Noninvasive Follicular Thyroid Neoplasm Research Articles

The histologic outcomes of indeterminate thyroid nodules with rat sarcoma mutations: A case series.

Molecular testing is an adjunct test for thyroid fine needle aspirations with indeterminate diagnoses, with certain mutations showing a greater risk of malignancy (ROM). Rat sarcoma (RAS) point mutations are the most common alterations in indeterminate thyroid nodules. While they can have a high ROM, they are also found in benign disease. This study describes the histologic outcomes of indeterminate nodules with RAS mutations. Bethesda III and IV thyroid nodules with ThyroSeq results showing RAS mutations (NRAS, KRAS, and HRAS) were identified between November 1, 2018 and February 28, 2023. Baseline patient characteristics, ThyroSeq results, and surgical diagnoses were collected. We identified 18 nodules with RAS mutations from 17 patients. Fourteen were NRAS (isolated NRAS in 6; NRAS with other abnormalities [NRAS+] in 8); one was isolated KRAS; and three were HRAS with other abnormalities (HRAS+). NRAS Q16R was the most common amino acid change. Twelve cases had follow-up. Two were malignant, a minimally invasive follicular carcinoma (NRAS+) and a papillary thyroid carcinoma, follicular variant (HRAS+). Three were noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP), 2 HRAS+ and 1 NRAS+. Four were follicular adenomas, one being atypical (3 NRAS+ and one isolated NRAS). One was an oncocytic adenoma (isolated NRAS). Two were nodular hyperplasias (isolated NRAS and NRAS+, respectively). Twenty-eight percent of our RAS-mutated nodules were malignant or NIFTP. All three HRAS-mutated nodules were malignant or NIFTP. The three isolated RAS mutations with follow up were benign (adenomas or nodular hyperplasia). These findings were in line with the literature.

Three-dimensional nuclear architecture distinguishes thyroid cancer histotypes.

Molecular markers can serve as diagnostic tools to support pathological analysis in thyroid neoplasms. However, because the same markers can be observed in some benign thyroid lesions, additional approaches are necessary to differentiate thyroid tumor subtypes, prevent overtreatment and tailor specific clinical management. This applies particularly to the recently described variant of thyroid cancer referred to as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). This variant has an estimated prevalence of 4.4% to 9.1% of all papillary thyroid carcinomas worldwide. We studied 60 thyroid lesions: 20 classical papillary thyroid carcinoma (CPTC), 20 follicular variant of PTC (FVPTC) and 20 NIFTP. We examined morphological and molecular features to identify parameters that can differentiate NIFTP from the other PTC subtypes. When blindly investigating the nuclear architecture of thyroid neoplasms, we observed that NIFTP has significantly longer telomeres than CPTC and FVPTC. Super-resolved 3D-structured illumination microscopy demonstrated that NIFTP is heterogeneous and that its nuclei contain more densely packed DNA and smaller interchromatin spaces than CPTC and FVPTC, a pattern that resembles normal thyroid tissue. These data are consistent with the observed indolent biological behavior and favorable prognosis associated with NIFTP, which lacks BRAFV600E mutations. Of note, next-generation thyroid oncopanel sequencing was unable to distinguish the thyroid cancer histotypes in our study cohort. In summary, our data suggest that 3D nuclear architecture can be a powerful analytical tool to diagnose and guide clinical management of NIFTP.

Ultrasound features and risk stratification system in NIFT-P and other follicular patterned thyroid tumors.

NIFT-P (non-invasive follicular thyroid neoplasm with papillary-like nuclear features) is an encapsulated follicular variant of papillary thyroid carcinoma (PTC) with non-aggressive clinical behavior. However, since its diagnosis is exclusively possible after surgery, it represents a clinical challenge. Neck ultrasound (US) shows good sensitivity and specificity in suggesting malignancy in thyroid nodules. However, few information is available about its ability in identifying NIFT-P. The aim of this study was to evaluate the US features of NIFT-P, comparing them with other follicular patterned thyroid tumors, and to test the ability of the main US risk stratification system (RSS) in identifying NIFT-P. We retrospectively evaluated 403 consecutive patients submitted to thyroid surgery, with positive histology for at least one nodule being NIFT-P, follicular variant of PTC (FV-PTC), follicular thyroid carcinoma (FTC) or follicular adenoma (FA). The US features of NIFT-P (n=116), FV-PTC (n=170), FTC (n=76) and FA (n=90) were reported. FV-PTC and FTC more frequently showed irregular margins, presence of calcifications, "taller than wide" shape, and the absence of halo compared to NIFT-P. Furthermore, FTC but also FA were larger and more frequently hypoechoic than NIFT-P. Most cases (77%) showed an indeterminate cytology. Regardless of the US RSS considered, NIFT-P and FA were less frequently classified in the high-suspicious category compared to FV-PTC and FTC. US features of NIFT-P are frequently superimposable to those of nodules with low-suspicious of malignancy. NIFT-P is almost never classified in the high-suspicious category according to the main US RSS. Therefore, although the pre-operative identification of NIFT-P remains a challenge, neck US can be integrated in the algorithm of management of nodules with indeterminate cytology, suggesting a possible conservative approach in those with low-suspicious features.

Reevaluating diagnostic categories and associated malignancy risks in thyroid core needle biopsy.

As the application of core needle biopsy (CNB) in evaluating thyroid nodules rises in clinical practice, the 2023 Korean Thyroid Association Management Guidelines for Patients with Thyroid Nodules have officially recognized its value for the first time. CNB procures tissue samples preserving both histologic structure and cytologic detail, thereby supplying substantial material for an accurate diagnosis and reducing the necessity for repeated biopsies or subsequent surgical interventions. The current review introduces the risk of malignancy within distinct diagnostic categories, emphasizing the implications of noninvasive follicular thyroid neoplasm with papillary-like nuclear features on these malignancy risks. Prior research has indicated diagnostic challenges associated with follicular-patterned lesions, resulting in notable variation within indeterminate diagnostic categories. The utilization of mutation-specific immunostaining in CNB enhances the accuracy of lesion classification. This review underlines the essential role of a multidisciplinary approach in diagnosing follicular-patterned lesions and the potential of mutation-specific immunostaining to strengthen diagnostic consensus and inform patient management decisions.

Further Analysis Confirms that Isolated Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features Is a Low-Risk Thyroid Neoplasm

Further Analysis Confirms that Isolated Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features Is a Low-Risk Thyroid Neoplasm

A Shift in Molecular Drivers of Papillary Thyroid Carcinoma Following the 2017 World Health Organization Classification: Characterization of 554 Consecutive Tumors With Emphasis on BRAF-Negative Cases

Most studies for comprehensive molecular profiling of papillary thyroid carcinoma (PTC) have been performed before the 2017 World Health Organization (WHO) classification, in which the diagnostic criteria of follicular variants of PTC have been modified and noninvasive follicular thyroid neoplasm with papillary-like nuclear features has been introduced. This study aims to investigate the shift in the incidence of BRAF V600E mutations in PTCs following the 2017 WHO classification and to further characterize the histologic subtypes and molecular drivers in BRAF-negative cases. The study cohort consisted of 554 consecutive PTCs larger than 0.5 cm between January 2019 and May 2022. Immunohistochemistry for BRAF VE1 was performed for all cases. Compared with a historical cohort of 509 PTCs from November 2013 to April 2018, the incidence of BRAF V600E mutations was significantly higher in the study cohort (86.8% vs 78.8%, P = .0006). Targeted RNA-based next-generation sequencing using a FusionPlex Pan Solid Tumor v2 panel (ArcherDX) was performed for BRAF-negative PTCs from the study cohort. Eight cribriform-morular thyroid carcinomas and 3 cases with suboptimal RNA quality were excluded from next-generation sequencing. A total of 62 BRAF-negative PTCs were successfully sequenced, including 19 classic follicular predominant PTCs, 16 classic PTCs, 14 infiltrative follicular PTCs, 7 encapsulated follicular PTCs, 3 diffuse sclerosing PTCs, 1 tall cell PTC, 1 solid PTC, and 1 diffuse follicular PTC. Among them, RET fusions were identified in 25 cases, NTRK3 fusions in 13 cases, BRAF fusions in 5 cases including a novel TNS1::BRAF fusion, NRAS Q61R mutations in 3 cases, KRAS Q61K mutations in 2 cases, NTRK1 fusions in 2 cases, an ALK fusion in 1 case, an FGFR1 fusion in 1 case, and an HRAS Q61R mutation in 1 case. No genetic variants, from our commercially employed assay, were detected in the remaining 9 cases. In summary, the incidence of BRAF V600E mutations in PTCs significantly increased from 78.8% to 86.8% in our post–2017 WHO classification cohort. RAS mutations accounted for only 1.1% of the cases. Driver gene fusions were identified in 8.5% of PTCs and were clinically relevant given the emerging targeted kinase inhibitor therapy. Of the 1.6% of cases for which no driver alteration was detected, the specificity of drivers tested and tumor classification require further investigation.

Sonographic and clinicopathological differences between non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) and minimally invasive encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Large (>4 cm) Intrathyroidal Encapsulated Well-Differentiated Follicular Cell-Derived Carcinoma Without Vascular Invasion May Have Negligible Risk of Recurrence Even When Treated with Lobectomy Alone.

Background: Thyroid carcinoma >4 cm in size is staged as T3a. The current American Thyroid Association guidelines recommend subtotal/total thyroidectomy and consideration for postoperative radioactive iodine (RAI) treatment for these tumors. In this retrospective cohort study, we aimed to explore the clinical course of large encapsulated thyroid carcinoma without other risk factors. Methods: Eighty-eight patients with large (>4 cm) encapsulated well-differentiated thyroid carcinoma resected between 1995 and 2021 were included in this retrospective cohort study. Exclusion criteria were tall cell variant, any extent of vascular invasion, extrathyroidal extension (microscopic or gross), high-grade histology, noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), infiltrative tumors, positive resection margin, and cases with follow-up <1 year. The primary outcomes are risk of nodal metastasis at the initial resection, disease-free survival (DFS), and disease-specific survival (DSS). Results: The tumor histotype was follicular carcinoma (n = 18, 21%), oncocytic (Hurthle cell) carcinoma (n = 8, 9%), and papillary thyroid carcinoma (PTC; n = 62, 70%). Among PTC, 38 were encapsulated follicular variant, 20 classic type, and 4 solid variant. Four cases had extensive capsular invasion (CI), 61 (69%) had focal CI, whereas 23 did not have CI. Thirty-two cases (36%) were treated with lobectomy/hemithyroidectomy alone, and 55 patients (62%) did not receive RAI. Five patients had nodal metastasis at the time of primary resection, all of whom had classic-type PTC. The median follow-up period was 4.8 years (interquartile range: 3.2-9.7 years). No recurrence, being local, regional, or distant, was observed in the entire cohort, including those patients treated with lobectomy alone without RAI. The 10-year DFS and DSS were 100%, respectively. Conclusion: Large intrathyroidal encapsulated well-differentiated thyroid carcinoma without vascular invasion follow an extremely indolent clinical course with negligible risk of recurrence. Lobectomy alone without RAI may be the appropriate treatment strategy for this selected group of patients.

A new paradigm for epidermal growth factor receptor expression exists in PTC and NIFTP regulated by microRNAs.

Identification of molecular alterations associated with tumor behavior is necessary to guide clinical management. The 2022 WHO classification has organized the thyroid follicular cell-derived neoplasms into benign, low-risk and high-risk neoplasms, and emphasized the value of biomarkers that may provide differential diagnostic and prognostic information to avoid overtreatment of low risk neoplasms. This work aims to study the epidermal growth factor receptor (EGFR) expression, functional and spatial dynamics in relation to specific miRNAs alterations in papillary thyroid cancer (PTC) and in non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) considered as models of high-risk and low-risk thyroid tumors respectively. Primary thyroid cultured cells were used for miRNA gain/loss of function and luciferase reporter assays. Paraffin embedded tissues were used for real time PCR, immuno-fluorescence stain and confocal microscopy experiments. Our results showed that in PTC, EGFR mRNA is reduced as an effect of miR-146b-5p upregulation. The EGF expression is low and the ERK pathway is inhibited. The EGFR protein high cytoplasmic expression and colocalization with the endosomal/exosomal markers, ALIX and CD63, suggest the occurrence of stress-induced EGFR internalization, accumulation in endosomal vesicles and secretion via exosomes. In NIFTP EGFR transcription is increased in association with downregulation of miR-7-5p and the EGFR/ERK pathway is active indicating dependence on the canonical EGFR pathway for growth. Downregulation of transcript level along with cytoplasmic accumulation of undegraded protein is a new pattern of EGFR regulation associated with malignancy in thyroid. Further research is needed to elucidate the intracellular trafficking defects responsible for this specific EGFR dynamic in PTC.

A comparison of the WHO 2004 and WHO 2017 thyroid tumor classifications.

The category of borderline malignancy or unknown malignant potential was added to the WHO's 2017 classification of thyroid tumours. A new histological variety of papillary tumours and Hurthle cell tumours was given as a separate entity. The classification has also adopted the Turin criteria for histological diagnosis of poorly differentiated cancer (PDC). Descriptive study. From July 2018 to June 2022, 200 thyroid neoplasm patients at a tertiary care facility in western Maharashtra were participated in the prospective research over a period of 4 years. The descriptive statistics were used to analyse the collected data. This study was undertaken to compare the old (2004) and new (2016) WHO classifications and their importance in the treatment of thyroid malignancies. Out of 200 cases, the age range of 31 to 40 years had the greatest number of cases. The ratio of females to males was 5:1. In our study, according to the WHO 2004 classification, malignant tumours comprised 57.5% of the cases, while benign tumours 42.5% of the cases. When tumours were subcategorized, the most frequent benign tumour was follicular adenoma (43.5%) and malignant tumour was papillary thyroid carcinoma (37%). Malignant tumours made up 47.5% of the cases when the tumours were reclassified using the revised WHO 2017 classification, followed by borderline tumours with 27.5% of the cases and benign tumours with 25% of the cases. The most frequent borderline tumour was NIFTP (Noninvasive follicular thyroid neoplasm with papillary-like nuclear features) (17.5%), the most prevalent malignant tumour was papillary carcinoma (including its variant) (32%), and the most frequent benign tumour was follicular adenoma (27%). We concluded that the inclusion of the Boderline Category in the new WHO classification significantly improved thyroid cancer management. WHO 2017 classification prevents under diagnosis (in the case of benign tumors) and over diagnosis (in the case of malignant tumors).

A Comprehensive Study on the Diagnosis and Management of Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features.

Background: Since the noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTPs) was introduced in 2016, most retrospective studies have included cases diagnosed as encapsulated follicular variant of papillary thyroid carcinoma. We investigate a cohort diagnosed with NIFTP at resection. Methods: Retrospective institutional cohort of NIFTP from 2016 to 2022, including clinical, cytological, and molecular data for 319 cases (6.6% of thyroid surgeries, 183 cases as NIFTP-only). Results: The patient cohort had unifocal or multifocal thyroid nodules. Female:male ratio was 2.7:1, mean age was 52 years and median NIFTP size was 2.1 cm. NIFTP was associated with multiple nodules in 23% patients (n = 73) and 12% of NIFTP were multifocal (n = 39). Fine needle aspiration (FNA) of NIFTP (n = 255) were designated as nondiagnostic = 5%, benign = 13%, atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) = 49%, follicular neoplasm/suspicious for follicular neoplasm (FN/SFN) = 17%, suspicious for malignancy = 12%, or malignant = 4%. Molecular alterations were identified in 93% (n = 114), RAS or RAS-like. Thyroid Imaging Reporting and Data System (TI-RADS) score 4 was recorded in 50% of NIFTP, followed by scores 3 and 5 (26% and 20%, respectively). We also investigated the factors associated with extent of surgery. In our NIFTP-only group (n = 183), 66% were identified after hemithyroidectomy (HT) and 34% after total thyroidectomy (TT). On univariate analysis, TT patients demonstrated higher Bethesda category by FNA, more often had aberrant preoperative thyroid function, and/or underwent an FNA of additional nodule(s). With multivariable regression, Bethesda V NIFTP, in the presence of other nodules being evaluated by FNA and aberrant preoperative thyroid function, independently predicts TT. Bethesda II NIFTP correlated significantly with HT. Fifty-two patients (28%) with NIFTP-only had at least one postoperative surveillance ultrasound. In the NIFTP-only cohort, no HT patients had completion thyroidectomy or received postoperative radioactive iodine. No recurrence or metastases were recorded with median follow-up of 35 months (6-76 months; n = 120). Conclusions: Given this large cohort of NIFTP, including a large subset of isolated NIFTP-only, some with >6 years of follow-up and no tumor recurrences, consensus practical guidelines are needed for adequate postoperative management. Given the American Thyroid Association (ATA) provides guidelines for management of low-risk malignancies, guidance regarding that for borderline/biologically uncertain tumors, including NIFTP, is a reasonable next step.

P53 expression in cytology samples may represent a marker of early-stage cancer.

TP53 gene plays a major role in the negative control of cell proliferation and in the regulation of signaling cascades. TP53 mutation may have a relevant role in the malignant transformation of thyroid cells as well as thyroid tumor progression. TP53 mutation has been detected only in few well differentiated thyroid carcinomas and is absent in benign conditions. A total of 162 prospective thyroid cytology and corresponding histological samples diagnosed from atypia of indeterminate significance (AUS) to malignant, were studied via immunocytochemistry for p53. Hence, 50 benign lesions (B) were used as negative control. Molecular analysis for p53 only was performed. The cytology resulted in 50 B, 48 AUS, 40 follicular neoplasms (FNs), 23 suspicious for malignancy (SFM), and 1 malignant (M) case. The authors reported 102 negative and 60 positive p53 cases. The 60 positive cases included 27 cases with weak and/or focal cytoplasmic positivity (+1) and 33 with cases moderate (2+) to strong (3+) cytoplasmic and/or nuclear expression. Overall, 71 cases had histology (2 B, 11 AUS, 37 FN, 20 SFM, and 1 M) including 61.7% benign and 38.2% malignant diagnoses. Only 16 of 71 (5 FN, 10 SFM, and 1 M) were p53-positive. Furthermore, 100% AUS and 86.5% FN cases were p53-negative, none of which had malignant histology. All p53-positive cases were associated with a larger nodule size, tall-cell variant subtype, multifocality, extra thyroidal infiltration, and nodal metastases. Noninvasive follicular thyroid neoplasm with papillary like nuclear features were negative for p53. Few discrepancies in p53 intensity were observed on histology; there were no differences with the molecular testing. p53 might be useful in discriminating thyroid follicular lesions. p53 is likely to be a useful diagnostic marker in recognizing indeterminate lesions that are well-differentiated thyroid cancers.

Characteristics of PTEN Mutation in Thyroid Tumours: A Retrospective Chart Review

While some studies suggest that PTEN mutations correlate with a low-risk phenotype in pediatric thyroid nodules, the relationship between the mutation and malignancy in the adult populations is abstruse. This study investigated whether PTEN mutations result in thyroid malignancy, and whether these malignancies are aggressive. This multicenter study involved 316 patients who underwent preoperative molecular testing, and subsequent lobectomy or total thyroidectomy at two quaternary care hospitals. A four-year retrospective review was performed on the 16 charts of patients that opted for surgery following a positive PTEN mutation on molecular testing results from January 2018 to December 2021. Of the total 16 patients, 37.5% (n = 6) had malignant tumours, 18.75% (n = 3) had non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs), and 43.75% (n = 7) had benign disease. Aggressive features were detected in 33.33% of the malignant tumours. Malignant tumours were found to have a statistically significant higher allele frequency (AF). The aggressive nodules were all poorly differentiated thyroid carcinomas (PDTCs) with copy number alterations (CNAs) and the highest AFs.

Transoral Thyroidectomy: Initial Results of the European TOETVA Study Group

BackgroundThe aim of this study was to evaluate a new surgical technique by the European Transoral Endoscopic Thyroidectomy Vestibular Approach (TOETVA) Study Group.MethodsThis study included 391 patients (47 [(12%]) male and 344 [(88%)] female) who had undergone endoscopic thyroid or parathyroid surgery via the vestibular approach between February 2016 and May 2022 at nine centers. The data were analyzed with regard to complications, surgery time and specimen retrieval.ResultsOverall, 376 (96.2%) TOETVA and 15 (3.8%) transoral endoscopic parathyroidectomy vestibular approach interventions were performed with an average surgery time of 145 (± 61.2) minutes and 509 nerves at risk. The specimens were retrieved via a transoral vestibular and retroauricular approach in 66 (16.9%) patients and via a transaxillary approach in 8 (2%). Benign histology including Grave’s disease was identified in 272 (69.6%) patients, 1 (0.3%) presented noninvasive follicular thyroid neoplasms with papillary-like nuclear features, and 103 (26.3%) showed differentiated thyroid carcinoma. Solitary parathyroid adenoma were removed in 15 (3.8%) patients. Conversion to open surgery was necessary in 13 (3.3%) and revision had to be performed in 2 (0.5%) patients. Transient recurrent laryngeal nerve palsy (RLNP) was present in 18 (4.6%) and permanent RLNP in 2 (0.5%) patients. Fifteen (3.8%) patients experienced transient hypoparathyroidism after thyroidectomy. No case of permanent hypoparathyroidism was observed. Postoperative surgical site infection occurred in 1 (0.3%) patient. Despite a higher rate of sensory and motor disorders and skin discoloration at discharge, permanent disorders were present in only 3 (0.8%) and 16 (4.1%) patients, respectively.ConclusionOur results show that transoral endoscopic surgery, performed by experienced endocrine surgeons, is a safe alternative to conventional thyroid surgery.

Risk stratification of cytologically indeterminate thyroid nodules with nondiagnostic or benign cytology on repeat FNA: Implications for molecular testing and surveillance.

Evidence guiding the management of cytologically indeterminate thyroid nodules with nondiagnostic (ND) or benign cytology on repeat fine-needle aspiration (FNA) is limited. This study evaluates the utility of molecular testing and estimates the risk of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) and cancer among such nodules. This was a retrospective single-institution review of thyroid nodules from adults that were classified as atypia of undetermined significance (AUS) or follicular neoplasm (FN) on initial FNA and underwent repeat FNA for cytology and Afirma testing (June 2013-July 2021). The association between repeat FNA cytology and RNA yield for Afirma was determined. Histologic outcomes were integrated with Afirma results to define end points for each nodule. A total of 691 AUS and FN nodules underwent repeat FNA and Afirma testing. Diagnostic Afirma results were obtained in 98% of cases overall and in 91% of nodules with ND cytology on repeat FNA. Using combined molecular and histologic end points, the NIFTP and/or cancer prevalence for nodules with ND cytology on repeat FNA was 9% (95% confidence interval [CI], 0.042-0.182), falling between those nodules classified as benign (5%; 95% CI, 0.029-0.094) and those classified as AUS or FN (18%; 95% CI, 0.140-0.218) on repeat FNA, although not reaching statistical significance from either subgroup (p=.38 and .10, respectively). AUS and FN nodules that are ND on repeat FNA have low but nonnegligible risk of NIFTP and/or cancer and may benefit from molecular testing, given the low test failure rate in this subgroup. Conversely, AUS and FN nodules reclassified as benign on repeat FNA have a very low risk of NIFTP and/or cancer and are unlikely to benefit from molecular testing.

MicroRNA expression profiling of RAS-mutant thyroid tumors with follicular architecture: microRNA signatures to discriminate benign from malignant lesions

PurposeRAS mutations represent common driver alterations in thyroid cancer. They can be found in benign, low-risk and malignant thyroid tumors with follicular architecture, which are often diagnosed as indeterminate nodules on preoperative cytology. Therefore, the detection of RAS mutations in preoperative setting has a suboptimal predictive value for malignancy. In this study, we investigated differentially expressed microRNA (miRNA) in benign and malignant thyroid tumors with follicular architecture carrying mutations in RAS genes.MethodsTotal RNA was purified from 60 RAS-mutant follicular-patterned thyroid tumors, including follicular adenoma (FA), noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), papillary and follicular thyroid carcinoma cases (PTC, FTC); 22 RAS-negative FAs were used as controls. The expression analysis of 798 miRNAs was performed by digital counting (nCounter nanoString platform).ResultsComparing RAS-mutant and RAS-negative FAs, 12 miRNAs showed significant deregulation, which was likely related to the oncogenic effects of RAS mutations. Twenty-two miRNAs were differentially expressed in RAS-mutant benign versus malignant tumors. Considering the tumor type, 24 miRNAs were deregulated in PTC, 19 in NIFTP, and seven in FTC and compared to FA group; among these, miR-146b-5p, miR-144-3p, and miR-451a showed consistent deregulation in all the comparisons with the highest fold change.ConclusionsThe miRNA expression analysis of follicular-patterned thyroid tumors demonstrated that RAS mutations influences miRNA profile in benign tumors. In addition, several miRNAs showed a histotype-specific deregulation and could discriminate between RAS-mutant benign and RAS-mutant malignant thyroid lesions, thus deserving further investigation as potential diagnostic markers.

Spatially Resolved Molecular Approaches for the Characterisation of Non-Invasive Follicular Tumours with Papillary-like Features (NIFTPs).

Noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) are low-risk thyroid lesions most often characterised by RAS-type mutations. The histological diagnosis may be challenging, and even immunohistochemistry and molecular approaches have not yet provided conclusive solutions. This study characterises a set of NIFTPs by Matrix-Assisted Laser Desorption/Ionisation (MALDI)-Mass Spectrometry Imaging (MSI) to highlight the proteomic signatures capable of overcoming histological challenges. Archived formalin-fixed paraffin-embedded samples from 10 NIFTPs (n = 6 RAS-mutated and n = 4 RAS-wild type) were trypsin-digested and analysed by MALDI-MSI, comparing their profiles to normal tissue and synchronous benign nodules. This allowed the definition of a four-peptide signature able to distinguish RAS-mutant from wild-type cases, the latter showing proteomic similarities to hyperplastic nodules. Moreover, among the differentially expressed signals, Peptidylprolyl Isomerase A (PPIA, 1505.8 m/z), which has already demonstrated a role in the development of cancer, was found overexpressed in NIFTP RAS-mutated nodules compared to wild-type lesions. These results underlined that high-throughput proteomic approaches may add a further level of biological comprehension for NIFTPs. In the future, thanks to the powerful single-cell detail achieved by new instruments, the complementary NGS-MALDI imaging sequence might be the correct methodological approach to confirm that the current NIFTP definition encompasses heterogeneous lesions that must be further characterised.

Non-invasive follicular thyroid neoplasm with papillary-like nuclear feature: clinical, pathological, and molecular update 5 years after the nomenclature revision.

The term non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was proposed in 2016 and incorporated as a new entity in the World Health Organization (WHO) classification of tumours of endocrine organs in 2017. Since then, there has been debate regarding the histological criteria for the diagnosis, the need for molecular studies or the risk of lymph node metastasis or recurrence associated with this entity. Over the years, the concept of NIFTP evolved, now including both small (<1 cm) and large (>4 cm) tumours and oncocytic lesions. On the other hand, recent data on NIFTP in the setting of thyroid follicular nodular disease or frequent coexistence of malignant tumours raised concerns regarding the follow-up of these patients. Today, both pathologists and clinicians still face several challenges in the diagnosis, treatment, and follow-up of patients with NIFTP.

Noninvasive Follicular Thyroid Neoplasm With Papillary-Like Nuclear Features: What a Surgeon Should Know.

The inclusion of the less aggressive follicular form of papillary thyroid cancer (PTC) is associated with an increase in the incidence of the condition, with the follicular variant of PTC being the most common of all variants. The majority of individuals with the encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) are treated as though they have classic thyroid cancer, despite the availability of mounting evidence to contradict the aforementioned. According to numerous research, a certain type of noninvasive-EFVPTC (NI-EFVPTC) demonstrated poor histopathologic diagnostic reproducibility and has received aggressive treatment similar to that of a classical thyroid neoplasm. Therefore, to replace the term NI-EFVPC, a new nomenclature for these tumors, called "noninvasive follicular thyroid neoplasm with papillary-like nuclear characteristics" (NIFTP), was introduced in the year 2016. The present paper explores this recently introduced terminology, clinical, histologic, and molecular features, and diagnostic criteria.

Non-Invasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features: Pitfalls of Cytological and Histopathologic Diagnosis

Classical papillary thyroid carcinoma (PTC) is the commonest primary thyroid neoplasm. Besides PTC, significant histological variants that differ from classical PTC in regard to the morphological, cytologic and histologic features are mentioned; among them is follicular variant papillary thyroid carcinoma (FVPTC). The update WHO classification and the update Bethesda system reclassified FVPTC introduced a new entity which is "non-invasive follicular thyroid neoplasm with papillary like nuclear features" (NIFTP) that is characterized by an indolent behavior with encapsulated noninvasive growth features. Recently this entity is considering one of an indeterminate cytological categories (category III-IV-V). Update studies are found a combination of triple diagnostic procedures included sonographical, cytologic and molecular investigations can be suspecting preoperative diagnosis. Methods: A total of 150 selected cases of solitary thyroid nodules (STNs) with preoperative FNAC have an indeterminate follicular patterned cytological lesions with their underlying thyroidectomies that were collected in a 5-year period included in this article. Results: Majority of our cases were females and suffering from neck swelling. Cytollogically all the enrolled cases were lying in the indeterminate categories and histologically they were encapsulated with variable sizes follicles, nuclear features, no vascular invasion, no psammoma bodies, no tumor necrosis or mitosis. Also, there is no any extra-thyroid invasion. Conclusion: The accurate diagnosis of this entity “”NIFTP” carries many congratulations in regard that is “not malignant” category among both update TBSRTC and the final histopathological examination of the excised thyroid tissue.