Langerhans cell histiocytosis

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Langerhans cell histiocytosis
Langerhans cell histiocytosis - very high mag.jpg
Micrograph showing a Langerhans cell histiocytosis with the characteristic reniform Langerhans cells accompanied by abundant eosinophils. H&E stain.
Specialty Hematology

Langerhans cell histiocytosis (LCH) is an abnormal clonal proliferation of Langerhans cells, abnormal cells deriving from bone marrow and capable of migrating from skin to lymph nodes.

Contents

Symptoms range from isolated bone lesions to multisystem disease. [1] 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). [2] These diseases are related to other forms of abnormal proliferation of white blood cells, such as leukemias and lymphomas. [3]

The disease 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. [4] [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. [5] A similar set of diseases has been described in canine histiocytic diseases. [6]

LCH is clinically divided into three groups: unifocal, multifocal unisystem, and multifocal multisystem. [7]

Unifocal

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. [8] When found in the skin it is called cutaneous single system Langerhans cell LCH. This version can heal without therapy in some rare cases. [9] This primary bone involvement helps to differentiate eosinophilic granuloma from other forms of Langerhans Cell Histiocytosis (Letterer-Siwe or Hand-Schüller-Christian variant). [10]

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, often leading to diabetes insipidus. The triad of diabetes insipidus, exophthalmos, and lytic bone lesions is known as the Hand-Schüller-Christian triad . Peak onset is 2–10 years of age. [11]

Multifocal multisystem

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%. [12]

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. PLCH develops when an abundance of monoclonal CD1a-positive Langerhans (immature histiocytes) proliferate the bronchioles and alveolar interstitium, and this flood of histiocytes recruits granulocytes like eosinophils and neutrophils and agranulocytes like lymphocytes further destroying bronchioles and the interstitial alveolar space that can cause damage to the lungs. [13] It is hypothesized that bronchiolar destruction in PLCH is first attributed to the special state of Langerhans cells that induce cytotoxic T-cell responses, and this is further supported by research that has shown an abundance of T-cells in early PLCH lesions that are CD4+ and present early activation markers. [14] Some affected people recover completely after they stop smoking, but others develop long-term complications such as pulmonary fibrosis and pulmonary hypertension. [15]

Signs and symptoms

CT scan showing LCH infiltrating peri-orbital tissue (arrowed). CT of periorbital Langerhans cell histiocytosis.jpg
CT scan showing LCH infiltrating peri-orbital tissue (arrowed).
A patient with Hand-Schuller-Christian disease which is a subtype of Langerhans Cell Histiocytosis. Hans-Schuller-Christian.jpg
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.

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. [23] [24]

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. [25] [26] [27] 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. [28] 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. [29]

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%). [30] This study documented the first recurrent mutation in LCH samples. Two independent studies have confirmed this finding. [31] [32] Presence of this activating mutation could support the notion to characterize LCH as myeloproliferative disorder.

Diagnosis

Micrograph showing Langerhans Cell Histiocytosis. H&E stain. Langerhans cell histiocytosis - high mag.jpg
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. [33] 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. [34]

Imaging may be evident in chest X-rays with micronodular and reticular changes of the lungs with cyst formation in advanced cases. MRI and High-resolution CT may show small, cavitated nodules with thin-walled cysts. MRI scan of the brain can show three groups of lesions such as tumourous/granulomatous lesions, nontumourous/granulomatous lesions, and atrophy. Tumourous lesions are usually found in the hypothalamic-pituitary axis with space-occupying lesions with or without calcifications. In non-tumourous lesions, there is a symmetrical hyperintense T2 signal with hypointense or hyperintense T1 signal extending from grey matter into the white matter. In the basal ganglia, MRI shows a hyperintense T1 signal in the globus pallidus. [35]

Assessment of endocrine function and bone marrow biopsy are also performed when indicated. [36]

Treatment

Guidelines for management of patients up to 18 years with Langerhans cell histiocytosis have been suggested. [43] [44] [45] [46] 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.[ citation needed ]

Prognosis

There is a general excellent prognosis for the disease as those with localized disease have a long life span. With multi-focal disease 60% have a chronic course, 30% achieve remission and mortality is up to 10%. [47] A full recovery can be expected for people who seek treatment and do not have more lesions at 12 and 24 months. However, 50% of children under 2 with disseminated Langerhans cell histiocytosis die of the disease. The prognosis rate decreases for patients who experience lung involvement. Whereas patients with skin and a solitary lymph node involvement generally have a good prognosis. [48] Although there is a general good prognosis for Langerhans cell histiocytosis, approximately 50% of patients with the disease are prone to various complications such as musculoskeletal disability, skin scarring and diabetes insipidus. [48]

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; [49] and in adults even rarer, in about 1 in 560,000. [50] It has been reported in elderly but is vanishingly rare. [51] It is most prevalent in Caucasians, and affects males twice as often as females. [52] In other populations too the prevalence in males is slightly more than in females. [53]

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. [54]

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. [55] 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.[ citation needed ]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.[ citation needed ]

Nomenclature

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. [56]

Related Research Articles

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<span class="mw-page-title-main">Letterer–Siwe disease</span> Medical condition

Letterer–Siwe disease, (LSD) or Abt-Letterer-Siwe disease, is one of the four recognized clinical syndromes of Langerhans cell histiocytosis (LCH) and is the most severe form, involving multiple organ systems such as the skin, bone marrow, spleen, liver, and lung. Oral cavity and gastrointestinal involvement may also be seen. LCH and all its subtypes are characterized by monoclonal migration and proliferation of specific dendritic cells.

<span class="mw-page-title-main">Erdheim–Chester disease</span> Medical condition

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<span class="mw-page-title-main">Lymphangiomatosis</span> Medical condition

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<span class="mw-page-title-main">Juvenile xanthogranuloma</span> Medical condition

Juvenile xanthogranuloma is a form of histiocytosis, classified as "non-Langerhans cell histiocytosis", or more specifically, "type 2".

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<span class="mw-page-title-main">Chronic multifocal Langerhans cell histiocytosis</span> Medical condition

Chronic multifocal Langerhans cell histiocytosis, previously known as Hand–Schüller–Christian disease, is a type of Langerhans cell histiocytosis (LCH), which can affect multiple organs. The condition is traditionally associated with a combination of three features; bulging eyes, breakdown of bone, and diabetes insipidus, although around 75% of cases do not have all three features. Other features may include a fever and weight loss, and depending on the organs involved there may be rashes, asymmetry of the face, ear infections, signs in the mouth and the appearance of advanced gum disease. Features relating to lung and liver disease may occur.

<span class="mw-page-title-main">Rosai–Dorfman disease</span> Medical condition

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Benign cephalic histiocytosis(BCH) is a non-Langerhan's histiocytosis that is uncommon and self-limiting, usually beginning towards the end of the first year of life. Gianotti et al. originally described it in 1971. Initially affecting the head and neck, this condition is characterized by several small eruptions of yellow to reddish-brow papules that heal on their own. Histological investigations have demonstrated that this disorder is associated with dermal proliferation of histiocytes, characterized by intracytoplasmic comma-shaped bodies, covered vesicles, and desmosome-like structure.

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T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a malignancy of B cells. B-cells are lymphocytes that normally function in the humoral immunity component of the adaptive immune system by secreting antibodies that, for example, bind to and neutralize invasive pathogens. Among the various forms of B-cell lymphomas, THRLBCL is a rarely occurring subtype of the diffuse large B-cell lymphomas (DLBCL). DLBCL are a large group of lymphomas that account for ~25% of all non-Hodgkin lymphomas worldwide. THRLBCL is distinguished from the other DLBCL subtypes by the predominance of non-malignant T-cell lymphocytes and histiocytes over malignant B-cells in its tumors and tissue infiltrates.

<span class="mw-page-title-main">Histiocyte Society</span>

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Crystal-storing histiocytosis is a form of histiocytosis which mostly occurs in people with monoclonal gammopathies. Histiocytosis is an excessive number of histiocytes. In the vast majority of crystal-storing histiocytosis cases, immunoglobulins accumulate within the cytoplasm of histiocytes; in rare cases clofazimine, cystine, silica, or Charcot–Leyden crystals may be found in the histiocytes instead. Non-immunoglobulin crystal-storing histiocytosis is mostly associated with non-malignant disorders, such as chronic inflammation or autoimmune abnormality conditions such as rheumatoid arthritis, Crohn's disease, or Helicobacter pylori gastritis. It may be a localised or generalised disease. Examples of locations where histiocytosis may occur include the lungs, pleura, stomach, kidney, bone marrow, thyroid, thymus, and parotid gland. The disease is described as generalised if two or more unrelated sites are involved.

References

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  2. ↑ "UpToDate". UpToDate. Retrieved October 18, 2023.
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  31. ↑ 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. Bibcode:2012PLoSO...733891S. doi: 10.1371/journal.pone.0033891 . PMC   3323620 . PMID   22506009.
  32. ↑ 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{{cite journal}}: Cite journal requires |journal= (help)
  33. ↑ Padmanaban, Kamalakannan; Kamalakaran, Arunkumar; Raghavan, Priyadharshini; Palani, Triveni; Rajiah, Davidson (August 21, 2022). "Langerhans Cell Histiocytosis of the Mandible". Cureus. Cureus, Inc. 14 (8): e28222. doi: 10.7759/cureus.28222 . ISSN   2168-8184. PMC   9486456 . PMID   36158441.
  34. ↑ Tillotson, Cara V.; Anjum, Fatima; Patel, Bhupendra C. (July 17, 2023). "Langerhans Cell Histiocytosis". StatPearls Publishing. PMID   28613635 . Retrieved October 18, 2023.
  35. ↑ Monsereenusorn, Chalinee; Rodriguez-Galindo, Carlos (October 2015). "Clinical Characteristics and Treatment of Langerhans Cell Histiocytosis". Hematology/Oncology Clinics of North America. 29 (5): 853–873. doi:10.1016/j.hoc.2015.06.005. PMID   26461147.
  36. ↑ Kaltsas, G. A.; Powles, T. B.; Evanson, J.; Plowman, P. N.; Drinkwater, J. E.; Jenkins, P. J.; Monson, J. P.; Besser, G. M.; Grossman, A. B. (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 & Metabolism. The Endocrine Society. 85 (4): 1370–1376. doi: 10.1210/jcem.85.4.6501 . ISSN   0021-972X. PMID   10770168.
  37. 1 2 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. S2CID   70911084.
  38. ↑ 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.
  39. ↑ 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. S2CID   32685876.
  40. ↑ 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. doi:10.1093/ajcp/94.5.627. PMID   2239828.
  41. ↑ 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.
  42. ↑ 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. S2CID   40092500.
  43. ↑ 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. PMC   4557042 . PMID   23109216.
  44. ↑ 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 . PMC   3667012 . PMID   23672541.
  45. ↑ "Langerhans cell histiocytosis — Histiocyte Society Evaluation and Treatment Guidelines". April 2009. Archived from the original on 2018-01-21. Retrieved 2015-04-28.{{cite journal}}: Cite journal requires |journal= (help)
  46. ↑ PDQ Pediatric Treatment Editorial Board (2002). "Langerhans Cell Histiocytosis Treatment (PDQ®): Health Professional Version". Langerhans Cell Histiocytosis Treatment (PDQ®). National Cancer Institute (US). PMID   26389240. and 1
  47. ↑ 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.
  48. 1 2 Tillotson CV, Anjum F, Patel BC. Langerhans Cell Histiocytosis. [Updated 2022 Jul 18]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430885/
  49. ↑ "MedlinePlus Medical Encyclopedia: Histiocytosis" . Retrieved 2007-05-10.
  50. ↑ "Histiocytosis Association of Canada". Archived from the original on 2007-05-14. Retrieved 2007-05-16.
  51. ↑ 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. S2CID   20706403.
  52. ↑ 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.
  53. ↑ 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.
  54. ↑ 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.
  55. ↑ House (season 3) In CSI, season 15 episode 4, a student has LCH.
  56. ↑ Jolles, S. (April 2002). "Paul Langerhans". Journal of Clinical Pathology. 55 (4): 243. doi:10.1136/jcp.55.4.243. PMC   1769627 . PMID   11919207.
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