Case Of Langerhans Cell Histiocytosis Research Articles

A case of Langerhans cell histiocytosis with hyperosmolar hyperglycemic syndrome

朗格汉斯组织细胞增生症（LCH）是一种可侵犯多器官多系统的罕见疾病，异质性大。本例患者因闭经在中医医院就诊未被识别，直至高血糖高渗状态急诊收入海南省人民医院内分泌科，结合垂体磁共振成像（MRI），多学科会诊考虑下丘脑肿瘤，予以手术治疗，组织病理显示大量淋巴细胞和浆细胞浸润，但未行免疫组化，误诊为淋巴细胞性垂体炎。此后因累及股骨而手术，病理证实LCH，并出现眼眶骨、皮肤和肝脏受累，虽经血液内科积极治疗但效果差，最终因多器官功能衰竭死亡。.

Suggested Case of Langerhans Cell Histiocytosis in a Cretaceous dinosaur

Susceptibility to diseases is common to humans and dinosaurs. Since much of the biological history of every living creature is shaped by its diseases, recognizing them in fossilized bone can furnish us with important information on dinosaurs’ physiology and anatomy, as well as on their daily activities and surrounding environment. In the present study, we examined the vertebrae of two humans from skeletal collections with Langerhans Cell Histiocytosis (LCH), a benign osteolytic tumor-like disorder involving mainly the skeleton; they were diagnosed in life, along with two hadrosaur vertebrae with an apparent lesion. Macroscopic and microscopic analyses of the hadrosaur vertebrae were compared to human LCH and to other pathologies observed via an extensive pathological survey of a human skeletal collection, as well as a three-dimensional reconstruction of the lesion and its associated blood vessels from a µCT scan. The hadrosaur pathology findings were indistinguishable from those of humans with LCH, supporting that diagnosis. This report suggests that hadrosaurids had suffered from larger variety of pathologies than previously reported. Furthermore, it seems that LCH may be independent of phylogeny.

Muscle Infiltrative Adult Multisystem Langerhans Cell Histiocytosis Detected on Fluorodeoxyglucose Positron Emission Tomography/ Computed Tomography - A Rare Case.

Langerhans cell histiocytosis (LCH) is a disease of unknown pathogenesis characterized by the accumulation of Langerhans cells which show immunopositivity for S-100 and CD1a. LCH with skeletal muscle involvement has been rarely described in literature. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is an important tool in identifying the sites of involvement in LCH. We present a rare case of muscle invasive LCH where 18F-FDG PET/CT showed involvement of multiple other sites such as the liver, bones, bone marrow, and possibly the thyroid gland in our case. Further, the current case also shows that liver involvement by LCH (possibly fibrotic phase) can be negative on PET but show lesions on CT.

Pediatric langerhans cell histiocytosis of the temporal bone: A rare case report and review of literature

Langerhans cell histiocytosis (LCH) is a rare cancer involving clonal proliferation of Langerhans cells (LCs) resembling epidermal dendritic cells. It can involve any organ or system. Temporal bone LCH is often confused with ear inflammatory lesions and malignant tumors. Diagnosis is based on clinical, radiological, and pathological findings. The definitive diagnosis is made on biopsy and by immunohistochemical demonstration of CD 1a and or Langerin positivity in the clonally neoplastic cells. The course of LCH is variable from spontaneous regression to repeated recurrences and death. The main form of treatment is chemotherapy. We describe a case of multifocal multisystem LCH in a 4-year-old child who presented with recurrent chronic suppurative otitis media and an external auditory canal polyp.

Langerhans Cell Histiocytosis of the Temporal Bone

Background: Langerhans cell histiocytosis (LCH) of the temporal bone is an uncommon disease that primarily affects the pediatric population; fewer than 40 adult cases have been reported in the literature. We present a rare case of LCH of the temporal bone in an adult patient and describe its clinical presentation, histopathologic findings, and management.Case Report: A 21-year-old male presented to the emergency department with progressively worsening right-sided ear pain refractory to outpatient oral antibiotics. Physical examination revealed mastoid tenderness and decreased right-sided hearing. Computed tomography (CT) scan suggested coalescent mastoiditis; the patient responded to inpatient antibiotics and was discharged. He returned 9 days later with persistent symptoms. Repeat CT scan revealed an osteolytic lesion on the temporal bone, and the patient was indicated for surgery. Intraoperative histology was consistent with LCH. Subsequent surveillance magnetic resonance imaging (MRI) suggested persistence of disease, and the patient responded to a course of radiation. Three months following radiotherapy, surveillance MRI and positron emission tomography scans revealed no evidence of recurrent disease.Conclusion: Diagnosis of LCH of the temporal bone is frequently delayed because of misdiagnosis of more common otologic diseases, including otitis media, otitis externa, and mastoiditis. The clinician's index of suspicion for LCH should be high if imaging reveals an osteolytic defect of the temporal bone; confirmation is via immunohistostaining of biopsy samples. The majority of cases respond to surgery, radiation, chemotherapy, or combination therapy, but delays in diagnosis and treatment may increase morbidity. Increased physician awareness of LCH of the temporal bone, particularly among adults, may help to improve patient outcomes.

Retrospective study of Langerhans cell histiocytosis in ear, nose and neck.

Langerhans cell histiocytosis (LCH) is a rare clinical disorder. We retrospectively analysed the clinical manifestations, treatments and prognoses of LCH cases involving the ear, nose, and neck. 28 cases with confirmed LCH in ear, nose or neck were reviewed. We recorded patient age, sex, chief complaints, accompanying symptoms, lesional sites, radiological data, treatments and pathologies. Whole-exome sequencing was performed on the patient diagnosed with LCH and Treacher-Collins syndrome (TCS). The mean age was 14.86years. Most LCH was in the ear (93%), usually in the mastoid. The most common symptoms were an ear mass and a purulent discharge. Imaging was not very useful. Treatments included surgery, chemotherapy, and radioactive particle implantation. Some cases exhibited multisystem involvement. Most patients enjoyed good prognoses. One patient was diagnosed with both temporal LCH and TCS. Whole-exome sequencing revealed a heterozygous c.261_272delAGGTACCCTTCC(p.87_91delRGTLPinsR) mutation in exon 2 of the POLR1D gene (NM_015972). LCH mostly occurs in children. In head and neck it affects principally the mastoid part of the temporal bone. Treatments include surgery, chemotherapy, and irradiation. Most patients enjoy good prognoses. LCH accompanied by TCS is rare and increases the difficulty of diagnosis; molecular data aid in TCS identification.

BRAFV600E-Positive Precursors As Molecular Markers of Bone Marrow Involvement in Pediatric Langerhans Cell Histiocytosis

Introduction: The BRAF mutation V600E, the most common somatic mutation in Langerhans cell histiocytosis (LCH), has been reported in approximately 50% of LCH patients and is associated with certain high-risk clinical features. Precursors harboring this mutation can differentiate into Langerhans cells resulting in infiltrates in multiple organs under inflammatory conditions. However, BRAF status in the bone marrow of pediatric LCH patients is unclear. The present study examined somatic mutations in paired tumor and bone marrow samples, using a highly sensitive assay involving next-generation targeted sequencing and droplet digital polymerase chain reaction (PCR) for pediatric LCH patients. Methods: Between 1996 and 2019, in total of 17 Japanese pediatric patients with LCH were enrolled. The male/female ratio was 7/11. Ages of onset of LCH were median 13 months (range 5-193 months). At diagnosis of LCH, 2 patients were positive for risk organ involvement, 15 were negative. We retrospectively performed mutational analyses of 17 LCH cases using formalin-fixed paraffin-embedded LCH tumor specimens to provide templates for PCR-based targeted amplicon sequencing with customized primers to detect mutations in exons 12 and 15 in BRAF, and exons 2 and 3 in MAP2K1. Thereafter, we identified somatic mutations in the 17 paired bone marrow samples via droplet digital allele-specific PCR, targeting BRAF V600E and BRAF exon 12 in-frame deletion 496-500 (Ex12 in-del). Results: We detected BRAF V600E in 11 of 17 tumor samples (65%) and the BRAF Ex 12 in-del in 3 of 17 tumors (18%). We identified BRAF V600E in bone marrow samples in 10 of the 11 cases (90%) with the mutation in the tumor at low variant allele frequency (median 0.25%, range 0.14-7.0%). BRAF Ex 12 in-del was not detected in the bone marrow. Cases with detectable bone marrow involvement included eight patients with multi-system disease affecting multiple organs, one patient with multi-focal bone disease, and one patient with single-system disease. Clinical phenotypes including relapse did not correlate with BRAF V600E upon detection in the bone marrow. Conclusion: We established the sensitive assay based on PCR-based targeted NGS for detecting somatic mutations in LCH even accessible for formalin-fixed, paraffin-embedded clinical specimens. Bone marrow involvement is frequently detectable at the molecular level in pediatric LCH with the BRAF V600E mutation. A prospective study is warranted to evaluate the clinical impact of mutational burden in bone marrow. Disclosures Kudo: Unum Therapeutics: Patents & Royalties. Imai:Juno Therapeutics: Patents & Royalties.

Delayed Diagnosis of Langerhans Cell Histiocytosis Presenting With Thyroid Involvement and Respiratory Failure: A Pediatric Case Report

Langerhans cell histiocytosis (LCH) is a rare disease with localized to disseminated clinical features. Thyroid involvement in LCH is rare and presenting as either a single-organ or multisystem disease, it is usually misinterpreted as another thyroid disorder. Therefore, the LCH diagnosis is often delayed. We report a pediatric case of LCH with thyroid involvement as the initial clinical manifestation progressing to respiratory failure. Clinicians should note insidious extrathyroidal laboratory abnormalities and consider infiltrative thyroid diseases, such as LCH. Systematic clinical and laboratory investigations are needed to prevent delayed diagnosis because the classic features of LCH may become evident only over time.

2256 A Unique Case of Concurrent Langerhans Cell Histiocytosis and Autoimmune Hepatitis Complicated by a Lower Gastrointestinal Bleed

INTRODUCTION: Autoimmune hepatitis (AIH) and Langerhans Cell Histiocytosis (LCH) are two independently rare disease processes that can have similar presentations. There have been no documented cases of concurrent AIH and LCH. We illustrate a complex case that required an interdisciplinary approach to ultimately diagnose and treat the patient. This unique presentation contributes to the medical literature of the two rare diseases. CASE DESCRIPTION/METHODS: 20-year-old male with no significant history presented with worsening jaundice, diffuse, pruritic rash, and abdominal pain over one month. On admission, the patient’s labs showed significantly elevated liver function tests (LFTs), eosinophilia, and anemia. Exam was notable for diffuse lymphadenopathy (LAD), hepatosplenomegaly, and a diffuse, non-blanching, morbilliform rash. Interdisciplinary workup was notable for positive anti smooth muscle antibody (ASMA), and anti-neutrophilic antibody (ANA). A liver biopsy was done and showed findings of severe inflammation with interface activity, consistent with AIH. A lymph node (LN) biopsy showed findings consistent with LCH, including histiocyte clusters (HC). He was started on high dose steroids with LAD/LFT improvement; yet, his hospital stay was complicated by a gastrointestinal (GI) bleed requiring a hemicolectomy. The patient was ultimately transferred to a larger referral center where he continued to improve with steroids and was ultimately discharged with close follow up. DISCUSSION: LCH tends to affect skin or bones; however, LN and GI involvement are relatively uncommon. This case was notable for a LN biopsy showing HC with reniform nuclei, nuclear grooves and eosinophils with immunohistochemical stains positive for S-100, CD1a, fascin, langerin, CD45, and CD68, consistent with LCH. The resected colon showed atypical histiocyte proliferation positive for fascin, CD4, and CD68. Key findings can help support a diagnosis of AIH, such as elevated LFTs, ASMA, and ANA, as well as a liver biopsy showing inflammation with interface activity, eosinophils, plasma cells, and characteristic fibrosis, all of which were found in this patient. In either case, steroids were indicated and ultimately helped the patient clinically improve. Such a case is distinct since the LCH appeared to be a systemic process, with findings of diffuse LAD, questionable GI involvement, and no liver involvement, but rather concurrent AIH. This case was further notable for a complication of a lower GI bleed requiring a hemicolectomy.

Hepatic Langerhans Cell Histiocytosis (LCH) Mimicking Antimitochondrial Antibody (AMA)–Negative Primary Biliary Cholangitis (PBC), Presenting as a Harbinger of Multisystem LCH

Abstract Objectives LCH is a rare systemic disorder characterized by an infiltration of CD1a+/Langerin+ histiocytes. LCH commonly involves bone, skin, and lymph nodes in children. Hepatic involvement is rarely observed in multisystem LCH. We describe an exceptional case of hepatic LCH in an adult, mimicking AMA-negative PBC, preceding the diagnosis of multisystem LCH. Methods A 65-year-old man presented with intermittent pruritus, weakness, dyspnea, fever, and chills that have been progressive for 4 years. Physical examination was unremarkable. Laboratory work revealed elevated alkaline phosphatase (471 U/L; ref 40-120 U/L), GGT (271 U/L; ref 0-41 U/L), total bilirubin (2.0 mg/dL; ref 0.0-1.2 mg/dL), and direct bilirubin (1.1 mg/dL; ref 0.0-0.3 mg/dL). Indirect bilirubin, AST, and ALT were within normal limits. Liver biopsy was performed. Results Liver biopsy showed lobular and portal nonnecrotizing granulomas with one “florid duct lesion” with duct injury, suggestive of PBC. Tests for autoimmune diseases including AMA were negative. ERCP was negative for biliary obstruction. One month after the liver biopsy, he developed flaking, red, and burning rash on the right scalp, forehead, and epigastric skin. A skin biopsy at an outside institution revealed dermal and epidermal infiltration of CD1a-positive histiocytes with indented nuclei and pale eosinophilic cytoplasm, consistent with LCH. Subsequent reexamination of the liver biopsy showed that the histiocytes within the florid duct lesion were positive for CD1a and S-100, while the remaining granulomas were negative. The following day, a small focus of LCH was noted in his gastric biopsy performed for gastritis symptoms. Conclusion Hepatic LCH may mimic AMA-negative PBC histologically and clinically, and may present as a harbinger of multisystem LCH. While rendering the diagnosis would be challenging without prior history of LCH and with focal involvement, awareness of such presentation and communication with clinical colleagues may be helpful.

Pancreatic Langerhans cell histiocytosis in a cat

In contrast to pulmonary Langerhans cell histiocytosis (LCH), which is a proliferative disorder of Langerhans cells that affects the lungs and other organs of cats, LCH involving a single organ system has not been documented in cats, to our knowledge. Herein we describe a case of pancreatic LCH in a 9-y-old castrated male Domestic Shorthaired cat that was evaluated for possible renal transplantation. The cat was hypoglycemic, hyperinsulinemic, and azotemic. Ultrasound examination revealed a diffusely enlarged, normoechoic pancreas. The cat was euthanized because of severe renal azotemia and the possibility of pancreatic neoplasia. Grossly, the pancreas was enlarged, and both kidneys were pale white, firm, and had irregular capsular surfaces. Histologically, the pancreas was expanded with interlobular, intraparenchymal, and ductal clusters of round-to-polygonal cells admixed with fibrous connective tissue and scattered lymphocytes. Infiltrating cells had a moderate amount of eosinophilic cytoplasm, round-to-indented nuclei with finely stippled chromatin and 1 or 2 nucleoli, and were strongly immunoreactive for CD18, ionized calcium-binding adapter molecule 1, and e-cadherin. The morphologic and immunohistochemical features of the pancreatic changes were consistent with single-system LCH.

BRAF V600E mutation in childhood Langerhans cell histiocytosis correlates with multisystem disease and poor survival

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia of children with systemic involvement and poor outcome. The altered RAS-RAF-MEK-ERK cell signalling pathway due to somatic mutation of BRAF V600E is the most common genetic abnormality associated with the disease. In the current study, we highlight the frequency of BRAF V600E in our cohort of LCH cases (n = 31) and its relation with clinical outcome.On Real-Time PCR and Sanger sequencing, BRAF V600E was detected in 6/31 (19%) patients. All cases positive for BRAF V600E mutation had multisystem involvement/disseminated disease compared to BRAF mutation negative cases (100% v/s 41%, p = 0.0348). Univariate analysis also revealed significant correlation of mutation positivity with risk category (p = 0.09). The event free survival and overall survival at 36 months for BRAF mutation positive group compared to mutation negative group was 17% v/s 72% (Log rank test p = 0.0110) and 32.5% v/s 82% (p = 0.0330), respectively.In our study, BRAF V600E positivity was low (19%) however, all positive cases had multisystem involvement and a poor three year survival confirming BRAF V600E to be a poor prognostic marker.

Blueberry muffin baby: A case of Langerhans cell histiocytosis

Blueberry muffin baby: A case of Langerhans cell histiocytosis

Clinical analysis of pediatric Langerhans cell histiocytosis with craniofacial bone involvement

Objective To investigate the clinical characteristics and outcomes of pediatric Langerhans cell histiocytosis (LCH) with craniofacial bone involvement. Methods A retrospective analysis was performed on 145 pediatric LCH patients with craniofacial bone involvement registered at Beijing Children′s Hospital Affiliated to Capital Medical University from January 2007 to July 2013.The patients were divided into 2 groups: central nervous system risk craniofacial bone involvement group(CNS-RISK) and non-central nervous system risk craniofacial bone involvement group(non-CNS-RISK). All patients were assessed at 5 weeks, 11 weeks, 25 weeks and 52 weeks respectively after chemotherapy started, and 3 months, 6 months, 1 year and 3 years after chemotherapy withdrawal.Statistics and related risk analysis was performed respectively. Results A total of 145 craniofacial bone involved LCH cases were included, which was composed of 62.5% of 232 LCH cases hospitalized during the same period.The median age of these patients was 29 months, and median follow-up time period was 31 months.The most commonly involved craniofacial bone was parietal bone(78 cases, 53.8%), followed by temporal bone(59 cases, 40.7%) and frontal bone(57 cases, 39.3%). The onset age was significantly different (26 months vs.54 months, Z=-2.777, P<0.05) between CNS-RISK group (103 cases) and non-CNS-RISK group (42 cases). Moreover, compared with non-CNS-RISK group, CNS-RISK group showed higher ratio of patients classified as multisystem involvement of risk organs (72/103 cases, 69.9%)vs.(15/42 cases, 35.7%)(χ2=16.908, P<0.05), and a higher rate of overall relapse rate (45/103 cases, 43.7%) vs. (7/42 cases, 16.7%) (χ2=9.427, P<0.05), a lower survival rate of 3-year relapse-free survival rate [(66.9±5.7)% vs.(88.2±7.8)%, Z=2.205, P<0.05]. The incidence of diabetes insipidus was 13.7% in 232 LCH patients.Compared with patients without craniofacial bone involvement, patients with craniofacial bone involvement demonstrated a higher rate of diabetes insipidus [(27/145 cases, 18.6%) vs.(5/87 cases, 5.7%), χ2=7.579, P=0.006]. But the incidence of diabetes insipidus showed no statistical difference between CNS-RISK group and non-CNS-RISK group (21.3% and 11.9%, χ2=1.760, P=0.185). Diabetes insipidus was not found in single system LCH with Single-Bone CNS-RISK lesions.Till the end of follow-up, 1 out of 145 patients died.Among 145 patients, 5 cases had a single-bone CNS-RISK lesion.They received systemic chemotherapy.One showed reactivation, and none of them died.Multivariate analysis of variance showed that all the independent factors indicating diabetes insipidus included parietal bone, frontal bone, maxilla and mandible involvement(HR=2.697, 3.487, 5.425, all P<0.05), while independent factors indicating relapse included temporal bone, maxilla and mandible involvement(HR=3.712, 3.380, all P<0.05). Conclusions Among involved craniofacial bones, the parietal bone is most commonly involved.LCH occurs averagely at an earlier age in CNS-RISK group, along with lower 3-year relapse-free survival rate, high relapse rate, and more patients classified as multisystem LCH involvement of risk organs.The incidence of diabetes insipidus in children with craniofacial bone involvement with single system CNS-RISK is low.Patients with the parietal bone, frontal bone, maxilla and mandible involvement at diagnosis are at a increasing risk a significantly to develop DI during the course of disease. Key words: Langerhans cell histiocytosis; Child; Craniofacial bone; Clinical characteristics.

Pulmonary Langerhans cell histiocytosis in adults: A case report.

BACKGROUNDLangerhans cell histiocytosis (LCH) is a rare disease of unknown aetiology. While it may affect any organ of the body, few cases of solitary lung involvement are published in the literature. Here, we report a rare case of pulmonary LCH (PLCH) in an adult.CASE SUMMARYA 52-year-old male presented to hospital in July 2018 with complaints of progressively worsening cough with sputum, breathlessness, easy fatigability, and loss of appetite since 2016, and a 32-year history of heavy cigarette smoking (average 30 cigarettes/d). Physical examination showed only weakened breathing sounds and wheezing during lung auscultation. Chest computed tomography (CT) showed irregular micronodules and multiple thin-walled small holes. Respiratory function tests showed a slight decrease. Ultrasonic cardiogram showed mild tricuspid regurgitation and no pulmonary hypertension. Fibreoptic bronchoscopy was performed with transbronchial biopsies from the basal segment of right lower lobe. LCH was confirmed by immunohistochemistry. The final diagnosis was PLCH without extra-pulmonary involvement. We suggested smoking cessation treatment. A 3-mo follow-up chest CT scan showed clear absorption of the nodule and thin-walled small holes. The symptoms of cough and phlegm had improved markedly and appetite had improved. There was no obvious dyspnoea.CONCLUSIONImaging manifestations of nodules, cavitating nodules, and thick-walled or thin-walled cysts prompted suspicion of PLCH and lung biopsy for diagnosis.

Relevance of Bone Scintigraphy in the Diagnostic Algorithm for Examining Treatment-Naive Pediatric Patients with Langerhans Cell Histiocytosis: a Retrospective Cohort Study

Background. Histiocytosis is a heterogeneous group of rare diseases of unknown etiology. Langerhans cell histiocytosis (LCH) is characterized by an abnormal proliferation of histiocytes (activated dendric cells and macrophages). LCH is the most common form of histiocytosis, it is a potentially fatal diseases. Early detection of LCH plays an important role in its prognosis and outcome. However, the role of advanced methods of nuclear medicine in diagnosis of LCH is still to be researched. We have long-term experience in observing pediatric patients with LCH. Taking into the account the difficulty of diagnostic task for bone scintigraphy in identifying lytic bone destruction, we stated the following objective of the study. Objective. Our aim was to perform retrospective analysis of bone scintigraphy examinations of treatment-naive pediatric patients with LCH and calculate the diagnostic efficacy of bone scintigraphy. Methods. We retrospectively analyzed 55 examinations of treatment-naive pediatric patients (the median age was 5.9 years) with proven case of LCH (2014–2018). Results. During examination we visualized 82 lesions with pathological level of accumulation of radiopharmaceutical in 55 patients. 78 with high level of accumulation (&gt;120%); 3 with slightly increased level of accumulation (100–120%) and 1 with lower than normal level of accumulation (&lt;100%). The median level of accumulation of radiopharmaceutical was 276%: max. level of accumulation was 1422% (patient with subtotal involvement of femoral bone), min. — 60% (patient with lytic destruction in orbital bone). During X-Ray we found out 91 pathological focuses of bone lytic destruction. In 3 patients with polyostotic form we found extra focuses on scintigraphy, which were confirmed with following examination and X-Ray. 8 lesions were not found on scintigraphy in 8 patients. Сonclusion. Bone scintigraphy with 99mTc-MDP in treatment-naïve pediatric patients with proven case of LCH showed sensitivity — 91.0%, specificity — 50.0%, NPV — 11.1%, and PPV — 98.8%.

Progress towards molecular-based management of childhood Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is characterized by inflammatory lesions containing abundant CD1a+ CD207+ histiocytes that lead to the destruction of affected tissues. This disease has a remarkable pleiotropic clinical presentation and most commonly affects young children. Although the current mortality rate is very low for childhood LCH patients (<2%), reactivation frequently occurs after a long period of disease control and the rates of permanent complications and sequelae remain high. Advances in genomic sequencing technologies in this past decade have highlighted somatic molecular alterations responsible for the disease in around 80% of childhood LCH cases. More than half of these cases harbored the BRAFV600E mutation, and most other mutations also concerned proteins involved in the MAPKinase pathway. In addition to improving what is known about the LCH pathology, this molecular knowledge provides opportunities to optimize patient management. The BRAFV600E mutation is associated with more severe presentations of the disease, a high reactivation rate, and a high permanent complication rate; this mutation therefore paves the way for future stratified management approaches. These therapies may be based on the patient's molecular status as well as other clinical characteristics of the disease that are independently associated with undesired events. Moreover, as observed in patients with solid tumors, the BRAFV600E allele can be detected in the circulating cell-free DNA of patients with severe BRAFV600E-mutated LCH. Quantification of the plasmatic BRAFV600E load for this group of patients can precisely monitor response to therapy. Finally, targeted therapies, such as BRAF inhibitors, are new therapeutic options especially designed for refractory multisystemic LCH involving risk organs. However, the long-term efficacy, long-term tolerance, optimal protocol scheme, and appropriate modalities of administration for these innovative therapies for children still need to be defined, a huge challenge.

Head and neck Langerhans cell histiocytosis: two case reports and review of the literature

Langerhans cell histiocytosis (LCH) is an inflammatory neoplasia of myeloid precursor cells driven by mutations in the mitogen-activated protein kinase (MAPK) pathway. It can present as single or multisystem LCH. It occurs in 0.5–5.4 per million people. While it can occur at any age, it is more common in children, predominantly males, under the age of 4 years. The unifocal single system variety is the most prevalent and least aggressive presentation, making up to 70% of cases. It can affect bone (80%), lymph nodes (5–10%) or lungs (15%). The mandible and sphenoid are the least common locations; therefore, when present, it could be easily mistaken for a variety of pathologies. Depending on the clinical features, treatment can range from simple observation to chemotherapy and/or radiation. We present 2 cases of unifocal single system LCH located at the mandible and skull base, and describe the diagnostic work up and treatment.

Cytological diagnosis of Langerhans cell histiocytosis: A series of 47 cases.

Langerhans cell histiocytosis (LCH) is a rare disease affecting predominantly children and young adults but can be found in any age group. Diagnosis of LCH is often difficult and can be delayed because of its rarity. The present study highlights the cytomorphological features in a large cohort of cases. An accurate cytological diagnosis may avoid unnecessary biopsy and guide appropriate management. Fourty seven (47) cases of LCH diagnosed on cytological material & fine-needle aspiration (FNA) over a period of 14 years (2003-2016) were retrieved from the archives. The cytological smears were evaluated and microscopic findings collected by semi-quantitative assessment done by two different pathologists RESULT: The age at the diagnosis of the patients ranged from 9 months to 28 years. The majority of cases were in the age group of 0-5 years. The most common site was head and neck region, which included cervical lymphadenopathy and scalp swelling. Two cases were diagnosed each from inguinal lymph node and bronchio-alveolar lavage (BAL). Cytological smears in the majority of the cases were moderate to highly cellular (58%) and showing abundant Langerhans cell in (72%) of cases. Areas of necrosis were seen in 38%, while 78% of cases showed giant cells. The majority of cases showed mild eosinophilia (61%), sparse lymphocytosis (83%) and mild neutrophilic infiltration (64%). There were 1-2 mitoses per 10 high power field in 12 cases (25.5%). No abnormal mitoses were identified. The presence of cells with features of Langerhans cells associated with the expression of selected immunohistochemical markers allow the diagnosis of LCH on cytological samples, sparing more invasive procedure as a biopsy.

BRAF V600E Mutation: A Significant Biomarker for Prediction of Disease Relapse in Pediatric Langerhans Cell Histiocytosis.

Langerhans cell histiocytosis (LCH) is a rare disease presenting with usually a localized disease but sometimes a widespread aggressive disorder especially in children. Among the somatic mutations in RAF-MEK-ERK pathway, especially BRAF mutation has been detected so far in LCH. We aimed in this study to investigate the prognostic significance of the mutations of target genes playing a role in the RAF-MEK-ERK pathway in pediatric LCH. Mutation analyses were performed on tumor DNA extracted from formalin-fixed paraffin-embedded biopsy specimens of 38 pediatric LCH cases using a direct sequencing technique for BRAF, ARAF, MAP2K1, and MAP3K1 genes. The mutational status was correlated statistically with survival, clinical progression (disease relapse), and the established clinical prognostic parameters of LCH such as age, gender, localization, multisystem disease, central nervous system risk lesions, and risk organ or special-site involvement. BRAF V600E mutation was detected in 14 cases (36.8%), whereas ARAF mutation was found in only 1 case. No mutations were identified for MAP2K1 and MAP3K1 genes. The association of BRAF V600E mutation was significant in children with multisystem disease, younger age (<2 years), skin, and special organ involvement. BRAF V600E mutation was an independent predictive parameter for disease relapse. We therefore conclude that BRAF V600E mutation may be a significant marker for predicting disease progression in LCH and a candidate for targeted therapy for children with disease relapse and multisystem disease.