# Clinical Behavior of Aggressive Variants of Papillary Thyroid Carcinoma: A Retrospective Case–Control Study

## TL;DR

This study compares the aggressiveness of different subtypes of papillary thyroid carcinoma to determine which require more cautious treatment.

## Contribution

The study identifies high-risk subtypes of papillary thyroid carcinoma that show significantly worse clinical outcomes.

## Key findings

- High-risk variants (tall cell, diffuse sclerosing, columnar cell, hobnail) showed significantly more aggressive clinicopathological characteristics and worse survival outcomes.
- Intermediate-risk variants (solid variant) did not show significant differences in aggressiveness compared to classic papillary thyroid carcinoma.
- Oncocytic and Warthin-like variants had similar survival but were associated with some unfavorable clinicopathological features.

## Abstract

Papillary thyroid carcinoma is one of the most indolent malignancies in the human population. However, there are several rare subtypes of this cancer, which are characterized by higher rates of recurrence, metastases, and death. Not all of these subtypes act with the same level of aggression. This is why the aim of this research is to investigate the aggressiveness profile of each of the subtypes, especially with regard to some newer information in the literature about them. In doing so, we could stipulate which subtypes and tumor characteristics would require additional caution and treatment steps in everyday practice.

Background/Objectives: Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy. The classic variant (cPTC) is characterized by indolent behavior and excellent prognosis. However, rare subtypes of PTC most often exhibit adverse clinical behavior. The aim of the study was to assess the aggressiveness of rare variants of PTC by analyzing clinicopathological characteristics (CPCs) and survival outcomes. Methods: We analyzed 80 patients with rare PTC variants treated between 2009 and 2019 who were compared with cPTC and matched with a control group for age and tumor size. The variants were categorized into high-risk (HRV: tall cell, diffuse sclerosing, columnar cell, and hobnail variants), intermediate-risk (IRV: solid variant (SV)), and low-risk (LRV: oncocytic (OV) and Warthin-like (WLV)) variants. Different CPCs (capsule and blood vessel invasion, lymphonodal metastases, microscopic and macroscopic extrathyroid extension, multifocal and bilateral presentation) and survival outcomes—overall (OS), disease-specific (DSS), and disease-free survival (DFS) were compared. Results: HRVs exhibited significantly more aggressive CPCs and worse OS, DSS, and DFS compared to cPTC (p < 0.001). IRVs showed no significant difference in CPCs or survival outcomes compared to cPTC. LRVs showed excellent survival but were associated with several unfavorable CPCs. Multivariate analysis identified classification in HRVs as the only independent predictor of recurrence (p = 0.014). Conclusions: Tumors in the HRV group should retain their status as aggressive PTC variants due to unfavorable behavior and poorer prognosis. SVs, despite earlier assumptions, do not exhibit aggressive characteristics. Although the OV and WLV have similar survival to cPTC, their potential for adverse CPCs requires caution.