Lymphoma & related disorders

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WHO classification T/NK cell



Topic Completed: 14 May 2021

Minor changes: 25 May 2021

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PubMed Search: WHO classification T/NK cell

Syeda F. Absar, M.D., M.P.H.
Patricia Tsang, M.D., M.B.A.
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Cite this page: Absar SF, Tsang P. WHO classification T/NK cell. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomanonBwhotcell.html. Accessed December 2nd, 2021.
Definition / general
  • Significant advances have occurred in the classification of T cell and natural killer (NK) cell neoplasms as a result of genomic studies and gene expression profiling (GEP)
  • New and provisional entities created
  • Novel molecular genetic data included for many of the entities
  • Several changes in the nomenclature have been incorporated
Highlights of 2016 WHO classification of mature T / NK cell neoplasms
  • T cell prolymphocytic leukemia (T-PLL)
    • Whole exome and targeted sequencing have demonstrated recurrent mutations in genes of the JAK / STAT signaling pathway, including:
      • JAK3 (30 - 40% of cases)
      • STAT5B (21 - 36% of cases)
      • JAK1 (minority of cases)
    • Alterations of ATM, TCL1 and MTCP1 in the pathogenesis of T-PLL
    • Mutations in epigenetic modifiers, such as EZH2 and BCOR, identified in a small proportion of cases
  • Adult T cell leukemia / lymphoma
    • Derived from regulatory T cells (CD4+, CD25+, FOXP3+)
    • Etiologically linked to the human T cell leukemia virus (HTLV-1)
    • High frequency of TP53 and IRF4 mutations (aggressive)
    • High number of copy aberrations, including deletions of CDKN2A and PDL1 amplification (aggressive)
    • STAT3 mutations (indolent)
  • Intestinal T cell lymphomas
    • EATL: previously named enteropathy associated T cell lymphoma (EATL) type I (linked to celiac disease)
      • T cell receptor (TCR) alpha / beta+
      • No amplification or gains of MYC
      • 9p losses
      • Mutations in components of the JAK / STAT pathway
    • Monomorphic epitheliotropic intestinal T cell lymphoma (MEITL), previously named EATL, type II
      • T cell receptor (TCR) gamma / delta+ with nuclear expression of megakaryocyte-associated tyrosine kinase (MATK)
      • Amplification or gains of MYC
      • Activating mutations in STAT5B and JAK3
      • Most recurrently mutated gene in MEITL: SETD2
    • Intestinal T cell lymphoma, NOS
    • New provisional entity: indolent T cell lymphoproliferative disorder of the GI tract
      • Presents with nonspecific GI symptoms
      • May involve small intestine, oral cavity, stomach, colon or multiple sites
      • CD3+, CD8+ (rarely CD4+), TIA1+, granzyme B-
      • Low proliferative rate
      • Not associated with Epstein-Barr virus infection
      • No mutations in genes of the JAK / STAT pathway
  • Hepatosplenic T cell lymphoma
    • Aggressive, derives from nonactivated cytotoxic T cells
    • Affects liver, spleen, bone marrow
    • Express T cell receptor gamma / delta+, cytotoxic molecules and aberrantly multiple killer immunoglobulin receptors (Kirs) clustered under CD158
    • Few cases derived from T cell receptor alpha / beta+ cells
    • Mutations in:
      • Chromatin modifiers (SETD2) (67% of cases)
      • STAT5B (40% of cases)
      • STAT3 (very rare)
  • Subcutaneous panniculitis-like T cell lymphoma
    • Subcutaneous nodules where tumor cells infiltrate the subcutaneous fat
    • Cytotoxic CD8+ cell with expression of cytotoxic molecules
    • Cases with a T cell receptor gamma / delta phenotype are not included here but classified as cutaneous gamma delta T cell lymphoma
  • Cutaneous T cell lymphomas (An Bras Dermatol 2018;93:871)
    • Mycosis fungoides and Sézary syndrome
      • Derived from CD4+ cells
      • CD8 positivity more common in the pediatric population
      • Mutations affect interleukin 2 (IL2) signaling pathways
      • Mutations involve JAK / STAT pathway that leads to constitutive activation of STAT3
      • Inactivation of CDKN2A (9p21.3)
  • Primary cutaneous CD30+ T cell lymphoproliferative disorders include:
    • Lymphomatoid papulosis (LyP)
      • Papular / nodular lesions that resolve within weeks
      • Large CD30+ cells in the dermis
      • Histologic subtypes:
        • Type A, > 80%, sparse large and atypical neoplastic cells in mixed inflammatory infiltrate, CD4+, CD8-
        • Type B, < 5%, epidermotropic infiltrate of small lymphocytes CD4+, CD8-, can be CD30-
        • Type C, ~10%, cohesive infiltrate of large and atypical cells in sparse inflammatory cells, CD4+, CD8-
        • Type D, < 5%, infiltration of small and medium atypical epidermotropic cells, CD4-, CD8+
        • Type E, < 5%, angiocentric and angiodestructive pattern, CD4-, CD8+
      • Clonal rearrangement of the T cell receptor chain genes demonstrable in majority of LyP
      • DUSP22-IRF4, fusion in small subset of LyP (< 5%), small and epidermotropic lymphocytes associated with large neoplastic cells in the dermis (CD4- CD8+ or CD4- CD8-)
    • Primary cutaneous anaplastic large cell lymphoma (ALCL)
      • Solitary or multiple nodules with favorable prognosis
      • Distinct from systemic ALCL that affects the skin secondarily
      • Activated CD4+ phenotype with frequent expression of cytotoxic molecules
      • Lacks expression of EMA and ALK
      • T cell receptor rearrangement in most cases
      • Does not carry t(2;5) translocation, unlike systemic ALCL
      • DUSP22-IRF4 locus in 6p25.3 in 20 - 57% (J Invest Dermatol 2010;130:816)
      • NPM1-TYK2 in ~5% (Blood 2014;124:3768)
      • Overexpression of skin homing chemokine receptor genes CCR10 and CCR8 (An Bras Dermatol 2018;93:871)
  • Peripheral T cell lymphomas (PTCL), NOS
    • Cases remaining in this category show cytological and phenotypic heterogeneity
    • Expresses genes for cell adhesion, apoptosis, proliferation, transcription and signal transduction
    • At least 3 subtypes, characterized by overexpression of:
      • GATA3, regulators of the T cell differentiation into Th2 cells (poor survival)
      • TBX2 (also known as T-bet), regulators of the T cell differentiation into Th1 cells
      • Cytotoxic genes
  • Angioimmunoblastic T cell lymphoma (AITL) and other nodal lymphomas of T follicular helper (TFH) cell origin
    • Arise from TFH cells (TFH phenotype defined by the expression of at least 2, preferably 3, of the following markers: CD10, BCL6, PD1, CXCR5, ICOS and SAP)
    • Angioimmunoblastic T cell lymphoma (AITL)
      • Express whole T follicular helper (TFH) gene signature with expression of the 6 TFH associated genes in majority of cases
      • Mutations in a variety of genes; encoding epigenetic modifiers (i.e. IDH2, TET2), the small GTPase RHOA (60% of cases) and rarely, genes encoding components of the T cell receptor signaling pathway (i.e. FYN, CD28)
      • Mutations of IDH2 R172 specific for AITL
    • Follicular T cell lymphoma
      • Has T follicular helper (TFH) phenotype but lacks the characteristic histological features of AITL
      • Translocation t(5;9)(q32;q22) leading to fusion of ITK-SYK
    • Nodal peripheral T cell lymphoma (PTCL) with a T follicular helper phenotype
      • Previously classified as PTCL, NOS
      • Include cases that express CD4 and at least 2 T follicular helper markers and share certain pathological features of AITL
      • Mutations in TET2, RHOA and DNMT3A
  • Anaplastic large cell lymphoma (ALCL), ALK positive
    • Recurrent chromosomal translocation t(2;5)(p23;q35) involving ALK gene at 2p23 and the nucleophosmin NPM1 gene at 5q35
    • Nodal or extranodal involvement
    • Cytologic spectrum including cases with neoplastic small cells
    • Most have T cell phenotype and the remainder, null phenotype
    • > 90% of the cases shows rearrangement of the T cell receptor chain genes
    • Cells characteristically express ALK in both the nucleus and cytoplasm
    • Recurrent chromosomal translocation t(2;5)(p23;q35) involving ALK gene at 2p23 and the nucleophosmin NPM1 gene at 5q35
    • BCL6, PTPN12, SERPINA1 and CEBPB genes are overexpressed
    • Transcripts related to STAT3 regulators, cytotoxic molecules and T helper 17 cell associated molecules can be highly expressed
  • Anaplastic large cell lymphoma (ALCL), ALK negative
    • No longer a provisional entity in the 2016 WHO classification
    • Often displays a T cell phenotype with loss of several T cell antigens and strong expression of CD30 and cytotoxic molecules
    • Most cases have the T cell receptor chain genes rearranged
    • Constitutive activation of the JAK / STAT pathway through mutations of JAK1 or STAT3 or translocations involving tyrosine kinases other than ALK
    • Rearrangements of DUSP22 at 6p25.3 (33% of cases)
    • Rearrangements of TP63 (about 8%)
    • Expression of 3 genes (TNFRSF8, BATF and TMOD1) allows differentiation of ALK negative ALCL from PTCL, NOS (Blood 2012;120:1274)
  • Breast implant associated anaplastic large cell lymphoma
    • New provisional entity
    • Very rare form of ALCL (ALK negative) seen in female patients with breast implants
    • Usually localized disease that is confined to the serosal cavity and fibrous capsule surrounding the implant
    • Cytology and immunophenotype are similar to ALK negative ALCL
    • T cell receptor chain rearrangement in most cases
    • Recurrent activating JAK1 and STAT3 mutations
    • Typically excellent prognosis with surgery and removal of the implants
Summary of changes in 2016 WHO classification of mature T / NK cell lymphoid neoplasms
Entity Changes
T cell large granular lymphocytic leukemia STAT3 and STAT5B mutations observed in a subset,
the latter of which is less frequent and shows an association
with more clinically aggressive disease
Systemic Epstein-Barr virus+ T cell lymphoma of childhood Name changed from lymphoproliferative disorder to lymphoma
due to its fulminant clinical course and desire to clearly
distinguish it from chronic active Epstein-Barr virus infection
Hydroa vacciniforme-like lymphoproliferative disorder Name changed from lymphoma to lymphoproliferative disorder
due to its relationship with chronic active Epstein-Barr virus infection
and a spectrum in terms of its clinical course
Enteropathy associated T cell lymphoma (EATL) Diagnosis only to be used for cases formerly known as type I
enteropathy associated T cell lymphoma (EATL), typically associated
with celiac disease
Monomorphic epitheliotropic intestinal T cell lymphoma Formerly type II EATL; segregated from type I EATL into a separate
entity with distinct clinicopathologic features and lack of association
with celiac disease
Indolent T cell lymphoproliferative disorder of the GI tract New indolent provisional entity with superficial monoclonal
intestinal T cell infiltrate; some cases show progression
Lymphomatoid papulosis New subtypes described with similar clinical behavior but atypical
histologic / immunophenotypic features
Primary cutaneous gamma delta T cell lymphoma Important to exclude other cutaneous T cell lymphoid lesions that
may also be derived from gamma delta T cells, such as mycosis
fungoides or lymphomatoid papulosis
Primary cutaneous acral CD8+ T cell lymphoma New indolent provisional entity, originally described as originating
in the ear
Primary cutaneous CD4+ small / medium T cell lymphoproliferative disorder No longer to be diagnosed as an overt lymphoma due to limited clinical
risk, localized disease and similarity to clonal drug reactions
Remains a provisional entity
Peripheral T cell lymphoma (PTCL), NOS Subsets based on phenotype and molecular abnormalities being
recognized that may have clinical implications but mostly not routinely
evaluated in practice at this time
Nodal T cell lymphomas with T follicular helper (TFH) phenotype An umbrella category created to highlight the spectrum of nodal
lymphomas with a TFH phenotype, including angioimmunoblastic T cell
lymphoma, follicular T cell lymphoma and other nodal PTCL with a TFH phenotype
Overlapping recurrent molecular / cytogenetic abnormalities
among subtypes, especially in epigenetic modifiers and RHOA
GTPase, that could potentially impact therapy
ALK negative anaplastic large cell lymphoma Now a distinct entity that includes cytogenetic subsets that
appear to have prognostic implications (e.g. 6p25 rearrangements at
IRF4-DUSP22 locus)
Breast implant associated anaplastic large cell lymphoma New provisional entity distinguished from other ALK- ALCL; typically
localized disease associated with excellent outcome

2016 WHO classification of mature T / NK cell neoplasms
  • T cell prolymphocytic leukemia
  • T cell large granular lymphocytic leukemia
  • Chronic lymphoproliferative disorder of NK cells
  • Aggressive NK cell leukemia
  • Systemic Epstein-Barr virus+ T cell lymphoma of childhood*
  • Hydroa vacciniforme-like lymphoproliferative disorder*
  • Adult T cell leukemia / lymphoma
  • Extranodal NK / T cell lymphoma, nasal type
  • Enteropathy associated T cell lymphoma
  • Monomorphic epitheliotropic intestinal T cell lymphoma*
  • Indolent T cell lymphoproliferative disorder of the GI tract*
  • Hepatosplenic T cell lymphoma
  • Subcutaneous panniculitis-like T cell lymphoma
  • Mycosis fungoides
  • Sézary syndrome
  • Primary cutaneous CD30+ T cell lymphoproliferative disorders
    • Lymphomatoid papulosis
    • Primary cutaneous anaplastic large cell lymphoma
  • Primary cutaneous gamma delta cell lymphoma
  • Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T cell lymphoma
  • Primary cutaneous acral CD8+ T cell lymphoma*
  • Primary cutaneous CD4+ small / medium T cell lymphoproliferative disorder*
  • Peripheral T cell lymphoma, NOS
  • Angioimmunoblastic T cell lymphoma
  • Follicular T cell lymphoma*
  • Nodal peripheral T cell lymphoma with T follicular helper phenotype*
  • Anaplastic large cell lymphoma, ALK+
  • Anaplastic large cell lymphoma, ALK-*
  • Breast implant associated anaplastic large cell lymphoma*

    *Asterisks denote current changes relative to the 2008 WHO classification
    Italics denote provisional entities
Entities with name change (previous designations in the 2008 WHO classification are shown in parentheses)
  • Systemic Epstein-Barr virus+ T cell lymphoma in childhood (systemic Epstein-Barr virus+ T cell lymphoproliferative disorder)
  • Hydroa vacciniforme lymphoproliferative disorder (hydroa vacciniforme-like lymphoma)
  • Enteropathy associated T cell lymphoma (enteropathy associated T cell lymphoma, type 1)
  • Monomorphic epitheliotropic intestinal T cell lymphoma (enteropathy associated T cell lymphoma, type 2)
  • Primary cutaneous CD4+ small / medium T cell lymphoproliferative disorder (primary cutaneous CD4+ small / medium T cell lymphoma)
Diagrams / tables

Images hosted on other servers:

Gene mutations in JAK / STAT pathway

Board review style question #1
Which of the following is true about angioimmunoblastic T cell lymphomas (AITL)?

  1. IDH2 R172 mutation is a recurrent genetic alteration seen in a subset of AITL
  2. Phenotypic variants include T cell and null cell types
  3. They are associated with Epstein-Barr virus (EBV) and ALK gene alterations
  4. They represent the extranodal manifestation of peripheral T cell lymphomas characterized by an absence of T follicular helper (TFH) markers
Board review style answer #1
A. IDH2 R172 mutation is a recurrent genetic alteration seen in a subset of AITL

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Reference: WHO classification T/NK cell
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