Langerhans Cell Histiocytosis

Langerhans cell histiocytosis (LCH), formerly known as Histiocytosis X, is a rare condition that can produce painful lytic bone lesions in children. There is ongoing debate as to whether the neoplasm is caused by a primary proliferation of dendritic histiocytes (a type of antigen-presenting white blood cell) or by a reactive process. These histologic lesions represent 3 clinical syndromes. When Langerhans cell histiocytosis presents as a single bone lesion, it is called an eosinophilic granuloma. When it presents as a multifocal entity with possible soft-tissue involvement or multi-organ involvement, it is known by the eponym Hand-Schüller-Christian disease. Although Hand-Schüller-Christian disease is often described as a clinical triad of exophthalmos, lytic bone lesions (multifocal eosinophilic granulomas), and diabetes insipidus, the complete triad is not always present. The final disease characterized by the presence of these lesions is Letterer-Siwe disease which is the most severe form of this disorder characterized by multi-organ system involvement typically in children less than 3 years of age with an associated high mortality.

Epidemiology

Langerhans cell histiocytosis is an uncommon disorder, with an incidence of about 5 cases per million individuals annually in the United States. It predominantly affects children, with nearly all diagnoses occurring in people under the age of 20. Isolated eosinophilic granuloma lesions in bone typically present between ages 5 and 15 years but can be seen at any age. The systemic forms of Langerhans cell histiocytosis usually present earlier, between ages 1 and 5 years. Males are affected more frequently than females, with a male-to-female ratio of approximately 2:1. Overall, 80% of these lesions are monostotic, occurring in a single bone, and can be found throughout the skeleton. The skull is the most frequent location overall. The femur is the most frequently affected long bone; lesions there are typically found in the proximal metaphysis. Langerhans cell histiocytosis can also develop in flat bones such as the skull, mandible, ribs, and iliac wing.

Clinical Features

Most patients with Langerhans cell histiocytosis present with mild pain or tenderness in the affected area that can be worse at night. Rarely do patients present with systemic symptoms such as a fever. When the lesion occurs within a weight-bearing long bone, patients can develop mechanical pain due to cortical thinning. Patients with lesions of the spine frequently present with localized pain and restricted spine motion. Cervical lesions may present with torticollis.

Laboratory findings are usually unremarkable but can include an elevated erythrocyte sedimentation rate. When the lesion is part of one of the associated systemic diseases, there can be palpable soft-tissue masses. In some cases, the lung can be affected, leading to pulmonary fibrosis. Skin and mucosal lesions of the oral cavity can be seen, especially in older patients.

These patients are typically managed by pediatric hematology-oncology specialists. To determine the overall disease burden, staging studies are performed with a skeletal survey, bone scan, or low-dose whole-body computed tomography (CT) and chest X-ray. CT and/or magnetic resonance imaging (MRI) are indicated for specific areas of involvement. For example, a brain MRI is indicated in patients who report polyuria or polydipsia to evaluate the pituitary fossa.

Radiologic Features

Langerhans cell histiocytosis lesions seen on plain radiographs are typically intra-medullary lytic diaphyseal lesions with a moth-eaten border (Figure 1). A benign or more aggressive periosteal reaction may be visible. A hallmark radiographic finding of eosinophilic granuloma of the spine is vertebra plana, or collapse of a vertebral body. (Figure 2). This finding is typical of but not diagnostic for eosinophilic granuloma and can be seen with any locally aggressive tumor that lyses vertebral body bone resulting in collapse. On bone scans, there is usually moderate radiotracer uptake. On MRI of LCH bone lesions, T1-weighted images show marrow replacement and associated inflammation, while T2-weighted images show marrow involvement and associated marrow and periosteal edema. Soft-tissue masses may also be seen. Given these radiologic features, eosinophilic granuloma is often mistaken for lymphoma, bone sarcoma, or infection.

Figure 1: AP radiograph of the proximal femur in a skeletally immature patient, demonstrating the characteristic lytic lesion of eosinophilic granuloma.

Figure 2: Lateral radiograph of the lumbar spine demonstrating vertebra plana.

Pathology

Under low-power microscopy, a mixed inflammatory infiltrate is visible, which includes Langerhans cells, eosinophils, lymphocytes, and occasionally multinucleated giant cells. At higher magnification, the key diagnostic cells, Langerhans cells, become more apparent. These cells have abundant pale eosinophilic cytoplasm and characteristic folded, grooved, or indented nuclei often described as ‘coffee-bean’ shaped.

Immunohistochemistry is crucial for diagnosis. The Langerhans cells stain positively for S100, CD1a, and CD207 (also known as langerin). These markers are highly specific for Langerhans cell histiocytosis (Figure 3A-3C). Eosinophils, while often present and perhaps the most visible histologic feature, are not the diagnostic feature. They have pink cytoplasm and bilobed nuclei.

Figure 3: (A) Low- and (B) high-power H&E stains of eosinophilic granuloma, demonstrating eosinophils with bilobed nuclei and pink cytoplasm and intervening foamy histiocytes. (C) Eosinophilic granuloma stains positively for CD1a. (Courtesy of Dr. Gord Zhu)

The combination of morphology and immunohistochemistry is usually sufficient for diagnosis, and electron microscopy is rarely necessary. If electron microscopy is performed, so-called Birbeck granules can be seen within the Langerhans cells. These have a characteristic ‘tennis-racket’ appearance.

Differential Diagnosis

Osteomyelitis
Ewing sarcoma
Lymphoma
Multiple myeloma (adults)
Metastatic neuroblastoma
Rhabdomyosarcoma
Small-cell osteosarcoma

Disease Course: Treatment and Prognosis

The treatment of Langerhans cell histiocytosis is primarily determined by the extent of disease involvement; namely whether the disease presents as a single bone lesion, multifocal bone disease, or multisystem disseminated disease that involves organs beyond the skeletal system.

Notably, some isolated Langerhans cell histiocytosis lesions (i.e., eosinophilic granuloma) can spontaneously regress. Thus, for non-painful lesions, especially those that are difficult to access, observation may be sufficient once a histologic diagnosis is confirmed. Vertebral lesions in young children can cause kyphosis or scoliosis and must be monitored clinically. If the lesion is painful and accessible with minimal morbidity, surgical excision and curettage with or without fixation is indicated. Low-dose radiation or steroid injection can be performed for lesions that are not easily accessible.

In cases of polyostotic or disseminated disease, chemotherapy with vinblastine or other chemotherapy drugs has been successfully utilized in the pediatric population. Compared to those with single-site disease, patients with multiorgan involvement have much poorer outcomes, characterized by the potential for increasing organ failure and functional impairment.

Survival and disease-free recurrence rates for monostotic disease are excellent, approaching 100%. For polyostotic disease, 10-year survival rates are approximately 95%, and for multisystem disease, about 70%, though extensive organ involvement can lower that rate.

Key Test Topics

Eosinophils have pink cytoplasm and bilobed nuclei but are not the diagnostic cell — Langerhans cells are
CD1a and S100 positivity.
Birbeck granules.
Excision and curettage can used for local treatment if observation is not successful or contraindicated by the effect of the tumor on the host bone.