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

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
  • 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 of Selected Lymphoma Subtypes (based on WHO classification and 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