Article Update

Wednesday, July 8, 2020


Langerhans cell histiocytosis (LCH) is a rare disorder caused by the proliferation of Langerhans cells in various tissues. Historically, the disease was categorized based on the grouping of symptoms and organs affected, with names such as Letterer-Siwe disease and Hand- Schüller-Christian disease. Over the last decade, the classification of LCH has been standardized. The new classification does not remove the eponyms that have been used for years but rather categorizes the LCH into subgroups based on prognosis and amount of involvement. These histiocytoses are a heterogeneous group of diseases that may affect both the skin and various internal organs. The main pathological finding is the accumulation of pathological Langerhans cells within the affected tissue. The diagnosis is made on clinical, histological, laboratory, and radiographic findings. The newer classification of LCH is based on the number of organ systems involved. It includes the subtypes of restricted single-system LCH, extensive multisystem LCH, and single-system pulmonary LCH. The extensive multisystem form of LCH can be further divided into those cases with and without organ dysfunction. Prognosis and therapy depend on the organ systems involved and the number of systems implicated. Optimal therapy has yet to be determined.

Clinical Findings: LCH is a very rare condition that affects approximately 8 of every 1,000,000 people. There is a 2:1 male-to-female predilection, and all races are affected equally. Usually, the condition is first noticed in childhood, but adult-onset disease does occur. LCH isolated to the skin has one of the best prognoses of all of the forms of LCH. Most cases of LCH manifest first in the skin, even before the development of systemic findings; therefore, all patients with cutaneous LCH should be routinely screened for systemic diseases.

In infants, the typical presenting skin findings are those of a persistent papulosquamous eruption on the scalp that resembles cradle cap. On closer inspection, small petechiae are observed. These petechiae are very characteristic for LCH and can be easily overlooked. The scalp form is often misdiagnosed as seborrheic dermatitis early in infancy, and frequently it is not until the child is 3 to 6 months old and the rash has persisted that the diagnosis of LCH is entertained. The other common presentation in children is that of persistent diaper dermatitis. The rash has a unique predisposition to affect the groin folds and can be quite inflammatory and resistant to typical therapy for irritant contact dermatitis or diaper rash. The groin rash appears as red to yellowish-orange papules that coalesce into plaques. Ulcerations and erosions are common. Superinfection with bacteria often leads to an odor. Both of these forms are almost always considered to be another diagnosis before LCH is considered and a skin biopsy is done to prove the diagnosis. Other skin findings that can be observed by the astute clinician are adenopathy, ear inflammation and drainage from the external ear, and soft tissue swelling. The soft tissue swelling is seen only in those patients with underlying bony disorders. Gingival hypertrophy may also be seen, but it is often subtle. Infants may also have premature eruption of their teeth, which is most commonly noticed by the still breast-feeding mother.
Twenty percent of patients do not exhibit any cutaneous signs of disease and present solely with varying systemic complaints. The most common extracutaneous form of LCH, formerly designated eosinophilic granuloma, is now called single-system unifocal bone disease. Children present with a painless to slightly tender soft tissue swelling overlying the bony area of involvement, most commonly the calvarium. Palpation of the swelling reveals the fluctuant nature of the soft tissue distention, and in some cases the defect in the underlying bone can be felt. Plain radiographs can help delineate the extent of disease. If one area of bony involvement is found, a skeletal survey should be performed to evaluate for other silent bony lesions, which can occur in up to 15% of cases. The involved bone has a radiolucent appearance that is sharply demarcated from the surrounding bone. Bony involvement has been described to occur in almost every bone in the body. Most cases are inconsequential, but if the involvement affects a critical portion of the spine, the possibility of weakening of the joint and potential fracture could have life-threatening implications. The term “floating teeth” has been used to describe the finding of radiolucent aspects of the mandible that give the appearance that the teeth are floating without the support of the under- lying bone.
LCH can be a life-threatening, progressive disease. The lymphatic system, lungs, hypothalamus, and pituitary are commonly involved. Lymphadenopathy in the region of skin or bony involvement is usually seen. Biopsies of lymph nodes can show involvement with Langerhans cells or dermatopathic changes.
Lung involvement is almost always a component of multisystem disease. Radiographs may be normal or may show cystic spaces or a nonspecific interstitial infiltrate. Pulmonary function testing may reveal a decrease in diffusion capacity and a decrease in forced expiratory volume. Lung abnormalities are very frequently seen in adults with LCH.
The pituitary stalk can also be affected in this disease. The eponym Hans-Schüller-Christian disease describes those patients with LCH who have the constellation of diabetes insipidus, lytic bony lesions, and exophthalmos. The involvement of the pituitary stalk leads to the diabetes insipidus. The lack of antidiuretic hormone causes the excretion of large amounts of dilute urine and increased thirst. The skull is the bony region most commonly involved.
Letterer-Siwe disease is the name given to the constellation of symptoms that include severe skin involvement, hepatosplenomegaly, anemia, and leukopenia. These patients have early onset of disease in infancy and have a poor prognosis because of the aggressiveness and extent of the disease load.
The diagnosis and prognosis of LCH depend on the number of organ systems involved and the extent of disease. Treatment likewise depends on these factors, and a multidisciplinary approach should be taken.
Pathogenesis: The exact etiology is unknown, and there is considerable ongoing research to determine whether this is a clonal malignant process or a reactive process. The Langerhans cells that are present within the areas of involvement have a different morphology from their normal counterparts. The affected Langerhans cells are round, without dendritic processes, and have been found to express different cell surface markers. The initiating factor or factors for these findings are as yet only theoretical. No gene defect has been described.

Histology: Histological findings from the skin and other involved tissues are only slightly different. The main pathology is found within the sheets of abnormal-appearing Langerhans cells. On microscopic evaluation, the cells have kidney bean–shaped nucleus and show varying amounts of epidermotropism. Immunohistochemical staining shows CD1a, S100 and CD207 positivity. On electron microscopy, the characteristic tennis racket–shaped Birbeck granules are seen.
Treatment: Therapy is determined by the extent and location of disease state. Mild, localized cutaneous single-system disease may be observed and watched carefully for the development of systemic involvement. Supportive care is given with topical anti-inflammatory agents and antiinfectives to help treat and prevent possible infections, especially infections of the groin region in infants. A small percentage of patients experience spontaneous remission. Single bony lesions may also remit spontaneously.
Bony lesions have been treated with resection of the involved tissue, with curettage of the region, and with systemic steroid therapy. The use of steroids has been associated with recurrences after the drug is stopped.
Multisystem disease is treated in myriad manners, depending on the burden of disease, the systemic involvement, and the patient’s symptoms. The disease can be difficult to treat, and systemic chemotherapies are the mainstay of treatment. Vinblastine or etoposide based regimens are most commonly used as first-line therapy. Some refractory disease has been treated with ablative chemotherapy and subsequent bone marrow transplantation.

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