A previously healthy 6-month-old boy presented to the pediatric dermatology clinic for evaluation of a persistent, pruritic eruption. This eruption involved the scalp, extremities, and inguinal creases and was intensely pruritic. The patient had been previously treated with multiple topical corticosteroids and antifungals, all with minimal improvement. He born at full term and was otherwise well and thriving. Review of systems was negative.
Examination revealed erythematous to yellow scaly, greasy plaques, some with underlying purpuric papules in the frontal, temporal, and vertex of the scalp (Figures 1 and 2), post-auricular regions (Figure 3), and the conchae of both ears. There were also scattered papules and purpura noted in the inguinal creases (Figure 4), and hyperkeratotic yellow papules on the extensor extremities. He had no abnormal lymphadenopathy or hepatosplenomegaly. The remainder of his examination was normal. A diagnostic skin biopsy was performed.
The patient’s biopsy revealed a dense infiltrate of large histiocytes with a reniform (kidney-shaped) nucleus. These cells stained with CD1a, confirming the diagnosis of Langerhans cell histocytosis (LCH). His initial skeletal survey and laboratory testing were normal. One month after presentation to dermatology, he developed a mass in the right mandible area. Imaging revealed a lytic expansile lesion consistent with LCH. He was initially treated with vinblastine and is currently on methotrexate for persistent symptomatic skin disease.
Langerhans cells are derived from the bone marrow and normally reside in the epidermis as the antigen presenting cells of the skin.1 LCH is a disorder characterized by infiltration of the skin and other tissues with Langerhans cells. It represents a disease spectrum that has historically been classified into four overlapping syndromes: Letterer-Siwe disease, Hand-Schuller-Christian disease, eosinophilic granuloma, and congenital self-healing reticulohistiocytosis. Letterer-Siwe disease describes the acute, diffuse presentation of LCH, generally presenting in children aged younger than 2 years with multi-organ disease. Classic Hand-Schuller-Christian disease comprises the triad of diabetes insipidus, exophthalmos, and bone lesions. In contrast, eosinophilic granuloma affects older children, with the most common presentation being a single granulomatous lesion of the bone. Finally, congenital self-healing reticulohistiocytosis is a variant of LCH presenting as red-brown nodules in a neonate, which often spontaneously involute. Although historically, LCH was divided into these four separate entities, it has become clear that there is significant clinical overlap among these syndromes. Furthermore, all patients with LCH should undergo a thorough evaluation for multi-organ disease and be followed long-term for disease progression, which renders subtyping of LCH cases to limited clinical importance.
Disease expression in LCH patients can range from mild, asymptomatic, single-organ involvement to severe, progressive multisystem disease. Children aged 1 to 3 years are most commonly affected, and the disorder is more common in boys than girls with a male:female ratio of 2:1.
The precise etiology of LCH remains unclear, and hypotheses include somatic mutations, viral infection, immune or cytokine dysregulation, and programmed cell death.2,3,4,5 In one recent study, 57% of LCH specimens were found to have the BRAF V600E mutation, which has also been described in cutaneous melanomas.6 Several investigators have demonstrated clonality in LCH tissue, further suggesting that LCH may be best regarded as a neoplastic disorder.5,7,8
LCH can involve multiple organ systems, with skin and bone being the most common sites of involvement. The lymph nodes, liver, spleen, lungs, gastrointestinal tract, thymus, bone marrow, oral mucosa, kidney, endocrine glands, and central nervous system can also be involved.9
Diabetes insipidus is the most common endocrinopathy in LCH and is more likely when bony involvement of the skull is present. Cutaneous involvement is extremely common in LCH, with a persistent eruption often being the presenting complaint. Classically, affected children present with scaly red-brown papules in the scalp and flexural areas that may have associated crusting. Erosion, ulceration, and hemorrhage are common secondary changes, particularly in the intertriginous regions. Involvement of the palms, soles, and nails can occur, as can deeper nodules. The eruption of LCH is often misdiagnosed as seborrheic dermatitis, irritant diaper dermatitis, intertrigo, arthropod bites, scabies, and varicella infection. When seborrheic dermatitis or diaper dermatitis is refractory to multiple treatments, LCH should be considered. Likewise, when a diagnosis of arthropod bites, scabies, or varicella is made but the patient fails to improve in the expected time course, the diagnosis should be reconsidered.
LCH is diagnosed by examination of tissue specimens of affected organs, often the skin. Histologic examination reveals an infiltrate of Langerhans cells, which can he confirmed by positive CD1a, Langerin, and S100 staining. The recommended evaluation for the patient with LCH includes a physical examination, complete blood count, coagulation studies, hepatic function panel, urine osmolality, skeletal survey, and a chest radiograph.10 The prognosis for patients with LCH is quite variable and depends on the extent of organ involvement. In general, an older age at diagnosis, lack of organ dysfunction, and good response to therapy are all good prognostic indicators. Failure to respond to treatment after 6 weeks of therapy is a predictor of poor outcome.9,11 Multisystem disease with hematopoietic, liver, lung, or spleen involvement also carries a worse prognosis, and mortality in these patients approaches 55%,12 even with aggressive treatment. Patients with limited disease tend to do better, but even these patients must be followed long-term for persistent and progressive disease.
A diagnosis of LCH also raises concern for an increased risk of malignancy. Specifically, LCH patients seem to be at an increased risk for retinoblastoma, acute lymphoblastic leukemia, or acute myologenous leukemia. Interestingly, there also may be an increased incidence of LCH developing in patients who have pre-existing leukemias or solid tumors. The mechanism of these associations remains unclear and may be related to treatment with chemotherapy or radiation.8
Therapy for LCH depends on the extent of the disease. Patients with skin-only disease are often observed with no treatment, and lesions may improve spontaneously. Topical nitrogen mustard is considered in extensive cutaneous cases, and in patients with severe disease, systemic therapy may be considered.13 Isolated bone lesions may resolve spontaneously, as well, but painful lesions may be treated with curettage, excision, intralesional steroids, or radiation therapy.14,15 Most patients with multisystem disease are treated with systemic chemotherapy, such as vinblastine or etoposide, often with systemic corticosteroids given during induction.12
LCH is a rare but potentially fatal disorder, and diagnosis is often delayed. It is therefore essential that the pediatrician is familiar with the cutaneous lesions of LCH so that appropriate evaluation can be promptly initiated.