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

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
        • 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
        • 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