Autoimmune Lymphoproliferative Syndrome

Autoimmune Lymphoproliferative Syndrome

Sa A. Wang, MD

Autoimmune lymphoproliferative syndrome (ALPS) involving lymph node. The paracortex of the lymph node is markedly expanded. Small lymphoid follicles are also present.

ALPS involving lymph node. The paracortex is populated by small lymphocytes and many large immunoblasts with prominent nucleoli.



  • Autoimmune lymphoproliferative syndrome (ALPS)


  • Disease of disrupted lymphocyte homeostasis as result of defective Fas-mediated apoptosis


Genetic Mutations in FAS Pathway

  • FAS pathway mutations cause ALPS

  • FAS mutations are usually heterozygous

  • Multiple types have been described

  • Type I: Accounts for approximately 65% of all ALPS cases

    • 3 type I subtypes

      • Ia: Germline mutations in FAS (TNFRSF6, CD95, APO1) gene

      • Ib: Germline mutations in FAS ligand gene

      • Is: Somatic mutations in FAS gene

  • Type II: Germline mutations in gene encoding caspase 10

  • Type III: No identifiable genetic mutations in FAS pathway

    • Accounts for approximately 20-30% of all ALPS cases

  • Type IV: Very rare

    • Gain-of-function mutation in NRAS

    • Patients have ALPS phenotype but normal Fas-mediated apoptosis

  • ALPS is multistep process requiring more than a single genetic hit for clinical expression

  • In most cases, mutations are inherited in autosomal dominant fashion

    • Therefore, penetrance is 100% at cellular level

    • Penetrance for clinical phenotype of ALPS is variable

      • Significant proportion of family members can have mutation without phenotype of ALPS

      • Additional factors must contribute to expression of disease

CASPASE 8 Mutations

  • Once considered part of ALPS

  • Present with lymphadenopathy and defective Fas-mediated apoptosis

  • Profound apoptotic defects in B, T, and NK cells

  • Patients often have mucocutaneous herpes virus infections

  • Therefore, CASP8 mutations are now considered to represent a distinct disease



  • Chronic nonmalignant lymphoproliferation, often appearing in 1st year of life

    • Chronic &/or recurrent lymphadenopathy in ˜ 80% of patients

    • Splenomegaly with/without hypersplenism in ˜ 85% of patients

    • Hepatomegaly in ˜ 45% of patients

    • Lymphocytic interstitial pneumonia

  • Autoimmune diseases in ˜ 70% of patients

    • Cytopenias are most frequent

      • Autoimmune hemolytic anemia

      • Immune thrombocytopenia

      • Autoimmune neutropenia

      • More than 1 lineage is often affected

    • Evans syndrome

      • Originally described in 1951

      • Autoimmune destruction of erythrocytes and platelets

      • Subset of these patients has ALPS

    • Other less common autoimmune phenomena in ALPS include

      • Skin rash: Often of urticarial nature

      • Autoimmune hepatitis

      • Autoimmune glomerulonephritis

      • Autoimmune thyroiditis

      • Uveitis and Guillain-Barré syndrome

      • Vasculitis and panniculitis

      • Autoimmune colitis

      • Autoimmune cerebellar syndrome

      • Patients followed into adulthood have increased risk of pulmonary fibrosis

  • ALPS patients have increased risk of malignancies of various types

    • Increased risk of Hodgkin lymphoma and non-Hodgkin lymphoma

      • 51x increased risk of Hodgkin lymphoma

      • 14x increased risk of non-Hodgkin lymphoma

      • Usually not related to Epstein-Barr virus infection

    • Increased risk of carcinomas

      • Thyroid, breast, liver, tongue, skin

    • Increased risk of leukemias

    • Some ALPS patients present with multiple neoplasms (thyroid/breast adenomas, gliomas)

  • Presentation related to type of genetic mutation

    • Homozygous or compound heterozygous FAS mutations lead to

      • Severe lymphoproliferation before, at, or shortly after birth

      • Patients typically succumb to lymphoproliferation &/or autoimmunity at early age

    • Mutations in any domain of Fas lead to same clinical phenotype of ALPS

      • Lymphoma is most often associated with mutations affecting intracellular domains of Fas

Laboratory Tests

  • Peripheral blood lymphocytosis

  • Serum

    • Elevated concentrations of IgG, IgA, and IgE; normal or decreased concentration of IgM

    • Increased levels of interleukin (IL)-10

    • Increased levels of vitamin B12

  • Autoimmune antibodies

    • Autoantibodies to red cells, platelets, and neutrophils are often found

    • Anti-smooth muscle and anti-phospholipid antibodies can be positive

    • Anti-nuclear antibodies and rheumatoid factor can be positive

  • Flow cytometric immunophenotyping of peripheral blood shows increased double negative T cells

    • Double negative T cells (DNT) = TCR-α/β(+), CD3(+), CD4(-), CD8(-)

      • Normal range: DNT cells have been expressed as percentage of total lymphocytes; total T cells and TCR-α/β(+) T cells in various studies

      • Normal range may differ according to patient age and flow cytometry gating strategy

      • DNT cells are increased if > 1% of total T cells (peripheral blood)

      • Markedly increased (3-60%) DNTs in peripheral blood is very specific for ALPS

      • Present in all subtypes of ALPS

      • Found in peripheral blood, lymph nodes, spleen, and other tissues

      • Role of DNT cells in ALPS, and whether these cells are pathogenic or merely a marker of disease, remains to be determined

    • Other flow cytometry findings

      • Increased TCR-γ/δ(+) DNT cells

      • Increased CD8(+), CD57(+) T cells

      • Increased CD5(+) B cells

      • Increased HLA-DR(+) T cells

      • Decreased CD27(+) B cells

      • Decreased CD4(+), CD25(+) regulatory T cells

    • DNT can be increased in other autoimmune diseases

      • Usually low-level increase of DNT in these diseases

      • Systemic lupus erythematosus

      • Immune thrombocytopenic purpura

    • FAS mutations in 100% of DNT population in somatic ALPS patients suggests that these cells contribute to disease pathogenesis

  • In vitro Fas-mediated apoptosis assays are helpful for diagnosis of ALPS

    • Isolate peripheral blood mononuclear cells from ALPS patient

    • Activate T cells with mitogen and expand with IL-2 in culture for 28 days

    • Expose T cells to anti-Fas IgM antibody

      • Normal T cells: Rapid cell death and apoptosis

      • ALPS T cells: No or impaired cell death

    • Type of ALPS mutation yields different results for in vitro Fas-mediated apoptosis

      • Type I: Often exhibit defective FAS-induced apoptosis

      • Types II and III: No defective FAS-induced apoptosis

  • Molecular genetic assays

    • FAS

      • FAS germline mutations identified throughout entire coding region and exons/introns of FAS

      • Sequencing of entire coding region and intron/exon boundaries of FAS gene detects ˜ 90% of mutations

      • FAS somatic mutation detection often performed on sorted DNT cells

    • FASLG

      • Sequence analysis of entire coding region of FASLG gene is available clinically

    • CASP10

      • Sequence analysis of entire coding region of CASP10 gene is available clinically

Natural History

  • Nonmalignant lymphoproliferative manifestations in ALPS often regress or improve over time

  • Autoimmunity shows no permanent remission with advancing age

  • Risk for development of lymphoma appears to be lifelong


  • Some patients with ALPS require no treatment

  • Hemolytic anemia and thrombocytopenia

    • Prednisone

    • Immunosuppressant

      • Mycophenolate mofetil (Cellcept)

      • Sirolimus (rapamycin)

    • Only a few patients respond to intravenous immunoglobulin

    • Rituximab: Anti-CD20 monoclonal chimeric antibody

      • Percentage of ALPS patients are predisposed to develop common variable immunodeficiency disease (CVID) upon rituximab treatment

      • Reserved for patients who fail all other therapies

    • Splenectomy to control autoimmune cytopenias is discouraged

      • ALPS patients have increased risk of developing post-splenectomy sepsis despite vaccination and antibiotic prophylaxis

      • No long-term effect to control cytopenia(s)

  • Bone marrow (hematopoietic stem cell) transplantation carries risks

    • Reduced-intensity transplant can reduce transplant-associated risks


  • Refer to natural history

Recently Proposed Diagnostic Criteria for ALPS

  • Major

    • 1: Chronic nonmalignant lymphoproliferation

      • > 6 months

      • Splenomegaly &/or lymphadenopathy of at least 2 nodal groups

    • 2: Marked elevation of peripheral blood DNTs of at least 5%

    • 3: Defective in vitro Fas-mediated apoptosis

    • 4: Identifiable genetic mutation, germline or somatic

      • FAS, FASL, CASP10, NRAS

  • Minor

    • 1: Autoimmune cytopenias

      • Thrombocytopenia, neutropenia, &/or hemolytic anemia

      • Proven to be immune-mediated by autoantibody detection or response to immunosuppressive agent

    • 2: Moderate elevation in DNTs

    • 3: Elevated serum IgG

    • 4: Elevated serum IL-10

    • 5: Elevated serum vitamin B12

    • 6: Elevated plasma Fas ligand level

  • Diagnosis established if

    • 3 major criteria present or

    • 2 major + 2 minor criteria present


Radiographic Findings

  • Imaging studies detect lymphadenopathy or hepatosplenomegaly

  • Lymphoproliferations in ALPS are FDG PET avid

  • Cannot distinguish benign from malignant; therefore, biopsy needed


Lymph Nodes

Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Autoimmune Lymphoproliferative Syndrome

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