Citations

Myeloid sarcoma (MS) is a tumor mass involving any extramedullary site composed of myeloid-lineage blasts with myeloid, myelomonocytic, or monocytic differentiation. Distinguishing MS from malignant histiocytic neoplasms (MHNs) is diagnostically challenging due to morphologic and immunophenotypic overlap, particularly for MS with monocytic differentiation, which can mimic MHNs, especially the subtypes of histiocytic sarcoma and interdigitating dendritic cell sarcoma, leading to potential misdiagnosis and inappropriate management. Cyclin D1 overexpression is implicated in MHNs, but its utility in differentiating these entities has not been systematically characterized. We evaluated cyclin D1 immunostaining in 43 MS cases and 30 MHNs. The median age at MS diagnosis was 59 years (range: 0.1 to 90), while the median age at MHN diagnosis was 62 years (range: 9 to 90), with heterogeneous sites of involvement. Cyclin D1 evaluation showed 100% MHNs with strong cyclin D1 positivity in ≥50% tumor cells, compared with 7% MS with weak-to-intermediate positivity in a minor subset of tumor cells. Additional immunohistochemical evaluation showed no difference in PU.1 expression in MHNs (93%) versus MS (84%) but demonstrated a higher proportion of OCT2-positivity in MHNs over MS (52% vs. 23%, P <0.05). Our study demonstrates a high sensitivity (100%) and specificity (93%) in utilizing cyclin D1 to distinguish MHNs (mature phenotype) from MS (immature phenotype) in diagnostic practice. It is particularly valuable in challenging scenarios of MS with the absence of immature/myeloid lineage-defining markers (MPO, CD34, or CD117) and provides a cost-effective tool to resolve this diagnostic pitfall, ensuring an accurate subclassification.

Abstract Malignant histiocytic neoplasms (MHNs) are rare tumors derived from the mononuclear phagocyte system (MPS), encompassing histiocytic sarcoma, Langerhans cell sarcoma, interdigitating dendritic cell sarcoma, and other high-grade MPS lineage tumors. Despite advances in understanding histiocytic neoplasms, MHNs remain diagnostically challenging and lack standardized treatment algorithms. Current classification systems differ in lineage framing and fail to address mixed or ambiguous phenotypes, contributing to diagnostic uncertainty and inconsistent care. To address these gaps, the Histiocyte Society convened an international working group of pathologists and oncologists, including World Health Organization and International Consensus Classification contributors, to harmonize nomenclature, define minimum diagnostic criteria, and develop pragmatic treatment recommendations. Using a modified Delphi process and case-based review, the group formulated &gt;40 consensus statements spanning classification, pathology, molecular testing, clinical evaluation, and therapeutic strategies. Key recommendations include the adoption of a unified MHN designation, use of a minimum immunophenotypic panel, integration of broad molecular profiling, and the documentation of previous hematopoietic malignancy. Treatment algorithms emphasize surgical resection for unifocal disease and targeted therapy or immune checkpoint inhibition for multifocal disease when actionable mutations or programmed death ligand 1 expression are present. These consensus recommendations aim to reduce diagnostic ambiguity, standardize reporting, and improve outcomes for both pediatric and adult patients. Future priorities include international registries to refine risk stratification and biomarker-driven trials exploring targeted therapy, immunotherapy, and combination approaches.

Abstract The phase 1/2 Intergroup study E4412 investigated checkpoint blockade with nivolumab (Nivo) and ipilimumab (Ipi) combined with the CD30 targeting antibody-drug conjugate brentuximab vedotin (BV) in relapsed/refractory classic Hodgkin lymphoma. A total of 147 patients aged ≥12 years were randomized between BV/Nivo and BV/Ipi/Nivo; 132 patients were included in the primary efficacy analysis. The complete response (CR) rate, was 64.7% (52.2, 75.9) for BV/Nivo and 70.3% (57.6, 81.1) for BV/Ipi/Nivo (1-sided P = .29). The median survival follow-up was 38.0 months (interquartile range, 32.6-48.1). Progression-free survival (PFS) did not significantly differ between the 2 arms (hazard ratio [HR], 0.78, confidence interval [CI], 0.39-1.57; 1-sided P = .24). Treatment-related grade 3+ toxicities in the adult cohort, excluding rash, were similar between both arms (38.5% BV/Nivo and 39.3% BV/Ipi/Nivo); there was a higher frequency of grade 3 rash with BV/Ipi/Nivo (24.6%) compared with BV/Nivo (9.2%). We compared PFS by stem cell transplantation (SCT) status in a planned before hoc comparison; 58 patients received SCT, and 36-month PFS (from SCT) was &gt;90% for both arms. Sixty-six patients were progression free after the first scan and did not undergo SCT. The 36-month PFS was 73.0% (54.5, 85.0) for BV/Ipi/Nivo compared with 45.8% (26.3, 63.4) for BV/Nivo (HR, 0.45; CI, 0.19-1.08; 1-sided P = .03). The study did not meet its primary end point of superior CR rate for the triplet, but it supports the use of checkpoint antibody-drug conjugate induction prior to auto SCT, and there is an intriguing signal of disease control for patients wishing to defer or avoid SCT with the triplet of BV/Ipi/Nivo. This trial was registered at www.clinicaltrials.gov as NCT01896999.

Erdheim-Chester disease (ECD) is a rare disease characterized by the accumulation of neoplastic histiocytes in various extra-nodal tissues. Tissue biopsies involved by ECD are difficult to distinguish from reactive inflammatory infiltrates given the bland appearance of the neoplastic histiocytes. Confirmation of the ECD diagnosis often relies on molecular studies to confirm BRAF V600E mutation or other activating mutations involving MAPK pathway genes. In this study, we examined the diagnostic utility of cyclin D1 and pERK as immunohistochemical markers of MAPK pathway activation in ECD compared with its histopathologic mimics. The cohort included 41 clinically confirmed ECD patients, most with known genetic alterations in MAPK pathway genes (n=38). In 3 cases no mutation was identified. 37 of 41 (90%) of ECD cases showed cyclin D1 overexpression, with frequent staining in the cytoplasm as well as the nucleus. pERK expression was observed in 32 of 39 (82%) cases. Cyclin D1 staining was negative in histopathologic mimics of ECD, apart from weak patchy staining in fat necrosis and uniform staining in a subset of cases of juvenile/adult xanthogranuloma. While not entirely sensitive or specific, in the proper clinical and radiologic context strong nuclear and cytoplasmic cyclin D1 expression within histiocytic infiltrates helps to support a diagnosis of ECD.

Abstract Histiocytic neoplasms with xanthogranulomatous morphology encompass a continuum of disorders—from isolated cutaneous juvenile xanthogranuloma (JXG) or adult xanthogranuloma (AXG) to the multisystem Erdheim-Chester disease (ECD)—that share overlapping histopathologic and molecular features. In this article, we (1) define the spectrum of xanthogranuloma lesions, highlighting morphologic and immunohistochemical commonalities; (2) examine the clinical and radiographic criteria that distinguish localized juvenile xanthogranuloma/adult xanthogranuloma from classical Erdheim-Chester disease and related entities; (3) review the latest insights into MAPK pathway alterations that blur traditional diagnostic boundaries; and (4) outline contemporary management strategies, including approaches to staging “occult” disease, patient selection for BRAF and MEK inhibitors, and the role of other targeted and nontargeted agents. Readers will gain practical frameworks for recognizing early or atypical presentations, integrating molecular testing into routine practice, and optimizing personalized therapy across the xanthogranuloma family.

Abstract Introduction Histiocytic neoplasms (HN) are a rare, heterogeneous group of hematologic disorders derived from myeloid-dendritic cell lineages. The most common forms include Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), and Rosai-Dorfman disease (RDD). These disorders are driven by recurrent activating mutations in the MAPK pathway, most frequently involving BRAF, MAP2K1, PIK3CA, KRAS, and NRAS. This discovery enabled a major therapeutic advance with the use of BRAF and MEK inhibitors, resulting in durable responses. For patients harboring KRAS mutations, MEK inhibitors (MEKi) remain the primary therapeutic approach. However, the impact of KRAS mutation subtypes on treatment response remains poorly understood. Our study aimed to characterize the spectrum of KRAS mutations in LCH, ECD, and RDD and evaluate the responses to MEKi, providing insights to guide future treatment strategies. Methods We conducted a retrospective review of patients with LCH, ECD, and RDD who were evaluated at Mayo Clinic or University of Alabama at Birmingham. Patients were included if next-generation sequencing identified a KRAS mutation. The response assessment was based on radiographic evaluation under the most recent Histiocyte Society consensus guideline. Results We identified 23 patients with a KRAS mutation: 17 females (73.9%) and 6 males (26.1%), with a median age at diagnosis of 61 years (range, 20–78). RDD accounted for 73.9% (17/23) and ECD for 26.1% (6/23); no KRAS mutations were detected in LCH patients. The most frequent KRAS variants were p.K117N (34.8%), p.G12D (17.4%), p.A146T (13.0%), p.G13C (8.7%), and p.G13D (8.7%), with additional variants including p.T58I, p.A59G, p.A146P, and p.A146V. Mutation distribution differed by disease group: p.G12D was more common in ECD (50%) than RDD (5.9%) (p=0.01), whereas p.K117N occurred in 47.1% of RDD and was absent in ECD. Regarding treatment, 57% (13/23) received MEKi, all initially cobimetinib, with 1 patient switched to trametinib due to progression. Of the 10 patients who did not receive MEKi, 1 was treated with vemurafenib for a concurrent BRAF p.V600E mutation; 3 remained on observation; 2 underwent surgery without recurrence; 3 received other systemic therapies including corticosteroid, methotrexate, rituximab, lenalidomide, or sirolimus; and 1 developed diffuse large B-cell lymphoma, treated with R-CHOP. The overall response rate in the 12 patients on MEKi (excluding 1 patient too early for assessment) was 75%—3 (25%) CR and 6 (50%) PR (including 1 who initially progressed on cobimetinib but responded to trametinib). All 3 non-responders had RDD. Among the 5 patients with p.K117N, 3 had no response to cobimetinib, 1 achieved PR, and 1 achieved CR; notably, 1 non-responder switched to trametinib and achieved PR in 2 months. All 3 patients with codon 146 mutations achieved PR. Of the 2 patients with p.G12D, 1 achieved CR with a co-occurring MAP2K1 mutation, and 1 had no response. No additional genotype–response patterns were observed. Similar heterogeneity has been reported in prior studies. In a phase II cobimetinib trial, an ECD patient with p.R149G achieved PR, whereas another ECD patient with p.G12R and an LCH patient with p.G13C achieved CR in the presence of co-occurring ARAF and NRAS mutations, respectively. A retrospective cohort described an ECD patient with p.K117N achieving PR on dabrafenib and trametinib with a concurrent BRAF mutation and another with p.G12A achieving PR on trametinib. In a multicenter analysis of trametinib, a patient with p.A59T (co-occurring BRAF and NRAS mutations) had no response, whereas another with p.A146P achieved PR. Collectively, these findings, together with our data, underscore that KRAS-mutated histiocytoses exhibit heterogeneous responses to MEKi, likely influenced by variant type and co-mutations. Discussion KRAS mutations represent an important subset of MAPK pathway alterations in HN, although their prevalence varies by disease type and appears extremely rare in LCH, with no cases identified in our cohort. The most common variants include p.K117N and p.G12D, which may be linked to suboptimal response to MEKi in the absence of concurrent MAPK pathway alterations. As MEKi acts downstream, efficacy likely depends on the level of pathway activation conferred by specific KRAS variants. Larger studies are needed to confirm these observations and identify mutation-specific predictors to guide personalized treatment.