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

Indications for Testing

Most common presentation for lymphoma is adenopathy with or without fever, night sweats and fatigue

Laboratory Testing

See the Lymphoma Phenotyping Testing algorithm for specific test ordering recommendations
Initial testing involves the following
- CBC with peripheral smear
- Liver chemistries
- Lactate dehydrogenase (LD)
- Serum uric acid, potassium, calcium, phosphorus
- HIV, HTLV1 for at-risk patients
Disease-specific testing
- ATLL – HTLV1 serology
- NK-cell nasal type lymphomas – EBV
Molecular
- T-cell clonality studies to identify TCR rearrangements
- IGH rearrangement by PCR
Cytogenetics/FISH – establish lymphoma subtypes

Histology

Bone marrow biopsy
- Goal – ≥2 cm length
- Classified as involved or not
- Flow cytometry may be helpful in classification
- Some reactive T-cell infiltrates, especially in the skin, may be negative for CD7 in many of the cells
Immunophenotyping to identify the malignancy of 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 co-expression of CD10)
- Markers – kappa, lambda, CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD16, CD19, CD20, CD23, CD25, CD26, CD30, CD45, CD56, CD57, CD103
Immunohistochemistry
- Stains – CD1a, CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD15, CD21, CD23, CD25, CD30, CD34, CD43, CD45RO, CD56, CD57, Ki-67, EBER-EBV, ALK, BF-1, Muc-1, TIA-1, TdT
- Others available – CD20, CD45RA-MT2, CD95, BCL-2, c-Myc
- Mycosis fungoides/Sézary syndrome – skin biopsy (see topic for specific markers)

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 LD (≤1 times normal) – all scored as 0
- Patients placed in 4 risk groups
- Limited usefulness in follicular lymphoma, mantle cell lymphoma, NK-cell lymphoma, nasal-type, hepatosplenic lymphoma and enteropathy-type lymphoma
Other prognostic systems include
- Prognostic index for peripheral T-cell lymphoma not otherwise specified (PTCL/NOS) – uses bone marrow involvement, age, performance status, LD
- Bologna score – uses immunohistochemistry (CD15, EBV, Ki76)
- Korean prognostic NK-cell score – uses B symptoms, LD, stage, regional node involvement
- NK prognostic score – uses stage, performance status, extranodal involvement, nasal type (non vs (+))

Differential Diagnosis

Lymphomas
- B-cell lymphoma
- Hodgkin lymphoma
Reactive lymphocytosis
Sarcoidosis
Other malignancy
- Head and neck cancer
- Metastatic cancer
Infections

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
- ~66,000 NHL diagnosed annually
Age – usually adults (incidence increases with age)
Sex – unequal distribution; based on specific type

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

Precursor T-cell neoplasm
T-cell prolymphocytic leukemia
T-cell large granular lymphocytic leukemia
Chronic lymphoproliferative disorder of NK-cells (provisional entity)
Aggressive NK-cell leukemia
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 lymphoma
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
- Human T-lymphotropic virus type 1 (HTLV1) – ATLL
- EBV – nasal NK-cell lymphomas
Chromosomal rearrangements
- Predominantly on T-cell receptor (TCR) genes
Host susceptibility factors – congenital or acquired
- Gliadin allergy – enteropathy-type T-cell
- Immunosuppression with antigenic stimulation hepatosplenic
- Unspecified

Clinical Presentation of Selected Lymphoma Subtypes (based on WHO classification)

Precursor T-cell neoplasm
- Precursor T-lymphoblastic lymphoma/leukemia
  - Incidence – rare, 2% of NHL
  - Age – median is 20 years
  - Sex – M>F
  - Symptoms – frequent infection, lymphadenopathy, mediastinal masses
  - Prognosis – good
Mature T-cell and NK-cell neoplasms
- T-cell prolymphocytic leukemia
  - Incidence – rare, 2% of mature lymphocytic leukemias
  - Age – median is 65 years
  - Symptoms – lymphadenopathy, hepatosplenomegaly
- 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
- Aggressive NK-cell leukemia
  - Incidence – rare, almost always associated with EBV
  - Age – median is 42 years
  - Sex – M:F, equal
  - Ethnicity – more common in Asians
  - Symptoms – fever, cytopenias
  - Prognosis – poor, aggressive course
- Adult T-cell leukemia/lymphoma (ATLL)
  - Distinct T-cell lymphoma associated with 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
    - ATLL – M>F
    - HAM/TSP – M<F
  - Transmission
    - Parenteral
    - Sexual
  - Classified into 4 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/T-cell lymphoma, nasal type
  - Incidence – rare; associated with EBV
  - Sex – M>F
  - Ethnicity – more common in South America (particularly native American population) and Asia
  - Symptoms – nasal symptoms, palate lesions, skin lesions
  - Prognosis – usually aggressive
- Enteropathy-associated T-cell lymphoma
  - Incidence – rare, associated with celiac disease
  - Symptoms – much like celiac disease
  - Prognosis – poor, recurrence frequent
- 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 NHL
  - 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
- 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
- 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+
- Peripheral T-cell lymphoma, unspecified type
  - Incidence – 30% of peripheral T-cell lymphomas, 5-7% of NHL
  - 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 NHL
  - 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 NHL 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 in 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

Tests generally appear in the order most useful for common clinical situations

Test name: CBC with Platelet Count & Automated Differential

ARUP #: 0040003

Methodology: Automated Cell Count with Flow Cell Differential

Use:

Initial test in evaluation of lymphoma

Test name: Hepatic Function Panel

ARUP #: 0020416

Methodology: Refer to individual components.

Use:

Initial test in evaluation of lymphoma

May provide prognostic information

Test name: Lactate Dehydrogenase, Serum or Plasma

ARUP #: 0020006

Methodology: Quantitative Enzymatic

Use:

Initial test in evaluation of lymphoma

May provide prognostic information

Test name: Uric Acid, Serum or Plasma

ARUP #: 0020026

Methodology: Quantitative Spectrophotometry

Use:

Initial test in evaluation of lymphoma

May provide prognostic information

Test name: Leukemia/Lymphoma Phenotyping (Comprehensive - Whole Blood)

ARUP #: 0096299

Methodology: Flow Cytometry

Use:

Use for whole blood specimens to identify tumor cell populations, aid in selection of appropriate therapy and assessment of clinical behavior and prognosis

T-cell antigens include CD1, CD2, CD3, CD4, CD5, CD7, CD8, TCR alpha-beta, TCR gamma-delta, cytoplasmic CD3, CD26

Other antigens include CD11c, CD16, CD25, CD30, CD34, CD38, CD41, CD42b, CD45, CD56, CD57, CD61, HLA-DR, glycophorin, TdT, bcl-2

Test name: Leukemia/Lymphoma Phenotyping (Comprehensive - Bone Marrow)

ARUP #: 0095244

Methodology: Flow Cytometry

Use:

Use for bone marrow specimens to identify neoplastic populations, aid in selection of appropriate therapy and assessment of clinical behavior and prognosis

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

Other antigens include CD11c, CD16, CD25, CD30, CD34, CD38, CD41, CD42b, CD45, CD56, CD57, CD61, HLA-DR, glycophorin, TdT, bcl-2

Test name: Leukemia/Lymphoma Phenotyping (Comprehensive - Miscellaneous)

ARUP #: 0095243

Methodology: Flow Cytometry

Use:

Use for fluid and tissues to identify tumor cell populations, aid in selection of appropriate therapy and assessment of clinical behavior and prognosis

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

B-cell antigens include CD10, CD19, CD20, CD22, CD23, CD103, kappa, lambda, FMC7, cytoplasmic kappa, cytoplasmic lambda

Myelo/mono antigens include CD11b, CD13, CD14 (Mo2), CD14 (MY4), CD15, CD33, CD64, CD117, myeloperoxidase

Other antigens include CD11c, CD16, CD25, CD30, CD34, CD38, CD41, CD42b, CD45, CD56, CD57, CD61, HLA-DR, glycophorin, TdT, bcl-2

Test name: T-Cell Clonality by Flow Cytometry Analysis of TCR V-Beta

ARUP #: 0093199

Methodology: Flow Cytometry

Use:

Aid in further characterization of phenotypically abnormal T-cell populations identified by flow cytometry and determine whether monoclonality is present based on expression of T-cell antigen receptor beta chain variable regions (TCR V-Beta)

Test name: T-Cell Clonality Screening Assay by PCR, Fluid

ARUP #: 0055567

Methodology: Polymerase Chain Reaction/Fragment Analysis

Use:

Aid in identification and diagnosis of T-cell lymphomas

Limitations:

"Not detected" result does not entirely exclude the presence of a T-cell receptor gamma rearrangement (or monoclonal T-cell population) in the sample

"Not detected" PCR screening result should be terminally analyzed by restriction fragment Southern blot hybridization (RF-SBH) to definitively exclude T-cell monoclonality

Test name: T-Cell Clonality Screening Assay by PCR, Tissue

ARUP #: 0055568

Methodology: Polymerase Chain Reaction/Fragment Analysis

Use:

Aid in identification and diagnosis of T-cell lymphomas

Limitations:

"Not detected" result does not entirely exclude the presence of a T-cell receptor gamma gene rearrangement (or monoclonal T-cell population) in the sample

"Not detected" PCR screening result should be terminally analyzed by RF-SBH to definitively exclude T-cell monoclonality

Test name: T-Cell Clonality Assessment by Restriction Fragment-Southern Blot Hybridization, Tissue

ARUP #: 0055594

Methodology: Restriction Fragment Southern Blot Hybridization

Use:

Aid in identification and diagnosis of T-cell lymphomas

Definitive confirmation of negative PCR T-cell clonality screening test

Fixed tissue sample required

Test name: T-Cell Clonality Assessment by Restriction Fragment-Southern Blot Hybridization, Fluid

ARUP #: 0055596

Methodology: Restriction Fragment Southern Blot Hybridization

Use:

Aid in identification and diagnosis of T-cell lymphomas

Definitely confirms negative PCR T-cell clonality

Limitations:

Negative result does not entirely exclude the presence of a T-cell receptor gene rearrangement (or monoclonal T-cell population) in the sample

Test name: Human T-Lymphotropic Virus Types I/II Antibodies with Reflex to HTLV I/II Confirmation

ARUP #: 0051164

Methodology: Qualitative Enzyme Immunoassay/Qualitative Western Blot

Use:

Aid in diagnosis of adult T-cell leukemia/lymphoma

Test name: Epstein-Barr Virus Antibody to Early D Antigen (EA-D), IgG

ARUP #: 0050225

Methodology: Semi-Quantitative Chemiluminescent Immunoassay

Use:

Aid in diagnosis of NK-cell nasal-type lymphomas

Test name: CD2 by Immunohistochemistry

ARUP #: 2003505