Follicular Neoplasm Research Articles

Diagnostic Performance of Thyroid FNA: Experience of Belarusian National Referral Thyroid Cancer Center.

A fine-needle aspiration (FNA) biopsy is a basic procedure to verify the morphology of thyroid nodules. However, significant variations in the diagnostic performance of FNA, as well as fluctuations in the rate of malignancy (ROM) in different categories of the Bethesda System for Reporting Thyroid Cytopathology, have been discovered in many studies. The development and employment of additional molecular tests in daily clinical practice require an understanding of the prevalence and structure of thyroid malignancy in each category of the Bethesda system. Current research is a continuous retrospective cohort study of the results of the examination and treatment of 1652 patients with thyroid tumors who have undergone primary surgery in 2021 at a national referral thyroid cancer center. FNA diagnostic performance was studied by comparing cytological diagnoses with histological outcomes. The authors evaluated ROM in each Bethesda category and identified the tumors representing a diagnostic pitfall. The overall ROM was 72.4%. When considering ROM in each Bethesda category, it was 16.7% in Bethesda I, 10.1% in Bethesda II, 23.0% in Bethesda IV, 74.8% in Bethesda V, 99.4% in Bethesda VI. The false-positive rate was 65.0%, false negative-0.67%. Follicular and oncocytic adenomas, as well as the follicular variant of papillary thyroid cancer, were the most troublesome entities for patients' management. ROM was comparable to the values implied by the Bethesda system. Follicular tumors were the main source of high false-positive rates. This necessitates the refinement of existing tests and the development of new diagnostic tests to overcome the abovementioned problems.

Detection of RAS p.Q61R by Immunohistochemistry in Practice: A Clinicopathologic Study of 217 Thyroid Nodules with Molecular Correlates.

RAS p.Q61R is the most prevalent hot-spot mutation in RAS and RAS-like mutated thyroid nodules. A few studies evaluated RAS p.Q61R by immunohistochemistry (RASQ61R-IHC). We performed a retrospective study of an institutional cohort of 150 patients with 217 thyroid lesions tested for RASQ61R-IHC, including clinical, cytologic and molecular data. RASQ61R-IHC was performed on 217 nodules (18% positive, 80% negative, and 2% equivocal). RAS p.Q61R was identified in 76% (n = 42), followed by RAS p.Q61K (15%; n = 8), and RAS p.G13R (5%; n = 3). NRAS p.Q61R isoform was the most common (44%; n = 15), followed by NRAS p.Q61K (17%; n = 6), KRAS p.Q61R (12%; n = 4), HRAS p.Q61R (12%; n = 4), HRAS p.Q61K (6%; n = 2), HRAS p.G13R (6%; n = 2), and NRAS p.G13R (3%; n = 1). RASQ61R-IHC was positive in 47% of noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP; 17/36), 22% of follicular thyroid carcinomas (FTC; 5/23), 10% of follicular thyroid adenomas (FTA; 4/40), and 8% of papillary thyroid carcinomas (PTC; 9/112). Of PTC studied (n = 112), invasive encapsulated follicular variant (IEFVPTC; n = 16) was the only subtype with positive RASQ61R-IHC (56%; 9/16). Overall, 31% of RAS-mutated nodules were carcinomas (17/54); and of the carcinomas, 94% (16/17) were low-risk per American Thyroid Associated (ATA) criteria, with only a single case (6%; 1/17) considered ATA high-risk. No RAS-mutated tumors recurred, and none showed local or distant metastasis (with a follow-up of 0-10 months). We found that most RAS-mutated tumors are low-grade neoplasms. RASQ61R-IHC is a quick, cost-effective, and reliable way to detect RAS p.Q61R in follicular-patterned thyroid neoplasia and, when malignant, guide surveillance.

Molecular Alterations in Suspicious for Follicular Neoplasm (Oncocytic Type) Category of The Bethesda System for Reporting Thyroid Cytopathology

Molecular Alterations in Suspicious for Follicular Neoplasm (Oncocytic Type) Category of The Bethesda System for Reporting Thyroid Cytopathology

Prevalence of malignancy in thyroid nodules with AUS cytopathology: A retrospective cross-sectional study.

Category III (AUS; Atypia of Undetermined Significance) of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) was established to describe thyroid nodule features that are neither benign nor cancerous. This study aims to evaluate the rate of thyroid malignancy in patients diagnosed with AUS at the Armed Forces Hospital Southern Region (AFHSR), Saudi Arabia. The patients (508) diagnosed with AUS in their thyroid nodules underwent fine-needle aspiration cytology (FNAC). Data were collected through a chart-based approach, reviewing patients' medical records and relevant information. Among the cases, the majority were females (84.6%). Among the different age groups, individuals between 40 and 50 years had the highest prevalence of thyroid nodules (32.5%). Approximately 27% of patients exhibited tumor sizes larger than 4 cm. FNAC results revealed 16.5% benign, 26% AUS, and 22.4% follicular neoplasm cases. Histopathology indicated 54.1% of benign and 37.2% of malignant cases. Papillary carcinoma accounts for 80.4% of all malignant cases. A significant correlation was observed between FNAC and postoperative histopathology (P value < 0.05). Hypoechoic nodules exhibited 33.9% of malignant cases, and calcification was observed in 25% of the cases. A significant association was found between malignancy and echogenicity and between malignancy and calcification (P value = 0.003 and 0.001, respectively). The findings of this study identify malignancy in thyroid nodules with AUS cytopathology, particularly in the Southern region of Saudi Arabia. The correlation between pre-surgery FNAC and postoperative histopathology supports FNAC's diagnostic value. Additionally, echogenicity and calcification can potentially contribute to predicting nodule malignancy.

Machine Learning Streamlines the Morphometric Characterization and Multiclass Segmentation of Nuclei in Different Follicular Thyroid Lesions: Everything in a NUTSHELL

The diagnostic assessment of thyroid nodules is hampered by the persistence of uncertainty in borderline cases and further complicated by the inclusion of noninvasive follicular tumor with papillary-like nuclear features (NIFTP) as a less aggressive alternative to papillary thyroid carcinoma (PTC). In this setting, computational methods might facilitate the diagnostic process by unmasking key nuclear characteristics of NIFTP. The main aims of this work were to (1) identify morphometric features of NIFTP and PTC that are interpretable for the human eye and (2) develop a deep learning model for multiclass segmentation as a support tool to reduce diagnostic variability. Our findings confirmed that nuclei in NIFTP and PTC share multiple characteristics, setting them apart from hyperplastic nodules (HP). The morphometric analysis identified 15 features that can be translated into nuclear alterations readily understandable by pathologists, such as a remarkable internuclear homogeneity for HP in contrast to a major complexity in the chromatin texture of NIFTP and to the peculiar pattern of nuclear texture variability of PTC. A few NIFTP cases with available next-generation sequencing data were also analyzed to initially explore the impact of RAS-related mutations on nuclear morphometry. Finally, a pixel-based deep learning model was trained and tested on whole-slide images of NIFTP, PTC, and HP cases. The model, named NUTSHELL (NUclei from Thyroid tumors Segmentation to Highlight Encapsulated Low-malignant Lesions), successfully detected and classified the majority of nuclei in all whole-slide image tiles, showing comparable results with already well-established pathology nuclear scores. NUTSHELL provides an immediate overview of NIFTP areas and can be used to detect microfoci of PTC within extensive glandular samples or identify lymph node metastases. NUTSHELL can be run inside WSInfer with an easy rendering in QuPath, thus facilitating the democratization of digital pathology.

Re-evaluation of the concept of basaloid follicular hamartoma associated with naevoid basal cell carcinoma syndrome: a morphological, immunohistochemical and molecular study

Naevoid basal cell carcinoma syndrome (NBCCS) is a rare genodermatosis caused by germline mutations in genes of the Sonic Hedgehog pathway (SHH) and is characterised by early onset of multiple basal cell carcinomas (BCCs). Although skin tumours with follicular differentiation, notably basaloid follicular hamartoma (BFH), have been reported in NBCCS, their relations with BCC are poorly defined. In this context, the aim of this study was to clarify morphological, immunohistochemical ​and molecular features of BFH arising in a context of NBCCS.A total of 140 skin tumours from NBCCS and 140 control BCC tumours were reviewed, blinded to clinical data and classified as BCC or BFH. The morphological characteristics of these two groups were then compared. Twenty cases were submitted for immunohistochemical and molecular analysis. Thirty-three tumours among the exploratory cohort were classified as BFH and were exclusively detected in NBCCS patients. Histopathological criteria that were significantly different from BCC were as follows: a small size (<1.5 mm), connection to a hair follicle, arborescent organoid architecture, lack of cytologic atypia and infundibulocystic differentiation. Immunohistochemical analysis confirmed activation of the SHH pathway in these lesions. Targeted next-generation sequencing suggested that MYCN and GLI2/3 amplifications and TP53 mutations might be involved in progression of these follicular tumours to BCC.Our study confirms the high prevalence of BFH representing up to 24% of skin tumours in NBCCS and potentially being BCC precursors.

Pathology diagnosis of intraoperative frozen thyroid lesions assisted by deep learning

BackgroundThyroid cancer is a common thyroid malignancy. The majority of thyroid lesion needs intraoperative frozen pathology diagnosis, which provides important information for precision operation. As digital whole slide images (WSIs) develop, deep learning methods for histopathological classification of the thyroid gland (paraffin sections) have achieved outstanding results. Our current study is to clarify whether deep learning assists pathology diagnosis for intraoperative frozen thyroid lesions or not.MethodsWe propose an artificial intelligence-assisted diagnostic system for frozen thyroid lesions that applies prior knowledge in tandem with a dichotomous judgment of whether the lesion is cancerous or not and a quadratic judgment of the type of cancerous lesion to categorize the frozen thyroid lesions into five categories: papillary thyroid carcinoma, medullary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid tumor, and non-cancerous lesion. We obtained 4409 frozen digital pathology sections (WSI) of thyroid from the First Affiliated Hospital of Sun Yat-sen University (SYSUFH) to train and test the model, and the performance was validated by a six-fold cross validation, 101 papillary microcarcinoma sections of thyroid were used to validate the system’s sensitivity, and 1388 WSIs of thyroid were used for the evaluation of the external dataset. The deep learning models were compared in terms of several metrics such as accuracy, F1 score, recall, precision and AUC (Area Under Curve).ResultsWe developed the first deep learning-based frozen thyroid diagnostic classifier for histopathological WSI classification of papillary carcinoma, medullary carcinoma, follicular tumor, anaplastic carcinoma, and non-carcinoma lesion. On test slides, the system had an accuracy of 0.9459, a precision of 0.9475, and an AUC of 0.9955. In the papillary carcinoma test slides, the system was able to accurately predict even lesions as small as 2 mm in diameter. Tested with the acceleration component, the cut processing can be performed in 346.12 s and the visual inference prediction results can be obtained in 98.61 s, thus meeting the time requirements for intraoperative diagnosis. Our study employs a deep learning approach for high-precision classification of intraoperative frozen thyroid lesion distribution in the clinical setting, which has potential clinical implications for assisting pathologists and precision surgery of thyroid lesions.

Matrix Metalloproteinases 9 Expresion of Thyroid Follicular Neoplasm FNAB and Its Relationship with Thyroid Malignancy Histopathology

Background Fine-Needle Aspiration Biopsy (FNAB) thyroid nodules is not easy to distinguish betwen follicular malignancy and follicular benign lession. Malignancy diagnosis can only be made from histopathology examination by examing tumor invation to capsule and vaskular. Matrix Metalloproteinase 9 (MMP-9) examination can be added to help making initial diagnois. MMP-9 is a proteolytic enzyme that plays important role in cancer progressivity, especially in thyroid. High MMP-9 expression will lead to earlier degradation of thyroid and its will make the cell metastasist easier. This study is to examine MMP-9 expression of thyroid follicular neoplasm related tomalignancy through histopathology examination and the diagnostic test of FNAB MMP-9 expression and histophatologic examination. Methods We used 42 sample FNAB follicular thyroid in Anatomic Pathology laboratories RSUP M Djamil Padang and histopathologic examination was performed. Immunohistochemical was staining with primary antibody MMP-9 then its expression were assessed in stroma and cytoplasmic cell tumour. Results MMP-9 expression was found positive in malignancy histopathologic (80.9%). Expression of MMP-9 at FNAB folikullar neoplasm thyroid is significant in malignant histopathologic thyroid (p=0.017). MMP-9 Sensitivity in thyroid follicular noduleFNAB is quite good (88.575) and its specificity is 51.14%. Conclusion Increased MMP-9 expression of FNAB follicular thyroid neoplasm is associated with histopathologic malignancy.

Comparison of ultrasound findings of papillary thyroid carcinoma subtypes based on the 2022 WHO classification of thyroid neoplasms.

The present study aimed to analyze and compare sonographic features of papillary thyroid carcinoma (PTC) subtypes to determine whether ultrasound (US) may aid in differentiating particular subtypes. This retrospective study enrolled 133 patients diagnosed with 142 histopathologically proven PTCs as per the fifth edition of the World Health Organization classification of thyroid neoplasms between January 2013 and May 2023. US features based on the American College of Radiology and European Thyroid Imaging and Reporting Data Systems (TIRADS), and histopathological characteristics of nodules were assessed and compared. Histopathological analysis yielded 55 (38.7%) classic PTC, 32 (22.5%) invasive encapsulated follicular variant (IEFV) PTC, 20 (14.1%) oncocytic subtype, 14 (9.9%) non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), 11 (7.8%) infiltrative follicular subtype, 7 (4.9%) tall cell subtype, 2 (1.4%) solid subtype, and 1 (0.7%) diffuse sclerosing subtype. The US findings indicating malignancy, such as taller-than-wide shape, irregular margins, echogenic foci, and higher TIRADS categories, were more frequently demonstrated in nodules with classic PTC and the tall cell subtype, in line with their histopathological features. Conversely, IEFV-PTC and NIFTP rarely exhibited these high-risk sonographic features. US appearance of the oncocytic subtype more frequently overlapped with IEFV-PTC, yet hypo/very hypoechoic nodules with larger nodular diameters and higher TIRADS scores may favor the diagnosis of this subtype. US features of certain subtypes may guide the differential diagnosis regarding shape, margin, echogenic foci, and TIRADS category of nodules; however, definitive subtyping is not yet possible using US images alone.

Comprehensive genomic profiling of infiltrative follicular variant of papillary thyroid carcinoma.

Infiltrative follicular variant of papillary thyroid carcinoma (IFVPTC) exhibits nuclear characteristics typical of papillary thyroid carcinoma (PTC) but demonstrates a follicular growth pattern. The diagnosis of IFVPTC presenting with atypical nuclear features of PTC poses challenges for both preoperative cytopathology and postoperative histopathology. In such cases, molecular markers are needed to serve as diagnostic aids. Given the limited knowledge of IFVPTC's genomic features, this study aimed to characterize its genetic alterations and identify clinically relevant molecular markers. Whole-exome sequencing of 50 IFVPTC tumor-normal pairs identified single-nucleotide variants, somatic copy number alterations (sCNAs), and subclonal architecture. Key mutations were verified via polymerase chain reaction and Sanger sequencing, whereas valuable biomarkers were validated via immunohistochemistry (IHC). This study found that endogenous processes rather than exogenous mutagens dominated the shaping of the genome of IFVPTC during tumorigenesis. BRAF V600E was the only common trunk mutation and significantly mutated gene in IFVPTC. Subcloning analysis found that most IFVPTC samples harbored two or more coexisting clones. sCNA analysis revealed that human leukocyte antigen C (HLA-C) and HLA-A were significantly amplified. Subsequent IHC investigations indicated that HLA-C shows promise in averting the misclassification of challenging-to-interpret IFVPTC and invasive encapsulated follicular variant of PTC (I-EFVPTC) as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Although there were several similarities between classic PTC and IFVPTC, they differed significantly in their sCNA patterns. This study provides valuable insights into IFVPTC's genetic alterations and highlights the potential of HLA-C IHC to distinguish challenging-to-interpret IFVPTC and I-EFVPTC from NIFTP, which will enhance the understanding of its molecular features for improved diagnosis and management.

Efficacy of Follicular Cell Pattern Analysis in Thyroid Fine-needle Aspiration Cytology Evaluation.

Fine-needle aspiration cytology (FNAC) is widely utilized for thyroid lesion diagnosis but faces challenges such as sample inadequacy and overlapping cytological features. This study examines how accurately these patterns correlate with histopathological diagnoses, shedding light on FNAC's limitations and diagnostic potential. To study the application of the architectural pattern of follicular cells in the interpretation of thyroid lesions and to demonstrate the diagnostic accuracy (DA) of FNAC. Cross-sectional study carried over 1 year. A total of 110 cases were reviewed by the cytopathologists. The prominent follicular cell architecture, namely macrofollicular, microfollicular, papillary, trabecular, three-dimensional clusters, and dispersed cells, was described in each case. In addition to these patterns, cellular morphology and background features were also noted, and a final cytological diagnosis was established. The cytology diagnosis was correlated with the histopathological diagnosis. Sensitivity, specificity, positive predictive value, negative predictive value, DA of FNAC in diagnosing nonneoplastic and neoplastic lesions. Macrofollicular pattern was seen in 80.26% of colloid goiter cases. Microfollicular pattern was observed in 72.2% of follicular neoplasm. About 62.5% of papillary thyroid carcinomas showed a papillary pattern. The trabecular pattern was seen in 42.86% of chronic lymphocytic thyroiditis and 16.67% of follicular neoplasms. The sensitivity and specificity of FNAC in diagnosing neoplastic lesions was 92.59% and 97.59%, respectively. FNAC is a simple, rapid, definite, and cost-effective primary diagnostic tool for thyroid evaluation. Cell architecture pattern is a simple and appropriate approach that complements cell morphology and background details in arriving at the final cytological diagnosis of thyroid lesions.

Follicular neoplasms with nuclear atypia versus other types of atypia: Should follicular neoplasms be stratified according to the presence of nuclear atypia?

The third edition of The Bethesda System (TBS) subclassifies the atypia of undetermined significance (AUS) category on the basis of the presence of nuclear atypia (AUS-Nuclear). This approach is supported by studies showing significant differences in the risk of malignancy (ROM) between AUS-Nuclear and those without (AUS-Other). Although aspirates of follicular neoplasms (FNs) are characterized by marked architectural atypia, TBS recognizes the infrequent occurrence of FNs with mild nuclear atypia (FN-Nuclear). Furthermore, limited studies have shown significant differences in ROM between FN-Nuclear and those without (FN-Other). This study explored potential differences in ROM, molecular-derived risk of malignancy (MDROM), and molecular alterations between FN-Nuclear and FN-Other. A retrospective database search identified 93 FN aspirates. Cytology slides, molecular reports, and histologic follow-ups were reviewed. Both groups' benign call rate (BCR), positive call rate (PCR), MDROM, and ROM were computed and compared. Eighty-six percent of aspirates (80 of 93) comprised FN-Other, whereas 14% (13 of 93) were FN-Nuclear. The BCR and PCR for FN-Other were 51% and 49%, respectively. In contrast, they were 23% and 77% for FN-Nuclear, respectively. The MDROM significantly differed between FN-Other (30%) and FN-Nuclear (56%) (p<.05). HRAS mutation was the most common molecular alteration in FN-Nuclear, whereas mutations in NRAS/KRAS and copy number alterations were more common in FN-Other. The ROM1/ROM2 in FN-Other and FN-Nuclear were 16%/31% and 54%/88%, respectively. These results reveal that FN-Nuclear exhibits significantly higher MDROM and ROM than FN-Other, which provides support for a subclassification scheme for FNs based on the presence of nuclear atypia.

Evaluation of CTLA-4 and PD-L1 Expression in Thyroid Carcinoma and Its Prognostic Significance.

Introduction Immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed death-ligand 1 (PD-L1) have revolutionised treatment and improved outcomes in various malignancies. We aimed to evaluate CTLA-4 and PD-L1 immunoexpression in thyroid tumours and correlated them with clinicopathological parameters. Methods The study included 90 cases of thyroid malignancies comprising papillary thyroid carcinoma (PTC) (n = 64, 54.2%), follicular thyroid carcinoma (FTC) (n = 19, 16.1%), anaplastic thyroid carcinoma (ATC) (n = 3, 2.5%), and poorly differentiated carcinoma (n = 4, 3.4%), two cases (1.69%) of non-invasive follicular thyroid neoplasm with papillary-like nuclear features(NIFTP) along with 26 cases (22%) of benign thyroid lesions. CTLA-4 (UMAB249) and PD-L1 (SP263) expression were assessed in all the cases of thyroid tumours. Results were compared with clinicopathologic parameters and overall survival. Results PD-L1 was positive in all three cases of anaplastic thyroid carcinoma (ATC), 33% (n = 21) cases of PTC, and 16% (n = 3) cases of FTC. PD-L1 positivity was significantly associated at tumour proportion score (TPS) ≥1% with lymphovascular invasion and age ≤40 years and at TPS ≥50% with tumour necrosis and N-stage. Immune proportion score (IPS) did not correlate with any clinicopathological parameters except for the N-stage. CTLA-4 was positive in six cases of PTC (1-5%); five showed lymph node involvement (p = 0.032). IPS was positive in 14 cases, and a significant association was seen with lymph node metastasis, lymphocytic infiltration, and lymphovascular invasion. Three cases of PTC showed co-expression for PD-L1 and CTLA-4 in tumour cells. No significant association was seen between PD-L1 expression and survival. Conclusion The current data suggest that PD-L1 is expressed in differentiated thyroid carcinoma, mainly PTC and ATC, indicating higher responsiveness to immunotherapy. A subset of PTC showed co-expression of PD-L1 and CTLA-4. These findings suggest the need for further investigation to utilise combinational immunotherapy, including anti-PD-L1 and anti-CTLA-4.

Fate of nondiagnostic thyroid fine needle aspirations.

Thyroid nodules may be detected during the workup of thyroid hormone abnormalities and as incidental findings during unrelated imaging studies. The diagnosis of a thyroid nodule is mainly established by performing fine needle aspiration (FNA) under ultrasound guidance. Thyroid nodules are classified as nondiagnostic, defined in the Bethesda System for Reporting Thyroid Cytopathology as samples with excess blood, cyst fluid only, and lack of thyroid follicular cells. The current study evaluates a series of nondiagnostic FNAs to assess whether repeat sampling improves yield and what patient management, and outcomes are after a nondiagnostic FNA. Thyroid FNAs from 2016 to 2023 were retrieved from our institution archives. All cases were performed under ultrasound guidance and with rapid on-site evaluation. Cases were assigned the Bethesda System Category. Nondiagnostic FNAs were further reviewed for repeat FNA procedures, potential molecular testing, or diagnostic resections. In total 3104 thyroid FNAs were reviewed, with 153 (4.9%) being nondiagnostic. Of the 154 FNAs, there were 129 patients with an average age of 60 and a male-to-female ratio of 1:3.2. Of the 130 patients, there were 50 patients who underwent 55 repeat FNAs. Thirty-seven (67%) of the repeats were benign, 13 (24%) were nondiagnostic again, and 5 (9%) were atypia of undetermined significance (AUS). Molecular testing was performed on repeat FNAs diagnosed AUS. Four cases showed no mutations and had a high likelihood of being benign. One case did have an NRAS Q61R mutation, and resection revealed a noninvasive follicular thyroid neoplasm with papillary-like nuclear features. Seventeen (13% of all cases) with nondiagnostic FNA were resected. Twelve (71%) thyroidectomies showed benign adenomatous nodules. The remainder showed incidental papillary thyroid microcarcinoma (0.1 cm), an infarcted follicular adenoma, a noninvasive follicular thyroid neoplasm with papillary-like nuclear features, and metastatic renal cell carcinoma (2×). Thyroid nodules with nondiagnostic cytology are reassuring of being highly likely a benign nodule. Only 5 of the 55 (9%) repeat FNAs yielded abnormalities, with only one of those being truly a follicular neoplasm (confirmed by molecular testing and resection). No primary thyroid malignancies have been identified in follow-up (repeat FNA or surgery). Clinical and ultrasound follow-up may be more appropriate management for nondiagnostic thyroid FNAs.

Oncocytic/Hürthle cell lesions have the same implied risk of neoplasm/malignancy as their follicular counterparts.

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. 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. 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. The predominance of oncocytes does not modify the implied RON, ROM for categories of AUS or FN\ON, even after the adoption of NIFTP.

Proteomics profile in encapsulated follicular patterned thyroid neoplasms

Diagnosing encapsulated follicular-patterned thyroid tumors like Invasive Encapsulated Follicular Variant of Papillary Thyroid Carcinoma (IEFVPTC), Non-invasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP), and Well-Differentiated Tumor of Uncertain Malignant Potential (WDT-UMP) remains challenging due to their morphological and molecular similarities. This study aimed to investigate the protein distinctions among these three thyroid tumors and discover biological tumorigenesis through proteomic analysis. We employed total shotgun proteome analysis allowing to discover the quantitative expression of over 1398 proteins from 12 normal thyroid tissues, 13 IEFVPTC, 11 NIFTP, and 10 WDT-UMP. Principal component analysis revealed a distinct separation of IEFVPTC and normal tissue samples, distinguishing them from the low-risk tumor group (NIFTP and WDT-UMP). IEFVPTC exhibited the highest number of differentially expressed proteins (DEPs) compared to the other tumors. No discriminatory proteins between NIFTP and WDT-UMP were identified. Moreover, DEPs in IEFVPTC were significantly associated with thyroid tumor progression pathways. Certain hub genes linked to the response of immune checkpoint inhibitor therapy, revealing the potential predictor of prognosis. In conclusion, the proteomic profile of IEFVPTC differs from that of low-risk tumors. These findings may provide valuable insights into tumor biology and offer a basis for developing novel therapeutic strategies for follicular-patterned thyroid neoplasms.

Study of non-invasive follicular thyroid neoplasm: A borderline entity

ABSTRACT 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.

3D Virtual Histopathology by Phase-Contrast X-Ray Micro-CT for Follicular Thyroid Neoplasms.

Histological analysis is the core of follicular thyroid carcinoma (FTC) classification. The histopathological criteria of capsular and vascular invasion define malignancy and aggressiveness of FTC. Analysis of multiple sections is cumbersome and as only a minute tissue fraction is analyzed during histopathology, under-sampling remains a problem. Application of an efficient tool for complete tissue imaging in 3D would speed-up diagnosis and increase accuracy. We show that X-ray propagation-based imaging (XPBI) of paraffin-embedded tissue blocks is a valuable complementary method for follicular thyroid carcinoma diagnosis and assessment. It enables a fast, non-destructive and accurate 3D virtual histology of the FTC resection specimen. We demonstrate that XPBI virtual slices can reliably evaluate capsular invasions. Then we discuss the accessible morphological information from XPBI and their significance for vascular invasion diagnosis. We show 3D morphological information that allow to discern vascular invasions. The results are validated by comparing XPBI images with clinically accepted histology slides revised by and under supervision of two experienced endocrine pathologists.

RAS-Mutant Follicular Thyroid Tumors: A Continuous Challenge for Pathologists.

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.

THADA-IGF2BP3 gene fusions in thyroid fine needle aspiration is involved in the pathway to "noninvasive follicular thyroid neoplasm with papillary-like nuclear features".

The increased usage and adaptation of molecular testing of thyroid fine needle aspirations (FNA) has expanded the variety and number of gene fusions identified. While the identified number of molecular alterations is increasing, the definitive association between preoperative molecular analysis and phenotype has yet to be established. The aim of this study was to examine Thyroid adenoma-associated (THADA)-IGF2BP3 molecular fusions with FNA categorization, surgical pathology diagnosis, and other molecular alterations detected by ThyroSeq Genomic Classifier testing. FNA cytology samples of thyroid nodules from 04/2017 to 01/2023 with the diagnosis of atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS; Bethesda III) or follicular neoplasm suspicious for follicular neoplasm (FN/SFN; Bethesda IV) with associated ThyroSeqV3 testing were reviewed. Parameters including patient demographics, FNA diagnosis, ThyroSeq V3 results, and surgical pathology follow up were examined. 87 out of 249 (35%) FNA specimens of thyroid nodules displayed molecular alterations. 64 cases (74%) had a cytology diagnosis of AUS and 23 (26%) had FN. RAS mutation was observed in 48 cases. On surgical follow-up, 17 (35%) cases showed non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), while 14 (29%) patients had a malignant diagnosis. THADA-IGF2BP3 fusions were seen in 8 cases, all with NIFTP on surgical pathology follow-up (100%). Analysis of THADA-IGF2BP3 fusion, in our institutional series, shows close association with NIFTP cases. THADA-IGF2BP3 fusion, which seems to be a favorable prognostic indicator in general, may serve as a molecular marker for non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP).