- General Information About Langerhans Cell Histiocytosis (LCH)
- Childhood LCH
- Histopathologic, Immunologic, and Cytogenetic Characteristics of LCH
- Presentation of LCH in Children
- Diagnostic Evaluation of Childhood LCH
- Follow-up Considerations in Childhood LCH
- Treatment of Childhood LCH
- Treatment of Recurrent, Refractory, or Progressive Childhood LCH
- Late Disease and Treatment Effects of Childhood LCH
- Adult LCH
- Treatment of Adult LCH
- Changes to the Summary (01 / 30 / 2013)
- About This PDQ Summary
- Get More Information From NCI
Langerhans Cell Histiocytosis Treatment (PDQ®): Treatment - Health Professional Information [NCI]
This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Langerhans Cell Histiocytosis Treatment
General Information About Langerhans Cell Histiocytosis (LCH)
The histiocytic diseases in children and adults include three major classes of disorders of which only one, Langerhans cell histiocytosis (LCH), a dendritic cell disorder, will be discussed. Erdheim-Chester disease (primarily found in adults) and juvenile xanthogranuloma (diagnosed in children and adults) are macrophage disorders. Other disorders of the macrophage/monocytoid lineages include Rosai-Dorfman disease and hemophagocytic lymphohistiocytosis. Malignant disorders include malignant histiocytosis of various histiocyte lineages (formerly called histiocytic sarcoma) and the monocytic or myelomonocytic leukemias.
LCH results from the clonal proliferation of immunophenotypically and functionally immature, morphologically rounded LCH cells along with eosinophils, macrophages, lymphocytes, and occasionally, multinucleated giant cells. The term LCH cells is used because there are clear morphologic, phenotypic, and gene expression differences between Langerhans cells of the epidermis (LC cells) and those in LCH lesions (LCH cells). Controversy exists regarding whether the clonal proliferation of LCH cells results from a malignant transformation or is the result of an immunologic stimulus.[2,3]
Whether the clonal proliferation of LCH cells is a result of neoplastic changes or immunologic abnormalities, the primary treatment is with chemotherapeutic agents. Some of the chemotherapy drugs used have immunomodulatory activity as well.
Langerhans cell histiocytosis is the terminology currently preferred over histiocytosis X, eosinophilic granuloma, Abt-Letterer-Siwe disease, Hand-Schuller-Christian disease, or diffuse reticuloendotheliosis. This is because the pathologic histiocyte common to all of these diagnoses was identified by electron microscopy to have characteristic Birbeck granules identical to those of the LC cell found scattered in the dermal-epidermal junction of the skin.[4,5] More recent work has shown that the pathologic histiocyte (LCH cell) has a gene expression profile of a myeloid dendritic cell and not the skin LC.
The nomenclature used for LCH indicates the disease extent. LCH may involve a single organ (single-system LCH), which may be a single site (unifocal) or involve multiple sites (multifocal); or LCH may involve multiple organs (multisystem LCH), which may involve a limited number of organs or it may be disseminated.
Children and adolescents with Langerhans cell histiocytosis (LCH) should be treated by a multidisciplinary team of health professionals who are experienced with this disease and its treatment. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
Clinical trials organized by the Histiocyte Society have been accruing patients on childhood treatment studies since the 1980s. Information on centers enrolling patients on these trials can be found on the NCI Web site.
Because of treatment advances, the outcome for children with LCH involving high-risk organs (spleen, liver, and bone marrow) has improved.[1,2] The high-risk designation comes from the high mortality rate (35%) in those who do not respond well to therapy in the first 6 weeks. The outcome for children with LCH involving low-risk organs (skin, bones, lymph nodes, and pituitary gland) has always been excellent, but the major challenge is to reduce the 20% to 30% incidence of recurrent lesions.
Children with high-risk or low-risk disease should be followed annually to document and attempt to correct adverse side effects of therapy or the disease. (Refer to the Late Disease and Treatment Effects of Childhood LCH section of this summary for more information about the incidence, type, and monitoring of late effects of childhood cancer and its therapy.)
The incidence of LCH has been estimated to be two to ten cases per million children aged 15 years or younger.[3,4] The male/female (M/F) ratio is close to one and the median age of presentation is 30 months. A report from Stockholm County, Sweden described an incidence of 8.9 cases of LCH per million children with a total of 29 cases in 10 years. A majority of these cases were diagnosed between September and February (M/F = 1.2). A 4-year survey of 251 new LCH cases in France found an unusual incidence of 4.6 per million children younger than 15 years (M/F = 1.2). Identical twins with LCH, and non-twin siblings or multiple cases in one family, have been reported. A survey of LCH in northwest England (Manchester) revealed an overall incidence of 2.6 cases per million child years.
Solvent exposure in parents and perinatal infections have a weak association with LCH, but there is no increase in cases after viral epidemics. An increased frequency of family members with thyroid disease has been reported.
Prognosis is closely linked to the extent of disease at presentation and whether high-risk organs (liver, spleen, and/or bone marrow) are involved. Patients with single-system disease and low-risk multisystem disease do not usually die from LCH, but recurrent disease may result in considerable morbidity and significant late effects.
Prognostic factors in LCH have been identified and can be categorized as follows:
- Age at diagnosis: Although age younger than 2 years was once thought to portend a worse prognosis, data from the LCH-II study showed that patients aged 2 years or younger without high-risk organ involvement had the same response to therapy as older patients. By contrast, the overall survival (OS) was poorer in neonates with risk-organ involvement compared with infants and children with the same extent of disease.
- Response to treatment: Response to therapy at 6 to 12 weeks has been shown to be a more important prognostic factor than age. The overall response to therapy is influenced by the duration and intensity of treatment.[1,2]
- Organ involvement: Involvement of craniofacial bones including orbital, mastoid, and temporal bones is associated with an increased risk of diabetes insipidus in addition to increased frequency of anterior pituitary hormone deficiencies and neurologic problems. (Refer to the Endocrine system subsection in the Multisystem Disease Presentation section of this summary for more information on diabetes insipidus.)
Histopathologic, Immunologic, and Cytogenetic Characteristics of LCH
Cell of Origin and Biologic Correlates
Modern classification of the histiocytic diseases divides them into dendritic cell–related, monocyte/macrophage-related, or true malignancies. Langerhans cell histiocytosis (LCH) is a dendritic cell disease.[1,2] The Langerhans cells (LCH cells) in LCH lesions are immature cells that express the monocyte marker CD14, which is not found on normal skin LCs. Comprehensive gene expression array data analysis on LCH cells is consistent with the concept that the skin LC is not the cell of origin for LCH. Rather it is likely to be a myeloid dendritic cell, which expresses the same antigens (CD1a and CD207) as the skin LC.
LCH lesions also contain lymphocytes, macrophages, neutrophils, eosinophils, fibroblasts, and sometimes multinucleated giant cells. In the brain, the following three types of histopathologic findings have been described in LCH:
- Mass lesions in meninges or choroid plexus with CD1a-positive LCH cells and predominantly CD8-positive lymphocytes.
- Mass lesions in connective tissue spaces with CD1a-positive LCH cells and predominantly CD8-positive lymphocytes causing an inflammatory response and neuronal loss.
- Predominantly CD8+ lymphocyte infiltration with neuronal degeneration, microglial activation, and gliosis.
Normally, the LC is a primary presenter of antigen to naïve T-lymphocytes. However, in LCH, the LCH cell does not efficiently stimulate primary T-lymphocyte responses. Antibody staining for the dendritic cell markers, CD80, CD86, and class II antigens, has been used to show that in LCH, the abnormal cells are immature dendritic cells that present antigen poorly and are proliferating at a low rate.[3,6,7] Transforming growth factor-beta (TGF-beta) and interleukin (IL)-10 are possibly responsible for preventing LCH cell maturation in LCH. The expansion of regulatory T cells in LCH patients has been reported. The population of CD4-positive CD25(high) FoxP3(high) cells was reported to comprise 20% of T cells and appeared to be in contact with LCH cells in the lesions. These T cells were present in higher numbers in the peripheral blood of LCH patients than in controls and returned to a normal level when patients were in remission.
Cytogenetic and Genomic Studies
Studies showing clonality in LCH using polymorphisms of methylation-specific restriction enzyme sites on the X-chromosome regions coding for the human androgen receptor, DXS255, PGK, and HPRT were published in 1994.[11,12] Biopsies of lesions with single-system or multisystem disease were found to have a proliferation of LCH cells from a single clone. Pulmonary LCH in adults is usually nonclonal. Cytogenetic abnormalities in LCH have rarely been reported. One study described an abnormal clone t(7;12)(q11.2;p13) from a vertebral lesion of one patient. This study also reported nonclonal karyotypic abnormalities in three patients. An increase in chromosomal breakage was also noted.
Comparative genomic hybridization has been used to analyze bone and pulmonary LCH cells with conflicting results.[13,15,16,17] Thus, there is some doubt if comparative genomic hybridization can reliably identify mutations in LCH.
One report has shown significantly shortened telomeres in lesional LCH cells compared with LCs in inflammatory disorders such as dermatopathic lymphadenitis. However, another group found telomere length of LCH cells from skin multisystem lesions were long compared with those from bone lesions that were heterogeneous in length. Telomerase was more often expressed in skin LCH lesions than in bone lesions. In another study evaluation of peripheral blood leukocyte DNA from high-risk LCH patients showed polymorphisms of two cytokine genes (IL-4 and interferon gamma), which were associated with high-expressor phenotypes.
Activating mutation of the BRAF gene (V600E) was detected in 35 of 61 (57%) LCH biopsy samples, with mutations being more common in patients younger than 10 years (76%) than in patients aged 10 years and older (44%). Activating BRAF mutations are also found in selected nonmalignant conditions (e.g., benign nevi)  and low-grade malignancies (e.g., pilocytic astrocytoma).[23,24] All of these conditions have in common a generally indolent course with spontaneous resolution sometimes occurring. This distinctive clinical course may be a manifestation of oncogene-induced senescence.[22,25]
Cytokine Analysis by Immunohistochemical Staining and Gene Expression Array Studies
Immunohistochemical staining of LCH lesions have shown apparent upregulation of the chemokines CCR6 and possibly CCR7.[26,27] In an analysis of gene expression in LCH by gene array techniques, 2,000 differentially expressed genes were identified. Of 65 genes previously reported to be associated with LCH, only 11 were found to be upregulated in the array results. The most highly upregulated gene in both CD207 and CD3-positive cells was osteopontin; other genes that activate and recruit T cells to sites of inflammation are also upregulated. The expression profile of the T cells was that of an activated regulatory T-cell phenotype with increased expression of FOXP3, CTLA4, and osteopontin. These findings support a previous report on the expansion of regulatory T cells in LCH. There was pronounced expression of genes associated with early myeloid progenitors including CD33 and CD44, which is consistent with an earlier report of elevated myeloid dendritic cells in the blood of LCH patients. A model of "Misguided Myeloid Dendritic Cell Precursors" has been proposed whereby myeloid dendritic cell precursors are recruited to sites of LCH by an unknown mechanism and the dendritic cells in turn recruit lymphocytes by excretion of osteopontin, neuropilin-1, and vannin-1.
Several investigators have published studies evaluating the level of various cytokines or growth factors in the blood of patients with LCH that have included many of the genes found not to be upregulated by the gene expression results discussed above. One explanation for elevated levels of these proteins is a systemic inflammatory response with the cytokines/growth factors being produced by cells outside the LCH lesions. A second possible explanation is that macrophages in the LCH lesions produce the cytokines measured in the blood or are concentrated in lesions.
IL-1 beta and prostaglandin GE2 levels were measured in the saliva of patients with oral LCH lesions or multisystem high-risk patients with and without oral lesions; levels of both were higher in patients with active disease and decreased after successful therapy.
Human Leukocyte Antigen (HLA) Type and Association With LCH
Specific associations of LCH with distinct HLA types and extent of disease have been reported. In a study of 84 Nordic patients, those with only skin or bone involvement more frequently had HLA-DRB1*03 type than those with multisystem disease. In 29 patients and 37 family members in the United States, the Cw7 and DR4 types were significantly more prevalent in Caucasians with single-bone lesions.
Presentation of LCH in Children
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 and single-system or multisystem disease presentation as noted below.
Specific organs are considered high-risk or low-risk organs when involved with disease presentation. Risk refers to the risk of mortality.
- High-risk organs include liver, spleen, and bone marrow.
- Low-risk organs include skin, bone, lymph nodes, gastrointestinal tract, pituitary gland, and central nervous system (CNS).
Additionally, patients may present with a single organ (single-system LCH), which may be a single site (unifocal) or involve multiple sites (multifocal); or LCH may involve multiple organs (multisystem LCH), which may involve a limited number of organs or it may be disseminated. Treatment decisions for patients are based upon whether high-risk or low-risk organs are involved and whether LCH presents as a single-system or multisystem disease. Patients can have LCH of the skin, bone, lymph nodes, and pituitary in any combination and still be considered at low-risk of death, although there may be relatively high-risk for long-term consequences of the disease.
Single-System Disease Presentation
In single-system 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, pituitary gland, and thyroid.
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). Similar to that of stage 4S 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.
A review of patients presenting in the first 3 months of life with skin-only LCH, compared the clinical and histopathologic findings in 21 children whose skin LCH regressed with 10 children who did not regress. Patients with regressing disease had distal lesions that appeared in the first 3 months of life and were necrotic papules or hypopigmented macules. Nonregressing patients who required systemic therapy were more often intertriginous. Immunohistochemical studies showed no difference in IL-10, Ki-67, or E-cadherin expression and T-reg number between the two clinical groups.
- 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, under the breasts, or 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. Hypermobile teeth (floating teeth) and tooth loss may occur.[6,7] Lesions of the oral mucosa may precede evidence of LCH elsewhere.
LCH can occur in any bone of the body, although the hands and feet are often spared. Sites of LCH in children include the following:
- Lytic lesion of the skull: The most frequent site of LCH in children is a lytic lesion of the skull, which may be asymptomatic or painful. It is often surrounded by a soft tissue mass which may impinge on the dura.
- Femur, ribs, humerus, and vertebra: The second most frequently involved skeletal sites are femur, ribs, humerus, and vertebra. Spine lesions may involve any vertebra, although involvement of the cervical vertebrae is most common and spine lesions are frequently associated with other bone lesions. Spine lesions may result in collapse of the vertebral body (vertebra plana). Vertebral lesions with soft tissue extension often present with pain and may present with significant neurologic deficits, an indication for an urgent magnetic resonance imaging (MRI) scan.
- Orbit: Proptosis from an LCH mass in the orbit mimics rhabdomyosarcomas, neuroblastoma, and benign fatty tumors of the eye.
- Facial bones and anterior or middle cranial fossae: 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 and an increased risk of other CNS disease.
Lymph nodes and thymus
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 diabetes insipidus. (Refer to the Endocrine subsection in the Multisystem Disease Presentation section of this summary for more information.) Anterior pituitary involvement often results in growth failure and delayed or precocious puberty.
Thyroid involvement has been reported in LCH. Symptoms include massive thyroid enlargement, hypothyroidism, and respiratory symptoms.
Multisystem Disease Presentation
In multisystem LCH, the disease presents in multiple organs or body systems including bone, abdominal/gastrointestinal system (liver and spleen), lung, bone marrow, endocrine system, CNS, skin, and lymph nodes.
Bone and other organ systems
LCH patients may present with multiple bone lesions as a single site (single-system multifocal bone) or bone lesions with other organ systems involved (multisystem including bone). A review of single-system multifocal bone and multisystem including bone patients treated on the Japanese LCH study (JLSG-02) found patients in the multisystem including bone group were more likely to have lesions in the temporal bone, mastoid/petrous bone, orbit, and zygomatic bone (CNS-risk). Patients with multisystem including bone had a higher incidence of diabetes insipidus, correlating with the higher frequency of lesions in the noted facial bones. There was no difference in the outcome to treatment, which is more intense in the JLSG-02 study compared with the LCH-II study.
In LCH, the liver and spleen are considered high-risk organs, and involvement of these organs affects prognosis. Involvement in this context means the liver and spleen are enlarged from direct infiltration of LCH cells or as a secondary phenomenon of excess cytokines, which cause macrophage activation or infiltration of lymphocytes around bile ducts. LCH has a portal (bile duct) trophism that leads to biliary damage and ductal sclerosis. A percutaneous (peripheral) liver biopsy may not be diagnostic of the infiltrate that tends to be more central in the liver, but will show the upstream obstructive effects of distal biliary occlusion. Hepatic enlargement can be accompanied by dysfunction, leading to hypoalbuminemia with ascites, hyperbilirubinemia, and clotting factor deficiencies. Sonography, computed tomography (CT), or 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.
Liver (sclerosing cholangitis)
One of the most serious complications of hepatic LCH is cholestasis and sclerosing cholangitis. This usually occurs months after initial presentation, but on occasion may be present at diagnosis. The median age of children with this form of hepatic LCH is 23 months.
Patients with hepatic LCH present with hepatomegaly or hepatosplenomegaly, and elevated alkaline phosphatase, liver transaminases, and gamma glutamyl transpeptidase levels. Biopsies show no LCH cells but infiltrating lymphocytes surrounding the bile ducts may be present. It is thought that cytokines, such as TGF-beta, elaborated by lymphocytes during the active phase of the disease, leads to fibrosis and sclerosis around the bile ducts.
Seventy-five percent of children with sclerosing cholangitis will not respond to chemotherapy because the LCH is no longer active, but the fibrosis and sclerosis remain. Liver transplantation is the only alternate treatment when hepatic function worsens. In one series of 28 children undergoing liver transplantation, 78% survived and 29% had recurrence of LCH but only two cases of recurrent LCH occurred in the transplanted liver. The patients who undergo liver transplant for LCH may have a higher incidence of posttransplant lymphoproliferative disease.
Massive splenomegaly may lead to cytopenias because of hypersplenism and may cause respiratory compromise. Splenectomy typically provides only transient relief of cytopenias, as increased liver size and reticuloendothelial activation results in peripheral blood cell sequestration and destruction. Although rare, LCH infiltration of the pancreas and kidneys has been reported. Splenectomy is only performed as a life-saving measure.
Other gastrointestinal manifestations
A few patients with diarrhea, hematochezia, perianal fistulas, or malabsorption have been reported.[18,19] Diagnosing gastrointestinal involvement with LCH is difficult because of patchy involvement. Careful endoscopic examination including multiple biopsies is usually needed.
In LCH, the lung is less frequently involved in children than in adults, in whom smoking is a key etiologic factor. The cystic/nodular pattern of disease reflects the cytokine-induced destruction of lung tissue. Classically, the disease is symmetrical and predominates in the upper and middle lung fields, sparing the costophrenic angle and giving a very characteristic picture on high-resolution CT scan. Confluence of cysts may lead to bullous formation and 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. Declining diffusion capacity may also herald the onset of pulmonary hypertension. In young children with diffuse disease, therapy can halt progress of the tissue destruction and normal repair mechanisms may restore some function.
Pulmonary involvement is present in approximately 25% of children with multisystem low-risk and high-risk LCH. However, a multivariate analysis of pulmonary disease in multisystem LCH did not show pulmonary disease to be an independent prognostic factor, with a 5-year overall survival rate of 94% versus 96% for those with or without pulmonary involvement.
Most patients with bone marrow involvement are young children who have diffuse disease in the liver, spleen, lymph nodes, and skin who present with significant thrombocytopenia and anemia with or without neutropenia. 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. All of the bone marrow biopsy specimens (22 of 22 specimens) in one study had increased numbers of dysplasia of megakaryocytes, often with emperipolesis (active penetration by one cell into and through a larger cell). Patients with LCH who are considered at very high risk sometimes present with hemophagocytosis involving the bone marrow. The cytokine milieu driving LCH is probably responsible for the epiphenomenon of macrophage activation.
Diabetes insipidus, caused by LCH-induced damage to the anti-diuretic hormone (ADH)–secreting cells of the posterior pituitary, is the most frequent endocrine manifestation in LCH. MRI scans usually show nodularity and/or thickening of the pituitary stalk and loss of the pituitary bright spot on T2-weighted images. Pituitary biopsies are rarely done and usually 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 pituitary abnormalities.
Approximately 4% of patients present with an apparently idiopathic presentation of diabetes insipidus before other lesions of LCH are identified, 7% concomitantly with another location and 14% after extrapituitary diagnosis of LCH. A report of 26 patients who presented with isolated diabetes insipidus as the initial manifestation of LCH described their natural history. Eleven of the patients presenting with isolated central diabetes insipidus also had anterior pituitary deficits. These included secondary amenorrhea, panhypopituitarism, growth hormone deficiency, hypoadrenalism, and abnormalities of gonadotropins. Twenty-two of the 26 patients ultimately developed extrapituitary lesions of LCH, including bone (n = 15), lung (n = 9), and skin (n = 9), in a median time of 1 year (range, 1 month to 14.2 years).
Patients with diabetes insipidus have a 50% to 80% chance of developing other lesions diagnostic of LCH within 1 year of identifying diabetes insipidus. A study of 589 patients with LCH revealed the 10-year risk of pituitary involvement was 24%. These investigators did not see a decreased incidence of diabetes insipidus in chemotherapy-treated patients, but this may reflect the length of the therapy and/or the number of drugs used. Using longer therapy and more drugs, the German-Austrian-Dutch (Deutsche Arbeits-gemeinschaft für Leukaemieforschung und-therapie im Kindesalter [DAL]) Group and the Japanese Langerhans Cell Group found the cumulative incidence to be 12%.[30,31] Diabetes insipidus followed initial LCH diagnosis by a mean of 1 year and growth hormone deficiency occurred 5 years later.
Patients with multisystem disease and craniofacial involvement at the time of diagnosis, particularly of the orbit, mastoid, and temporal bones, carried a significantly increased risk of developing diabetes insipidus during their course (relative risk, 4.6), with 75% of patients with diabetes insipidus having these CNS-risk bone lesions. This risk increased when the disease remained active for a longer period of time or reactivated. The risk for development of diabetes insipidus in this population was 20% at 15 years after diagnosis. The incidence of diabetes insipidus was lower in patients treated with more intensive chemotherapy regimens on the JLSG-96 and JLSG-02 studies in Japan (8.9% for multisystem patients) than on the LCH-I and LCH-II studies (14.2%).[31,32,33] Fifty-six percent of diabetes insipidus patients will develop anterior pituitary hormone deficiencies (growth, thyroid, or gonadal-stimulating hormones) within 10 years of the onset of diabetes insipidus. Diabetes insipidus occurs in 11% of patients treated with multiagent chemotherapy and in up to 50% of patients treated less aggressively.[34,35]
Central nervous system
CNS disease manifestations
LCH patients may develop mass lesions in the hypothalamic-pituitary region, the choroid plexus, the grey matter, or the white matter. These lesions contain CD1a-positive LCH cells and CD8-positive lymphocytes, and are, therefore, active LCH lesions.
Patients with large pituitary tumors (>6.5 mm) have a high risk of anterior pituitary dysfunction and neurodegenerative CNS LCH. A retrospective study of 22 patients found that all had radiologic signs of neurodegenerative CNS LCH detected at a median time of 3 years and 4 months after LCH diagnosis and that it worsened in 19 patients. Five had neurologic dysfunction. Eighteen of 22 patients had anterior pituitary dysfunction and 20 had diabetes insipidus. Growth hormone deficiency occurred in 21 patients; luteinizing hormone/follicle-stimulating hormone deficiency occurred in ten patients; and thyroid hormone deficiency occurred in ten patients.
LCH CNS neurodegenerative syndrome
A chronic neurodegenerative syndrome that is manifested by dysarthria, ataxia, dysmetria, and sometimes behavior changes develops in 1% to 4% of LCH patients. These patients may develop severe neuropsychologic dysfunction. MRI scan 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. The radiologic findings may precede the onset of symptoms by many years or be found coincidently. A study of 83 LCH patients who had at least two MRI studies of the brain for evaluation of craniofacial lesions, diabetes insipidus, and/or other endocrine deficiencies of neuropsychological symptoms has been published. 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. Fourteen of the 47 patients had subtle deficits in short-term auditory memory.
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. Seven of these patients had diabetes insipidus and five patients had radiographic evidence of LCH CNS neurodegenerative changes. Patients with craniofacial lesions had lower performance and verbal intelligence quotient scores than those with other LCH lesions.
Histological evaluation of these neurodegenerative lesions shows a prominent T-cell infiltration, usually in the absence of the CD1a-positive dendritic cells along with microglial activation and gliosis. The neurodegenerative form of the disease has been compared to a paraneoplastic inflammatory response.
Diagnostic Evaluation of Childhood LCH
The complete evaluation of any patient, whether presenting with single-system or multisystem disease, should include the following:
- History and physical exam: A complete history and physical exam with special attention to the skin, lymph nodes, ears, oral pharynx, gingiva, tongue, teeth, bones, lungs, thyroid, liver and spleen size, bone abnormalities, growth velocity, and history of excessive thirst and urination.
- Neurologic exam.
Other tests and procedures include the following:
- Blood tests: Blood tests include complete blood count with leukocyte differential and platelet count, liver function tests (e.g., bilirubin, albumin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and prothrombin time/partial thromboplastin time in patients with hepatomegaly, jaundice, elevations of liver enzymes, or low albumin), and serum electrolytes.
- Urine tests: Urine tests include urinalysis and a water-deprivation test if diabetes insipidus is suspected.
- Bone marrow aspirate and biopsy: The bone marrow aspirate and biopsy is indicated for patients with multisystem disease who have unexplained anemia or thrombocytopenia. The biopsy should be stained with anti-CD1a and/or anti-CD207 (langerin) and anti-CD163 immunostains to facilitate the detection of Langerhans cell histiocytosis (LCH) cells.
Radiologic and imaging tests: Radiologic tests for the first level of screening include skeletal survey, skull series, bone scans, and chest x-ray. Newer diagnostic imaging modalities, such as somatostatin analogue scintigraphy or fludeoxyglucose F 18 (18F-FDG) PET scans, augment, but do not replace the standard tests.[1,2,3,4,5]
- Computed tomographic (CT) scan: CT scan of the head may be indicated if orbital, mastoid, or other maxillofacial involvement is suspected. Imaging tests may include magnetic resonance imaging (MRI) scan with gadolinium contrast of the brain for patients with diabetes insipidus or suspected brain or vertebral involvement.
CT scan of the lungs may be indicated for patients with abnormal chest x-rays or pulmonary symptoms. High-resolution CT scans may show evidence of pulmonary LCH when the chest x-ray is normal, thus in infants and toddlers with normal chest x-rays, a CT scan may be considered.
LCH causes fatty changes in the liver or hypodense areas along the portal tract, which can be identified by CT scans.
- 18F-FDG PET scan: 18F-FDG PET scan abnormalities have been reported in the brains of seven LCH patients with neurologic and radiographic signs of neurodegenerative disease. There was good correlation with MRI findings in the cerebellar white matter, but less so in the caudate nuclei and frontal cortex. It was suggested that PET scans of patients at high risk for developing neurodegenerative LCH could show abnormalities earlier than MRI.
- MRI: MRI findings of patients with diabetes insipidus include thickening and nodularity of the pituitary stalk with loss of the pituitary bright spot reflecting absence of anti-diuretic hormone. Later in the course, the stalk generally atrophies and this should not be used as evidence of response to therapy.
All patients with vertebral body involvement need careful assessment of associated soft tissue which may impinge on the spinal cord.
MRI findings of central nervous system LCH include T2 FLAIR enhancement in the pons, basal ganglia, white matter of the cerebellum, and mass lesions or meningeal enhancement. In a report of 163 patients, meningeal lesions were found in 29% and choroid plexus involvement in 6%. Paranasal sinus or mastoid lesions were found in 55% of patients versus 20% of controls, and accentuated Virchow-Robin spaces in 70% of patients versus 27% of controls.
- Computed tomographic (CT) scan: CT scan of the head may be indicated if orbital, mastoid, or other maxillofacial involvement is suspected. Imaging tests may include magnetic resonance imaging (MRI) scan with gadolinium contrast of the brain for patients with diabetes insipidus or suspected brain or vertebral involvement.
Biopsy: Lytic bone lesions, skin, and lymph nodes are the most frequent sites biopsied for diagnosis of LCH. A liver biopsy is indicated when a child with LCH presents with hypoalbuminemia not caused by gastrointestinal LCH or other etiology. These patients usually have elevated levels of bilirubin or liver enzymes. An open lung biopsy may be necessary for obtaining tissue for diagnosis of pulmonary LCH when bronchoalveolar lavage is nondiagnostic.
A pathologic diagnosis is always required except in the case of isolated vertebra plana without a soft tissue mass or isolated pituitary stalk disease when the risk outweighs the benefit of a firm diagnosis. The LCH cells are large cells with abundant pink cytoplasm on hematoxylin and eosin staining with a bean-shaped folded nucleus. LCH cells should stain with antibodies to CD1a or anti-langerin (CD207) to confirm the diagnosis of LCH. Other types of histiocytes and macrophages may stain with S-100, so this is not considered sufficient to establish the diagnosis of LCH.
Follow-up Considerations in Childhood LCH
Patients with diabetes insipidus and/or skull lesions in the orbit, mastoid, or temporal bones appear to be at higher risk for Langerhans cell histiocytosis (LCH) central nervous system (CNS) involvement and LCH CNS neurodegenerative syndrome. These patients should have magnetic resonance imaging (MRI) scans with gadolinium contrast at the time of LCH diagnosis and every 1 to 2 years thereafter for 10 years to detect evidence of CNS disease. The Histiocyte Society CNS LCH Committee does not recommend any treatment for radiologic CNS LCH of the neurodegenerative type if there is no associated clinical neurodegeneration. However, being aware of its presence is important and careful neurologic examinations and appropriate imaging with MRIs is suggested at regular intervals. Brain stem auditory evoked responses should also be done at regular intervals to define the onset of clinical CNS LCH as early as possible, as this may affect response to therapy. When clinical signs are present, intervention may be indicated.
For children with LCH in the lung, pulmonary function testing and chest computed tomography scans are sensitive methods for detecting disease progression.
Specific long-term follow-up guidelines after treatment of childhood cancer or in those who have received chemotherapy have been published by the Children's Oncology Group, and are available on the CureSearch Web site.
Treatment of Childhood LCH
Depending on the site and extent of disease, treatment of Langerhans cell histiocytosis (LCH) may include surgery, radiation therapy, or oral, topical, and intravenous medication. The recommended duration of therapy is 6 months for patients who require chemotherapy for bone, skin, or lymph node involvement. For patients with liver, spleen, bone marrow, or lung involvement, treatment is based upon data from the German-Austrian-Dutch (Deutsche Arbeits-gemeinschaft für Leukaemieforschung und-therapie im Kindesalter [DAL]) Group trials, which treated patients for 1 year and had fewer relapses (29%) than the LCH-I and LCH-II trials, in which patients received 6 months of treatment and had a 50% chance of relapse. Future trials will assess whether even longer duration of therapy will reduce the incidence of reactivations and late effects.
It is preferable that LCH patients be enrolled in a clinical trial whenever possible so that advances in therapy can be achieved more quickly, utilizing evidence-based recommendations and to ensure optimal care. Information about clinical trials for LCH in children is available from the Histiocyte Society Web site.
Standard Treatment Options by Organ, Site or System Involvement
The standard treatment of LCH is best chosen based on data from international trials with large numbers of patients. However, some patients may have LCH involving only the skin, mouth, pituitary gland, or other sites not studied in these international trials. In such cases therapy recommendations are based upon case series which lack the evidence-based strength of the trials.
Treatment of low-risk disease (single-system or multisystem)
Isolated skin involvement
- Topical steroids, although topical steroid creams are rarely effective.
- Oral methotrexate (20 mg/m2) weekly for 6 months.
- Oral thalidomide 50 mg to 200 mg nightly.
- Topical application of nitrogen mustard is effective for cutaneous LCH that is resistant to oral therapies, but not for disease involving large areas of skin.[5,6]
- Psoralen and long-wave ultraviolet radiation (PUVA).
Single skull lesions of the frontal, parietal, or occipital regions, or single lesions of any other bone
- Curettage only, curettage plus injection of methylprednisolone, or radiation therapy may be used.[8,9]; [Level of evidence: 3iiiA] LCH bone lesions may not need complete excision, as this only increases healing time and the risk of long-term complications.
Skull lesions in the mastoid, temporal, or orbital bones
The purpose of treating patients with skull lesions in the mastoid, temporal, or orbital bones is to decrease the chance of developing diabetes insipidus and other long-term problems, although the efficacy of this, and the optimal length of therapy, have yet to be proven in a prospective trial.
- Twelve months of vinblastine and prednisone (based upon comparative results noted above regarding DAL-HX trials versus the LCH-I and LCH-II studies): Weekly vinblastine (6 mg/m2) for 7 weeks then every 3 weeks for good response. Daily prednisone (40 mg/m2) for 4 weeks then tapered over 2 weeks. Afterward prednisone is given for 5 days at 40 mg/m2 every 3 weeks with the vinblastine injections.
- There is some controversy about whether systemic therapy is required for the first presentation with unifocal bone even in the central nervous system (CNS) risk bones. Ear, nose, and throat surgeons have reported a series of patients with orbital or mastoid lesions who received only surgical curettage. None of these patients developed diabetes insipidus. However, when comparing the incidence rates of diabetes insipidus in patients who received little or no chemotherapy (20%–50% incidence of diabetes insipidus) versus diabetes insipidus incidence rates reported by the German-Austrian-Dutch (Deutsche Arbeits-gemeinschaft für Leukaemieforschung und-therapie im Kindesalter [DAL]) Group HX-83 trial (10% incidence of diabetes insipidus in patients treated for LCH), it appears that the weight of evidence from the DAL HX-83 trial supports treatment to prevent diabetes insipidus in patients with LCH of the mastoid, temporal, or orbital bones.[13,14] It should be noted, however, that the DAL HX studies used more drugs and treated for a duration of 12 months. Nonetheless, the CNS study group of the Histiocyte Society believes prevention of the potentially devastating consequences of CNS and endocrine disease with relatively low-toxicity chemotherapy is worthwhile; acknowledging that the overall level of evidence is low (Level of evidence: 3iii) and that prospective trials are needed.
Vertebral or femoral bone lesions at risk for collapse
- Radiation therapy is indicated for patients with bone lesions of the vertebrae or femoral neck, which are at risk of collapse or fracture.[15,16] Low-dose radiation therapy may be used to try to promote resolution in an isolated vertebral or femoral neck lesion at risk for fracture, where chemotherapy is not usually indicated (single bone lesion). Despite the low dose required (700–1,000 cGy), radiation therapy should be used with caution in the area of the thyroid gland, brain, or any growth plates.
- When instability of the cervical vertebrae and neurologic symptoms are present, bracing or spinal fusion may be needed. Patients with soft tissue extension from the vertebral lesions are often treated successfully with chemotherapy.[Level of evidence: 3iiDiii]
Multiple bone lesions; or combinations of skin, lymph node, or pituitary gland with or without bone lesions
- Vinblastine and prednisone: Six months of treatment with weekly vinblastine (6 mg/m2) for 7 weeks then every 3 weeks for good response. Prednisone (40 mg/m2) is given daily for 4 weeks then tapered over 2 weeks. Afterwards prednisone is given for 5 days at 40 mg/m2 every 3 weeks with the vinblastine injections. A short (<6 months) treatment course with only a single agent (e.g., prednisone) is not sufficient, and the number of relapses is higher. An 18% reactivation rate with a multidrug regimen for 6 months versus a historical reactivation rate of 50% to 80% with surgery alone, or with a single-drug treatment regimen has been reported. A comprehensive review of the DAL and Histiocyte Society clinical trials revealed a reactivation rate of 46% at 5 years.[Level of evidence: 3iii]. Most disease reactivations were in bone, skin, or other nonrisk locations.
- Pamidronate is also effective for treating LCH bone lesions. A nationwide survey from Japan described 16 children treated with bisphosphonates for bone LCH. All had bone disease; none had risk-organ disease. The majority received six courses of pamidronate at 1 mg/kg/course given at 4-week intervals. In 12 of 16 patients, all active lesions including skin (n = 3) and soft tissues (n = 3) resolved. Eight remained disease free at a median of 3.3 years.
Treatment of high-risk multisystem disease
Spleen, liver, and bone marrow (may or may not include skin, bone, lymph node, lung, or pituitary gland)
- The standard therapy length recommended for LCH involving the spleen, liver, or bone marrow (high-risk organs) is based upon LCH-I, LCH-II, and the DAL-HX-83 studies and varies from 6 months (LCH-I and LCH-II) to 1 year (DAL-HX-83).[11,14] In the LCH-II and HISTSOC-LCH-III studies, the standard arm consisted of vinblastine and prednisone as described above under multifocal bone, but 6-mercaptopurine was added to the continuation phase of the protocol. The LCH-II study was a randomized trial to compare treatment of patients with vinblastine, prednisone, and mercaptopurine or vinblastine, prednisone, mercaptopurine, and etoposide.[Level of evidence: 1iiA]
There was no statistical significance in outcomes (response at 6 weeks, 5-year probability of survival, relapses, and permanent consequences) between the two treatment groups. Hence, etoposide has not been used in subsequent Histiocyte Society trials. Late review of the results, however, has shown reduced mortality of patients with risk-organ involvement in the etoposide arm. Although controversial, a comparison of patients in the LCH-I trial with patients in the LCH-II trial suggested that increased treatment intensity promoted additional early responses and reduced mortality.
It is important to note that those studies included lungs as risk organs. However, subsequent analyses have shown that lung involvement lacks prognostic significance.
- The Japan LCH Study Group (JLSG) reported 5-year response and overall survival rates of 78% and 95%, respectively, for patients with multisystem disease treated on the JLSG-96 trial (6-week induction regimen of cytosine arabinoside, vincristine, and prednisolone followed by 6 months of maintenance therapy with cytarabine, vincristine, prednisolone, and low-dose intravenous methotrexate). If patients had a poor response to the initial regimen, they were switched to a salvage regimen of intensive combination doxorubicin, cyclophosphamide, methotrexate, vincristine, and prednisolone.
The important finding of this study was the decreased mortality compared with previous JLSG studies and to the LCH-II study, and was attributed to the early move to salvage therapy for patients with nonresponsive disease, improved salvage therapy, and better supportive care.
Treatment of CNS disease
Although CNS LCH arises initially at areas where the blood brain barrier is deficient, drugs that cross the blood-brain barrier, such as cladribine (2-CdA), or other nucleoside analogs, such as cytarabine, seem to be the best option for active CNS LCH lesions.
- Treatment of mass lesions with cladribine (2-CdA) has been effective in 13 reported cases.[26,27]; [Level of evidence: 3iiiDiii] Mass lesions included enlargement of the hypothalamic-pituitary axis, parenchymal mass lesions, and leptomeningeal involvement. Doses of 2-CdA ranged from 5 mg/m2 to 13 mg/m2 given at varying frequencies.[Level of evidence: 3iiiDiii]
- LCH patients with mass lesions in the hypothalamic-pituitary region, the choroid plexus, the grey matter, or the white matter may respond to chemotherapy.[29,30] Treatment with vinblastine with or without corticosteroids for patients with CNS mass lesions (20 patients; mainly pituitary) demonstrated an objective response in 15 patients, with 5 of 20 patients demonstrating a complete response and 10 of 20 patients demonstrating a partial response.
- For treatment of symptoms of LCH CNS neurodegenerative syndrome, dexamethasone, 2-CdA, retinoic acid, intravenous immunoglobulin (IVIg), infliximab, and cytarabine with or without vincristine have been used.[Level of evidence: 3iiiDiii]; [28,31,32,33,34,35] Retinoic acid was given at a dose of 45 mg/m2 daily for 6 weeks, then 2 weeks per month for 1 year. IVIg (400 mg/m2) was given monthly and chemotherapy consisting of oral prednisolone with or without oral or intravenous methotrexate and oral 6-mercaptopurine were given for at least 1 year. Magnetic resonance imaging (MRI) findings were stable but clinical efficacy was difficult to judge as patients were reported to have no progression in their neurologic symptoms. A study using cytarabine with or without vincristine reported improvement in the clinical and MRI findings.[Level of evidence: 3iiiC] Seven of eight patients have been followed for more than 2 years after stopping therapy and have had stable neurologic and radiographic findings.
In the Japan LCH Study Group-96 Protocol study patients received cytarabine 100 mg/m2 daily on days 1 to 5 during induction and 150 mg/m2 on day 1 of each maintenance cycle (every 2 weeks for 6 months). Three of 91 patients developed neurodegenerative disease, which is similar to the experience on Histiocyte Society studies.
Reactivation of single-system and multisystem LCH
Reactivation of LCH after complete response has been reported; usually occurring within the first 9 to 12 months after stopping treatment. The percentage of patients with reactivations was 17.4% for single-site disease; 37% for single-system, multifocal disease; 46% for multisystem (nonrisk organ) disease; and 54% for patients with risk-organ involvement. Forty-three percent of reactivations were in bone, 11% in ears, 9% in skin, and 7% develop diabetes insipidus; a lower percentage of patients had lymph node, bone marrow, or risk-organ relapses. The median time to reactivation was 12 to 15 months in nonrisk patients and 9 months in risk patients. One-third of patients had more than one reactivation varying from 9 to 14 months after the initial reactivation. Patients with reactivations were more likely to have long-term sequelae in the bones, diabetes insipidus, or other endocrine, ear, or lung problems.
A comprehensive review of the DAL and Histiocyte Society clinical trials revealed a reactivation rate of 46% at 5 years for patients with multisystem LCH, with most reactivations occurring within 2 years of first remission. A second reactivation occurred in 44%, again within 2 years of the second remission. Involvement of the risk organs in these reactivations only occurred in those who were initially in the high-risk group (meaning they had liver, spleen, or bone marrow involvement at the time of original diagnosis).[Level of evidence: 3iiiDiii] Most reactivations, even in patients with high-risk disease who initially responded to therapy, were in bone, skin, or other nonrisk locations.
The percentage of reactivations in multisystem disease was identical in the Japanese trial, [Level of evidence: 1iiA] and the LCH-II trial  (45% and 46%, respectively). There was not a statistically significant difference in reactivations between the high-risk and low-risk groups. Both the DAL-HX and Japanese studies concluded that intensified treatment increased rapid response, particularly in young children and infants younger than 2 years, and together with rapid switch to salvage therapy for nonresponders, reduced mortality for patients with high-risk multisystem LCH.
Treatment Options for Childhood LCH No Longer Considered Effective
Treatments for LCH in any location which have been used in the past but are no longer recommended include cyclosporine  and interferon-alpha. Extensive surgery is also not indicated. Curettage of a circumscribed skull lesion may be sufficient if the lesion in not in the temporal, mastoid, or orbital areas (CNS-risk). Patients with disease in these particular sites are recommended to receive 6 months of systemic therapy with vinblastine and prednisone. For lesions of the mandible, extensive surgery may destroy any possibility of secondary tooth development. Surgical resection of groin or genital lesions is contraindicated as these lesions can be healed by chemotherapy.
Radiation therapy use in LCH has been significantly reduced in pediatric patients, and even low-dose radiation therapy should be limited to single-bone vertebral body lesions or other single-bone lesions compressing the spinal cord or optic nerve that do not respond to chemotherapy.
Assessment of Response to Treatment
Response assessment remains one of the most difficult areas in LCH therapy unless there is a specific area that can be followed clinically or with sonography, CT, or MRI scans of areas such as the skin, hepato/splenomegaly, and other mass lesions. Clinical judgment including evaluation of pain and other symptoms remains important.
Bone lesions may take many months to heal and are difficult to evaluate on plain radiographs, although sclerosis around the periphery of a bone lesion suggests healing. CT or MRI scans are useful in assessing response of a soft tissue mass associated with a bone lesion, but is not particularly helpful in an isolated lytic bone lesion. Technetium bone scans remain positive in healing bone. PET scans may be helpful in following the response to therapy since intensity of the PET image diminishes with healing of a bone or other lesion.
For children or adults with lung LCH, pulmonary function testing and high resolution CT scans are sensitive methods for detecting disease progression. Residual interstitial changes reflecting residual fibrosis or residual inactive cysts must be distinguished from active disease and somatostatin analogue scintigraphy may be useful in this regard.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood Langerhans cell histiocytosis. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Treatment of Recurrent, Refractory, or Progressive Childhood LCH
Recurrent Low-Risk Organ Involvement
The optimal therapy for patients with relapsed or recurrent Langerhans cell histiocytosis (LCH) has not been determined. Several regimens exist. Patients with recurrent bone disease who reoccur months after stopping vinblastine and prednisone can benefit from treatment with a reinduction of vinblastine weekly and daily prednisone for 6 weeks. If there is no active disease or very little evidence of active disease, treatment can be changed to every 3 weeks with the addition of oral mercaptopurine nightly. An alternative treatment regimen employs vincristine, prednisone, and cytosine arabinoside. Cladribine (2-CdA) at 5 mg/m2 /day for 5 days per course has also been shown to be effective therapy for recurrent low-risk LCH (multifocal bone and low-risk multisystem LCH) with very little toxicity as long as the therapy was limited to a maximum of six courses.
A phase II trial of thalidomide for LCH patients (ten low-risk patients; six high-risk patients) who failed primary and at least one secondary regimen demonstrated complete (four out of ten) and partial (three out of ten) responses for the low-risk patients. Complete remission was defined as healing of bone lesions on plain radiographs (n = 3) or complete resolution of skin rash (n = 4, including 3 with bone lesions that had complete resolution). Partial response was defined as healing of bone lesion, but then worsening of a skin rash that was partially resolved. However, dose-limiting toxicities, such as neuropathy and neutropenia, may limit the overall usefulness of thalidomide.
Refractory High-Risk Organ Involvement
A new treatment plan is indicated when a patient with multisystem involvement shows progressive disease after 6 weeks of standard treatment, or has not had a partial response by 12 weeks. Data from the German-Austrian-Dutch Group studies have shown that these children have only a 10% chance of surviving. Results of the LCH-II trial revealed that patients treated with vinblastine/prednisone who did not respond well by 6 weeks had a 27% chance of survival.[Level of evidence: 1iiA] Those treated with vinblastine/prednisone/etoposide with a good response at 6 weeks had a 52% chance of survival. Reports about the use of 2-CdA and 2'-deoxycoformycin as salvage therapies for LCH have been published.[3,11] In this trial, these drugs were more often effective for patients with bone, skin, or lymph node involvement. Only one-third of patients with LCH of the liver, bone marrow, spleen, or lung responded. Another study demonstrated that patients with multiple reactivations or high-risk disease could be effectively treated with continuous infusion 2-CdA for 3 days. Seven of ten patients on this trial required no more therapy. Two patients with multiorgan LCH that was resistant to other agents, including 2-CdA, responded to treatment with clofarabine.[Level of evidence: 3iiiDii]
Patients with refractory high-risk organ (liver, spleen, or bone marrow) involvement and resistant multisystem low-risk organ involvement have been treated with an intensive acute myeloid leukemia–like protocol. Prompt change of therapy to cladribine (2-CdA) and/or cytosine arabinoside may provide an improvement in overall survival (OS).; [Level of evidence: 3iiiDii]; [Level of evidence: 3iiiDiv] This is a very intense regimen and requires that physicians are able to treat infectious and metabolic complications. Responses may be delayed.
Hematopoietic stem cell transplantation (HSCT) has been used in patients with multisystem high-risk organ involvement that is refractory to chemotherapy.[17,18,19,20] The use of reduced-intensity conditioning, especially for patients that have received intensive chemotherapy just prior to HSCT, may reduce toxic deaths and improve outcome.
Late Disease and Treatment Effects of Childhood LCH
The reported overall incidence of long-term consequences of Langerhans cell histiocytosis (LCH) has ranged from 20% to 70%. The reason for this wide variation is due to case definition, sample size, therapy used, method of data collection, and follow-up duration. Of note, in one study of the quality of life of long-term survivors of skeletal LCH, the quality of life scores were not significantly different from healthy control children and adults. In addition, the quality of life scores were very similar between those with and without permanent sequelae.
Children with low-risk organ involvement (skin, bones, lymph nodes, or pituitary gland) have an approximately 20% chance of developing long-term sequelae. Those with diabetes insipidus are at risk for panhypopituitarism and should be monitored carefully for adequacy of growth and development. In a retrospective review of 141 patients with LCH and diabetes insipidus, 43% developed growth hormone (GH) deficiency. [3,4,5] The 5-year and 10-year risks of GH deficiency among children with LCH and diabetes insipidus were 35% and 54%, respectively. There was no increased reactivation of LCH in patients who received GH compared with those who did not.
Growth and development problems are more frequent because of the young age at presentation, and the more toxic effects of long-term prednisone therapy in the very young child. Patients with multisystem involvement have a 71% incidence of long-term problems.[2,3,4,5]
Hearing loss has been found in 38% of children treated for LCH. Seventy percent of LCH patients in this study had ear involvement which included aural discharge, mastoid swelling, and hearing loss. Of those with computed tomography or magnetic resonance imaging (MRI) abnormalities in the mastoid, 59% had hearing loss.[Level of evidence: 3iiiC]
Neurologic symptoms secondary to vertebral compression of cervical lesions have been reported in 3 out of 26 LCH patients with spinal lesions. Central nervous system (CNS) LCH occurs most often in children with LCH of the pituitary or CNS-risk skull bones (mastoid, orbit, or temporal bone). Significant cognitive defects and MRI abnormalities may develop in some long-term survivors with CNS-risk skull lesions. Some patients have markedly abnormal cerebellar function and behavior abnormalities, while others have subtle deficits in short-term memory and brain stem-evoked potentials.
Orthopedic problems from lesions of the spine, femur, tibia, or humerus may be seen in 20% of patients. These problems include vertebral collapse or instability of the spine that may lead to scoliosis, and facial or limb asymmetry.
Diffuse pulmonary disease may result in poor lung function with higher risk for infections and decreased exercise tolerance. These patients should be followed with pulmonary function testing, including the diffusing capacity of carbon monoxide and ratio of residual volume to total lung capacity.
Liver disease may lead to sclerosing cholangitis, which rarely responds to any treatment other than liver transplantation.
Dental problems characterized by loss of teeth have been significant for some patients, usually related to overly aggressive dental surgery.
Bone marrow failure secondary to LCH or from therapy is rare and is associated with a higher risk of malignancy. Patients with LCH have a higher-than-normal risk of developing secondary cancers.[12,13] Leukemia (usually acute myeloid) occurs after treatment, as does lymphoblastic lymphoma. Concurrent LCH/malignancy has been reported in a few patients, and some patients have had their malignancy first, followed by development of LCH. Three patients with T-cell acute lymphoblastic leukemia (T-ALL) and aggressive LCH, for which the two disorders had shared markers of clonality, have been reported.[14,15] One study reported two cases in which clonality with the same T-cell receptor gamma genotype was found. The authors of this study emphasized the plasticity of lymphocytes developing into Langerhans cells. In the second study, one patient with LCH after T-ALL who had the same T-cell receptor gene rearrangements and activating mutations of the NOTCH1 gene was described.
An association between solid tumors and LCH has also been reported. Solid tumors associated with LCH include retinoblastoma, brain tumors, hepatocellular carcinoma, and Ewing sarcoma.
The natural history of disease in adult Langerhans cell histiocytosis (LCH), with the exception of pulmonary LCH, is unknown. It is unclear whether there are significant differences from childhood LCH, although it appears that multisystem-risk LCH is less aggressive than childhood high-risk disease. The risk of reactivations is unknown.
It is estimated that one to two adult cases of LCH occur per million population. The true incidence of this disease is impossible to know because large published studies usually are from referral centers and the disorder often is under-diagnosed. A survey from Germany reported that 66% of the LCH patients were women with an average age of 43.5 years for all patients.
Presentation of adult LCH by organ, site, or system
Adult LCH patients may have symptoms and signs for many months before a definitive diagnosis and treatment. LCH in adults is often similar to that in children, and appears to involve the same organs, although the proportions may be different. There is a predominance of lung disease in adults, usually occurring as single-system disease and closely associated with smoking and with some unique biologic characteristics. An ongoing German registry with 121 registrants showed that 62% had single-organ involvement and 38% had multisystem involvement, while 34% of the total had lung involvement. The median age at diagnosis was 44 years ± 12.8 years. The most common organ involved was lung followed by bone and skin. All organ systems found in childhood LCH were seen, including endocrine and central nervous system, liver, spleen, bone marrow, and gastrointestinal tract. The major difference is the much higher incidence of isolated pulmonary LCH in adults, particularly in young adults who smoke. Other differences appear to be the more frequent involvement of genital and oral mucosa. There may possibly be a difference in the distribution of bone lesions, but both groups suffer reactivations of bone lesions and progression to diabetes insipidus, although the exact incidence is unknown in adults..
Presenting symptoms from published studies are (in order of decreasing frequency) dyspnea or tachypnea, polydipsia and polyuria, bone pain, lymphadenopathy, weight loss, fever, gingival hypertrophy, ataxia, and memory problems. Among the signs of LCH are skin rash, scalp nodules, soft tissue swelling near bone lesions, lymphadenopathy, gingival hypertrophy, and hepatosplenomegaly. Patients who present with isolated diabetes insipidus should be carefully observed for onset of other symptoms or signs characteristic of LCH. At least 80% of patients with diabetes insipidus had involvement of other organ systems including: bone (68%), skin (57%), lung (39%), and lymph nodes (18%).
Skin and oral mucosa
Thirty-seven percent of adults with LCH have skin involvement which usually occurs as part of multisystem disease. Skin-only LCH occurs but it is less common in adults than in children. The prognosis in adult skin-only LCH is excellent with 100% probability of 5-year survival. The cutaneous involvement is clinically similar to that seen in children and may take many forms.
Many patients have a papular rash with brown, red, or crusted areas ranging from the size of a pinhead to a dime. In the scalp, the rash is similar to that of seborrhea. Skin in the inguinal region, genitalia, or around the anus may have open ulcers that do not heal after antibacterial or antifungal therapy. The lesions are usually asymptomatic but may be pruritic. In the mouth, swollen gums or ulcers along the cheeks, roof of the mouth, or tongue may be signs of LCH.
Diagnosis of LCH is usually made by skin biopsy performed for persistent skin lesions.
The relative frequency of bone involvement in adults differs from that in children: mandible (30% vs. 7%) and skull (21% vs. 40%).[1,2,3,4] The frequency in adults of vertebrae (13%), pelvis (13%), extremities (17%), and rib (6%) lesions are similar to those found in children.
Pulmonary LCH in adults is usually single-system disease, but in a minority of patients other organs may be involved, including bone (18%), skin (13%), and diabetes insipidus (5%).
Pulmonary LCH is more prevalent in smokers than in nonsmokers and the male/female ratio may be near unity depending on the incidence of smoking in the population studied.[6,7] Patients with pulmonary LCH usually present with a dry cough, dyspnea, or chest pain, although nearly 20% of adults with lung involvement have no symptoms.[8,9] Chest pain may indicate a spontaneous pneumothorax (10%–20% of adult pulmonary LCH cases). The LCH cells in adult lung lesions were shown to be mature dendritic cells expressing high levels of the accessory molecules CD80 and CD86, unlike LCs found in other lung disorders. In addition, pulmonary LCH in adults appears to be primarily a reactive process, rather than a clonal proliferation as seen in childhood LCH.
The course of pulmonary LCH in adults is variable and unpredictable. Fifty-nine percent of patients do well with either spontaneous remission with cessation of smoking, or with some form of therapy. Adults with pulmonary LCH who have minimal symptoms have a good prognosis, although some have steady deterioration over many years. Age older than 26 years and lower FEV1/FVC ratio and higher RV/TLC ratio are adverse prognostic variables. About 10% to 20% have early severe progression to respiratory failure, severe pulmonary hypertension, and cor pulmonale. Adults who have progression with diffuse bullae formation, multiple pneumothoraces, and fibrosis have a poor prognosis.[13,14] The remainder have a variable course with stable disease in some patients and relapses and progression of respiratory dysfunction in others, some after many years. One study reported that smoking cessation did not increase the longevity of pulmonary LCH patients, apparently because the tempo of disease is so variable. Patients receiving lung transplantation for treatment of pulmonary LCH have a 77% survival rate at 1 year and 54% survival rate at 10 years, with a 20% chance of LCH recurrence.
The most frequent pulmonary function abnormality finding in patients with pulmonary LCH is a reduced carbon monoxide diffusing capacity in 70% to 90% of cases.[12,17] A high-resolution computed tomography (CT) scan, which reveals a reticulonodular pattern classically with cysts and nodules, usually in the upper lobes and sparing the costophrenic angle, is characteristic of LCH. Despite the typical CT findings, most pulmonologists agree that a lung biopsy is needed to confirm the diagnosis. The presence of cystic abnormalities on high-resolution CT scans appears to be a poor predictor of which patients will have progressive disease. A study correlating lung CT findings and lung biopsy results in 27 pulmonary LCH patients has shed some light on pulmonary LCH. Thin-walled and bizarre cysts had active LCs and eosinophils. Fifty-two percent of patients improved, most with smoking cessation, and some with steroid treatment within 14 months of diagnosis. Four patients (15%) were stable, and nine (33%) progressed over 22 months.
Liver involvement in adults has been reported in 27% of a series of adult LCH patients with multiorgan disease. Hepatomegaly (48%) and liver enzyme abnormalities (61%) were present. CT and ultrasound imaging abnormalities are often found. The early histopathologic stage of liver LCH includes infiltration of CD1a+ cells and periductal fibrosis with inflammatory infiltrates with or without steatosis. The late stage is biliary tree sclerosis and treatment with ursodeoxycholic acid is suggested.
In a large series of patients from the Mayo Clinic, 31% had multisystem LCH compared with 69% registered on the Histiocyte Society adult registry; this likely reflects referral bias.[5,22] In the adult multisystem patients, the organs involved include the following:
- Skin (50%).
- Mucocutaneous (40%).
- Diabetes insipidus (29.6%).
- Hepatosplenomegaly (16%).
- Hypothyroidism (6.6%).
- Lymphadenopathy (6%).
Treatment of Adult LCH
Standard Treatment Options
The lack of clinical trials limits the ability to make evidence-based recommendations for adult patients with Langerhans cell histiocytosis (LCH).
Most investigators have previously recommended treatment according to the guidelines given above for standard treatment of children with Langerhans cell histiocytosis. It is unclear, however, whether adult LCH responds as well as the childhood form of the disease. In addition, the drugs used in the treatment of children appear to be less well-tolerated in adults. Excessive neurologic toxicity from vinblastine, for example, prompted closure of the LCH-A1 trial.
Treatment of pulmonary LCH
It is difficult to judge the effectiveness of various treatments for pulmonary LCH as patients can recover spontaneously or have stable disease without treatment. Smoking cessation is mandatory in view of the apparent causal effect of smoking in pulmonary LCH. It is not known if steroid therapy is efficacious in the treatment of adult pulmonary LCH because reported case series did not control for smoking cessation. Most adult patients with LCH have gradual disease progression with continued smoking. The disease may regress or progress with the cessation of smoking.
Lung transplant may be necessary for adults with extensive pulmonary destruction from LCH. This multicenter study reported 54% survival at 10 years posttransplant with 20% of patients having recurrent LCH that did not impact survival; longer follow-up of these patients is needed. The best strategy for follow-up of pulmonary LCH includes physical examination, chest radiographs, lung function tests, and high-resolution computed tomography (CT) scans.
Treatment of bone LCH
Similar to children, adults with single-bone lesions should undergo curettage of the lesion followed by observation, with or without intralesional corticosteroids. Extensive or mutilating surgery is contraindicated at any site, including the teeth or jaw bones. Systemic chemotherapy will cause bone lesions to regress and the involved teeth and jaw bones cannot reform. For those failing chemotherapy, low-dose radiation therapy may be indicated and should be tried prior to any mutilating surgery. Radiation therapy is also indicated for impending neurological deficits from vertebral body lesions or visual problems from orbital lesions.
A variety of chemotherapy regimens, including 2-CdA have been published in a relatively limited number of patients. (Refer to the Chemotherapy section of this summary for more information.)
Anecdotal reports have described the successful use of the bisphosphonate pamidronate in controlling severe bone pain in patients with multiple osteolytic lesions.[4,5,6] Successful use of oral bisphosphonates have also been described and may be a useful and relatively low-toxic way of treating adult bone LCH. In view of the increased toxicity of chemotherapy in adults, bisphosphonate therapy could be used prior to chemotherapy in multifocal bone disease. Response of other organs, such as skin and soft tissue, to bisphosphonate therapy has been reported.
Another approach using anti-inflammatory agents (pioglitazone and rofecoxib) coupled with trofosfamide in a specific timed sequence was successful in two patients with disease resistant to standard chemotherapy treatment.
Treatment of single-system skin disease
- Localized lesions can be treated by surgical excision, but as with bone, mutilating surgery, including hemivulvectomy, should be avoided unless the disease is refractory to available therapy.
- Topical therapies are described in greater detail in the childhood isolated skin involvement section of this summary and include topical or intralesional corticosteroid, topical tacrolimus, imiquimod, and psoralen and long-wave ultraviolet radiation (PUVA). Therapies such as PUVA may be more useful in adults where long-term toxicity may be less of a consideration.[10,11,12]
- Systemic therapy for severe skin LCH includes oral methotrexate, oral thalidomide, oral interferon-alpha, or combinations of interferon and thalidomide.[13,14] Recurrences after stopping treatment may occur but may respond to retreatment.
- Oral isotretinoin has achieved remission in some refractory cases of skin LCH in adults.
Chemotherapy for the treatment of single-system and multisystem disease
Chemotherapy is generally used for skin LCH associated with multisystem disease in adults.
- A single-center, retrospective review of 58 adult LCH patients reported on the efficacy and toxicities of treatment with vinblastine/prednisone, cladribine, and cytarabine. Patients treated with vinblastine/prednisone had the worst outcome, with 84% not responding within 6 weeks or relapsing within a year. The no-response/relapse rate was 59% for cladribine and 21% for cytarabine. Grade 3 or 4 neurotoxicity occurred in 75% of patients treated with vinblastine. Grade 3 or 4 neutropenia occurred in 37% of patients treated with cladribine and in 20% of patients receiving cytarabine.
- Etoposide has been used with some success in single-system and multisystem LCH. Use of prolonged oral etoposide in adults with skin LCH has been reported with minimal toxicity, while 3-day courses of intravenous etoposide 100 mg/m2 /day achieved complete remission in a small number of patients with resistant single-system and multisystem disease. Another study at the same center found that azathioprine was the most successful drug for localized disease in adults with the addition of etoposide for refractory and multisystem disease.
- For patients who do not respond to front-line therapy with etoposide, 2-CdA is effective for adults with skin, bone, lymph node, and probably pulmonary and central nervous system (CNS) disease.[19,20] The first study that used 2-CdA to treat refractory and recurrent skin LCH disease reported on three patients (ages 33, 51, and 57 years) who received two to four courses of 2-CdA at 0.7 mg/kg intravenously over 2 hours/day for 5 days. In a series of five adults (one untreated and four with refractory LCH treated with 2-CdA at the same dose noted above), three patients achieved a complete remission and two patients achieved a partial remission.
- An adult lymphoma treatment regimen, MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone and bleomycin), was used in three patients with multisystem LCH and four with single-system multifocal bone LCH from 1995 to 2007. Total duration of therapy was 12 weeks, response was seen in all patients, two with partial response and five with complete response. Three recurrences were seen after stopping therapy. Despite the small number of patients and the retrospective nature of the study, MACOP-B may be useful as salvage therapy in adult patients with LCH and deserves further study.
- Anecdotal reports have described the successful use of the bisphosphonate pamidronate in controlling severe bone pain in patients with multiple osteolytic lesions.[4,5,6]
- Imatinib mesylate has been effective in the treatment of four adult LCH patients who had skin, lung, bone, and/or CNS involvement.[23,24] Another adult LCH patient did not respond to imatinib mesylate.
- A case report suggests some benefit to treating neurodegenerative CNS LCH disease with infliximab, a tumor necrosis factor-alpha inhibitor.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with adult Langerhans cell histiocytosis. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Changes to the Summary (01 / 30 / 2013)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Presentation of Langerhans Cell Histiocytosis (LCH) in Children
Added text about how pulmonary involvement is present in approximately 25% of children with multisystem low-risk and high-risk LCH; however, a multivariate analysis of pulmonary disease in multisystem LCH did not show pulmonary disease to be an independent prognostic factor (cited Ronceray et al. as reference 22).
Revised text to state that the incidence of diabetes insipidus was lower in patients treated with more intensive chemotherapy regimens on the JLSG-96 and JLSG-02 studies in Japan (8.9% for multisystem patients) than on the LCH-I and LCH-II studies (14.2%) (cited 2001 Gadner et al. and 2008 Gadner et al. as references 32 and 33, respectively).
Treatment of Childhood LCH
Revised text to state that curettage only, curettage plus injection of methylprednisolone, or radiation therapy may be used to treat single skull lesions of the frontal, parietal, or occipital regions, or single lesions of any other bone (cited Gramatovici et al. as reference 9).
Added text to state that it is important to note that the cited studies included lungs as risk organs. However, subsequent analyses have shown that lung involvement lacks prognostic significance (cited Ronceray et al. as reference 24).
Revised text to state that treatment with vinblastine with or without corticosteroids for patients with central nervous system (CNS) mass lesions (20 patients; mainly pituitary) demonstrated an objective response in 15 patients, with 5 of 20 patients demonstrating a complete response and 10 of 20 patients demonstrating a partial response.
Treatment of Adult LCH
Added text about a retrospective review of 58 adult LCH patients that reported on the efficacy and toxicities of treatment with vinblastine/prednisone, cladribine, and cytarabine (cited Cantu et al. as reference 16).
Added text to state that a case report suggests some benefit to treating neurodegenerative CNS LCH disease with infliximab, a tumor necrosis factor-alpha inhibitor (cited Chohan et al. as reference 26).
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood and adult Langerhans cell histiocytosis. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
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The lead reviewers for Langerhans Cell Histiocytosis Treatment are:
- Robert J. Arceci, MD, PhD (Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital)
- Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
- Thomas G. Gross, MD, PhD (Nationwide Children's Hospital)
- Kenneth L. McClain, MD, PhD (Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital)
- Carlos Rodriguez-Galindo, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
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Last Revised: 2013-01-30
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