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Dear Editor, We recently reported genetic and epigenetic aberrations in the telomerase reverse transcriptase (TERT) gene in follicular thyroid tumors, further supporting the notion that expression of TERT could constitute a prognostic tool for these lesions [1]. We also showed that screening for TERT aberrancies showed a high specificity for distinguishing follicular thyroid carcinoma (FTC) and follicular tumor of uncertain malignant potential (FTUMP) from follicular thyroid adenoma (FTA). Screening for such molecular changes (TERT promoter mutations and/or aberrant methylation, copy number gain, and mRNA expression) is, however, not as well established as immunohistochemistry (IHC) in most clinical pathology laboratories. In addition, a reliable TERT antibody has not yet showed satisfactory results in thyroid cancer, with conflicting results in the interpretation of the staining patterns. Moreover, these previous studies were not correlated to various TERT gene aberrancies, thereby preventing an essential correlation to underlying genetics. Our aimwith this study was to evaluate if TERT immunoreactivity correlates to TERT promoter mutations or mRNA expression in FTCs, to see whether TERT IHC could be used as a surrogate marker for the causal genetic analyses that previously have been shown to correlate to a malignant phenotype in follicular tumors. The cohort comprised of 51 FTC cases (denoted T1-T51) operated at Karolinska University Hospital, Stockholm, Sweden, between 2014 and 2016. Of these, 27 were widely invasive (WIFTCs), 17 were minimally invasive (MIFTC) and seven were encapsulated angio-invasive (EAIFTC) according to the 2017 WHO classification algorithm (Table 1). T1-T28 were denoted as part of the validation cohort with known TERT promoter mutational status and TERT mRNA expression from our previous study [1], and an additional 23 cases (T29-T51) without available genetic information were retrieved from our pathology registries as an expansion cohort. Informed consent was obtained from all individual participants included in the study, and clinical followup was retrieved for all patients. Out of 51 FTCs, 38 cases included corresponding normal thyroid tissue on the same slide which allowed comparison of the immunoreactivity with nontumorous thyroid tissue. All cases were formalin-fixed paraffinembedded (FFPE) and cut into 4 μm thick sections and stained using the Envision+ Dual Link System-HRP (DAB+) (DAKO, Carpenteria, CA, USA). The tissue slides were incubated with the monoclonal primary antibody anti-telomerase reverse transcriptase (ab32020, Abcam, Cambridge, UK) for 30 min at a dilution of 1:100. As a positive control, primary FUCH-1 (fibroblast cells infected with TERT [2] with approximately 10% expressing the protein) were used and BJ cells from human foreskin (ATCC® CRL-2522TM, Manassas, VA, USA) were used as a negative control. The optimal primary antibody concentration for our experiments was determined through serial dilutions using positive and negative controls (data not shown). The tissue slides were counterstained with hematoxylin and subsequently evaluated independently by two experienced pathologists and graded as displaying Bnegative/no immunoreactivity,^ Bweak immunoreactivity,^ or Bstrong immunoreactivity.^ The cell component that showed immunoreactivity was also taken into consideration and described as Bnuclear,^ Bcytoplasmic,^ or Bperinuclear.^ The FUCH-1 TERTexpressing cells showed strong nuclear and cytoplasmic immunoreactivity whereas the BJ cells showed no immunoreactivity (Fig. 1). Among the FTCs, 20 (39%) showed strong immunoreactivity, 19 (37%) showed weak immunoreactivity and 12 (24%) cases showed negative immunoreactivity (Table 1). A single FTC case (T44) showed * Johan O. Paulsson johan.paulsson@ki.se

TERT Immunohistochemistry Is a Poor Predictor of TERT Promoter Mutations and Gene Expression in Follicular Thyroid Carcinoma