Histiocytic Neoplasms Research Articles

Updates on Langerhans cell histiocytosis and other histiocytosis in children: invited review-challenges and novelties in paediatric tumours.

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.

Approach to the Patient: From Endocrinopathy to the Diagnosis of a Histiocytic Disorder.

Endocrinopathies are frequently the initial presentation of histiocytic neoplasms, which are rare hematologic disorders affecting multiple organ systems. Langerhans cell histiocytosis and Erdheim-Chester disease are 2 such disorders known to infiltrate the hypothalamus and/or pituitary gland, leading to arginine vasopressin deficiency (AVP-D) and anterior pituitary dysfunction (APD) in 20% to 30% of cases, often as the first manifestation. Conversely, histiocytic disorders account for a notable proportion (10-15%) of all pituitary stalk lesions. The diagnosis of histiocytoses is often delayed in such cases due to the nonspecific presentation of endocrinopathies and pituitary involvement. Consequently, endocrinologists are at the frontline and uniquely positioned to achieve early diagnosis by recognizing the varied nonendocrine features of these disorders. This article provides an overview of the endocrine manifestations of histiocytic disorders and presents a simplified algorithm to guide the diagnostic workup in cases presenting with "idiopathic" AVP-D or APD. Such cases should be evaluated for histiocytic neoplasms with additional imaging studies and biopsies of suspected disease sites. If no disease site beyond the pituitary is identified, the risks and benefits of a pituitary stalk lesion biopsy must be carefully considered. While treatments of histiocytic neoplasms are highly efficacious, endocrinopathies are considered permanent and require long-term hormone replacement. It remains unclear whether early diagnosis and novel targeted therapies can reverse these endocrine disorders. Therefore, the role of the endocrinologist role is critical in the diagnosis and management of these rare diseases.

Anxiety and Depression in Patients with Histiocytic Neoplasms and their Associated Clinical Features.

Anxiety and depression are common in many cancers but have not been systematically studied in patients with histiocytic neoplasms (HN). 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 HN. A registry-based cohort of patients with HN completing PROs including the Hospital Anxiety and Depression Scale (HADS) from 2018-2023 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 (OR) and 95% confidence intervals (CI). In 215 patients, approximately 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 twelve-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.

IRF8 Demonstrates Positivity in a Significant Subset of Histiocytic and Dendritic Cell Neoplasms.

Histiocytic and dendritic cell neoplasms, especially histiocytic sarcoma, can show morphologic and phenotypic overlap with immature monocytic neoplasms. IRF8 immunohistochemical staining has been demonstrated to be useful in identifying monoblasts, but it has not been extensively studied in histiocytic and dendritic cell neoplasms. IRF8 immunohistochemistry was performed on cases of histiocytic sarcoma (HS, n=6), Langerhans cell histiocytosis (LCH, n=25), Rosai Dorfman disease (RDD, n=17), follicular dendritic cell sarcoma (FDCS, n=3), and Erdheim Chester disease (ECD, n=5), along with a control group that included a subset of myeloid neoplasms with monocytic differentiation. Of 89 total cases, IRF8 was positive in 3/6 cases of HS, 3/5 cases of ECD, 12/17 cases of RDD, 7/25 cases of LCH, and 0/3 cases of FDCS. Control cases were stained similarly to previous reports, with IRF8 expression roughly correlating to monoblast count and normal staining in other control groups. We demonstrate that IRF8 is expressed in a significant subset of tested neoplasms of histiocytic and dendritic cell lineage. While we confirmed that IRF8 is useful to identify monoblasts, these results highlight that IRF8 cannot be reliably used to distinguish histiocytic sarcomas from myeloid neoplasms of monocytic lineages, and caution is advised interpreting IRF8 staining in that setting.

Radiology-pathology correlation: Rosai-Dorfman disease.

Rosai-Dorfman Disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is a rare non-Langerhans cell histiocytic neoplasm. Although the disease classically presents as massive painless lymphadenopathy in young adults, RDD can also involve the central nervous system in some patients. CNS lesions, can cause headaches, neurologic deficits, and even neurologic deficits. The imaging appearance of CNS RDD typically mimics that of meningiomas: well-circumscribed dural-based lesions that often have dural tails. However, some imaging clues also exist that might help a radiologist recognize RDD, even before histopathologic confirmation. This radiology-pathology report of a patient with CNS RDD highlights the most pertinent clinical, imaging, and pathologic features of CNS RDD, and discusses what the neuroradiologist needs to know about the disease.

The effect of methylation on the let-7-BCL2L1-BCL2 axis and the potential use of hypomethylating and BH3 mimetic drugs in histiocytic neoplasms.

The effect of methylation on the let-7-BCL2L1-BCL2 axis and the potential use of hypomethylating and BH3 mimetic drugs in histiocytic neoplasms.

Total Hip Replacement in a Patient with Erdheim-Chester's Disease: A Case Report.

Erdheim-Chester's disease (ECD) is a rare multisystem disorder considered as a neoplasm of non-Langerhans cell histiocytes. We report a case of uncemented total hip arthroplasty in a 74-year-old patient with ECD for femoral neck fracture with pathological involvement of distal metaphysis and diaphysis. We reviewed the literature on bony involvement. Adequate osseointegration was achieved in our case; however, longer follow-up is essential. Vigilant reporting of bony involvement, such as pathological fractures, fracture healing, deformities, osteosynthesis, and outcome of joint replacement surgeries, is needed in ECD-like bone diseases.

Recurrent CLTC::SYK fusions and CSF1R mutations in juvenile xanthogranuloma of soft tissue

AbstractJuvenile xanthogranuloma (JXG) is a histiocytic neoplasm that usually presents in the skin. Rarely, extracutaneous localizations occur; the genetic drivers of this clinical variant of JXG remain incompletely characterized. We present detailed clinicopathologic and molecular data of 16 children with extracutaneous JXG and 5 adults with xanthogranulomas confined to the central nervous system (CNS) or soft tissue. Tissue samples were obtained through the Dutch Nationwide Pathology Databank and analyzed with an innovative sequencing technique capable of detecting both small genomic variants and gene rearrangements. Targetable kinase alterations were detected in 16 of 16 children and 1 of 5 adults. Alterations included CLTC::SYK fusions in 6 children and CSF1R mutations in 7 others; all below 2 years of age with soft tissue tumors. One child had a CSF1R mutation and MRC1::PDGFRB fusion. Most were treated surgically, although spontaneous regression occurred in 1 of 6 with CLTC::SYK and 2 of 7 with CSF1R mutations, underscoring that treatment is not always necessary. Tumors with CLTC::SYK fusions generally lacked Touton giant cells but exhibited many other histologic features of JXG and concordant methylation profiles. Using multispectral immunofluorescence, phosphorylated–spleen tyrosine kinase expression was localized to CD163+ histiocytes; tumors with CLTC::SYK fusions also demonstrated mTOR activation, cyclin D1 expression, and variable phosphorylated–extracellular signal-regulated kinase expression. BRAFV600E was detected in 1 child and 1 adult with CNS-xanthogranulomas; both responded to BRAF inhibition. Finally, a TPM3::NTRK1 fusion or MAP2K1 deletion was detected in 2 children with systemic JXG who experienced spontaneous disease regression. This study advances the molecular understanding of histiocytic neoplasms and may guide diagnostics and clinical management.

Erdheim–Chester disease: An elusive diagnosis in a 50‐year‐old Ethiopian man presenting with diffuse sclerotic bone lesion

Key Clinical MessageDiagnosis of Erdheim–Chester disease (ECD) requires the clinician to be familiar with its various manifestations, classic radiologic and histologic features. This case highlights the significance of considering ECD in any patient presenting with bone pain and symmetric osteosclerosis of long bones of extremities to allow for early diagnosis and treatment.AbstractErdheim–Chester disease (ECD) is a rare non‐Langerhans histiocytic disorder with diverse clinical manifestations, ranging from indolent, localized presentation to life‐threatening, multi‐systemic disease. Delayed or erroneous diagnosis is common. The presence of classic radiographic finding along with foamy histiocytes that is positive for CD68 but negative for CD1a on histologic examination establishes the diagnosis. We report a second case of ECD from Ethiopia. A 50‐year‐old Ethiopian man presented with a 13‐year history of bilateral lower leg bone pain, cold intolerance, somnolence, constipation, impotence, decreased libido, and secondary infertility. The diagnosis was suspected when skeletal X‐ray revealed bilateral symmetric sclerosis of metadiaphysis of femur, tibia, and humerus. The demonstration of foamy histiocytes that were positive for CD68 but negative for CD1a on histologic examination with immunohistochemical staining confirmed the diagnosis. Evaluation for the extent of the disease revealed coated aorta sign, hairy kidney sign, and cystic lesion with ground glass opacity of lung, primary hypothyroidism, and hypergonadotropic hypogonadism. ECD is rare histiocytic neoplasm with wide range of clinical features which often delay the diagnosis. Clinician should be mindful of the various presentations and the classic radiographic and histologic features of ECD. This case highlights the significance of entertaining ECD in any patient presenting with lower leg bone pain and symmetric osteosclerosis of long bones of lower extremities to allow for early diagnosis and treatment.

Imaging in Erdheim-Chester Disease.

Erdheim-Chester disease (ECD) is a rare, multisystemic, inflammatory, non-Langerhans cell histiocytic neoplasm. The discovery of recurrent and somatic mutations in the mitogen-activated protein kinase signaling pathway, most commonly BRAFV600E, has led to a reclassification of ECD from an inflammatory disorder to a neoplastic process. It is now included in the revised 2016 World Health Organization classification of hematopoietic tumors and in the Langerhans group in the revised 2016 Histiocytosis Classification of the Histiocyte Society. When symptomatic, ECD most commonly manifests with bone pain and fatigue. Also, neurologic manifestations, central diabetes insipidus, exophthalmos, and periorbital xanthelasma-like lesions are frequently encountered. Pathologic findings may vary depending on the site of biopsy and may display a spectrum of features. Thus, due to the diverse clinical presentation and variable histologic findings, imaging can often show the first sign of the disease. Radiologic findings are, however, interpreted in conjunction with clinical and histologic findings to establish the diagnosis of ECD. From providing classic findings that facilitate diagnosis to helping radiologists determine the extent of disease and predicting a prognosis, the role of radiology in ECD has evolved with the understanding of the disease itself. Insights into the molecular pathogenesis and the development of targeted therapeutic agents along with approval of vemurafenib and cobimetinib have necessitated revision of the guidelines for the management of ECD. The authors discuss various radiologic findings of ECD and differential diagnoses by using an organ system-based approach and briefly describe the revised consensus recommendations for evaluation, diagnosis, and treatment based on the International Medical Symposia on ECD from a radiologist's perspective. ©RSNA, 2024 Supplemental material is available for this article. The full digital presentation is available online.

Erdheim-Chester Disease Masquerading as CLIPPERS.

To present 4 patients with Erdheim-Chester disease (ECD) based on clinical, radiologic, histopathologic, and molecular genetic findings who had enhancing brainstem lesions and were initially believed to have chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Case series. Although patients with ECD can demonstrate clinical and imaging features similar to CLIPPERS, refractoriness to corticosteroids, lack of fulfillment of specific MRI criteria (i.e., enhancing lesions >3 mm, T2 abnormalities that exceed areas of T1 postgadolinium enhancement), and systemic findings such as "hairy kidney" appearance and metadiaphyseal osteosclerosis on 18F-fluorodeoxyglucose PET-CT help discriminate it from CLIPPERS. ECD is a histiocytic neoplasm characterized by multiorgan infiltration of clonal histiocytes carrying activating variants of the MAPK-ERK pathway. Neurologic involvement occurs in up to 40% of ECD with frequent brainstem lesions that can mimic acquired neuroinflammatory disorders, such as CLIPPERS. ECD is an important CLIPPERS mimic with distinct pathophysiology and targeted treatments. We highlight the need to consider histiocytic disorders among other alternate diagnoses when findings are not classic for CLIPPERS.

Revised Diagnosis From Histiocytic Neoplasm to Optic Chiasm Glioblastoma After Genetic Analysis.

A 46-year-old man presented with left eye blurring. Automated visual field testing showed an incongruous right hemianopia, with sparing of the lower temporal quadrant in the right eye. MRI revealed foci of gadolinium enhancement in the optic chiasm and optic tracts. Serologic testing (including myelin oligodendrocyte glycoprotein and neuromyelitis optica antibodies) and cerebrospinal fluid analysis were negative. Whole-body PET/CT scan found no malignancy. Biopsy of the optic chiasm revealed a moderately cellular neoplasm composed of atypical, discohesive cells with enlarged nuclei, prominent eosinophilic nucleoli, and abundant vacuolated cytoplasm. Immunohistochemical stains for CD68 and S100 were positive, whereas those for GFAP, OLIG2, SOX10, and multiple others were negative, supporting a diagnosis of histiocytic neoplasm. Five weeks later, results became available from next-generation sequencing targeting the coding regions of hundreds of malignancy-associated genes and select introns. Alterations associated with histiocytic neoplasms (i.e. BRAF and MAP2K1 mutations) were absent. However, there was a nonsense mutation in the PTEN gene, a hotspot mutation in the TERT gene promotor, and focal amplifications of the CDK4 and MDM2 genes. Additionally, there was chromosome 6q loss, 7 gain, and 10q loss. Based on these findings, the diagnosis was revised to glioblastoma, IDH-wildtype, CNS WHO grade 4. The patient began treatment with temozolomide while continuing radiation therapy. This case illustrates how next-generation sequencing can at times provide more accurate diagnostic information than standard tissue histopathology.

Histological evidence of MAPK pathway activation across subtypes of adult orbital xanthogranulomatous disease irrespective of the detection of oncogenic mutations

Adult orbital xanthogranulomatous disease (AOXGD) is a spectrum of histiocytoses with four subtypes. Mitogen-activated protein kinase (MAPK) pathway mutations have been detected in various histiocytic neoplasms, little is known about this in AOXGD. Targeted regions of cancer- and histiocytosis-related genes were analyzed and immunohistochemical staining of phosphorylated ERK (pERK), cyclin D1 and PU.1 was performed in 28 AOXGD and 10 control xanthelasma biopsies to assess MAPK pathway activation.Mutations were detected in 7/28 (25%) patients. Positive staining for pERK and/or cyclin D1 was found across all subtypes in 17/27 (63%) patients of whom 12/17 (71%) did not harbour a mutation. Xanthelasma tissue stained negative for pERK and cyclin D1. Relapse occurred in 5/7 (71%) patients with a MAPK pathway mutation compared to 8/21 (38%) patients in whom no mutation could be detected.Molecular analysis and evaluation for systemic disease is warranted to identify patients at risk of recurrent xanthomatous disease.

NF1 mutation and TUBB3 amplification in gastric histiocytic sarcoma: a case report and literature review.

Histiocytic sarcoma is a rare neoplasm of mature histiocytes with an aggressive clinical courseandpoor response to treatment. Primary gastric histiocytic sarcomais rarerand just reported sporadically.Histiocytic sarcoma is a rare neoplasm of mature histiocytes with an aggressive clinical courseandpoor response to treatment. Primary gastric histiocytic sarcomais rarerand just reported sporadically. A case of a 71-year-old female admitted with a one-year history of upper abdominal pain exacerbated after meals. After CT scans revealed a bulged mass atthe lesser curvature of the gastric body, the patient underwent endoscopic submucosal dissection. Microscopically, non-cohesive neoplastic cells diffuselyinfiltrated lamina propria and submucosa, and diffusely expressed LCA, CD4, CD163, CD68 (KP1),CyclinD1, Lysozyme, and Vimentin. PD-L1 (22CS) expression evaluated as CPS 60. The final pathological diagnosis was gastric histiocytic sarcoma.Subsequently, next-generation sequencing identified a nonsense mutation in exon 21 ofNF1gene [c.2446C > T (p.R816*)]andtheTUBB3gene amplification (copy number: 4.55).The patient refused further treatment and died of the tumorhalf a year later. This case broadens the spectrum of differential diagnosis of gastric cancerand emphasizes the value of immunohistochemicaland molecular testsin the accurate diagnosis of histiocytic sarcoma. Furthermore, we performed literature review of 11 cases of gastric histiocytic sarcoma so as to strengthen the understanding of the clinicopathologic features, treatment, and prognosis.

ETMR-31. A UNIQUE CASE OF CNS DIFFUSE, NON-SYSTEMIC ALK+ HISTIOCYTOSIS IN A PEDIATRIC PATIENT

Abstract BACKGROUND Histiocytic disorders are a group of rare diseases with accumulation of of macrophages, monocytes, or dendritic cells in various parts of the body. ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 that is very rarely described in pediatrics. METHODS A 20 month old male presented to an adult hospital after a prolonged period of headaches, vomiting, and loss of developmental milestones. Imaging demonstrated severe hydrocephalus and extensive thickened leptomeningeal enhacement with mass effect. He underwent VP shunt placement and revision, a T7-T10 laminectomy, and tumor debulking. Extensive molecular testing, including DNA and RNA analysis by NGS was performed and a CLTC::ALK fusion was identified, along with Tier III DNA variants, yielding a diagnosis consistent with ALK-Positive Histiocytosis, with diffusivity in the CNS system. Full evaluation demonstrated no involvement of the peripheral nervous system or other systemic involvement. He initially demonstrated signs of neuro-irritation, altered tone, and lower extremity clonus. RESULTS After review of very little literature published on similar patients, although none with a clinical picture matching his, he was started on a treatment course of high dose dexamethasone, vinblastine, and lorlatinib targeting the ALK+, likely driver, mutation of his disease. On evaluation scans two months into treatment, he showed no change in his disease burden. He was transitioned to clofarabine cycles with daily lorlatinib for continued targetted therapy. After six total cycles, he demonstrated a high partial to complete remission (allowing for evidence of scarred tissue) and tremendous neurologic and developmental milestone gains. CONCLUSIONS This case demonstrates a unique presentation in which there is little described in the literature in way of clinical features or treatment standards, and further none exactly similar to this patient. After undergoing extensive evaluation and therapy modication, he responded remarkably well and continues to have optimal quality of life.

Real-world experience with targeted therapy in patients with histiocytic neoplasms in the Netherlands and in Belgium

AbstractHistiocytic disorders are rare hematologic neoplasms characterized by a notable dependence on mitogen-activated protein kinase signaling. Targeted therapy is an emerging treatment option, yet the number of reported patients remains limited. Here, we describe 40 patients with histiocytic neoplasms who were treated with targeted therapy in 7 tertiary referral hospitals from the Netherlands and Belgium. The cohort comprised of 6 (15%) children and 34 (85%) adults with diverse histiocytoses, including Langerhans cell histiocytosis (LCH; n = 12), Erdheim–Chester disease (n = 14), central nervous system xanthogranuloma (n = 2), Rosai–Dorfman disease (n = 3), histiocytic sarcoma (n = 2), ALK–positive histiocytosis (n = 1), and mixed/unclassifiable histiocytosis (n = 6). Five patients were included in a clinical trial; 35 (88%) received BRAF/MEK inhibitors outside of trials. Among these 35 patients with available follow-up data, median time on targeted treatment was 1.9 years (range, 0.04-5.8 years). Complete or partial responses were observed in 25 of 27 (93%) patients treated for multisystemic and/or solid lesions and 2 of 8 (25%) patients treated for neurodegenerative LCH. Responses were generally durable, although 10 patients lost response after dose reduction or therapy interruption. Responses were recaptured in 9 of 10 cases. Two patients developed new or progressive neurodegenerative lesions: 1 during and 1 after vemurafenib therapy. At last follow-up, 8 adults had stopped targeted therapy because of toxicity. This study corroborates the favorable outcomes of BRAF/MEK inhibition in patients with histiocytosis described previously. However, it also highlights limitations and calls for prospective studies.

Concurrent enhancer of Zeste homolog 2 (EZH2) over-expression with BRAFV600E mutation predicts a poor outcome in patients with Langerhans cell histiocytosis (LCH): A pilot study.

e18536 Background: Prior studies demonstrated upregulated EZH2 protein expression and p-ERK1/2 cascade signaling in histiocytic and dendritic cell neoplasms. BRAFV600E is the most common driver mutation reported in LCH patients (34-64%). In melanoma studies, a signaling pathway with BRAFV600E activating mutation resulted in upregulation of EZH2. The frequency of EZH2 co-expression with BRAFV600E is unknown in LCH. Given the limited durable responses after discontinuation of treatment with BRAF inhibitors in histiocytic disorders, we investigated the prognostic role of EZH2 overexpression and BRAFV600E mutation in LCH. Methods: We analyzed a cohort of 27 consecutive patients (pts) diagnosed with LCH at Moffitt Cancer Center and Tampa General Hospital between 2010-2022. Immunohistochemical (IHC) staining using antibodies against EZH2 (D2C9 clone, Cell Signaling) and BRAFV600E (VE1 clone, Ventana medical systems) were performed. Expression was assessed by an IHC score of stain intensity (0, 1+, 2+ and 3+) multiplied by percent positive cells (H score). H score ≥ 30 was considered as positive. Pyrosequencing was performed to detect BRAFV600E mutations and correlated with VE1 staining results. A positive outcome from either IHC or PCR was deemed indicative of mutation positivity, given the robust presence of mutation representation in melanoma studies through IHC. Results: Entire cohort were grouped for pts who had both EZH2 overexpression and BRAFV600E mutation (EZH2/BRAFV600E) versus those who did not. Out of 27 pts, 25.9% (n=7) had both EZH2/BRAFV600E. EZH2/BRAFV600E group differed from control group by age ( p=0.046). BRAFV600E mutation was identified in 37.03% (10) pts, and 40.7% (11) showed expression of VE1 by IHC study. Discrepancies between PCR and IHC study were observed in 4 pts and potentially attributable to the restricted availability of tissue samples. 63% and 48.1% of pts were positive for EZH2 and BRAFV600E respectively. 6 pts were observed, 8 underwent surgery with or without radiation, 12 received induction chemotherapy, and only 1 received a BRAF inhibitor. After 18.6 months of median follow up, 92.6% pts were alive. Overall response rate (ORR) to the 1st line therapy was 55.6%. In univariate analysis of OS, H score and BRAFV600E mutation trended towards worse OS but were not statistically significant owing to small sample size. However, BRAFV600E mutation and EZH2 over expression demonstrated a poor overall survival (OS) ( p=0.012). Conclusions: Our study indicates that concurrent presence of BRAFV600E mutation and EZH2 overexpression correlates with poor OS in LCH pts. We hypothesize that in a subset of LCH pts combination therapy targeting both EZH2 and BRAFV600E may improve ORR or overcome resistance to BRAF inhibitor monotherapy. However, the results of our pilot study need to be validated on a larger sample set.

Localized anaplastic lymphoma kinase-positive histiocytosis in a cerebellar hemisphere with long-term treatment: illustrative case.

Anaplastic lymphoma kinase (ALK)-positive histiocytosis (ALK-H) is an emerging entity in the category of histiocytic neoplasms that was first reported as a multisystemic disease in three infants in 2008. The clinicopathological spectrum of ALK-H has been expanded to include localized disorders in specific organs, but the features of this subtype are not well known. The authors report a case of ALK-H localized in the central nervous system that was difficult to treat and review the relevant literature. The authors reviewed archival histiocytic tumors at their institute and found a pediatric case of ALK-H localized in a cerebellar hemisphere that had previously been reported as histiocytic sarcoma. Chemotherapy (approximately 1 year), additional surgery, and conventional chemotherapy (approximately 2.5 years) led to clinical remission, and maintenance chemotherapy was continued (approximately 1.5 years). Three years after completing treatment, a high-grade glioma was found in a cerebral hemisphere, and the patient died of the glioma 2 years later. Although the prognosis of ALK-H is generally good according to prior cases, the authors' case required long-term conventional chemotherapy, suggesting the tumor displayed aggressive characteristics. Early administration of ALK inhibitors may be necessary.

Mixed histiocytic disorders: Nature versus nurture?

Histiocytic diseases arise from MAPK mutations in myeloid progenitors. Depending on whether the progenitor follows a dendritic cell or macrophage/monocyte lineage the final histology results in Langerhans cell histiocytosis, Rosai-Dorfman disease or Erdheim-Chester disease. Commentary on: Friedman etal. Mixed histiocytic neoplasms: A multicentre series revealing diverse somatic mutations and responses to targeted therapy. Br J Haematol 2024;205:127-137.

Treatment of histiocytic neoplasms with intralesional steroids: A case series report

Introduction and importanceRosai-Dorfman disease was first described in the 1960s and is characterized by hyperproliferation of histiocytes, which presents as painless lymphadenopathy with fever, night sweats, and weight loss. This disease often affects young adults and children of African descent. Different types of RDD exist, including familial, classical (nodal), extranodal, neoplasia-associated, and immune-associated. While this disease can cause significant pain, there is currently no consensus on treatment. Case presentationThis case series outlines three cases of bony involvement of histiocytic neoplasms and our technique for intralesionoal steroid injections. Two cases were successfully treated with intralesional steroid injections and one patient was treated with oral steroids. Clinical discussionHistiocytic neoplasms can cause significant pain for patients and there is no standardized treatment as of yet. An interesting finding on MRI was a characteristic peripheral edema we termed the “Halo Sign”. Steroids are believed to exert their benefit in treating this disease by apoptosis and reducing tumoral swelling. ConclusionThis case series demonstrates the successful management of bony involvement of RDD with intralesional steroids similar to eosinophilic granuloma. While intralesional steroid injection has previously been described for other types of RDD, this is the first description of bony RDD treated with this technique to our knowledge.