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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 138ELangerhans’ Cell Histiocytosis

, MD.

The Histiocytic Disorders

The histiocytic disorders are rare conditions resulting from or associated with the localized or generalized proliferation of cells of the mononuclear system. Langerhans’ cell histiocytosis (LCH) (previously called histiocytosis X) is from a proliferation of antigen presenting dendritic cells.

Langerhans’ Cell Histiocytosis

The first clinical description of LCH was published over a century ago, but the etiology and pathogenesis remain unknown. LCH is considered to be a reactive disorder in which cells similar to normal Langerhans’ cells of the skin cause damage to organs by excessive production of cytokines and prostaglandins. There is a wide spectrum of presentation from the single bone lesion to an aggressive leukemia-like disease that primarily affects children less than 2 years of age.


LCH lesions are characterized by the accumulation of abnormal Langerhans’ cells in locations in which they are not normally found. These abnormal cells resemble normal skin Langerhans’ cells in that they co-express S-100 neuroprotein and CD1a antigen and contain cytoplasmic Birbeck granules.1 Unlike the skin Langerhans’ cells, they are not morphologically dendritic. T lymphocytes, multinucleated giant histiocytes, and eosinophils accompany these abnormal Langerhans’ cells. Reactive granulocytes and plasma cells may also be present.2 Monoclonal CD1a-positive histiocytes have been detected in all forms of the disease.3,4 Although monoclonality is often associated with neoplasia, the significance in LCH is unclear. Cytogenetic studies have failed to reveal any characteristic somatic mutations.2

Histiocytes, including Langerhans’ cells, elaborate numerous cytokines. The production of prostaglandin E2 and IL-1 may account for some of the systemic symptoms, including fever and wasting.5,6 Cytokines detected also include IL-3, IL-4, IL-8, GM-CSF, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, and leukemia-inhibiting factor.7 This aberrant or uncontrolled cytokine production is thought to play a major role as a mediator in the pathogenesis of the disease.8

The lesions are hypothesized to result from an abnormal response to a viral infection resulting from an underlying immunodeficiency.8 However, few studies have confirmed this hypothesis. Evidence of immune dysfunction, such as abnormal immunoglobulin levels, impaired mitogen responses, and abnormal T-suppressor cell levels, have been observed inconsistently.9,10 Although one study showed an association of LCH with human herpes virus infection,11 several comprehensive studies have failed to confirm this finding or identify other potential viral causes.12,13


LCH occurs in all age groups, but 50% occur in children aged 1 to 15 years.14 The male to female ratio is 2:1. Although under-reported, given the wide range in severity of disease, LCH is still rare with an annual incidence estimated at 5.4 per million children per year.15 With the exception of a few cases,16 familial recurrence of LCH does not occur.

The etiology of LCH remains poorly understood. Several studies have attempted to identify risk factors associated with LCH. In a preliminary exploratory study at the University of Minnesota, elevated risk was observed with maternal urinary tract infection during pregnancy, feeding problems, and blood transfusions.17 A study conducted in Denmark of 90 children with LCH did not identify any risk factors.18 In a large case-control study conducted at the University of Minnesota, factors were analyzed in a group of 459 children with LCH and compared with healthy children and children with cancer.19 Significant associations were noted with infections in the neonatal period, solvent exposure, childhood vaccinations, and thyroid disease. Infections acquired in utero were not associated with an elevated risk for LCH; however, the increased risk in the neonatal period is suggestive of an immune dysregulatory process or infectious cause of the disease. The link to thyroid disease may indicate an autoimmune process.

Clinical Presentation

LCH cells have been found in nearly all organs within the body. The clinical presentation varies widely from single-system disease, often resolving spontaneously or requiring minimal therapy, to multisystem disease, which often requires intensive therapy and may be associated with a significant risk of mortality if organ dysfunction is present.

Single-system disease is usually confined to bone and may involve one or more sites. Skeletal survey is essential in detecting the full extent of disease. The skull is most commonly affected, followed by the proximal long bones and axial skeleton. Pain or lumps are typical symptoms, and pathologic fracture may occur in weight-bearing bones. Radiographs generally demonstrate osteolytic lesions, although periosteal reaction may make distinction from bone tumors more difficult. Bone involvement occurs more frequently in the older age group.

Skin involvement is noted in approximately one-third of children with LCH.20 The lesions are typically erythematous papules that may progress to ulceration or depigment and resolve. In approximately 10% of patients, especially male infants,21–23 the skin is the only site of involvement and the disease usually resolves spontaneously (Hashimoto-Pritzker disease).24 Lymph node involvement is less frequent, occurring in less than 10% of children with LCH. It may be seen with both limited or multisystem disease.20

The aggressive presentation of multisystem disease is typically seen in children less than 2 years of age. Organs involved include the bone marrow, liver, spleen, and lungs. The presentation is often similar to an acute leukemia with evidence of bone marrow suppression, massive hepatosplenomegaly, and constitutional symptoms. Lung involvement is manifested by respiratory distress with tachypnea, retractions, and persistent cough. Radiographs reveal diffuse interstitial infiltration. Chronic respiratory failure may develop with development of multiple cystic areas and bullae. Pneumothorax may occur as a result of rupture of these bullae.25

Diabetes insipidus (DI) is a well-described complication of LCH. At the Mayo Clinic, 14% of 314 patients with LCH developed this complication.26 DI is more common in patients with skull lesions and extraosseus disease.27,28 Diagnosis may be made by the finding of reduced plasma or urinary vasopressin levels after water deprivation and by the loss of the posterior pituitary bright signal on magnetic resonance imaging (MRI).20 Other central nervous system (CNS) manifestations include cerebellar dysfunction, usually manifested by gait disturbance. This may progress to cranial nerve deficits and fatal CNS degeneration. The lesions are detectable on MRI.29 Involvement of the skull, meninges, or choroid plexus may exert a mass effect, but the incidence of the development of these symptoms is not well known.29

Therapy for Single-System Disease

Single-system LCH warrants conservative management as the disease frequently regresses completely. Bone lesions of the skull, spine, and long bones often resolve spontaneously so that they may be observed without specific therapy. However, for lesions that are persistent, painful, or cosmetically deforming, therapy is indicated. Surgical curettage of the lesion with or without the instillation of corticosteroids is most often used. Complete resection of the lesion is not necessary to induce a complete response. Bone lesions located in areas inaccessible to surgery or in places that might compromise vital organs such as the spinal cord, optic nerve, or sella turcica can be treated with low-dose radiation therapy. Multiple bone lesions or lymphadenopathy may be treated with systemic therapy. Options here include oral corticosteroids alone30 or in conjunction with oral methotrexate,31 or intravenous vinblastine. Indomethacin is also effective for bone lesions presumably because of its analgesic and antiprostaglandin effects.32

A seborrheic-like dermatitis of the scalp is another common presentation of LCH. This may respond to the regular use of a selenium-based shampoo or topical corticosteroids. More resistant skin lesions may be treated with the topical application of 20% nitrogen mustard solution.33

Solitary lymph node involvement may be treated with an excisional biopsy, whereas regional nodal involvement may respond to a short course of oral corticosteroids.30 Refractory nodal disease, particularly for those nodes that discharge into the skin, may necessitate the use of chemotherapy.34

Therapy for Multisystem Disease

Spontaneous regression of multisystem disease may occur so that close observation of asymptomatic patients is warranted. However, if organ dysfunction or failure to thrive develops, treatment should be started. The goal of treatment is to control the disease and prevent permanent organ damage, rather than eradicate the disease completely. Standard therapy consists of cytotoxic chemotherapy alone or in conjunction with corticosteroids. Chemotherapeutic agents that have been employed include chlorambucil, cyclophosphamide, cytarabine, daunomycin, etoposide, 6-mercaptopurine, methotrexate, nitrogen mustard, procarbazine, vinblastine, and vincristine.

Several nonrandomized clinical trials of chemotherapy have been completed. In the Italian AIEOP-CNR-HX 83 study,35 patients received induction therapy with sequential vinblastine, doxorubicin, and etoposide. The poorest prognostic group then received continuation therapy with nine courses of vincristine, cyclophosphamide, doxorubicin, and prednisolone. Overall mortality was only 8% but rose to 54% in the poorest prognostic group. The Austrian/German DAL-HX 83/9036 used a 6-week induction regimen of vinblastine, etoposide, and prednisolone. Maintenance therapy was risk adapted; low-risk patients (multifocal bone disease) received 6-mercaptopurine, vinblastine, and prednisolone; intermediate-risk patients (soft-tissue involvement but no organ dysfunction) also received etoposide; and high-risk patients (soft-tissue involvement with organ dysfunction) received etoposide and methotrexate. Overall mortality was also low at 9% but increased to 38% for the highest risk subgroup. The 15% DI rate in the Austrian/German study was appreciably lower than previous reports.

The Histiocyte Society sponsored the first randomized trial, LCH-1.37 Patients were randomized to receive 24 weeks of either vinblastine (6 mg/m2) weekly or etoposide 150 mg/m2 every 3 weeks, in conjunction with an initial pulse of high-dose methylprednisolone (30 mg/kg daily for 3 days). Of the 192 patients with multisystem disease registered on the trial, 136 were randomized. Overall mortality was 18%. DI developed in 42% of patients. No significant differences were observed between the two arms with respect to initial response, probability of reactivation, or mortality. However, the study did reveal that evaluation of response at 6 weeks was predictive of eventual outcome. The Histiocyte Society is currently evaluating a new protocol, LCH-2.30 This trial is comparing the effect of continuous oral prednisolone combined with vinblastine with or without the addition of etoposide in high-risk patients. The trial also includes continuation therapy with 6-mercaptopurine, vinblastine, and prednisolone as used in the DAL-HX 83/90 study. The trial will help to clarify the roles of etoposide and continuation therapy in the management of multisystem LCH.

Numerous experimental therapies have been used in nonresponders. The purine analogue, 2-chlorodeoxyadenosine (2-cda), has shown efficacy in low-grade lymphoproliferative disorders and is toxic to monocytes in vitro and in vivo.38 Responses have been produced in refractory LCH patients in several small series.39,40 This agent is being evaluated further. Immunosuppressive therapies including cyclosporin A41,42 and antithymocyte globulin43 have been shown to be effective in some patients. Immunomodulation with thalidomide has been reported to have some objective responses in adults with LCH but much more work will need to be done to better clarify its role.44 Allogeneic bone marrow transplantation following myeloablative conditioning has been used to successfully treat a small number of patients with refractory disease and is currently being evaluated as a salvage therapy in the LCH-2 trial.43 A more specific therapy under investigation is the use of a monoclonal antibody directed against CD1a.45 The antibody has been shown to localize sites of disease but much more work needs to be done to demonstrate a therapeutic role.

DI arises from involvement of the posterior pituitary. Once symptoms of thirst and polyuria occur, the chance of reversing DI is small. There are reports of responses to pituitary irradiation administered within the first 48 hours of symptoms or in patients with laboratory evidence of partial pituitary dysfunction.46 Similarly, chemotherapy (particularly with etoposide-containing regimens) has been reported to reverse some cases of DI.47 However, the majority of patients do not either respond or maintain the response.48 Lifelong replacement with desmopressin is generally required.

As several antineoplastic agents and radiation therapy have been associated with secondary malignancies, the risk-benefit ratio of such therapies must be carefully considered in patients with LCH. For example, etoposide, a very effective agent in patients with multisystem disease, has been implicated in secondary leukemia.49 Therefore, its use should be restricted to those patients with organ dysfunction, and the cumulative dosage and schedule of administration should be designed to minimize the risk of leukemogenesis.


Untreated LCH may resolve spontaneously or may disseminate and cause organ dysfunction, leading to chronic problems or death. Several studies have identified prognostic indicators to better guide therapy. Lahey determined that organ dysfunction was an important factor in a review of 83 patients treated with chemotherapy by the Children’s Cancer Study Group.50 The Southwest Oncology Group identified organ dysfunction and age as important factors on the basis of retrospective data from 155 children with LCH: good risk was defined as older patients without organ dysfunction, intermediate risk included children less than 2 years but without organ dysfunction, and poor risk was the children less than 2 years with organ dysfunction who had a probability of survival of less than 50%.51

More recent studies have determined that response to therapy is an important risk factor. In the Austrian-German DAL-HX 83/90 study, response was assessed after 6 weeks of induction chemotherapy. After a median observation time of 7 years and 6 months, 19% of the good responders had died in contrast to 89% of the nonresponders.36 Similarly in the LCH-1 trial, 8% of the good responders versus 47% of the nonresponders died after a maximum follow-up time of 2 years and 2 months.37

The inactive lesions may have late sequelae that can significantly impact the quality of life of survivors of LCH. Patients with bone involvement are at risk for orthopedic problems, poor dentition, and small stature. Chronic aural involvement may result in deafness. DI necessitates lifelong desmopressin replacement. Chronic respiratory failure may be a consequence of pulmonary fibrosis. Cirrhosis of the liver may result from hepatic involvement.

The role of treatment in the prevention of late relapses still needs to be demonstrated. Therefore, the intensity of therapy must be modulated against the perceived risks. Intensive chemotherapy should be reserved for high-risk children with multisystem disease, whereas the morbidity of therapy can be spared for low-risk patients.


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Bookshelf ID: NBK20892


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