To review and update the clinical presentation, pathology, treatment strategies, and follow-up of the orbital and ocular adnexal histiocytic tumors.

The review included the publications in English literature up to January 2024.

Out of 263 screened publications, 73 studies on Langerhans cell histiocytosis (LCH), juvenile and adult onset xanthogranuloma (JXG, AOXG), Erdheim-Chester disease (ECD), Rosai-Dorfman disease (RDD), and histiocytic sarcoma (HS) were included. Diagnosis is based on histological characteristics and markers on immunohistochemical staining. Treatment options vary depending on the type of histiocytic tumors, number of lesions, number of involved organs, and presence of vital organ involvement such as central nervous system. Surgery is the first diagnostic step for all and serves as the primary treatment for LCH and XG. Systemic chemotherapy is the primary treatment for EDC, RDD, and HS and the treatment of choice for the patients with multifocal or multi-organ involvement as well as recurrent or refractory lesions, regardless of the type of histiocytic tumor. Radiotherapy is an adjunctive primary treatment for the patients with HS. It is reserved for recurrent or refractory lesions in the other types. Targeted therapy is currently in progress and may replace the systemic chemotherapy in patients with LCH, XG, and EDC.

Surgical debulking is diagnostic in all and therapeutic in LCH, JXG, and AOXG. All recurrent, refractory, multifocal, and multi-organ tumors require additional systemic chemotherapy with or without radiotherapy. Follow-up imaging every 3 to 6 months for the first 2 years and then annually is recommended.

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.

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.

BRAF V600E mutations are frequently found in histiocytic/dendritic cell neoplasms such as Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH), but few reports have also described BRAF mutations in Rosai-Dorfman disease (RDD), and even these cases may predominantly represent mixed histiocytosis. BRAF mutations have been studied in histiocytic/dendritic cell neoplasms and described to be associated with increased risk of relapse and long-term consequences, but few studies have examined BRAF V600E mutation in RDD, which is recognized as a neoplasm given the high frequency of MAPK pathway alterations. Here, we report a case of BRAF V600E-mutated RDD in a patient who presented with generalized lymphadenopathy. During our evaluation of this patient, we also found expression of PD-L1 in neoplastic histiocytes. During our review period, only few cases of RDD reported to harbor BRAF mutation or were evaluated for the expression of PDL1 by neoplastic cells. Given the potential challenges in distinguishing RDD from other histiocytic/dendritic cell neoplasms, including mixed histiocytosis with similar clinicopathological manifestations, we will discuss the current state of knowledge regarding the frequency and clinical impact of BRAF V600E in RDD, as well as the role of BRAF mutations in RDD pathogenesis. Distinction of BRAF V600E mutated histiocytic/dendritic cell neoplasms requires consideration of distinctive histopathological and immunophenotypic findings in appropriate clinical and radiologic setting. Given the increasing use of BRAF inhibitors as well as checkpoint blockade inhibitors to treat a number of cancers, we will discuss the clinical implications of the presence of BRAF V600E mutation and PD-L1 expression in RDD.

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 myeloid neoplastic disorder characterized by lesions with CD1a-positive/Langerin (CD207)-positive histiocytes and inflammatory infiltrate that can cause local tissue damage and systemic inflammation. Clinical presentations range from single lesions with minimal impact to life-threatening disseminated disease. Therapy for systemic LCH has been established through serial trials empirically testing different chemotherapy agents and durations of therapy. However, fewer than 50% of patients who have disseminated disease are cured with the current standard-of-care vinblastine/prednisone/(mercaptopurine), and treatment failure is associated with long-term morbidity, including the risk of LCH-associated neurodegeneration. Historically, the nature of LCH-whether a reactive condition versus a neoplastic/malignant condition-was uncertain. Over the past 15 years, seminal discoveries have broadly defined LCH pathogenesis; specifically, activating mitogen-activated protein kinase pathway mutations (most frequently, BRAFV600E) in myeloid precursors drive lesion formation. LCH therefore is a clonal neoplastic disorder, although secondary inflammatory features contribute to the disease. These paradigm-changing insights offer a promise of rational cures for patients based on individual mutations, clonal reservoirs, and extent of disease. However, the pace of clinical trial development behind lags the kinetics of translational discovery. In this review, the authors discuss the current understanding of LCH biology, clinical characteristics, therapeutic strategies, and opportunities to improve outcomes for every patient through coordinated agent prioritization and clinical trial efforts.

Langerhans cell histiocytosis (LCH) is characterized by diabetes insipidus and is an uncommon occurrence. Pathological biopsies still have a certain degree of diagnostic probability. We present a case in which LCH initially affected the pituitary gland. This resulted in a misdiagnosis of chronic inflammation upon pathological examination.

A 25-year-old female exhibited symptoms of diabetes insipidus. Magnetic resonance imaging revealed an enhanced foci in the pituitary gland. After surgical resection of the pituitary lesion, the pathological diagnosis was chronic inflammation. However, the patient later experienced bone destruction in the skull and lower limb bones. After the lower limb bone lesion was compared with the initial pituitary lesion, the final diagnosis was modified to LCH. The patient was treated with multiple chemotherapy courses. However, the patient's condition gradually worsened, and she eventually passed away at home.

LCH should be considered when patients exhibit diabetes insipidus and absence of high signal intensity in the pituitary gland on sagittal T1-weighted image and abnormal enhancement in the pituitary region.

Histiocytosis is one of the most challenging diseases in medical practice. Because of the broad spectrum of clinical manifestations, systemic involvements, unknown etiology, and complex management, different types of histiocytosis are still a big question mark for us. Orbital histiocytosis is characterized by the abnormal proliferation of histiocytes in orbital tissues. It could affect the orbit, eyelid, conjunctiva, and uveal tract. Orbital histiocytosis can cause limited eye movement, proptosis, decreased visual acuity, and epiphora. In this study, we review the novel findings regarding the pathophysiology, diagnosis, and treatment of different types of histiocytosis, focusing on their orbital manifestations.

This review was performed based on a search of the PubMed, Scopus, and Embase databases or relevant published papers regarding orbital histiocytosis on October 9th, 2023. No time restriction was proposed, and articles were excluded if they were not referenced in English.

391 articles were screened, most of them being case reports. The pathophysiology of histiocytosis is still unclear. However, different mutations are found to be prevalent in most of the patients. The diagnostic path can be different based on various factors such as age, lesion site, type of histiocytosis, and the stage of the disease. Some modalities, such as corticosteroids and surgery, are used widely for treatment. On the other hand, based on some specific etiological factors for each type, alternative treatments have been proposed.

Significant progress has been made in the detection of somatic molecular changes. Many case studies describe various disease patterns influencing the biological perspectives on different types of histiocytosis. It is necessary to continue investigating and clustering data from a broad range of patients with histiocytosis in children and adults to define the best ways to diagnose and treat these patients.

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.

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.

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.