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Context Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was introduced as a new entity replacing the diagnosis of noninvasive encapsulated follicular variant of papillary thyroid carcinoma (PTC). Significant variability in the incidence of NIFTP diagnosed in different world regions has been reported. Objective To investigate the rate of adoption of NIFTP, change in practice patterns, and uniformity in applying diagnostic criteria among pathologists practicing in different regions. Methods Two surveys distributed to pathologists of the International Endocrine Pathology Discussion Group with multiple-choice questions on NIFTP adoption into pathology practice and whole slide images of 5 tumors to collect information on nuclear score and diagnosis. Forty-eight endocrine pathologists, including 24 from North America, 8 from Europe, and 16 from Asia/Oceania completed the first survey and 38 the second survey. Results A 94% adoption rate of NIFTP by the pathologists was found. Yet, the frequency of rendering NIFTP diagnosis was significantly higher in North America than in other regions (P =.009). While the highest concordance was found in diagnosing lesions with mildly or well-developed PTC-like nuclei, there was significant variability in nuclear scoring and diagnosing NIFTP for tumors with moderate nuclear changes (nuclear score 2) (case 2, P <.05). Pathologists practicing in North America and Europe showed a tendency for lower thresholds for PTC-like nuclei and NIFTP than those practicing in Asia/Oceania. Conclusion Despite a high adoption rate of NIFTP across geographic regions, NIFTP is diagnosed more often by pathologists in North America. Significant differences remain in diagnosing intermediate PTC-like nuclei and respectively NIFTP, with more conservative nuclear scoring in Asia/Oceania, which may explain the geographic differences in NIFTP incidence. [ABSTRACT FROM AUTHOR]

Background: Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a newly recognized entity with benign clinical characteristics. We aim to compare NIFTP with invasive encapsulated follicular variant papillary carcinoma (fvPTC) and to discuss the management. Methods: Records of patients with fvPTC and NIFTP between 2016 and 2022 were reviewed retrospectively. Two groups were compared according to demographics, surgical management, postoperative management, and long-term follow-up. Results: Twenty patients were included in the study, with 10 in NIFTP group and 10 in fvPTC group. The mean age at operation was 14.10 ± 2.61 years. Demographics and preoperative nodule sizes (P =.912) were statistically similar between the 2 groups. Although lobectomy was more common in the NIFTP group, this difference was not statistically significant compared to the fvPTC group in terms of surgical treatment. Postoperatively, while no patient received radioactive iodine treatment(RAI) in NIFTP group, 6 patients in fvPTC group did (P =.011). Five patients in NIFTP group and 3 in the fvPTC group were followed up with lobectomy only, without any adverse events or recurrence, for 47.50 ± 19.25 and 30.10 ± 19.25 months, respectively. Conclusion: In conclusion, NIFTP appears to be an indolent disease in children. Therefore, observation with lobectomy is sufficient, and RAI is not necessary. [ABSTRACT FROM AUTHOR]

Follicular-patterned thyroid neoplasms comprise a diverse group of lesions that pose significant challenges in terms of differential diagnosis based solely on morphologic and genetic features. Thus, the identification of easily testable biomarkers complementing microscopic and genetic analyses is a highly anticipated advancement that could improve diagnostic accuracy, particularly for noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs). These tumors exhibit considerable morphological and molecular heterogeneity, which may complicate their distinction from structurally similar neoplasms, especially when genetic analyses reveal shared genomic alterations (e.g., RAS mutations). Here, we integrated next-generation sequencing (NGS) with matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to perform a proteogenomic analysis on 85 NIFTPs (n = 30 RAS-mutant [RAS-mut] and n = 55 RAS-wild type [RAS-wt]), with the aim to detect putative biomarkers of RAS-mut lesions. Through this combined approach, we identified four proteins that were significantly underexpressed in RAS-mut as compared to RAS-wt NIFTPs. These proteins could serve as readily accessible markers in morphologically borderline cases showing RAS mutations. Additionally, our findings may provide insights into the distinct pathogenic pathways through which RAS-mut and RAS-wt NIFTPs arise, highlighting the pivotal role of constitutive RAS–mitogen-activated protein kinase (MAPK) pathway activation in the development and progression of RAS-mut tumors. [ABSTRACT FROM AUTHOR]

BRAFK601E is an uncommon mutation typically found in encapsulated follicular-patterned thyroid tumors. Previous studies on BRAFK601E-positive thyroid tumors were conducted before the implementation of the non-invasive follicular neoplasm with papillary-like nuclear features (NIFTP) diagnosis. This study aimed to characterize BRAFK601E-positive tumors and evaluate changes in the diagnosis and management of these patients after the introduction of NIFTP. We evaluated 25 thyroid tumors that were positive for BRAFK601E and diagnosed considering the NIFTP criteria. Clinicopathologic characteristics and recurrence rates of these tumors were compared to 29 BRAFK601E-positive tumors diagnosed prior to the acceptance of the NIFTP diagnosis. RNA-seq analysis was performed on 10 BRAFK601E-positive tumors. In the current study, 72% of BRAFK601E-positive tumors were diagnosed as non-invasive tumors on resection, with NIFTP (48% of all tumors) being the most common diagnosis. BRAFK601E-positive tumors exhibited a RAS-like gene expression profile with a BRAF-RAS score (BRS) and thyroid differentiation score (TDS) distinct from BRAFV600E-positive tumors (P < 0.001). Since 2016, patients with BRAFK601E-positive tumors less frequently underwent total thyroidectomy (41% vs 100%, P < 0.001) and received radioiodine (7% vs 75%, P < 0.001). None of the tumors positive for an isolated BRAFK601E mutation from the current or 2016 studies showed recurrences on follow-up. Our study demonstrates that most BRAFK601E-positive tumors are low-risk, RAS-like tumors, which were diagnosed as NIFTP in half of all study cases. Since 2016, patients with BRAFK601E-positive nodules have received less aggressive treatment. The risk of recurrence of BRAFK601E-positive tumors without other high-risk features appears to be low, and lobectomy without radioiodine is likely a sufficient treatment for these patients. [ABSTRACT FROM AUTHOR]

Thyroid cancers are the most common endocrine organ cancers. Encapsulated follicular variant papillary thyroid carcinomas (EFVPTC) are quite slow (indolent). Non-invasive follicular thyroid neoplasm with papillary nuclear feature (NIFTP) is a new entity identified as a result of studies in recent years. If the patient instead of EFVPTC develops NIFTP, cancer will not be recognized and the treatment will change. Three groups, in which CD44, p53, Ki-67, p27, HBME-1, galectin-3, cytokeratin-19, CD56 were used as markers, were evaluated. Nuclear score assessment was also conducted in the NIFTP group. The results were compared with each other. Significant differences were detected in the intensities and percentages of CK19, HBME-1, CD56, CD44 staining and galectin-3 staining intensity. In group 1, cytokeratin-19, galectin-3, HBME-1 and CD44 expression were not as low as in the other groups, while CD56 staining was detected more frequently. p53, p27 and Ki-67 staining showed no obvious expression differences between the groups. The NIFTP group showed different IHC results compared to encapsulated invasive FVPTC and common invasive FVPTC. When evaluating whether the IHC expression patterns used in PTCs differ in NIFTP cases, it was found that CD44 could serve as an additional IHC stain that may guide pathologists during the diagnosis.

Introduction: There are conflicting results on whether the presence of oncocytes modifies the risk of neoplasm (RON) or malignancy (ROM) for thyroid fine‐needle aspirates (FNAs): Atypia of undetermined significance AUS and Follicular Neoplasm, FN, or Oncocytic Neoplasm, ON. To our knowledge, the effect of non‐invasive follicular thyroid neoplasm with papillary‐like nuclear features (NIFTP) has not yet been studied. We compared RON and ROM between follicular type AUS (AUS‐FT) and oncocytic type AUS (AUS‐OT) and between FN and ON. Materials and Methods: We retrospectively analysed all thyroid FNAs with the diagnostic category of AUS‐other or Neoplasm (2005–2015). AUS‐FT had predominance of microfollicles and AUS‐OT had predominance of oncocytes. Histology follow‐up was then reviewed and RON, ROM was then calculated and compared (significant at p < 0.05). We repeated the search for 2018 to evaluate for NIFTP effect. Results: Pre‐NIFTP, 859/5063 cases (17%) were AUS‐FT, AUS‐OT, FN, and ON. Histology follow‐up was available for 297 cases (35%). RON was 83/183 (45%) for AUS‐FT, 35/76 (46%) for AUS‐OT, 15/25 (60%) for FN and 11/13 (85%) for ON. Post‐NIFTP, RON was 11/31 (35%) for AUS‐FT, 5/8 (63%) for AUS‐OT, 1/2 (50%) for FN and 4/5 (80%) for ON. For both periods, RON, ROM of AUS‐FT was not significantly different than AUS‐OT, and no significant differences were observed comparing FN and ON. Conclusion: The predominance of oncocytes does not modify the implied RON, ROM for categories of AUS or FN\ON, even after the adoption of NIFTP. [ABSTRACT FROM AUTHOR]

Background NIFTP is a recently introduced entity in the WHO classification of tumours of endocrine organs. It is a diagnosis made exclusively on histopathological examination of thyroid lesions. However a preoperative suspicion can be made correlating with the ultrasonographic and cytological findings. Most of these cases may be over diagnosed in cytological evaluation as Papillary thyroid carcinoma or as a Follicular variant of Papillary thyroid carcinoma. A thorough histopathological examination of all thyroidectomy specimens is the key to diagnosis of NIFTP and thus we undertook this study. Methods A retrospective analysis of thyroidectomy specimens with a histopathological diagnosis of NIFTP was done from May 2022 to May 2024, of two years duration which were received in the Department of Pathology in our Tertiary care centre at Wayanad. The slides were retrieved from the archives and the clinical, radiological and cytology evaluation data was collected from the HIS (Hospital Information System). All 7 cases were compared with their cytology reports. Statistical quantitative analysis was conducted for demographic, ultrasound findings, cytology and histopathological diagnosis. Results were presented as frequency/percentage for categorical variables. Qualitative analysis examined with detailed descriptions of cases. Results Of these cases, about 71% were females, most of them above 40 years and ultrasound diagnosis of about 57.1% cases were TIRADS III. Cytological evaluation had 42.8 % cases with Bethesda category II and 28.5% Suspicious for Malignancy. Conclusion NIFTP may not be conclusively diagnosed or suspected in a preoperative radiological or cytological evaluation. Histopathologically it may be an incidental finding in a benign multinodular goitre. So surgeons might need to have a high index of suspicion for cases of benign, solitary or multinodular thyroid lesions. [ABSTRACT FROM AUTHOR]

Background: Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was firstly described in 2016. Since NIFTP is thought a non-malignant tumor, the Bethesda system for thyroid cytology proposes two estimations of risk of malignancy of the diagnostic categories, one considering NIFTP as cancer and another one considering it as a benign neoplasm. The present study aimed to review NIFTPs in a single center, re-assess them across categories of three Thyroid Imaging Reporting and Data Systems (TIRADSs), and define the indication for biopsy according to the category-specific size cut-offs. Methods: The study period was from 2017 to 2023. The institutional database was searched for histologically proven NIFTPs with preoperative ultrasound images. NIFTPs were re-assessed according to the American College of Radiology (ACR), European (EU), and Korean (K) TIRADSs. The indication for biopsy was defined according to TIRADS category-specific size threshold. Results: Twenty NIFTPs from 19 patients were included. The median size of the NIFTPs was 23 mm. According to ultrasound, 80–85% of NIFTPs were at low-intermediate risk and 5–15% at high risk without significant difference among the tree TIRADSs (p = 0.91). The indication for FNA, according to three TIRADSs, was found in 52–58% of cases with no significant difference among systems (p = 0.96). Conclusion: NIFTPs have heterogeneous presentation according to TIRADSs with very low indication rate for FNA. [ABSTRACT FROM AUTHOR]

The classification of thyroid nodules, particularly those with a follicular growth pattern, has significantly evolved. These tumors, enriched with RAS or RAS-like mutations, remain challenging for pathologists due to variables such as nuclear atypia, invasion, mitotic activity, and tumor necrosis. This review addresses the histological correlates of benign, low-risk, and malignant RAS-mutant thyroid tumors, as well as some difficult-to-classify follicular nodules with worrisome features. One prototypical RAS-mutant nodule is non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). The assessment of nuclear characteristics in encapsulated/well-demarcated non-invasive RAS-mutant follicular-patterned tumors helps distinguish between follicular thyroid adenoma (FTA) and NIFTP. Despite this straightforward concept, questions about the degree of nuclear atypia necessary for the diagnosis of NIFTP are common in clinical practice. The nomenclature of follicular nodules lacking clear invasive features with increased mitotic activity, tumor necrosis, and/or high-risk mutations (e.g., TERT promoter or TP53) remains debated. Invasion, particularly angioinvasion, is the current hallmark of malignancy in RAS-mutant follicular-patterned neoplasms, with follicular thyroid carcinoma (FTC) as the model. Assessing the tumor interface is critical, though full capsule evaluation can be challenging. Multiple levels and NRASQ61R-specific immunohistochemistry can aid in identifying invasion. Controversies around vascular invasion persist, with ancillary stains like CD31, ERG, and CD61 aiding in its evaluation. Moreover, the review highlights that invasive encapsulated follicular variant papillary thyroid carcinoma (IEFVPTC) is closely associated with FTC, suggesting the need for better nomenclature. The concept of "high-grade" differentiated carcinomas, applicable to FTC or IEFVPTC with necrosis and/or high mitotic activity, is also discussed. [ABSTRACT FROM AUTHOR]

BackgroundThe risk of malignancy in thyroid nodules is higher in children than in adults, often necessitating a more aggressive endocrine and surgical approach. However, given that not all solid thyroid nodules are malignant, a more conservative approach may also be appropriate in certain cases.ObjectiveThis study aims to present an illustrative analysis of the pathological foundations underlying the sonographic appearance of benign, borderline, and malignant thyroid nodules in the pediatric population at a single tertiary thyroid center.MethodsA total of 47 well-documented pediatric patients referred for thyroid surgery between 2010 and 2023 were analyzed. This retrospective assessment included an examination of demographic data, hormonal profiles, ultrasound findings, and histopathology reports.ResultsUltrasound and histopathology of thyroid nodules provided insights into subgroup differentiation. Benign nodules like dyshormonogenetic goiter showed solid hypoechoic features on ultrasound and dense fibrosis on histopathology, while thyroid follicular nodular disease exhibited isoechoic nodules with halos, histologically revealing dilated follicles. In borderline tumors, well-differentiated tumor of uncertain malignant potential (WDT-UMP) nodules were hypo/hyperechoic with occasional capsular invasion, resembling papillary thyroid carcinoma (PTC) features histologically. Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) appeared as well-defined hypoechoic nodules with a hypoechoic rim, with histology showing follicular architecture and PTC nuclear features, but no invasion. Follicular tumor of uncertain malignant potential (FT-UMP) displayed hypo/hyperechoic patterns and indistinct borders, with uncertain capsular invasion and no PTC nuclear features. Malignant lesions showed distinct patterns: PTC as hypoechoic, irregular nodules with mixed vascularization, follicular thyroid carcinoma as large, hyperechoic nodules with invasive features, and poorly differentiated thyroid carcinoma (PDTC) as heterogeneous hypoechoic masses.ConclusionBecause of the significant overlap in sonographic features among benign, borderline, and certain malignant thyroid lesions in pediatric patients, ultrasonography alone is insufficient for accurate risk stratification. This overlap necessitates referrals for fine-needle aspiration biopsy (FNAB) in children more frequently than in adults. Future studies utilizing artificial intelligence (AI) to predict clinical outcomes in thyroid nodule diagnostics may offer new advancements, particularly given the increasing number of pediatric patients with solid thyroid lesions.

Background: Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a newly added entity in the fourth edition of the WHO Classification of Tumors of Endocrine Organs (2017). It is regarded as a neoplasm with very low malignant potential, thus affecting further treatment of the patients. Aims: To study the recently diagnosed entity, NIFTP, as not many cases have been reported of the same. Materials and Methods: A retrospective analysis of all thyroid neoplasms received in the Department of Pathology of our institute over two years was done. Out of the 188 cases that we reported, 38 were of non-invasive follicular neoplasms. Results: Thirty-two patients were female, whereas six patients were male. Thirty-five patients presented with solitary thyroid nodule and the others had an ill-defined thyroid swelling. Thirty-four patients had normal thyroid profile while two patients each presented with hypothyroidism and hyperthyroidism. Conclusion: It is crucial to carefully study the histopathological features of solitary thyroid swellings and correlate with clinical and radiological findings. The recently added diagnostic category of NIFTP helps clinicians prevent over-treatment of a group of low-risk thyroid tumors. [ABSTRACT FROM AUTHOR]

The term noninvasive tumor with a follicular growth pattern and nuclear features of papillary thyroid cancer (NIFTP) is used to describe a tumor currently considered as a pre-malignant lesion for which a conservative therapeutic approach (i.e., lobectomy without radioiodine therapy) is strongly suggested. However, some patients with NIFTP and loco-regional or distant metastases have been already reported. We present an adult male patient with a final histological diagnosis of NIFTP and lymph node metastasis noted at post-therapy whole-body scintigraphy performed some days after radioiodine therapy. [ABSTRACT FROM AUTHOR]

Background: Noninvasive follicular thyroid neoplasm with papillary‐like features (NIFTP) was introduced in 2016 replacing noninvasive follicular variant of papillary thyroid carcinoma, with recommendations to label them "noncancer." To avoid reducing risk of malignancy (ROM) and overdiagnosing NIFTP as malignant, some authors required restricted cytologic criteria (RC) for a definitive diagnosis of papillary thyroid carcinoma (PTC), including papillae, psammoma bodies. or ≥3 nuclear pseudoinclusions. Since then, NIFTP criteria have been revised, biologic behavior better understood, and incidence reported to be much lower than initially anticipated. This study examines the impact of RC on PTC cytologic diagnoses, ROM, and detection of clinically significant carcinomas (CSC). Materials and Methods: A total of 207 thyroid FNAs originally diagnosed as PTC and suspicious for PTC (SPTC) with surgical follow‐up were evaluated. RC were retrospectively applied to cases as a requirement for diagnosing PTC, and cases that did not meet RC were reclassified as SPTC. ROMs and diagnostic accuracies of pre‐ and post‐RC diagnoses were correlated with followup CSC. Results: RC were met in 118/142 (83%) and 20/65 (31%) of cases originally diagnosed as PTC and SPTC, respectively. Post‐RC, 29% (19/65) of CSC originally diagnosed as SPTC were upgraded to PTC, and 17% (24/142) of CSC originally diagnosed as PTC were downgraded to SPTC. No NIFTPs were diagnosed as malignant. Conclusions: RC should not be required for a definitive diagnosis of PTC when other nuclear features of PTC are diffuse and overt. Applying RC, however, helps the pathologist arrive at a more definitive diagnosis of PTC in suspicious cases. Restrictive criteria are not required for a definitive diagnosis of papillary thyroid carcinoma, but they are helpful in arriving at a definitive diagnosis in suspicious cases. [ABSTRACT FROM AUTHOR]

Objective: To categorize the cytological pattern according to Bethesda System for Reporting Thyroid Cytopathology and correlate them with the histopathological diagnosis. Calculate the sensitivity, specificity, accuracy of thyroid lesions and also the risk of malignancy in each category. Material &Methods: A retrospective re- evaluation of all consecutive thyroid fine-needle aspiration cytology fine-needle aspiration cytology smears was done from 2016 to 2019. Results: 429 patients were subjected to fine-needle aspiration cytology while histopathology was available for 109 cases. The sensitivity was 84.6% and specificity was96.4% with accuracy of 93.6%. The risk of malignancy for categories I, II, III, IV, V and VI was 0%, 1.4%, 20%, 20%, 100% and 100% respectively. Conclusion: The study shows application of Bethesda System for Reporting Thyroid Cytopathology in a tertiary care centre in a developing country is a successful step to bring about uniformity and standardise thyroid cytology reporting by reducing the ambiguity.

Objective: In 2016 a group of expert endocrine pathologists proposed a new terminology, NIFTP (Non-invasive follicular thyroid neoplasm with papillary-like nuclear features) for a histological subtype of thyroid carcinoma (encapsulated follicular variant of papillary thyroid carcinoma, non-invasive type). In this study, we aimed to assess on a retrospective basis the epidemiological trend and overall incidence of NIFTP in Mureș county, Romania, over a six-year period (2016-2021).

Few studies have focused on reclassifying follicular adenomas (FAs) as noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs), but none have been conducted in America or Europe. The aims of this study were to analyze the prevalence of NIFTP reclassified from follicular variant of papillary thyroid carcinomas (FVPTCs) and FAs before NIFTP was defined in the literature, the rate of NIFTP among PTC (papillary thyroid carcinomas) established in real time between 2017 and 2022, and demographic, ultrasonographic, and cytologic characteristics of NIFTPs compared with FVPTCs and FAs. This was a retrospective cohort study of tumors diagnosed as PTCs (n = 247) and FAs (n = 144) at a Brazilian hospital. Overall, 13.4% of PTCs and 7% of FAs were reclassified as NIFTPs. The rate of real-time diagnosed NIFTPs among PTC was 12.3%. The median tumor size was larger among NIFTPs (3.0 cm) than FVPTCs (1.1 cm; P < 0.01). A high-risk ultrasonographic pattern was rare in NIFTPs (5.6%). The cytologic classifications differed between FVPTCs and NIFTPs (P < 0.01), and the most frequent category among NIFTPs was 'follicular neoplasm' (52.6%). The category 'suspicious for malignancy' was frequent in FVPTCs and rare (5.3%) in NIFTPs. In conclusion, FVPTCs and FAs may be reclassified as NIFTPs. The prevalence of NIFTPs reclassified from FAs was lower in our cohort than in Asian studies. The rate of NIFTPs reclassified from PTC was similar to that of NIFTPs diagnosed in real time and was aligned with rates reported in studies from America and Europe. Preoperative features could not differentiate NIFTPs from FVPTCs or FAs. [ABSTRACT FROM AUTHOR]

Introduction: 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). Settings and Design: Descriptive study Methods and Material: 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. Statistical Analysis Used: The descriptive statistics were used to analyse the collected data. Aim: This study was undertaken to compare the old (2004) and new (2016) WHO classifications and their importance in the treatment of thyroid malignancies. Results: 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%). Conclusion: 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). [ABSTRACT FROM AUTHOR]

This multi‐institutional study investigated non‐invasive follicular thyroid neoplasm with papillary‐like nuclear features (NIFTP) frequency and its diagnostic significance in Japan. We reviewed 4008 thyroid nodules resected in six institutions before NIFTP was proposed. Overall, 26 cases diagnosed as non‐invasive encapsulated follicular variant of papillary thyroid carcinoma (PTC) and 145 cases of follicular thyroid adenoma (FTA) were included. Of these nodules, 80.8% and 31.0%, respectively, were NIFTPs. In five institutions, NIFTPs were more commonly found in FTA than in PTC nodules. When NIFTP was included with PTC, the overall prevalence was 2.3%, with rates in five institutions below 5.0% (0.8%–4.4%). One NIFTP case with nuclear score 3 revealed nodal metastasis 2.5 years post‐resection, and the carcinoma cells were immunohistochemically positive for BRAF. FTAs or NIFTPs with nuclear score 2 did not metastasize. NIFTP was more common among FTA than among PTC nodules, possibly due to underdiagnosis of PTC on nuclear findings. Considering the clinical findings, molecular pathogenesis, and therapeutic strategy in Japan, NIFTP with nuclear score 2 is not different from FTA, and use of this entity terminology is not meaningful. In contrast, NIFTP with nuclear score 3 has potential for metastasis and BRAFV600E mutation. Therefore, in NIFTP cases, nuclear scores 2 and 3 should be separately reported. [ABSTRACT FROM AUTHOR]

Simple Summary: The incidence of thyroid cancer (TC) has increased greatly since the 1970s, mostly because of higher detection of the small forms of papillary thyroid cancer (PTC). Despite this main and popular opinion, an increase in the occurrence of the larger forms of TC has also been observed. Due to some noticed trends concerning TC incidence and behavior, the management of these neoplasms has also changed in recent years. "Cancer screening activity", which is the most popular of the aforementioned events, might have increased the PTC number during the analyzed period. However, the observed increase in the occurrence of TC continued to a point in time where there was a slowdown and even a reversal. This phenomenon is still debated and worthy of further investigation. Because of ambiguous and widely debated observations concerning the incidence, trend, and management of TC, we performed this analysis. We drew attention to some events, such as "cancer screening activity", introduction of noninvasive follicular neoplasm with papillary-like nuclear features (NIFTP) to TC types, possibility of papillary thyroid microcarcinoma (PTMC) active surveillance (AS), occurrence of personalized medicine in TC management, and, finally, COVID-19 pandemic time. Because of the opinion that all changes have been made mostly by PTC, we compared it to the remaining types of TC in terms of incidence, clinical and pathological characteristics, and treatment. We analyzed patients treated in a single surgical center in eastern Europe (Poland). The prevalence of TC significantly increased from 5.15% in 2008 to 13.84% in 2015, and then significantly decreased to 1.33% in 2022 when the COVID-19 pandemic lasted (p < 0.0001). A similar trend was observed for PTC, when the incidence significantly increased to 13.99% in 2015 and then decreased to 1.38% in 2022 (p < 0.0001). At that time, the NIFTP category was introduced, and observation of PTMC began. The prevalence of FTC and MTC also increased until 2015 and then decreased. Significant differences in age, types of surgery, necessity of reoperation, and pTNM between PTCs and other types of TCs were observed. The average age was significantly lower in PTC patients than in patients with the remaining types of TC (p < 0.0001). Four milestones, including NIFTP introduction, the possibility of PTMC AS, personalized cancer medicine, and the COVID-19 pandemic, may have influenced the general statistics of TC. [ABSTRACT FROM AUTHOR]

Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a low-risk thyroid tumor with a favorable prognosis. Nonetheless, differentiating NIFTP from other thyroid tumors remains challenging, necessitating reliable diagnostic markers. This study is aimed at discovering NIFTP-specific mRNA markers through RNA sequencing analysis of thyroid tumor tissues. We performed mRNA expression profiling for 74 fresh frozen thyroid tissue samples, including NIFTP and benign and malignant follicular-cell-derived tumors. NIFTP/malignant tumors showed 255 downregulated genes and 737 upregulated genes compared to benign tumors. Venn diagram analysis revealed 19 significantly upregulated and 7 downregulated mRNAs in NIFTP. Akaike information criterion analysis allowed us to select OCLN, ZNF423, LYG1, and AQP5 mRNA markers. We subsequently developed a predictive model based on logistic regression analysis using these four mRNAs, which we validated in independent samples (n = 90) using a qRT-PCR assay. This model demonstrated high accuracy in predicting NIFTP in discovery dataset (AUC (area under the receiver operating characteristic) = 0.960) and the validation dataset (AUC = 0.757). Our results suggest that OCLN, ZNF423, LYG1, and AQP5 mRNA markers might serve as reliable molecular markers for identifying NIFTP among other thyroid tumors, ultimately aiding in accurate diagnosis and management of NIFTP patients. [ABSTRACT FROM AUTHOR]

Background: An increasing amount of data is being published, which risk-stratify thyroid tumors according to genetic signatures and histological morphology. Typically, follicular patterned lesions have been shown to harbor RAS-like mutations with more indolent behaviors. Our study aims to examine the extent of similarity among three groups of follicular patterned lesions with papillary nuclear features—noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) with capsular invasion and/or angioinvasion, and infiltrative follicular variant of papillary thyroid carcinoma (iFVPTC)—to help clarify whether NIFTP and EFVPTC represent a histological continuum and the degree to which the genomic landscape further separates higher risk follicular patterned tumors such as iFVPTC from more indolent ones (EFVPTC and NIFTP). Methods: ThyroSeq test results were compared for cases with histological NIFTP, EFVPTC, and iFVPTC in this retrospective study. Genetic drivers were subcategorized by level of aggressiveness. Gene expression alterations (GEAs) and copy number alterations (CNAs) were compared among the three histological groups. Results: NIFTP and EFVPTC cases displayed predominantly RAS-like alterations (100% and 75%, respectively) and RAS-like GEAs (55.2% and 47.2%, respectively), and many showed CNAs with 22q-loss. Despite a predominance of RAS-like alterations, EFVPTC cases showed molecular heterogeneity with significantly more intermediate and aggressive drivers (22.3% of cases) than NIFTP (0%) (p = 0.0068). iFVPTC cases displayed molecular profiles in between that of traditional follicular patterned lesions and classical papillary thyroid carcinoma, predominantly displaying intermediate and aggressive drivers (61.6%), which was significantly higher than that of EFVPTC (22.3%, p = 0.0158) and NIFTP (0%, p < 0.0001), illustrating the higher MAP kinase activity of iFVPTC. There was no significant difference, however, in comparing GEAs among the three histological groups. Conclusions: While follicular patterned lesions with papillary nuclear features overall tend to display RAS-like alterations, EFVPTC cases, followed by iFVPTC in this series, showed increasing proportions of more aggressive drivers. EFVPTC and NIFTP show much molecular overlap, with predominance of RAS-like alterations, suggesting that these tumors are part of a genetic continuum, while still ranked differentially. Preoperative molecular testing can potentially distinguish EFVPTC and iFVTPC from NIFTP based on a particular molecular signature, optimizing patient management. [ABSTRACT FROM AUTHOR]

There is no accepted consensus or algorithm for the preoperative diagnosis of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in patients with thyroid nodules. In this study, we evaluated the importance of preoperative neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in the differential diagnosis of NIFTP. Pathology preparations of 209 patients with a follicular variant of papillary thyroid carcinoma (FVPTC) diagnosed after thyroid surgery in a tertiary health center between January 2010 and January 2020 were re-evaluated. Patients were divided into NIFTP and encapsulated follicular variant papillary thyroid carcinoma (EFVPTC) to compare. Of the patients, 58 (27.7%) were NIFTP, and 151 (72.3%) were EFVPTC. There was no statistically significant difference in terms of age (p = 0.46), tumor size (p = 0.51), gender (p = 0.48), and surgical technique (p = 0.78) between the groups. The probability of the neutrophil-to-lymphocyte ratio (NLR) > 2 is more common in the EFVPTC group. It was statistically significant that the NIFTP group was 1.96 times more likely to have NLR > 2 (OR: 1.96, 95% CI: 1.06–3.63) (p < 0.05). However, there was no risk difference between the groups in terms of the platelet-to-lymphocyte ratio (PLR) (OR: 0.76, 95% CI: 0.41–1.43) (p > 0.05). The diagnosis of NIFTP should be kept in mind in the evaluation of patients whose thyroid fine-needle aspiration (FNA) biopsy results are in the intermediate group. NIFTP exhibits better prognostic findings than classic thyroid papillary cancer and EFVPTC. Therefore, preoperative diagnosis of NIFTP in line with laboratory, ultrasonography, and FNA findings will save the patient from unnecessary overtreatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Intoduction: 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. Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Noninvasive follicular thyroid neoplasm with papillary-like features (NIFTP), represents a distinct class of thyroid neoplasms with very low risk of adverse outcome and a set of strict histologic criteria. Introduction of NIFTP as a non-cancer has had an appreciable decrease in risk of malignancy and body of literature on this entity continues to grow. In this study, we reviewed clinical, fine-needle aspiration cytology (FNAC), imaging, and molecular findings of histologically proven NIFTPs at our institution. Thyroid resections during an 11-year period, with histologic diagnosis of follicular variant of papillary thyroid carcinoma (FVPTC), were retrospectively reviewed to identify NIFTP. Ultrasonographic appearance, FNA findings, and molecular findings were also reviewed. Of 244 cases of FVPTC identified, 74 (30%) cases were reclassified as NIFTP. Mean tumor size was 2.5 cm. Of 33 patients with lymph node dissection, none had lymph node metastases. On imaging, 36 NIFTP (49%) showed vascularity, 25 (33%) were isoechoic to hypoechoic, there were calcifications in 14 cases (19%), and 7 cases (9%) showed a hypoechoic rim. Bethesda III/IV was the most common interpretation rendered on FNAC (31%). Seven cases had NRAS mutations and 1 case had BRAF V600E mutation. The remaining cases were either negative for BRAF V600E or had no identifiable molecular alterations. A significant percentage of tumors previously diagnosed as FVPTC were reclassified as NIFTP. This tumor cannot be reliably diagnosed preoperatively on FNAC, shows no characteristic features on ultrasound and has low suspicion of malignancy. BRAF V600E mutations are infrequent in NIFTP. • 31% of tumors that were previously diagnosed as FVPTC in our institution were reclassified as NIFTP. • NIFTP are indolent with no increased incidence of lymph node metastases and no signs of recurrence after mean follow-up of 48 months. • NIFTP cannot be reliably diagnosed preoperatively on FNAC alone, and a majority of these cases fall under Bethesda III/IV category. • The majority of NIFTP show absence of the BRAF V600E mutation. [ABSTRACT FROM AUTHOR]

Non-invasive follicular thyroid neoplasm with papillary like nuclear features (NIFTP) was introduced in 2017 WHO Classification of Endocrine Tumors. In this study, we aim to characterize the molecular and ultrasonographic profiles of NIFTP and evaluate the performance of fine needle aspiration (FNA) cytology. Consecutive thyroid resections at our institution between 2018 and 2022 were collected; 1282 thyroid resections were identified. NIFTP was diagnosed in 109 cases (prevalence: 8.5 %); 65 (60 %) were the targeted nodules with an average size of 2.5 cm. Among these 65 targeted, 27 had Afirma testing results, 44 had Thyroid Imaging Reporting and Data System (TIRADS) scores, and 53 had FNA results. Of the 27 cases with Afirma reports, 23 were labeled "suspicious", including 5 with RAS -related mutations (risk of malignancy (ROM) 75 %) and 17 without a reportable genetic alternation (ROM 50 %). 60 % cases with TIRADS scores were classified as TIRADS 4, while 16 % were classified as TIRADS 5. The majority of the 53 FNA cases had a diagnosis of AUS/FLUS (53.7 %) or FN (31.5 %). One additional targeted nodule with a diagnosis of NIFTP had BRAFV600E mutation and was reclassified as papillary thyroid carcinoma. In summary, the majority of the targeted NIFTPs had "suspicious" Afirma testing results (85 %), TIRADS 4 scores (60 %) and either AUS/FLUS (53.7 %) or FN (31.5 %) FNA results. The sensitivity and specificity of cytology for diagnosing NIFTP were 90 % and 57 %, respectively, with a positive predictive value (PPV) of 16 % and negative predictive value of 98 %. • Non-invasive follicular thyroid neoplasm with papillary like nuclear features: low-risk tumor • 85 % had indeterminate thyroid nodule fine-needle aspiration cytologic results. • 60 % had Thyroid Imaging Reporting and Data System (TIRADS) score of 4 (Suspicious of malignancy). • 85 % had suspicious Afirma results, majority classified as "Others" with a ROM of 50 %. • The sensitivity and negative predictive value of cytology were 90 % and 98 %. [ABSTRACT FROM AUTHOR]

IntoductionIdentification 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.MethodsPrimary 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.ResultsOur 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.ConclusionDownregulation 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.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Differentiated thyroid carcinoma is one of the commonest malignancies in head and neck region. Among differentiated thyroid carcinoma, papillary carcinoma is the commonest. Encapsulated follicular variant of papillary thyroid carcinoma tumors are very indolent tumors which behave like benign tumors. Many tumors have been over diagnosed and over treated in spite of their indolent nature. We aimed to find out if total thyroidectomy is really required for very low grade tumors like encapsulated FVPTC. We operated 672 patients of thyroid disease during 2012 to 2020 in SMS Medical College, Jaipur. Out of 256 patients, 199 patients (78%) had papillary carcinoma of thyroid. Classical variant was present in 40% and follicular variant was present in 35% (N—69). Out of 69 patients with follicular variant of PTC, 59 patients had well encapsulated type of follicular variant of PTC while 10 patients had invasive type of follicular variant of PTC. Encapsulated FVPTC are less aggressive and indolent tumors. They should be treated more conservatively. Hemithyroidectomy is sufficient treatment for its complete cure. Out of 69 patients with Follicular variant of PTC, 59 patients had encapsulated disease. Out of 59 patients, 14 (24%) had bilateral nodular disease. 45 (77%) patients had unilateral disease; multicentric in one lobe in 9 (15%) patients and unicentric in 36 (61%) patients. However, encapsulated FVPTC was only found in predominant lobe and the non dominant lobe had benign disease. [ABSTRACT FROM AUTHOR]

Context: Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was introduced as a new entity replacing the diagnosis of noninvasive encapsulated follicular variant of papillary thyroid carcinoma (PTC). Significant variability in the incidence of NIFTP diagnosed in different world regions has been reported., Objective: To investigate the rate of adoption of NIFTP, change in practice patterns, and uniformity in applying diagnostic criteria among pathologists practicing in different regions., Methods: Two surveys distributed to pathologists of the International Endocrine Pathology Discussion Group with multiple-choice questions on NIFTP adoption into pathology practice and whole slide images of 5 tumors to collect information on nuclear score and diagnosis. Forty-eight endocrine pathologists, including 24 from North America, 8 from Europe, and 16 from Asia/Oceania completed the first survey and 38 the second survey., Results: A 94% adoption rate of NIFTP by the pathologists was found. Yet, the frequency of rendering NIFTP diagnosis was significantly higher in North America than in other regions (P = .009). While the highest concordance was found in diagnosing lesions with mildly or well-developed PTC-like nuclei, there was significant variability in nuclear scoring and diagnosing NIFTP for tumors with moderate nuclear changes (nuclear score 2) (case 2, P < .05). Pathologists practicing in North America and Europe showed a tendency for lower thresholds for PTC-like nuclei and NIFTP than those practicing in Asia/Oceania., Conclusion: Despite a high adoption rate of NIFTP across geographic regions, NIFTP is diagnosed more often by pathologists in North America. Significant differences remain in diagnosing intermediate PTC-like nuclei and respectively NIFTP, with more conservative nuclear scoring in Asia/Oceania, which may explain the geographic differences in NIFTP incidence., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)