Langerhans cell histiocytosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2]

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.^[1][2][3] 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).^{[4][5][6][7][8][9]} 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.^{[1][5][2][6][8]} Common symptoms of Langerhans cell histiocytosis include bone pain, rash, fever, and failure to thrive.^[6][8][5] 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.^[5][6] 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.^[10]

The clinical presentation of Langerhans cell histiocytosis was first described by Dr. Alfred Hand Jr., an American pediatrician, in 1893.^[1] 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.^[7][11]

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.^[9][6]

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.^[1][2][3] 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).^{[4][5][6][7][8][9]}

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.^[1][2][3]

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.^[12][13]

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.^{[1][5][2][6][8]}

Common risk factors in the development of Langerhans cell histiocytosis are cigarette smoking and family history.^[9]

According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for Langerhans cell histiocytosis.^[14]

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.^{[15][5][1][3][6][8]}

Common symptoms of Langerhans cell histiocytosis include bone pain, rash, fever, and failure to thrive.^[6][8][5]

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.^[5][6]

Laboratory findings consistent with the diagnosis of Langerhans cell histiocytosis include abnormal complete blood count, erythrocyte sedimentation rate (ESR), basic metabolic panel, and immunohistochemistry.^[1][6][8][5]

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.^[8][16]

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.^[8][16]

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.^[8][16]

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.^[17][1]

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.^[18][8][16]

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.^[1][2][3]

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.^[10]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2]

The clinical presentation of Langerhans cell histiocytosis was first described by Dr. Alfred Hand Jr., an American pediatrician, in 1893.^[1] 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.^[2][3]

• The clinical presentation of Langerhans cell histiocytosis was first described by Alfred Hand Jr., an American pediatrician, in 1893.^[1]
• The term Hand-Schüller-Christian disease was first used to describe the clinical entity following the work of Dr. Artur Schüller and Dr. Henry Christian.^[2]
• Between the years 1920 and 1940, Dr. Erich Letterer and Dr. Sture Siwe used the term eosinophilic granuloma (Letterer–Siwe disease) to describe a similar clinical entity of the disease.
• It was not until the year 1941 that Dr. Sidney Farber, a pathologist at Boston Children’s Hospital, unified the clinically similar conditions under the term histiocytosis X.
• Following the advances of electron microscopy, the term Birbeck granules was first used to describe the particles found in Langerhan cells in 1961.^[4]
• The phagocytic nature of Langerhan cells was first described in 1973 by Dr. Christian Nezelof.^[3]
• The term Langerhans cell histiocytosis was finally agreed upon in 1987 by the the Writing Group of the Histiocyte Society.^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2]

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).^{[1][2][3][4][5][6]}

• Langerhans cell histiocytosis arises from epidermal dendritic cells, which are normally involved in the process of antigen presentation to lymphocytic cells.^[7][8][9]

• Langerhans cells originally arise from the bone marrow, then the cells migrate to other organs such as:^[10][11][12]

• Skin
• Lymph nodes
• Lungs
• Hypothalamic–pituitary axis
• Gastrointestinal tract
• CNS
• Oral cavity

• Organ involvement is variable among patients with Langerhans cell histiocytosis. The disease process may range from an isolated cutaneous or bone involvement to a life-threatening multi-system condition.
• The skeletal distribution of Langerhans cell histiocytosis involves the following sites:^[13][14][15]

• The skull (most common bone involved)
• Ribs
• Humerus
• Vertebra

• 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.
• Facts consistent with the neoplastic process hypothesis include the following:

• The infiltration of organs by monoclonal population of pathologic cells
• The presence of specific recurrent cytogenetic and genomic abnormalities
• The successful treatment of a subset of disseminated Langerhans cell histiocytosis using chemotherapeutic regimens

• Facts consistent with the reactive immune condition hypothesis include the following:

• The evidence of spontaneous remissions that may occur among certain cases of Langerhans cell histiocytosis
• The extensive secretion of multiple cytokines by dendritic cells and bystander-cells (a phenomenon known as cytokine storm)
• The favorable prognosis and relatively good survival rate among patients with no organ dysfunction

• The uncontrolled monoclonal proliferation of Langerhans cells will initiate a non-specific inflammatory response, which will lead to the accumulation of various immune system cells such as:^[1][2][5][6]

• Eosinophils
• Macrophages
• Lymphocytes
• Multinucleated giant cells

• Langerhans cell histiocytosis may result in bone marrow failure due to malignant cell infiltration of the bone marrow. The manifestation of bone marrow failure among patients with Langerhans cell histiocytosis may include:^[3][4]

• Anemia
• Recurrent bleeding
• Recurrent infections

• The infiltration of the hypothalamic–pituitary axis by Langerhans cells will lead to a deficiency in both anterior and posterior pituitary hormones, which may result in:

• Central diabetes insipidus
• Growth retardation
• Delayed puberty

• Langerhans cell histiocytosis may also infiltrate the lymph nodes, spleen, and liver.

• Development of Langerhans cell histiocytosis is the result of multiple genetic mutations.^[7][8][9]
• Genes commonly involved in the pathogenesis of Langerhans cell histiocytosis include:

• BRAF BRAF V600E gene mutation located on Chromosome 7
• MAP2K1 gene mutation located on Chromosome 15

• Less common genetic mutations involved in the pathogenesis of Langerhans cell histiocytosis include:^[16][17]

• ARAF gene mutation located on the X-chromosome
• ERBB3 gene mutation located on chromosome 12

• The aforementioned genetic mutations, which occur among patients of Langerhans cell histiocytosis, will lead to constitutive activation of downstream extracellular signal-related kinase (ERK) and mitogen-activated protein kinase (MEK).
• Induction of ERK activation is a universal feature that is found in most of the cases of Langerhans cell histiocytosis.
• The MAPK/ERK pathway (also known as the Ras-RAF-MEK-ERK pathway) is a cascade of proteins that transmit cellular signal from receptors found on the surface of the cell to the nucleus, this ultimately results in the activation of cellular DNA production.^[18]

• Langerhans cell histiocytosis is associated with a number of syndromes such as Hashimoto-Pritzker disease.^[3]

• On gross pathology, scaly erythema, red papules, and extensive eruptions located on the scalp are characteristic finding of Langerhans cell histiocytosis.^[3]
• The image below demonstrates the cutaneous scalp lesions observed among Langerhans cell histiocytosis patients:

• Characteristic findings of Langerhans cell histiocytosis on light microscopy may include:^[7][8][9]

• Clusters of dendritic cells
• Kidney-shaped nucleus
• Abundant foamy cytoplasm
• Fine, granular chromatin pattern
• Prominent eosinophils
• Fibrosis
• Other inflammatory cells may be present (neutrophils, plasma cells, and multinucleated giant cells)

• On electron microscopy Langerhans cell histiocytosis is characterized by Birbeck granules, which are electron dense, cytoplasmic, tennis racket-like bodies.^{[1][2][3][4][5][6]}
• On immunohistochemistry Langerhans cell histiocytosis is characterized by:

• CD1a +ve
• S100 +ve
• CD207 (langerin) +ve

Illustrated below is a series of microscopic images demonstrating Langerhans cell histiocytosis:^[6]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2]

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.

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.^[1][2][3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2]Syed Hassan A. Kazmi BSc, MD [3]

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.^[1][2]

• Langerhans cell histiocytosis must be differentiated from other diseases that cause bone pain, cutaneous lesions, hepatosplenomegaly, and palpable lymph nodes, such as:^[1][2]

• Lymphoma
• Mastocytosis
• Cat-scratch disease
• Hypersensitivity reaction
• Acrodermatitis enteropathica
• Erdheim-Chester disease
• Wiskott-Aldrich syndrome
• Seborrheic dermatitis
• Sinus histiocytosis with massive lymphadenopathy
• Kimura disease
• Eosinophilic pustular folliculitis
• Erythema toxicum neonatorum
• Acropustulosis of infancy

• Psoriasis must be differentiated from other diseases that cause papulosquamous or erythematosquamous rash, especially when the psoriatic lesions are localized in such sites as the palms, soles, scalp, body folds, penis, and nails. The differential diagnosis of psoriasis includes:

Langerhans cell histiocytosis must be differentiated from other diseases that cause bone pain, edema, and erythema.

Langerhans cell histiocytosis must be differentiated from other cavitary lung lesions.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2]

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 0.5 per 100,000 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.

• Langerhans cell histiocytosis is a rare disease that tends to affect children and adolescents.^{[1][2][3][4][5]}

• The incidence of Langerhans cell histiocytosis is approximately 0.5 per 100,000 individuals in the United States.^{[1][2][3][4][5]}

• Langerhans cell histiocytosis commonly affects individuals younger than 15 years of age.^{[1][2][3][4][5]}
• The median age at diagnosis depends on the specific subtype of the disease, such as:

• Pulmonary Langerhans cell histiocytosis is usually first diagnosed among adults.
• Unifocal Langerhans cell histiocytosis and multifocal unisystem Langerhans cell histiocytosis are usually first diagnosed among individuals of 2-10 years of age.
• Multifocal multisystem Langerhans cell histiocytosis is usually first diagnosed among individuals younger than 2 years of age.

• Males are more commonly affected with Langerhans cell histiocytosis than females. The male to female ratio is approximately 2 to 1.^{[1][2][3][4][5]}

• Langerhans cell histiocytosis usually affects Caucasian and Hispanic individuals. African American individuals are less likely to develop Langerhans cell histiocytosis.^{[1][2][3][4][5]}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2]

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

Common risk factors in the development of Langerhans cell histiocytosis are:^[1][2][3]

• Cigarette smoking
• Family history
• Maternal urinary tract infection during the index pregnancy
• Feeding problems during infancy
• Blood transfusions during infancy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2]

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

According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for Langerhans cell histiocytosis.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2]

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.

• 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.^[1]
• Pulmonary Langerhans cell histiocytosis generally exhibits an insidious and progressive disease pattern that makes it a diagnostic challenge to catch the disease at an early disease phase. The mean age of the patients at the time of presentation, therefore, may not reflect the true age of disease onset. Pulmonary LCH typicaly presents as bronchiolitis that may progress to intraluminal fibrosis and elastic fiber degradation and lung remodeling.^[2][3][4]

• Common complications of Langerhans cell histiocytosis include:^{[5][6][1][7][8][9]}

• Pulmonary fibrosis
• Pulmonary hypertension
• Pathological bone fractures
• Anemia
• Recurrent bleeding
• Recurrent infections
• 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.^{[5][6][1][7][8][9]}
• The 5-year survival rate of patients with unifocal Langerhans cell histiocytosis is approximately 99%.
• The 5-year survival rate of patients with multifocal unisystem Langerhans cell histiocytosis is approximately 97%.
• The 5-year survival rate of patients with multifocal multisystem Langerhans cell histiocytosis (with risk of organ failure) is approximately 77%.
• The table below lists prognostic factors for Langerhans cell histiocytosis patients:

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