Single Site Disease Presentation
        Skin
        Oral mucosa
        Bone
        Lymph nodes and thymus
        Pituitary gland
Multisystem Disease Presentation
        Liver and spleen
        Lung
        Bone marrow
        Endocrine system
        Gastrointestinal system
        Central nervous system

Langerhans cell histiocytosis (LCH) usually presents with a skin rash or painful bone lesion. Systemic symptoms of fever, weight loss, diarrhea, edema, dyspnea, polydipsia, and polyuria, relate to specific organ involvement as well as single site (single system) or multisystem disease presentation as noted below.

In LCH, specific organs are considered high-risk or low-risk organs when involved with disease presentation. High-risk organs include liver, spleen, lung and bone marrow. Low-risk organs include skin, bone, lymph nodes and the pituitary gland. Additionally, patients may present with disease in one site or organ (single site or single system) or in multiple sites or organs (multisystem or multisite). Treatment decisions for patients are based upon whether high-risk or low-risk organs are involved and whether LCH presents as a single site or multisystem disease. Patients can have LCH of the skin, bone, lymph nodes, and pituitary in any combination and still be considered low-risk.

In single site LCH, as the name implies, the disease presents with involvement of a single site or organ, including skin and oral mucosa, bone, lymph nodes and thymus, and pituitary gland.

• Infants: Seborrheic involvement of the scalp may be mistaken for prolonged cradle cap in infants. Infants may also present with brown to purplish papules over any part of their body (Hashimoto-Pritzker disease).[1] Similar to that of stage IVS neuroblastoma, this manifestation may be self-limited as the lesions often disappear with no therapy during the first year of life. However, these patients must be watched very closely for systemic disease which may present after the initial skin lesions.[2,3] In a report of 61 neonatal cases from 1,069 patients in the Histiocyte Society database, nearly 60% had multisystem disease and 72% had risk organ involvement.[4] The overall survival was poorer in neonates with risk organ involvement compared with infants and children with the same extent of disease. Response to therapy at 12 weeks was more important than age.



• Children and Adults: Children and adults may develop a red papular rash in the groin, abdomen, back, or chest that resembles a diffuse candidal rash. Seborrheic involvement of the scalp may be mistaken for a severe case of dandruff in older individuals. Ulcerative lesions behind the ears, involving the scalp, genitalia, or perianal region are often misdiagnosed as bacterial or fungal infections.

In the mouth, presenting symptoms include gingival hypertrophy, and ulcers of the soft or hard palate, buccal mucosa, or on the tongue and lips. Lesions of the oral mucosa may precede evidence of LCH elsewhere.[5]

The most frequent site of LCH in children is a lytic lesion of the skull,[6] which may be asymptomatic or painful. LCH can occur in any bone of the body. The most frequently involved skeletal sites are skull, femur, ribs, vertebra, and humerus. Spine lesions are most often located in the cervical vertebrae and are frequently associated with other bone lesions. Proptosis from an LCH mass in the orbit mimics rhabdomyosarcomas, neuroblastoma, and benign fatty tumors of the eye. Some skull lesions are not only lytic but may have an accompanying soft tissue mass that impinges on the dura. Lesions of the facial bones or anterior or middle cranial fossae (e.g., temporal, sphenoid, ethmoid, zygomatic) with intracranial tumor extension comprise part of a CNS-risk group. These patients have a threefold increased risk for developing diabetes insipidus (DI) and an increased risk of other central nervous system (CNS) disease (see below).

The cervical nodes are most frequently involved and may be soft- or hard-matted groups with accompanying lymphedema. An enlarged thymus or mediastinal node involvement can mimic lymphoma or an infectious process and may cause asthma-like symptoms. Accordingly, biopsy with culture and histologic examination is mandatory for these presentations.

The posterior part of the pituitary gland can be affected in patients with LCH causing central DI (see Endocrine and Central Nervous System sections below). Anterior pituitary involvement often results in growth and sexual maturation failure.

In multisystem LCH, the disease presents in multiple organs or body systems including liver and spleen, lung, bone marrow, endocrine system, gastrointestinal system, and CNS.

In LCH, the liver and spleen are considered high risk organs and involvement of these organs effects prognosis, so enlargement of either liver or spleen is a worrisome finding. Hepatic enlargement can be accompanied by dysfunction, leading to hypoalbuminemia with ascites, hyperbilirubinemia, and clotting factor deficiencies. Sonography, computed tomography (CT), or magnetic resonance imaging (MRI) of the liver will show hypoechoic or low-signal intensity along the portal veins or biliary tracts when the liver is involved with LCH.[7] One of the most serious complications of hepatic LCH is cholestasis and sclerosing cholangitis.[8] The median age of children with hepatic LCH is 23 months and they present with hepatomegaly or hepatosplenomegaly, elevated alkaline phophatase, liver transminases and gamma glutamyl transpeptidase. Biopsies show no Langerhans cells (LCs) so it is thought that cytokines elaborated by lymphocytes may damage the bile ducts. Seventy-five percent of children with sclerosing cholangitis will not respond to chemotherapy; liver transplantation is the only alternate treatment when hepatic function worsens. Massive splenomegaly may lead to cytopenias because of hypersplenism and respiratory compromise. Performing a splenectomy for these problems is not customary, although one may be forced to do this when salvage chemotherapy is not working fast enough. Unfortunately, splenectomy typically provides only transient relief of cytopenias, as increased liver size and reticuloendothelial activation results in peripheral blood cell sequestration and destruction.

In LCH, the lung is also considered a high-risk organ, but is less frequently involved in children than in adults, in whom smoking is a key etiologic factor.[9] The cystic/nodular pattern of disease leads to the destruction of lung tissue. A spontaneous pneumothorax can be the first sign of LCH in the lung, although patients may present with tachypnea or dyspnea. Ultimately, widespread fibrosis and destruction of lung tissue leads to severe pulmonary insufficiency. A study reporting outcomes for children with only low-risk organ disease (skin, bone, lymph nodes or pituitary gland) or pulmonary plus low-risk organs revealed that patients with pulmonary involvement had a 5-year survival of 83% as opposed to 94% for those with only low-risk organ involvement.[10] Declining diffusion capacity may also herald the onset of pulmonary hypertension.[11] In young children with diffuse disease, therapy can halt progress of the tissue destruction and normal repair mechanisms may restore some function.

Most patients with bone marrow involvement are young children who have diffuse disease in the liver, spleen, lymph nodes, skin and significant thrombocytopenia or neutropenia.[12] Others have only mild cytopenias and are found to have bone marrow involvement with LCH by sensitive immunohistochemical or flow cytometric analysis of the bone marrow.[13] Patients with LCH who are considered at very high risk sometimes present with hemophagocytosis involving the bone marrow.[14] The cytokine milieu driving LCH is probably responsible for the epiphenomenon of macrophage activation. These patients may be confusing as to which histiocytic syndrome is primary: hemophagocytic lymphohistiocytosis or LCH. Evidence of bone involvement or the characteristic LCH skin rash can simplify the diagnostic dilemma, but careful clinical evaluation is needed in these cases.

Diabetes insipidus is the most frequent endocrine manifestation in LCH. Some patients may present with an apparent idiopathic presentation of DI before other lesions are identified. A review of such patients found that 51% will have other lesions diagnostic of LCH within a year of identifying DI.[15] A study of 589 LCH patients in France revealed the 10-year risk of pituitary involvement was 24%.[16] These investigators did not see a decreased incidence of DI in chemotherapy-treated patients (see Central Nervous System section below). The German-Austrian-Dutch (DAL) Group found the cumulative incidence to be 12%.[17] DI followed initial LCH diagnosis by a mean of 1 year and growth hormone deficiency 5 years later.

Patients with multisystem disease and craniofacial involvement at the time of diagnosis, particularly of the ear, eye, and oral region, carried a significantly increased risk of developing DI during their course (relative risk, 4.6).[18] This risk increased when the disease remained active for a longer period of time or reactivated. The risk for development of DI in this population was 20% at 15 years after diagnosis.

A few patients with diarrhea, hematochezia, perianal fistulas, diarrhea or malabsorption have been reported.[19,20] Diagnosing gastrointestinal involvement with LCH is difficult because of patchy involvement. Careful endoscopic examination including multiple biopsies is usually needed.

DI (considered both an endocrine and a central nervous system manifestation of LCH) can present as an acute or chronic condition

DI caused by damage to the posterior pituitary region by LCH is the most frequent initial sign (and acute manifestation) in the CNS.[17] DI is the presenting symptom in approximately 4% of patients subsequently found to have LCH. DI occurred in 12% of all LCH patients in the DAL studies.[17] Six percent of patients presented with this manifestation at the time of diagnosis. Pituitary biopsies are rarely done and most often only when the stalk is greater than 6.5 mm or there is a hypothalamic mass. Most often the diagnosis is established by biopsying the skin, bone, or lymph node of a patient who also has the pituitary abnormalities noted above.

Ten percent to 24% of all LCH patients will develop DI sometime during the course of their treatment and usually within 4 years from diagnosis of another lesion.[16] The frequency of DI appears to be increased in patients with bone lesions in the orbit, mastoid, and temporal bone since 75% of patients with DI have these CNS-risk lesions.[17] However, another study did not find this association despite showing that the risk of ear, nose, and throat involvement was higher in patients with endocrinopathies.[16] Additional data showed that 56% of DI patients will develop anterior pituitary hormone deficiencies (growth, thyroid, or gonadal-stimulating hormones) within 10 years of the onset of DI. DI occurs in 11% of patients treated with multiagent chemotherapy and in up to 50% of patients treated less aggressively.[21,22]

LCH patients may develop mass lesions of the choroid plexus, grey matter, or white matter.[23] These lesions contain CD1a-positive LCs and CD8+ lymphocytes.[24]

Another chronic CNS problem that occurs in 1% to 4% of LCH patients is a neurodegenerative syndrome that is manifested by dysarthria, ataxia, dysmetria, and sometimes behavior changes. MRI results from these patients show hyperintensity of the dentate nucleus and white matter of the cerebellum on T2-weighted images or hyperintense lesions of the basal ganglia on T1-weighted images and/or atrophy of the cerebellum.[25] The radiologic findings may preceed the onset of symptoms by many years or be found coincidently. A study of 83 LCH patients who had at least two MRI imaging studies of the brain for evaluation of craniofacial lesions, DI, and/or other endocrine deficiencies of neuropsychological symptoms has been published.[26] Forty-seven of 83 patients (57%) had radiological neurodegenerative changes at a median time of 34 months from diagnosis. Of the 47 patients, 12 (25%) had clinical neurological deficits that presented 3 to 15 years after the LCH diagnosis.

A study of CNS-related permanent consequences (neuropsychologic deficits) in 14 of 25 LCH patients followed for a median of 10 years has been published.[27] Seven of these patients had DI and five patients had radiographic evidence of LCH CNS neurodegenerative changes.[27] Patients with craniofacial lesions had lower performance and verbal intelligence quotient scores than those with other LCH lesions. Another study reported significant deficits in two LCH patients with abnormalities of the cerebellum and pituitary as shown by MRI scans.[28]

Histological evaluation of these neurodegenerative lesions has been shown to contain a prominent T-cell infiltration in the absence of the CD1a+ dendritic cells along with microglial activation and gliosis. Rarely, CD1a+ Langerhans cells are observed. The neurodegenerative form of the disease has been compared to a paraneoplastic inflammatory response.[24]

References

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