The confusing state of the histiocytoses
Authors: A.C. Chu
Journal: British Journal of Dermatology (2000)

The histiocytoses are reactive or malignant conditions in which various tissues, including the skin, are infiltrated by cells of the monocyte macrophage lineage. They are a heterogeneous group of disorders that are made very confusing by their rarity and by the large number of terms that have been used to describe them. The Writing Group of the Histiocyte Society1 have reclassified the histiocytoses into three classes: Class 1: Langerhans cell histiocytosis. Class 2: Non-Langerhans cell histiocytoses Class 3: Malignant histiocytoses. This classification has been generally adopted and has been very useful, particularly in Langerhans cell histiocytosis. It still leaves, however, an enormous group of Class 2 histiocytoses that are very diverse and still very confusing. Many of these conditions have been reported in the literature only on a few occasions and full investigation of the patients, particularly with respect to histology and immune histochemistry, have not been performed. Histiocytes in themselves are a diverse group of cells, having the CD34+ bone marrow precursor as their progenitor cell2 but then entering a number of rather confusing ontological pathways to finally become morphologically recognizable cells in the skin and other tissues. One type of histiocyte was first identified in 1986 by Hedington,3 who termed the cell 'a dermal dendrocyte'. Unfortunately, little is known about the kinetics and turnover of the dermal dendrocyte and, although we assume that the bone marrow CD34+ cell is the precursor, this has not been scientifically demonstrated. Dermal dendrocytes are MHC Class II antigen-positive, suggesting a role in antigen presentation, but functional studies on their immune function have not been conducted to date. An important surface marker for the dermal dendrocyte is the blood clotting transglutaminase Factor XIIIa. The presence of this factor on the dermal dendrocytes has led to speculation that this cell could have a function in controlling blood loss following damage to the superficial plexus of blood vessels in the skin. In normal human skin dermal dendrocytes are found in the upper papillary dermis perivascularly and around adnexal structures. Within the Class 2 histiocytoses, studies have shown that a number of these clinically distinct entities share the same immunophenotype. These include benign cephalic histiocytosis, juvenile xanthogranuloma, generalized eruptive histiocytosis, xanthoma disseminatum and progressive nodular histiocytosis.4 In all these conditions, particularly at the early stages, Factor XIII+ cells are found. In one large histopathological study, biopsies from benign cephalic histiocytosis, generalized eruptive histiocytosis and juvenile xanthogranuloma were examined in a blinded fashion. In all specimens examined, three distinct patterns of proliferation of histiocytes were observed; papillary dermal, lichenoid and diffuse. In benign cephalic histiocytosis, generalized eruptive histiocytosis and early non-xanthomatous juvenile xanthogranuloma, the three conditions could not be specifically differentiated from each other on histopathological grounds. With time, the juvenile xanthogranulomas become more xanthomatized and can then be more specifically differentiated from the other two entities. In another case report, a 4-year-old boy initially developed generalized eruptive histiocytosis on clinical, histological and structural grounds but subsequently developed yellowish confluent papules and diabetes insipidus and on this occasion, the diagnosis of xanthoma disseminatum was made.5 The two cases of progressive nodular histiocytosis reported in this issue of the BJD6, 7 demonstrate the variable morphology and prolonged evolution of this disorder (durations of 14 and 26 years in these two patients), as well as the uncertainty about the relevance of associated systemic diseases. We would propose that the histiocytoses of dermal dendrocytes represent a spectrum of diseases in which the dermal dendrocyte shows different levels of maturation (Fig. 1). Histological examination of benign cephalic histiocytosis, juvenile xanthogranuloma, generalized eruptive histiocytosis, xanthoma disseminatum and progressive nodular histiocytosis shows a spectrum of cell types from plump dendritic histiocytes to mature spindle shaped cell. In benign cephalic histiocytosis and juvenile xanthogranuloma, the cells appear to be the most immature and the disease has the shortest life-span, resolving after a few months. At the other end of the spectrum, progressive nodular histiocytosis is a disease of mature spindle-shaped cells, and the disease is progressive with no tendency to spontaneous remission and is very resistant to treatment. At the more mature end of the spectrum is xanthoma disseminatum where the disease resolves, but usually only after many years and at the later stages, is dominated histologically by spindle shaped cells. Histiocytoses associated with different levels of maturation of the dermal dendrocyte. With maturation of the dermal dendrocytes in these conditions, the cells appear to become less responsive to treatment with radiotherapy or chemotherapy. Widespread juvenile xanthogranuloma is sensitive to radiotherapy and chemotherapy, while progressive nodular histiocytosis is resistant to all forms of therapy. It is possible that early in the disease progressive nodular histiocytosis and xanthoma disseminatum may be sensitive to treatment but as the cells become more mature, they become resistant to treatment. There is therefore a powerful argument for early aggressive treatment in these conditions, particularly in xanthoma disseminatum where occular, central nervous system and meningeal involvement can cause significant morbidity, and in progressive nodular histiocytosis where the disease causes severe disfigurement.6, 7