Prevalence and diagnostic significance of non-invasive follicular thyroid neoplasm with papillary-like nuclear features in Japan-A multi-institutional study.

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.

Lipid droplet accumulation and adipophilin expression in follicular thyroid carcinoma.

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.

Overexpression of mir-129-1, miR-146b, mir-183, and mir-197 in follicular thyroid carcinoma and adenoma tissues.

Follicular thyroid carcinoma (FTC) is responsible for approximately 10% of thyroid malignancies. Since this type of malignancy indicates no capsular and vascular invasions, adenoma and follicular carcinoma of thyroid are not distinguishable. It has been proved that microRNAs, which regulate approximately 30% of coding proteins, have an association with follicular thyroid adenoma (FTA) and carcinoma of the thyroid. Therefore, the aim of this study was to assess the expression of some miRNAs for detecting the most appropriate miRNA as potential biomarker in the diagnosis of FTA and FTC patients. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was applied to determine the expression levels of miR-129-1, miR-146b,-183 and miR-197 in 48 cases (16 FTC, 16 FTA and 16 hyperplasia/multinodular goiter (MNG) cases). The significance of miRNA differential expression levels among groups were assessed using Multivariate test by Statistical Package for Science Software (SPSS v.20) and Graph Pad Prism v.8. Results indicated that all of the miRNAs had significant overexpression in FTC and FTA versus MNG cases, and also increased expression level in FTC in comparison with FTA, however it was not significant. The results of ROC curve analysis determined the significant overexpression and prognostic value of miR-129-1 in FTA cases and miR-146b in both FTA and FTC cases compared to MNG group. Although all of the earlier mentioned microRNAs were overexpressed in FTC and FTA cases, the ROC curve results demonstrated that miR-129-1 had agreeable AUC for FTA cases. Therefore, it seems that it's cut-off point could be helpful in distinguishing between FTA and multinodular goiter cases. On the other hand, although miR-146b has excellent diagnostic value in both FTA and FTC groups, it seems that this microRNA is unable to act as a specific biomarker to discriminate between FTA and FTC cases. This data need to be confirmed in a large cohort study and other biological samples such as plasma.

Effect of single-nucleotide polymorphism in TERT promoter on follicular thyroid tumor development.

Follicular thyroid neoplasm is a common tumor, and consists of follicular thyroid adenoma (FTA) and carcinoma (FTC). The mechanisms of tumor development of FTA and FTC are not well-understood. Single-nucleotide polymorphisms (SNPs) and point mutations in the telomerase reverse transcriptase (TERT) promoter have been associated with tumor development of many cancers. In order to clarify the significance of TERT promoter SNPs and mutations, including rs2853669 (-245T>C), C228T, and C250T, we analyzed 59 FTA patients and 19 FTC patients. Rs2853669 was found in 67.8% (40/59) and 57.9% (11/19) of FTAs and FTCs, respectively, and homozygous rs2853669 (CC) was more frequently found in FTC than in FTA. Furthermore, in FTA, rs2853669 was significantly associated with tumor size greater than 2.0 cm (P < 0.05). C228T was found in 5.1% and 36.8% of FTAs and FTCs, respectively. Frequencies of rs2853669 or/and C228T mutation were 71.2% in FTAs and 73.7%, in FTCs, and were significantly associated with larger tumor sizes in FTAs (P < 0.05). Rs2853669 is considered to be associated with tumor development in FTA and FTC.

[The impact of elective central lymph node dissection on postoperative pathological staging and surgical complication rate in patients with results of fine needle spiration biopsy suspicious for follicular neoplasm of thyroid].

OBJECTIVE: Introduction: Follicular-patterned lesions of the thyroid are common; these include follicular adenoma, follicular cancer and follicular variant of papillary cancer. At present, preoperative discrimination between follicular adenoma and follicular cancer is infeasible and most patients require surgery to confirm diagnosis. The aim: To assess the impact of elective central lymph node dissection on postoperative pathological staging and early surgical complication rate in patients operated for suspicion for follicular neoplasm or suspicion for oxyphilic neoplasm of thyroid. PATIENTS AND METHODS: Materials and Methods: Eighty consecutive patients operated between 2016-2018 in Third Department of General Surgery UJCM because of suspicious for follicular neoplasm of the thyroid were included into the study. Inclusion criteria were: the result of fine needle aspiration biopsy " suspicious for follicular/oxyphilic neoplasm", absence of invasive neoplasm features as follows infiltration of surrounding tissue or lymph nodes/distant metastases, informed consent. In all patients elective central lymph node dissection was performed. Surgical early postoperative complications were reported and the rate was compared between the study group and the control group consisting of patients operated on in the same period for benign nodular goitre. RESULTS: Results: In 10 (12,5%) patients thyroid cancer was diagnosed, including 8 (80%) patients with papillary cancer and 2 (20%) patients with follicular cancer. The most common benign lesion was follicular adenoma diagnosed in 42 (60%) patients. There were 129 lymph nodes dissected (mean 1.6 lymph node per 1 patient), all lymph nodes were clear of cancer cells. In 26 patients there were no lymph nodes in postoperative preparation. Metastatic lymph nodes were not identified in any patients of the study group with final diagnosis of thyroid cancer. No significant differences were identified in prevalence of early postoperative complications among the study group and the control group patients: unilateral recurrent laryngeal nerve (RLN) palsy 3.4% vs. 1.49%; p= 0,08), hypocalcemia (5% vs. 5.4%; p=0.86), postoperative hemorrhage (1.25% vs. 0.44; p=0.29). CONCLUSION: Conclusions: Elective central lymph node dissection at experienced surgical hands does not improve postoperative pathological staging and is not associated with higher risk of early postoperative complications.

Differences in Mutational Profile between Follicular Thyroid Carcinoma and Follicular Thyroid Adenoma Identified Using Next Generation Sequencing.

We aimed to identify differences in mutational status between follicular thyroid adenoma (FTA) and follicular thyroid cancer (FTC). The study included 35 patients with FTA and 35 with FTC. DNA was extracted from formalin-fixed paraffin-embedded (FFPE) samples from thyroidectomy. Next-generation sequencing (NGS) was performed with the 50-gene Ion AmpliSeq Cancer Hotspot Panel v2. Potentially pathogenic mutations were found in 14 (40%) FTA and 24 (69%) FTC patients (OR (95%CI) = 3.27 (1.22-8.75)). The number of mutations was higher in patients with FTC than FTA (p-value = 0.03). SMAD4 and STK11 mutations were present only in patients with FTA, while defects in FBXW7, JAK3, KIT, NRAS, PIK3CA, SMARCB1, and TP53 were detected exclusively in FTC patients. TP53 mutations increased the risk of FTC; OR (95%CI) = 29.24 (1.64-522.00); p-value = 0.001. FLT3-positivity was higher in FTC than in the FTA group (51.4% vs. 28.6%; p-value = 0.051). The presence of FLT3 and TP53 with no RET mutations increased FTC detectability by 17.1%, whereas the absence of FLT3 and TP53 with a presence of RET mutations increased FTA detectability by 5.7%. TP53 and FLT3 are candidate markers for detecting malignancy in follicular lesions. The best model to predict FTA and FTC may consist of FLT3, TP53, and RET mutations considered together.

[The analysis of genetic and clinicopathologic characteristics in patients with follicular thyroid neoplasm].

Objective: To explore the molecular characteristics of follicular variant papillary thyroid carcinoma (FVPTC), follicular thyroid adenoma (FTA) and follicular thyroid carcinoma (FTC), and investigate their role in tumorigenesis, differential diagnosis and prognosis evaluation in patients with follicular thyroid neoplasm. Methods: We retrospectively analyzed 50 surgical resection samples of follicular thyroid neoplasm. DNA was obtained from formalin-fixed, paraffin-embedded tissue, and subjected to next-generation sequencing (NGS) to analyze 50 hotspots for mutation in genes. Results: 47 samples passed quality control, including 29 FVPTCs, 8 FTAs and 10 FTCs. 75.9% of FVPTCs harbored mutated genes: BRAF V600E (31.0%, 9/29) was the most frequent, followed by TP53 (27.6%, 8/29), and N/KRAS (20.7%, 6/29). In contrast, 37.5% (3/8) FTAs carried NRAS Q61R mutation with 12.5% (1/8) FTA carrying mutated BRAF G466E. 20% (2/10) FTCs harbored NRAS Q61R mutation, and 20% (2/10) FTCs with TP53 mutations. BRAF V600E gene mutation only appeared in FVPTC, and was associated with age of onset and lymph node metastasis. There was no significant correlation between N/KRAS mutations and clinical pathologic features. Patients with lymph node metastasis group seems to have more TP53 mutation. Conclusions: BRAF V600E gene mutation can be used to identity FVPTC from FTA/FTC. N/KRAS mutations cannot be used as the exclusive indicator of benign and malignant in thyroid follicular tumor. TP53 mutations play an important role in the process of follicular thyroid neoplasm, indicating more aggressive behavior and poor prognosis.

Computed Tomography Findings for Diagnosing Follicular Thyroid Neoplasms.

Since no diagnostic method has been established to distinguish follicular thyroid carcinoma (FTC) from follicular thyroid adenoma (FTA), surgery has been the only way to reach a diagnosis of follicular neoplasm. Here we investigated the computed tomography (CT) features of follicular neoplasms, toward the goal of being able to identify specific CT features allowing the preoperative differentiation of FTC from FTA. We retrospectively analyzed the cases of 205 patients who underwent preoperative CT of the neck and were histopathologically diagnosed with FTC (n=31) or FTA (n=174) after surgery between January 2002 and June 2016 at several hospitals in Japan. In each of these 205 cases, non-enhanced and contrast-enhanced CT images were obtained, and we analyzed the CT features. On univariate analysis, inhomogeneous features of tumor lesions on contrast-enhanced CT were more frequently observed in FTC than in FTA (p=0.0032). A multivariate analysis identified inhomogeneous features of tumor lesions on contrast-enhanced CT images as an independent variable indicative of FTC (p=0.0023). CT thus offers diagnostic assistance in distinguishing FTC from FTA.

Gene Expression (mRNA) Markers for Differentiating between Malignant and Benign Follicular Thyroid Tumours.

Distinguishing between follicular thyroid cancer (FTC) and follicular thyroid adenoma (FTA) constitutes a long-standing diagnostic problem resulting in equivocal histopathological diagnoses. There is therefore a need for additional molecular markers. To identify molecular differences between FTC and FTA, we analyzed the gene expression microarray data of 52 follicular neoplasms. We also performed a meta-analysis involving 14 studies employing high throughput methods (365 follicular neoplasms analyzed). Based on these two analyses, we selected 18 genes differentially expressed between FTA and FTC. We validated them by quantitative real-time polymerase chain reaction (qRT-PCR) in an independent set of 71 follicular neoplasms from formaldehyde-fixed paraffin embedded (FFPE) tissue material. We confirmed differential expression for 7 genes (CPQ, PLVAP, TFF3, ACVRL1, ZFYVE21, FAM189A2, and CLEC3B). Finally, we created a classifier that distinguished between FTC and FTA with an accuracy of 78%, sensitivity of 76%, and specificity of 80%, based on the expression of 4 genes (CPQ, PLVAP, TFF3, ACVRL1). In our study, we have demonstrated that meta-analysis is a valuable method for selecting possible molecular markers. Based on our results, we conclude that there might exist a plausible limit of gene classifier accuracy of approximately 80%, when follicular tumors are discriminated based on formalin-fixed postoperative material.

TERT promoter mutation as an early genetic event activating telomerase in follicular thyroid adenoma (FTA) and atypical FTA.

BACKGROUND: The telomerase reverse transcriptase (TERT) promoter mutations C228T and C250T have been found in many malignancies, including in thyroid carcinomas. However, it is unclear how early these mutations occur in thyroid tumorigenesis. METHODS: The study included primary tumors from 58 patients initially diagnosed with follicular thyroid adenoma (FTA), a benign entity, 18 with atypical FTA (AFTA) having an uncertain malignant potential, and 52 with follicular thyroid carcinoma (FTC). Sanger sequencing was used to investigate the mutational status of the TERT promoter. Telomere length and TERT messenger RNA (mRNA) expression were determined using quantitative polymerase chain reaction (PCR). Telomerase activity was assessed using a Telomerase PCR enzyme-linked immunosorbent assay kit. RESULTS: The C228T mutation was identified in 1 of 58 FTA (2%) and 3 of 18 AFTA (17%) samples. These 4 tumors all expressed TERT mRNA and telomerase activity, whereas the majority of C228T-negative adenomas lacked TERT expression (C228T versus wild-type, P = .008). The C228T mutation was associated with NRAS gene mutations (P = .016). The patient with C228T-mutated FTA later developed a scar recurrence and died of FTC, whereas none of the remaining 57 patients with FTA had recurrence. No recurrence occurred in 3 patients with AFTA who carried C228T during the follow-up period (36-285 months). Nine of the 52 FTCs (17%) exhibited the TERT mutation (8 of 9 C228T and 1 of 9 C250T), and the presence of the mutation was associated with shorter patient survival. CONCLUSIONS: TERT promoter mutations may occur as an early genetic event in thyroid follicular tumors that have not developed malignant features on routine histopathological workup.

The alternative value of thyroid stimulating hormone instead of thyroglobulin in differentiation of follicular thyroid neoplasm in Hashimoto's thyroiditis.

Purposes: To provide novel aspects for the preoperative diagnosis and appropriate differentiation strategies for follicular thyroid carcinoma (FTC) and follicular thyroid adenoma (FTA). Methods: Among 25,765 cases, a total of 326 patients with follicular thyroid neoplasms between 2013 and 2019 were enrolled. Patient demographics, perioperative parameters, surgical profiles and oncologic outcomes were collected and analyzed. Results: There were no significant differences in preoperative ultrasound findings between FTA and FTC patients. The true positive rate (sensitivity) and true negative rate (specificity) of fine needle aspiration (FNA) for FTA patients were 0.6956 and 0.5000, respectively, and those for FTC patients were 0.0714 and 0.9348, respectively. Patients with FTC presented significantly higher serum thyroglobulin (TG) levels than patients with FTA. Preoperative TG level was positively related to tumor invasiveness and recurrence or distant metastases in FTC patients. There were 55 patients with Hashimoto's thyroiditis (HT), accounting for 16.87% of enrolled patients. HT patients had significantly lower serum TG concentrations than antibody-negative patients. Among HT patients, no significant differences were observed in TG levels between the FTA and FTC groups. Instead, FTA patients had significantly higher serum thyroid stimulating hormone (TSH) levels and lower serum T3 (Triiodothyronine) levels compared to FTC patients. Serum TSH level >1.736U/L was associated with benign follicular neoplasms in HT patients according to the receiver operating characteristic (ROC) curve. Conclusion: Distinguishing FTC from FTA remains a challenge for ultrasonography and FNA. Serum TG should be measured as a risk factor of FTC. However, in HT patients, serum TSH levels can serve as a more reliable indicator for differentiating FTC from FTA preoperatively.

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.

Comparison of the diagnostic performance of three ultrasound thyroid nodule risk stratification systems for follicular thyroid neoplasm: K-TIRADS, ACR -TIRADS and C-TIRADS.

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). CONCLUSION: 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.

Follicular adenoma with bizarre nuclei and wild-type P53 expression: A case report and literature review.

Introduction: 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. Case report: 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. Conclusions: 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.

Complexity of diagnosis and management of a giant thyroid nodule: A case report and a concise literature.

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.

Follicular Thyroid Adenoma and Follicular Thyroid Carcinoma-A Common or Distinct Background? Loss of Heterozygosity in Comprehensive Microarray Study.

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.

Deep learning based on ultrasound to differentiate pathologically proven atypical and typical medullary thyroid carcinoma from follicular thyroid adenoma.

OBJECTIVES: 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. CONCLUSION: 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.

Prognostic Utility of the Ki-67 Labeling Index in Follicular Thyroid Tumors: a 20-Year Experience from a Tertiary Thyroid Center.

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.

Proteotypic Differences of Follicular-Patterned Thyroid Neoplasms.

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.

The Value of Sonography in Distinguishing Follicular Thyroid Carcinoma from Adenoma.

PURPOSE: Differentiation between follicular thyroid carcinomas (FTCs) and follicular thyroid adenomas (FTAs) is difficult and the sonographic features of FTC are not yet fully established. The purpose of this study is to explore the sonographic features of FTC and the value of sonography in differentiating FTCs from FTAs. PATIENTS AND METHODS: A total of 28 pathologically proven FTCs and 53 FTAs in 78 patients who were performed thyroid surgery were included in this retrospective study. The sonographic features of each tumor including an interrupted halo, satellite nodule(s) with or without halo ring, local irregularity of margin and cluster of grapes sign were evaluated. A mode image of FTC halo was built up in our study. The frequencies of the sonographic features were compared by chi-square test or Fisher exact test between FTCs and FTAs. The relative risk of malignancy was assessed by logistic regression analysis. RESULTS: Logistic regression analysis showed that a thick, irregular and/or interrupted halo with or without satellite nodule(s), hypoechoic or marked hypoechoic echogenicity, a predominantly solid pattern, cluster of grapes sign, micro-or macro-calcifications, rim calcifications correlated with significant increases in relative risk for FTCs (odds ratio 11.48 (1.37-96.56), 6.74 (1.05-43.30), 17.51 (1.78-172.53), 9.55 (1.44-63.46), 9.36 (1.25-70.15) and 17.45 (1.04-292.65), respectively, p<0.05). Two new sonographic features, an interrupted halo and satellite nodule(s) with or without halo ring, can only be found in FTCs. CONCLUSION: An interrupted halo and satellite nodule(s) with or without halo ring are specific sonographic features for FTCs. Sonography could play a role in differentiating follicular thyroid carcinoma from adenoma.