Mod. Pathol. [JOURNAL]
Sun
200 papers
Artificial Intelligence-informed Architectural Insights of 3-dimensional Glandular Networks Identify Patients With Prostate Cancer at a Higher Risk of Biochemical Recurrence.
Salguero-Lopez J, Medina S, Serafin R … +16 more , Wang R, Abdeltawab H, Manandhar S, Mutha P, Dhamdhere R, Chow S, Bishop KW, Daniel RE, Tokuyama N, Pathak T, True LD, Corredor G, Romero E, Lal P, Liu JTC, Madabhushi A
Mod Pathol · 2026 May · PMID 42190816 · Publisher ↗
Pathologists diagnose and grade prostate cancer using thin 2-dimensional (2D) histologic sections, but these 3 to 5 micron sections are too thin to visualize complete glandular networks and 3-dimensional (3D) spatial rel...
Pathologists diagnose and grade prostate cancer using thin 2-dimensional (2D) histologic sections, but these 3 to 5 micron sections are too thin to visualize complete glandular networks and 3-dimensional (3D) spatial relationships of adenocarcinomas. We hypothesized that understanding volumetric glandular organization would reveal architectural features associated with prostate cancer progression and biochemical recurrence (BCR). We analyzed 2 archived prostatectomy cohorts using different sampling methods: simulated 1 mm core-needle biopsies from the University of Washington and 3 × 1 mm-punch biopsies from the University of Pennsylvania. We used open-top light-sheet microscopy to visualize intact tissue networks and developed GlaSkeN, a computational pathology framework to quantify 3D prostatic gland architecture. GlaSkeN used deep learning to segment glandular structures from 3D images and then constructed skeleton-based representations to extract volumetric features, including branch length, branching angles, torsion, and curvature. We analyzed associations between architectural features and 5-year BCR-free survival using 6-fold cross-validated Cox regression. GlaSkeN identified 3D architectural features significantly associated with BCR in both cohorts: the University of Washington (hazard rati [HR], 5.18; 95% CI, 1.18-22.68; C-index = 0.68; P = .019) and the University of Pennsylvania (HR, 2.04; 95% CI, 1.14-3.65; C-index = 0.62; P < .05). In multivariable analysis, GlaSkeN remained prognostic after controlling for clinicopathological variables (HR, 2.30; 95% CI, 1.13-4.7; P = .021). Limitations include different sampling methods between cohorts and limited sample sizes. This 3D analysis captured glandular organization, spatial connectivity, and branching patterns unassessable in 2D cross-sections. GlaSkeN identified glandular architecture features associated with BCR independent of standard clinical variables, suggesting 3D architecture could provide additional prognostic information to complement current histopathological grading. Validation in larger independent cohorts is warranted.
Multiomics Integration Identifies a Molecular Subtype of Intrahepatic Cholangiocarcinoma With Enhanced Benefit From Adjuvant Therapy.
Li Z, Li H, Rong W … +9 more , Sun B, Wang B, Li J, Yuan Y, Zhang H, Wang B, Shi S, Wu F, Xiao T
Mod Pathol · 2026 May · PMID 42173286 · Publisher ↗
Intrahepatic cholangiocarcinoma (iCCA) is a molecularly heterogeneous liver cancer with a poor prognosis. Improved stratification is needed to guide postoperative therapy. In this study, we applied integrative multiomics...
Intrahepatic cholangiocarcinoma (iCCA) is a molecularly heterogeneous liver cancer with a poor prognosis. Improved stratification is needed to guide postoperative therapy. In this study, we applied integrative multiomics analysis to classify iCCA and identify biomarkers predictive of adjuvant treatment benefit. Using publicly available datasets (including whole exome sequencing, RNA sequencing, proteomics, and phosphoproteomics from FU-iCCA cohort and a transcriptomic cohort GSE244807), we defined 3 robust molecular subtypes of iCCA. These subtypes exhibited distinct genomic alterations, pathway activation, and immune microenvironments, with significant differences in overall survival (OS). Through protein-protein interaction network analysis and consensus feature selection using 10 clustering algorithms, we prioritized 8 marker genes distinguishing the subtypes. A Cox proportional-hazards model constructed from these markers stratified patients into high- and low-risk groups. High-risk iCCA, characterized by elevated expression of markers such as CLDN18, MUC1, and MUC5AC, had significantly worse OS in the absence of adjuvant therapy. Notably, in an independent validation of 174 patients with iCCA who underwent resection (single-center cohort), high expression of any of these 3 markers were associated with markedly prolonged OS in patients who received adjuvant chemotherapy or chemoembolization, compared with those who did not. In contrast, marker-negative patients showed no clear benefit from adjuvant therapy. In conclusion, our multiomics approach identified a high-risk, mucin-enriched subtype of iCCA. CLDN18, MUC1, and MUC5AC emerge as candidate predictive biomarkers for adjuvant chemotherapy benefit in iCCA, warranting prospective validation to improve personalized postoperative management.
Genetic Profile, Treatment Response, and Outcomes of BCR::ABL1-Positive Mixed-Phenotype Acute Leukemia: A Study From the BCR::ABL1 Pathology Group.
Shen Q, Huang X, Wang X … +17 more , Shuai W, Fang H, Jabbour E, Chen W, Tashakori M, Khanlari M, Wu X, Shao L, Zhang L, El Hussein S, Konoplev S, Khoury JD, Tang G, Wang W, Wang SA, Medeiros LJ, Hu S
Mod Pathol · 2026 May · PMID 42173285 · Publisher ↗
Mixed-phenotype acute leukemia (MPAL) with BCR::ABL1 fusion is rare, and its clinicopathological features, genetic landscape, therapeutic response, and patient outcomes remain incompletely defined, as does its relationsh...
Mixed-phenotype acute leukemia (MPAL) with BCR::ABL1 fusion is rare, and its clinicopathological features, genetic landscape, therapeutic response, and patient outcomes remain incompletely defined, as does its relationship to blast-phase chronic myeloid leukemia. In this multicenter study of 44 patients, 86.4% had B/myeloid MPAL, 72.7% showed lymphoid predominance, 40.9% had complex karyotypes, and 68.3% harbored somatic mutations, most commonly RUNX1 mutations (46.3%). RUNX1 mutations frequently co-occurred with acute myeloid leukemia (AML)-associated alterations, whereas DNMT3A, TET2, and BCORL1 mutations were restricted to RUNX1-mutated cases. In contrast, acute lymphoblastic leukemia (ALL)-associated alterations (IKZF1 mutation/deletion and ETV6 mutations) were confined to RUNX1-wild-type patients. TP53 and signaling pathway mutations (NRAS, KRAS, PTPN11, and FLT3) were not detected. Forty-two patients received induction chemotherapy and/or immunotherapy combined with tyrosine kinase inhibitors: 74.2% of lymphoid-predominant patients and 63.6% of myeloid-predominant patients received ALL- and AML-type therapies, respectively. Ten patients relapsed, and 2 had primary refractory disease; some exhibited a dynamic shift in predominant lineage immunophenotype, chromosomal alterations, and somatic mutations at the relapse or refractory stage. The overall remission rate was 86.8%, with no significant differences across ALL-, AML-, or hybrid-type regimens. After a median follow-up of 24.2 months, the median overall survival was 52.5 months. Complex karyotype was associated with inferior overall survival compared with cases lacking additional chromosomal alterations (P = .02), whereas RUNX1 mutations were not. No significant differences in genetic profiles, treatment response, or outcomes were observed between patients with and without chronic myeloid leukemia-like features. This study provides a comprehensive genomic and clinical characterization of BCR::ABL1-positive MPAL, supporting improved risk stratification and future therapeutic strategies.
Recurrent SWI/SNF Deficiency Defines a Subset of Peripheral T-Cell Lymphoma With Distinct Clinicopathologic Features.
Bledsoe JR, Ferry JA, Li J … +23 more , Sassoon A, Stonhill MA, Siegele B, Liang X, Dalton J, Mochel MC, Ivashkevich Y, Johari V, Sadigh S, Selove W, Sood S, Ward N, Woda B, Degar B, Feraco AM, Rowe J, Davies K, Al-Ibraheemi A, Amador C, Kovach AE, Fleming MD, Harris MH, Tsai HK
Mod Pathol · 2026 May · PMID 42162914 · Publisher ↗
Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) rarely occurs in pediatric and young adult populations, where little is known about its clinicopathologic and molecular features. We characterized 16 cases...
Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) rarely occurs in pediatric and young adult populations, where little is known about its clinicopathologic and molecular features. We characterized 16 cases of PTCL, NOS diagnosed in patients ≤21 years old. Seven (44%) cases demonstrated SMARCB1/INI1 loss by immunohistochemistry and SMARCB1/INI1 alterations by next-generation sequencing, including biallelic SMARCB1/INI1 deletion (n = 4), stop codon variant with 1-copy deletion (n = 1) or copy-neutral loss-of-heterozygosity (n = 1), and frameshift variant (n = 1). One case demonstrated biallelic SMARCE1 alterations (a nonsense variant and copy-neutral loss-of-heterozygosity), which, to our knowledge, has not been previously described in a hematopoietic neoplasm. The SWI/SNF-intact group harbored pathogenic TET2, PTEN, EZH2, or TP53 variants. CDKN2A deletions were present in 3 of 7 SWI/SNF-deficient and 0 of 4 SWI/SNF-intact cases. Chromosome 22q11.2 alterations were present on karyotype in 2 of 3 SMARCB1/INI1-deficient cases. SWI/SNF deficiency was associated with intermediate-to-large cell cytomorphology, frequent mitotic (88%; P = .041) and apoptotic (88%) activity, Reed-Sternberg-like cells (63%), necrosis (50%), and fibrosis (50%). All cases expressed CD45 and CD43 at initial diagnosis. SWI/SNF-deficient cases predominantly demonstrated a CD4/CD8, TCRab, and PTCL-GATA3 phenotype, whereas SWI/SNF-intact cases predominantly demonstrated a CD8/CD4, TCRgd, and PTCL-TBX21 phenotype. A PTCL-TBX21 phenotype was more common in SWI/SNF-intact than in SWI/SNF-deficient cases (P = .041). Cytotoxic markers were expressed in 71% of SWI/SNF-deficient and 88% of SWI/SNF-intact cases. Decreased or absent CD3 expression characterized 88% of SWI/SNF-deficient and 13% of SWI/SNF-intact cases (P = .01). Moreover, 63% of SWI/SNF-deficient cases demonstrated decreased or absent expression of ≥3 pan-T-cell antigens, compared with 13% of SWI/SNF-intact cases. Treatment was heterogeneous. Primary treatment failure or relapse occurred in 4 of 8 SWI/SNF-deficient and 4 of 7 SWI/SNF-intact cases. The median overall survival and event-free survival were 48.7 and 47.5 months for the SWI/SNF-deficient group, and 16.4 and 8.9 months for the SWI/SNF-intact group (P = nonsignificant). Death due to disease or therapy-related complications occurred in 4 of 8 (50%) cases in the SWI/SNF-deficient group and 6 of 7 (86%) of cases in the SWI/SNF-intact group. Our findings expand the knowledge of the clinicopathologic and molecular features of pediatric PTCL and highlight SWI/SNF-deficient T-cell lymphoma as a biologically distinct type of PTCL that is associated with characteristic clinicopathologic features.
VGLL3-Rearranged Spindle Cell Rhabdomyoblastic Tumor: A Clinicopathologic and Molecular Genetic Study of 18 Cases With Consistently Indolent Behavior.
Baranov E, Ameline B, Berthold R … +27 more , Perry KD, Torres-Mora J, Maclean F, Abrahao-Machado LF, Michal M, Kerr DA, Lu L, Hou T, Malik F, Goldfaden JS, Prasad JL, Gestrich C, Stelow E, Fanburg-Smith JC, LeGallo R, Zadeh S, Haglund de Flon F, Zhang PJ, Hartmann W, Miele E, Stejskal V, Alaggio R, Agaimy A, Nielsen GP, Demicco EG, Baumhoer D, Dehner CA
Mod Pathol · 2026 May · PMID 42128056 · Publisher ↗
A rare spindle cell tumor with a skeletal muscle phenotype, male predilection, exclusive involvement of the head and neck region, particularly the tongue, and a suggested indolent course has been previously reported as v...
A rare spindle cell tumor with a skeletal muscle phenotype, male predilection, exclusive involvement of the head and neck region, particularly the tongue, and a suggested indolent course has been previously reported as vestigial-like 3 (VGLL3)-rearranged spindle cell rhabdomyosarcoma (SRMS). We report 18 cases with extended clinical follow-up, detailed molecular results, and methylation profiling. Tumors occurred in 5 females, 12 males, and 1 patient of unknown sex with a median age of 58 years (range, 22-71). Tumors involved the tongue (n = 13), lower lip (2), retropharyngeal region (n = 1), thyroid/parathyroid (n = 1), and palatine tonsil (1), with a median size of 1.2 cm. Treatment details (15 patients) revealed that 13 patients underwent excision only, whereas 1 patient underwent adjuvant chemotherapy and 1 patient underwent adjuvant radiation therapy. Follow-up (11 patients) showed no local recurrence or metastases. At the last follow-up (median, 45 months; range, 1-326 months), all patients were alive without evidence of disease. Histologically, tumors showed spindled to histiocytoid cells arranged in a fascicular, storiform, or haphazard architecture with variably collagenous stroma, rounded to infiltrative borders, and often diffusely growing through skeletal muscle, adipose tissue, and entrapped nerves. Necrosis was consistently absent with a median mitotic rate of 1/10 high-power fields (range, 0-7/10). By immunohistochemistry, tumors diffusely expressed desmin (n = 18), multifocal MyoD1 (n = 15), and/or myogenin (n = 12), and sometimes smooth muscle actin (n = 7). Molecular testing revealed EP300::VGLL3 (n = 6), TCF12::VGLL3 (n = 5), and PPARGC1A::VGLL3 (n = 1) fusions with VGLL3 rearrangement by fluorescence in situ hybridization in 3 cases. One archival tumor failed molecular and methylation testing despite multiple attempts, likely due to decreased DNA/RNA integrity, yet was included given classic morphologic features. Methylation data (n = 12) revealed that all but 1 tumor formed a distinct group separate from other fusion-driven rhabdomyosarcomas, including 5 infantile/congenital SRMS. We describe a well-characterized series of these rare tumors with extended follow-up data confirming lack of progression or recurrence. Furthermore, our DNA methylation profiling data support the view that these tumors form a distinct cluster, regardless of VGLL3 fusion partner and are separate from morphologic mimics and other fusion-driven SRMS, including 5 cases of congenital SRMS. We propose that these neoplasms may be better classified as VGLL3-rearranged spindle cell rhabdomyoblastic tumors to reflect their indolent behavior and to prevent overtreatment.
Intraductal Papillary Squamous Neoplasm (IPSN) of the Pancreas: Histological and Molecular Characterization of a Novel and Distinct Intraductal Cancer Precursor.
Bevere M, Pea A, Adsay V … +26 more , Basturk O, Brosens LA, Esposito I, Hruban RH, Klimstra D, Hong SM, Singhi AD, Lee SS, Mattiolo P, Pasini D, Mafficini A, Piccoli P, Pedron S, Ciulla C, Brighenti A, Franzina C, Paiella S, Malleo G, Salvia R, Milella M, De Robertis R, D'Onofrio M, Corbo V, Lawlor RT, Scarpa A, Luchini C
Mod Pathol · 2026 May · PMID 42128055 · Publisher ↗
We report 6 intraductal papillary squamous neoplasms (IPSNs) of the pancreas, a rare but distinctive tumor whose biological features remain largely unknown. Five cases were investigated using an integrated approach combi...
We report 6 intraductal papillary squamous neoplasms (IPSNs) of the pancreas, a rare but distinctive tumor whose biological features remain largely unknown. Five cases were investigated using an integrated approach combining histomorphological evaluation, immunohistochemistry, and multiregional molecular profiling through whole-exome DNA sequencing and whole-transcriptome RNA sequencing. Only targeted DNA sequencing was available on a sixth recently diagnosed case. Histologically, the intraductal lesions were characterized by large, confluent papillae with fibrovascular cores lined by multilayered epithelial cells with diffuse squamous differentiation. All cases harbored a concomitant invasive carcinoma. The associated invasive carcinomas consistently included a pancreatic tubular/ductal adenocarcinoma; in 5 cases, a poorly differentiated squamous cell carcinoma was also present, the proportion/features of which met the diagnostic criteria of adenosquamous carcinoma in 2 of them. Genomic analyses revealed that IPSNs and their matched invasive carcinomas shared the majority of somatic alterations, supporting a shared clonal origin for the 2 components. Activating KRAS mutations and biallelic inactivation of CDKN2A were detected in all cases. Recurrent mutations involved members of the SWI/SNF chromatin-remodeling complex and KMT2D. Additionally, FGFR1 and MYC amplifications were identified in 2 distinct cases (1 case each). Molecular alterations restricted to the invasive component involved mediators of the transforming growth factor-β signaling pathway. Transcriptomic profiling demonstrated a basal-like expression pattern in all IPSNs and squamous cell carcinomas, although in 2 cases, the matched pancreatic tubular/ductal adenocarcinoma shifted toward a classical transcriptomic subtype. In conclusion, through integrated histological assessment and multiregional molecular sequencing, we demonstrate that IPSN represents a bona fide precursor of invasive pancreatic cancer, a new addition to the intraductal neoplasms category. This study challenges the current paradigm that pancreatic squamous epithelium plays no role in the initiation of pancreatic carcinogenesis, providing the first evidence of its involvement in early tumorigenic processes and yielding immediate implications for pancreatic tumor classification and biological understanding.
Fibrotubular Tumors of the Thyroid: An Emerging Thyroid Neoplasm Characterized by Distinctive Morphology and Recurrent OCLN::PRKCI Gene Fusions Spanning the Adenoma-Carcinoma Spectrum.
Hahn E, Nikitski AV, Wald AI … +4 more , Seethala RR, Chiosea SI, Peel RL, Nikiforov YE
Mod Pathol · 2026 May · PMID 42128054 · Publisher ↗
The histopathologic and genomic landscape of thyroid tumors is well characterized, although new genetic alterations and tumor types are being described. We present 2 cases of thyroid tumors originating from follicular ce...
The histopathologic and genomic landscape of thyroid tumors is well characterized, although new genetic alterations and tumor types are being described. We present 2 cases of thyroid tumors originating from follicular cells that had highly unusual and distinct morphologic features and carried an OCLN::PRKCI gene fusion. These tumors were well circumscribed, encapsulated, and composed of irregularly shaped tubular and follicular structures surrounded by layers of distinct fibrocollagenous basement membrane material positive for type IV collagen and laminin; they showed no definitive nuclear features of papillary carcinoma. Importantly, whereas one of the tumors had no invasive growth, the other demonstrated tumor capsule invasion, compatible with the adenoma-carcinoma spectrum seen in thyroid follicular and oncocytic tumors. Gene expression profiles of these tumors differed from those of common types of papillary thyroid carcinoma. The unusual and reproducible histopathologic characteristics and unique molecular profiles of these tumors support their designation as a distinct type of thyroid neoplasm that exists in noninvasive and invasive forms and, therefore, can be designated as fibrotubular adenoma and carcinoma. Recognition of this distinct entity is important for improving diagnostic accuracy and avoiding overtreatment of this likely indolent type of thyroid neoplasia.
CTNNB1-Mutant High-Grade Endometrial Carcinoma: Clinical Outcome and Prevalence of Pilomatrix-Like and Corded Hyalinized Morphologies in an Institutional Case-Control Series.
Coiner BL, Sharma AE, Ordulu Z … +2 more , Nucci MR, Parra-Herran C
Mod Pathol · 2026 May · PMID 42128053 · Publisher ↗
The occurrence of somatic CTNNB1 pathogenic mutations has been recently recognized in high-grade endometrial carcinoma (HG-EMC) in association with pilomatrix-like (PM-L) morphology and an aggressive clinical course, hig...
The occurrence of somatic CTNNB1 pathogenic mutations has been recently recognized in high-grade endometrial carcinoma (HG-EMC) in association with pilomatrix-like (PM-L) morphology and an aggressive clinical course, highlighting the need for further study on the biologic and clinical importance of CTNNB1 alterations in HG-EMC. Thus, we document the clinical and pathologic characteristics of an institutional cohort of HG-EMC with and without CTNNB1 alterations. Of all the HG-EMCs subjected to next-generation sequencing in a 10-year period, those with pathogenic CTNNB1 alterations were selected (CTNNB1mut), along with a control group matched based on age and histologic type (CTNNB1wt). An additional search for institutional HG-EMCs with abnormal nuclear β-catenin expression and/or related morphologies was performed. All cases with material available were reviewed for the presence of PM-L, solid basaloid morphology with geographic necrosis (SB-GN), and corded and hyalinized characteristics. The following 27 molecularly confirmed CTNNB1mut HG-EMC were identified: 17 of 27 (63%) were of the nonspecific molecular profile (NSMP), 9 of 27 (33%) were mismatch repair deficient (MMRd), and 1 of 27 (4%) were POLE mutant. Five additional HG-EMC cases with abnormal β-catenin were included. All were endometrioid grade 3 (26/32; 81%) or dedifferentiated (6/32; 19%). Compared with CTNNB1wt controls (n = 50), which mostly presented with International Federation of Gynecology and Obstetrics stage I disease, CTNNB1mut HG-EMC were more frequently International Federation of Gynecology and Obstetrics stages III and IV (P = .0005) and NSMP (63% vs 22%; P = .0005). Although there was no statistical difference in survival between CTNNB1mut and CTNNB1wt groups, when separated based on molecular group, MMRd CTNNB1mut showed significantly worse disease-specific survival than MMRd CTNNB1wt HG-EMC. Among cases amenable to morphologic review (CTNNB1mut n = 26; CTNNB1wt n = 37), PM-L features were only seen in 8 CTNNB1mut HG-EMCs and none of the controls. SB-GN features were observed in both the cohorts. Corded and hyalinized morphology was not observed. HG-EMCs with driver CTNNB1 mutations were endometrioid or dedifferentiated and belonged to the NSMP and MMRd molecular groups. Importantly, they were more likely to present at an advanced clinical stage compared with CTNNB1wt tumors. Moreover, we found significant survival differences in MMRd HG-EMC based on CTNNB1 status. SB-GN was common in HG-EMC but not specific. Conversely, PM-L when strictly defined (requiring central keratinization with shadow cells) was specific for CTNNB1mut status.
RNF43 Mutations Are Associated With the Classical Molecular Subtype, Vigorous Antitumor Immune Responses, and Prolonged Survival in Pancreatic Adenocarcinoma.
Wenning AS, Bräutigam K, Aeschbacher P … +4 more , Acharjee A, Gloor B, Perren A, Karamitopoulou E
Mod Pathol · 2026 May · PMID 42107534 · Publisher ↗
RNF43 mutations were correlated with microsatellite status in colorectal cancer and with fewer and later recurrences in pancreatic ductal adenocarcinoma (PDAC). Here, we undertake a detailed assessment of RNF43 mutations...
RNF43 mutations were correlated with microsatellite status in colorectal cancer and with fewer and later recurrences in pancreatic ductal adenocarcinoma (PDAC). Here, we undertake a detailed assessment of RNF43 mutations in PDAC. A total of 313 PDACs (308 microsatellite stable [MSS] and 5 microsatellite-instable [MSI] cases) underwent next-generation sequencing (Oncomine Tumor Mutation Load assay; Thermo Fisher). Spatial analyses (NanoString) classified PDACs according to their transcriptomic and proteomic immune signaling. Fluorescent imaging was used to define spatial compartments (tumor: pancytokeratin/CD45 and leukocytes: pancytokeratin/CD45). Each of 20 PDACs with RNF43 mutations (RNF43) and without RNF43 mutations (RNF43) underwent multiplex immunofluorescence analysis to determine immune status. A total of 153 PDACs (22 RNF43 and 131 RNF43 cases) underwent bulk RNA sequencing to assign into molecular subtypes. Overall, 24 RNF43 mutations were identified (22 MSS PDACs and 2 MSI PDACs). The incidence of RNF43 mutations in MSS PDACs (7.1%) was consistent with The Cancer Genome Atlas (6.7%). However, RNF43 mutations were more frequent among MSI PDACs (40%). Additionally, RNF43 had differential frequencies of other mutations (including Wnt pathway genes), higher tumor mutational burden values (5.5 mut/mb vs 1.67 mut/mb; P < .01), and significantly longer overall survival (47 vs 18 months; P < .0001) than RNF43. Moreover, RNF43 exhibited significantly higher densities of CD8 T lymphocytes, dendritic cells, and B lymphocytes (P < .001) and an upregulation of ITGAX, CD11c, CD8, and HLA-DR compared with RNF43. Patients with RNF43 PDACs were more often of the classical molecular subtype (20/22, 90.9%). RNF43 PDACs showed high tumor mutational burden values, suggesting increased neoantigen load coupled with an abundance of antigen-presenting immune cells and an upregulation of immune determinants promoting antigen presentation. All this contributes to stronger antitumor immune responses and improved clinical outcomes.
Phenotypic Characterization of Richter Transformation and De Novo Diffuse Large B-Cell Lymphoma With or Without Monoclonal B-Cell Lymphocytosis.
Martin-Moro F, Alcoceba M, Romero S … +18 more , Marquet-Palomanes J, Alonso-Castronuño D, Astibia-Mahillo B, Andreu R, Perez-Alonso R, Rodriguez-Martin E, De Ramon C, Solano I, Martin Garcia-Sancho A, Piris-Villaespesa M, Blanco O, Roldan-Santiago E, Garcia-Marco JA, Subira D, Navarro-Bailon A, Garcia-Cosio M, Garcia-Vela JA, Lopez-Jimenez J
Mod Pathol · 2026 May · PMID 42092725 · Publisher ↗
Richter transformation diffuse large B-cell lymphoma type (DLBCL-RT) is a biologically complex process that requires a comprehensive workup for an accurate diagnosis. Detailed information regarding DLBCL-RT immunophenoty...
Richter transformation diffuse large B-cell lymphoma type (DLBCL-RT) is a biologically complex process that requires a comprehensive workup for an accurate diagnosis. Detailed information regarding DLBCL-RT immunophenotype is limited. We used multiparametric flow cytometry and immunohistochemistry to assess the phenotypic profile of 63 patients diagnosed with DLBCL-RT. Cases partially retained the immunophenotype of the previous chronic lymphocytic leukemia (CLL), although modulation of markers, such as CD43, CD5, CD200, CD23, and CD38, was common. Moreover, the phenotype of DLBCL-RT differed according to prior exposure or not to CLL therapy, with treatment-naïve patients showing more immunophenotypic variations against prior CLL compared with those who received therapy before transformation. With respect to the prognostic impact of antigenic markers, cases expressing CD20 exhibited higher overall survival compared with CD20-negative cases, whereas CD43 expression was associated with worse prognosis. DLBCL-RT cases exhibited several antigenic differences in CLL-associated markers compared with an independent cohort of nontransformed DLBCL without concurrent CLL-like monoclonal B-cell lymphocytosis (MBL) (n = 28). In contrast, a separate cohort of patients with de novo DLBCL and concomitant CLL-like MBL (n = 25) exhibited biological similarities to DLBCL-RT, including comparable phenotypic profiles and a high rate of clonal relatedness between MBL and DLBCL. We conclude that DLBCL-RT is associated with a CLL-like immunophenotype influenced by pre-existing CLL characteristics, and we propose that, in some cases, de novo DLBCL with concomitant MBL may be considered as RT.
NTRK Fusion Landscape in 195 Positive Cases of 17 Tumors: A Chinese Multicenter Retrospective Study With Optimized Pan-TRK Immunohistochemistry (IHC) Screening.
Wu S, Wang J, Yang W … +17 more , Han Y, Zhang Z, Chen G, Meng B, Sun Y, Liu Y, Li W, Li S, Wang L, Zhang H, Guo L, Liu Y, Liu X, Hong R, Li K, Pang J, Liang Z
Mod Pathol · 2026 Apr · PMID 42066846 · Publisher ↗
Neurotrophic tyrosine receptor kinase (NTRK) fusions are crucial in tumorigenesis and in guiding targeted therapy with TRK inhibitors. However, their rarity, fusion heterogeneity, and limitations of conventional pan-TRK...
Neurotrophic tyrosine receptor kinase (NTRK) fusions are crucial in tumorigenesis and in guiding targeted therapy with TRK inhibitors. However, their rarity, fusion heterogeneity, and limitations of conventional pan-TRK immunohistochemistry (IHC) impede accurate clinical detection. This multicenter retrospective study analyzed 374 next-generation sequencing/fluorescence in situ hybridization-validated samples (195 NTRK positive and 179 NTRK negative) collected from 12 Chinese centers to investigate fusion heterogeneity and refine the interpretation of pan-TRK IHC. We developed an amplification protocol by combining the traditional pan-TRK IHC (EPR17341) with the OptiView Amplification Kit and established new interpretation criteria. A total of 40 solid tumor types were included, and 23 unique fusion partners were identified. Papillary thyroid cancer was the most common NTRK-positive tumor (49.74%) and harbored all 3 NTRK subtypes. Among NTRK-positive samples, NTRK3 (74.87%) was the most prevalent subtype, followed by NTRK1 (23.59%). ETS variant transcription factor 6 (ETV6) was the most frequent fusion partner identified in 122 of 195 cases. It was uniquely shared across all 3 NTRK subtypes, with its fusion to NTRK1 being reported for the first time. NTRK1 and NTRK3 exhibited marked fusion partner specificity, with no overlap in their associated partners except for ETV6. The optimized pan-TRK IHC protocol significantly improved staining efficiency by enhancing intensity and clarity. Consequently, the newly established criteria (cytoplasmic intensity ≥1 in ≥50% of tumor cells or any nuclear intensity ≥1) exhibited outstanding detection performance, achieving an overall sensitivity of 94.36% and increasing specificity to 79.89% compared with 60.22% under the conventional protocol. Particularly, the detection sensitivity for NTRK3 fusions was significantly enhanced and reached 95.89%. This study contributes to clarifying NTRK fusion distribution in patients and validates a standardized, sensitive pan-TRK IHC strategy for clinical screening.
Copy Number-low/TP53-mutated Endometrial Cancer With Wild-type p53 Immunoexpression: Implications for Risk Stratification and Management When Using Next-generation Sequencing for Molecular Classification.
Rabban JT, Wolsky RJ, Kayraklioglu N … +3 more , Davies KD, Aisner DL, Devine WP
Mod Pathol · 2026 Jun · PMID 42025847 · Publisher ↗
Endometrial cancers with the Cancer Genome Atlas (TCGA) molecular profile of TP53-mutated, POLE-wild-type, and microsatellite-stable generally exhibit a high burden of copy number (CN) alterations and carry an increased...
Endometrial cancers with the Cancer Genome Atlas (TCGA) molecular profile of TP53-mutated, POLE-wild-type, and microsatellite-stable generally exhibit a high burden of copy number (CN) alterations and carry an increased risk for adverse outcomes, meriting maximal adjuvant therapy. In contrast, the prognosis associated with a TP53 mutation that coexists with a POLE mutation or microsatellite instability aligns with that of ultramutated or hypermutated cancers, respectively. In this study, we characterized a rare molecular subclass of endometrial cancers defined by TP53 mutation but low burden of CN alterations, wild-type p53 immunoexpression (immunohistochemistry [IHC]), and low TP53 variant allele frequency (median 13% and maximum 47%). Among 723 consecutive endometrial cancers prospectively classified using next-generation sequencing, 16 (2.2%) were CN-low/TP53-mutated/p53 wild-type IHC. Two additional cases were identified in a separate retrospective cohort of 32 recurrent low-grade early-stage endometrial cancers, bringing the total to 18 cases. They affected postmenopausal patients, exhibited low-grade endometrioid histotype, and were mostly confined to the uterus without lymphovascular space invasion. The recurrence rate was 6.25% (1/16) in the prospective cohort, and none died, placing their prognosis closer to that of CN-low than CN-high cancers. We conclude that next-generation sequencing-based TCGA classification of TP53-mutated, POLE-wild-type, microsatellite-stable endometrial cancers with TP53 variant allele frequency < 50% requires further evaluation using CN analysis and/or p53 IHC to detect this rare molecular category. IHC-based TCGA classification, such as the ProMisE protocol, will not be able to detect these cases because the p53 IHC pattern is wild-type and there are no distinguishing morphological features; this may be of relevance for analyzing ProMisE protocol-based clinical trials and outcomes studies. Long-term outcome studies are needed to refine risk stratification and treatment decisions for this unique molecular class of endometrial cancers that further contributes to the evolving understanding that the clinical significance of TP53 mutation in endometrial cancer is complex and depends on coexisting molecular alterations.
Clinical and Molecular Evaluation of HER2-Low and HER2-Ultralow Breast Cancer in the Penelope-B Clinical Trial Cohort.
Denkert C, Rachakonda S, Pehl A … +34 more , Marmé F, Martin M, Karn T, Untch M, Bonnefoi H, Kim SB, Hirmas N, Bear H, Witkiewicz AK, Im SA, DeMichele A, Van't Veer L, McCarthy N, Stiewe T, Jank P, Gelmon KA, García-Sáenz JA, Westhoff C, Kelly CM, Reimer T, Olivé MM, Knudsen ES, van Mackelenbergh M, Rojo F, Frickel N, Fasching PA, Teply-Szymanski J, Toi M, Rugo HS, Gnant M, Makris A, Felder B, Nekljudova V, Loibl S
Mod Pathol · 2026 Jun · PMID 42025846 · Publisher ↗
The DestinyBreast (DB)04 and DB06 trials have shown clinical activity of trastuzumab-deruxtecan (T-DXd) in HER2-low and HER2-ultralow metastatic breast cancer. The identification of HER2-low and HER2-ultralow breast canc...
The DestinyBreast (DB)04 and DB06 trials have shown clinical activity of trastuzumab-deruxtecan (T-DXd) in HER2-low and HER2-ultralow metastatic breast cancer. The identification of HER2-low and HER2-ultralow breast cancer is therefore essential for personalized therapy with T-DXd. We evaluated 723 residual tumors from the Penelope-B trial (NCT01864746) and correlated different levels of HER2 protein expression with prognosis and messenger RNA (mRNA) profiles, including HER2 transcripts. In Penelope-B, 57.68% (n = 417) of 723 residual tumors were HER2 low. The HER2-ultralow category was assigned to 109 (15.08%) tumors, and 197 (27.25%) tumors were completely HER2 negative (HER2 0). In Kaplan-Meier analysis, there were no survival differences among these 3 subgroups. There was no significant difference in HER2 mRNA expression between HER2-0 and HER2-ultralow tumors (P = .08). In contrast, there was a highly significant difference in HER2 mRNA expression between HER2-ultralow and HER2-low tumors (P < .0001) and between HER2-low and HER2-positive tumors (P < .0001). The extracellular protease cathepsin L, which has been suggested as a biomarker for extracellular cleavage of T-DXd, was detectable in all HER2-related subgroups and was a negative prognostic factor for invasive disease-free survival and overall survival (P = .0001) in preneoadjuvant core biopsies. In our study, we were able to characterize HER2 low as a clinically relevant and molecular defined tumor group with significantly increased HER2 expression. In contrast, for HER2 ultralow, we did not observe a defined molecular phenotype, despite the clinically relevant regulatory approval of T-DXd also in the ultralow subgroup. Additional investigations are needed to identify biomarkers beyond HER2 for T-DXd response as a basis for refined criteria for treatment eligibility.
CDKN2A Deletions But Not Point Mutations May Explain Discordant Phenotype of Human Papilloma Virus (HPV) DNA-positive and p16-Negative HPV-Associated Squamous Cell Carcinoma.
Koller M, Ermakov MS, Regauer S … +1 more , Kashofer K
Mod Pathol · 2026 May · PMID 42001713 · Publisher ↗
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Mature Tertiary Lymphoid Structures in Breast Cancers Are Associated With Antitumor Immunity and Better Prognosis.
Yu S, Dekker M, Zwager MC … +5 more , Slagter-Menkema L, van der Sluis T, Schröder CP, van Vugt MATM, van der Vegt B
Mod Pathol · 2026 Jun · PMID 41997561 · Publisher ↗
Tertiary lymphoid structures (TLSs) are immune cells accumulated in nonlymphoid tissues, with an inner core of B cells encompassed by T cells. The aim of this study was to evaluate the clinical importance of mature TLSs...
Tertiary lymphoid structures (TLSs) are immune cells accumulated in nonlymphoid tissues, with an inner core of B cells encompassed by T cells. The aim of this study was to evaluate the clinical importance of mature TLSs in breast cancer, including their association with immunotherapy response and their role in modulating the tumor immune microenvironment. We analyzed histopathological data of 726 consecutive primary breast cancers and transcriptomic data of 824 breast cancer samples from the publicly available The Cancer Genome Atlas database to estimate the clinical and immunological values of mature TLSs in breast cancer. Additionally, we utilized pretreatment transcriptomic data of 69 patients with breast cancer from the publicly available I-SPY2 clinical trial to investigate the relation between TLS-related gene signatures and patient responses to immune checkpoint inhibitors. The existence of mature TLSs was identified in ⁓5.6% (41/726) of all patients with breast cancer (hormone receptor-positive human epidermal growth factor receptor-2 negative (HR+HER2-): 0.92%; triple-negative breast cancer (TNBC): 14.96%; and human epidermal growth factor receptor-2 positive (HER2+): 10.98%) and was independently associated with improved recurrence-free survival after adjusting for subtypes, tumor-infiltrating lymphocyte levels, and tumor stage after the multivariable Cox regression analysis in our patient cohort. Notably, the presence of mature TLSs was related to immune cell infiltration in our breast cancer patient cohort. In line with these findings, TLS-related gene signatures analyzed through transcriptomic data reliably reflected the existence of mature TLSs and were related to better clinical responses to immune checkpoint inhibitors in patients with breast cancer. In conclusion, our findings show that mature TLS formation is linked with immune cell infiltration, contributes to a favorable prognosis, and may function as a potential complementary biomarker for immunotherapy response in breast cancer.
MetAssist 2.0: A Generalizable Artificial Intelligence Framework for Lymph Node Metastasis Detection Across Multiple Cancer Types.
Garcia-Baroja J, Dislich B, Zens P … +11 more , Zagrapan B, Parokkaran FM, Wütschert L, Weber SE, Christe L, Neppl C, Rau T, Perren A, Tolkach Y, Zlobec I, Khan A
Mod Pathol · 2026 Jun · PMID 41997560 · Publisher ↗
Lymph node metastasis assessment is critical for cancer staging, yet the process is labor intensive and prone to variability, particularly when evaluating micrometastases or isolated tumor cells that can directly alter t...
Lymph node metastasis assessment is critical for cancer staging, yet the process is labor intensive and prone to variability, particularly when evaluating micrometastases or isolated tumor cells that can directly alter treatment decisions. We present MetAssist 2.0, a modular artificial intelligence system that combines a pathology foundation model with transformer-based segmentation to automate metastasis detection across cancer types. Trained on colorectal and upper gastrointestinal cancers, it was validated on 8144 slides spanning 7 cancer types and 14 multi-institutional cohorts. MetAssist 2.0 achieved at least 90% sensitivity in 13 cohorts and 91% specificity in 11 cohorts, including challenging subtypes such as mucinous adenocarcinoma and tumor deposits. With only 10 annotated slides, the system adapted to unseen cancer types via few-shot fine-tuning. As a triage tool for colorectal cancer, it could reduce pathologist workload by up to 72% with 98% sensitivity and revealed metastases missed in routine reporting. These results demonstrate broad generalizability and near-clinical-grade performance, positioning MetAssist 2.0 for integration into the pathology workflows.
Histopathologic Evaluation and Reporting in Inflammatory Bowel Disease: A Consensus Document Sponsored by the Rodger C. Haggitt Gastrointestinal Pathology Society.
Polydorides AD, Liu X, Hu S … +8 more , Drage MG, Colombel JF, McGovern DPB, De Hertogh G, Deshpande V, Vieth M, GIPS IBD Review Panel, Panarelli NC
Mod Pathol · 2026 Jun · PMID 41985626 · Publisher ↗
The histopathologic evaluation and diagnosis of specimens from patients with inflammatory bowel diseases (IBDs), including ulcerative colitis and Crohn disease, is complicated, yet clinically important. Therefore, formal...
The histopathologic evaluation and diagnosis of specimens from patients with inflammatory bowel diseases (IBDs), including ulcerative colitis and Crohn disease, is complicated, yet clinically important. Therefore, formalized recommendations about appropriate terminology and necessary elements to include in the corresponding report are likely to benefit practicing pathologists. This consensus document was initiated and sponsored by the Rodger C. Haggitt Gastrointestinal Pathology Society after the majority of respondents in a survey indicated that IBD reporting guidelines would inform their daily practice. The document presented herein provides recommendations for the macroscopic and histologic examination of samples from patients with suspected or confirmed IBD at 3 distinct tiers of disease evolution: initial diagnosis with endoscopic biopsies, assessment of disease activity during colonoscopic surveillance, and evaluation of long-term prognosis after surgery. Given its complexity and importance, IBD-related neoplasia will be considered in a separate, forthcoming document. These recommendations, presented as 20 main position statements, each following a brief review of the pertinent literature and some with additional supplemental statements, reflect the strength of available published evidence. They were subjected to review, voting, and approval by all authors and, in addition, by a group of surgical pathologists and gastroenterologists with documented interest and experience in the diagnosis and treatment of patients with IBD. We hope this document is the first in a dynamic series with subsequent iterations and revisions incorporating emerging data and evolving approaches to management.
Desert Immune Phenotype in Endometrial Carcinoma: A Distinct Subgroup With Poor Prognosis and Targetable Mutations.
Kaya M, Lin LH, Oosting J … +15 more , Powell ME, Davidson EJ, Leary A, Mileshkin LR, Shepherd L, de Bruyn M, Jobsen J, Kroep JR, Creutzberg CL, Horeweg N, Léon-Castillo A, Parra-Herran C, Smit VTHBM, Nucci MR, Bosse T
Mod Pathol · 2026 Jun · PMID 41967711 · Publisher ↗
Accurate assessment of the tumor immune microenvironment is increasingly important for risk stratification in endometrial carcinoma (EC). Existing immune profiling methods often rely on immunohistochemistry and digital q...
Accurate assessment of the tumor immune microenvironment is increasingly important for risk stratification in endometrial carcinoma (EC). Existing immune profiling methods often rely on immunohistochemistry and digital quantification to distinguish inflamed and excluded phenotypes, whereas the Desert phenotype-marked by minimal immune infiltration-may be identifiable on routine hematoxylin and eosin (H&E) slides. Therefore, we developed a qualitative histological scoring system to define the Desert phenotype on H&E slides and used it to examine clinicopathological and molecular associations, evaluate prognostic relevance, and assess interobserver reproducibility. Five expert gynecological pathologists defined consensus criteria for the Desert phenotype in a molecularly classified development cohort (n = 20) and applied them to a testing cohort from the randomized PORTEC-3 trial (n = 380), which included patients with high-risk EC randomized to radiotherapy or chemoradiotherapy. In the PORTEC-3 cohort, 28% of tumors displayed the Desert phenotype. Desert EC were enriched for the no specific molecular profile (NSMP) and p53-abnormal (p53abn) molecular classes and exhibited a distinct mutational profile, including a higher prevalence of CTNNB1 and AKT1 mutations, an effect that was driven by the NSMP subgroup. Desert EC had worse recurrence-free survival compared with Non-Desert EC. Across molecular classes, worse overall survival was only observed in Desert p53abn EC compared to Non-Desert p53abn EC. Interobserver agreement was moderate (κ = 0.57). To conclude, the Desert immune phenotype, as identified on routine H&E slides with moderate agreement, is a biologically distinct and prognostically significant subset of EC. Future work to improve reproducibility is essential to validate its potential for clinical use both for risk stratification and for guiding immunotherapy.
Distinctive Near-Haploid Fibromyxoid Neoplasm: A Clinicopathologic and Molecular Genetic Study of a Unique, Clinically Indolent Neoplasm of Soft Tissue.
Einarsson H, Sukov WR, Molligan JF … +1 more , Folpe AL
Mod Pathol · 2026 Jun · PMID 41967710 · Publisher ↗
Despite advances in molecular genetics that have helped elucidate the pathogenesis of many soft tissue neoplasms, subsets of fibromyxoid tumors remain difficult to subclassify because of their nonspecific morphologic and...
Despite advances in molecular genetics that have helped elucidate the pathogenesis of many soft tissue neoplasms, subsets of fibromyxoid tumors remain difficult to subclassify because of their nonspecific morphologic and immunohistochemical features, and lack of discrete molecular alterations. We report 7 cases of a distinctive fibromyxoid soft tissue neoplasm characterized at the cytogenomic level by massive loss of heterozygosity, resulting in a near-haploid or pseudohyperdiploid cytogenome. The tumors occurred in superficial and deep soft tissue locations (mesentery, mediastinum, thigh, pelvis, leg, orbit, and head) of 5 males and 2 females (median age, 45 years). They ranged in size from 2.6 to 14 cm (median, 5 cm) and were composed of small, bland spindled cells in a variably vascularized, fibromyxoid stroma with abundant wiry collagen. Mitotic activity was low, and necrosis was absent in all but 1 case, which demonstrated foci of infarct-type necrosis. One tumor showed infiltrative growth into surrounding tissue while all others were circumscribed and noninfiltrative. Immunohistochemistry demonstrated CD34 (5/5) and desmin (3/5) expression; S100 protein, SOX10, MUC4, and GLUT1 were negative, among others. All tumors demonstrated massive loss of heterozygosity with copy number gain and retained heterozygosity of selected chromosomes, including chromosomes 8 and 19, evaluated with OncoScan single-nucleotide polymorphism array. Biallelic inactivation of NF1 was seen in 2 cases, including 1 in a patient with neurofibromatosis type 1. Three patients showed possible evidence of stable locally recurrent/residual disease following incomplete resection while all other patients were free of disease (median follow-up, 17 months). The tumors presented in this study are essentially identical to those of a very recently reported series of 5 cases, strongly suggesting that these collectively represent a novel entity, which we propose terming distinctive near-haploid fibromyxoid neoplasm.
p62/SQSTM1 Accumulation Defines an Epithelial-Mesenchymal Transition (EMT)/Twist1-Associated Infiltrative Phenotype in Pancreatic Neuroendocrine Tumors.
Matsumoto T, Yamamoto T, Osajima S … +13 more , Nakanishi Y, Noguchi S, Mizuuchi Y, Murakami M, Ueda K, Takigawa K, Shimo M, Miyawaki K, Kato K, Fujimori N, Nakata K, Aishima S, Oda Y
Mod Pathol · 2026 Jun · PMID 41967709 · Publisher ↗
Pancreatic neuroendocrine tumors (PNETs) lack clinically validated biomarkers for risk stratification and treatment selection. p62 (also known as SQSTM1)-a multifunctional adaptor protein degraded by autophagy-has been a...
Pancreatic neuroendocrine tumors (PNETs) lack clinically validated biomarkers for risk stratification and treatment selection. p62 (also known as SQSTM1)-a multifunctional adaptor protein degraded by autophagy-has been associated with adverse outcomes, but its correlation with invasion and metastasis in PNETs remains unclear. We retrospectively analyzed 194 PNETs resected between January 1994 and December 2022. The expression of p62, LC3B, E-cadherin, and Twist1 was evaluated using immunohistochemistry, and targeted transcriptomic profiling (nCounter) was performed to compare p62-high and p62-low groups. High p62 expression was associated with shorter overall survival and disease-free survival and higher frequencies of lymph node metastasis and an infiltrating growth pattern. In tumors with an infiltrating growth pattern, p62 expression was higher at the invasive front than in the tumor center, supporting a spatial association with histopathologic invasion. Transcriptomic profiling showed enrichment of epithelial-mesenchymal transition (EMT) pathways in the p62-high group, including upregulation of TWIST1, a key EMT-related transcription factor. Consistently, p62-high tumors showed reduced membranous E-cadherin and increased cytoplasmic and nuclear Twist1 expression. In a subgroup of small tumors (≤20 mm), p62-high status was not associated with significantly different survival, but it remained associated with infiltrative histopathologic features. Collectively, high p62 expression was associated with an aggressive, infiltrative PNET phenotype and an EMT/Twist1-associated signature, suggesting that p62 may capture a biologic state characterized by infiltrative behavior and complement risk stratification within current World Health Organization frameworks.
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