Cutaneous Manifestations of the Histiocytoses

Pathogenesis

The pathogenesis of LCH was uncertain until recently and there was much debate as to whether to classify LCH as a reactive or neoplastic condition. Studies have not shown evidence of an infectious etiology, and demonstrated elevated levels of multiple cytokines and interleukins in LCH are believed to be produced by the LCH inflammatory cell infiltrate rather than being responsible for causing the disease.

The recent major discovery of recurrent BRAF 600E mutations provides strong evidence to regard LCH as a neoplastic condition. Rare cases of familial LCH have been documented as well, and several older studies have demonstrated consistent clonality in LCH tissue. Given these later findings, LCH appears to represent a clonal neoplastic disorder.

Clinical Manifestations

Langerhans cell histiocytosis (LCH) is a rare disorder. Although it most commonly presents in children from ages 1 to 3 years it can occur at any age and is more common in males. The disease ranges from mild asymptomatic involvement of a single organ to severe, multiorgan system involvement with a high mortality. Given the wide range of disease expression, it is not surprising that the etiology of the disease was uncertain until later in the twentieth century, with four previously described syndromes found to represent overlapping clinical variants of LCH. These variants include Letterer–Siwe disease, Hand–Schuller–Christian disease, eosinophilic granuloma, and Hashimoto–Pritzker (congenital self-healing reticulohistiocytosis). While it is well recognized that LCH is one disease with a broad clinical spectrum, it is still helpful to note the older variants for perspective.

The acute form of LCH with diffuse and multisystem involvement was previously referred to as Letterer–Siwe disease. While it usually presents in infants less than 2 years of age, it can occur at any age. It presents as erythematous to skin-colored crusted 1 to 2-mm vesiculopustules, sometimes with secondary impetiginization, involving the scalp ( Fig. 22-1 ), neck, intertriginous areas, and bathing trunk area ( Fig. 22-2 ). Coalescing areas can become fissured, and petechia and purpura are also common. Soft tissue nodules can occur and rare presentations include ulcerative lesions and a papular form imitating molluscum contagiosum. Nail changes have also been described. The lungs, liver, spleen, and bone are commonly involved during the disease course. Lytic bone lesions are painful and primarily affect the cranium, vertebrae, and flat bones. So-called risk organ involvement includes the marrow (hematopoietic system), liver, lungs, and spleen. The prognosis of this form of LCH is variable. In those patients with risk organ involvement, especially in children less than 2 years of age, there is a high risk of mortality and systemic treatment is required.

Some patients present with a chronic and progressive form of disease. This form most often presents during childhood. Although LCH in adults is very uncommon, a chronic progressive course is a common mode of presentation in adults. Bone lesions are very frequent in this form (at least 80%) and approximately one-third of patients develop skin or mucous membrane lesions. LCH cells also infiltrate the posterior pituitary gland in approximately 30% of patients causing diabetes insipidus. Rarely, exophthalmos develops as a late finding. The triad of diabetes insipidus, bone lesions, and exophthalmos was previously referred to as Hand–Schuler–Christian disease. The skin lesions, favoring the scalp, upper trunk, and intertriginous areas, are initially similar to those described in the acute form, but ulcerating nodules can develop especially in the gingival and genital areas. Lesions can occur in crops, older lesions can become xanthomatous, and some may spontaneously regress leaving scars. The cranium is the most common site of bone involvement. Chronic otitis media is also common and can be a clue to the presence of cranial involvement. Although patients with this variant tend to have persistent or progressive disease, most will survive with treatment.

Eosinophilic granuloma is a localized variant of LCH with a striking predilection for the bone. It most commonly occurs in older children. The most common presentation is a single, often asymptomatic granulomatous cranial lesion, though any bone can be affected. The lung can also be involved, which may be confused with but likely overlaps with a separate variant of LCH, pulmonary Langerhans cell histiocytosis (PLCH). Development of PLCH has a strong association with cigarette smoking and usually occurs in young adult males, with a predilection for Caucasian men. In eosinophilic granuloma, skin and mucous membrane lesions are rare although mucocutaneous nodules can present in the periorofacial, genital, or perianal regions. Patients with this variant can have a prolonged course but have an overall good prognosis.

Congenital self-healing reticulocytosis (Hashimoto–Pritzker) presents in newborn infants as a solitary lesion, multiple, or diffuse 2-mm to several centimeter red-brown papules or nodules, which may, over time, ulcerate and crust. Vesicular lesions can also occur. The vast majority of cases are limited to the skin but, uncommonly, involvement of the liver, colon, marrow, and spleen have been described. The prognosis is excellent as the lesions spontaneously regress over 2 to 3 months. However, postlesional scars can be permanent sequelae.

Differential Diagnosis

The differential diagnosis is extensive and includes seborrheic dermatitis, eczema, diaper dermatitis, Darier’s disease, urticaria pigmentosa, arthropod bites, scabies, leukemia, B- and T-cell lymphomas, and some of the non-Langerhans cell histiocytoses (especially indeterminate cell histiocytosis, benign cephalic histiocytosis, generalized eruptive histiocytosis, and xanthoma disseminatum). Ear involvement can easily be mistaken for chronic otitis media or otitis externa. As this is predominantly a disease of the pediatric population, it may not be suspected in adults leading to delay in diagnosis.