The 5th edition of the World Health Organization classification of hematolymphoid tumors: lymphoid neoplasms. Part 1

Introduction

In 2022, the World Health Organization (WHO) is set to release an update to its pivotal 2017 publication on the classification of hematolymphoid tumors: lymphoid neoplasms. This revised 5th edition (WHO-HAEM5) will include a restructuring of entities into a hierarchical system, updates to nomenclature, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities. Below, we provide part one of a summarized overview of the upcoming 5th edition, published on behalf of the WHO by Alaggio et al. in Leukemia. This part in our series focuses on updates and new additions to B-cell lymphoid proliferations and lymphomas. Upcoming additions to this series will address T-cell lymphoid malignancies specifically, as well as diffuse large B-cell lymphoma in detail.¹

The International Agency for Research on Cancer (IARC) laid the groundwork for WHO-HAEM5 by first developing the governance rules and classification principles for the entire 5th Edition series of the WHO classification of tumors. Following this, a multidisciplinary author team was formed including hematopathologists, hematologists, oncologists, geneticists, epidemiologist, molecular biologists, and other experts in the field. The resulting product is hoped to be a continuation and systematic evolution of the prior classifications, with the overarching goal of allowing for continuity in daily practice and ongoing clinical trials. The system of classification used by the authors follows a hierarchical system of increasing complexity, exampled below with germinal center B-cell-like diffuse large B-cell lymphoma (Figure 1).¹

Figure 1. Overview of the hierarchical system of classification* 

DLBCL-NOS, diffuse large B-cell lymphoma-not otherwise specified.
*Adapted from Alaggio, et al.¹

Figure 2 and Figure 3 provide an overview of the changes and new additions to the B-cell lymphoid proliferations and lymphomas classification. Any classifications that remained the same have not been included in our summary.

Figure 2. Changes to B-cell lymphoid proliferations and lymphomas classification* 

DLBCL, diffuse large B-cell lymphoma; HHV8, human herpesvirus-8; KSHV, Kaposi's sarcoma-associated herpesvirus.
*Adapted from Alaggio, et al.¹

Figure 3. New additions to B-cell lymphoid proliferations and lymphomas category*

*Adapted from Alaggio, et al.¹

B-cell lymphoid proliferations and lymphomas¹

Tumor-like lesions with B-cell predominance

This is a new family/class for WHO-HAEM5, encompassing five distinct entities. Castleman disease is now subdivided into three separate disease classifications, which can be diagnosed using an integrated diagnostic algorithm. IgG4-related disease is another new addition to this category, which can have many features which overlap with Castleman disease.

B-lymphoblastic leukemia/lymphomas (B-ALL)

B-ALL can now be diagnosed at the family/class level based on morphology and immunophenotype as B-ALL, not further classified. Molecular genetic subtyping can further define the disease into a range of updated classifications (Figure 2). Most precursor B-cell neoplasms are classified based on ploidy changes, chromosomal rearrangements, or the presence of other genetic drivers. Further refinements to classification reflect the incorporation of additional genetic findings due to advances in diagnostic methodologies.

Preneoplastic and neoplastic small lymphocytic proliferations

This family is organized into two separate entities: monoclonal B-cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), with MBL having three distinct subtypes; low-count MBL or clonal B-cell expansion, CLL/SLL-type MBL, and non-CLL/SLL-type MBL. These subtypes are characterized by immune impairment with suboptimal response to vaccinations and increased risk of infection. Cell surface targets form the basis for subcategorization of CLL, as well as specific genetic aberrations.

Splenic B-cell lymphomas and leukemias

Following nomenclature updates to this family, the term splenic B-cell lymphoma/leukemia with prominent nucleoli now replaces both hairy cell leukemia variant and CD5-negative B-cell prolymphocytic leukemia.

Marginal zone lymphomas

The marginal zone lymphoma category has been updated to contain primary cutaneous marginal zone lymphoma, due to its distinct clinicopathological features.

Follicular lymphoma

The follicular lymphoma (FL) family contains FL, in situ follicular B-cell neoplasm, pediatric-type FL and duodenal-type FL. Only the FL subtype has undergone significant alteration, with in situ follicular neoplasia being updated to in situ follicular B-cell neoplasm.

Mantle cell lymphoma

The classification in situ follicular neoplasia has been revised and is now termed in situ mantle cell neoplasm.

Large B-cell lymphomas

This wide-spanning family has undergone significant revision, with updates to existing terms and the addition of several new classifications. Burkitt-like lymphoma with 11q aberration is now classified as high-grade B-cell lymphoma with 11q aberrations. B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classic Hodgkin lymphoma has been replaced by mediastinal grey zone lymphoma. New entities in this category include fibrin-associated large B-cell lymphoma, fluid overload-associated large B-cell lymphoma and primary large B-cell lymphoma of immune-privileged sites.

KSHV/HHV8-associated B-cell lymphoid proliferations and lymphomas

The organization and nomenclature of this category, specifically the presence of the Kaposi sarcoma herpesvirus/human herpesvirus 8 (KSHV/HHV8) terms, has been designed to reflect and accommodate the common practices of both hematopathologists and of virologists. The former classification of HHV8-positive germinotropic lymphoproliferative disorder has been updated to KSHV/HHV8-positive germinotropic lymphoproliferative disorder.

Lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation

WHO-HAEM5 has introduced major changes to the classification of immunodeficiency-associated lymphoproliferative disorders based on a new system of unified nomenclature. One such change is the reclassification of lymphoproliferative diseases associated with primary immune disorders to inborn error of immunity-associated lymphoid proliferations and lymphomas. In addition, this family has seen the addition of three new entities: hyperplasias arising in immune deficiency/dysregulation, polymorphic lymphoproliferative disorders arising in immune deficiency/dysregulation, and lymphomas arising in immune deficiency/dysregulation.

Plasma cell neoplasms and other diseases with paraproteins

Monoclonal gammopathy of renal significance and cold agglutinin disease are two new entities that fall under the umbrella of plasma cell neoplasms/other diseases with paraproteins. The latter is grouped with other monoclonal gammopathies, whilst the former is grouped with diseases associated with abnormal monoclonal immunoglobulin deposition. Further updates to this category include the reclassification of primary amyloidosis as immunoglobulin-related amyloidosis, and light- and heavy-chain deposition disease being reclassified as monoclonal immunoglobulin deposition disease.

Conclusion

WHO-HAEM5 represents a significant overhaul of the WHO system of classification of hematolymphoid tumors. Updates to this comprehensive classification hierarchy reflect the dramatic increase in information regarding lymphoid tumors, their molecular complexity, and advances in diagnostic techniques and understanding.