Lymphoproliferative Disorders

Basics

Description

  • Lymphoproliferative disorders are a class of nonmalignant diseases characterized by uncontrolled growth of lymphoid tissues (spleen, bone marrow, liver, lymph nodes).
  • Can be congenital or acquired
  • Based on recent advances in next generation sequencing technology, new disorders are defined constantly.
  • Most common in children include
    • Autoimmune lymphoproliferative syndrome (ALPS)
    • Castleman disease (CD)
    • Rosai–Dorfman disease (RDD)
    • EBV-associated lymphoproliferative disorder (ELD)
    • X-linked lymphoproliferative syndrome (XLP)
  • Rarer disorders (not discussed in detail)
    • Angioimmunoblastic lymphadenopathy
    • Caspase-8 deficiency syndrome (CEDS)
    • Dianzani autoimmune lymphoproliferative disease
    • Kikuchi-Fujimoto syndrome
    • Lymphomatoid granulomatosis
    • Lymphomatoid papulosis
    • Ocular adnexal lymphoid proliferation
    • RAS-associated leukoproliferative disorder (RALD)
    • p110δ activating mutation causing senescent T cells lymphadenopathy and immunodeficiency (PASLI)
    • CTLA-4 haploinsufficiency with autoimmune infiltration (CHAI)
    • LRBA deficiency with autoantibodies, regulatory T-cell defects, autoimmune infiltration and enteropathy (LATAIE)
    • X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (X-MEN)
    • Interleukin-2-inducible T-cell kinase (ITK) deficiency

Epidemiology

All uncommon

Risk Factors

Often multifactorial with inherited genetic defect and acquired infection

Genetics

  • ALPS (80% of patients have identifiable mutation)
    • 60–70% germline mutation in FAS (TNFRSF6)
    • 10% somatic mutation in FAS
    • 2% germline mutation in CASP10
    • <1% germline mutation in FASL
  • XLP
    • Majority of cases mutation in SH2DIA
    • XLP-like syndrome caused by X-linked inhibitor of apoptosis protein (XIAP) mutations

Pathophysiology

  • ALPS
    • Defective FAS-mediated apoptosis leads to abnormal lymphocyte survival with subsequent lymphoproliferation, autoimmunity, and cancer.
  • CD
    • Largely unknown but can be triggered by HHV-8 infection, especially in immunocompromised patients
  • ELD
    • EBV triggered lymphoproliferative disorder found in patients on chronic immune suppression typically after organ or bone marrow transplant (post-transplant lymphoproliferative disorder [PTLD]) or with inherited immune deficiency
  • XLP
    • Mutation in SH2D1A leads to abnormal production of SAP protein in NK and T cells, leading to defective SAP-SLAM signaling and inability to appropriately respond to EBV infection.

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