Case 4 -

Langerhans Cell Histiocytosis (Histiocytosis X) Lorenzo Cerroni Medical University of Graz Graz, Austria

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Clinical History A 15-year-old boy presented with sudden onset of eroded papules and small vesicles on the glans penis and preputium. A biopsy was taken under local anesthesia. Histology revealed an ulcerated, nodular infiltrate of mononuclear mid-sized cells, some with reniform nuclei. The infiltrate was located in the dermis with involvement of the epidermis by epidermotropic cells. Several mitoses could be seen. Immunohistochemical analyses showed positivity for S-100 and CD1a. A diagnosis of Langerhans cell histiocytosis was made, and a circumcision was performed. Staging investigations at presentation were negative. Three-and-a-half years later localized lung involvement was discovered during an investigation due to chronic pulmonary infection. The patient received long-term antibiotic treatment and is alive 4 years after first diagnosis. Case 4 - Figure 1 - Eroded papules and small vesicles on the glans penis and prepuce. Case 4 - Figure 2 - There is an ulcerated, nodular infiltrate of mononuclear mid-sized cells, some with reniform nuclei located in the dermis with involvement of the epidermis by epidermotropic cells. Several mitoses could be seen. Immunohistochemical analyses showed positivity for S-100 and CD1a. A diagnosis of Langerhans cell histiocytosis was made, and a circumcision was performed. Case 4 - Figure 3 - There is an ulcerated, nodular infiltrate of mononuclear mid-sized cells, some with reniform nuclei located in the dermis with involvement of the epidermis by epidermotropic cells. Several mitoses could be seen. Immunohistochemical analyses showed positivity for S-100 and CD1a. A diagnosis of Langerhans cell histiocytosis was made, and a circumcision was performed. Discussion: Langerhans cell histiocytosis, formerly termed "histiocytosis X", is the prototype of the histiocytoses, a protean group of clonal proliferative disorders characterized by the proliferation of histiocytes. The term "histiocytes" has been criticized in the past, but is still used to denote at least 5 different cell types and their associated disorders: macrophages, Langerhans cells, indeterminate cells, sinus histiocytes, and dermal dendrocytes. Langerhans cell histiocytosis is caused by the uncontrolled proliferation of Langerhans cells. Langerhans cells derive from the bone marrow, and after maturation (involving phenotypic changes) are found in the spinous layer of the epidermis. On electron microscopy (nowadays largely of historical value in the identification of these cells and of the diseases associated with them) they show the characteristical tennis racket-like granules named after Birbeck. They can be stained by anti-S100 protein antibodies and with antibodies directed to CD1a (these last being more specific). Langerhans cell histiocytosis is a group of disorders including acute disseminated Langerhans cell histiocytosis (Letterer-Siwe disease), chronic Langerhans cell histiocytosis (Hand-Schuller-Christian disease), so-called eosinophilic granuloma, congenital self-healing histiocytosis (Hashimoto-Pritzker disease), and indeterminate cell histiocytosis. The pathogenesis of these disorders is yet unknown, and no certain causative agent has been identified so far. Familial cases have been described, pointing at a possible genetic basis for Langerhans cell histiocytosis. Aberrant expression of chemokine receptors or dysregulation of chemokine production may explain the abnormal proliferation and retention of neoplastic cells. The clinical features of cutaneous Langerhans cell histiocytosis vary depending on the subtype. Patients with acute disseminated Langerhans cell histiocytosis (Letterer-Siwe disease) are often children presenting with eczematous, scaly and/or crusted papules and small plaques, sometimes simulating the clinical picture of seborrheic dermatitis. Lesions may arise on the mucosal regions. Although in most patients skin lesions are disseminated, sometimes a localized form of the disease may be observed with several papules clustered at a single body site. Skin lesions of indeterminate cell histiocytosis are very similar, but patients are more often adults. But for the lack of Birbeck granules these two forms of Langerhans cell histiocytosis are indistinguishable. Congenital self-healing retisulohistiocytosis is characterized by a smaller number of more hemorrhagic lesions, that usually present as ulcerated nodules. Cutaneous manifestations of Hand-Schuller-Christian disease and of eosinophilic granuloma are less common and do not show distinctive clinical diagnostic aspects. Staging investigations of the hematologic, pulmonary, hepatic, splenic, renal and skeletal systems should be performed in every patient in order to determine the extent of disease. The histopathological features of Langerhans cell histiocytosis are variable, too. Typical cases reveal a lichenoid infiltrate of medium-sized cells with pale cytoplasm and characteristic reniform nuclei. The epidermis may show psoriasiform hyperplasia, and epidermotropism is common. Other lesions may be characterized by a nodular arrangement of the neoplastic cells. A variable infiltrate of lymphocytes and eosinophils is present in both the lichenoid and the nodular forms. Staining for S-100 protein or CD1a are helpful in confirming the lineage of the cells. Immunohistochemical stainings may be especially helpful in cases presenting with a lichenoid infiltrate and epidermotropism, where the differential diagnosis includes mainly mycosis fungoides and other epidermotropic lymphomas. It is not possible to subclassify Langerhans cell histiocytoses on the basis of histopathological aspects only, as all subtypes present with overlapping features. On electron microscopy, Birbeck granules are absent in indeterminate cell histiocytosis (hence the name) and in most cases of congenital self-healing reticulohistiocytosis. Although localized forms are usually characterized by a benign biologic behaviour, widespread variants show commonly multisystem involvement and may have a bad prognosis. Treatment of these forms includes administration of complex multidrug regimens including etoposide, vinblastin, predisolone, and mercaptopurine. Localized skin lesions may be treated by CO2 laser vaporisation, curettage, or surgical excision. The recent demonstration that anti-CD52 antibody (alemtuzumab) binds to neoplastic cells in Langerhans cell histiocytosis (but not on normal Langerhans cells) may provide new strategies in patients with generalized systemic disease. 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