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Synonyms: histiocytosis X, eosinophilic granuloma, Hand-Schüller-Christian disease, Letterer-Siwe disease
Langerhans' cell histiocytosis (LCH) is one of the 'histiocytosis syndromes', as defined by the Histiocyte Society. LCH is an abnormal proliferation and dissemination of histiocytes. It is named after the appearance of the cells, which resemble the normal dentritic cells first noted by Langerhans.
LCH may affect one or many organs. The clinical presentation and severity are varied. It was formerly considered as a disease of childhood, but is now recognised as often presenting in adulthood.
Previous classifications of LCH include the following diseases and terms, which are now included under the 'umbrella' of LCH:
- Histiocytosis X.
- Eosinophilic granuloma.
- Letterer-Siwe disease.
- Hand-Schüller-Christian disease.
- Hashimoto-Pritzker syndrome.
- Other terms including self-healing histiocytosis, pure cutaneous histiocytosis, Langerhans' cell granulomatosis, Type II histiocytosis, and the generic term 'nonlipid reticuloendotheliosis'.
The clinical manifestations of LCH are very variable, ranging from very benign forms to a disseminated, aggressive disease that causes significant mortality.
There is a risk-stratification system based on degree of organ involvement and number of organs involved.
- LCH is rare in children (about 3-5 cases per million children aged 0-14 years).
- LCH is also rare in adults but the prevalence and incidence are uncertain because of the lack of population-based studies.
- This is largely unknown. It may be a disorder of immune regulation.
- Cigarette smoking appears to have a role in causing or potentiating the pulmonary form of LCH.
- The presentation is variable and depends on the organ or system affected, and ranges from a self-healing disease to chronic recurrences.
- The spectrum of symptomatic disease varies from a single bony lesion to multiple bony, skin and visceral lesions.
- Common presentations in one study were bony lesions, respiratory symptoms, malaise, abnormal CXR or diabetes insipidus (DI).
- Average age at presentation (in one study) was 24 years.
Clinical features of LCH (listed by organ system)
Bony lesions - osseous LCH:
- Well-localised bone pain is a common presenting symptom, with pain during both activity and rest.
- Bone pain usually correlates with a radiologically evident lesion.
- There may be tender swelling of the soft tissue overlying the bone.
- Common sites for bone LCH are skull, proximal femur and ribs.
- Involvement of other organs is common.
- Rarely, bone lesions may cause pathological fractures.
Skull and brain involvement may cause:
- Endocrine disorders involving the hypothalamic-pituitary axis (see below).
- Neurological features, including cerebellar disorders and raised intracranial pressure.
- Ocular and periorbital disease, including proptosis and uveitis.
- Gum and dental disease.
- ENT disease - eg, otitis media, sinusitis.
- Skull lesions, which may be visible/palpable.
Lungs - pulmonary LCH:
- Non-productive cough and dyspnoea.
- Abnormal CXR.
- Spontaneous pneumothorax.
- Haemoptysis (rarely).
- Chest pain (rarely).
Endocrine - thalamic axis LCH:
- DI is relatively common - presenting with polyuria and polydipsia.
- Other types of hypopituitarism can also occur - eg, growth hormone deficiency.
Skin and mucous membranes - mucocutaneous LCH:
- Skin rashes- may be macular, papular, nodular or petechial.
- Skin rashes in neonates may regress spontaneously.
- Scalp lesions may be scaly.
- Mucosal ulceration and bleeding can occur.
- Vesiculopustular lesions are common in congenital LCH.
- This is fairly common.
- There are usually no symptoms unless the enlarged nodes damage or obstruct nearby organs
- Weight loss, fever, night sweats and anorexia
Hepatosplenomegaly and gastrointestinal (GI):
- Hepatosplenomegaly is uncommon; it may reflect a later stage or more aggressive form of LCH.
- GI features are uncommon; may involve infiltration of GI tract leading to ulceration and GI bleeding.
- LCH can involve other organs - for example, scrotal mass was a rare presentation in one study.
Assessment and investigations
The diagnosis of LCH should be based on histologic and immunological examination of a lesional biopsy. Investigations will otherwise depend on the clinical presentation, but usually include:
- Full examination, height and weight.
- Blood tests: FBC, clotting studies, U&E, LFT, urine osmolality.
- Plain X-ray - for bone pain or suspected bone lesions.
- Skeletal survey.
- CT/MRI scans.
- Endoscopy if GI involvement is suspected.
- Biopsy of lesions - may show:
- Multinucleated Langerhans' cells, histiocytes and eosinophils.
- Birbeck's granules on electron microscopy.
- Antigens for CD1a glycoprotein and S100 cytoplasmic protein (diagnostic).
- For suspected pulmonary involvement, investigations are:
- Plain CXR - may show upper lobe infiltrates.
- Lung function tests - may show impaired diffusing capacity.
- CT scan - may show typical changes of pulmonary LCH.
- Bronchoscopy or surgical lung biopsy.
- Bone marrow biopsy is sometimes required for staging.
The definitive diagnosis is made on the biopsy features (above).
- Treatment may be local or systemic, depending on the number and location of LCH lesions.
- Because LCH is rare, there are relatively few clinical trials and less experience available to inform treatment.
- Treatment may involve surgical excision, radiotherapy, chemotherapy, or combinations of these.
- The prognosis and treatment protocol depend on the number of organs involved, which organ systems are involved and the degree of organ dysfunction.
- Recommendations and protocols are available from the Histiocytosis Association.
The following is an overview of current possible treatments, according to organs involved.
Limited cutaneous disease:
- No treatment (it may remit).
- Topical steroids.
- Topical nitrogen mustard.
- Psoralen combined with ultraviolet A (PUVA) therapy.
Localised bone lesions:
- Surgical curettage is the usual treatment (for accessible sites).
- Other treatments for bone lesions include:
- Intralesional steroids.
- Early chemotherapy (vinblastine and prednisolone) for bony lesions at crucial anatomical sites.
- Surgical excision of single nodes with LCH.
- Regional node involvement may respond to a course of systemic steroids.
- Chemotherapy for nodes resistant to treatment.
- Smoking cessation - an essential part of treatment which can stabilise symptoms in most patients. This may be the only treatment required.
- Corticosteroids are the main treatment (after smoking cessation).
- Chemotherapy may be used for progressive disease not responding to steroids, but this is a last resort because its efficacy is uncertain. Drugs which have been used in this context are vinblastine, methotrexate, cyclophosphamide, etoposide and cladribine.
- Lung transplantation can be considered for advanced disease.
- Drugs used include prednisolone, vinblastine and 6-mercaptopurine.
- Stem cell transplantation may be used in patients with a poor prognosis whose LCH has not responded to conventional treatment.
Lifelong follow-up is required because of the possibility of late recurrence or late complications. Complications of LCH may occur at any time from presentation or many years later. Complications can arise even in patients without multi-organ involvement. It is estimated that about 50% of LCH patients have late complications of the disease or its treatment. Complications include:
- DI (relatively common) - treated with desmopressin.
- Late relapse or progression to systemic involvement.
- Hypothalamic-pituitary dysfunction.
- Cognitive dysfunction.
- Cerebellar involvement.
- There may be an increased risk of other neoplasms.
- Prognosis depends on the extent and nature of of organ involvement. The clinical course of LCH is very variable, ranging from a self-healing solitary bone lesion to widely disseminated life-threatening disease.
- However, organ dysfunction, rather than the extent of the lesions, is the most important prognostic feature.
- The majority of cases have a good prognosis. In one study, 90% of LCH patients achieved disease-free survival after treatment.
- For patients requiring chemotherapy, the response after six weeks of treatment is a major prognostic factor.
- Pulmonary LCH has a variable course. Most patients have a good prognosis: symptoms may be mild, and stabilisation or spontaneous improvement is possible. Some patients have progressive pulmonary LCH leading to progressive respiratory impairment.
- Neonates with LCH limited to the skin and mucous membranes may have a good prognosis.
Further reading & references
- Leonidas JC, Guelfguat M, Valderrama E; Langerhans' cell histiocytosis. Lancet. 2003 Apr 12;361(9365):1293-5.
- Badalian-Very G, Vergilio JA, Degar BA, et al; Recent advances in the understanding of Langerhans cell histiocytosis. Br J Haematol. 2012 Jan;156(2):163-72. doi: 10.1111/j.1365-2141.2011.08915.x. Epub 2011 Oct 24.
- Satter EK, High WA; Langerhans Cell Histiocytosis: A case report and summary of the current recommendations of the Histiocyte Society. Dermatol Online J. 2008 Mar 15;14(3):3
- Minkov M; Multisystem Langerhans cell histiocytosis in children: current treatment and future directions. Paediatr Drugs. 2011 Apr 1;13(2):75-86. doi: 10.2165/11538540-000000000-00000.
- Juvet SC, Hwang D, Downey GP; Rare lung diseases III: pulmonary Langerhans' cell histiocytosis. Can Respir J. 2010 May-Jun;17(3):e55-62.
- Vassallo R, Ryu JH; Pulmonary Langerhans' cell histiocytosis. Clin Chest Med. 2004 Sep;25(3):561-71, vii.
- Girschikofsky M, Arico M, Castillo D, et al; Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net. Orphanet J Rare Dis. 2013 May 14;8:72. doi: 10.1186/1750-1172-8-72.
- Allen CE, McClain KL; Langerhans cell histiocytosis: a review of past, current and future therapies. Drugs Today (Barc). 2007 Sep;43(9):627-43.
- Hait E, Liang M, Degar B, et al; Gastrointestinal tract involvement in Langerhans cell histiocytosis: case report Pediatrics. 2006 Nov;118(5):e1593-9. Epub 2006 Oct 9.
- Ng-Cheng-Hin B, O'Hanlon-Brown C, Alifrangis C, et al; Langerhans cell histiocytosis: old disease new treatment. QJM. 2011 Feb;104(2):89-96. doi: 10.1093/qjmed/hcq206. Epub 2010 Nov 16.
- The Histiocytosis Association
- Matsuki E, Tsukada Y, Nakaya A, et al; Successful treatment of adult onset Langerhans cell histiocytosis with multi-drug combination therapy. Intern Med. 2011;50(8):909-14. Epub 2011 Apr 15.
- McClain KL, Natkunam Y, Swerdlow SH; Atypical cellular disorders. Hematology Am Soc Hematol Educ Program. 2004:283-96.
- Abla O, Egeler RM, Weitzman S; Langerhans cell histiocytosis: Current concepts and treatments. Cancer Treat Rev. 2010 Jun;36(4):354-9. doi: 10.1016/j.ctrv.2010.02.012. Epub 2010 Feb 25.
- Battistella M, Fraitag S, Teillac DH, et al; Neonatal and early infantile cutaneous langerhans cell histiocytosis: comparison of self-regressive and non-self-regressive forms. Arch Dermatol. 2010 Feb;146(2):149-56. doi: 10.1001/archdermatol.2009.360.
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Dr Naomi Hartree
Dr Colin Tidy
Dr Adrian Bonsall