How is autoimmune lymphoproliferative syndrome (ALPS) diagnosed?

Updated: Jul 29, 2019
  • Author: Akaluck Thatayatikom, MD, RhMSUS; Chief Editor: Harumi Jyonouchi, MD  more...
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In evaluating a child with chronic lymphadenopathy or splenomegaly with or without cytopenias, one must evaluate for and rule out numerous diagnoses, including malignancies and chronic infection. A history of constitutional symptoms (eg, weight loss, anorexia, pallor, early fatigue, easy bruising, or frequent ear and throat infection) in conjunction with the physical findings previously mentioned (see Presentation) warrants an evaluation to exclude these conditions.

Depending on the patient’s history and risk factors, the initial evaluation may include a complete blood count (CBC) with differential, as well as immunoglobulin, serum lactate dehydrogenase (LDH), and uric acid levels. Additionally, in a highly suspected case of ALPS, the DNT cell count and levels of vitamin B12, IL-10, and soluble FASLG should be obtained.

Pediatric patients who have acute lymphadenopathy with concerning or atypical features (including fixed or hard nodes or massive lymphadenopathy) or chronic lymphadenopathy without an identified cause should be referred to a pediatric hematologist for consideration of lymph node biopsy and further evaluation.

Lymph node biopsy findings are unique in autoimmune lymphoproliferative syndrome (ALPS), and hematologists, surgeons, and pathologists involved in performing and interpreting biopsy results should be familiar with these findings and include the diagnosis of ALPS if these findings are present on biopsy.

To meet the criteria for a definitive diagnosis of ALPS, both of the 2 required criteria and at least 1 of the primary accessory criteria must be present (see the image below). A probable diagnosis of ALPS includes the required criteria with one secondary accessory. Some patients with probable ALPS have an ALPS-like disorder and should be tested for these conditions (Table 1).

The 2 required diagnostic criteria for ALPS are as follows:

  • Chronic, nonmalignant, noninfectious lymphadenopathy or splenomegaly lasting at least 6 months

  • Elevated T-cell receptor (TCR) α/β CD3+ CD4/CD8 T cells, or double-negative T (DNT) cells (≥1.5% of total lymphocytes or 2.5% of CD3+ lymphocytes), in the setting of normal or elevated lymphocyte counts

The primary accessory criteria are as follows:

  • Defective lymphocyte apoptosis in 2 separate assays

  • A somatic or germline pathogenic mutation in FAS, FASLG, or CASP10

The secondary accessory criteria are as follows:

  • An elevated plasma level (>200 pg/mL) of soluble Fas ligand (FasL), elevated plasma interleukin (IL)–10 levels (>20 pg/mL), elevated plasma IL-18 levels (>500 pg/mL), or elevated serum or plasma vitamin B12 levels (>1500 ng/L)

  • Typical immunohistochemical findings as reviewed by an experienced hematopathologist

  • Autoimmune cytopenia (hemolytic anemia, neutropenia, or thrombocytopenia) plus elevated immunoglobulin G (IgG) levels (polyclonal)

  • Family history of a nonmalignant, noninfectious lymphoproliferation, with or without autoimmunity

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