Lymphomas, T-Cell/NK-Cell - T-Cell/NK-Cell Lymphomas

Diagnosis

Indications for Testing

  • Elevated white blood cell count and lymphocytes (absolute lymphocytosis >4,000/μL or abnormal morphology)
  • 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
    • T-cell clonality testing may be necessary to distinguish between benign and reactive T-cell populations
      • Next generation sequencing – more sensitive than other methods used for T-cell clonality determination
      • 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

Clinical Background

T-cell and NK-cell non-Hodgkin lymphomas (NHL) represent a small portion of the lymphomas diagnosed in the U.S.

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

WHO Classification of Mature T- and NK-cell Neoplasms (2008)

  • 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 of childhood
  • Adult T-cell leukemia/lymphoma (ATLL)
  • Extranodal NK-/T-cell lymphoma, nasal type
  • Enteropathy-associated T-cell lymphoma
  • Hepatosplenic T-cell lymphoma
  • Subcutaneous panniculitis-like T-cell lymphoma
  • Mycosis fungoides
  • Sézary syndrome
  • Primary cutaneous CD30-positive T-cell lymphoproliferative disorders
  • Primary cutaneous gamma-delta T-cell lymphomas
  • Peripheral T-cell lymphoma, NOS (not otherwise specified)
  • Angioimmunoblastic T-cell lymphoma
  • Anaplastic large-cell lymphoma (ALCL), ALK-positive
  • ALCL, ALK-negative (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 of Selected Lymphoma Subtypes (based on WHO classification)

  • Precursor T-cell neoplasm
    • Precursor T-lymphoblastic lymphoma/leukemia
      • Incidence – rare, 2% of non-Hodgkin lymphomas
      • Age – median is 20 years
      • 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 years
      • 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 years
      • Sex – M:F, equal
      • Genetics – TCR clonality positive
      • Symptoms – fever, skin rash, arthritis, autoimmune hemolytic anemia, eosinophilia, extranodal site involvement
      • Prognosis – aggressive tumor with poor prognosis
      Anaplastic large-cell lymphoma (ALCL), ALK-positive
      • Incidence – 2-3% of non-Hodgkin lymphomas in adults, 10-20% of childhood lymphomas
      • Age – mean is 35 years; 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 – often presents with extranodal disease
      • Prognosis – overall 5-year survival rate ~70% for ALK-positive (49% for ALK-negative)
      • Tendency to late relapses – relapses often respond to additional therapy
      ALCL, ALK negative
      • Similar morphology and immunophenotype as ALK-positive ALCL without ALK over-expression
      • Age – 40-65 years
      • Sex – M>F, 1.5:1
      • Genetics – majority of cases show clonal rearrangement of TCR
      • Symptoms
        • Advanced stage III-IV disease
        • 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 lymphocytic leukemias
      • Age – median is 65 years
      • Symptoms – lymphadenopathy, hepatosplenomegaly
      Aggressive NK-cell leukemia
      • Almost always associated with Epstein-Barr virus
      • Incidence – rare
      • Age – median is 42 years
      • Sex – M:F, equal
      • Ethnicity – more common in Asians
      • Symptoms – fever, cytopenias
      • Prognosis – poor, aggressive course
      T-cell large granular lymphocyte leukemia
      • Incidence – rare, 2-3% of mature lymphocytic leukemias
      • Age – majority 45-75 years, rare <25 years
      • Sex – M:F, equal
      • Symptoms – lymphadenopathy rare; symptoms related to bone marrow involvement
      • Prognosis – indolent course
      Chronic lymphoproliferative disorder of NK cells
      • Incidence – rare
      • Age – median is 60 years
      • 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 years
      • 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 years, majority >30 years
      • 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
      • Associated with celiac disease
      • Incidence – rare
      • Symptoms – much like celiac disease
      • Prognosis – poor, recurrence frequent
      Mycosis fungoides/Sézary syndrome
      • Incidence – 1/100,000
      • Age – mean is 60 years
      • 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)
      • Associated with human T-lymphotropic virus type 1 (HTLV1)
      • Prevalence – 15-20 million globally infected with HTLV1
        • Endemic in Japan, Caribbean and South American countries, and sub-Saharan Africa
      • Age – median is 58 years
        • HTLV1-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) – 30s-40s
      • Sex
        • Adult T-cell leukemia/lymphoma – M>F
        • HAM/TSP – M<F
      • Transmission
        • 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
      • Associated with Epstein-Barr virus
      • 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

Indications for Laboratory Testing

  • 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
Test Name and Number Recommended Use Limitations Follow Up
Leukemia/Lymphoma Phenotyping by Flow Cytometry 2008003
Method: Flow Cytometry

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

Monitor therapy in patients with established diagnosis of hematopoietic neoplasms

Specimens include peripheral blood, bone marrow, CSF, fluids, and tissues

Markers selected based on clinical history, previous flow studies, and pathologist interpretation

Available markers

T cell: CD1, CD2, CD3, CD4, CD5, CD7, CD8, TCR alpha-beta, TCR gamma-delta, cytoplasmic CD3

B cell: CD10, CD19, CD20, CD22, CD23, CD103, kappa, lambda, CD200, 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 by Next Generation Sequencing 2008409
Method: Massive Parallel Sequencing

Diagnosis/monitoring of T-cell lymphoproliferative disorders

Monitor minimal residual disease (MRD) in T-cell lymphoproliferative disorders (can detect previously identified clonal populations at very low levels)

Analytical sensitivity – 10% tumor cells for initial diagnosis; 0.1% tumor cells in follow-up specimen when monitoring for MRD

Clonal TCRG gene rearrangements below the limit of detection will not be reported

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

Diagnosis of T-cell lymphoproliferative disorders

   
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

Aid in diagnosis of adult T-cell leukemia/lymphoma

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
Aid in diagnosis and possibly in monitoring of NK-cell nasal-type lymphomas    
CD2 by Immunohistochemistry 2003505
Method: Immunohistochemistry

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

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

   
CD1a by Immunohistochemistry 2003502
Method: Immunohistochemistry

Aid in identifying some T-cell lymphoblastic lymphomas and leukemias

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

   
CD3 by Immunohistochemistry 2003508
Method: Immunohistochemistry

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

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

   
CD4 by Immunohistochemistry 2003511
Method: Immunohistochemistry

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

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

   
CD5 by Immunohistochemistry 2003514
Method: Immunohistochemistry

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

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

   
CD7 by Immunohistochemistry 2003517
Method: Immunohistochemistry

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

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

   
CD8 by Immunohistochemistry 2003520
Method: Immunohistochemistry

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

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

   
CD10 (CALLA) by Immunohistochemistry 2003523
Method: Immunohistochemistry

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

   
CD15, Leu M1 by Immunohistochemistry 2003529
Method: Immunohistochemistry

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

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

   
CD19 by Immunohistochemistry 2005114
Method: Immunohistochemistry

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

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

   
CD21 (Dendritic Cell) by Immunohistochemistry 2003535
Method: Immunohistochemistry

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

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

   
CD23 by Immunohistochemistry 2003541
Method: Immunohistochemistry

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

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

   
CD25 by Immunohistochemistry 2003544
Method: Immunohistochemistry

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

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

   
CD30 (Ki-1) by Immunohistochemistry 2003547
Method: Immunohistochemistry

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

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

   
CD34, QBEnd/10 by Immunohistochemistry 2003556
Method: Immunohistochemistry

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

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

   
CD43, L60 (Leu 22) by Immunohistochemistry 2003568
Method: Immunohistochemistry

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

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

   
CD56 (NCAM) by Immunohistochemistry 2003589
Method: Immunohistochemistry

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

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

   
CD57 by Immunohistochemistry 2003592
Method: Immunohistochemistry

Aid in identifying NK lymphocyte-mediated cytotoxicity, NK-cell and T-cell subset tumors, and neural tissue neoplasms

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

   
Ki-67, MIB-1, by Immunohistochemistry 2004519
Method: Immunohistochemistry

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

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

   
Anaplastic Lymphoma Kinase 1 (ALK-1) by Immunohistochemistry 2003439
Method: Immunohistochemistry

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

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

   
BF-1 by Immunohistochemistry 2003466
Method: Immunohistochemistry

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

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

   
Muc-1 by Immunohistochemistry 2004002
Method: Immunohistochemistry

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

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

   
T-cell Intracytoplasmic Antigen (TIA-1) by Immunohistochemistry 2004148
Method: Immunohistochemistry

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

   
Granzyme B by Immunohistochemistry 2007173
Method: Immunohistochemistry

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

   
TdT by Immunohistochemistry 2004142
Method: Immunohistochemistry

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

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

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Hepatic Function Panel 0020416
Method: Quantitative Enzymatic/Quantitative Spectrophotometry

Identify hepatic dysfunction

May provide prognostic information

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

CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Rule out infectious process; identify lymphocytosis

Lactate Dehydrogenase, Serum or Plasma 0020006
Method: Quantitative Enzymatic

May provide prognostic information

Uric Acid, Serum or Plasma 0020026
Method: Quantitative Spectrophotometry

May provide prognostic information

CD20, L26 by Immunohistochemistry 2003532
Method: Immunohistochemistry
BCL-2 by Immunohistochemistry 2004513
Method: Immunohistochemistry
Potassium, Plasma or Serum 0020002
Method: Quantitative Ion-Selective Electrode
Calcium, Ionized, Serum 0020135
Method: Ion-Selective Electrode/pH Electrode
Phosphorus, Inorganic, Plasma or Serum 0020028
Method: Quantitative Spectrophotometry