Rech, Karen L.

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 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 BACKGROUND Mixed histiocytic neoplasms with overlapping features of Erdheim-Chester Disease (ECD) and Rosai-Dorfman Disease (RDD) are extremely rare and diagnosis may be delayed due to lack of awareness and complex histology features. METHODS We report a case of mixed ECD/RDD misdiagnosed as IgG4-related disease and review the literature. RESULTS A 50-year-old man presented for evaluation of spastic paraparesis in the context of a thoracic dural lesion. Two years prior he developed an inflammatory monoarthritis concerning for rheumatoid arthritis unresponsive to methotrexate. Six months prior he developed leg spasms, gait spasticity, and urinary incontinence. MRI demonstrated a T2 hypointense enhancing epidural mass with spinal cord compression. Epidural biopsy showed fibrosis and non-specific inflammation. Given elevated serum IgG4 (170 mg/dL) and clinical findings, he was diagnosed with IgG4-related disease. He received high dose prednisone and etanercept without radiographic or clinical improvement. He then presented to our institution. Given high concern for RDD, he underwent FDG-PET CT which demonstrated an infiltrative process and FDG avid regions in the upper thoracic spinal cord, paranasal sinus, renal hilum, perivascular abdominal vessels, testicle, and multiple joint effusions. Biopsy of left testicle demonstrated CD163-positive histiocytes which coexpressed S100, cyclin D1, and OCT2, consistent with RDD. Biopsy of the left shoulder synovium demonstrated an atypical CD163-positive histiocytic infiltrate expressing Factor XIIIa, cyclin D1 and S100 (partial), and appeared negative for OCT2, consistent with ECD. The atypical histiocytes in both biopsies were negative for CD1a and BRAF V600E by immunohistochemistry. Genomic sequencing of the testicular tissue demonstrated a MAP2K1 (Q56P) alteration. He was treated with radiation therapy targeting the dural lesion with temporarily worsening symptoms improved with steroids and started on cobimetinib. DISCUSSION This case expands on the phenotypic description of mixed ECD/RDD. Histiocytic neoplasms should be considered in the differential diagnosis of dural based lesions.

ABSTRACTAimTo report a novel case of biopsy‐proven, mass spectrometry‐confirmed, wild‐type transthyretin amyloidosis (ATTRwt) in nerve.MethodsThe patient was identified and evaluated in the peripheral nerve clinic. Our nerve laboratory's pathology database and the literature were searched for prior evidence of pathologically confirmed cases of ATTRwt.ResultsA 94‐year‐old man with a history of lumbar spinal stenosis presented to the neurology clinic with subacute‐on‐chronic progressive, upper limb predominant weakness along with numbness and tingling paresthesia. Electromyography (EMG) revealed multiple mononeuropathies involving the right median nerve at the wrist, right ulnar nerve, and right distal radial nerve superimposed upon an axonal predominant peripheral neuropathy along with multilevel lumbosacral radiculopathies. Extensive serology for causes of neuropathy and multiple mononeuropathies returned unremarkable. A diagnostic right superficial radial nerve biopsy was performed and showed congophilic material within a small epineurial vessel wall in the nerve tissue. Amyloid typing by mass spectrometry was performed and revealed ATTRwt. TTR gene sequencing returned normal. The patient was diagnosed with ATTRwt neuropathy and started on diflunisal therapy for neuropathy treatment.ConclusionThis case confirms the presence of ATTRwt deposition directly in nerve tissue as the likely cause of the patient's large fiber and multiple mononeuropathies, expanding our current understanding of ATTRwt‐associated disease. Proving the direct association of ATTRwt and neuropathy may open up amyloid‐specific treatments for this disease.

Abstract Objective The aim of this study was to evaluate a large cohort of gallbladder amyloid cases to determine clinical and morphologic features. Methods Cholecystectomy specimens (N = 118) typed using proteomics-based techniques between 2008 and 2023 were identified. Clinical and morphologic features were reviewed. Results Six amyloid types were identified: ATTR (n = 63, 53.4%), AL (n = 46, 39.0%), AA (n = 4, 3.4%), AApoA1 (n = 2, 1.7%), ALECT2 (n = 2, 1.7%), and AEFEMP1 (n = 1, 0.8%). Amyloidogenic mutations were detected in 3 ATTR cases and 2 AApoA1 cases. Morphologic review (n = 26) revealed perimuscular vessel involvement in all cases. Amyloidosis was an unexpected diagnosis first made on the cholecystectomy specimen in half of the patients with clinical information (n = 10). All 9 patients with follow-up had evidence of systemic disease. In 2 patients, cholecystic involvement was initially missed and only retrospectively identified after the diagnosis of cardiac amyloidosis. Conclusions In patients with clinical data, amyloidosis was often unexpected, the gallbladder was commonly the first tissue sampled with amyloidosis, and all patients had systemic disease. Thorough review of cholecystectomy specimens with careful inspection of perimuscular vessels, coupled with a low threshold for ordering Congo red stain in elderly individuals and amyloid typing using a robust method such as proteomics, can prevent a delay in amyloid diagnosis and management.

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.