Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Current Hematologic Malignancy Reports
Published in: Current Hematologic Malignancy Reports 6/2023

23-10-2023 | Lymphoma

Updates in the Classification of T-cell Lymphomas and Lymphoproliferative Disorders

Authors: Naoki Oishi, Reham Ahmed, Andrew L. Feldman

Published in: Current Hematologic Malignancy Reports | Issue 6/2023

Login to get access

Abstract 

Purpose of Review

Mature T/NK-cell neoplasms comprise a heterogeneous group of diseases with diverse clinical, histopathologic, immunophenotypic, and molecular features. A clinically relevant, comprehensive, and reproducible classification system for T/NK-cell neoplasms is essential for optimal management, risk stratification, and advancing understanding of these diseases. Two classification systems for lymphoid neoplasms were recently introduced: the 5th edition of World Health Organization classification (WHO-HAEM5) and the 2022 International Consensus Classification (ICC). In this review, we summarize the basic framework and updates in the classification of mature T/NK-cell neoplasms.

Recent Findings

WHO-HAEM5 and ICC share basic concepts in classification of T/NK-cell neoplasms, emphasizing integration of clinical presentation, pathology, immunophenotype, and genetics. Major updates in both classifications include unifying nodal T-follicular helper-cell lymphomas into a single entity and establishing EBV-positive nodal T/NK-cell lymphoma as a distinct entity. However, some differences exist in taxonomy, terminology, and disease definitions.

Summary

The recent classifications of mature T/NK-cell neoplasms are largely similar and provide new insights into taxonomy based on integrated clinicopathologic features.
Literature
1.
•• Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: lymphoid neoplasms. Leukemia. 2022;36:1720–48. The most recent version of the World Health Organization (WHO) classification.PubMedPubMedCentralCrossRef
2.
•• Campo E, Jaffe ES, Cook JR, et al. The International Consensus Classification of mature lymphoid neoplasms: a report from the Clinical Advisory Committee. Blood. 2022;140:1229–53. The 2022 International Consensus Classification (ICC) by the Clinical Advisory Committee.PubMedPubMedCentralCrossRef
3.
Oishi N, Feldman AL. Current concepts in nodal peripheral T-cell lymphomas. Surg Pathol Clin. 2023;16:267–85.PubMedCrossRef
4.
Feldman AL, Laurent C, Narbaitz M, et al. Classification and diagnostic evaluation of nodal T- and NK-cell lymphomas. Virchows Arch. 2023;482:265–79.PubMedCrossRef
5.
de Leval L, Feldman AL, Pileri S, et al. Extranodal T- and NK-cell lymphomas. Virchows Arch. 2023;482:245–64.PubMedCrossRef
6.
Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127:2375–90.PubMedPubMedCentralCrossRef
7.
8.
Staber PB, Herling M, Bellido M, et al. Consensus criteria for diagnosis, staging, and treatment response assessment of T-cell prolymphocytic leukemia. Blood. 2019;134:1132–43.PubMedPubMedCentralCrossRef
9.
Patil P, Cieslak A, Bernhart SH, et al. Reconstruction of rearranged T-cell receptor loci by whole genome and transcriptome sequencing gives insights into the initial steps of T-cell prolymphocytic leukemia. Genes Chromosom Cancer. 2020;59:261–7.PubMedCrossRef
10.
11.
Shi M, He R, Feldman AL, et al. STAT3 mutation and its clinical and histopathologic correlation in T-cell large granular lymphocytic leukemia. Hum Pathol. 2018;73:74–81.PubMedCrossRef
12.
13.
Andersson EI, Tanahashi T, Sekiguchi N, et al. High incidence of activating STAT5B mutations in CD4-positive T-cell large granular lymphocyte leukemia. Blood. 2016;128:2465–8.PubMedPubMedCentralCrossRef
14.
15.
Karube K, Takatori M, Sakihama S, et al. Clinicopathological features of adult T-cell leukemia/lymphoma with HTLV-1-infected Hodgkin and Reed-Sternberg-like cells. Blood Adv. 2021;5:198–206.PubMedPubMedCentral
16.
Tamaki T, Karube K, Sakihama S, et al. a comprehensive study of the immunophenotype and its clinicopathologic significance in adult T-cell leukemia/lymphoma. Mod Pathol. 2023;36: 100169.PubMedCrossRef
17.
Karube K, Aoki R, Sugita Y, et al. The relationship of FOXP3 expression and clinicopathological characteristics in adult T-cell leukemia/lymphoma. Mod Pathol. 2008;21:617–25.PubMedCrossRef
18.
Takatori M, Sakihama S, Miyara M, et al. A new diagnostic algorithm using biopsy specimens in adult T-cell leukemia/lymphoma: combination of RNA in situ hybridization and quantitative PCR for HTLV-1. Mod Pathol. 2021;34:51–8.PubMedCrossRef
19.
Yamada K, Miyoshi H, Yoshida N, et al. Human T-cell lymphotropic virus HBZ and tax mRNA expression are associated with specific clinicopathological features in adult T-cell leukemia/lymphoma. Mod Pathol. 2021;34:314–26.PubMedCrossRef
20.
21.
• Kogure Y, Kameda T, Koya J, et al. Whole-genome landscape of adult T-cell leukemia/lymphoma. Blood. 2022;139:967–82. A comprehensive molecular study of adult T-cell luekemia/lymphoma (ATLL).PubMedPubMedCentralCrossRef
22.
Kataoka K, Nagata Y, Kitanaka A, et al. Integrated molecular analysis of adult T cell leukemia/lymphoma. Nat Genet. 2015;47:1304–15.PubMedCrossRef
23.
Kataoka K, Shiraishi Y, Takeda Y, et al. Aberrant PD-L1 expression through 3’-UTR disruption in multiple cancers. Nature. 2016;534:402–6.PubMedCrossRef
24.
Moffitt AB, Ondrejka SL, McKinney M, et al. Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2. J Exp Med. 2017;214:1371–86.PubMedPubMedCentralCrossRef
25.
Sharma A, Oishi N, Boddicker RL, et al. Recurrent STAT3-JAK2 fusions in indolent T-cell lymphoproliferative disorder of the gastrointestinal tract. Blood. 2018;131:2262–6.PubMedPubMedCentralCrossRef
26.
27.
Margolskee E, Jobanputra V, Lewis SK, et al. Indolent Small Intestinal CD4+ T-cell Lymphoma Is a Distinct Entity with Unique Biologic and Clinical Features. Tran DQ, ed. PLoS One. 2013;8:e68343.PubMedPubMedCentralCrossRef
28.
Soderquist CR, Patel N, Murty VV, et al. Genetic and phenotypic characterization of indolent T-cell lymphoproliferative disorders of the gastrointestinal tract. Haematologica. 2020;105:1895–906.PubMedPubMedCentralCrossRef
29.
Takeuchi K, Yokoyama M, Ishizawa S, et al. Lymphomatoid gastropathy: A distinct clinicopathologic entity of self-limited pseudomalignant NK-cell proliferation. Blood. 2010;116:5631–7.PubMedCrossRef
30.
Mansoor A, Pittaluga S, Beck PL, et al. NK-cell enteropathy: a benign NK-cell lymphoproliferative disease mimicking intestinal lymphoma: clinicopathologic features and follow-up in a unique case series. Blood. 2011;117:1447–52.PubMedPubMedCentralCrossRef
31.
32.
Yabe M, Miranda RN, Medeiros LJ. Hepatosplenic T-cell Lymphoma: a review of clinicopathologic features, pathogenesis, and prognostic factors. Hum Pathol. 2018;74:5–16.PubMedCrossRef
33.
34.
35.
Feldman AL, Oishi N, Ketterling RP, et al. Immunohistochemical approach to genetic subtyping of anaplastic large cell lymphoma. Am J Surg Pathol. 2022;46:1490–9.PubMedPubMedCentralCrossRef
36.
Ravindran A, Feldman AL, Ketterling RP, et al. Striking association of lymphoid enhancing factor (LEF1) overexpression and DUSP22 rearrangements in anaplastic large cell lymphoma. Am J Surg Pathol. 2021;45:550–7.PubMedCrossRef
37.
Feldman AL, Dogan A, Smith DI, et al. Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively parallel genomic sequencing. Blood. 2011;117:915–9.PubMedPubMedCentralCrossRef
38.
39.
Luchtel RA, Dasari S, Oishi N, et al. Molecular profiling reveals immunogenic cues in anaplastic large cell lymphomas with DUSP22 rearrangements. Blood. 2018;132:1386–98.PubMedPubMedCentralCrossRef
40.
Vasmatzis G, Johnson SH, Knudson AR, et al. Genome-wide analysis reveals recurrent structural abnormalities of TP63 and other p53-related genes in peripheral T-cell lymphomas. Blood. 2012;120:2280–9.PubMedPubMedCentralCrossRef
41.
Karube K, Feldman AL. “Double-hit” of DUSP22 and TP63 rearrangements in anaplastic large cell lymphoma. ALK-negative Blood. 2020;135:700–700.PubMed
42.
Crescenzo R, Abate F, Lasorsa E, et al. Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma. Cancer Cell. 2015;27:516–32.PubMedPubMedCentralCrossRef
43.
Fitzpatrick MJ, Massoth LR, Marcus C, et al. JAK2 rearrangements are a recurrent alteration in CD30+ systemic T-cell lymphomas with anaplastic morphology. Am J Surg Pathol. 2021;45:895–904.PubMedCrossRef
44.
Hu G, Dasari S, Asmann YW, et al. Targetable fusions of the FRK tyrosine kinase in ALK-negative anaplastic large cell lymphoma. Leukemia. 2018;32:565–9.PubMedCrossRef
45.
Parilla Castellar ER, Jaffe ES, Said JW, et al. ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes. Blood. 2014;124:1473–80.CrossRef
46.
Pedersen MB, Hamilton-Dutoit SJ, Bendix K, et al. DUSP22 and TP63 rearrangements predict outcome of ALK-negative anaplastic large cell lymphoma: a Danish cohort study. Blood. 2017;130:554–7.PubMedPubMedCentralCrossRef
47.
Onaindia A, de Villambrosía SG, Prieto-Torres L, et al. DUSP22 -rearranged anaplastic lymphomas are characterized by specific morphological features and a lack of cytotoxic and JAK/STAT surrogate markers. Haematologica. 2019;104:e158–62.PubMedPubMedCentralCrossRef
48.
Hapgood G, Ben-Neriah S, Mottok A, et al. Identification of high-risk DUSP22-rearranged ALK-negative anaplastic large cell lymphoma. Br J Haematol. 2019;186:e28–31.PubMedPubMedCentralCrossRef
49.
Qiu L, Tang G, Li S, et al. DUSP22 rearrangement is associated with a distinctive immunophenotype but not outcome in patients with systemic ALK-negative anaplastic large cell lymphoma. Haematologica. 2022;108:1604–15.PubMedCentralCrossRef
50.
51.
• Laurent C, Nicolae A, Laurent C, et al. Gene alterations in epigenetic modifiers and JAK-STAT signaling are frequent in breast implant-associated ALCL. Blood. 2020;135:360–70. An extensive study on the genetics of breast implant-associated ALCL.PubMedPubMedCentral
52.
Quesada AE, Zhang Y, Ptashkin R, et al. Next generation sequencing of breast implant-associated anaplastic large cell lymphomas reveals a novel STAT3-JAK2 fusion among other activating genetic alterations within the JAK-STAT pathway. Breast J. 2021;27:314–21.PubMedCrossRef
53.
Oishi N, Hundal T, Phillips JL, et al. Molecular profiling reveals a hypoxia signature in breast implant-associated anaplastic large cell lymphoma. Haematologica. 2020;106:1714–24.PubMedCentralCrossRef
54.
Oishi N, Feldman AL. CA9 expression in breast implant-associated anaplastic large cell lymphoma presenting in a lymph node. Histopathology. 2022;81:270–2.PubMedPubMedCentralCrossRef
55.
Sakata-Yanagimoto M, Enami T, Yoshida K, et al. Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nat Genet. 2014;46:171–5.PubMedCrossRef
56.
Fujisawa M, Sakata-Yanagimoto M, Nishizawa S, et al. Activation of RHOA–VAV1 signaling in angioimmunoblastic T-cell lymphoma. Leukemia. 2018;32:694–702.PubMedCrossRef
57.
Palomero T, Couronné L, Khiabanian H, et al. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat Genet. 2014;46:166–70.PubMedPubMedCentralCrossRef
58.
Streubel B, Vinatzer U, Willheim M, et al. Novel t(5;9)(q33;q22) fuses ITK to SYK in unspecified peripheral T-cell lymphoma. Leukemia. 2006;20:313–8.PubMedCrossRef
59.
Huang Y, Moreau A, Dupuis J, et al. Peripheral T-cell lymphomas with a follicular growth pattern are derived from follicular helper T cells (TFH) and may show overlapping features with angioimmunoblastic T-cell lymphomas. Am J Surg Pathol. 2009;33:682–90.PubMedPubMedCentralCrossRef
60.
Basha BM, Bryant SC, Rech KL, et al. Application of a 5 marker panel to the routine diagnosis of peripheral T-cell lymphoma with t-follicular helper phenotype. Am J Surg Pathol. 2019;43:1282–90.PubMedCrossRef
61.
Ruan J, Moskowitz AJ, Mehta-Shah N, et al. Multicenter phase 2 study of oral azacitidine (CC-486) plus CHOP as initial treatment for peripheral T-cell lymphoma. Blood. 2023;141:2194–205.PubMed
62.
Ghione P, Faruque P, Mehta-Shah N, et al. T follicular helper phenotype predicts response to histone deacetylase inhibitors in relapsed/refractory peripheral T-cell lymphoma. Blood Adv. 2020;4:4640–7.PubMedPubMedCentralCrossRef
63.
Falchi L, Ma H, Klein S, et al. Combined oral 5-azacytidine and romidepsin are highly effective in patients with PTCL: a multicenter phase 2 study. Blood. 2021;137:2161–70.PubMedCrossRef
64.
Drieux F, Ruminy P, Abdel-Sater A, Lemonnier F, Viailly PJ, Fataccioli V, et al. Defining signatures of peripheral T-cell lymphoma with a targeted 20-marker gene expression profiling assay. Haematologica. 2020;105(6):1582–92.
65.
Heavican TB, Bouska A, Yu J, et al. Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma. Blood. 2019;133:1664–76.PubMedPubMedCentralCrossRef
66.
Wang T, Feldman AL, Wada DA, et al. GATA-3 expression identifies a high-risk subset of PTCL, NOS with distinct molecular and clinical features. Blood. 2014;123:3007–15.PubMedPubMedCentralCrossRef
67.
Amador C, Greiner TC, Heavican TB, et al. Reproducing the molecular subclassification of peripheral T-cell lymphoma-NOS by immunohistochemistry. Blood. 2019;134:2159–70.PubMedPubMedCentralCrossRef
68.
• Herek TA, Bouska A, Lone W, et al. DNMT3A mutations define a unique biological and prognostic subgroup associated with cytotoxic T cells in PTCL-NOS. Blood. 2022;140:1278–90. A study showing the distinct molecular profile of peripheral T-cell lymphoma (PTCL) of cytotoxic phenotype.PubMedPubMedCentralCrossRef
69.
Nicolae A, Bouilly J, Lara D, et al. Nodal cytotoxic peripheral T-cell lymphoma occurs frequently in the clinical setting of immunodysregulation and is associated with recurrent epigenetic alterations. Mod Pathol. 2022;35:1126–36.PubMedCrossRef
70.
Pongpruttipan T, Sukpanichnant S, Assanasen T, et al. Extranodal NK/T-cell lymphoma, nasal type, includes cases of natural killer cell and αβ, γδ, and αβ/γδ T-cell origin. Am J Surg Pathol. 2012;36:481–99.PubMedCrossRef
71.
Kato S, Asano N, Miyata-Takata T, et al. T-cell receptor (TCR) phenotype of nodal Epstein-Barr virus (EBV)-positive cytotoxic T-cell lymphoma (CTL): a clinicopathologic study of 39 cases. Am J Surg Pathol. 2015;39:462–71.PubMedCrossRef
72.
Hong M, Lee T, Young Kang S, et al. Nasal-type NK/T-cell lymphomas are more frequently T rather than NK lineage based on T-cell receptor gene, RNA and protein studies: lineage does not predict clinical behavior. Mod Pathol. 2016;29:430–43.PubMedCrossRef
73.
Oishi N, Satou A, Miyaoka M, et al. Genetic and immunohistochemical profiling of NK/T-cell lymphomas reveals prognostically relevant BCOR -MYC association. Blood Adv. 2023;7:178–89.PubMedCrossRef
74.
Montes-Mojarro IA, Chen B-J, Ramirez-Ibarguen AF, et al. Mutational profile and EBV strains of extranodal NK/T-cell lymphoma, nasal type in Latin America. Mod Pathol. 2020;33:781–91.PubMedCrossRef
75.
Jiang L, Gu Z-H, Yan Z-X, et al. Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma. Nat Genet. 2015;47:1061–6.PubMedCrossRef
76.
• Dong G, Liu X, Wang L, et al. Genomic profiling identifies distinct genetic subtypes in extra-nodal natural killer/T-cell lymphoma. Leukemia. 2022;36:2064–75. A molecular study demonstrating genetic heterogeneity of extranodal NK/T-cell lymphoma.PubMedPubMedCentralCrossRef
77.
Xiong J, Cui B-W, Wang N, et al. Genomic and transcriptomic characterization of natural killer T cell lymphoma. Cancer Cell. 2020;37:403-419.e6.PubMedCrossRef
78.
Quintanilla-Martinez L, Swerdlow SH, Tousseyn T, et al. New concepts in EBV-associated B, T, and NK cell lymphoproliferative disorders. Virchows Arch. 2023;482:227–44.PubMedCrossRef
79.
Kato S, Yamashita D, Nakamura S. Nodal EBV+ cytotoxic T-cell lymphoma: A literature review based on the 2017 WHO classification. J Clin Exp Hematop. 2020;60:30–6.PubMedPubMedCentralCrossRef
80.
Ng S-B, Chung T-H, Kato S, et al. Epstein-Barr virus-associated primary nodal T/NK-cell lymphoma shows a distinct molecular signature and copy number changes. Haematologica. 2018;103:278–87.PubMedPubMedCentralCrossRef
81.
Wai CMM, Chen S, Phyu T, et al. Immune pathway upregulation and lower genomic instability distinguish EBV-positive nodal T/NK-cell lymphoma from ENKTL and PTCL-NOS. Haematologica. 2022;107:1864–79.PubMedPubMedCentralCrossRef
Metadata
Title
Updates in the Classification of T-cell Lymphomas and Lymphoproliferative Disorders
Authors
Naoki Oishi
Reham Ahmed
Andrew L. Feldman
Publication date
23-10-2023
Publisher
Springer US
Published in
Current Hematologic Malignancy Reports / Issue 6/2023
Print ISSN: 1558-8211
Electronic ISSN: 1558-822X
DOI
https://doi.org/10.1007/s11899-023-00712-9

Other articles of this Issue 6/2023

Current Hematologic Malignancy Reports 6/2023 Go to the issue

ReviewPaper

Measurable Residual Disease Monitoring in Lymphoma

ReviewPaper

NK Cell Therapeutics for Hematologic Malignancies: from Potential to Fruition

ReviewPaper

Developing Targeted Therapies for T Cell Acute Lymphoblastic Leukemia/Lymphoma

ReviewPaper

Experimental and Computational Approaches to Measure Telomere Length: Recent Advances and Future Directions

ReviewPaper

Management of advanced phase CML

ReviewPaper

Central Nervous System Relapse in T and NK cell Lymphomas
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits