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.

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.

Whole Exome Sequencing of Intermediate-Risk Acute Myeloid Leukemia without Recurrent Genetic Abnormalities Offers Deeper Insights into New Diagnostic Classifications.

Two new diagnostic classifications of acute myeloid leukemia (AML) were published in 2022 to update current knowledge on disease biology. In previous 2017-edition categories of AML with myelodysplasia-related changes, AML was not otherwise specified, but AML with mutated RUNX1 experienced profound changes. We performed whole exome sequencing on a cohort of 69 patients with cytogenetic intermediate-risk AML that belonged to these diagnostic categories to correlate their mutational pattern and copy-number alterations with their new diagnostic distribution. Our results show that 45% of patients changed their diagnostic category, being AML myelodysplasia-related the most enlarged, mainly due to a high frequency of myelodysplasia-related mutations (58% of patients). These showed a good correlation with multilineage dysplasia and/or myelodysplastic syndrome history, but at the same time, 21% of de novo patients without dysplasia also presented them. RUNX1 was the most frequently mutated gene, with a high co-occurrence rate with other myelodysplasia-related mutations. We found a high prevalence of copy-neutral loss of heterozygosity, frequently inducing a homozygous state in particular mutated genes. Mild differences in current classifications explain the diagnostic disparity in 10% of patients, claiming a forthcoming unified classification.

Impact of the International Consensus Classification of myelodysplastic syndromes.

The impact of the 2022 International Consensus Classification (ICC) of myelodysplastic syndromes (MDS) needs study. We analysed data from 989 MDS subjects classified using the 2016 World Health Organization (WHO) criteria to determine the impact of the new proposal. Our analyses suggested the ICC criteria of MDS-SF3B1 identifies a more homogenous disease entity than the WHO 2016 criteria of myelodysplastic syndromes with ring sideroblasts (MDS-RS). MDS, not otherwise specified with single lineage dysplasia (MDS, NOS-SLD) patients had a better prognosis than MDS, NOS with multilineage dysplasia (MDS, NOS-MLD) patients. MDS with mutated TP53 and MDS/acute myeloid leukaemia with mutated TP53 patients had the briefest survivals. These data support the ICC of MDS, which allows more accurate diagnoses and risk stratification.

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.

[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.

International consensus classification of hippocampal sclerosis and etiologic diversity in children with temporal lobectomy.

INTRODUCTION: The distribution of hippocampal sclerosis (HS) subtypes, according to the classification of the International League Against Epilepsy (ILAE), has been reported mainly in adult patients. We aimed to review the pathological findings in children who had anterior temporal lobectomy accompanied with amygdalohippocampectomy, in view of the current classification, and evaluate postsurgical outcome with respect to HS subtypes in childhood. METHODS: Seventy children who underwent temporal resections for treatment of medically refractory epilepsy, with a minimum follow-up of 2 years, were included; the surgical hippocampus specimens were re-evaluated under the HS ILAE classification. RESULTS: Neuropathological evaluations revealed HS type 1 in 38 patients (54.3%), HS type 2 in 2 (2.8%), HS type 3 in 21 patients (30%), and no HS in 9 patients (12.9%). Of 70 patients, 23 (32.9%) had dual pathology, and the most common pattern was HS type 3 with low-grade epilepsy-associated brain tumors (LEAT). The distribution of HS types with respect to age revealed that HS type 3 and no HS subgroups had significantly more patients younger than 12 years, compared with those of HS type 1 (90.5%, 77.8% vs 47.4%, respectively). History of febrile seizures was higher in HS type 1. Prolonged/recurrent febrile seizures were most common in patients 12 years and older, whereas LEAT was the most common etiology in patients under 12 years of age (p < 0.001). Patients with HS type 1 had longer duration of epilepsy and an older age at the time of surgery compared with patients with HS type 3 and no HS (p: 0.031, p: 0.007). At final visit, 74.3% of the patients were seizure-free. Seizure outcome showed no significant difference between pathological subtypes. CONCLUSIONS: Our study presents the distribution of HS ILAE subtypes in an exclusively pediatric series along with long-term seizure outcome. The study reveals that the leading pathological HS subgroup in children is HS type 1, similar with adult series. Hippocampal sclerosis type 2 is significantly less in children compared with adults; however, HS type 3 emerges as the second most predominant group because of dual pathology, particularly LEAT. Further studies are required regarding clinicopathological features of isolated HS in pediatric cohort. Seizure-free outcome was favorable and similar in all HS types in children. The proportion of HS types may be better defined in pediatric patients with temporal resections, as the current HS ILAE classification becomes more widely used, and may help reveal the surgical and cognitive outcome with respect to HS types.

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.

Comparison of disease and risk classifications of AML before and after incorporation of NGS analysis of bone marrow samples.

Mutation profiling by next-generation sequencing (NGS) has facilitated understanding of the molecular pathogenesis of acute myeloid leukemia (AML), and has been incorporated into the new disease classification (International Consensus Classification; ICC) and risk classification (European LeukemiaNet [ELN] 2022; ELN2022). We compared disease subtypes between the previous disease classification (4th edition of the WHO classification; WHO-4) and the ICC in 91 patients with AML diagnosed at our institution. We also compared disease risk classifications using the previous risk classification (ELN2017) and the ELN2022. Targeted sequencing of bone marrow samples was conducted at Kyoto University. We found that entities under AML with recurrent genetic abnormalities were well-established, with almost no change from the WHO-4 to the ICC. In contrast, 16.7% of cases of AML, not otherwise specified in the WHO-4 were reclassified into AML with mutated TP53, and 36.7% were reclassified into AML with myelodysplasia-related gene mutations or cytogenetic abnormalities per the ICC. Meanwhile, the ELN2017 and ELN2022 showed no difference in concordance indexes in multivariate Cox regression analysis for progression-free and overall survival. The superiority of the ELN2022 over the ELN2017 could not be confirmed in our single-center retrospective study, and further investigation including multicenter prospective studies is needed.

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.

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.

TP53 Mutation Status in Myelodysplastic Neoplasm and Acute Myeloid Leukemia: Impact of Reclassification Based on the 5th WHO and International Consensus Classification Criteria: A Korean Multicenter Study.

Background: TP53 mutations are associated with poor prognosis in myelodysplastic neoplasm (MDS) and AML. The updated 5th WHO classification and International Consensus Classification (ICC) categorize TP53-mutated MDS and AML as unique entities. We conducted a multicenter study in Korea to investigate the characteristics of TP53-mutated MDS and AML, focusing on diagnostic aspects based on updated classifications. Methods: This study included patients aged ≥ 18 yrs who were diagnosed as having MDS (N=1,244) or AML (N=2,115) at six institutions. The results of bone marrow examination, cytogenetic studies, and targeted next-generation sequencing, including TP53, were collected and analyzed. Results: TP53 mutations were detected in 9.3% and 9.2% of patients with MDS and AML, respectively. Missense mutation was the most common, with hotspot codons R248/R273/G245/Y220/R175/C238 accounting for 25.4% of TP53 mutations. Ten percent of patients had multiple TP53 mutations, and 78.4% had a complex karyotype. The median variant allele frequency (VAF) of TP53 mutations was 41.5%, with a notable difference according to the presence of a complex karyotype. According to the 5th WHO classification and ICC, the multi-hit TP53 mutation criteria were met in 58.6% and 75% of MDS patients, respectively, and the primary determinants were a TP53 VAF >50% for the 5th WHO classification and the presence of a complex karyotype for the ICC. Conclusions: Collectively, we elucidated the molecular genetic characteristics of patients with TP53-mutated MDS and AML, highlighting key factors in applying TP53 mutation-related criteria in updated classifications, which will aid in establishing diagnostic strategies.

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.

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.

International Consensus Classification of myeloid and lymphoid neoplasms: myeloproliferative neoplasms.

The recently published International Consensus Classification (ICC) of myeloid neoplasms summarized the results of an in-depth effort by pathologists, oncologists, and geneticists aimed to update the 2017 World Health Organization classification system for hematopoietic tumors. Along these lines, several important modifications were implemented in the classification of myeloproliferative neoplasms (MPNs). For chronic myeloid leukemia, BCR::ABL1-positive, the definition of accelerated and blast phase was simplified, and in the BCR::ABL1-negative MPNs, the classification was slightly updated to improve diagnostic specificity with a more detailed and better validated morphologic approach and the recommendation of more sensitive molecular techniques to capture in particular early stage diseases. In this regard, high sensitive single target (RT-qPCR, ddPCR) or multi-target next-generation sequencing assays with a minimal sensitivity of VAF 1% are now important for a proper diagnostic identification of MPN cases with low allelic frequencies at initial presentation. This review discusses the updated diagnostic criteria of MPN according to the ICC, particularly by highlighting the new concepts and how they can be applied in clinical settings to obtain an appropriate prognostic relevant diagnosis.

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.

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.

[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.

Extranodal T- and NK-cell lymphomas.

Non-cutaneous extranodal NK/T cell lymphoproliferations constitute a heterogenous group of rare neoplasms, occurring primarily in the gastro-intestinal tract, nasal area, spleen, and liver. Their nomenclature refers to their usual clinical presentation and predilection for specific anatomic sites-i.e. extranodal NK/T-cell lymphoma, nasal-type, hepatosplenic T-cell lymphoma, primary intestinal T-cell lymphomas, indolent lymphoproliferative disorders of the gastrointestinal tract, and breast implant-associated anaplastic large cell lymphoma. Extranodal tissues may also be involved by T-cell leukemias, or other entities usually presenting as nodal diseases. Primary extranodal entities range from indolent to highly aggressive diseases. Here, we will review the clinicopathologic features of the pertinent entities including the recent advances in their molecular and genetic characterization, with an emphasis on the changes introduced in the 2022 International Consensus Classification of lymphoid neoplasms, and highlight the diagnostic criteria helpful to sort out the distinction with potential mimickers.