Clinical characteristics and outcomes of Langerhans cell histiocytosis at a single institution in Thailand: a 20-year retrospective study

Abstract Background Langerhans cell histiocytosis (LCH) is a rare disease characterized by the various systems involved and clinical manifestations with a wide range of symptoms. Objectives To describe clinical characteristics, imaging, treatment, and outcomes of pediatric LCH at Phramongkutklao Hospital, Bangkok, Thailand. Methods We conducted a 20-year retrospective review of the medical records of patients diagnosed with LCH from birth to 21 years old from January 1, 1997, to December 31, 2016. Results In all, 14 patients with median age of 2.5 years were studied. Six (43%) patients had single-system (SS) LCH. Five patients (63%) with multisystem (MS) LCH (n = 8. 57%) had risk-organ involvement (RO+). All patients had plain X-ray imaging of their skull with 11 (79%) showing abnormal findings. Tc-99m bone imaging and fluorodeoxyglucose F18 (FDG) positron emission tomography (PET)-computed tomography (CT) demonstrated abnormal findings in 8 (89%) and 4 (29%) patients, respectively. The 5-year event-free survival (EFS) for patients with RO+ MS-LCH was less than that for those without risk-organ involvement (RO−) MS-LCH and SS-LCH (20% vs. 100%, P = 0.005). Hematological dysfunction, hypoalbuminemia, and conjugated hyperbilirubinemia may be worse prognostic factors for RO+ MS-LCH. Conclusion FDG-PET-CT might have a greater accuracy to detect LCH disease than conventional plain X-ray and Tc-99m bone imaging. RO+ MS-LCH has been encountered with relapse and poor outcomes. Hematopoietic involvement, hypoalbuminemia, and conjugated hyperbilirubinemia may be worse prognostic factors for RO+ MS-LCH.

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Biological and clinical significance of somatic mutations in Langerhans cell histiocytosis and related histiocytic neoplastic disorders

Hematology ◽

10.1182/asheducation-2015.1.559 ◽

2015 ◽

Vol 2015 (1) ◽

pp. 559-564 ◽

Cited By ~ 27

Author(s):

Carl E. Allen ◽

D. Williams Parsons

Keyword(s):

Langerhans Cell Histiocytosis ◽

Somatic Mutations ◽

Mapk Pathway ◽

Clinical Manifestations ◽

Langerhans Cell ◽

Braf V600e ◽

Common Mechanism ◽

Recurrent Mutations ◽

Wide Range ◽

Neoplastic Disorders

AbstractLangerhans cell histiocytosis (LCH), juvenile xanthogranuloma (JXG), and Erdheim–Chester disease (ECD) represent histiocytic disorders with a wide range of clinical manifestations. Until recently, mechanisms of pathogenesis have been speculative and debate has focused on classification of these conditions as reactive versus neoplastic. Genomic studies have been challenged by scarce tissue specimens, as well as heterogeneous nature of the lesions with variable infiltration of pathologic histiocytes. Whole-exome sequencing recently revealed a very low frequency of somatic mutations in LCH, JXG, and ECD compared to other neoplastic disorders. However, at least in the cases of LCH and ECD, there is a very high frequency of activating mutations in MAPK pathway genes, most notably BRAF-V600E, as well as MAP2K1, in LCH and NRAS in ECD. In ECD, recurrent mutations in the PI3K pathway gene PIK3CA have also been described. The heterogeneous clinical manifestations of these disorders may therefore be the cumulative result of activation of MAPK mutations (along with modifying signals from other pathways) at distinct stages of myeloid differentiation. Implications of this model include redefinition of LCH, JXG, and ECD as a group of clinically diverse myeloid neoplastic disorders with a common mechanism of pathogenesis. This model supports refocusing therapeutic strategies for these diseases on a personalized approach based on specific mutations and the cell(s) of origin.

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EVOLUTION OF TREATMENT OF CHILDREN WITH LANGERHANS CELL HISTIOCYTOSIS

PEDIATRIA Journal named after G N SPERANSKY ◽

10.24110/0031-403x-2021-100-3-107-120 ◽

2021 ◽

Vol 100 (3) ◽

pp. 107-120

Author(s):

M. Minkov ◽

◽

Keyword(s):

Intracellular Signaling ◽

Langerhans Cell Histiocytosis ◽

Standard Treatment ◽

Organs At Risk ◽

Severe Disease ◽

Clinical Manifestations ◽

Maintenance Phase ◽

Langerhans Cell ◽

Mitogen Activated Protein Kinase ◽

Wide Range

Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm caused by mutations in proteins in the intracellular signaling MAPK (mitogen-activated protein kinase) pathways. Its rarity, wide range of clinical manifestations, and varied course made it difficult to conduct clinical trials. The use of different stratification systems made it even more difficult to compare the published results. The review attempts to summarize approaches to treatment of LCH in children since the 1960s. Materials and methods of research: searches for original papers in PubMed were performed using combinations of the keywords Langerhans cell histiocytosis, X histiocytosis, pediatrics, children, treatment, and therapy. Only full articles published in English and German languages were included in the review. Conclusion: a combination of vinblastine and prednisolone as an intensive initial phase (6–12 weeks) followed by a less intensive maintenance phase of 12 months is the standard treatment of disseminated LCH. Mortality in multisystem LCH is caused by damage to the organs at risk (hematopoiesis, liver and spleen) and is especially high (up to 60–70%) if the patient does not respond to standard treatment. In the remaining patients, mortality is almost negligible, with the main problems being the recurrence of the disease and its irreversible effects in 50% of the survivors. Although systemic therapy has clearly improved survival in patients with the most severe disease, its role in sustaining disease control and prevention of irreversible consequences in patients with low-risk disease is less obvious.

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BRAF Mutation Correlates With High-Risk Langerhans Cell Histiocytosis and Increased Resistance to First-Line Therapy

Journal of Clinical Oncology ◽

10.1200/jco.2015.65.9508 ◽

2016 ◽

Vol 34 (25) ◽

pp. 3023-3030 ◽

Cited By ~ 107

Author(s):

Sébastien Héritier ◽

Jean-François Emile ◽

Mohamed-Aziz Barkaoui ◽

Caroline Thomas ◽

Sylvie Fraitag ◽

...

Keyword(s):

High Risk ◽

Langerhans Cell Histiocytosis ◽

Clinical Manifestations ◽

Langerhans Cell ◽

Response To Therapy ◽

Organ Involvement ◽

Wild Type ◽

Response To Chemotherapy ◽

The Impact

Purpose Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with a broad spectrum of clinical manifestations and outcomes in children. The somatic BRAFV600E mutation occurs frequently, but clinical significance remains to be determined. Patients and Methods BRAFV600E mutation was investigated in a French LCH cohort. We analyzed associations between mutation status and clinical presentation, extent of disease, reactivation rate, response to therapy, and long-term permanent sequelae. Results Among 315 patients with successfully determined BRAF status, 173 (54.6%) carried a BRAFV600E mutation. Patients with BRAFV600E manifested more severe disease than did those with wild-type BRAF. Patients with BRAFV600E comprised 87.8% of patients (43 of 49) with multisystem LCH with risk organ involvement (liver, spleen, hematology), 68.6% of patients (35 of 51) with multisystem LCH without risk organ involvement, 43.9% of patients (86 of 196) with single-system LCH, and 42.1% of patients (8 of 19) with lung-involved LCH (P < .001). BRAFV600E mutation was also associated with organ involvement that could lead to permanent, irreversible damage, such as neurologic (75%) and pituitary (72.9%) injuries. Compared with patients with wild-type BRAF, patients with BRAFV600E more commonly displayed resistance to combined vinblastine and corticosteroid therapy (21.9% v 3.3%; P = .001), showed a higher reactivation rate (5-year reactivation rate, 42.8% v 28.1%; P = .006), and had more permanent, long-term consequences from disease or treatment (27.9% v 12.6%; P = .001). Conclusion In children with LCH, BRAFV600E mutation was associated with high-risk features, permanent injury, and poor short-term response to chemotherapy. Further population-based studies should be undertaken to confirm our observations and to assess the impact of BRAF inhibitors for this subgroup of patients who may benefit from targeted therapy.

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“Langerhan Cell Histiocytosis –Review Of Literature”

Anatomical Science ◽

10.24294/as.v1i2.637 ◽

2018 ◽

Vol 1 (2) ◽

Author(s):

Ashutosh Jaysing Thorat ◽

Pawan Vilasrao Dawane

Keyword(s):

Langerhans Cell Histiocytosis ◽

Clinical Manifestations ◽

Disease Process ◽

Surgical Excision ◽

Langerhans Cell ◽

Treatment Modalities ◽

Review Of Literature ◽

Immature Dendritic Cells ◽

Wide Range ◽

Criteria For Diagnosis

Background: Langerhans cell histiocytosis is a relatively rare unique disease process characterized by an abnormal proliferation of immature dendritic cells usually affecting children and young adults.Discussion: Histiocytosis are rare diseases of great biological variability and a wide range of clinical manifestations. The first manifestations of LCH may occur in the oral cavity may vary from a continuous gingival infection or a dental abscess to necrotizing ulcerating defects or a painful jaw swelling.The criteria for diagnosis of LCH includes identification of the characteristic clinical features histopathological, Immunohistochemical findings. Various treatment modalities has been adopted including wide surgical excision along with radiotherapy,chemotherapy ,isolated radiotherapy and use of alkalizing agents.Keywords- Langerhans cell histiocytosis, Histiocytosis X , Osteolysis of skull

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

Journal of oncology: diagnostic radiology and radiotherapy ◽

10.37174/2587-7593-2020-3-1-21-37 ◽

2020 ◽

Vol 3 (1) ◽

pp. 21-37

Author(s):

A. S. Krylov ◽

A. D. Ryzhkov ◽

S. M. Kaspshik ◽

M. A. Krylova ◽

E. E. Stanyakina ◽

...

Keyword(s):

Bone Scintigraphy ◽

Langerhans Cell Histiocytosis ◽

Pediatric Patients ◽

Bone Destruction ◽

Langerhans Cell ◽

Whole Body ◽

Unknown Etiology ◽

X Ray ◽

Treatment Naïve ◽

Proven Case

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.

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A Painful Shoulder Revealing Langerhans Cell Histiocytosis

Asian Journal of Pediatric Research ◽

10.9734/ajpr/2020/v3i430137 ◽

2020 ◽

pp. 24-27

Author(s):

N. A. R. Ranaivo ◽

M. L. Rakotomahefa Narison ◽

M. Bemena ◽

S. H. Raobijaona

Keyword(s):

Langerhans Cell Histiocytosis ◽

Clinical Presentation ◽

Bone Lesion ◽

Langerhans Cell ◽

Irregular Boundary ◽

X Ray ◽

Multidisciplinary Consultation ◽

Life Threatening ◽

Spontaneous Improvement ◽

The Right

Introduction: Langerhans cell histiocytosis is a systemic proliferative disease. It is a rare disease that can affects all tissues. Evolution can be spontaneously favorable. Multi-organ involvement may be life-threatening. We report the case of an toddler with bone lesion and issues. Case Report: It was a 33-month-old infant with right shoulder pain. Clinically, she had a swelling in the front side of the right shoulder with a limited abduction. X-ray of the right shoulder showed osteolysis with an irregular boundary of the right humeral head. The blood work was normal. In view of the painful swelling of the right shoulder, a biopsy was performed. Histological examination confirmed the diagnosis of Langerhans histiocytosis. A conservative treatment was decided after a multidisciplinary consultation meeting. After six months, spontaneous improvement was noted. Conclusion: Langerhans cell histiocytosis is a proliferative pathology that can affect one or more organs. The clinical presentation is polymorphic according to the affected organ. An extension assessment is fundamental in the management in order to determine the treatment.

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A Case Report of Pediatric Langerhans Cell Histiocytosis: Current Approach and Diagnostic Challenges for Dermatologist

Serbian Journal of Dermatology and Venerology ◽

10.2478/sjdv-2020-0012 ◽

2020 ◽

Vol 12 (3) ◽

pp. 79-86

Author(s):

Irwan Junawanto ◽

Khairuddin Djawad ◽

Sri Rimayani ◽

Farida Tabri ◽

Nurelly N. Waspodo ◽

...

Keyword(s):

Langerhans Cell Histiocytosis ◽

Poor Prognosis ◽

Clinical Manifestations ◽

Current Approach ◽

Myeloproliferative Disorder ◽

Langerhans Cell ◽

Histopathologic Examination ◽

Chemotherapy Treatment ◽

Cutaneous Manifestations ◽

Patient Organ

Abstract Langerhans Cell Histiocytosis (LCH) is a chronic and rare myeloproliferative disorder caused by disorders in Lang-erhans cell proliferation in various organs and tissues. LCH has a wide variety of clinical manifestations, making it difficult to diagnose. Cutaneous manifestations are polymorphic in the form of purpura, papule, vesicles and pustules. LCH can involve vital organs such as the liver and lungs as well as the hematopoiesis system that usually gives a poor prognosis. The prognosis is also influenced by the age of patient, organ dysfunction and response to the first 6 weeks of chemotherapy treatment. A 3-year-old girl reported a major complaint of an abscess-like lesion in the region of neck accompanied by an extensive purpura of scalp, neck and inguinal areas accompanied by vulvar erosions. The immunohistochemical and histopathologic examination support LCH and the clinical improvement after intravenous administration of intravenous 3 mg/m2 Vinblastine chemotherapy, 75 mg/m2 etoposide, oral 40 mg/m2 per prednisone. After the 6th cycle of chemotherapy, the patient died.

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Investigation of Immune Microenvironment in Children with Langerhans Cell Histiocytosis

10.21203/rs.3.rs-105172/v1 ◽

2020 ◽

Author(s):

Fuyong Zhang ◽

Weihong Wang ◽

Yunfang Zhen ◽

Jin Dai ◽

Lunqing Zhu ◽

...

Keyword(s):

T Lymphocytes ◽

Rare Disease ◽

Treatment Option ◽

Langerhans Cell Histiocytosis ◽

Clinical Characteristics ◽

Langerhans Cell ◽

Immune Microenvironment ◽

Tissue Samples ◽

Cd8 T Lymphocytes ◽

New Treatment

Abstract Background: Langerhans cell histiocytosis (LCH) is a rare disease that mainly occur in children. The aim of this investigation is to explore the immune microenvironment of LCH and feasibility of immunotherapy for children with LCH. Methods: Tissue samples were collected from 15 children with LCH and their clinical characteristics were recorded. The expressions of PD-1 ligand 1(PD-L1) and the presence of CD8 T lymphocytes were assessed by immunohistochemistry (IHC). Results: Of the total 15 patients, 8 of them were PD-L1 positive and it accounted for 53.33% and 9 of them were CD8 T lymphocytes positive and it accounted for 60%. There were 8 out of the 15 patients that were both PD-L1 positive and CD8 positive and they accounted for 53.33%.Conclusions: Our results showed that the expression of PD-L1 and presence of CD8 T lymphocytes occurred in the microenvironment of LCH. The findings indicated a possible new treatment option for LCH in children.

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