Revised criteria for diagnosis of NIFTP reveals a better correlation with tumor biological behavior

Abstract

The recent reclassification of a follicular variant of papillary thyroid carcinoma (FVPTC), subset as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), aims to avoid overtreatment of patients with an indolent lesion. The diagnosis of NIFTP has recently been revisited using more rigid criteria. This study presents histological and molecular findings and a long clinical follow-up of 94 FVPTC, 40 cases of follicular adenoma (FTA) and 22 cases of follicular carcinoma (FTC) that were classified before the advent of the NIFTP reclassification. All slides were reviewed using these rigid criteria and analysis of numerous sections of paraffin blocks and reclassified as 7 NIFTPs, 2 EFVPTCs, 29 infiltrative FVPTC (IFVPTCs), 57 invasive EFVPTC (I-EFVPTCs), 39 FTAs and 22 FTCs. Remarkably, EFVPTC and NIFTP patients were all free of disease at the end of follow-up and showed no BRAF mutation. Only one NIFTP sample harbored mutations, an NRAS Q61R. PAX8/PPARG fusion was found in I-EFVPTCs and FTC. Although additional studies are needed to identify a specific molecular profile to aid in the diagnosis of lesions with borderline morphological characteristics, we confirmed that the BRAF V600E mutation is an important tool to exclude the diagnosis of NIFTP. We also show that rigorous histopathological criteria should be strongly followed to avoid missing lesions in which more aggressive behavior is present, mainly via the analysis of capsule or vascular invasion and the presence of papillary structures.

Keywords: BRAF V600E; NIFTP; PAX8-PPARG; RAS; papillary thyroid carcinoma.

Figure 1

Sankey diagram to visualize histotype distribution changes across the different classification approaches. (A) Original diagnostic: FVPTC (n = 94), FTA (n = 40) and FTC (n = 23). (B) Histotypes assignment was performed according to criteria defined by Seethala et al. (14). The samples classified as NIFTPs were previously classified as EFVPTC (6 out of 7) or FTA (1 out of 7). Most EFVPTC were reclassified as I-EFVPTC (n = 15) or IFVPTC (n = 1). None of the FTC cases changed category.

Figure 2

Histology of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTPs) and encapsulated follicular variant of papillary thyroid carcinomas (EFVPTC). (A and B) Representative image of a NIFTP sample showing the characteristics necessary for the diagnosis: (A) an expansive growth pattern with a well-delineated interface with the surrounding thyroid parenchyma and the absence of an invasion signal. This well-delimited interface can be noted even macroscopically (detail). (B) In addition, NIFTP samples must have papillary-like nuclei, as in this photomicrography. (C and D) EFVPTC cases excluded from the NIFTP group due to the presence of true papillae in the middle of the follicular architecture: (C) sample #9 and (D) sample #10, according to Table 1. (E and F) FTA sample whose diagnosis was changed to NIFTP: (E) a thick capsule can be seen around the tumor. There are no signs of invasion of the vessel or capsule, and only follicular architecture is observed. (F) At the periphery of the lesion, however, the nuclei show irregular membranes, overlap, grooves, indentations and chromatin clearing, which are sufficient criteria for the diagnosis of NIFTP (Hematoxylin-eosin, original magnifications of 40x (A and E), 400× (B), 200× (C, D and F).

Figure 3

Percentage of the mutations in FVPTC across different classifications: (A) Post-NIFTP era. (B) Percentage of mutations in the FTA and FTC samples after histological reclassification.