Chapter 21 Langerhans Cell Histiocytosis 21 in Skin and Mucous Membranes In Langerhans cell histiocytosis accumulations of a young adults and the elderly. In small children the special kind of Langerhans cells give rise to granulo- lesions appear as vesicular or pustular papules, occa- mas, which may appear in any tissue or organ. In the sionally as nodules, or as dermatitis (eczema). In the old literature the disease was described as three dis- latter case they may be mistaken for diaper dermatitis eases of different severity and different histopatho- or seborrheic dermatitis. Commonly affected regions logic pattern with the ability to change from one kind are the trunk, groin, armpits, scalp, the area behind of disease to one of the others: Letterer-Siwe disease the ears, and the auditory meatus. Sometimes the oral (the most serious form), Hand-Schüller-Christian dis- mucosa, including the gingiva, is affected with loosen- ease, and eosinophilic granuloma (the most benign). ing of the teeth. The disease may be unifocal, but in Lichtenstein (1953) asserted that the three diseases many patients there are, or later develop, lesions even were manifestations of the same nosologic entity and in other organs (Stein et al. 2001). In old patients the coined the concept histiocytosis X. However, Nezelof disease appears as scattered hemorrhagic infiltrated et al. (1973) found histogenetic arguments for a Lang- lesions, papules, or nodules (Aoki et al. 1998; Stefa- erhans cell origin of the disease, which led to the more nato et al. 1998). appropriate designation Langerhans cell histiocytosis (LCH). The disease may appear at any age, but is most com- 21.2 mon in childhood. There is a prevalence for males. It Histopathologic Appearance is regarded as a benign reactive process with a variable As already mentioned, Langerhans cells are bone-mar- course and morbidity depending on the site of the le- row-derived dendritic cells normally present in the sions and, most important, on whether the disease is skin and mucous membranes. They cannot be identi- unifocal or multifocal (Lieberman et al. 1996; Titge- fied in routinely stained sections, but may be visual- meyer et al. 2001). However, in some patients with ized by means of histochemical staining with S-100 multisystem disease the outcome is fatal, most often and CD1a antibodies (Sect. 4.4.2). The granulomas due to circulatory failure or infections. Rare complica- in LCH consist of polymorphic histiocyte-like cells, tions are diabetes insipidus, which is due to granulo- which like normal Langerhans cells, are S-100- and mas located in the posterior part of the pituitary gland CD1a-positive, and also contain Birbeck granules (see or hypothalamus, exophthalmia due to retroorbital Glossary). They are here called LCH cells. granulomas, and otitis media caused by infiltrate in LCH cells are of different sizes, but usually have the temporal bone. In both unifocal and multifocal a rich well-demarcated and finely granular cyto- disease, bones are the most common sites with prefer- plasm. The nuclei are usually clear, sometimes vacu- ence for (in order) skull, femur, pelvic bones, ribs and olated, and vary conspicuously in shape. They may vertebrae (Lieberman et al. 1996). The most common be rounded, oval, kidney-shaped, lobulated or deeply soft-tissue organs that may be involved in unifocal or cleaved and contain one or several non-prominent nu- multifocal disease are lungs, lymph nodes and skin. cleoli. Usually there is only one nucleus, but scattered or several multinucleated giant cells may be present. A few mitotic figures may be observed. In addition to 21.1 LCH cells, there is a variable admixture of eosinophils, Clinical Appearance neutrophils and lymphocytes. The granulomas are Skin lesions are most common in the neonatal period loosely composed, often not well demarcated. They and in small children, but also occur in older children, are mostly confined to the upper dermis, but may be 148 21 Langerhans Cell Histiocytosis in Skin and Mucous Membranes Fig. 21.1 Langerhans cell histiocytosis. a A dense infiltrate of in a shows LCH cells with abundant cytoplasm and different- LCH cells in the papillae and upper dermis invade and destroy shaped nuclei. The arrow indicates a mitotic figure in anaphase. the epidermis giving rise to saw-tooth rete ridges and a super- H&E ficial crusted pustule. b Close-up of the area indicated (arrows) Fig. 21.2 Langerhans cell histiocytosis. a The upper arrowhead clear dust. The epidermis is covered with a crust.b Fibrinoid indicates a small accumulation of LCH cells and the lower ar- necrosis with disintegrating neutrophils and nuclear dust in the rowhead an area of fibrinoid necrosis. At the arrow there is a middle of the dermis. The area is partly walled of by a band of small venule with fibrinoid wall necrosis, hemorrhage and nu- LCH cells (arrowheads). H&E massive and reach down to the dermal–subcutaneous disease could be missed as in genital and oral lesions. interface. Characteristically the LCH cells invade the Extravasation of erythrocytes is a prominent feature. epidermis and in the center of the lesion give rise to a Sometimes neutrophilic venular vasculitis may occur, small ulcer covered by a crust. In some settings the in- affecting only scattered vessels. flammatory cells prevail and the true character of the 21.3 Examples 149 Fig. 21.3 Langerhans cell histiocytosis. a To the right of a hair follicle (asterisk) there is a dense infiltrate of LCH cells with a mitotic figure in metaphase (arrow). b In this area there are in addition to LCH cells many neutrophils and eosinophils and a multinucleated LCH cell (arrow). c A vessel with fibrinoid wall necrosis and the lumen filled with a cluster of cells. H&E 21.3 ophils, neutrophils, lymphocytes, and extravasated Examples erythrocytes. A biopsy from the bone lesion revealed a granu- Case 1. Langerhans Cell Histiocytosis loma which consisted of LCH cells and a high number The patient had from the neonatal period suffered from of eosinophils. In the tonsil, aggregates of LCH cells a severe and therapy-resistant dermatitis in the groin but only a moderate number of eosinophils were ob- and on the scalp and auricles. At 6 months a nodule in served (Fig. 21.1). the right temporal area with underlying bone destruc- tion was also detected, and at the age of 10 months the Case 2. Langerhans Cell Histiocytosis left tonsil was affected. This 1-year-old boy for some time had had scattered Histologic investigation of two skin lesions from papulopustules all over the body and spells of fever. the abdominal wall showed in the papillae and upper Investigation revealed a high ESR (85 mm/h), pal- dermis dense infiltrates of LCH cells, which in the pable lymph nodes, and multiple bone lesions. The center of the lesion invaded and ulcerated the epi- disease became generalized and the patient died about dermis. A few mitotic figures, but no giant cells were 18 months later due to circulatory failure. A biopsy observed. There was a moderate admixture of eosin- specimen was taken from a lesion on the back. 150 21 Langerhans Cell Histiocytosis in Skin and Mucous Membranes Fig. 21.4 Langerhans cell histiocytosis. a Biopsy specimen from the axilla. There is a dense cell infiltrate in the dermis. The upper half is composed of LCH cells, which have also migrated into the epidermis and form intraepidermal abscesses (arrows); the lower part consists of lymphocytes. The arrowhead indicates a venule with fibrinoid wall necrosis. b Specimen from the inner aspect of the lower lip. A partly necrotic venule (arrow) is sur- rounded by a compact infiltrate of LCH cells and inflammatory cells, mainly neutrophils. c The arrow indicates a multinucleated LCH cell. H&E Histologic investigation revealed at all levels of the dermis large infiltrates of LCH cells, a fair number of which were multinucleated. No mitotic figures were seen. In and between the infiltrates there were areas of fibrinoid necrosis with accumulation of neutrophils. In the upper dermis a single small vessel with fibrinoid wall necrosis was noted; extravasation of erythrocytes was prominent. The cell infiltrate appeared to gnaw at the epidermis, which in the central part showed a small ulceration. There were many lymphocytes, but only sparse eosinophils (Fig. 21.2). Case 3. Langerhans Cell Histiocytosis A 17-year-old girl had been bothered for a long time by large genital ulcers. She also had diabetes insipi- dus and later developed lung infiltrates. At the age of 41 years she was in good health and, with the ex- ception of remaining diabetes insipidus, she had no symptoms. Histologic investigation showed widespread infil- trates of LCH cells that reached from the epidermis to the dermal–subcutaneous interface. A fair number of these cells were large and had two or three nuclei. Scattered mitotic figures were noted. Scattered LCH cells invaded the epidermis. Eosinophils were numer- ous. The tissue was edematous and contained a single totally necrotic venule which was filled with LCH cells and lymphocytes and surrounded by nuclear frag- ments and neutrophils. Many venules were stuffed with erythrocytes, but only a sparse number were ob- served outside vessels (Fig. 21.3). Case 4. Langerhans Cell Histiocytosis A 25-year-old woman had suffered from the age of 15 years from itching and oozing lesions in the vulva, perianal region, axilla, and scalp with periods of spon- taneous healing. For about a year she had also had vesicular and granulomatous lesions on the gingiva and loosening teeth. She presented with erythematous, scaling and pustular lesions in the areas named above 21.4 Comment 151 Fig. 21.5 Langerhans cell histiocytosis. a A small infiltrate of LCH cells is located close to a rete ridge in the papillary dermis.