Noninvasive Follicular Thyroid Neoplasm With
Papillary-Like Nuclear Features (NIFTP): Implications for the Risk
of Malignancy (ROM) in the Bethesda System for
Reporting Thyroid Cytopathology (TBSRTC)
Haijun Zhou, MD, PhD1; Zubair W. Baloch, MD, PhD2; Ritu Nayar, MD1; Tommaso Bizzarro, MD3; Guido Fadda, MD, MIAC3; Deepti Adhikari-Guragain, MD2; Joseph Hatem, MD2; Luigi M. Larocca, MD3;
Julia Samolczyk, MD, MIAC1; Jamie Slade, MD1; and Esther Diana Rossi, MD, PhD, MIAC 3
BACKGROUND: The introduction of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) affects the risk of malignancy (ROM) mostly in the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) cat-egories. In this multi-institutional, retrospective study, the authors investigated variations in the impact of an NIFTP diag-nosis on the associated ROM for each TBSRTC category with an emphasis on the influence of pathologist and institutional diagnostic thresholds on the ROM. METHODS: Baseline data on cytology and histology diagnostic categories were collected over a 3-year period at 3 academic center hospitals (institutions A, B, and C). Histology slides for all cases diagnosed as follicular variant of papillary thyroid carcinoma (FVPTC) were re-reviewed at each institution, and those that qualifying as NIFTP were separated from other PTCs. RESULTS: The collective case cohort from the 3 institutions included 15,973 thyroid fine-needle aspiration cytology (FNAC) specimens and 5090 thyroid surgical resection specimens. Signifi-cant differences in baseline cytology and histology data were noted among the 3 institutions. The number of cases classi-fied as NIFTP compared with FVPTC was highly variable (institution A, 14%; institution B, 39%; and institution C, 12%). For 3250 resected thyroid nodules with a previous FNAC diagnosis, the average decrease in ROM after the exclusion of NIFTP for all TBSRTC categories was as follows: institution A, 9.8%; institution B, 3.9%; and institution C, 1.3%. CONCLUSIONS: The institutional frequency of NIFTP histopathology diagnosis and cytology baseline data will impact the ROM associated with specific FNAC diagnoses, especially among the indeterminate TBSRTC categories. The range of ROM for each TBSRTC diagnostic category is reflective of the inherent diagnostic thresholds and interobserver and interinstitutional var-iability in the diagnosis of thyroid lesions. Cancer Cytopathol 2018;126:20-6.VC2017 American Cancer Society.
KEY WORDS: Bethesda system; malignancy; noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP); risk of malignancy (ROM); thyroid nodules.
INTRODUCTION
Thyroid fine-needle aspiration cytology (FNAC) is an essential step for the evaluation and management of thyroid
nodules.1,2Currently, most thyroid FNAC specimens are classified based on various tiered classification schemes,
and the most is the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). This system includes 6
Corresponding author: Esther Rossi, MD, PhD, MIAC, Division of Anatomic Pathology and Histology, Fondazione Universitaria Policlinico “A.Gemelli,“ Universita Cattolica del Sacro Cuore, School of Medicine, Largo Francesco Vito, 1-00168 Rome, Italy; E-mail: esther.rossi@ policlinicogemelli.it
1
Department of Pathology, Northwestern University, Feinberg School of Medicine and Northwestern Memorial Hospital, Chicago, Illinois;2 Depart-ment of Pathology, Hospital of University of Pennsylvania, Philadelphia, Pennsylvania; 3
Department of Anatomic Pathology and Histology, “A. Gemelli” University Polyclinic Foundation, University Rome, Italy.
Presented in abstract form at the United States and Canadian Academy of Pathology (USCAP) 2017 Annual Meeting; March 4-10, 2017; San Antonio, Texas.
Received: July 7, 2017; Revised: August 17, 2017; Accepted: August 29, 2017 Published online September 20, 2017 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/cncy.21926, wileyonlinelibrary.com
diagnostic categories1,3-6 which are associated with a sug-gested risk of malignancy (ROM) and are used along with the clinical and radiologic impression for the subsequent
management of patients with thyroid nodules.1
The most common malignant tumor encountered in the thyroid is papillary thyroid carcinoma (PTC). It has been well documented in the literature that the incidence of PTC has nearly tripled over the past few decade, largely because of “incidentalomas” detected by the widespread use of imaging studies. The majority of these are small (ie, measuring < 1 cm), encapsulated, and of no biologic sig-nificance. There has also been an exponential, yet poorly reproducible rise in the histopathologic diagnosis of encap-sulated/noninvasive follicular variant of PTC (NI-FVPTC). However, unlike classic PTC or its other var-iants, the biologic behavior of NI-FVPTC is similar to that
of follicular adenoma,7,8 with virtually nonexistent
metas-tases and recurrences.9-11
The reclassification of NI-FVPTC into a low-risk neoplasm by a panel of endocrine experts has been a recent
hot topic in the medical literature and lay press.12-15The
new diagnostic term for NI-FVPTC, noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), is meant to convey the better prognosis of this variant and avoid overtreatment (ie, near-total
thyroidec-tomy and radioactive iodine treatment).16
Retrospective analyses have demonstrated that introduction of the NIFTP nomenclature has affected the ROM for each of the TBSRTC diagnostic catego-ries. Various institutions have demonstrated that, if NIFTP were no longer termed carcinoma, then there would be an appreciable decrease in the ROM for the TBSRTC diagnostic categories atypia of undetermined significance/follicular lesion of undetermined signifi-cance (AUS/FLUS), follicular neoplasm/suspicious for follicular neoplasm (FN/SFN), and suspicious for
malignancy (SM).17,18 This has raised well founded
concerns among cytopathologists regarding how to clas-sify follicular-patterned lesions that have the focal fea-tures of PTC on cytology and how this change in approach will affect downstream patient management.
In the current study, we add our multi-institutional, retrospective experience to the existing literature on the impact of reclassifying NIFTPs on the ROM for each diag-nostic Bethesda category. In addition, we also present how this change in ROM depends both on the pathologist and on the institutional diagnostic trends in the use of
TBSRTC cytology categories and subsequent histopatho-logic diagnosis.
MATERIALS AND METHODS
The case cohort comprised FNAC cases and thyroid resec-tion cases collected from 3 academic instituresec-tions: the Hos-pital of the University of Pennsylvania (Philadelphia, PA), Catholic University Hospital (Rome, Italy), and North-western University/NorthNorth-western Memorial Hospital (Chi-cago, IL; institution A, B, and C, respectively). Institutional review board approval was obtained at all the institutions.
At all 3 institutions, most thyroid nodules were eval-uated and biopsied under ultrasound guidance by clini-cians and radiologists. All FNAC specimens from Catholic University were processed using a liquid-based cytology method with ThinPrep 5000 processing (Hologic, Marl-borough, MA) and alcohol-fixed Papanicolaou stain; whereas, at the other 2 institutions, specimens were proc-essed as both air-dried Diff-Quick–stained and alcohol-fixed Papanicolaou-stained smears.
Thyroid FNAC cases from January 1, 2013, to December 30, 2015, were identified through a retrospec-tive laboratory database search at each institution and were classified according to TBSRTC as nondiagnostic (ND), benign, AUS/FLUS, FN/SFN, SM, or malignant (M). The thyroid resection cases for the same period were also collected and classified according to World Health Organi-zation diagnostic categories as adenomatoid nodule, follic-ular adenoma, follicfollic-ular carcinoma, PTC and its variants, or other benign and malignant lesions.
Cytologic-histologic correlation was performed by matching the FNAC-sampled nodule with the correspond-ing surgical follow-up diagnosis. Cases of incidental papil-lary thyroid microcarcinoma within the surgical resection specimen that were not the target of the FNAC were excluded from our analyses.
All surgical pathology reports with a diagnosis of FVPTC were analyzed. All cases that fit the description of NI-FVPTC were reviewed by 1 or more of the authors. NIFTP cases were identified from within the NI-FVPTC cohort(s) based on the sampling of the tumor (complete sub-mission of the tumor nodule) and diagnostic inclusion and
exclusion criteria.16The ROM for each TBSRTC diagnostic
category was calculated by dividing the total number of malig-nant cases by the number of cases that had surgical follow-up.
RESULTS
Institutional TBSRTC Rates and Thyroid Surgical Resection Pathology
All 3 institutions included in this study have a large volume of thyroid cytology specimens (see Table 1). In total, 15,973 thyroid FNAC cases were retrieved from the 3 institutions. The overall TBSRTC diagnostic category rates, irrespective of follow-up surgical resection at institu-tions A, B, and C were as follows: ND rate, 4%, 5%, and 6%, respectively; benign rate, 66%, 79%, and 75%, respectively; AUS/FLUS rate, 13%, 5%, and 9%, respec-tively; FN/SFN rate, 10%, 5%, and 3%, respecrespec-tively; SM rate, 2%, 2%, and 1%, respectively; and M rate, 5%, 4%, and 6%, respectively. The trends in the cytology reporting rate for nodules at each individual institution were quite comparable in 4 TBSRTC categories; however, the rates for AUS/FLUS and FN/SFN were significantly higher at institution A.
The 3-year thyroid resection pathology data from all 3 institutions, irrespective of prior cytology, were collected (Table 2). In total, 5090 thyroid surgical resection cases were retrieved, and the diagnostic rate for PTC in surgical pathology specimens for institution A, B, and C was 65%, 22%, and 41%, respectively. Of these, FVPTC as a per-centage of all PTC cases by report review was 34%, 46%, and 23% for institution A, B and C, respectively; and, on retrospective review of reports and slides, NIFTP as a per-centage of all FVPTC was 14%, 39% and 12%, respec-tively. It is noteworthy that institution B had a significantly lower rate of malignancy yield and PTC but much higher rates of FVPTC, NIFTP, and follicular ade-noma diagnoses.
NIFTP and ROM Decrease
In total, 3250 resected thyroid nodules had a previous, matched FNAC diagnosis from the 3 institutions (Table 3). Upon reclassifying the cases of NI-FVPTC as NIFTP, the impact on ROM varied widely among all 3 institu-tions. The greatest decrease in ROM was noted in the indeterminate categories AUS/FLUS, FN/SFN, and SM. The ROM decrease ranged from 5.2% to 15% for AUS/ FLUS, from 3.9% to 11.2% for FN/SFN, and from 0% to 26.8% for SM. At all 3 institutions, there was no change in the ROM (0%) for the ND category; the ROM
decrease was minimal (range, 0%-2.5%) for the benign TABLE
1. Intr oduction of the Ca tegory “Nonin v asiv e F ollicu lar T h yr oid Neoplasm W ith Papillary -Lik e Nuclear F eatur es” Decr eases the Risk of Malignancy for T h yr oid Bethes da Reporting Cat eg ories V ariously in Differ ent Insti tutions Fr om 2013 to 2015 Institu tion A Ins titution B Ins titution C TBSR TC Categ ories T ota l No . No . Malig nant Withou t NIFTP No. With NIFTP (%) RO M Decr eas e, % T otal No. No. Malign ant Witho ut NIF TP No . With NI FTP (%) ROM De cr ease, % T otal No. No. Mali gnan t Witho ut NIF TP No . With NIF TP (%) ROM Decr ease, % Nondiagnosti c 1 4 2 0 0.0 53 2 0 0.0 36 2 0 0.0 Benign 121 1 3 2.5 770 6 6 0.8 275 10 0 0.0 AUS/FLUS 133 20 20 15.0 353 19 26 7.3 97 30 5 5.2 FN/SFN 232 59 26 11.2 250 58 16 6.4 102 18 4 3.9 Suspicious 56 35 15 26.8 180 104 14 7.8 30 26 0 0.0 Malignant 135 130 4 3.0 158 151 7 4.4 255 250 1 0.4 T otal 691 247 68 (27.5) 9.8 1764 340 69 (3.9) 3.9 795 336 10 (1.3) 1.3 Abbreviations: AUS/FLUS, atypia o f undetermined significance/follicul a r lesion of undetermined significance; FN/SFN, follicular neoplasm/su spicio u s for follicular neoplasm; NIFTP , noninvasive follicular thyr oid neo-plasm with papillary-like nuclear features; ROM, risk o f malignancy; TBSRTC, the Bethesda System for Reporting Thyr oid Cytopathology .
category; and the ROM decrease was low (range, 0.4%-4/ 4%) for the M category. The total rate of ROM decrease varied from 9.8 % at institution A, to 3.9% at institution B, to 1.3% at institution C.
NIFTP and ROM Decrease in the Current Study and Literature Reports
The aggregate data from this study were compared with previously published reports and professional society
meet-ing abstracts (Table 4)17-24for thyroid nodules that had a
previous matched FNAC diagnosis. With the introduction of NIFTP, decreases in the ROM for cytology diagnostic categories were quite variable among different institutions.
For the Bethesda categories, the ROM decrease varied as follows: benign, 0% to 7.8%; AUS/FLUS, 3.3% to 17.6%; FN/SFN, 2% to 36%; SM, 0% to 41.5%; and M, 0% to 12.8%.
We also compared the previous matched FNAC diagnosis for the histopathology diagnosis of NIFTP, both in our current study and in previously published reports
(Table 5).17,18,23,25-28 For the benign category, NIFTP
correlations with prior FNA diagnosis varied widely (benign, 0%-30.4%; AUS/FLUS, 5.2%-61%; FN/SFN, 3.9%-40.6%; SM, 0%-41.5%; and M, 0%-12.7%).
DISCUSSION
Introduction of the new NIFTP nomenclature will have sig-nificant consequences for the management of patients with thyroid nodules. This diagnosis in itself describes a low-grade/low-risk neoplasm with a less than 1% chance of recurrence, as anticipated, and thus will prevent overtreat-ment (ie, near total thyroidectomy and radioactive iodine
ablation).16 Several published studies have demonstrated
that the exclusion of NIFTP from the M category will impact the preoperative cytologic diagnosis classified
TABLE 2. All 3 Institutions Have a Large Volume of Thyroid Fine-Needle Aspiration Specimens and Have Comparable Reporting Rates for the Bethesda System for Reporting Thyroid Cytopathology Categories in During 2013 Through 2015
No. of Specimens (%)
Diagnosis Institution A Institution B Institution C
Total FNA volume 3393 7544 5036
ND 138 (4) 379 (5) 329 (6) Benign 2234 (66) 5974 (79) 3780 (75) AUS/FLUS 428 (13) 358 (5) 428 (9) Neoplasm/SFN 339 (10) 376 (5) 149 (3) SM 72 (2) 147 (2) 31 (1) Malignant 172 (5) 310 (4) 283 (6) Abbreviations: AUS/FLUS, atypia of undetermined significance/follicular lesion of undetermined significance; FNA, fine-needle aspiration; FN/SFN, follicular neoplasm/suspicious for follicular neoplasm; ND, nondiagnostic; SM, suspicious for malignancy.
TABLE 3. Percentages of Noninvasive Follicular Thyroid Neoplasm With Papillary-Like Nuclear Features and Follicular Variant of Papillary Carcinoma Cases Vary Among Surgical Resection Diagnoses in 3 Institutions From 2013 to 2015
No. of Specimens (%)
Diagnosis Institution A Institution B Institution C
Total no. of resections 2120 1714 1256 All PTC 1368 (65) 386 (22) 529 (41) FVPTC among PTC 469 (34) 177 (46) 124 (23) NIFTP among FVPTC 66 (14) 69 (39) 15 (12) Follicular/Hurthle cell carcinoma 25 (1) 13 (1) 24 (2) Follicular/Hurthle cell adenoma 145 (18) 770 (43) 316 (25) Benign: Hyperplasia and other 449 (21) 595 (34) 387 (31)
Abbreviations: FVPTC, follicular variant of papillary thyroid carcinoma; NIFTP, noninvasive follicular thyroid neoplasm with papillary-like nuclear features; PTC, papillary thyroid carcinoma.
TABLE 4. Decrease in the Risk of Malignancy of the Bethesda System for Reporting Thyroid Cytopathology Categories if the Noninvasive Follicular Variant of Papillary Thyroid Carcinoma Is Retrospectively Considered as a Nonmalignant Neoplasm (now Noninvasive Follicular Thyroid Neoplasm With Papillary-Like Nuclear Features)
Percentage Decrease in the ROM of TBSRTC Categories
Study ND Benign AUS/FLUS FN/SFN SM M
Current study Institution A 0.0 2.5 15 11.2 26.8 3.0 Institution B 0.0 0.8 7.3 6.4 7.8 4.4 Institution C 0.0 0.0 5.2 3.9 0.0 0.4 Average 0 1.1 9.2 7.1 11.5 7.8 Literature review Faquin 201617 1.4 3.5 13.6 15.1 23.4 3.3 Strickland 201518 1.9 7.8 17.6 8.0 41.5 5.1 Lau 201719 0.0 5.0 16.0 36.0 32.0 1.0 Shahi 201720 N/A 1.7 10.1 7.7 9.1 1.1 Range 201721 0.0 0.0 5.0 2.0 24.0 0.0 Li 201722 0.0 1.2 3.3 5.9 2.3 0.6 Canberk 201623 6.5 1.0 15 20 24 11 Layfield 201724 0.0 3.6 2.3 2.5 17.0 12.8 Average 1.2 2.9 10.3 12.1 21.6 4.3 Abbreviations: AUS/FLUS, atypia of undetermined significance/follicular lesion of undetermined significance; FN/SFN, follicular neoplasm/suspicious for follicular neoplasm; M, malignant; ND, nondiagnostic; ROM, risk of malignancy; SM, suspicious of malignancy; TBSRTC, the Bethesda System for Reporting Thyroid Cytopathology.
according to TBSRTC.17,18,29,30 The most notable effect will be observed as a “decrease in ROM” in the indetermi-nate diagnostic categories of AUS/FLUS, FN/SFN, and SM.
In a study of 6943 patients from 5 academic institu-tions, Faquin et al demonstrated that the impact of NIFTP reclassification on the ROM was mostly relevant for the inde-terminate categories, including decreases ranging from 5.2% to 13.6% for AUS/FLUS; from 9.9% to 15.1% for FN/
SFN; and from 17.6% to 23.4% for SM.17 Howitt and
coworkers analyzed a series of 72 NIFTPs and observed the most significant decrease in the ROM (48.6%) in the SM
cat-egory.29Similar findings have been reported by Ustun et al30
In the current multi-institutional study, we also observed that the reclassification of NI-FVPTC as NIFTP decreased the ROM for the indeterminate categories (8.7% for AUS/ FLUS, 7.9% for FN/SFN and 10.9% for SM); however, the impact overall, and especially on the SM category, was signifi-cantly lower that than in many published studies.
It is important to note that, in the current study, we attribute the variable decrease in ROM to the considerable
variability in pathologists’ cytologic and histopathologic diagnostic thresholds and in clinicians’ thresholds for surgi-cal management. This is striking even, in institutions such as ours with a significant case load and experience in
thy-roid pathology (Table 4).17-24 According to the literature,
the majority of NIFTPs belong to the indeterminate cate-gories, and they were and are handled with suggestions for the specific diagnostic categories in TBSRTC. Indeed, as demonstrated by our results, the ROM variability is directly related to the rates of AUS/FLUS, FN/SFN, and SM on FNA cytology and the frequency of diagnosis of FVPTC and NI-FVPTC (now NIFTP) and follicular ade-noma in the follow-up surgical pathology specimens. In addition, the rates of ROM may also differ among institu-tions because of patient-specific demographics/history, radiologic features of biopsied nodules (low vs high suspi-cion), and thresholds for clinicians’ surgical management. In the current study, we did not analyze these factors.
The FVPTC rate as a percentage of all PTCs at insti-tutions A, B, and C was 34%, 46%, and 23%, respectively; and the follicular adenoma rate was 18%, 43%, and 25%, respectively. After a review of slides and reclassification of FVPTC, the NIFTP rate as a percentage of all FVPTCs was 14%, 39%, and 12%, respectively.
The reporting rate of NIFTP on histopathology is
quite variable in the published data,17,18,23,25-28which may
be caused by multiple factors, including patient demo-graphics, referral patterns, and the diagnostic threshold of individual cytopathologists and surgical pathologists. Cur-rently, FVPTC represents a significant proportion (approx-imately 15%-20%) of PTC diagnoses with increasing
incidence.7,12,13,18,31,32 With the nomenclature change
from NI-FVPTC to NIFTP, a significant fraction of these
PTCs will be excluded from classification as malignant.16
This will place a significant challenge on preoperative cytology diagnosis, because NIFTP is ultimately a histopa-thology interpretation, and its diagnosis is to be made after the application of strict inclusion and (more important) exclusion criteria. Although cytology features like high cel-lularity, greater nuclear enlargement, fewer grooves, etc, favor IFVPTC versus NIFTP, distinct reproducible cyto-logic diagnostic criteria are not available to differentiate
NIFTP from IFVPTC on cytology.26,27,33-35Therefore, it
is critical that pathologists review their personal and insti-tutional thresholds for TBSRTC diagnostic categories and closely monitor cytology quality-assurance measures, spe-cifically cytologic-histologic correlation, to avoid the stigma
TABLE 5. Correlation of Preceding Fine-Needle Aspiration Categories From the Bethesda System for Reporting Thyroid Cytopathology Diagnostic With the Percentage of Cases Retrospectively Classified as Noninvasive Follicular Variant of Papillary (now Noninvasive Follicular Thyroid Neoplasm With Papillary-Like Nuclear Features)
Percentage of Cases Classified Into TBSRTC Diagnostic Categories as
Nonin-vasive FVPTC (now NIFTP) at Follow-Up Study ND Benign AUS/FLUS FN/SFN SM M
Current study Institution A 0.0 2.5 15 11.2 26.8 3.0 Institution B 0.0 0.8 7.3 6.4 7.8 4.4 Institution C 0.0 0.0 5.2 3.9 0.0 0.4 Average 0 1.1 9.2 7.2 11.5 7.8 Literature review Strickland 201518 1.9 7.8 17.6 8.0 41.5 5.1 Faquin 201617 0.6 8.7 31.2 26.5 24.3 8.7 Baser 201625a 13 30.4 30.4 13 13 0 Bizzaro 201626 0 0 13.5 40.6 35.1 10.8 Ibrahim & Wu 201627 0 17 61 17 5 0 Maletta 201628 0 0 15 56 27 2 Canberk 201623 6 1.1 14.2 18.1 24.6 12.7 Average 3.07 9.28 26.1 25.6 24.3 5.6 Abbreviations: AUS/FLUS, atypia of undetermined significance/follicular lesion of undetermined significance; FN/SFN, follicular neoplasm/suspicious for follicular neoplasm; FVPTC, follicular variant of papillary thyroid carci-noma; M, malignant; ND, nondiagnostic; NIFTP, noninvasive follicular thy-roid neoplasm with papillary-like nuclear features; ROM, risk of malignancy; SM, suspicious of malignancy; TBSRTC, the Bethesda System for Report-ing Thyroid Cytopathology.
of increasing false-positive diagnoses. Similarly, those prac-ticing surgical pathology of the thyroid should review their grossing technique for encapsulated thyroid tumors and their relative thresholds for diagnosing follicular adenoma versus FVPTC.
In conclusion, the current study confirms the find-ings reported by others and highlights the inherent interin-stitutional differences in cytology and histology reporting of thyroid lesions and their potential corresponding effect on the suggested ROM associated with TBSRTC diagnos-tic categories. A range in decreased ROM among the TBRSTC categories is valid with the new terminology of NIFTP, but caution is warranted in making assumptions about the rate of decrease without considering the baseline cytology and histology reporting characteristics of an indi-vidual practice setting. In addition, it should be remem-bered that a follow-up finding of NIFTP after a cytology diagnosis does not equate to a completely benign lesion. It is a low-risk neoplasm, which portends an indolent clinical course with <1% chance of recurrence. Thus it may be important for future studies to consider a 3-pronged approach for cytologic-histologic correlation (benign, neo-plasm, and malignant) rather than the traditional binary approach of benign or malignant.
FUNDING SUPPORT
No specific funding was disclosed.CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.AUTHOR CONTRIBUTIONS
Haijun Zhou: Conceptualization, methodology, software, validation, formal analysis, investigation, resources, data curation, writing–original draft, writing–review and edit-ing, visualization, supervision, and project administration. Zubair Baloch: Conceptualization, formal analysis, writ-ing–review and editing, and supervision. Ritu Nayar: Conceptualization, methodology, validation, formal analy-sis, investigation, resources, data curation, writing–review and editing, visualization, supervision, and project admin-istration. Tommaso Bizzarro: Formal analysis, investiga-tion, resources, and data curation. Guido Fadda: Conceptualization, methodology, validation, resources, and supervision. Deepti Adhikari Guragain: Resources
and writing–review and editing. Joseph Hatem:
Investigation. Luigi M Larocca: Resources, writing–review and editing, and supervision. Julia Samolczyk: Data cura-tion. Jamie Slade: Investigation, writing–original draft, and writing–review and editing. Esther Diana Rossi: Con-ceptualization, methodology, software, validation, formal analysis, investigation, data curation, writing–original draft, writing–review and editing, visualization, and supervision. REFERENCES
1. Ali SZ, Cibas ES. The Bethesda System for Reporting Thyroid Cytopathology II. Acta Cytol. 2016;60:397-398.
2. Cooper DS, Doherty GM, Haugen BR, et al. Revised American Thyroid Association management guidelines for patients with thy-roid nodules and differentiated thythy-roid cancer. Thythy-roid. 2009;19: 1167-1214.
3. Ali SZ. Thyroid cytopathology: Bethesda and beyond. Acta Cytol. 2011;55:4-12.
4. Baloch ZW, Cibas ES, Clark DP, et al. The National Cancer Insti-tute Thyroid Fine Needle Aspiration State of the Science Confer-ence: a summation [serial online]. Cytojournal. 2008;5:6.
5. Bongiovanni M, Spitale A, Faquin WC, Mazzucchelli L, Baloch ZW. The Bethesda System for Reporting Thyroid Cytopathology: a meta-analysis. Acta Cytol. 2012;56:333-339.
6. Cibas ES, Alexander EK, Benson CB, et al. Indications for thyroid FNA and pre-FNA requirements: a synopsis of the National Can-cer Institute Thyroid Fine-Needle Aspiration State of the Science Conference. Diagn Cytopathol. 2008;36:390-399.
7. Baloch Z, LiVolsi VA, Henricks WH, Sebak BA. Encapsulated fol-licular variant of papillary thyroid carcinoma. Am J Clin Pathol. 2002;118:603-605; author reply 605-606.
8. Ghossein RA, Hiltzik DH, Carlson DL, et al. Prognostic factors of recurrence in encapsulated Hurthle cell carcinoma of the thyroid gland: a clinicopathologic study of 50 cases. Cancer. 2006;106: 1669-1676.
9. Vaccarella S, Dal Maso L, Laversanne M, Bray F, Plummer M, Franceschi S. The impact of diagnostic changes on the rise in thy-roid cancer incidence: a population-based study in selected high-resource countries. Thyroid. 2015;25:1127-1136.
10. Davies L, Morris LG, Haymart M, et al. American Association of Clinical Endocrinologists and American College of Endocrinology disease state clinical review: the increasing incidence of thyroid can-cer. Endocr Pract. 2015;21:686-696.
11. Pitoia F, Jerkovich F, Urciuoli C, et al. Implementing the modified 2009 American Thyroid Association risk stratification system in thyroid cancer patients with low and intermediate risk of recur-rence. Thyroid. 2015;25:1235-1242.
12. Rivera M, Tuttle RM, Patel S, Shaha A, Shah JP, Ghossein RA. Encapsulated papillary thyroid carcinoma: a clinico-pathologic study of 106 cases with emphasis on its morphologic subtypes (his-tologic growth pattern). Thyroid. 2009;19:119-127.
13. Baloch ZW, Shafique K, Flannagan M, Livolsi VA. Encapsulated classic and follicular variants of papillary thyroid carcinoma: com-parative clinicopathologic study. Endocr Pract. 2010;16:952-959. 14. Liu Z, Zhou G, Nakamura M, et al. Encapsulated follicular
thy-roid tumor with equivocal nuclear changes, so-called well-differen-tiated tumor of uncertain malignant potential: a morphological, immunohistochemical, and molecular appraisal. Cancer Sci. 2011; 102:288-294.
15. Piana S, Frasoldati A, Di Felice E, Gardini G, Tallini G, Rosai J. Encapsulated well-differentiated follicular-patterned thyroid carci-nomas do not play a significant role in the fatality rates from thy-roid carcinoma. Am J Surg Pathol. 2010;34:868-872.
16. Nikiforov YE, Seethala RR, Tallini G, et al. Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: a paradigm shift to reduce overtreatment of indolent tumors. JAMA Oncol. 2016;2:1023-1029.
17. Faquin WC, Wong LQ, Afrogheh AH, et al. Impact of reclassify-ing noninvasive follicular variant of papillary thyroid carcinoma on the risk of malignancy in The Bethesda System for Reporting Thy-roid Cytopathology. Cancer Cytopathol. 2016;124:181-187. 18. Strickland KC, Howitt BE, Marqusee E, et al. The impact of
non-invasive follicular variant of papillary thyroid carcinoma on rates of malignancy for fine-needle aspiration diagnostic categories. Thyroid. 2015;25:987-992.
19. Lau RP, Paulsen JD, Brandler TC, Simsir A, Zhou F. Impact of the reclassification of noninvasive encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) to noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) on the current management guidelines of the Bethesda System for Reporting Thyroid Cytopathology [serial online]. Mod Pathol. 2017;30:103A.
20. Shahi M, Yousaf H, Amin K, Li F. Impact of new nomenclature ”non-invasive follicular neoplasm with papillary like nuclear features“ on the Bethesda System for Reporting Thyroid Cytopa-thology (TBSRTC). An institutional experience [serial online]. Mod Pathol. 2017;30:116A.
21. Range DE, Harrison G, Jiang X. The impact of reclassification of encapsulated follicular variant of papillary thyroid carcinoma on the risk of malignancy in the Bethesda System for Reporting of Thyroid Cytopathology [serial online]. Mod Pathol. 2017;30:147A. 22. Li W, Smola B, Pang J, Lew M, Sciallis A, Jing X. Implementing
NIFTP may potentially impact the risk of malignancy for thyroid nodules categorized as FLUS and SFN [serial online]. Mod Pathol. 2017;30:104A.
23. Canberk S, Gunes P, Onenerk M, et al. New concept of the encapsulated follicular variant of papillary thyroid carcinoma and its impact on the Bethesda System for Reporting Thyroid Cytopa-thology: a single-institute experience. Acta Cytol. 2016;60:198-204. 24. Layfield LJ, Baloch ZW, Esebua M, Kannuswamy R, Schmidt RL.
Impact of the reclassification of the non-invasive follicular variant of papillary carcinoma as benign on the malignancy risk of the Bethesda System for Reporting Thyroid Cytopathology: a meta-analysis study. Acta Cytol. 2017;61:187-193.
25. Baser H, Topaloglu O, Tam AA, et al. Comparing clinicopatho-logic and radiographic findings between TT-UMP, classical, and non-encapsulated follicular variants of papillary thyroid carcinomas. Endocr Pathol. 2016;27:233-242.
26. Bizzarro T, Martini M, Capodimonti S, et al. Young Investigator Challenge: the morphologic analysis of noninvasive follicular thy-roid neoplasm with papillary-like nuclear features on liquid-based cytology: some insights into their identification. Cancer. 2016;124: 699-710.
27. Ibrahim AA, Wu HH. Fine-needle aspiration cytology of noninva-sive follicular variant of papillary thyroid carcinoma is cytomorpho-logically distinct from the invasive counterpart. Am J Clin Pathol. 2016;146:373-377.
28. Maletta F, Massa F, Torregrossa L, et al. Cytological features of “noninvasive follicular thyroid neoplasm with papillary-like nuclear features” and their correlation with tumor histology. Hum Pathol. 2016;54:134-142.
29. Howitt BE, Chang S, Eszlinger M, et al. Fine-needle aspiration diagnoses of noninvasive follicular variant of papillary thyroid carci-noma. Am J Clin Pathol. 2015;144:850-857.
30. Ustun B, Chhieng D, Prasad ML, et al. Follicular variant of papil-lary thyroid carcinoma: accuracy of FNA diagnosis and implica-tions for patient management. Endocr Pathol. 2014;25:257-264. 31. Gupta S, Ajise O, Dultz L, et al. Follicular variant of papillary
thy-roid cancer: encapsulated, nonencapsulated, and diffuse: distinct biologic and clinical entities. Arch Otolaryngol Head Neck Surg. 2012;138:227-233.
32. Otto KJ, Lam JS, MacMillan C, Freeman JL. Diminishing diagno-sis of follicular thyroid carcinoma. Head Neck. 2010;32:1629-1634. 33. Brandler TC, Zhou F, Liu CZ, et al. Can noninvasive follicular thyroid neoplasm with papillary-like nuclear features be distin-guished from classic papillary thyroid carcinoma and follicular adenomas by fine-needle aspiration? Cancer. 2017;125:378-388. 34. Strickland KC, Vivero M, Jo VY, et al. Preoperative cytologic
diag-nosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features: a prospective analysis. Thyroid. 2016;26:1466-1471. 35. Zhao L, Dias-Santagata D, Sadow PM, Faquin WC. Cytological, molecular, and clinical features of noninvasive follicular thyroid neoplasm with papillary-like nuclear features versus invasive forms of follicular variant of papillary thyroid carcinoma. Cancer. 2017; 125:323-331.
