Histiocytoses D76.3

In the classification adopted in 1987 (Working Group of the Histiocyte Society), histiocytoses were divided into:

• Langerhans cell histiocytoses
• Non-Langerhans cell histiocytoses
• Malignant histiocytoses.

This classification took into account morphological and functional findings on macrophages, dendritic cellsand monocytes.

The expanded classification of histiocytoses published in 2016 (Emile JF et al 2016) is based on clinical, radiological, phenotypic, genetic, and/or molecular features. In this classification, histiocytoses are divided into 5 groups, each of which can be assigned definable entities.

• L group - Langerhans cell group
• C-group - Cutaneous non-Langerhans cell histiocytoses
• R group -Rosai-Dorfman disease
• M group -Malignant histiocytoses
• H group - Hemophagocytic lymphohistiocytosis and macrophage activation syndromes

Mono- or polyorganic, localized or disseminated (also generalized), benign or malignant neoplasms caused by the proliferation of cells of the monocytic-phagocytic system (MPS/ see histiocytes below). The monocyte-phagocytic system includes the dendritic cells that occur in various organs. Their main task is to present antigens to naive T lymphocytes. This takes place via their MHC molecules (major histocompatibility complex).

The representatives of these specialized dendritic cells in multilayered squamous epithelia are the Langerhans cells. Langerhans cells express CD1a and Langerin (CD207) and have the characteristic Bierbeck granules. They can be well characterized by this special profile.

After activation, they migrate to the regional lymph nodes and transform into interdigitating dendritic cells.

Like monocytes and macrophages, all dendritic cells are derived from pluripotent bone marrow cells.

Histiocytosis occurs in all age groups with varying clinical manifestations.

Histiocytes are tissue-stable macrophages.

Classification of histiocytoses (Emile JF et al. 2016).

L-group (Langerhans cell group/s.u. Langerhans cell histiocytoses)

• Eosinophilic granuloma (localized).
• Congenital self-healing histiocytosis/localized(Hashimoto-Pritzker).
• Abt-Letterer-Siwe disease (disseminated)
• Hand-Schüller-Christian disease (disseminated)
• Indeterminate cell histiocytosis (ICH)
• Erdheim-Chester disease (ECD)
• Mixed LCH/ECD

C group (Cutaneous non-Langerhans cell histiocytoses/cutaneousnon-Langerhans cell histiocytoses with/without significant systemic involvement)

Xanthogranuloma (XG) - family (see below Xanthogranulomas )

• Juvenile xanthogranuloma (JXG/ historically: nevoxanthoendothelioma)
• Adult xanthogranuloma (AXG)
• Scalloped cell xanthogranuloma (rare dendritic to stellate variant of adult xanthogranuloma)
• Reticulohistiocytoma (reticulohistiocytic granuloma/ RH).
• Benige cephalic histiocytosis (BZH)
• Generalized eruptive histiocytosis (GEH)
• Progressive nodular histiocytosis (PNH)
• Xanthelasma
• Verruciform xanthoma(s)
• Generalized eruptive histiocytosis
• Papular xanthoma (PX)
• Diffuse normlipemic plane xanthoma (with paraproteinemia)
• Xanthoma disseminatum (papular xanthomas)
• Multicentric reticulohistiocytosis
• Progressive nodular histiocytosis
• Spindle cell xanthogranuloma
• Progressive mucinous histiocytosis (familial variant of progressive nodular histiocytosis)

Non-xanthogranuloma family

• Cutaneous Rosai-Dorfman disease (RDD)
• Multicentric reticulohistiocytosis
• Necrobiotic xanthogranuloma (with paraproteinemia) (NXG)

R group (Rosai-Dorfman group)

• Familial Rosai-Dorfman disease (Faisalabad histiocytosis) (RDD)
• Sporadic Rosai-Dorfman disease (classic/systemic RDD, extra-nodal RDD, RDD with neoplasia or immune disease, RDD unclassified)

M group (malignant histiocytoses; very rare).

• Primary malignant histiocytoses (manifest primarily in the skin)
• Secondary malignant histiocytoses (hematologic neoplasms diagnosed hematologically with secondary skin involvement) - Langerhans cell sarcoma

H-group (hemophagocytic lymphohistiocytoses)

• Primary hemophagocytic lymphohistiocytosis (familial/monogenetic) (HLH)
• Secondary hemophagocytic lymphohistiocytosis (acquired/non-Mendelian)
• HLH of unclear origin (idiopathic hemophagocytic lymphohistiocytosis)

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Instead of the previously listed classification according to entities (probably these are not entities but only different manifestations and courses of a single underlying disease), a stratification for the classical Langerhans cell histiocytoses has proven useful, especially also for therapy studies. This classification includes the involvement of organs at risk(liver, spleen, bone marrow).

Single-system disease:

• Monoorganic solitary involvement: skin/unilocular skeletal involvement/solitary lymph node/LCH of the lung.
• Monoorganic multiple infestation: e.g. multilocular skeletal infestation/infestation of multiple lymph nodes.

Multi-system disease (involvement of multiple organ systems including skin (old name: Abt-Letterer-Siwe disease, Hand-Schüller-Christian disease).

• Low risk: patient > 2 years; no involvement of the hematopoietic system, liver, or spleen
• High risk: patient < 2 years, or patient > 2 years with involvement of the organs at risk (hematopoietic system, liver, spleen).

See the respective clinical pictures below.

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2. Emile JF et al (2016) Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood 127: 262-281
3. Goerdt S (1998) Histiocytic tumors. In: Garbe C, Rassner G Dermatology, guidelines and quality assurance for diagnosis and therapy. Springer Verlag, Berlin Heidelberg New York pp 372-378.
4. Kilborn TN et al (2003) Paediatric manifestations of Langerhans cell histiocytosis: a review of the clinical and radiological findings. Clin Radiol 58: 269-278
5. Lichtenstein L (1953) Histiocytosis X. Integration of eosinophilic granuloma of bone, Letterer-Siwe Disease, and Schüller-Christian Disease as related manifestations of a single nosologic entity. Arch Pathol 56: 84-102
6. Ruzicka T et al (2003) Clinical course and therapy of Langerhans cell histiocytosis in children and Adults. Dermatologist 54: 148-155
7. Scheker LE (2003) Neonatal lupus erythematosus mimicking langerhans cell histiocytosis. Pediatr Dermatol 20: 164-166
8. Singh A et al (2003) Adult langerhans cell histiocytosis limited to the skin. Dermatology 207: 157-161
9. Utiikal J et al (2003) The cutaneous non-Langerhans cell histiocytoses. JDDG 1: 471-491
10. Walsh LJ (1991) MS-I sinusoidal endothelial antigen is expressed by factorXIIIa+, HLA-DR+ dermal perivascular dendritic cells. Lab Invest 65: 732-741