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.

Diagnosis

Indications for Testing

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

Laboratory Testing

  • Phenotyping by flow cytometry
  • 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

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
  • 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
        • 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
        • 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

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: CD1a, CD2, CD3, CD4, CD5, CD7, CD8, TCR γ-δ, cytoplasmic CD3

B cell: CD10, CD19, CD20, CD22, CD23, CD103, CD200, kappa, lambda, cytoplasmic kappa, cytoplasmic lambda

Myeloid/monocyte: CD11b, CD13, CD14 (Mo2), CD14 (MY4), CD15, CD33, CD64, CD117, myeloperoxidase

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

Aid in the diagnosis of T-cell lymphoproliferative disorders

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

Stained and returned to client pathologist for interpretation; consultation available if needed

Detect IRF4/DUSP22 rearrangements which can contribute to diagnosis and prognosis in B-cell and T-cell lymphomas

Aid in differentiating T-cell leukemias and lymphomas from B-cell leukemias and lymphomas

Stained and returned to client pathologist for interpretation; consultation available if needed

Aid in differentiating T-cell leukemias and lymphomas from B-cell leukemias and lymphomas

Stained and returned to client pathologist for interpretation; consultation available if needed

Detect ALK fusion proteins (IHC) and ALK gene rearrangements (FISH) in solid tumors

Detect IDH1 and IDH2 mutations in whole blood or bone marrow

May have prognostic significance in patients with hematologic malignancies, depending on the clinical and genetic context

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

Do not use for diagnosis of infectious mononucleosis

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

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

Stained and returned to client pathologist for interpretation; consultation available if needed

Aid in identifying some T-cell lymphoblastic lymphomas and leukemias

Stained and returned to client pathologist for interpretation; consultation available if needed

Aid in identifying lymphoblastic lymphoma, Burkitt lymphoma, follicular lymphoma, and CML; aid in differential diagnosis of small B-cell lymphomas and subtyping of lymphoblastic leukemias; helpful in angioimmunoblastic T-cell lymphomas

Stained and returned to client pathologist for interpretation; consultation available if needed

Aid in histologic differential diagnosis of T-cell/NK-cell leukemia/lymphoma

Stained and returned to client pathologist for interpretation; consultation available if needed

Related Tests

Identify hepatic dysfunction

May provide prognostic information

Panel includes albumin; alkaline phosphatase; aspartate aminotransferase; alanine aminotransferase; bilirubin, direct; protein; bilirubin, total

Rule out infectious process; identify lymphocytosis

May provide prognostic information

May provide prognostic information

Assay interference (negative) may be observed when high concentrations of N-acetylcysteine (NAC) are present

Negative interference has also been reported with NAPQI (an acetaminophen metabolite) but only when concentrations are at or above those expected during acetaminophen overdose

 

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References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®