Ultrasound and cytological characteristics of non-invasive follicular thyroid neoplasm with papillary-like nuclear features compared to papillary carcinomas

Journal Pre-proof Ultrasound and cytological characteristics of non-invasive follicular thyroid neoplasm with papillary-like nuclear features compared to papillary carcinomas ´ Lucie Boursier Sabelle Clerc Urmes Julie Garon Marc Klein Lea Demarquet

PII:

S0003-4266(20)30002-0

DOI:

https://doi.org/doi:10.1016/j.ando.2019.10.004

Reference:

ANDO 1149

To appear in:

Annales d’Endocrinologie

Please cite this article as: Boursier L, Urmes SC, Garon J, Klein M, Demarquet L, Ultrasound and cytological characteristics of non-invasive follicular thyroid neoplasm with papillary-like nuclear features compared to papillary carcinomas, Annales d’Endocrinologie (2020), doi: https://doi.org/10.1016/j.ando.2019.10.004

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Résumé Introduction : L’acronyme NIFTP, néoplasme folliculaire thyroïdien non invasif avec caractéristiques nucléaires du carcinome papillaire, anciennement variant folliculaire non invasif encapsulé du carcinome papillaire, a été retiré de la catégorie des carcinomes du fait de son caractère indolent et de son bon pronostic. Ce changement impacte la prise en charge clinique et chirurgicale puisque ces tumeurs ne nécessitent plus de thyroïdectomie totale, ni d’irathérapie complémentaire pour les tumeurs de moins de 4 cm. L’objectif de notre travail est d’identifier les différences préopératoires échographiques et cytologiques entre les NIFTP et les carcinomes papillaires (CPT). Matériel et méthodes : Cette étude rétrospective inclut 81 patients ayant bénéficié d’une thyroïdectomie totale ou d’une lobectomie avec un diagnostic histologique de carcinome papillaire, NIFTP ou de variant folliculaire invasif de carcinome papillaire, entre le 1er janvier 2016 et le 31 mai 2018. Les données de l’échographie et de la cytologie ont été analysées et comparées entre NIFTP et non-NIFTP (carcinome papillaire et variant folliculaire invasif de carcinome papillaire). Résultats : Quatorze NIFTP, 67 carcinomes papillaires, dont 20 variants folliculaires, ont été inclus. En comparaison aux carcinomes papillaires, les nodules correspondant à des NIFTP sont plus isoéchogènes (69,2 % vs 17,4 % ; p = 0,0007), présentent des contours réguliers (92,3 % vs 31,1 % ; p = 0,0001) et ont un score TI-RADS 2, 3 ou 4a. Sur le plan cytologique, les NIFTP se répartissent préférentiellement dans les catégories III, IV et V de la classification de Bethesda. Seule la présence de pseudo-inclusions nucléaires est ressortie comme significativement associée au groupe non NIFTP (p = 0,0031).

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Conclusion : Les NIFTP apparaissent majoritairement non suspects à l’échographie préopératoire et de signification indéterminée à la cytologie. Ces différences par rapport aux carcinomes papillaires peuvent permettre de suspecter le diagnostic en préopératoire et d’adapter au mieux la prise en charge chirurgicale.

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Abstract Introduction: NIFTP (non-invasive follicular thyroid neoplasm with papillary-like nuclear features, formerly non-invasive encapsulated follicular variant of papillary thyroid carcinoma) has been removed from the carcinoma category because of its indolent character and good prognosis. This change impacts clinical and surgical management, since these tumors no longer require total thyroidectomy, or complementary radioactive iodine therapy for <4-cm tumor. The aim of the present study was to identify preoperative ultrasound and cytological differences between NIFTP and papillary thyroid carcinoma (PTC). Materials and methods: A retrospective study included 81 patients who underwent total thyroidectomy or thyroid lobectomy with histologic diagnosis of PTC, NIFTP or invasive follicular variant of PTC (IFVPTC) between 1 January 2016 and 31 May 2018. Ultrasound and cytological data were analyzed and compared between NIFTP and non-NIFTP (PTC and invasive follicular variant of PTC). Results: Fourteen NIFTPs, 67 PTCs, including 20 IFVPTCs, were included. In comparison with nonNIFTP PTC, nodules in NIFTP were more often isoechoic (69.2% vs. 17.4%; P=0.0007), with smooth borders (92.3% vs. 31.1%; P=0.0001) and TI-RADS score 2, 3 or 4a. Cytologically, NIFTPs were mainly in categories AUS/FLUS, FN and SusM of the Bethesda System for Reporting Thyroid Cytopathology. Only nuclear pseudo-inclusions were significantly associated with non-NIFTP (P=0.0031).

Conclusion: NIFTP appears non-suspect on preoperative ultrasound and indeterminate on cytology. These differences with respect to PTC can guide diagnosis and surgical treatment. Mots clés Bethesda ; carcinome papillaire ; cytologie ; échographie ; néoplasme folliculaire thyroïdien non invasif avec caractéristiques nucléaires du carcinome papillaire (NIFTP) ; thyroïde Keywords: Bethesda System for Reporting Thyroid Cytopathology; cytology; non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP); papillary carcinoma; thyroid; ultrasonography

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Introduction

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Thyroid nodules are very common in the general population, with clinical prevalence of 6% in women and 1% in men [1]. If we include nodules discovered incidentally on ultrasound, prevalence increases from 19% to 68% [2]. The majority are benign, only 5% being malignant [3]. Ultrasound associated to fine-needle aspiration (FNA) biopsy characterizes the nodules and guides management. The incidence of thyroid cancer has increased in recent years, particularly for papillary thyroid carcinoma (PTC), which accounts for about 84% of thyroid cancers [4]. Many variants of papillary carcinoma have enriched the anatomopathological classification, constituting approximately 20% of papillary carcinomas. In 2016, Nikiforov et al. advocated replacing the non-invasive encapsulated follicular variant of papillary thyroid carcinoma (nEFVPTC) by “non-invasive follicular thyroid neoplasm with papillary-like nuclear features” (NIFTP), based on the indolent course and good prognosis of this subtype in the literature. This change removes NIFTP from the “carcinoma” category [5], impacting not only pre-surgical risk of malignancy [6,7] but also surgical and postsurgical management. The risk of malignancy in thyroid cytology decreased with the introduction of the concept NIFTP tumors, in particular for the cytological categories “Atypia or Follicular Lesion of Undetermined Significance” (III: AUS/FLUS), and “Suspicious for Follicular Neoplasm or Follicular Neoplasm” (IV: FN), “Suspicious for Malignancy” (V: SusM), on the 2017 Revision of the Bethesda System for Reporting Thyroid Cytopathology (BSRTC). In regard to surgical and post-surgical management, the American Thyroid Association (ATA) and French Societies guidelines propose conservative surgery by lobectomy in NIFTP tumors of less than 4 cm, with exhaustive study of the capsule, and no complementary radioactive iodine therapy [8]. For tumors longer than 4 cm, the guidelines propose optional adjuvant radioactive iodine therapy. Cervical ultrasound associated to thyroglobulin monitoring is recommended for follow-up. As conservative surgery by lobectomy is sufficient for NIFTP, it would be useful to distinguish preoperatively between NIFTP and PTC. Very few studies have attempted to compare ultrasound features between NIFTP and PTC. Hahn et al., in their retrospective study, highlighted the contribution of ultrasonography, which was superior to cytology in differentiating NIFTP from PTC. NIFTP shows non-suspect ultrasound characteristics: isoand hyperechoic, peripheral halo and absence of microcalcification [9]. Brandler et al. compared ultrasound features between NIFTP and PTC and follicular adenoma (FA): the ultrasound aspect of NIFTP was largely similar to that of FA, but differed from PTC, showing benign features such as smooth border, perinodular and intranodular Doppler flow pattern and absence of microcalcification [10]. On thyroid cytology, NIFTP can occur in all 6 BSRTC categories, but mainly in AUS/FLUS, FN and SusM [10,11]. This is why risk of malignancy changed more significantly in these categories with the introduction of NIFTP. In the study by Hahn et al., NIFTP was mainly found in the SusM category. According to Zaho et al., in 2017, comparing cytological results between NIFTP and invasive follicular variant of papillary carcinoma (IFVPTC), 54% of NIFTP cases were AUS/FLUS or FN versus only 28% of cases of IFVPTC. The aim of the present study was to identify ultrasound and cytological differences between NIFTP and PTC. Materials and methods The study was single-center, retrospective and descriptive. Patients Analysis included all patients undergoing thyroidectomy or lobectomy in the endocrinology and ENT surgery department of the University Hospital of Nancy (France) with histologic diagnosis of NIFTP, PTC or follicular variant of papillary carcinoma, between January 1, 2016 and May 31, 2018. PTC cases were excluded if < 1cm size. Patients under the age of 18 were also excluded. 81 patients were included. Method 2

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The following clinical and paraclinical data were collated: gender, age, individual history of cervical irradiation, family history of thyroid cancer, clinical signs of compression, and thyroid biological status (euthyroidism, hypothyroidism and hyperthyroidism). The following nodule ultrasound features were collated: size, echogenicity (hyperechoic, isoechoic, hypoechoic and very hypoechoic), Doppler flow pattern (perinodular, intranodular or both), presence or absence of microcalcifications, composition (solid or complex), border regularity, and TI-RADS classification. Fine-needle aspiration data comprised nodule BSRTC category and cytological features: nuclear enlargement, nuclear contour irregularities, nuclear clearing, incisure, pseudoinclusion, overlap, superposition, and very, moderately or poorly material cellular. Type of surgery and post-surgical complications (transient or permanent hypoparathyroidism, dysphonia or compressive hematoma) were collated from medical files. Statistical analysis The database was anonymized and encoded as an Excel workbook.

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Quantitative variables were expressed as mean and standard deviation and qualitative variables as numbers and percentages. Comparative statistical analyses for parametric tests were performed using Pearson chi-square test for qualitative variables and ANOVA (= Student t test) for quantitative variables. Comparisons between non-parametric variables were performed by Fisher exact tests for qualitative variables and Wilcoxon tests for quantitative variables. Analysis used SAS software, version 9.4 (SAS Institute, Inc., Cary, N.C.). P values <0.05 were defined as statistically significant. Results Main features One hundred and fifty five patients over 18 years of age with histologic diagnosis of thyroid cancer underwent total thyroidectomy or thyroid lobectomy in the endocrinology and ENT surgery department of Nancy University Hospital between January 1, 2016 and May 31, 2018. The 24 patients with histologic diagnosis of medullary thyroid cancer, follicular cancer, anaplastic cancer or poorly differentiated thyroid cancer were excluded. Fifty patients with papillary microcarcinoma (< 1cm) were also excluded. In total, 81 patients were included. There were 62 women (76.5%) and 19 men (23.5%), with a mean age of 48.1 years (median age, 48 years). Four had a risk factor for thyroid cancer: 3 with family history of thyroid cancer and 1 with history of cervical radiotherapy. Thus, 79.1% were euthyroid, 11.1% hypothyroid and 9.7% hyperthyroid. Histology results were distributed as follows: 14 NIFTPs (17.2%), 47 classical papillary carcinomas (58%), and 20 invasive follicular variants of papillary carcinoma (FVPTC), encapsulated or not (24.7%). Preoperative ultrasound findings, including TI-RADS and EU-TI-RADS scores, were available for 66 patients (81.4%) and cytology results for 60 (74%). Seventy-three patients (90.1%) underwent total thyroidectomy and 8 (9.9%) thyroid lobectomy. Surgery was complicated for 24 patients (29.6%), mainly in total thyroidectomy associated with lymph node dissection. Transient hypoparathyroidism was the most common post-thyroidectomy complication (14 patients), followed by recurrent paralysis (8 patients). NIFTP features The 14 NIFTPs were in 12 women and 2 men, with a mean age of 54.7 years. One patient had history of cervical radiotherapy. The majority of patients (11 patients) were euthyroid; 2 were hypothyroid. Mean tumor size on histology was 24 mm (range, 10-60 mm). 12 NIFTPs were treated by total thyroidectomy, 2 with associated lymph node dissection; 2 were treated by thyroid lobectomy. Preoperative ultrasound data were available in 13 cases: 9 nodules were isoechoic, 2 moderately hypoechoic and 1 very hypoechoic. One nodule had irregular borders; the others had smooth borders. There were no capsule invasions. The majority of nodules were solid. Microcalcifications were found in only 1 case. Two nodules were classified as TI-RADS 2, 6 as TI-RADS 3, 2 as TIRADS 4a and 3 as TI-RADS 4b. Preoperative cytological data were available for 11 cases. On the BSRTC classification, 1 nodule was category I (non-diagnostic: ND), 1 category II (benign), 3 category III (AUS/FLUS), 2 category IV (FN) and 4 category V (SusM); none were category VI (malignant).

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NIFTP versus non-NIFTP The non-NIFTP group included classical PTC and encapsulated or non-encapsulated IFVPTC. The general characteristics of the 2 groups are listed in Table 1. On ultrasound, NIFTP nodules were more often isoechoic (69.2% vs 17.4%) whereas non-NIFTP nodules were very hypoechoic (40% vs 7.7%). There was no significant difference in solid or mixed nodule composition between the 2 groups. Non-NIFTP nodules predominantly had irregular borders (68.9%) while NIFTP nodules had smooth borders (92.3%) (NIFTP vs. non-NIFTP: p=0.0001). A significant association was found between presence of microcalcifications and diagnosis of PTC (NIFTP vs. non-NIFTP: p=0.0014): microcalcifications were present in 58.1% of non-NIFTPs and in only 7.7% of NIFTPs. Doppler flow pattern was not significantly different between the 2 groups (NIFTP vs. non-NIFTP: p=0.4288). On the TIRADS classification, there was a significant difference (p <0.0001), with 84.5% of non-NIFTP nodules classified as 4b or 5, while 77% of NIFTPs were classified as 2, 3 or 4a, and none as TIRADS 5 (Table 2). On cytology, 6 non-NIFTPs and 1 NIFTP were classified as non-diagnostic (BSRTC category I). Most non-NIFTPs belonged to category V (49%) or VI (28.6%), and NIFTPs to category III (27.3%), IV (18.2%) or V (36.4%). Many cytological characteristics were compared between NIFTP and nonNIFTP, but only the only difference was for nuclear pseudo-inclusions, more often present in the non-NIFTP group (p=0.031).Total thyroidectomy predominated as treatment in both groups: 90.9% in non-NIFTP and 85.7% in NIFTP. Lymph node dissection was performed more frequently in nonNIFTP (p=0.037) (Table 3). Discussion Our study demonstrated that there are differences between NIFTP and papillary carcinoma, which may suggest that pre-surgical diagnosis could be derived from ultrasound and cytology findings. The proportion of NIFTPs was about 17%, in agreement with the literature [4,12]. Nodule echogenicity, irregular or smooth borders, TIRADS scores and Bethesda categories significantly differed between NIFTP and PTC. One of the first studies to suggest that NIFTP could be diagnosed in the pre-surgical stage was by Maletta et al., analyzing the histological and cytological features of 96 NIFTPs. The nuclear characteristics of NIFTP were similar on histology and cytology [13]. Rosario et al. analyzed the ultrasound and cytological features of NIFTP [12]. They retrospectively examined and classified 120 thyroid nodules corresponding to NIFTP according to the American Thyroid Association (ATA) and BSRTC; 58.3% were classified as moderately suspect, 32.5% as slightly suspect and only 5% as highly suspect on ATA score.

The present results agree with the literature regarding ultrasound features. According to Hahn et al., NIFTPs are more frequently iso- or hyper-echoic, with a peripheral halo and without microcalcification, as in our study. They also reported significantly fewer nodules classified as K-TI-RADS 5 (with strong suspicion of malignancy, equivalent to category TIRADS 5) in the NIFTP than in the non-NIFTP group. However, no NIFTP nodules were classified as TI-RADS 5 in the present study. Brandler et al. focused specifically on the ultrasound features of NIFTP in comparison with papillary carcinoma and follicular adenoma [10]. Microcalcifications were significantly associated with PTC. There was also a significant association between irregular borders and PTC, and between perinodular and intranodular Doppler flow and NIFTP. Conversely, contrary to the studies cited above and to the present study, echogenicity did not differentiate NIFTP from PTC, despite a tendency toward isoechoicity in NIFTP and hypoechoicity in PTC. Isoechoicity alone does not support diagnosis of NIFTP but, when associated with other ultrasound signs such as smooth borders and absence of microcalcification, it can suggest diagnosis of NIFTP before surgery. In the literature, NIFTP nodules appear in all 6 BSRTC categories but mostly in AUS/FLUS, FN and SusM [11,14]. Precisely, in the above-cited study by Rosario et al., more than 50% of nodules belonged cytologically to the indeterminate categories (AUS/FLUS and FN) and 25% showed cytology indicative of malignancy (SusM) [12], which was similar to the present results for the

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AUS/FLUS and FN categories, which accounted for about 45% of NIFTP nodules. We found a higher proportion of nodules “suspicious for malignancy” (category V), at 38%. Brandler et al. compared the cytology of 56 NIFTPs and 65 PTCs. NIFTPs were distributed as 37.5% AUS/FLUS, 26.8% FN and 17.9% SusM, while more than 80% of PTCs were “suspicious” [14]. In the present study, the proportion of SusM NIFTP nodules was higher, at 36.4%. Recently, a meta-analysis by Bongiovanni et al. showed that three-quarters of 915 cases of NIFTP were AUS/FLUS, FN or SusM [15]. In PTC, the rate of “suspicious” nodules in the present study was lower than in the literature. This can be explained by the association of classical papillary carcinomas and their invasive follicular variants in the same group. This predominant distribution of NIFTP nodules in BSRTC category SusM was also found by Hahn et al. Very few studies analyzed and compared the cytological features of NIFPT and PTC. Brandler et al. found significantly more nuclear pseudo-inclusions (86.6% vs. 8.9%), papillae (70.1% vs. 5.4%), nuclear crowding (98.5% vs. 82.1%), nuclear enlargement (98.5% vs. 83.9%), nuclear contour irregularities (46.3% vs. 10.7%), calcifications (46.3% vs. 10.7%) and nuclear grooves (88% vs. 35.7%). In the present study, only nuclear pseudo-inclusions were significantly associated with PTC (NIFTP vs. non-NIFTP: p= 0.031).

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Total thyroidectomy was the predominant treatment in the present series (90.3%), compared with thyroid lobectomy (9.6%). In Zaho et al.’s study, the proportion of lobectomy was greater: 54% of NIFTPs were treated by lobectomy [11].

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Conclusion The present study demonstrated that there are ultrasonographic and cytological differences between NIFTP and papillary carcinoma. NIFTP nodules are more often isoechoic (69.2%) with regular contours (92.3%) and with TIRADS score of 2, 3 or 4a. Cytologically, these nodules mainly belong to BSRTC categories of undetermined significance (AUS/FLUS and FN) (45.5%), although a third (36.4%) these nodules are "suspicious for malignancy" (SusM). Ultrasound and cytological features may help to suspect NIFTP preoperatively, but are insufficient to fully guide the surgical procedure. Recent advances in molecular mutation screening for micro-ARN expression might provide new diagnostic evidence that could be combined with ultrasound and cytology data to improve management. There is no doubt that in coming years decision-trees will combine these three types of data, leading to more conservative surgery. These results will have to be validated in prospective studies based on these preliminary data. No potential conflict of interest was reported. References [1]Vander JB, Gaston EA, Dawber TR. The significance of nontoxic thyroid nodules. Final report of a 15-year study of the incidence of thyroid malignancy. Ann Intern Med 1968;69(3):537‑ 40. [2]Guth S, Theune U, Aberle J, Galach A, Bamberger CM. Very high prevalence of thyroid nodules detected by high frequency (13 MHz) ultrasound examination. Eur J Clin Invest 2009;39(8):699‑ 706. [3] Wémeau J-L, Sadoul J-L, d’Herbomez M, Monpeyssen H, Tramalloni J, Leteurtre E, et al. Guidelines of the French society of endocrinology for the management of thyroid nodules. Ann Endocrinol 2011;72(4):251‑ 81. [4] Fagin JA, Wells SA. Biologic and Clinical Perspectives on Thyroid Cancer. N Engl J Med 2016;375(11):1054‑ 67. [5]Nikiforov YE, Seethala RR, Tallini G, Baloch ZW, Basolo F, Thompson LDR, et al. Nomenclature Revision for Encapsulated Follicular Variant of Papillary Thyroid Carcinoma. JAMA Oncol 2016;2(8):1023‑ 9. [6]Strickland KC, Howitt BE, Marqusee E, Alexander EK, Cibas ES, Krane JF, et al. The Impact of Noninvasive Follicular Variant of Papillary Thyroid Carcinoma on Rates of Malignancy for FineNeedle Aspiration Diagnostic Categories. Thyroid Off J Am Thyroid Assoc 2015;25(9):987‑ 92. [7] Lau RP, Paulsen JD, Brandler TC, Liu CZ, Simsir A, Zhou F. Impact of the Reclassification of « Noninvasive Encapsulated Follicular Variant of Papillary Thyroid Carcinoma » to « Noninvasive Follicular Thyroid Neoplasm With Papillary-Like Nuclear Features » on the Bethesda System for Reporting Thyroid Cytopathology: A Large Academic Institution’s Experience. Am J Clin Pathol 2017;149(1):50‑ 4.

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[8]Zerdoud S, Giraudet A-L, Leboulleux S, Leenhardt L, Bardet S, Clerc J, et al. Radioactive iodine therapy, molecular imaging and serum biomarkers for differentiated thyroid cancer: 2017 guidelines of the French Societies of Nuclear Medicine, Endocrinology, Pathology, Biology, Endocrine Surgery and Head and Neck Surgery. Ann Endocrinol 2017;78(3):162‑ 75. [9]Hahn SY, Shin JH, Lim HK, Jung SL, Oh YL, Choi IH, et al. Preoperative differentiation between noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) and non-NIFTP. Clin Endocrinol (Oxf) 2017;86(3):444‑ 50. [10] Brandler TC, Yee J, Zhou F, Cho M, Cangiarella J, Wei X-J, et al. Does noninvasive follicular thyroid neoplasm with papillary-like nuclear features have distinctive features on sonography? Diagn Cytopathol 2018;46(2):139‑ 47. [11] 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 Cytopathol 2017;125(5):323‑ 31. [12]Rosario PW, Mourão GF, Nunes MB, Nunes MS, Calsolari MR. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features. Endocr Relat Cancer 2016;23(12):893‑ 7. [13] Maletta F, Massa F, Torregrossa L, Duregon E, Casadei GP, Basolo F, 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‑ 42. [14]Brandler TC, Zhou F, Liu CZ, Cho M, Lau RP, Simsir A, et al. Can noninvasive follicular thyroid neoplasm with papillary-like nuclear features be distinguished from classic papillary thyroid carcinoma and follicular adenomas by fine-needle aspiration? Cancer Cytopathol 2017;125(6):378‑ 88. [15] Bongiovanni M, Giovanella L, Romanelli F, Trimboli P, et al. Cytological diagnoses associated with noninvasive follicular thyroid neoplasms with papillary-like nuclear features according to the Bethesda system for reporting thyroid cytopathology: A systematic review and meta-analysis. Thyroid 2019;29(2):222‑ 228

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Table 1. General characteristics of patients NIFTP and non-NIFTP Non-NIFTP n=67 n (%)

Total n=81 n (%)

12 (85.7%) 2 (14.3%) 54.7 +/- 19.4 1

50 (74.6%) 17 (25.4%) 46.8 +/- 15.3 0

62 (76.5%) 19 (23.5%) 48.2 +/- 16.2 1

0

3

3

1

Biologie Euthyroid

11

46

57 (79.2%)

.7229

Hypothyroid Hyperthyroid

2 0

6 7

/

5

Surgical Total thyroidectomy

Echogenicity Isoechoic Hyperechoic Hypoechoic Very hypoechoic Missing data Composition Solide

.1546 .17

/

/ /

/ /

/

/

20.8 +/- 14.4 17 (25.4%) 12 (17.9%)

21.4 +/-14.7 17 (21%) 12 (14.8%)

.4708 .0340

12 (85.7%) 2 (14.3%)

61 (91%) 6 (9%)

73 (90.1%)

.6239

8 (9.9%) 33 (40.7%)

.6239 .0373

NIFTP n=14 n (%)

Non-NIFTP n=67 n (%)

Total n=81 n (%)

p NIFTP vs nonNIFTP

9 (69.2%)

8 (17.4%)

17 (28.8%)

.0007

0

1 (2.2%)

1 (1.7%)

1

3 (23.1%) 1 (7.7%) 1

16 (34.8%) 22 (47.8%) 20

19 (32.2%) 23 (39%) 21 (25.9%)

.5172 .0099

8 (61.5%)

33 (71.7%)

41 (69.5%)

.5091

-p

/

/

8

/ 24 +/- 16.5

7

re

/

47

0 0

Thyroid lobectomy Lymph node dissection 2 (14.3%) 31 (46.3%) Legend: SD: Standard Deviation Statistically significant defined by p<.05 Table 2. Ultrasound features NIFTP vs non-NIFTP Study / Ultrasoun features

.5013

.6295 .3373

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Histologie Follicular variant Invasive encapsulated follicular variant Invasive follicular variant Classical papillary carcinoma Tumor size (mean +/-ET) (mm) Vascular embol Capsular invasion

p NIFTP vs nonNIFTP

8 (11.1%) 7 (9.7%)

lP

Main features Women Men age (mean +/-SD) (years) Cervical radiotherapy Family history of thyroid cancer

ro of

NIFTP n=14 n (%)

Study

.1142

/

7

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Doppler flow pattern perinodular mixed: perinodular and intranodular mostly intranodular Missing data

17 (28.8%)

1

2

21

23 (39%)

/

12 (92.3%) 1 (7.7%) 1

14 (31.1%) 31 (68.9%) 22

26 (44.8%) 32 (55.2%) 23 (39%)

1 (7.7%) 12 (92.3%) 1

25 (58.1%) 18 (41.9%) 24

26 (46.4%) 30 (53.6%) 25

3

9 (25%)

12 (28.6%)

3

20 (55.6%)

23 (54.8%)

0 8

7 (19.45) 31

7 (16.7%) 39 (48.1%)

/

22.9 +/- 13.2

24.3 +/- 13.9

.1002

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lP

Size 30 +/- 15.8 (mean +/-SD) (mm) TIRADS 2 (15.4%) 2 6 (46.2%) 3 2 (15.4%) 4a 3 (23.1%) 4b 0 5 1 Missing data Legend: SD: Standard Deviation Statistically significant defined by p<.05

ro of

No Missing data

13 (28.3%)

-p

Missing data Borders Smooth Irregular Missing data Microcalcifications Yes

4 (30.8%)

0 1 (2.2%) 6 (13.3%) 22 (48.9%) 16 (35.6%) 22

re

Mixed

2 (3.4%) 7 (12.1%) 8 (13.8%) 16 ( 27.6%) 25 (43.1%) 23 (39%)

.0001 /

.0014 /

.4288

<.0001

/

Table 3. Cytological features NIFTP vs non-NIFTP Study / Cytological features Bethesda System for Reporting Thyroid Cytopathology (BSRTC) I "non diagnostic" II "benign"

III “Atypia or Follicular Lesion of Undetermined Significance” IV “Suspicious for Follicular Neoplasm or Follicular Neoplasm” V “Suspicious for Malignancy” VI "malignant"

NIFTP n=14 n (%)

Non-NIFTP n=67 n (%)

Total n=81 n (%)

1 (9.1%) 1 (9.1%)

6 (12.2%) 3 (6.1%)

7 (11.7%) 4 (6.7%)

3 (27.3%)

1 (2%)

4 (6.7%)

p NIFTP vs nonNIFTP

.0045 2 (18.2%)

1 (2%)

3 (5%)

4 (36.4%)

24 (49%)

28 (46.7%)

0

14 (28.6)

14 (23.3%)

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Missing data

3

18

21

/

6 3

14 53

20 56

.4895

1 3

12 31

13 34

.1467

2 3

15 31

17 34

.2823

6 3

26 31

32 34

.2923

4 3

21 31

25 34

.3027

19 34

.0319

Nuclear enlargement Yes Missing data Superposition Yes Missing data

Yes Missing data Nuclear contours irregularities Yes Missing data

Yes Missing data

-p

Nuclear grooves

18 31

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lP

re

Pseudo-inclusions 1 Yes 3 Missing data Legend: SD: Standard Deviation Statistically significant defined by p<.05

ro of

Nuclear crowding

9

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