Form Of Langerhans Cell Histiocytosis Research Articles

Letterer-Siwe disease presenting with gastrointestinal and cutaneous manifestations.

Histiocytosis is a set of distinct proliferative illnesses defined by the proliferation and infiltration of varied numbers of dendritic cells, macrophages, and monocytes in the afflicted tissues. The skin and other organs may be impacted by the inflammatory infiltration. It can occur at any age. The severity of the symptoms can range from mild to severe, depending on the degree and type of organ involvement. Although certain forms of histiocytosis can be fatal, others can be treated successfully without sequelae. Langerhans cell histiocytosis manifests itself clinically in both children and adults. A combination of clinical, histological, and radiological tests is required to achieve a diagnosis. A severe, multisystemic, acute form of Langerhans cell histiocytosis is called Letterer-Siewe illness, which usually affects infants in their first year of life. In this article, we provide a brief literature review and a case study of a 9-month-old girl who presented with recurring gastrointestinal problems as the first sign of Letterer-Siwe disease.

The use of BRAF-inhibitors as monotherapy and in combination with cytosine arabinoside and 2-chloro-2’deoxyadenosine in pediatric patients with different forms of Langerhans cell histiocytosis

Background. Langerhans cell histiocytosis (LCH) is a rare disease that occurs due to abnormal proliferation and expansion of myeloid precursors. The occurrence of mutations in genes that encode key kinases of MAPK-signaling pathway leads to its pathological activation and has been shown the cause of disease. Mutations in BRAF and MAP2K1 genes are the most frequent among LCH patients. The effectiveness of BRAF-inhibitors in LCH patients has been shown in numerous studies.The purpose of the study – analyze the experience of BRAF-inhibitor vemurafenib administration as monotherapy and in combination with cytosine arabinoside (ARA-C) and 2-chloro-2'-deoxyadenosine (2-CdA) in pediatric patients with different forms of LCH.Materials and methods. Fifteen patients with various forms of LCH were enrolled in the study. BRAF mutations were detected in 14 patients, mutation in the MAP2K1 gene was detected in one case. Patients with “risk organ” (RO) involvement were included in the first group (n = 9). These patients received combined therapy with vemurafenib and ARA-C/2-CdA. Patients without RO involvement, included in group 2 (n = 6), received vemurafenib as monotherapy. The assessment of the response to the therapy in group 1 was carried out in accordance with the DAS scale, in group 2 in accordance with the RECIST v1.1. The toxicity assessment in both groups was carried out in accordance with the CTCAE v5.0.Results. All patients in group 1 achieved non-active disease status with a median of 35 (28–61) days. In group 2 partial response to vemurafenib was achieved in 5 cases. Relapse after targeted therapy termination was diagnosed in two patients. Photodermatitis was the most common side effect of targeted therapy.Conclusions. The use of vemurafenib was effective in both groups. There were no cases of grade III–IV toxicity according to CTCAE v5.0 associated with vemurafenib administration in this study. The combination of vemurafenib and ARA-C/2-CdA showed high efficacy and good tolerability in group 1. Two cases of disease relapse after targeted therapy cessation in group 2 show that the monotherapy approach does not always allow to achieve long-term remission in LCH patients.

Modern approaches to the treatment of relapses and refractory forms of Langerhans cell histiocytosis. Literature review

Despite of good outcomes in treatment of patients with newly diagnosed Langerhans cell histiocytosis (LCH), recurrences have been reported in 29.9 % of patients. There are currently no generally accepted standards for the treatment of recurrences and refractory forms of LCH. The prognosis of patients, suffering from this pathology, remains unfavorable. Current treatment approaches of recurrences and refractory forms of LCH include using of BRAF- and MEK-inhibitors and cellular treatment technologies. The article provides a literature review of current approaches to the treatment of recurrences and refractory forms of LCH and identifies the prospects for further research.

ГИСТИОЦИТОЗ ИЗ КЛЕТОК ЛАНГЕРГАНСА У БЛИЗНЕЦОВ: ОБЗОР ЛИТЕРАТУРЫ И КЛИНИЧЕСКОЕ НАБЛЮДЕНИЕ

Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder in children and is characterized by clonal expansion of myeloid precursors. The pathological cells are morphologically and phenotypically similar to Langerhans cells. LCH is considered as a sporadic disease as yet with undescribed hereditary factors for its development. However, hereditary predisposition to the development of this pathology cannot be excluded. There are cases of the LCH development in twins described, both in monozygotic and dizygotic. Article represents bibliographical review on the familial forms of Langerhans cell histiocytosis and clinical case of the Langerhans cell histiocytosis development in twin girls.

ГИСТИОЦИТОЗ ИЗ КЛЕТОК ЛАНГЕРГАНСА У БЛИЗНЕЦОВ: ОБЗОР ЛИТЕРАТУРЫ И КЛИНИЧЕСКОЕ НАБЛЮДЕНИЕ

Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder in children and is characterized by clonal expansion of myeloid precursors. The pathological cells are morphologically and phenotypically similar to Langerhans cells. LCH is considered as a sporadic disease as yet with undescribed hereditary factors for its development. However, hereditary predisposition to the development of this pathology cannot be excluded. There are cases of the LCH development in twins described, both in monozygotic and dizygotic. Article represents bibliographical review on the familial forms of Langerhans cell histiocytosis and clinical case of the Langerhans cell histiocytosis development in twin girls.

Diagnostic and therapeutic difficulties in the cutaneous form of Langerhans cell histiocytosis in infant

Diagnostic and therapeutic difficulties in the cutaneous form of Langerhans cell histiocytosis in infant

MEK-inhibitors in treatment of Langerhans cell histiocytosis

Background. There are increasing data of targeted therapy efficacy of different types of Langerhans cell histiocytosis (LCH) with inhibitors of BRAF-specific serin-threonine kinase (BRAF-inhibitors) in cases with BRAF V600E mutation published last years. At the same time there are no published data of use of inhibitors of MAPK/ERK pathway (MEK-inhibitors) in pediatric patients with BRAF-negative forms of LCH.Purpose of the study is to evaluate efficacy and safety of MEK-inhibitor (cobimetinib) in eight pediatric BRAF V600E-negative refractory LCH patients.Materials and methods. The study included 8 children with various forms of LCH. All patients received therapy according to the LCH-IV protocol and were diagnosed with progression of LCH during or after termination of the treatment. The response to the therapy was assessed in accordance with the international scale Response Evaluation Criteria in Solid Tumors (RECIST v.1.1). The assessment of the toxicity was performed in accordance with the international scale of Common Terminology Criteria for Adverse Events (CTCAE v.5.0).Results. Complete response was not achieved in any patient. Partial response was established in 5 cases. One patient was diagnosed with disease progression in three months after termination of the therapy. The incidence of adverse events was high.Conclusion. Cobimetinib therapy is effective in BRAF V600E-negative refractory pediatric LCH patients. The response to the treatment can be delayed. All cases of the toxicity were dose depended and successfully resolved after dose correction. Further research is needed to define duration of treatment and optimal dosage.

Neutralizing Anti-IL-17A Antibody Demonstrates Preclinical Activity Enhanced by Vinblastine in Langerhans Cell Histiocytosis.

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm characterised by the accumulation into granulomas of apoptosis-resistant pathological dendritic cells (LCH-DCs). LCH outcome ranges from self-resolving to fatal. Having previously shown that, (i) monocyte-derived DCs (Mo-DCs) from LCH patients differentiate into abnormal and pro-inflammatory IL-17A-producing DCs, and (ii) recombinant IL-17A induces survival and chemoresistance of healthy Mo-DCs, we investigated the link between IL-17A and resistance to apoptosis of LCH-DCs. In LCH granulomas, we uncovered the strong expression of BCL2A1 (alias BFL1), an anti-apoptotic BCL2 family member. In vitro, intracellular IL-17A expression was correlated with BCL2A1 expression and survival of Mo-DCs from LCH patients. Based on the chemotherapeutic drugs routinely used as first or second line LCH therapy, we treated these cells with vinblastine, or cytarabine and cladribine. Our preclinical results indicate that high doses of these drugs decreased the expression of Mcl-1, the main anti-apoptotic BCL2 family member for myeloid cells, and killed Mo-DCs from LCH patients ex vivo, without affecting BCL2A1 expression. Conversely, neutralizing anti-IL-17A antibodies decreased BCL2A1 expression, the downregulation of which lowered the survival rate of Mo-DCs from LCH patients. Interestingly, the in vitro combination of low-dose vinblastine with neutralizing anti-IL-17A antibodies killed Mo-DCs from LCH patients. In conclusion, we show that BCL2A1 expression induced by IL-17A links the inflammatory environment to the unusual pro-survival gene activation in LCH-DCs. Finally, these preclinical data support that targeting both Mcl-1 and BCL2A1 with low-dose vinblastine and anti-IL-17A biotherapy may represent a synergistic combination for managing recurrent or severe forms of LCH.

Eosinophilic Granuloma: A Rare and Often Benign Condition Presenting as a Lump on the Head, which was Easily Treated.

Eosinophilic granuloma is a localized benign form of Langerhans cell histiocytosis.It is essential to exclude the presence of bone lesions in other locations and/or systemic involvement.The prognosis is good, with surgical resection, when necessary, being a curative intervention, although sometimes (as in this case) a conservative approach is sufficient.

Adult pulmonary Langerhans cell histiocytosis might consist of two distinct groups: isolated form and extrapulmonary recidivism type.

BackgroundAdult pulmonary Langerhans cell histiocytosis (PLCH) is a rare form of Langerhans cell histiocytosis (LCH) that typically occurs in cigarette smokers. The clinical course of PLCH is unpredictable; the disease may resolve spontaneously, or lead to multi-organ failure and death. To better understand this idiopathic disease, we retrospectively overviewed a cohort of Asian patients with PLCHs.MethodsHerein, we have provided detailed clinicopathological features and molecular findings of PLCHs in a Southwestern Chinese population, including the expressions of apoptotic protein P16, programmed cell death 1 (PD-1), and programmed cell death-ligand 1 (PD-L1). Importantly, the BRAFV600E mutation was observed in this cohort.ResultsIn accordance with the follow up data, the cohort was subdivided into two groups, an isolated pulmonary group and extrapulmonary recidivism group. Among the isolated group, the participants were predominantly young males (<40 years old), with a history of smoking, respiratory symptoms (cough and difficulty breathing), showed more cystic lesions in computed tomography (CT) scanning, had more cellular Langerhans granulomas under the microscope, overexpression of P16 (66.7%), high PD-1 (100%) and low PD-L1 (33.3%) expressions, and no BRAFV600E mutation was detected. In contrast, the extrapulmonary recidivism group showed significantly older age (>40 years old), recurrent spontaneous pneumothorax, more nodular changes in CT scanning, more interstitial fibrosis histologically, expression rates of 100% of P16, 66.7% of PD-1, and 33.3% of PD-L1; and importantly, BRAFV600E mutation was detected in 33.3% of this subdivision.ConclusionsWe found that adult PLCH might consist of two distinct groups: an isolated form and extrapulmonary recidivism PLCH. Overexpression of P16 could be a diagnostic biomarker for PLCH. An extremely low mutation rate of the BRAF gene in adult PLCH in our cohort indicated that there might be other pathogeneses for this disease among Asian patients.

Manifestation of Langerhans cell histiocytosis in the oral cavity: The authors’ experience

Abstract Background. Langerhans cell histiocytosis is a rare reactive proliferative disorder marked by excess proliferation and accumulation of mononuclear phagocytes in tissues and organs. Usually, organs and systems where Langerhans cells are normally found are involved. Lesions may be limited to one system and be single- or multisite, or many systems may be involved. The etiology is not fully known. According to one of the hypotheses, immune dysfunction due to exuberant response to an unknown antigen may be the cause. The most common clinical symptoms include skin lesions, bone pain, exophthalmos, and enlarged lymph nodes, affecting the liver and spleen. Gingivitis, pocket granulation tissue, ulceration of the gingival papilla, alveolar bone atrophy leading to loosening and loss of teeth are observed in the oral cavity. The aim of the study was to determine the type and incidence of oral manifestations in patients diagnosed with Langerhans cell histiocytosis. Methods. We evaluated patients’ medical records to obtain data on the children’s age at diagnosis, sex, the form of Langerhans cell histiocytosis, clinical picture (systemic and local oral symptoms), and radiological findings. Dental examinations (clinical and radiological) were performed to assess oral mucosa and periodontal tissues, and medical records were analyzed for the course and treatment of histiocytosis. Results. The analysis included the medical records of 43 patients with Langerhans cell histiocytosis. Oral lesions in the form of gingivitis, pathological tooth mobility, and expansion of alveolar mandibular bone were observed in 7 patients. Conclusions. Langerhans cell histiocytosis may be accompanied by maxillary, gingival, and mucosal lesions.

Adult form of Langerhans cell histiocytosis with pulmonary and hepatic involvement mimicking malignancy in a patient with chronic hepatitis C infection

Langerhans cell histiocytosis (LCH) is a myeloid neoplasm with inflammatory properties. There are few published reports of adult LCH with liver involvement, which is still poorly understood, but shows high morbidity and mortality. We report a case of a 37-year-old woman suffering from hepatitis C showing a LCH affecting the lung as well as the liver. Consistent with histology, we found an early stage of a proliferative/granulomatous phase of hepatobiliary LCH, whereas pulmonary findings showed a nodular stage of adult pulmonary LCH. Although hepatocellular carcinoma is a common malignancy in patients suffering from hepatitis C, it is crucial to keep in mind differential diagnosis for newly appearing liver lesions.

HAND–SCHULLER–CHRISTIAN DISEASE PRESENTING WITH A CLASSICAL TRIAD AND ORAL MANIFESTATIONS: A RARE CASE REPORT

Hand–Schuller–Christian disease is a multifocal disease that characteristically involves the bone and extraskeletal involvement of the reticuloendothelial system. The most common age group affected is children between 1 and 5 years old. It is a disseminated form of Langerhans cell histiocytosis with a typical triad of exophthalmos, diabetes insipidus, and lytic bone lesions, although seen in only half of the patients. We present such an uncommon case presenting with the classical triad along with oral manifestation such as floating teeth and hepatitis with typical radiological findings.

A Case of Eosinophilic Granuloma Presenting as Post-traumatic Scalp Hematoma

Eosinophilic granuloma (EG) is a benign local bone disease . Here, we report a case of EG and describe the MRI findings which had progressed rapidly after minor head trauma. A 5-year-old healthy boy admitted to our clinic for a rapidly growing skull lesion. He had a minor head trauma history which occurred one month before admission. Computed tomography (CT) scan demonstrated a well defined lytic lesion on frontal bone. Our radiologic diagnosis was EG which was confirmed by the postoperative histopathologic diagnosis. Solitary EG lesions are a common form of Langerhans cell histiocytosis. Although the exact etiology of EG is not clear, autoimmune disorders, inflammation are considered to be etiological factors. Also, minor trauma is considered in etiologic factors. We can suggest with the posttraumatic radiological findings that the minor trauma may be a factor for initiation and aggravation on the pathways of development of EG.

Treating Langerhans cell histiocytosis, globally.

Treating Langerhans cell histiocytosis, globally.

Pulmonary Langerhans cell histiocytosis - a rare type of a rare disease

Introduction: Langerhans cell histiocytosis is a rare disease (0.4 in 100,000) with a still highly debated aetiology - either a reactive or a neoplastic process. It is most commonly divided into single-system and multisystem disease. The pulmonary form is part of the former group and occurs mostly in adolescent and adult smokers (2nd through 4th decade of life). Aim: The aim of this report is to provide more clinical data of one rarely documented disorder. Materials and Methods: We present a 42-year-old male patient with a respiration-associated pain of unknown origin. His physical examination was unremarkable. A CT scan was indicated, revealing multiple thin-walled cystic lesions and multiple small nodules in the pulmonary parenchyma, predominantly in the middle and upper lung segments, which was suggestive of pulmonary Langerhans cell histiocytosis. Through a video assisted thoracoscopy, several of the nodules were resected and sent for biopsy. Results: The patient was discharged on the day after the operation. The biopsy confirmed the diagnosis of Langerhans cell histiocytosis. Since systemic corticosteroids were contraindicated in this particular case, the patient was counseled to cease smoking. On the follow-up CT a tendency for a reversal of the condition was observed. Conclusion: The pulmonary form of Langerhans cell histiocytosis is a rare disease, most commonly seen in relatively young smokers with non-specific presentation. The biopsy is the only definitive diagnostic procedure. The disease may resolve spontaneously or after smoking cessation. In more severe cases corticosteroids, chemotherapy or lung transplantation may be considered.

Histiocytóza z indeterminovaných buněk - vymizení kožní infiltrace po ozáření elektronovým svazkem a aplikace 2-chlorodeoxyadenozinu: kazuistika

Indeterminate cell histiocytosis is a rare disease belonging to the group of malignant histiocytic diseases. The disease predominantly affects the skin. The disease appeared in the described patient at the age of 80 years. Morphs began to develop on the skin and rapidly spread over the whole body including the face. Only the hands and feet were left uncovered. The patients skin samples were taken from 2 sites for histological examination. The resulting conclusion was indeterminate cell histiocytosis. The treatment we chose was analogous to the procedures for Langerhans cell histiocytosis. We chose PUVA phototherapy as the first-line treatment. This treatment is frequently efficient for skin forms of Langerhans cell histiocytosis. In the described case, however, PUVA phototherapy did not influence the disease activity at all. As the second-line treatment, we used low-energy electron beam irradiation in the total dose of 36.2 Gy. This treatment had a positive impact, morphs began to diminish and slowly disappear from the skin. But they have not disappeared completely, therefore we assessed the treatment effect of the radiotherapy itself as partial remission of the disease. Within the third-line treatment, we used 2-chlorodeoxyadenosine in a dose of 5 mg/m2/per day, administered via subcutaneous injection over 5 consecutive days in monthly intervals. There were three cycles of this treatment administered overall. The treatment with 2-chlorodeoxyadenosine was tolerated without any adverse effects. The patient aged 82 years was only administered 3 cycles of 2-chlorodeoxyadenosine. When after the 3rd cycle the skin was free from any pathological morphs and only some pigmentation spots remained, we finished the treatment. The skin expressions of indeterminate cell histiocytosis completely disappeared after electron beam irradiation and the following administration of 3 cycles of 2-chlorodeoxyadenosine. The remission was short, however, after 6 months the disease recurred and the treatment is planned to resume. We assume the disease regresses following administration of 2-chlorodeoxyadenosine, but more than 3 treatment cycles will probably be needed to reach a longer-term response.Key words: electron beam irradiation - indeterminate cell histiocytosis - 2-chlorodeoxyadenosine.

Congenital self-healing reticulohistiocytosis in a newborn: A rare variant

Congenital self-healing reticulohistiocytosis or congenital self-healing Langerhans cell histiocytosis (LCH) or Hashimoto-Pritzker syndrome is a rare, benign, auto involuting form of LCH. It usually presents at birth or soon thereafter with spontaneously regressing multiple or solitary dusky papules or nodules. The actual incidence remains unknown probably because of its benign and self-limiting nature. Herein, we present a similar case present since birth because of its rarity in nature.

Clinicopathological pattern of cranial unifocal Langerhans cell histiocytosis: A study at medical college hospital.

Background:Eosinophilic granuloma (EG) of bone refers to a generally benign form of Langerhans cell histiocytosis localized to the bone. Patients may present with a solitary lesion (monostotic) or multiple sites of involvement (polyostotic).Materials and Methods:This study was done to evaluate the clinicopathological pattern of 6 cases of EGs of the skull diagnosed at a tertiary care hospital. All patients of EG were included with the help of medical records over a 5-year period that is, November 2009 to November 2014. They all had been preoperatively evaluated by skull X-ray and computed tomography. To rule out a multifocal disease scintigraphy was performed in all cases preoperatively. Surgical excision was performed, and EG was diagnosed on histopathology and immunohistochemistry.Results:There was a male predominance. Parietal bone was the most common affected bone. Total excision of the lesion was performed in all cases. No patient received postoperative radiotherapy. The follow-up period ranged from 6 months to 3 years. No tumor recurrence was noted.Conclusion:With an unknown etiology, nonspecific clinical and radiological findings with diagnosis possible only on histopathological examination, EG needs to be considered in the differential diagnosis as a skull mass, especially in children.

Cladribine (2-chlorodeoxyadenosine) in frontline chemotherapy for adult Langerhans cell histiocytosis: A single-center study of seven cases

Background. Adult Langerhans cell histiocytosis is a rare disorder with diverse clinical manifestations and inconsistent treatment outcomes to conventional therapeutic regimens. Cladribine (2-chlorodeoxyadenosine) repeatedly proved effective in cases of relapsed multifocal and multisystem disease forms. In this retrospective study we present an analysis of cladribine in frontline systemic therapy. Material and methods. A cohort of seven male patients with biopsy proved multisystem (six cases) and multifocal (one case) Langerhans cell histiocytosis received cladribine at a dose of 5 mg/m2 subcutaneously (five cases) or by two-hour intravenous infusion (two cases) over five consecutive days, every four weeks for a median of four courses (range 4–6). The treatment was enhanced with cyclophosphamide (300 mg intravenously on days 1–5 in cycles 4–6) and corticoids (dexamethasone 24 mg orally or methylprednisolone 250 mg intravenously on days 1–5 in cycles 4–6) in two patients, with radiotherapy (20 Gy on skin or bone lesions) in three patients and with photochemotherapy (psoralen plus ultraviolet A light, PUVA) on skin lesions in one patient. Results. All patients achieved clinically relevant treatment response confirmed by positron emission tomography (PET). Durable complete remissions were maintained in six patients (86%), including two patients with hypophysis involvement, with the median follow-up of 37 months (range 15–94; 49.8 ± 35.2 []). One patient had an aggressive, early relapsing disease requiring further treatment lines. The treatment-related toxicities consisted of transient bone marrow suppression affecting the leukocytes predominantly. Grade 3 lymphopenia occurred in five patients (71%) and grade 3 neutropenia in one patient (14%). Conclusion. Cladribine, both as a single agent as well as in combination with an alkylating cytostatic and corticoids, represents an effective treatment option with favorable toxicity profile for adult patients with multisystem or aggressive multifocal form of Langerhans cell histiocytosis.