Goyal, Gaurav

Abstract Purpose. Malignant histiocytoses (MHs) including Langerhans cell sarcoma (LCS), interdigitating dendritic cell sarcoma (IDCS), and histiocytic sarcoma (HS) are rare, aggressive neoplasms of the macrophage-dendritic cell lineage. Prognosis is generally poor, particularly in disseminated disease. While mutation-specific therapies are increasingly used in indolent histiocytic neoplasms, their role in MH remains unclear due to the frequent presence of complex mutational profiles. Our understanding of the genomic landscape of MH is limited. This study aimed to comprehensively characterize the molecular alterations in MH.Methods. We conducted a retrospective chart review of MH patients seen at Mayo Clinic and the University of Alabama at Birmingham who underwent comprehensive next-generation sequencing (NGS), including DNA ± RNA analysis. A systematic literature review using PubMed identified additional MH cases with available molecular data.Results. We identified 17 institutional MH cases (3 IDCS, 3 LCS, 11 HS) and 72 cases from the literature (6 IDCS, 11 LCS, 55 HS) with NGS data. Among the 89 total patients, 26 (29%) had DNA-only sequencing and 63 (71%) had combined DNA/RNA sequencing. Twelve patients (n=12; 13%) had a single mutation; the majority had multiple alterations. The most frequently mutated genes were: RAS (n=26; 29%), CDKN1/2 (n=26; 29%), MAP2K1 (n=15; 17%), PTEN (n=11; 12%), BRAF non-V600E (n=8; 9%), PTPN11 (n=8; 9%), CREBBP (n=8; 9%), TET2 (n=8; 9%), DNMT3A (n=7; 8%), fusions (n=7; 8%), BRAFV600E (n=6; 7%), and NF1 (n=4; 4%). Fusions included BRAF::NRF11, BRAF::CLIP2, BRAF::MBP, EGFR::CYTOR, CDKN2A::ADGRG6, IGH::BCL6, and CLIP2-BRAF. Two patients had no alteration detected. Non-V600E BRAF mutations included D594G (n=3), G596R (n=1), G466A (n=1), N581T (n=1), N581I (n=1), and N581S (n=1). Common co-mutations with BRAF included CDKN2A/B (n=9), TP53 (n=6), KRAS/NRAS (n=5), and PDGFR (n=1). Only 2 of 15 MAP2K1-mutated patients (13%) had isolated mutations; the rest had co-mutations, most frequently TP53 (n=3) and BCL2 (n=3). MAP2K1 mutations included F53I (n=2), C121S (n=2), I103N (n=1), Q56P(n=3), E203K (n=1), F53-K57del (n=1), and F53-Q58del (n=1).NRAS mutations (n=6) included Q16K (n=2), G12C (n=1), Q61R (n=1), and 2 unspecified. KRAS mutations (n=20) included G13D (n=3), Q61H (n=3), G12V (n=2), K117N (n=1), V14I (n=1), and 10 unspecified. The most frequent co-mutational pattern (24%) was RAS plus another gene: BRAF (n=3), TP53 (n=6), MAP2K1 (n=2), PTEN (n=4), and CDKN2A/B (n=6).Twelve patients (12/26; 46%) were treated with targeted therapies. Responses included 6 partial and 5 complete responses. Median duration of response was 27.5 months (range 7–54). The sole non-responder had co-occurring NRASand TP53 mutations and received trametinib. Responders received a range of agents matched to their mutations: trametinib (BRAFV600E, MAP2K1F53I, KRASQ16H/PTEND24G/EPHB1R327C, MAP2K1F53I/BCL2/CDKN1B/KIT, and CALR), dabrafenib + trametinib(BRAFG596R/KRASQ61H), imatinib (MAP2K1C121S/METG28881T/DUSP2G137D/HIST1H3BC97Y/GRIN2AS1216C and PTPN11/STK11/GNA11/JAK2), chidamide + sintilimab(IDH2G515A/RHOAG50T/TET23344delC), sirolimus(PTEN/FGFR3/SETD2) and sorafenib (BRAFD594G/KRASK117N/TP53). Most responders (8/11) had multiple mutations; only 3 had single alterations, suggesting multi-mutant MH may still be targetable. Common complex patterns included BRAF+CDKN2A + CDKN2B (n=4), BRAF + CDKN2A + TP53 (n=2), and BRAF + CDKN2A + KRAS (n=2).Conclusion. The MAPK pathway (BRAF, MAP2K1, RAS) is the most altered signaling axis in MH, often accompanied by mutations in tumor suppressors and cell cycle regulators such as TP53, CDKN2A/B, and PTEN. Most MH patients exhibit multiple genomic alterations. Despite this complexity, durable clinical responses to targeted agents are achievable, even in heavily mutated cases. These findings support the use of comprehensive genomic profiling in MH to identify therapeutic targets and guide precision treatment strategies.

Abstract Background Erdheim-Chester disease (ECD) is a very rare histiocytic/dendritic cell neoplasm driven by mutations in genes of the MAPK pathway, such as BRAFV600E. Its clinical presentation is highly heterogeneous, and data on its natural history and prognosis in large cohorts are limited. Here, we investigated the clinical features and outcomes of a very large international cohort of patients with ECD. Methods We included patients diagnosed with ECD between 1990 and 2024, followed at 13 referral centers in Europe and the Americas, who had available clinical and follow-up data (with a minimal follow-up duration of 6 months). We analyzed the clinical presentation, treatment, and outcomes, and sought to identify predictors of survival. The study was conceived and conducted within the ECD Global Alliance network. Results A total of 1044 patients with ECD were included. The median age at diagnosis was 57 years (IQR 46-66), and the male-to-female ratio was 2.2. The median age at the first ECD manifestation was 55 years (IQR 43-65). Bone pain (20%), kidney and urinary manifestations (18%), and diabetes insipidus (11%) were the most frequently reported initial features. The median number of involved sites was 4 (IQR 3-6), most frequently including the long bones (n=768, 74%), the retroperitoneum, (n=605, 58%), the periaortic space (n=449, 43%), the CNS (n=368, 35%), the facial/orbit area (n=347, 33%), and the heart (n=334, 32%). Among 955 tested patients, 572 (60%) harbored the BRAFV600E mutation, and 86 (9%) a MAP2K1 mutation. Clinical and/or pathology overlap with Langerhans cell histiocytosis and Rosai-Dorfman-Destombes disease was observed in 115 (11%) and 42 (4%) patients, respectively. Clonal hematopoiesis was identified in 217 of 556 tested patients (39%), and a history of second cancer was reported in 272 patients (26%), including both solid (14%) and hematologic (12%) neoplasms. First-line treatment mostly included interferon-alpha (n=342, 33%) and BRAFi/MEKi (n=314, 30%), while second- and third-line treatments mostly consisted of BRAFi/MEKi (55% and 63%, respectively). After a median follow-up of 51 months (IQR 20-89), 222 (21%) patients died; causes of death were related to ECD in almost half of the patients (n=101). A multivariate Cox regression model identified the following factors as significantly associated with increased mortality: older age (HR 1.058, 95%CI 1.033-1.083; p<0.001), pseudo-neurodegenerative lesions (HR 2.280, 95%CI 1.337-3.891; p=0.022), elevated CRP at diagnosis (HR 2.574, 95%CI 1.024-6.467; p=0.044), and second hematologic cancer (HR 2.639, 95%CI 1.602-4.348; p<0.001). Conclusions Despite advances in treatments over the last decade, ECD remains associated with substantial mortality. Age, neurodegenerative lesions, elevated CRP levels, and the presence of a second hematologic cancer are the main predictors of poor survival.

Abstract Background Adult xanthogranuloma (AXG) is a rare clonal histiocytic neoplasm (HN) with a poorly defined mutational landscape. Clinically and immunophenotypically, AXG can resemble other HNs such as Erdheim-Chester Disease (ECD) which frequently harbor MAPK pathway alterations and carry BRAF V600E mutations in close to 50% of cases. However, due to the rarity of AXG, the prevalence of the BRAF V600E mutation and the broader mutational landscape is not well known. In this study, we characterize the mutational profile of AXG. Methods We conducted a retrospective analysis of patients diagnosed with AXG at our institution between January 1, 2016, and July 15, 2025. The study was approved by the institutional review board. To ensure inclusion of true AXG cases, only patients with a confirmed histopathologic diagnosis and without multisystemic involvement or characteristic imaging findings of ECD, such as symmetric long bone osteosclerosis, were included. BRAF alterations were identified by immunohistochemistry (IHC) and/or next-generation sequencing (NGS). We also performed an extensive literature review of mutational studies in AXG and included cases that underwent comprehensive NGS. Results Seventeen patients with AXG were identified. The median age at diagnosis was 40 years (range: 18–75 years). Out of the 17 patients, 11 (65%) reported the face as the primary site of disease, and 11 (65%) had solitary lesions. Of the 17 patients, 13 (76%) underwent BRAF V600E IHC staining, and none tested positive. Twelve (71%) patients had tissue samples analyzed via NGS, and none exhibited the BRAF V600E mutation. Eight of the 12 (67%) patients with NGS testing harbored other alterations involving the MAPK pathway. These included BRAF fusions (n=3), KRAS mutations (n=2), and individual cases with TRAF7 mutation, ALK1 fusion and FGFR1 fusion. One patient was found to have a mutation in WRN, which is not previously reported in AXG. Three patients had no identifiable pathogenic alterations on NGS. Ten patients were monitored without treatment, 2 underwent surgical resections and 3 received chemotherapy (1 had a complete response [CR], 2 achieved a partial response). One patient with FGFR1 fusion was treated with pemigatinib and achieved a CR for over 3 years. One patient with TRAF mutation obtained a CR after treatment with rituximab. We also identified 51 cases of AXG with adequate mutational testing reported in the literature, which reported findings similar to ours. In a retrospective study from France involving 29 patients, MAPK alterations were observed in 55% of cases: however, only 10% harbored BRAF V600E mutations (1). Another analysis of 270 patients with various HN subtypes included 13 individuals with AXG, none had BRAF mutations. MAP2K1 mutations were seen in 31% of patients (2). Taken together, across a combined cohort of 68 AXG patients, the most common alterations were: KRAS mutations (16%), fusions (14%), MAP2K1 mutations (7%) and BRAF V600E (6%). Among fusions, the most involved gene was BRAF (50%), and GAB2 was the most common fusion partner (n=2). In total, 59% of patients had MAPK alterations. These findings collectively underscore the diverse mutational landscape of AXG and highlight the rarity of BRAF V600E mutations relative to closely related HNs. Conclusion We present a series of AXG cases with mutational profiling, from our institution and the published literature. We demonstrate that MAPK alterations are frequently observed in AXG and are driven by heterogeneous mutations. In contrast to other HNs where BRAF V600E mutations are common, we identified no such mutations in our cohort and found only rare cases in the literature. Our institutional data, along with findings from the existing literature, suggest that AXG may have a distinct molecular profile compared to other HNs. A deeper understanding of its mutational landscape may offer insights into disease biology and identify therapeutic targets. ReferencesAnnabi E, Mahévas T, Chasset et al. Clinical, Histopathologic, and Molecular Features and Treatment of Multiple Xanthogranuloma in Adults. JAMA Dermatol. 2025;161(7):765-768. doi:10.1001/jamadermatol.2025.0886.Durham BH, Lopez Rodrigo E, Picarsic J, et al. Activating mutations in CSF1R and additional receptor tyrosine kinases in histiocytic neoplasms. Nat Med. 2019;25(12):1839-1842. doi:10.1038/s41591-019-0653-6

Abstract Background:Erdheim-Chester Disease (ECD) is a rare, incurable histiocytic neoplasm. Since its recognition in 1930, our understanding of ECD's pathophysiology has evolved. The identification of its clonal nature after 2015 established ECD as a cancer, prompting increased disease awareness and treatment advances. Targeted therapies show promising responses, but changes in ECD mortality over time have not been extensively documented. Methods:A multi-institutional retrospective cohort study analyzed adults with ECD consecutively seen at Mayo Clinic MN, AZ, and FL and the University of Alabama at Birmingham between 2007 and 2024. Clinical and prognostic data were abstracted. Overall survival was estimated using the Kaplan-Meier method and compared to expected survival using U.S. Census data, based on age at diagnosis (by calendar year), date of diagnosis, and sex. Standardized mortality ratios (SMRs) were calculated by dividing the number of observed deaths in the study population by the expected number of deaths using U.S. population data. Risk of death was compared by date of diagnosis (pre- and post-2015) using Cox proportional hazards analysis. Statistical analysis was performed with R software. Results:A total of 159 ECD patients were included (median age 58 years [range 19-82], 65% male). Forty-nine patients were diagnosed between 1990-2014 and 110 between 2015-2024. Median follow-up for the entire cohort was 4.0 years (95% CI: 3.2-4.4). Median follow-up for those diagnosed between 1990-2014 was 10.4 years (CI: 3.2-16.8), compared to 3.5 years (CI: 3.0-4.2) for those diagnosed between 2015-2024. The 5-year overall survival rate was 80% (95% CI: 72-88). Patients with ECD had an increase in mortality over expected, with 28 deaths compared to an expected 11.2, an SMR of 2.5 (95% CI: 1.7-3.6, p<0.001). Of 17 patients with an identified cause of death, death was attributable to ECD in 11 (65%), secondary malignancy in 1 (7%), and unrelated causes in 5 (29%). Cause of death was unknown in 11 patients. Among deaths, 11 (39%) were treated with targeted therapy, 8 (29%) with chemotherapy, and 1 (4%) received both. One patient (4%) received steroids, 1 received immunomodulator and targeted therapy (4%), and 6 (21%) received no disease-directed therapy. Of the patients whose death was related to ECD, 10 (91%) had multisystem disease. For 49 patients diagnosed pre-2015, 14 deaths occurred during the follow-up, significantly higher than the expected 5.2 deaths based on U.S. population data (SMR of 2.7 [95% CI: 1.5-4.4, p=0.001]). Among those diagnosed between 2015 and 2024, 14 deaths occurred, compared to expected 6.1 (SMR of 2.3 [95% CI: 1.3-3.8, p=0.006]). In an age- and sex-adjusted Cox proportional hazards model, diagnosis after 2015 vs. diagnosis prior to 2015 yielded a hazard ratio of 0.59 (95% CI: 0.27-1.31, p=0.19). Conclusion:The mortality rate of ECD patients remains higher than the general population, despite advancements in disease recognition and development of targeted therapies. While our data suggest a possible trend toward improved survival among patients diagnosed after 2015, we did not find statistically significant evidence of decreased mortality compared to those diagnosed prior to 2015. Larger cohorts with longer follow-up periods are needed to draw definitive conclusions regarding mortality.

Abstract Erdheim-Chester disease (ECD) is a rare systemic histiocytic neoplasm, with cardiac morbidities, including cardiovascular (CV) risk factors and cardiac conditions, playing a significant yet poorly understood role in the disease burden. This study evaluated the prevalence, characteristics, and prognosis of ECD in patients with (ECD-C) and without cardiac involvement (ECD-noC) and compared the burden of cardiac morbidities with matched controls. Patients diagnosed with ECD between 1990 and 2021 at a tertiary center were included, with cardiac involvement centrally assessed using radiographic studies. Cardiac morbidities were compared with a control group without ECD, matched for age, sex, body mass index, and smoking history. Among 104 patients with ECD, 39 (37%) had cardiac involvement. Patients with ECD-C had higher rates of hypertension (67% vs 46%), hyperlipidemia (67% vs 40%), heart failure (36% vs 8%), and pericardial effusion (28% vs 2%) than those with ECD-noC. Compared with the matched non-ECD cohort, patients with ECD had higher prevalence of coronary artery disease (20% vs 7%), heart failure (18% vs 4%), and antihypertensive drug use (55% vs 40%). Notably, patients with ECD-C had inferior progression-free survival (PFS) from frontline therapy compared with patients with ECD-noC (5-year PFS, 28.3% vs 70.5%). These findings highlight the burden of CV risk factors and cardiac conditions in ECD, even without a clinical diagnosis of ECD-C. Importantly, this cardiac morbidity burden is substantial for patients with ECD-C compared with ECD-noC. Our findings highlight the need for comprehensive cardiac risk assessment and management strategies to improve patient outcomes.

Mesenchymal dendritic cell neoplasms represent a distinct category of hematologic malignancies that challenge traditional classifications of histiocytic and classical dendritic/Langerhans cell neoplasms. Historically grouped under the broader umbrella of dendritic cell neoplasms, these entities differ significantly in their ontogeny, histopathologic features, molecular alterations, and clinical behavior. They are categorized into three main subtypes including follicular dendritic cell sarcoma, fibroblastic reticular cell tumor, and EBV-positive inflammatory follicular dendritic cell sarcoma/fibroblastic reticular cell tumor. They originate from mesenchymal stromal cells, and genetic alterations activating the NF- κβ pathway are frequent in follicular dendritic cell sarcomas. Immunophenotypic characterization is critical to distinguish these from other hematologic malignancies including histiocytic and classical dendritic/Langerhans cell neoplasms and other solid (non-hematopoietic) cancers. This review recapitulates current knowledge on existing classifications, details their diverse ontogeny from classical dendritic cell neoplasms, and provides insights into their clinicopathologic characteristics to improve diagnostic accuracy. We detail two case studies that demonstrate the challenges involved in the histopathologic diagnosis of these rare tumors, necessitating a comprehensive workup. Integrating developmental biology into practical diagnostic algorithms is essential to improve recognition and classification of these underdiagnosed neoplasms, ultimately guiding timely management.

7073 Background: The Optimized HLH Inflammatory (OHI) index (Zoref-Lorenz et al., Blood , 2022), based on serum soluble CD25 (sCD25) and ferritin, is a prognostic tool identifying inflammation in the hemophagocytic lymphohistiocytosis (HLH) spectrum and early mortality risk. Prior studies were retrospective and enriched with HLH-suspected cases. We hypothesized that the OHI index would predict outcomes in unselected diffuse large B-cell lymphoma (DLBCL). Methods: 670 newly diagnosed DLBCL patients from a prospective cohort (2002–2015) were analyzed: 335 for discovery and 335 for validation. Pre-treatment serum sCD25 and ferritin levels were quantified via ELISA, and we evaluated original thresholds (sCD25 ≥ 3,900 U/mL; ferritin ≥ 1,000 ng/mL) and developed DLBCL-optimized thresholds (using receiver operator curves) for predicting 500-day mortality. We also evaluated event-free survival (EFS), EFS at 24 months (EFS24), and overall survival (OS). Results: The median age was 64, and 51% were male. Using original thresholds, 4.2% (n=14) of patients were OHI+, with a 5.6-fold higher risk of 500-day mortality (95% CI 1.6–17; p<0.001). Optimized thresholds identified 23.6% (n=78) as OHI+ with a 9.2-fold higher 500-day mortality risk (95% CI 4.0–24; p<0.001). Optimized OHI+ also had a higher risk of EFS24 failure and inferior EFS and OS (Table). OHI+ patients had higher rates of B symptoms (35% vs. 20%; p=0.027), elevated LDH (76% vs. 34%; p<0.001), worse performance status (ECOG ≥2: 38% vs. 12%; p<0.001), and advanced-stage disease (Stage IV: 57% vs 38%; p<0.001), though IPI scores (3–5) were not significantly different (44% vs 36%; p=0.28). Adjusting for age and IPI, OHI+ independently predicted 500-day mortality (OR=5.0; CI 1.9–13; p=0.001), EFS24 failure (OR=3.2; CI 1.5–6.5; p=0.0018), and inferior long-term EFS (HR=2.2; CI 1.1–4.3; p=0.030) and OS (HR=2.0; CI 1.0–4.0; p=0.040) at a median follow up of 9.8 years in living patients. In validation, optimized OHI predicted 500-day mortality, EFS24 failure, and long-term OS and EFS (Table). Cytokine profiling revealed elevated inflammatory markers in OHI+ patients, including IL1a (p=0.008), CCL2 (p=0.03), CXCL10 (p<0.001), and CXCL9 (p<0.001), reflecting systemic hyperinflammation. Conclusions: The OHI index is a powerful predictor of early and long-term outcomes in DLBCL patients. Optimized thresholds identify a larger OHI+ group, highlighting hyperinflammation’s critical role in poor outcomes. These findings support its use in routine management and clinical trial design for novel therapies. Odds ratios or hazard ratios and p-values for optimized OHI+ and DLBCL prognosis. Outcome Discovery Validation OR for 500-day mortality 9.2; p<0.001 4.0; p=0.002 OR for EFS24 failure 5.2; p <0.001 6.3; p<0.001 HR for OS 2.3; p<0.001 1.8; p=0.006 HR for EFS 2.4; p<0.001 2.5; p<0.001

Abstract Among 64 patients with Erdheim-Chester disease treated with a BRAF inhibitor (median follow-up 4 years), we found high response rates (85%) but frequent discontinuations (61%), primarily because of adverse events. Additionally, patients experienced poor health-related quality of life and high symptom burden.