Superficial spindle cell tumour with TNC::PDGFD fusion is a distinct entity from dermatofibrosarcoma protuberans

Dermatofibrosarcoma protuberans (DFSP) is a locally aggressive and infiltrative dermohypodermal spindle cell neoplasm, genetically characterised by COL1A1::PDGFB fusion in most cases.1Mentzel T. Pedeutour F. Dermatofibrosarcoma protuberans. In: WHO Classification of Tumours Editorial Board.5th edition. WHO Classification of Tumours: Soft Tissue and Bone Tumours. IARC Press, Lyon2020Google Scholar Alternative fusion transcripts with PDGFD have been detected in a minority of cases.2Dadone-Montaudié B. Alberti L. Duc A. et al.Alternative PDGFD rearrangements in dermatofibrosarcomas protuberans without PDGFB fusions.Mod Pathol. 2018; 31: 1683-1693Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Recently, Chen et al. reported an undescribed TNC::PDGFD fusion transcript in a well-circumscribed and nodular subcutaneous spindle cell neoplasm and discussed the possibility of a DFSP subtype.3Chen Y. Shi Y.-Z. Feng X.-H. Wang X.-T. He X.-L. Zhao M. Novel TNC-PDGFD fusion in fibrosarcomatous dermatofibrosarcoma protuberans: a case report.Diagn Pathol. 2021; 16: 63Crossref PubMed Scopus (8) Google Scholar Here we report another case of spindle cell neoplasm with TNC::PDGFD and discuss its relationship with the DFSP spectrum. The local Ethics Committee in Human Research of Tours (France) approved the study (no. ID RCB2009-A01056-51). A 49-year-old woman presented with a slowly growing infracentimetric tumour at the tip of the nose. A clinical differential was a basal cell carcinoma and surgical resection was performed. Histopathological examination revealed a well-circumscribed mesenchymal neoplasm, measuring 5 mm in diameter and located in the dermis and subcutis without connection to the epidermis (Fig. 1A,B). The neoplasm was composed of small monomorphous spindle-shaped cells with regular small folded or indented nuclei and a moderate amount of eosinophilic cytoplasm (Fig. 1C). Pleomorphism, mitotic activity, and necrosis were not seen. These cellular fields were centred by large hyaline lobulated areas composed of dense collagen bundles with scattered small nuclei and inconspicuous cytoplasms (Fig. 1D). These features were reminiscent of immature cartilage while no lamellar bone or fibrillar ossification was seen. Immunohistochemical investigation of the case showed negativity for CD34 (Fig. 2A), CKAE1/AE3, EMA, BerEP4, p63, SOX10, PS100, Melan-A, GFAP, SMA, Desmin, CD31, neuron-specific enolase (NSE), neurofilament (NF), MUC4, pan-TRK, ALK5A4 and β-catenin (Fig. 2B). Therefore, RNA sequencing was performed on formalin-fixed, paraffin-embedded (FFPE) tissue using the Archer FusionPlex Sarcoma Panel (ArcherDX, USA) on a MiSeq (300 cycles; Illumina USA). Sequencing data were analysed via the Archer automated analysis pipeline, which revealed a TNC::PDGFD fusion transcript. Platelet Derived Growth Factor D (PDGFD) is located on chromosome 11q22.3 and encodes a platelet-derived growth factor family protein. Binding and activation of its homologous receptor PDGFR-β can regulate cell proliferation, migration, invasion, and angiogenesis by the crosstalk of many signalling pathways.4Wang Z. Kong D. Li Y. Sarkar F. PDGF-D signaling: a novel target in cancer therapy.Curr Drug Targets. 2009; 10: 38-41Crossref PubMed Scopus (58) Google Scholar Recently, fusions involving PDGFD have been reported in DFSP cases lacking COL1A1::PDGFB fusion. In these cases, a fusion was observed between PDGFD and COL6A3 or EMILIN2 in 40% of the cases. Similarly to COL1A1::PDGFB fusions, PDGFD rearrangements can result in autocrine activation by signalling of the PDGFR-β receptor tyrosine kinase.5Lee P.-H. Huang S.-C. Wu P.-S. et al.Molecular characterization of dermatofibrosarcoma protuberans: the clinicopathologic significance of uncommon fusion gene rearrangements and their diagnostic importance in the exclusively subcutaneous and circumscribed lesions.Am J Surg Pathol. 2022; 46: 942-955Crossref PubMed Scopus (4) Google Scholar Tenascin-C (TNC) is located on chromosome 9q33.1 and is a member of the tenascin gene family which encodes extracellular matrix proteins with a wide range of different functions with a spatially and temporally restricted tissue distribution.6Chiovaro F. Chiquet-Ehrismann R. Chiquet M. Transcriptional regulation of tenascin genes.Cell Adh Migr. 2015; 9: 34-47Crossref PubMed Scopus (69) Google Scholar Its expression is induced by stress or mechanical and chemical injury and has oncogenic properties through the promotion of cell proliferation, migration and angiogenesis, which has been described as an important factor of metastatic spread by providing protection against apoptosis.7Yoshida T. Akatsuka T. Imanaka-Yoshida K. Tenascin-C and integrins in cancer.Cell Adh Migr. 2015; 9: 96-104Crossref PubMed Scopus (113) Google Scholar In a recent study, TNC was found as a fusion partner of the NRG1 gene in non-small cell lung cancers and in papillary renal cell carcinomas,8Jonna S. Feldman R.A. Swensen J. et al.Detection of NRG1 gene fusions in solid tumors.Clin Cancer Res. 2019; 25: 4966-4972Crossref PubMed Scopus (104) Google Scholar which could promote pathological signalling through activation of MAP-kinase and other canonical pathways.9Ptáková N. Martínek P. Holubec L. et al.Identification of tumors with NRG1 rearrangement, including a novel putative pathogenic UNC5D-NRG1 gene fusion in prostate cancer by data-drilling a de-identified tumor database.Genes Chromosomes Cancer. 2021; 60: 474-481Crossref PubMed Scopus (8) Google Scholar Furthermore, the TNC::USP6 fusion has also been documented in a primary aneurismal bone cyst.10Šekoranja D. Zupan A. Mavčič B. et al.Novel ASAP1-USP6, FAT1-USP6, SAR1A-USP6, and TNC-USP6 fusions in primary aneurysmal bone cyst.Genes Chromosomes Cancer. 2020; 59: 357-365Crossref PubMed Scopus (30) Google Scholar Recently, Chen et al. reported a subcutaneous spindle cell tumour with TNC::PDGFD fusion and proposed that it could represent a subtype of fibrosarcomatous DFSP.3Chen Y. Shi Y.-Z. Feng X.-H. Wang X.-T. He X.-L. Zhao M. Novel TNC-PDGFD fusion in fibrosarcomatous dermatofibrosarcoma protuberans: a case report.Diagn Pathol. 2021; 16: 63Crossref PubMed Scopus (8) Google Scholar The tumour was well-circumscribed, a feature recently described in PDGFD-rearranged DFSP.11Campbell K. Bridge J.A. DiMaio D. Wilson J. Shalin S.C. Gardner J.M. Dermatofibrosarcoma protuberans with platelet-derived growth factor-D rearrangement; two cases with morphologically distinct presentations.J Cutan Pathol. 2022; 49: 274-277Crossref PubMed Scopus (2) Google Scholar However, in our observation, the well-delimitated nodular silhouette, the lack of infiltration, the hyaline hypocellular areas and the negativity of CD34 were not in keeping with the diagnosis of DFSP. Therefore, although confirmation of more cases is required for further characterisation, the morphological and immunohistochemical characteristics observed in these two cases suggest that superficial TNC::PDGFD-rearranged spindle cell tumours may constitute a distinct entity. The authors state that there are no conflicts of interest to disclose.