Spermatocytic tumor (ST) is a rare type of germ cell tumor that occurs exclusively in the postpubertal testis and typically affects elderly men. Most STs are benign, but rare cases exhibit aggressive clinical behavior, often in association with transition to sarcomatoid histology. Limited molecular analyses have been performed on STs; therefore, their genomic and epigenomic features remain incompletely described. Twenty-seven samples from 25 individual patients were analyzed with a combination of DNA sequencing panels, genomic methylation profiling, SNP array, isochromosome (12p) [i(12p)] FISH, and immunohistochemistry. The series included five metastasizing tumors (three with sarcomatoid transformation, one anaplastic, and one conventional) and 20 non-metastasizing tumors (14 anaplastic and six conventional). Anaplastic tumors comprised a monomorphic population of intermediate-sized neoplastic cells, as previously described. Multiomic analyses demonstrated that there were two genomic subgroups of STs: one with diploid genomes and hotspot RAS/RAF variants and the other with global ploidy shift and absence of recurrent mutations. Relative gain of chromosome 9 was a consistent finding in both subgroups. A comparison of metastasizing and non-metastasizing cases demonstrated that aggressive behavior was associated with the acquisition of pathogenic TP53 mutations and/or relative gains of 12p/i(12p). In cases with sarcomatoid transformation, TP53 mutations seem to underlie the transition to sarcomatoid histology. Genomic methylation analysis demonstrated that aggressive cases with gains of 12p cluster closer to pure seminomas than to STs without gains of 12p. In conclusion, STs include two genomic subgroups, characterized by global ploidy shifts without recurrent mutations and diploid genomes with RAS/RAF hotspot mutations, respectively. Biologic progression was associated with relative gains of 12p and TP53 mutations. The findings in STs with relative gains of 12p suggest that they may exhibit biologic characteristics akin to those seen in germ cell neoplasia in situ-related germ cell tumors rather than non-germ cell neoplasia in situ-derived STs. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
The Journal of pathology. 2023 Oct 04 [Epub ahead of print]
Sounak Gupta, Lynette M Sholl, Yiying Yang, Adeboye O Osunkoya, Jennifer B Gordetsky, Kristine M Cornejo, Kvetoslava Michalova, Fiona Maclean, Eugénia Dvindenko, Matija Snuderl, Michelle S Hirsch, William J Anderson, Ross A Rowsey, Rafael E Jimenez, John C Cheville, Peter M Sadow, Maurizio Colecchia, Costantino Ricci, Thomas M Ulbright, Daniel M Berney, Andres Martin Acosta
Department of Pathology, Mayo Clinic, Rochester, MN, USA., Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Department of Pathology, New York University, New York, NY, USA., Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA., Department of Pathology, Vanderbilt University, Nashville, TN, USA., Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Department of Pathology, Charles University, Plzen, Czech Republic., Department of Pathology, Douglass Hanly Moir Pathology, Macquarie University, Sydney, NSW, Australia., Department of Pathology, Instituto Português de Oncologia, Lisbon, Portugal., Department of Pathology, Universita Vita Salute San Raffaele, Milan, Italy., Pathology Unit, Maggiore Hospital-AUSL Bologna, Bologna, Italy., Department of Pathology, Indiana University, Indianapolis, IN, USA., Centre for Cancer Biomarkers & Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK.