enrichment of inflammatory and interferon-gamma response signatures. Epigenetically, LGMS formed a unique methylation cluster closest to inflammatory myofibroblastic tumor, with numerous differentially methylated regions and higher immune infiltration, particularly monocytes, compared with other fibroblastic tumors. These findings establish LGMS as a genomically stable, epigenetically distinct myofibroblastic sarcoma driven by USP6 overexpression and an inflammation-enriched transcriptome. They support its recognition as a standalone entity, facilitate integration into methylation-based sarcoma classifiers for improved diagnostic precision, and nominate USP6-associated pathways and immune checkpoint blockade as promising therapeutic strategies for recurrent or unresectable disease.
Stage-Independent Real-Time Subtype Classification and Comprehensive Biopsy Profiling of Urothelial Carcinomas by the Lund Taxonomy System.
Eriksson P, Cotillas EA, Mattsson CA … +7 more , Zadoroznyj A, Bernardo C, Sjödahl G, Edsjö A, Heidenblad M, Liedberg F, Höglund M
Mod Pathol · 2026 Jun · PMID 41936844 · Publisher ↗
Bladder cancer is a heterogeneous malignancy with diverse clinical outcomes, and conventional pathological assessment alone is insufficient to capture its underlying biology. Gene expression profiling can stratify tumors...
Bladder cancer is a heterogeneous malignancy with diverse clinical outcomes, and conventional pathological assessment alone is insufficient to capture its underlying biology. Gene expression profiling can stratify tumors into molecular subtypes with prognostic and predictive potential, but the reliability of transcriptomic classification and its clinical utility remains to be established. The translational/observational UROSCANSEQ study (ISRCTN15459149) prospectively evaluates RNA-based Lund Taxonomy (LundTax) molecular subtype classification in a clinical setting. Among 784 consecutive biopsies collected between 2018 and 2022, RNA sequencing was successful for 90% of all biopsies, encompassing 662 bladder cancer patients with a stage distribution of 48% Ta, 27% T1, 24% ≥T2, and 1% CIS. We demonstrate that the LundTax subtype classification algorithm, applied to individual samples, accurately identifies cancer cell phenotypes with characteristic gene and protein expression patterns in a manner robust to RNA quality, data preprocessing strategies, and batch effects, supporting its clinical feasibility across both non-muscle-invasive and muscle-invasive disease. We further extend the LundTax framework by incorporating single-sample molecular risk scores reflecting tumor grade, proliferation, and progression risk, as well as tumor microenvironment signatures. Both risk scores and overall immune and stromal content in biopsies were significantly associated with an increased risk of clinical progression in noninvasive disease. In a separate analysis of the relative cellular composition of the tumor microenvironment, however, only the fraction of natural killer cells remained significant. Together, the expanded LundTax system provides a comprehensive molecular portrait of individual tumor biopsies. By explicitly separating cancer cell-intrinsic phenotypes, prognostic indexes, and microenvironmental signals, the framework minimizes biological confounding and establishes a strong foundation for future studies evaluating clinical outcomes and treatment responses.
Genetic, Immunohistochemical and mRNA In Situ Hybridization Profiling of Condyloma with Concurrent Squamous Cell Carcinoma and High-Grade Squamous Intraepithelial Lesion.
Samghabadi P, Ding C, Khorsandi N … +3 more , Lu KL, Devine WP, Gasper C
Mod Pathol · 2026 Jun · PMID 41936843 · Publisher ↗
Condyloma acuminatum is a human papilloma virus (HPV)-associated papillary lesion of the lower anogenital tract. Although a majority are benign, rarely the coexistence of high-grade squamous intraepithelial lesion (HSIL)...
Condyloma acuminatum is a human papilloma virus (HPV)-associated papillary lesion of the lower anogenital tract. Although a majority are benign, rarely the coexistence of high-grade squamous intraepithelial lesion (HSIL) or invasive squamous cell carcinoma (SCC) with condyloma has been reported, which is important to recognize and diagnose. In this study, we examined the clinicopathologic, immunohistochemical (IHC), and HPV mRNA in situ hybridization (RISH) signal patterns of 63 condylomas, 35 condylomas with concurrent HSIL, 15 condylomas with concurrent SCC, 8 warty HSILs, and 17 warty SCCs. The genetic features of 10 condylomas with concurrent SCC and 14 warty SCCs were also examined. The search included cases in all sites of the lower anogenital tract. HPV-independent lesions were excluded. Our findings show that condylomas with concurrent HSIL or SCC often display different patterns of p16 immunohistochemical (IHC) staining and low-risk and high-risk (HR) HPV RISH-staining patterns depending on the area of the lesion evaluated. Our findings also support previous studies showing that condylomas can harbor both and low-risk and HR-HPV types either alone or in combination. HR-HPV RISH signal patterns were also more varied in condylomas with concurrent HSIL and SCC compared with warty HSIL or warty SCC. Follow-up data revealed that 38% of condylomas recurred and 26% progressed to HSIL. For condylomas with concurrent HSIL, 43% recurred and 9% progressed to SCC. Condylomas with concurrent SCC were associated with mutations in ASXL1, TERT, and CDKN2A/CDKN2B, whereas warty SCC was associated with mutations in PIK3CA, KMT2C, and FAT1.
SH2D1A/SAP Reflects Immune Activation in Melanoma and Is a Superior Predictive Biomarker of Immune Checkpoint Inhibitor Response: A Proteomic Analysis.
Fusco F, Weigel J, Schliemann M … +12 more , Schneider A, Zhou Y, Persa OD, Posch C, Krackhardt A, Förg S, Schott C, Steiger K, Mogler C, Gaumann A, Kuster B, Kuhn PH
Mod Pathol · 2026 May · PMID 41887467 · Publisher ↗
Immune checkpoint inhibitors (ICIs) have markedly improved outcomes in malignant melanoma, yet accessible, tissue-based predictive biomarkers of response remain limited. PD-L1 expression, which remains widely used, offer...
Immune checkpoint inhibitors (ICIs) have markedly improved outcomes in malignant melanoma, yet accessible, tissue-based predictive biomarkers of response remain limited. PD-L1 expression, which remains widely used, offers some prognostic value but performs poorly at low expression levels. We performed liquid chromatography-mass spectrometry proteomic profiling on 185 melanoma samples, including 52 pretreatment samples from ICI responders and nonresponders. Differential expression and pathway analyses identified a 73-protein immune activation signature correlating with ICI response. Within this immune context, SH2D1A (SAP), a regulator of T- and natural killer-cell cytotoxicity, emerged as a top candidate biomarker. Internal immunohistochemical validation confirmed its strong predictive accuracy (area under the receiver operating characteristic curve: 0.93; sensitivity: 88%; specificity: 91%) in distinguishing responders from nonresponders, outperforming PD-L1, CD3, and CD8. Notably, SH2D1A retained its predictive power in PD-L1-low tumors (combined positive score < 10), suggesting clinical use in which the current markers fall short. Independent validation in an external tissue microarray cohort revealed attenuated predictive performance, likely reflecting the impact of intratumoral heterogeneity, as further suggested by whole-slide validation. Nevertheless, SH2D1A remained significantly enriched in tumors that responded to ICIs and was associated with improved survival outcomes, outperforming CD3, CD8, and PD-L1. In conclusion, these results suggest that SH2D1A provides information beyond established immune infiltration- and exhaustion-related markers, supporting further investigation of its potential role in biomarker-guided prediction of ICI response in melanoma.
Defining Prognostic Markers and Clinical Outcomes in Epithelioid Malignant Peripheral Nerve Sheath Tumor.
Richman LP, Michaels PD, Nief C … +7 more , Jo VY, Hariri DJ, Nielsen GP, Dong F, Mazzola E, Hornick JL, Schaefer IM
Mod Pathol · 2026 May · PMID 41881192 · Publisher ↗
Epithelioid malignant peripheral nerve sheath tumor (EMPNST) is recognized as a distinct entity in the 2026 World Health Organization classification, defined by characteristic morphology and frequent SMARCB1 (INI1) loss,...
Epithelioid malignant peripheral nerve sheath tumor (EMPNST) is recognized as a distinct entity in the 2026 World Health Organization classification, defined by characteristic morphology and frequent SMARCB1 (INI1) loss, which differentiates it from conventional MPNST. Limited data suggest EMPNST may have a more favorable prognosis, but prognostic markers remain undefined. We studied 78 primary EMPNSTs and compared them with 60 conventional MPNSTs. Patients with EMPNST included 41 females and 37 males, with a median age of 45 (range, 6-84) years. Necrosis was observed in 20% of cases, cytologic atypia was mild (25%), moderate (57%), or severe (18%), and mitoses ranged from 0 to 42/10 (median 7/10) high-power fields. SMARCB1 loss was observed in 81% of EMPNSTs and correlated with prominent nucleoli (64%, P < .001). EMPNSTs predominantly arose in the lower extremities, with 32% superficial, whereas conventional MPNSTs were mostly truncal. Targeted sequencing in 34 EMPNSTs identified SMARCB1 inactivation in 77% of cases, which was associated with SMARCB1 loss (P < .001), and recurrent alterations targeting 2q35/XRCC5 in 59% of cases. Among 34 patients with follow-up (median, 43 months; range, 0-225), 9 developed local recurrence, 15 metastases, and 10 died of disease. Compared with conventional MPNST, EMPNST demonstrated longer median progression-free survival (34 vs 19 months, P value for global difference of survival curves = .35); overall survival was not reached in EMPNST (vs 85 months in conventional MPNST, P value for global difference of survival curves = .16). In multivariable analysis, tumor size and mitotic rate were independently associated with poor prognosis (hazard ratio [HR], 5.2; 95% CI, 1.5-17.7; HR, 1.1; 95% CI, 1.01-1.2, respectively). A risk score integrating tumor size > 5 cm, mitoses > 7 of 10 high-power fields, and necrosis predicted poor outcomes (HR, 4.1; 95% CI, 1.4-12). In conclusion, EMPNST tumor size and mitotic activity are key prognostic factors, supporting a simple risk stratification model. SMARCB1 inactivation is the most frequent genomic event, followed by gains at 2q35 potentially targeting XRCC5, highlighting molecular underpinnings for this distinct sarcoma subtype.
Recurrent Epidermal Growth Factor Receptor 2 (ERBB2) Mutations Drive the Pathogenesis of Multifocal Neurofibroma Variants.
Yeung MCF, Lefkowitz RA, Antonescu CR
Mod Pathol · 2026 May · PMID 41881191 · Publisher ↗
Recurrent Epidermal Growth Factor Receptor 2 (ERBB2) mutations have been recently documented in a small group of hybrid neurofibroma/schwannoma peripheral nerve sheath tumors (PNST) in patients with presumed sporadic sch...
Recurrent Epidermal Growth Factor Receptor 2 (ERBB2) mutations have been recently documented in a small group of hybrid neurofibroma/schwannoma peripheral nerve sheath tumors (PNST) in patients with presumed sporadic schwannomatosis. Prompted by 2 cases of plexiform neurofibromas harboring ERBB2 hotspot mutations, but lacking germline alterations, we sought to investigate the clinicopathologic features of PNST demonstrating this genetic alteration. ERBB2-mutant PNST cases were selected from the institutional molecular database, using a matched tumor-normal targeted DNA-sequencing panel. Clinical history, radiologic findings, and follow-up information were retrieved from chart review. Pathologic features, and genomic and germline findings, were reviewed. We identified 5 patients; all except 1 were women, with a median age of 34 years (range: 24-40 years). All revealed multiple PNSTs with a segmental distribution on imaging, including the pelvis (n = 2), upper limb (n = 2), and stomach (n = 1). None of the patients had a family history or displayed clinical features of neurofibromatosis type 1, except for 1 patient with faded café-au-lait macules. All excised lesions were neurofibromas, including plexiform (n = 4), intraneural with Schwann cell micronodule (n = 2), and diffuse (n = 1) subtypes. None of the cases showed features of schwannoma. All cases harbored ERBB2 kinase domain mutations (exon 19, n = 3; exon 20, n = 2; exon 21, n = 1). One additional case had 2 concurrent ERBB2 mutations in exons 20 and 21. On germline testing, only 1 patient showed pathogenic variants (MUTYH mutation). None showed germline or somatic alterations in NF1, NF2, SMARCB1, and LZTR1 or chromosome 22q loss. Patients had stable disease with no significant radiologic progression or malignant transformation, 1 being enrolled on an HER2 inhibitor trial for 7 years owing to unresectable disease with satisfactory disease control. PNST harboring oncogenic ERBB2 mutations are multifocal, spanning various neurofibroma variants, including plexiform type, in the absence of clinical or germline evidence of syndromic disease. Our findings suggest ERBB2 mutations may represent an alternative mechanism driving neurofibroma genesis, with potential therapeutic implications.
Dentinogenic Ghost Cell Tumor Harbors CTNNB1 Hotspot Mutations and Forms a Histologic Spectrum With Adenoid Ameloblastoma.
Oh KY
Mod Pathol · 2026 May · PMID 41875734 · Publisher ↗
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Multiple Myeloma and Mimicry: Gastrointestinal Tract Histologic Findings in Patients Following Chimeric Antigen Receptor T-cell Therapy and Anti-CD38 Monoclonal Antibodies.
Ortiz Requena D, Montgomery EA, Ronquillo NR … +2 more , Garcia-Buitrago M, Yantiss RK
Mod Pathol · 2026 May · PMID 41864428 · Publisher ↗
Chimeric antigen receptor T-cell (CAR-T) therapy is a type of immunotherapy that uses genetically engineered T-cells with synthetic receptors targeting malignant cells that express specific antigens. CAR-T therapy primar...
Chimeric antigen receptor T-cell (CAR-T) therapy is a type of immunotherapy that uses genetically engineered T-cells with synthetic receptors targeting malignant cells that express specific antigens. CAR-T therapy primarily targets B-cell maturation antigen expressed by multiple myeloma and CD19 expressed in several lymphoid malignancies. Data regarding patterns of gastrointestinal injury associated with CAR-T therapy are limited, and thus, we conducted this study to characterize the changes observed in biopsy samples from patients who have received this treatment. We retrospectively reviewed 14 cases from 8 patients who received CAR-T therapy, including 43 sets of mucosal biopsies and 3 surgical resection specimens. Information regarding symptoms, endoscopic findings, medications, and infections was recorded. The study patients were adults (mean age, 63 years; median, 62.5 years) and included 5 men and 3 women. Seven had refractory/relapsed multiple myeloma, and 1 had diffuse large B-cell lymphoma. Gastrointestinal symptoms included diarrhea (88%) or nausea and/or vomiting (22%), which developed a mean of 294 days (range, 41-700 days) after CAR-T therapy. Endoscopic findings were variable; a minority of patients had normal examinations or only mild erythema, whereas others had mucosal granularity and ulcers in the upper and lower gastrointestinal tract. Five patients underwent evaluation for gastrointestinal infection; enteropathogenic Escherichia coli was detected in 1 patient. None of the patients received any medications known to cause gastrointestinal injury for at least 3 months before the endoscopic procedure. Tissue samples contained regenerative-appearing glands and/or crypts lined by cells with attenuated cytoplasm; apoptotic epithelial cells and intraepithelial lymphocytosis were uniformly present, being most pronounced in the deep mucosa. Inflammation was minimal; the lamina propria was mostly hypocellular to normocellular with decreased or absent plasma cells. Immunohistochemical stains were negative for cytomegalovirus and adenovirus. Our findings suggest that CAR-T therapy causes gastrointestinal injury characterized by epithelial cell apoptosis and intraepithelial lymphocytosis and predominantly affects crypts and glands in the deep mucosa. Recognizing this pattern may help pathologists suggest the presence of CAR-T therapy-induced injury in the appropriate clinical context.
Evaluation of DICER1 Immunohistochemistry as a Potential Surrogate for Mutation Status in Ovarian Sex Cord-Stromal Tumors.
Němejcová K, Hájková N, Kendall Bártů M … +10 more , Šafanda A, Švajdler M, Shatokhina T, Laco J, Matěj R, Hausnerová J, Škarda J, Náležinská M, Zima T, Dundr P
Mod Pathol · 2026 May · PMID 41839237 · Publisher ↗
Diagnosing ovarian sex cord-stromal tumors can be difficult in some cases due to the overlapping morphologic and immunohistochemical (IHC) features, especially for adult granulosa cell tumors (AGCTs), juvenile granulosa...
Diagnosing ovarian sex cord-stromal tumors can be difficult in some cases due to the overlapping morphologic and immunohistochemical (IHC) features, especially for adult granulosa cell tumors (AGCTs), juvenile granulosa cell tumors (JGCTs), Sertoli-Leydig cell tumors (SLCTs), and thecomas. In such situations, molecular testing can be helpful, as these tumors are often associated with specific genetic alterations. SLCTs, for instance, are known to be associated with DICER1 mutations. However, expression of DICER1 has not yet been systematically investigated in sex cord-stromal tumors. We evaluated the potential use of DICER1 IHC for detecting DICER1 mutations in ovarian sex cord-stromal tumors, including 267 AGCTs, 38 SLCTs, 5 JGCTs, and 21 Leydig cell tumors/steroid cell tumors (SCTs). Specifically, DICER1 positivity was found in 21 of 38 (55.3%) of SLCTs and 16 of 21 (76.2%) of SCTs. All DICER1-positive moderately differentiated SLCTs harbored a DICER1 mutation. One DICER1-negative moderately differentiated SLCT carried 2 DICER1 mutations. Additionally, 3 of 10 well-differentiated SLCTs showed IHC positivity. No SCT harbored a DICER1 mutation. Among AGCTs, 4 of 267 (1.5%) were DICER1 positive, and 1 of these cases harbored 2 DICER1 mutations. No JGCT demonstrated a DICER1 mutation or expression. In cases with both analyses available, DICER1 expression was found in 39 of 273 (14.3%), whereas 21 of 273 (7.7%) harbored a DICER1 mutation. Using an optimal cutoff of ≥10% positive tumor cells, IHC closely matched mutational status (sensitivity of 90.5%, specificity of 92.1%). Our study found substantial concordance between DICER1 IHC and mutation status in a subset of sex cord-stromal tumors, suggesting that IHC detection of DICER1 protein may serve as a useful surrogate marker for DICER1 mutation, especially in SLCTs and AGCTs. This could be particularly valuable in settings where molecular testing is limited by cost and/or availability. However, in SCTs, the DICER1 expression is common but unrelated to DICER1 mutation. This suggests that alternative mechanisms, potentially involving androgen-related pathways, may contribute to DICER1 expression in these tumors.
Comprehensive Clinicopathologic Evaluations of 149 Metaplastic Carcinomas of the Breast Treated With Neoadjuvant and Adjuvant Chemotherapy.
Xu J, Gao Y, Liu Y … +14 more , Zhang H, Zhang G, Hou Y, Guo H, Wei S, Yang W, Hsiao WY, Meisel J, Kalinsky K, King T, Peng L, Lin X, Chang J, Li X
Mod Pathol · 2026 May · PMID 41839236 · Publisher ↗
Metaplastic breast cancer (MBC) is a rare subtype of breast cancer, and its clinical presentations and outcome are not clear. This multi-institutional study comprehensively evaluated the clinicopathologic features, treat...
Metaplastic breast cancer (MBC) is a rare subtype of breast cancer, and its clinical presentations and outcome are not clear. This multi-institutional study comprehensively evaluated the clinicopathologic features, treatment patterns, and outcomes of 149 MBC cases. In total, 149 MBC cases diagnosed from 2005 to 2023 were included and compared with 350 non-MBC triple-negative breast cancer (TNBC) cases diagnosed from 2004 to 2019: 62 MBCs and 174 TNBCs were treated with neoadjuvant chemotherapy (NACT) and 87 MBCs and 176 TNBCs with adjuvant chemotherapy (ACT). We evaluated pathologic variables, including necrosis, lymphovascular invasion, tumor-infiltrating lymphocytes (TILs), tumor nuclear grade, Nottingham grade, tumor size, the presence of ductal carcinoma in situ, and the presence and percentage of different metaplastic components. Clinical data, including age, race, estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status, local recurrence-free survival, and metastasis-free survival (MFS), were retrieved. The median follow-up time was 58.9 months for all patients. Only 8.1% of patients with MBC (n = 5) achieved pathologic complete response (pCR) when treated with NACT compared with 37.9% of TNBC patients (P < .0001). None of the patients with MBC who achieved pCR developed metastasis. No clinicopathologic variables were associated with the pCR rate in MBC. The proportion of metaplastic components was not associated with the pCR rate or MFS in MBC cases. Patients with MBC treated with NACT had significantly shorter MFS than those treated with ACT (P = .011). In patients with MBC who did not achieve pCR after NACT, larger tumor size was associated with shorter MFS (P < .001). In patients with MBC who received ACT, higher TILs level was associated with longer MFS (P = .016). This study with large cohorts showed patients with MBC had a low pCR rate to NACT, and those patients who achieved pCR had excellent prognosis. Therefore, it is important to identify which patients benefit from NACT. The proportion of metaplastic component was not associated with the pCR rate or MFS, supporting the current recommendation that breast carcinoma with any metaplastic component should be diagnosed as MBC. Finally, higher TILs levels were associated with improved MFS in patients with MBC treated with ACT. Further investigation is warranted to define biomarkers and patient selection for NACT versus ACT in MBC.
Ultramutated Colonic Adenocarcinoma With Mismatch Repair Deficiency and Distinctive Mutational Signature Following Solid Organ Transplantation.
Ling-Lin Pai E, Halper-Stromberg E, Herzog C … +2 more , Odintsov I, Baranov E
Mod Pathol · 2026 Apr · PMID 41806570 · Publisher ↗
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Comprehensive Cytogenomic Profiling of T-Lymphoblastic Leukemia Using Optical Genome Mapping, Karyotyping, and Next-Generation Sequencing.
Tang G, Reynolds A, Ravandi-Kashani F … +15 more , Medeiros LJ, Kornblau SM, Jabbour EJ, Jain N, Short NJ, Hu S, Wei Q, Loghavi S, Ok CY, Toruner G, Ling J, Liang S, Verma T, Zou YS, Wang SA
Mod Pathol · 2026 May · PMID 41796805 · Publisher ↗
In this study, we used optical genome mapping (OGM), conventional karyotyping, and next-generation sequencing to analyze cytogenomic alterations in 91 cases of T-cell acute lymphoblastic leukemia/lymphoma (T-ALL). Wherea...
In this study, we used optical genome mapping (OGM), conventional karyotyping, and next-generation sequencing to analyze cytogenomic alterations in 91 cases of T-cell acute lymphoblastic leukemia/lymphoma (T-ALL). Whereas karyotyping detected abnormal karyotypes in 55% of cases, OGM identified cytogenetic abnormalities in 97.8% of the cases and provided clinically relevant information beyond karyotyping in ∼70% of cases. OGM detected gene rearrangements in 80% of cases, including 24 recurrent gene fusions and 21 previously unreported putative gene fusions in T-ALL. Copy number variants were detected in 93% of cases, with interstitial deletions the most common. Gene mutations were detected in 93% of cases, with NOTCH1 being most frequent (in 57% of cases). Combining all data, most T-ALL cases harbored 3 or more cytogenomic aberrations. Specific cytogenomic alterations differed among T-ALL subtypes as follows: rearrangements of BCL11B and PICALM::MLLT10, deletions of 7p, and mutations involving DNMT3A, WT1, TET2, IDH2, and FLT3 were common in early T-precursor and near-early T-precursor subtypes. Rearrangements of TLX1, KMT2A, STIL::TAL1, and NUP214::ABL1, deletions of 9p, and FBXW7 mutations were frequently associated with the cortical subtype. We conclude that integration of OGM and next-generation sequencing with karyotyping enables comprehensive cytogenomic profiling of T-ALL that improves detection of clinically relevant genomic alterations and may inform disease classification and future studies of risk stratification.
NKG2C Improves Diagnostic Specificity of Natural Killer (NK) Cell Receptor Restriction by Identifying Nonneoplastic Adaptive NK Cell Clones.
Wilk AJ, Gitana G, Oak J
Mod Pathol · 2026 May · PMID 41786213 · Publisher ↗
Natural killer (NK) cell neoplasms are a diverse group of entities with often nonspecific clinical presentations, making immunophenotyping essential for diagnosis. Immunophenotyping using flow cytometry can identify clon...
Natural killer (NK) cell neoplasms are a diverse group of entities with often nonspecific clinical presentations, making immunophenotyping essential for diagnosis. Immunophenotyping using flow cytometry can identify clonal NK cell populations by detecting restricted expression patterns of NK cell receptors such as killer cell immunoglobulin-like receptors (KIRs). However, reactive NK cells may also demonstrate KIR restriction through expansion of self-KIR-expressing NK cells, leading to identification of NK clones of uncertain significance (NK-CUS). A well-described reactive NK subset, termed "adaptive" NK cells, arises in response to cytomegalovirus (CMV) infection or reactivation, is often KIR-restricted, and is defined by coexpression of CD57 and the activating receptor NK group 2, member C (NKG2C). Because CMV reactivation is common among patients undergoing evaluation for hematolymphoid malignancy, we hypothesized that NK-CUS may frequently correspond to this nonneoplastic adaptive NK cell subset. Here, we described a flow cytometry panel for immunophenotypic characterization of cytotoxic lymphocytes that includes NKG2C, enabling detection of nonneoplastic adaptive NK cells. We showed that NK-CUS frequently represent reactive NKG2C adaptive NK cells. We described several cases that meet diagnostic criteria for NK-large granular lymphocytic leukemia and demonstrated that the NK cell clones are nonneoplastic NKG2C adaptive NK cells arising in the setting of CMV viremia. Further, we showed that NKG2C expression is uncommon in neoplastic NK cell proliferations with recurrent molecular or cytogenetic abnormalities. Collectively, we demonstrated that NKG2C has a high specificity for reactive NK cell populations, and its inclusion in NK cell immunophenotyping panels is a useful strategy to more reliably distinguish between neoplastic and reactive NK cell populations.
Investigating Genetic Risk to Oxaliplatin-Induced Sinusoidal Obstruction Syndrome in Colorectal Cancer Through Routinely Available Next-Generation Sequencing Data.
Zhang M, Wang P, Kong Y … +5 more , Gaudio DD, Parente N, Hayden A, Setia N, Hart J
Mod Pathol · 2026 May · PMID 41786212 · Publisher ↗
Sinusoidal obstruction syndrome (SOS) is a known adverse effect of oxaliplatin, causing significant morbidity and cessation of chemotherapy. Recent studies suggest single-nucleotide polymorphisms of certain genes may pre...
Sinusoidal obstruction syndrome (SOS) is a known adverse effect of oxaliplatin, causing significant morbidity and cessation of chemotherapy. Recent studies suggest single-nucleotide polymorphisms of certain genes may predispose carriers to oxaliplatin-induced liver toxicity. This study aims to evaluate candidate SOS-predisposing single-nucleotide polymorphisms by correlating routinely available next-generation sequencing (NGS) data with clinical and histologic evidence of SOS. Seventy-nine colorectal cancer cases with liver metastases and clinical NGS data were identified. A combination of clinical, biochemical, and histologic criteria was used to identify 12 cases with confirmed SOS. In addition, 10 control cases were selected with no clinical or histologic evidence of SOS. Clinical data and SOS-related findings were collected. For each patient, the expanded panel NGS data obtained for clinical management were reanalyzed to assess 12 polymorphisms in ERCC1, ERCC2, ABCB1, GSTP1, DPYD, MTHFR, ABCC2, UGT1A1, GSTT1, and GSTM1 known to be associated with oxaliplatin toxicity, as identified in the PharmGKB database. Statistical analyses, including the Fisher exact test and odds ratios, were performed. The strongest nominal signal was observed in the prevalence of ERCC1 rs11615 (A>G) in SOS and control groups (allelic P = .006; false discovery rate q = 0.072). The odds ratio for developing SOS associated with rs11615 (A>G) was 0.15 (95% CI: 0.04-0.59), indicating a protective effect of ERCC1 rs11615 (A>G). There was a noticeable numerical increase in ascites frequency, levels of aspartate aminotransferase and alanine aminotransferase, and the frequency of neuropathy in the SOS group, although not statistically significant. These findings highlight the use of expanded analysis of routinely obtained NGS panel results at the time of colorectal cancer diagnosis at many medical centers to personalize the chemotherapy regimen. Our data suggest that patients who carry the ERCC1 rs11615 (A>G) variant may be protected from developing oxaliplatin-induced SOS, and those lacking the G allele should be monitored more carefully after oxaliplatin use.
Primary Angiosarcomas of the Thyroid: New Insights Into the Genetic Background and Potentially Targetable Therapeutic Markers of an Ultrarare Disease.
Ingenwerth M, Pretzell I, Bednaric E … +8 more , Basol C, Herold T, Kalbourtzis S, Brandenburg T, Machlah Y, Führer-Sakel D, Hamacher R, Theurer S
Mod Pathol · 2026 May · PMID 41786211 · Publisher ↗
Thyroid angiosarcomas (TASs) are listed as a distinct entity in the World Health Organization classification of malignant tumors and represent highly aggressive neoplasms, with early metastasis and overall survival of fe...
Thyroid angiosarcomas (TASs) are listed as a distinct entity in the World Health Organization classification of malignant tumors and represent highly aggressive neoplasms, with early metastasis and overall survival of few months. Owing to their rarity, data on tumorigenesis, molecular alterations, and potential therapeutic targets remain limited. We present a series of 16 primary TAS subjected to systematic molecular profiling and immunohistochemical assessment of clinically relevant, druggable biomarkers, such as fibroblast activation protein (FAP), SSTR2A, claudin 18.2, FOLR1, PD-L1, HER2, TROP2, and nectin-4. Next-generation sequencing was used to detect pathogenic DNA alterations, complemented by an RNA-based Archer fusion assay for gene fusion detection. MYC gene amplification was evaluated by fluorescence in situ hybridization. The cohort comprised 13 male and 3 female patients, with a median age of 71 years. PD-L1 expression was identified in 62.5% of tumors, whereas FAP and TROP2 were positive in 56% and 37.5%, respectively. Claudin 18.2 expression was observed in 1 case and weak SSTR2A staining in 2 cases. FOLR1, HER2, and nectin-4 were uniformly negative. Molecular analysis revealed pathogenic alterations in 56% of tumors, predominantly TP53 mutations, accompanied by additional variants affecting mitogen activated kinase- and PI3K-related pathways. No oncogenic gene fusions were detected. MYC gene amplification was present in 31% of cases. This study represents the largest cohort of primary TAS reported to date and provides an expanded characterization of their molecular and immunophenotypic features. The frequent expression of PD-L1 and FAP highlight potential avenues for targeted therapy. The broader-than-expected mutational landscape, including recurrent TP53 mutations, alterations in mitogen activated kinase and PI3K pathways, and notable MYC amplification, further refines current understanding of TAS biology. These findings offer a basis for the development of prospective therapeutic strategies in this rare and aggressive malignancy.
Clinical Utility of Next-Generation Sequencing in Tumors Diagnosed as Lung Squamous Cell Carcinoma: Real-World Data of Diagnostic and Therapeutic Implications.
Odintsov I, Siegmund SE, Pecci F … +6 more , Ricciuti B, LoPiccolo J, Sands JM, Wang CI, Sholl LM, Dong F
Mod Pathol · 2026 May · PMID 41786210 · Publisher ↗
Lung squamous cell carcinoma (LUSC) is the second most common subtype of non-small cell lung carcinoma (NSCLC), typically associated with a poor prognosis. Unlike lung adenocarcinoma, the application of next-generation s...
Lung squamous cell carcinoma (LUSC) is the second most common subtype of non-small cell lung carcinoma (NSCLC), typically associated with a poor prognosis. Unlike lung adenocarcinoma, the application of next-generation sequencing (NGS) in LUSC has lagged because of the long-standing perception of low therapeutic yield, primarily based on highly selected, resected cohorts. We sought to determine the real-world clinical utility of NGS in LUSC. We analyzed an institutional cohort of 576 tumors initially diagnosed as LUSC that underwent NGS profiling. We defined "clinical yield" as either diagnostic reclassification or the identification of a targetable mitogenic alteration. Twenty cases (3.5%) were reclassified, including rediagnosis to cutaneous squamous cell carcinoma, transformed adenocarcinoma (post targeted therapy), and rare entities such as nuclear protein of the testis-rearranged carcinoma and lymphoepithelial carcinoma. Primary mitogenic drivers were identified in 83 cases (14.4% of the total cohort), of which 43 (7.5% of the total cohort) harbored alterations with currently Food and Drug Administration-approved therapies for NSCLC (including KRAS, EGFR, MET, ALK, and ROS1). Overall clinical yield-defined as the sum of diagnostic reclassifications and identification of NSCLC-specific targetable alterations-was 11.0% (63/576). Univariate and multivariate analysis demonstrated that never or light smoking history was the strongest independent predictor of clinical yield, with 57.3% of tumors in this subset being reclassified or harboring a strong driver. Our findings demonstrate that NGS provides significant diagnostic and therapeutic value in a real-world LUSC cohort, challenging the historical premise of low yield. Although clinicodemographic features can help prioritize testing in resource-limited settings, the identification of targetable drivers across all smoking groups supports the universal application of comprehensive NGS for all patients diagnosed with LUSC.
Cutaneous Epithelioid/Pleomorphic Rhabdomyosarcoma, Melanoma in Disguise? An Immunohistochemical, Molecular, and Epigenetic Study of 13 Patients.
Ulici V, Ameline B, John I … +12 more , Dermawan JK, Karunamurthy A, Dehner CA, Fernandez AP, Azzato E, Hattery T, Kilpatrick SE, Isaacson AL, Ko JS, Fritchie KJ, Baumhoer D, Billings SD
Mod Pathol · 2026 May · PMID 41780801 · Publisher ↗
Rhabdomyosarcomatous transdifferentiation is a rare but well-documented phenomenon in melanoma, and, in these cases, recognition of a conventional component by either morphology or immunophenotype is essential for the co...
Rhabdomyosarcomatous transdifferentiation is a rare but well-documented phenomenon in melanoma, and, in these cases, recognition of a conventional component by either morphology or immunophenotype is essential for the correct diagnosis. However, tumors that are entirely transdifferentiated can be impossible to distinguish from primary rhabdomyosarcoma. We analyzed a cohort of cases diagnosed as cutaneous epithelioid/pleomorphic rhabdomyosarcoma using genetic/epigenetic techniques and compared them with melanoma. Cases diagnosed as cutaneous epithelioid/pleomorphic rhabdomyosarcoma were retrieved, and clinicopathologic features were documented. NRAS p.Q61R and BRAF p.V600E immunohistochemistry, targeted DNA next-generation sequencing, and DNA methylation profiling were performed. A total of 13 cases of cutaneous epithelioid/pleomorphic rhabdomyosarcomas were identified in 10 males and 3 females (62-90 years; median, 83 years). Cases included tumors arising in the head and neck (n = 9), upper extremity (n = 2), lower extremity (n = 1), and back (n = 1). Using immunohistochemistry, 1 tumor (of 13) was positive for NRAS Q61R; all were negative for BRAF V600E expression (0/13). Targeted DNA next-generation sequencing revealed 1 case each to harbor HRAS c.34G>A p.G12S and BRAF c.1363G>A p.G455R mutations, respectively. Tumor mutation burden was interpretable in 5 cases and ranged from 3 to 80 Mut/Mb (median 38 Mut/Mb); 4 of 5 cases had tumor mutation burden > 10 Mut/Mb. A DNA UV light mutational signature was present in all cases with evaluable data (6/6). DNA methylation profiling showed 7 (of 9) cases to cluster with desmoplastic melanoma, whereas 1 case formed a partial match for head and neck squamous cell carcinoma, and the final case matched with TFCP2-rearranged rhabdomyosarcoma. At the last follow-up, 4 patients died from the disease, 2 died from unknown causes, 2 were alive without disease, and 1 was alive with disease. The majority of cutaneous epithelioid/pleomorphic rhabdomyosarcoma show clinical, genetic, and epigenetic profiles similar to melanoma, suggesting that a major subset represents transdifferentiated melanoma.
Emerging Molecularly Defined Bone and Soft Tissue Diagnoses: When Do They Matter?
Davis JL, Samiei A
Mod Pathol · 2026 Apr · PMID 41759784 · Publisher ↗
With the rapid advancement of molecular pathology and the explosion of genomic data, our understanding of neoplasms continues to evolve. In this review, we introduce 3 recently classified mesenchymal neoplasms, the categ...
With the rapid advancement of molecular pathology and the explosion of genomic data, our understanding of neoplasms continues to evolve. In this review, we introduce 3 recently classified mesenchymal neoplasms, the categorization of which was refined based on their underlying molecular genetic profiles. These entities were recently highlighted by the senior author at the United States and Canadian Academy of Pathology Long Course. To underscore the importance of their proper recognition, this review was prepared to reach a broader audience. Recognition of these tumors is particularly important because their mimickers often have markedly disparate prognoses and management strategies, making accurate diagnosis critical. The 3 entities discussed in this study are the following: (1) SRF-rearranged myoid neoplasms (formerly cellular myofibroma), (2) superficial CD34-positive fibroblastic tumors, and (3) kinase-altered spindle cell neoplasms. This review aimed to highlight the key clinicopathologic features of these tumors to facilitate accurate diagnosis, discuss ancillary studies that assist in navigating the differential diagnoses, and outline strategies to avoid common diagnostic pitfalls. Finally, we emphasize when molecular characterization may be necessary to guide diagnosis and support appropriate clinical management.
Complexity and Challenges of Translating the Dark Zone Signature Into Immunohistochemistry in Diffuse Large B-Cell Lymphoma.
Momose S, Sawada K, Nedeva T … +12 more , Yamamoto W, Yamashita T, Imada H, Takayanagi N, Naganuma K, Takahashi Y, Tabayashi T, Adachi A, Higashi M, Scott DW, Rosenwald A, Rauert-Wunderlich H
Mod Pathol · 2026 Apr · PMID 41747827 · Publisher ↗
Diffuse large B-cell lymphoma/high-grade B-cell lymphoma with MYC and BCL2 rearrangements (DLBCL/HGBCL-MYC/BCL2) is a distinct disease entity with worse prognosis and is usually diagnosed with identification of MYC and B...
Diffuse large B-cell lymphoma/high-grade B-cell lymphoma with MYC and BCL2 rearrangements (DLBCL/HGBCL-MYC/BCL2) is a distinct disease entity with worse prognosis and is usually diagnosed with identification of MYC and BCL2 rearrangements by fluorescence in situ hybridization analysis. Recent progress in gene expression analysis has identified a dark zone signature (DZsig), which characterizes a gene expression profile (GEP) for DLBCL/HGBCL-MYC/BCL2. Notably, DZsig includes both MYC/BCL2-double-hit and non-double-hit cases with DLBCL and high-grade and Burkitt morphologies; importantly, the latter group is present in numbers that are comparable with or greater than the former group. Although GEP analysis can identify cases exhibiting HGBCL-like biology regardless of double-hit status, GEP analysis will not be globally applied to DLBCL cases because of cost and equipment constraints. Therefore, simpler surrogate approaches for detecting DZsig, such as immunohistochemistry (IHC), are desired. Here, we attempted to develop an IHC approach that can serve as an alternative to GEP or fluorescence in situ hybridization assays using 287 tumors with DLBCL morphology, regardless of double-hit status. Our strategy for detecting DZsig by IHC (IHC-DZ) is based on a 2-step algorithm, which involves applying the Hans classifier and antibodies to MYC, ALOX5, and LMO2. The DZ-IHC algorithm had a sensitivity, specificity, positive predictive value, and negative predictive value of 76.2%, 95.5%, 59.3%, and 98.1%, respectively. The 5-year overall survival rates were 55% for IHC-DZ germinal center B-cell (GCB)-type tumors, 82% for IHC-DZ GCB-type tumors, and 69% for non-GCB-type tumors (P < .01), which is similar to that reported using the GEP assay. To date, this represents the largest cohort evaluated for DZsig selection by IHC; nevertheless, the algorithm is not yet adequate for routine application owing to its suboptimal positive predictive value, and further improvements are needed for clinical implementation.
Tumor Deposits in Staging of Colorectal Cancer: Implications for Treatment Strategies.
Peparini N
Mod Pathol · 2026 Apr · PMID 41740436 · Publisher ↗
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