High risk Langerhans cell histiocytosis in children: the role of salvage in improving the outcome. A single center experience.

BACKGROUND: In pediatric multi-system high risk organs (RO +) Langerhans cell histiocytosis (LCH), failing 1st line treatment has the highest mortality. We aim to present the outcome of failure of 1st line whether due to disease progression (DP) at end of induction or reactivation (REA) after initial better status response. PATIENTS AND METHODS: Sixty-seven RO + LCH patients with hemopoietic, hepatic or splenic involvement, treated between 2007 and 2019 were retrospectively analyzed. The median follow-up (IQR) is 6 years (4-8.8 y).They were subjected to 2 eras of treatment; one with salvage by 2-Cda based regimen (2-CdABR) and another without. RESULTS: Of 67 patients, M/F 40/27, median age 1.74 y (0.2-10 y), 42 failed 1st line (62.7%). Of them DP n = 22 (52%) and REA n = 20 (48%). Of those with DP, 9/22 patients received 2-CdABR, where 5 survived in better status. While the remaining 13 did not receive 2-CdABR and all of them died. Otherwise, of those with REA, 12/20 reactivated on RO + mode. Of them, 8/12 received 2-CdABR, where only one survived in better status and the remaining 4 received vinblastine-based regimen,where 2 died and 2 were rescued. RO + 5-year overall survival (OS) was 65% (CI 95% 54 -78) while the event free survival (EFS) 36% (26.3-50.1). The OS of DP 27% (14-54) versus REA 67% (49-93) p 0.004. OS of DP with 2-CdABR 56% (31-97.7) versus 8% without (2-51), p < 0.001. While OS of REA with 2-CdABR 38% (13-100) versus 74% without (53-100) p 0.7. CONCLUSION: Survival of RO + remains limited. Failure of 1st line in RO + due to DP carries worse prognosis in relation to REA. In DP those who were not salvaged by 2-CdABR, showed dismal outcome. This could not be shown when applied in REA.

Phase II study in children and adults under 40 years with newly diagnosed Langerhans cell histiocytosis: protocol for an LCH-19-MSMFB clinical trial in Japan.

INTRODUCTION: Although the prognosis of Langerhans cell histiocytosis (LCH) is excellent, the high recurrence rate and permanent consequences, such as central diabetes insipidus and LCH-associated neurodegenerative diseases, remain to be resolved. Based on previous reports that patients with high-risk multisystem LCH show elevated levels of inflammatory molecules, we hypothesised that dexamethasone would more effectively suppress LCH-associated inflammation, especially in the central nervous system (CNS). We further hypothesised that intrathecal chemotherapy would effectively reduce CNS complications. We administer zoledronate to patients with multifocal bone LCH based on an efficacy report from a small case series. METHODS AND ANALYSIS: This phase II study (labelled the LCH-19-MSMFB study) is designed to evaluate the significance of introducing dexamethasone and intrathecal chemotherapy for multisystem disease and zoledronate for multifocal bone disease in previously untreated, newly diagnosed children, adolescents (under 20 years) and adults under 40 years. The primary endpoint is the 3-year event-free survival rate by risk group of under 20 years and the 3-year event-free survival rate of 20 years and over. ETHICS AND DISSEMINATION: This study was approved by the Central Review Board of the National Hospital Organisation Nagoya Medical Centre (Nagoya, Japan) on 21 January 2022 and was registered in the Japan Registry of Clinical Trials (https://jrct.niph.go.jp/en-latest-detail/jRCTs041210027). Written informed consent will be obtained from all patients and/or their guardians. TRIAL REGISTRATION NUMBER: jRCTs041210027.

Langerhans Cell Histiocytosis Presenting with Pneumothorax and Diabetes Insipidus.

Secondary spontaneous pneumothoraces occur in patients with known underlying lung disease. Patients with emphysema, bullae, and cystic lesions in the lungs are at high risk of developing pneumothorax. Cystic lung diseases like Langerhans cell histiocytosis (LCH) can present with complications like pneumothorax. Other common presenting features include maculopapular rashes and bone lesions. It can also be associated with endocrinopathies, most commonly central diabetes insipidus (CDI). We here present a case of a 22-year-old male who presented with pneumothorax, polyuria, and polydipsia. He was diagnosed with LCH on transbronchial lung biopsy, associated with CDI, and was treated with thoracoscopy-guided autologous blood patch for persistent air leak and subcutaneous cytarabine.

A prediction model for reactivation of Langerhans cell histiocytosis based on machine-learning algorithms.

Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplasm characterized by the clonal proliferation of myeloid progenitor cells. The reactivation rate of LCH exceeds 30%. However, an effective prediction model to predict reactivation is lacking. To select potential prognostic factors of LCH and construct an easy-to-use predictive model based on machine-learning algorithms. Clinical records of LCH inpatients in the Second Xiangya Hospital of Central South University, from 2008 to 2022, were retrospectively studied. Seventy-six patients were classified into a reactivated/progressive group or a stable group. Clinical features and laboratory outcomes were compared, and machine-learning algorithms were used for building prognostic prediction models. Clinical classification (single-system LCH, multiple-system LCH, and central nervous system/lung LCH), level of anemia, bone involvement, skin involvement, and elevated monocyte count were the best performing factors and were finally chosen for the construction of the prediction models. Our results show that the above-mentioned five factors can be used together in a prediction model for the prognosis of LCH patients. The major limitations of this study include its retrospective nature and the relatively small sample size.

Histiocitosis de células de Langerhans en un paciente con lesión perianal. Caso clínico / Langerhans cell histiocytosis in a patient with perianal lesion. A case report

La histiocitosis de células de Langerhans es una expresión de células dendríticas mieloides, asociada a un componente inflamatorio significativo y compromiso sistémico variado. La edad más frecuente de presentación es entre 1 y 4 años, y predomina en el sexo masculino. Se comunica el caso de un niño de 5 años de edad cuya forma de presentación fue una lesión granulomatosa con fístula perianal, afectación pulmonar y de oído externo. El abordaje interdisciplinario permitió llegar al diagnóstico, realizar las intervenciones necesarias e iniciar el tratamiento adecuado.

Langerhans cell histiocytosis is an expression of myeloid dendritic cells, associated with a significant inflammatory component and varied systemic involvement. The most common age at presentation is between 1 and 4 years, and it prevails among male subjects. Here we describe the case of a 5-year-old boy who presented with a granulomatous lesion with perianal fistula and lung and external ear involvement. An interdisciplinary approach helped to make a diagnosis, provide the necessary interventions, and start an adequate treatment.

Mixed histiocytic disorders: Nature versus nurture?

Histiocytic diseases arise from MAPK mutations in myeloid progenitors. Depending on whether the progenitor follows a dendritic cell or macrophage/monocyte lineage the final histology results in Langerhans cell histiocytosis, Rosai-Dorfman disease or Erdheim-Chester disease. Commentary on: Friedman et al. Mixed histiocytic neoplasms: A multicentre series revealing diverse somatic mutations and responses to targeted therapy. Br J Haematol 2024;205:127-137.

Smoking-Related Interstitial Lung Disease and Emphysema.

Diagnosis and treatment of patients with smoking-related lung diseases often requires multidisciplinary contributions to optimize care. Imaging plays a key role in characterizing the underlying disease, quantifying its severity, identifying potential complications, and directing management. The primary goal of this article is to provide an overview of the imaging findings and distinguishing features of smoking-related lung diseases, specifically, emphysema/chronic obstructive pulmonary disease, respiratory bronchiolitis-interstitial lung disease, smoking-related interstitial fibrosis, desquamative interstitial pneumonitis, combined pulmonary fibrosis and emphysema, pulmonary Langerhans cell histiocytosis, and E-cigarette or vaping related lung injury.

Langerhans cell histiocytosis of the suprasellar region: diagnosis based on thyroid cytology.

Langerhans cell histiocytosis (LCH) may present as unifocal disease of the suprasellar region, with symptoms and signs of hypopituitarism, arginine vasopressin deficiency (AVP-D), and weight gain. Transcranial biopsy is necessary to define diagnosis and guide treatment decisions, but it is associated with significant morbidity. We describe a patient with Hashimoto thyroiditis and a single hypothalamic mass in whom LCH diagnosis was made by thyroid fine-needle aspiration cytology (FNAC) performed despite nonspecific findings in thyroid imaging, on the basis of a slightly elevated [18F]-fluorodeoxyglucose (FDG) avidity on PET/CT and volume increase during follow-up.

Clinical features and treatment outcomes of liver involvement in paediatric Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder in children, and liver involvement in LCH is rare. This retrospective study reported the clinical features and prognosis of patients with hepatic LCH. Liver involvement was defined by histopathological findings, liver dysfunction or abnormalities, or ultrasound imaging. A total of 130 patients (14.5%) with hepatic LCH out of 899 in the LCH population were enrolled. Patients with liver involvement had greater frequencies of skin, lung, hearing system, and haematologic system involvement, and hemophagocytic lymphohistiocytosis (P<0.001, 0.001, 0.002, 0.009, and <0.001, respectively). Overall survival and progression-free survival were lower in LCH patients with liver involvement than in those without liver involvement (P<0.001 and <0.001). In patients with liver involvement, the overall survival (OS) and progression-free survival (PFS) rates were lower in patients with cholangitis than in those without cholangitis (P<0.020 and 0.030). For the treatment response, the response rate of hepatic LCH patients to initial first-line therapy (n=89) was 22.5%. However, there was no significant difference in the response rate or recurrence rate between patients who shifted from first-line treatment to second-line treatment (n=29) or to targeted therapy (n=13) (P=0.453 and 1.000). The response rate of hepatic LCH patients who received initial second-line therapy (n=13) was 38.5%. Two of these patients subsequently experienced bone recurrence. The response rate of hepatic LCH patients who received initial targeted therapy (n=16) was 75.0%. Three patients subsequently experienced recurrence, including 2 in the bone and 1 in the liver and skin. A total of 39.3% of patients who received second-line treatment had severe myelosuppression (grade III-IV), and 50.8% had varying degrees of gastrointestinal events, whereas there was no severe toxicity in patients who received first-line treatment and targeted therapy. Four patients underwent liver transplantation because of liver cirrhosis. The patients' liver disease improved within a follow-up period of 18-79 months. This study demonstrated that LCH with liver involvement, especially cholangitis, indicates a poor prognosis. Targeted therapy provides a good treatment response and less toxicity. However, it may relapse after withdrawal. Liver transplantation is still a reliable salvage option for patients with end-stage liver disease.

Langerhans Cell Histiocytosis in Sphenoid Sinus: Uncommon Bone Involvement.

BACKGROUND Langerhans cell histiocytosis (LCH) is a rare and uncontrolled proliferation of dendritic cells of myeloid origin. The incidence of LHC was estimated at 5 cases per million children ages 0-15 years old. The most common places for this tumor are the jaw, vertebra, pelvis, and the extremities. The disease with multisystem involvement can present a mortality rate of 20% and one-third of children have multisystem involvement. We present a case with unusual bone involvement of the anterior cranial base with a challenging diagnosis and a complex surgical approach. CASE REPORT We report the case of a 6-year-old boy who manifested the disease with daily holocranial headache, worse in the frontal region and refractory to analgesia for 10 days, strabismus homonymous, diplopia, and right palpebral ptosis. The tumor affected the sphenoid sinus, internal carotid artery, and sella turcica, and made contact with the pituitary gland. A joint surgery with Otorhinolaryngology and Neurosurgery was performed by nasal endoscopic access to the skull base by means of the right medial turbinectomy (for the access) and right sphenoid opening, septectomy and opening of the left sphenoid to work with 4 hands and, after resection of lesion, inside the sphenoid. CONCLUSIONS This patient had rare bone involvement from LCH and atypical clinical presentation next to the important and delicate structures of the anterior skull base, but had a satisfactory outcome.

Nationwide Study of Factors Impacting Survival Outcome and Consequences in Children with Reactivation/Refractory Langerhans Cell Histiocytosis.

BACKGROUND: Disease reactivation/refractory remains a major challenge in managing Langerhans cell histiocytosis (LCH). Outcomes and late sequelae should be explored. METHODS: A multi-institutional retrospective study was conducted to describe clinical characteristics, predictive factors, outcomes and late sequelae of pediatric reactivation/refractory LCH in Thailand. RESULTS: In all, 47 patients were studied, 25 (53.2%) patients had disease reactivation and 22 (46.8%) patients had refractory LCH. The median reactivation and refractory time were 1.59 and 0.33 years from diagnosis, respectively (p <0.001). The most common site of reactivation/refractory was the bone (n = 26, 55%), and 20 (42.6%) patients developed late sequelae. The 5-year overall survival (OS) was 76.1%. Patients with reactivation and refractory LCH performed similarly in 5-year OS (88% vs. 63%, p = 0.055). Prognostic factors associated with mortality were liver, spleen, hematopoietic system and lung reactivation (p <0.05). Lung reactivation was the only independent risk factor associated with the survival outcome (p = 0.002). CONCLUSIONS: The outcomes of pediatric patients between reactivation and refractory LCH in Thailand were similarly desirable and mortality was minimal although late sequelae may evolve. Pulmonary reactivation/refractory was an independent risk factor associated with survival.

Advances in our understanding of genetic markers and targeted therapies for pediatric LCH.

INTRODUCTION: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm, encompassing a diverse clinical spectrum ranging from localized bone or skin lesions to a multisystemic life-threatening condition. Over the past decade, there has been an expansion in understanding the molecular biology of LCH, which translated into innovative targeted therapeutic approaches. AREAS COVERED: In this article, we will review the molecular alterations observed in pediatric LCH and the relationship between these molecular changes and the clinical phenotype, as well as targeted therapies in LCH. EXPERT OPINION: Mitogen-activated protein kinase (MAPK) pathway mutation is a hallmark of LCH and is identified in 80% of the cases. Notably, BRAFV600E mutation is seen in ~50-60% of the cases, ~30% has other MAPK pathway mutations, while 15-20% have no detected mutations. While the first line therapeutic approach is vinblastine and prednisone, targeted therapies - specifically BRAF/MEK inhibitors - emerged as a promising second-line salvage strategy, particularly when a mutation is identified. Most patients respond to BRAF/MEK inhibitors but at least 75% reactivate after stopping, however, most patients respond again when restarting inhibitors.

From mutation to management: Advancing Langerhans cell histiocytosis treatment through combination therapies.

The treatment landscape for relapsed Langerhans cell histiocytosis (LCH) is fraught with uncertainty due to a scarcity of data. Karri et al.'s study provides promising evidence that combining MAPK pathway inhibitors with chemotherapy could improve outcomes, even for patients with multiple relapses. Although larger studies are needed, this approach suggests a shift towards more aggressive, potentially curative strategies in the management of LCH. Commentary on: Karri et al. Clinical, radiological and molecular responses to combination chemotherapy with MAPK pathway inhibition in relapsed and refractory Langerhans cell histiocytosis. Br J Haematol 2024;204:1882-1887.

Juvenile xanthogranuloma manifesting with LCH-associated neurodegenerative disease-like radiological findings.

Here, we describe two patients with juvenile xanthogranuloma (JXG) manifesting with Langerhans cell histiocytosis (LCH)-associated neurodegenerative disease (ND)-like radiological findings. One patient showed typical radiological abnormalities at onset, which worsened with progressing central nervous system symptoms 7 years after LCH-oriented chemotherapy. Another showed spontaneous regression of clinical symptoms, with a transient radiological change 1 year after salvage chemotherapy for recurrence of JXG. These data regarding JXG-associated ND will facilitate future investigation of the disease, as well as development of therapeutic interventions.

Langerhans cell histiocytosis: NACHO update on progress, chaos, and opportunity on the path to rational cures.

Langerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder characterized by lesions with CD1a-positive/Langerin (CD207)-positive histiocytes and inflammatory infiltrate that can cause local tissue damage and systemic inflammation. Clinical presentations range from single lesions with minimal impact to life-threatening disseminated disease. Therapy for systemic LCH has been established through serial trials empirically testing different chemotherapy agents and durations of therapy. However, fewer than 50% of patients who have disseminated disease are cured with the current standard-of-care vinblastine/prednisone/(mercaptopurine), and treatment failure is associated with long-term morbidity, including the risk of LCH-associated neurodegeneration. Historically, the nature of LCH-whether a reactive condition versus a neoplastic/malignant condition-was uncertain. Over the past 15 years, seminal discoveries have broadly defined LCH pathogenesis; specifically, activating mitogen-activated protein kinase pathway mutations (most frequently, BRAFV600E) in myeloid precursors drive lesion formation. LCH therefore is a clonal neoplastic disorder, although secondary inflammatory features contribute to the disease. These paradigm-changing insights offer a promise of rational cures for patients based on individual mutations, clonal reservoirs, and extent of disease. However, the pace of clinical trial development behind lags the kinetics of translational discovery. In this review, the authors discuss the current understanding of LCH biology, clinical characteristics, therapeutic strategies, and opportunities to improve outcomes for every patient through coordinated agent prioritization and clinical trial efforts.

Congenital localized cutaneous Langerhans cell histiocytosis in a Holstein calf.

Distinct solitary dermal nodules, either covered by an alopecic, or sometimes ulcerated, epidermis, were noticed on the head of a stillborn Holstein calf. The head was submitted for autopsy, and the nodules were found to consist of homogeneous, diffuse pale-yellow, soft-tissue masses with distinct margins that elevated the epidermis above the adjacent skin. Histologically, the dermal nodules were well-delineated on the deep margin approaching the cutaneous muscle and consisted of perivascular neoplastic infiltrates of round cells that in some places coalesced into sheets that extended into the dermis and subcutis. Neoplastic cells separated adnexa and collagen. Immunohistochemistry revealed intense tumor cell expression of vimentin, Iba1, E-cadherin, and CD204; expression of CD18 was faint. The masses were diagnosed as Langerhans cell histiocytosis. Congenital cutaneous Langerhans cell histiocytosis has not been reported previously in cattle, to our knowledge, and should be included in the differential diagnosis of congenital nodular skin lesions.

Mixed histiocytic neoplasms: A multicentre series revealing diverse somatic mutations and responses to targeted therapy.

Histiocytic neoplasms are diverse clonal haematopoietic disorders, and clinical disease is mediated by tumorous infiltration as well as uncontrolled systemic inflammation. Individual subtypes include Langerhans cell histiocytosis (LCH), Rosai-Dorfman-Destombes disease (RDD) and Erdheim-Chester disease (ECD), and these have been characterized with respect to clinical phenotypes, driver mutations and treatment paradigms. Less is known about patients with mixed histiocytic neoplasms (MXH), that is two or more coexisting disorders. This international collaboration examined patients with biopsy-proven MXH with respect to component disease subtypes, oncogenic driver mutations and responses to conventional (chemotherapeutic or immunosuppressive) versus targeted (BRAF or MEK inhibitor) therapies. Twenty-seven patients were studied with ECD/LCH (19/27), ECD/RDD (6/27), RDD/LCH (1/27) and ECD/RDD/LCH (1/27). Mutations previously undescribed in MXH were identified, including KRAS, MAP2K2, MAPK3, non-V600-BRAF, RAF1 and a BICD2-BRAF fusion. A repeated-measure generalized estimating equation demonstrated that targeted treatment was statistically significantly (1) more likely to result in a complete response (CR), partial response (PR) or stable disease (SD) (odds ratio [OR]: 17.34, 95% CI: 2.19-137.00, p = 0.007), and (2) less likely to result in progression (OR: 0.08, 95% CI: 0.03-0.23, p < 0.0001). Histiocytic neoplasms represent an entity with underappreciated clinical and molecular diversity, poor responsiveness to conventional therapy and exquisite sensitivity to targeted therapy.

The plasma-soluble CSF1R level is a promising prognostic indicator for pediatric Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is a rare hematologic neoplasm characterized by the clonal proliferation of Langerhans-like cells. Colony-stimulating factor 1 receptor (CSF1R) is a membrane-bound receptor that is highly expressed in LCH cells and tumor-associated macrophages. In this study, a soluble form of CSF1R protein (sCSF1R) was identified by plasma proteome profiling, and its role in evaluating LCH prognosis was explored. We prospectively measured plasma sCSF1R levels in 104 LCH patients and 10 healthy children using ELISA. Plasma sCSF1R levels were greater in LCH patients than in healthy controls (p < .001) and significantly differed among the three disease extents, with the highest level in MS RO+ LCH patients (p < .001). Accordingly, immunofluorescence showed the highest level of membrane-bound CSF1R in MS RO+ patients. Furthermore, the plasma sCSF1R concentration at diagnosis could efficiently predict the prognosis of LCH patients treated with standard first-line treatment (AUC = 0.782, p < .001). Notably, dynamic monitoring of sCSF1R levels could predict relapse early in patients receiving BRAF inhibitor treatment. In vitro drug sensitivity data showed that sCSF1R increased resistance to Ara-C in THP-1 cells expressing ectopic BRAF-V600E. Overall, the plasma sCSF1R level at diagnosis and during follow-up is of great clinical importance in pediatric LCH patients.

Intestinal Langerhans cell histiocytosis presenting with symptoms similar to inflammatory bowel disease: a case report.

Background: Langerhans cell histiocytosis is a rare disease characterized by the abnormal proliferation of Langerhans cells within a single organ or multiple organs. This case report aims to improve the knowledge of the presentation of gastrointestinal Langerhans cell histiocytosis to facilitate the diagnosis and management of this rare disorder. Case presentation: A 19-month-old female presented with repeatedly mucinous bloody stools. The abdominal ultrasound revealed a slightly enlarged spleen. The initial colonoscopy revealed chronic enteritis with a very early onset inflammatory bowel disease. After anti-inflammatory treatment without improvement, an intestinal biopsy was performed at The Forth Affiliated Hospital of Zhejiang University. The final intestinal biopsy and histopathology examination confirmed the presence of Langerhans cell histiocytosis. After diagnosis, additional lung and head imaging examinations revealed no abnormalities. Her condition improved gradually after being treated with chemotherapy (vincristine and prednisone) and molecular-targeted drug(dalafinil) treatment. Conclusion: The clinical symptoms of Langerhans cell histiocytosis involving the gastrointestinal tract are not specific and may resemble symptoms observed in inflammatory bowel disease and other primary gastrointestinal tumors. Therefore, in cases of infants presenting with inflammatory gastrointestinal symptoms that do not resolve after treatment, a biopsy is essential to obtain a differential diagnosis.