Langerhans cell histiocytosis
Micrograph showing a Langerhans cell histiocytosis with the characteristic reniform Langerhans cells accompanied by abundanteosinophils.H&E stain.
Specialty	Hematology

Langerhans cell histiocytosis (LCH) is an abnormal clonal proliferation ofLangerhans cells, abnormalcells deriving frombone marrow and capable of migrating from skin tolymph nodes.

Symptoms range from isolated bone lesions tomultisystem disease.^[1] LCH is part of a group of syndromes calledhistiocytoses, which are characterized by an abnormal proliferation ofhistiocytes (an archaic term for activateddendritic cells andmacrophages).^[2] These diseases are related to other forms of abnormal proliferation ofwhite blood cells, such asleukemias andlymphomas.^[3]

The disease has gone by several names, includingHand–Schüller–Christian disease,Abt-Letterer-Siwe disease,Hashimoto-Pritzker disease (a very rare self-limiting variant seen at birth) andhistiocytosis X, until it was renamed in 1985 by theHistiocyte Society.^[4][1]

The disease spectrum results fromclonal accumulation andproliferation of cells resembling the epidermaldendritic cells calledLangerhans cells, sometimes calleddendritic cell histiocytosis. These cells in combination withlymphocytes,eosinophils, and normalhistiocytes form typical LCH lesions that can be found in almost anyorgan.^[5] A similar set of diseases has been described incanine histiocytic diseases.^[6]

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

Unifocal LCH, also calledeosinophilic granuloma (an older term which is now known to be amisnomer), 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]

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 thepituitary stalk, often leading todiabetes insipidus. The triad of diabetes insipidus,exophthalmos, and lytic bone lesions is known as theHand-Schüller-Christian triad. Peak onset is 2–10 years of age.^[11]

Multifocal multisystem LCH, also calledLetterer-Siwe disease, is an often rapidly progressing disease in which Langerhans 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) is a unique form of LCH in that it occurs almost exclusively incigarette smokers. It is now considered a form of smoking-relatedinterstitial 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 recruitsgranulocytes like eosinophils andneutrophils andagranulocytes 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 aspulmonary fibrosis andpulmonary hypertension.^[15]

LCH provokes a non-specificinflammatory 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.^[16]
• Skin: Commonly seen are a rash which varies from scalyerythematous lesions to red papules pronounced inintertriginous 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.^[17]
• Endocrine glands:Hypothalamic pituitary axis commonly involved.^[18]Central Diabetes insipidus can be the first manifestation of LCH.^[19][20]Anterior pituitaryhormone deficiency is usually permanent.^[21]
• Lungs: some patients are asymptomatic, diagnosed incidentally because of lung nodules on radiographs; others experience chronic cough and shortness of breath.^[22]
• Less frequentlygastrointestinal tract,central nervous system, andoral cavity.^[23]

The pathogenesis of Langerhans cell histiocytosis (LCH) is a matter of debate. There are ongoing investigations to determine whether LCH is a neoplastic (cancerous) or reactive (non-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 ascytokine storm) in the lesional tissue, favorable prognosis and relatively good survival rate in patients without organ dysfunction or risk organ involvement.^[24][25]

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.^[26][27][28] 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.^[29] 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.^[30]

An activating somatic mutation of a proto-oncogene in theRaf family, theBRAF 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%).^[31] This study documented the first recurrent mutation in LCH samples. Two independent studies have confirmed this finding.^[32][33] Presence of this activating mutation could support the notion to characterize LCH as myeloproliferative disorder.

Diagnosis is confirmedhistologically bytissuebiopsy. Hematoxylin-eosin stain of biopsy slide will show features of Langerhans Cell e.g. distinct cell margin, pink granularcytoplasm.^[34] Presence ofBirbeck granules onelectron microscopy andimmuno-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.^[35] Electron microscopyor immunohistochemistry (only one of the two is required) may be used to definitively diagnose Langerhans cell histiocytosis, in the presence of other pathologic and histologic qualities of the disease.^[36]

Imaging may be evident inchest X-rays withmicronodular andreticular changes of the lungs with cyst formation in advanced cases.MRI and High-resolutionCT 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 symmetricalhyperintense T2 signal with hypointense or hyperintense T1 signal extending from grey matter into the white matter. In thebasal ganglia, MRI shows a hyperintense T1 signal in theglobus pallidus.^[37]

Assessment ofendocrine function and bone marrow biopsy are also performed when indicated.^[38]

• S-100 protein is expressed in a cytoplasmic pattern^[39][40]
• peanut agglutinin (PNA) is expressed on the cell surface and perinuclearly^[41][42]
• major histocompatibility (MHC) class II is expressed (as is typical for Langerhans cells, which are antigen-presenting cells)
• CD1a^[39]
• langerin (CD207), a Langerhans Cell–restricted protein that induces the formation ofBirbeck granules and is constitutively associated with them, is a highly specific marker.^[43][44]

Guidelines for management of patients up to 18 years with Langerhans cell histiocytosis have been suggested.^{[45][46][47][48][clarification needed]} 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 asalkylating agents,antimetabolites,vinca alkaloids either singly or in combination can lead to complete remission in diffuse disease.^{[citation needed]}

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%.^[49] 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.^[50]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.^[50]

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;^[51] and in adults even rarer, in about 1 in 560,000.^[52] It has been reported in elderly but is vanishingly rare.^[53] It is most prevalent in Caucasians, and affects males twice as often as females.^[54] In other populations too the prevalence in males is slightly more than in females.^[55]

LCH is usually a sporadic and non-hereditary condition butfamilial clustering has been noted in limited number of cases.Hashimoto-Pritzker disease is a congenital self-healing variant of Hand-Schüller-Christian disease.^[56]

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.^[57]

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