FET:CREB fusions have been described in a variety of tumors from various phenotypes. Recently, these fusion transcripts were reported in intracranial tumors, variably named intracranial mesenchymal myxoid tumors or angiomatoid fibrous histiocytomas. Controversy remains concerning the terminology for these tumors. Here, we report 11 cases of central nervous system mesenchymal tumors with proven FET:CREB fusion. Most DNA methylation profiles were not classifiable using the Heidelberg Brain Tumor or Sarcoma Classifier (v11b4/v12.2). However, by using unsupervised t-SNE and hierarchical clustering analyses, six of the cases constituted a distinct cluster. The remaining four tumors showed no obvious relation to any of the other referenced classes but were close to the clusters of extra-CNS angiomatoid fibrous histiocytomas (n = 1), clear cell sarcomas (n = 1), or solitary fibrous tumors (n = 2). Our findings confirm that intracranial FET:CREB-fused tumors do not represent a single molecular tumor entity, although most samples clustered close to each other, indicating the existence of a distinct epigenetic group that could potentially be partially masked by the low number of cases included. Further analyses are needed to characterize intracranial FET:CREB fused-defined tumors in more detail.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/bpa.13010

An integrative histopathological and epigenetic characterization of primary intracranial mesenchymal tumors, FET:CREB-fused broadening the spectrum of tumor entities in comparison with their soft tissue counterparts.


 
 The findings of the ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformation) trial, which determined that medical management was superior to prophylactic interventional therapy for the treatment of unruptured cerebral arteriovenous malformations (cAVMs), remain polarizing and controversial.
 
 
 
 Adult cAVM patient admissions were identified in the National Inpatient Sample from 2009 to 2019. The incidence of cAVM rupture and in‐hospital mortality were compared between the pre‐ (2009–2013) and post‐ARUBA trial eras (2014–2019) using complex samples‐weighted estimates and multivariable logistic regression analyses. A control cohort composed of an alternate pathology (ruptured and unruptured cerebral aneurysms) was also assessed during the study period to evaluate potential bias.
 
 
 
 
 Among 121 415 hospitalizations for cAVM during the study period, 31 389 (25.9%) were admissions for ruptured malformations. The incidence of ruptured cAVM increased in the post‐ARUBA trial era (13.3% versus 34.4%;
 P
 <0.001) as well as rates of in‐hospital mortality (2.0% versus 7.6%;
 P
 <0.001). Following multivariable regression analysis adjusting for age, illness severity, and acute neurological condition, the post‐ARUBA trial era was independently associated with both cAVM rupture (adjusted odds ratio [OR], 1.99; [95% CI, 1.72–2.29];
 P
 <0.001) and in‐hospital mortality (adjusted OR, 1.94; [95% CI, 1.37–2.75];
 P
 <0.001). Control cohort comparative analysis revealed that rates of hospitalizations for ruptured cerebral aneurysms relative to all aneurysm admissions did not differ before and after 2014 (84.5% versus 84.3%;
 P
 =0.185).
 
 
 
 
 The incidence of ruptured cAVM increased following 2014, potentially a reflection of a paradigm shift to conservative and noninterventional management strategies in patients with unruptured cAVM. Further studies may be necessary to exclude other confounders contributing to this rise.


Increase in Ruptured Cerebral Arteriovenous Malformations and Mortality in the United States: Unintended Consequences of the ARUBA Trial?

In 2014, A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) concluded that medical management alone for cranial arteriovenous malformations (AVMs) had better clinical outcomes than interventional treatment. The impact of the ARUBA study on changes in the rates of intervention and outcomes is unknown. Thus, we investigated whether the conclusions from ARUBA may have influenced treatment modalities and outcomes of unruptured AVMs. The National Inpatient Sample (NIS) was queried between 2006 and 2018, for adult patients with an AVM who were admitted on an elective basis. Interventions included open, endovascular, and stereotactic surgeries. Join-point regression was used to assess differences in slopes of treatment rate for each modality before and after the time-point. Logistic regression was used to assess the odds of non-routine discharge and hemorrhage between the two time-points for each treatment modality. Linear regression was used to assess the mean length of stay (LOS) for each treatment modality between the two time-points. A total of 40,285 elective admissions for AVMs were identified between 2006 and 2018. The rate of intervention was higher pre-ARUBA (n = 15,848; 63.8%) compared to post-ARUBA (n = 6985; 45.2%; difference in slope − 8.24%, p < 0.001). The rate of open surgery decreased, while endovascular and stereotactic surgeries remained the same, after the ARUBA trial time-point (difference in slopes − 8.24%, p < 0.001; − 1.74%, p = 0.055; 0.20%, p = 0.22, respectively). For admissions involving interventions, the odds of non-routine discharge were higher post-ARUBA (OR 1.24; p = 0.043); the odds of hemorrhage were lower post-ARUBA (OR 0.69; p = 0.025). There was no statistical difference in length of stay between the two time-points (p = 0.22). The rate of intervention decreased, the rate of non-routine discharge increased, and rate of hemorrhage decreased post-ARUBA, suggesting that it may have influenced treatment practices for unruptured AVMs.

Elective intervention for unruptured cranial arteriovenous malformations in relation to ARUBA trial: a National Inpatient Sample study

Chromosomal translocations with gene fusions are uniquely rare events in paraganglioma, mostly involving UBTF::MAML3 gene fusion. Precedent literature suggests that tumors involving MAML3 gene fusion correlate with poor clinical outcomes. Herein, we report a case of metastatic sporadic paraganglioma harboring EWSR1::CREM gene fusion in a 36‐year‐old male, that has not been previously described. The patient presented with large paraspinal mass that was resected the same year. Tumor recurred 3‐years later and on further work‐up, patient was found to have metastases involving both lungs. Histopathologic evaluation of the original primary tumor showed tightly packed irregular nests and cords of cells containing palely eosinophilic cytoplasm. Features considered atypical included: areas of solid growth pattern, coagulative tumor necrosis, focal cellular atypia and angiolymphatic invasion were also identified. By immunohistochemistry, the tumor cells were positive for synaptophysin and chromogranin and negative for keratin. The S100 stain highlights the sustentacular cells and the Ki‐67 proliferation index of 15%. The recurrence specimen was similar but showed increased cellularity, atypia, necrosis, and proliferative activity (Ki‐67 proliferation index of 35%). CT guided biopsy of the right lung lesion was consistent with metastasis. Next generation sequencing identified EWSR1::CREM fusion. The breakpoints were found in chromosome 22: 29683123 for EWSR1 exon 7 (NM_005243.3) and at chromosome 10:35495823 for CREM exon 6 (NM_001267562.1). Fluorescence in situ hybridization for EWSR1 gene rearrangement was positive. In summary, we report a case of metastatic paraganglioma with EWSR1::CREM gene fusion, not previously described in this entity, and expands on the phenotypic diversity within the genetic landscape of EWSR1::CREM gene fusion positive tumors.

Metastatic sporadic paraganglioma with EWSR1::CREM gene fusion: A unique molecular profile that expands the phenotypic diversity of the molecular landscape of the EWSR1::CREM gene fusion positive tumors

A novel histomolecular tumor of the central nervous system, the "intracranial mesenchymal tumor (IMT), FET-CREB fusion-positive" has recently been identified in the literature and will be added to the 2021 World Health Organization Classification of Tumors of the Central Nervous System. However, our latest study using DNA-methylation analyses has revealed that intracranial FET-CREB fused tumors do not represent a single molecular tumor entity. Among them, the main subgroup presented classical features of angiomatoid fibrous histiocytoma, having ultrastructural features of arachnoidal cells, for. Another tumor type with clear cell component and histopathological signs of aggressivity clustered in close vicinity with clear cell sarcoma of soft tissue. Herein, we report one case of IMT with a novel SMARCA2-CREM fusion which has until now never been described in soft tissue or the central nervous system. We compare its clinical, histopathological, immunophenotypic, genetic and epigenetic features with those previously described in IMT, FET-CREB fusion-positive. Interestingly, the current case did not cluster with IMT, FET-CREB fusion-positive but rather presented histopathological (clear cell morphology with signs of malignancy), clinical (with a dismal course with several recurrences, metastases and finally the patient's death), genetic (fusion implicating the CREM gene), and epigenetic (DNA-methylation profiling) similarities with our previously reported clear cell sarcoma-like tumor of the central nervous system. Our results added data suggesting that different clinical and histomolecular tumor subtypes or grades seem to be included within the terminology "IMT, FET-CREB fusion-positive", and that further series of cases are needed to better characterize them.

/pdf/a-novel-smarca2-crem-fusion-expanding-the-molecular-spectrum-53070w6g1y.pdf

Cameron M. McDougall

Papers

Microsurgery for Unruptured Cerebral Arteriovenous Malformations in the National Inpatient Sample is More Common Post-ARUBA

Broadening the Age of Incidence of Intracranial Angiomatoid Fibrous Histiocytoma With EWSR1-CREM Fusion: A Case Report.

Intracranial mechanical thrombectomy without extracranial revascularization for a tandem occlusion with robust Circle of Willis: Case report