Carcinoma showing thymus-like differentiation (CASTLE) is a rare malignancy arising in the thyroid or neck, with an uncertain cellular origin that complicates both diagnosis and treatment. To better understand its molecular underpinnings and identify potential therapeutic avenues, we conducted integrated whole-exome and transcriptome sequencing on six CASTLE and six thymic carcinoma samples. Whole-exome sequencing (WES) was performed on all 12 samples, while RNA sequencing was successful for 1 CASTLE and 6 thymic carcinoma samples. Our analysis included somatic mutation profiling, mutational signature deconvolution, differential gene expression, and characterization of tumor microenvironment for the cases with available data, with comparisons to genomic data from other thyroid cancers. CASTLE tumors demonstrated a higher median tumor mutational burden than thymic carcinoma and lacked the common BRAF and RAS mutations typically found in thyroid cancers. They harbored alterations in genes such as TRHDE, cilia-associated genes (ANKS6, CFAP46, DNAH6), and Wnt signaling components (TRRAP, BCL9L), as well as mutational signatures suggestive of mismatch repair deficiency and oxidative damage. MSIsensor-pro analysis of the WES data provided support for the potential for mismatch repair deficiency in a subset of CASTLE samples. Exploratory transcriptomic analysis from a single CASTLE case showed downregulation of thyroid follicular markers and an "immune-hot", lymphocyte-rich microenvironment, closely resembling that of thymic carcinoma. While these findings require validation in larger cohorts, they support a thymic origin for CASTLE and establish its molecular distinction from follicular-derived thyroid cancers. The immunogenic tumor landscape suggests that immune checkpoint inhibitors, particularly those targeting PD-1/PD-L1, may be a promising therapeutic strategy, alongside emerging targets for precision oncology.

ABSTRACT:Malignant histiocytic neoplasms (MHNs) are rare tumors derived from the mononuclear phagocyte system (MPS), encompassing histiocytic sarcoma, Langerhans cell sarcoma, interdigitating dendritic cell sarcoma, and other high-grade MPS lineage tumors. Despite advances in understanding histiocytic neoplasms, MHNs remain diagnostically challenging and lack standardized treatment algorithms. Current classification systems differ in lineage framing and fail to address mixed or ambiguous phenotypes, contributing to diagnostic uncertainty and inconsistent care. To address these gaps, the Histiocyte Society convened an international working group of pathologists and oncologists, including World Health Organization and International Consensus Classification contributors, to harmonize nomenclature, define minimum diagnostic criteria, and develop pragmatic treatment recommendations. Using a modified Delphi process and case-based review, the group formulated >40 consensus statements spanning classification, pathology, molecular testing, clinical evaluation, and therapeutic strategies. Key recommendations include the adoption of a unified MHN designation, use of a minimum immunophenotypic panel, integration of broad molecular profiling, and the documentation of previous hematopoietic malignancy. Treatment algorithms emphasize surgical resection for unifocal disease and targeted therapy or immune checkpoint inhibition for multifocal disease when actionable mutations or programmed death ligand 1 expression are present. These consensus recommendations aim to reduce diagnostic ambiguity, standardize reporting, and improve outcomes for both pediatric and adult patients. Future priorities include international registries to refine risk stratification and biomarker-driven trials exploring targeted therapy, immunotherapy, and combination approaches.

The fifth edition of the WHO classification of haematolymphoid tumours (WHO-HEM5) introduces significant updates to the classification of acute lymphoblastic leukaemia, ALAL (including mixed phenotype acute leukaemia (MPAL)), myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK), and histiocytic and dendritic cell neoplasms, reflecting the advances in the understanding of the genetic basis of these diseases. This review provides an overview of these changes, highlighting a shift to a more refined molecular-genetic approach. The incorporation of newly recognised genetic subtypes into the classification scheme underscores the evolving landscape of these entities. Challenges in diagnosing ALAL/MPAL and MLN-TK are discussed, along with recent insights into histiocytic and dendritic cell neoplasms, including newly defined entities such as ALK-positive histiocytosis.The review also explores the practical implications of WHO-HEM5, particularly in resource-limited settings, where comprehensive molecular testing may be unavailable. While morphology and immunohistochemistry remain essential diagnostic tools, strategic use of flow cytometry and targeted fluorescence in situ hybridisation can facilitate risk-adapted classification and improve survival in regions with limited resources and therapeutic options. Future large-scale studies are necessary to establish the diagnostic and prognostic value of these newly genetically defined entities for diverse healthcare environments, and to standardise guidelines in refining disease classification and optimising patient outcomes.

The fifth edition of the WHO Classification of Haematolymphoid Tumors (WHO-HAEM5) introduces significant advancements in the understanding and diagnosis of mature T cell and NK cell, and stroma-derived neoplasms, and incorporates molecular and genetic data/findings accrued over the past years. The classification has been reorganised using a hierarchical system, employed across the fifth edition of the WHO classification of tumours of all organ systems. This review highlights recent developments, evolving concepts, and key updates since the revised fourth edition (WHO-HAEM4R). It enumerates the minimal/essential criteria necessary for diagnosis and classification, constituting not only the importance of clonality analysis in the workup of certain T cell neoplasms and the detection of infectious agents and specific genetic alterations in a subset of entities but also the applicability of these criteria in resource-constrained settings. 'Stroma-derived neoplasms of lymphoid tissues discussed in this review is a new category introduced in HAEM5 that encompasses mesenchymal tumours occurring exclusively in lymph nodes and spleen and mesenchymal dendritic cell neoplasms previously classified as 'histiocytic/dendritic cell neoplasms'.

We present a review of mature B-cell neoplasms as described in the fifth edition of the WHO classification of haematolymphoid tumours (WHO-HAEM5). Entities have expanded, and definitions are increasingly reliant on genomic and other technologies. However, the WHO-HAEM5 employs a hierarchical structure with family (class)-level definitions that group several specific entities. This approach enables the assignment of a family-level diagnosis when criteria for specific entities cannot be met due to resource constraints. To facilitate application in resource-limited settings, WHO-HAEM5 divides diagnostic criteria into 'essential' and desirable criteria for most entities. This review focuses on changes and updates in B-cell lymphoma classification, providing guidance on how to apply the WHO classification in resource-limited settings.

BACKGROUND:Lung adenocarcinoma (LUAD) in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve LUAD risk prediction. METHODS:PRSs were developed using genome-wide association study summary statistics from East Asian (8,002 cases; 20,782 controls) and European (2,058 cases; 5,575 controls) populations. Single-ancestry models included PRS-25, PRS-CT, and LDpred2; multi-ancestry models included LDpred2+PRS-EUR128, PRS-CSx, and CT-SLEB. Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium (FLCCA) and externally validated in the Nanjing Lung Cancer Cohort (NJLCC). We assessed predictive accuracy via AUC, with 10-year and (age 30-80) absolute risks estimates. RESULTS:The best multi-ancestry PRS, using East Asian and European data via CT-SLEB (clumping and thresholding, super learning, empirical Bayes), outperformed the best East Asian-only PRS (LDpred2; AUC = 0.629, 95% CI:0.618,0.641), achieving an AUC of 0.640 (95% CI : 0.629,0.653) and odds ratio of 1.71 (95% CI : 1.61,1.82) per SD increase. NJLCC Validation confirmed robust performance (AUC =0.649, 95% CI: 0.623, 0.676). The top 20% PRS group had a 3.92-fold higher LUAD risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year LUAD risk at age 50 (0.42%) by age 41, nine years earlier. CONCLUSIONS:Multi-ancestry PRS approaches enhance LUAD risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.

Histiocytic and dendritic cell neoplasms of hematopoietic origin are derived from or show differentiation towards the cells of the mononuclear phagocyte system. Plasmacytoid dendritic cell proliferations/neoplasms include mature plasmacytoid dendritic cell proliferations identified in the context of a defined myeloid neoplasm and blastic plasmacytoid dendritic cell neoplasm, an aggressive tumor with a poor outcome. Malignant histiocytic (macrophage/dendritic cell) neoplasms occur de novo or in the setting of another hematological malignancy, typically "transdifferentiated" from associated lymphoid neoplasia. Recurrent alterations in the MAPK pathway have been shown to have a key role in their pathogenesis. Neoplasms derived from follicular dendritic cells and fibroblastic reticular cells originate from a mesenchymal precursor. The major entities in this group include follicular dendritic sarcoma, which has recently been shown to harbor recurrent alterations in NF-κB pathway genes, and EBV positive inflammatory follicular dendritic cell sarcoma/tumor, a rare lesion with an inflammatory pseudotumor-like morphology and association with EBV infection. At the joint Workshop of the Chinese Society of Hematopathology (CSHP), the European Association for Haematopathology (EA4HP) and the Society for Hematopathology (SH) on histiocytic/dendritic cell proliferations, neoplasms, and their mimics in Hefei, China, April 2024, there were 16 cases submitted to session 3 on plasmacytoid dendritic cell proliferations and neoplasms, and a total of 42 submissions to session 4 on malignant histiocytic and dendritic cell neoplasms, including stroma-derived neoplasms. A summary of the findings and conclusions arising from discussion of the workshop cases are presented in this report.

This manuscript represents a review of lymphoblastic leukemia/lymphoma (acute lymphoblastic leukemia/lymphoblastic lymphoma), acute leukemias of ambiguous lineage, mixed-phenotype acute leukemias, myeloid/lymphoid neoplasms with eosinophilia and defining gene rearrangements, histiocytic and dendritic neoplasms and genetic tumor syndromes of the 5th edition of the World Health Organization Classification of Tumors of the Haematopoietic and Lymphoid Tissues (WHO-HEM5). The diagnostic clinicopathologic, cytogenetic and molecular genetic features are discussed. The differences in comparison to the 4th revised edition of the WHO classification of hematolymphoid neoplasms are highlighted.

The World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues has been the internationally accepted standard for over 20 years. The fifth edition of the WHO Classification (WHO-HEM5) is a multidisciplinary effort by pathologists, clinicians and other specialists that builds upon the revised fourth edition published in 2017. Entities in WHO-HEM5 are organized hierarchically. There are several changes in WHO-HEM5 from the previous edition, including addition of new entities, deletion of some entities and recognition or revision of some subtypes reflecting scientific developments and clinical advances during the past few years. Essential and desirable criteria for each entity are included. Here we introduce WHO-HEM5. Four reviews will follow that emphasize important aspects of the classification.

This review focuses on mature T cells, natural killer (NK) cells, and stroma-derived neoplasms in the fifth edition of the World Health Organization classification of hematolymphoid tumors, including changes from the revised fourth edition. Overall, information has expanded, primarily due to advancements in genomic understanding. The updated classification adopts a hierarchical format. The updated classification relies on a multidisciplinary approach, incorporating insights from a diverse group of pathologists, clinicians, and geneticists. Indolent NK-cell lymphoproliferative disorder of the gastrointestinal tract, Epstein-Barr virus-positive nodal T- and NK-cell lymphoma, and several stroma-derived neoplasms of lymphoid tissues have been newly introduced or included. The review also provides guidance on how the fifth edition of the World Health Organization classification of hematolymphoid tumors can be applied in routine clinical practice. (c) 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Epstein-Barr virus (EBV) is an oncogenic virus associated with various malignancies, including classical Hodgkin lymphoma (cHL). Despite its known association, the specific role of humoral immune response to EBV remains poorly characterized in cHL. To address this, we conducted a study using a custom protein microarray to measure the antibody responses in cHL patients and matched healthy controls recruited from an East-Asian hospital-based case-control study. We identified 16 IgG antibodies significantly elevated in EBV-positive cHL compared with controls, defining an "East-Asian antibody signature of EBV-positive cHL." We evaluated responses against these 16 antibodies in a distinct European population, leveraging data from our previous European cHL case-control study from the UK, Denmark, and Sweden. A subset of antibodies (14/16, 87.5%) from the "East-Asian antibody signature of EBV-positive cHL" exhibited significant associations with cHL in the European population. Conversely, we assessed the "European antibody signature of EBV-positive cHL" identified in our prior study which consisted of 18 EBV antibodies (2 IgA, 16 IgG), in the East-Asian population. A subset of these antibodies (15/18, 83.3%) maintained significant associations with cHL in the East-Asian population. This cross-comparison of antibody signatures underscores the robust generalizability of EBV antibodies across populations. Five anti-EBV IgG antibodies (LMP-1, TK, BALF2, BDLF3, and BBLF1), found in both population-specific antibody signatures, represent a "core signature of EBV-positive cHL." Our findings suggest that the antibody responses targeting these core EBV proteins reflect a specific EBV gene expression pattern, serving as potential biomarkers for EBV-positive cHL independent of population-specific factors.

The purpose of this review is to give an overview on the conceptual framework and major developments of the upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid tumours (WHO-HAEM5) and to highlight the most significant changes made in WHO-HAEM5 compared with the revised 4th edition (WHO-HAEM4R) of lymphoid and stromal neoplasms. The changes from the revised 4th edition include the reorganization of entities by means of a hierarchical system that is realized throughout the 5th edition of the WHO classification of tumors of all organ systems, a modification of nomenclature for some entities, the refinement of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities. For the first time, tumor-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms are included in the classification.

3130 Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of pts with advanced solid tumors with HTMB treated with N+I are reported. Methods: Eligible pts had measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options or prior immune checkpoint inhibitor tx. PD-L1 expression testing was not required. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. HTMB was defined a priorias ≥9 mutations/megabase (Muts/Mb) via a qualifying test for TAPUR or approved by the Molecular Tumor Board. Pts received I at 3 mg/kg every 3 weeks (wks) for 4 doses with N at 1 mg/kg IV every 3 wks for 4 doses. N alone was then continued at 240 mg every 2 wks or 480 mg every 4 wks until disease progression. Low accruing histology-specific cohorts with HTMB were collapsed into 1 cohort for analysis. Primary endpoint was disease control (DC) per investigator defined as complete (CR) or partial (PR) response per RECIST v. 1.1, or stable disease (SD) of at least 16 wks duration (SD16+). The hypothesized null DC rate of 15% was evaluated by a 1-sided exact binomial test (α= 0.10; 86% power based on alternative DC rate of 35%). Secondary endpoints were progression-free survival (PFS), overall survival (OS), objective response (OR), duration of response (DOR), duration of SD, and safety. DOR is time from documented OR to progressive disease (PD); duration of SD is time from tx start to PD. Results: 26 pts with 13 tumor types with HTMB were enrolled. Table shows demographics and outcomes. Tissue tumor mutational burden (TMB) ranged from 8 to 374 Muts/Mb (median= 16). 1 CR (small intestine; TMB= 48 Muts/Mb; DOR= 36 wks), 7 PR (biliary tract, site unspecified [3], soft tissue sarcoma, uterus, vagina; median TMB= 17 Muts/Mb; median DOR= 20 wks [range, 5-231]) and 1 SD16+ (pancreas; TMB= 26 Muts/Mb; duration of SD= 26 wks) were observed for a DC rate of 35% (1-sided 90% CI: 22 to 100) and OR rate of 31% (95% CI: 14 to 52). The null hypothesis was rejected (p=0.011). Notably, 1 pt (uterus, 374 Muts/Mb) is still on tx with an ongoing 66-wk PR as of Jan 2024. Most pts, including 8/9 with DC, were microsatellite stable. 10 pts had ≥1 grade 3 tx-related adverse event (AE) or serious AE. Conclusions: N+I showed antitumor activity in pts with advanced solid tumors with HTMB. Additional study is warranted to confirm the efficacy of N+I in pts with HTMB. Clinical trial information: NCT02693535 . [Table: see text]

The classification of tumors is essential in the diagnosis and clinical management of patients with malignant neoplasms. The World Health Organization (WHO) provides a globally applicable classification scheme of neoplasms and it was updated several times. In this review, we briefly outline the cornerstones of the upcoming 5th edition of the World Health Organization Classification of Haematolymphoid Tumours on lymphoid neoplasms. As is adopted throughout the 5th edition of the WHO classification of tumors of all organ systems, entities are listed by a hierarchical system. For the first time, tumor-like lesions have been included in the classification, and modifications of nomenclature for some entities, revisions of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities are presented along with mesenchymal lesions specific to the stroma of lymph nodes and the spleen. In addition to specific outlines on constitutional and somatic genetic changes associated with given entities, a separate chapter on germline predisposition syndromes related to hematologic neoplasms has been added.

Polyethylene glycol (PEG)-asparaginase (pegaspargase) is a key agent in chemotherapy for acute lymphoblastic leukemia (ALL), but recipients frequently experience allergic reactions. We hypothesized that by decreasing antibody-producing CD20-positive B cells, rituximab may reduce these reactions. Children and adolescents (aged 1–18 years) with newly diagnosed B-ALL treated on the St. Jude Total XVII study were randomized to induction therapy with or without rituximab on day 3 (cohort 1) or on days 6 and 24 (cohort 2). Patient clinical demographics, CD20 expression, minimal residual disease (MRD), rituximab reactions, pegaspargase allergy, anti-pegaspargase antibodies, and pancreatitis were evaluated. Thirty-five patients received rituximab and 37 did not. Among the 35 recipients, 16 (45.7%) experienced a grade 2 or higher reaction to rituximab. There were no differences between recipients and non-recipients in the incidence of pegaspargase reactions ( P > 0.999), anti-pegaspargase antibodies ( P = 0.327), or pancreatitis ( P = 0.480). CD20 expression on day 8 was significantly lower in rituximab recipients ( P < 0.001), but there were no differences in MRD levels on day 8, 15, or at the end of induction. Rituximab administration during induction in pediatric patients with B-ALL was associated with a high incidence of infusion reactions with no significant decrease in pegaspargase allergies, anti-pegaspargase antibodies, or MRD.

Significant variations exist related to the end of induction practices in the management of Acute Promyelocytic Leukemia (APL). These variations include all-trans retinoic acid (ATRA)-arsenic trioxide (ATO) in fixed doses versus continuation until hematologic complete remission (CR) and performance versus omission of post-induction bone marrow biopsy to confirm morphological CR. A retrospective chart review was conducted of 61 patients (42 low/intermediate-risk and 19 high-risk) aged ≥ 18 years with newly diagnosed APL treated with fixed duration ATRA-ATO +/- cytoreduction at a tertiary medical center from December 2012 through March 2020. Of the 54 patients with post-induction bone marrow biopsy results, 52 (96%) demonstrated no morphologic evidence of APL while the remaining were equivocal. After 2.6 years median follow-up, no relapses occurred. The estimated 2-year overall survival rate of 95% suggests excellent outcomes with a fixed ATO induction regimen and safe omission of post-induction bone marrow biopsy irrespective of hematologic parameters.

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset ( n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (P interaction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications.