New developments in non-Hodgkin lymphoid malignancies

Pathology. 2021 Apr;53(3):349-366. doi: 10.1016/j.pathol.2021.01.002. Epub 2021 Mar 5.


The revised fourth edition of the World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues (2017) reflects significant advances in understanding the biology, genetic basis and behaviour of haematopoietic neoplasms. This review focuses on some of the major changes in B-cell and T-cell non-Hodgkin lymphomas in the 2017 WHO and includes more recent updates. The 2017 WHO saw a shift towards conservatism in the classification of precursor lesions of small B-cell lymphomas such as monoclonal B-cell lymphocytosis, in situ follicular and in situ mantle cell neoplasms. With more widespread use of next generation sequencing (NGS), special entities within follicular lymphoma and mantle cell lymphoma were recognised with recurrent genetic aberrations and unique clinicopathological features. The diagnostic workup of lymphoplasmacytic lymphoma and hairy cell leukaemia has been refined with the discovery of MYD88 L265P and BRAF V600E mutations, respectively, in these entities. Recommendations in the immunohistochemical evaluation of diffuse large B-cell lymphoma include determining cell of origin and expression of MYC and BCL2, so called 'double-expressor' phenotype. EBV-positive large B-cell lymphoma of the elderly has been renamed to recognise its occurrence amongst a wider age group. EBV-positive mucocutaneous ulcer is a newly recognised entity with indolent clinical behaviour that occurs in the setting of immunosuppression. Two lymphomas with recurrent genetic aberrations are newly included provisional entities: Burkitt-like lymphoma with 11q aberration and large B-cell lymphoma with IRF4 rearrangement. Aggressive B-cell lymphomas with MYC, BCL2 and/or BCL6 rearrangements, so called 'double-hit/triple-hit' lymphomas are now a distinct entity. Much progress has been made in understanding intestinal T-cell lymphomas. Enteropathy-associated T-cell lymphoma, type II, is now known to not be associated with coeliac disease and is hence renamed monomorphic epitheliotropic T-cell lymphoma. An indolent clonal T-cell lymphoproliferative disorder of the GI tract is a newly included provisional entity. Angioimmunoblastic T-cell lymphoma and nodal T-cell lymphomas with T-follicular helper phenotype are included in a single broad category, emphasising their shared genetic and phenotypic features. Anaplastic large cell lymphoma, ALK- is upgraded to a definitive entity with subsets carrying recurrent rearrangements in DUSP22 or TP63. Breast implant-associated anaplastic large cell lymphoma is a new provisional entity with indolent behaviour. Finally, cutaneous T-cell proliferations include a new provisional entity, primary cutaneous acral CD8-positive T-cell lymphoma, and reclassification of primary small/medium CD4-positive T-cell lymphoma as lymphoproliferative disorder.

Keywords: 2017 World Health Organization Classification; EBV-positive mucocutaneous ulcer; NOS; anaplastic large cell lymphoma ALK–; breast implant-associated anaplastic large cell lymphoma; diagnostic criteria; high grade B-cell lymphoma; in situ follicular neoplasia; indolent mantle cell lymphoma; large B-cell lymphoma with IRF4 rearrangement; monoclonal B-cell lymphocytosis; monomorphic epitheliotropic intestinal T-cell lymphoma.

Publication types

  • Review

MeSH terms

  • Dual-Specificity Phosphatases / genetics
  • Gene Rearrangement
  • Herpesvirus 4, Human / isolation & purification*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Interferon Regulatory Factors / genetics
  • Lymphoma, B-Cell / classification*
  • Lymphoma, B-Cell / genetics
  • Lymphoma, B-Cell / pathology
  • Lymphoma, Non-Hodgkin / classification*
  • Lymphoma, Non-Hodgkin / genetics
  • Lymphoma, Non-Hodgkin / pathology
  • Lymphoma, T-Cell / classification*
  • Lymphoma, T-Cell / genetics
  • Lymphoma, T-Cell / pathology
  • Lymphoproliferative Disorders / classification*
  • Lymphoproliferative Disorders / genetics
  • Lymphoproliferative Disorders / pathology
  • Mitogen-Activated Protein Kinase Phosphatases / genetics
  • Mutation
  • Myeloid Differentiation Factor 88 / genetics
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-6 / genetics
  • Sequence Analysis, DNA
  • Transcription Factors / genetics
  • Tumor Suppressor Proteins / genetics
  • World Health Organization


  • BCL2 protein, human
  • BCL6 protein, human
  • Interferon Regulatory Factors
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins c-bcl-6
  • TP63 protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins
  • interferon regulatory factor-4
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Mitogen-Activated Protein Kinase Phosphatases
  • DUSP22 protein, human
  • Dual-Specificity Phosphatases