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The hyalinizing trabecular adenoma/tumor is a rare and poorly characterized follicular-derived thyroid neoplasm recently shown to harbor recurrent PAX8–GLIS1or PAX8–GLIS3gene fusions. Here we sought to define the repertoire of genetic alterations of hyalinizing trabecular tumors, and whether PAX8–GLIS3fusions are pathognomonic for hyalinizing trabecular tumors. A discovery series of eight hyalinizing trabecular tumors was subjected to RNA-sequencing (n= 8), whole-exome sequencing (n= 3) or targeted massively parallel sequencing (n= 5). No recurrent somatic mutations or copy number alterations were identified in hyalinizing trabecular tumor, whereas RNA-sequencing revealed the presence of a recurrent genetic rearrangement involving PAX8(2q14.1) and GLIS3(9p24.2) genes in all cases. In this in-frame fusion gene, which comprised exons 1–2 of PAX8and exons 3–11 of GLIS3, GLIS3is likely placed under the regulation of PAX8. Reverse transcription RT-PCR and/or fluorescence in situ hybridization analyses of a validation series of 26 hyalinizing trabecular tumors revealed that the PAX8–GLIS3gene fusion was present in all hyalinizing trabecular tumors (100%). No GLIS1rearrangements were identified. Conversely, no PAX8–GLIS3gene fusions were detected in a cohort of 237 control thyroid neoplasms, including 15 trabecular thyroid lesions highly resembling hyalinizing trabecular tumor from a morphological standpoint, as well as trabecular/solid follicular adenomas, solid/trabecular variants of papillary carcinoma, and Hurthle cell adenomas or carcinomas. Our data provide evidence to suggest that the PAX8–GLIS3fusion is pathognomonic for hyalinizing trabecular tumors, and that the presence of the PAX8–GLIS3fusion in thyroid neoplasms may be used as an ancillary marker for the diagnosis of hyalinizing trabecular tumor, thereby avoiding overtreatment in case of misdiagnoses with apparently similar malignant tumors.

Merkel cell carcinoma is an aggressive neuroendocrine skin tumor, for which several non-conclusive prognostic factors of adverse clinical behavior have been reported. As promoter methylation of the immune checkpoint receptor CD279/PD-1/PDCD1(mPDCD1) has been shown to be a prognostic factor in different cancers, we investigated its role in Merkel cell carcinoma. mPDCD1was assessed retrospectively in a cohort of 69 Merkel cell carcinoma patients from the University of Bologna, University of Turin and University of Insubria. Kaplan-Meier curves and log-rank tests were calculated for all variables. To assess the influence of mPDCD1, the Cox proportional hazards model and different Royston-Parmar models were evaluated. High PDCD1methylation (mPDCD1high) was associated with a higher overall mortality at both the univariate analysis (log rank test: χ2= 5.17, p= 0.023; permutation test: p= 0.023) and the multivariate analysis (HR = 2.111, p= 0.042). The other variables associated with a higher overall mortality at the multivariate analysis were clinical stage III-IV (HR = 2.357, p= 0.008), size > 2 cm (HR = 2.248, p= 0.031) and Merkel cell polyomavirus (HR = 0.397, p= 0.015). Further, mPDCD1highwas strongly associated with older age (81 vs 76 years, p= 0.042), absence of immune cells (92.6%, p< 0.001), no expression of PD-L1 by immune cells (70.4%, p= 0.041) and by both immune and tumor cells (70.4%, p= 0.001). mPDCD1is a valid prognostic parameter in patients affected by Merkel cell carcinoma. In addition, it could provide an estimate of the global PD-1/PD-L1 expression with potentially relevant implications from a therapeutic point of view.