Non-Invasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features Is Not a Cytological Diagnosis, but It Influences Cytological Diagnosis Outcomes: A Systematic Review and Meta-Analysis

Abstract

Background: A low-risk thyroid tumour, non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was introduced in 2016. NIFTP criteria require a thorough histological examination to rule out capsular and lymphovascular invasion, which denies the possibility of preoperative cytological diagnosis. Nevertheless, since the adoption of the new entity, the cytology of NIFTP has been a subject of interest. Objectives: The present systematic review and meta-analysis investigate the cytological diagnosis of NIFTP. Method: An online PubMed literature search was conducted between March 1, 2020, and June 30, 2020, for all original articles considering the cytology of histologically proven NIFTP. The studies including data on fine needle aspiration specimens classified by The Bethesda System for Reporting Thyroid Cytology (TBSRTC) categories, risk of malignancy (ROMs) in the TBSRTC categories, and cytomorphological features of NIFTP were included in the meta-analysis. Non-English studies and case reports were excluded. The data were tabulated and statistical analysis was performed with Open Meta-Analyst program. Results: Fifty-eight studies with a total of 2,553 NIFTP cases were included in the study. The pooled prevalence of NIFTP cases was calculated among 25,892 surgically resected cases from 20 studies and the results show that NIFTP consisted 4.4% (95% confidence interval [CI]: 3.5–5.4%) of all cases. Most of the NIFTP cases (79.0%) belonged to the intermediate categories of TBSRTC. The pooled distribution of NIFTP cases in each TBSRTC category was 1.3% (95% CI: 0.8–1.7%) in non-diagnostic (ND), 8.9% (95% CI: 6.9–10.8%) in benign, 29.2% (95% CI: 25.0–33.4%) in atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS), 24.2% (95% CI: 19.6–28.9%) in follicular neoplasm (FN), 19.5% (95% CI: 16.1–22.9%) in suspicious for malignancy (SM), and 6.9% (95% CI: 5.2–8.7%) in malignant. Compared to pre-NIFTP era, the pooled risk differences of ROM were reduced by 2.4% in ND, 2.7% in benign, 8.2% in AUS/FLUS, 8.2% in FN, 7.3% in SM, and 1.1% in the malignant category. The cytomorphological features of NIFTP were similar to follicular variant of papillary thyroid carcinoma (FVPTC) but lesser to papillary thyroid carcinoma (PTC). Conclusions: Based on our results, NIFTP remains a histological diagnosis. Although cytomorphological features cannot be used in differentiating NIFTP from FVPTC, they may guide in separating NIFTP from PTC. Features such as papillae, microfollicles, giant cells, psammoma bodies, and the amount of papillary-like nuclear features should be taken into account when suspicious of NIFTP. NIFTP should not have papillae or psammoma bodies, and giant cells were rarely observed.

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

“…On the other hand, microfollicles were more frequent in NIFTP than in PTC. On nuclear level, chromatin clearing, contour irregularities, enlargement, grooves, and pseudoinclusions were statistically significantly more expressed in PTC cases than in NIFTP cases [ 67 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 ].…”

“…On contrary, FVPTC showed papillae, giant cells, nuclear elongation, enlargement, grooves and pseudoinclusions more frequently than NIFTP. Importantly, the presence of chromatin clearing, contour irregularities, crowding and psammoma bodies revealed no statistically significant differences between NIFTP and FVPTC cases [ 67 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 ].…”

“…In the majority of published series, NIFTP cases were placed in intermediate categories of TBSRTC, whereby 29.8% of cases are in atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), 28.0% in follicular neoplasm (FN) and 21.2% in suspicious for malignancy (SM) categories. However, 1.8% of the samples were categorized as non-diagnostic (ND) category, 10.2% as benign category and 8.4% as malignant category according to a meta-analysis conducted by Haaga et al [ 93 ]. Ruanpeng et al and Bongiovanni et al showed, in their meta-analyses, similar NIFTP cases distribution in TBSRTC categories: 3.6% and 3% cases were placed in ND category, 10.0% and 10% in benign category, 34.2% and 30% in AUS/FLUS category, 22.7% and 21% in FN category, 22.4% and 24% in SM category and 7.5% and 8% in malignant category [ 24 , 96 ].…”

“…In summary, ROMs decreased in the intermediate categories that are characterized by the high prevalence of histologically diagnosed FVPTC and NIFTP cases [ 97 , 98 , 99 , 100 ]. In a recent meta-analysis, pooled risk differences of ROM were performed in each TBSRTC category, independently resulting in the following reductions: 2.4% (I2 was 0%) in ND, 2.7% (I2 was 2%) in benign, 8.2% (I2 was 43%) in AUS/FLUS, 8.2% (I2 was 53%) in FN, 7.3% (I2 was 89%) in SM, and 1.1% (I2 was 45%) in malignant category when NIFTP was reclassified [ 93 ]. Similarly, Layfield et al conducted a meta-analysis of three published studies and their own data in 2017, which showed significantly lower ROM in all TBSRTC categories except for the ND category [ 101 ].…”

“…Interestingly, the risk differences of ROM were reduced by 2.6% (I2 was 0%) in ND, 2.7% (I2 was 0%) in benign, 4.7% (I2 was 0%) in AUS/FLUS, 6.0% (I2 was 45%) in FN, 1.8% (I2 was 29%) in SM and 0.3% (I2 was 28%) in malignant category in Asian countries in comparison to non-Asian countries with corresponding figures being 1.9% (I2 was 0%) in ND, 1.9% (I2 was 5%) in benign, 9.7% (I2 was 52%) in AUS/FLUS, 9.1% (I2 was 27%) in FN, 14.7% (I2 was 73%) in SM and 1.7% (I2 was 0%) in malignant category [ 93 ]. The differences between the Asian and non-Asian series were statistically significant in AUS/FLUS ( p = 0.023), FN ( p = 0.001) and malignant ( p = 0.008) categories, as revealed in meta-analysis by Haaga et al [ 93 ]. The thyroid pathology practice specificities and ethnic and mutational background contribute to the differences in Asian and non-Asian series [ 23 ].…”