Follicular Thyroid Neoplasm Research Articles

Impact of a genomic classifier on indeterminate thyroid nodules: an institutional experience

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. 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. 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%]). 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.

Expression of Matrix Metalloproteinases in Thyroid Follicular Neoplasm Fnab

Fine-Needle Aspiration Biopsy (FNAB) thyroid nodules is difficult to distinguish betwen follicular malignancy and follicular benign lesion (1). The diagnosis of malignancy can only be made from histopathology examination by examing tumor invation to capsule and vascular (2,3). Matrix Metalloproteinase 9 (MMP-9) examination can be added to help making initial diagnosis. MMP-9 is a proteolytic enzyme that plays important role in cancer progressivity, especially in thyroid. High MMP-9 expression will lead to earlier degradation of thyroid and its will make the cell metastasist easier (4). This study aims to examine MMP-9 expression of thyroid follicular neoplasm FNAB.
 We used 42 sample of follicular thyroid neoplasm FNAB obtained from the Pathology Anatomic laboratories in RSUP M Djamil Padang, West Sumatera. Immunohistochemical was staining with primary antibody MMP-9 then its expression were assessed in stroma and cytoplasmic tumour. In this study FNAB follicular thyroid nodules were found in the age group 21-45 years (57.1%), women (88.1%), and MMP-9 expression was found as much as 80.9%.

Follicular Lesions with Papillary Nuclear Characteristics: Differences in Chromatin Detected by Computerized Image Analysis.

Follicular lesions of the thyroid with papillary carcinoma nuclear characteristics are classified as infiltrative follicular variant of papillary thyroid carcinoma-FVPTC (IFVPTC), encapsulated/well demarcated FVPTC with tumour capsular invasion (IEFVPTC), and the newly described category "non-invasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP) formerly known as non-invasive encapsulated FVPTC. This study evaluated whether computerized image analysis can detect nuclear differences between these three tumour subtypes. Slides with histological material from 15 cases of NIFTP and 33 cases of FVPTC subtypes (22 IEFVPTC, and 11 IFVPTC) were analyzed using the Image J image processing program. Tumour cells were compared for both nuclear morphometry and chromatin textural characteristics. Nuclei from NIFTP and IFVPTC tumours differed in terms of chromatin textural features (grey intensity): mean (92.37 ± 21.01 vs 72.99 ± 14.73, p = 0.02), median (84.93 ± 21.17 vs 65.18 ± 17.08, p = 0.02), standard deviation (47.77 ± 9.55 vs 39.39 ± 7.18; p = 0.02), and coefficient of variation of standard deviation (19.96 ± 4.01 vs 24.75 ± 3.31; p = 0.003). No differences were found in relation to IEFVPTC. Computerized image analysis revealed differences in nuclear texture between NIFTP and IFVPTC, but not for IEFVPTC.

Pathology and molecular profile of differentiated thyroid carcinoma

The clinical term of differentiated thyroid carcinoma (DTC) includes follicular (FTC) and papillary thyroid carcinomas (PTC). In diagnostic thyroid pathology, however, the term differentiated carcinoma (NOS) is used only very rarely for tumors with morphological features of both FTC and PTC. The current World Health Organization (WHO) classification of thyroid tumors introduced the entity of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). As aresult, the diagnostic criteria for PTC had to be adjusted (compulsory histological demonstration of invasion and/or papillae), which also significantly limited the diagnostic potential of a fine needle biopsy (FNB) of the thyroid. The FTC is now divided into three distinct subgroups. Moreover, the WHO classification also established the diagnostic criteria of poorly differentiated thyroid carcinoma (PDTC), which has to be distinguished from both differentiated carcinomas and benign adenomas. This article also summarizes the current diagnostic status of molecular pathological analyses of thyroid tumors.

Reciprocal Dysregulation of MiR-146b and MiR-451 Contributes in Malignant Phenotype of Follicular Thyroid Tumor.

Over the last few years, incidental thyroid nodules are being diagnosed with increasing frequency with the use of highly sensitive imaging techniques. The ultrasound thyroid gland examination, followed by the fine-needle aspiration cytology is the standard diagnostic approach. However, in cases of the follicular nature of nodules, cytological diagnosis is not enough. Analysis of miRNAs in the biopsy presents a promising approach. Increasing our knowledge of miRNA’s role in follicular carcinogenesis, and development of the appropriate the miRNA analytical technologies are required to implement miRNA-based tests in clinical practice. We used material from follicular thyroid nodes (n.84), grouped in accordance with their invasive properties. The invasion-associated miRNAs expression alterations were assayed. Expression data were confirmed by highly sensitive two-tailed RT-qPCR. Reciprocally dysregulated miRNAs pair concentration ratios were explored as a diagnostic parameter using receiver operation curve (ROC) analysis. A new bioinformatics method (MiRImpact) was applied to evaluate the biological significance of the observed expression alterations. Coupled experimental and computational approaches identified reciprocal dysregulation of miR-146b and miR-451 as important attributes of follicular cell malignant transformation and follicular thyroid cancer progression. Thus, evaluation of combined dysregulation of miRNAs relevant to invasion and metastasis can help to distinguish truly malignant follicular thyroid cancer from indolent follicular adenoma.

Weight of Evidence and Human Relevance Evaluation of the Benfluralin Mode of Action in Rats (Part II): Thyroid carcinogenesis

Benfluralin is an herbicide of the dinitroaniline class used to control grasses and weeds. In a 2 year dietary study in rats, benfluralin increased incidences of thyroid follicular adenoma and carcinoma at high dietary concentrations (≥2500 ppm). The benfluralin toxicology database suggests the mode of action (MOA) is initiated by induction of liver metabolizing enzymes, particularly thyroid hormone specific UGTs, a major pathway for T4 clearance in rats. As reported with phenobarbital, this effect triggers negative feedback regulation, increasing thyroid stimulating hormone (TSH) release into circulating blood. When sustained over time, this leads to thyroid changes such as follicular hypertrophy, hyperplasia and thyroid follicular tumors with chronic exposures. The described MOA was previously established in rat studies with various chemical activators of xenobiotic receptors in the liver. It is generally considered as non-relevant in humans, due to differences between humans and rats in T4 turnover and susceptibility to this carcinogenic MOA. A structured methodology based on the IPCS/MOA/Human Relevance framework was used in the evaluation of available benfluralin data, and the conclusion was determined that the carcinogenic potential of benfluralin in the thyroid is not relevant in humans.

High risk of malignancy in cases with atypia of undetermined significance on fine needle aspiration of thyroid nodules even after exclusion of NIFTP.

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. 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. 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%. 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.

“Not Just Any Thyroid Follicular Tumor”

“Not Just Any Thyroid Follicular Tumor”

Minimally invasive video-assisted thyroidectomy in Asian patients: experience from Singapore.

Minimally invasive video-assisted thyroidectomy (MIVAT) although well established in Europe has not yet gained widespread acceptance in Asia. We describe our learning experience in the first reported series of 105 cases from Singapore. A retrospective analysis of outcomes in 105 patients who underwent MIVAT from April 2011 to 2018 was performed. The inclusion criteria were - symptomatic benign thyroid pathologies and follicular lesions or neoplasms needing a hemi-thyroidectomy. A thyroid lobe volume less than 35 mL was used as cut-off. Patients underwent surgeon-performed thyroid ultrasound with biopsy of solid nodules. All cases were operated by one surgeon using standard Miccoli technique with energy device used in all cases. From a total of 424 patients with nodular goitres undergoing thyroidectomy, 105 (24%) symptomatic eligible patients underwent the MIVAT procedure (M:F - 23:82). The mean incision lengths at start and completion were 1.7 cm (range 1.5-2 cm) and 2.4 cm (range 2-2.7 cm), respectively. Mean operating time was 97 min (range 59-160 min). There were four conversions (3.8%) in the first 25 cases and four patients (3.8%) experienced transient hoarseness with full recovery. Visual analogue pain scores at 6 and 24 h post-operatively were 2.7 and 1.1, respectively. Scar satisfaction was reported as excellent (75%), satisfactory (23%) and poor (2%). Although technically more demanding, MIVAT is a safe and useful operation in a thyroid surgeon's armamentarium. The limitation of goitre size, however, allows only a small percentage of symptomatic patients to undergo this procedure.

Clinical progress of noninvasive follicular thyroid neoplasm with papillary-like nuclear features

Clinical progress of noninvasive follicular thyroid neoplasm with papillary-like nuclear features

The importance of risk of neoplasm as an outcome in cytologic-histologic correlation studies on thyroid fine needle aspiration.

The introduction of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) altered the practice of thyroid pathology and reduced the risk of malignancy (ROM) associated with the indeterminate categories in the Bethesda system for reporting thyroid cytopathology (TBSRTC). It has been proposed that the evaluation of the risk of neoplasm (RON) is important in cytologic-histologic correlation studies. A total of 5224 thyroid aspirates were performed at our institution during an 8-year period. Of the 1475 cases (28%) with surgical follow-up, the histologic diagnoses comprised benign non-neoplastic (BNN, n = 669), follicular adenoma (FA, n = 188), NIFTP (n = 42), papillary microcarcinoma (PMC) (n = 223), and malignant neoplasm excluding PMC (n = 353). The RON was calculated to include neoplasia with low risk biologic behavior (FA, NIFTP, PMC) and malignant neoplasms. In contrast, the ROM was reserved for malignant neoplasms excluding PMC. The RON for each TBSRTC category was: nondiagnostic (ND) 38.3%, benign 20.9%, atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) 63.2%, follicular neoplasm or suspicious for follicular neoplasm (FN/SFN) 83.9%, suspicious for malignancy (SFM) 94%, and malignant 100%. The ROM excluding PMC was: ND 14%, benign 1.6%, AUS/FLUS 17.8%, FN/SFN 28.4%, SFM 84.4%, and malignant 99.5%. The RON and ROM support the recommended management guidelines from TBSRTC for all categories, except for FN/SFN. Histopathologic follow-up of FN/SFN aspirates in our study contain a very high rate of neoplasm (83.9%), which might support the management preference of conservative surgery.

Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features: Epidemiology and Long-Term Outcomes in a Strictly Defined Cohort.

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.

Correlation of ThyroSeq Results with Surgical Histopathology in Cytologically Indeterminate Thyroid Nodules.

The ThyroSeq next-generation sequencing test refines the risk of malignancy in cytologically indeterminate thyroid nodules. Specific genetic alterations have distinct cancer probabilities and clinical phenotypes. There is limited data on the association between specific genetic alterations and histopathologic features. The aim of this study was to evaluate specific ThyroSeq alterations in prognosticating high-risk histopathologic characteristics. We performed a retrospective single-institution study of all patients diagnosed with indeterminate thyroid nodules (May 2016-December 2019) who had a mutation identified with ThyroSeq v2 or v3 and underwent surgical resection. Specific genetic alterations were correlated with surgical histopathology. The main outcomes were risk of malignancy and structural recurrence risk based on histopathologic features and the 2015 American Thyroid Association (ATA) risk stratification. Of the 78 nodules, 50 (64%) were thyroid cancer or noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) on surgical histopathology. Nodules with high-risk TERT or TP53 combination mutations (TERT/TP53) and those with BRAF-like mutations were associated with a 100% probability of cancer and higher rates of extrathyroidal extension and regional nodal involvement than nodules with RAS-like mutations. Among nodules with RAS-like mutations, there was an even distribution between benign, NIFTP, and malignant results, the latter of which were all ATA low risk for structural disease recurrence. Overall, TERT/TP53 and BRAF-like ThyroSeq mutations are associated with an increased cancer probability and risk of recurrence defined by histopathologic features, while RAS-like mutations are associated with lower cancer probability and indolent disease. Individualized management, including extent of surgery, should be considered based on specific genetic alterations found in cytologically indeterminate thyroid nodules.

The Clinical Utility of Molecular Testing in the Management of Thyroid Follicular Neoplasms (Bethesda IV Nodules).

FN present a management quandary as they are often benign but may also be aggressive TC. Consensus recommendations have historically advised thyroidectomy for definitive diagnosis. Although MT have robust benefit in hypothetical cost analyses, under current management guidelines a real-time study of their clinical utility in FN is awaited. We investigate if MT use for FN directs appropriate thyroidectomy for TC while triaging to surveillance nodules that are likely benign. Data were analyzed for 389 consecutive patients managed from 11/14 to 9/19 for 405 FN, excluding oncocytic neoplasms. TC was defined as same-nodule histologic malignancy. When obtained, MT was performed using ThyroSeq (TS) v2 or 3. With a mean nodule size of 2.7 ± 1.3 cm, MT was used in 89% and was positive in 39%. When MT was positive, thyroidectomy was more often utilized (91% v. MT- 27%; P < 0.001) and more likely for histologic TC (70% vs 16%, P < 0.001). With preoperative MT, all American Thyroid Association intermediate, high-risk, and medullary TC were positive whereas all MT- malignancies were low-risk. With TSv3, ultrasound surveillance was more likely for MT- FN (90% vs TSv2 65%, P < 0.001), and occurred for a total of 174 MT- FN. With mean follow-up of 24.6 months, 82% remained stable in size. MT use for FN increased the surgical yield of cancer by 4-fold, identified all potentially aggressive malignancies, and allowed apparently safe nonoperative surveillance for >80% of MT-negative patients. Thyroid nodule MT optimizes patient outcomes sufficiently to justify its incorporation into routine practice.

Additional Surgery for Occult Risk Factors After Lobectomy in Solitary Thyroid Nodules is Predicted by Cytopathology Classification and Tumor Size

Clinical practice for differentiated thyroid cancer is moving towards lobectomy rather than total thyroidectomy in patients at low risk of recurrence. However, recurrence risk assessment depends on post-operative findings, while the surgical decision is based on preoperative factors. We determined the preoperative predictors of occult higher-risk pathology and rates of completion thyroidectomy among surgical candidates with nonbenign thyroid nodules 10 to 40 mm and no evidence of extrathyroidal extension or metastasis on preoperative evaluation. Thyroid surgery cases at a single institution from 2005-2015 were reviewed to identify those meeting American Thyroid Association (ATA) criteria for lobectomy. ATA-based risk stratification from postoperative surgical pathology was compared to preoperative cytopathology, ultrasound, and clinical findings. Of 1,995 thyroid surgeries performed for nonbenign thyroid nodules 10 to 40 mm, 349 met ATA criteria for lobectomy. Occult high-risk features such as tall cell variant, gross extrathyroidal invasion, or vascular invasion were found in 36 cases (10.7%), while intraoperative lymphadenopathy led to surgical upstaging in 13 (3.7%). Intermediate risk features such as moderate lymphadenopathy or minimal extrathyroidal extension were present in an additional 44 cases. Occult risk features were present twice as often in Bethesda class 6 cases (35%) as in lower categories (12 to 17%). In multivariable analysis, Bethesda class and nodule size, but not age, race, sex, or ultrasound features, were significant predictors of occult higher-risk pathology. Most solitary thyroid nodules less than 4 cm and with cytology findings including atypia of undetermined significance through suspicious for papillary thyroid cancer would be sufficiently treated by lobectomy. ATA = American Thyroid Association; CND = central neck dissection; DTC = differentiated thyroid cancer; ETE = extrathyroidal extension; FNA = fine needle aspiration; FTC/HCC = follicular thyroid carcinoma/Hurthle cell carcinoma; NIFTP = noninvasive follicular thyroid neoplasm with papillary-like nuclear features; OR = odds ratio; PTC = papillary thyroid cancer; US = ultrasound.

Real-World Performance of the American Thyroid Association Risk Estimates in Predicting 1-Year Differentiated Thyroid Cancer Outcomes: A Prospective Multicenter Study of 2000 Patients.

Background: One of the most widely used risk stratification systems for estimating individual patients' risk of persistent or recurrent differentiated thyroid cancer (DTC) is the American Thyroid Association (ATA) guidelines. The 2015 ATA version, which has increased the number of patients considered at low or intermediate risk, has been validated in several retrospective, single-center studies. The aims of this study were to evaluate the real-world performance of the 2015 ATA risk stratification system in predicting the response to treatment 12 months after the initial treatment and to determine the extent to which this performance is affected by the treatment center in which it is used. Methods: A prospective cohort of DTC patients collected by the Italian Thyroid Cancer Observatory web-based database was analyzed. We reviewed all records present in the database and selected consecutive cases that satisfied inclusion criteria: (i) histological diagnosis of DTC, with the exclusion of noninvasive follicular thyroid neoplasm with papillary-like nuclear features; (ii) complete data of the initial treatment and pathological features; and (iii) results of 1-year follow-up visit (6-18 months after the initial treatment), including all data needed to classify the estimated response to treatment. Results: The final cohort was composed of 2071 patients from 40 centers. The ATA risk of persistent/recurrent disease was classified as low in 1109 patients (53.6%), intermediate in 796 (38.4%), and high in 166 (8.0%). Structural incomplete responses were documented in only 86 (4.2%) patients: 1.5% in the low-risk, 5.7% in the intermediate-risk, and 14.5% in the high-risk group. The baseline ATA risk class proved to be a significant predictor of structural persistent disease, both for intermediate-risk (odds ratio [OR] 4.67; 95% confidence interval [CI] 2.59-8.43) and high-risk groups (OR 16.48; CI 7.87-34.5). Individual center did not significantly influence the prediction of the 1-year disease status. Conclusions: The ATA risk stratification system is a reliable predictor of short-term outcomes in patients with DTC in real-world clinical settings characterized by center heterogeneity in terms of size, location, level of care, local management strategies, and resource availability.

Impact of Noninvasive Follicular Thyroid Neoplasm With Papillary-Like Nuclear Features on Revised Bethesda System Malignancy Rates at a Single Institution

BackgroundThe 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). MethodsThis 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. ResultsOf 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%. ConclusionsA 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.

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): Diagnostic updates and molecular advances.

The noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a strictly defined thyroid lesion, reclassified in 2016, in order to more accurately reflect the biological behavior of the tumor and thus, modify the way the lesion is clinically approached and perceived both by practitioners and patients. Additionally, this newly specified designation also allows for more uniformity in reporting for general pathologists less comfortable to exclude overt malignancy with certain nuclear features. In recent years, increasing molecular analyses correlated with longitudinal clinical outcomes have fostered improved diagnostic and treatment paradigms. Important revisions made to the definition of NIFTP in 2018 include the prohibition of any true papillae formation and the exclusion of lesions harboring the BRAF V600E mutation and other high-risk genetic abnormalities. These changes reflect the imperfection of the current criteria in outcome prediction and the global efforts for improvement. NIFTP are lesions with a wide range of size and cytomorphology. Although not addressed in the original series, large (≥4cm) and oncocytic NIFTP have recently been shown to incur no recurrence or metastatic risk. Molecularly, NIFTP have a similar mutational profile as other follicular thyroid neoplasms, with frequent RAS family mutations and PAX8-PPARɤ fusions. However, the transcriptomic landscape is highly heterogenous, adding difficulty to gene expression-based cytopathologic classification. This review summarizes the evolution of the NIFTP concept and important advances in recent literature.

Malignancy is in the eye of the beholder: Pathologic diagnosis of challenging follicular neoplasms in the era of noninvasive follicular thyroid neoplasms with papillary-like nuclear features and immunohistochemical and molecular adjuncts

BackgroundClassification of thyroid follicular neoplasms can be challenging for pathologists. Introduction of noninvasive follicular thyroid neoplasms with papillary-like nuclear features, the utilization of immunohistochemistry, and molecular analysis are all thought to be valuable diagnostic adjuncts. Our aim was to determine whether interobserver variability for follicular neoplasms has improved since the application of these adjuncts. MethodsOne representative section from a cohort of follicular neoplasms previously proven difficult for pathologists were examined independently by 7 pathologists and assigned to 1 of 3 diagnostic categories (benign, neoplasms with papillary-like nuclear features, or malignant). This process was carried out separately 3 times: (1) after viewing hematoxylin and eosin stain slides, (2) hematoxylin and eosin stain in conjunction with immunohistochemistry, and (3) hematoxylin and eosin stain/immunohistochemistry in conjunction with molecular analysis. The interobserver variability and overall agreement were then calculated using the free-marginal kappa coefficient. ResultsAgreement on hematoxylin and eosin stain was 57%, with a kappa coefficient of 0.36 (minimal agreement). The agreement improved slightly with the application of immunohistochemistry (kappa coefficient = 0.49 [weak agreement] and a percentage agreement 67%). The level of agreement decreased slightly after the addition of molecular analysis (kappa coefficient = 0.43 [weak agreement] and percentage agreement 62%). ConclusionDespite attempts to standardize the diagnostic criteria for neoplasms with papillary-like nuclear features and the utilization immunohistochemistry and molecular analysis, attaining pathologic consensus for difficult follicular neoplasms of the thyroid remains a challenge.

A closer look at NIFTP.

Despite the rise in the incidence of papillary thyroid carcinoma (PTC) during the last 30years, the mortality rate due to PTC has remained static. One reason for this phenomenon is the indolent nature of some of the tumors that are diagnosed as PTC. A subgroup of tumors, which often exhibited such indolent behavior, was encapsulated/well-circumscribed follicular lesions that showed PTC nuclear features. Despite their indolent behavior, these tumors were managed as was any other PTC, often with total thyroidectomy and radioactive iodine (RAI) treatment. In order to prevent overtreatment of these tumors, they were recently reclassified as "non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)." Since it is proposed that NIFTP be managed in a more conservative manner, its diagnosis is now based on strict histological criteria. The genetic basis of these diagnostic criteria and the utility of molecular markers in the diagnosis of NIFTP are currently being scrutinized. The aim of this review is to discuss the events that led to the emergence of the term NIFTP, as well as its histological and molecular background.