May 2006

Fig.3

Fig.4

Diagnosis: Adult-Onset Langerhans Cell Histiocytosis

Histopathology: Biopsies from the scalp and groin revealed an infiltrate of mononuclear cells with reniform nuclei and eosinophilic cytoplasm (Fig 3,4). Immunohistochemistry was positive for vimentin, CD1a and S100 and negative for CK56 and
melan A.

Course and Treatment: A CT scan revealed a lung nodule indicating likely multi-system disease. The patient was referred to oncology for further evaluation and chemotherapy.

Discussion:
Langerhans cell histiocytosis (LCH) is a group of disorders characterized by a clonal proliferation of CD1a and S-100 positive histiocytes which contain Birbeck granules. The pathogenesis of LCH is widely debated. Infectious, genetic, and autoimmune etiologies have all been considered; however, it is still unclear whether LCH represents a reactive or neoplastic proliferation (1). Historically, LCH was termed histiocytosis X and included the subtypes of Letterer-Siwe disease, Hand-Schüller-Christian disease, eosinophilic granuloma, and congenital self-healing reticulohistiocytosis. Letterer-Siwe disease describes the disseminated form of LCH which usually occurs in children under 2 and often involves the lung, liver, and lymph nodes in addition to the skin. Hand-Schüller-Christian disease refers to the classic triad of diabetes insipidus, exophthalmos, and bone lesions. Eosinophilic granuloma is a variant with involvement limited to the bone. Hashimoto-Pritzker disease, or congenital self-healing reticulohistiocytosis, refers to localized skin disease which occurs in newborns and regresses without intervention (2). Recently, it has been recognized that there is significant overlap between these subtypes and many cases do not fit well into any of these categories. Therefore, the current classification system recommends the designation of cases of LCH as either single-system (SS) or multi-system (MS) rather than as one of the historically named variants (3).

LCH most commonly presents in children, but can occur at any age. It is a rare disease in adults with an estimated incidence of 1-2 cases per million (4). The most common presenting signs of LCH in adults include pain secondary to bone lesions, weight loss, and fever (5). When LCH does occur in adulthood, it is most often a multi-system disease. Common sites of disease include lung, skin, bone, liver, and lymph nodes. Less frequently, the CNS, gastrointestinal tract, or bone marrow are involved. Diabetes insipidus is an important complication in adults as well as children and occurs in up to 30% of cases of LCH (5). Approximately 20-30% of adults with LCH have isolated single-system pulmonary disease (5). This appears to be a distinct variant related to tobacco use. Isolated cutaneous LCH is extremely rare in adults, but up to 50% of patients with multi-system disease will have cutaneous manifestations. The most classic lesions of LCH are red-brown papules and nodules that are often scaly and crusted; however, the morphology of the skin lesions can be variable, and petechiae, purpura, vesicles and pustules have all been described (2).

Diagnosis of LCH must be made by biopsy of involved tissue, most often from skin, bone, or lungs lesions. Histopathology reveals an infiltrate of Langerhans cells in the epidermis and papillary dermis. These cells can be identified by their large size and characteristic reniform nucleus with a nuclear groove. Immunohistochemistry with positive staining for CD1a and S100 or electron microscopy demonstrating Birbeck granules is necessary to differentiate LCH from the non-Langerhans cell histiocytoses (2). Once a diagnosis of LCH is made in an adult, a comprehensive evaluation including a bone scan, skeletal survey, chest X-ray, and abdominal ultrasound should be performed as systemic involvement is often asymptomatic at presentation (4).

A retrospective study of 274 adults with LCH found that the probability of survival at 5 years postdiagnosis was 92.3% overall, 100% for patients with single-system disease, 87.8% for isolated pulmonary disease, and 91.7% for multisystem disease (5). Risk organ involvement (liver, spleen, lungs, and lymph nodes) with organ dysfunction and suboptimal response to initial treatment are poor prognostic factors (4). Single-system disease can often be treated conservatively with surgical resection, intralesional or systemic corticosteroids, or radiotherapy (4). Patients with disseminated disease require systemic chemotherapy. The optimal regimen has not been determined but usually includes prednisone and vinblastine as initial agents (5).

REFERENCES

1. McClain KL, Natkunam Y, Swerdlow SH. Atypical cellular disorders.Hematology Am Soc Hematol Educ Program. 2004;1:283-96.
2. Dermatology. Jean Bolognia, Joseph L Jorizzo, Ronald P Rapini. Elsevier Inc., 2003.
3. Favara BE, Feller AC, Pauli M, et al. Contemporary classification of histiocytic disorders. The WHO Committee On Histiocytic/Reticulum Cell Proliferations. Reclassification Working Group of the Histiocyte Society. Med Pediatr Oncol. 1997;29:157-66.
4. Stockschlaeder M, Sucker C. Adult Langerhans cell histiocytosis.Eur J Haematol. 2006;76:363-8.
5. Arico M, Girschikofsky M, Genereau T, Klersy C, McClain K, Grois N, Emile JF, Lukina E, De Juli E, Danesino C. Langerhans cell histiocytosis in adults. Report from the International Registry of the Histiocyte Society. Eur J Cancer. 2003;39:2341-8.

Case presented by Drs. Kara Nunley, Kim Crone, and Milan Anadkat.