Reclassification of Myelodysplastic Neoplasms According to the 2022 World Health Organization Classification and the 2022 International Consensus Classification Using Open-Source Data: Focus on SF3B1- and TP53-mutated Myelodysplastic Neoplasms.

Background: In 2022, the WHO and International Consensus Classification (ICC) published diagnostic criteria for myelodysplastic neoplasms (MDSs). We examined the influence of the revised diagnostic criteria on classifying MDSs in a large population. Methods: We retrieved an open-source pre-existing dataset from cBioPortal and included 2,454 patients with MDS in this study. Patients were reclassified based on the new diagnostic 2022 WHO and ICC criteria. Survival analysis was performed using Cox regression to validate the new criteria and to assess risk factors. Results: Based on the 2022 WHO criteria, 1.4% of patients were reclassified as having AML. The 2022 WHO criteria provide a superior prognostic/diagnostic model to the 2017 WHO criteria (Akaike information criterion, 14,152 vs. 14,516; concordance index, 0.705 vs. 0.681). For classifying MDS with low blast counts and SF3B1 mutation, a variant allele frequency cut-off of 5% (2022 WHO criteria) and the absence of RUNX1 co-mutation (2022 ICC criteria) are diagnostically relevant. For classifying MDSs with mutated TP53, a blast count cut-off of 10% (2022 ICC criteria) and multi-hit TP53 (2022 WHO criteria) are independent risk factors in cases with ≥10% blasts. Conclusions: Our findings support the refinements of the new WHO criteria. We recommend the complementary use of the new WHO and ICC criteria in classifying SF3B1- and TP53-mutated MDSs for better survival prediction.

Pediatric lymphoproliferative disorders associated with inborn errors of immunity.

Both non-malignant and malignant lymphoproliferative disorders (LPD) are commonly seen in patients with inborn errors of immunity (IEI), which may be the presenting manifestations or may develop during the IEI disease course. Here we review the clinical, histopathological, and molecular features of benign and malignant LPD associated with IEI and recognize the diagnostic challenges.

New classifications of B-cell neoplasms: a comparison of 5th WHO and International Consensus classifications.

In 2024, the World Health Organization (WHO) launched a new classification of lymphoid neoplasms, a revision of the previously used Revised 4th Edition of their classification (WHO-4R). However, this means that two classifications are now in simultaneous use: the 5th Edition of the WHO classification (WHO-5) and the International Consensus Classification (ICC). Instead of a comprehensive review of each disease entity, as already described elsewhere, this review focuses on revisions made in both the WHO-5 and ICC from WHO-4R and discrepancies between them regarding B-cell neoplasms. Similarities include cutaneous marginal zone lymphoma, cold agglutinin disease, non-primary effusion lymphoma-type effusion-based lymphoma, and gray zone lymphoma. Differences include plasma cell neoplasms, high-grade B-cell lymphoma (double hit lymphoma), follicular lymphoma, LPD with immune deficiency and dysregulation, extranodal large B-cell lymphoma, transformations of indolent B-cell lymphomas, and diffuse large B-cell lymphoma, not otherwise specified. Understanding the similarities and differences between the two latest classifications will aid daily diagnostic practice and future research on lymphoid neoplasms.

Validation and comparison of 5th edition World Health Organization classification (WHO 2022) and International Consensus Classification proposals for MDS-SFB31.

The criteria of myelodysplastic syndromes (MDS) with mutated SFB31 (MDS-SFB31) proposed by the 5th edition of the WHO classification (WHO 2022) and the International Consensus Classification (ICC) need validation. We analysed 125 consecutive MDS cases with SFB31 mutation or ring sideroblasts (RS) ≥15% without excess blasts. We found that SFB31-negative MDS with RS had significantly different clinical features and worse prognosis. According to WHO 2022, the detection of ≥15% RS may substitute for SF3B1 mutation and our analyses support this proposal for similar prognosis of two groups after excluding high-risk genetic features referred by WHO 2022. Patients with variant allele frequency (VAF) <10% SFB31 tend to have briefer survival, supporting the VAF 10% threshold of ICC. Patients with multilineage dysplasia (MLD) had significantly shorter OS than those with single lineage dysplasia. MLD is still a powerful morphological marker of worse outcome in WHO 2022 and ICC-defined MDS-SF3B1.

What is new in acute myeloid leukemia classification?

Recently, the International Consensus Classification (ICC) and the 5th edition of the World Health Organization classification (WHO2022) introduced diagnostically similar yet distinct approaches, which has resulted in practical confusion. This review compares these classification systems for acute myeloid leukemia (AML), building up on the revised 4th edition of WHO (WHO2016). Both classifications retain recurrent genetic abnormalities as a primary consideration. However, they differ in terms of blast threshold. The ICC mandates a minimum of 10% blasts in the bone marrow or peripheral blood, whereas the WHO2022 does not specify a blast cut-off. AML with BCR::ABL1 requires > 20% blast count in both classifications. In WHO2022, AML with CEBPA mutation requires > 20% blasts. TP53 mutation, a new entity is exclusive to ICC, diagnosed with > 20% blasts and variant allele frequency > 10%. AML with myelodysplasia-related changes is defined by cytogenetic or gene mutation-based criteria, not morphological dysplasia. Eight genes were common to both groups: ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, and ZRSR2. An additional gene, RUNX1, was included in the ICC classification. AML cases defined by differentiation (WHO2022) and AML not otherwise specified (ICC) are categorized as lacking specific defining genetic abnormalities, WHO2022 labels this as a myeloid neoplasm post cytotoxic therapy (MN-pCT), described as an appendix after specific diagnosis. Similarly, in ICC, it can be described as "therapy-related", without a separate AML category.

New Approaches for the Treatment of AML beyond the 7+3 Regimen: Current Concepts and New Approaches.

Fifty years have passed since the development of the first chemotherapy regimen for treating acute myelogenous leukemia (AML), with the approval in 1973 of the cytarabine daunorubicin (7+3) regimen. Until recently, patients diagnosed with AML had very limited treatment options and depended primarily on chemotherapy in combinations, doses, or schedules of the same drugs. Patients with advanced age, comorbidities, or relapsed or refractory disease were left with no effective options for treatment. New advances in the understanding of the biology and the molecular and genetic changes associated with leukemogenesis, as well as recent advances in drug development, have resulted in the introduction over the last few years of novel therapeutic agents and approaches to the treatment of AML as well as a new classification of the disease. In this article, we will discuss the new classification of AML; the mechanisms, actions, and indications of the new targeted therapies; the chemotherapy combinations; and the potential role of cellular therapies as new treatment options for this terrible disease.

Review and Updates on Systemic Mastocytosis and Related Entities.

Mast cell disorders range from benign proliferations to systemic diseases that cause anaphylaxis and other diverse symptoms to mast cell neoplasms with varied clinical outcomes. Mastocytosis is the pathologic process of the accumulation of abnormal mast cells in different organs, mostly driven by KIT mutations, and can present as cutaneous mastocytosis, systemic mastocytosis (SM), and mast cell sarcoma. The WHO 5th edition classification divides systemic mastocytosis into bone marrow mastocytosis, indolent systemic mastocytosis, smoldering systemic mastocytosis, aggressive systemic mastocytosis, systemic mastocytosis with an associated hematologic neoplasm, and mast cell leukemia. The new ICC classifies SM slightly differently. The diagnosis of SM requires the integration of bone marrow morphologic, immunophenotypic, and molecular findings, as well as clinical signs and symptoms. Moreover, understanding the wide range of clinical presentations for patients with mast cell disorders is necessary for accurate and timely diagnosis. This review provides an updated overview of mast cell disorders, with a special emphasis on SM, including the latest approaches to diagnosis, prognostic stratification, and management of this rare disease.

The 2022 classifications of lymphoid neoplasms : Keynote.

Classification of hematological neoplasms in the past 25 years has been generated through international efforts to achieve broad consensus among professionals. In recent years, the understanding of lymphoid neoplasms has advanced notably, particularly with the impact of genomic studies. Two classifications of these neoplasms were produced in 2022. The International Consensus Classification (ICC) was generated following the same successful process used for the third, fourth, and updated fourth editions of the World Health Organization (WHO) Classification of Hematologic Neoplasms, coordinated by a steering committee approved by the Executive Committees of the European Association for Haematopathology and the Society of Hematopathology. The topics were prepared by different working groups and subsequently discussed in the clinical advisory committee (CAC) meeting with the participation of a large group of pathologists, clinicians, and scientists who all approved the classification after reaching consensus on all topics. Simultaneously, the International Agency for Cancer Research (IARC) of the WHO has produced the fifth edition of the classification of these neoplasms with a group of professionals appointed by the agency who discussed the proposed classification in different meetings. The definition and criteria for diagnosis of many entities have been refined in both proposals. Terminology for some diseases has been adapted to the current knowledge of their biology. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many entities. Although most categories are similar in both classifications, there are also conceptual differences and differences in the diagnostic criteria for some diseases.

Tips and Tricks to Facilitate the Combined Iliofemoral Endarterectomy With Stenting for Heavily Calcified Common Femoral Artery Atherosclerosis With Involvement of the External Iliac Artery.

BACKGROUND: Management of a heavily calcified atherosclerotic occlusive disease involving the common femoral artery (CFA) and external iliac artery (EIA), poses a surgical challenge. Though the current guidelines recommend open surgical therapy for such lesions, this approach is neither easy nor represents the current real-life practice. PURPOSE: To describe tips and tricks facilitating the hybrid technique for the management of distal iliofemoral atherosclerotic disease, where classic endarterectomy is inadequate or ill-performed. TECHNIQUE: A contralateraly inserted guidewire reaches the distal iliac artery via the crossover technique and is directly retrieved from the femoral arteriotomy immediately after removal of the anterior plaque segment. The retrieved and secured guidewire enables extensive retrograde CFA endarterectomy over the wire with avusion proximally to the inguinal ligement, followed by patch arterioplasty. Externalizing the guidewire from the patch enables traction on it and facilitates advancement of the stent through tortuous or stenosed iliac vessels as well as accurate stent deployment to cover the margin of the EIA residual plaque. Moreover, this manipulation enables ipsilateral placement of a sheath and passage of a second, retrograde guidewire to perform kissing stenting in the common iliac vessels. Chronic thrombotic lesions require covered stents to avoid thrombus propagation and meticulous flushing before completion of the femoral patching. CONCLUSIONS: The combined iliofemoral endarterectomy with stenting does not require advanced endovascular skills and prevents complications associated with incomplete femoral endarterectomy. Extensive avulsion endarterectomy proximal to the inguinal ligament is efficiently and safely performed over a retrieved crossover guidewire, enabling precise residual stenting above the flexion site.

[Current state of treatment for myelodysplastic syndromes].

Myelodysplastic syndromes (MDS) are hematopoietic stem cell neoplasms characterized by bone marrow failure with a propensity to develop into acute myeloid leukemia (AML). Recent advances in genome-wide analyses have enabled identification of most somatic gene mutations responsible for MDS, and multiplex gene-panel testing for hematological malignancies will be available soon. Thus, identification of genetic abnormalities is now enabling precise diagnosis and risk-stratification of MDS. Recently, two diagnostic classification systems for MDS have been published as updates to the previous WHO classification of myeloid tumors. The IPSS-M has also been proposed as a new risk-stratification system based on genetic abnormalities and known prognostic factors. Following identification of pathological processes in MDS, therapeutic agents that can alter the course of disease, including azacitidine and lenalidomide, were approved and became available in Japan. Several novel therapeutic agents are under development as well. This paper will discuss updated diagnostic and risk-stratification systems, as well as standard treatment strategies for MDS.

Updates in the Classification of T-cell Lymphomas and Lymphoproliferative Disorders.

PURPOSE OF REVIEW: Mature T/NK-cell neoplasms comprise a heterogeneous group of diseases with diverse clinical, histopathologic, immunophenotypic, and molecular features. A clinically relevant, comprehensive, and reproducible classification system for T/NK-cell neoplasms is essential for optimal management, risk stratification, and advancing understanding of these diseases. Two classification systems for lymphoid neoplasms were recently introduced: the 5th edition of World Health Organization classification (WHO-HAEM5) and the 2022 International Consensus Classification (ICC). In this review, we summarize the basic framework and updates in the classification of mature T/NK-cell neoplasms. RECENT FINDINGS: WHO-HAEM5 and ICC share basic concepts in classification of T/NK-cell neoplasms, emphasizing integration of clinical presentation, pathology, immunophenotype, and genetics. Major updates in both classifications include unifying nodal T-follicular helper-cell lymphomas into a single entity and establishing EBV-positive nodal T/NK-cell lymphoma as a distinct entity. However, some differences exist in taxonomy, terminology, and disease definitions. The recent classifications of mature T/NK-cell neoplasms are largely similar and provide new insights into taxonomy based on integrated clinicopathologic features.

A Comparison of the Fifth World Health Organization and the International Consensus Classifications of Mature T-Cell Lymphomas.

Peripheral T-cell lymphomas (PTCLs) are a rare subset of non-Hodgkin lymphomas that often carry significant difficulty in diagnosis and classification because of their rarity and biological complexity. Previous editions of the World Health Organization (WHO) classifications of hemopoietic neoplasms in 2001, 2008, and 2017 aimed to standardize hemopoietic neoplasm diagnosis in general. Since then, crucial clinico-pathological, immunophenotypic, and recent molecular discoveries have been made in the field of lymphomas, contributing to refining diagnostic criteria of several diseases, upgrading entities previously defined as provisional, and identifying new entities. In 2022, two different models were proposed to classify hematolymphoid neoplasms: the 5th edition of the WHO classification (WHO-HAEM5) and the International Consensus Classification (ICC). Of note, a common nosography is mandatory to ensure progress in health science and ensure the basis for a real precision medicine. In this article, the authors summarized the main differences with the previous fourth WHO edition and reviewed the main discrepancies between the two newest classifications, as far as PTCLs are concerned.

Application of the International Consensus Classification and World Health Organization 5th edition classification to a series of myeloid neoplasms.

OBJECTIVES: Two new classifications of myeloid neoplasms have recently been published: the International Consensus Classification (ICC) and the 5th edition of the World Health Organization classification (WHO5). We sought to examine the real-world impact of dueling classifications on patient diagnoses. METHODS: Our institutional pathology database was searched, and 237 specimens with a diagnosis of myeloid neoplasia were randomly selected. For each case, a classification based on the WHO5 and the ICC was assigned. The WHO5 and ICC diagnoses were compared to determine their degree of concordance. RESULTS: After applying the WHO5 and ICC diagnostic criteria, 134 (56.5%) cases were classified as concordant, 63 (26.6%) cases had terminological differences, 37 (15.6%) cases had minor diagnostic discrepancies, and 3 (1.3%) cases had major diagnostic discrepancies. Cases with minor diagnostic discrepancies included 25 cases of myelodysplastic syndrome (MDS), 10 cases of acute myeloid leukemia (AML), and 2 cases of myeloid precursor lesions. Cases with major diagnostic discrepancies included 2 cases that were diagnosed as MDS, not otherwise specified (NOS), according to the ICC but classified as AML with NPM1 alteration and AML with RBM15::MRTFA according to the WHO5 and 1 case that was characterized as chronic myelomonocytic leukemia according to the ICC and as AML with NPM1 alteration according to the WHO5. CONCLUSIONS: This study confirms that a majority of cases are classified similarly using the 2 systems. Given the overall similarity of the systems, future harmonization of the classifications should be pursued to avoid confusion and multiple diagnoses.

A Panel-Based Method for the Reproduction of Distinct Molecular Subtype Classifications of Muscle-Invasive Urothelial Bladder Cancer.

Transcriptome-based molecular subtype classification of muscle-invasive urothelial bladder cancer was shown to have prognostic and therapy-predictive relevance and thus may help to inform therapeutic decision-making. However, current classification systems rely on whole transcriptome analysis, which is expensive, requires higher amounts of tissue samples, and therefore is not compatible with the daily clinical routine. Therefore, we developed a simple and robust gene panel-based classifier method to reproduce various relevant molecular classification systems (TCGA, MDA, GSC, LundTax, and Consensus). This approach was then tested on institutional cohorts of frozen and formalin-fixed and paraffin-embedded tissue samples using reverse transcription quantitative PCR and NanoString analyses. Here, we provide a step-by-step description of our panel-based subtype classifier method.

Optimizing identification of consensus molecular subtypes in muscle-invasive bladder cancer: a comparison of two sequencing methods and gene sets using FFPE specimens.

BACKGROUND: Molecular subtypes predict prognosis in muscle-invasive bladder cancer (MIBC) and are explored as predictive markers. To provide a common base for molecular subtyping and facilitate clinical applications, a consensus classification has been developed. However, methods to determine consensus molecular subtypes require validation, particularly when FFPE specimens are used. Here, we aimed to evaluate two gene expression analysis methods on FFPE samples and to compare reduced gene sets to classify tumors into molecular subtypes. METHODS: RNA was isolated from FFPE blocks of 15 MIBC patients. Massive analysis of 3' cDNA ends (MACE) and the HTG transcriptome panel (HTP) were used to retrieve gene expression. We used normalized, log2-transformed data to call consensus and TCGA subtypes with the consensusMIBC package for R using all available genes, a 68-gene panel (ESSEN1), and a 48-gene panel (ESSEN2). RESULTS: Fifteen MACE-samples and 14 HTP-samples were available for molecular subtyping. The 14 samples were classified as Ba/Sq in 7 (50%), LumP in 2 (14.3%), LumU in 1 (7.1%), LumNS in 1 (7.1%), stroma-rich in 2 (14.3%) and NE-like in 1 (7.1%) case based on MACE- or HTP-derived transcriptome data. Consensus subtypes were concordant in 71% (10/14) of cases when comparing MACE with HTP data. Four cases with aberrant subtypes had a stroma-rich molecular subtype with either method. The overlap of the molecular consensus subtypes with the reduced ESSEN1 and ESSEN2 panels were 86% and 100%, respectively, with HTP data and 86% with MACE data. CONCLUSION: Determination of consensus molecular subtypes of MIBC from FFPE samples is feasible using various RNA sequencing methods. Inconsistent classification mainly involves the stroma-rich molecular subtype, which may be the consequence of sample heterogeneity with (stroma)-cell sampling bias and highlights the limitations of bulk RNA-based subclassification. Classification is still reliable when analysis is reduced to selected genes.

Navigating the Heterogeneity of Follicular Lymphoma and its Many Variants: An Updated Approach to Diagnosis and Classification.

Follicular lymphoma (FL) is a lymphoid neoplasm composed of follicle center (germinal center) B cells, with varying proportions of centrocytes and centroblasts, that usually has a predominantly follicular architectural pattern. Over the past decade, our understanding of FL has evolved significantly, with new recognition of several recently defined FL variants characterized by distinct clinical presentations, behaviors, genetic alterations, and biology. This manuscript aims to review the heterogeneity of FL and its variants, to provide an updated guide on their diagnosis and classification, and to describe how approaches to the histologic subclassification of classic FL have evolved in current classification schemes.

[Classification of peripheral T-cell lymphomas : News and open questions]. / Klassifikation peripherer T-Zell-Lymphome : Neuigkeiten und offene Fragen.

Recently, two new classifications were released: the International Consensus Classification (ICC) drafted by the Clinical Advisory Committee and the short version of the 5th Edition of the WHO classification of hematolymphoid tumors. In light of new clinical, morphological, and molecular data, both classifications also revised the classification of peripheral T­cell lymphomas. In addition to relatively minor changes in terminology and disease definitions, both new classifications mirror the considerable gain of knowledge on the genetic alterations of different T­cell lymphoma entities. The present review summarizes the most important changes for T­cell lymphomas in both classifications, the differences between the classifications, and diagnostically relevant issues.

TP53 in AML and MDS: The new (old) kid on the block.

MDS and AML are clonal hematopoietic stem cell disorders of increasing incidence, having a variable prognosis based, among others, on co-occurring molecular abnormalities. TP53 mutations are frequently detected in these myeloid neoplasms and portend a poor prognosis with known therapeutic resistance. This article provides a timely review of the complexity of TP53 alterations, providing updates in diagnosis and prognosis based on new 2022 International Consensus Classification (ICC) and World Health Organization (WHO) guidelines. The article addresses optimal testing strategies and reviews current and arising therapeutic approaches. While the treatment landscape for this molecular subgroup is under active development, further exploration is needed to optimize the care of this group of patients with unmet needs.

Diagnostic approaches and future directions in Burkitt lymphoma and high-grade B-cell lymphoma.

Since the 2016 WHO update, progress has been made in understanding the biology of Burkitt lymphoma (BL) and the concept of high-grade B-cell lymphomas (HGBCL) that allows some degree of refinement. The summary presented here reviews in detail the discussions of the Clinical Advisory Committee and expands upon the newly published 2022 International Consensus Classification for lymphoid malignancies (Campo et al. Blood, 2022). BL remains the prototypic HGBCL and diagnostic criteria are largely unchanged. HGBCL with MYC and BCL2 and HGBCL with MYC and BCL6 rearrangements are now separated to reflect biologic and pathologic differences. HGBCL, NOS remains a diagnosis of exclusion that should be used only in rare cases. FISH strategies for diffuse large B-cell lymphoma (DLBCL) and HGBCL are discussed in detail for these diseases. Advances in integrative analysis of mutations, structural abnormalities, copy number, and gene expression signatures allow a more nuanced view of the heterogeneity of DLBCL, NOS as well as definitions of HGBCL and point to where the future may be headed for classification of these diseases.

The International Consensus Classification of myelodysplastic syndromes and related entities.

The International Consensus Classification (ICC) of myeloid neoplasms and acute leukemia has updated the classification of myelodysplastic syndromes (MDSs) and placed MDS in a broader group of clonal cytopenias that includes clonal cytopenia of undetermined significance (CCUS) and related entities. Although subject to some interobserver variability and lack of specificity, morphologic dysplasia remains the main feature that distinguishes MDS from other clonal cytopenias and defines MDS as a hematologic malignancy. The ICC has introduced some changes in the definition of MDS whereby some cases categorized as MDS based on cytogenetic abnormalities are now classified as CCUS, while SF3B1 and multi-hit TP53 mutations are now considered to be MDS-defining in a cytopenic patient. The ICC has also recognized several cytogenetic and molecular abnormalities that reclassify some cases of MDS with excess blasts as acute myeloid leukemia (AML) and has introduced a new MDS/AML entity that encompasses cases with 10-19% blasts that lie on the continuum between MDS and AML. Two new genetically defined categories of MDS have been introduced: MDS with mutated SF3B1 and MDS with mutated TP53, the latter requiring bi-allelic aberrations in the TP53 gene. The entity MDS, unclassifiable has been eliminated. These changes have resulted in an overall simplification of the MDS classification scheme from 8 separate entities (including 1 that was genetically defined) in the revised 4th edition WHO classification to 7 separate entities (including 3 that are genetically defined) in the ICC.