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Reliable, easy-to-read patient information on common medical conditions โ€” written in plain language, free of jargon, and grounded in current evidence. Browse the most frequent diagnoses, understand what they mean for everyday life, and learn which steps and questions help you have a focused conversation with your doctor.

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Langerhans cell histiocytosis

Introduction

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Synonyms and keywords: Histiocytosis X; Histiocytosis X syndrome; Hand-Schรผller-Christian disease; Letterer-Siwe disease; Eosinophilic granulomatosis unspecified; Langerhans cell granulomatosis; Langerhans cell histiocytosis-Hashimoto-Pritzker type; Langerhans cell histiocytosis, disseminated (clinical); Langerhans cell histiocytosis, unifocal (clinical); Langerhans cell histiocytosis of the lung; Non-lipid reticuloendotheliosis; Eosinophilic granuoloma; Pulmonary histiocytosis X; Pulmonary Langerhans cell granulomatosis

Overview

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.[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]

Historical Perspective

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]

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.[9][6]

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.[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]

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.[1][2][3]

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.[12][13]

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.[1][5][2][6][8]

Risk Factors

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

Screening

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

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.[15][5][1][3][6][8]

Diagnosis

History and Symptoms

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

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.[5][6]

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.[1][6][8][5]

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.[8][16]

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.[8][16]

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.[8][16]

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.[17][1]

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.[18][8][16]

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.[1][2][3]

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.[10]

References

  1. โ†‘ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 DiCaprio MR, Roberts TT (2014). “Diagnosis and Management of Langerhans Cell Histiocytosis”. J Am Acad Orthop Surg. 22 (10): 643โ€“652. doi:10.5435/JAAOS-22-10-643. PMIDย 25281259.
  2. โ†‘ 2.0 2.1 2.2 2.3 2.4 2.5 Grana N (2014). “Langerhans cell histiocytosis”. Cancer Control. 21 (4): 328โ€“34. PMIDย 25310214.
  3. โ†‘ 3.0 3.1 3.2 3.3 3.4 Harmon CM, Brown N (2015). “Langerhans Cell Histiocytosis: A Clinicopathologic Review and Molecular Pathogenetic Update”. Arch Pathol Lab Med. 139 (10): 1211โ€“4. doi:10.5858/arpa.2015-0199-RA. PMIDย 26414464.
  4. โ†‘ 4.0 4.1 Collin M, Bigley V, McClain KL, Allen CE (2015). “Cell(s) of Origin of Langerhans Cell Histiocytosis”. Hematol Oncol Clin North Am. 29 (5): 825โ€“38. doi:10.1016/j.hoc.2015.06.003. PMCย 4699587. PMIDย 26461145.
  5. โ†‘ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 Langerhans Cell Histiocytosis Treatment (PDQยฎ): Health Professional Version. National Cancer Institute (2015) http://www.cancer.gov/types/langerhans/hp/langerhans-treatment-pdq Accessed on February, 3 2016
  6. โ†‘ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 Langerhans cell histiocytosis. Wikipedia (2015) https://en.wikipedia.org/wiki/Langerhans_cell_histiocytosis Accessed on February, 2 2016
  7. โ†‘ 7.0 7.1 7.2 Badalian-Very G, Vergilio JA, Fleming M, Rollins BJ (2013). “Pathogenesis of Langerhans cell histiocytosis”. Annu Rev Pathol. 8: 1โ€“20. doi:10.1146/annurev-pathol-020712-163959. PMIDย 22906202.
  8. โ†‘ 8.00 8.01 8.02 8.03 8.04 8.05 8.06 8.07 8.08 8.09 8.10 8.11 Langerhans cell histiocytosis. Radiopeadia (2015) http://radiopaedia.org/articles/langerhans-cell-histiocytosis Accessed on February, 3 2016
  9. โ†‘ 9.0 9.1 9.2 9.3 Langerhans cell histiocytosis. Libre Pathology (2015) http://librepathology.org/wiki/index.php/Langerhans_cell_histiocytosis#cite_note-10 Accessed on February, 3 2016
  10. โ†‘ 10.0 10.1 Langerhans Cell Histiocytosis Treatmentโ€“for health professionals (PDQยฎ). National Cancer Institute (2015) http://www.cancer.gov/types/langerhans/hp/langerhans-treatment-pdq#section/_91 Accessed on February, 8 2016
  11. โ†‘ Nezelof C (1979). “Histiocytosis X: a histological and histogenetic study”. Perspect Pediatr Pathol. 5: 153โ€“78. PMIDย 317149.
  12. โ†‘ Langerhans cell histiocytosis. PathologyOutlines (2015) http://www.pathologyoutlines.com/topic/lymphnodesLCH.html Accessed on February, 4 2016
  13. โ†‘ Langerhans Cell Histiocytosis. National Organization for Rare Disoders (2015) http://rarediseases.org/rare-diseases/langerhans-cell-histiocytosis/ Accessed on February, 4 2016
  14. โ†‘ Recommendations. U.S Preventive Task Force (2015) http://www.uspreventiveservicestaskforce.org/BrowseRec/Search?s=Langerhans+cell+histiocytosis+ Accessed on February, 4 2016
  15. โ†‘ Komp DM, El Mahdi A, Starling KA, Easley J, Vietti TJ, Berry DH; et al. (1980). “Quality of survival in histiocytosis X: a Southwest Oncology Group study”. Med Pediatr Oncol. 8 (1): 35โ€“40. PMIDย 6969347.
  16. โ†‘ 16.0 16.1 16.2 16.3 Khung S, Budzik JF, Amzallag-Bellenger E, Lambilliote A, Soto Ares G, Cotten A; et al. (2013). “Skeletal involvement in Langerhans cell histiocytosis”. Insights Imaging. 4 (5): 569โ€“79. doi:10.1007/s13244-013-0271-7. PMCย 3781243. PMIDย 23907805.
  17. โ†‘ Chaudhary A, Debnath J, Thulkar S, Seth T, Sinha A (2006). “Imaging findings in hepatic Langerhans’ cell histiocytosis”. Indian J Pediatr. 73 (11): 1036โ€“8. PMIDย 17127788.
  18. โ†‘ Sager S, Yilmaz S, Sager G, Halac M (2010). “Tc 99m bone scan and fluorodeoxyglucose positron emission tomography in evaluation of disseminated langerhans cell histiocytosis”. Indian J Nucl Med. 25 (4): 164โ€“7. doi:10.4103/0972-3919.78253. PMCย 3109824. PMIDย 21713226.


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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]

Historical Perspective

Historical Perspective

Overview

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]

Historical Perspective

  • The clinical presentation of Langerhans cell histiocytosis was first described by Alfred Hand Jr., an American pediatrician, in 1893.[1]
  • The term Hand-Schรผller-Christian disease was first used to describe the clinical entity following the work of Dr. Artur Schรผller and Dr. Henry Christian.[2]
  • Between the years 1920 and 1940, Dr. Erich Letterer and Dr. Sture Siwe used the term eosinophilic granuloma (Lettererโ€“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]

References

  1. โ†‘ 1.0 1.1 DiCaprio MR, Roberts TT (2014). “Diagnosis and Management of Langerhans Cell Histiocytosis”. J Am Acad Orthop Surg. 22 (10): 643โ€“652. doi:10.5435/JAAOS-22-10-643. PMIDย 25281259.
  2. โ†‘ 2.0 2.1 Badalian-Very G, Vergilio JA, Fleming M, Rollins BJ (2013). “Pathogenesis of Langerhans cell histiocytosis”. Annu Rev Pathol. 8: 1โ€“20. doi:10.1146/annurev-pathol-020712-163959. PMIDย 22906202.
  3. โ†‘ 3.0 3.1 Nezelof C (1979). “Histiocytosis X: a histological and histogenetic study”. Perspect Pediatr Pathol. 5: 153โ€“78. PMIDย 317149.
  4. โ†‘ Mc Dermott R, Ziylan U, Spehner D, Bausinger H, Lipsker D, Mommaas M, Cazenave JP, Raposo G, Goud B, de la Salle H, Salamero J, Hanau D (January 2002). “Birbeck granules are subdomains of endosomal recycling compartment in human epidermal Langerhans cells, which form where Langerin accumulates”. Mol. Biol. Cell. 13 (1): 317โ€“35. doi:10.1091/mbc.01-06-0300. PMCย 65091. PMIDย 11809842.
  5. โ†‘ Kobayashi M, Tojo A (December 2018). “Langerhans cell histiocytosis in adults: Advances in pathophysiology and treatment”. Cancer Sci. 109 (12): 3707โ€“3713. doi:10.1111/cas.13817. PMCย 6272080. PMIDย 30281871.


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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]

Pathophysiology

Pathophysiology

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).[1][2][3][4][5][6]

Pathogenesis

Origin of Langerhans Cells

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

Organ Involvement in Langerhans Cell Histiocytosis

  • 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]

Disregulation of Immune Response

  • 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

Non-Specific Inflammatory Response

  • 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]

Bone Marrow Failure

  • 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]

Tissue Infiltration

  • 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:

Genetics

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

Associated Conditions

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

Gross Pathology

  • 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:

Microscopic Pathology

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

References

  1. โ†‘ 1.0 1.1 1.2 Collin M, Bigley V, McClain KL, Allen CE (2015). “Cell(s) of Origin of Langerhans Cell Histiocytosis”. Hematol Oncol Clin North Am. 29 (5): 825โ€“38. doi:10.1016/j.hoc.2015.06.003. PMCย 4699587. PMIDย 26461145.
  2. โ†‘ 2.0 2.1 2.2 Langerhans Cell Histiocytosis Treatment (PDQยฎ): Health Professional Version. National Cancer Institute (2015) http://www.cancer.gov/types/langerhans/hp/langerhans-treatment-pdq Accessed on February, 3 2016
  3. โ†‘ 3.0 3.1 3.2 3.3 3.4 Langerhans cell histiocytosis. Wikipedia (2015) https://en.wikipedia.org/wiki/Langerhans_cell_histiocytosis Accessed on February, 2 2016
  4. โ†‘ 4.0 4.1 4.2 Badalian-Very G, Vergilio JA, Fleming M, Rollins BJ (2013). “Pathogenesis of Langerhans cell histiocytosis”. Annu Rev Pathol. 8: 1โ€“20. doi:10.1146/annurev-pathol-020712-163959. PMIDย 22906202.
  5. โ†‘ 5.0 5.1 5.2 Langerhans cell histiocytosis. Radiopeadia (2015) http://radiopaedia.org/articles/langerhans-cell-histiocytosis Accessed on February, 3 2016
  6. โ†‘ 6.0 6.1 6.2 6.3 Langerhans cell histiocytosis. Libre Pathology (2015) http://librepathology.org/wiki/index.php/Langerhans_cell_histiocytosis#cite_note-10 Accessed on February, 3 2016
  7. โ†‘ 7.0 7.1 7.2 DiCaprio MR, Roberts TT (2014). “Diagnosis and Management of Langerhans Cell Histiocytosis”. J Am Acad Orthop Surg. 22 (10): 643โ€“652. doi:10.5435/JAAOS-22-10-643. PMIDย 25281259.
  8. โ†‘ 8.0 8.1 8.2 Grana N (2014). “Langerhans cell histiocytosis”. Cancer Control. 21 (4): 328โ€“34. PMIDย 25310214.
  9. โ†‘ 9.0 9.1 9.2 Harmon CM, Brown N (2015). “Langerhans Cell Histiocytosis: A Clinicopathologic Review and Molecular Pathogenetic Update”. Arch Pathol Lab Med. 139 (10): 1211โ€“4. doi:10.5858/arpa.2015-0199-RA. PMIDย 26414464.
  10. โ†‘ Tamaki K, Stingl G, Katz SI (May 1980). “The origin of Langerhans cells”. J. Invest. Dermatol. 74 (5): 309โ€“11. PMIDย 7391603.
  11. โ†‘ Collin M, Milne P (January 2016). “Langerhans cell origin and regulation”. Curr. Opin. Hematol. 23 (1): 28โ€“35. doi:10.1097/MOH.0000000000000202. PMCย 4685746. PMIDย 26554892.
  12. โ†‘ Jaitley S, Saraswathi T (May 2012). “Pathophysiology of Langerhans cells”. J Oral Maxillofac Pathol. 16 (2): 239โ€“44. doi:10.4103/0973-029X.99077. PMIDย 22923897.
  13. โ†‘ Munn S, Chu AC (April 1998). “Langerhans cell histiocytosis of the skin”. Hematol. Oncol. Clin. North Am. 12 (2): 269โ€“86. PMIDย 9561900.
  14. โ†‘ Zhang XH, Zhang J, Chen ZH, Sai K, Chen YS, Wang J, Ke C, Guo CC, Chen ZP, Mou YG (April 2017). “Langerhans cell histiocytosis of skull: a retrospective study of 18 cases”. Ann Palliat Med. 6 (2): 159โ€“164. doi:10.21037/apm.2016.11.04. PMIDย 28061539.
  15. โ†‘ Khung S, Budzik JF, Amzallag-Bellenger E, Lambilliote A, Soto Ares G, Cotten A, Boutry N (October 2013). “Skeletal involvement in Langerhans cell histiocytosis”. Insights Imaging. 4 (5): 569โ€“79. doi:10.1007/s13244-013-0271-7. PMCย 3781243. PMIDย 23907805.
  16. โ†‘ ARAF. Wikipedia (2015) https://en.wikipedia.org/wiki/ARAF Accessed on February, 3 2016
  17. โ†‘ ERBB3. Wikipedia (2015) https://en.wikipedia.org/wiki/ERBB3 Accessed on February, 3 2016
  18. โ†‘ MAPK/ERK pathway. Wikipedia (2015) https://en.wikipedia.org/wiki/MAPK/ERK_pathway Accessed on February, 3 2016


Template:WikiDoc Sources

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

Causes

Causes

Overview

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.

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.[1][2][3]

References

  1. โ†‘ DiCaprio MR, Roberts TT (2014). “Diagnosis and Management of Langerhans Cell Histiocytosis”. J Am Acad Orthop Surg. 22 (10): 643โ€“652. doi:10.5435/JAAOS-22-10-643. PMIDย 25281259.
  2. โ†‘ Grana N (2014). “Langerhans cell histiocytosis”. Cancer Control. 21 (4): 328โ€“34. PMIDย 25310214.
  3. โ†‘ Harmon CM, Brown N (2015). “Langerhans Cell Histiocytosis: A Clinicopathologic Review and Molecular Pathogenetic Update”. Arch Pathol Lab Med. 139 (10): 1211โ€“4. doi:10.5858/arpa.2015-0199-RA. PMIDย 26414464.


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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]

Differentiating Langerhans cell histiocytosis from other Diseases

Differentiating Langerhans cell histiocytosis from other Diseases

Overview

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]

Differentiating Langerhans cell histiocytosis from other Diseases

Disease Rash Characteristics Signs and Symptoms Associated Conditions Images
Cutaneous T cell lymphoma/Mycosis fungoides[3]
Pityriasis rosea[4]
  • Pink or salmon in color, which may be scaly; referred to as “herald patch”
  • Oval shape
  • Long axis oriented along the cleavage lines
  • Distributed on the trunk and proximal extremities
  • Squamous marginal collarette and a โ€œfir-treeโ€ or โ€œChristmas treeโ€ distribution on posterior trunk
  • Secondary to viral infections
  • Resolves spontaneously after 6-8 weeks
Pityriasis lichenoides chronica
  • Recurrent lesions are usually less evenly scattered than in cases of psoriasis
  • Brownish red or orange-brown in color
  • Lesions are capped by a single detachable, opaque, mica-like scale
  • Often leave hypopigmented macules
Nummular dermatitis[7]
  • Lesions commonly relapse after occasional remission or may persist for long periods
  • Pruritus
Secondary syphilis[8]
  • Round, coppery, red colored lesions on palms and soles
  • Papules with collarette of scales
Bowenโ€™s disease[9]
  • Erythematous, small, scaly plaque, which enlarges erratically over time
  • Scale is usually yellow or white and it is easily detachable without any bleeding
  • Well-defined margins
Exanthematous pustulosis[11]
Hypertrophic lichen planus[13]
Sneddonโ€“Wilkinson disease[15]
  • Flaccid pustules that are often generalized and have a tendency to involve the flexural areas
  • Annular configuration
Small plaque parapsoriasis[19]
  • Erythematous plaques with fine scaly surface
  • May present with elongated, finger-like patches
  • Symmetrical distribution on the flanks
  • Known as digitate dermatosis
  • Lesions may be asymptomatic
  • May be mildly pruritic
  • May fade or disappear after sun exposure during the summer season, but typically recur during the winter
Intertrigo[21]
Langerhans cell histiocytosis[22]
  • Scaling and crusting of scalp
Tinea manuum/pedum/capitis[26]
  • Scaling, flaking, and sometimes blistering of the affected areas
  • Hair loss with a black dot on scalp in case of tinea capitis
Seborrheic dermatitis

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

Disease Findings
Soft tissue infection
(Commonly cellulitis) 		History of skin warmness, swelling and erythema. Bone probing is the definite way to differentiate them.[29][30]
Osteonecrosis
(Avascular necrosis of bone) 		Previous history of trauma, radiation, use of steroids or biphosphonates are suggestive to differentiate osteonecrosis from ostemyelitis.[31][32]
MRI is diagnostic.[33][34]
Charcot joint Patients with Charcot joint commonly develop skin ulcerations that can in turn lead to secondary osteomyelitis.
Contrast-enhanced MRI may be diagnostically useful if it shows a sinus tract, replacement of soft tissue fat, a fluid collection, or extensive marrow abnormalities. Bone biopsy is the definitive diagnostic modality.[35]
Bone tumors May present with local pain and radiographic changes consistent with osteomyelitis.
Tumors most likely to mimic osteomyelitis are osteoid osteomas and chondroblastomas that produce small, round, radiolucent lesions on radiographs.[36]
Gout Gout presents with joint pain and swelling. Joint aspiration and crystals in synovial fluid is diagnostic for gout.[37]
SAPHO syndrome
(Synovitis, acne, pustulosis, hyperostosis, and osteitis) 		SAPHO syndrome consists of a wide spectrum of neutrophilic dermatosis associated with aseptic osteoarticular lesions.
It can mimic osteomyelitis in patients who lack the characteristic findings of pustulosis and synovitis.
The diagnosis is established via clinical manifestations; bone culture is sterile in the setting of osteitis.
Sarcoidosis It involves most frequently the pulmonary parenchyma and mediastinal lymph nodes, but any organ system can be affected.
Bone involvement is often bilateral and bones commonly affected include the middle and distal phalanges (producing โ€œsausage fingerโ€), wrist, skull, vertebral column, and long bones.
Langerhans’ cell histiocytosis The disease usually manifests in the skeleton and solitary bone lesions are encountered twice as often as multiple bone lesions.
The tumours can develop in any bone, but most commonly originate in the skull and jaw, followed by vertebral bodies, ribs, pelvis, and long bones.[38]

Differential diagnosis

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

Causes of

lung cavities

Differentiating Features Differentiating radiological findings Diagnosis

confirmation

  • CXR and CT demonstrates cavities in the upper lobe of the lung
  • Sputum smear positive for acid-fast bacilli and nucleic acid amplification tests (NAAT) is used on sputum or any sterile fluid for rapid diagnosis and is positive for mycobacteria.
  • Any age group
  • Acute, fulminant life threating complication of prior infection
  • >100.4 ยฐF fever, with hemodynamic instability
  • Worsening pneumonia-like symptoms
  • CBC is positive for causative organism
  • Children and elderly are at risk
  • Empyema appears lenticular in shape and has a thin wall with smooth luminal margins
  • Pulmonary nodules with cavities and infiltrates are a frequent manifestation on CXR
  • Elderly females of 40-50 age group
  • Manifestation of rheumatoid arthritis
  • Presents with other systemic symptoms including symmetric arthritis of the small joints of the hands and feet with morning stiffness are common manifestations
  • Pulmonary nodules with cavitation are located in the upper lobe (Caplan syndrome) on X-ray
  • On CXR bilateral adenopathy and coarse reticular opacities are seen
  • CT of the chest demonstrates extensive hilar and mediastinal adenopathy
  • Additional findings on CT include fibrosis (honeycomb, linear, or associated with bronchial distortion), pleural thickening, and ground-glass opacities.[45]
  • Common appearance on CT is patchy consolidation,often accompanied by ground-glass opacities and nodules.[49]
  • Exclusively afflicts smokers, with a peak age of onset of between 20 and 40 years
  • Clinical presentation varies, but symptoms generally include months of dry cough, fever, night sweats, and weight loss
  • Skin is involved in 80% of the cases, scaly erythematous rash is typical
  • Thin-walled cystic cavities are the usual radiographic manifestation, observed in over 50% of patients by either CXR or CT scans.[51]
  • Biopsy of the lung

References

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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]

Epidemiology and Demographics

Epidemiology and Demographics

Overview

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.

Epidemiology and Demographics

Prevalence

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

Incidence

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

Age

  • 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.

Gender

  • 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]

Race

  • 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]

References

  1. โ†‘ 1.0 1.1 1.2 1.3 1.4 DiCaprio MR, Roberts TT (2014). “Diagnosis and Management of Langerhans Cell Histiocytosis”. J Am Acad Orthop Surg. 22 (10): 643โ€“652. doi:10.5435/JAAOS-22-10-643. PMIDย 25281259.
  2. โ†‘ 2.0 2.1 2.2 2.3 2.4 Langerhans Cell Histiocytosis Treatment (PDQยฎ): Health Professional Version. National Cancer Institute (2015) http://www.cancer.gov/types/langerhans/hp/langerhans-treatment-pdq Accessed on February, 3 2016
  3. โ†‘ 3.0 3.1 3.2 3.3 3.4 Grana N (2014). “Langerhans cell histiocytosis”. Cancer Control. 21 (4): 328โ€“34. PMIDย 25310214.
  4. โ†‘ 4.0 4.1 4.2 4.3 4.4 Langerhans cell histiocytosis. Wikipedia (2015) https://en.wikipedia.org/wiki/Langerhans_cell_histiocytosis Accessed on February, 2 2016
  5. โ†‘ 5.0 5.1 5.2 5.3 5.4 Langerhans cell histiocytosis. Radiopeadia (2015) http://radiopaedia.org/articles/langerhans-cell-histiocytosis Accessed on February, 3 2016


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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]

Risk Factors

Risk Factors

Overview

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

Risk Factors

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

References

  1. โ†‘ Langerhans cell histiocytosis. Libre Pathology (2015) http://librepathology.org/wiki/index.php/Langerhans_cell_histiocytosis#cite_note-10 Accessed on February, 3 2016
  2. โ†‘ Hamre M, Hedberg J, Buckley J, Bhatia S, Finlay J, Meadows A, Nesbit M, Smithson A, Robison L (February 1997). “Langerhans cell histiocytosis: an exploratory epidemiologic study of 177 cases”. Med. Pediatr. Oncol. 28 (2): 92โ€“7. PMIDย 8986144.
  3. โ†‘ Satter EK, High WA (2008). “Langerhans cell histiocytosis: a review of the current recommendations of the Histiocyte Society”. Pediatr Dermatol. 25 (3): 291โ€“5. doi:10.1111/j.1525-1470.2008.00669.x. PMIDย 18577030.


Template:WikiDoc Sources

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

Screening

Screening

Overview

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

Screening

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

References

  1. โ†‘ Recommendations. U.S Preventive Task Force (2015) http://www.uspreventiveservicestaskforce.org/BrowseRec/Search?s=Langerhans+cell+histiocytosis+ Accessed on February, 4 2016


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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]

Natural History, Complications and Prognosis

Natural History, Complications and Prognosis

Overview

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.

Natural History

  • 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]

Complications

Prognosis

  • 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:
Prognostic Factor Description
Age
  • A younger age at the time of diagnosis is associated with a worse prognosis.
Organ involvement
  • A more extensive organ involvement is associated with a worse prognosis.
Response to treatment
  • A modest response rate after 6 weeks of therapy is associated with a worse prognosis.
Cellular markers
  • The expression of metalloproteinase and gelosin on a cellular level is associated with a worse prognosis.

References

  1. โ†‘ 1.0 1.1 1.2 DiCaprio MR, Roberts TT (2014). “Diagnosis and Management of Langerhans Cell Histiocytosis”. J Am Acad Orthop Surg. 22 (10): 643โ€“652. doi:10.5435/JAAOS-22-10-643. PMIDย 25281259.
  2. โ†‘ Y. Fukuda, F. Basset, P. Soler, V. J. Ferrans, Y. Masugi & R. G. Crystal (1990). “Intraluminal fibrosis and elastic fiber degradation lead to lung remodeling in pulmonary Langerhans cell granulomatosis (histiocytosis X)”. The American journal of pathology. 137 (2): 415โ€“424. PMIDย 2386203. Unknown parameter |month= ignored (help)
  3. โ†‘ P. Soler, M. Kambouchner, D. Valeyre & A. J. Hance (1992). “Pulmonary Langerhans’ cell granulomatosis (histiocytosis X)”. Annual review of medicine. 43: 105โ€“115. doi:10.1146/annurev.me.43.020192.000541. PMIDย 1580576.
  4. โ†‘ D. M. Howarth, G. S. Gilchrist, B. P. Mullan, G. A. Wiseman, J. H. Edmonson & P. J. Schomberg (1999). “Langerhans cell histiocytosis: diagnosis, natural history, management, and outcome”. Cancer. 85 (10): 2278โ€“2290. PMIDย 10326709. Unknown parameter |month= ignored (help)
  5. โ†‘ 5.0 5.1 Komp DM, El Mahdi A, Starling KA, Easley J, Vietti TJ, Berry DH; et al. (1980). “Quality of survival in histiocytosis X: a Southwest Oncology Group study”. Med Pediatr Oncol. 8 (1): 35โ€“40. PMIDย 6969347.
  6. โ†‘ 6.0 6.1 Langerhans Cell Histiocytosis Treatment (PDQยฎ): Health Professional Version. National Cancer Institute (2015) http://www.cancer.gov/types/langerhans/hp/langerhans-treatment-pdq Accessed on February, 3 2016
  7. โ†‘ 7.0 7.1 Harmon CM, Brown N (2015). “Langerhans Cell Histiocytosis: A Clinicopathologic Review and Molecular Pathogenetic Update”. Arch Pathol Lab Med. 139 (10): 1211โ€“4. doi:10.5858/arpa.2015-0199-RA. PMIDย 26414464.
  8. โ†‘ 8.0 8.1 Langerhans cell histiocytosis. Wikipedia (2015) https://en.wikipedia.org/wiki/Langerhans_cell_histiocytosis Accessed on February, 2 2016
  9. โ†‘ 9.0 9.1 Langerhans cell histiocytosis. Radiopeadia (2015) http://radiopaedia.org/articles/langerhans-cell-histiocytosis Accessed on February, 3 2016


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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]

Diagnosis

Diagnosis

History amd Symptoms | Physical Examination | Laboratory Findings | Electrocardiogram | Chest X Ray | CT | MRI | Echocardiography or Ultrasound | Other Imaging Findings | Other Diagnostic Studies

Treatment

Treatment

Medical Therapy | Surgery | Primary Prevention | Secondary Prevention | Cost-Effectiveness of Therapy | Future or Investigational Therapies

Case Studies

Case Studies

Case #1

Related chapters
Resources

Resources

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