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

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

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BACKGROUND: Disseminated bacillus Calmette-Guérin (BCG) disease is a rare but serious BCG complication in children. Early diagnosis and timely interventions are essential to improve prognosis. However, its manifestations can closely mimic those of Langerhans cell histiocytosis (LCH), which usually leads to a high rate of misdiagnoses. Herein we report the first case of successful application of biopsy tissue metagenomic next-generation sequencing (mNGS) in the differential diagnosis of disseminated BCG disease and LCH.
METHODS: A 5-month-old female infant was transferred to our center for the treatment of paroxysmal cough, intermittent hematochezia and trunk rash. Examination on admission showed moderate anemia, erythropenia, thrombocytopenia and hepatosplenomegaly. The immunohistochemistry of her intestinal biopsy samples showed CD1a (+) and Langerin (+). Genetic testing of both peripheral blood and bone marrow samples suggested BRAFV600E mutation. Hence, she was initially diagnosed with LCH. However, no improvement was observed after a course of systemic chemotherapy. The left axillary lymph node and colonic mucosal biopsy specimens were sent for mNGS which resulted in sequence reads of Mycobacterium bovis-BCG. Triple antimycobacterial therapy was started according to the diagnosis.
RESULTS: The diagnosis of this case was corrected as disseminated BCG disease by mNGS. Currently, she is doing well clinically and continues to follow-up at our outpatient clinic.
CONCLUSIONS: This case suggests that mNGS is a valuable tool in the differential diagnosis of disseminated BCG disease and LCH, which can improve the early diagnosis rate of disseminated BCG disease.

BACKGROUND: The pediatric pulmonary multisystem Langerhans cell histiocytosis (PPM LCH) is associated with either low risk or high risk organ(s). The nodulo-cystic lung lesions although pathognomonic, yet are very variable in severity and remain a source of controversy in certifying pulmonary LCH diagnosis. The study aimed to examine the prognostic value of clinical respiratory manifestations and radiological lung lesions severity. This is through associating a CT chest triad of bilateral, extensive and diffuse lesions. It is a retrospective study of 350 LCH patients who received systemic treatment at Children\'s Cancer Hospital Egypt during the period from 2007 to 2020.
RESULTS: Sixty-seven patients (67/350-19.1%) had PPM LCH at presentation. Severe lung lesions were present in 24 of them. The median follow-up period was 61 months (IQR: 3.4-8.3). The 5-year overall survival (OS) and event free survival (EFS) was 89% and 56.6% respectively. The EFS, for severe radiological lesions triad was 38% ± 20.7 versus 66% ± 16.2 for non-severe lesions triad p 0.002, while for presence of chest X-ray changes 27% ± 22.344 versus absence of chest X ray changes 66% ± 14.7 p 0.001, for clinical respiratory manifestations 13% ± 13.9 versus none 62% ± 22.9 p < 0.001, for RO- with severe lung lesions 47% ± 30.4 versus RO- without severe lung lesions 69% ± 5.9 p 0.04. There was a tendency for the independent prognostic impact of severe lung involvement; aHR = 1.7 (95% CI 0.92-3.13, p = 0.09).
CONCLUSIONS: Although the lung is a low -risk organ per se in LCH, our study demonstrates a non negligeable prognostic impact of severe lung involvement in the risk stratification of pediatric LCH. This warrants further study and external validation.

Rosai-Dorfman disease (RDD) is one of 3 major types of histiocytosis, along with Erdheim-Chester disease and Langerhans cell histiocytosis. While historically, RDD was considered a benign self-limited condition, current data show MAPK/ERK pathway mutations in 30% to 50% of cases, indicative of a clonal process. Rosai-Dorfman disease was incorporated as a histiocytic neoplasm in the fifth edition of the World Health Organization classification of hematopoietic tumors and the International Consensus Classification.
We discuss the diagnosis of RDD using 2 illustrative cases, interpretative challenges, and a diagnostic algorithm.
Rosai-Dorfman disease involves nodal and extranodal sites, including skin, sinuses, salivary gland, orbit, central nervous system, kidney, and bone. In a subset, RDD can coexist with other neoplasms (lymphomas, other histiocytosis) or autoimmune disease. Morphologically, RDD histiocytes are characterized by enlarged round to oval nuclei, distinct nucleoli, and voluminous cytoplasm with engulfment of inflammatory cells (emperipolesis). By immunohistochemistry, they express CD68, CD163 (majority), S100, OCT2, and cyclin D1. Appropriate use of ancillary studies is important to support the diagnosis of RDD while excluding other histiocytic neoplasms and reactive histiocytic proliferations.
Management of RDD is dependent on the extent of organ involvement and clinical symptoms. In patients who require therapy, next-generation sequencing is recommended to identify MAPK/ERK pathway mutations for targeted therapy.

Flexible bronchoscopes are increasingly being used in diagnostic and therapeutic medicine and have obviated the need for and risks associated with general anesthesia. Here the authors present the case of a 2-y-old girl who was diagnosed with isolated pulmonary Langerhans cell histiocytosis by histopathology; a lung biopsy sample was obtained using a cryoprobe via a flexible bronchoscope. The girl was brought in with complaints of loss of weight, appetite loss, and rapid breathing for the past 2 mo. Examination revealed hypoxia, tachypnea, clubbing with failure to thrive, and bilateral crepitations on auscultation. Imaging studies showed ground-glass opacities with multiple cystic lesions in both lungs. A preliminary diagnosis of LCH was made, and transbronchial cryobiopsy was done via a flexible bronchoscope. Histopathology confirmed the diagnosis with Cluster of differentiation 1a (CD1a) staining. A flexible bronchoscope can be a useful tool for obtaining lung biopsy samples using a cryoprobe in children.

Radiographic skeletal survey (R-SS) is the standard imaging technique for the initial staging of Langerhans cell histiocytosis (LCH). Whole-body magnetic resonance imaging (WB-MRI) has been proposed as an effective, radiation-free alternative.
We prospectively assessed patients with LCH followed at three tertiary centers in Italy and Austria. Two national study protocols were independently designed, and data were then pooled to increase the power of their findings. R-SS and WB-MRI were performed at diagnosis and repeated at the follow-up to confirm the nature of the identified lesions and to study their evolution.
Data from 67 patients were analyzed (52 from Italy and 15 from Austria). Compared to R-SS, WB-MRI identified 29 additional skeletal lesions in 14 patients (including two false-positive lesions). Two skeletal lesions were detected at R-SS and missed at WB-MRI (false negative). Per-lesion sensitivity rates were 78.6% (95% CI: 71.0-85.9) for R-SS and 98.4% (95% CI: 94.4-99.8) for WB-MRI, respectively. Based on WB-MRI findings, six patients would have been upstaged to a higher risk class than staging with R-SS.
WB-MRI had a significantly higher detection rate for skeletal lesions compared to R-SS. Clinical and radiology expertise is required to avoid upstaging and overtreatment.

Introduction Langerhans cell histiocytosis (LCH) is a rare, clonal disorder characterized by proliferation and tissue infiltration by myeloid dendritic cells, most commonly occurring in pediatric populations. It often manifests as skeletal lesions with possible pelvic involvement. Few studies have characterized and reviewed outcomes after treatment of isolated pelvic LCH lesions. Methods A retrospective single-institution review was conducted on diagnoses of patients younger than 18 with a diagnosis of unifocal or multifocal skeletal LCH lesions involving the pelvis. Clinical presentations, lesion sites, focal classification, radiographic findings, treatments, complications, and recurrence rates were reviewed. Results Twenty patients had unifocal or multifocal LCH pelvic lesions (11 males, nine females). The median age at diagnosis was 3.5 years (0.8-21.6). Eight cases (40%) involved unifocal lesions, and twelve (60%) involved multifocal lesions, with the most common associated skeletal disease occurring at the ilium. 100% of cases had a lytic bone lesion with no pathologic fractures. All cases were treated nonoperatively with chemotherapy medications, corticosteroids, or observation alone. 75% of cases were treated with chemotherapy with a 100% resolution rate. The median length of follow-up was 4.5 years (0.4-16.7).  Conclusion Our study found that chemotherapy alone or chemotherapy with corticosteroid supplementation are appropriate options for unifocal pelvic LCH lesions. In contrast, pelvic lesions that are part of a multifocal presentation may be managed adequately with varied chemotherapy regimens. Corticosteroid therapy and observation alone may also be reasonable for a single organ system, multifocal, skeletal lesions that are anatomically accessible for biopsy and small in number or size.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare haematological neoplasm characterized by the accumulation of CD1a+, CD207/Langerin+ histiocytes within inflammatory lesions. LCH can involve any organ, but osteolytic bone lesions are most often encountered. Unifocal bone lesions may regress spontaneously after a thick needle biopsy has been taken.
METHODS: In this case report, we describe the initial presentation of a single BRAFV600E mutated osteolytic LCH lesion in the left proximal humerus of a 46-year-old previously healthy woman. Despite multiple surgical interventions, she unexpectedly experienced progressive disease manifestation with significant soft tissue extension to the surrounding musculature, subcutis and epidermis. Because the disease manifestation remained loco-regional, radiotherapy (RT) (total dose of 20 Gy in 10 fractions) was initiated.
CONCLUSIONS: The patient achieved a complete remission without any side effects. This case highlights that RT is a rational and relative mild local treatment option for patients with aggressive LCH affecting the bone and surrounding soft tissue.