Langerhans cell histiocytosis

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Langerhans cell histiocytosis[edit | edit source]

Langerhans cell histiocytosis
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Langerhans cell histiocytosis (LCH) is a rare cancer involving clonal proliferation of Langerhans cells, abnormal cells deriving from bone marrow and capable of migrating from skin to lymph nodes. Symptoms range from isolated bone lesions to multisystem disease. LCH is part of a group of syndromes called histiocytoses, which are characterized by an abnormal proliferation of histiocytes (an archaic term for activated dendritic cells and macrophages). These diseases are related to other forms of abnormal proliferation of white blood cells, such as leukemias and lymphomas.

The cancer has gone by several names, including Hand–Schüller–Christian disease, Abt-Letterer-Siwe disease, Hashimoto-Pritzker disease (a very rare self-limiting variant seen at birth) and histiocytosis X, until it was renamed in 1985 by the Histiocyte Society.[1]

Classification[edit | edit source]

Alternative names
Histiocytosis X

Histiocytosis X syndrome

Subordinate terms
Hand-Schüller-Christian disease

Letterer-Siwe disease
Histiocytosis X, unspecified
Eosinophilic Granulomatosis
Langerhans Cell granulomatosis
Langerhans Cell Histiocytosis, Hashimoto-Pritzker Type
Langerhans Cell Histiocytosis of lung
Langerhans Cell Histiocytosis, disseminated (clinical)
Langerhans Cell Histiocytosis, unifocal (clinical)

The disease spectrum results from clonal accumulation and proliferation of cells resembling the epidermal dendritic cells called Langerhans cells, sometimes called dendritic cell histiocytosis. These cells in combination with lymphocytes, eosinophils, and normal histiocytes form typical LCH lesions that can be found in almost any organ.[2] A similar set of diseases has been described in canine histiocytic diseases.

LCH is clinically divided into three groups: unifocal, multifocal unisystem, and multifocal multisystem.[3]

Unifocal[edit | edit source]

Unifocal LCH, also called eosinophilic granuloma (an older term which is now known to be a misnomer), is a disease characterized by an expanding proliferation of Langerhans cells in one organ, where they cause damage called lesions. It typically has no extraskeletal involvement, but rarely a lesion can be found in the skin, lungs, or stomach. It can appear as a single lesion in an organ, up to a large quantity of lesions in one organ. When multiple lesions are scattered throughout an organ, it can be called a multifocal unisystem variety. When found in the lungs, it should be distinguished from Pulmonary Langerhans cell hystiocytosis—a special category of disease most commonly seen in adult smokers.[4] When found in the skin it is called cutaneous single system Langerhans cell LCH. This version can heal without therapy in some rare cases.[5] This primary bone involvement helps to differentiate eosinophilic granuloma from other forms of Langerhans Cell Histiocytosis (Letterer-Siwe or Hand-Schüller-Christian variant).[6]

Multifocal unisystem[edit | edit source]

Seen mostly in children, multifocal unisystem LCH is characterized by fever, bone lesions and diffuse eruptions, usually on the scalp and in the ear canals. 50% of cases involve the pituitary stalk, often leading to diabetes insipidus. The triad of diabetes insipidus, exopthalmos, and lytic bone lesions is known as the Hand-Schüller-Christian triad. Peak onset is 2–10 years of age.

Multifocal multisystem[edit | edit source]

Multifocal multisystem LCH, also called Letterer-Siwe disease, is an often rapidly progressing disease in which Langerhans Cell cells proliferate in many tissues. It is mostly seen in children under age 2, and the prognosis is poor: even with aggressive chemotherapy, the five-year survival is only 50%.[7]

Pulmonary Langerhans cell histiocytosis (PLCH)[edit | edit source]

Pulmonary Langerhans cell histiocytosis (PLCH) is a unique form of LCH in that it occurs almost exclusively in cigarette smokers. It is now considered a form of smoking-related interstitial lung disease. Some affected people recover completely after they stop smoking, but others develop long-term complications such as pulmonary fibrosis and pulmonary hypertension.[8] PLCH patients, families, and caregivers are encouraged to join the NIH Rare Lung Diseases Consortium Contact Registry. This is a privacy protected site that provides up-to-date information for individuals interested in the latest scientific news, trials, and treatments related to rare lung diseases.

Signs and symptoms[edit | edit source]

CT scan showing LCH infiltrating peri-orbital tissue (arrowed).
A patient with Hand–Schüller–Christian disease which is a subtype of Langerhans Cell Histiocytosis.

LCH provokes a non-specific inflammatory response, which includes fever, lethargy, and weight loss. Organ involvement can also cause more specific symptoms.

  • Bone: The most-frequently seen symptom in both unifocal and multifocal disease is painful bone swelling. The skull is most frequently affected, followed by the long bones of the upper extremities and flat bones. Infiltration in hands and feet is unusual. Osteolytic lesions can lead to pathological fractures.[9]
  • Skin: Commonly seen are a rash which varies from scaly erythematous lesions to red papules pronounced in intertriginous areas. Up to 80% of LCH patients have extensive eruptions on the scalp.
  • Bone marrow: Pancytopenia with superadded infection usually implies a poor prognosis. Anemia can be due to a number of factors and does not necessarily imply bone marrow infiltration.
  • Lymph node: Enlargement of the liver in 20%, spleen in 30% and lymph nodes in 50% of Histiocytosis cases.[10]
  • Endocrine glands: Hypothalamic pituitary axis commonly involved.[11] Diabetes insipidus is most common.[12] Anterior pituitary hormone deficiency is usually permanent.[13]
  • Lungs: some patients are asymptomatic, diagnosed incidentally because of lung nodules on radiographs; others suffer from chronic cough and shortness of breath.[14]
  • Less frequently gastrointestinal tract, central nervous system, and oral cavity.[15]

Pathophysiology[edit | edit source]

The pathogenesis of Langerhans cell histiocytosis (LCH) is a matter of debate. There are ongoing investigations to determine whether LCH is a reactive (non-cancerous) or neoplastic (cancerous) process. Arguments supporting the reactive nature of LCH include the occurrence of spontaneous remissions, the extensive secretion of multiple cytokines by dendritic cells and bystander-cells (a phenomenon known as cytokine storm) in the lesional tissue, favorable prognosis and relatively good survival rate in patients without organ dysfunction or risk organ involvement.[16][17]

On the other hand, the infiltration of organs by monoclonal population of pathologic cells, and the successful treatment of subset of disseminated disease using chemotherapeutic regimens are all consistent with a neoplastic process.[18][19][20] In addition, a demonstration, using X chromosome–linked DNA probes, of LCH as a monoclonal proliferation provided additional support for the neoplastic origin of this disease.[21] While clonality is an important attribute of cancer, its presence does not prove that a proliferative process is neoplastic. Recurrent cytogenetic or genomic abnormalities would also be required to demonstrate convincingly that LCH is a malignancy.

An activating somatic mutation of a proto-oncogene in the Raf family, the BRAF gene, was detected in 35 of 61 (57%) LCH biopsy samples with mutations being more common in patients younger than 10 years (76%) than in patients aged 10 years and older (44%).[22] This study documented the first recurrent mutation in LCH samples. Two independent studies have confirmed this finding.[23][24] Presence of this activating mutation could support the notion to characterize LCH as myeloproliferative disorder.

Diagnosis[edit | edit source]

Micrograph showing Langerhans Cell Histiocytosis. H&E stain.

Diagnosis is confirmed histologically by tissue biopsy. Hematoxylin-eosin stain of biopsy slide will show features of Langerhans Cell e.g. distinct cell margin, pink granular cytoplasm. Presence of Birbeck granules on electron microscopy and immuno-cytochemical features e. g. CD1 positivity are more specific. Initially routine blood tests e.g. full blood count, liver function test, U&Es, bone profile are done to determine disease extent and rule out other causes. Radiology will show osteolytic bone lesions and damage to the lung. The latter may be evident in chest X-rays with micronodular and interstitial infiltrate in the mid and lower zone of lung, with sparing of the Costophrenic angle or honeycomb appearance in older lesions. MRI and CT may show infiltration in sella turcica. Assessment of endocrine function and bonemarrow biopsy are also performed when indicated.

Treatment[edit | edit source]

Guidelines for management of patients up to 18 years with Langerhans cell histiocytosis have been suggested.[31][32][33][34] Treatment is guided by extent of disease. Solitary bone lesion may be amenable through excision or limited radiation, dosage of 5-10 Gy for children, 24-30 Gy for adults. However systemic diseases often require chemotherapy. Use of systemic steroid is common, singly or adjunct to chemotherapy. Local steroid cream is applied to skin lesions. Endocrine deficiency often require lifelong supplement e.g. desmopressin for diabetes insipidus which can be applied as nasal drop. Chemotherapeutic agents such as alkylating agents, antimetabolites, vinca alkaloids either singly or in combination can lead to complete remission in diffuse disease.

Prognosis[edit | edit source]

Excellent for single-focus disease. With multi-focal disease 60% have a chronic course, 30% achieve remission and mortality is up to 10%.[35]

Prevalence[edit | edit source]

LCH usually affects children between 1 and 15 years old, with a peak incidence between 5 and 10 years of age. Among children under the age of 10, yearly incidence is thought to be 1 in 200,000;[36] and in adults even rarer, in about 1 in 560,000.[37] It has been reported in elderly but is vanishingly rare.[38] It is most prevalent in Caucasians, and affects males twice as often as females.[39] In other populations too the prevalence in males is slightly more than in females.[40]

LCH is usually a sporadic and non-hereditary condition but familial clustering has been noted in limited number of cases. Hashimoto-Pritzker disease is a congenital self-healing variant of Hand-Schüller-Christian disease.[41]

In popular culture[edit | edit source]

In the 10th episode of season 3 of House entitled "Merry Little Christmas", the primary patient is a girl with dwarfism who has a variety of symptoms, who is ultimately diagnosed with Langerhans cell histiocytosis.[42]

Also in the 5th episode, season 1 of "The Good Doctor", Dr. Murphy tries to diagnose Langerhans cell histiocytosis in a boy with a previously diagnosed osteosarcoma. cell histiocytosis citation needed (April 2018)


In an episode of Mystery Diagnosis, "The Woman Who Saw Pink", Brooke Rohrer has experiencing symptoms of abdominal pain, was diagnosed with Langerhans cell histiocytosis.

Nomenclature[edit | edit source]

Langerhans cell histiocytosis is occasionally misspelled as "Langerhan" or "Langerhan's" cell histiocytosis, even in authoritative textbooks. The name, however, originates back to its discoverer, Paul Langerhans.[43]

See also[edit | edit source]

References[edit | edit source]

  1. ↑ , Histiocytosis syndromes in children. Writing Group of the Histiocyte Society, Lancet, 1987, Vol. 1(Issue: 8526), pp. 208–9, DOI: 10.1016/S0140-6736(87)90016-X, PMID: 2880029,
  2. ↑ , Spontaneous gonadotrophin deficiency recovery in an adult patient with Langerhans cell Histiocytosis (LCH), Pituitary, 2005, Vol. 8(Issue: 2), pp. 169–74, DOI: 10.1007/s11102-005-4537-z, PMID: 16379033,
  3. ↑ , Robbins and Cotran pathologic basis of disease, St. Louis, Mo:Elsevier Saunders, 2005, ISBN 978-0-8089-2302-2, Pages: 701–,
  4. ↑ , Robbins and Cotran Pathologic Basis of Disease, 9th edition, Philadelphia, PA:Elsevier, ISBN 978-1-4557-2613-4,
  5. ↑ Afsar, Fatma Sule, Histiocitose de Células de Langerhans Autolimitada e de Início Tardio: Relato de Uma Entidade Raríssima, Revista Paulista de Pediatria, Vol. 35(Issue: 1), pp. 115–119, DOI: 10.1590/1984-0462/;2017;35;1;00015, PMID: 28977321, PMC: 5417814,
  6. ↑ , Nelson Textbook of Pediatrics, 19th edition, Saunders, 2011, ISBN 978-1-4377-0755-7, Pages: 1773–7,
  7. ↑ Langerhans Cell Histiocytosis at eMedicine
  8. ↑ , Rare lung diseases III: pulmonary Langerhans' cell histiocytosis, Canadian Respiratory Journal, 2010, Vol. 17(Issue: 3), pp. e55–62, DOI: 10.1155/2010/216240, PMID: 20617216, PMC: 2900147,
  9. ↑ , Langerhans cell histiocytosis of bone, Radiographics, Vol. 12(Issue: 4), pp. 801–23, DOI: 10.1148/radiographics.12.4.1636041, PMID: 1636041,
  10. ↑ Langerhans Cell Histiocytosis - Patient UK Full text, ,
  11. ↑ , Hypothalamo-pituitary abnormalities in adult patients with langerhans cell histiocytosis: clinical, endocrinological, and radiological features and response to treatment, The Journal of Clinical Endocrinology and Metabolism, Vol. 85(Issue: 4), pp. 1370–6, DOI: 10.1210/jcem.85.4.6501, PMID: 10770168,
  12. ↑ , Risk factors for diabetes insipidus in langerhans cell histiocytosis, Pediatric Blood & Cancer, Vol. 46(Issue: 2), pp. 228–33, DOI: 10.1002/pbc.20425, PMID: 16047354,
  13. ↑ , Anterior pituitary function and computed tomography/magnetic resonance imaging in patients with Langerhans cell histiocytosis and diabetes insipidus, Medical and Pediatric Oncology, Vol. 21(Issue: 9), pp. 649–54, DOI: 10.1002/mpo.2950210908, PMID: 8412998,
  14. ↑ , Immunohistochemical analysis of langerin in langerhans cell histiocytosis and pulmonary inflammatory and infectious diseases, The American Journal of Surgical Pathology, Vol. 31(Issue: 6), pp. 947–52, DOI: 10.1097/01.pas.0000249443.82971.bb, PMID: 17527085,
  15. ↑ , Role of multidisciplinary approach in a case of Langerhans cell histiocytosis with initial periodontal manifestations, Int J Clin Exp Pathol, Vol. 8(Issue: 10), pp. 13539–45, PMID: 26722570, PMC: 4680515,
  16. ↑ , Spontaneous remission of multi-system histiocytosis X, Lancet, 1984, Vol. 1(Issue: 8371), pp. 253–4, DOI: 10.1016/S0140-6736(84)90127-2, PMID: 6142997,
  17. ↑ , Specific polymorphisms of cytokine genes are associated with different risks to develop single-system or multi-system childhood Langerhans cell histiocytosis, British Journal of Haematology, 2006, Vol. 132(Issue: 6), pp. 784–7, DOI: 10.1111/j.1365-2141.2005.05922.x, PMID: 16487180,
  18. ↑ Steen, A.E., Successful treatment of cutaneous Langerhans cell histiocytosis with low-dose methotrexate, British Journal of Dermatology, Vol. 145(Issue: 1), pp. 137–140, DOI: 10.1046/j.1365-2133.2001.04298.x, PMID: 11453923,
  19. ↑ , Neurodegenerative central nervous system Langerhans cell histiocytosis and coincident hydrocephalus treated with vincristine/cytosine arabinoside, Pediatr Blood Cancer, 2010, Vol. 54(Issue: 3), pp. 416–23, DOI: 10.1002/pbc.22326, PMID: 19908293, PMC: 3444163,
  20. ↑ Minkov, M., Cyclosporine A therapy for multisystem Langerhans cell histiocytosis, Medical and Pediatric Oncology, Vol. 33(Issue: 5), pp. 482–485, DOI: <482::AID-MPO8>3.0.CO;2-Y 10.1002/(SICI)1096-911X(199911)33:5<482::AID-MPO8>3.0.CO;2-Y, PMID: 10531573,
  21. ↑ Willman, Cheryl L., Langerhans'-Cell Histiocytosis (Histiocytosis X) -- A Clonal Proliferative Disease, New England Journal of Medicine, Vol. 331(Issue: 3), pp. 154–160, DOI: 10.1056/NEJM199407213310303, PMID: 8008029,
  22. ↑ , Recurrent BRAF mutations in Langerhans cell histiocytosis, Blood, 2010, Vol. 116(Issue: 11), pp. 1919–23, DOI: 10.1182/blood-2010-04-279083, PMID: 20519626, PMC: 3173987,
  23. ↑ , B-RAF mutant alleles associated with Langerhans cell histiocytosis, a granulomatous pediatric disease, PLOS ONE, 2012, Vol. 7(Issue: 4), pp. e33891, DOI: 10.1371/journal.pone.0033891, PMID: 22506009, PMC: 3323620,
  24. ↑ , 1372 Frequent BRAF V600E Mutations Are Identified in CD207+ Cells in LCH Lesions, but BRAF Status does not Correlate with Clinical Presentation of Patients or Transcriptional Profiles of CD207+ Cells, , Full text,
  25. ↑ 25.0 25.1 , CD1a and S100 antigen expression in skin Langerhans cells in patients with breast cancer, The Journal of Pathology, Vol. 163(Issue: 1), pp. 25–30, DOI: 10.1002/path.1711630106, PMID: 2002421,
  26. ↑ , Prognostic significance of p53, bcl-2, vimentin, and S100 protein-positive Langerhans cells in endometrial carcinoma, Human Pathology, Vol. 29(Issue: 5), pp. 455–62, DOI: 10.1016/s0046-8177(98)90060-0, PMID: 9596268,
  27. ↑ , Comparison of peanut agglutinin and S100 stains in the paraffin tissue diagnosis of Langerhans cell histiocytosis, The British Journal of Dermatology, Vol. 119(Issue: 4), pp. 513–9, DOI: 10.1111/j.1365-2133.1988.tb03255.x, PMID: 2461216,
  28. ↑ , Histiocytosis X. S-100 protein, peanut agglutinin, and transmission electron microscopy study, American Journal of Clinical Pathology, Vol. 94(Issue: 5), pp. 627–31, DOI: 10.1093/ajcp/94.5.627, PMID: 2239828,
  29. ↑ , Langerin, a novel C-type lectin specific to Langerhans cells, is an endocytic receptor that induces the formation of Birbeck granules, Immunity, 2000, Vol. 12(Issue: 1), pp. 71–81, DOI: 10.1016/S1074-7613(00)80160-0, PMID: 10661407,
  30. ↑ , Immunohistochemical expression of Langerin in Langerhans cell histiocytosis and non-Langerhans cell histiocytic disorders, The American Journal of Surgical Pathology, Vol. 32(Issue: 4), pp. 615–9, DOI: 10.1097/PAS.0b013e31815b212b, PMID: 18277880,
  31. ↑ , Langerhans cell histiocytosis (LCH): Guidelines for diagnosis, clinical work-up, and treatment for patients till the age of 18 years, Pediatric Blood & Cancer, Vol. 60(Issue: 2), pp. 175–184, DOI: 10.1002/pbc.24367, PMID: 23109216, PMC: 4557042,
  32. ↑ , Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net, Orphanet Journal of Rare Diseases, Vol. 8(Issue: 1), pp. 72, DOI: 10.1186/1750-1172-8-72, PMID: 23672541, PMC: 3667012,
  33. ↑ , Langerhans cell histiocytosis - Histiocyte Society Evaluation and Treatment Guidelines, , Full text,
  34. ↑ , Langerhans Cell Histiocytosis Treatment (PDQ®), , Full text, and 1
  35. ↑ , Quality of survival in Histiocytosis X: a Southwest Oncology Group study, Med. Pediatr. Oncol., 1980, Vol. 8(Issue: 1), pp. 35–40, DOI: 10.1002/mpo.2950080106, PMID: 6969347,
  36. ↑ MedlinePlus Medical Encyclopedia: Histiocytosis Full text, ,
  37. ↑ Histiocytosis Association of Canada Full text, ,
  38. ↑ , Langerhanszell-Histiozytose im Alter, Der Hautarzt, 1998, Vol. 49(Issue: 1), pp. 23–30, DOI: 10.1007/s001050050696, PMID: 9522189,
  39. ↑ , Langerhans' cells histiocytosis: a case report, International Journal of Pediatric Otorhinolaryngology, 1999, Vol. 48(Issue: 1), pp. 83–7, DOI: 10.1016/S0165-5876(99)00013-0, PMID: 10365975,
  40. ↑ , Langerhans cell histiocytosis in adults: Report from the International Registry of the Histiocyte Society, European Journal of Cancer, 2003, Vol. 39(Issue: 16), pp. 2341–8, DOI: 10.1016/S0959-8049(03)00672-5, PMID: 14556926,
  41. ↑ , Congenital self-healing reticulohistiocytosis (Hashimoto-Pritzker disease): Ten-year experience at Dallas Children's Medical Center, Journal of the American Academy of Dermatology, 2007, Vol. 56(Issue: 2), pp. 290–4, DOI: 10.1016/j.jaad.2006.09.001, PMID: 17224372,
  42. ↑ House (season 3) In CSI, season 15 episode 4, a student has LCH.
  43. ↑ Jolles, S., Paul Langerhans, Journal of Clinical Pathology, Vol. 55(Issue: 4), DOI: 10.1136/jcp.55.4.243, PMID: 11919207, PMC: 1769627,


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