Carina A. Dehner

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.

Keratin-positive giant cell–rich tumor (KPGCT) is a newly described bone and soft tissue tumor. The tumor is characterized by scattered keratin-positive cells and the presence of HMGA2::NCOR2 fusions. It is not known if the HMGA2::NCOR2 fusion is located in the keratin-positive cells, and little is known about how KPGCT develops. KPGCT shares some histologic features with tenosynovial giant cell tumor (TGCT), a soft tissue tumor with CSF1 rearrangements. Single-nuclei RNA sequencing and Xenium spatial transcriptomics were used to elucidate the most likely mechanisms driving KPGCT and compare KPGCT to TGCT. We identified a population of cells coexpressing keratin, HMGA2 , and CSF1 as the likely neoplastic cells; these cells constitute the minority of the cells in the tumor. These cells express no synovial markers, confirming KPGCT as a distinct entity, separate from TGCT. The bulk of the tumor consists of CSF1R -expressing macrophages and multinucleated giant cells (MNGCs), suggesting an important role for CSF1–CSF1R signaling. In addition, we find that the likely neoplastic cell population shows activation of the hippo signaling pathway, a possible central pathway in KPGCT tumorigenesis. The CSF1–CSF1R axis likely stimulates the migration and proliferation of macrophages, which form the majority of cells in the tumor, as well as their differentiation into MNGCs. These results provide a rationale for the use of CSF1R inhibitors, which have already shown efficacy in TGCT, as a therapy for KPGCT.

Recently, a distinct, bland spindle cell neoplasm with rhabdomyoblastic phenotype, and VGLL3 rearrangement has been described. These tumors have a striking predilection for the head and neck area and so far, followed an indolent course. It remains unclear whether these tumors are best classified as true rhabdomyosarcomas. There are 11 reports of such tumors with limited follow‐up. Here, we report an additional case with local recurrence, long‐term follow‐up and spatial profiling. The tumor occurred in the right buccal mucosa/oral commissure of a 47‐year‐old man. On clinical examination, the mass was firm, measuring ~1.5 cm. Biopsy and subsequent wedge excision were performed. Histologically, the tumor was composed of bland, small, spindle to ovoid cells, arranged in short fascicles and vaguely storiform architecture. The tumor cells diffusely infiltrated into skeletal muscle. There was a background of inflammatory cells including small lymphocytes and histiocytes. Neoplastic cells were positive for SMA, demsin, PAX7, myogenin and MyoD1. Whole transcriptome sequencing revealed a TCF12::VGLL3 fusion. Digital spatial profiling (DSP) identified pan‐AKT expression, differential expression in the MAPK pathway, and revealed that the tumor attracted a dense T‐cell rich inflammatory infiltrate. The patient had a lesion in the same location 6 years prior that underwent incisional biopsy, showed intense inflammatory infiltrate, and was interpreted as benign. FISH for VGLL3 on this tissue was positive for rearrangement. No additional adjuvant treatment was given, and the patient is alive without disease, 8 months after the major resection. Long term follow‐up of 6 years with only local recurrence lends further support to the notion that these neoplasms are a class of indolent/low‐grade rhabdomyoblastic tumors that are biologically and clinically distinct from fully malignant spindle cell rhabdomyosarcomas.

Superficial rhabdomyosarcomas (RMS) represent a rare and diagnostically challenging group of malignant neoplasms that may arise in, involve, or metastasize to the skin. Although RMS is the most common soft tissue sarcoma of childhood, cutaneous and superficial presentations are uncommon and encompass a heterogeneous spectrum of clinicopathologic scenarios. These include primary cutaneous RMS of conventional subtypes, newly recognized molecularly defined entities such as TFCP2 -rearranged RMS, rhabdomyosarcomatous transdifferentiation of primary cutaneous malignancies, and metastatic RMS to the skin. Each of these entities may closely mimic a variety of benign and malignant cutaneous tumors, leading to potential diagnostic pitfalls. This review provides a comprehensive overview of superficial RMS, with emphasis on histopathologic features, immunophenotypic profiles, molecular alterations, and key differential diagnoses relevant to dermatopathologists and surgical pathologists. Conventional primary cutaneous RMS subtypes—including alveolar, embryonal, pleomorphic, and spindle cell/sclerosing variants—are discussed alongside emerging entities such as FUS/EWSR1::TFCP2 -rearranged RMS, which frequently demonstrate epithelial marker expression and ALK overexpression. In addition, rhabdomyosarcomatous transdifferentiation of melanoma and squamous cell carcinoma is reviewed, highlighting the importance of clinicopathologic correlation and molecular testing to avoid misclassification. Cutaneous metastases of RMS, though exceedingly rare, are also addressed. Recognition of these diverse presentations requires integration of morphologic assessment, immunohistochemistry, and increasingly, molecular diagnostics. Continued clinicopathologic studies and molecular characterization will be essential to refine classification, improve diagnostic accuracy and enhance understanding of the biologic behavior of superficial RMS.

Dermatofibrosarcoma protuberans (DFSP) is a locally aggressive fibroblastic neoplasm characterized by recurrent COL1A1::PDGFB fusions that drive autocrine PDGFR‐β activation. Recent sequencing studies have revealed rare DFSPs with alternative noncanonical PDGFB or PDGFD rearrangements, underscoring the genetic diversity of PDGF‐ligand activation in this tumor. Here, we describe two conventional DFSPs harboring previously unreported fusions: FGL2::PDGFD and TGFBI::PDGFB . In the first case, FGL2(ex1)::PDGFD(ex6) replaces the PDGFD N‐terminal CUB domain with the FGL2 signal peptide, a configuration predicted to generate a constitutively active, secreted PDGFD ligand. In the second case, TGFBI(ex14)::PDGFB(ex3) juxtaposes PDGFB to the highly expressed extracellular matrix gene TGFBI , providing an alternative promoter context for PDGFB overexpression. Both cases showed classic DFSP morphology and diffuse CD34 expression. These findings expand the molecular landscape of DFSP and illustrate convergent mechanisms of PDGFR‐β activation achieved through diverse yet functionally equivalent genomic rearrangements.

Purpose:Fusion-positive myoepithelial tumors (MET) are clinicopathologically heterogeneous and variably termed mixed tumors and myoepithelial carcinomas. As FET-rearranged METs lack ductal/epithelial differentiation, we test whether FET-rearranged METs are epigenetically distinct from adnexal PLAG1-rearranged METs, which we hypothesize to be analogues of salivary gland METs.Experimental Design:DNA methylation profiling from a multi-institutional cohort of 52 fusion-positive skin, soft-tissue, and bone MET cases was performed and compared with diverse tumor types, including salivary METs. The MET subgroups harbored EWSR1::KLF15, EWSR1/FUS::KLF17, EWSR1::PBX1, EWSR1::PBX3, EWSR1/FUS::POU5F1, SS18::POU5F1, EWSR1::ZNF444, and PLAG1 rearrangements. Pooled clinicopathologic and outcome analysis with new and published cases (total 185) was performed.Results:The MET subgroups showed significant heterogeneity in age, site, and histology. Specifically, EWSR1::KLF15 METs affected predominantly young children (<5 years); EWSR1::PBX1/PBX3 METs were enriched in skin/bone; and EWSR1/FUS::POU5F1, SS18::POU5F1, and EWSR1::KLF15 METs tended to display malignant histology. Conversely, PLAG1-rearranged tumors were predominantly benign, arising in older adults and located in the skin. DNA methylation profiling revealed that FET-rearranged METs were epigenetically related to SS18::POU5F1 METs and FET::NFATC2 sarcomas but entirely distinct from PLAG1-rearranged adnexal and salivary METs. Histologic features were correlated with the degree of genome-wide copy-number variation. The median disease-specific survival was shortest in SS18::POU5F1 (31 months), EWSR1::PBX3 (38 months), and EWSR1::KLF15 (45 months) METs. On multivariate analysis, age <25 years was a significant predictor of worse progression-free survival.Conclusions:FET-rearranged METs are epigenetically unrelated to cutaneous and salivary gland METs, and their malignant counterparts are best classified as sarcomas rather than carcinomas.

Suppl. Figure S2. Unsupervised hierarchical clustering heatmap of DNA methylation beta values (top 5000 by variance) across selected tumor types. Shown are the genes corresponding to the top 100 cpg sites.