Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm with heterogeneous presentations. The discovery of BRAFV600E and other MAPK pathway mutations drastically transformed the treatment landscape, especially for high-risk LCH and CNS-LCH. While treatment strategies for children and adults are somewhat similar, response assessment methodologies remain highly dichotomized.Currently, separate treatment response criteria exist for children and adults, especially in therapeutic trials. Considering the rapid evolution of targeted MAPK-inhibitor therapies, along with ultrasensitive detection of minimal residual disease biomarkers (e.g., circulating BRAFV600E-encoding DNA) and sophisticated imaging tools (18F-FDG-PET and whole-body MRI), harmonization of response criteria in LCH is clearly warranted. The Histiocyte Society Global LCH Treatment Response Harmonization Task Force, a collaborative network of pediatric and adult LCH experts, is set to propose updated pediatric LCH treatment response criteria, which will also serve as the foundation for a universal response assessment tool for pediatric and adult LCH. In this review, we focus on the past, present, and likely future of response assessment in LCH patients, and discuss needs that remain unmet in the targeted therapy era.

Histiocytic lesions, now classified as a myeloid-derived neoplasia, consist of mutated monocyte-derived dendritic and macrophage cells infiltrating tissues. They are primarily driven by kinase-activating alterations in mitogen-activated protein kinase (MAPK), Phosphatidylinositol 3-kinase (PI3K)/AKT, or other receptor tyrosine kinase (RTK) signalling pathways, leading to extracellular signal-regulated kinase (ERK) overexpression and growth survival. In children, these include Langerhans cell histiocytosis (LCH), juvenile xanthogranuloma (JXG), Rosai-Dorfman-Destombes disease (RDD), and ALK-positive histiocytosis. Additional diagnostic challenges are discussed including mixed histiocytosis and malignant histiocytic neoplasms (MHN), including Histiocytic Sarcoma and Langerhans cell sarcoma, described in terms of primary or secondary disease, if after a prior hematologic malignancy.

Langerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder characterized by inflammatory lesions with clonal histiocytes. LCH is driven by activating mitogen-activated protein kinase (MAPK) pathway mutations. BRAFV600E is the most common mutation and is associated with more extensive disease at presentation and risks of front-line treatment failure, liver disease, and LCH-associated neurodegeneration. Genetic ancestry influences LCH with highest incidence in Hispanic populations. MAPK inhibitors are effective, but do not achieve cure in most cases. Clinical trials prospectively testing risk-stratification based on somatic mutation and/or detectable mutation in peripheral blood may improve outcomes for LCH patients.

Langerhans cell histiocytosis (LCH) is a rare disease. It mainly involves abnormal proliferation and aggregation of Langerhans cells, a type of cell of the immune system.Langerhans cytosis is more common in the bone, but it has rarely been reported in the mediastinum.

We present a case of mediastinal thymus tumor presented with Langerhans cell histiocytosis. A 40-year-old female patient presented with left chest and back pain in April 2024. Imaging revealed abnormal signal lesions on the patient's left rib and anterior superior mediastinum. The clinical diagnosis was bone destruction and mediastinal space occupation, and the postoperative pathological diagnosis was Langerhans cell histiocytosis.

Langerhans cytosis is characterized by mediastinal and thymus occupation and is relatively rare in clinical practice. For patients who tolerate surgery for a single or local lesion, surgical removal of the primary lesion should be considered. However, for patients with multiple lesions or distant metastases, clinicians should evaluate whether surgery will benefit the patient. After surgical treatment, targeted therapy or immunotherapy should be performed.

Histiocytic neoplasms are a diverse group of disorders arising from macrophages, dendritic cells, and monocytes of the mononuclear phagocyte system. These neoplasms encompass a clinical spectrum from indolent, self-limited, and localized conditions to highly aggressive malignancies. Since the publication of the Revised Fourth Edition of the World Health Organization (WHO) classification, advances in molecular diagnostics have improved our understanding of the pathogenesis and classification of these disorders. In contrast to the Revised Fourth Edition, the International Consensus Classification (ICC) now recognizes Rosai-Dorfman-Destombes disease as a neoplastic disorder and introduces ALK-positive histiocytosis as a distinct entity. This manuscript reviews the current concepts regarding histiocytic neoplasms, focusing on the diagnostic criteria recommended by the ICC based on histopathology, immunophenotype, molecular alterations, as well as clinical and imaging characteristics.

We are presenting two individuals with biallelic C-C chemokine receptor type 2 (CCR2) deficiency carrying the novel c.644C>T p.L215P variant, who presented with chronic respiratory symptoms during infancy and developed multiple diffuse cystic lesions during childhood.

The patients were diagnosed by means of whole exome sequencing and functional validation of the variant was performed in primary patient cells.

While size and extent of the cysts were stable over years, progressive lung function decline was noted in adolescence and adulthood respectively. The CCR2 p.L215P variant was found to be loss-of-expression and patient monocytes displayed a migration defect upon stimulation with the CCR2 ligand C-C motif ligand 2 (CCL2).

With a follow-up of up to 25 years, this report expands our understanding of lung disease in CCR2 deficiency and offers another monogenic cause of cystic lung disease. Early genetic diagnosis of affected individuals might allow potentially curative treatment by haematopoietic stem cell transplantation.

Adult multisystem Langerhans cell histiocytosis (MS-LCH) is rare and has a poor prognosis. A 67-year-old man with MS-LCH presented with a hepatic tumor rupture and multiple masses in the lungs, liver, and pancreas. Despite the initial aggressive disease course and involvement of organs at risk, the patient experienced spontaneous regression and lesion disappearance following smoking cessation without chemotherapy. A literature review revealed a distinct subset of MS-LCH that can be managed by smoking cessation and careful observation through follow-up imaging. This suggests that careful observation through follow-up imaging may be a reasonable alternative to chemotherapy in select adult cases of MS-LCH.

This study aimed to characterise the clinical features and treatment regimens of patients with lupus who have lymphadenopathy (LAP), as well as to investigate the presence and potential implications of Langerhans cells (LCs) infiltration in lymph nodes.

A case-control study was conducted to identify the clinical characteristics of newly diagnosed, treatment-naïve patients with lupus who have LAP. Lymph node biopsies were performed, and LC infiltration was assessed using immunohistochemical staining for S100, CD1a and Langerin.

A total of 59 patients with SLE who have LAP (SLE-LAP) were enrolled, with 81 patients with SLE without LAP serving as controls. The SLE-LAP group exhibited significantly higher frequencies of fever (64.4% vs 35.8%, p<0.001), anaemia (71.2% vs 42.0%, p<0.001), serous effusion (27.1% vs 11.1%, p=0.015), myositis (10.2% vs 1.2%, p=0.045) and elevated CRP levels (44.1% vs 22.2%, p=0.006). Moreover, autoantibodies, including anti-Smith (37.3% vs 16.0%, p=0.004), anticardiolipin IgG (27.1% vs 11.1%, p=0.015), IgM (42.4% vs 9.9%, p<0.001) and IgA (8.5% vs 0.0%, p=0.027), were more frequently detected in the LAP group. LC infiltration was confirmed in 29 of the 59 lymph node biopsies (49.2%). Immunohistochemical analysis revealed a scattered (58.6%) or focal (41.4%) distribution of LCs. Patients with LC infiltration predominantly presented with fever (72.4%), anaemia (64.3%), skin rashes (62.1%) and arthritis (62.1%). However, no significant differences in clinical manifestations were observed between LC-positive and LC-negative patients.

LC infiltration in the lymph nodes of patients with SLE is relatively common and should be carefully evaluated to prevent misdiagnosis. The role of LCs in the autoimmune response and pathogenesis of SLE warrants further investigation.

Pheochromocytoma is a neuroendocrine neoplasm that originates from chromaffin cells of the adrenal medulla. Langerhans cell histiocytosis (LCH) is a proliferative disease of histiocyte-like cells, often associated with activating mutations of the mitogen-activated protein kinase (MAPK) pathway. We present a case of a 49-year-old male with a history of pheochromocytoma, which metastasized to the inferior vena cava eight years after left adrenalectomy. At the same time, it was found that the pheochromocytoma in the metastasis was complicated with LCH, a combination that has not been previously reported. Genetic analysis was carried out by next-generation sequencing (NGS) technology. Somatic mutations of BRAF and RAD54B were detected in Langerhans cells and EPAS1 in pheochromocytoma.

We report a case of multifocal Langerhans cell histiocytosis (LCH) in a previously healthy four-year-old male child who initially presented to the chiropractic clinic with a three-week history of progressive left-sided limping and nocturnal leg pain. Upon evaluation, the patient demonstrated an antalgic gait, point tenderness over the left femur and tibia, and constitutional symptoms including low-grade fevers, fatigue, and recent weight loss. Radiographic evaluation revealed multiple lesions in the left femur, tibia, and pelvis, with subsequent MRI confirming infiltrative lesions and a pathological fracture of the femoral neck. PET scan identified additional lesions in the skull, spine, and right humerus with no visceral involvement. Biopsy of the femoral lesion confirmed LCH with CD1a and CD207 (langerin) positivity and BRAF V600E mutation. The patient was classified as having multifocal bone disease without risk of organ involvement, and treatment was commenced with vinblastine and prednisone per standard protocol. This case highlights the importance of recognizing red flag symptoms in pediatric limping presentations, demonstrates the critical role played by non-oncology providers in early detection of serious pathology, and illustrates the characteristic radiographic and histopathological features of multifocal LCH. The case further emphasizes how recent advances in understanding LCH's molecular pathogenesis as a clonal neoplastic disorder driven by mitogen-activated protein kinase (MAPK) mutations have refined our approach to the diagnosis and treatment of this rare but significant pediatric condition.

Kimura disease (KD) is a rare, chronic, inflammatory condition, predominantly found in male patients of Asian ethnicity. It typically presents between 50-60 years of age and usually with bilateral disease. Angiolymphoid hyperplasia with eosinophilia (ALHE) remains the main differential diagnosis, although histological analysis is essential in differentiating from other similarly presenting pathologies. In this case, we present an atypical case of unilateral orbital KD in a middle-aged, Caucasian, male gentleman and no evidence of regional lymphadenopathy along with a literature review of orbital KD and the differential diagnoses, histological features and management modalities available, adding to the sparse literature on the topic. At present, no recognised diagnostic criteria for KD are available, with histopathological analysis through incisional or excisional biopsy being the primary diagnostic method. Complete surgical excision with or without corticosteroid management remains the most common treatment modality although management is shifting to steroid-sparing immunomodulatory therapy. To the best of our knowledge, this is the first case to describe maintenance therapy of KD using mycophenolate mofetil.

Gastrointestinal tract involvement in Langerhans cell histiocytosis (LCH) is extremely rare, with limited documentation of endoscopic manifestations. We report a 19-month-old girl who presented with repeated diarrhea and bloody stools, accompanied by recurrent pulmonary infections, anemia, hypoproteinemia, thrombocytopenia, coagulopathy, and hepatosplenomegaly with lymphadenopathy. Initial treatment with antibacterial agents, mesalazine, thalidomide, and prednisone led to temporary improvement; however, the symptoms repeatedly relapsed. She underwent three digestive endoscopies, but until the third endoscopy, a definitive diagnosis of Langerhans cell histiocytosis was established through biopsy. While upper gastrointestinal tract findings were not significant, notable changes were observed in the colorectal region. A colonoscopy revealed progression from erythema to diffuse hyperemia and edema, with erythema, erosion, and superficial ulcers extending into the distal ileal mucosa. Genetic analysis identified a BRAF-V600E mutation. Following treatment with chemotherapy (vincristine and prednisone) and the BRAF inhibitor dabrafenib, the patient demonstrated significant clinical improvement within days. At the 1-year follow-up, the patient had normal bowel movements and a weight gain of 2.5 kg. Early gastrointestinal endoscopy with multiple biopsies in suspected children can facilitate early detection. Dabrafenib is a viable treatment option for Langerhans cell histiocytosis.

Treatment options for single-system Langerhans cell histiocytosis (LCH) range from observation to chemotherapy. Among these options, corticosteroid injection is appealing due to the feasibility, preservation of structure and function as well as the low complication rate. Therefore, this study aimed to investigate the effectiveness of intralesional injection of triamcinolone acetonide (TA) for the treatment of craniofacial LCH and present a typical case. 11 patients diagnosed with LCH of the jaws who received intralesional injection of TA at Hospital of Stomatology, Sun Yat-sen University from April 2014 to May 2021 were involved. Clinicopathologic data were collected and analyzed. The 11 subjects included 7 males and 4 females (mean age 14.6±16.9 y). Most lesions were located in the mandible (n=9, 81.8%). The effective rate of intralesional injection of TA was 90.9%. The average initial dosage and average accumulative dosage were 33.2±21.0 and 99.5±88.7 mg, respectively. The mean time needed for complete ossification of the lesion was 12.5±8.2 months. The mean follow-up time was 20±13.4 months. Although the effective rate was similar between children and adults (100% versus 75%, P=0.364), the initial dosage, accumulative dosage, number of injections, and time needed for complete ossification of the lesion were all lower in children (P<0.05). In conclusion, intralesional injection of TA is a suitable treatment option for craniofacial LCH, especially in children. Studies that incorporate a larger patient cohort should be conducted to verify the current findings.

Anxiety and depression are common in many cancers but, to our knowledge, have not been systematically studied in patients with histiocytic neoplasms (HNs). We sought to estimate rates of anxiety and depression and identify clinical features and patient-reported outcomes (PROs) associated with anxiety and depression in patients with HNs. A registry-based cohort of patients with HNs completing PROs including the hospital anxiety and depression scale (HADS) from 2018 to 2023 was identified. Moderate or severe anxiety or depression were respectively defined as a score of ≥11 on the HADS anxiety or depression subscales. Associations of variables, including other validated PROs, with moderate or severe anxiety or depression were modeled with logistic regression to estimate odds ratios and 95% confidence intervals. In 215 patients, ∼1 in 3 met the criteria for anxiety or depression, and 1 in 7 met the criteria for moderate or severe anxiety or depression. These estimates remained stable over a 12-month trajectory. Rates of depression, but not anxiety, significantly differed across HN types, with patients with Erdheim-Chester disease experiencing the highest rate. In addition, neurologic involvement, unemployment, and longer undiagnosed illness interval were significantly associated with increased risk of depression. Financial burden, financial worry, and severe disease-related symptoms were correlated with increased risk of both anxiety and depression. Conversely, increased general and cognitive health-related quality of life (HRQoL) were correlated with decreased risk of both anxiety and depression. In patients with HN, anxiety and depression are prevalent, stable over time, and correlated with financial burden, symptom severity, and HRQoL. This trial was registered at www.clinicaltrials.gov as #NCT03329274.

Langerhans cell histiocytosis (LCH) rarely presents in the oral and maxillofacial region, and while isolated and small collections of Langerhans-type cells have been found in periapical cysts, there have been no reported cases of LCH arising in periapical cysts.

A 58-year-old female presented with isolated erythematous dry skin lesions and a radiolucent lesion of the anterior maxilla. Microscopic examination of the enucleation specimen revealed a periapical cyst with large collections of atypical cells with grooved folded nuclei with eosinophils consistent with LCH. Immunohistochemistry (IHC) was performed to confirm the diagnosis. BRAF mutation status was evaluated with the BRAF p. V600E antibody and the automated real-time PCR-based Idylla™ assay, capable of qualitative detection of 5 mutations in codon 600 of the BRAF gene.

The LCH cells were positive for S100, CD1a, and Langerin (CD 207) and negative for BRAF p. V600E mutations. Ki-67 was 45%.

The association of LCH with a periapical cyst could be explained by the active surveillance and migration of neoplastic Langerhans-type cells in blood to the site of apical chronic inflammation, in a patient with LCH. Careful attention to morphologic features in conjunction with Langerin IHC, helps exclude other closely-related dendritic tumours. BRAF p. V600E testing, ideally with real-time PCR assays, can help identify patients who may benefit from BRAF inhibitor therapies. New generations of sequencing that cover a large panel of genetic alterations beyond the frequent BRAF p. V600E mutations (e.g. rare in-frame BRAF deletions), could provide valuable information about the extent, prognosis and treatment of LCH patients.

Langerhans cell histiocytosis (LCH) is characterized genetically by diverse gene mutations of the mitogen-activated protein kinase signaling cascade. BRAFN486_T491delinsK mutation is a rare mutation that involves the β2-αC ring domain, causing activation of the mitogen-activated protein kinase pathway, and is predicted to be resistant to the chemotherapy and BRAFV600E inhibitor in adult LCH cases. Here, we report a childhood LCH case with this novel BRAF mutation and had a good response to conventional chemotherapy. This case report suggests that children with BRAFN486_T491delinsK mutation might differ from adult counterparts in terms of clinical behavior, and conventional chemotherapy might still be an effective therapy.

Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm with inflammatory characteristics. This study aims to investigate the correlation between sCD25 levels and clinical characteristics, as well as prognosis, in pediatric LCH.

Serum sCD25 levels were measured in 370 LCH patients under 18 years old using ELISA assays. The patients were divided into two cohorts based on different treatment regimens. We further assessed the predictive value for the prognosis impact of sCD25 in a test cohort, which was validated in the independent validation cohort.

The median serum sCD25 level at diagnosis was 3908 pg/ml (range: 231-44 000pg/ml). sCD25 level was significantly higher in multi-system and risk organ positive (MS RO+) LCH patients compared to single-system(SS) LCH patients (p < 0.001). Patients with elevated sCD25 were more likely to have involvement of risk organs, skin, lung, lymph nodes, or pituitary (all p < 0.05). sCD25 level could predict LCH progression and relapse, with an area under the ROC curve of 60.6 %. The optimal cutoff value was determined at 2921 pg/ml. Patients in the high-sCD25 group had significantly worse progression-free survival compared to those in the low-sCD25 group (p < 0.05).

Elevated serum sCD25 level at initial diagnosis was associated with high-risk clinical features and worse prognosis. sCD25 level can predict the progression/recurrence of LCH following first-line chemotherapy.

Tissue eosinophilia is a common finding during histopathologic evaluation and recognizing its presence oftentimes aids pathologists in arriving at the correct diagnosis. The head and neck region is an anatomic location where an abundance of eosinophil-rich disorders occur. In this review, we seek to provide an overview of eosinophil morphology, production, regulation, lifecycle, recruitment, function, and mediators. We will also summarize the most commonly diagnosed eosinophil-rich disorders, both non-neoplastic and neoplastic, occurring in the head and neck.

Dermatologic lesions with notable eosinophilic infiltration of the head and neck region represent a diverse group of conditions, ranging from benign to malignant proliferations.

We performed a comprehensive literature review focusing on head and neck dermatologic conditions that commonly present with a prominent eosinophilic infiltrate.

This review provides an overview of common entities showing prominent associated eosinophilic inflammatory infiltrates in this region, including epithelioid hemangioma, eosinophilic cellulitis (Wells syndrome), eosinophilic folliculitis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), granuloma faciale, and Langerhans cell histiocytosis (LCH).

Eosinophils play a key role in the pathogenesis of these disorders, although the exact mechanisms remain poorly understood. Accurate diagnosis is crucial for differentiating these conditions, as they can share similar histologic features. This review aims to enhance understanding of these eosinophilic dermatologic conditions, improving diagnostic accuracy and treatment strategies.

Targeted delivery has emerged as a critical strategy in the development of novel therapeutics. The advancement of nanomedicine hinges on the safe and precise cell-specific delivery of protein-based therapeutics to the immune system. However, major challenges remain, such as developing an efficient delivery system, ensuring specificity, minimizing off-target effects, and attaining effective intracellular localization. Our strategy utilizes lipid-based nanoparticles conjugated with a glycomimetic ligand. These nanoparticles selectively bind to langerin, a C-type lectin receptor expressed on Langerhans cells in the skin. We opted for cytotoxic proteins, namely cytochrome c and saporin, as model proteins to showcase the potential of delivering intact proteins to Langerhans cells. These proteins are recognized for their ability to induce apoptosis upon entry into the cytosol. We observed specific killing of cells expressing langerin in vitro, and in primary Langerhans cells isolated from mouse and human skin ex vivo with minimal off target effects. By delivering functional proteins within lipid nanoparticles to Langerhans cells, our approach offers new potential to deliver effective therapeutics with minimal side effects.

Langerhans cell histiocytosis (LCH) is a condition characterized by clonal proliferation of the phagocytic cells derived from the bone marrow. In this article, we present an exceedingly rare case of congenital/neonatal LCH in a 3-week-old girl who initially presented with an isolated swelling of the eyelid, initially misdiagnosed as a chalazion. Subsequently, a biopsy was performed, and histopathological evaluation confirmed the diagnosis of LCH. A staging work-up revealed no evidence of multisystem involvement, and thus, local steroid injection was performed as the initial treatment for the residual lesion. Cases of localized LCH that manifest as eyelid masses are rare, and most reported cases involve children over the age of one year. To the best of our knowledge, this case represents the first reported instance of neonatal LCH presenting as an eyelid mass. Although neonatal LCH is rare, ophthalmologists must be aware of this presentation and include it in the differential diagnosis for eyelid lesions in infants during the first month of life.

Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm that predominantly affects young children.

To investigate genetic alterations and their correlation with clinical characteristics and prognosis in pediatric LCH.

We performed targeted sequencing to detect mutations in LCH lesions from pediatric patients.

A total of 30 genomic alterations in 5 genes of the MAPK pathway were identified in 187 of 223 patients (83.9%). BRAF V600E (B-Raf proto-oncogene, serine/threonine kinase) was the most common mutation (51.6%), followed by MAP2K1 (mitogen-activated protein kinase kinase 1) alterations (17.0%) and other BRAF mutations (13.0%). ARAF (A-Raf proto-oncogene, serine/threonine kinase) and KRAS (KRAS proto-oncogene, GTPase) mutations were relatively rare (2.2% and 0.9%, respectively). Additionally, FNBP1 (formin-binding protein 1)::BRAF fusion and MAP3K10 (mitogen-activated protein kinase kinase 10) mutations A17T and R823C were identified in 1 case each, with possible constitutive activation of ERK1/2 phosphorylation. BRAF V600E was more frequent in patients with risk organ involvement, while MAP2K1 mutation was more prevalent in patients with single-system LCH (P = .001). BRAF V600E was associated with craniofacial bone, skin, liver, spleen, and ear involvement (all P < .05). Patients with other BRAF mutations had a higher proportion of spinal column involvement (P = .006). Univariate analysis showed a significant difference in progression-free survival among the 4 molecular subgroups for patients treated with first-line therapy (P = .02). According to multivariate analysis, risk organ involvement was the strongest independent adverse prognostic factor (hazard ratio, 8.854; P < .001); BRAF or MAP2K1 mutation was not an independent prognostic factor.

Most pediatric patients with LCH carry somatic mutations involving the MAPK pathway, correlating with clinical characteristics and outcomes for first-line chemotherapy.

Langerhans cell histiocytosis (LCH) is a disease caused by clonal expansion of CD1a+/CD207+ cells and is characterized by organ involvement and dysfunction. Treatment of LCH in children is risk-adapted, and multisystem LCH requires systemic therapy. Although systemic treatments such as chemotherapy and BRAF/MEK inhibitors have improved the cure rate of LCH, disease reactivation rates remain 30%, and eventually some patients progress to relapse-refractory LCH. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a promising salvage treatment strategy for children with relapse-refractory LCH. However, many questions such as the efficacy and indications of allo-HSCT, as well as suitable conditioning regimen are still undetermined for children with LCH. This review aimed to provide an update on advances in allo-HSCT for LCH in children, including indications, stem cell sources, conditioning regimens, chimerism, transplant-related complications, outcomes, and treatment of relapse.

To retrospectively evaluate the clinical features and prognostic factors of pediatric LCH patients treated in a single center of China.

Pediatric LCH cases were treated following the SD-LCH protocol at the Affiliated Provincial Hospital of Shandong First Medical University in Jinan, China. An analysis was conducted on 82 recently identified LCH cases to retrospectively evaluate the initial symptoms, therapeutic alternatives, and extended results. Follow-ups were conducted until July 31, 2023.

The median age at diagnosis was 2 (0.25-12) years. 42 (51.2%) were SS-LCH, and 40 (48.8%) were MS-LCH. The most common organ involved was bone (82.9%). Over the 16-year follow-up period, the 5-year EFS and OS rates were 75.2 ± 5% and 90.9 ± 3.3%, respectively. The cumulative reactivation rate was 23.2%. The 5-year EFS rate in SS-LCH and MS-LCH patients were 90.2 ± 4.6% and 58.8 ± 8.3%, and the 5-year OS rate in SS-LCH and MS-LCH patients were 90.2 ± 4.6% and 81.2 ± 6.5%, respectively. The 5-year OS and EFS rate in RO+ LCH and RO- LCH patients were 79.5 ± 7.5%, 53.8 ± 9.6% and 87.5 ± 11.7%, 76.2 ± 14.8%, insignificantly. Multivariate Cox regression showed that liver involvement predicted poor EFS and hematological system involvement was an independent prognostic factor for OS. Detection of the BRAF V600E mutation and targeted therapy significantly improved the prognosis post-2017.

Liver or hematological system involvement indicates a poor prognosis, and the SD-LCH protocol improves prognosis for pediatric LCH patients.

Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm that can involve nearly any organ, leading to multisystem damage. Nail involvement in LCH is particularly uncommon. Here we report a case of a young boy with multisystem LCH initially presenting with nail changes.

We described a boy who presented with a 2-year history of asymptomatic changes characterized by onycholysis, subungual hyperkeratosis, and purpuric striae affecting most fingernails and toenails, initially attributed to onychomycosis. Two years later, he developed multisystem involvement affecting the pituitary gland, lungs, skin, liver, and spleen. The patient succumbed shortly after histopathological confirmation via skin biopsy due to massive gastrointestinal hemorrhage secondary to cirrhosis-induced portal hypertension.

Nail lesions may serve as the initial manifestation of LCH, often preceding other characteristic disease symptoms. This early presentation provides critical diagnostic opportunities for timely intervention. Consideration of LCH, biopsy, and comprehensive evaluation of organ involvement is essential to reduce the rate of misdiagnosis and the potential for unrecognized high-risk disease.

Nail involvement in LCH, while rare, may serve as an early clinical indicator of multisystem disease.

Histiocytoses constitute a group of heterogeneous disorders characterized by involvement of variable organs by neoplastic macrophage or dendritic cells. They may affect both adults and children with a predilection to the skin, bone, lungs, lymph nodes, and CNS. The coexistence of different types of histiocytoses in the same patient is an extremely rare phenomenon. We describe a very rare case of co-occurring pulmonary Langerhans cell histiocytosis with multiple cutaneous reticulohistiocytomas with a common BRAF- V600E mutation as the driver genetic event in both the lung and skin lesions. The presence of a common BRAF- V600E mutation provides evidence of their clonal relation and contributes to our understanding in the pathogenesis of multiple, co-occurring histiocytic proliferations.

Langerhans cell histiocytosis (LCH) is a rare disorder characterized by the proliferation of abnormal Langerhans cells, often presenting with symptoms that mimic common dermatological conditions such as hidradenitis suppurativa (HS). Accurate diagnosis is essential because LCH can affect multiple organ systems and necessitates distinct therapeutic approaches.

We report a rare case of a 39-year-old male with a 7-year history of diabetes insipidus (DI), who presented with polyuria, polydipsia, and enlarging purulent lesions in the axilla and groin. MRI revealed a pituitary lesion, and subsequent histopathological examination confirmed LCH. The patient underwent surgical interventions to address recurring cerebrospinal fluid (CSF) leaks and manage the underlying LCH.

Histopathology confirmed LCH with positive markers for CD1a and S-100 proteins. Post-surgery, the patient's symptoms, including polyuria and polydipsia, resolved without complications. There was no recurrence of CSF leakage or other LCH-related symptoms during follow-up. This case illustrates the diagnostic challenges of LCH when it mimics common conditions such as HS and underscores the importance of a multidisciplinary approach, particularly when standard treatments are ineffective.

Surgical intervention was pivotal in the resolution of symptoms, highlighting the necessity for timely and accurate diagnosis to improve outcomes in multifocal LCH cases.

Langerhans cell histiocytosis is a rare condition characterized by aberrant function and proliferation of the mononuclear phagocyte system. It can occur across all age ranges. This case report involves an adult female presenting with multisystem involvement and pleural effusion. A hypothesis suggests that chronic inflammatory states, resulting from cytokine production and the release of proinflammatory factors, alter vascular permeability, potentially leading to clinical manifestations such as fluid distribution abnormalities, including pleural effusion. Symptomatic multisystemic disease requires chemotherapy initiation. In this case, treatment could not be started due to unresolved empyema despite surgical intervention.

Blueberry muffin baby syndrome is a condition initially described in 1960 to classify the cutaneous manifestations of newborns with rubella. Subsequently, congenital diseases related to TORCH syndrome and blood dyscrasias have been included under this syndrome. Among the conditions associated with this syndrome is Langerhans Cell Histiocytosis, an uncommon condition with variable involvement of one or more organs, often affecting the skin. One of its forms of presentation is Hashimoto-Pritzker disease, a self-limited congenital Langerhans Cell Histiocytosis with exclusively skin involvement. First described in 1973 and with approximately 100 reported cases, its presentation as part of the Blueberry muffin baby syndrome is infrequent. Its prognosis is excellent, but long-term follow-up is required due to the possibility of relapses or subsequent visceral involvement.

Langerhans cell histiocytosis (LCH), juvenile xanthogranuloma (JXG) family lesions, and Rosai-Dorfman-Destombes disease (RDD) are now classified by the World Health Organization (WHO) under the heading of histiocytic/dendritic cell neoplasms. Each disease may manifest as a focal lesion, as multiple lesions, or as a widespread aggressive systemic disease with visceral organ involvement. Erdheim-Chester disease (ECD) is a rare systemic disease process of adults with limited cases in children. Challenges in diagnosis and novel disease presentations, including ALK-positive histiocytosis (a newly recognized WHO entity), mixed histiocytosis, and secondary histiocytic lesions following a prior leukemia/lymphoma are also discussed. Malignant histiocytic neoplasms (MHN) are distinct high-grade histiocytosis, which while rare in childhood occur both as primary disease and as secondarily after a prior hematologic malignancy. Of note, despite its name, hemophagocytic lymphohistiocytosis (HLH) is not considered a histiocytic neoplasm and does not define one specific disease "entity." HLH is a spectrum of hyperinflammation with various triggers and is not covered for the purposes of this targeted review.

Isolated gastric Langerhans cell histiocytosis (LCH) occurs extremely rarely in adults. We characterized the clinicopathological and molecular genetics of this rare entity. We retrospectively analyzed the clinicopathologic and prognostic features of 3 patients with isolated gastric LCH during the past 10 years, with a review of an additional 20 patients from the literature. A total of 23 patients with isolated gastric LCH were included in this study. There were 15 males and 8 females, with a mean age of 44.5 (median, 48; range, 21-68) years. Stomach discomfort and abdominal pain were the most common presenting symptoms. The lesions were mainly concentrated in the gastric body and antrum (21/23). Gastroscopy often revealed an elevated lesion/polyp. Molecular tests showed that BRAF-V600E gene mutations were found in 10/11 (42%) patients, while none of the patients (0/5) harbored KRAS gene mutations. None of the 23 patients received further treatment. Twenty patients had follow-up results (from 4 to 66 months). One patient with atypical morphological features died of unknown cause 2 months after removal of the tumor. One patient was found to have secondary lesions in the skull and axillary region. The other 18 patients survived without any evidence of disease progression during the follow-up period. In the daily diagnosis of gastroscopic biopsy, it is necessary to be aware of the possibility of LCH in patients with lesions in the gastric body or antrum if endoscopy reveals bulge/polypoid changes and heavy microscopic inflammation. In addition, we should be alert to the possibility of LCH with malignant transformation if the histological morphology exhibits tumor cell nucleoli and mitotic figures or necrosis. The immunohistochemical marker CD56 may help differentiate between LCH and Langerhans cell sarcoma when the morphology is difficult to determine. Molecular detection has shown that the mutation rate of BRAF in gastric LCH is up to 90.9%; more work is needed as the number of cases is small. Current data show a good prognosis for isolated gastric LCH in adults, but long-term follow-up for early detection of disease progression or systemic involvement is necessary.

Are children born after assisted reproductive technology (ART) at higher risk of developing Langerhans cell histiocytosis (LCH)?

Records of children born after ART recorded by the UK Human Fertilisation & Embryology Authority were linked to National Registry of Childhood Tumours records to determine the number of children developing LCH. Calculated person-years at risk were used in conjunction with the incidence of LCH in the general population to determine the expected number of cases if the cohort had the same incidence as the general population with similar age and sex, over the same calendar years. The standardized incidence ratio (SIR) was derived as the ratio of observed to expected cases. Exact 95% CI were calculated.

In total, 118,155 children born after ART contributed 796,633 person-years follow-up (average follow-up 6.74 years). Eight cases of LCH were identified, compared with 3.75 cases expected (SIR 2.135, 95% CI 0.92-4.21; P = 0.074). Significantly more cases were associated with intracytoplasmic sperm injection (ICSI) (SIR 4.02, 95% CI 1.31-9.39) and male factor infertility (SIR 5.41, 95% CI 1.47-13.84). Most cases of LCH had single-system disease (n = 6).

This study found that significantly more cases of LCH were identified in children born after ICSI and in children whose parents had male factor infertility. A non-significant excess of cases in children born after ART was identified. Absolute excess risk was small. Given the rarity of LCH and the small number of cases included in this large cohort, further studies into the risk of LCH in children born after ART are indicated.

Langerhans cell histiocytosis (LCH) is the most prevalent histiocytic disorder in pediatric populations, with a highly heterogeneous clinical presentation. Currently, the correlation between clinical phenotypes and molecular alterations in childhood LCH, besides the BRAFV600E mutation, has not been sufficiently studied.

This study presented data on 33 pediatric LCH patients treated at our center who exhibited various molecular alterations other than the BRAFV600E mutation. Additionally, we comprehensively reviewed pediatric LCH cases with non-BRAFV600E molecular alterations reported from January 2010 to August 2024.

A total of 309 pediatric LCH patients with molecular alterations beyond BRAFV600E were enrolled in the study, among whom 33 were from our center. In these LCH cases, 49 kinds of MAP2K1 mutations, 31 kinds of BRAF mutations, and 4 kinds of ARAF mutations were found. At our center, two patients with multisystem LCH with risk organ involvement, both with BRAFN486_P490del mutation, showed poor response to induction chemotherapy for 6 weeks. Among the 303 LCH patients with MAP2K1 or other BRAF alterations, patients with the MAP2K1 mutation had a higher prevalence of single-system bone involvement (SS-bone) than patients carrying the BRAF mutation (p = 0.0072). Within the MAP2K1 group, exon 3 mutations exhibited a stronger association with SS-bone than exon 2 mutations (p = 0.042). Additionally, patients with the BRAF exon 15 mutation and MAP2K1 exon 2 mutation had higher rates of LCH onset before age 3 compared with patients carrying the BRAF exon 12 mutation and MAP2K1 exon 3 mutation (p = 0.037; p = 0.0015). Patients carrying the BRAF mutation in exon 15 had higher rates of liver involvement compared with patients carrying the exon 12 (p = 0.042).

Pediatric LCH patients often carry recurrent somatic MAP2K1 and BRAF mutations, which are associated with clinical manifestations.

Introduction In the UK, more than 18 million extractions are performed annually. Healing after extraction is often uneventful, but there are rare cases where weeks or months pass and an extraction socket does not heal.Aim The aim of this study is to provide a review of cases in which a non-healing extraction socket is attributed to a serious systemic disease or malignancy, or an adverse consequence of systemic therapy.Methods PubMed, Embase, Scopus, ProQuest and Google Scholar databases were searched using the term 'non-healing extraction socket'. Results were subsequently restricted to humans and English language.Results A total of 50 cases of non-healing extraction socket (28 women and 22 men with an average age of 55.2 years) were identified. The total number of extracted teeth was 71. Malignancy (primary and metastatic) was the most common definitive diagnosis, followed by medication-related osteonecrosis of the jaw.Discussion There are cases in which an extraction socket does not show any sign of proper healing, even after a lengthy period. Some of these cases are caused by primary or metastatic cancer, or other serious disorders.Conclusion Dentists should be vigilant when encountering a non-healing extraction socket, as this may herald an undiagnosed serious disease or malignancy.

Histiocytic disorders include a range of uncommon illnesses marked by the buildup of cells that have developed into macrophages, dendritic cells, or monocytes in diverse tissues and organs. Over 100 distinct subtypes have been documented, exhibiting a diverse array of clinical symptoms, presentations, and histologic features that can be confused with other clinical conditions leading to delayed diagnosis. They affect both children and adults, generating a variety of clinical symptoms that can be limited to one position, numerous areas within one system, or affect many systems in the body. We provide our experiences handling two cases of histiocytic disease in underdeveloped countries where targeted treatment choices are unavailable. The first patient was a 32-year-old female with polyuria, skin lesions, and macroadenoma on MRI. Histopathological and immune-histochemical assessment of skin lesions confirmed the diagnosis of Langerhans cell histiocytosis. The patient responded well to steroids and oral and intrathecal methotrexate. The second patient was a 38-year-old male with recurrent skin lesions followed by retro-orbital discomfort and proptosis. The retro-orbital mass was surgically excised followed by a recurrence a few months later. Histopathological and immune-histochemical assessment confirmed the diagnosis of extranodal Rosai-Dorfman disease. He showed a partial response to methotrexate followed by a remarkable response to rituximab. Because of the wide variety of clinical symptoms, the diversity of experts engaged in assessing and treating these patients, and the scarcity of cases accessible, there is still a need to develop an evidence-based technique for evaluating and treating this complicated disease, especially in resource-limited settings.

The detection of mutations from circulating tumor DNA (ctDNA) represents a promising enrichment technique. In this retrospective study, the significance of ctDNA and imaging in Langerhans cell histiocytosis (LCH) monitoring was first examined, and the broader role of ctDNA in monitoring LCH was additionally explored.

First, data visualization and survival analysis models were used to generalize the concordance between cfBRAFV600E molecular response and radiographic response on clinical outcomes. Next, the molecular response of cfBRAFV600E was observed from a dynamic perspective. A comparative analysis was then conducted between cfBRAFV600E and ltBRAFV600E status, examining their relationship to clinical manifestations and prognosis of LCH.

Eventually, 119 participants were enrolled in this trial between 2019 and 2023. Progression-free survival (PFS) was significantly shorter in patients with both radiologic and cfDNA molecular progression (17.67 versus 24.67 months, p < 0.05) compared to those without. A critical cfBRAFV600E value of 0.03% has been determined for the first time. Both cfBRAFV600E and ltBRAFV600E mutations were associated with a higher proportion of children under 3 years of age, skin and spleen involvement, and a lower 3-year PFS rate. In contrast to ltBRAFV600E, cfBRAFV600E was linked to a higher proportion of risk organ invasion LCH (52% vs. 27.9%, p < 0.05) and a better therapeutic response at the sixth week (24% vs. 4.7%, p < 0.05). Furthermore, in patients with risk organ invasion-LCH and multisystem-LCH subtypes, cfBRAFV600E was associated with a significantly lower 3-year PFS.

In summary, these findings enhanced and supplemented the implications of ctDNA and imaging analysis application in children with LCH.

Langerhans cell histiocytosis (LCH) is a systemic neoplasia with diverse clinical manifestations, predominantly affecting bone and skin. However, in children, LCH presenting primarily with cholestasis is rare.

We present the case of a 22-month-old boy who was admitted to our hospital with a history of intermittent fever and abdominal distension for over 2 months, and jaundice for over 1 month. Prior to admission, the child had been managed with anti-infective and anti-inflammatory drugs and supportive care at multiple hospitals without significant improvement. He was then referred to our facility for further treatment. Upon admission, a series of laboratory tests, imaging studies, and pathological examinations were conducted, revealing the presence of diabetes insipidus, sclerosing cholangitis (SC), and liver cirrhosis. These findings led to a clinical diagnosis of LCH. Given the absence of definitive pathological evidence, his progression to decompensated liver cirrhosis and his pronounced growth retardation, the child was deemed a candidate for living donor liver transplantation. Following the liver transplant, pathological examination of the explanted liver tissue confirmed the clinical diagnosis of LCH. The child received postoperative chemotherapy, which resolved his systemic symptoms and normalized liver function. There was no evidence of LCH recurrence. The symptoms of diabetes insipidus were controlled with desmopressin acetate, however, the existing destructive lesions in the pituitary gland persisted.

Sclerosing cholangitis is a late and severe form of liver involvement in LCH that may be accompanied by lesions in other tissues or organs. Along with pathological evidence, a diagnosis should be made based on characteristic rashes, osteolytic lesions, and thickening of the pituitary stalk. In children with LCH complicated by SC for whom pathological diagnostic evidence cannot be obtained, liver transplantation may be considered once signs of decompensated liver cirrhosis appear, followed by systemic chemotherapy to control active disease. This strategy represents a therapeutic approach with the potential to achieve a better prognosis in children with LCH.

A 69-year-old male presented with a superior palpebral conjunctival white leukoplakic lesion. Excisional biopsy showed Langerhans cell histiocytosis. Positron emission tomography scanning revealed no lesions beyond this site. Native Langerhans cells are known to exist in the conjunctiva, yet only a few cases in the literature have described Langerhans cell histiocytosis of the conjunctiva, mostly in children. Conjunctival Langerhans cell histiocytosis has rarely been reported in an adult as leukoplakia. The authors advocate excisional biopsy for palpebral conjunctival Langerhans cell histiocytosis in older patients if the morbidity of closure is minimal, in addition to surveillance for multifocal disease.