Langerhans cell histiocytosis

Classification

LCH is clinically divided into three groups: unifocal, multifocal unisystem, and multifocal multisystem. Unifocal LCH, historically termed eosinophilic granuloma, involves a single organ, typically bone, though skin, lungs, or stomach may rarely be affected. When multiple lesions occur in one organ, it is called multifocal unisystem disease. Cutaneous single-system LCH refers to skin-only involvement and may resolve without therapy in rare cases.

Multifocal unisystem LCH, seen mostly in children, presents with fever, bone lesions, and diffuse eruptions on the scalp and ear canals; 50% of cases involve the pituitary stalk, often causing diabetes insipidus. The triad of diabetes insipidus, exophthalmos, and lytic bone lesions is known as the Hand–Schüller-Christian triad, with peak onset between 2 and 10 years. Multifocal multisystem LCH, or Letterer-Siwe disease, is a rapidly progressing form mostly in children under 2, with a poor prognosis: even with aggressive chemotherapy, five-year survival is only 50%.

LCH lesions consist of Langerhans cells combined with lymphocytes, eosinophils, and normal histiocytes, and can occur in almost any organ. A similar set of diseases has been described in canine histiocytic diseases.

Signs and symptoms

LCH provokes a non-specific inflammatory response including fever, lethargy, and weight loss. The most common symptom is painful bone swelling, with the skull most frequently affected, followed by long bones of the upper extremities and flat bones; osteolytic lesions can lead to pathological fractures. Skin involvement includes a rash ranging from scaly erythematous lesions to red papules, especially in intertriginous areas, and up to 80% of patients have extensive scalp eruptions.

Lymph node enlargement occurs in 50% of cases, splenic enlargement in 30%, and liver enlargement in 20%. Endocrine involvement commonly affects the hypothalamic-pituitary axis, and central diabetes insipidus may be the first manifestation. Lung involvement can be asymptomatic or cause chronic cough and shortness of breath.

Pathophysiology

The pathogenesis of LCH is debated, with arguments for both a reactive and a neoplastic process. Support for a reactive nature includes spontaneous remissions, extensive cytokine secretion in lesional tissue, and favorable prognosis in patients without organ dysfunction. Evidence for a neoplastic process includes monoclonal proliferation of pathologic cells, successful treatment with chemotherapy, and demonstration of clonality using X chromosome–linked DNA probes.

However, clonality alone does not prove malignancy; recurrent cytogenetic or genomic abnormalities would be needed to confirm LCH as a malignancy. An activating somatic mutation of the BRAF proto-oncogene was detected in 57% of LCH biopsy samples, with mutations more common in patients younger than 10 years (76%) than in those aged 10 and older (44%). This finding supports the notion of LCH as a myeloproliferative disorder.

Diagnosis

Diagnosis is confirmed by tissue biopsy. Hematoxylin-eosin staining shows distinct cell margins and pink granular cytoplasm. More specific features include Birbeck granules on electron microscopy and immunocytochemical markers such as CD1 positivity. Either electron microscopy or immunohistochemistry is required for definitive diagnosis, along with other pathologic and histologic qualities.

Imaging may reveal micronodular and reticular changes on chest X-rays, with cyst formation in advanced lung disease; MRI and high-resolution CT can show small cavitated nodules with thin-walled cysts. Brain MRI may demonstrate tumorous lesions in the hypothalamic-pituitary axis, nontumorous lesions with symmetrical T2 hyperintensity, or atrophy. Endocrine function assessment and bone marrow biopsy are performed when indicated. S-100 protein, peanut agglutinin, MHC class II, CD1a, and langerin (CD207) are expressed in LCH cells.

Did You Know?

• LCH is usually sporadic and non-hereditary, but familial clustering has been noted in a limited number of cases.
• Among LCH survivors, quality of life (SF-36) may be reduced in long-term follow-up despite generally favorable survival.