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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]

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.

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]

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]

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).

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]

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]

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]

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]

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]

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]

Abstract Background The term non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was recently proposed as a non-malignant thyroid lesion with indolent behavior that does not require post-operative radio-iodine treatment. We are reporting a case of NIFTP with bone metastasis that is the second case reported so far. Case presentation We describe a 38-year-old woman who presented with an indeterminate thyroid nodule and underwent total thyroidectomy with the finding of NIFTP on careful pathologic examination. However, her initial follow-up evaluation revealed a serum thyroglobulin level of > 300 ng/ml and a diagnostic whole body 131I scan demonstrated a focus of increased uptake in the left hemipelvis, confirmed on CT scan to be a lytic lesion in the left iliac bone. She was treated with 7.4GBq (200 mCi) of 131I and her follow-up 1 year later revealed an undetectable serum thyroglobulin and a negative whole body 131I scan with no visible uptake in the iliac bone indicating an excellent response. Conclusion This case presentation reminds us to be alert to the rare occurrence of distant metastasis in NIFTP and the need for a case by case analysis and continuing post-operative follow-up for detection of residual or recurrent disease.

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

Besides the two main histologic types of papillary thyroid carcinoma (PTC), the classical PTC (CL-PTC) and the follicular variant PTC (FV-PTC), several other variants are described. The encapsulated FV-PTC variant was recently reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) due to its similarities to benign lesions. Specific molecular signatures, however, are still unavailable. It is well known that improper DNA repair of dysfunctional telomeres may cause telomere-related genome instability. The mechanisms involved in the damaged telomere repair processing may lead to detrimental outcomes, altering the three-dimensional (3D) nuclear telomere and genome organization in cancer cells. This pilot study aimed to evaluate whether a specific 3D nuclear telomere architecture might characterize NIFTP, potentially distinguishing it from other PTC histologic variants. Our findings demonstrate that 3D telomere profiles of CL-PTC and FV-PTC were different from NIFTP and that NIFTP more closely resembles follicular thyroid adenoma (FTA). NIFTP has longer telomeres than CL-PTC and FV-PTC samples, and the telomere length of NIFTP overlaps with that of the FTA histotype. In contrast, there was no association between BRAF expression and telomere length in all tested samples. These preliminary findings reinforce the view that NIFTP is closer to non-malignant thyroid nodules and confirm that PTC features short telomeres.

Background: The introduction of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) has been shown to decrease the risk of malignancy (ROM) in The Bethesda System for Reporting Thyroid Cytopathology. This knowledge may alter the management of patients with thyroid nodules. Objectives: To correlate cytological diagnosis with histological diagnosis for establishing the ROM of all Bethesda system categories after the introduction of NIFTP. Methods: This was a retrospective cohort study. All consecutive fine-needle aspiration cytology (FNAC) specimens collected from January 1, 2013, to December 31, 2017, at King Abdullah Medical City, Jeddah, Saudi Arabia, were assessed, and patients who underwent surgical excision of thyroid nodules were further analyzed. The ROM and overall ROM for each Bethesda category were calculated with and without considering NIFTP as a malignant tumor. Results: Overall, 1066 FNAC specimens were collected, of which 281 had a surgical correlation. Our cases included 18 (6.4%) non-diagnostic (ND), 109 (38.8%) benign, 28 (9.9%) atypia/follicular lesion of undetermined significance (AUS/FLUS), 39 (13.8%) follicular neoplasm or suspicion for follicular neoplasm (FN/SFN), 20 (7.1%) suspicion for malignancy (SM), and 67 (23.8%) malignant (POM) cases. After considering NIFTP diagnosis on resection specimens, the ROM decreased as follows: ND, 38.8% to 27.7% (P = 0.2388); benign, 21.1% to 11.9% (P = 0.0343); AUS/FLUS, 50% to 39.2% (P = 0.2089); FN/SFN, 53.8% to 33.3% (P = 0.0336); SM, 85% to 75% (P = 0.2147); POM, 95.5% to 88% (P = 0.0582). Conclusion: The introduction of NIFTP would significantly decrease the ROM of thyroid FNAC in both benign and FN/SFN categories of the Bethesda system. [ABSTRACT FROM AUTHOR]

Objective The primary objective of this study is to comprehensively evaluate nodular thyroid lesions. By analyzing the morphological characteristics of surgically resected specimens and biopsies, the aim is to establish correlations between the patterns, corresponding clinical diagnoses and radiological findings. Furthermore, the study will investigate cases where there is a discrepancy between imaging and pathological assessments, with the goal of understanding the contributing factors to this discordance and improving diagnostic accuracy. Methodology This retrospective observational study utilized convenience sampling to recruit participants. Sample size was determined using GPower software (Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany). Statistical analysis was performed using Jamovi 2.3.28 (Jamovi Research, Vienna, Austria). The Chi-square test was employed to assess the association between the Thyroid Imaging Reporting and Data System (TIRADS) score and histopathological diagnosis. Receiver operating characteristic (ROC) analysis was conducted to identify the optimal TIRADS cut-off point for classifying nodules as malignant and to evaluate the diagnostic accuracy of TIRADS. Discordant cases between histopathological and radiological findings were analyzed to investigate potential discrepancies. Result Taking into consideration histopathology report as a gold standard, correlation of TIRADS with histopathology findings, TIRADS showed 73.08% sensitivity and 81.08% specificity, showing the strongest balance between sensitivity and specificity, as demonstrated by the Youden's Index and Metric Score. The area under the curve (AUC) remains constant at 0.805, suggesting a consistent overall discriminative ability of the TIRADS scale. Conclusion A primary advantage of this study is its exclusive focus on surgically resected nodules, which allows for definitive histological confirmation and thereby ensures the most accurate diagnostic assessment., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Research Ethics Committee (for Medical PG Students), , Sri Ramachandra Institute of Higher Education and Research issued approval CSP-MED/24/JUL/106/234. Institutional Research Ethics Committee (for Medical PG Students), Sri Ramachandra Institute of Higher Education and Research, thank you for submitting the study proposal. Institutional Ethics Committee approves the project. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Rajyakodi et al.)

Background: The term non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was recently proposed as a non-malignant thyroid lesion with indolent behavior that does not require post-operative radio-iodine treatment. We are reporting a case of NIFTP with bone metastasis that is the second case reported so far. Case presentation: We describe a 38-year-old woman who presented with an indeterminate thyroid nodule and underwent total thyroidectomy with the finding of NIFTP on careful pathologic examination. However, her initial follow-up evaluation revealed a serum thyroglobulin level of > 300 ng/ml and a diagnostic whole body 131I scan demonstrated a focus of increased uptake in the left hemipelvis, confirmed on CT scan to be a lytic lesion in the left iliac bone. She was treated with 7.4GBq (200 mCi) of 131I and her follow-up 1 year later revealed an undetectable serum thyroglobulin and a negative whole body 131I scan with no visible uptake in the iliac bone indicating an excellent response. Conclusion: This case presentation reminds us to be alert to the rare occurrence of distant metastasis in NIFTP and the need for a case by case analysis and continuing post-operative follow-up for detection of residual or recurrent disease. [ABSTRACT FROM AUTHOR]

Background and Objectives: We aimed to assess the diagnostic value of various immuno-histochemical (IHC) markers and panels for differentiation among benign follicular nodules (BFNs), non invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs), non invasive encapsulated follicular variants of papillary thyroid carcinoma (NEFVPTCs), and infiltrative FVPTC (IFVPTC). Materials and Methods: Sixty-three cases were classified as BFNs, NIFTPs, NEFVPTCs, or IFVPTCs and were evaluated using the following markers: CK19, CD56, galectin-3, CITED1, HBME1, VE1, and TROP-2. Results: The IHC results for NIFTP and NEFVPTC exhibited no statistically significant differences. In differentiating IFVPTCs from BFNs and NIFTPs/NEFVPTCs, galectin-3 and TROP-2 were the markers with the highest sensitivity plus high specificity, respectively. In various combinations, panel co-expression of two markers, including galectin-3 and/or HBME-1 and/or TROP-2, and the combination of galectin-3 and TROP-2 co-expression could achieve 100% in all aspects. In terms of discrimination of BFNs from NIFTP/NEFVPTC, CK19 was the single most sensitive marker (81.3%), while CD56 was the most specific (100%). The panel consisting of CK19 and/or HBME-1 exhibited the greatest sensitivity (96.9%), but the panel with CD56 and/or HBME-1 exhibited the greatest specificity (90.5%). Conclusions: Our results broaden the use of IHC markers for differential diagnoses among the four groups of follicular-based lesions. In addition, the similar IHC profiles of NIFTP and NEFVPTC also suggest the original criterion of <1% papillae within tumors, providing a reliable NIFTP diagnosis. Their close relationship may represent a spectrum of progressing neoplasia. [ABSTRACT FROM AUTHOR]

Abstract Background An international group of experts recommended reclassifying non-invasive follicular variant of papillary thyroid cancers (FVPTC) as ‘non-invasive follicular thyroid neoplasm with papillary-like nuclear features’ (NIFTP) in April 2016. The purpose of this study was to establish preoperative clinical, laboratory, ultrasonographic, and cytological variables, which can differentiate NIFTP from FVPTC. Methods We conducted a retrospective chart review of consecutive patients from a single institution evaluated between January 2012 and December 2017. 203 adult patients underwent lobectomy or total thyroidectomy for a FVPTC during that period. Each patient’s medical chart was reviewed and information on pre-operative variables was recorded. An expert pathologist reviewed all surgical specimens and reclassified a subset of FVPTC as NIFTP according to the specific criteria. Results Overall, 44 patients were included in the NIFTP group and 159 in the non-NIFTP group. Mean age was 50.1 years in the NIFTP group and 50.7 in the non-NIFTP group. Most patients were female (86.4% (38/44) in the NIFTP group vs 79.8% (127/159) in the non-NIFTP group). More patients underwent lobectomy in the NIFTP group (50% (22/44) vs 16.4% (26/159) in the non-NIFTP group, p =

The recent reclassification of a follicular variant of papillary thyroid carcinoma (FVPTC), subset as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), aims to avoid overtreatment of patients with an indole nt lesion. The diagnosis of NIFTP has recently been revisited using more rigid criteria. Th is study presents histological and molecular findings and a long clinical follow-up of 94 FVPTC , 40 cases of follicular adenoma (FTA) and 22 cases of follicular carcinoma (FTC) that w ere classified before the advent of the NIFTP reclassification. All slides were reviewed u sing these rigid criteria and analysis of numerous sections of paraffin blocks and reclassified as 7 NIFTPs, 2 EFVPTCs, 29 infiltrative FVPTC (IFVPTCs), 57 invasive EFVPTC (I-EFVPTCs), 39 FTAs and 22 FTCs. Remarkably, EFVPTC and NIFTP patients were all free of disease at the end of follow-up and showed no BRAF mutation. Only one NIFTP sample harbored mut ations, an NRAS Q61R. PAX8/PPARG fusion was found in I-EFVPTCs and FTC. Although additional stu dies are needed to identify a specific molecular profile to aid in the diagnosis of lesions with borderline morphological characteristics, we confirmed that the BRAF V600E mutation is an important tool to exclude the diagnosis of NIFTP. We also show that rigorous histopathological criteria should be strongly followed to avoid missing lesions in which more aggressive behavior is present, mainly via the analysis of capsule or vascular invasion and the presence of papillary structures.

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

Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was introduced as a separate entity by the World Health Organization in 2017 with strict inclusion and exclusion criteria. Most NIFTP cases have been reported in adults and few cases have been diagnosed in children. Here, we present a classic case of NIFTP affecting a 10-year old female child. We also review previous reports of NIFTP in children regarding size, focality, nodal metastasis, recurrence, type of operation and follow-up data. The present report adds a new case of NIFTP in the paediatric age group characterized by multifocality, absence of nodal invasion and indolent course until last follow-up, recommending less aggressive management.

Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was introduced as a separate entity by the World Health Organization in 2017 with strict inclusion and exclusion criteria. Most NIFTP cases have been reported in adults and few cases have been diagnosed in children. Here, we present a classic case of NIFTP affecting a 10-year old female child. We also review previous reports of NIFTP in children regarding size, focality, nodal metastasis, recurrence, type of operation and follow-up data. The present report adds a new case of NIFTP in the paediatric age group characterized by multifocality, absence of nodal invasion and indolent course until last follow-up, recommending less aggressive management.

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

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

Currently around the world has significantly increased the detection of thyroid nodules. Patients are 60 years old have nodules in the thyroid gland in about 50% of cases and the growth of diagnostics nodules is mainly due to the expansion of the using of screening ultrasound of the thyroid gland. The gold standard of diagnosis after ultrasonography remains fine-needle aspiration biopsy, however, approximately 1030% of cases, cytological result is indeterminate. The indeterminate diagnosis category represents a challenge to clinicians, as most nodules in cases of indeterminate thyroid FNAs are found to be benign in the surgically resected specimens. In this regard, additional methods are needed for pre-operative diagnosis, which would help to understand the nature of thyroid nodules, to reduce the number of diagnostic operations and to improve the quality of patient treatment. In recent years, significant changes have occurred in the diagnosis of thyroid tumors, which we will consider in this review: revision of the protocol TI-RADS, classification Bethesda, change in histological classification and the emergence of a new group of NIFTP. A large number of studies in the field of molecular diagnostics, we will consider the possibility of using molecular testing for diagnostic purposes and the introduction of these methods in clinical practice.

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

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

The renaming of encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) to noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was proposed by a group of experts in 2016 to prevent overtreatment of indolent, low-risk thyroid cancers. The aim of this study was to estimate the incidence and outcome for patients meeting the NIFTP criteria in a well-defined geographic region. Our cohort consisted of 134 patients with papillary thyroid carcinoma from the Region of Southern Denmark (RSD), 2007 to 2011. Patients were retrieved from the Danish Thyroid Cancer (DATHYRCA) Database. All potential NIFTP cases were reviewed by a thyroid pathologist. We identified no cases meeting all diagnostic criteria, but one probable NIFTP case from 2007 to 2011. The patient was treated according to the national guidelines and is alive and recurrence-free after 106 months of follow-up. Molecular testing showed KRAS mutation. In a population based set up the incidence rate of NIFTP is very low. [ABSTRACT FROM AUTHOR]

Background: The noninvasive Encapsulated follicular variant of papillary thyroid cancer (EFVPTC) has been reclassified as Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) without a significant risk for malignant behavior. However the evaluation remains a challenge for clinicians. We sought to determine whether programmed death-ligand 1 (PD-L1) expression may serve as a biomarker to predict invasiveness of EFVPTC and assist to distinguish these neoplasms from NIFTP. Methods: Immunohistochemical staining of PD-L1 expression was performed in sections of 174 Formalin-fixed paraffin-embedded (FFPE) tissue blocks from surgery removed thyroid nodules. Results: Cytoplasmic PD-L1 expression was significantly increased in invasive EFVPTC (4.76 ± 1.49) as compared to NIFTP (3.06 ± 2.16, p

ALK fusions are found in various tumors, including thyroid cancer, and serve as a diagnostic marker and therapeutic target. Spectrum and outcomes of ALK fusions found in thyroid nodules and cancer are not fully characterized. We report a series of 44 ALK- translocated thyroid neoplasms, including 31 identified preoperatively in thyroid flne- needle aspirates (FNA). The average patients' age was 43 years (range, 8-76 years); only one with radiation history. All 19 resected thyroid nodules with ALK fusion identified preoperatively were malignant. Among nodules with known surgical pathology (n = 32), 84% were papillary thyroid carcinomas (PTCs) and 16% poorly differentiated thyroid carcinomas (PDTCs). PTCs showed infiltrative growth with follicular architecture seen exclusively (30%) or in combination with papillary and/or solid growth (37%). Tumor multifocality was seen in 10 (31%) PTC cases. Most PDTC had a well-differentiated PTC component. Lymph node metastases were identified in 10/18 (56%) patients with neck dissection. The most common ALK fusion partners were STRN (n = 22) and EML4 (n = 17). In five cases, novel ALK fusion partners were discovered. All five PDTCs carried STRN-ALK fusion. On follow-up, ten patients were free of disease at 2-108 months, whereas two patients with PDTC died of disease. In summary, ALK fusion-positive thyroid carcinomas are typically infiltrative PTC with common follicular growth, which may show tumor dedifferentiation associated with increased mortality. Compared to EML4-ALK, STRN-ALK may be more common in PDTC, and ~10% of ALK fusions occur to rare gene partners. When ALK fusion is detected preoperatively in FNA samples, malignancy should be expected. [ABSTRACT FROM AUTHOR]

Purpose: Fine-needle aspiration biopsy (FNAB) is regarded by the Bethesda system as the gold-standard investigation for stratifying the risk of malignancy of a thyroid nodule. However, some limitations affect the adequacy of the obtained materials, resulting in 30% of the cytological results remaining in the indeterminate category. We aimed to investigate the diagnostic value of the BRAF mutation in cytologically indeterminate thyroid nodules after the reclassification of a variant thyroid carcinoma. Patients and methods: In this prospective diagnostic study, 76 patients with FNAB findings of atypia of undetermined significance (AUS) and suspicious for malignancy (SUS) were included. The BRAF V600 mutation from FNAB was confirmed by a PCR-based method (Sanger sequencing combined with allele-specific real-time PCR techniques) and immunohistochemistry (IHC). Pathological specimens and features, including noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), were reviewed and compared to the FNAB results. Results: Using the PCR-based method, the BRAF mutation was positive in 13/76 cases (17.1%), with the diagnostic values of 16.7% sensitivity, 100% specificity, 100% positive predictive value (PPV), and 82.8% negative predictive value (NPV) in the AUS compared to 73.3% sensitivity, 100% specificity, 100% PPV, and 20% NPV in the SUS. For the IHC technique, only 20 of the 76 cytological specimens were qualified for testing. The BRAF mutation was positive in 13/20 cases, with the diagnostic values of 100% sensitivity, 63.6% specificity, 42.9% PPV, and 100% NPV in the AUS compared to 100% sensitivity and PPV in the SUS. The BRAF mutation was not found in the pathological reports for NIFTP. Conclusion: The malignancy rate is high in our data, with specific and acceptable accuracy rates for the BRAF mutation from FNAB found by using the PCR-based method. NIFTP has been introduced after the pathological reclassification. Molecular diagnosis might be useful to establish the nature of the disease. [ABSTRACT FROM AUTHOR]

Papillary thyroid carcinoma (PTC) is defined by an invasive growth pattern and classic nuclear features: enlarged, grooved, overlapping nuclei with chromatin clearing and intranuclear cytoplasmic pseudoinclusions (INCP). True INCPs are characteristic of PTC, but may infrequently be seen in noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP). Nuclear abnormalities that mimic INCP (“pseudo-pseudoinclusions”) are common in a variety of thyroid lesions. H&E and ubiquitin-stained whole tissue sections of classic PTC (n = 25) and NIFTP (n = 35) were evaluated. On H&E, true INCPs were present in all (100%) PTCs and absent in all NIFTPs (0%). Pseudo-pseudoinclusions were present in 13 (37%) NIFTPs. In 24 (96%) PTCs, ubiquitin was strongly expressed within INCPs. In NIFTPs, optically clear nuclei or pseudo-pseudoinclusions did not express ubiquitin (0/35). Occasionally, nuclear vacuoles in NIFTP demonstrated a marginated staining pattern, in which strong ubiquitin expression was seen at the periphery of the nucleus, but the central pale area was negative. In addition, 2 NIFTPs demonstrated intrafollicular psammomatoid calcifications which were strongly ubiquitin-positive. Psammoma bodies in PTC were ubiquitin-negative in the majority of cases. We report a previously undescribed finding: strong ubiquitin expression in true INCPs in PTC, absence of true INCPs in NIFTP, and absence of ubiquitin expression in pseudo-pseudoinclusions in NIFTP. This finding supports the difference between true INCPs (found only in PTC) and pseudo-pseudoinclusions (found in NIFTP). Using strict histologic criteria and ubiquitin immunostaining, the presence of true pseudoinclusions may exclude a diagnosis of NIFTP. Caution should be exercised when interpreting nuclear vacuoles or pseudo-pseudoinclusions. [ABSTRACT FROM AUTHOR]

Introduction. The encapsulated, non-invasive subtype of follicular variant of papillary thyroid carcinoma (FVPTC) represents approximately 10% to 20% of all thyroid cancers. Many studies over the past decade have shown that these tumors carry an indolent clinical course, with no recurrence, even in patients treated by lobectomy. Their reclassification as neoplasms with "very low malignant potential" has recently been suggested by an international group of experts and a new terminology was proposed: "non-invasive follicular thyroid neoplasm with papillarylike nuclear features" (NIFTP). However, a diagnosis of NIFTP is still challenging for many pathologists in daily practice. Presentation of case series. By presenting six illustrative cases of NIFTP, this article aims to highlight the diagnostic criteria and the burden difficulties when dealing with NIFTP cases. Characteristic histological features, inclusion and exclusion criteria for NIFTP, as well as sampling guidelines and differential diagnosis challenges are all discussed. Conclusions. The diagnosis of NIFTP is not straightforward and requires meeting strict inclusion and exclusion criteria. Total sampling of the tumor capsule in these cases is mandatory in order to exclude invasion (capsular and/or vascular). A diagnosis of NIFTP promotes a less-aggressive patient management that is, no need for completion thyroidectomy or radioactive iodine therapy. [ABSTRACT FROM AUTHOR]

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The 2017 edition of the WHO book on Classification of Tumours of Endocrine Organs includes a new section entitled 'Other encapsulated follicular-patterned thyroid tumours', in which the newly created NIFTP (non-invasive follicular thyroid neoplasm with papillary-like nuclear features) is identified and described in detail. Despite deleting the word 'carcinoma' from its name, NIFTP is not a benign tumor either and is best regarded as a neoplasm with 'very low malignant potential'. The main goal of the introduction of NIFTP category is to prevent overdiagnosis and overtreatment. Sampling constraints, especially when dealing with heterogeneous and/or large nodules, and difficulties in the invasiveness evaluation, are the major weaknesses of the histological characterization of NIFTP. At the cytological level, NIFTP can be separated from classic papillary carcinoma (cPTC) but not from encapsulated, invasive follicular variant PTC. The impact of NIFTP individualization for cytopathology is the drop of rates of malignancy for each Bethesda category in general and for indeterminate categories in particular. The biggest impact will be seen in institutions with a high frequency of FVPTC. The introduction of NIFTP has changed the utility of predictive values of molecular tests because RAS mutations and PAX8-PPARg rearrangements are frequently detected in NIFTP. This turns less promising the application of mutation detection panels as indicators of malignancy and will probably contribute to switch to a rule-out approach of molecular testing. Selection for surgery will go on being determined by a combined detection of clinical, cytological and ultrasound suspicious features. [ABSTRACT FROM AUTHOR]

Introduction The follicular variant of papillary thyroid cancer (FVPTC) can be noninvasive or invasive. The invasive form of FVPTC commonly harbors BRAF mutations whereas RAS mutations are more often associated with noninvasive FVPTC and a favorable clinical outcome. Case report A 47-year-old man presented with a metastasis to his right iliac bone as the initial manifestation of a 1.6 cm invasive FVPTC. After total thyroidectomy, the patient underwent additional treatment, including thyroid hormone suppressive treatment to non-detectable TSH levels, repeated courses of radioiodine treatment, external beam radiation, and treatment with the tyrosine kinase inhibitor sorafenib. Despite these therapeutic efforts, the disease progressed with growth of the iliac mass and additional metastatic spread to cervical and lumbar vertebrae causing increasing pain and disability. The patient succumbed to the disease four years after presentation. Retrospective next-generation sequencing of the primary tumor using a pan-cancer targeted mutation and gene fusion panel revealed NRAS Q61K mutation and no other oncogenic alterations. Discussion The study challenges the concept that thyroid neoplasms with isolated RAS mutations are often associated with favorable clinical behavior and may be candidates for conservative management. Conclusion An isolated RAS mutation in invasive FVPTC may be associated with an aggressive clinical behavior. [ABSTRACT FROM AUTHOR]

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