Recurrence Of Langerhans Cell Histiocytosis Research Articles

8155 Isolated Hypothalamic-Pituitary Langerhans' Cell Histiocytosis in Adult Patients

Abstract Disclosure: A. Vu: None. M. Aguilera: None. J. Shakil: None. R. Al-Ward: None. Introduction: Langerhans cell histiocytosis (LCH) is an infiltrative disease due to clonal proliferation of immature dendritic cells mainly affecting children and seen in adults in less than 30% of cases. It can present as localized or with systemic manifestations, with isolated hypothalamic-pituitary lesions being exceptionally rare. Our report adds to the limited published literature by presenting two cases of isolated hypothalamic-pituitary LCH diagnosed in adults. Furthermore, one of the cases reveals a rare association with papillary thyroid cancer (PTC). Case 1: 35-year-old woman with no past medical history presented with 4 year history of amenorrhea and weight gain and more recently, polyuria and polydipsia. Further investigations showed hypogonadotropic hypogonadism, central hypothyroidism, and mildly elevated prolactin. She couldn’t complete water deprivation test due to extreme thirst. A dedicated pituitary MRI showed marked infundibular enlargement, concerning for hypophysitis. An extensive workup including assessments for autoimmune etiology, sarcoidosis, infections, and low-grade tumors, did not identify a definitive etiology. A PET scan was obtained (to rule out LCH and Erdheim Chester disease), which showed increased uptake in the pituitary stalk. Due to otherwise negative workup, transsphenoidal biopsy of the pituitary lesion was done. Post-procedure, diabetes insipidus (DI) was diagnosed due to elevated sodium while fasting for the procedure. Tissue examination revealed increased histiocytes and lymphocytes, and a positive BRAF V600E mutation confirming LCH as the underlying diagnosis. Case 2: 26-year-old male with history of LCH limited to the skull, in remission for 8 years after chemotherapy, presented with 4-week history of polyuria, polydipsia and weight loss. A 24-hour urine collection resulted in 6.5L of urine. During water deprivation test, there was notable increase in serum sodium, serum osmolarity, and urine osmolarity. Initial pituitary MRI was normal, but subsequent imaging revealed the loss of the posterior pituitary bright spot. PET scan showed focal FDG avidity in the right lower thyroid lobe, confirmed on fine needle aspiration as PTC with BRAF mutation. He underwent total thyroidectomy and is currently receiving chemotherapy for LCH recurrence. Discussion: LCH is infrequent in adults, presenting with variable manifestations based on affected organs. In the multifocal form, the hypothalamic-pituitary axis is involved in 5-50% of cases. Our report describes two unique cases with only four other reported cases of isolated hypothalamic-pituitary axis LCH in adults. Central diabetes insipidus can be seen before the diagnosis or as the disease progresses. Pituitary biopsy, although invasive, should be considered when the diagnosis is not clear. The association of PTC with a BRAF mutation is extremely rare and has been reported. Presentation: 6/2/2024

Possible involvement of CXCR3-CXCR6 + CD4 + T cells in Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is a condition characterized by proliferation of Langerhans cells and wide-range pathologies, ranging from single granulomatous lesions to multi-organ involvement, associated with tissue destruction. LCH pathogenesis remains obscure although association with interleukin (IL)-17A has been reported. We report here a case that illustrates the potential pathogenic role of helper T17 (Th17) cells in LCH-related bone destruction. The patient was a 66-year-old woman. The clinical course included craniectomy and bone mass excision in X-9, diagnosis of LCH confirmed by histopathology, followed by 26-month chemotherapy. In August X, the patient was diagnosed with complete central diabetes insipidus. Symptoms improved after treatment with desmopressin. Pituitary magnetic resonance imaging showed swelling extending from the suprasellar region to the pituitary stalk, suggestive of LCH recurrence. This was followed by chemotherapy combined with mercaptopurine hydrate. RESULTS: Subsequent peripheral blood lymphocyte analysis showed marked increase in activated Th17 cells (CXCR3-CXCR6+ CD4+ T cells). Double staining for CD4 and IL-17 by immunofluorescence of pathological tissue samples obtained during temporal bone mass excision, which confirmed the diagnosis of LCH in X-9, showed areas of combined presence of CD4-positive cells and IL-17-positive cells. Chemotherapy resulted in size reduction of the pituitary lesion and decrease in peripheral blood-activated Th17 cells. We found abundant peripheral blood-activated Th17 cells and high percentages of IL-17-producing cells in osteolytic bone lesions in LCH. This finding, together with the decrease in peripheral blood-activated Th17 cells following chemotherapy, suggests the potential involvement of activated Th17 cells in LCH-related osteolysis.

Liver Transplantation for Langerhans Cell Histiocytosis: A US Population-Based Analysis and Systematic Review of the Literature.

Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder. Liver involvement is seen in 10.1% to 19.8% of patients with LCH and can lead to secondary sclerosing cholangitis requiring liver transplantation (LT). We describe the characteristics and outcomes of patients undergoing LT for LCH. All patients undergoing a first LT for LCH in the United States were identified in the Scientific Registry of Transplant Recipients (SRTR) database (1987-2018). The Kaplan-Meier curve method and log-rank tests evaluated post-LT survival. A systematic literature review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement. A total of 60 LCH LT recipients were identified in the SRTR, and 55 patients (91.7%) were children with median total bilirubin levels at LT of 5.8mg/dL (interquartile range [IQR], 2.7-12.9). A total of 49 patients (81.7%) underwent deceased donor LT (DDLT). The 1-year, 3-year, and 5-year patient survival rates were 86.6%, 82.4%, and 82.4%, respectively. The systematic review yielded 26 articles reporting on 50 patients. Of the patients, 41 were children (82.0%), 90.0% had multisystem LCH, and most patients underwent DDLT (91.9%; n=34/37). Pre-LT chemotherapy was administered in 74.0% and steroids in 71.7% (n=33/46) of the patients, and a recurrence of LCH to the liver was reported in 8.0% of the patients. Of the 50 patients, 11 (22.0%) died during a median follow-up of 25.2months (IQR, 9.0-51.6), and the 1-year patient survival rate was 79.4%. LT can be considered as a feasible life-saving option for the management of liver failure secondary to LCH in well-selected patients.

NFB-05. AN UNUSUAL PRESENTATION OF RECURRENT LANGERHANS CELL HISTIOCYTOSIS OF THE CRANIOFACIAL BONES IN A PATIENT WITH NEUROFIBROMATOSIS TYPE I

Neurofibromatosis type 1 (NF1), predisposes patients to benign and malignant tumors due to lack of suppression of the mitogen activated protein kinase (MAPK) signaling pathway. Langerhans cell histiocytosis (LCH) manifests in numerous ways, from localized lesions to multisystem organ involvement secondary to a constitutively active MAPK signaling cascade often driven by BRAF mutations. While both LCH and NF1 are characterized by overactive MAPK signaling, there are few reports of the two diseases occurring simultaneously. We report a novel case of a patient with underlying NF1 and recurrent LCH without a BRAFV600E mutation. She initially presented at 2 years of age with an aggressive appearing mass of the left temporal bone found on surveillance imaging. Pathology was consistent with Langerhans histiocytosis and she was treated with the LCH-III protocol for patients with high-risk LCH due to the location of her lesion. Five years after completion of therapy, MRI demonstrated development of a calvarial mass consistent with relapsed LCH in a new risk site. Lesional curettage was performed and pathology confirmed recurrence of LCH with juvenile xanthogranulomatous features. BRAF testing of blood and the lesion were negative for any BRAF alterations. Further genomic evaluation of the tumor is in progress at this time to evaluate for other known mutations associated with LCH. The patient is currently receiving monthly cytarabine treatment which she has tolerated to date. Our patient represents a unique presentation of recurrent LCH in a patient with NF1 and further molecular evaluation may help identify other drivers of LCH activation.

Langerhans Cell Histiocytosis With Vertebral Involvement Diagnosed and Treated Over the Last 15 Years in a Single Canadian Pediatric Academic Institution.

We report 11 children with vertebral lesion of Langerhans cell histiocytosis (LCH) diagnosed and treated between 2000 and 2015. Vertebral lesions were usually present at LCH diagnosis. No child developed neurologic symptoms. Among 29 vertebral lesions, only 2 were unstable. Chemotherapy was used in all children but 3. A LCH recurrence was observed in 6 patients, involving vertebrae in 4 cases. All children were disease-free at their last follow-up. Sequelae were more often radiologic than clinical. Since potential recurrences and incomplete bone regeneration exist, discussion about optimal treatment and long-term follow-up of vertebral lesions are essential.

THINKING OUTSIDE THE LUNG: MULTISYSTEM LANGERHANS CELL HISTIOCYTOSIS (MS-LCH)

SESSION TITLE: Diffuse Lung Disease 1 SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/09/2018 01:15 pm - 02:15 pm INTRODUCTION: Langerhans Cell Histiocytosis (LCH) is rare disorder that is characterized by clonal proliferation of infiltrative dendritic cells affecting one or more organs. The incidence of LCH in adults is 2 per million. LCH is associated with wide range of clinical presentations, from localized or ‘single-system disease’ with excellent survival rate to involving 2 or more organs or ‘multisystem disease (MS-LCH)’ with poor prognosis. We report a rare case of MS-LCH in adult. CASE PRESENTATION: A 60-year-old female smoker presented to the pulmonary clinic for abnormal chest CT chest. Her medical work-up was initiated due to low grade fevers, night sweats, diarrhea, persistent productive cough and progressive dyspnea over 3 months. She also reported a recent transient episode of erythematous skin rash that resolved spontaneously. Her CT abdomen showed mass like thickening of sigmoid colon, multiple hepatic lesions and retroperitoneal adenopathy. The FNA of liver mass showed focal steatosis and mild portal fibrosis. Chest CT revealed diffuse thin-walled cysts of various shapes and sizes with associated parenchymal destruction. The cystic lesions were predominant in the upper lungs. Bronchoscopy with TBBx and EBUS-TBNA of mediastinal lymphadenopathy were performed. Histopathology of TBBx revealed histocyte-like mononuclear cells along with eosinophils and lymphocytes, suggestive of LCH. The immunostains of the mononuclear cells were positive for CD1a and S100, confirming the diagnosis of LCH. Flow cytometry from her mediastinal lymph nodes also showed CD1a and S100 positivity. Bone scan showed increase uptake in calvarium, tibia and facial bones suggestive of neoplastic involvement of LCH. With the history, investigation and clinical findings, the diagnosis of MS-LCH was made. Based on the current literature, she was started on intensive combination chemotherapy of vinblastine, prednisone plus 6-mercaptopurine. She continues to improve clinically. DISCUSSION: LCH is a rare neoplasm of Langerhans type cells that is uncommon in adult. MS-LCH is frequently associated with fatal prognosis when there is involvement of risk organs. Therefore, treatment of MS- LCH should be aggressive and longer (12 month). On the other hand, isolated P-LCH has excellent prognosis, and likely to be cured with smoking cessation. Recurrence of LCH has been shown in patient with BrafV600 mutation. Cladribine has been used as 2nd-line treatment in recurrent or resistant cases of all types of LCH. CONCLUSIONS: In summary, LCH should be considered in the differential diagnosis of a patient with unexplained multiorgan disease. Early recognition, diagnosis and treatment are very crucial for the survival, especially in the MS-LCH. Reference #1: Earlam K et al., 2016. Pulmonary Langerhans Cell Histiocytosis and Diabetes Insipidus in a Young Smoker. Can Respir J; 3740902 Reference #2: Lian C et al., 2016. Langerhans Cell Histiocytosis in Adults: A Case Report and Review of the Literature. Oncotarget; 7(14):18678-18683 Reference #3: Tazi A., 2006. Adult Pulmonary Langerhans’s Cell Histiocytosis. Eur Respir J; 27(6):1272-1285 DISCLOSURES: No relevant relationships by Jessita Singh Natasha Albert Messiah Dhas, source=Web Response No relevant relationships by Anna Kyu Chen, source=Web Response No relevant relationships by Sudheer Penupolu, source=Web Response

Cholesteatoma as a complication of Langerhans Cell Histiocytosis of the temporal bone: A nationwide cross-sectional analysis

ObjectiveTo determine if patients with Langerhans Cell Histiocytosis (LCH) of the temporal bone have a higher risk of developing cholesteatoma. MethodsReview of literature and cross-sectional weighted analysis of patients under 19 with a diagnosis of LCH from the National Inpatient Sample (NIS) and Kids' Inpatient Database (KID) from 2000 to 2013. ICD-9 codes and demographics were analyzed; pairwise comparisons and multivariate analyses were performed. ResultsOnly seven cases of cholesteatoma after the treatment for LCH of the temporal bone have been documented in the literature. No significant association between cholesteatoma and LCH was seen (OR 0.747 [0.149–3.751]). Patients with LCH did have a higher incidence of chronic otitis media, chronic otitis externa, chronic sinusitis, hearing loss, and otitis media with effusion. ConclusionOur results show that patients with Langerhans Cell Histiocytosis do not appear to have a higher risk of developing cholesteatoma. However they are more likely to be diagnosed with chronic otitis externa which should be differentiated from cholesteatoma or recurrence of LCH.

Specificities of sclerosing cholangitis in childhood

Sclerosing cholangitis (SC) is a chronic cholestatic disease characterized by inflammation and obliterative fibrosis of the bile ducts, leading to biliary cirrhosis and ultimately to liver failure. Four main clinical forms can be distinguished in children: i) neonatal SC, most probably a genetic disease transmitted by autosomal recessive inheritance; ii) SC associated with strong features of autoimmunity (referred as autoimmune sclerosing cholangitis) with quite good response to immuno-suppression iii) primary SC of unknown etiology (i.e. without features of autoimmunity) and iv) SC secondary to various diseases, including Langerhans cell histiocytosis and immunodeficiencies. Ursodesoxycholic acid is considered the treatment of choice for all forms of SC but without proof of its effectiveness in preventing progression to secondary biliary cirrhosis. In patients with immunodeficiencies, early bone marrow transplantation is the only way to prevent secondary SC. Liver transplantation remains the only validated treatment in children with biliary cirrhosis. Recurrence of SC after liver transplantation has not been clearly demonstrated in children; however, recurrence of Langerhans cell histiocytosis with bile duct injury has been reported. For patients with severe immunodeficiency, a two-step liver then bone marrow transplantation protocol may be proposed.

Unstable Pathological Fracture of the Odontoid Process Caused by Langerhans Cell Histiocytosis

A case report and literature review. To illustrate the spontaneous resolution of unstable pathological fracture of the odontoid process of the C2 caused by Langerhans cell histiocytosis (LCH) in early childhood. The involvement of atlantoaxial LCH is very rare and its treatment is unfamiliar to surgeons. Therefore, the management of pediatric LCH of the odontoid process and the C2 body is challenging and must be adapted according to the patient's needs; it could range from observation to surgical intervention. A case of pathological fracture of the odontoid process with torticollis diagnosed with LCH of the odontoid process and C2 body and involving right femur in early childhood is presented. A histopathological study showed LCH. The patient underwent brace immobilization and systemic chemotherapy. The patient showed successful bony remodeling without LCH recurrence on CT. The neck pain was resolved, and there was no limitation in neck movement. Immobilization and systemic chemotherapy with close observation are adequate for the management of patients despite the unstable pathological fracture of the odontoid process.

Liver Transplantation in an Adult With Sclerosing Cholangitis due to Multisystem Langerhans Cell Histiocytosis

To the Editor: Langerhans cell histiocytosis (LCH) is a rare hematopoietic disorder characterized by proliferation of CD1a+ dendritic cells. An association between LCH and sclerosing cholangitis (SC) has rarely been reported in adults with only four cases of liver transplantation for LCH associated SC in the literature (1). We have recently managed such a patient with SC secondary to LCH who eventually required liver transplantation, and feel the case adds to the evidence that liver transplantation can be efficacious in treating some rare diseases, such as LCH, and that posttransplant immunosuppression can prevent recurrence. Furthermore, it highlights the ethical implications of using valuable organs when evidence for transplant is scarce. The patient was diagnosed with SC in 2006, aged 39, following previous gallstone pancreatitis and chronically abnormal liver function with intermittent pruritis. He was then independently diagnosed with LCH in 2007 after a symptomatic scapula mass was biopsied. His SC progressed despite repeated biliary duct dilatations and by 2008 he was being considered for liver transplant with a Model for End-stage Liver Disease (MELD) score of 15. Pretransplant liver biopsy revealed immunostaining diagnostic of LCH (Figure 1). He underwent successful orthotopic liver transplantation in March 2009 and was immunosuppressed postoperatively with tacrolimus and prednisolone. Due to subsequent hyperglycemia this was changed to cyclosporine and mycofenolate mofetil. At present, he is well with normalized liver function and no signs of transplant rejection in two subsequent liver biopsies. Liver biopsy: (A) portion of a segmental bile duct (BD) infiltrated by Langerhans cells (arrows), CD1a [panel (B)] and S100 immunoreactive [panel (D)]. High-power view of mass of Langerhans cells with eosinophils (Eos) [panel (C)]. Liver transplantation has been shown to be the only successful treatment of end-stage biliary cirrhosis in patients with LCH (1). Chemotherapy in this group may actually cause deterioration in liver function. Our decision to transplant was precipitated by the patient's liver failure and rising MELD score. A recent study of 1130 patients demonstrated survival benefit at 1 year posttransplant once a patient's MELD score reached 15 irrespective of pathogenesis (2). In rare diseases where evidence of efficacy is limited to a few case reports, deterioration in liver function may therefore best guide a decision to consider transplantation. Due to the systemic nature of LCH, there is the additional concern of disease recurrence posttransplant. Reassuringly, only one recurrence within an adult graft has previously been described (3). Immunosuppression posttransplant could reduce recurrence rates and this may suggest an immune mechanism in the pathogenesis of LCH. In liver transplantation secondary to LCH the ideal immunosuppressant would prevent graft rejection and LCH recurrence. There is currently no convincing evidence which agent most effectively achieves this. Cyclosporine has been the most extensively documented immunosuppressant used to treat LCH. However evidence of its efficacy is mainly in the form of case series and these have demonstrated widely varying results (4, 5). To our knowledge there is no literature on the use of other immunosuppressants such as mycophenolate mofetil, mammalian target of rapamycin (mTOR) inhibitors or calcineurin inhibitors as anti-LCH agents. Of note Jorden et al. have shown that pathological Langerhans cells aberrantly express CD52, whereas normal Langerhans cells do not (6). Therefore alemtuzumab, an anti-CD52 monoclonal antibody previously shown to be efficacious in preventing graft rejection (7), may also have activity against LCH. The immunological mechanisms involved in this disease, although as yet poorly understood, provide the opportunity for posttransplant immunosuppression to have a dual role in preventing graft rejection and disease recurrence. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

Cholesteatoma Secondary to Temporal Bone Involvement by Langerhans Cell Histiocytosis

To describe secondary acquired cholesteatoma in patients previously treated for Langerhans cell histiocytosis (LCH). To focus on misleading symptoms suggesting LCH relapse. This study involved 3 patients aged 12, 20, and 58 months whose conditions were diagnosed with LCH. All 3 had involvement of the mastoid and of the skin of the external ear canal (EAC) at diagnosis. They were treated with steroids and vinblastine. Serial computed tomographic (CT) scans and clinical follow-up. Exploratory surgery of the mastoid. Otorrhea recurred in all 3 patients at 24, 17, and 26 months, respectively, with difficulties to clinically identify a hole in the posterior part of the EAC. The otorrhea was considered a sign of a new occurrence of LCH, leading to systemic chemotherapy in 2 cases. A CT scan showed a defect in the posterior wall of the EAC and suggested cholesteatomatous invasion of the mastoid (2 true cholesteatomas and 1 precholesteatomatous case).Surgery (canal wall up mastoidectomies) successfully removed the cholesteatoma (bilateral in 2 cases) and reconstructed the bony defect using cartilage. Biopsies ruled out LCH recurrence. Secondary acquired cholesteatoma (through a bony defect of the EAC) may occur in patients previously treated for LCH. Recurrence of symptoms and bone destruction on CT may wrongly suggest LCH recurrence. Surgery allows removal of the cholesteatoma as well as EAC reconstruction and control biopsy.

Recurrence of langerhans cell histiocytosis in the graft after liver transplantation in adults

Recurrence of langerhans cell histiocytosis in the graft after liver transplantation in adults

Pediatric liver transplantation for langerhans' cell histiocytosis

Langerhans' cell histiocytosis (LCH) represents 15% to 20% of sclerosing cholangitis (SC) in children. In LCH-associated SC, a very poor response to chemotherapy has been reported, and spontaneous prognosis is very bad. Few cases of orthotopic liver transplantation (OLT) for LCH have been reported and little is known about the risk of recurrence and the effect of immunosuppression after OLT. Since 1986, five children (mean age ± SD, 12.6 ± 3.6 years) underwent OLT for SC complicating LCH. All patients presented with growth retardation, and severe liver disease including repeated episodes of variceal bleeding (n = 5), liver insufficiency (n = 4), jaundice (n = 5), and ascitis (n = 4). Four patients presented with previous abdominal surgery (mesocaval shunt in two and explorative laparotomy in two). OLT was performed using a whole (n = 2) or a reduced liver graft (n = 3). Pathological examination of the recipient liver showed biliary cirrhosis in all cases. Three patients are alive and well 9 to 88 months after OLT. None presented with recurrence of LCH or SC within the liver graft or in other organs. General condition (including growth and puberty) improved dramatically in the three surviving patients. Absence of recurrence after up to 7 years of follow-up after liver transplantation in our patients, as well as in all other reported cases, is encouraging and shows that OLT may be indicated in end-stage liver disease complicating LCH. Furthermore, cyclosporine may be beneficial for preventing recurrence of LCH, in which autoimmunologic mechanisms have been advocated. (Hepatology 1995;21:129-133).

Pediatric liver transplantation for langerhans' cell histiocytosis

Langerhans' cell histiocytosis (LCH) represents 15% to 20% of sclerosing cholangitis (SC) in children. In LCH-associated SC, a very poor response to chemotherapy has been reported, and spontaneous prognosis is very bad. Few cases of orthotopic liver transplantation (OLT) for LCH have been reported and little is known about the risk of recurrence and the effect of immunosuppression after OLT. Since 1986, five children (mean age ± SD, 12.6 ± 3.6 years) underwent OLT for SC complicating LCH. All patients presented with growth retardation, and severe liver disease including repeated episodes of variceal bleeding (n = 5), liver insufficiency (n = 4), jaundice (n = 5), and ascitis (n = 4). Four patients presented with previous abdominal surgery (mesocaval shunt in two and explorative laparotomy in two). OLT was performed using a whole (n = 2) or a reduced liver graft (n = 3). Pathological examination of the recipient liver showed biliary cirrhosis in all cases. Three patients are alive and well 9 to 88 months after OLT. None presented with recurrence of LCH or SC within the liver graft or in other organs. General condition (including growth and puberty) improved dramatically in the three surviving patients. Absence of recurrence after up to 7 years of follow-up after liver transplantation in our patients, as well as in all other reported cases, is encouraging and shows that OLT may be indicated in end-stage liver disease complicating LCH. Furthermore, cyclosporine may be beneficial for preventing recurrence of LCH, in which autoimmunologic mechanisms have been advocated.