Systemic Langerhans Cell Histiocytosis Research Articles

Telomere length shortening in Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is a clonal, proliferative disorder of phenotypically immature CD1a(+) Langerhans cells (LC). The aetiology of LCH is unknown and data supporting an immune dysregulatory disorder as well as a clonal neoplasm have been reported. Telomere shortening has been associated with cancers and premalignant lesions as well as promoting chromosomal instability. To determine whether LCH LC have altered telomere lengths, we used dual detection of CD1a expression by immunofluorescence and telomere length by fluorescence in situ hybridization of LCH LC and lymphocytes in local, multisystem and systemic LCH and compared these with telomere lengths of LC and lymphocytes in reactive lymph nodes. LCH LC showed significantly shorter telomere lengths than LC from reactive lymph nodes or unaffected skin. Lymphocyte telomere lengths showed similar profiles among the different samples. These data show a significant telomere shortening in LCH LC in all stages of disease involvement compared with LC from reactive lymph nodes, suggesting that LCH may share mechanisms of telomere shortening and survival with clonal preneoplastic disorders and cancer, although an initiating infectious or immune event is still possible.

Telomere Length Shortening in Langerhans Cell Histiocytosis.

The purpose of this study was to analyze telomere lengths in Langerhans Cell Histiocytosis (LCH). LCH is a clonally derived, proliferative disorder of phenotypically immature CD1a+ Langerhans cells (LCs). The etiology of LCH is unknown and data supporting an immune dysregulatory disorder as well as a clonal neoplasm have been reported. Telomere shortening has been associated with cancers and premalignant lesions as well as being important in promoting chromosomal instability. We therefore conducted a study to quantitatively determine the telomere lengths in LCH. Tissue arrays of reactive lymph nodes, local, multisystem, and systemic LCH containing 9, 7, 12, and 10 specimens respectively were used. These tissue arrays included 2 specimens that had unaffected skin represented, providing an opportunity to examine non-pathologic LCs. The tissue arrays were first hybridized with a N-terminal covalently linked Cy3-labeled, telomere specific peptide nucleic acid (PNA) probe to stain telomeres. The slides were then processed for indirect immunofluorescence to identify LCs using an anti-CD1a primary antibody followed by an anti-mouse IgG fraction Alexa Fluor 488. Finally, slides were counterstained with 4′-6-diamidino-2-phenylindole (DAPI). Digital fluorescent telomere signals were visualized using a Nikon Eclipse E400 epifluorescence microscope and telomere lengths were analyzed with ImageJ software. A total of 1039 measurements were made from 38 individuals. A significant shortening of telomeres was demonstrated in LCH LCs of local, multisystem and systemic LCH in comparison to telomere lengths of reactive lymph node LCs and normal skin, which were not significantly different. To investigate whether telomere length shortening of LCH LCs is selective, we analyzed the telomere length in lymphocytes in LCH specimens and in the reactive lymph node specimens. There was no significant evidence of telomere shortening of lymphocytes in LCH compared to lymphocytes in reactive lymph nodes (p=0.1862). These data show significant telomere shortening in the LCs in all stages of disease involvement with more variability among local cases. These observations suggest that in most cases LCH may share important mechanisms of telomere shortening and survival with clonal pre-neoplastic disorders and cancer.

Complete remission of nodular pulmonary Langerhans cell histiocytosis lesions induced by 2-chlorodeoxyadenosine in a non-smoker

Pulmonary Langerhans cell histiocytosis (LCH) is an uncommon cause of interstitial lung disease. Corticosteroids and chemotherapeutic agents are frequently used to treat symptomatic patients but their efficacy is unclear. We describe a 66-year-old with biopsy-proven pulmonary and systemic LCH, whose pulmonary abnormalities responded dramatically to treatment with 2-chlorodeoxyadenosine (2-CdA). We propose that, in selected cases, 2-CdA should be considered in the management of pulmonary LCH.

Congenital systemic Langerhans cell histiocytosis presenting as hydrops fetalis

Congenital Langerhans cell histiocytosis (LCH) encompasses a wide spectrum of disease involvement and severity. Congenital "self-healing" cutaneous LCH represents one end of the spectrum, whereas the case we encountered represents the other extreme. A rare case of congenital LCH with severe multiorgan involvement presenting as hydrops fetalis is described in this report. Hydrops fetalis has not previously been associated with congenital LCH. The overall clinical features of this infant closely mimicked those of disseminated congenital infection, and he ran a fulminant and rapidly fatal course. A high index of suspicion is required to diagnose congenital LCH in the early neonatal period. Hydrops fetalis is an ominous sign and probably reflects severe systemic disease compromising the well-being of the fetus.

Congenital systemic Langerhans cell histiocytosis presenting as hydrops fetalis

Congenital systemic Langerhans cell histiocytosis presenting as hydrops fetalis

Langerhans Cell Histiocytosis with Central Diabetes Insipidus: A Case Report

Central diabetes insipidus (DI) is a syndrome characterized by thirst, polydipsia and polyuria. Langerhans cell histiocytosis is one of the etiologies of DI. Recently we experienced a central DI associated with Langerhans cell histiocytosis. The 44 years old female patient complained right hip pain, polydipsia and polyuria. We carried out water deprivation test. After vasopressin injection, urine osmotic pressure was increased from 109 mOsmol/kg to 327 mOsmol/kg (300%). Brain MRI showed a thickened pituitary stalk and air bubble like lesions sized with 5cm, 7cm was shown on fifth L-spine and right hip bone at hip bone CT. CT guided biopsy revealed abnormal histiocytes proliferation and abundant lymphocytes. The final diagnosis was central DI associated with systemic Langerhans cell histiocytosis invading hip bone, L-spine and pituitary stalk. Desmopressin and etoposide chemotherapy were performed to the patient.

Pulmonary Langerhans' cell histiocytosis: molecular analysis of clonality.

Pulmonary Langerhans' cell histiocytosis (LCH) is a form of Langerhans' cell disease that primarily affects smokers in the third to fifth decade. Extrapulmonary manifestations are rare. Its clinical course is typically characterized by stabilization or regression of bilateral micronodular infiltrates seen on chest radiographs; progression to honeycomb fibrosis is rare. Because the clinical course of pulmonary LCH is distinct from systemic multiorgan LCH, currently thought to be a clonal proliferative disorder, we examined the X-linked polymorphic human androgen receptor assay (HUMARA) locus to assess clonality in female patients with one or more discrete LCH cell nodules in open lung biopsies. Langerhans' cells (LCH cells) were excised from formalin-fixed, paraffin-embedded tissue by microdissection to assure a relatively pure cellular population, and studies for differential methylation patterns at the HUMARA locus were performed. Twenty-four nodules in 13 patients were evaluated. Seven (29%) were clonal and 17 (71%) were nonclonal. Of six cases with multiple discrete nodules, three (50%) showed a nonclonal LCH cell population. In one biopsy with five nodules, two nodules were clonal with one allele inactivated, one nodule was clonal with the other allele inactivated, and two nodules were nonclonal. In contrast to systemic LCH, pulmonary LCH appears to be primarily a reactive process in which nonlethal, nonmalignant clonal evolution of LCH cells may arise in the setting of nonclonal LCH cell hyperplasia. Cigarette smoking may be the stimulus for pulmonary LCH in contrast to other forms of LCH.

Rare single system diseases

There are many rare conditions to be found in textbooks of respiratory paediatrics which are often difficult to place in to any standard form of classification. The expertise of any single paediatrician or centre in the management of such problems is inevitably limited, and so treatment is never "evidence based" but depends on individual experience and information contained in case reports or small series in the literature. The investigation and management of such cases is often complex and should be performed in large regional centres. In this article we will discuss pulmonary alveolar microlithiasis, disorders of the lymphatic system, lymphoid bronchiolitis and pulmonary langerhans cell histiocytosis.

Radiotherapy in the Treatment of Langerhans Cell Histiocytosis

To further clarify the role of radiotherapy (XRT) for the treatment of Langerhans cell histiocytosis (LCH) we retrospectively analysed 13 patients treated with megavoltage irradiation. Localisation of LCH, radiation doses and techniques, and treatment results were determined. XRT alone was used in 9 patients with localised LCH. In 8 patients a complete remission was induced with doses between 10 - 20 Gy. Two relapses occurred but were controlled after a second radiation course. One patient developed systemic LCH. Four patients with systemic LCH were irradiated to treat local problems. Complete remissions were achieved in two patients, frequent relapses occurred in the other two patients. Five patients had evidence of cerebral LCH causing diabetes insipidus. In two patients a cerebral LCH-tumour was detectable. Tumour growth was abrogated in these cases. XRT could not revert diabetes insipidus but no progression of tumour growth and the associated hormonal dysfunction occurred.

Cytogenetic abnormalities in PHA-stimulated lymphocytes from patients with Langerhans cell histocytosis. AIEOP-Istiocitosi Group.

The aetiopathogenesis of Langerhans cell histiocytosis (LCH) is still undefined. Constitutional abnormalities in LCH have rarely been reported. One study showed chromosomal instability in lesional cells from three patients. No chromosomal studies are available on peripheral blood lymphocytes. Peripheral blood lymphocytes were analysed for the presence of chromatid and/or chromosomal breaks and structural rearrangements. A fluorescence in situ hybridization (FISH) painting technique was also applied in two cases. Sixteen patients with multisystem (MS, n = 11) or single system (SS, n = 5) LCH were studied. either at the diagnosis (n = 8), during treatment (n = 2) or during follow-up, when asymptomatic (n = 6). Thirteen patients had chromosomal abnormalities. Eleven patients (69%) had chromatid and chromosomal breaks in 7-45% of cells. Overall, chromosome and chromatid breaks were significantly more frequent in the 11 patients with MS disease than in the five patients with SS disease: the mean percentage of cells showing chromosome and chromatid breaks was 13.4% in MS patients vs. 6.2% in SS patients (P = 0.003). Chromosomal abnormalities may be found in phytohaemagglutinin (PHA)-stimulated peripheral blood lymphocytes of LCH patients at diagnosis, during the disease course and even during long-term follow-up, more frequently in MS disease. Chromosome instability may be considered as either a basic genetic instability or as a landmark of reaction to an environmental agent (viral?) that, through genome alteration, may play a role in histiocyte proliferation and, in some cases, also in the increased risk of malignancy.

Treatment of Relapsed Langerhans Cell Histiocytosis by Cyclosporin a Combined with Etoposide and Prednisone

Optimal treatment for Langerhans cell histiocytosis (LCH) has not yet been established. High-risk patients with systemic LCH may have a fatal course of the disease despite intensive treatment. New approaches using cyclosporin A (CSA) showed promising results. Here, we report on a 4-year-old boy who presented with systemic LCH of skin, liver, bone, bone marrow, and soft tissue infiltrates. The patient was refractory to conventional therapy including VP16, prednisone, 6-mercaptopurine, methotrexate, and vinblastine. Therefore the patient was treated with CSA as continuous therapy (serum levels were kept between 300 and 400 ng/mL) as well as intensification with VP16 and prednisone every 4 weeks. As early as 4 months after starting this treatment, clinical symptoms completely disappeared except for a slightly enlarged liver. During the next 12 months all clinical symptoms except a limited skin involvement vanished although treatment with VP16 and prednisone was stopped and CSA serum levels were kept between 100 and 150 ng/mL. In conclusion, intensive therapy using high-dose CSA combined with VP16 and prednisone might be a therapeutic option for patients with otherwise refractory LCH.

Cyclosporine therapy for refractory Langerhans cell histiocytosis.

Optimal treatment for Langerhans Cell Histiocytosis (LCH) has not yet been established. Preliminary reports suggest some effect of cyclosporine (CSA), both alone or in combination with steroids and/or vinblastine, in untreated cases. Twelve children (6 females and 6 males, age at diagnosis 3 months to 4 years) with biopsy proven, systemic LCH received oral CSA (12 mg/kg/day in two divided doses given daily) as a second-line therapy following chemotherapy including vinblastine and/or etoposide (10 cases) or steroid alone (one case); one child was not pretreated. A total of 16 CSA courses were administered to the 12 patients: 8 were completed, 4 were interrupted as unsuccessful, and 4 are still ongoing. CSA related toxicity consisted of hypertrichosis and transient hypertension and was never limiting. Treatment was associated with a clinical response in 8/12 patients: 3 had a complete response and are off therapy, and 5 had a partial response; disease reactivation following first favorable response required additional CSA courses in 3 patients. Four patients failed to respond to CSA: two died of progressive disease, while two had a favorable response to CSA + VP16. Favorable response to CSA was not related to CSA trough and peak levels and was usually observed during the first 2 weeks of CSA therapy. CSA is effective for treatment of LCH also in pretreated children with progressive disease including life-threatening organ dysfunction. Long-lasting complete remission may be achieved after 6 to 12 months of CSA therapy. When disease reactivation occurs after treatment withdrawal, a second course may be followed by favorable response. As minimal or no adverse effects are observed during or after prolonged CSA therapy, this may also be safely used in young patients.

Acute promyelocytic leukemia with t(15; 17) abnormality after chemotherapy containing etoposide for langerhans' cell histiocytosis

CancerVolume 74, Issue 5 p. 1650-1652 CorrespondanceFree Access Acute promyelocytic leukemia with t(15; 17) abnormality after chemotherapy containing etoposide for langerhans' cell histiocytosis Juan A. Lopez-Andreu M.D., Juan A. Lopez-Andreu M.D. Hospital Infantil La Fé Unidad de Oncología Pediátrica Valencia, SpainSearch for more papers by this authorJosep Ferrís Ph. D., Josep Ferrís Ph. D. Hospital Infantil La Fé Unidad de Oncología Pediátrica Valencia, SpainSearch for more papers by this authorAmparo Verdeguer M.D., Amparo Verdeguer M.D. Hospital Infantil La Fé Unidad de Oncología Pediátrica Valencia, SpainSearch for more papers by this authorCarlos Esquembre M.D., Carlos Esquembre M.D. Hospital Infantil La Fé Unidad de Oncología Pediátrica Valencia, SpainSearch for more papers by this authorVictoria Castel Ph. D., Victoria Castel Ph. D. Hospital Infantil La Fé Unidad de Oncología Pediátrica Valencia, SpainSearch for more papers by this authorKeizo Horibe M.D., Keizo Horibe M.D. Department of Pediatrics, Nogoya University School of Medicine Nagoya, JapanSearch for more papers by this author Juan A. Lopez-Andreu M.D., Juan A. Lopez-Andreu M.D. Hospital Infantil La Fé Unidad de Oncología Pediátrica Valencia, SpainSearch for more papers by this authorJosep Ferrís Ph. D., Josep Ferrís Ph. D. Hospital Infantil La Fé Unidad de Oncología Pediátrica Valencia, SpainSearch for more papers by this authorAmparo Verdeguer M.D., Amparo Verdeguer M.D. Hospital Infantil La Fé Unidad de Oncología Pediátrica Valencia, SpainSearch for more papers by this authorCarlos Esquembre M.D., Carlos Esquembre M.D. Hospital Infantil La Fé Unidad de Oncología Pediátrica Valencia, SpainSearch for more papers by this authorVictoria Castel Ph. D., Victoria Castel Ph. D. Hospital Infantil La Fé Unidad de Oncología Pediátrica Valencia, SpainSearch for more papers by this authorKeizo Horibe M.D., Keizo Horibe M.D. Department of Pediatrics, Nogoya University School of Medicine Nagoya, JapanSearch for more papers by this author First published: 1 September 1994 https://doi.org/10.1002/1097-0142(19940901)74:5<1650::AID-CNCR2820740528>3.0.CO;2-UCitations: 2AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume74, Issue51 September 1994Pages 1650-1652 ReferencesRelatedInformation

Solitary congenital self-healing reticulohistiocytosis

Congenital self-healing reticulohistiocytosis (CSHR) was first described in 1973 by Hashimoto and Pritzker. Since then, both multiple and solitary forms have been described. We report a further case of solitary congenital self-healing reticulohistiocytosis. CSHR is a rare disorder which frequently presents a diagnostic dilemma in the newborn. Nodular forms of systemic Langerhans cell histiocytosis may present in a manner similar to CSHR. Because their differentiation on histopathological grounds is impossible, physical examination, laboratory investigations, and follow-up are necessary to ensure a lack of systemic involvement. Although previously thought to represent a rare variant of CSHR, solitary lesions of CSHR account for almost 25% of reported cases. A review of the literature relating to solitary CSHR, and a consideration of the differential diagnosis of a solitary congenital nodule, are also presented.

Treatment of Langerhans cell histiocytosis in children with etoposide.

Ten children with Langerhans cell histiocytosis (LCH) were treated with etoposide. For five patients, this was the initial diagnosis. The other five had failed to respond to previous therapies. Etoposide (100 mg/m2) was given intravenously twice a week for 4 weeks, followed by maintenance therapy every 2 to 4 weeks for 2 years. All 10 patients responded to etoposide, and 6 of them (60%) have been in complete remission for 3 to 36 months without any side effects. One patient relapsed with diabetes insipidus, one with a soft tissue mass, and two others developed multiple bone lesions. Chemotherapy with etoposide appears to be effective and safe for the treatment of children with systemic LCH.