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Background: Molecular testing (MT) refines risk stratification for thyroid nodules that are indeterminate for cancer by fine needle aspiration (FNA) cytology. Criteria for selecting nodules for MT vary and remain largely untested, raising questions about the best strategy for maximizing the usefulness of MT while minimizing the harms of overtesting. We used a unique data set to examine the effects of repeat FNA cytology-based criteria for MT on management decisions and nodule outcomes. Methods: This was a study of adults (age 25-90 years; 281 women and 72 men) with cytologically indeterminate (Bethesda III/IV) thyroid nodules who underwent repeat FNA biopsy and Afirma Gene Expression Classifier (GEC) testing ( N  = 363 nodules from 353 patients) between June 2013 and October 2017 at a single institution, with follow-up data collected until December 2019. Subgroup analysis was performed based on classification of repeat FNA cytology. Outcomes of GEC testing, clinical/sonographic surveillance of unresected nodules, and histopathologic diagnoses of thyroidectomies were compared between three testing approaches: (i) Reflex (MT sent on the basis of the initial Bethesda III/IV FNA), (ii) SemiRestrictive (MT sent if repeat FNA is Bethesda I-IV), and (iii) Restrictive (MT sent only if repeat FNA is Bethesda III/IV) testing approaches. Results: Restricting MT to nodules that remain Bethesda III/IV on repeat FNA would have missed 4 low-risk cancers and 3 noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) (collectively 2% of the test population) but would have avoided diagnostic surgery for 42 benign nodules (12% of the test population). The Restrictive testing strategy was more specific (delta 0.126 confidence interval [CI 0.093 to 0.159] and 0.129 [CI 0.097 to 0.161], respectively) but less sensitive (delta -0.339 [CI -0.424 to -0.253] and -0.340 [CI -0.425 to -0.255], respectively) than the Reflex and SemiRestrictive approaches for detecting NIFTP or cancer. Conclusions: Repeat FNA cytology can guide the selection of cytologically indeterminate thyroid nodules that warrant MT. The Restrictive model of performing Afirma GEC only on nodules with two separate biopsies showing Bethesda III/IV cytology would reduce the rate of diagnostic surgery for histologically benign nodules while missing only rare low-risk tumors. Given the low but nontrivial risks of thyroidectomy, the higher specificity of the Restrictive testing approach disproportionately outweighs the potential harms.

Objectives: To analyze risk of malignancy (ROM) in Bethesda categories (BCs) and the impact of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) reclassification on malignancy risk and surgical outcome., Methods: In this retrospective study based on fine-needle aspiration samples with histologic follow-up, ROM was analyzed in BCs. Possible cases of NIFTP were reviewed, followed by the analysis of impact of this reclassification on ROM in BCs., Results: The incidence of NIFTP was 6.9% among excised thyroid nodules and 16.8% among all resected neoplastic lesions. ROM for BCs I to VI was 37.5%, 9.6%, 40.0%, 46.5%, 88.8%, and 96.8%, respectively. Risk of neoplasia was 50.0%, 13.8%, 55.0%, 71.2%, 88.8%, and 96.8% respectively. When NIFTPs were considered nonmalignant lesions, ROM decreased by 6.3%, 4.3%, 20%, 19.1%, 22.5%, and 1.5% in each Bethesda category (I-VI), respectively. Inability to diagnose NIFTP preoperatively led to overtreatment in 16.2%., Conclusions: Prevalence of NIFTP in Asian countries may be higher than expected. Substantial cases of NIFTP have a benign preoperative cytology; hence, cases of follicular adenoma and adenomatous colloid nodule should be included in the review. NIFTP reclassification has significantly reduced the ROM in indeterminate BCs, suggesting diagnostic lobectomy rather than total thyroidectomy. Countries should establish their own malignancy risk range and parameters., (© American Society for Clinical Pathology, 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: To determine the rate of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in a multi-institutional series from the Iberian Peninsula and describing this NIFTP cohort., Methods: Retrospective study of papillary thyroid carcinoma (PTC) or well-differentiated tumours of uncertain malignant potential (WDT-UMP) diagnosed between 2005 and 2015 and measuring ≥5 mm in adult patients from 17 hospitals. Pathological reports were reviewed to determine the cases that fulfil the original criteria of NIFTP and histology was reassessed. Rates were correlated with the number of PTC and its follicular variant (FVPTC) of each institution. Demographic data, histology, management, and follow-up of the reclassified NIFTP cohort were recorded., Results: A total of 182 cases with NIFTP criteria were identified: 174/3372 PTC (rate: 5.2%; range: 0-12.1%) and 8/19 WDT-UMP (42.1%). NIFTP rate showed linear correlation with total PTC (p: 0.03) and FVPTC (p: 0.007) identified at each centre. Ultrasound findings were non-suspicious in 60.1%. Fine-needle cytology or core biopsy diagnoses were undetermined in 49.7%. Most patients were treated with total thyroidectomy. No case had nodal disease. Among patients with total thyroidectomy, 89.7% had an excellent response evaluated 1 year after surgery. There were no structural persistence or relapses. Five patients showed residual thyroglobulin after 90 months of mean follow-up., Conclusions: NIFTP rate is low but highly variable in neighbouring institutions of the Iberian Peninsula. This study suggests pathologist's interpretation of nuclear alterations as the main cause of these differences. Patients disclosed an excellent outcome, even without using the strictest criteria.

Background: Molecular tests are being used increasingly as an auxiliary diagnostic tool so as to avoid a diagnostic surgery approach for cytologically indeterminate thyroid nodules (ITNs). Previous test versions, Thyroseq v2 and Afirma Gene Expression Classifier (GEC), have proven shortcomings in malignancy detection performance., Objective: This study aimed to evaluate the diagnostic performance of the established Thyroseq v3, Afirma Gene Sequencing Classifier (GSC), and microRNA-based assays versus prior iterations in ITNs, in light of "rule-in" and "rule-out" concepts. It further analyzed the impact of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) reclassification and Bethesda cytological subtypes on the performance of molecular tests., Methods: Pubmed, Scopus, and Web of Science were the databases used for the present research, a process that lasted until September 2020. A random-effects bivariate model was used to estimate the summary sensitivity, specificity, positive (PLR) and negative likelihood ratios (NLR), and area under the curve (AUC) for each panel. The conducted sensitivity analyses addressed different Bethesda categories and NIFTP thresholds., Results: A total of 40 eligible studies were included with 7,831 ITNs from 7,565 patients. Thyroseq v3 showed the best overall performance (AUC 0.95; 95% confidence interval: 0.93-0.97), followed by Afirma GSC (AUC 0.90; 0.87-0.92) and Thyroseq v2 (AUC 0.88; 0.85-0.90). In terms of "rule-out" abilities Thyroseq v3 (NLR 0.02; 95%CI: 0.0-2.69) surpassed Afirma GEC (NLR 0.18; 95%CI: 0.10-0.33). Thyroseq v2 (PLR 3.5; 95%CI: 2.2-5.5) and Thyroseq v3 (PLR 2.8; 95%CI: 1.2-6.3) achieved superior "rule-in" properties compared to Afirma GSC (PLR 1.9; 95%CI: 1.3-2.8). Evidence for Thyroseq v3 seems to have higher quality, notwithstanding the paucity of studies. Both Afirma GEC and Thyroseq v2 performance have been affected by NIFTP reclassification. ThyGenNEXT/ThyraMIR and RosettaGX show prominent preliminary results., Conclusion: The newly emerged tests, Thyroseq v3 and Afirma GSC, designed for a "rule-in" purpose, have been proved to outperform in abilities to rule out malignancy, thus surpassing previous tests no longer available, Thyroseq 2 and Afirma GEC. However, Thyroseq v2 still ranks as the best rule-in molecular test., Systematic Review Registration: http://www.crd.york.ac.uk/PROSPERO, identifier CRD42020212531., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Silaghi, Lozovanu, Georgescu, Georgescu, Susman, Năsui, Dobrean and Silaghi.)

Background: Thyroid neoplasms with follicular architecture can have overlapping morphologic features and pose diagnostic confusion among pathologists. Various immunohistochemical stains have been investigated as potential diagnostic markers for PTC, among which HBME1 and CK19 have gained popularity. Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) poses similar diagnostic challenges with interobserver variability and is often misdiagnosed as adenomatoid nodule or follicular adenoma. This study aims to evaluate expression of HBME1 and CK19 in NIFTPs in comparison to other well-differentiated thyroid neoplasms and benign mimickers., Method: Seventy-three thyroid cases diagnosed over a period of 3 years at Methodist University Hospital, Memphis, TN, USA, were included in this study: 9 NIFTP; 18 papillary thyroid carcinoma (PTC); 11 follicular variant of papillary thyroid carcinoma, invasive (I-FVPTC); 24 follicular adenomas (FA); and 11 multinodular goiters/adenomatoid nodules (MNG). A tissue microarray (TMA) was constructed and HBME1 and CK19 immunohistochemistry was performed., Results: 77.8% of NIFTPs, 88.9% of PTCs, 81.8% of I-FVPTCs, 16.7% of FAs, and 18.2% of MNGs showed HBME-1 expression. 66.7% of NIFTPs, 83.3% of PTCs, 81.8% of I-FVPTCs, 33.3% of FAs, and 45.4% of MNGs expressed CK19. Difference in expression of HBME1 and CK19 was statistically significant for NIFTP vs FA (qualitative; p < 0.05) and NIFTP vs MNG (p < 0.05). No statistically significant difference was found for HBME1 in NIFTP vs PTC (conventional and FVPTC), p ≥ 0.2. Sensitivity of HBME1 and CK19 for NIFTP were 78% and 67%, ~ 88% each for PTC, and 89% and 100% for FVPTC, respectively, while specificity of HBME1 and CK19 for NIFTP were 53% each, ~ 62% each for PTC, and ~55% each for FVPTC., Conclusion: Our study indicated that HBME1 and CK19 are valuable markers in differentiating NIFTPs from morphologic mimics like follicular adenoma and adenomatoid nodules/multinodular goiter. While HBME1 and CK19 are both sensitive in diagnosing lesions with PTC-like nuclear features, CK19 stains a higher number of benign lesions in comparison to HBME1. No increase in sensitivity or specificity in diagnosis of NIFTP, PTC, or FVPTC was noted on combining the two antibodies.

In 2016, encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) was reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). In 2018 the criteria for NIFTP were widened by the inclusion of the complete lack of papillae. Secondary criteria, which include molecular examination, are helpful but not required for NIFTP diagnose. The aim of this study was to assess the molecular background of NIFTP and to answer the question if the aplication of revised criteria for NIFTP diagnosis is associated with the lack of oncogenic mutation. Repeat histopathological assessment of 1117 cases of papillary thyroid carcinoma (PTC) from 2000-2016 was conducted. Using initial (2016) and revised (2018) diagnostic criteria, NIFTP was diagnosed in 23 and 13 patients respectively. 50 tumor genes hotspots mutation analysis was conducted. BRAF V600E mutations were detected in patients who fulfilled only initial NIFTP criteria. Other high-risk mutations ( TP53 ) were found in both groups of patients. The application of restrictive, revised diagnostic criteria for NIFTP negates the need for BRAF V600E examination, but these tumors still can harbor other high-risk oncogenic mutations nonetheless. Thus, molecular examination should be considered as a necessary step in NIFTP diagnostic process., Competing Interests: CONFLICT OF INTEREST The authors declare no potential conflicts of interest., (Copyright: © 2021 Kuchareczko et al.)

Introduction: Indeterminate thyroid cytology (ITC) occurs in 20% to 25% of cases, and the associated risk of malignancy ranges from 5% to 30%. The genomic classifier ThyroSeq (CBLPath/UPMC, Rye Brook, NY), a targeted next-generation sequencing technology, could classify ITC nodules as malignant and nonmalignant. We sought to characterize our institutional experience with ThyroSeq testing., Materials and Methods: We retrospectively identified all patients seen from January 2015 through November 2019 who had ITC nodules analyzed with ThyroSeq. Relevant clinical, pathologic, and resection data were reviewed., Results: Of the 133 cases identified, diagnostic categories included atypia (or follicular lesion) of undetermined significance) (n = 65 [48.9%]), suspicious for follicular neoplasm (SFN) (n = 48 [36.1%]), and suspicious for Hürthle cell neoplasm (n = 20 [15.0%]). About half of the papillary thyroid carcinoma (PTC) cases (n = 9 [56.3%]) and more than one-third of the noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) cases (n = 3/8 [37.5%]) were classified as SFN. Most patients (n = 87 [65.4%]) did not undergo resection; of these, 73 (83.9%) were negative for all molecular alterations. Of the 54 cases with molecular alterations, isolated RAS or RAS-like variants were most common (n = 35 [64.8%]); 9 (25.7%) were identified in PTC and 8 (22.9%) in NIFTP. NRAS was the most common alteration (n = 20 [37.0%]), followed by HRAS (n = 6 [11.1%]), which was mostly detected in NIFTP cases (n = 4 of 6 [66.7%])., Conclusion: Resection was avoided in 73 patients (54.9%) because of negative ThyroSeq results. ThyroSeq v2 and v3 offered a more accurate categorization of ITC nodules, improved patient management, and reduced unnecessary surgical procedures., (Copyright © 2021 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

The current edition of the WHO classification of thyroid tumors (2017) contains a number of very relevant changes with considerable consequences for the diagnostic assessment of thyroid specimens. This applies to both the histomorphological examination of surgical specimens and the preoperative fine needle biopsy (FNB). In addition, molecular pathological examinations are becoming increasingly important in the diagnosis of thyroid tumors. Changes affect practically all areas of thyroid tumor diagnostics. Some of these changes have far-reaching consequences that justify a comprehensive commentary and query of the knowledge acquired in the form of this CME article.

Introduction: Non-invasive follicular thyroid neoplasm with papillary-like features (NIFTP) is a recently characterized lesion with very low malignant potential. This has allowed for less aggressive management of this tumor subtype. Papillary thyroid carcinoma (PTC) has malignant potential and requires different considerations in management., Presentation of Case: A 33-year-old woman presented to our Thyroid Surgery Clinic with a left neck swelling slowly enlarging over 4 years, and recent right-sided neck pain. Neck ultrasound and fine needle aspiration for cytology found bilateral thyroid nodules, labelled as 'follicular lesion of undetermined significance' (FLUS). Final pathology report after total thyroidectomy identified four distinct tumors: bilateral NIFTP lesions and bilateral papillary microcarcinomas., Discussion: Management of NIFTP comprises partial or total thyroidectomy without further intervention. Management of PTC is the same but with the possible addition of radioactive ablation due to the increased malignant potential. This is the first report of bilateral NIFTP lesions and bilateral papillary microcarcinomas co-occurring together in the same patient, so management was challenging. The decision was made to give the patient low dose radioactive iodine ablation and continue monitoring. Ultrasound of the neck follow up 6 months later showed no residual thyroid tissue or local recurrence., Conclusion: Although rare, NIFTP can co-occur with PTC. Bilateral NIFTP with bilateral PTC is extremely rare. Surgeons and pathologists need to be aware of this rare entity that can co-occur in both thyroid lobes. Total thyroidectomy is the definitive treatment. Post-surgery surveillance is important and follow up needs to be watchful for any recurrence or metastasis., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: A subset of encapsulated/circumscribed follicular variant of papillary thyroid carcinoma (FVPTC) was reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in 2016 to reduce overtreatment of a low-risk tumor. Study objectives were to describe the epidemiology and long-term outcomes of NIFTP in a high-volume, urban, tertiary referral center. Methods: Among patients enrolled in the Boston Medical Center (BMC) Thyroid Cancer Registry, 110 cases of FVPTC underwent index thyroid surgery at BMC between 2000 and 2016. Historically, BMC pathologists assess all malignant nodules using sections ≤0.3 cm with evaluation of the entire nodule and capsule. After review of pathology reports to identify potential NIFTPs, slides were rereviewed using criteria established by the NIFTP Working Group in 2016 and 2018. We evaluated interobserver reliability using Cohen's Kappa coefficient. Results: Among 110 FVPTCs, 15 (13%) met NIFTP criteria; 11 women and 4 men, age range 31-64 (mean 47.5) years. Mean tumor diameter was 1.7 cm (compared with 2.2 cm for FVPTC). Among NIFTP cases, there were no lymph node metastases, distant metastases, or tumor recurrences. All NIFTP cases were American Thyroid Association (ATA) low risk compared with only 68% of FVPTC ( p  = 0.011). Among FVPTCs, 14% had positive lymph nodes at index operation. Four patients (4%) had distant metastases. Mean follow-up time was 46 and 69 months for FVPTC and NIFTP, respectively. Among FVPTCs with an excellent response to therapy (2015 ATA guidelines), there were no recurrences. Just over half ( n  = 8) of patients with NIFTP received postoperative radioactive iodine (RAI) therapy. Concordance between pathologists was high for ruling out NIFTP (75%), but only 36% for ruling in NIFTP. Overall, for NIFTP designation, Cohen's Kappa was 0.39, which is considered fair. Conclusions: Although this is a relatively small cohort, all NIFTP specimens underwent updated pathology review consistent with current guidelines; mean follow-up was nearly 6 years. NIFTP represents a small fraction of the total papillary neoplasia diagnosed at this tertiary referral center (2.3%). None of the NIFTP cohort experienced an adverse oncologic event, and there were no regional or distant metastases. Over 50% of patients with NIFTP received RAI. Thus, the NIFTP reclassification may substantially reduce the number of patients who require adjuvant therapies, such as completion surgery or RAI.

Context: US papillary thyroid carcinoma (PTC) incidence recently declined for the first time in decades, for reasons that remain unclear., Objective: This work aims to evaluate PTC incidence trends, including by histologic subtype and size, and noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)., Design: This descriptive study uses US Surveillance, Epidemiology, and End Results-18 cancer registry data (2000-2017)., Patients: Participants included individuals diagnosed with PTC (2000-2017) or NIFTP (2016-2017)., Results: During 2000 to 2015, PTC incidence increased an average 7.3% per year, (95% CI, 6.9% to 7.8%) during 2000 to 2009, and 3.7% per year (95% CI, 0.2% to 7.3%) during 2009 to 2012, before stabilizing in 2012 to 2015 (annual percentage change [APC] = 1.4% per year, 95% CI, -1.8% to 4.7%) and declining in 2015 to 2017 (APC = -4.6% per year, 95% CI, -7.6% to -1.4%). The recent declines were observed for all sizes of PTC at diagnosis. Incidence of follicular variant of PTC (FVPTC) sharply declined in 2015 to 2017, overall (APC = -21.1% per year; 95% CI, -26.5% to -15.2%) and for all tumor sizes. Observed increases in encapsulated papillary carcinoma (classical PTC subtype) and NIFTP each accounted for 10% of the decline in FVPTC. Classical PTC incidence continuously increased (2000-2009, APC = 8.7% per year, 95% CI, 8.1% to 9.4%; 2009-2017, APC = 1.0% per year, 95% CI, 0.4% to 1.5%), overall and for all sizes except smaller than 1 cm, as did incidence of other PTC variants combined (2000-2017, APC = 5.9% per year, 95% CI, 4.0% to 7.9%)., Conclusion: The reasons underlying PTC incidence trends were multifactorial. Sharp declines in FVPTC incidence during 2015 to 2017 coincided with clinical practice and diagnostic coding changes, including reclassification of noninvasive encapsulated FVPTC from a malignant to in situ neoplasm (NIFTP). Observed increases in NIFTP accounted for 10% of the decline in FVPTC., (Published by Oxford University Press on behalf of the Endocrine Society 2020.)

Background: Fine needle aspiration cytopathology (FNAC) is the most reliable tool for evaluating thyroid nodules. However, diagnosing Bethesda category III, atypia/follicular lesion of undetermined significance (AUS/FLUS), is a major limitation. The aim of this study was to evaluate the risk of malignancy (RoM) in AUS/FLUS nodules. A systematic review was also carried out analyzing the largest series., Methods: Totally 1750 cases (9%) diagnosed with AUS/FLUS were evaluated retrospectively out of 19 392 cases within last 13 years. All patients undergoing surgery for AUS/FLUS were included into the study. Histopathology results were correlated; the impact of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) diagnosis on RoM is evaluated., Results: Of the 280 patients (16%) undergoing surgery, neoplasia were detected in 177 (RoN:63.2%) and malignancy in 119 (RoM:42.5%) of these neoplasia. Follicular variant of papillary thyroid carcinoma (FVPTC) was the commonest malignancy (55.5%). Additional 58 (20.7%) nodules were neoplastic, of which 26 (9.3%) were encapsulated follicular tumors with unknown malignancy potential (FT-UMP) and 32 (11.4%) were follicular adenomas. The remaining 103 patients (36.8%) had non-neoplastic nodules. After reevaluation of the encapsulated FVPTC cases, 20 of them were NIFTP and RoM dropped to 35.4% with a relative decrease of 16.7% and an absolute decrease of 7.1%., Conclusion: In our series, 42.5% of nodules with AUS/FLUS were malignant; 63.2% of them were neoplastic. The RoM and RoN for AUS/FLUS nodules are still much higher than the revised expected RoM of international guidelines even after NIFTP cases excluded. Therefore, current recommendations should be reevaluated periodically in view of detailed clinicopathologic studies., (© 2020 Wiley Periodicals LLC.)

Background: The Bethesda System for Reporting Thyroid Cytopathology (BSRTC) standardizes thyroid cytopathology reporting in six tier diagnostic categories. In recent years, noninvasive encapsulated follicular variant of papillary thyroid carcinoma was reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). This study examines the impact of NIFTP on the BSRTC risk of malignancy (ROM)., Methods: This was a retrospective review of prospectively collected data from 565 patients who underwent fine needle aspiration and thyroidectomy at a single institution. ROM for each Bethesda category was analyzed and calculated with NIFTP classified as a malignant and nonmalignant lesion. Absolute and relative differences between ROM were compared., Results: Of 565 patients, 19 were Bethesda I, 159 were Bethesda II, 178 were Bethesda III, 46 were Bethesda IV, 42 were Bethesda V, and 121 were Bethesda VI. ROM differences with NIFTP classified as malignant versus nonmalignant for each class were as follows: Bethesda I, no change; Bethesda II, 18%-14%; Bethesda III, 55%-48%; Bethesda IV, 50%-35%; Bethesda V, 93%-91%; and Bethesda VI, 99%-98%. Absolute ROM differences for each category were as follows: Bethesda I, 0%; Bethesda II, 4%; Bethesda III, 7%; Bethesda IV, 15%; Bethesda V, 2%; and Bethesda VI, 1%., Conclusions: A decreasing trend in absolute and relative ROM was seen in Bethesda II, III, and IV categories; however, exclusion of NIFTP as a malignant lesion did not significantly alter the ROM of BSRTC categories. Surgeons should assess their respective institution's experiences with NIFTP and the BSRTC., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The thyroid is an unusual site for metastasis, and metastases in a preexisting primary thyroid tumor are exceedingly rare. We report the first case of a patient with colon cancer who was diagnosed with a thyroid metastasis in a noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). A 55-year-old male patient presented with a 19 mm thyroid nodule in the inferior left lobe. It was EU-TIRADS 5 on echography and suspicious of papillary thyroid carcinoma (Bethesda V) on cytology. Macroscopically, the nodule was fleshy and completely encapsulated. At frozen section examination, it demonstrated follicular architecture with mild atypia. Inside the nodule was a focus of tumor with glandular architecture, marked cellular atypia, and necrosis. These findings suggested a secondary malignancy. The patient's medical history was significant for metastatic colon cancer. The definitive histology showed features of metastatic colorectal adenocarcinoma within a NIFTP. Immunohistochemical studies were confirmatory with expression of CDX2 and CK20 localized to the metastatic focus. PAX8, TG, and TTF were negative in the metastasis but expressed in the surrounding NIFTP lesion. The possibility of a metastasis to the thyroid may be considered in patients presenting with a solitary thyroid nodule with a previous history of cancer. Metastatic colorectal adenocarcinoma occurring in a NIFTP has never been reported before now, although metastases to the thyroid are documented in the literature. In cases of a secondary malignancy to the thyroid, treatment is controversial.

Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was introduced as a separate entity by the World Health Organization in 2017 with strict inclusion and exclusion criteria.  Most NIFTP cases have been reported in adults and few cases have been diagnosed in children. Here, we present a classic case of NIFTP affecting a 10-year old female child. We also review previous reports of NIFTP in children regarding size, focality, nodal metastasis, recurrence, type of operation and follow-up data. The present report adds a new case of NIFTP in the paediatric age group characterized by multifocality, absence of nodal invasion and indolent course until last follow-up, recommending less aggressive management., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Abdou AG et al.)

Introduction: The Bethesda System for the Reporting of Thyroid Cytopathology (TBSRTC) is used to categorize and diagnose thyroid nodules by fine needle aspiration biopsy (FNAB). Each category in TBSRTC is associated with an estimated risk of malignancy (ROM). A subset of noninvasive encapsulated follicular variant of papillary thyroid carcinoma (niEFVPTC) was reclassified as a nonmalignant tumor: noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). We studied the impact of this reclassification on the reported ROM in TBSRTC., Material and Methods: We searched our institutional files for thyroid FNAB with surgical follow-up. ROM for each TBSRTC category was calculated. Subsequently, cases of niEFVPTC were reviewed and reclassified as NIFTP, if appropriate. ROM for each category was then recalculated after the reclassification., Results: Twenty-six NIFTP were identified; the corresponding FNABs were distributed among all six TBSRTC categories. The majority of NIFTP FNAB were in the AUS/FLUS and suspicious for malignancy (SUSP) categories, 12 (46.2%) and 8 (30.8%), respectively. While the ROM changed for all diagnostic categories, the greatest change in ROM after reclassification was seen in these two categories. Absolute ROM for AUS/FLUS decreased from 25.0% to 21.0% and SUSP, from 71.7% to 58.3%, changes that were statistically significant., Conclusions: The reclassification of niEFVPTC to NIFTP has significantly impacted the ROM in the TBSRTC at our institution. While there was a decrease in ROM for all categories, the greatest reduction to ROM was in the categories of AUS/FLUS and FN. These changes to the ROM should help guide surgical approach moving forward., (© 2020 Wiley Periodicals, Inc.)

The recently adopted terminology of "Noninvasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP) reflects the indolent behavior of these tumors. In contrast to conventional papillary thyroid carcinomas, NIFTP can be managed conservatively. The purpose of this study was to investigate changes in surgical and pathologic practice patterns at our institution since the introduction of the NIFTP diagnosis in 2016. A retrospective analysis of all thyroid specimens received in our laboratory between January 2015 and April 2017 was performed. The final cohort consisted of 1508 thyroidectomy specimens from 1508 patients (1153 (76.5%) women and 355 (23.5%) men), of which 1011 (67%) were total thyroidectomies and 497 (33%) were partial thyroidectomies. There were 558 (69.2%) total thyroidectomies and 248 (30.8%) partial thyroidectomies performed prior to introduction of the NIFTP diagnosis and 453 (64.5%) and 249 (35.5%) total and partial thyroidectomies, respectively, after the change in nomenclature. Within a year following the initial use of this diagnosis, 67 NIFTP cases were identified (9.5% of all thyroidectomies), whereas compared with the year preceding it, malignant diagnoses decreased from 54.5 (439) to 44.6% (313), and the benign category remained unchanged from 44.5 (367) to 45.9% (322). For the entirely submitted 67 NIFTP cases, the mean number of blocks submitted was 14.7 (0.98 blocks/g); for malignant lesions 17.7 (0.92 blocks/g); and for benign lesions 16.6 (0.75 blocks/g). The results of our study suggest that NIFTP are encountered in almost 10% of thyroidectomies at our institution with expected shifts in cytology and surgical pathology diagnoses as a result of the change in nomenclature. During this time period, significant shifts towards less aggressive surgical management were not observed. All 67 NIFTP nodules were submitted entirely with no significant difference in the number of cassettes submitted for NIFTP nodules as compared with follicular variant papillary thyroid carcinoma (PTC), classic variant PTC, or follicular adenoma.

Background: Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) lacks the carcinoma label, avoiding aggressive therapy, physiological, social and financial impact of cancer diagnosis. Unfortunately, the preoperative diagnosis is still a challenge. Varied incidence of NIFTP has been document with limited data on preoperative cytological, radiological characteristics and the impact on risk of malignancy in each category of the Bethesda system of reporting thyroid cytopathology., Method: Retrospective analysis of 20 NIFTPs with an attempt to provide a preoperative diagnostic algorithm based on the cytological and ultrasound features along with incidence and implication on risk of malignancy in various Bethesda categories with its impact on patient management., Result: Incidence of NIFTP in our study was higher in comparison to that documented from other Asian countries. TIRADS 3 was the most common sonographic diagnosis. NIFTP was commonly preceded by indeterminate or benign Bethesda category. Major impact of excluding NIFTP form malignant category was seen on Bethesda categories II and IV with 20% and 27% reduction in risk of malignancy, respectively., Conclusion: Retrospective analysis should not be confined only to follicular variant of papillary thyroid carcinoma but cases of follicular adenoma and adenomatous colloid nodule should always be included in review to ascertain the true incidence of NIFTP. NIFTPs are less likely to have malignant preoperative cytology. NIFTP shares major cytological and ultrasound features with follicular adenoma, adenomatous colloid nodule and minimally invasive follicular papillary carcinoma. When analyzed together, taking minor findings in consideration, can favor a diagnosis., (© 2019 Wiley Periodicals, Inc.)

Rigid diagnostic criteria for NIFTP have been recently proposed. The frequency of NIFTP using the new criteria is unknown, and whether abortive papillae are associated with BRAFV600E mutation has not been studied. The aim of this study is to identify NIFTP by a retrospective review of Follicular Variant of Papillary Thyroid Carcinoma (FVPTC), and to study its incidence as well as the association between immunohistochemical BRAFV600E expression and abortive papillae in NIFTP. Thyroid tumors diagnosed as FVPTC or NIFTP over a period of 18 years (2000–2017) were identified using the laboratory information system. The final pathology reports were reviewed and potential NIFTP were retrieved. The archived slides for these cases were independently reviewed by 2 pathologists. BRAFV600E (clone: VE1) immunostain was performed on representative tumor blocks. Clinical information including follow-up data was obtained from the electronic medical records. Among the 1918 cases with the diagnosis of papillary thyroid carcinoma (PTC), 589 (30.7%) of FVPTC and 136 cases of potential NIFTP were identified. After the review of the archived pathology slides, 29 lesions were morphologically reclassified as NIFTP. Four (13.7%) of these were positive for BRAFV600E; no association was found between the presence of abortive papillae and BRAFV600Eexpression (p =0.3). Exclusion of the 4 cases with BRAFV600Eexpression resulted in 25 lesions of final NIFTP, representing 4.2% of the FVPTC and 1.3% of the PTC. The mean age of the NIFTP patients was 50 years, 87.5% were females. The mean size of the lesions was 1.4 cm (0.1–4.0 cm). Intranuclear pseudoinclusions were not identified, and abortive papillae were identified in 60% of NIFTP. The average follow-up was 70 (28–166) months. There were no adverse events (recurrence or metastasis) in the NIFTP group. When strictly defined, NIFTP comprises 1.3% of cases perviously classified as PTC. In morphological NIFTP, no correlation is found between the presence of abortive papillae and the BRAFV600E expression. Intranuclear pseudo-inclusions are not observed in NIFTP. Modification of current morphological criteria to include BRAFV600E immunohistochemistry test may stratify NIFTP with benign outcome. • NIFTP is a rare lesion with a benign behavior when strict criteria are applied. • No correlation exists between the presence of abortive papillae and BRAFV600E mutation. • Intranuclear pseudo-inclusions are not observed in NIFTP. [ABSTRACT FROM AUTHOR]

Context: Non-invasive forms of encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) were reclassified as non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in order to reduce overtreatment. A few studies showed neck lymphadenopathy at diagnosis, or even distant metastasis in patients with NIFTP., Objective: Our aim was to report the frequency, clinical features and long-term progression of histologically confirmed NIFTP, using data from the French Marne-Ardennes thyroid cancer registry, and to compare findings against FVPTC., Methods: This was a retrospective study on data for follicular variant of PTC (FVPTC) diagnosed between 1975 and 2015 obtained from the specialized Marne-Ardennes thyroid cancer registry. Pathology reports were used to select appropriate cases from a large series, and FVPTC specimens were reviewed by endocrine pathologists. Strict diagnostic criteria were used for reclassification as NIFTP., Results: In total, 115 cases were reviewed histologically out of 383 cases of FVPTC. Sixty-five met all criteria for NIFTP and were consequently reclassified. Incidence of NIFTP was 16.9% of cases of FVPTC. Fifty patients were women (76.9%); median age was 47 years. Mean NIFTP size was 2.6 cm. There were no significant differences in age, gender or tumor size between NIFTP and FVPTC. Fifty patients underwent total thyroidectomy and 15 lobectomy. There were no lymph node metastases at diagnosis, and none of the patients (N=17) who underwent central and/or lateral neck dissection had positive findings on microscopic examination. 46 patients (70.8%) received radioiodine (RAI). Patients were followed up for 1.9-27.3 years (median 14.6 years) after initial treatment. All patients remained in complete remission during follow-up., Conclusion: Consistently with previous studies, our results showed the indolent course of NIFTP and that risk of recurrence after complete resection is very low (zero in our cohort), even when size is ≥4cm and in absence of adjuvant RAI treatment. Prospective studies are needed to confirm those results., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

The past half century has seen a number of advances in pathology of thyroid diseases, especially neoplastic lesions. These include the description of new entities, the definition of prognostically important lesions, the incorporation of fine needle aspiration biopsy and its functional risk stratification of diagnoses into the clinical evaluation and therapeutic recommendations of the patient with thyroid nodules and the understanding of thyroid neoplastic development, diagnostic and prognostic parameters by use of molecular analysis so that such techniques are becoming standard of care for patients with thyroid tumors. The histopathologist and cytopathologist have been and continue to be at the forefront in the definition and understanding of these areas of thyroid disease. This review describes many of the most important advances in this area in an attempt bring the practicing pathologist up to date in these developments., (Copyright © 2019 Elsevier Inc. All rights reserved.)

This article examines more uncommon thyroid entities, including anaplastic thyroid carcinoma, poorly differentiated thyroid carcinoma, rare papillary thyroid carcinoma variants, medullary thyroid carcinoma, non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), and multiple adenomatous nodules in the setting of Cowden syndrome. These entities were chosen based on their clinical significance and because they can be diagnostically challenging due to their morphologic diversity and overlap with other thyroid tumors. This article addresses the diagnostic features of each entity, focusing on how to avoid potential pitfalls and mimics while also highlighting the clinical implications of each diagnosis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is considered an indolent neoplasm of the thyroid. Currently, this entity presents a diagnostic challenge on preoperative fine-needle aspiration (FNA) cytology., Methods: Cases of NIFTP and noninvasive encapsulated follicular variant of papillary thyroid carcinoma from January 1994 to August 2018 were retrieved from our institution's pathology databases, and their clinical and cytopathologic features were reviewed., Results: A total of 45 patients with NIFTP were identified. Thirty-nine of 45 patients had presurgical thyroid FNAs, 27 of which showed abnormal cytology (27/39). NIFTPs were most often classified in the indeterminate diagnostic categories on presurgical FNAs (78%), including suspicious for follicular neoplasm (8/27), atypia of undetermined significance (8/27) and suspicious for malignancy (5/27). Six patients had a cytologic diagnosis of papillary thyroid carcinoma (6/27) on thyroid FNAs. Fourteen out of 27 cases with abnormal FNAs had in-house cytology available for review. The most frequent cytologic features observed in NIFTPs included architectural abnormalities, such as crowded clusters (13/14), nuclear overlapping (13/14), predominance or presence of individual microfollicles (11/14), and abundant to scattered isolated cells (10/14). The papillary-like nuclear features observed included nuclear enlargement (14/14), eccentric nucleoli (13/14), nuclear membrane irregularity (12/14), pale chromatin (12/14), nuclear grooves (10/14), and elongated nuclear contour (8/14)., Conclusions: The NIFTPs were most frequently categorized as atypia of undetermined significance and suspicious for follicular neoplasm on cytology. Recognition of the architectural and nuclear features of NIFTP can be helpful in distinguishing NIFTPs from other entities, such as papillary thyroid carcinoma and follicular neoplasms., (© 2019 Wiley Periodicals, Inc.)

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.

The recent description of noninvasive follicular tumor with papillary-like nuclear features (NIFTP) creates several diagnostic and therapeutic challenges for both the pathologist and the attending clinician. Given the concern about overtreatment of these neoplasms, the best way to manage the patients by a surgical procedure and postsurgical follow-up is still under discussion. We aimed to identify predictors of synchronous disease (eg, bilateral cancers) that can influence the appropriate type of surgery and long-term surveillance. We reevaluated the original diagnosis and the presence of contralateral lesions in 94 cases retrieved from our archives that were seen between 2010 and 2017. In 74 cases, the diagnosis was NIFTP, and in 20 cases, the diagnosis was infiltrative follicular variant of papillary thyroid carcinoma (IFVPTC). Bilateral disease was found in 17% of the cases. In 13 (18%) of those cases, NIFTP was the primary lesion, and in 3 (15%), it was IFVPTC. The contralateral disease was predominantly invasive: 6 cases of micropapillary carcinoma, 5 of papillary thyroid carcinoma, 3 of IFVPTC, and 2 of NIFTP. Despite the higher frequency of contralateral disease in NIFTP, there was no statistically significant difference with IFVPTC. In the patients with multifocal NIFTP, 2 (15%) of the contralateral malignancies showed microscopic extrathyroidal extension (P < .05). We conclude that close monitoring of the contralateral lobe is appropriate in patients with FVPTC, particularly NIFTP, if they are not submitted to total thyroidectomy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The re-naming of noninvasive follicular variant papillary thyroid cancer to the apparently non-malignant, noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) impacts the prevalence of malignancy rates, thereby affecting mutation frequency in papillary thyroid cancer. Preoperative assessment of such nodules could affect management in the future. The original publications following the designation of the new nomenclature have been extensively reviewed. With the adoption of NIFTP terminology, a reduction in the follicular variant of papillary thyroid cancer (FVPTC) prevalence is anticipated, as is a modest reduction of papillary thyroid cancer (PTC) prevalence that would be distributed mainly across indeterminate thyroid nodules. Identifying NIFTP preoperatively remains challenging. RAS mutations are predominant but the presence of BRAF V600E mutation has been observed and could indicate inclusion of the classical PTC. The histological diagnosis of NIFTP to designate low-risk encapsulated follicular variant papillary thyroid cancers (EFVPTCs) would impact malignancy rates, thereby altering the mutation prevalence. The histopathologic criteria have recently been refined with an exclusion of well-formed papillae. The preoperative identification of NIFTP using cytomorphology and gene testing remains challenging. [ABSTRACT FROM AUTHOR]

Cyclin D1 protein is aberrantly overexpressed in thyroid cancers, but mutations of the CCND1 gene are rare in these tumors. We investigated the CCND1 rs9344 (G870A) polymorphism and the expression profiles of wild-type CCND1a and shortened oncogenic isoform CCND1b at the mRNA and protein levels in 286 thyroid tumors. Genotype AA of rs9344 was associated with high expression of CCND1b mRNA and was more frequently found in thyroid cancer than in benign tumors. The mRNA expression levels of CCND1b were higher in papillary thyroid carcinoma (PTC) than in benign or other malignant tumors. However, the expression of CCND1a mRNA showed no association with the parameters. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was distinguished from PTC by low expression of CCND1b at mRNA and protein levels. We further observed that cyclin D1b immunostaining helped to avoid the misdiagnosis of classic PTC with predominant follicular pattern as NIFTP in a separate cohort. Nuclear cyclin D1b expression was associated with aggressive clinicopathologic features in PTC. These findings suggest that cyclin D1b overexpression can be used as a diagnostic and predictive biomarker in thyroid tumors and may be functionally involved in the development and progression of the disease. [ABSTRACT FROM AUTHOR]

The non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) and encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) are distinguished from classical papillary thyroid carcinoma with predominantly follicular architecture (CPTCPFA) by distinct histomorphologic and molecular features. CPTCPFA frequently harbor the oncogenic variant BRAFV600E while NIFTP and EFVPTC are largely RAS driven. CPTCPFA have rare papillae and intranuclear pseudoinclusions that may distinguish them from NIFTP or EFVPTC. We evaluated for BRAFV600E mutation using mutation-specific BRAF (VE1) antibody immunohistochemistry (BRAFVE) as part of an immunomorphologic tumor panel, often including HBME1, for follicular-patterned lesions with nuclear atypia. An archival search identified cases of NIFTP, CPTCPFA, or EFVPTC between 2015-2017, and demographic data, tumor characteristics, molecular data, and metastases were documented. Our search yielded 275 tumors across categories, and 208 were tested with BRAFVE. Sixty-one NIFTP and 31 sub-centimeter NIFTP were tested, and none (0/92) were positive for BRAFVE. Nineteen CPTCPFA and 14 sub-centimeter CPTCPFA were tested with 18 of 33 (54.5%) BRAFVE positive. Sixty-one EFVPTC and 21 sub-centimeter EFVPTC were tested, with 12 of 81 (14.8%) positive. Mean follow-up time was 1.5 years. Six (4.6%) patients with concurrent classical papillary thyroid carcinoma had local lymph node metastases at time of NIFTP diagnosis, as did 15 of 111 (13.5%) EFVPTC. Six of 34 (14.7%) CPTCPFA had local nodal metastases with five being considered the primary lesion. One EFVPTC (0.9%), BRAFVE negative, metastasized to femur. The findings indicate that BRAFVE used in conjunction with routine sampling of follicular-patterned tumors is a useful diagnostic adjuvant., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: Hürthle cell adenoma is a rare benign lesion of the thyroid gland, however, controversies about its potential malignant behavior still remain. Among thyroid neoplasms, papillary carcinoma is the most common variant with great variety of histological subtypes demonstrating different biological behavior., Aim: To raise the awareness of possible coexistence of these two lesions and discussion about possible therapeutic approaches., Case Report: A 42 year old female patient was examined because of the pain in the thyroid area. Cytological examination suggested Hürthle cell adenoma. Subsequently, right thyroid lobectomy was performed. Intraoperative frozen sections confirmed the diagnosis, yet final histological analysis revealed encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC), now reclassified as noninvasive follicular thyroid neoplasm with papillary- like nuclear features (NIFTP) within the adenoma, which was not noticed through scintigraphy, ultrasound, cytological and frozen section analysis., Conclusions: Problems concerning both diagnostic and therapeutic approach to these lesions are being discussed, since opinions reported in the literature are divided, posing great challenge for the clinician in determining adequate therapeutic procedures.

Genomic, clinical, and pathologic studies have prompted a more risk-stratified approach to the management of patients with thyroid nodules. The recent nomenclature change concerning noninvasive follicular thyroid neoplasm with papillary-like nuclear features reflects the clinical trend toward conservative treatment choices for carefully selected low-risk thyroid neoplasms. These developments have occurred in parallel with a growing array of molecular tests intended to improve clinical triage for patients with indeterminate fine needle aspiration diagnoses. This review discusses the implications of the nomenclature revision on the interpretation of thyroid fine needle aspiration and updates available ancillary molecular tests for thyroid fine needle aspirations., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Several Western studies showed that the recent introduction of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) significantly decreased risk of malignancy for cytological diagnostic categories. We aimed to determine the impact of NIFTP on risk of malignancy within a cohort of thyroid nodules from Asian countries, and to compare distribution of diagnostic categories between NIFTP and invasive encapsulated follicular variant of papillary thyroid carcinoma (eFV-PTC). Consecutive thyroid fine-needle aspirates from six institutions were retrospectively analysed. Histopathology slides with a diagnosis of eFV-PTC were reviewed and reclassified into invasive eFV-PTC and NIFTP. The risk of malignancy was calculated with and without NIFTP. Of 11,372 thyroid nodules, 2044 had available surgical follow-up. NIFTP was diagnosed in 59 cases, which constituted 2.9% of all excised nodules, and 5.3% of malignant nodules. Preoperative cytological diagnoses for NIFTP were non-diagnostic (10.2%), benign (18.6%), atypia of undetermined significance/follicular lesion of undetermined significance (22.0%), follicular neoplasm/suspicious for follicular neoplasm (FN/SFN) (32.2%), suspicious for malignancy (SM) (11.9%), and malignant (5.1%). The only category which showed a relative reduction in risk of malignancy after reclassification of more than 20%, was FN/SFN (24.4%). There was a significantly higher prevalence of benign cytology in NIFTP (p = 0.04) and SM/malignant in invasive eFV-PTC (p = 0.05). A majority of NIFTP cases were classified in indeterminate categories, which decreased the corresponding risk of malignancy. However, the magnitude of NIFTP impact was much lower than in the Western reports. Asian countries may not experience significant effects of NIFTP reclassification on the practice of thyroid cytopathology., (Copyright © 2018 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was recently proposed as a designation for a subset of follicular variant papillary thyroid carcinoma (FVPTC). Encapsulated FVPTC has been shown to be a fairly indolent tumor, and NIFTP are expected to represent the most indolent subset of these tumors. Many of the exclusion criteria for NIFTP related to architecture and a lack of psammoma bodies are designed to preclude the inclusion of more aggressive non-FVPTC tumors in this indolent group and also exclude the diagnosis of FVPTC. In addition to strict application of histologic features to ensure that NIFTP represents a subset of encapsulated FVPTC without invasion, other exclusion criteria including high mitotic activity and necrosis may also lead to a lack of one-to-one correlation between the diagnosis of NIFTP and encapsulated FVPTC without invasion. In this series, 50 cases previously diagnosed as FVPTC over a 2-year period from a large academic center are retrospectively reviewed for reclassification as NIFTP. Additionally, cases not meeting criteria for NIFTP are more accurately classified using the most up to date WHO criteria. Prior BRAF V600E mutation testing was examined for these tumors when available. Seventeen of 50 (34%) tumors met criteria for classification as NIFTP and, 17 (34%) were classified as encapsulated FVPTC with invasion. Strict application of architectural features led to classification of 12 (24%) tumors as non-FVPTC with a variety of more aggressive designations. Tumors classified as NIFTP and encapsulated FVPTC with invasion lacked lymph node metastases (0/4; 0/7, respectively) and BRAF mutations (0/12; 0/13, respectively). In contrast, infiltrative FVPTC, encapsulated PTC with or without invasion, and conventional PTC showed more aggressive features with lymph node metastases and BRAF V600E mutations. One case not meeting criteria for NIFTP maintained the diagnosis of encapsulated FVPTC without invasion but demonstrated significant mitotic activity (three mitoses/ten HPF) and lacked lymph node metastases and BRAF V600E mutation. These findings demonstrate the importance of using strict criteria, especially the lack of true papillary architecture, for the diagnosis of NIFTP and encapsulated FVPTC to ensure that only truly indolent tumors will be included in these diagnoses and to allow tumors with potential for more aggressive behavior to be appropriately treated.

Background: The noninvasive encapsulated follicular variant of papillary carcinoma (nEFVPTC) has recently been reclassified to "noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)," removing this entity from the malignant category. This re-categorization has had major implications for clinical management. NIFTP has overlapping cytohistologic features with papillary thyroid carcinoma (PTC) and with follicular adenomas (FA), but sonographic data comparing NIFTP to PTC and FA is lacking. Our study examines the sonographic features of NIFTP as compared with PTC and FA., Methods: Ultrasound scans and Doppler blood flow from subjects who had pre-surgical sonograms and fine needle aspiration biopsies with final surgical pathology diagnoses of NIFTP/nEFVPTC, classical PTC, and FA between 01/2013-08/2016 were assessed. Sonographic and Doppler features as well as Bethesda System (TBS) diagnoses were recorded and analyzed., Results: 40 NIFTP, 58 classical PTC, and 23 FA cases were included. The most common NIFTP pre-surgical TBS cytology diagnosis was Atypia of Undetermined Significance (AUS/FLUS) (40%). NIFTP cases predominantly displayed wider-than-tall shape (100%), smooth borders (75%), occurrence in multinodular glands (82.5%), heterogeneous echogenicity (50%), both perinodular and intranodular Doppler flow patterns (70%), minimal Doppler flow grade (62.5%), and no calcifications (90%)., Conclusions: Our study demonstrates that NIFTP, PTC, and FA display several distinguishing and overlapping sonographic and Doppler features. Sonographic features appear to complement cytology findings and may help raise pre-operative concern for NIFTP in the proper clinical setting, potentially leading to a more conservative management approach., (© 2017 Wiley Periodicals, Inc.)

Background: BRAF mutation status and prevalence of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) has not yet been reported in Korea. The aim of this study was to investigate the significance of the V600E mutation in the follicular variant of papillary thyroid carcinoma (FVPTC) and to determine the prevalence of NIFTP in BRAF V600E mutation in the follicular variant of papillary thyroid carcinoma (FVPTC) and to determine the prevalence of NIFTP in BRAF V600E mutation-prevalent Korean patients., Methods: This study retrospectively analyzed 1,417 consecutive patients who underwent total thyroidectomy with routine prophylactic central lymph node dissection for papillary thyroid carcinoma (PTC). BRAF V600E mutation-positive and -negative groups for FVPTC. Pathologists reviewed the pathology slides according to consensus diagnostic criteria for the encapsulated FVPTC and NIFTP.BRAF V600E mutation-positive and -negative groups for FVPTC. Pathologists reviewed the pathology slides according to consensus diagnostic criteria for the encapsulated FVPTC and NIFTP., Results: The prevalence of the BRAF V600E mutation in all subtypes of PTC was 61.0% (861/1,411). FVPTC presented a BRAF V600E mutation rate of 27.3%. The FVPTC patients with BRAF = 0.021). The prevalence of NIFTP was 0.18% among all PTC patients (2/1,411) and the proportion of NIFTP among FVPTC was 9.1% (2/22).V600E mutation were older than those with no BRAF V600E mutation ( P = 0.021). The prevalence of NIFTP was 0.18% among all PTC patients (2/1,411) and the proportion of NIFTP among FVPTC was 9.1% (2/22)., Conclusion: The BRAF V600E mutation and very low prevalence of NIFTP compared with that reported in western studies.BRAF V600E mutation and very low prevalence of NIFTP compared with that reported in western studies., Competing Interests: Disclosure: The authors have no potential conflicts of interest to disclose.

Papillary thyroid cancer (PTC), which accounts for 85-90% of all thyroid cancers, is generally an indolent tumor with long term survival rates >95%. A reliable definitive diagnosis of PTC is usually straightforward in fine needle aspirates of conventional PTC whenever the characteristic papillary and/or flat honeycomb sheet-like architecture and the typical nuclear features of chromatin pallor, nuclear enlargement, crowding, grooves and pseudoinclusions are encountered. Conventional PTC, however, has diminished in relative frequency as compared to PTC variants, especially the noninvasive follicular variant of PTC, an indolent tumor which has recently been reclassified as "noninvasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP). These PTC variants are characterized by various architecture, cell type and shape, and stromal features, some of which can be recognized cytologically. Awareness of the cytomorphological spectrum and of the characteristic cytological features of these PTC variants is important to avoid diagnostic pitfalls. In this article, we review the different variants of PTC, including their cytomorphologic features, differential diagnosis, and salient molecular features. Diagn. Cytopathol. 2017;45:714-730. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Among thyroid papillary carcinomas (PTCs), the follicular variant is the most common and includes encapsulated forms (EFVPTCs). Noninvasive EFVPTCs have very low risk of recurrence or other adverse events and have been recently proposed to be designated as noninvasive follicular thyroid neoplasm with papillary-like nuclear features or NIFTP, thus eliminating the term carcinoma. This proposal is expected to significantly impact the risk of malignancy associated with the currently used diagnostic categories of thyroid cytology. In this study, we analyzed the fine needle aspiration biopsy (FNAB) cytology features of 96 histologically proven NIFTPs and determined how the main nuclear features of NIFTP correlate between cytological and histological samples. Blind review of FNAB cytology from NIFTP nodules yielded the diagnosis of "follicular neoplasm" (Bethesda category IV) in 56% of cases, "suspicious for malignancy" (category V) in 27%, "atypia of undetermined significance/follicular lesion of undetermined significance" (category III) in 15%, and "malignant" (category VI) in 2%. We found good correlation (κ=0.62) of nuclear features between histological and cytological specimens. NIFTP nuclear features (size, irregularities of contours, and chromatin clearing) were significantly different from those of benign nodules but not from those of invasive EFVPTC. Our data indicate that most of the NIFTP nodules yield an indeterminate cytological diagnosis in FNAB cytology and nuclear features found in cytology samples are reproducibly identified in corresponding histology samples. Because of the overlapping nuclear features with invasive EFVPTC, NIFTP cannot be reliably diagnosed preoperatively but should be listed in differential diagnosis of all indeterminate categories of thyroid cytology., (Copyright © 2016 Elsevier Inc. All rights reserved.)