pmTOR is a marker of aggressiveness in papillary thyroid carcinomas Catarina Tavares, DVM, a,b,c Maria Jo~ao Coelho, MSc, a,b,d Miguel Melo, MD, PhD, a,b,e,f Adriana Gaspar da Rocha, MD, a,b,g Ana Pestana, MSc, a,b,c Rui Batista, MSc, a,b,c Catarina Salgado, MSc, a,b Catarina Eloy, MD, PhD, a,b Luciana Ferreira, MSc, a,b,c Elisabete Rios, MD, a,b,c,h,i Manuel Sobrinho-Sim~ oes, MD, PhD, a,b,c,h,i and Paula Soares, PhD, a,b,c,h Porto and Coimbra, Portugal Background. Activation of the mTOR pathway has been observed in thyroid cancer, but the biologic consequences regarding tumor behavior and patient prognosis remain poorly explored. Methods. We aimed to evaluate the associations of the mTOR pathway with clinicopathologic and molecular features and prognosis through the immunocharacterization of pmTOR and pS6 expression (as readouts of the pathway) in a series of 191 papillary thyroid carcinomas. Results. pmTOR expression was associated with distant metastases (P = .05) and persistence of disease (P = .05). Cases with greater expression of pmTOR were submitted to more 131 I treatments (r[102] = 0.2; P = .02) and a greater cumulative dose of radioactive iodine (r[100] = 0.3; P = .01). Positive pmTOR expression showed to be an independent risk factor for distant metastases (odds ratio = 18.2; 95% confidence interval 2.1–157.9; P = .01). In contrast, pS6 expression was associated with absence of extrathyroid extension (P = .001), well-defined tumor margins (P = .05), and wild-type BRAF status (P = .01). There was no correlation between the expression of pmTOR and pS6 expression (r[140] = 0.1; P = .3). Conclusion. pmTOR expression is an indicator of aggressive, metastatic papillary thyroid carcinoma, being possibly implicated in refractoriness to therapy, while pS6 expression is associated with less aggressive pathologic features. Further studies are needed to understand better the biologic consequences of activation of the mTOR pathway in the behavior of thyroid cancer, namely the contribution of other pmTOR downstream effectors. (Surgery 2016;j:j-j.) From the Instituto de Investigac¸ ~ ao e Inovac¸ ~ ao em Sa ude, Universidade do Porto (i3S), a the Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), b and the Medical Faculty, c University of Porto; the Institute of Biomedical Sciences of Abel Salazar of the University of Porto (ICBAS), d Porto, Portugal; the Department of Endocrinology, Diabetes, and Metabolism, e University and Hospital Center of Coimbra; the Medical Faculty, f University of Coimbra; the University and Hospital Center of Coimbra, g Coimbra, Portugal; the Department of Pathology and Oncology, h Medical Faculty of the University of Porto; and the Department of Pathology, i Hospital de S.Jo~ ao, Porto, Portugal Supported by FCT (Portuguese Foundation for Science and Technology) through PhD grants to Catarina Tavares (SFRH/ BD/87887/2012), Ana Pestana (SFRH/BD/110617/2015), and Rui Batista (SFRH/BD/111321/2015) and by a CNPq PhD grant (National Counsel of Technological and Scientific Development, Brazil), Science without Borders (Process n# 237322/2012-9), for Luciana Ferreira. Miguel Melo received a grant from Genzyme for the research project “Molecular bio- markers of prognosis and response to therapy in differentiated thyroid carcinomas.” Further funding was obtained from FEDER---Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020---Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT---Fundac¸ ~ao para a Ci^encia e a Tecnologia/ Ministerio da Ci^encia, Tecnologia e Inovac¸ ~ao in the framework of the project, “Institute for Research and Innovation in Health Sciences (POCI-01-0145- FEDER-007274)” and from the project, “Advancing cancer research: from basic knowledgment to application”; NORTE- 01-0145-FEDER-000029; “Projetos Estruturados de I&D&I,” funded by Norte 2020---Programa Operacional Regional do Norte. The authors report no biomedical financial interests or poten- tial conflicts of interest. Accepted for publication June 23, 2016. Reprint requests: Paula Soares, PhD, IPATIMUP, Rua J ulio Amaral de Carvalho, 45, 4200-135 Porto, Portugal. E-mail: psoares@ipatimup.pt. 0039-6060/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2016.06.050 SURGERY 1 ARTICLE IN PRESS