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Histiocyte Disorders


1.1 Definition

Non-malignant histiocytoses are a group of disorders involving a pathologic increase in the number of histiocytes (mononuclear phagocytic cells and the mainly-antigen-presenting cells of bone marrow origin). They include three major groups of diseases, namely dendritic cell-related histiocytoses , macrophage-related histiocytoses, and Rosai-Dorfman disease.

1.2 Referral

Diagnosis and treatment of histiocytoses is complex and multidisciplinary. Therefore, it is recommended that patients with histiocytoses be referred to experienced institutions. A co-operative approach co-ordinated by a paediatric or medical oncologist and involving a pathologist, a radiologist, and one or more of the following specialists: an orthopaedic surgeon, an endocrinologist, a dermatologist, a pulmonologist and others, is essential in Langerhans cell histiocytosis.

1.3 Selected reviewsArceci on Langerhans cell histiocytosis in childhood

Egeler and D’Angio on Langerhans cell histiocytosis in childhood

Favara on pathology of hemophagocytic lymphohistiocytosis

Foucar et al. on Rosai-Dorfman disease

Henter et al. on diagnosis and treatment of hemophagocytic lymphohistiocytosis

Janka on familial hemophagocytic lymphohistiocytosis in general

Malpas and Norton and Novice et al. on disseminated Langerhans cell histiocytosis in the adults

Pritchard et al on all aspects of Langerhans cell histiocytosis

Weitzman and Jaffe on uncommon histiocytic disorders


2.1 Histological types

2.1.1 Type of cell

There are two major types of histiocytes:

  • the mainly antigen-presenting dendritic cells (interdigitating reticulum cells and dendritic reticulum cells in spleen and lymph nodes and Langerhans cells in skin and bronchial epithelium) and
  • the mainly antigen-phagocytosing macrophages (circulating monocytes, alveolar macrophages of the lung, Kupffer cells of the liver, osteoclasts and microglial cells).
2.1.2 Grouping

Histological grouping is based on the type of histiocyte primarily involved in the disease process (WGHS 1987; Favara 1997; Pritchard 2001). The commonest types are listed below:

Dendritic cell-related histiocytoses

  • Langerhans cell histiocytosis (LCH), (previously Histiocytosis X) (includes eosinophilic granuloma, Hand-Schüller-Christian disease and Letterer-Siwe disease)
  • single system disease (many regard the often smoking-induced isolated pulmonary Langerhans cell disease of adults as a separate LCH entity)
  • multisystem disease
  • Juvenile xanthogranuloma – dermal dendrocyte phenotype

Macrophage-related histiocytoses

  • Hemophagocytic Lymphohistiocytosis (HLH)
  • Primary Hemophagocytic Lymphohistiocytosis, also called Familial Hemophagocytic Lymphohistiocytosis (FHL)(may present as a sporadic or as a familial disease, and often in association with an infection)
  • Secondary Hemophagocytic Lymphohistiocytosis
    Infection-associated Hemophagocytic syndrome (IAHS)
    Malignancy-associated Hemophagocytic syndrome (MAHS)
    Macrophage activation syndrome (MAS) Others, including fat overload syndrome
  • Rosai-Dorfman disease (Sinus histiocytosis with massive lymphadenopathy, SHML)


Arceci RJ. The histiocytoses: the fall of the Tower of Babel. Eur J Cancer 1999; 35: 747-67; Discussion 767-9. [Medline]

Egeler RM, D’Angio GJ. Langerhans cell histiocytosis. J Pediatr 1995; 127: 1-11 [Medline]

Favara BE, Feller AC, Pauli M, Jaffe ES, Weiss LM, Arico M, et al. Contemporary classification of histiocytic disorders. The WHO Committee On Histiocytic/Reticulum Cell Proliferations. Reclassification Working Group of the Histiocyte Society. Med Pediatr Oncol 1997; 29: 157-166 [Medline]

Favara BE. Hemophagocytic lymphohistiocytosis: a hemophagocytic syndrome. Semin Diagn Pathol 1992; 9: 63-74 [Medline]

Henter J-I, Arico M, Elinder G, Imashuku S, Janka G. Familial hemophagocytic lymphohistiocytosis (primary HLH). Hematol/Oncol Clin North Am 1998; 12: 417-433 [Medline]

Janka GE. Familial hemophagocytic lymphohistiocytosis. Eur J Pediatr 1983; 140: 221-230 [Medline]

Ladisch S, Jaffe ES. The histiocytosis. In: Pizzo PA, Poplack DG, editors. Principles and Practice of Pediatric Oncology, 3rd ed. Philadelphia: Lippincott; 1997. p. 615-631. [Medline]

Malpas JS, Norton AJ. Langerhan’s cell histiocytosis in the Adult. Medical and Pediatric oncology 1996; 27: 540-546 [Medline]

Novice FM, Collison DW, Kleinsmith DM, Osband ME, Burdakin JH, Coskey RJ. Letterer-Siwe disease in adults. Cancer 1989; 63: 166-174 [Medline]

Pritchard J and Malone M. Histiocyte disorders. In: Peckham M, Pinedo HM, Veronesi U, editors. Oxford Textbook of Oncology. 2nd ed. Oxford: Oxford University Press. 2001. p. 2457-2475. [Medline]

Pritchard J, Beverley PCL, Chu AC, D’Angio GJ, Davis IC, Malpas JS (eds). The proceedings of the Nikolas symposia on the histiocytoses 1989-1993. Br J Cancer 1994; 70 (Suppl XXIII), S1-S72 [Medline]

Weitzman S, Jaffe R. Uncommon histiocytic disorders: the non-Langerhans cell histiocytoses. Pediatr Blood Cancer 2005; 45: 256-264 [Medline]

WGHS. The Writing Group of the Histiocyte Society. Histiocytosis syndromes in children. Lancet 1987; i: 208-9 [Medline]

Prof. Jan-Inge Henter (Author)
Karolinska Hospital – Stockholm, Sweden

Prof. Jon Pritchard (Reviewer)
Passed away on January 20th, 2007

Dr. Carlo Tondini (Editor)
START Clinical Editor – Ospedali Riuniti – Bergamo, Italy