A detailed histological and molecular assessment of the diffuse sclerosing variant of papillary thyroid carcinoma.

Abstract

Diffuse sclerosing variant papillary thyroid carcinoma (DS-PTC) is characterized clinically by a predilection for children and young adults, bulky neck nodes and pulmonary metastases. Previous studies have suggested infrequent BRAFV600E mutation but common RET gene rearrangements.Using strict criteria, we studied 43 DS-PTCs (1.9% of unselected PTCs in our unit). 79% harboured pathogenic gene rearrangements involving RET, NTRK3, NTRK1, ALK, or BRAF; with the remainder driven by BRAFV600E mutations. All ten pediatric cases were all gene-rearranged (p=0.02).Compared to BRAFV600E mutated tumors, gene rearrangement was characterized by psammoma bodies involving the entire lobe (p=0.038), follicular predominant or mixed follicular architecture (p=0.003), pulmonary metastases (24% vs none, p = 0.04), and absent classical, so called 'BRAF-like' atypia (p=0.014). There was no correlation between the presence of gene rearrangement and recurrence-free survival.Features associated with persistent/recurrent disease included pediatric population (p = 0.030), gene-rearranged tumors (p = 0.020), microscopic extrathyroidal extension (p=0.009), metastases at presentation (p=0.007) and Stage II disease (p=0.015).We conclude DS-PTC represents 1.9% of papillary thyroid carcinomas and actionable gene rearrangements are extremely common in DS-PTC. DS-PTC can be divided into two distinct molecular subtypes and all BRAFV600E negative tumors (1.5% of papillary thyroid carcinomas) are driven by potentially actionable oncogenic fusions.Copyright © 2023. Published by Elsevier Inc.