Prevalence of differentiated high-grade thyroid carcinoma among well-differentiated tumors: a systematic review and meta-analysis

Background: The current edition of the World Health Organization classification of endocrine tumors introduced grading for follicular cell derived thyroid cancer. Tumors with necrosis and/or high mitotic count but not fulfilling Turin criteria for poorly differentiated carcinoma will be reclassified as differentiated high-grade thyroid carcinoma (DHGTC). However, the impact of this reclassification has not been evaluated. We here performed a systematic review and meta-analysis to estimate the prevalence of this new entry across thyroid tumor subtypes. Methods: In this systematic review and meta-analysis, studies reporting data on necrosis and/or mitoses in well-differentiated thyroid carcinoma (WDTC) were used to estimate the prevalence of DHGTC. Heterogeneity and potential publication bias were also evaluated. PRISMA guidelines were followed, and quality assessment was performed using a modification of the Newcastle-Ottawa scale. The study has been registered in the International prospective register of systematic reviews (PROSPERO, ID: CRD42022378716). Results: In clinically unselected patients, the prevalence of DHGTC in WDTC was 0.072 (95% CI 0.045-0.113). The proportion of high-grade tumors greatly varied across growth patterns and subtypes. Overall, the prevalence of DHGTC was higher in follicular thyroid carcinoma (FTC, 0.146, 95% CI 0.101-0.205) than in papillary thyroid carcinoma (PTC, 0.059, 95% CI 0.036-0.097). Diffuse sclerosing, follicular and classic subtype PTC had the lowest rates of high-grade features (i.e., 0.018, 95% CI 0.004-0.084; 0.036, 95% CI 0.010-0.124; and 0.042, 95% CI 0.027-0.066 respectively), while a greater proportion of solid trabecular and histologically aggressive PTC could be reclassified as DHGTC (i.e., 0.154, 95% CI 0.067-0.314; and 0.168, 95% CI 0.108-0.252 respectively). Similar proportions were obtained for minimally and widely invasive FTC (i.e., 0.136, 95% CI 0.058-0.287; and 0.152, 95% CI 0.086-0.254 respectively). Finally, in a cohort of patients with poor prognosis (i.e., fatal cases, metastatic and radioiodine resistant tumors, cases with biochemical recurrence) the proportion of DHGTC was 0.287 (95% CI 0.155-0.469). Conclusions: Following the current WHO indications, some tumors will be reclassified as DHGTC. The proportion of tumors with high-grade features is relevant in FTC, solid trabecular and histologically aggressive PTC subtypes. A remarkable enrichment in DHGTC among patients with poor prognosis confirms the negative impact of high-grade features on outcome.