Eur. J. Pediat. Dermatol. 25, 27-52, 2015 Histiocytoses. Bonifazi E., Milano A. Pediatric Dermatology, Bari Italy Summary The histiocytoses are diseases caused by the proliferation of histiocytes in various organs, including the skin; they have a very variable clinical spectrum and prognosis ranging from an often fatal multisystem involvement to a self-healing single lesion in a single organ. The classification of histiocytosis, which is based on the origin cell and malignancy potential, divides them into Langerhans cell histiocytosis (Class I), non-Langerhans histiocytosis (Class II) and malignant histiocytosis (Class III). In each of these classes numerous clini- cal forms have been described, but these forms according to some Authors only represent different developmental stages of the same disease. Letterer-Siwe disease is the most fre- quent form among Class I histiocytoses and juvenile xanthogranuloma and Rosai-Dorfman disease are the most frequent forms among Class II Histiocytoses. In Class I histiocytoses the histologic examination is not able to distinguish between severe and mild forms; the observation of the skin lesions can help in this differentiation. Key words Histiocytosis, Langerhans cell, Letterer-Siwe disease, Hashimoto-Pritzker disease, Lan- gerhans cell histiocytoma, juvenile xanthogranuloma, cephalic histiocytosis. he histiocytoses are diseases caused by cell and malignancy potential, divides them into the proliferation of histiocytes in different Langerhans cell histiocytosis (Class I), non-Lan- organs; they have a very variable clinical gerhans histiocytosis (Class II) and malignant Tspectrum and prognosis ranging from an often histiocytosis (Class III). fatal multisystem involvement to a self-healing single lesion in a single organ. The stem cell from which the istiocytoses derive is a bone marrow Langerhans Cell Histiocytosis (Class I) CD34+ cell; from the latter under the influence of environmental cytokines derive CD1a+, S-100 It includes the clinical diseases known as +, langerin+ Langerhans cells, macrophages that Letterer-Siwe disease, Hand-Schuller-Christian take different names depending on the tissue in disease and eosinophilic granuloma of bone, which they reside and finally dermal dendritic gathered in the chapter of the so-called histio- cells with some phenotypic aspects of antigen cytosis X; to these three clinical pictures it was presenting cells and of monocytes and macro- added in 1973 another clinical picture known as phages, but CD1a negative. The classification Hashimoto-Pritzker disease (38). Before treating of histiocytosis, which is based on the origin these diseases separately, let’s see some general 27 Bonifazi, Milano characteristics, bearing in mind that the major tors there are reports discussing clinically identi- differences are found in their clinic, while it is cal LCH in monozygotic twins (44), mutations virtually impossible to distinguish between them of B-RAF (61) and expression of the p16 protein from a histopathological point of view. (66). Etiology. No environmental factors responsi- Histopathology. The histologic appearance of ble for the disease are known, but an epidemiolo- the Langerhans cell (LC) is characteristic (Fig. gical study of 177 cases (37) of Langerhans cell 2): large size, 20-30 microns in diameter, abun- histiocytosis (LCH) highlights the possible role dant eosinophilic cytoplasm, nucleus with lax of maternal urinary infections, nutritional pro- chromatin and a more or less profound incision blems and blood transfusions in the first month for which its look varies from bean-shaped to lo- of life. As regards the possible role of genetic fac- bulated. Fig. 1 Fig. 2 Fig. 1, 2: Letterer-Siwe disease; you can see the significant edema of the superficial dermis (Fig. 1, H&E, 20x). In Fig. 2 (H&E, 400x) you can see the characteristic of the Langerhans cells: large cells with bean-shaped nucleus, abundant cytoplasm with definite borders; there are also many eosinophils. Fig. 3 Fig. 4 Fig. 3, 4: Positive stain with S-100 protein (Fig. 3, 250x) both in pathological Langerhans cells of the dermis and in normal ones of the epidermis. In Fig. 4 Birbeck granules inside the nucleus on electron microscopy. 28 Histiocytoses In the recent lesions these cells usually con- As regards the immunohistochemistry Lan- stitute the majority of the infiltrate; in the older gerhans cell reacts with S-100 (Fig. 3), CD1a, lesions, especially when the disease is in spon- langerin, CD68, HLA-DR receptors; there are no taneous or drug-induced remission, the cell may significant differences in susceptibility to S-100, show lipid vacuoles until it takes an aspect simi- CD1a, langerin (76). The ultramicroscopic mar- lar to those observed in Hand-Schuller-Christian ker of LCH is represented by Birbeck granules disease (2). (Fig. 4). In addition to the LC there may be other cells, Skin lesions. The most characteristic and fre- mainly lymphocytes and eosinophils (Fig. 2), and quent skin lesion of LCH is a 1 mm in diame- in some cases a granuloma-like infiltrate very si- ter papule with well-defined margins, sometimes milar to that found in eosinophilic granuloma of purpuric. The purpuric appearance is not due to bone. liver involvement or thrombocytopenia because Initially, the infiltrate occupies the superficial it is present also when there is not a liver or bone dermis, where it is surrounded by a very edema- marrow dysfunction as in the self-healing forms tous stroma (Fig. 1), and the middle dermis; the (7, 8). The other lesions observed in the LCH de- epidermis does not appear affected by the infiltra- rive from this primary lesion, which can erode te. However, when the latter grows significantly, and become crusty or grow and become a nodule it extends upwards, eroding the epidermis, and in or ulcerate or overload of lipids becoming xantho- depth to reach in the larger nodules the muscular matous. The stromal edema that characterizes the layer. primitive papule may explain the exudative, even Fig. 5 Fig. 6 Fig. 5, 6: Please note the difference in morphology, distribution and number of skin lesions between Hashimoto- Pritzker disease (Fig. 5) and Letterer-Siwe disease (Fig. 6). 29 Bonifazi, Milano bullous with infiltrated base or pustular varicella- are self-healing forms of LCH: usually we are de- like lesions that are observed in the congenital aling with pure cutaneous forms already present form of Hashimoto-Pritzker. Lesional polymor- at birth or that arise within the first months of life, phism is more evident in congenital forms where but there are also self-healing forms affecting the the lesions are fewer and less close to each other adult or other organs such as lymph nodes, bones, (Fig. 5), while the acquired forms are usually mo- lungs and liver (4, 8, 31, 33). nomorphic with high prevalence of micropapular Because the skin lesions are not seldom the lesions (Fig. 6). first to appear and as the initially pure cutaneous With regard to the distribution of the lesions, forms of LCH may later become multisystem, the in the acquired forms prevail the seborrheic sites dermatologist has the difficult task of trying to - scalp, behind the ears, central chest and para- identify the predictive signs of multisystem in- vertebral areas level with the trunk, diaper area volvement. (Fig. 6) -; on the other hand, in the congenital From this point of view it seems useful to con- form of Hashimoto-Pritzker the lesions affect the sider the distribution of the skin lesions, their entire skin surface without preferring seborrheic number and diameter, the existence or absence of locations. polymorphism and the presence of more or less As regards the evolutionary trend of the lesions, deep ulcerated lesions. when LCH lasts several months, the lesions cha- We already said that in the multisystem forms racteristically appear in subintrant crops. of LCH the lesions are distributed in seborrheic The skin lesions are common in all forms of locations while in the self-healing forms any LCH, but have a different meaning for the der- cutaneous site can be affected. Important is the matologist and the oncologist. The latter gives number of skin lesions that can be counted in unfavorable prognostic significance to the pre- the self-healing forms where there can also be sence of skin lesions (17, 22) because when the- an isolated lesion – LC histiocytoma –, while in se lesions are in addition to visceral lesions, are the multisystem forms the skin lesions are some- an expression of a greater spread of the disease. times so numerous as to cover the whole skin: in On the other hand, the dermatologist, when re- these cases, when more than 60% of the skin is cognizing the pathognomonic lesions of LCH affected by ulcerated lesions, there may be as in (9), knows that they may be the expression of an burns a dysfunction of the skin. Also the diame- exclusive skin involvement and that may resolve ter and the polymorphism of the skin lesions is spontaneously; it is indeed difficult for the der- important: in the multisystem forms you usually matologist to be the first specialist to diagnose a see 1 mm in size, monomorphic papules, while in multisystem LCH, while he knows and must re- the self-healing forms there is considerable poly- member that an initially pure cutaneous form can morphism ranging from grossly nodular lesions turn into a multisystem disease (29). to varicella-like pustular lesions with infiltrated Until a few decades ago the pessimistic in- base till to nodular Kaposi-like lesions. terpretation of the significance of skin lesions prevailed and any histopathological diagnosis of LCH led to prescribe an aggressive systemic Letterer-Siwe disease chemotherapy even when there were only skin lesions. Letterer-Siwe disease, potentially the severest To change this interpretation were important form in this group, has a debated pathogenesis, the reports in 1981 of Osband et Al. (57) who being according to some Authors a monoclonal first treated with thymic extracts systemic forms proliferation of Langerhans cells (72), according of LCH, in 1973 of Hashimoto and Pritzker re- to others a reactive form (25).