Langerhans cell histiocytosis overview

# Overview
Langerhans cell histiocytosis arises from epidermal dendritic cells (Langerhans cells), which are normally involved in the process of antigen presentation to lymphocytic cells. Langerhans cells originally arise from the bone marrow, then the cells migrate to other organs such as the skin, lymph nodes, and lungs. The exact pathogenesis of Langerhans cell histiocytosis is not fully understood. It is thought that Langerhans cell histiocytosis is the result of either a true neoplastic process or a reactive immune condition. Genes commonly involved in the pathogenesis of Langerhans cell histiocytosis include BRAF gene and MAP2K1 gene. On gross pathology, scaly erythema, red papules, and extensive eruptions located on the scalp are characteristic finding of Langerhans cell histiocytosis. Characteristic findings of Langerhans cell histiocytosis on light microscopy may include clusters of dendritic cells with kidney-shaped nucleus and abundant foamy cytoplasm. On electron microscopy Langerhans cell histiocytosis is characterized by Birbeck granules, which are electron dense, cytoplasmic, tennis racket-like bodies. On immunohistochemistry Langerhans cell histiocytosis is characterized by positivity to CD1a, S100, and CD207 (langerin). Langerhans cell histiocytosis is a rare disease that tends to affect children and adolescents. The median age at diagnosis depends on the specific subtype of the disease. The incidence of Langerhans cell histiocytosis is approximately 5 per 1,000,000 individuals in the United States. Males are more commonly affected with Langerhans cell histiocytosis than females. The male to female ratio is approximately 2 to 1. Langerhans cell histiocytosis usually affects Caucasian and Hispanic individuals. African American individuals are less likely to develop Langerhans cell histiocytosis. Common symptoms of Langerhans cell histiocytosis include bone pain, rash, fever, and failure to thrive. Langerhans cell histiocytosis patients often appear cachectic. Physical examination of patients with Langerhans cell histiocytosis is usually remarkable for scaly erythematous lesions located on the scalp and extremities, localized bone tenderness, and hepatosplenomegaly. Observation is recommended for all pediatric patients with an isolated Langerhans cell histiocytosis skin involvement. Medical therapy is suggested only for symptomatic cutaneous disease that presents with either extensive rash, sever pain, skin ulceration, or bleeding. Medical therapies used for the treatment of isolated skin lesions of Langerhans cell histiocytosis include topical steroids, nitrogen mustard, and oral thalidomide. Curettage is the mainstay treatment for single skull lesions that involve the frontal, parietal, or occipital bones. The most commonly used systemic chemotherapy regimen for the management of multiple bone lesions is a combination of vinblastine AND prednisone. The standard therapy recommended for Langerhans cell histiocytosis involving the spleen, liver, or bone marrow (high-risk organs) consists of vinblastine AND prednisone AND 6-mercaptopurine for a 12 month period.

# Historical Perspective
The clinical presentation of Langerhans cell histiocytosis was first described by Dr. Alfred Hand Jr., an American pediatrician, in 1893. The term histiocytosis X was first used to describe the disease by Dr. Sidney Farber, a pathologist at Boston Children's Hospital, in 1941. The term Langerhans cell histiocytosis was finally agreed upon in 1987 by the the Writing Group of the Histiocyte Society.

# Classification
Langerhans cell histiocytosis may be classified according to the extent of organs involvement into 4 groups: pulmonary Langerhans cell histiocytosis, unifocal Langerhans cell histiocytosis, multifocal unisystem Langerhans cell histiocytosis, and multifocal multisystem Langerhans cell histiocytosis.

# Pathophysiology
Langerhans cell histiocytosis arises from epidermal dendritic cells (Langerhans cells), which are normally involved in the process of antigen presentation to lymphocytic cells. Langerhans cells originally arise from the bone marrow, then the cells migrate to other organs such as the skin, lymph nodes, and lungs. The exact pathogenesis of Langerhans cell histiocytosis is not fully understood. It is thought that Langerhans cell histiocytosis is the result of either a true neoplastic process or a reactive immune condition. Genes commonly involved in the pathogenesis of Langerhans cell histiocytosis include BRAF gene and MAP2K1 gene. On gross pathology, scaly erythema, red papules, and extensive eruptions located on the scalp are characteristic finding of Langerhans cell histiocytosis. Characteristic findings of Langerhans cell histiocytosis on light microscopy may include clusters of dendritic cells with kidney-shaped nucleus and abundant foamy cytoplasm. On electron microscopy Langerhans cell histiocytosis is characterized by Birbeck granules, which are electron dense, cytoplasmic, tennis racket-like bodies. On immunohistochemistry Langerhans cell histiocytosis is characterized by positivity to CD1a, S100, and CD207 (langerin).

# Causes
There are no established direct causes for Langerhans cell histiocytosis. Common genetic mutations involved in the development of Langerhans cell histiocytosis can be found here.

# Differentiating Langerhans cell histiocytosis from other Diseases
Langerhans cell histiocytosis must be differentiated from other diseases that cause bone pain, cutaneous lesions, hepatosplenomegaly, and palpable lymph nodes, such as cat-scratch disease, mastocytosis, sinus histiocytosis with massive lymphadenopathy.

# Epidemiology and Demographics
Langerhans cell histiocytosis is a rare disease that tends to affect children and adolescents. The median age at diagnosis depends on the specific subtype of the disease. The incidence of Langerhans cell histiocytosis is approximately 5 per 1,000,000 individuals in the United States. Males are more commonly affected with Langerhans cell histiocytosis than females. The male to female ratio is approximately 2 to 1. Langerhans cell histiocytosis usually affects Caucasian and Hispanic individuals. African American individuals are less likely to develop Langerhans cell histiocytosis.

# Risk Factors
Common risk factors in the development of Langerhans cell histiocytosis are cigarette smoking and family history.

# Screening
According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for Langerhans cell histiocytosis.

# Natural History, Complications and Prognosis
The clinical course of Langerhans cell histiocytosis may range from a unifocal disease that spontaneously regress to a rapidly progressive disease with multi-system involvement. Common complications of Langerhans cell histiocytosis include pulmonary fibrosis, pathological bone fractures, and central diabetes insipidus. Depending on the extent of the tumor at the time of diagnosis, the prognosis may vary. However, the prognosis is generally regarded as excellent.

# Diagnosis

## History and Symptoms
Common symptoms of Langerhans cell histiocytosis include bone pain, rash, fever, and failure to thrive.

## Physical Examination
Langerhans cell histiocytosis patients often appear cachectic. Physical examination of patients with Langerhans cell histiocytosis is usually remarkable for scaly erythematous lesions located on the scalp and extremities, localized bone tenderness, and hepatosplenomegaly.

## Laboratory Findings
Laboratory findings consistent with the diagnosis of Langerhans cell histiocytosis include abnormal complete blood count, erythrocyte sedimentation rate (ESR), basic metabolic panel,  and immunohistochemistry.

## X-Ray
Chest X-ray may be helpful in the diagnosis of Langerhans cell histiocytosis. Findings on Chest X-ray suggestive of Langerhans cell histiocytosis include mild hyperinflation, coarse reticular interstitial markings, and peripheral ring shadows suggesting cysts formation.

## CT
CT scan may be helpful in the diagnosis of Langerhans cell histiocytosis. Findings on CT scan suggestive of Langerhans cell histiocytosis include multiple osteolytic lesions causing full thickness bone destruction.

## MRI
MRI may be helpful in the diagnosis of Langerhans cell histiocytosis. Findings on T1 weighted MRI imaging suggestive of Langerhans cell histiocytosis include a well-defined, isointense, brain lesion associated with reactive dural enhancement.

## Ultrasound
Abdominal ultrasound may be helpful in the diagnosis of Langerhans cell histiocytosis gastrointestinal lesions among the pediatric population. Findings on abdominal ultrasound suggestive of Langerhans cell histiocytosis include well-defined, hyperechoic, band-like, periportal hepatic lesions.

## Other Imaging Findings
On Tc 99m MDP whole body bone scintigraphy, Langerhans cell histiocytosis is characterized by an increased uptake of Tc 99m at hitiocytic lesion located around the ribs, spine, and pelvis.

## Other Diagnostic Tests
The definitive diagnosis of Langerhans cell histiocytosis is confirmed by a biopsy. Charecterstic findings for Langerhans cell histiocytosis on microscopic histopathological analysis can be found here.

# Treatment

## Medical therapy
Observation is recommended for all pediatric patients with an isolated Langerhans cell histiocytosis skin involvement. Medical therapy is suggested only for symptomatic cutaneous disease that presents with either extensive rash, sever pain, skin ulceration, or bleeding. Medical therapies used for the treatment of isolated skin lesions of Langerhans cell histiocytosis include topical steroids, nitrogen mustard, and oral thalidomide. Curettage is the mainstay treatment for single skull lesions that involve the frontal, parietal, or occipital bones. The most commonly used systemic chemotherapy regimen for the management of multiple bone lesions is a combination of vinblastine AND prednisone. The standard therapy recommended for Langerhans cell histiocytosis involving the spleen, liver, or bone marrow (high-risk organs) consists of vinblastine AND prednisone AND 6-mercaptopurine for a 12 month period.