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.

It is crucial for doctors to decide whether a thyroid nodule is benign or malignant when a patient presents with one, as it will significantly impact how the patient is managed in the future. However, it is not as straightforward to determine between the two; even a physical examination, thyroid function test, ultrasonography, and biopsy have been well performed. It can be more stressful if a patient has an increased risk of malignancy, such as age (below 20- and above 60-year-old), solid nodule, rapid growth, hoarseness, lymphadenopathy, and microcalcifications on the ultrasonography. The aim of this case was to present the management of a giant thyroid nodule with malignancy presentation and a benign biopsy finding. A 41-year-old male complained of a palpable neck mass, hoarseness, and dysphagia. The thyroid function test was normal. Ultrasonography revealed suspicion of malignancy with category 4 of American College of Radiology-Thyroid Imaging Reporting and Data System (ACR-TIRADS). The biopsy revealed follicular neoplasm, and was classified as Bethesda IV. The patient underwent a total thyroidectomy due to the large tumor size and symptoms. Histopathological findings post-surgery revealed a follicular thyroid adenoma. This case highlights a complex diagnosis and management of follicular thyroid neoplasm due to their potential for both benign and malignant. Comprehensive pre- and post-operative care is essential to determine the nature of nodules. Post-operative follow-up care might improve the patient\'s outcome and prevent complications.

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

UNASSIGNED: Thyroid cancer is the most common endocrine tumor in humans. Follicular adenoma/carcinoma is the second most common subtype. Multiple histological patterns have been identified. Follicular adenoma with bizarre nuclei is one of the patterns associated with p53 mutation and has an unclear clinical prognosis.
UNASSIGNED: A 74-year-old female presented with incidental findings of elevated TSH levels and normal thyroid markers. Ultrasound was performed and revealed multiple bilateral thyroid nodules measuring up to 1.9 cm. Fine needle aspiration was performed, and cytology showed one Bethesda category 5 nodule. Total thyroidectomy with neck dissection was performed, and the pathology showed follicular adenoma with bizarre nuclei. Based on the results of immunohistochemistry, the neoplastic cells exhibited staining for wild-type p53 and low levels of the proliferation index Ki-67.
UNASSIGNED: We report a rare case of thyroid follicular adenoma with bizarre nuclei. In contrast to previous reports of this tumor, our patient showed a p53 wild-type pattern using immunohistochemistry. More studies are needed to better understand the etiology and clinical prognosis of this tumor.

OBJECTIVE: To explore the diagnostic performance of the currently used ultrasound-based thyroid nodule risk stratification systems (K-TIRADS, ACR -TIRADS, and C-TIRADS) in differentiating follicular thyroid adenoma (FTA) from follicular thyroid carcinoma (FTC).
METHODS: Clinical data and preoperative ultrasonographic images of 269 follicular thyroid neoplasms were retrospectively analyzed. All of them were detected by Color Doppler ultrasound instruments equipped with high-frequency liner array probes (e.g. Toshiba Apoli500 with L5-14MHZ; Philips IU22 with L5-12MHZ; GE LOGIQ E9 with L9-12MHZ and MyLab Class C with L9-14MHZ). The diagnostic performance of three TIRADS classifications for differentiating FTA from FTC was evaluated by drawing the receiver operating characteristic (ROC) curves and calculating the cut-off values.
RESULTS: Of the 269 follicular neoplasms (mean size, 3.67±1.53 cm), 209 were FTAs (mean size, 3.56±1.38 cm) and 60 were FTCs (mean size, 4.07±1.93 cm). There were significant differences in ultrasound features such as margins, calcifications, and vascularity of thyroid nodules between the FTA and FTC groups (P < 0.05). According to the ROC curve comparison analysis, the diagnostic cut-off values of K-TIRADS, ACR-TIRADS, and C-TIRADS for identifying FTA and FTC were K-TR4, ACR-TR4, and C-TR4B, respectively, and the areas under the curves were 0.676, 0.728, and 0.719, respectively. The difference between ACR-TIRADS and K-TIRADS classification was statistically significant (P = 0.0241), whereas the differences between ACR-TIRADS and C-TIRADS classification and between K-TIRADS and C-TIRADS classification were not statistically significant (P > 0.05).
CONCLUSIONS: The three TIRADS classifications were not conducive to distinguishing FTA from FTC. It is necessary to develop a novel malignant risk stratification system specifically for the identification of follicular thyroid neoplasms.

Pre- and postsurgical differentiation between follicular thyroid adenoma (FTA) and follicular thyroid cancer (FTC) represents a significant diagnostic challenge. Furthermore, it remains unclear whether they share a common or distinct background and what the mechanisms underlying follicular thyroid lesions malignancy are. The study aimed to compare FTA and FTC by the comprehensive microarray and to identify recurrent regions of loss of heterozygosity (LOH). We analyzed formalin-fixed paraffin-embedded (FFPE) samples acquired from 32 Caucasian patients diagnosed with FTA (16) and FTC (16). We used the OncoScan™ microarray assay (Affymetrix, USA), using highly multiplexed molecular inversion probes for single nucleotide polymorphism (SNP). The total number of LOH was higher in FTC compared with FTA (18 vs. 15). The most common LOH present in 21 cases, in both FTA (10 cases) and FTC (11 cases), was 16p12.1, which encompasses many cancer-related genes, such as TP53, and was followed by 3p21.31. The only LOH present exclusively in FTA patients (56% vs. 0%) was 11p11.2-p11.12. The alteration which tended to be detected more often in FTC (6 vs. 1 in FTA) was 12q24.11-q24.13 overlapping FOXN4, MYL2, PTPN11 genes. FTA and FTC may share a common genetic background, even though differentiating rearrangements may also be detected.

Follicular neoplasms of the thyroid include follicular thyroid carcinoma (FTC) and follicular thyroid adenoma (FTA). However, the differences in cytological findings between FTC and FTA remain undetermined. Here, we aimed to evaluate the accumulation of lipid droplets (LDs) and the expression of adipophilin (perilipin 2/ADRP/ADFP), a known LD marker, in cultured FTC cells. We also immunohistochemically compared adipophilin expression in the FTC and FTA of resected human thyroid tissues. Cultured FTC (FTC-133 and RO82W-1) possessed increased populations of LDs compared to thyroid follicular epithelial (Nthy-ori 3-1) cells. In vitro treatment with phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling inhibitors (LY294002, MK2206, and rapamycin) in FTC-133 cells downregulated the PI3K/Akt/mTOR/sterol regulatory element-binding protein 1 (SREBP1) signaling pathway, resulting in a significant reduction in LD accumulation. SREBP1 is a master transcription factor that controls lipid metabolism. Fluorescence immunocytochemistry revealed adipophilin expression in the LDs of FTC-133 cells. Immunohistochemical analysis of surgically resected human thyroid tissues revealed significantly increased expression of adipophilin in FTC compared with FTA and adjacent non-tumorous thyroid epithelia. Taken together, LDs and adipophilin were abundant in cultured FTC; the evaluation of adipophilin expression can help distinguish FTC from FTA in surgical specimens.

OBJECTIVE: To investigate the feasibility and value of deep learning based on grayscale ultrasonography in the differentiation of pathologically proven atypical and typical medullary thyroid carcinoma (MTC) from follicular thyroid adenoma (FTA).
METHODS: The preoperative 770 ultrasound images consisted of 354 MTCs (66% were typical MTCs with a high suspicion sonographic pattern, 34% were atypical MTCs with a suspicion pattern of intermediate or less) and 416 FTAs. All images were delineated manually by a senior sonographer to achieve the regions of interest. Two deep neural networks of ResNet-34 and ResNet-18 were performed on the training set (n = 690). The test data set (n = 80) was subsequently evaluated by the two models and two sonographers, their diagnostic performances and misdiagnosis lesions were compared and analyzed.
RESULTS: The ResNet-34 model shows higher diagnostic ability than the junior sonographer with an area under the receiver operating curve of 0.992 (95% CI: 0.840-0.970)versus 0.754 (95% CI:0.645-0.843). Moreover, 12 of 16 atypical MTCs were successfully identified by the ResNet-34, which is significantly better than the senior and junior sonographer, suggesting that these patients could benefit from timely serological examination and surgical strategy at an earlier stage.
CONCLUSIONS: Deep learning to differentiate MTC from FTA on grayscale ultrasound may be a useful diagnostic support tool, especially in atypical MTC and FTA. Moreover, the computing time of deep learning is short, which will help to incorporate it into real-time ultrasound diagnosis.

The diagnosis of follicular-patterned thyroid tumors such as follicular thyroid adenoma (FA), follicular thyroid carcinoma (FTC), and follicular variant of papillary thyroid carcinoma (FvPTC) remains challenging. This study aimed to explore the molecular differences among these three thyroid tumors by proteomic analysis. A pressure cycling technology (PCT)-data-independent acquisition (DIA) mass spectrometry workflow was employed to investigate protein alterations in 52 formalin-fixed paraffin-embedded (FFPE) specimens: 18 FA, 15 FTC, and 19 FvPTC specimens. Immunohistochemical (IHC) analysis of 101 FA, 67 FTC, and 65 FvPTC specimens and parallel reaction monitoring (PRM) analysis of 20 FA, 20 FTC, and 20 FvPTC specimens were performed to validate protein biomarkers. A total of 4107 proteins were quantified from 52 specimens. Pairwise comparisons identified 287 differentially regulated proteins between FTC and FA, and 303 between FvPTC and FA and 88 proteins were co-dysregulated in the two comparisons. However, only 23 discriminatory proteins between FTC and FvPTC were detected. Additionally, the quantitative results for ANXA1 expression based on IHC staining and PRM-MS quantification were consistent with the proteomic results, showing that ANXA1 can be used to distinguish FvPTC from FA and FTC. The differentially regulated proteins found in this study can differentiate FA from FvPTC. In addition, ANXA1 is a promising biomarker for differentiating FvPTC from the other thyroid tumors.

Follicular thyroid tumors pose a diagnostic challenge on the preoperative level, as the discrimination between follicular thyroid carcinoma (FTC) and adenoma (FTA) demands careful histopathological investigation. Moreover, prognostication of FTCs is mostly based on tumor size and extent of invasive properties, while immunohistochemical markers pinpointing high-risk cases are lacking. We have routinely established a Ki-67 labeling index for follicular thyroid tumors since 1999. To assess the potential value of Ki-67 as an adjunct tool to (1) correctly separate FTCs from FTAs and (2) help identify poor-prognosis FTCs, we collected histopathological and clinical data from 818 follicular thyroid tumors with a histological Ki-67 labeling index established in clinical routine practice (516 FTAs, 252 FTCs, and 50 follicular thyroid tumors of uncertain malignant potential (FT-UMPs)). The Ki-67 labeling index was higher in FTCs (mean 5.8%) than in FTAs (mean 2.6%) (P < 0.001), and a receiver operating characteristic curve analysis revealed a cut-off value of 4% to separate FTC from FTA with a sensitivity and specificity of 65% and 83%, respectively. Similarly, a Ki-67 labeling index above 4% was found to identify FTCs that later metastasized from clinically indolent FTCs with a sensitivity and specificity of 80% and 48%, respectively. Ki-67 constituted an independent predictor of future FTC metastases/recurrence and death of disease, and a value > 4% was a reliable prognostic marker within individual pT staging groups. We conclude that Ki-67 is a potentially valuable marker for the prognostication of FTCs, and future implementation in the histopathological assessments of follicular thyroid tumors could be beneficial if reproduced in international series.