Citations

ABSTRACT Myxoid liposarcoma (MLS) accounts for 20%–30% of all liposarcomas, with most cases harboring the fusion gene FUS::DDIT3 , while approximately 5% exhibit the EWSR1::DDIT3 fusion. We report the case of a 26‐year‐old male patient with a right upper arm mass. The tumor displayed the classic histological features of MLS, including small spindle/ovoid cells, variable univacuolated lipoblasts, and a prominent myxoid stroma with delicate arborizing vasculature. Despite these characteristic features, fluorescence in situ hybridization (FISH) revealed no apparent rearrangement of the DDIT3 locus. Next‐generation sequencing (NGS) identified a novel fusion transcript in which SMARCA2 exon 4 was fused in‐frame with DDIT3 exon 2. Chromosomal microarray analysis demonstrated the unbalanced nature of the rearrangement, with partial deletions of 0.243 and 0.176 Mb flanking the centromeric end of the DDIT3 locus on 12q13.3 (which also included GLI ) and disrupting the SMARCA2 locus on 9p24, respectively. The resultant chimeric fusion protein is predicted to lack the SMARCA2 DNA‐binding domains while retaining the DDIT3 leucine zipper dimerization domain. These findings indicate an unusual and complex rearrangement, leading to the recruitment of a novel DDIT3 partner gene. Moreover, they emphasize that the functional aspects of myxoid liposarcoma fusion genes depend on the retention of the key DDIT3 domain. Finally, this case illustrates how classic morphology can appropriately trigger reflex molecular analyses, which may, in turn, uncover novel fusion genes or other molecular alterations.

ABSTRACTBackgroundDifferentiating metastatic melanoma from histologic mimics such as malignant gastrointestinal neuroectodermal tumor (GNET), malignant melanotic nerve sheath tumor (MMNST), and epithelioid malignant peripheral nerve sheath tumor (EMPNST) poses significant diagnostic challenges due to overlapping morphology and immunophenotypes. PRAME is a novel immunohistochemical marker increasingly used to distinguish melanoma from its mimics, but remains underexplored in these rare tumor types.MethodsPRAME immunohistochemistry was performed on four GNETs, seven MMNSTs, 10 EMPNSTs, 16 metastatic melanomas (including eight undifferentiated melanomas), and two MITF‐rearranged melanocytic tumors. PRAME expression was scored from 0 to 4+ based on the percentage of tumor nuclei showing moderate to strong staining.ResultsAll GNETs, MMNSTs, and MITF‐rearranged tumors were PRAME‐negative. EMPNSTs showed variable expression: six were negative (0–1), one equivocal (2+), and three positive (3–4+). Fifteen of 16 melanomas were PRAME‐positive. PRAME scores differed significantly among tumor types (p = 1.99 × 10−5). PRAME demonstrated high sensitivity and specificity for distinguishing metastatic melanoma from primary mimickers including GNET and MMNST, but low specificity in EMPNST (71.4%).ConclusionsPRAME reliably distinguishes metastatic melanoma from GNET and MMNST, supporting its use in this differential. However, its reduced specificity in EMPNST limits its standalone diagnostic value in this context, emphasizing the need for a multimodal approach.

Abstract Astrocytes, the most abundant glial cells in the central nervous system (CNS), play essential roles in maintaining neuronal homeostasis, synaptic regulation, and blood–brain barrier integrity. However, these cells can undergo senescence—a cellular state characterized by irreversible growth arrest and the secretion of proinflammatory factors—in response to aging and pathological stressors, contributing to synaptic dysfunction and neurodegenerative diseases. This review examines the molecular mechanisms driving astrocytic senescence, including oxidative stress, DNA damage, and inflammatory signaling pathways such as NF-κB and the senescence-associated secretory phenotype. A particular focus is placed on the diverse array of known chemical inducers of astrocyte senescence, such as pesticides and heavy metals, which provide critical insights into the processes governing cellular aging in the brain. By analyzing the effects of these inducers, we highlight their implications for neurodegenerative disease progression and brain aging. Understanding astrocytic senescence offers new insights into age-related neuropathology and presents promising avenues for targeted therapies in neurodegenerative disorders induced by environmental toxicants.

Myoepithelial tumors are typically characterized by distinct molecular profiles that have been shown to correlate with their anatomical locations. EWSR1 or FUS rearrangements are common in cutaneous, soft tissue and bone tumors, whereas salivary gland myoepithelial tumors are frequently associated with PLAG1 and HMGA2 alterations. This apparent molecular divergence led some previous studies to doubt a common pathogenetic relationship between myoepithelial tumors of soft tissue and bone with their salivary gland counterparts. Herein, we present primary intraosseous myoepithelioma harboring HMGA2::WIF1 fusion. This fusion has been previously identified in a range of salivary gland myoepithelial tumors including myoepitheliomas, myoepithelial carcinomas arising from pleomorphic adenomas, and pleomorphic adenomas themselves. Primary myoepithelial tumors of the bone are exceedingly rare, and to our knowledge, HMGA2 rearrangements have not been previously reported in soft tissue or bone myoepithelial neoplasms. Through this report, we aim to enhance the existing literature on myoepithelial neoplasms, while highlighting the importance of recognizing primary bone myoepitheliomas and contributing to a broader understanding of the pathogenetic landscape of myoepithelial tumors across diverse tissue types.

Erythema elevatum diutinum is a distinct and rare form of chronic, recurrent leukocytoclastic vasculitis that typically presents with firm, smooth erythematous to violaceous papules or nodules symmetrically distributed over the extensor surfaces. Herein, we report an unusual case of erythema elevatum diutinum in a 32-year-old female who presented with a several-year history of chronic recurrent palpable purpura prior to the development of classic nodular lesions. This presentation facilitated a timely diagnosis and highlighted the histopathologic progression of the disease broadening the clinical spectrum of erythema elevatum diutinum.

Objectives: To evaluate the clinical heterogeneity of sarcomas by examining associations between histological subtypes, metastatic patterns, treatment modalities, and survival outcomes. Methods: We analyzed data from 97,062 adult patients diagnosed with sarcoma between 2000 and 2020, using the Surveillance, Epidemiology, and End Results (SEER) database. Fourteen histological subtypes were included. Propensity score matching (PSM) was employed to adjust for baseline differences, and Cox proportional hazards models were used to identify prognostic variables. Results: The most prevalent subtypes were sarcoma not otherwise specified (31.9%), leiomyosarcoma (17.1%), and liposarcoma (13.9%). Metastatic patterns differed significantly by subtype; liver metastases were most common in sarcomas with small blue round cell (SBRC) features (8.9%) and stromal sarcoma (6.1%), while lung metastases were frequently observed in Ewing sarcoma (10.0%) and rhabdomyosarcoma (9.7%). Median overall survival (mOS) varied widely, ranging from 234 months in chondrosarcoma to 16–20 months in rhabdomyosarcoma and SBRC sarcoma. Overall, patients with primary sarcoma had significantly better survival than those with treatment-related disease (119.0 vs. 45.0 months, p < 0.0001), with this trend consistent across most subtypes. Treatment responses were subtype- and size-dependent. For instance, surgery plus radiotherapy improved outcomes in giant cell sarcoma regardless of tumor size, whereas chemotherapy provided benefit only in tumors larger than 5 cm. Combined surgery and radiotherapy offered additional survival benefit in select subtypes, including chordoma, leiomyosarcoma (>5 cm), and synovial sarcoma (<5 cm). Conclusions: Sarcomas exhibit substantial clinical and prognostic heterogeneity across histological subtypes. These findings underscore the importance of subtype-specific, individualized treatment strategies in optimizing patient outcomes.

ABSTRACT We report a case of a primary cutaneous spindle cell sarcoma (SCS) with FN1 :: FGFR1 fusion. The tumor lacked the typical histologic and immunohistochemical features associated with other FN1 ‐rearranged neoplasms, such as phosphaturic mesenchymal tumors (PMT) and calcified chondroid mesenchymal neoplasms (CCMN). Unlike PMTs, which often feature a cartilaginous matrix and are associated with tumor‐induced osteomalacia (TIO), the present case lacked these characteristics and did not show FGF23 mRNA expression. Immunohistochemically, the tumor cells showed patchy staining for CD34 but were negative for markers such as ERG, desmin, S100, and pan‐TRK. The fusion event in this case involves the loss of the FGFR1 Ig1 (D1) domain, a mechanism proposed to drive oncogenesis by releasing FGFR1 from autoinhibition. Despite the preservation of other FGFR1 domains, no evidence of FGF23 signaling was detected, and the patient had no clinical history of TIO. This case underscores the complexity of oncogenesis in FN1 :: FGFR1 ‐rearranged neoplasms, a form of “promiscuous” gene fusion, where similar fusions lead to diverse tumor phenotypes. It emphasizes the importance of incorporating molecular testing in diagnosing spindle cell sarcomas, particularly those occurring in acral sites, to identify this underrecognized entity.

The emergence of pathologist-driven molecular reflex testing for tumoural biomarkers is a significant advancement in cancer diagnostics, facilitating targeted cancer therapy for our patients. Based on our experience, the Canadian landscape of pathologist-driven reflex biomarker testing for melanoma lacks standardization and is plagued by a lack of awareness by pathologists and clinicians. This paper comprehensively examines the approaches to reflex biomarker testing for melanoma patients across Canada, highlighting the regional variations in the criteria for initiating molecular testing, the biomarkers tested, and the molecular techniques employed. We also discuss the clinical relevance of biomarkers, emphasizing their alignment with the National Comprehensive Cancer Network ® (NCCN ® ) Clinical Practice Guidelines in Oncology (NCCN Guidelines ® ) as well as ancillary tests such as BRAF VE1 immunohistochemistry to detect BRAF V600E mutation and molecular techniques such as real-time polymerase chain reaction, matrix-assisted laser desorption ionization-time of flight mass spectrometry and next-generation sequencing. Our proposed standardized minimum criteria for reflex testing prioritize melanomas with Breslow thickness >4 mm or disseminated disease, who will most benefit from enhanced delivery of biomarkers and expedited access to targeted therapies while attempting to balance cost-effectiveness and utilization of public healthcare resources with patient outcomes.