Langerhans cell histiocytosis

Langerhans cell histiocytosis
Micrograph showing a Langerhans cell histiocytosis with the characteristic reniform Langerhans cells accompanied by abundant eosinophils. H&E stain.
Classification and external resources
Specialty	Hematology
ICD-10	C96.5 C96.6
ICD-9-CM	202.5, 277.89, 516.5
ICD-O	M9752/3,M9751/1
OMIM	604856
DiseasesDB	5906
eMedicine	derm/216 article/1100579
MeSH	D006646

Langerhans cell histiocytosis (LCH) is a rare disease involving clonal proliferation of Langerhans cells, abnormal cells deriving from bone marrow and capable of migrating from skin to lymph nodes. Clinically, its manifestations range from isolated bone lesions to multisystem disease. LCH is part of a group of clinical 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 disease has gone by several names, including Hand–Schüller–Christian disease, Abt-Letterer-Siwe disease, and histiocytosis X, until it was renamed in 1985 by the Histiocyte Society.^[1]

Classification

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

Unifocal LCH, also called Eosinophilic Granuloma (an older term which is now known to be a misnomer), is a slowly progressing disease characterized by an expanding proliferation of Langerhans Cells in various bones. It is a monostotic (involving only one bone) or polyostotic (involving more than one bone) disease. It typically has no extraskeletal involvement, but rarely an identical lesion can be found in the skin, lungs, or stomach. 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] This primary bone involvement helps to differentiate Eosinophilic Granuloma from other forms of Langerhans Cell Histiocytosis (Letterer-Siwe or Hand-Schüller-Christian variant.^[5]

Multifocal unisystem

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, 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

Multifocal multisystem LCH, also called Letterer-Siwe disease, is a 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%.^[6]

Pulmonary Langerhans Cell Histiocytosis (PLCH)

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 patients recover completely after they stop smoking, but others develop long-term complications such as pulmonary fibrosis and pulmonary hypertension.^[7] 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.

Prevalence

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;^[8] and in adults even rarer, in about 1 in 560,000.^[9] It has been reported in elderly but is vanishingly rare.^[10] It is most prevalent in Caucasians, and affects males twice as often as females.^[11] In other populations too the prevalence in males is slightly more than in females.^[12]

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.^[13]

Pathophysiology

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.^[14][15]

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.^[16][17][18] 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.^[19] 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.

Activating mutation of a protooncogen 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%).^[20] This study documented the first recurrent mutation in LCH samples. Two independent studies have confirmed this finding.^[21][22] Presence of this activating mutation could support the notion to characterize LCH as myeloproliferative disorder.

Signs and symptoms

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.^[23]
• 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.^[24]
• Endocrine glands: Hypothalamic pituitary axis commonly involved.^[25] Diabetes insipidus is most common.^[26] Anterior pituitary hormone deficiency is usually permanent.^[27]
• Lungs: some patients are asymptomatic, diagnosed incidentally because of lung nodules on radiographs; others suffer from chronic cough and shortness of breath.^[28]
• Less frequently gastrointestinal tract, central nervous system, and oral cavity.^[29]

Diagnosis

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.

• S-100 protein is expressed in a cytoplasmic pattern^[30][31]
• peanut agglutinin (PNA) is expressed on the cell surface and perinuclearly^[32][33]
• major histocompatibility (MHC) class II is expressed (because histiocytes are macrophages)
• CD1a^[30]
• langerin (CD207), a Langerhans Cell–restricted protein that induces the formation of Birbeck granules and is constitutively associated with them, is a highly specific marker.^[34][35]

Treatment

Guidelines for management of patients up to 18 years with Langerhans cell histiocytosis has been suggested.^{[36][37][38][39]} Treatment is guided by extent of disease. Solitary bone lesion may be amenable through excision or limited radiation, dosage of 5-10 Gys for children, 24-30 Gys 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

Excellent for single-focus disease. With multi-focal disease 60% have a chronic course, 30% achieve remission and mortality is up to 10%.^[40]

In popular culture

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.^[41]

Nomenclature

Langerhans cell histiocytosis is occasionally misspelt as "Langerhan" or "Langerhan's" cell histiocytosis, even in authoritative textbooks. The name, however, originates back to its discoverer, Paul Langerhans.^[42]

See also

• X-type histiocytosis

References

1. The Writing Group of the Histiocyte Society (1987). "Histiocytosis syndromes in children. Writing Group of the Histiocyte Society". Lancet 1 (8526): 208–9. doi:10.1016/S0140-6736(87)90016-X. PMID 2880029.
2. Makras P, Papadogias D, Kontogeorgos G, Piaditis G, Kaltsas G (2005). "Spontaneous gonadotrophin deficiency recovery in an adult patient with Langerhans cell Histiocytosis (LCH)". Pituitary 8 (2): 169–74. doi:10.1007/s11102-005-4537-z. PMID 16379033.
3. Cotran, Ramzi S.; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; Robbins, Stanley L. (2005). Robbins and Cotran pathologic basis of disease. St. Louis, Mo: Elsevier Saunders. pp. 701–. ISBN 0-8089-2302-1.
4. Kumar, Vinay; Abbas, Abul; Aster, Jon (2015). Robbins and Cotran Pathologic Basis of Disease (9th ed.). Philadelphia, PA: Elsevier. p. 622. ISBN 978-1-4557-2613-4.
5. Ladisch, Stephan (2011). "Histiocytosis Syndromes of Childhood". In Kliegman, Robert M.; Stanton, Bonita F.; St. Geme, Joseph; Schor, Nina; Behrman, Richard E. Nelson Textbook of Pediatrics (19th ed.). Saunders. pp. 1773–7. ISBN 978-1-4377-0755-7.
6. Langerhans Cell Histiocytosis at eMedicine
7. Juvet, Stephen C; Hwang, David; Downey, Gregory P (2010). "Rare lung diseases III: pulmonary Langerhans' cell histiocytosis". Canadian Respiratory Journal 17 (3): e55–62. PMC 2900147. PMID 20617216.
8. "MedlinePlus Medical Encyclopedia: Histiocytosis". Retrieved 2007-05-10.
9. "Histiocytosis Association of Canada". Retrieved 2007-05-16.
10. Gerlach, Beatrice; Stein, Annette; Fischer, Rainer; Wozel, Gottfried; Dittert, Dag-Daniel; Richter, Gerhard (1998). "Langerhanszell-Histiozytose im Alter" [Langerhans cell histiocytosis in the elderly]. Der Hautarzt (in German) 49 (1): 23–30. doi:10.1007/s001050050696. PMID 9522189.
11. Sellari-Franceschini, S.; Forli, F.; Pierini, S.; Favre, C.; Berrettini, S.; Macchia, P.A. (1999). "Langerhans’ cells histiocytosis: a case report". International Journal of Pediatric Otorhinolaryngology 48 (1): 83–7. doi:10.1016/S0165-5876(99)00013-0. PMID 10365975.
12. Aricò, M.; Girschikofsky, M.; Généreau, T.; Klersy, C.; McClain, K.; Grois, N.; Emile, J.-F.; Lukina, E.; De Juli, E.; Danesino, C. (2003). "Langerhans cell histiocytosis in adults: Report from the International Registry of the Histiocyte Society". European Journal of Cancer 39 (16): 2341–8. doi:10.1016/S0959-8049(03)00672-5. PMID 14556926.
13. Kapur, Payal; Erickson, Christof; Rakheja, Dinesh; Carder, K. Robin; Hoang, Mai P. (2007). "Congenital self-healing reticulohistiocytosis (Hashimoto-Pritzker disease): Ten-year experience at Dallas Children's Medical Center". Journal of the American Academy of Dermatology 56 (2): 290–4. doi:10.1016/j.jaad.2006.09.001. PMID 17224372.
14. Broadbent, V.; Davies, E.G.; Heaf, D.; Pincott, J.R.; Pritchard, J.; Levinsky, R.J.; Atherton, D.J.; Tucker, S. (1984). "Spontaneous remission of multi-system histiocytosis X". Lancet 1 (8371): 253–4. doi:10.1016/S0140-6736(84)90127-2. PMID 6142997.
15. Filippi, Paola; De Badulli, Carla; Cuccia, Mariaclara; Silvestri, Annalisa; De Dametto, Ennia; Pasi, Annamaria; Garaventa, Alberto; Prever, Adalberto Brach; del Todesco, Alessandra; Trizzino, Antonino; Danesino, Cesare; Martinetti, Miryam; Arico, Maurizio (2006). "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 132 (6): 784–7. doi:10.1111/j.1365-2141.2005.05922.x. PMID 16487180.
16. Steen, A.E.; Steen, K.H.; Bauer, R.; Bieber, T. (1 July 2001). "Successful treatment of cutaneous Langerhans cell histiocytosis with low-dose methotrexate.". British Journal of Dermatology 145 (1): 137–140. doi:10.1046/j.1365-2133.2001.04298.x. PMID 11453923.
17. Allen CE, Flores R, Rauch R, Dauser R, Murray JC, Puccetti D, Hsu DA, Sondel P, Hetherington M, Goldman S, McClain KL (2010). "Neurodegenerative central nervous system Langerhans cell histiocytosis and coincident hydrocephalus treated with vincristine/cytosine arabinoside". Pediatr Blood Cancer 54 (3): 416–23. doi:10.1002/pbc.22326. PMC 3444163. PMID 19908293.
18. Minkov, M.; Grois, N.; Broadbent, V.; Ceci, A.; Jakobson, A.; Ladisch, S. (1 November 1999). "Cyclosporine A therapy for multisystem Langerhans cell histiocytosis". Medical and Pediatric Oncology 33 (5): 482–485. doi:10.1002/(SICI)1096-911X(199911)33:5<482::AID-MPO8>3.0.CO;2-Y. PMID 10531573.
19. Willman, Cheryl L.; Busque, Lambert; Griffith, Barbara B.; Favara, Blaise E.; McClain, Kenneth L.; Duncan, Marilyn H.; Gilliland, D. Gary (21 July 1994). "Langerhans'-Cell Histiocytosis (Histiocytosis X) -- A Clonal Proliferative Disease". New England Journal of Medicine 331 (3): 154–160. doi:10.1056/NEJM199407213310303. PMID 8008029.
20. Badalian-Very G, Vergilio JA, Degar BA, MacConaill LE, Brandner B, Calicchio ML, Kuo FC, Ligon AH, Stevenson KE, Kehoe SM, Garraway LA, Hahn WC, Meyerson M, Fleming MD, Rollins BJ (2010). "Recurrent BRAF mutations in Langerhans cell histiocytosis". Blood 116 (11): 1919–23. doi:10.1182/blood-2010-04-279083. PMC 3173987. PMID 20519626.
21. Satoh T, Smith A, Sarde A, Lu HC, Mian S, Mian S, Trouillet C, Mufti G, Emile JF, Fraternali F, Donadieu J, Geissmann F (2012). "B-RAF mutant alleles associated with Langerhans cell histiocytosis, a granulomatous pediatric disease". PLoS ONE 7 (4): e33891. doi:10.1371/journal.pone.0033891. PMC 3323620. PMID 22506009.
22. Peters, Tricia L.; Tsz-Kwong Chris Man; Price, Jeremy; George, Renelle; Phaik Har Lim; Kenneth Matthew Heym; Merad, Miriam; McClain, Kenneth L.; Allen, Carl E. (10 December 2011). "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". Oral and Poster Abstracts presented at 53rd ASH Annual Meeting and Exposition
23. Stull, MA; Kransdorf, MJ; Devaney, KO (July 1992). "Langerhans cell histiocytosis of bone.". Radiographics : a review publication of the Radiological Society of North America, Inc 12 (4): 801–23. doi:10.1148/radiographics.12.4.1636041. PMID 1636041.
24. "Langerhans Cell Histiocytosis - Patient UK". Retrieved 2007-05-10.
25. Kaltsas, GA; Powles, TB; Evanson, J; Plowman, PN; Drinkwater, JE; Jenkins, PJ; Monson, JP; Besser, GM; Grossman, AB (April 2000). "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 85 (4): 1370–6. doi:10.1210/jc.85.4.1370. PMID 10770168.
26. Grois, N; Pötschger, U; Prosch, H; Minkov, M; Arico, M; Braier, J; Henter, JI; Janka-Schaub, G; Ladisch, S; Ritter, J; Steiner, M; Unger, E; Gadner, H; DALHX- and LCH I and II Study, Committee (February 2006). "Risk factors for diabetes insipidus in langerhans cell histiocytosis.". Pediatric blood & cancer 46 (2): 228–33. doi:10.1002/pbc.20425. PMID 16047354.
27. Broadbent, V; Dunger, DB; Yeomans, E; Kendall, B (1993). "Anterior pituitary function and computed tomography/magnetic resonance imaging in patients with Langerhans cell histiocytosis and diabetes insipidus.". Medical and pediatric oncology 21 (9): 649–54. doi:10.1002/mpo.2950210908. PMID 8412998.
28. Sholl, LM; Hornick, JL; Pinkus, JL; Pinkus, GS; Padera, RF (June 2007). "Immunohistochemical analysis of langerin in langerhans cell histiocytosis and pulmonary inflammatory and infectious diseases.". The American journal of surgical pathology 31 (6): 947–52. doi:10.1097/01.pas.0000249443.82971.bb. PMID 17527085.
29. Cisternino A, Asa'ad F, Fusco N, Ferrero S, Rasperini G (Oct 2015). "Role of multidisciplinary approach in a case of Langerhans cell histiocytosis with initial periodontal manifestations". Int J Clin Exp Pathol 8 (10): 13539–45. PMID 26722570.
30. Wilson, AJ; Maddox, PH; Jenkins, D (January 1991). "CD1a and S100 antigen expression in skin Langerhans cells in patients with breast cancer.". The Journal of pathology 163 (1): 25–30. doi:10.1002/path.1711630106. PMID 2002421.
31. Coppola, D; Fu, L; Nicosia, SV; Kounelis, S; Jones, M (May 1998). "Prognostic significance of p53, bcl-2, vimentin, and S100 protein-positive Langerhans cells in endometrial carcinoma.". Human pathology 29 (5): 455–62. doi:10.1016/s0046-8177(98)90060-0. PMID 9596268.
32. McLelland, J; Chu, AC (October 1988). "Comparison of peanut agglutinin and S100 stains in the paraffin tissue diagnosis of Langerhans cell histiocytosis.". The British journal of dermatology 119 (4): 513–9. doi:10.1111/j.1365-2133.1988.tb03255.x. PMID 2461216.
33. Ye, F; Huang, SW; Dong, HJ (November 1990). "Histiocytosis X. S-100 protein, peanut agglutinin, and transmission electron microscopy study.". American journal of clinical pathology 94 (5): 627–31. PMID 2239828.
34. Valladeau J, Ravel O, Dezutter-Dambuyant C, Moore K, Kleijmeer M, Liu Y, Duvert-Frances V, Vincent C, Schmitt D, Davoust J, Caux C, Lebecque S, Saeland S (2000). "Langerin, a novel C-type lectin specific to Langerhans cells, is an endocytic receptor that induces the formation of Birbeck granules". Immunity 12 (1): 71–81. doi:10.1016/S1074-7613(00)80160-0. PMID 10661407.
35. Lau, SK; Chu, PG; Weiss, LM (April 2008). "Immunohistochemical expression of Langerin in Langerhans cell histiocytosis and non-Langerhans cell histiocytic disorders.". The American journal of surgical pathology 32 (4): 615–9. doi:10.1097/PAS.0b013e31815b212b. PMID 18277880.
36. Haupt, Riccardo; Minkov, Milen; Astigarraga, Itziar; Schäfer, Eva; Nanduri, Vasanta; Jubran, Rima; Egeler, R. Maarten; Janka, Gritta; Micic, Dragan; Rodriguez-Galindo, Carlos; Van Gool, Stefaan; Visser, Johannes; Weitzman, Sheila; Donadieu, Jean (February 2013). "Langerhans cell histiocytosis (LCH): Guidelines for diagnosis, clinical work-up, and treatment for patients till the age of 18 years". Pediatric Blood & Cancer 60 (2): 175–184. doi:10.1002/pbc.24367. PMID 23109216.
37. Girschikofsky, Michael; Arico, Maurizio; Castillo, Diego; Chu, Anthony; Doberauer, Claus; Fichter, Joachim; Haroche, Julien; Kaltsas, Gregory A; Makras, Polyzois; Marzano, Angelo V; de Menthon, Mathilde; Micke, Oliver; Passoni, Emanuela; Seegenschmiedt, Heinrich M; Tazi, Abdellatif; McClain, Kenneth L (2013). "Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net". Orphanet Journal of Rare Diseases 8 (1): 72. doi:10.1186/1750-1172-8-72.
38. "Langerhans cell histiocytosis - Histiocyte Society Evaluation and Treatment Guidelines". April 2009.
39. "Langerhans Cell Histiocytosis Treatment (PDQ®)". and 1
40. Komp D, El Mahdi A, Starling K, Easley J, Vietti T, Berry D, George S (1980). "Quality of survival in Histiocytosis X: a Southwest Oncology Group study". Med. Pediatr. Oncol. 8 (1): 35–40. doi:10.1002/mpo.2950080106. PMID 6969347.
41. House (season 3) In CSI, season 15 episode 4, a student has LCH.
42. Jolles, S. (April 2002). "Paul Langerhans". Journal of Clinical Pathology 55 (4): 243. PMC 1769627. PMID 11919207.

External links

• EuroHistioNet (EHN) a EU network granted by the EU commission with a multilanguage web site
• Images of LCH MedPix(r)Database
• Histiocyte Society An International Community Dedicated to Research and Treatment
• Seven Part Video Series
• Langerhans Cell Histiocytosis, article by the Sydney Children's Hospital
• 5-Minute Clinical Consult
• synd/2224 at Who Named It?
• The Histiocytosis Association is an organization dedicated to helping diagnosed patients find trained doctors in their area, raising awareness, finding local emotional support, and assisting interested people in finding more information.