Lymphomas represent a heterogeneous group of lymphoid neoplasms characterized by diverse clinical presentations, histopathological features, and prognoses. Historically, lymphoma classification has relied heavily on morphology and immunophenotyping. However, the advent of high-throughput molecular technologies has revolutionized our understanding of lymphoma biology, revealing distinct genetic and molecular landscapes that underpin disease pathogenesis and clinical behavior. In this paper, we will explore the transformative impact of molecular characterization on lymphoma classification, with a particular focus on its integration into contemporary diagnostic frameworks, including the recent WHO-HEMAT5 classification.

B-cell non-Hodgkin lymphomas (B-NHL) represent 90% of lymphoid malignancies; in this field, molecular insights have significantly refined diagnostic accuracy, risk stratification, and therapeutic approaches. We will delve into the molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL), discussing the prognostic and predictive implications of gene expression profiling (GEP)-defined molecular subtypes (e.g., germinal center B-cell-like [GCB] and activated B-cell-like [ABC]) and recurrent genetic alterations such as mutations in MYD88, CD79B, and translocations involving MYC, BCL2, and BCL6. The molecular underpinnings of follicular lymphoma (FL), mantle cell lymphoma (MCL), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) will also be examined, highlighting the roles of specific chromosomal translocations (e.g., t(14;18) in FL, t(11;14) in MCL) and recurrent somatic mutations (e.g., EZH2 in FL, TP53 and IGHV mutational status in CLL) in defining distinct disease entities and guiding targeted therapies. The integration of these molecular markers into the WHO-HEMAT5 classification provides a more precise framework for diagnosis and prognostication, moving beyond purely morphological assessments.

The remaining 10% of lymphoid malignancies consist of the more challenging landscape of T-cell non-Hodgkin lymphomas (T-NHL). T-NHL are generally rarer and often associated with aggressive clinical courses and poorer outcomes, partly due to their greater molecular heterogeneity and the historical lack of effective targeted therapies. We will discuss emerging molecular classifications for common T-NHL subtypes, including peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic large cell lymphoma (ALCL). Key recurrent genetic alterations such as mutations in TET2, IDH2, RHOA, and components of the JAK/STAT pathway will be highlighted, demonstrating their utility in refining diagnosis, understanding disease biology, and identifying potential therapeutic vulnerabilities. While the molecular classification of T-NHL is still evolving, these discoveries are paving the way for more accurate subtyping and the development of much-needed precision medicine strategies.

In conclusion, the integration of molecular features into lymphoma classification represents a paradigm shift, enabling a more granular and clinically relevant categorization of these complex malignancies. This molecular-driven approach, exemplified by the WHO-HEMAT5 classification, is crucial for advancing personalized medicine in lymphoma, leading to more accurate diagnoses, refined prognostication, and the rational selection of targeted therapies, ultimately improving patient outcomes.

Pier Paolo Piccaluga is currently Associate Professor of Pathology at the Department of Medical and Surgical Sciences, Bologna University School of Medicine as well as co-founder and Executive Physician at the Biobank of Research, IRCCS S. Orsola-Malpighi Hospital. He has been responsible for many years for the Molecular Hematopathology Laboratory.  

In 2018 he was appointed for teaching at Queen Mary University of London (UK) and Jomo Kenyatta University of Agriculture and Technology, Nairobi (Kenya), and since 2023 at University of Nairobi and University of Botswana.

He is the author of more than 250 publications indexed in the Current Contents (including Nature Medicine, Journal of Clinical Investigation, Journal of Experimental Medicine, Journal of Clinical Oncology, Blood, Lancet Oncology, and Lancet Infectious Diseases, with a total impact factor >1,000, a mean impact factor >6, and an H-index of 63 (ranked among the VIA-Academy Top Italian Scientists).

Author of several presentations at national and international conferences.

Involved in several clinical trials as coordinator or sub-investigator. Winner of several prizes for study and research. Involved/PI in several research project granted by national and international recognized organisms.

Editor in Chief: World Journal of Hematology, Advances in Precision Medicine, Journal of Cancer Biomoleculars and Therapeutics