Impact of the WHO-5 classification of haematolymphoid tumours on clinical practice

The most significant changes pertain to the group of follicular lymphomas (FLs). In addition to the common “classic” FL (cFLs), FLs with unusual cytological features (uFLs; [2]; Fig. 1a), are now defined. Moreover, a group of FLs with a predominantly diffuse growth pattern (dFLs; [3]; Fig. 1b), is now acknowledged. Traditionally, cFLs were categorized into grades I/II, IIIA, and IIIB based on the number of centroblasts (CB) per microscopic high-power field ([4]; specifically the absolute number of CB in neoplastic follicles per 0.458 mm² in area had to be counted or estimated). However, a notable change in the new classification is the henceforth merely optional nature of morphological grading for cFL, which is now considered obsolete due to limited reproducibility [5] and minimal clinical differences [6] between FL I/II and FL IIIA. Lymphomas formerly known as FL 3B composed entirely of CB in a follicular growth pattern is now designated as follicular large B‑cell lymphoma (FLBCL; [2, 7]). The uFLs are characterized by medium-sized tumour cells with a predominately immature or blastoid appearance (Fig. 1a) or large centrocytes (CC). This subtype is clinically, pathologically and genetically distinct from cFL and may be associated with poorer prognosis [2].

The dFL (Fig. 1b) often form large tumour masses in the inguinal region, present in limited stages and have a relatively good prognosis [3, 8]. They usually lack BCL‑2 rearrangements, whereas mutations of STAT6 are frequently found [9].

Follicular lymphomas occurring at special sites, such as duodenal-type FL [10] and primary cutaneous FL [11], as well as paediatric-type FL [12] are still acknowledged as separate entities due to their specific clinico-pathological features.

The key changes of the new classification of FL with regard to prior classifications are listed in Table 2.

Large B‑cell NHLs comprise a heterogeneous group, with diffuse large B‑cell lymphoma, not otherwise specified (DLBCL, NOS), representing the largest subgroup [13]; within this group, histologically, genetically as well as clinically diverse lesions are found. Alongside DLBCL, NOS, 17 other specific large B‑cell entities are listed based on genetic characteristics, clinical context or specific (extranodal) localization. The classification now differentiates between classic Burkitt lymphoma and high-grade B-cell lymphomas with 11q aberrations (HGBCL-11q; [14]), which are morphologically and immunophenotypically similar but distinct in terms of mutation profiles. Additionally, extranodal lymphomas of immunoprivileged sites are now grouped together, encompassing primary CNS, vitreoretinal and testicular LBCLs, characterized by anatomical and functional immunoregulatory barriers, as well as largely identical morphological and genetic features [15‐17]. Other extranodal LBCLs (e.g. skin, ovary, breast) are expected to be included in this category in the future.

The newly termed “mediastinal grey zone lymphoma” corresponds to the entity previously classified as “unclassified B‑cell lymphoma with intermediate features between DLBCL and classical Hodgkin lymphoma” in WHO-4R; the new term should be reserved solely for lesions localized in the mediastinum [18].

A comprehensive restructuring occurred in the WHO-5-HAEM for the group of immunodeficiency- (ID) and dysregulation (IDD)-associated diseases. Whereas previous classifications listed diseases based on the underlying form of IDD (e.g. primary and secondary ID, iatrogenic ID, post-transplantation-associated ID), the WHO-HAEM5 now adopts a different approach due to the fundamentally identical forms of lymphoproliferations that can occur in the ID setting regardless of the underlying cause. The histological diagnosis (i.e. hyperplasia, polymorphic lymphoproliferation, mucocutaneous ulcer, manifest lymphoma) is prioritized, followed by any potential viral association (EBV, KSHV/HHV8), and then the specific type of IDD. This new nomenclature avoids inconsistencies regarding terminology and diagnostic criteria for similar lesions in different forms of underlying IDD, thereby facilitating multidisciplinary collaboration in clinical management. Of note is the inclusion of relatively “newly” described forms of IDD [19]: This chapter also includes lymphoproliferative disorders (LPDs) that occur after polychemotherapy for solid tumours and haematologic neoplasms, as well as immunosenescence-associated lymphomas [20] and those resulting from CAR-T cell [21] or checkpoint inhibitor therapies [22].

An unfortunate development regarding the classification update should also be emphasized: After nearly 30 years of a globally accepted consensus classification—beginning with the REAL classification in 1994 and continuing through successive editions of the WHO Blue Books until 2017—we are now sadly challenged with two different classifications released in close succession. In parallel with the WHO draft published in Leukemia in June 2022 [23], a second classification of haematolymphoid neoplasms drafted by the International Consensus Classification (ICC) was released in the September 2022 issue of Blood [24]. Both classifications were authored by highly prominent, but distinct groups of experts.

The two classifications for the lymphatic system are based on essentially the same scientific findings and publications from recent years and, luckily, differ only slightly. This is in contrast to the classifications for myeloid and histiocytic/dendritic system lesions, which exhibit more significant discrepancies. The most notable differences in the lymphoid classifications pertain to rare lymphomas/leukaemias (e.g. B‑cell prolymphocytic leukaemia, which is still recognized by the ICC, while it has been removed from the WHO classification). Moreover, the controversial omission of FL grading in the WHO remains mandatory in the ICC classification. Within the group of LBCL there are slight differences concerning, e.g. the rare subtype of LBCL with IRF4 rearrangement, which is a separate entity in WHO-5-HAEM, whereas in ICC it is a subtype of FL. For a detailed comparison of the differences between the two classifications, please refer to additional literature [25]. The concurrent use of both systems carries the risk of conflicting classifications within certain lymphoma subtypes, leading to uncertainty in diagnosis and management. It is therefore indispensable for both parties to reach a unified and coordinated classification as soon as possible in order to resolve this dilemma.

The new WHO-5-HAEM classification is user-friendly and easy to apply due to its improved hierarchical reporting structure. Particular attention has been paid to the clinical relevance of the various examinations required for reporting. The definition of “essential” and “desirable” diagnostic criteria facilitates primary reporting, even in non-specialized laboratories, thereby contributing to accelerated diagnostics. The restructuring, homogeneous grouping and nomenclature of IDD-associated lymphoproliferations allow for improved clinical applicability, including uniform clinico–therapeutic approaches. New chapters on diagnostically important reactive lymphoproliferations (“mimics”), transformed lymphomas and genetic predisposition syndromes reflect their increasing clinical significance. A reorganization and somewhat controversial change in the chapter on follicular lymphomas, with the elimination of mandatory grading, is likely to lead to further discussion in the future. In this sense, the new classification should be seen as a continuous spectrum of knowledge accumulation and expansion, rather than a rigid concept, especially considering the rapid increase in molecular insights.