Molecular Correlates and Nuclear Features of Encapsulated Follicular-Patterned Thyroid Neoplasms

Abstract

Background Assessing nuclear features is diagnostically challenging in the aspect of thyroid pathology. The aim of this study was to determine whether pathologists could distinguish BRAF -like and RAS -like nuclear features morphologically and identify morphological features to differentiate thyroid tumors with RAS -like mutations from encapsulated papillary thyroid carcinoma (PTC) with predominant follicular growth and BRAF V600E mutation. Methods Representative whole slide images of 16 encapsulated thyroid tumors with predominant follicular growth were reviewed by 12 thyroid pathologists using a web browser-based image viewer. Total nuclear score was calculated from semi-quantitatively scored eight nuclear features. The molecular profile of RAS and BRAF genes was determined by Sanger sequencing. Results Total nuclear score ranging 0 to 24 could differentiate BRAF -like tumors from RAS -like tumors with a cut-off value of score 14. The interobserver agreement was the highest for the assessment of nuclear pseudoinclusions (NPIs) but the lowest for nuclear elongation and sickle-shaped nuclei. NPIs were found in tumors with BRAF V600E mutation, but not in tumors with RAS -like mutations. Total nuclear scores were significantly higher for tumors with BRAF V600E than for those with RAS -like mutations ( P <0.001). Conclusion Our results suggest that NPIs and high nuclear scores have diagnostic utility as rule-in markers for differentiating PTC with BRAF V600E mutation from benign or borderline follicular tumors with RAS -like mutations. Relaxation of rigid criteria for nuclear features resulted in an overdiagnosis of PTC. Immunostaining or molecular testing for BRAF V600E mutation is a useful adjunct for cases with high nuclear scores to identify true PTC.

Update from the 2022 World Health Organization Classification of Thyroid Tumors: A Standardized Diagnostic Approach

“…IEFVPTC has a RAS-like mutational and transcriptomic profile similar to that of FA and FTC (Fig. 1), whereas classic PTC and the infiltrative follicular subtype of PTC have BRAF V600E -like molecular profiles [11][12][13][14][15]. IEFVPTCs have a fibrous capsule or well-defined border and lack the histologic features of infiltrative follicular PTC.…”

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

“…This diagnostic tendency (low threshold of diagnostic nuclear features of PTC) made non-invasive encapsulated follicular variant PTC the most frequent histological subtype in Western patient cohorts [4,19,22,39,40], but not in Asian patients where only fully developed nuclear features indicated follicular variant PTCs [24][25][26][41][42][43][44]. This different threshold for malignancy in follicular pattern tumors was confirmed as the cause of the significant observer variation among pathologists when evaluating the same specimens [17,18,[45][46][47][48], particularly between Asian and Western pathologists [17,18,45]. It was attributed to non-scientific factors, particularly severe malpractice climates and defensive clinical attitudes [49,50].…”

“…Renshaw and Gould explained their motivation to over-diagnose uncertain cases rather than under-diagnose them in North American practice [51]. The gap between North America and the rest of the world became wider, and non-invasive encapsulated follicular variant PTC accounted for nearly 30% of PTC in North American practice [22,39,40,52,53], whereas it was low (1-5%) in most Asian thyroid practices [24,25,[41][42][43][44]48], some European institutes [14,[54][55][56], and a few US centers [25,57]. Hodak et al discussed this overdiagnosis in their excellent commentary, suggesting that for many patients with thyroid cancer, we may often be violating the important dictum primum non nocere (first, do no harm patients) [58].…”

Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP): Tumour Entity with a Short History. A Review on Challenges in Our Microscopes, Molecular and Ultrasonographic Profile

“…The Asian continent was represented by 28 institutions from 9 countries and the incidence varied from 0.4% in China to 14.4% in India with 2.1% NIFTP Asian rate on average [ 18 ]. The reasons for discrepancy are multifactorial, and may be as follows: racial and ethnical background and mutation profile represent biological factors [ 18 ], but the threshold for diagnosing PTC nuclear features was shown to differ in American vs. Japanese and Korean series [ 18 , 19 , 20 , 21 , 22 ]. In addition, data collection from surgical or cytological databases played a role [ 18 ].…”