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autoimmune lymphoproliferative syndrome

Tuesday 6 April 2004

Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder associated with defects in Fas-mediated apoptosis, characterized most often by childhood onset of lymphadenopathy, splenomegaly, hypergammaglobulinemia, and autoimmune phenomena.

Synopsis

- early childhood onset
- prominent nonmalignant lymphadenopathy,
- hepatosplenomegaly
- autoimmune manifestations
- expanded populations of CD4− CD8− (double-negative T cells)
- in vitro defects in lymphocytes apoptosis.
- splenomegaly
- prominent adenopathies

  • architecture distorted but not totally effaced.
  • marked paracortical expansion by lymphocytes in variable stages of immunoblastic transformation
  • paracortex expanded by numerous CD3+ T cells with pale cytoplasm (medium-sized clear cells, CD3+ T lymphocytes, plasma cells, immunoblasts with mitotic activity)
  • hyperplastic as well as regressive follicles
  • reactive follicles in the cortex
  • +/- large histiocytes with round nuclei and emperipolesis (Rosai-Dorfman disease-like)
  • population of CD4− CD8− cells, mostly around lymphoid follicles (ie, CD4+ cells and CD8+ cells together being less than CD3+ cells)
  • sheets of CD57+ cells, especially around the follicles
  • high Ki-67 cell proliferation index in the interfollicular and paracortical areas

- hypergammaglobulinemia
- autoimmune phenomena

Associations

- sinus histiocytosis with massive lymphadenopathy (SHML) features (15958855)
- disseminated histiocytic sarcoma and associated Rosai-Dorfman disease (20216376)

Types

- ALPS type 1 (FAS or FAS-L related ALPS)

  • ALPS type 1a (ALPS1A): mutations in TNFRSF6 gene encoding Fas (CD95/Apo-1).
  • ALPS type 1b (ALPS1B): mutations in TNFSF6 at 1q23 (Fas-ligand mutations) (MIM.134638) (CD178)

- ALPS type 2 (ALPS2) (caspases-related ALPS)

  • ALPS type 2a (ALPS2a): CASP10 germline mutations
  • ALPS type 2b (ALPS2b): CASP8 germline mutations

- ALPS type 3 (ALPS2) (unknown gene)

Etiology

In most patients, there is a genetic defect in FAS (APT1/TNFRSF-6) gene, which encodes Fas protein (also called APO-1 or CD95), a cell-surface receptor that regulates lymphocyte survival by triggering programmed cell death or apoptosis.

In a low percentage of ALPS cases, the genetic mutation involves CASPASE-8 (CASP8), CASPASE-10 (CASP10), or FAS LIGAND genes.

Differential diagnosis

- sinus histiocytosis with massive lymphadenopathy (SHML) features (15958855)

References

- Development of disseminated histiocytic sarcoma in a patient with autoimmune lymphoproliferative syndrome and associated Rosai-Dorfman disease. Venkataraman G, McClain KL, Pittaluga S, Rao VK, Jaffe ES. Am J Surg Pathol. 2010 Apr;34(4):589-94.PMID: 20216376

- Gualco G, van den Berg A, Koopmans S, Bacchi LM, Carneiro SS, Ruiz E Jr, Vecchi AP, Chan JK. Autoimmune lymphoproliferative syndrome in a patient with a new minimal deletion in the death domain of the FAS gene. Hum Pathol. 2008 Jan;39(1):137-41. PMID: 18070632

- Maric I, Pittaluga S, Dale JK, Niemela JE, Delsol G, Diment J, Rosai J, Raffeld M, Puck JM, Straus SE, Jaffe ES. Histologic features of sinus histiocytosis with massive lymphadenopathy in patients with autoimmune lymphoproliferative syndrome. Am J Surg Pathol. 2005 Jul;29(7):903-11. PMID: 15958855

- van den Berg A, Tamminga R, de Jong D, Maggio E, Kamps W, Poppema S. FAS gene mutation in a case of autoimmune lymphoproliferative syndrome type IA with accumulation of gammadelta+ T cells. Am J Surg Pathol. 2003 Apr;27(4):546-53. PMID: 12657942

- Siegel RM, et al: The multifaceted role of Fas signaling in immune cell homeostasis and autoimmunity. Nat Immunol 1:469, 2000.

- Ströbel P, Nanan R, Gattenlohner S, Muller-Deubert S, Muller-Hermelink HK, Kreth HW, Marx A. Reversible monoclonal lymphadenopathy in autoimmune lymphoproliferative syndrome with functional FAS (CD95/APO-1) deficiency. Am J Surg Pathol. 1999 Jul;23(7):829-37. PMID: 10403307

- Lim MS, Straus SE, Dale JK, Fleisher TA, Stetler-Stevenson M, Strober W, Sneller MC, Puck JM, Lenardo MJ, Elenitoba-Johnson KS, Lin AY, Raffeld M, Jaffe ES. Pathological findings in human autoimmune lymphoproliferative syndrome. Am J Pathol. 1998 Nov;153(5):1541-50. PMID: 9811346

- Pathological findings in human autoimmune lymphoproliferative syndrome. Lim MS, Straus SE, Dale JK, Fleisher TA, Stetler-Stevenson M, Strober W, Sneller MC, Puck JM, Lenardo MJ, Elenitoba-Johnson KS, Lin AY, Raffeld M, Jaffe ES. Am J Pathol. 1998 Nov;153(5):1541-50. PMID: 9811346