T-Cell/NK-Cell Lymphomas

T-cell and NK-cell non-Hodgkin lymphomas (NHL) represent a small portion of the lymphomas diagnosed in the U.S. Laboratory testing methods include flow cytometry and PCR.

Tabs Content

Clinical Overview

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

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, Ki-67, EBER-EBV, ALK, BF-1, Muc-1, TIA-1, granzyme B, TdT
- 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
    
    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

ARUP Lab Tests

Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Leukemia/Lymphoma Phenotyping by Flow Cytometry 2008003
Method: Flow Cytometry

Recommended Use

Aid in evaluation of hematopoietic neoplasms (ie, leukemia, lymphoma)

Specimens include bone marrow, whole blood, tissue, or fluid

Monitor therapy in patients with established diagnosis of hematopoietic neoplasms

Markers selected based on provided clinical history and/or previous test results

Antigens included

T cell: CD1, CD2, CD3, CD4, CD5, CD7, CD8, TCR α-β, TCR γ-δ,, cytoplasmic CD3

B cell: CD10, CD19, CD20, CD22, CD23, CD103, kappa, lambda, FMC7, cytoplasmic kappa, cytoplasmic lambda

Myelo/Mono: CD11b, CD13, CD14 (Mo2), CD14 (MY4), CD15, CD33, CD64, CD117, myeloperoxidase

Misc: CD11c, CD16, CD25, CD30, CD34, CD38, CD41, CD42b, CD45, CD56, CD57, CD61, HLA-DR, glycophorin, TdT, bcl-2, ALK-1, CD123, CD138, CD200, CD26, CD45

T-Cell Clonality Screening by PCR 0055567
Method: Polymerase Chain Reaction/Capillary Electrophoresis

Recommended Use

Aid in the diagnosis of T-cell lymphoproliferative disorders

T-Cell Clonality by Flow Cytometry Analysis of TCR V-Beta 0093199
Method: Flow Cytometry

Recommended Use

Diagnosis of T-cell lymphoproliferative disorders

Limitations

Lacks sensitivity of NGS

Human T-Lymphotropic Virus (HTLV) Types I/II Antibodies by ELISA with Reflex to HTLV-I/II Confirmation by Western Blot 0051164
Method: Qualitative Enzyme-Linked Immunosorbent Assay/Qualitative Western Blot

Recommended Use

Aid in diagnosis of adult T-cell leukemia/lymphoma

Reflex pattern – if HTLV I/II screen is repeatedly reactive, HTLV I/II confirmation by Western blot will be added

Epstein-Barr Virus by PCR 0050246
Method: Qualitative Polymerase Chain Reaction

Recommended Use

Do not use for diagnosis of infectious mononucleosis

Order to detect Epstein-Barr virus (EBV) in individuals suspected of having EBV-related disease

CD2 by Immunohistochemistry 2003505
Method: Immunohistochemistry

Recommended Use

Aid in histologic diagnosis of T-cell/NK-cell lymphomas