AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

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• Workup
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• Medication
• Follow-up
• Miscellaneous
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INTRODUCTION

Section 2 of 11  

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• Introduction
• Clinical
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• Workup
• Treatment
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• Follow-up
• Miscellaneous
• Multimedia
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Background

Langerhans cell histiocytosis (LCH) is a group of idiopathic disorders characterized by the proliferation of specialized bone marrow–derived Langerhans cells (LCs) and mature eosinophils.

In 1868, Paul Langerhans discovered the epidermal dendritic cells that now bear his name. The ultrastructural hallmark of the LC, the Birbeck granule, was described a century later. The term LCH is generally preferred to the older term, histiocytosis X. This new name emphasizes the histogenesis of the condition by specifying the type of lesional cell and removes the connotation of the unknown (X) because its cellular basis has now been clarified.

The working group of the Histiocyte Society has divided histocytic disorders into 3 different groups: (1) dendritic cell histiocytosis, (2) erythrophagocytic macrophage disorders, and (3) malignant histiocytosis. LCH belongs in group 1 and encompasses a number of diseases. The clinical spectrum includes on one end, an acute fulminant, disseminated disease called Letterer-Siwe disease and, on the other end, solitary or few, indolent and chronic, lesions of bone or other organs called eosinophilic granulomas. The intermediate clinical form called Hand-Schüller-Christian disease is characterized by multifocal, chronic involvement and classically presents as the triad of diabetes insipidus, proptosis, and lytic bone lesions. A congenital self-healing form called Hashimoto-Pritzker disease has also been described.

Pathophysiology

The pathogenesis of LCH is unknown. An ongoing debate exists over whether this is a reactive or neoplastic process. Arguments supporting the reactive nature of this disorder include the occurrence of spontaneous remissions, the failure to detect aneuploidy, metaphase or karyotypic abnormalities, and the good survival rate in patients without organ dysfunction. On the other hand, the infiltration of organs by aberrant cells, a possible lethal evolution, and the cancer-based modalities of successful treatment are all consistent with a neoplastic process. In addition, the demonstration of LCH as a monoclonal proliferation by X chromosome–linked DNA probes supports a neoplastic origin for this proliferation; however, the presence of this finding in distinct subtypes with different evolutions demands further investigations to evaluate its significance.

Evidence exists for a role of immune dysfunction in the pathogenesis of LCH by the creation of a permissive immunosurveillance system. Abnormalities of suppressor cell number and function have been documented in several reports. Increased levels of messenger RNA for macrophage colony-stimulating factor and platelet-derived growth factor have been detected in cells from a pulmonary LCH lesion.

In addition, some studies indicate that expression of Bcl-2 family proteins and of FADD, FLICE, and FLIP proteins in the Fas signaling pathway may be involved in the pathogenesis of LCH.

Frequency

United States

LCH is a rare disease. The estimated annual incidence ranges from 0.5-5.4 cases per million persons per year. Approximately 1200 new cases per year are reported in the United States.

Mortality/Morbidity

More than one half of patients younger than 2 years with disseminated LCH and organ dysfunction die of the disease; whereas, unifocal LCH and most cases of congenital self-healing histiocytosis are self-limited. Multifocal chronic LCH is self-limited in most cases, although increased mortality has been observed among infants with pulmonary involvement.

Race

The prevalence of LCH seems to be higher among whites than other races.

Sex

The incidence of LCH is greater in males than in females, with a male-to-female ratio of 2:1.

Age

LCH affects patients from neonates to adults. The age at onset varies according to the variety of LCH.

• Letterer-Siwe disease occurs predominantly in children younger than 2 years.
• The chronic multifocal form, including Hand-Schüller-Christian syndrome, has a peak of onset in children aged 2-10 years.
• Localized eosinophilic granuloma occurs mostly frequently in those aged 5-15 years.

CLINICAL

Section 3 of 11  

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History

The clinical presentation of LCH is dependent on the extent of dissemination.

• Unifocal LCH is characterized by the development of solitary bony lesions at any site. It is least common in the hands and the feet. These lesions are often asymptomatic and are found as incidental findings during investigation for unrelated disorders.
• Patients with multifocal disease have a protean history depending on the location of osteolytic lesions and the degree of organ dysfunction. Patients with Hand-Schüller-Christian syndrome (which occurs in 25% of patients with multifocal LCH) often present with recurrent episodes of otitis media and mastoiditis or with polyuria and polydipsia.
• Letterer-Siwe disease presents with symptoms suggestive of a systemic infection or malignancy with a generalized skin eruption, anemia, and hepatosplenomegaly.
• The congenital form of LCH manifests as skin lesions at birth or during the early postnatal period.
• • Cutaneous nodules and ulceration occur early in life.
  • Rarely, purpuric lesions occur with a blueberry muffin presentation.
  • Symptoms of organ involvement may also occur.

Physical

Signs of LCH depend on the localization and the extent of the disease. The clinical spectrum of LCH is broad, and an individual case may differ markedly from the prototypes described.

• Chronic unifocal LCH (eosinophilic granuloma of bone) classically presents as a solitary calvarial lesion in young adults; other sites of involvement include the vertebra, the rib, the mandible, the femur, the ilium, and the scapula.
• • Lesions are usually asymptomatic, but bone pain and a soft tissue mass may occur.
  • When the calvarial lesions extend into the nervous system, a variety of neurologic manifestations may be seen.
  • Bony lesions may cause otitis media by destruction of the temporal and mastoid bones, proptosis secondary to orbital masses, loose teeth from infiltration of the mandibles, or pituitary dysfunction due to involvement of the sella turcica.
  • Spontaneous fractures can result from osteolytic lesions of the long bones, and vertebral collapse with spinal cord compression has occasionally been described.
  • Cutaneous disease presents with noduloulcerative lesions in the oral, perineal, perivulvar, or retroauricular regions.
  • Pulmonary lesions may be the presenting and only manifestation. In adults, the pulmonary system is most frequently involved.
  • Rarely, solitary cerebral lesions may occur.
• The classic multifocal form of LCH (Hand-Schüller-Christian disease) includes diabetes insipidus; exophthalmos; and bony defects, particularly of the cranium.
• • Lesions may affect a variety of systems, including the liver (20%), the spleen (30%), and the lymph nodes (50%).
  • Pulmonary involvement may occur.
  • Osteolytic lesions of the long bones can lead to spontaneous fractures.
  • One third of patients have mucocutaneous lesions, most frequently infiltrated nodules and ulcerated plaques, especially in the mouth, the axillae, and the anogenital region. Other cutaneous manifestations include extensive coalescing, scaling, or crusted papules.
• Patients with acute disseminated LCH (multiorgan involvement) present with fever; anemia; thrombocytopenia; pulmonary infiltrates; skin lesions; and enlargement of the lymph nodes, the spleen, and the liver.
• • Cutaneous abnormalities are present in almost 80% of patients; frequently, this is the first sign.
  • The eruption may be extensive, involving the scalp, the face, the trunk, and the buttocks as well as the intertriginous areas. Lesions consist of closely set petechiae and yellow-brown papules topped with scale and crust. The papules may coalesce to form an erythematous, weeping eruption mimicking seborrheic dermatitis.
  • Intertriginous lesions are often exudative, and secondary infection and ulceration may occur.
  • Osteolytic lesions are not common in the disseminated form of LCH, but the mastoid can be affected, resulting in a clinical picture of otitis media that may be the presenting complaint. Aural discharge, conductive hearing loss, and postauricular swelling have been described.
  • Patients with pulmonary involvement present with chest pain, hemoptysis, dyspnea, failure to thrive, cystic changes, and pneumothorax; if lung disease is extensive, oxygen diffusion and lung capacity may be reduced.
  • Neurologic involvement may produce seizures, vertigo, headache, ataxia, and cognitive defects.
• Congenital self-healing histiocytosis presents at birth or during the early neonatal period with firm, red-brown, painless, papulonodules (1-10 mm in diameter) or vesicles and crusts that are scattered over the scalp, the face, and, to a lesser extent, the trunk and the extremities. Ulceration may occur in the lesions.
• • Solitary lesions may occur.
  • Lesions may be followed by residual hypopigmented or hyperpigmented macules.

Causes

The etiology of LCH remains unknown.

• LC proliferation may be induced by a viral infection, a defect in intercellular communication (T cell–macrophage interaction), and/or a cytokine-driven process mediated by tumor necrosis factor, interleukin 11, and leukemia inhibitory factor.
• Cigarette smoking may play a role as a chronic irritant in the development of eosinophilic granuloma of the lung.

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

Rosai-Dorfman disease
Xanthoma disseminatum
Neonatal pustular melanosis
Congenital candidiasis
Perinatal listeriosis
Perinatal herpes simplex
Neonatal varicella
Leukemia
Lymphoma
Myeloma

WORKUP

Section 5 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Blood cell count
• • Recommended baseline diagnostic evaluation includes a CBC count and differential, a reticulocyte count, an erythrocyte sedimentation rate, a direct and indirect Coombs test, and immunoglobulin levels.
  • In case of anemia, leukopenia, or thrombocytopenia, a bone marrow aspirate is required.
• Coagulation studies may be indicated.
• If liver function test results are abnormal, a biopsy of the liver should be considered to differentiate LCH from cirrhosis.
• Urine osmolarity is measured after overnight water deprivation to screen for diabetes insipidus.

Imaging Studies

• Chest radiographs (posteroanterior and lateral)
• • LCH can present as a micronodular and interstitial infiltrate in the mid zone and base of the lung, with sparing of the costophrenic angles.
  • Older lesions show a honeycomb appearance.
  • Patients with radiographically demonstrated pulmonary involvement, in whom chemotherapy is being considered, require a biopsy of the lung preceded by bronchoalveolar lavage (BAL) to exclude opportunistic infections. If the BAL is diagnostic, the biopsy of the lung can be obviated.
• Skeletal radiograph survey
• • Unifocal LCH presents as a single osteolytic lesion, usually affecting long or flat bones (in children, the calvaria and the femur; in adults, the ribs).
  • Multifocal LCH show osteolytic lesions involving the calvaria, the sella turcica, the mandible, the vertebrae, and/or the long bones of the upper extremities.
  • Although a radionuclide bone scan is suggested for establishing the extent of osseous involvement, the latter is not as sensitive as the skeletal radiograph survey in most patients.
• CT scan or MRI of the hypothalamic-pituitary region may reveal abnormalities of these organs. In particular, magnetic resonance spectroscopy may be valuable in the early detection and evaluation of the neurodegenerative component.

Other Tests

• A small bowel series and a biopsy are indicated in cases of unexplained diarrhea, failure to thrive, and malabsorption.
• Hormonal studies of the hypothalamic-pituitary axis may reveal abnormalities.
• Visual and neurologic testing may be required.

Procedures

• A biopsy of the skin is extremely helpful in establishing the diagnosis.

Histologic Findings

The histologic picture unifies the varied presentations of LCH, which are influenced by location and age of the lesion. The key to diagnosis is to identify the pathologic LCs. The latter resembles the normal LC of the skin except it is not dendritic.

It consists of a large, ovoid, mononuclear cell that is 15-25 mm in diameter, with a folded nucleus, a discrete nucleolus, and a moderate amount of slightly eosinophilic homogeneous cytoplasm. When the indentation of the nucleus affects its center, it acquires a reniform pattern; however, if it is peripheral, the nucleus has a coffee-bean shape.

Because of the absence of distinctive morphologic characteristics of the LCH cell, special studies are used to identify the cell. The Birbeck granule is the distinctive ultrastructural hallmark of the LC. It consists of an intracytoplasmic membranous body that is 33 nm wide and 190-360 nm long, possessing a short, rodlike shape with a dotted line down the midline of the space between the membranes (resembling a zipper) and a terminal expansion in the form of a vesicle giving a racquet appearance. Although these granules are resistant to destruction by formalin fixation and paraffin embedding, the sensitivity of detection in such specimens is slightly decreased. Birbeck granules are rarely detected in lesions of the liver, the gastrointestinal tract, and the spleen. LCs also contain laminated substructures of lysosomes, tuboreticular structures, and trilaminar membranous loops.

Enzyme histochemical studies (alpha-D-mannosidase and adenosine triphosphatase [ATPase]) have been replaced by immunohistochemical techniques. S-100 protein is strongly expressed in a cytoplasmic pattern, while peanut agglutinin (PNA) has a characteristic cell surface and paranuclear dot expression. LCH cells are positive for major histocompatibility (MHC) class II and CD1a (which is found on fresh or frozen tissue) and with the mononuclear antibody O10 on paraffin-embedded tissue. The pathologic LC expresses phenotypic markers of an activated normal LC in its early stages. Fine needle aspiration combined with immunohistochemistry of the cell preparation plays an important role in determining the extent or the recurrence of the disease.

The Writing Group of the Histiocyte Society (1987) has proposed 3 levels of certainty in the diagnosis of LCH based on the clinical features, histopathology, and special immunohistochemical techniques. A presumptive diagnosis is based on a typical clinical presentation and light microscopic findings. A designated diagnosis includes light microscopy in combination with positive S-100 and PNA staining studies. To make a definitive diagnosis, identification of Birbeck granules and CD1a antigens is required.

TREATMENT

Section 6 of 11  

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Medical Care

The choice of a therapeutic regimen is based on the severity of the LCH. The International LCH Study of the Histiocyte Society proposes the stratification of LCH cases by the number of systems involved. They further categorize those cases with single-system involvement by the number of sites within that system (eg, monostotic vs polyostotic bone disease, solitary vs multiple lymph node involvement). In addition, the presence or the absence of organ dysfunction is used to stratify patients with multisystemic disease. The presence of any organ dysfunction is an indicator of a poorer prognosis.

• Single-system disease
• • Solitary bone lesions are treated locally with curettage or excision.
  • Painful bone lesions may require intralesional steroid injection (triamcinolone acetonide).
  • Polyostotic bone lesions are best treated with indomethacin or a short course of systemic steroids.
  • Rarely, lesions that are unusually large and painful occur in inaccessible sites or involve vital structures. They require radiation (3-6 Gy [300-600 rad]).
  • Localized skin disease is best treated with moderate-to-potent topical steroids (eg, mometasone furoate [Elocon] cream 0.1%, triamcinolone [Kenalog] cream 0.1%, fluocinolone [Synalar] ointment 0.025%) or super-potent topical steroids (eg, clobetasol propionate 0.05%).
  • In cases of severe cutaneous involvement, topical nitrogen mustard (20% solution) may be used, based on its easy administration especially in outpatient settings and freedom from adverse effects.
  • Psoralen plus ultraviolet A (PUVA) is another excellent treatment for cutaneous only LCH or for cutaneous disease in multisystemic disease. It consists of photosensitizing psoralens (8-methoxypsoralen or 5-methoxypsoralen) either applied topically or ingested systemically 2 h prior to treatment with long-wave ultraviolet A (320-400 nm). The purpose of this treatment is to induce remission of skin diseases by repeated and controlled phototoxic reaction. The photoconjugation of psoralens with DNA produces an antiproliferative reaction in the skin, generates programmed cell death (apoptosis), and induces down-regulation of the cutaneous immune system.
  • For single lymph node infiltration, excision is the treatment of choice.
  • Regional lymph node enlargement can be treated with a short course of systemic steroids.
  • Treatment-resistant nodes with sinus tracts to the skin may require systemic chemotherapy.
• Multisystem disease
• • Systemic chemotherapy is indicated for cases of multisystem disease and those cases of single-system disease that are not responsive to other treatment.
  • The combination of cytotoxic drugs and systemic steroids is effective. Low-to-moderate doses of methotrexate, prednisone, and vinblastine are used.
• Two large clinical trials have examined differences in efficacy between chemotherapeutic agents.
• • One cooperative clinical trial in Europe used vinblastine, etoposide, and prednisolone for 6 weeks followed by mercaptopurine, vinblastine, and prednisolone for 1 year. If soft tissue was involved, treatment was supplemented with etoposide, and, if there was organ dysfunction, methotrexate was added. Initial complete resolution occurred in 86% of patients, with a mortality rate of 9% and a disease-free survival rate of 77% at a median of 6 years.
  • The LCH1 trial was sponsored by the Histiocyte Society and used etoposide or vinblastine for 24 weeks. The survival rate was slightly better in the European trial, but the difference was not statistically significant. A greater probability of developing diabetes insipidus occurred in the LCH1 trial.
  • The LCH-II clinical trial compared, in a randomized fashion, the effectiveness of the combination of vinblastine, oral prednisone, and mercaptopurine, to the same combination with the addition of etoposide. The results of LCH-II are expected to soon be published.
  • The LCH III study is an ongoing prospective clinical study involving a randomized clinical trial for multisystem "risk" patients, a randomized clinical trial for multisystem "low-risk" patients, and a pilot study for patients with single-system multifocal bone disease and localized "special sites."
  • The LCH-A-I clinical trial is another open study aimed to define and implement a uniform initial evaluation and stratification of adults with single-system disease, CNS lesions, isolated pulmonary disease, and multisystem LCH.
• In cases of resistant LCH, a combination of cyclosporin A, antithymocyte globulin, and prednisolone may be used for patients who do not have a matched donor for a bone marrow transplantation (BMT). In patients with LCH with a very poor prognosis (conferred at age <2 y, rapid disease progression, and vital organ dysfunction), BMT or reduced-intensity condition stem cell transplantation may be warranted.
• Potential treatments in the future include 2-chlorodeoxyadenosine (2CDA), monoclonal antibody targeting with indium-labeled anti-CD1a, cytokine inhibitors, alemtuzumab, and all-trans retinoic acid.
• Diabetes insipidus is treated symptomatically with desmopressin acetate (DDAVP).

Consultations

• A referral to an orthopedic surgeon has important diagnostic and management implications when bone lesions are present.
• An otolaryngologist may aid in the treatment of otitis media caused by destruction of the temporal and mastoid bones.
• An ophthalmologist is suggested for a vision check and an assessment of the need of decompression in patients with proptosis.
• Consultation with a dentist is indicated if loose teeth result from infiltration of the mandibles.
• Referral to an endocrinologist may help in the design of treatment of the endocrine abnormalities.

MEDICATION

Section 7 of 11  

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The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Corticosteroids

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Drug Name	Prednisolone (AK-Pred, Articulose-50, Delta-Cortef, Econopred, Inflamase)
Description	Also known as delta hydrocortisone, metacortandralone, prednisolone acetate, and prednisolone sodium phosphate. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability.
Adult Dose	5-60 mg/d PO/IV/IM
Pediatric Dose	0.1-2 mg/kg/d PO/IV/IM qd or divided bid/qid
Contraindications	Absolute: Systemic fungal infection, herpes simplex keratitis, hypersensitivity (usually with corticotropin, occasionally with IV preparations) Relative: Hypertension, active TB, CHF, prior psychosis, +IPPD, glaucoma, severe depression, DM, active PUD, cataracts, osteoporosis, recent bowel anastomosis, and pregnancy
Interactions	Ketoconazole, erythromycin, clarithromycin, estrogens, and birth control pills may increase levels Aminoglutethimide, phenytoin, PB, rifampin, cholestyramine, and ephedrine may decrease levels Levels of potassium-depleting diuretics (potentiates potassium loss and digitalis toxicity) and cyclosporine may increase; levels of isoniazid, insulin (resistance is induced), and salicylates may decrease; monitor anticoagulant therapy and theophylline levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Use lower dose in hypothyroidism, liver disease, obesity (due to decrease in cortisol-binding globulin increase in free fraction of steroid) Perform general medical assessment before treatment (a DEXA scan may be useful); check blood pressure; ophthalmologic evaluation may assess and prevent ocular complications; skin tests and/or chest radiographs detect potential for TB reactivation; abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Drug Name	Methylprednisolone (Adlone, A-methaPred, depMedalone, Depoject, Depopred)
Description	Also known as 6-alpha-methylprednisolone, methylprednisolone acetate, and methylprednisolone sodium succinate. By reversing increased capillary permeability and suppressing PMN activity, may decrease inflammation.
Adult Dose	2-60 mg/d PO qd or divided bid/qid initially, followed by gradual dose reduction to lowest possible level consistent with maintaining adequate clinical response Sodium succinate: 10-80 mg/d IM qd; 10-40 mg IV over several min and repeat IV/IM at intervals depending on clinical response Sodium acetate: 10-80 mg IM q1-2wk
Pediatric Dose	Sodium succinate: 0.5-1.7 mg/kg/d or 5-25 mg/m2/d PO/IM/IV in divided doses q6-12h Pulse therapy: 15-30 mg/kg/dose over 30 min or more qd for 3 d
Contraindications	Absolute: Systemic fungal infection, herpes simplex keratitis, hypersensitivity (usually with corticotropin, occasionally with IV preparations) Relative: Hypertension, active TB, CHF, prior psychosis, +IPPD, glaucoma, severe depression, DM, active PUD, cataracts, osteoporosis, recent bowel anastomosis, and pregnancy
Interactions	Ketoconazole, erythromycin, clarithromycin, estrogens, and birth control pills may increase levels Aminoglutethimide, phenytoin, PB, rifampin, cholestyramine, and ephedrine may decrease levels Levels of potassium-depleting diuretics (potentiates potassium loss and digitalis toxicity) and cyclosporine may increase; levels of isoniazid, insulin (resistance is induced), and salicylates may decrease; monitor anticoagulant therapy and theophylline levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Store intact vials of methylprednisolone sodium succinate at controlled room temperature Use lower dose in hypothyroidism, liver disease, obesity (due to decrease in cortisol-binding globulin increase in free fraction of steroid) Perform general medical assessment before treatment (a DEXA scan may be useful); check blood pressure; ophthalmologic evaluation may assess and prevent ocular complications; skin tests and/or chest radiographs detect potential for TB reactivation; abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Drug Category: Nonsteroidal anti-inflammatory drugs

These agents are the most commonly used medications to control mild to moderate pain and to decrease inflammation.

Drug Category: Antineoplastic agents

These agents inhibit cell growth and proliferation.

Drug Name	Vinblastine (Alkaban-AQ, Velban)
Description	Inhibits microtubule formation, which, in turn, disrupts formation of mitotic spindle, causing cell proliferation to arrest at metaphase.
Adult Dose	4-20 mg/m2 (0.1-05 mg/kg) IV q7-10d or 5 d continuous infusion of 1.4-1.8 mg/m2/d or 0.1-0.5 mg/kg/wk
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; bone marrow suppression
Interactions	Phenytoin plasma levels may be reduced when administered concomitantly with vinblastine; with mitomycin, toxicity may significantly increase
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in patients with impaired liver function and neurotoxicity; when patient is receiving mitomycin C, monitor closely for shortness of breath and bronchospasm; store intact vials under refrigeration (2-8°C) and protect from light

Drug Name	Etoposide (Toposar, VePesid)
Description	Inhibits topoisomerase II and causes DNA strand breakage, causing cell proliferation to arrest in late S or early G2 portion of the cell cycle.
Adult Dose	150-200 mg/m2/d IV qd for 3 d q3wk
Pediatric Dose	60-120 mg/m2/d IV for 3-5 d q3-6wk
Contraindications	Documented hypersensitivity; IT administration may cause death
Interactions	May prolong the effects of warfarin and increase the clearance of methotrexate; cyclosporine and etoposide have additive effects in cytotoxicity of tumor cells
Pregnancy	D - Unsafe in pregnancy
Precautions	FDA currently recommends that procedures for proper handling and disposal of antineoplastic agents be considered; severe myelosuppression with resulting infection or bleeding may occur; adjust dose in hepatic or renal impairment; store intact vials of injection at room temperature and protect from light; store oral capsules under refrigeration

Drug Name	Mercaptopurine (Purinethol)
Description	Purine analog that inhibits DNA and RNA synthesis, causing cell proliferation to arrest.
Adult Dose	Induction: 2.5-5 mg/kg/d (100-200 mg) PO Maintenance: 1.5-2.5 mg/kg/d PO; 80-100 mg/m2 PO qd
Pediatric Dose	Maintenance: 75 mg/m2 PO qd
Contraindications	Documented hypersensitivity; severe liver disease; severe bone marrow suppression
Interactions	Inhibits anticoagulation effects of warfarin by unknown mechanism; toxicity increases when administered with allopurinol; hepatic toxicity increases when used in combination with doxorubicin
Pregnancy	D - Unsafe in pregnancy
Precautions	FDA recommends that procedures for proper handling and disposal of antineoplastic agents be considered; may cause birth defects; caution in patients with prior myelosuppression; patients may be at risk for pancreatitis

Drug Name	Methotrexate (Folex, Rheumatrex)
Description	Antimetabolite that inhibits DNA synthesis and cell reproduction in malignant cells. Adjust dose gradually to attain satisfactory response. Refer to individual protocols; may be administered through various routes.
Adult Dose	30-40 mg/m2/wk to 100-7500 mg/m2 PO/IV/IM, intra-arterially or intrathecally, with leucovorin rescue
Pediatric Dose	5-15 mg/m2/wk PO/IM as single dose or 3 divided doses given 12 h apart
Contraindications	Pregnancy or desire to get pregnant, active peptic ulcer, alcoholism, primary/secondary immunodeficiency, blood dyscrasias, active hepatitis, cirrhosis, chronic renal failure, active infections Relative contraindications include history of excessive ethanol intake or substance abuse, increased LFT results, recent hepatitis, DM, obesity, history of heritable liver disease, unreliable patient, CrCl <50 mL/min, males contemplating conception (must discontinue for 3 mo)
Interactions	Salicylates, NSAIDS, dipyridamole, probenecid, retinoids, ethanol, triamterene, pyrimethamine, sulfonamides, TCN, chloramphenicol, penicillin or other broad-spectrum antibiotics, trimethoprim, dapsone, theophylline, phenytoin, phenothiazines, barbiturates, and nitrofurantoin (impair folic acid absorption), ascorbic acid, phenylbutazone, cyclosporin, aminoglycosides
Pregnancy	D - Unsafe in pregnancy
Precautions	Avoid pregnancy during therapy and for at least 3 mo after cessation of therapy; stop excessive alcohol intake; the need to monitor therapy with repeated liver biopsies is controversial; monitor CBC counts and liver enzyme levels during therapy; discontinue if blood cell counts significantly decrease; aspirin, NSAIDs, or low-dose steroids may be concomitantly administered with MTX (possibility of increased toxicity with NSAIDs, including salicylates, has not been tested); caution in obesity Administer 5- to 10-mg test dose, check CBC count and LFT results in 1 wk; if results are good, continue qwk 1-time 7.5-mg doses (may split if GI upset, ie, 8 am, 8 pm, 8 am dosing); increase dose by 2.5 mg/wk each month; may taper by 2.5 mg/wk each month when decreasing dose to lowest possibility

Drug Category: Phototherapy agents

PUVA has been a successful therapy for some patients. Purpose of this treatment is to induce remission of skin diseases by repeated and controlled phototoxic reaction. Photoconjugation of psoralens with DNA produces an antiproliferative reaction in the skin, generates programmed cell death (apoptosis), and induces down-regulation of the cutaneous immune system.

FOLLOW-UP

Section 8 of 11  

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Complications

• Complications appear in 30-50% of patients with LCH.
• • The most common complications are orthopedic disabilities, hearing impairment, diabetes insipidus, and neuropsychologic defects.
  • Patients with multisystem disease, craniofacial involvement, long-standing disease, or reactivation may be at increased risk of developing diabetes insipidus.
  • Less common sequelae are chronic pulmonary dysfunction, liver cirrhosis, and growth retardation.

Prognosis

• The clinical course of LCH is variable. Patients with unifocal LCH generally have an excellent prognosis.
• • After an initial bone scan and radiographic survey to assess the extent of the disease, follow-up studies after treatment should be performed at 6-month intervals for 3 years.
  • If no additional lesions are present at 1 year, the development of subsequent lesions is unlikely.
  • A full recovery is also expected in cases of solitary lymph node involvement or isolated skin disease.
• Multifocal LCH has a variable prognosis, especially in patients at the extremes of age with pulmonary involvement. It is worse than those with unifocal disease but better than disseminated disease. Sixty percent of patients with multifocal disease have a chronic course, 30% of patients undergo complete remission, and 10% of patients with multifocal LCH die.
• Letterer-Siwe disease (disseminated) has a high mortality rate. The prognosis in these patients depends on the patient's age, the extent of disease, and the degree of organ dysfunction. The mortality rate is 50% or more.
• The congenital form of histiocytosis tends to resolve spontaneously within weeks to months.
• • Although the absence of systemic disease at presentation and the tendency of resolution of the disease are favorable, long-term follow-up care to detect evidence of relapse or progression in these patients is suggested.
  • Relapse in these patients has been reported up to 5 years after the initial disappearance of the disease.
  • Cutaneous lesions usually disappear by 3 months leaving residual hypopigmentation.
• Infrequently, a case originally diagnosed as chronic focal LCH may progress to multifocal or even disseminated disease.

MISCELLANEOUS

Section 9 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to diagnose cases of LCH resulting in delayed treatment
• Failure to consider cases of LCH among the differential diagnoses when cutaneous lesions do not respond to topical corticosteroids and failure to perform a biopsy in this case
• Failure to recognize that a cutaneous eruption of LCH can closely simulate an eczematous rash, resulting in misdiagnosis
• Note: Skin involvement occurs in more than 80% of patients with disseminated disease and in 30% of patients with less extensive multisystem disease.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Letterer-Siwe disease. Bilateral inguinal erosive plaques and erythematous papules on the abdomen. Courtesy of Dr Neil S. Prose.
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Media file 2:  Abdominal area of an infant with multiple erythematous papules covered by scale and/or crust.
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Media file 3:  Typical purpuric lesions in Langerhans cell histiocytosis (must be distinguished from seborrheic dermatitis).
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Media file 4:  On a plain skull radiograph, lesions are typically lytic, with sharp borders and a punched out appearance.
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Media file 5:  High-power views. Marked epidermotropism is noted (left). The lesional cells are large, with abundant pink cytoplasm and reniform nuclei. An admixture of inflammatory cells, including occasional eosinophils, is present (right).
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Media file 6:  High-power views. Diffuse immunoreactivity for S-100 protein (right). Langerhans cells and lymphocytes (left, hematoxylin and eosin).
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Media file 7:  Widespread positivity for CD1a. Note the presence of epidermotropism (right). Langerhans cells and lymphocytes are present in the epidermis and the papillary dermis (left, hematoxylin and eosin).
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Media file 8:  Electron microscopy. Tennis racquet form of Birbeck granules with a small terminal expansion.
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REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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