Volume 36, Issue 1

The landscape of haematological malignancies is constantly evolving, driven by advances in our understanding of their genetic basis. This has cumulated within the 5 th Edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours published in short form in 2022 [1, 2] and being available in full length both as “Blue Book” (in print expected early 2024) as well as web-based classification (see: https://tumourclassification.iarc.who.int/welcome/). Similarly, the importance of genetic alterations for the classification is highlighted in other classification systems related to haematologic neoplasms [3–5]. In this special issue of the Medizinische Genetik, we present a comprehensive overview of the genetic alterations contributing to the classification of haematolymphoid neoplasms in the 5 th Edition of the WHO classification (WHO-HAEM5) and its diagnostic relevance in the context of various haematological malignancies.

During the last five decades, chromosome analysis identified recurring translocations and inversions in leukemias and lymphomas, which led to cloning of genes at the breakpoints that contribute to oncogenesis. Such molecular cytogenetic methods as fluorescence in situ hybridization (FISH), copy number (CN) arrays or optical genome mapping (OGM) have augmented standard chromosome analysis. The use of both cytogenetic and molecular methods, such as reverse transcription-polymerase chain reaction (RT-PCR) and next generation sequencing (NGS), including whole-genome sequencing (WGS), discloses alterations that not only delineate separate WHO disease entities but also constitute independent prognostic factors, whose use in the clinic improves management of patients with hematologic neoplasms.

In recent years, technology developments and increase in knowledge have led to profound changes in the diagnostics of haematologic neoplasms, particularly myeloid neoplasms. Therefore an updated, fifth edition of the World Health Organization (WHO) classification of haematolymphoid neoplasms (WHO-HAEM5) will be issued in 2024. In this context, we present a practical guide for analysing the genetic aspects of clonal haematopoiesis of indeterminate potential (CHIP), clonal cytopenia of undetermined significance (CCUS), myelodysplastic neoplasms (MDS), and acute myeloid leukaemia (AML) based on WHO-HAEM5. This guide navigates through the genetic abnormalities underlying myeloid neoplasms which are required to be detected for classification according to WHO-HAEM5 and provides diagnostic algorithms.

Within the World Health Organization (WHO) classification of haematopoietic neoplasms, particularly its fifth version from 2022 (WHO-HAEM5), myeloid neoplasms are not only grouped into myeloproliferative (MPN) and myelodysplastic neoplasms (MDS). There is also a group of haematological disorders that share features of both categories termed myelodysplastic /myeloproliferative neoplasms (MDS/MPN). In this article, we aim to provide a comprehensive and practical guide to WHO-HAEM5 highlighting the genetic alterations that underlie MPN and MDS/MPN. This guide provides an overview of the overlapping commonalities among these entities, as well as their unique characteristics.

We present a practical guide for analyzing the genetic aspects of lymphoblastic leukaemia/lymphoma according to the 5th edition of the World Health Organization (WHO) classification of haematolymphoid neoplasms (WHO-HAEM5) issued in 2024. The WHO-HAEM5 acknowledges the increasing importance of genetics in the diagnosis of lymphoid neoplasia. Classification is based on the established genetic subtypes according to cell lineage, with precursor cell neoplasms followed by mature malignancies. This guide describes those genetic abnormalities in acute precursor B- and T-cell neoplasms required for risk stratification, and for treatment, providing diagnostic algorithms under the headings of ‘essential’ and ‘desirable’ diagnostic criteria.

The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours (WHO-HAEM5) provides a revised classification of lymphoid malignancies including chronic lymphocytic leukemia (CLL) and plasma cell myeloma/multiple myeloma (PCM/MM). For both diseases the descriptions of precursor states such as monoclonal B-cell lymphocytosis and monoclonal gammopathy of uncertain significance (MGUS) have been updated including a better risk stratification model. New insights on mutational landscapes and branching evolutionary pattern were embedded as diagnostic and prognostic factors, accompanied by a revised structure for the chapter of plasma cell neoplasms. Thus, the WHO-HAEM5 leads to practical improvements of biological and clinical relevance for pathologists, clinicians, geneticists and scientists in the field of lymphoid malignancies. The present review gives an overview on the landscape of genetic alterations in CLL and plasma cell neoplasms with a focus on their impact on classification and treatment.

The identification of recurrent genomic alterations in tumour cells has a significant role in the classification of mature B- and T-cell lymphomas. Following the development of new technologies, such as next generation sequencing and the improvement of classical technologies such as conventional and molecular cytogenetics, a huge catalogue of genomic alterations in lymphoid neoplasms has been established. These alterations are relevant to refine the taxonomy of the classification of lymphomas, to scrutinize the differential diagnosis within different lymphoma entities and to help assessing the prognosis and clinical management of the patients. Consequently, here we describe the key genetic alterations relevant in mature B- and T-cell lymphomas.