What is new in the 5th edition of the World Health Organization classification of mature B and T/NK cell tumors and stromal neoplasms?

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.

Follicular Lymphoma Presenting With Symptomatic Bone Involvement: A Clinicopathologic and Molecular Analysis of 16 Cases.

Primary bone lymphoma (PBL) is rare and mostly represented by diffuse large B-cell lymphomas (DLBCL). Follicular lymphoma (FL), albeit commonly disseminating to the bone marrow, rarely presents primarily as bone lesions. Here, we studied 16 patients (12 men:4 women, median age 60 years) who presented with bone pain and/or skeletal radiologic abnormalities revealing bone FL. Lesions were multifocal in 11 patients (spine ± appendicular skeleton), and unifocal in 5 patients (femoral, tibial, or vertebral). An infiltrate of centrocytes and centroblasts (CD20+ CD5- CD10+ BCL2+ BCL6+) with abundant reactive T cells and an increased reticulin fibrosis massively replaced the marrow spaces between preserved bone trabeculae. The pattern was diffuse ± nodular, often with paratrabecular reinforcement and/or peripheral paratrabecular extension. Ki-67 was usually <15%. Two cases had necrosis. BCL2 rearrangement was demonstrated in 14 of 14 evaluable cases (with concomitant BCL6 rearrangement in one). High-throughput sequencing revealed BCL2, KMT2D, and TNFRSF14 to be the most frequently mutated genes. After staging, 5 qualified for PBL (3 limited stage) and 11 had stage IV systemic FL. All patients received rituximab ± polychemotherapy as firstline treatment, and 7 received local therapy (6 radiotherapy and 2 surgery). Three patients experienced transformation to DLBCL. At the last follow-up (15/16, median 48 months), 11 patients achieved complete remission, including all cases with PBL and most patients with limited extraosseous disease (3-year progression-free survival 71%). One patient died of unrelated cause (3-year overall survival 91%). FL may manifest as a localized or polyostotic bone disease. A minority represent PBL, whereas most reveal systemic disease.

The fifth edition of the WHO classification of mature B-cell neoplasms: open questions for research.

The fifth edition of the World Health Organization Classification of Haematolymphoid Tumours (WHO-HAEM5) is the product of an evidence-based evolution of the revised fourth edition with wide multidisciplinary consultation. Nonetheless, while every classification incorporates scientific advances and aims to improve upon the prior version, medical knowledge remains incomplete and individual neoplasms may not be easily subclassified in a given scheme. Thus, optimal classification requires ongoing study, and there are certain aspects of some entities and subtypes that require further refinements. In this review, we highlight a selection of these challenging areas to prompt more research investigations. These include (1) a 'placeholder term' of splenic B-cell lymphoma/leukaemia with prominent nucleoli (SBLPN) to accommodate many of the splenic lymphomas previously classified as hairy cell leukaemia variant and B-prolymphocytic leukaemia, a clear new start to define their pathobiology; (2) how best to classify BCL2 rearrangement negative follicular lymphoma including those with BCL6 rearrangement, integrating the emerging new knowledge on various germinal centre B-cell subsets; (3) what is the spectrum of non-IG gene partners of MYC translocation in diffuse large B-cell lymphoma/high-grade B-cell lymphoma and how they impact MYC expression and clinical outcome; how best to investigate this in a routine clinical setting; and (4) how best to define high-grade B-cell lymphoma not otherwise specified and high-grade B-cell lymphoma with 11q aberrations to distinguish them from their mimics and characterise their molecular pathogenetic mechanism. Addressing these questions would provide more robust evidence to better define these entities/subtypes, improve their diagnosis and/or prognostic stratification, leading to better patient care. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

The 5th edition of the World Health Organization Classification of mature lymphoid and stromal tumors - an overview and update.

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.

The IPTA Nashville Consensus Conference on Post-Transplant lymphoproliferative disorders after solid organ transplantation in children: III - Consensus guidelines for Epstein-Barr virus load and other biomarker monitoring.

The International Pediatric Transplant Association convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post-transplant lymphoproliferative disorders after solid organ transplantation in children. In this report from the Viral Load and Biomarker Monitoring Working Group, we reviewed the existing literature regarding the role of Epstein-Barr viral load and other biomarkers in peripheral blood for predicting the development of PTLD, for PTLD diagnosis, and for monitoring of response to treatment. Key recommendations from the group highlighted the strong recommendation for use of the term EBV DNAemia instead of "viremia" to describe EBV DNA levels in peripheral blood as well as concerns with comparison of EBV DNAemia measurement results performed at different institutions even when tests are calibrated using the WHO international standard. The working group concluded that either whole blood or plasma could be used as matrices for EBV DNA measurement; optimal specimen type may be clinical context dependent. Whole blood testing has some advantages for surveillance to inform pre-emptive interventions while plasma testing may be preferred in the setting of clinical symptoms and treatment monitoring. However, EBV DNAemia testing alone was not recommended for PTLD diagnosis. Quantitative EBV DNAemia surveillance to identify patients at risk for PTLD and to inform pre-emptive interventions in patients who are EBV seronegative pre-transplant was recommended. In contrast, with the exception of intestinal transplant recipients or those with recent primary EBV infection prior to SOT, surveillance was not recommended in pediatric SOT recipients EBV seropositive pre-transplant. Implications of viral load kinetic parameters including peak load and viral set point on pre-emptive PTLD prevention monitoring algorithms were discussed. Use of additional markers, including measurements of EBV specific cell mediated immunity was discussed but not recommended though the importance of obtaining additional data from prospective multicenter studies was highlighted as a key research priority.

The IPTA Nashville consensus conference on Post-Transplant lymphoproliferative disorders after solid organ transplantation in children: II-consensus guidelines for prevention.

The International Pediatric Transplant Association (IPTA) convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post-transplant lymphoproliferative disorder after solid organ transplantation in children. In this report from the Prevention Working Group, we reviewed the existing literature regarding immunoprophylaxis and chemoprophylaxis, and pre-emptive strategies. While the group made a strong recommendation for pre-emptive reduction of immunosuppression at the time of EBV DNAemia (low to moderate evidence), no recommendations for use could be made for any prophylactic strategy or alternate pre-emptive strategy, largely due to insufficient or conflicting evidence. Current gaps and future research priorities are highlighted.

Primary Central Nervous System Anaplastic Large Cell Lymphoma, ALK Positive.

OBJECTIVES: Primary central nervous system anaplastic large cell lymphoma, anaplastic lymphoma kinase positive (primary CNS ALCL, ALK+) is a rare CNS lymphoma whose description is limited to case reports. These tumors have a variable clinical course, and prognosis is primarily determined by age. We present the largest case series to date of primary CNS ALCL, ALK+, with observational data. METHODS: A retrospective search of multiple academic centers was performed to identify cases of primary CNS ALCL, ALK+. We also performed a review of published cases of primary CNS ALCL, ALK+. Clinical history, radiography, pathology, and genetic testing data were obtained to determine the prognostic implications in the context of clinical course. RESULTS: We identified three cases of primary CNS ALCL, ALK+ from our databases. A literature review identified 30 published reports of 31 individual cases. Clinical features for the combined 34 cases included a median age of 18.5 years, with a male to female ratio of 4.7:1, and the most common symptom was headache. Genetic studies demonstrated an ALK rearrangement by fluorescence in situ hybridization, and a gene fusion assay confirmed an NPM1-ALK gene fusion in one case. CONCLUSIONS: We present the largest case series to date of a rare primary CNS lymphoma with additional diagnostic and clinical information.

Update from the 5th Edition of the World Health Organization Classification of Head and Neck Tumors: Hematolymphoid Proliferations and Neoplasia.

In the 5th edition of the World Health Organization (WHO) Classification of Head and Neck Tumours, the discussion of hematolymphoid proliferations is substantially reorganized and expanded in comparison to the prior edition. The 5th edition includes, in addition to hematolymphoid neoplasms, reactive lymphoid proliferations. Much more information on hematolymphoid proliferations that commonly affect cervical lymph nodes, in addition to those affecting extranodal sites in the head and neck, is included. For the first time, there are dedicated sections on multiple entities, including recently described lymphoproliferative disorders such as EBV+ mucocutaneous ulcer and pediatric-type follicular lymphoma, and several types of histiocytic neoplasms. Tremendous advances have been made in understanding the genetic features that underlie the pathogenesis of hematolymphoid neoplasms, and these have been incorporated into the WHO Classification.

Histiocytic and Dendritic Cell Sarcomas of Hematopoietic Origin Share Targetable Genomic Alterations Distinct from Follicular Dendritic Cell Sarcoma.

BACKGROUND: Histiocytic and dendritic cell neoplasms are a diverse group of tumors arising from monocytic or dendritic cell lineage. Whereas the genomic features for Langerhans cell histiocytosis and Erdheim-Chester disease have been well described, other less common and often aggressive tumors in this broad category remain poorly characterized, and comparison studies across the World Health Organization diagnostic categories are lacking. METHODS: Tumor samples from a total of 102 patient cases within four major subtypes of malignant histiocytic and dendritic cell neoplasms, including 44 follicular dendritic cell sarcomas (FDCSs), 41 histiocytic sarcomas (HSs), 7 interdigitating dendritic cell sarcomas (IDCSs), and 10 Langerhans cell sarcomas (LCSs), underwent hybridization capture with analysis of up to 406 cancer-related genes. RESULTS: Among the entire cohort of 102 patients, CDKN2A mutations were most frequent across subtypes and made up 32% of cases, followed by TP53 mutations (22%). Mitogen-activated protein kinase (MAPK) pathway mutations were present and enriched among the malignant histiocytosis (M) group (HS, IDCS, and LCS) but absent in FDCS (72% vs. 0%; p < .0001). In contrast, NF-κB pathway mutations were frequent in FDCSs but rare in M group histiocytoses (61% vs. 12%; p < .0001). Tumor mutational burden was significantly higher in M group histiocytoses as compared with FDCSs (median 4.0/Mb vs. 2.4/Mb; p = .012). We also describe a pediatric patient with recurrent secondary histiocytic sarcoma treated with targeted therapy and interrogated by molecular analysis to identify mechanisms of therapeutic resistance. CONCLUSION: A total of 42 patient tumors (41%) harbored pathogenic mutations that were potentially targetable by approved and/or investigative therapies. Our findings highlight the potential value of molecular testing to enable precise tumor classification, identify candidate oncogenic drivers, and define personalized therapeutic options for patients with these aggressive tumors. IMPLICATIONS FOR PRACTICE: This study presents comprehensive genomic profiling results on 102 patient cases within four major subtypes of malignant histiocytic and dendritic cell neoplasms, including 44 follicular dendritic cell sarcomas (FDCSs), 41 histiocytic sarcomas (HSs), 7 interdigitating dendritic cell sarcomas (IDCSs), and 10 Langerhans cell sarcomas (LCSs). MAPK pathway mutations were present and enriched among the malignant histiocytosis (M) group (HS, IDCS, and LCS) but absent in FDCSs. In contrast, NF-κB pathway mutations were frequent in FDCSs but rare in M group histiocytosis. A total of 42 patient tumors (41%) harbored pathogenic mutations that were potentially targetable by approved and/or investigative therapies.

Bone Marrow and Peripheral Blood Findings in Patients Infected by SARS-CoV-2.

OBJECTIVES: Coronavirus disease 19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is associated with diverse clinical, including hematologic, abnormalities. We describe peripheral blood and bone marrow findings in deceased and living patients with COVID-19. METHODS: We examined bone marrows from 20 autopsies and 2 living patients with COVID-19 using H&E-stained slides and immunohistochemical stains. Clinical history and laboratory values were reviewed. HScore was calculated to estimate risk of hemophagocytic lymphohistocytosis (HLH). RESULTS: The deceased patients included 12 men and 8 women (aged 32 to >89 years; median, 63 years). Hematologic abnormalities included frequent neutrophilic leukocytosis, lymphopenia, anemia, and thrombocytopenia; one patient showed striking erythrocytosis. The bone marrows were all normocellular to hypercellular, most showing maturing trilineage hematopoiesis with myeloid left shift. In all 19 evaluable bone marrows, hemophagocytic histiocytes were identified. The HScore for secondary HLH ranged from 35 to 269 (median, 125; >169 in 5 patients). Coinfections were identified in 6 patients. In 2 living patients, bone marrow showed maturing trilineage hematopoiesis, including one showing few hemophagocytic histiocytes. CONCLUSIONS: Peripheral blood from deceased patients with COVID-19 frequently showed neutrophilic leukocytosis, lymphopenia, and, rarely, secondary polycythemia; hemophagocytosis was common in their bone marrow. Consistent with other studies, we provide histopathologic evidence of secondary HLH development in patients with COVID-19.

Tonsillar p16-Positive Follicular Dendritic Cell Sarcoma Mimicking HPV-Related Oropharyngeal Squamous Cell Carcinoma: A Case Report and Review of Reported Cases.

Follicular dendritic cell sarcoma (FDCS) is a rare entity which can share morphologic features with non-keratinizing squamous cell carcinoma. Recent reports suggest that up to half of FDCSs show immunohistochemical positivity for p16 (Zhang et al., in Hum Pathol 66:40-47, 2017), a stain that is conventionally used in the risk stratification of oropharyngeal squamous cell carcinoma (OPSCC). Herein, we report a case of p16-positive FDCS with clinical and histomorphologic overlap with human papilloma virus (HPV)-related OPSCC.

IgG4-related Lymphadenopathy: A Comparative Study of 41 Cases Reveals Distinctive Histopathologic Features.

Lymphadenopathy is common in patients with immunoglobulin G4-related disease (IgG4-RD). However, the described histopathologic features of IgG4-related lymphadenopathy have been shown to be largely nonspecific. In an attempt to identify features specific for nodal IgG4-RD we examined the histopathologic features of lymph nodes from 41 patients with established IgG4-RD, with comparison to 60 lymph nodes from patients without known or subsequent development of IgG4-RD. An increase in immunoglobulin (Ig) G4-positive plasma cells >100/HPF and IgG4/IgG ratio >40% was identified in 51% of IgG4-RD cases and 20% of control cases. Localization of increased IgG4-positive plasma cells and IgG4/IgG ratio to extrafollicular zones was highly associated with IgG4-RD, particularly when identified in regions of nodal fibrosis (P<0.0001; specificity: 98.3%), or in the context of marked interfollicular expansion (P=0.022; specificity: 100%). Other features characteristic of IgG4-RD included frequent eosinophils associated with IgG4-positive plasma cells, phlebitis (P=0.06), and perifollicular granulomas (P=0.16). The presence of an isolated increase in intrafollicular IgG4-positive plasma cells and IgG4/IgG ratio was more frequently present in control cases than IgG4-RD (P<0.0001). This study confirms that increased IgG4-positive plasma cells and IgG4/IgG ratio are neither sensitive nor specific for the diagnosis of IgG4-related lymphadenopathy, and most described morphologic patterns are nonspecific. In contrast, nodal involvement by IgG4-rich fibrosis akin to extranodal IgG4-RD or diffuse interfollicular expansion by IgG4-positive plasma cells are highly specific features of true IgG4-related lymphadenopathy. Our findings provide for a clinically meaningful approach to the evaluation of lymph nodes that will assist pathologists in distinguishing IgG4-related lymphadenopathy from its mimics.

Scientific Advances and the Evolution of Diagnosis, Subclassification and Treatment of Lymphoma.

The diagnosis of lymphoma has evolved tremendously over time. Initially, diagnosis of lymphoma was largely based on morphology alone. Over time, immunophenotyping using flow cytometry and immunohistochemistry, and then in situ hybridization, have contributed dramatically to the pathologist's ability to recognize, diagnose and subclassify lymphomas more precisely. In recent years, cytogenetic and molecular genetic techniques have developed that allow evaluation of abnormalities in lymphomas, leading to an understanding of their pathogenesis and opening the door to targeted therapies that will lead to better outcomes for lymphoma patients.

Extranodal Marginal Zone Lymphoma of the Central Nervous System Includes Parenchymal-Based Cases With Characteristic Features.

OBJECTIVES: To define the clinicopathologic features of extranodal marginal zone lymphoma (EMZL) of the central nervous system (CNS), including cases arising in CNS parenchyma, which have been reported only rarely. METHODS: Twelve cases of CNS EMZL were identified, including 5 based in CNS parenchyma and 7 nonparenchymal cases arising in dura or choroid plexus. RESULTS: Histologically, parenchymal cases were perivascular infiltrates without a dominant lymphoid mass, whereas nonparenchymal cases were masses of small lymphocytes. Plasma cells were a larger component of the infiltrate in parenchymal cases (median, 30%; range, 20%-50%) than nonparenchymal cases (median, 0%; range, 0%-5%; P < .001), and plasma cells were clonal by immunohistochemistry in 4 of 5 parenchymal vs 1 of 7 nonparenchymal cases (P = .07). Fluorescence in situ hybridization for MALT1 rearrangement was positive in 1 of 3 parenchymal and none of 3 nonparenchymal cases. Chromosomal microarray was abnormal in 5 of 7 cases (71%), with chromosome 6/6q alterations identified in 3 cases. No patients with parenchymal disease but all 6 (100%) with nonparenchymal disease achieved complete remission. CONCLUSIONS: This case series, the first to include multiple parenchymal cases, clarifies the spectrum of clinical, pathologic, and genetic findings in CNS EMZL and suggests that parenchymal-based lesions may show less favorable prognosis than dural-based disease.

Correction to: Update on lymphoproliferative disorders of the gastrointestinal tract: disease spectrum from indolent lymphoproliferations to aggressive lymphomas.

This erratum is meant to address the error in which the names of one of the authors of the manuscript, was incorrect. Author assumes full responsibility for this error.

Lymphomas arising in immune-privileged sites: insights into biology, diagnosis, and pathogenesis.

Session 2 of the 2018 European Association of Hematopathology/Society for Hematopathology Workshop focused on lymphomas arising in immune-privileged sites: both lymphomas arising in the traditionally described "immune sanctuary" sites of the central nervous system (CNS) and testes, as well as those arising at sites of local immune privilege. Primary CNS large B cell lymphoma and primary testicular large B cell lymphoma were discussed, and the biology of these unique tumors was highlighted by several cases showing the classic mutation profile including MYD88 L265P and CD79B. The tendency of these tumors to involve both the CNS and testis was also reinforced by several cases. Four cases of low-grade B cell lymphomas (LGBCL) of the CNS were discussed. Two were classic Bing-Neel syndrome associated with LPL, and two were LGBCL with plasmacytic differentiation and amyloid deposition without systemic disease. Rare examples of systemic T and NK cell lymphomas involving the CNS were also discussed. Several cases of breast implant-associated anaplastic large cell lymphoma (BI-ALCL) were submitted showing the typical clinicopathologic features. These cases were discussed along with a case with analogous features arising in a patient with a gastric band implant, as well as large B cell lymphomas arising alongside foreign materials. Finally, large B cell lymphomas arising in effusions or localized sites of chronic inflammation (fibrin-associated diffuse large B cell lymphoma [DLBCL] and DLBCL associated with chronic inflammation) were described. The pathogenesis of all of these lymphomas is believed to be related to decreased immune surveillance, either innate to the physiology of the organ or acquired at a local site.