Diagnosis Of Langerhans Cell Histiocytosis Research Articles

Bone Scintigraphy in the Examining of Treatment-Naive Pediatric Patients With Langerhans Cell Histiocytosis

Introduction: Histiocytosis is a heterogeneous group of rare diseases of unknown etiology. LCH is characterized by an abnormal proliferation of histiocytes (activated dendric cells and macrophages). Langerhans cell histiocytosis (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.Purpose: Retrospective and prospective analysis of bone scintigraphy examinations of treatment-naive pediatric patients with LCH and calculate the diagnostic efficacy of bone scintigraphy. Material and methods: We analyzed 60 examinations of treatment-naive pediatric patients with proven case of LCH (2014-2019). The scanning was performed using whole body mode, 3 hours after intravenous injection of bone-seeking radiopharmaceutical 99mTc-MDP on Symbia E, T2 (Siemens, Germany). The median age was 5.6 years.Results: During examination we visualized 88 lesions with pathological level of accumulation of radiopharmaceutical in 60 patients. 84 with high level of accumulation (>120 %); 3 with slightly increased level of accumulation (100–120 %) and 1 with lower than normal level of accumulation (<100 %). The median level of accumulation of radiopharmaceutical was 268 %. 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 97 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.Сonclusions: We evaluated diagnostic accuracy of bone scintigraphy with 99mTc-MDP in treatment-naïve pediatric patients with proven case of LCH. Sensitivity, specificity, NPV and PPV — 91.6, 50.0, 11.1, 98.6 %, respectively.

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.

Pulmonary Langerhans cell histiocytosis with inguinal abscess: Unusual presentation

We report a case of a 30-year-old man who was treated as recurrent right inguinal abscess following a 2-month history of right inguinal swelling and intermittent fever with no respiratory symptoms. Resection of his right inguinal lymph node and the histopathological analysis revealed the diagnosis of Langerhans cell histiocytosis. In addition, the CT of the thorax showed presence of bilateral cystic lung changes consistent with pulmonary Langerhans cell histiocytosis.

Otological manifestations of Langerhans cell histiocytosis in a child - An enigma that persists!

Langerhans cell histiocytosis (LCH) is a rare nonmalignant entity commonly seen in the pediatric population which encompasses a variety of clinical presentations. Otological involvement in LCH is uncommon which can be manifested as symptoms similar to otomastoiditis or malignancy, thus diagnosis is often delayed. Herein, we report a 1-year 7-month-old boy presented with unresolving left otorrhea complicated with left postauricular swelling. Otoscopic examination revealed granulation tissue in the left external auditory canal. Initial diagnosis of left otomastoiditis was made until high-resolution contrast-enhanced computed tomography of the temporal bone showed soft-tissue masses occupying bilateral mastoids with bony destruction. Histopathological examination with immunohistochemical staining expressed CD1a cytoplasmic immunoreactivity. The diagnosis of LCH was made. This report serves to highlight such a rare clinical entity which often masquerades as other otological diseases and hence becomes a diagnostic challenge in the pediatric population.

Langerhans cell histiocytosis of the mandible – A rare case report

Langerhans cell histiocytosis (LCH) is a rare idiopathic disease that is characterized by the clonal proliferation of bone marrow-derived Langerhans cells. It usually occurs in children at an incidence of 2.6–5.4/10,00,000 children/year. The disease occurs with a slight male predilection. The peak age ranges from 1 to 4 years. The common oral findings include the gingival enlargement, oral ulcers, and loosening of teeth. The variable radiographic appearance mimicking odontogenic cyst, osteomyelitis, or a malignancy poses a diagnostic challenge. This rare case report emphasizes on the differential diagnosis of LCH.

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.

Langerhans cell histiocytosis: Diagnosis and Management

Langerhans cell histiocytosis (LCH) is a rare disorder characterized by abnormal clonal proliferation of Langerhans dendritic cells. The incidence of LCH is 1 to 3 cases per 1 million children worldwide, and occurs most frequently in children of 1–4 years of age. The etiopathogenesis of LCH, whether it is neoplastic or reactive, is still controversial. Langerhans cell histiocytosis has a wide spectrum of clinical features, and dermatological abnormalities usually occur early. The most frequent lesions are elevated yellowish-red translucent papules about 1–2 mm in diameter and generally located in seborrheic areas. The most recent classification (the Histiocyte Society study 2017) categorized LCH into four groups; a single system with involvement of unifocal or multifocal organs, lung LCH, and multi-system LCH with either low- or high-risk multiorgan involvement. The definitive diagnosis of LCH are typical morphology along with Birbeck granules and/or positive results on CD1a antigen stain on cells found on lesions. Treatment of LCH is multimodal, determined based on age, extent of lesion, organ involvement, and organ location. Keywords: histiocytosis, Langerhans cells, dendritic cells, children

AN ULCER AFFECTING THE GINGIVA AND HARD PALATE: AN INTERESTING CLINICAL PRESENTATION OF LANGERHANS CELL HISTIOCYTOSIS

A 37-year-old white female patient was referred for diagnosis of a lesion on alveolar ridge that extended to the hard palate. In reviewing her medical history, the patient reported headaches that led her to have a computed tomography (CT) scan performed. As a result, fibrous dysplasia of the ethmoidal sinus was diagnosed. Physical examination revealed an ulcerated lesion, with irregular contours, erythroplasic areas, partially covered by fibrin membrane, and without pain. Radiographic examination revealed the destructive character of the lesion, evidenced by the presence of bone loss between teeth 15 and 16. An incisional biopsy was performed and histopathologic examination revealed the presence of an intense proliferation of epithelioid histiocytic cells in addition to eosinophils and dispersed mononuclear cells. The diagnosis of Langerhans cell histiocytosis was established. The patient was referred to the oncologist for treatment.

Specific Guidelines Including Multidisciplinary Approach Is Critical of Management of Langerhans Cell Histiocytosis in Adults

The knowledge of Langerhans Cell Histiocytosis (LCH) is based on pediatric studies. Adults with LCH are usually treated with pediatric protocols. In 2001, guidelines for adults with LCH (GIMEMA LCH 2001) were proposed, in order to standardize the diagnostic and therapeutic approaches for this category of patients. The aims of this retrospective study are: a) to evaluate the role of a multidisciplinary assessment in adults with LCH, according to the GIMEMA LCH 2001 guidelines, and b) to analyze the results obtained with the GIMEMA LCH 2001 guidelines and those obtained with pediatric protocols. Pts aged >18 years with a diagnosis of LCH (S-100+, CD1a+, CD207+) managed at our Institution since 1985 to 2018 were considered. As diagnostic and treatment approaches, two different strategies were used over time: the GIMEMA LCH 2001 guidelines and the pediatric protocols. The GIMEMA LCH 2001 guidelines included a multidisciplinary diagnostic work-up with complete odontostomatologic, pulmonary and endocrinologic assessments; treatment strategy consisted of: wait and see or local therapy in unifocal single system (SS), indomethacin in bone multifocal SS and vinblastine combined with low-dose prednisone (PDN) in multi-system (MS), PDN in pulmonary honey-combing disease (PHCD) and cladribine in central nervous system involvement. DAL-HX 83 and 90, LCH-I and LCH II were the pediatric protocols utilized over time. Response to treatment was defined as complete (CR) or intermediate (IR). Persistence of the symptoms and/or appearance of new lesions were defined no response (NR). Progression was considered the appearance of symptoms and/or new lesions after initial response. One-hundred-thirty-one LCH pts (females 72, males 59) with a median age at diagnosis of 36 years (range 18 - 71) were considered. Median follow up was 43 months (range 12 - 330). One-hundred-seven patients were managed according to the GIMEMA LCH 2001 guidelines, 16 of them previously treated with a pediatric protocol. Pulmonary and/or oral involvements were identified in 31/107 (29%) and 12/107 (11%) patients, respectively, 5/16 (31%) and 3/16 (19%), respectively, of previously treated asymptomatic patients. Ninety-one newly diagnosed patients (median age at diagnosis: 36 years) were treated according to the GIMEMA LCH 2001 guidelines and 40 (median age at diagnosis: 33 years) were managed with pediatric protocols. All patients treated with the GIMEMA LCH 2001 were evaluable for response. In particular, all patients with SS-LCH achieved a response (100%), that was complete in 20/26 (76.9%) unifocal-SS and in 10/14 (71.4%) multifocal-SS. All but one patient with MS-LCH reached a response that was complete in 22/45 (48.9%). Of 6 pts with PHCD, 5 had a IR and one a CR. No pt presented CNS involvement at initial diagnosis. Thirty-nine of 40 pts managed with pediatric protocols were evaluable for response. All 13 pts with SS-LCH had a response that was complete in 6 (46.1%). Among 26 patients with MS-LCH, 3 of them with organ risk involvement achieved a response, that was complete in 1, while among 23 patients without organ risk, 12 (52.2%), 8 (34.8%) and 3 (13%) had a CR, IR and NR, respectively. Overall, 12 patients were lost to follow-up. Disease progression was recorded in 47/95 pts (49.5%) after a median time of 19 months (range: 6-147 months). The progression-free survival at 43 months was significantly better for patients treated according to the GIMEMA LCH 2001 guidelines compared to those managed with pediatric protocols, 67% (IC95% 53.14 - 80.86%) vs 48% (IC95% 31.37 - 64.63%), respectively (p 0.005). Overall, 7 deaths were recorded, 5 in patients treated with the pediatric protocols. The overall survival at 43 months, was similar in patients managed with the GIMEMA LCH 2001 guidelines and in those treated with pediatric protocols (97.9%, CI 95%: 93.75% - 100% and 97.3%, (IC95% 91.96% - 100%). BRAF V600E mutation was found in 13/35 (37%) evaluable cases. No differences in response and outcome between BRAFV600E-mutated patients and those not-mutated were found. Our experience in a large cohort of LCH adults shows that a multidisciplinary approach is useful in identifying organ involvement in adults, including those asymptomatic. This is critical for an adequate treatment. Moreover, guidelines specific for adults with LCH proved efficacy in improving the outcome in this category of patients. Disclosures No relevant conflicts of interest to declare.

Analysis of the Incidence and Diagnostic Pattern of Langerhans Cell Histiocytosis from the Population-Wide Healthcare Database in Korea

Introduction Langerhans cell histiocytosis (LCH) is a rare disease involving clonal proliferation of Langerhans cells. The reported incidence of LCH ranges from 0.5-5.4 cases per million persons per year, according to the prospective registry-based reports. However, due to the rarity of the disease and the limitation of prospective registries, the comprehensive understanding of nation-wide epidemiology has been limited. This study aimed to analyze the incidence by age and diagnostic patterns of LCH using the population-wide healthcare database in Korea. M ethods The claims data of the Health Insurance Review and Assessment (HIRA) contain information of 46 million patients per year, which accounts for about 95% of the total population of South Korea. The data include information regarding diagnoses, hospitalization, and prescription drugs. Since 2005, the "National cancer registration and reimbursement program" has been implemented, which reimburse for 90% of the medical expenses of patients with malignant diseases, including LCH. Therefore, all the patients with LCH have been registered in the database after a definite diagnosis. From the HIRA open data source, we extracted a claim data of patients corresponding to diagnosis codes of C95.0 (Multifocal and multisystemic -disseminated LCH), C96.5 (Multifocal and unisystemic LCH), or C96.6 (Unifocal LCH) during the period of 2010-2017. Data for 2010-2011 was used as a reference for overlapping patients, and the actual analysis was conducted with data from 2012 to 2017. Results During the period, a total of 59,929 insurance statements were issued, and 53,446 statements with only one identical diagnostic code and confirmative workups were selected for final analysis. The total incidence cases during the period of 2012 to 2017 were 899 cases, and the average number of the annual incidence was 150 cases. The incidence was 3.0 cases per million persons per year. There was a male predominance with a male-to-female ratio of 1.63:1 (558 cases:341 cases) in a whole cohort. For the detailed diagnosis codes, C96.6 was the most frequent as 93.4%, followed by C96.0 as 4.9%, and C96.5 as 1.7%. The average age at diagnosis was 26.6 years (range, 0.2~87 years) in all incidence cases, and 26.6 years for C96.0 group, 29.5 years for C96.5 group, and 25.9 years for C96.6 group, respectively. When patients were grouped by age at diagnosis, the age group of 0-4 years showed the highest annual incidence of 17.9 cases per million, followed by the group of 5-9 years as 8.9 cases per million, and the age group over 70 years showed the lowest annual incidence of 1.1 cases per million (Figure 1). There were no seasonal trends in the diagnosis of LCH. At diagnosis, 21.6% of patients were diagnosed at the department of neurosurgery, 21.5% at pediatrics, 19.3% at internal medicine, and 16.8% at orthopedic surgery. For examinations conducted at the time of diagnosis, simple radiography was conducted in 84.9% of patients, computed tomography in 32%, magnetic resonance imaging in 39.6%, bone scan in 47.1%, and bone marrow examination in 22.9% of patients. For treatment, most of the patients (93.7%) received at least one modality of treatments after diagnosis; 42.7% of patients underwent surgery only, 30.4% received topical steroids only, 12.6% underwent surgery followed by chemotherapy, and 10.5% received chemotherapy. For chemotherapy, vinblastine was the most frequently prescribed drug as used in 82.9% of patients who received chemotherapy, followed by methotrexate in 39.4%, and mercaptopurine in 38.9%. Conclusions This study was the first big data analysis regarding LCH in Korea, and the annual incidence of LCH was 3.0 cases per million persons per year. The incidence was highest at 0-4 years of age, and the incidence was significantly decreased with age. We plan to conduct further research on the treatment and outcomes of Korean LCH patients in conjunction with the data of ongoing prospective registry. Figure 1. The annual incidence of Langerhans Cell Histiocytosis by age at diagnosis Figure 1 Disclosures No relevant conflicts of interest to declare.

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.

Low-Dose BRAF-Inhibitors in the Treatment of Histiocytic Disorders with the BRAF-V600E Mutation

Introduction: The landmark VE-BASKET trial demonstrated that Erdheim-Chester disease (ECD) patients with the BRAF-V600E mutation can be effectively treated with vemurafenib 1920 mg/day. However, all patients required dose reductions due to adverse effects. The efficacy of low dose BRAF-inhibitors is not well established in ECD. Further, as Langerhans cell histiocytosis (LCH) also harbors BRAF-V600E mutations in 50-60% of patients, BRAF-inhibitors may be effective in this disease as well. In this study, we evaluated the efficacy of low dose BRAF-inhibitors (vemurafenib and dabrafenib) in the treatment of ECD and LCH. Methods: We conducted a retrospective study of ECD and LCH patients who were seen at our institution from January 1998 to July 2018. All patients had a diagnosis of ECD and LCH determined by clinical criteria in conjunction with histopathologic findings. Based on the standard doses approved for malignant melanoma and ECD, patients were categorized into the low dose BRAF-inhibitor group if they were treated with vemurafenib < 960 mg/day or dabrafenib ≤ 150mg/day at any point in time. We used a simple response criteria that defined clinical progressive disease (PD) as worsening of symptoms attributed to ECD/LCH or radiologic PD as a progression or worsening of proven or suspected lesions due to ECD/LCH. The minimum duration for symptom improvement to be considered a response was set at 3 months. Results: A total of 89 ECD patients and 186 LCH patients were identified. Within the ECD cohort, 24 of 44 (55%) patients who were tested had the BRAF-V600E mutation. Eight patients were included in the low dose BRAF-inhibitor group. The median age at diagnosis was 57 years (range 37-74) and 5 (63%) were male. The most common areas of involvement included bone (88%), cardiovascular system (63%), kidneys (63%), and brain parenchyma (50%). The median time of follow up was 66 months (range 23-165) and the median time on low-dose BRAF-inhibitor was 10 months (range 1-27) [Table 1]. Three patients had a starting dose of vemurafenib 1920 mg/day, 4 had 960 mg/day, and 1 had 480 mg/day. All patients required dose reductions and 50% of the patients ultimately discontinued vemurafenib due to side effects. Side effects included fatigue, pruritus, nausea, facial swelling, blisters, papillomas, and/or subcutaneous nodules. Four patients were able to remain on low-dose vemurafenib for a median follow up time of 24.5 months (range 12-28) with ongoing response and no signs of clinical or radiologic PD. Within the LCH cohort, 18 of 31 tested (58%) patients had the BRAF-V600E mutation. Four patients were included in the low dose BRAF-inhibitor group. The median age at diagnosis of this cohort was 43 years (range 34-69) and 2 (50%) were male. Areas of involvement included bone (100%), brain parenchyma (hypothalamus/optic stalk and pons; 50%), and skin (25%). The median time of follow up was 31 months (range 21-46) and the median time on low-dose BRAF-inhibitor was 4 months (range 3-24) [Table 2]. Two patients had a starting dose of vemurafenib 960mg/day. The patients with brain parenchymal involvement had a starting dose of dabrafenib 150mg/day or 100mg/day. All patients taking vemurafenib 960mg/day required dose reductions and one patient discontinued treatment due to skin blistering in her feet. In the patients taking dabrafenib, no side effects have yet been reported. 3 patients had an ongoing response and did not have clinical or radiologic PD. Patient #10 however, had clinical and radiologic PD after being on vemurafenib 720mg/day for 22 months. Conclusion: Our study suggests a potential role for lower doses of BRAF-inhibitors in ECD and LCH patients harboring BRAF-V600E mutations. Dabrafenib was found to be particularly efficacious and well-tolerated in LCH involving the brain parenchyma. However, patients who undergo dose reductions should be closely monitored due to the risk of disease progression. Careful balance of toxicities and efficacy is needed for optimizing patient outcomes with targeted therapies. Disclosures Bennani: Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Seattle Genetics: Other: Advisory board. OffLabel Disclosure: Vemurafenib and dabrafenib for Langerhans cell histiocytosis. Vemurafenib dosage for Erdheim-Chester disease is less than the approved dose of 960mg every 12 hours.

Revealing Homologous Clonality By Synchronous Trisomy 8 in Langerhans CELL Histiocytosis and ACUTE Myeloid Leukemia

Purpose Langerhans cell histiocytosis (LCH) is a disorder in which excess immature Langerhans cells build up in the body. Increasing reports have revealed LCH may share a common origin with myeloid-derived malignancies. Here we report a case of a 45-year-old male, diagnosed as synchronous LCH and acute myeloid leukemia (AML). Relevant tests have been performed to investigate the clonal relationship between LCH and AML. Methods The diagnosis of LCH and AML were based on skin and bone marrow biopsy respectively in Beijing Friendship Hospital, Capital Medical University. No cytotoxic drugs were used before the two diseases were diagnosed. Immunophenotyping was run by immunochemistry or flow cytometry. Karyotype analysis was carried out with G-banding, and the findings were confirmed by fluorescence in situ hybridization (FISH). Mutational analysis of BRAF, KRAS and NRAS genes were performed by ARMS-PCR. Additional gene screening was detected by next-generation sequencing (NGS). Results The case expressed CD1a, S-100, Langerin on the Langerhans cells and CD13, CD34, CD38, CD117, MPO on the leukemic blasts. No other intermingling markers was found on the LCH and AML except CD33 and CD68. Cytogenetic studies showed a karyotype with 47, XY, +8[10], and a confirmatory test revealed the existence of trisomy 8 in both skin and bone marrow lesions by FISH. Cell rate of trisomy 8 on skin, bone marrow and oral mucosa were 9%, 49% and 1%. Mutation analysis revealed KRAS c.436G>A:p.A146T (exon4) in AML and LCH cells, but BRAF c.1799T>A:p.V600E (exon15) only in LCH. Conclusion These findings suggest that LCH cells are derived from myeloid precursors in this case, and BRAF mutation may play an important role in pathogenesis of LCH. Disclosures No relevant conflicts of interest to declare.

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.

Langerhans cell histiocytosis in an adult patient

Aim: to present a clinical case of a rare dermatosis — Langerhans cell histiocytosis (LCH) in an adult patient.Materials and methods. A clinical and laboratory examination of a 64-year-old woman who had complained of rashes on the skin of the scalp, neck, trunk and lower extremities accompanied by itching was carried out. A histological study of skin biopsy samples from the lesion area, as well as an immunohistochemical study of Langerhans cell markers — langerin and S-100 protein — were performed.Results. Clinical manifestations of the disease, the presence of histiocytic infiltrate in the epidermis and dermis during the histological study and immunohistochemical detection of langerin infiltrate cells and S-100 protein were all consistent with the diagnosis of LCH. The therapy with methotrexate subcutaneously significantly improved the patient’s condition.Conclusion. Verification of the LCH diagnosis requires a histological study of skin biopsy samples and an immunohistochemical study of Langerhans cell markers. The efficacy of methotrexate in the treatment of this disease has been confirmed.

Tullio phenomenon and drop attacks – An unsuspected cause

Tullio phenomenon or loudness intolerance is most commonly associated with superior semicircular canal dehiscence. We describe a patient presenting solely with this phenomenon and found to have an unsuspected cause. A 43-years-old gentleman presented to us complaining of intolerance to loud noise, occasionally leading to falls, for six months. These complaints were insidious in onset and steadily progressing. Interestingly, the intolerance in heavy traffic used to subside on wearing a helmet. There was no history of hearing loss, tinnitus, earache, or ear discharge. Clinical tests of hearing including Rinne, Weber and absolute bone conduction test were within normal limits. The neurologic as well as systemic examination was normal. Pure tone audiometry (PTA) showed mild conductive hearing loss in left ear and brainstem auditory evoked response (BAER) was normal. Patient’s skull radiograph showed multiple large lytic lesions giving the appearance of “geographical skull”. Chest X-ray showed a lytic lesion with pathological fracture involving posterior part of in left sided rib. Computed Tomography of head with bone window also showed multiple lytic lesions in skull (Figure 1,2). Brain parenchyma was normal. Incisional biopsy of one of the skull lesions was performed, which was consistent with a diagnosis of Langerhans cell histiocytosis (LCH) (Figure 3). The patient showed considerable improvement after being initiated on Etoposide and Vinblastine. LCH is a rare cause of Tullio phenomenon. It appears that the loss of skull tissue due to lytic lesions leads to impairment of “modifier” function of intact skull, resulting in “volume conduction” and noise intolerance.

Langerhans Cell Histiocytosis of the Skull

This is a case of a pediatric male who presented with a postauricular mass and pain. Computed tomography and magnetic resonance imaging suggested a diagnosis of Langerhans cell histiocytosis. Characteristic imaging findings and initial workup for Langerhans cell histiocytosis are described.

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.

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 (>120%); 3 with slightly increased level of accumulation (100–120%) and 1 with lower than normal level of accumulation (<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%.

Langerhans cell histiocytosis of the jaw, a mimicker of osteomyelitis on CT and MR images: A retrospective analysis.

Differential diagnosis of Langerhans Cell Histiocytosis (LCH) in the jaw is essential for early treatment including systemic therapy. Records of 17 patients (6 men and 11 women; mean age, 14 years) with histologically confirmed LCH were reviewed. All the lesions occurred in the mandible. Most of the cases (n=12) were intraosseous type LCH, only 5 patients had alveolar type LCH. Patients complained of facial swelling and pain most likely. In the 14 patients who underwent CT and/or MR imaging, all LCH lesions were osteolytic, with a mean size of 23 mm. LCH presented as expansile lesions with periosteal new bone formation, perilesional sclerosis, fluid attenuation/signal within the lesion, and inflammatory changes in adjacent soft tissues on CT/MR images. Considering the major symptoms of LCH were swelling and pain, the differential diagnosis of LCH from osteomyelitis might be more difficult. The differential diagnosis for osteolytic lesions of the jaw with surrounding inflammatory changes should include LCH, especially in young patients.