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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.
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.[1] 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.[6]
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.[5] 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.[6] 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).[7] Identical twins with LCH, and non-twin siblings or multiple cases in one family, have been reported.[8] A survey of LCH in northwest England (Manchester) revealed an overall incidence of 2.6 cases per million child years.[9]
Over 90% of adult pulmonary LCH occurs in young adults who smoke, often more than 20 cigarettes per day.[10,11]
Risk Factors
Solvent exposure in parents and perinatal infections have a weak association with LCH, but there is no increase in cases after viral epidemics.[12] An increased frequency of family members with thyroid disease has been reported.[13]
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.[14]
Prognostic factors in LCH have been identified and can be categorized as follows:
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.[3] 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.[4] 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:
Immunologic Abnormalities
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.[6] 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.[3] The expansion of regulatory T cells in LCH patients has been reported.[7] 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.[7]
The etiology of LCH is unknown. Efforts to define a viral cause have not been successful.[8,9] One study has shown that 1% of patients have a positive family history for LCH.[10]
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.[13] 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.[14] 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.[18] 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.[19] 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.[20]
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%).[21] Activating BRAF mutations are also found in selected nonmalignant conditions (e.g., benign nevi) [22] 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.[7] 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.[28] 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.[4]
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.[4] 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.[29]
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.[30] 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.[31]
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.
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.
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.[5]
Oral mucosa
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:
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.
Pituitary gland
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.[10]
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).[11] 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.
Abdominal/gastrointestinal system
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.[12]
Liver (sclerosing cholangitis)
One of the most serious complications of hepatic LCH is cholestasis and sclerosing cholangitis.[13] 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.[14]
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.[15] The patients who undergo liver transplant for LCH may have a higher incidence of posttransplant lymphoproliferative disease.[16]
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.[17] 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.[20] 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.[21] 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.[22]
Bone marrow
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.[23] 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.[24] 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).[25] Patients with LCH who are considered at very high risk sometimes present with hemophagocytosis involving the bone marrow.[26] The cytokine milieu driving LCH is probably responsible for the epiphenomenon of macrophage activation.
Endocrine system
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.[27] 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.[28] 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.[27] A study of 589 patients with LCH revealed the 10-year risk of pituitary involvement was 24%.[29] 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.[30] 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.[36] These lesions contain CD1a-positive LCH cells and CD8-positive lymphocytes, and are, therefore, active LCH lesions.[37]
Patients with large pituitary tumors (>6.5 mm) have a high risk of anterior pituitary dysfunction and neurodegenerative CNS LCH.[38] 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.[39] 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.[40] 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.[41] Seven of these patients had diabetes insipidus and five patients had radiographic evidence of LCH CNS neurodegenerative changes.[41] 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.[37]
The complete evaluation of any patient, whether presenting with single-system or multisystem disease, should include the following:
Other tests and procedures include the following:
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.[7]
LCH causes fatty changes in the liver or hypodense areas along the portal tract, which can be identified by CT scans.[8]
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,[9] 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.
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.[10] Other types of histiocytes and macrophages may stain with S-100, so this is not considered sufficient to establish the diagnosis of LCH.[10]
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.[1] 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.[2] 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.[3]
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.
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.[1] 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
Single skull lesions of the frontal, parietal, or occipital regions, or single lesions of any other bone
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.[11]
Vertebral or femoral bone lesions at risk for collapse
Multiple bone lesions; or combinations of skin, lymph node, or pituitary gland with or without bone lesions
Treatment of high-risk multisystem disease
Spleen, liver, and bone marrow (may or may not include skin, bone, lymph node, lung, or pituitary gland)
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.[24]
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.[25]
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.
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.[25]
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.[36] 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.[36] 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.[36]
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).[20][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, [25][Level of evidence: 1iiA] and the LCH-II trial [23] (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 [37] and interferon-alpha.[38] 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.[39]
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.[40]
For children or adults with lung LCH, pulmonary function testing and high resolution CT scans are sensitive methods for detecting disease progression.[41] 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.[42]
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.
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.[1] An alternative treatment regimen employs vincristine, prednisone, and cytosine arabinoside.[2] 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.[3]
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.[4]
Indomethacin and bisphosphonates have also been used for recurrent LCH.[5,6,7,8]
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.[9] 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.[10][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.[11] Another study demonstrated that patients with multiple reactivations or high-risk disease could be effectively treated with continuous infusion 2-CdA for 3 days.[12] 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.[13][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).[14]; [15][Level of evidence: 3iiiDii]; [16][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.[21]
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.[1] 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.[2] 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.[3]
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.[5] 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.[6][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.[5] 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.[7] Some patients have markedly abnormal cerebellar function and behavior abnormalities, while others have subtle deficits in short-term memory and brain stem-evoked potentials.[8]
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.[9]
Liver disease may lead to sclerosing cholangitis, which rarely responds to any treatment other than liver transplantation.[10]
Dental problems characterized by loss of teeth have been significant for some patients, usually related to overly aggressive dental surgery.[11]
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.[14] 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.[15]
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.
General Information
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.[1] 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.[2]
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.[3].
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%).[4]
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.[5]
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.[5]
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.[1]
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%).[6]
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.[9] In addition, pulmonary LCH in adults appears to be primarily a reactive process, rather than a clonal proliferation as seen in childhood LCH.[10]
The course of pulmonary LCH in adults is variable and unpredictable.[6] 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.[11] Age older than 26 years and lower FEV1/FVC ratio and higher RV/TLC ratio are adverse prognostic variables.[12] 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.[15] One study reported that smoking cessation did not increase the longevity of pulmonary LCH patients, apparently because the tempo of disease is so variable.[12] 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.[16]
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.[18] The presence of cystic abnormalities on high-resolution CT scans appears to be a poor predictor of which patients will have progressive disease.[19] A study correlating lung CT findings and lung biopsy results in 27 pulmonary LCH patients has shed some light on pulmonary LCH.[20] 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.[21] 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.
Multisystem disease
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:
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.[1] 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.[2]
Lung transplant may be necessary for adults with extensive pulmonary destruction from LCH.[3] 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.[7] 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.[8]
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.[9]
Treatment of single-system skin disease
Chemotherapy for the treatment of single-system and multisystem disease
Chemotherapy is generally used for skin LCH associated with multisystem disease in adults.
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.
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.
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
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Langerhans Cell Histiocytosis Treatment are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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National Cancer Institute: PDQ® Langerhans Cell Histiocytosis Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/lchistio/HealthProfessional. Accessed <MM/DD/YYYY>.
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Last Revised: 2013-01-30
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text:
Lotus Praga LMP2 is heading to the United States of America for the fifth round of the FIA World Endurance Championship.
The venue for the 6 Hours of Austin will be the brand new Circuit of the Americas (COTA). It is located at the gates of Austin in Texas and is the newest race track on the calendar being opened in November 2012. COTA is 5,515 km in length and offers everything a race driver could ask for. The driving direction is counter-clockwise, which makes it physically demanding for the drivers and their neck muscles. After the start line, the cars have to climb up a hill to the first corner, which is the highest point of the circuit. The track was built by German architect Hermann Tilke and offers a mix of blind corners, hairpins and a one kilometer long back straight.
The 6 Hours of Austin will be the home race of Kevin Weeda, who will compete alongside his team mates James Rossiter and Vitantonio Liuzzi in Lotus Praga T128 LMP2 #31. The driver line up for the sister car #32 remains unchanged with Thomas Holzer, Dominik Kraihamer and Jan Charouz behind the wheel.
Lotus Praga LMP2 was working hard after the previous event in Interlagos to rebuild one of the cars that has been heavily damaged after a crash early in the race. The team will participate in the collective test session on Thursday, 19th September to get to know the new race track and to collect data in order to prepare the car for the race. The 6 Hours of Austin will start on Sunday, 22nd September, at 11:00 hours local time (18:00 hours CEST).
James Rossiter, Race Driver #31:
"I am really looking forward to being back in action in the FIA World Endurance Championship for Lotus Praga LMP2. The team has been making progress with the new car and I can't wait to drive the car again. Austin looks like an amazing track and should suit our car."
Jan Charouz, Race Driver #32:
"I am looking forward to racing in Austin as I always like coming back to America. When I was younger, I lived in Florida, so it is almost like my second home. The track looks very challenging and fun from onboard cameras and I think our car should be very quick there. Also, I think the test before the race will help us in developing the car further."
Home race for Praga Cars
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This is the second time that we are going through an hg pregnancy with my daughter. the first one ended in with the baby in heaven
and I am so afraid about this one i don't know what to do my daughter is so scared she insists on going to the er all the time although
they usually can't do anything but put her on saline etc. when we go home it starts all over again in a couple of days how do i help her to be less afraid, how do i help her to try some other medication, maybe some anti anxiety medication, how do i help her not be so afraid
of using a picc line i think if she uses one she will not be so afraid of dying from dehydration etc. and it will calm her down i feel so helpless!


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Federal Agency Says 48 Thai Welders Forced to Work Without Pay in Squalid Conditions
LOS ANGELES – The U.S. Equal Employment Opportunity Commission (EEOC) today announced a major litigation settlement with Trans Bay Steel, Inc. for an estimated $1 million in total monetary relief and compensation for 48 welders of Thai descent who were discriminated against and exploited due to their national origin.
EEOC charged that the class of Thai nationals, contracted under H2B visas by Trans Bay and a third party agency, were held against their will, had their passports confiscated, had their movements restricted, and were forced to work without pay. Additionally, some workers were confined to cramped apartments without any electricity, water, or gas.
At least 17 of the workers were told if they tried to leave the location where they were being forcibly held, the police and immigration officials would be called to arrest them. EEOC also contends that all the workers were made to pay exorbitant "fees" to the recruiting company which kept them in involuntary servitude. Ultimately, some of the workers escaped the slave-like conditions.
Trans Bay received a large sub-contract to provide services to retrofit the Bay Bridge and became the sponsoring employer for the workers. Trans Bay contracted with Kota Manpower Co., and Hi Cap Enterprises, Inc., to bring the skilled welders from Thailand to meet the needs of the project. While Kota and Hi-Cap brought over approximately 48 welders from Thailand, only nine of them went to work for Trans Bay. The remaining welders were brought to Los Angeles and Long Beach and forced to work without pay at Thai Restaurants owned by Kota Manpower and Hi-Cap, and forced to work other menial jobs without pay.
"The issues of human trafficking and slavery are an enforcement priority for the Commission," said Anna Y. Park, Regional Attorney in EEOC's Los Angeles District Office, which has jurisdiction for the southern half of California. "The EEOC is committed to the protection of all workers, particularly those most vulnerable in our society. The workers in this case sought out the American dream, but instead faced a nightmare."
EEOC conducted a comprehensive investigation of the charges and, after extensive negotiations, entered into a three-year consent decree with Trans Bay to resolve the case for an estimated $1 million in total monetary relief and compensation. Under the decree, Trans Bay will:
EEOC filed the lawsuit under Title VII of the Civil Rights Act of 1964, as amended in U.S. District Court for the Central District of California (U.S. EEOC v. Trans Bay Steel, Inc., Case Number CV 06-07766 CAS (JTLx)) after first attempting to resolve the matter out of court. Other injunctive measures contained in the consent decree include:
EEOC Los Angeles District Director Olophius E. Perry said, "Through the cooperative efforts between the federal government and non-profit organizations, a just resolution was reached that is a win/win for the workers and for the employer."
The EEOC worked closely with non-profit organizations such as the Thai Community Development Center, the Coalition to Abolish Slavery and Trafficking, and the Legal Aid Foundation of Los Angeles.
EEOC is the federal agency responsible for enforcing the nation's anti-discrimination laws in the workplace. Further information about the EEOC is available on its web site at www.eeoc.gov.
This page was last modified on December 8, 2006.
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Rolen stops by
BALTIMORE — Scott Rolen showed up inside the visitor's clubhouse at Camden Yards today, receiveing plenty of hand shakes all around. Sitting over with a group of players taking part in a card game, though, Jays second baseman Aaron Hill welcomed Rolen with this quip:
"We don't need you, bro. We just swept."
Before showing up at the ball yard, Rolen met with Dr. Thomas Graham, who performed surgery on the third baseman's right middle finger at the end of spring. Reports on Rolen's finger are good and he's already throwing (no ground balls, just catch) and hitting (with a protective rubber guard on his finger).
Rolen's finger is still tender, though, considering it hasn't healed completely from the surgery. So the timeline remains the same, even though he's ahead of schedule activity wise. That means he could be back toward the end of this month or some time in early May. More on his visit with us scribes on mlb.com in a while.
Also of note is that reliever Armando Benitez tweaked a hamstring covering first base in a Minor League game, according to Jays manager John Gibbons. Benitez is currently with Triple-A Syracuse, but Gibbons wasn't sure the extent of the pitcher's injury.
Catcher Rod Barajas was out of the lineup, but feeling better after tweaking a groin on Sunday. Gibbons said there'd be no need to DL Barajas and that he was available off the bench. Hill moves into the No. 3 hole with Alex Rios getting a day off and Mighty Joe Inglett remains in the starting lineup at third base.
Today's lineups:
TORONTO (7-5) at BALTIMORE (7-5)
at 7:05 p.m. ET at Camden Yards
David Eckstein, SS
Matt Stairs, RF
Aaron Hill, 2B
Vernon Wells, CF
Frank Thomas, DH
Lyle Overbay, 1B
Shannon Stewart, LF
Gregg Zaun, C
Joe Inglett, 3B
PITCHING: RHP Dustin McGowan
Brian Roberts, 2B
Melvin Mora, 3B
Nick Markakis, RF
Kevin Millar, 1B
Aubrey Huff, DH
Luke Scott, LF
Ramon Hernandez, C
Adam Jones, CF
Luis Hernandez, SS
PITCHING: RHP Matt Albers
18 Comments
It's about time Hill gets moved into the two hole where he belongs… I've been saying it for awhile now that his bat is a perfect #2 guy. He is a spray hitter who doesn't strike out much and has some pop.
That title for the line-up reads well in my eyes, even if it is early, it's nice to see. The more they win now (with a relatively healthy lineup), the more they can overcome injuries should they occur later in the season. Looking forward to McGowan on the mound tonight.
Rmatty, I can see Rolen hitting in the 2 spot as well but right now Hill is the best fit.
This blog doesn't seem to be as lively as it was a few months ago, what happened to all the Bastianites ?
Enigma, I was thinking the same thing. Everybody seems to have disapeared…..
Mcgowen keeps on getting pounded tonight. He is lucky that all those hits are mainly just single and that no more than 3 runs have scored on him so far.
I was going to ask the same thing, what has happened to all the posters here? Where's that nasty roughrider, Garry? lol.
I see Eckstein's off to a great start. Two errors in 11 games and a sky high batting average of .250.
I must also comment on the dumping of Johnson for Stewart, since this happened when I was away. Dumb move. With Eckstein Ssarting so well in the lead off role, it'd be damn nice to be able to put Reed in-to shake it up.
So did Bosox Brian show up, when we swept Boston in the series or was he ashamed to show his ugly face? lol
Gsumner, good to have you back. Maybe you can spark some debates here again.
Eckstein hasn't been doing much at all, I must admit. I pushed for him in the summer but things aren't looking good so far. Stewart isn't exactly tearing it up either which is a concern because those 2 guys are the only ideal lead off guys they have. Marco Scutaro should be back in the line-up tomorrow, in my opinion because his OBP was decent enough at the bottom of the order. I know it's second last on the team but .325 is nothing to sneeze at. It's been, almost 3 complete turns through the rotation and so far Burnett and McGowan need to pick up the slack a little bit. The offense as a whole has been inconsistant, though it was nice to see Rios get his first home-run tonight.
It was great to hear Buck Martiniz doing the colour commentating for the game, I really enjoyed the work he did when he was doing it for the Jays and to hear him again is always nice.
Wow, that 8th inning run really proved to key for the O's. Kinda makes you wonder why Rios wasn't starting today, with that homer in the 9th. Hope Hill can hit better the 2 spot, than he did last year.
Funny, Buck Martinez referenced the last time the Jays swept the Rangers was 3 game set, of which he caught the back end.
Anyway, the new free blog feature on mlb.com has got me to finally create one. I'm having fun with it, talkin Jays and many baseball related issues. Here is the link. http://homerfoodandhistory.mlblogs.com/
Looks like some of our prized guys are off to good starts in the minors.
AAA: Both Lind and Diaz are scorching it, with Lind at .366 Ba, .467 OBP and Diaz at .407 BA and OBP .407. Diaz is 3rd in the league in BA.
Diaz is a Vladimir Guerrero type of hitter, minus the power. His strike zone is as far as his bat reaches, so he gets few walks but hits the crap out of everything. I do not understand why JP signed Barajas after he stung us last year-particulary with a talent like Diaz ready to go. Time to dump Barajas and bring Diaz up. Lind seems to also be making a statement he belongs here.
My favorite minor league pitcher David Purcey is carrying right along like he did in the AFL and in 3 starts is 2-0, with an era of 1.89, whip of .95, 21k's and only 6 bb's in 19 innings. All 3 starts have been quality starts. The good news is, if we do have a starter go down, Purcey looks like he's ready to go. Certainly more depth than last year.
Shawn Camp, in relief, looks like he likes the Jays more than Tampa Bay, has gone 7 innings, given up 3 hits, struck out 10 and no bb's for an era of .000.
I've only seen two games so far, but in each of them Eckstein didn't get to balls that McDonald would have. That and his two errors and poor hitting makes me wonder why we're not playing Johnny Mac; he's only had 5 at bats so far. I hope I won't be able to say I told you guys os on Eckstein-I really hope he turns it around and plays a solider defense.
Inglett seems to have done a great job filling in for Scutaro; I wouldn't change them until Inglett slows down-he's batting .455.
Hill looks like he is enjoying hitting at the top of the lineup and the way hes going-BA of .320 and OBP ofover .400, maybe we should try him as lead off from tiem to time-particulary when Rolen comes back.
Hill, Rios, Wells, Rolen and then Stairs ( RH pitcher) or Thomas ( LHP) might be an interesting lienuep.
They have to give Eckstein a chance to get his bat going. I'd say give it about a month if he still is putting up the same numbers then J Mac is our guy. Stewart can lead off.
As for dumpin Barajas, to me he has looked better than Zaun in the games he as been able to play. I can really see Barajas taking the starting job away from Zaun later in the season.
I like Barajas so far. He called a beautiful game for Burnett against New York, he's hitting well, and runners are respecting his arm (only 2 sb this year).
There are a few other holes in the order besides Eckstein so far, but his average is climbing, and he's getting on base. He came from the NL, so he will get better as he gets to know the pitchers. I think he would make less errors if he was a bit taller. Maybe we should chip in for a pair of Air Nikes for him so he can get those balls that fly over his head.LOL. The positive side – I love the way he runs everything out, and you know he's giving everything he's got all the time. You can't put a stat to that.
Well, I only saw one game Barajas caught, and it looked like he wasn't on the same page as the pitcher ( Halliday). I don't know how the other guys have worked with him since I didn't see the games.
I think Zaun would be a better teacher for Diaz, since he knows the pitchers better. But as I said, I just think we should get Diaz up here whether we keep Zaun or Barajas.
I do hope Eckstein gets going. So far, he hasn't looked good on defense or offence. But, one way or the other, I think we need to get Johnny Mac in more often; he's only had 5 at bats.
Check out 2nd baseman Scott Campbell at AA New Hampshire.
This 23 year old was signed in 2006 from New Zealand. Last year started in Auburn and won a promotion to Lansing ( A-). We must like him, since this year he started in AA-New Hampshire and skipped Dunedin ( A+).
This year, he's played in 9 games with 37 at bats, but is hitting a staggering .486 with 2 homers.
I am right here, why would I be ashamed? The team I root for is the defending champs, LOL.
2 cities I wish the Red Sox would never visit, Seattle and Toronto. A house of horrors for the Red Sox over the last few seasons. This just in, they are the prettiest cities in the A.L., hands down, no doubt.
Of course Boston got swept in Toronto last September and all they did was win the World Series about 5 weeks later.
I think Toronto has the best rotation in the divison. If they ever had an injury in there rotation, they would be in trouble. They don't have the depth.
Of course with Toronto, it comes down to the bats. Will they hit? That is the biggest question and of course will they stay healthy? They always have there fair amount of injuries for some reason. Toronto could finish with 90 or more wins or they could finish with a similar record of last year. A funny team as you know gsumner. Well good luck anyway. It is a long season as you know. Filled with highs and lows. Remember Boston's longest winning streak last year was 7 games. The last 7 games they played in October and they became as you know the champions of the baseball world.
But just remember, that was last year, this is not…
Like what im hearing, from you guys, about Campbell and Diaz. I thought Diaz was still going to be a year away, I guess solid production can change that. Early this season, Barajas has prove to be better at throwing out running and a better hitter than Zaun. Zaun cannot even hold onto the bat. I don't know? Maybe carry 3 catchers for a bit?
There is that Rios homerun that I have been waiting for!
I hope our games arn't following any pattern, Sweep/Get swept/Sweep/lose first game (and hopefully dont get swept.
ok i know its early, but its really not time to start ripping on eckstein and barajas. eckstein has provided some gritt at the top of the order, and ive seen him just hacking out at bats and working to see as many pitches as he can. hes had a few mishaps, but come on hes not as good as johnny mac and we knew that comming into the season. but none he less, he provides more clutch hitting, and hes shown that this season alrighty, just grinding out the at bats. and for barajas, hes holding his own. maybe even playing better then zaun at this point. lets talk about diaz in late may or june, and just give him some time to continue to keep hitting in syracuse.
the one minor leaguer that has impressed me the most, and given me even more confidence in our rotation is purcey. in three starts hes alrighty 2-0 with a 1.89 ERA. but what impresses me the most is that hes given up only 12 hits and 6 walks in 19 innings to go along with 21 strickouts. i think purcey has shown that he is an option if we have an injury, and if he keeps going, who knows. remember he is a lefty starter, and thats something we could seriosuly use.
anyways lets hope for continued pitching the way weve been seeing it, and hopfully the offence shows up on a constant basis, because we all know it can be great, we just need some consistancy. Go Jays!
Johnny Mac really needs to get some more playing time.
Why sign him to a 2 year contract so he can ride the bench? There is no better defense ss in the league. Eckstein can hit a little better,but cannot get to as many balls. Let Jmac play alittle more its not like eckstein is hitting that great right now. As for Barajas he is doing a great job when he is playing, but Zaun knows the pitchures better. Well see what happens. Inglett is on a tear, so keep him in the lineup. What happens when Rolen gets back? Inglett so far has proven he can play at the big league level. Scutaro is in a hitting slump. Jmac can also play third. Its alittle frustrating letting him do nothing.


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As we observe the 40th anniversary of the federal endangered species act this month, it is affirming to look at the progress that's been made for rare wildlife in New Hampshire. Many of us can remember the "silent spring" that was the catalyst for this key federal legislation that provided protection for species facing possible extinction. By 1970, the pesticide DDT had devastated the nation's populations of osprey, bald eagles, peregrine falcons and other birds of prey. In response to this and other wildlife disasters, in 1973, Congress passed the Endangered Species Act.
New Hampshire passed a similar law in 1979, a time when no bald eagles, one peregrine falcon and just four ospreys nested here. Soon after, in 1980, the New Hampshire Fish and Game Department announced the state's first list of threatened and endangered wildlife species. At that time, Fish and Game had no staff dedicated to protecting rare wildlife. That began to change in 1988, when the state's Nongame and Endangered Wildlife Program was established.
Now in its 25th year, the Nongame Program is part of the N.H. Fish and Game Department's Wildlife Division. Over the years, the Non-game Program grew from a staff of one to a leader for statewide conservation efforts. It works with partners in the nonprofit and private sectors to protect threatened and endangered species in New Hampshire, and to keep common species common. This work is made possible with federal funding from State Wildlife Grants, expertise from conservation nonprofits, an annual financial matching grant from the State and financial support from private New Hampshire citizens. We have a lot to celebrate, thanks to the Nongame Program. Success stories include:
Karner blue butterflies, our official State Butterfly, were once gone from the state, but now breed in the wild here, thanks to intensive captive rearing and habitat restoration.
American pine marten are gaining ground in the Great North Woods.
Some 35 pairs of bald eagles breed in New Hampshire, and this iconic bird of prey has been removed from the Federal Endangered Species list.
Threatened and endangered common, Arctic and roseate terns breed and raise their young at the Isles of Shoals. This historic tern breeding site, once abandoned, is now the largest tern colony in the Gulf of Maine, with over 2,500 nesting pairs!
The success stories of the past 25 years give us hope for the future, as does a vitally important tool, developed in collaboration with conservation nonprofits and business partners — New Hampshire's Wildlife Action Plan. The plan provides local governments, land trusts, state agencies and businesses with a road map for restoring, protecting and maintaining critical habitats that are home to populations of the state's species of conservation and management concern. More than 2,000 people from 140 New Hampshire towns have already attended Wildlife Action Plan workshops, learning to identify and protect key habitats that benefit the greatest diversity of wildlife.
Our successes in the past 25 years have shown that, if we put our minds to it, we can take a wild species near extinction and bring it back. But that's an expensive process, and one of the goals of the Nongame Program is to keep wildlife off the endangered species list. The program is doing that well, thanks to a mix of private and public funding. The work that's being done to help rare species and their habitats helps all wildlife and improves the quality of the air and water we all need. The challenges of the next 25 years are likely to be greater still, and will require a unified effort from all of us. Find out how you can help at wildnh.com/nongame.


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I think it's interesting — no, not interesting, what's the word? — goofy — that while the better-than-expected but not-great remake of George Romero's DAWN OF THE DEAD was directed by someone called Zack Snyder, the similarly above-expectations but below-sensational remake of George Romero's THE CRAZIES is directed by someone called Breck Eisner.
(The heavily Romero-inflected ZOMBIELAND was helmed by Ruben Fleischer, which sounds a bit too much like an actual name but almost fits the pattern.)
Presumably, for the inevitable remakes of MONKEY SHINES, MARTIN, CREEPSHOW and THE DARK HALF, young directors-to-be are currently changing their names to Jerk Steiner, Rock Visser, Prick Meister and Stork Ulcer. And for the re-remakes of NIGHT OF THE LIVING DEAD et al, we will need reinforcements with names like Conk Ryder, Muck Pfister, Glock Pisser…
Meanwhile, George A Romero, without whom none of this mini-industry could exist, is still George A Romero. But maybe that's a mistake? For his forthcoming SURVIVAL OF THE DEAD, isn't there evidence aplenty that audiences would prefer to see a film by someone called Frisk Weezer or Spank Wicker? More market research is called for.


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GREELEY, Colo. (AP) -- Sheriff's deputies are investigating a Colorado livestock operation after an animal rights group released a video showing calves being dragged by their ears and legs, lifted by their tails, kicked and thrown.
Weld County Sheriff John Cooke issued a statement Friday saying three people were issued citations. He didn't give specifics. A spokesman didn't immediately return a call.
Cooke says deputies are investigating the Quanah Cattle Co. facility near Kersey, 55 miles northeast of Denver. The investigation began after the group Compassion Over Killing released a video it said was taken there.
The Greeley Tribune reports (http://tinyurl.com/mfqmrg4) the facility is owned by J.D. Heiskell & Co. of Tulare (too-LAHR'-ay), Calif.
J.D. Heiskell said it was dismayed by the video and is cooperating with authorities. It said it would improve training.