The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms

Rita Alaggio, Catalina Amador, Ioannis Anagnostopoulos, Ayoma D Attygalle, Iguaracyra Barreto de Oliveira Araujo, Emilio Berti, Govind Bhagat, Anita Maria Borges, Daniel Boyer, Mariarita Calaminici, Amy Chadburn, John K C Chan, Wah Cheuk, Wee-Joo Chng, John K Choi, Shih-Sung Chuang, Sarah E Coupland, Magdalena Czader, Sandeep S Dave, Daphne de Jong, Ming-Qing Du, Kojo S Elenitoba-Johnson, Judith Ferry, Julia Geyer, Dita Gratzinger, Joan Guitart, Sumeet Gujral, Marian Harris, Christine J Harrison, Sylvia Hartmann, Andreas Hochhaus, Patty M Jansen, Kennosuke Karube, Werner Kempf, Joseph Khoury, Hiroshi Kimura, Wolfram Klapper, Alexandra E Kovach, Shaji Kumar, Alexander J Lazar, Stefano Lazzi, Lorenzo Leoncini, Nelson Leung, Vasiliki Leventaki, Xiao-Qiu Li, Megan S Lim, Wei-Ping Liu, Abner Louissaint Jr, Andrea Marcogliese, L Jeffrey Medeiros, Michael Michal, Roberto N Miranda, Christina Mitteldorf, Santiago Montes-Moreno, William Morice, Valentina Nardi, Kikkeri N Naresh, Yasodha Natkunam, Siok-Bian Ng, Ilske Oschlies, German Ott, Marie Parrens, Melissa Pulitzer, S Vincent Rajkumar, Andrew C Rawstron, Karen Rech, Andreas Rosenwald, Jonathan Said, Clémentine Sarkozy, Shahin Sayed, Caner Saygin, Anna Schuh, William Sewell, Reiner Siebert, Aliyah R Sohani, Reuben Tooze, Alexandra Traverse-Glehen, Francisco Vega, Beatrice Vergier, Ashutosh D Wechalekar, Brent Wood, Luc Xerri, Wenbin Xiao, Rita Alaggio, Catalina Amador, Ioannis Anagnostopoulos, Ayoma D Attygalle, Iguaracyra Barreto de Oliveira Araujo, Emilio Berti, Govind Bhagat, Anita Maria Borges, Daniel Boyer, Mariarita Calaminici, Amy Chadburn, John K C Chan, Wah Cheuk, Wee-Joo Chng, John K Choi, Shih-Sung Chuang, Sarah E Coupland, Magdalena Czader, Sandeep S Dave, Daphne de Jong, Ming-Qing Du, Kojo S Elenitoba-Johnson, Judith Ferry, Julia Geyer, Dita Gratzinger, Joan Guitart, Sumeet Gujral, Marian Harris, Christine J Harrison, Sylvia Hartmann, Andreas Hochhaus, Patty M Jansen, Kennosuke Karube, Werner Kempf, Joseph Khoury, Hiroshi Kimura, Wolfram Klapper, Alexandra E Kovach, Shaji Kumar, Alexander J Lazar, Stefano Lazzi, Lorenzo Leoncini, Nelson Leung, Vasiliki Leventaki, Xiao-Qiu Li, Megan S Lim, Wei-Ping Liu, Abner Louissaint Jr, Andrea Marcogliese, L Jeffrey Medeiros, Michael Michal, Roberto N Miranda, Christina Mitteldorf, Santiago Montes-Moreno, William Morice, Valentina Nardi, Kikkeri N Naresh, Yasodha Natkunam, Siok-Bian Ng, Ilske Oschlies, German Ott, Marie Parrens, Melissa Pulitzer, S Vincent Rajkumar, Andrew C Rawstron, Karen Rech, Andreas Rosenwald, Jonathan Said, Clémentine Sarkozy, Shahin Sayed, Caner Saygin, Anna Schuh, William Sewell, Reiner Siebert, Aliyah R Sohani, Reuben Tooze, Alexandra Traverse-Glehen, Francisco Vega, Beatrice Vergier, Ashutosh D Wechalekar, Brent Wood, Luc Xerri, Wenbin Xiao

Abstract

We herein present an overview of the upcoming 5th edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4th edition. These include reorganization of entities by a hierarchical system as is adopted throughout the 5th edition of the WHO classification of tumours of all organ systems, modification of nomenclature for some entities, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities, as well as inclusion of tumour-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms.

Conflict of interest statement

The authors declare no competing interests.

© 2022. The Author(s).

Figures

Fig. 1. Summary of the relationship between…
Fig. 1. Summary of the relationship between splenic B-cell lymphoma entities as named and defined in the revised 4th edition of the WHO classification (WHO-HAEM4R) and in the present 5th edition (WHO-HAEM5).
Some cases previously classified as B-prolymphocytic leukaemia do represent (blastoid) mantle cell lymphoma (as was already indicated in WHO-HAEM4R) or prolymphocytic progression of CLL. Cases classified in WHO-HAEM4R as CLL/SLL with ≥ 15% of prolymphocytes are now classified as prolymphocytic progression of CLL, cases with

Fig. 2. Aetiology and recurrent genetic abnormalities…

Fig. 2. Aetiology and recurrent genetic abnormalities in extranodal marginal zone lymphoma (EMZL) of various…

Fig. 2. Aetiology and recurrent genetic abnormalities in extranodal marginal zone lymphoma (EMZL) of various sites.
An important clinical application is that BIRC3::MALT1 identifies those cases of the gastric EMZL not responding to H. pylori eradication. As many of the genes involved in EMZL have not been uniformly investigated across different sites, only the recurrent genetic changes fundamental to the understanding of EMZL pathogenesis are presented. The height of the boxes under sites does not reflect the frequencies of these lymphomas. trans translocation, mut mutation, del: deletion.

Fig. 3. Summary of the relationship between…

Fig. 3. Summary of the relationship between large B-cell lymphoma (LBCL) entities as named and…

Fig. 3. Summary of the relationship between large B-cell lymphoma (LBCL) entities as named and defined in the revised 4th edition of the WHO classification (WHO-HAEM4R) and in the present 5th edition (WHO-HAEM5).
* “Rare B-cell lymphomas” refer to those fulfilling definitions of specific clinico-pathological entities while incidentally bearing concomitant MYC and BCL2 rearrangements. Examples are fluid-overload-associated large B-cell lymphomas and rare follicular lymphomas. R rearrangement, G germline configuration.

Fig. 4. Algorithm for classification of aggressive…

Fig. 4. Algorithm for classification of aggressive B-cell lymphomas in WHO-HAEM5 in the light of…

Fig. 4. Algorithm for classification of aggressive B-cell lymphomas in WHO-HAEM5 in the light of MYC, BCL2 and BCL6 rearrangement and complex 11q gain/loss patterns.
HGBL high grade B-cell lymphoma, R rearrangement, G germline configuration.

Fig. 5. Summary of the relationship between…

Fig. 5. Summary of the relationship between immunodeficiency-associated lymphoid proliferations and lymphomas as named and…

Fig. 5. Summary of the relationship between immunodeficiency-associated lymphoid proliferations and lymphomas as named and defined in the revised 4th edition of the WHO Classification (WHO-HAEM4R) and in the present 5th edition (WHO-HAEM5).
The overarching concept applied in WHO-HAEM5 recognizes the pathological and biological similarities between proliferations presenting in various immune deficiency settings, while acknowledging their specific features. Outside the shared entities, unique proliferations are especially typical for various inborn errors of immunity (IEI). EBVMCU: EBV-positive mucocutaneous ulcer.

Fig. 6. Indolent NK-cell lymphoproliferative disorder of…

Fig. 6. Indolent NK-cell lymphoproliferative disorder of the gastrointestinal tract involving the stomach.

The gastric…

Fig. 6. Indolent NK-cell lymphoproliferative disorder of the gastrointestinal tract involving the stomach.
The gastric mucosa shows expansion of the lamina propria by an atypical lymphoid infiltrate. The tumour cells are medium-sized, often with pale-staining cytoplasm.

Fig. 7. Nodal TFH-cell lymphoma (nTFHL).

A…

Fig. 7. Nodal TFH-cell lymphoma (nTFHL).

A Nodal TFH-cell lymphoma, angioimmunoblastic-type (nTFHL-AI). The normal architecture…
Fig. 7. Nodal TFH-cell lymphoma (nTFHL).
A Nodal TFH-cell lymphoma, angioimmunoblastic-type (nTFHL-AI). The normal architecture of the lymph node is effaced. There is a diffuse infiltrate of medium-sized, slightly atypical lymphocytes, sometimes with clear cytoplasm. One of the hallmarks of the disease is the proliferation of arborizing post-capillary vessels consistent with high endothelial venules. B Nodal TFH-cell lymphoma, follicular-type (nTFHL-F). In this example, progressive transformation of germinal centre-like nTFHL-F, clusters of atypical lymphoid cells with pale cytoplasm are embedded in a background of small lymphocytes of mantle zone type. The inset shows strong expression of PD1 in the tumour cells. C Nodal TFH-cell lymphoma, not otherwise specified. This tumour is composed of a sheet-like proliferation of medium-sized to large neoplastic cells.

Fig. 8. Nodal EBV-positive T- and NK-cell…

Fig. 8. Nodal EBV-positive T- and NK-cell lymphoma.

This lymphoma shows a diffuse infiltrate of…

Fig. 8. Nodal EBV-positive T- and NK-cell lymphoma.
This lymphoma shows a diffuse infiltrate of relatively monotonous, medium-sized to large cells, sometimes reminiscent of centroblasts. Inset: in-situ hybridization for EBERs identifies EBV infection in virtually all tumour cells.
All figures (8)
Fig. 2. Aetiology and recurrent genetic abnormalities…
Fig. 2. Aetiology and recurrent genetic abnormalities in extranodal marginal zone lymphoma (EMZL) of various sites.
An important clinical application is that BIRC3::MALT1 identifies those cases of the gastric EMZL not responding to H. pylori eradication. As many of the genes involved in EMZL have not been uniformly investigated across different sites, only the recurrent genetic changes fundamental to the understanding of EMZL pathogenesis are presented. The height of the boxes under sites does not reflect the frequencies of these lymphomas. trans translocation, mut mutation, del: deletion.
Fig. 3. Summary of the relationship between…
Fig. 3. Summary of the relationship between large B-cell lymphoma (LBCL) entities as named and defined in the revised 4th edition of the WHO classification (WHO-HAEM4R) and in the present 5th edition (WHO-HAEM5).
* “Rare B-cell lymphomas” refer to those fulfilling definitions of specific clinico-pathological entities while incidentally bearing concomitant MYC and BCL2 rearrangements. Examples are fluid-overload-associated large B-cell lymphomas and rare follicular lymphomas. R rearrangement, G germline configuration.
Fig. 4. Algorithm for classification of aggressive…
Fig. 4. Algorithm for classification of aggressive B-cell lymphomas in WHO-HAEM5 in the light of MYC, BCL2 and BCL6 rearrangement and complex 11q gain/loss patterns.
HGBL high grade B-cell lymphoma, R rearrangement, G germline configuration.
Fig. 5. Summary of the relationship between…
Fig. 5. Summary of the relationship between immunodeficiency-associated lymphoid proliferations and lymphomas as named and defined in the revised 4th edition of the WHO Classification (WHO-HAEM4R) and in the present 5th edition (WHO-HAEM5).
The overarching concept applied in WHO-HAEM5 recognizes the pathological and biological similarities between proliferations presenting in various immune deficiency settings, while acknowledging their specific features. Outside the shared entities, unique proliferations are especially typical for various inborn errors of immunity (IEI). EBVMCU: EBV-positive mucocutaneous ulcer.
Fig. 6. Indolent NK-cell lymphoproliferative disorder of…
Fig. 6. Indolent NK-cell lymphoproliferative disorder of the gastrointestinal tract involving the stomach.
The gastric mucosa shows expansion of the lamina propria by an atypical lymphoid infiltrate. The tumour cells are medium-sized, often with pale-staining cytoplasm.
Fig. 7. Nodal TFH-cell lymphoma (nTFHL).
Fig. 7. Nodal TFH-cell lymphoma (nTFHL).
A Nodal TFH-cell lymphoma, angioimmunoblastic-type (nTFHL-AI). The normal architecture of the lymph node is effaced. There is a diffuse infiltrate of medium-sized, slightly atypical lymphocytes, sometimes with clear cytoplasm. One of the hallmarks of the disease is the proliferation of arborizing post-capillary vessels consistent with high endothelial venules. B Nodal TFH-cell lymphoma, follicular-type (nTFHL-F). In this example, progressive transformation of germinal centre-like nTFHL-F, clusters of atypical lymphoid cells with pale cytoplasm are embedded in a background of small lymphocytes of mantle zone type. The inset shows strong expression of PD1 in the tumour cells. C Nodal TFH-cell lymphoma, not otherwise specified. This tumour is composed of a sheet-like proliferation of medium-sized to large neoplastic cells.
Fig. 8. Nodal EBV-positive T- and NK-cell…
Fig. 8. Nodal EBV-positive T- and NK-cell lymphoma.
This lymphoma shows a diffuse infiltrate of relatively monotonous, medium-sized to large cells, sometimes reminiscent of centroblasts. Inset: in-situ hybridization for EBERs identifies EBV infection in virtually all tumour cells.

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