Rose Chami

Aim: Paediatric PLAG1 ‐rearranged fibromyxoid tumour (P‐FMT) is an emerging soft‐tissue neoplasm characterized by predominantly fibromyxoid morphology, minimal to absent adipocytic differentiation and consistent CD34 and desmin positivity. It is debated whether P‐FMT represents a distinct entity or a morphological variant of lipoblastoma. We aim to better characterize P‐FMT and assess its relationship with lipoblastoma. Methods and results: We assembled the largest cohort of P‐FMT ( n = 10) and performed comprehensive clinicopathological, molecular and epigenetic characterization. The cohort comprised five males and five females, aged 3 months to 10 years (median 4 years), with tumours arising in the extremities, trunk and neck. Histologically, all were well‐demarcated lesions with bland fibroblastic spindle cells in collagenous to myxoid stroma; two cases focally contained mature adipocytes. All tumours expressed CD34 and desmin. PLAG1 rearrangements were confirmed by fluorescence in situ hybridization or molecular sequencing, with fusion partners identified as COL1A2 ( n = 3), MEG3 ( n = 2), BOC ( n = 1), YWHAZ ( n = 1), EEF1A1 ( n = 1) and CHCHD7 ( n = 1). DNA methylation profiling demonstrated that all P‐FMTs grouped with lipoblastoma on hierarchical clustering and dimensionality reduction analysis and segregated from other mesenchymal tumours. Copy number profiles showed statistically significant chromosome 8 gain in both P‐FMT and lipoblastoma. All cases with follow‐up (median 22 months) demonstrated benign behaviour without recurrence. Conclusions: Our findings of morphological resemblance to fibroblastic lipoblastoma and multiple similarities to classic lipoblastoma, including identical immunophenotype, PLAG1 rearrangements with overlapping partners, common epigenetic signature and uniformly benign behaviour, support classification of P‐FMT as a fibroblastic or minimally adipocytic subtype within the lipoblastoma spectrum, rather than a distinct entity.

Pediatric fibroblastic, myofibroblastic, and myoid tumors encompass several entities, many with characteristic gene fusions that are now emerging as molecularly defined tumor groups. Here, we present two cases of spindle cell neoplasms with novel ACTB::FER promoter swap fusions. Both tumors presented in the extremities of pediatric patients (9‐year‐old and 6‐year‐old females) as superficial skin nodules with slow growth. Histologically, both tumors showed monomorphic spindle cell proliferation in short fascicles, but without significantly increased mitotic activity, high‐grade atypia, or necrosis. Both cases showed diffuse positivity for SMA with patchy desmin expression. RNA sequencing confirmed fusion breakpoints, revealing transcriptional upregulation of FER. Neither patient has had evidence of interval growth or recurrence to date. While the biological significance of ACTB::FER fusions remains unclear, their recurrence and the absence of other clear oncogenic drivers suggest a distinct molecular pathway that may define a novel entity. Fusions of ACTB and FER genes with different partners have been observed in rare aggressive mesenchymal tumors; however, the ACTB::FER promoter swap fusion is currently unrecognized in soft tissue tumors. We report the first two cases of soft tissue tumors harboring ACTB::FER fusions and expand the molecular spectrum of mesenchymal tumors with kinase gene alterations. Further, we highlight the importance of target‐agnostic approaches for the detection of rare kinase fusions, which may not be included on targeted next‐generation sequencing panels.

Background Hepatocellular adenomas (HCAs) are rare, benign hepatic tumors in children, with limited imaging data available for pediatric cases. Objective To describe the magnetic resonance imaging (MRI) and clinical features of histologically proven HCAs in children. Materials and methods Single-center retrospective review of pathology-proven HCA from January 2004 to February 2024. Patients with available pre-intervention imaging in our PACS were included. Two independent readers reviewed the imaging studies. The features were summarized using descriptive statistics and inter-reader agreement was assessed using Cohen’s kappa. Results This study included 11 children (6 boys and 5 girls; median age 15 years) with 13 pathologically proven HCAs. Three patients had type 1a glycogen storage disease. Five patients had a single lesion, while six had multiple lesions. The lesions were well-defined with a median average diameter of 3.6 cm. Most were homogenously T1 iso-intense (61.5%) and mildly hyperintense (76.9%) on T2-w fat saturated images. The atoll sign was present in two lesions. Intralesional fat was observed in 69.2% of cases: microscopic in eight lesions and macroscopic in one. Hemorrhage occurred in three (23.07%) lesions and necrosis in one (7.7%). Nine out of 10 (90%) lesions showed arterial phase hyperenhancement, and only 3/10 (30%) lesions retained contrast on hepatobiliary phase. In total, 6/13 (46.1%) lesions showed washout, and all received hepatobiliary agent. One lesion ruptured with the hemoperitoneum. Of the 11, 63.6% of patients underwent percutaneous biopsy and 36.4% underwent surgical resection. Conclusion MR imaging features are nonspecific, but homogenous slight T2 hyperintensity, arterial phase hyperenhancement, and intralesional fat content are common features. Hepatobiliary contrast uptake is variable. Graphical Abstract

Classical and mixed congenital mesoblastic nephroma (CMN) are characterized by an internal tandem duplication (ITD) of the EGFR gene, in contrast to cellular CMN that usually harbors an ETV6::NTRK3 gene fusion. This same fusion occurs in infantile fibrosarcoma, and this tumor can be considered as the soft tissue equivalent of cellular CMN. A soft tissue equivalent of classic/mixed CMN remains undefined at the genetic level. Since classical CMN resembles fibromatosis of soft tissue histologically, we asked whether fibromatosis in children might show EGFR ITD. ITD was investigated using the polymerase chain reaction and primers for exons 18 and 25 of the EGFR gene. Seven of the eight cases of classical or mixed CMN were positive by this approach, but none of the five cellular CMNs. Of 11 cases of fibromatosis (six plantar, two digital, and three desmoid), none were positive for EGFR ITD. Within the limits of this small study, we conclude that pediatric fibromatosis is likely not characterized by EGFR ITD. There are isolated reports of pediatric soft tissue tumors that harbor EGFR ITD, but these have the appearance of infantile fibrosarcoma or mixed CMN rather than fibromatosis. We did not find any such cases, since all 14 cases of infantile fibrosarcoma in our study had an ETV6::NTRK3 fusion. The soft tissue tumors with EGFR ITD are not a morphologic match for the low‐grade histology of classical CMN. Whether they have a similar favorable biology or behave more like fibrosarcoma with an ETV6::NTRK3 fusion or an alternative fusion involving other kinases remains to be determined.

Pediatric papillary thyroid carcinoma (PPTC) is clinically distinct from adult-onset disease. Although there are higher rates of metastasis and recurrence in PPTC, prognosis remains highly favorable. Molecular characterization of PPTC has been lacking. Historically, only 40% to 50% of childhood papillary thyroid carcinoma (PTC) were known to be driven by genomic variants common to adult PTC; oncogenic drivers in the remainder were unknown. This contrasts with approximately 90% of adult PTC driven by a discrete number of variants. In this study, 52 PPTCs underwent candidate gene testing, followed in a subset by whole-exome and transcriptome sequencing. Within these samples, candidate gene testing identified variants in 31 (60%) tumors, while exome and transcriptome sequencing identified oncogenic variants in 19 of 21 (90%) remaining tumors. The latter were enriched for oncogenic fusions, with 11 nonrecurrent fusion transcripts, including two previously undescribed fusions, STRN-RET and TG-PBF. Most fusions were associated with 3′ receptor tyrosine kinase (RTK) moieties: RET, MET, ALK, and NTRK3. For advanced (distally metastatic) tumors, a driver variant was described in 91%. Gene expression analysis defined three clusters that demonstrated distinct expression of genes involved in thyroid differentiation and MAPK signaling. Among RET-CCDC6–driven tumors, gene expression in pediatric tumors was distinguishable from that in adults. Collectively, these results show that the genomic landscape of pediatric PTC is different from adult PTC. Moreover, they identify genomic drivers in 98% of PPTCs, predominantly oncogenic fusion transcripts involving RTKs, with a pronounced impact on gene expression. Notably, most advanced tumors were driven by a variant for which targeted systemic therapy exists.Significance:This study highlights important distinctions between the genomes and transcriptomes of pediatric and adult papillary thyroid carcinoma, with implications for understanding the biology, diagnosis, and treatment of advanced disease in children.

Chromosomes, Genes, Breakpoints, and Fusion Validator Scores for Oncogenic Fusions. In the event of multiple splicing confirmations, the fusion with highest validator score is displayed.

BRAF-RAS Score (BRS) Designation by Oncogenic Variant

Demographics and Oncogenic Variants for Tumors evaluated by WES/RNASeq. NA-Not applicable (infiltrative tumors without defined borders)

Expression individual genes comprising the TDS