Lymphoma & related disorders
General
WHO 2016 T/NK cell
Editorial Board Member: Elizabeth Courville, M.D.
Deputy Editor-in-Chief: Genevieve M. Crane, M.D., Ph.D.
Last author update: 14 May 2021
Last staff update: 12 April 2024
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PubMed Search: WHO classification T/NK cell
Table of Contents
Definition / general | Highlights of 2016 WHO classification of mature T / NK cell neoplasms | Summary of changes in 2016 WHO classification of mature T / NK cell lymphoid neoplasms | 2016 WHO classification of mature T / NK cell neoplasms | Entities with name change (previous designations in the 2008 WHO classification are shown in parentheses) | Diagrams / tables | Additional references | Board review style question #1 | Board review style answer #1Cite this page: Absar SF, Tsang P. WHO 2016 T/NK cell. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomanonBwhotcell.html. Accessed April 16th, 2024.
Definition / general
- Note: this classification was replaced in 2022 and this topic will eventually be deleted
- 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
- Whole exome and targeted sequencing have demonstrated recurrent mutations in genes of the JAK / STAT signaling pathway, including:
- T cell large granular lymphocytic (T-LGL) leukemia and chronic lymphoproliferative disorder of natural killer (NK) cells
- Heterozygous activating mutations in
- STAT3 (33% of cases)
- STAT5B (< 5% of cases), associated with clinically aggressive disease
- WHO 2008 criteria for T-LGL leukemia required at least 2 × 109/L or greater numbers of circulating blood LGLs
- Revised version allows lower numbers of LGLs in the blood if other criteria for the disease, such as cytopenias, are met
- Heterozygous activating mutations in
- Epstein Barr virus (EBV)+ T cell and NK cell lymphomas include:
- Aggressive NK cell leukemia
- Very aggressive disease derived from activated NK cells and strongly associated with Epstein-Barr virus
- Characterized by 7p and 17p losses and 1q gains
- Systemic EBV+ T cell lymphoma of childhood
- Previously called systemic EBV+ lymphoproliferative disorder
- Very aggressive, life threatening clinical course usually associated with hemophagocytic
- Chronic active Epstein-Barr virus infection of T and NK cells, includes:
- Hydroa vacciniforme-like lymphoproliferative disorder (indolent cutaneous form)
- Severe mosquito allergy
- Chronic active Epstein-Barr virus infection of T and NK cell type, systemic form (less frequent; characterized by fever, hepatosplenomegaly and lymphadenopathy with or without cutaneous manifestations)
- Extranodal NK / T cell lymphoma, nasal type
- 6q deletions are common
- Recurrent mutations are found in genes of the JAK / STAT pathway (STAT3, STAT5B), tumor suppressors (TP53), oncogenes (RAS), epigenetic modifiers (MLL2, ARIDIA), cell cycle regulators and apoptosis
- Aggressive NK cell leukemia
- 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
- EATL: previously named enteropathy associated T cell lymphoma (EATL) type I (linked to celiac disease)
- 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)
- Mycosis fungoides and Sézary syndrome
- 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)
- Lymphomatoid papulosis (LyP)
- 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
- References: Int J Lab Hematol 2018;40:97, Blood 2016;127:2375
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 |
- Reference: Blood 2016;127:2375
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
Additional references
Board review style question #1
Which of the following is true about angioimmunoblastic T cell lymphomas (AITL)?
- IDH2 R172 mutation is a recurrent genetic alteration seen in a subset of AITL
- Phenotypic variants include T cell and null cell types
- They are associated with Epstein-Barr virus (EBV) and ALK gene alterations
- 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 2016 T/NK cell
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Reference: WHO 2016 T/NK cell
