T-Cell/NK-Cell Lymphomas

Diagnosis

Indications for Testing

• Adenopathy
• Fevers/night sweats
• Recurrent infections
• Unexplained lymphocytosis or abnormal manual differential

Laboratory Testing

• Phenotyping by flow cytometry
  • Aberrant T-cell or NK-cell phenotype
    • At least one of the following positive: CD56, CD57, CD16 – large granular lymphocytic leukemia (LGLL)
      • CD3+ – T-cell LGLL
        • Follow up with T-cell clonality testing
      • CD3- – NK-cell LGLL
    • Negative CD57, CD56, and CD16
      • CD10+, CD4+ – angioimmunoblastic T-cell lymphoma
      • CD4+/-, CD8+/- – consider peripheral T-cell lymphoma, not otherwise specified (NOS)
      • CD30+ – consider anaplastic large-cell lymphoma
      • CD4+, CD7, CD26 – consider Sézary syndrome
  • Nonrevealing phenotyping
    • Consider reactive lymphocytosis – most often due to infections
    • Viral – Epstein Barr virus, cytomegalovirus, human immunodeficiency virus,  human T-lymphotrophic virus type 1, hepatitis viruses, human herpesvirus 8
    • Other – M. tuberculosis, Rickettsia spp, brucella spp, Toxoplasma gondii, T. pallidum, Babesia microti
  • T-cell clonality testing may be necessary to distinguish between benign and reactive T-cell populations
    • Can detect previously identified clonal populations at very low levels – beneficial for MRD monitoring
• Genetic testing
  • Genetic variants associated with T-cell lymphomas include TCR, ALK, TP63, and IRF4/DUSP22 rearrangements; TCL1 and TRA translocations; and TET2/IDH1/IDH2/RHOA/DNMT3A and STAT3/STAT5B variants (NCCN, 2019)

Histology

• Bone marrow biopsy
  • Goal of ≥2 cm length
  • Classified as “bone marrow involvement” or “no bone marrow involvement”
• Immunophenotyping to identify lymphoid proliferation and to categorize the lymphoma
  • Flow cytometry testing by identification of aberrant antigen expression patterns (ie, loss of one or more pan-T-cell antigens or coexpression of CD10)
  • T-cell markers – kappa, lambda, CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD16, CD19, CD20, CD23, CD25, CD26, CD30, CD45, CD56, CD57, CD103
• Immunohistochemistry
  • T-cell stains – CD1a, CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD15, CD20, CD21, CD23, CD25, CD30, CD34, CD43, CD45RO, CD56, CD57, CXCL13, Ki-67, EBER-EBV, ALK, BF-1, Muc-1, TIA-1, granzyme B, TdT, TCR δ
  • Others available – CD20, CD45RA-MT2, CD95, BCL-2, c-Myc
• Skin biopsy – for mycosis fungoides/Sézary syndrome
  • Immunohistochemistry
  • T-cell receptor gene rearrangements
  • Flow cytometry for Sézary syndrome

Imaging Studies

CT/MRI – most useful in assessing where disease is present after diagnosis

Prognosis

• International Prognostic Index scoring system
  • Based on pretreatment clinical factors of age (≤60 years); tumor stage (I or II); number of extranodal sites (≤1); ECOG performance status (0 or 1); and serum lactate dehydrogenase (LD) (≤1 times normal) – all scored as 0
  • Patients placed in one of four risk groups
  • Limited usefulness in follicular lymphoma, mantle cell lymphoma, NK-cell lymphoma, nasal-type lymphoma, hepatosplenic lymphoma, and enteropathy-type lymphoma
• Other prognostic systems include
  • Prognostic index for peripheral T-cell lymphoma not otherwise specified – uses bone marrow involvement, age, performance status, LD
  • Bologna score – uses immunohistochemistry (CD15, EBV, Ki76)
  • Korean prognostic NK-cell score – uses β symptoms, LD, lymphoma stage, regional node involvement
  • NK prognostic score – uses stage, performance status, extranodal involvement, nasal type (non vs (+))

Differential Diagnosis

• Infections
  • Babesia microti
  • Bartonella spp
  • Cytomegalovirus
  • Epstein-Barr virus
  • Fungal disease
  • HIV
  • Human herpesvirus 8
  • Human T-lymphotropic virus type 1
  • M. tuberculosis
  • Toxoplasma gondii
  • Treponema pallidum
• Reactive lymphocytosis
• Malignancy
  • Head and neck cancer
  • Lymphomas – B-cell, Hodgkin
  • Metastatic cancer
• Sarcoidosis

Background

Epidemiology

• Incidence – 15-20% of all NHL lymphomas
  • >70,000 NHL diagnosed (NCCN, 2014)
• Age – usually adults (incidence increases with age)
• Sex – unequal distribution; based on specific type

Classification

• Classification of Mature T and NK Neoplasms (World Health Organization [WHO], 2016)
  • T-cell prolymphocytic leukemia
  • T-cell large granular lymphocytic leukemia
  • Chronic lymphoproliferative disorder of NK cells (provisional entity)
  • Aggressive NK-cell leukemia
  • Systemic Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disorder
  • Hydroa vacciniformelike lymphoproliferative disorder
  • Adult T-cell leukemia/lymphoma (ATLL)
  • 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 gastrointestinal (GI) tract (provisional entity)
  • Hepatosplenic T-cell lymphoma
  • Subcutaneous panniculitislike T-cell lymphoma
  • Mycosis fungoides
  • Sézary syndrome
  • Primary cutaneous CD30-positive T-cell lymphoproliferative disorders
    • Lymphomatoid papulosis
    • Primary cutaneous anaplastic large cell lymphoma
  • Primary cutaneous gamma-delta T-cell lymphomas
  • Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma (provisional entity)
  • Primary cutaneous acral CD8-positive T-cell lymphoma (provisional entity)
  • Primary cutaneous CD4-positive small/medium T-cell lymphoproliferative disorder (provisional entity)
  • Peripheral T-cell lymphoma, not otherwise specified (NOS)
  • Angioimmunoblastic T-cell lymphoma
  • Follicular T-cell lymphoma (provisional entity)
  • Nodal peripheral T-cell lymphoma with TFH phenotype (provisional entity)
  • Anaplastic large cell lymphoma (ALCL), ALK positive
  • ALCL, ALK negative
  • Breast implant-associated anaplastic large cell lymphoma (provisional entity)

Risk Factors

• Viral infection
  • Human T-lymphotropic virus type 1 (HTLV1) – ATLL
  • EBV – nasal NK-cell lymphomas
• Chromosomal rearrangements
  • Predominantly on T-cell receptor (TCRG) genes
• Host susceptibility factors – congenital or acquired
  • Gliadin allergy – enteropathy-type T-cell
  • Immunosuppression

Clinical Presentation

• Clinical presentation of selected lymphoma subtypes (WHO classification, 2016; Gru, 2015)
  • Precursor T-cell neoplasm
    • Precursor T-lymphoblastic lymphoma/leukemia
      • Incidence – rare, 2% of non-Hodgkin lymphomas
      • Age – median is 20 yrs
      • Sex – M>F
      • Symptoms – frequent infection, lymphadenopathy, mediastinal masses
      • Prognosis – good 
  • Mature T-cell and NK-cell neoplasms
    • Peripheral T-cell lymphoma, unspecified type
      • Incidence – 30% of peripheral T-cell lymphomas, 5-7% of non-Hodgkin lymphomas
      • Age – median is 60 yrs
      • Sex – M>F, 2:1
      • Genetics – TCR clonality is rarely positive
      • Symptoms – fever, nodal enlargement, extranodal involvement
      • Prognosis – aggressive course with liver and spleen involvement in >50% of cases
    • Angioimmunoblastic T-cell lymphoma
      • Incidence – 15-20% of T-cell lymphomas, 4-6% of non-Hodgkin lymphomas
      • Age – peak is 70 yrs
      • Sex – M:F, equal
      • Genetics – TCR clonality positive
      • Symptoms – fever, skin rash, arthritis, autoimmune hemolytic anemia (Coombs positive), eosinophilia, extranodal site involvement (eg, bone marrow, lung)
      • Prognosis – aggressive tumor with poor prognosis
    • Anaplastic large-cell lymphoma (ALCL), ALK-positive
      • Incidence – 2-3% of non-Hodgkin lymphomas in adults, 10-30% of childhood lymphomas
      • Age – mean is 35 yrs; includes nearly all pediatric cases
      • Sex – M>F, 3:1
      • Genetics – over-expression of ALK due to specific translocations, most common is t(2;5) or NPM-ALK translocation (40-60% of patients)
      • Symptoms – lymphadenopathy, often presents with extranodal disease (skin site is common)
      • Prognosis – overall 5-yr survival rate ~70% for ALK-positive (49% for ALK-negative)
        • Tendency to late relapses – relapses often respond to additional therapy
    • ALCL, ALK negative
      • Incidence – 1-2% of non-Hodgkin lymphoma in adults
      • Similar morphology and immunophenotype as ALK-positive ALCL without ALK over-expression
      • Age – 40-65 yrs
      • Sex – M>F, 1.5:1
      • Genetics
        • Majority of cases show clonal rearrangement of TCR
        • 6p25.3 locus rearrangements (IRF4/DUSP22) provide prognostic information in ALK-negative anaplastic large-cell lymphomas
      • Symptoms
        • Advanced stage III-IV disease common
        • Peripheral and/or abdominal lymphadenopathy
        • B symptoms – fever, weight loss
      • Prognosis – poor response to therapy
        • Favorable (90%) survival rate for primary cutaneous ALCL despite being negative for ALK1 protein
    • T-cell prolymphocytic leukemia
      • Incidence – rare, 2% of mature lymphoid leukemias
      • Age – median is 65 yrs
      • Symptoms – lymphadenopathy, hepatosplenomegaly, striking lymphocytosis
        • Cutaneous dissemination is common; skin lesions in ~30%
      • Prognosis – poor for most cases
    • Aggressive NK-cell leukemia
      • Almost always associated with Epstein-Barr virus
      • Incidence – rare
      • Age – median is 42 yrs
      • Sex – M:F, equal
      • Ethnicity – more common in Asians
      • Symptoms – fever, cytopenias
      • Prognosis – poor, aggressive course
    • T-cell large granular lymphocytic leukemia
      • Incidence – rare, 2-3% of mature lymphocytic leukemias
      • Age – mean 50-60 yrs, rare <25 yrs
      • Sex – M:F, equal
      • Ethnicity – more common in Asians
      • Symptoms – lymphadenopathy rare; symptoms related to bone marrow involvement (ie, neutropenia, anemia)
      • Prognosis – indolent course
    • Chronic lymphoproliferative disorder of NK cells
      • Incidence – rare
      • Age – median is 60 yrs
      • Sex – M:F, equal
      • Symptoms – persistent increase in blood NK cells (over period >6 months); may be asymptomatic or have cytopenias or systemic symptoms
        • Must exclude reactive causes
      • Prognosis – usually indolent but may have progressive cytopenias, immune dysfunction
    • Hepatosplenic T-cell lymphoma
      • Incidence – rare, 20% occur in setting of chronic immunosuppression (particularly in Crohn disease)
      • Age – 20s
      • Sex – M>F
      • Symptoms – hepatomegaly with bone marrow involvement (often manifested as thrombocytopenia)
    • Subcutaneous panniculitis-like T-cell lymphoma
      • Incidence – rare, <1% of non-Hodgkin lymphomas
      • Age – median is 35 yrs
      • Sex – M<F
      • Symptoms – nodular lesions below area of arms, legs and/or trunk; up to 20% have associated autoimmune disease
      • Prognosis – moderately good
    • Primary cutaneous CD30-positive T-cell lymphoproliferative disorders
      • Incidence – rare
      • Age – median is 60 yrs, majority >30 yrs
      • Sex – M>F, 2-3:1
      • Symptoms – nodules; plaques with necrosis and ulceration most commonly on face, trunk, and extremities
      • Prognosis – aggressive with poor prognosis if CD8+ or alpha-beta+
    • Enteropathy-associated T-cell lymphoma (EATL)
      • Incidence – rare (<5%)
      • Age – mean 57 yrs
      • Symptoms – abdominal pain, weight loss, fever
        • Associated with celiac disease (CD) (EATL1) or not associated with CD (EATL2)
        • Symptomatology matches celiac disease in EATL1
      • Prognosis – poor, recurrence frequent
    • Mycosis fungoides/Sézary syndrome
      • Incidence – 1/100,000
        • ~70% of cutaneous lymphomas
      • Age – mean is 60 yrs
      • Sex – M>F, 2:1
      • Classification – most common is mycosis fungoids; next most common is primary cutaneous lymphoproliferative disorders
      • Symptoms – usually manifest with history of persistent skin disease preceding diagnosis
      • Prognosis – variable, usually indolent until tumoral stage or systemic disease develops
        • Sézary syndrome is an aggressive leukemic form of mycosis fungoides with a poor prognosis
    • Adult T-cell leukemia/lymphoma (ATLL)
      • Prevalence – 15-20 million globally infected with HTLV1
        • Endemic in Japan, Caribbean and South American countries, and sub-Saharan Africa
        • Incidence – <2% of non-Hodgkin lymphoma in the U.S./Europe
      • Age – median is 58 yrs
        • HTLV1-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) – 30s-40s
      • Sex
        • Adult T-cell leukemia/lymphoma – M>F
        • HAM/TSP – M<F
      • Transmission
        • Associated with human T-lymphotropic virus type 1 (HTLV1)
        • Parenteral
        • Sexual
      • Classified into four subcategories – smoldering, chronic, lymphoma, acute
        • Smoldering and chronic – considered indolent
        • Lymphoma – ≤1% abnormal T-lymphocytes, histologically proven lymphadenopathy, no lymphocytosis
        • Acute – leukemic manifestation and tumor lesions; rapidly progressive course
    • Extranodal NK-cell/T-cell lymphoma, nasal type"]
      • Incidence – rare
      • Sex – M>F
      • Ethnicity – more common in South America (particularly native American population) and Asia
      • Symptoms – nasal symptoms (obstruction or bleeding), palate lesions, skin lesions
        • Associated with Epstein-Barr virus
      • Prognosis – usually aggressive
    • Peripheral T-cell lymphoma, not otherwise specified
      • Group of lymphomas that do not meet criteria for any other subtypes of mature lymphomas
        • Diagnosis of exclusion
      • Incidence – common subtype for peripheral T-cell lymphoma
      • Age – mean 60 yrs
      • Sex – M>F (2:1)
      • Symptoms – lymphadenopathy with or without extranodal extension
        • High percentage presents with stage 4 disease
      • Prognosis – poor