**Evaluation of Clinicopathological and Molecular Parameters on Disease Recurrence of Papillary Thyroid Cancer Patient: A Retrospective Observational Study**

**Salvatore Sorrenti 1,**†**, Giovanni Carbotta 1,**† **, Filippo Maria Di Matteo 1, Antonio Catania 1, Daniele Pironi <sup>1</sup> , Francesco Tartaglia <sup>1</sup> , Danilo Tarroni 1, Federica Gagliardi 1, Domenico Tripodi <sup>1</sup> , Mikiko Watanabe <sup>2</sup> , Stefania Mariani <sup>2</sup> , Eleonora D'Armiento 3, Poupak Fallahi 4, Alessandro Sindoni <sup>5</sup> , Corrado De Vito 5, Alessandro Antonelli <sup>4</sup> , Salvatore Ulisse 1,\* and Enke Baldini <sup>1</sup>**


Received: 14 October 2020; Accepted: 2 December 2020; Published: 4 December 2020

**Simple Summary:** Papillary thyroid cancer (PTC) patients are staged according to the Tumor-Node-Metastasis staging system (TNM). This work was aimed at comparing the usefulness of the 8th edition of TNM (TNM-8), currently used, and that of the previous one (TNM-7) for predicting disease-free interval (DFI) in a cohort of 1148 patients. Moreover, clinicopathological and molecular factors were statistically evaluated in order to determine which of these was/were the best predictor(s) of DFI. Results obtained from the multivariate analysis indicated that advanced tumor stages were independent risk factors for a lower DFI regardless of TNM, but the statistical model created with the TNM-7 was most accurate. When stage-determining factors were included individually in the multivariate analysis, LN metastases, tall cell variant, and age emerged as independent risk factors for a shorter DFI, with lateral LN metastases being the most relevant. No molecular parameters could improve the prediction of DFI provided by LN metastases.

**Abstract:** The American Joint Committee on Cancer has revised the Tumor-Node-Metastasis (TNM) staging system for papillary thyroid cancer (PTC) patients. We examined the impact of this new classification (TNM-8) on patient stratification and estimated the prognostic value of clinicopathological features for the disease-free interval (DFI) in a cohort of 1148 PTC patients. Kaplan–Meier analyses showed that all clinicopathological parameters analyzed, except age and multifocality, were associated significantly with DFI. Cox regression identified tall cell PTC variant and stage as independent risk factors for DFI. When the stage was replaced with age, tumor size, and lymph node (LN) metastases in the set of covariates, the lateral LN metastases stood out as the

strongest independent predictor of DFI, followed by tall cell variant and age. A noteworthy result emerging from these analyzes is that regression models had lower Akaike and Bayesian information criterions if variables were categorized based on the TNM-7. In addition, we examined data from a different PTC patient cohort, acquired from The Cancer Genome Atlas database, to verify whether the DFI prediction could be enhanced by further clinicopathological and molecular parameters. However, none of these was found to be a significant predictor of DFI in the Cox model.

**Keywords:** papillary thyroid cancer; prognosis; TNM; histology; multifocality; lymph node metastasis; vascular invasion; autoimmune thyroid diseases
