Review
Aggressive histiocytic disorders that can involve the skin

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Histiocytoses are a heterogeneous group of disorders that are characterized by the proliferation and accumulation of reactive or neoplastic histiocytes. Three classes of histiocytoses have been defined: class I, Langerhans cell disease; class II, non-Langerhans cell histiocytic disease without features of malignancy; and class III, malignant histiocytic disorders. Although the disorders in classes I and II usually have a benign appearance on histology and are commonly non-aggressive and self-healing, some can cause debilitating or even fatal outcomes. Such cases beg the question: what stimulates aggressive behavior of a classically benign disease? New molecular information may now provide insight into the driving force behind many of the aggressive histiocytoses. In this article, we review Langerhans cell disease and seven aggressive histiocytoses that can involve skin, discuss histologic features that may forecast a poor prognosis, and discuss the molecular findings that help to explain the pathophysiology of these aggressive histiocytic disorders.

Section snippets

Class I: Langerhans cell disease

The LC is now well accepted to be a cutaneous antigen presenting cell and not a tissue histiocyte. It is a bone marrow-derived cell that migrates into the epidermis and hair follicle epithelium.1 LCs stain positive for S-100 protein, CD1a, CD45, and CD101; CD1a staining is considered specific for LCs. When visualized with electron microscopy, LCs contain unique organelles, called Birbeck granules, which arise from the cytoplasmic membrane by receptor-specific endocytosis.8 An antigen called

Class II: Non-Langerhans cell histiocytic diseases

NLCDs are disorders in which histiocytes accumulate in tissues. Many of the diseases in this class are rare and poorly understood. The cell of origin for the NLCD is the monocyte/macrophage, a cell of diverse differentiation potential. Much less is known about the different pathways of differentiation in monocyte/macrophages than in other hematopoietic cells, such as lymphocytes and neutrophils. The monocyte/macrophage can become any of the following types of cell, explaining in part the

Class III: Malignant histiocytic disorders

Malignant histiocytoses are caused by malignant transformation of monocyte/macrophage stem cells. The prognosis of malignant histiocytosis is similar to leukemia or lymphoma.

Clinical

LCD encompasses a spectrum of overlapping diseases that were previously known as Letterer–Siwe disease, Hand-Schuller-Christian disease, eosinophilic granuloma, and Hashimoto–Pritzker disease.11 The clinical presentations of each subtype can vary greatly, however, and the above diseases were all recently reclassified as LCD, based on common immunologic and ultrastructural features.12 Although they are now classified together, it is still useful to review the clinical presentations of

Non-Langerhans cell histiocytoses/non-Langerhans cell histiocytic disease

NLCDs are diseases caused by infiltration of mononuclear phagocytes/histiocytes and include juvenile xanthogranuloma (JXG), multicentric reticulohistiocytosis (MRH), sea-blue histiocyte syndrome (SBHS), sinus histiocytosis with massive lymphadenopathy (SHML, also known as Rosai–Dorfman syndrome), necrobiotic xanthogranuloma (NXG), xanthoma disseminatum (XD), and hemophagocytic lymphohistiocytosis (HLH), which can all show aggressive behavior.

Summary

Clinical and histologic characteristics of LCD and seven different potentially aggressive histiocytic disorders, including JXG, MRH, SBHS, SHML, NXG, XD, HLH, and MH were reviewed in this article. Their unique histologic features are summarized in Table I. Except for LCD and MH, most are generally considered to be benign and self-limited. However, when histiocytes infiltrate vital organs, these “benign” histiocytoses may lead to a fatal outcome, hence the term “aggressive histiocytoses.” It is

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    Supported by a National Institutes of Health NIAMS Skin Diseases Research Center grant to Dr Gilliam (grant no. PO30-AR39750-13) and NIAMS R01 AR49284-03.

    Conflicts of interest: None identified.

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