Pathology

Multi-omic architecture defines four biologically distinct classic Hodgkin lymphoma subtypes

Integrative malignant cell sequencing, spatial transcriptomics, and imaging mass cytometry defined four classic Hodgkin lymphoma subtypes (CST, CN913, STB, CN2P). Each subtype showed distinct clinical features, mutational profiles, malignant-cell gene-expression programs, and immune–spatial architectures in the microenvironment. CSF2RB mutations typified the CST subtype, driving dysregulated oncogenic signaling and unique tumor–microenvironment crosstalk in functional models. These data support biologically grounded cHL subgroups with potential prognostic value and targetable vulnerabilities relevant to hematopathology practice. 1

Integrated sequencing clarifies drivers and vulnerabilities in endometrial stromal sarcoma

Whole-genome, whole-exome, and transcriptome sequencing of 80 endometrial stromal sarcomas mapped distinct low-grade and high-grade genetic architectures. Six hypermutated tumors carried POLE or mismatch repair mutations, suggesting an immunotherapy-responsive subset. RAD54B amplifications occurred in 18.8% of tumors, increased expression, and correlated with significantly shorter survival, supporting an oncogenic role. High-grade ESS frequently showed PTEN and TP53 mutations, chromosomal gains, cell-cycle regulator loss, and numerous private fusions. Low-grade ESS was characterized by canonical fusions such as JAZF1-SUZ12 with deletions in metabolic regulators including TSC2 and STK11. An NRAS Q61R-mutant xenograft responded dramatically to combined MEK and FAK inhibition, providing a preclinical rationale for targeted therapy. 2

Genomic signatures sharpen diagnosis and progression prediction in oligomonocytic CMML

In 911 patients with OM-CMML, overt CMML, or MDS, unsupervised clustering assessed genomic contributions to disease classification. Biallelic TET2 mutations or SRSF2–TET2 co-mutations defined CMML molecular signatures with distinct transcriptomes and monocytic bias. OM-CMML cases carrying these signatures showed classical monocytosis and higher risk of progression to overt CMML. A weighted genomic model combining these signatures with bone marrow monocyte frequencies improved prediction of progression beyond morphology. The authors present a diagnostic workflow integrating genomic determinants into the CMML framework for clinic-ready risk stratification. 3

Field-effect-aware urine MRD improves specificity for NMIBC response assessment

Age-related somatic mutations in normal-appearing urothelium create a field effect that confounds urine tumor DNA analysis in NMIBC. The authors developed a field-effect-informed utDNA MRD approach that filters likely background mutations to improve specificity. Applied to 261 samples from NMIBC patients undergoing surgery and adjuvant BCG, this assay defined surgical responders, BCG responders, and non-responders. Molecular predictors differed between treatment modalities, with pre-existing immune activation and higher mutation burden enriched in BCG responders. These results support field-effect-adjusted urine liquid biopsy for more accurate MRD assessment and treatment allocation. 4