Mod. Pathol. [JOURNAL]
Sun
200 papers
Biomarkers Informed by Single-Cell and Spatial Transcriptomics-Biomarkers for Grade 3 Follicular Lymphoma.
Kanzaria A, Arora S, Naik A … +12 more , Dhanushkodi N, Ho CC, Kaur N, Zhang J, Ren X, Fromm JR, Shadman M, Smith S, Gopal A, Roncador G, Holland E, Naresh KN
Mod Pathol · 2026 Mar · PMID 41521011 · Publisher ↗
Follicular lymphoma (FL) patients have variable outcomes, underscoring the need for biomarkers for improved risk stratification. Current FL grading systems, based on subjective centroblast counts, suffer from poor reprod...
Follicular lymphoma (FL) patients have variable outcomes, underscoring the need for biomarkers for improved risk stratification. Current FL grading systems, based on subjective centroblast counts, suffer from poor reproducibility, despite evidence linking grade 3 FL to worse prognosis. We aimed to identify objective biomarkers for centroblasts and centrocytes to improve FL prognostication. We reanalyzed publicly available spatial and single-cell transcriptomic data from normal germinal centers and FL samples. Reanalysis revealed distinct gene expression profiles: AICDA (AID) and CXCR4 were highly expressed in germinal center dark zone cells (centroblasts) and CD40 and TFRC (CD71) in light zone cells (centrocytes). Single-cell RNA sequencing of FL samples further showed AID and CXCR4 overexpression in malignant grade 3A cells and CD40 and CD71 in grades 1 to 2 cells. We validated these findings using immunohistochemistry (single and multiplex) on tonsils and 59 FL specimens (42 grades 1 to 2, 17 grade 3). Grade 3 FL showed significantly higher expression of AID, CD71, and Ki67 compared to grades 1 to 2, with CXCR4 approaching significance. Receiver operating characteristic curve analysis identified optimal cutoffs for AID (1.54%), CXCR4 (21.9%), Ki67 (21.6%), and CD71 (7.57%) to distinguish grade 3 from grades 1 to 2 FL, with AID showing the best discriminatory ability. Crucially, AID expression evaluation showed reproducibility across 2 different digital algorithms and 2 independent visual observers. Furthermore, we observed a trend toward shorter disease-specific survival in patients with both FL grade 3 and high AID expression. This prognostic observation held true regardless of whether AID overexpression was assessed via digital evaluation (cutoff: 1.54%) or visual estimation (cutoff: 2%). In conclusion, AID, CXCR4, CD71, and Ki67 are promising biomarkers for objectively identifying FL grade 3, potentially enhancing the reproducibility of grading and serving as independent prognostic tools. Further clinical validation in uniformly treated FL cohorts is warranted.
Spatial Molecular Plasticity Underpins Lethal Morphologies in Lung Adenocarcinoma.
Williams HL, Poulain N, Powley I … +14 more , Martinelli S, Bielik R, Leslie H, Nixon C, Wilson CR, Sereno M, He Z, Officer-Jones L, Ballantyne F, Pennie R, Wood CS, Lewis DY, Jamieson NB, Le Quesne J
Mod Pathol · 2026 Mar · PMID 41521010 · Publisher ↗
Adenocarcinoma of the lung (LUAD) is common and highly lethal. Clinical grading of LUAD strongly predicts recurrence and survival after surgery and is determined by morphological assessment of histological growth pattern...
Adenocarcinoma of the lung (LUAD) is common and highly lethal. Clinical grading of LUAD strongly predicts recurrence and survival after surgery and is determined by morphological assessment of histological growth patterns in resected tumors. In particular, the 2 archetypally lethal morphologies, solid, and micropapillary growth patterns, are highly distinct from each other, but little is known about their defining molecular features or how their appearances are related to their biology and mechanisms of lethality. Pure epithelial growth patterns and subregions were identified within 7 distinct LUAD growth patterns across 51 resected tumors and characterized using NanoString GeoMx digital spatial profiler in 160 epithelially pure regions of interest. Results were validated in 27 cases at the protein level using Akoya PhenoImager multiplex immunofluorescence, in 432 cases at the RNA level with TempO-Seq, and in 30 cases with an independent GeoMx digital spatial profiler. Analyses of gene expression reveal fundamental divergent evolutionary trajectories leading to solid and micropapillary growth. Additionally, we identify recurrent localized intratumoral plasticity in both growth patterns. These states can explain the origins of growth patterns and their mechanisms of virulence. Our work highlights dramatic divergence in gene expression programs between highly lethal modes of LUAD tumor growth. We go on to show how microscopically localized hypoxia in the primary tumor helps to establish and maintain cellular survival strategies and tumor architecture, suggesting morphology-specific mechanisms of LUAD tumor metastasis and suggesting new therapeutic vulnerabilities.
Utility of p53, p16, and MTAP Immunohistochemistry in Oral Epithelial Dysplasia With Concurrent Candidiasis: A Novel Pattern-based Approach.
Ji JX, El Maghrabi A, Ren HC … +14 more , Lee LH, Young S, Yip ST, Moodley J, Lai C, Shirsat H, Hahn E, Hoang LN, Mabray J, Patel P, Wang G, Poh CF, Ng TL, Ko YCK
Mod Pathol · 2026 Mar · PMID 41521009 · Publisher ↗
The diagnosis of oral epithelial dysplasia has a high degree of inter- and intraobserver variability. It is especially challenging to distinguish dysplasia from reactive squamous mucosa in the context of concurrent candi...
The diagnosis of oral epithelial dysplasia has a high degree of inter- and intraobserver variability. It is especially challenging to distinguish dysplasia from reactive squamous mucosa in the context of concurrent candidiasis. The accurate and timely diagnosis of dysplasia is imperative for patient outcomes, as progression to invasive squamous cell carcinoma will result in significant morbidity and mortality. The current management for patients with candidiasis is to treat with antifungals and rebiopsy if refractory. The treatment may be trialed for a few months, thus delaying appropriate treatment if underlying dysplasia is not identified. In this study, we collected cases of oral candidiasis with atypia and characterized them into molecularly defined groups using targeted next-generation sequencing, fluorescence in situ hybridization, and p53, p16, and MTAP immunohistochemistry. We identify a distinct molecular signature using immunohistochemical markers to capture oral dysplasia with concurrent candidiasis. We also postulate that p53 wild-type, p16 abnormal oral epithelial dysplasia cases are precursor lesions to p53 wild-type, p16 abnormal squamous cell carcinoma. In addition, we identify p53 wild-type, p16 wild-type oral epithelial dysplasia with verruciform and acanthotic features with HRAS or PIK3CA alterations as precursors to verrucous carcinoma. The proposed pattern-based p16 and p53 algorithm in our study will not only more accurately diagnose dysplasia in the context of oral candidiasis but may also provide prognostically significant information to guide clinical management of oral dysplastic lesions.
Corrigendum to "Aleukemic Chronic Myeloid Leukemia Without Neutrophilia and Thrombocytosis: A Report From the BCR::ABL1 Pathology Group" [Modern Pathology. 2024;37(2):100406].
Rivera D, Cui W, Gao J … +20 more , Peker D, Zhang QY, Dewar R, Qiu L, Konoplev S, Hu Z, Sasaki K, Hu AY, Shuyu E, Liu M, Fang H, Wang W, Tang G, Apperley JF, Hochhaus A, Cortes JE, Khoury JD, Medeiros LJ, Jabbour E, Hu S
Mod Pathol · 2026 Feb · PMID 41518888 · Publisher ↗
Abstract loading — click title to view on PubMed.
High-Grade Colorectal Adenocarcinomas With SMAD4 Deficiency.
Mirzabeigi Y, Shah N, Schwartz KR … +5 more , Duryea J, Delma KS, Montgomery EA, Poveda JC, McDonald OG
Mod Pathol · 2026 Mar · PMID 41506325 · Full text
Poor prognosis has been reported for patients with SMAD4 deficient (dSMAD4) colorectal adenocarcinomas (CRCs). However, it remains unclear whether unique tumor morphologies or other advanced disease signatures might stra...
Poor prognosis has been reported for patients with SMAD4 deficient (dSMAD4) colorectal adenocarcinomas (CRCs). However, it remains unclear whether unique tumor morphologies or other advanced disease signatures might stratify those patients. To reappraise this possibility across a homogenous cohort of CRC patients with advanced-stage disease, we leveraged next-generation sequencing data to identify 50 dSMAD4 CRCs at our institution. An equal number of next-generation sequencing-verified SMAD4 proficient (pSMAD4) CRCs were identified in parallel, yielding a control group with similar demographics, clinicopathologic parameters, and background genetic drivers as the dSMAD4 test group. Although both groups progressed to stage IV metastatic disease at high rates (dSMAD4: 90%, pSMAD4: 86%), dSMAD4 CRC specimens were enriched with overtly high-grade (HG) mucinous and nonmucinous histomorphologies (dSMAD4, 44%; pSMAD4, 12%; P = .0007). The HG subset drove poor prognosis in dSMAD4 CRCs, as those patients developed widely metastatic disease (P = .0048) with short overall and progression-free survival (P ≤ .0001). Metastasis of unknown primary was not uncommon for HG dSMAD4 CRCs, posing diagnostic challenges in those instances. However, all dSMAD4 CRCs retained positive immunolabeling for either CDX2 or SATB2 irrespective of grade, thereby aiding diagnosis and distinguishing the HG subset from other HG CRCs that lose these biomarkers. Our reappraisal identifies an underappreciated class of HG dSMAD4 CRCs that progresses rapidly to widely metastatic disease with a dismal prognosis. Although HG morphologies may mask CRC origins, immunohistochemistry retains diagnostic utility for dSMAD4 CRCs.
Agreement Across 10 Artificial Intelligence Models in Assessing Human Epidermal Growth Factor Receptor 2 (HER2) Expression in Breast Cancer Whole-Slide Images.
McKelvey B, Torres-Saavedra PA, Li J … +38 more , Broeckx G, Deman F, Ali S, Andrews HS, Arslan S, Azulay M, Balasubramanian S, Barrett JC, Caie P, Chen M, Cohen D, Dasgupta T, Fahrer D, Green G, Gustavson M, Hersey S, Hidalgo-Sastre A, Jiwani S, Joseph E, Jung W, Kulig K, Kushnarev V, Lennerz JK, Li X, Lodge M, Mancuso J, Montalto M, Mukhopadhyay S, Ntelemis F, Oberley M, Pandya P, Puig O, Richardson ET, Sarachakov A, Stewart M, McShane LM, Salgado R, Allen J
Mod Pathol · 2026 Feb · PMID 41489584 · Publisher ↗
Historically, eligibility for receiving human epidermal growth factor receptor 2 (HER2)-targeted therapies was limited to HER2-positive tumors (immunohistochemistry 3+ or in situ hybridization amplified), but recent adva...
Historically, eligibility for receiving human epidermal growth factor receptor 2 (HER2)-targeted therapies was limited to HER2-positive tumors (immunohistochemistry 3+ or in situ hybridization amplified), but recent advances in antibody-drug conjugates have expanded these criteria to include HER2-low and HER2-ultralow expression. This evolving therapeutic landscape underscores the need for precise and reproducible HER2 assessment. Digital and computational pathology tools may help address these needs, but their measurement variability must be evaluated to inform research and clinical use. We evaluated HER2 scoring variability across 10 independently developed computational pathology artificial intelligence models applied to 1124 whole-slide images from 733 patients with breast cancer. Analyses included American Society of Clinical Oncology-College of American Pathologists categorical scores (0, 1+, 2+, and 3+), H-scores, tumor cell staining percentages, and counts of total and stained invasive carcinoma cells. Agreement among models and 3 pathologists was assessed using pairwise overall percent agreement (OPA), Cohen kappa, and hierarchical clustering. Median model pairwise OPA for categorical HER2 scores was 65.1% (kappa, 0.51). Agreement was highest for HER2 3+ vs not 3+ (OPA, 97.3%; kappa, 0.86) and lowest for HER2-low cases, reflecting existing measurement challenges. For HER2 0 (negative) vs not 0 (positive) scoring, the average negative agreement was 65.3%, compared with the average positive agreement of 91.3%, suggesting more agreement in non-HER2 0 scores. H-score and cell count analyses indicated that scoring differences were more related to staining interpretation than tumor cell detection. Pathologists showed numerically higher concordance than models, but interobserver variability persisted. In exploratory analyses, sample type, staining artifacts, and heterogeneous HER2 expression appeared to be associated with discrepancies. Artificial intelligence-based HER2 scoring demonstrated high agreement in identifying HER2 3+ cases. Variability was most pronounced in borderline HER2 categories, particularly in HER2 low, underscoring the need for continued tool refinement for handling low-intensity staining. Standardized training data sets, validation frameworks, and regulatory alignment are important to improve reproducibility. Developing reference standards and benchmarking data sets is critical to evaluate performance, support regulatory decision-making, and ensure real-world applicability.
ALK Drives Nuclear Anaplastic Lymphoma Kinase (ALK) Expression in Histiocytic Neoplasms Without ALK Fusions.
Hélias-Rodzewicz Z, Ungureanu IA, Kemps PG … +19 more , Donadieu J, Héritier S, Barkaoui MA, Terrones N, Jannet RB, Bakari M, Satour T, Battistella M, Drabent P, Sohier P, Reimbold P, Jullié ML, Idbaih A, Cohen-Aubart F, Tazi A, Charlotte F, Fraitag S, Haroche J, Emile JF
Mod Pathol · 2026 Feb · PMID 41478363 · Publisher ↗
Anaplastic lymphoma kinase (ALK)-positive histiocytosis is a rare histiocytic neoplasm defined by oncogenic ALK fusions. The disease frequently involves the nervous system and is responsive to ALK inhibition. A distinct...
Anaplastic lymphoma kinase (ALK)-positive histiocytosis is a rare histiocytic neoplasm defined by oncogenic ALK fusions. The disease frequently involves the nervous system and is responsive to ALK inhibition. A distinct subset of histiocytoses expresses ALK in the absence of detectable ALK fusions. We aimed to determine the frequency and molecular characteristics of these ALK protein-positive, fusion-negative neoplasms. RNA was extracted from histiocytosis-affected tissue samples of 398 patients with diverse histiocytoses, converted to cDNA, and subjected to targeted sequencing using a custom gene panel. ALK fusions and gene expression levels were assessed; the presence of ALK isoforms was investigated using targeted digital PCR. In a subset of cases, ALK protein expression was evaluated using immunohistochemistry (clone 1A4). Of 398 cases, 303 (76%) passed quality control and were included in the analysis. Among these, 64 (21.5%) had substantial ALK gene expression, while not harboring ALK fusions. Immunohistochemistry revealed consistent nuclear and cytoplasmic ALK expression in these cases, whereas ALK expression in fusion-positive cases was restricted to the cytoplasm. Analysis of ALK intron 19 expression by targeted PCR revealed the presence of a novel ALK isoform (ALK), which was linked to nuclear ALK expression. No specific clinical or molecular features distinguished histiocytic neoplasms with ALK from those without. In conclusion, many histiocytic neoplasms express ALK but are not ALK-positive histiocytosis. Most cases can be identified by nuclear ALK expression, which is linked to alternative transcription initiation-a known mechanism of ALK activation independent of genetic aberrations. Future studies should elucidate whether these neoplasms respond to ALK inhibition.
Spatial Profiling Shows That Lymphatic Endothelial Cells Form the Core of Kaposi Sarcoma (KS).
Schneider JW, Eason AB, Chambers M … +7 more , Su H, Shifflett K, Guo S, Sanderson M, Bruce-Brand C, Burger H, Dittmer DP
Mod Pathol · 2026 Feb · PMID 41478362 · Full text
The lineage of the Kaposi sarcoma (KS) tumor cell remains elusive, limiting opportunities for targeted therapy. We performed concurrent spatial imaging of 5 bona fide lymphatic endothelial cell markers together with the...
The lineage of the Kaposi sarcoma (KS) tumor cell remains elusive, limiting opportunities for targeted therapy. We performed concurrent spatial imaging of 5 bona fide lymphatic endothelial cell markers together with the KS herpesvirus viral protein latency-associated nuclear antigen (LANA) in 30 well-characterized HIV-positive KS biopsies (n = 1,740,744 cells). Nodular KS lesions showed significantly more circular nuclei than plaque KS, indicating distinct cellular morphologies. Both forms contained dense areas of LANA-positive cells-termed "LANA nests." Among the endothelial cell markers, vascular endothelial growth factor receptor 3 was most abundantly expressed, although many vascular endothelial growth factor receptor 3-positive cells were LANA negative. Podoplanin and LYVE-1 consistently colocalized with each other, whereas CD31 and VE-Cadherin were variably expressed within and across lesions. Together, these observations reveal that KS lesions are composed of multiple microenvironments: LANA-dense nests, LANA-sparse fascicles, and mature lymphatic or blood vessels, some of which also harbored LANA-positive lining cells. At present, targeted therapies do not account for this variability; generally, responses are not based on pathology. Spatial changes in the tumor microenvironment that may provide insights into drug action and resistance mechanisms are missed.
Lowering the Diagnostic Threshold in Secondary Plasma Cell Leukemia? Comparison With Primary Cases and Implications for Flow Cytometry Immunophenotyping.
Shuai W, Hu Z, Yin CC … +13 more , Chen L, Wang W, Tang G, Sui D, Li S, Xu J, Ibrahim N, Pan Z, You MJ, Patel KP, Vega F, Medeiros LJ, Lin P
Mod Pathol · 2026 Feb · PMID 41456722 · Publisher ↗
In 2021, the International Myeloma Working Group lowered the threshold to establish the diagnosis of primary plasma cell leukemia (pPCL) from ≥20% to ≥5% circulating plasma cells (CPCs) as assessed by morphologic evaluat...
In 2021, the International Myeloma Working Group lowered the threshold to establish the diagnosis of primary plasma cell leukemia (pPCL) from ≥20% to ≥5% circulating plasma cells (CPCs) as assessed by morphologic evaluation (ME). However, the threshold for defining secondary PCL (sPCL) remains unclear. We retrospectively studied the clinicopathological features of 52 PCL patients, 30 pPCL and 22 sPCL, with ≥5% CPCs determined by either ME or flow cytometry immunophenotyping (FCI). FCI often revealed a higher percentage of CPCs than ME, likely due to difficulties in identifying morphologically abnormal plasma cells with certainty, and this discordance was statistically significant in sPCL patients. pPCL and sPCL both exhibited leukocytosis, thrombocytopenia, infrequent CD56 expression, high bone marrow tumor burden, and complex karyotypes. MYC rearrangement was observed only in sPCL cases. Paired cytogenetic data before and after leukemic transformation were available in a small subset of sPCL patients (8/22). Compared with the prior myeloma, sPCL more frequently harbored a complex karyotype, hypodiploidy, and additional cytogenetic abnormalities, most commonly gain of chromosome 1q. Using 5% CPCs as the diagnostic threshold, patients with sPCL had significantly poorer outcomes than patients with pPCL (P < .0001). Furthermore, the outcomes of sPCL patients with 5% to 19% CPCs were similarly poor as those patients with ≥20% CPCs (P = .4781), highlighting the need to recognize patients with ≥5% CPCs promptly. FCI appears to be a more sensitive method for this purpose in most cases. Using FCI, further studies are needed to determine whether a diagnostic threshold of 5% or lower may be used to establish the diagnosis of sPCL.
MEG3 Promoter Methylation and F11 Receptor (F11R) Overexpression Define a High-Risk Subtype of Diabetic Pancreatic Cancer.
Yamazaki K, Mizukami H, Yamada T … +14 more , Hara Y, Tamba H, Tatara Y, Wang Z, Itaya A, Kushibiki H, Ryuzaki M, Sasaki T, Ruike H, Ogasawara S, Tu Y, Ishido K, Itoh K, Hakamada K
Mod Pathol · 2026 Feb · PMID 41412328 · Publisher ↗
Long-standing diabetes mellitus (long-DM) (≧3 years) is associated with worse clinical outcomes in patients with pancreatic ductal adenocarcinoma (PDAC). Emerging evidence suggests that epigenetic alterations may contrib...
Long-standing diabetes mellitus (long-DM) (≧3 years) is associated with worse clinical outcomes in patients with pancreatic ductal adenocarcinoma (PDAC). Emerging evidence suggests that epigenetic alterations may contribute to this association; however, the underlying mechanisms remain largely unclear. This study aimed to elucidate the role of the tumor-suppressive long noncoding RNA maternally expressed gene 3 (MEG3) and related molecules in the development of PDAC with long-DM. A total of 117 patients who underwent surgical resection for PDAC at Hirosaki University Hospital were retrospectively analyzed. Histopathological assessment followed World Health Organization criteria and the Union for International Cancer Control tumor-node-metastasis classification. Promoter methylation of MEG3 was assessed via methylation-specific PCR using formalin-fixed paraffin-embedded tissue. MEG3 expression levels were assessed by real-time quantitative PCR. Additionally, proteomic profiling was performed using liquid chromatography-tandem mass spectrometry on formalin-fixed paraffin-embedded tissue samples. Among the 117 cases with PDAC, patients with long-DM exhibited significantly poorer tumor differentiation and reduced cancer-specific survival. MEG3 promoter methylation was more prevalent in patients with long-DM. MEG3 methylation was correlated with reduced MEG3 expression, increased venous invasion, higher recurrence rates, and worse prognosis. Proteomic analysis and protein structure prediction tool revealed F11 receptor (F11R) as a potential downstream effector of MEG3. F11R protein expression levels were evaluated using semiquantitative immunohistochemistry. Higher F11R expression was observed in patients with long-DM, correlating with poor histologic differentiation and unfavorable outcomes. Patients with PDAC showing simultaneous MEG3 methylation and F11R high expression were more likely to have long-DM, with additive effects of these changes and tumor recurrence. Our results demonstrated that MEG3 and its potential downstream regulator, F11R, could be involved in PDAC progression, particularly in patients with long-DM. The findings underscore the clinical significance of epigenetic regulation in DM-related PDAC, suggesting novel targets, such as MEG3 and F11R, for potential therapeutic intervention.
Optical Genome Mapping Is a Powerful Diagnostic Tool in Non-Hodgkin Lymphoma.
Verhasselt A, Ameye G, Vanhevel J … +13 more , Tousseyn T, Vets J, Hauben E, Meeus P, Bempt MV, Debackere K, Forsyth RA, Harbers L, Demeulemeester J, Michaux L, Rack K, Dewaele B, De Bie J
Mod Pathol · 2026 Feb · PMID 41391566 · Publisher ↗
Non-Hodgkin lymphoma (NHL) is a diverse and heterogeneous group of hematological malignancies. These lymphomas arise from the clonal proliferation of either B/T or natural killer lymphocytes, and their correct classifica...
Non-Hodgkin lymphoma (NHL) is a diverse and heterogeneous group of hematological malignancies. These lymphomas arise from the clonal proliferation of either B/T or natural killer lymphocytes, and their correct classification relies partly on identifying characteristic structural variants and copy number alterations. Current standard-of-care technologies for detecting these genomic features, chromosome banding analysis (CBA) and fluorescent in situ hybridization (FISH), are labor intensive and have specific limitations. CBA has low resolution and relies on viable cell culture, whereas the targeted approach of FISH does not provide the whole genome view required for comprehensive disease characterization. This highlights the need for higher-resolution nontargeted genomic methods. Previous studies have evaluated optical genome mapping (OGM) as a whole genome alternative for cytogenomic characterization in NHL diagnostics but were restricted in number and to cases with peripheral blood and/or bone marrow invasion. Here, we selected a comprehensive cohort of 110 NHL cases (79 B-NHL and 31 T-NHL/natural killer-NHL) derived from different types of tissue biopsies, all with established histopathological diagnoses. Seventy-eight samples were genomically well characterized at diagnosis by CBA and FISH. The remaining 32 cases were included because of previous CBA failure, although FISH data were available for 20 cases. OGM provided informative results in 94% of the cohort, with a high concordance rate of 97.6% compared with CBA/FISH in detecting clinically relevant aberrations. The 2 variants that were missed were both present at the detection threshold of OGM. In contrast, OGM successfully resolved 26 samples with previous CBA failure and detected 3 additional disease-defining events, resulting in diagnostic reclassification of 1 patient. Finally, OGM identified novel recurrent aberrations that warrant further investigation into their pathogenetic implications. To conclude, OGM robustly detects clinically relevant structural variants and copy number alterations and presents a promising alternative to CBA and FISH in routine diagnostic evaluation of NHL.
Quantitative Histology of Nonmetastatic Regional Lymph Nodes as a Novel Prognostic Indicator in Microsatellite Instability-High Colorectal Cancer.
Moon JH, Hong J, Chae SW … +7 more , Choi I, Kim C, Bae JM, Kang GH, Kim S, Jung M, Kim JH
Mod Pathol · 2026 Jan · PMID 41380849 · Publisher ↗
Regional lymph node metastasis is one of the main factors affecting cancer staging. However, the clinical and immunologic implications of nonmetastatic regional lymph nodes (nrLNs) remain poorly understood. Here, we inve...
Regional lymph node metastasis is one of the main factors affecting cancer staging. However, the clinical and immunologic implications of nonmetastatic regional lymph nodes (nrLNs) remain poorly understood. Here, we investigated the prognostic significance of the morphologic features of nrLNs in colorectal cancer (CRC) with microsatellite instability-high (MSI-H). Artificial intelligence-aided digital pathology-based quantification of 37 histologic parameters in 873 whole-slide images comprising 5785 nrLNs was performed in 2 independent cohorts of curatively resected MSI-H CRCs (discovery, n = 103; validation, n = 90). The prognostic value of each histologic parameter was evaluated by univariate and multivariate disease-free survival analyses. Quantitative immunohistochemical analysis of tumor-infiltrating immune cells and whole-exome and transcriptome sequencing using tumor tissues were performed to assess associations between prognostic nrLN histologic features and various tumor immuno-molecular factors. As a result, germinal center (GC)-related histologic parameters, including the maximum area, mean area, sum area, and maximum diameter of GCs in the nrLNs, were identified as independent prognostic factors in both cohorts. The prognostic GC-related factors of nrLNs were significantly associated with tertiary lymphoid structures and B cell pathways activation but were not or inversely correlated with the densities of tumor-infiltrating T cells and macrophages. No significant associations were found between prognostic nrLN GC features and major tumor molecular factors such as tumor mutational burden, driver mutations, consensus molecular subtype, or CpG island methylator phenotype. In conclusion, quantitative GC-related histology of nrLNs can serve as a prognostic indicator for MSI-H CRC. Our findings suggest that GC-activated nrLNs may represent B cell-mediated antitumor immunity, independent of tumor-infiltrating T cells and tumor-intrinsic molecular characteristics.
POU4F3 Plus Keratin AE1/AE3 or Pan-keratin: An Optimal Sentinel Lymph Node Protocol for Merkel Cell Carcinoma.
Maia-Silva D, DeSimone MS, Shore KT … +1 more , Hoang MP
Mod Pathol · 2026 Jan · PMID 41380848 · Publisher ↗
There is currently no standardized sentinel lymph node (SLN) immunohistochemistry (IHC) protocol for detecting Merkel cell carcinoma (MCC) metastases. A cost-effective, high-sensitivity panel could improve diagnostic acc...
There is currently no standardized sentinel lymph node (SLN) immunohistochemistry (IHC) protocol for detecting Merkel cell carcinoma (MCC) metastases. A cost-effective, high-sensitivity panel could improve diagnostic accuracy and resource utilization. We evaluated 226 SLNs from 81 MCC patients using a panel of POU4F3, keratin 20, and keratin AE1/AE3 or pan-keratin. Metastasis was defined as positive staining for any of the tested IHC markers. Patients' age ranged from 49 to 92 years (median, 73.5 years), with a male:female ratio of 1.8:1. Primary tumor sites were extremities (48.1%), head/neck (34.6%), and trunk (17.3%). SLN locations included cervical (29.6%), axillary (27%), femoral (20.8%), inguinal (9.7%), facial (7.1%), pelvic (3.1%), and epitrochlear (2.7%) sites. Metastases were identified in 102 of 226 SLNs (45%). Single-marker sensitivities were POU4F3 (96%, 98/102), keratin 20 (67%, 68/102), and keratin AE1/AE3 or pan-keratin (64%, 70/102). The most sensitive combinations were POU4F3 with keratin AE1/AE3 or pan-keratin (100% sensitivity) or POU4F3 with keratin 20 (98% sensitivity). Keratin 20 with keratin AE1/AE3 or pan-keratin was the least sensitive (74%). In 6 patients (7.4%), POU4F3 detected single metastatic cells in SLNs that were previously diagnosed at time of clinical diagnosis as negative by keratin 20 and keratin AE1/AE3 or pan-keratin panel. POU4F3 is the most sensitive individual IHC marker for detecting MCC SLN metastases. The optimal cost-effective panel is POU4F3 with keratin AE1/AE3 or pan-keratin, which achieves 100% sensitivity while reducing reliance on less effective stains. Adoption of this focused IHC panel may serve to standardize SLN evaluation for MCC and improve diagnostic accuracy and efficiency.
USP8-Rearranged Mesenchymal Tumors With Myofibroblastic Phenotype: A Comprehensive Clinicopathologic, Genetic, and Epigenetic Characterization.
Arciuolo D, Barresi S, Hiemcke-Jiwa L … +19 more , Black J, Willard N, Carta R, Roe M, Bukowinski A, Stracuzzi A, Kester L, Koudijs M, Dingemans W, Milano GM, Patrizi S, Gestrich C, John I, Azfar N, Bubar R, Skaugen J, Flucke U, Miele E, Alaggio R
Mod Pathol · 2026 Feb · PMID 41380847 · Publisher ↗
USP8 is one of the members of ubiquitin-specific proteases deconjugating ubiquitin from target proteins. Besides USP6, it can be involved in tumorigenesis of mesenchymal neoplasms by binding to an activating fusion partn...
USP8 is one of the members of ubiquitin-specific proteases deconjugating ubiquitin from target proteins. Besides USP6, it can be involved in tumorigenesis of mesenchymal neoplasms by binding to an activating fusion partner. Until now, USP8 fusion genes have been reported in calcified chondroid mesenchymal neoplasms, an inflammatory myofibroblastic tumor, a cardiac neoplasm, and a retroperitoneal sarcoma. In this study, we describe the clinicopathologic and genetic/epigenetic features of 7 USP8-associated tumors. The cohort included 5 male patients aged between 2 and 11 years, and 2 female patients aged 38 and 52 years. Lesions arose in the tongue, finger, hallux, arm, thoracic wall, right ventricle, and leg. Five neoplasms were resected. One was a recent case; the others were without evidence of disease after 0.5 to 3 years. Two lesions were only biopsied, 1 was a recent case and the other had no signs of progression after 4 years. Histology showed nodular or infiltrative lesions comprising bland-looking myofibroblastic spindle cells arranged in mainly short fascicles. The cellularity was variable, and the background was myxoid and/or collagenous. An inflammatory reaction was variably seen. One lesion, however, had features of a chondroid calcified mesenchymal neoplasm. Using RNA-sequencing, the following fusion partners of USP8 were found: SH3KBP1, RASA1, PDGFRA, CRK, PTPN11, and FARP1. Based on RNA-expression analysis, the 2 cases analyzed had a profile of nodular fasciitis; whereas using the Heidelberg Sarcoma Classifier, all cases had a similar methylation profile apart from other soft tissue tumor entities, suggesting that they form a separate group but are closely related to USP6-associated lesions. In conclusion, we broadened the spectrum of USP8-associated mesenchymal lesions in superficial, deep soft tissues and viscera (heart). Almost all lesions in this series displayed a myofibroblastic phenotype and harbored variable USP8 fusion partners. RNA-expression profiling indicated partial clustering with nodular fasciitis, suggesting some biological similarity. However, DNA methylation analysis consistently showed that these tumors formed a distinct epigenetic group, separate from both nodular fasciitis and inflammatory myofibroblastic tumors. Taken together, these findings support the concept of a USP8-rearranged myofibroblastic neoplasm as a potentially distinct entity, but the precise relationship with nodular fasciitis and inflammatory myofibroblastic tumor remains uncertain. Further studies integrating morphology, epigenetics, and transcriptomics are needed to clarify this relationship.
Redefining the Spectrum of Epstein-Barr Virus-Positive (EBV+) Diffuse Large B-cell Lymphoma and EBV+ Classic Hodgkin Lymphoma.
Nagase S, Nakamura N, Kikuti YY … +7 more , Carreras J, Tanigaki Y, Orita M, Ito A, Ikoma H, Kawada H, Masugi Y
Mod Pathol · 2026 Jan · PMID 41371409 · Publisher ↗
Epstein-Barr virus-positive (EBV+) diffuse large B-cell lymphoma (DLBCL) and EBV+ classic Hodgkin lymphoma (CHL) are major B-cell lymphomas with EBV infection in elderly patients. Although they are regarded as distinct c...
Epstein-Barr virus-positive (EBV+) diffuse large B-cell lymphoma (DLBCL) and EBV+ classic Hodgkin lymphoma (CHL) are major B-cell lymphomas with EBV infection in elderly patients. Although they are regarded as distinct clinicopathological entities, distinguishing EBV+ CHL from EBV+ DLBCL is often challenging because of their overlapping histologic and immunophenotypic features. We characterized the spectrum of EBV+ large B-cell lymphoma (LBCL) in 57 patients aged 50 years or older, including 35 EBV+ DLBCL (12 polymorphic EBV+ DLBCL [pDLBCL] and 23 monomorphic EBV+ DLBCL [mDLBCL]) and 22 EBV+ CHL. Gene expression profiling revealed interferon gamma (IFN-γ) enrichment with overexpression of indoleamine 2,3-dioxygenase 1 (IDO1), an immunosuppressive enzyme, in more than half of pDLBCL (5/8) but less in mDLBCL (3/19) and CHL (1/19). Fluorescence in situ hybridization showed a higher frequency of 9p24.1-altered cells in CHL (54%; IQR, 42%-89%) but lower frequencies in pDLBCL (18%; IQR, 12%-23%) and mDLBCL (5%; IQR, 0%-30%). Notably, immunohistochemical expression of PDL1 was higher in pDLBCL than in mDLBCL, suggesting IFN-γ-mediated upregulation. DLBCL with EBV latency type III (n = 13) exhibited lower tumor PDL1 expression and reduced IDO1-enriched microenvironment. Multivariate analysis of the total cohort revealed that both EBV latency type III and Eastern Cooperative Oncology Group performance status ≥2 were independently associated with shorter overall survival. The EBV+ LBCL spectrum was reclassified into 4 molecular groups: (1) EBV latency type III suggestive of immune senescence (n = 10, 22%), (2) high proportion of 9p24.1 alteration (n = 9, 20%), (3) high IFN-γ signature score (n = 9, 20%), and (4) low IFN-γ signature score (n = 18, 39%). Moreover, these groups were identified using the following surrogate immunohistochemical markers: EBNA2, PDL1, and IDO1. In conclusion, the molecular studies assessing the tumor-host interaction enhance the understanding of the EBV+ LBCL spectrum and benefit pathological diagnosis and clinical management.
Pathogenic POLE-Mutated Endometrial Carcinomas With a Nonultramutated Genome.
Srikumar S, Evans N, Tjota MY … +7 more , Alikhan M, Kaur A, Sabatini LM, Miller N, Bouma M, Maniar KP, Parilla M
Mod Pathol · 2026 Feb · PMID 41354358 · Publisher ↗
Endometrial carcinomas can be classified into 1 of 4 molecular subtypes, with the POLE-mutant subtype carrying the best prognosis. Pathogenic mutations in POLE are known to disrupt the proofreading function of DNA polyme...
Endometrial carcinomas can be classified into 1 of 4 molecular subtypes, with the POLE-mutant subtype carrying the best prognosis. Pathogenic mutations in POLE are known to disrupt the proofreading function of DNA polymerase epsilon, resulting in an ultramutated genome, typically defined as ≥100 mutations per megabase. Routine next-generation sequencing was implemented on all endometrial carcinoma cases at our institution beginning in December 2023 to aid in molecular subclassification. During this routine sequencing, 6 POLE-mutated cases, with confirmed pathogenic POLE mutations, were observed to have a tumor mutational burden <100; prior to universal testing, only 1 such case had been identified. Endometrial carcinoma cases with pathogenic POLE mutations and tumor mutational burden <100 may be globally under-recognized, as universal testing is not yet a widely standard practice. These cases with pathogenic POLE mutations and a nonultramutated genome were found to have a lower frequency of classic morphologic "POLE features," including high-grade histology, compared with classic ultramutated cases. The immunohistochemical profiles are also different from ultramutated counterparts, with a lower frequency of mismatch repair immunohistochemical abnormalities and p53 null or diffuse staining, and a higher likelihood of strong and diffuse estrogen receptor/progesterone receptor expression, aligning with fewer mutations in encoding genes. However, endometrial carcinoma with pathogenic POLE mutations, without ultramutation, appears to retain the "POLE-mutational signature" described in the literature. Additionally, clinical outcomes do not appear different; however, this phenomenon needs additional investigation.
Diagnostic Utility and Clinicopathologic Associations of Histone H3 Lysine 27 Trimethylation (H3K27me3) Immunohistochemistry for Merkel Cell Carcinoma.
Hrycaj S, Chan MP, Venneti S … +2 more , Harms KL, Harms PW
Mod Pathol · 2026 Jan · PMID 41352627 · Publisher ↗
Merkel cell carcinoma (MCC) is an aggressive cutaneous tumor that must be distinguished from other cutaneous tumors and metastatic small cell carcinoma (SmCC). Additional diagnostic markers are limited for MCC with immun...
Merkel cell carcinoma (MCC) is an aggressive cutaneous tumor that must be distinguished from other cutaneous tumors and metastatic small cell carcinoma (SmCC). Additional diagnostic markers are limited for MCC with immunophenotypic aberrancy. MCC can display immunohistochemical loss of the epigenetic marker histone H3 lysine 27 trimethylation (H3K27me3), but to our knowledge, the diagnostic utility of this observation has not been evaluated. In this study, we investigate H3K27me3 labeling in MCC (n = 195), cutaneous epithelial tumors (n = 48), noncutaneous SmCCs (n = 56), and olfactory neuroblastoma (n = 11), comparing with diagnostic markers, cytokeratin-20, neurofilament, SATB2, and POU4F3. H3K27me3 patterns in MCC included global loss, variable/mosaic labeling, and diffuse labeling. Global loss significantly associated with polyomavirus negativity, squamous atypia, and sarcomatoid change. Tumors with global loss displayed EZHIP expression (9 cases) and SUZ12 mutation (1 case). Low but retained H3K27me3 labeling was associated with longer overall and MCC-specific survival. Diagnostically, H3K27me3 labeling in MCC was significantly lower than potential mimics, and global loss of H3K27me3 was highly specific for MCC; stronger H3K27me3 labeling was not informative. Considering reduced/absent H3K27me3 as favoring MCC, diagnostic performance was similar to SATB2. However, H3K27me3 displayed consistent performance in MCC with challenging immunophenotypes, unlike SATB2. In summary, we expand upon descriptions of H3K27me3 labeling in MCC and characterize patterns of H3K27me3 in other tumor types including SmCCs and olfactory neuroblastoma. Our findings support diagnostic utility for the widely available marker H3K27me3 in MCC, with weaker labeling favoring MCC over mimics in challenging cases.
Histological Categorization of Desmoplastic Reaction in Triple-Negative Breast Cancer: Its Relevance to Neoadjuvant Chemoimmunotherapy Response and Tumor Biology.
Lu X, Luo B, Wei Y … +2 more , Bu H, Gou Z
Mod Pathol · 2026 Jan · PMID 41314289 · Publisher ↗
Neoadjuvant chemoimmunotherapy (NACi) is a new standard treatment for early-stage high-risk triple-negative breast cancer (TNBC). Desmoplastic reaction (DR) is an important characteristic in the tumor-associated stroma o...
Neoadjuvant chemoimmunotherapy (NACi) is a new standard treatment for early-stage high-risk triple-negative breast cancer (TNBC). Desmoplastic reaction (DR) is an important characteristic in the tumor-associated stroma of TNBC. Based on the presence or absence of myxoid stroma and keloid-like collagen bundles within the tumor-associated stroma, DR was classified into immature, intermediate, or mature type. The relationship between DR and NACi efficacy remains unclear. We retrospectively analyzed 209 TNBC patients who received NACi from 3 medical centers, and 75, 78, and 56 cases were categorized as mature, intermediate, and immature types of DR, respectively. The pathological complete response rate was the highest in the mature group (77.3%), followed by the intermediate (30.8%) and immature (17.9%) groups. Multivariate logistic regression analysis indicated that in addition to histological type, Ki-67, T stage, N stage, and stromal tumor-infiltrating lymphocytes, DR was also an independent predictor of pathological complete response. Cases with intermediate and immature stroma exhibited fewer stromal tumor-infiltrating lymphocytes, an immunosuppressive tumor microenvironment, and upregulation of genes related to extracellular matrix and epithelial-mesenchymal transition. These findings demonstrate the predictive value of DR for NACi efficacy in TNBC and highlight its potential as a histopathological biomarker. The association between DR and molecular hallmarks provides important insights into the biological basis of DR in TNBC.
CD38 Expression and 6q/9q Codeletion: Diagnostic Markers for Primary Cutaneous Cribriform Tumor.
Harms PW
Mod Pathol · 2026 Jan · PMID 41297323 · Publisher ↗
Abstract loading — click title to view on PubMed.
Diagnostic Discordance and Error in Breast Pathology: Causes, Classifications, and Medicolegal Implications.
Rakha EA, Quinn CM, Provenzano E … +2 more , Pinder SE, Ellis IO
Mod Pathol · 2026 Jan · PMID 41285251 · Publisher ↗
Diagnostic pathology is inherently interpretative and subject to interobserver variability. Although diagnostic concordance is a critical quality metric, distinguishing between acceptable variation, diagnostic error, and...
Diagnostic pathology is inherently interpretative and subject to interobserver variability. Although diagnostic concordance is a critical quality metric, distinguishing between acceptable variation, diagnostic error, and professional negligence is essential for both clinical care and medicolegal clarity. This review highlights the difference between interobserver variability (diagnostic disagreement/discordance) that remains within acceptable professional limits, diagnostic error (a deviation from expected standards due to cognitive, technical, or systemic factors), and negligence (a repeated, reckless, or unjustified deviation from established standards). Errors in pathology often reflect systemic vulnerabilities, such as workflow inefficiencies, inadequate quality control, or limited biopsy sampling, rather than individual performance alone. They may occur at any stage of the diagnostic pathway (preanalytical, analytical, or postanalytical) and arise from specimen misidentification, contamination or loss, inadequate sampling, or incomplete documentation. Pathologist-related errors encompass failure to recognize significant pathology, misinterpretation, omission of appropriate ancillary studies, insufficient workup of complex cases, including failure to seek a second opinion, or substandard reporting. Medicolegal implications are heightened when such errors result in delayed diagnosis or major misclassification, leading to patient harm. In breast pathology, interobserver variation in the classification of borderline lesions (eg, grading of phyllodes tumors) and in the interpretation of overlapping entities (eg, atypical apocrine lesions) is well recognized. Although such differences may influence management, they should be regarded as acceptable professional variability, rather than error or negligence. To minimize diagnostic risk and uphold standards, structured reporting, vigilance in complex cases, participation in quality assurance, explicit documentation of uncertainty, active multidisciplinary team engagement, and laboratory accreditation are strongly recommended. Supporting pathologists as diagnosticians and patient safety advocates, within a culture of openness, shared learning, and institutional support, remains central to diagnostic accuracy, transparency, and medicolegal defensibility.
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