Differential Clinicopathological Risk and Prognosis of Major Papillary Thyroid Cancer Variants

CONTEXT: Individualized management, incorporating papillary thyroid cancer (PTC) variant-specific risk, is conceivably a useful treatment strategy for PTC, which awaits comprehensive data demonstrating differential risks of PTC variants to support. OBJECTIVE: To establish the differential clinicopathological risk of major PTC variants-conventional PTC (CPTC), follicular-variant PTC (FVPTC), and tall-cell PTC (TCPTC). METHODS: Retrospective study of clinicopathological outcomes of 6,282 PTC patients (4,799 females and 1,483 males) from 26 centers and The Cancer Genome Atlas in 14 countries with a median age of 44 years (interquartile range [IQR], 33-56) and median follow-up time of 37 months (IQR 15-82). RESULTS: The cohort consisted of 4,702 (74.8%) CPTC, 1,126 (17.9%) FVPTC, and 239 (3.8%) TCPTC. The prevalence of high-risk parameters was significantly different among the three variants, including extrathyroidal invasion, lymph node metastasis, stages III/IV, disease recurrence, mortality and the use (need) of radioiodine treatment (all P < 0.001), being highest in TCPTC, lowest in FVPTC, and intermediate in CPTC, following an order of TCPTC>CPTC≫FVPTC. Recurrence and mortality in TCPTC, CPTC, and FVPTC were 27.3% and 6.7%, 16.1% and 2.5%, and 9.1% and 0.6%, corresponding to events per 1000 person-years (95% confidence interval-CI) of 92.47 (64.66-132.26) and 24.61 (12.31-49.21), 34.46 (30.71-38.66) and 5.87 (4.37-7.88), and 24.73 (18.34-33.35) and 1.68 (0.54-5.21), respectively. Mortality hazard ratios of CPTC and TCPTC over FVPTC were 3.44 (95% CI 1.07-11.11) and 14.96 (95% CI 3.93-56.89), respectively. Kaplan-Meier survival analyses showed the best prognosis in FVPTC, worst in TCPTC, and intermediate in CPTC in disease recurrence-free probability and disease-specific patient survival. This was particularly the case in patients ≥ 45 years old. CONCLUSION: This large multicenter study demonstrates differential prognostic risks of the three major PTC variants and establishes a unique risk order of TCPTC > CPTC ≫ FVPTC, providing important clinical implications for specific variant-based management of PTC.