The diagnosis, classification and treatment of hematopoietic neoplasms requires a precise definition of the individual entities that configure the broad spectrum of these diseases. Since the introduction of the Revised European American Lymphoma (REAL) classification in 1994, the approach to classification of these neoplasms incorporates clinical, morphologic, immunophenotypic and genetic information. While underlying cell lineage is a starting point, when possible, the normal cellular counterpart from which the tumor originates is defined. This combined approach has gained further relevance with the introduction of targeted therapies. Following publication of the REAL classification [1], the International Agency for Research on Cancer (IARC), in anticipation of developing the 3rd edition World Health Organization (WHO) classification of Hematolymphoid Neoplasm, approached Elaine Jaffe, contributor to the REAL classification and then President of the Society for Hematopathology (SH), asking the Society to partner with them to develop a similar approach for the classification of hematopoietic neoplasms. The partnership was ultimately between IARC, SH and the European Association for Haematopathology (EAHP). The Societies recognized that clinical features were also a key feature for accurate disease definition, and that input from treating physicians of these neoplasms was essential for any classification to be relevant and broadly accepted. World-wide consensus was regarded as critical after decades of different classification systems driven by individuals or regional groups. The SH and EAHP undertook planning for a Clinical Advisory Committee (CAC) meeting, which was supported by funds raised by the Societies, before developing a classification. In advance of the CAC, the participating pathologists developed key questions regarding the classification and during the CAC additional pathologists as well as hematologists, oncologists and geneticists provided input and discussion to arrive at a consensus. After the CAC, the pathologists worked to resolve final issues related to the CAC recommendations and published the classification in review papers prior to formal publication of the associated WHO “Blue Book.” The first such CAC took place in Arlie House, Virginia in 1997 and ultimately resulted in the 2001 3rd edition WHO classification, the first widely accepted WHO classification of hematopoietic tumors. This successful partnership between SH, EAHP and IARC continued with a similar process including the organization of CACs in 2007 and 2014, resulting in publications of the CAC conclusions in specific articles and ultimately with publication of the 4th edition and revised 4th edition WHO Blue Books in 2008 and 2017.

In 2020, Ian Cree, Head of the Evidence Synthesis and Classification Branch of the IARC in charge of the publication of the WHO blue books, notified SH and EAHP that IARC was ending the successful partnership with SH and EAHP for the 5th edition WHO classification of hematopoietic tumors and that they would no longer follow the process described above for the three prior books. The Executive Committees of the SH and EAHP together with many leaders in the hematopathology, hematology, oncology and genetics community considered that the proper development of a meaningful classification of these neoplasms required a similar process of discussion and consensus as developed for the three previous WHO classifications. Therefore, they organized different multidisciplinary working groups that culminated in the CAC meeting held in Chicago in September 2021. The CAC was followed by publication of the International Consensus Classification (ICC) of Myeloid and Lymphoid Neoplasms in two manuscripts [2, 3], (Table 1) as well as two additional manuscripts on the genomic approaches to these tumors [4, 5]. The ICC represents the natural progression of the prior WHO classifications, using the same approach with modification of previously described entities, and recognition of new entities, where relevant. Broad expert review and consensus were key to all conclusions.

Table 1 The International Consensus Classification of Myeloid and Lymphoid Neoplasms
Full size table

This Annual Review Issue further expands on the International Consensus Classification of Myeloid and Lymphoid Neoplasms, providing more in-depth descriptions of the entities with a focus on the pathologic aspects of the disorders. The 18 articles in this issue review advances in myeloid and lymphoid disorders in the context of the International Consensus Classification.

Acute lymphoblastic leukemia/lymphoma is now understood to be a genetically heterogenous disorder. The review by Duffield, Mullighan and Borowitz [6] highlights the rationale for the genetic subtypes, including new categories for precursor B, precursor T and early pre-T acute lymphoblastic leukemia. For precursor B neoplasms, the BCR::ABL1 positive group is now divided into single (blast) and multilineage disease with the latter having similarities to blast transformation of chronic myeloid leukemia. Additionally, subcategories of the BCR::ABL1-like lymphoblastic neoplasms are now described. Many new genetic categories are introduced, such as early pre-T-ALL with BCL11B abnormalities. Some of the genetic changes included in the classification are not currently tested for routinely, but introduction of these biologic subtypes will hopefully initiate an increase in testing capabilities, as was as the case for the development of targeted therapies.

The reviews on acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) by Weinberg et al [7] and Hasserjian et al. [8] respectively, also expand genetic categories of these disorders, but also recognize the continuum between these disorders by introducing a new category of MDS/AML in adults without traditional de novo AML cytogenetics or mutation abnormalities.

While there are fewer changes in the myeloproliferative neoplasms and myelodysplastic/myeloproliferative neoplasms, Gianelli et al. [9] and Prakash et al. [10] respectively, highlight the refinement of disease criteria. The ICC retains accelerated phase as a category in chronic myeloid leukemia and, in the setting of clonality, chronic myelomonocytic leukemia can now be diagnosed with lower peripheral blood monocyte counts.

Tzankov et al. [11] review the approach to eosinophilia and further characterize new genetic categories associated with tyrosine kinase abnormalities. Leguit et al. [12] review the criteria for mastocytosis including the clonal association between neoplastic mast cells and associated myeloid neoplasms.

Finally, pediatric and germline disorders are reviewed by Rudelius et al. [13] with expanded germline entities involving both myeloid and lymphoid neoplasms. The definition of juvenile myelomonocytic leukemia and related disorders are now separate from the myelodysplastic/myeloproliferative neoplasms.

For the lymphoid disorders, Sander et al. [14] review the diagnostic criteria and most recent information in chronic lymphocytic leukemia, B prolymphocytic leukemia, and mantle cell lymphoma including the spectrum from early lesions to aggressive transformed forms of these neoplasms. Novel genomic perspectives are updated with emphasis on alterations that may be of clinical interest in the near future. The spectrum of entities recognized under the term of “follicular lymphoma” (FL) has expanded in recent years, particularly with the identification of several entities that contrary to conventional FL do not carry the t(14,18). Laurent and colleagues [15] review issues related to grading FL, provide a comprehensive perspective of FLs negative for BCL2 rearrangement, and highlight the relevance of molecular studies in the differential diagnosis of these entities and other related lymphomas.

The spectrum of plasma cell neoplasm is reviewed by Fend et al. [16] addressing the refinement in the diagnostic criteria and variants of lymphoplasmacytic lymphomas, monoclonal gammopathies of unknown significance, and solitary plasmacytomas. Primary cold agglutinin disease is now recognized as a distinct entity in the ICC and discussed in this review. The relevance of genomic studies is emphasized by the subdivision of multiple myeloma in different genetic groups in the ICC.

Aggressive B-cell lymphomas are examined in two articles. Song et al. [17] present the heterogeneous group of diffuse large B-cell lymphomas including new emerging entities. Recent genomic studies are changing our view of these neoplasms. Although still not considered ready for clinical use, they open new perspectives that most likely will influence our practice in the coming years. High-grade B-cell lymphomas are a challenging group of neoplasms thoroughly reviewed by King et al. [18] The paradigm of these tumors is the well characterized Burkitt lymphoma in which recent genomic studies are distinguishing EBV positive and negative tumors. The manuscript provides the rationale for the new definition of these tumors based on the presence of MYC, BCL2, and BCL6 rearrangements and the new consideration of occasional TdT expression in these tumors.

The definition of classic Hodgkin lymphoma has not changed but the borders in the differential diagnosis with some diseases remains difficult. Tousseyn et al. [19] dissect these situations and provide insightful clues to identify the distinct entities. The article also addresses the rationale to change the historic term of “nodular lymphocyte predominant Hodgkin lymphoma” for the more biologically and clinically appropriate term of “nodular lymphocyte predominant B-cell lymphoma” included in the ICC. The change in the definition of gray zone lymphomas and the rational to restrict this term to “mediastinal gray zone lymphomas” is also presented in the light of recent genomic studies.

The presence of EBV in a lymphoproliferative disorder is always intriguing with epidemiological studies showing marked differences in geographical and ethnic distribution. Quintanilla-Martinez et al. [20] present a comprehensive view of all the B, T and NK lesions associated with this virus with new concepts, terminology and refinement of criteria proposed in the ICC. De Leval and colleagues [21] introduce the heterogeneous group of extranodal T and NK- cell lymphomas with lesions ranging from indolent to very aggressive behavior. As in other areas of the ICC, the new genomic information supports the characterization of these diseases and provides elements for refined diagnosis. Feldman et al. [22] address the predominantly nodal counterparts of T/NK-cell lymphomas. Lymphomas of T-follicular helper cell of origin are now recognized in the ICC as a single entity with three morphological variants sharing phenotypic and molecular features. Definitions of anaplastic large cell lymphoma and peripheral T cell lymphoma, NOS remain essentially unchanged but new subtypes are recognized based on genetic and gene expression profiles with impact in clinical behavior.

Goodlad et al. [23] address new advances in cutaneous lymphomas with the ICC segregation of primary cutaneous marginal zone lymphoma from MALT lymphomas. The term lymphoproliferative disorder is preferred over lymphoma for both this entity and primary cutaneous CD8-positive acral lesions. New biological insights illuminating the understanding of this group of diseases are also presented.

The goal of this special issue is to provide more details on the pathologic features of the entities of the International Consensus Classification of Myeloid and Lymphoid Neoplasms and to serve as a practical guide for diagnostic use of the classification. We thank all the participants of the Clinical Advisory Committee that helped develop the classification as well as the authors of this issue.