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Langerhans-Cell Histiocytosis

Langerhans Cell Histiocytosis

Langerhans cell histiocytosis (LCH), also called Histiocytosis X, is a rare disease characterized by the proliferation and accumulation of Langerhans cells in various tissues.


Presentation

Langerhans cell histiocytosis may present with a variety of non-specific and specific inflammatory symptoms in various organs of the body.
Non-specific symptoms include fever, lethargy and weight loss. Involvement of organs causes specific symptoms.

  • Bone: Skull is most commonly affected followed by long bones of upper extremities and flat bones. Painful swelling of bones is common. Lytic lesions may lead to pathologic fractures.
  • Skin: There are diffuse eruptions on the scalp as well as scaly erythematous lesions or red papules in other regions.
  • Lymph nodes: Lymph node enlargement and enlargement of lymphoid organs is also seen in langerhans cell histiocytosis.
  • Lungs: Chronic cough and dyspnea are seen in some patients. Lung nodules may be seen on radiographs.
  • Gastrointestinal and central nervous system are less frequently involved.
Splenomegaly
  • […] affects children, who present with fever, diffuse eruptions, particularly on the scalp and in the ear canals, frequent bouts of otitis media, mastoiditis, and upper respiratory tract infections, bone lesions and mild lymphadenopathy, hepatomegaly, and splenomegaly[histopathology-india.net]
  • Other symptoms that LCH can cause are enlargement of lymph nodes, hepatomegaly, splenomegaly, anorexia, night sweats, fever and weight loss [1, 2, 4].[cancerwall.com]
  • In case of splenomegaly other causes than LCH primarily have to be ruled out. Pancreatic involvement (mainly tumorous) is extremely rare.[doi.org]
  • Introduction Langerhans cell histiocytosis is a disease of myeloid dendritic cells, lymphocytes, and macrophages mixed with eosinophils and neutrophils. [1] The accumulation of these cells causes the classic lytic bone lesions, skin rashes, lymphadenopathy, splenomegaly[journals.plos.org]
  • Fever, splenomegaly and hepatomegaly are the most common early findings; b. Lymph node enlargement, skin rash, and neurologic abnormali ties may also occur.[hopkinsmedicine.org]
Generalized Lymphadenopathy
  • A 2-year-old boy presented with generalized lymphadenopathy, fever, and cough. The patient had hepatosplenomegaly, anemia, and lytic lesions in the skull. FNAC from the largest submandibular lymph node showed features of LCH.[ncbi.nlm.nih.gov]
Fever
  • A 10-year-old girl was seen with a 3-week history of right upper lid swelling and with no other symptoms or fever.[ncbi.nlm.nih.gov]
  • A 3 years old boy was hospitalized with a month's history of polydipsia, polyuria and low fever. There was no relevant family history.[ncbi.nlm.nih.gov]
  • The patient reported no pain at other sites, exhibited no fever or night sweats, and was unable to recall any recent injury.[ncbi.nlm.nih.gov]
  • A 2-year-old boy presented with generalized lymphadenopathy, fever, and cough. The patient had hepatosplenomegaly, anemia, and lytic lesions in the skull. FNAC from the largest submandibular lymph node showed features of LCH.[ncbi.nlm.nih.gov]
  • CASE REPORT: A 9-year-old girl had neck pain, neck tilt and left upper limb weakness, occasional fever and positive family history of tuberculosis.[ncbi.nlm.nih.gov]
Weight Loss
  • Langerhans cell histiocytosis may present with a variety of non-specific and specific inflammatory symptoms in various organs of the body.Non-specific symptoms include fever, lethargy and weight loss. Involvement of organs causes specific symptoms.[symptoma.com]
  • Symptoms and Signs Typical symptoms and signs of pulmonary Langerhans cell histiocytosis are dyspnea, nonproductive cough, fatigue, fever, weight loss, and pleuritic chest pain. Ten percent to 25% of patients have sudden, spontaneous pneumothorax.[msdmanuals.com]
  • Other symptoms include constitutional symptoms (fatigue and weight loss), pleuritic chest pain, or spontaneous pneumothorax 1,4. Up to a quarter of patients are asymptomatic.[radiopaedia.org]
  • LCH provokes a non-specific inflammatory response, which includes fever, lethargy, and weight loss. Organ involvement can also cause more specific symptoms.[en.wikipedia.org]
  • Other symptoms that LCH can cause are enlargement of lymph nodes, hepatomegaly, splenomegaly, anorexia, night sweats, fever and weight loss [1, 2, 4].[cancerwall.com]
Anemia
  • The patient had hepatosplenomegaly, anemia, and lytic lesions in the skull. FNAC from the largest submandibular lymph node showed features of LCH. The large cells of LCH showed positive immunostaining for S-100 protein on FNAC smears.[ncbi.nlm.nih.gov]
  • KEY TERMS Anemia — Abnormally low level of red blood cells in the blood. Biopsy — Surgical removal of tissue for examination.[encyclopedia.com]
  • Key terms Anemia — Abnormally low level of red blood cells in the blood. Biopsy — Surgical removal of tissue for examination.[medical-dictionary.thefreedictionary.com]
  • It is characterized by skin lesions; enlarged liver, spleen and lymph nodes; anemia and bleeding tendencies. The cause of Langerhans cell histiocytosis is unknown. It is not inherited or communicable.[chop.edu]
  • Anemia and destructive bony lesions are seen. Letterer-Siwe disease is rapidly fatal if untreated. With intensive chemotherapy, 5-year survival is about 50%.[histopathology-india.net]
Fatigue
  • Grade 3 toxicities included fatigue, diarrhea, and pain (one of each). Another severe adverse event involved soft tissue necrosis.[ncbi.nlm.nih.gov]
  • Symptoms are dyspnea, cough, fatigue, and pleuritic chest pain. Diagnosis is based on history and imaging tests and sometimes on bronchoalveolar lavage and biopsy findings. Treatment is smoking cessation.[msdmanuals.com]
  • […] or discharge Site: Eyes Possible symptoms: Vision problems or bulging eyes Site: Central nervous system Possible symptoms: Headache, dizziness, vomiting, excessive thirst, frequent urination Site: General symptoms Possible symptoms: Fever, weakness, fatigue[my.clevelandclinic.org]
  • A decrease in these cells may cause anemia and fatigue due to low red blood cells, increased infections due to low numbers of white blood cells, and the tendency to bruise easily and/or develop petechiae due to low numbers of platelets.[cincinnatichildrens.org]
  • Other symptoms include constitutional symptoms (fatigue and weight loss), pleuritic chest pain, or spontaneous pneumothorax 1,4. Up to a quarter of patients are asymptomatic.[radiopaedia.org]
Cough
  • A 50-year-old man was referred for dry cough and exertional dyspnea of more than 1 week. High-resolution computed tomography (HRCT) of the chest revealed symmetric nodules and cyst lesions with upper lobe infiltrate.[ncbi.nlm.nih.gov]
  • A 2-year-old boy presented with generalized lymphadenopathy, fever, and cough. The patient had hepatosplenomegaly, anemia, and lytic lesions in the skull. FNAC from the largest submandibular lymph node showed features of LCH.[ncbi.nlm.nih.gov]
  • Symptoms are dyspnea, cough, fatigue, and pleuritic chest pain. Diagnosis is based on history and imaging tests and sometimes on bronchoalveolar lavage and biopsy findings. Treatment is smoking cessation.[msdmanuals.com]
  • You also might have trouble breathing or have coughs. Diagnosis Your doctor will know if you have LCH after a tissue biopsy.[webmd.com]
Failure to Thrive
  • We describe a 16-month-old girl who initially presented with bilious vomiting, failure to thrive and a rash.[ncbi.nlm.nih.gov]
  • […] to thrive (when a child does not grow as expected) Loss of teeth Lung problems that lead to lung failure Neurological problems such as tremors, poor coordination or memory loss Pituitary gland problems that lead to growth failure Scars on the skin or[rileychildrens.org]
  • Symptoms in children may include: Abdominal pain Bone pain Delayed puberty Dizziness Ear drainage that continues long-term Eyes that appear to stick out more and more Irritability Failure to thrive Fever Frequent urination Headache Jaundice Limping Mental[nlm.nih.gov]
Hepatosplenomegaly
  • He also had hepatosplenomegaly and pulmonary involvement.[ncbi.nlm.nih.gov]
  • The patient had hepatosplenomegaly, anemia, and lytic lesions in the skull. FNAC from the largest submandibular lymph node showed features of LCH. The large cells of LCH showed positive immunostaining for S-100 protein on FNAC smears.[ncbi.nlm.nih.gov]
  • Patients are usually infants presenting with fever, hepatosplenomegaly, lymphadenopathy, bone and skin lesions, and pancytopenia 202.5 Excludes Applies To Acute: differentiated progressive histiocytosis histiocytosis X (progressive) infantile reticuloendotheliosis[icd9data.com]
  • Usually Letterer–Siwe disease occurs in infants less than 2 years old and presents clinical symptoms such as fever, skin rush, anemia, hepatosplenomegaly, lymphadenopathy, and bleeding diathesis. The clinical course is rapid and fatal.[springerplus.springeropen.com]
  • Patients are usually infants presenting with fever, hepatosplenomegaly, lymphadenopathy, bone and skin lesions, and pancytopenia. A multifocal, unisystem form of langerhans-cell histiocytosis.[icd10data.com]
Hepatomegaly
  • […] histiocytosis: Usually affects children, who present with fever, diffuse eruptions, particularly on the scalp and in the ear canals, frequent bouts of otitis media, mastoiditis, and upper respiratory tract infections, bone lesions and mild lymphadenopathy, hepatomegaly[histopathology-india.net]
  • Other symptoms that LCH can cause are enlargement of lymph nodes, hepatomegaly, splenomegaly, anorexia, night sweats, fever and weight loss [1, 2, 4].[cancerwall.com]
  • Prognosis Poor if 18 months at time of diagnosis; haemorrhagic skin lesions; hepatomegaly, anemia; thrombocytopenia; bone marrow involvement. histiocytosis X Langerhans' cell histiocytosis , see there. his·ti·o·cy·to·sis X ( his'tē-ō-sī-tō'sis ) Proliferation[medical-dictionary.thefreedictionary.com]
  • Fever, splenomegaly and hepatomegaly are the most common early findings; b. Lymph node enlargement, skin rash, and neurologic abnormali ties may also occur.[hopkinsmedicine.org]
  • Patients with hepatic LCH present with hepatomegaly or hepatosplenomegaly, and elevated alkaline phosphatase, liver transaminases, and gamma glutamyl transpeptidase levels.[cancer.gov]
Bilateral Proptosis
  • Orbital psuedotumor represents the second most common inflammatory disorder of the orbit in childhood and may present with unilateral or bilateral proptosis of explosive onset with restriction of ocular motility.[eyewiki.aao.org]
Scalp Rash
  • May show up as a severe scalp rash, groin rash or as reddish-brown pinhead spots on the body. Chronic ear discharge or enlargement of liver/spleen causing abdominal swelling.[kids-cancer.org]
  • rash often in infants) Ear pain or recurring ear infections Lethargy Low-grade fever Weight loss Diagnosing Langerhans cell histiocytosis requires a careful and complete medical workup and examination of your child.[chop.edu]
Bone Pain
  • Oral manifestations are unusual and are characterized by bone pain, tooth mobility, necrotic ulcers and local edema. The aim of this paper is to describe a clinical case of LCH in an oral cavity that mimicked oral squamous cell carcinoma.[ncbi.nlm.nih.gov]
  • Well-localised bone pain is a common presenting symptom, with pain during both activity and rest. Lesions are lytic. Bone pain usually correlates with a radiologically evident lesion but lesions can be painless.[patient.co.uk]
  • LCH can cause a wide range of symptoms, including abdominal pain, bone pain and dizziness. In rare, specific situations, LCH will go away without treatment. However, most patients will need therapy for the histiocytosis to go away.[rileychildrens.org]
  • Bone: Skull is most commonly affected followed by long bones of upper extremities and flat bones. Painful swelling of bones is common. Lytic lesions may lead to pathologic fractures.[symptoma.com]
  • Signs and Symptoms of Langerhans Cell Histiocytosis Site: Skin Possible symptoms: General rash, dandruff Site: Bone Possible symptoms: Lesions, bone pain, limping Site: Lung, liver, spleen Possible symptoms: Dysfunction Site: Teeth and gums Possible symptoms[my.clevelandclinic.org]

Workup

The diagnosis of langerhans cell histiocytosis is confirmed histologically by biopsy. Other investigations are carried out to determine the extent of disease.

  • Blood tests: These include complete blood count, differential leukocyte count, erythrocyte sedimentation rate, direct and indirect Coombs test and immunoglobulin levels.
  • Coagulation studies
  • Urine analysis: Urine specific gravity and osmolality are determined to rule out diabetes insipidus.
  • Liver function tests: Levels of total albumin and liver enzymes are required to differentiate langerhans cell histiocytosis from liver cirrhosis.
  • Chest radiographs: Radiography shows the involvement of lungs in the form of pulmonary infiltrates or cystic appearance. Older lesions may be seen to have honey comb appearance.
  • Skeletal radiograph survey: This is done to visualize osteolytic bone lesions.
  • CT/MRI scans: CT/MRI scans are necessary for early detection of neurodegenerative component of the disease.

In addition, certain other tests are carried out to determine the severity and extent of the disease process. These include:

  • Pulmonary function tests
  • Intestinal biopsy
  • Visual testing
  • Neurological tests
  • Hormonal studies
Hyperprolactinemia
  • We report a 35 year old woman with a 10 year history of multisystemic LCH who developed DI, mild hyperprolactinemia, gonadotrophin and partial growth hormone deficiency following a normal delivery that was accompanied with infundibular thickening on pituitary[ncbi.nlm.nih.gov]
  • Hyperprolactinemia and hypothalamic syndrome were found in 2 patients each. All these central endocrine alterations were always associated to DI. Five of the 10 MRI performed showed abnormalities.[ncbi.nlm.nih.gov]
  • Shan-Yi Ng,Mark Jean-Aan Koh,Yong-Kwang Tay Acta Paediatrica. 2013; : n/a 4 Different courses of recurrent or multisystem Langerhans cells histiocytosis in adults - Description of 22 cases from one centre 6 Cutaneous Xanthomatosis, Diabetes Insipidus, and Hyperprolactinemia[ijdvl.com]

Treatment

Treatment of langerhans cell histiocytosis mainly depends upon the extent of disease and the involvement of different organ systems of the body.

In case of solitary bone disease, the treatment is through excision or limited radiation. The dosage of radiation for children is 5 to 10 Gys while for adults is 24 to 30 Gys.

If there is systemic involvement, the use of steroids may be helpful in treatment. Based upon the severity of the disease, steroid therapy may be used alone or as adjunct to chemotherapy. Low to moderate doses of prednisolone, methoteraxate and vinblastin are used.
For patients with diabetes insipidus, desmopressin is an effective medication.

Other treatments may include:

Prognosis

The prognosis of patients with langerhans cell histiocytosis is determined by the severity of the disease. Unifocal disease carries a good prognosis while the outlook of patients with diffuse and refractory disease is poor. Complications arise in around 30 to 50% of the patients and are more common in those suffering from multifocal disease [10]. Common complications are skeletal abnormalities, diabetes insipidus, hearing impairment, skin scarring and neurodegenerative disorders. Less frequent sequlae are pulmonary dysfunction, liver cirrhosis, malignancies and growth retardation.

Etiology

Langerhans cell histiocytosis is is a non-inherited disease, although familial clustering is seen in a few cases. There is no specific infectious or hereditary cause of langerhans cell histiocytosis. Some studies suggest that activating mutation in the BRAF proto-oncogene can be responsible for this condition [3]. This mutation has been detected in 35 of 61 biopsy samples of the patients with langerhans cell histiocytosis. Out of these, 76% of the patients were younger than 10 years and 44% were older than 10 years of age.

Epidemiology

Langerhans cell histiocytosis is a rare disease affecting children 0 to 15 years of age. There are approximately 4 cases per million population [4]. The estimated annual incidence rate in the United States is 0.5 to 5.4 cases per million persons. The incidence rate among adults is about 1 in 560, 000 individuals per year. The disease occurs more commonly in Caucasian males, with a male to female ratio of 1:2.

Sex distribution
Age distribution

Pathophysiology

The pathophysiological mechanism of langerhans cell histiocytosis is debatable and it is not clear whether this disease is a reactive or neoplastic condition.
There are several remissions during the course of the disease which suggest that this disease is a reactive disorder [5]. Furthermore, the elaboration of several pro-inflammatory cytokines by dendritic cells and T-cells as well as no consistent genetic abnormalities in the patients also support the idea of langerhans cell histiocytosis as a reactive disorder [6] [7]. 
On the contrary, there are several pathogenic mechanisms which favor the possibility of a neoplastic pathophysiology. In langerhans cell histiocytosis, organs are infiltrated by monoclonal population of abnormal langerhans cells [8]. Also several of the anti-cancer modalities of treatment are effective against the disease.
The organ damage and characteristic lesions of langehans cell histiocytosis has been speculated to be due to proliferation of semi-mature dendritic cells. These abnormal misguided cells are recruited to specific sites in the body where they stimulate a cellular immune response which is responsible for the lesions at these anatomic sites. Specific findings from immunohistochemical and immunoflourescence analysis show a role of immune dysfunction in the pathogenesis of the disease. It is hypothesized that immature dendritic cells stimulate the regulatory T-cells which prevent the resolution of the lesions of this disease by inhibiting the immune response.
The role of interlukin-17 in causing inflammation and cellular destruction in this disease is also under investigation but it is still controversial [9].

Prevention

There are no proven preventine measures against Langerhans cell histiocytosis.

Summary

Langerhans cell histiocytosis is a rare idiopathic disorder characterized by excessive proliferation of langerhans cells, the antigen presenting immune cells found in the skin. There is accumulation of immature langerhans cells juxtaposed against a background of T-cells, macrophages and eosinophils. In addition to the epidermal langerhans cells, other cell types like dermal langerin+ dedritic cells, lymphoid tissue-resident langerin+ dendritic cells, and monocytes can also be the potential cellular origins for langerhans cell histiocytosis because these cell types are capable of acquiring phenotypic characteristics of langerhans cells [1] [2]. The disease causes a number of non-specific as well as specific inflammatory symptoms affecting bones, bone marrow, skin, lungs and endocrine organs etc. Langerhans cell histiocytosis usually affects children; the peak age of incidence being 5 to 15 years. Adults are less commonly affected.

Clinically, it is classified into three types:

  • Unifocal/Eosinophilic granuloma: This type only affects bones. There is no extra-skeletal involvement.
  • Multifocal unisystem/Hand-Schuller-Christian triad: This is characterized by fever, diffuse eruptions on ear canal and scalp and bone lesions. Damage to the pituitary stalk occurs in 50% of the cases. A specific triad of diabetes insipidus, exophthalmos and bone lesions is characteristic. Peak age of onset is 2-10 years.
  • Multifocal multisystem/Letterer-Siwe disease: In this type, langerhans cells proliferate in many tissues. It is a rapidly progressive disease with a poor prognosis.

Patient Information

Langerhans cell histiocytosis in a disorder of specific cells present in the skin and bone marrow. Their main function is to fight off infections but in this condition, there is accumulation of abnormal form of these cells in the blood and they cause damage to various organs of the body including bones, lungs, skin and liver etc. The disease commonly affects children. The treatment and prognosis depends upon severity of the disease process with an overall good outcome.

References

Article

  1. Egeler RM, van Halteren AG, Hogendoorn PC, Laman JD, Leenen PJ. Langerhans cell histiocytosis: fascinating dynamics of the dendritic cell-macrophage lineage. Immunological reviews. Mar 2010;234(1):213-232.
  2. Merad M, Ginhoux F, Collin M. Origin, homeostasis and function of Langerhans cells and other langerin-expressing dendritic cells. Nature reviews. Immunology. Dec 2008;8(12):935-947.
  3. Badalian-Very G, Vergilio JA, Degar BA, Rodriguez-Galindo C, Rollins BJ. Recent advances in the understanding of Langerhans cell histiocytosis. British journal of haematology. Jan 2012;156(2):163-172.
  4. Windebank K, Nanduri V. Langerhans cell histiocytosis. Archives of disease in childhood. Nov 2009;94(11):904-908.
  5. Egeler RM, Favara BE, van Meurs M, Laman JD, Claassen E. Differential In situ cytokine profiles of Langerhans-like cells and T cells in Langerhans cell histiocytosis: abundant expression of cytokines relevant to disease and treatment. Blood. Dec 15 1999;94(12):4195-4201.
  6. da Costa C, Szuhai, K, van Eijk, R, et al. No genomic aberrations in Langerhans cell histiocytosis as assessed by diverse molecular technologies. Genes Chromosomes Cancer. Mar 2009;48(3):239-249.
  7. Willman C, Busque, L, Griffith, BB, et al. Langerhans'-cell histiocytosis (histiocytosis X)--a clonal proliferative disease. N Engl J Med. Jul 1994;331(3):154-160.
  8. Willman CL. Detection of clonal histiocytes in Langerhans cell histiocytosis: biology and clinical significance. The British journal of cancer. Supplement. Sep 1994;23:S29-33.
  9. Allen CE MK. Interleukin-17A is not expressed by CD207(+) cells in Langerhans cell histiocytosis lesions. Nat Med. May 2009;15(5):483-484.
  10. Haupt R, Nanduri V, Calevo MG, et al. Permanent consequences in Langerhans cell histiocytosis patients: a pilot study from the Histiocyte Society-Late Effects Study Group. Pediatric blood & cancer. May 2004;42(5):438-444.

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Last updated: 2019-07-11 20:13