Genetic profiles of aggressive variants of papillary thyroid carcinomas

The prognosis of BRAFV600E-mutant papillary thyroid carcinoma (PTC) ranges from indolent to highly aggressive courses. To better define the genetic diversity of this subtype, we evaluated the survival according to the presence of an additional mutation in genes encoding functional groups (FGs) in BRAFV600E-mutant advanced PTC patients. Targeted next-generation sequencing was performed in primary tumors of 50 BRAFV600E-mutant PTCs with distant metastasis or aggressive variants. The mutation in genes encoding FGs included alterations in histone methyltransferases, SWI/SNF subunit, and the PI3K/AKT/mTOR pathway. The primary outcome was overall survival (OS). Fifteen patients only had the BRAFV600E-mutation (group 1), 22 had BRAFV600E and mutation other than FGs (group 2), and 13 had BRAFV600E and FG mutation (group 3). OS was significantly lower in patients with FG mutations (p = 0.001) than those without, and group 3 patients had the worst survival (p = 0.004). OS significantly varied among none, one, or two FG mutation sites (p = 0.005). Presence of FG mutation was independently associated with increased mortality (hazard ratio 11.65, 95% confidence interval 1.39–97.58, p = 0.024). Coexistence of mutations in BRAFV600E and genes encoding FGs was associated with high mortality. Identification of FG mutation in BRAFV600E-mutant PTCs may be valuable in risk stratifying this subtype.

Mutation in Genes Encoding Key Functional Groups Additively Increase Mortality in Patients with BRAFV600E-Mutant Advanced Papillary Thyroid Carcinoma

Song

Jin

Jang

et al. 2021

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

Kakudo

2022

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.

Advances in Thyroid Carcinoma

Landa

2022