Different Threshold of Malignancy for RAS-like Thyroid Tumors Causes Significant Differences in Thyroid Nodule Practice

SIMPLE SUMMARY: Histopathological diagnosis is prone to significant observer variation in the diagnosis of papillary thyroid carcinomas (PTCs) due to different thresholds of malignancy for RAS-like nuclear features (worrisome nuclear features of PTC). RAS-like PTCs in Western practice are differently classified by most Asian pathologists into follicular adenomas when they are not invasive, follicular carcinomas when they are invasive, and follicular variant PTCs when they have fully developed nuclear features. This commentary emphasizes that this observer variation in diagnosing RAS-like thyroid tumors among practices underlies several issues in thyroid nodule practice. ABSTRACT: Histopathological diagnosis of papillary thyroid carcinomas (PTCs) is prone to significant observer variation due to different thresholds of RAS-like nuclear changes among pathologists. This gap recently widened due to a defensive attitude by Western pathologists where malpractice litigation is significant. Cases with delicate RAS-like nuclear changes are follicular adenomas when they are noninvasive, follicular carcinomas when invasive, and follicular variant PTCs when they have fully developed PTC-type nuclear features in Asian practice. The different diagnostic threshold of PTC nuclear features resulted in a high (50–90%) incidence of BRAFV600E mutation of PTCs in most Asian countries, whereas it was low (35–50%) in most Western patient cohorts. The contamination of indolent RAS-like tumors in the malignant PTC category in Western patient cohorts explains why the BRAFV600E gene test identifies aggressive PTCs. However, the BRAFV600E test has no prognostic value for Asian PTC patients because most biologically benign or low-risk RAS-like tumors are excluded from PTC. All prognostic analyses of thyroid carcinomas before 2017 must be re-evaluated because most clinical guidelines were established based on data obtained from Western patient cohorts where a significant number of indolent RAS-like tumors were misclassified in the malignant category.