[Molecular and other ancillary tests proposed by The Bethesda system for reporting thyroid cytopathology 2023]. / Les tests moléculaires et autres techniques ancillaires en cytologie thyroïdienne selon Bethesda 2023.

For the first time the 2023 version of The Bethesda System for Reporting Thyroid Cytology dedicates a whole chapter (chapter 14) to ancillary studies almost exclusively represented by molecular testing. The latest data reported bring some evidence that molecular testing could help to optimize the diagnostic performance of « indeterminate ¼ categories (AUS and NF). Other studies suggest a promising role to guide the management of suspicious of malignancy and malignant categories. Indeed, the recognition of prognostic and predictive biomarkers analyzed on cytological samples, regardless of how it is collected, has progressed thanks to advances in our knowledge of molecular abnormalities of thyroid tumors. The chapter 14 is presented here highlighting the current and emerging roles of « in-house ¼ and commercialized molecular testing as presented by TSBRTC.

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.

Accuracy of the 'CUT' Score for Assessing Malignancy in Bethesda 3 and 4 Thyroid Nodules in North American Population: A Retrospective Study.

BACKGROUND: The CUT score is a thyroid nodule malignancy risk assessment scoring system intended to guide surgeons in treating Bethesda 3 and 4 thyroid nodules. It is based on clinical (C) and ultrasonographic (U) features and a five-tiered (T) representing cytology. PURPOSE: Our study aimed to assess the utility of the CUT score in predicting thyroid malignancy in the North American population. The main reason for creating this score is to reduce unnecessary surgeries on these challenging thyroid nodules. MATERIALS AND METHODS: A retrospective record review study applied the CUT score to 219 Bethesda 3 and 4 thyroid nodules. A total of 203 Bethesda 3 and 16 Bethesda 4 nodules from patients treated between January 2015 and December 2019 at a single institution were assessed. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the CUT diagnostic test. Binary logistic regression analysis was performed. Iteration of analysis was performed after stratification according to body mass index to assess CUT score accuracy in obese and non-obese patients. RESULTS: Of 219 nodules analyzed, 148 were characterized as benign and 71 as malignant. Prevalence rates of malignancy were 29.6% (n = 60) and 68.8% (n = 11) in Bethesda 3 and 4 nodules, respectively. The mean CU (clinical, ultrasonography) score was 5.35 ± 1.38 in benign nodules versus 4.96 ± 1.5 in malignant nodules (p = 0.08). The area under the curve (AUC = 0.433) for the association of CUT scores with nodule malignancy was not significant (p = 0.13). The CUT score was insignificant as a diagnostic test for nodule malignancy in obese (AUC = 0.45; p = 0.72) and non-obese patients (AUC = 0.39; p = 0.08). CONCLUSION: The CUT score did not correlate with preoperative malignancy risk estimates in Bethesda 3 thyroid nodules and, therefore, may have limited utility as a predictor of malignancy in these thyroid nodules.

Differentiate Thyroid Follicular Adenoma from Carcinoma with Combined Ultrasound Radiomics Features and Clinical Ultrasound Features.

Noninvasive differentiating thyroid follicular adenoma from carcinoma preoperatively is of great clinical value to decrease the risks resulted from excessive surgery for patients with follicular neoplasm. The purpose of this study is to investigate the accuracy of ultrasound radiomics features integrating with ultrasound features in the differentiation between thyroid follicular carcinoma and adenoma. A total of 129 patients diagnosed as thyroid follicular neoplasm with pathologically confirmed follicular adenoma and carcinoma were enrolled and analyzed retrospectively. Radiomics features were extracted from preoperative ultrasound images with manually contoured targets. Ultrasound features and clinical parameters were also obtained from electronic medical records. Radiomics signature, combined model integrating radiomics features, ultrasound features, and clinical parameters were constructed and validated to differentiate the follicular carcinoma from adenoma. A total of 23 optimal features were selected from 449 extracted radiomics features. Clinical and ultrasound parameters of sex (p = 0.003), interior structure (p = 0.035), edge (p = 0.02), platelets (p = 0.007), and creatinine (p = 0.001) were associated with the differentiation between benign and malignant follicular neoplasm. The values of area under curves (AUCs) of the radiomics signature, clinical model, and combined model were 0.772 (95% CI: 0.707-0.838), 0.792 (95% CI: 0.715-0.869), and 0.861 (95% CI: 0.775-0.909), respectively. A final corrected AUC of 0.844 was achieved for the combined model after internal validation. Radiomics features from ultrasound images combined with ultrasound features and clinical factors are feasible to differentiate thyroid follicular carcinoma from adenoma noninvasive before operation to decrease the unnecessary of diagnostic thyroidectomy for patients with benign follicular adenoma.

Radiofrequency ablation for treatment of thyroid follicular neoplasm with low SUV in PET/CT study.

OBJECTIVES: To evaluate the feasibility of radiofrequency ablation (RFA) on follicular neoplasm with low standard uptake value (SUV) in a Positron emission tomography (PET/CT) study. METHODS: From January 2018 to July 2019, 86 consecutive patients were diagnosed with follicular neoplasm. Of the patients, 28 with PET/CT scans were enrolled in this study. All patients received ultrasound, fine/core needle aspiration, and PET/CT scan prior to treatment. In accordance with previous studies, we recommended 6 patients who had follicular neoplasm with SUVmax ≥5 undergo surgical resection due to an elevated suspicion of malignancy. For 22 patients SUVmax <5, RFA was performed using the moving shot technique. Ultrasound was performed 6 to 12 months after each procedure. RESULTS: Statistically significant volume reductions during follow-up between values prior to RFA and 12 months post RFA were demonstrated (12.6 ± 20.9 vs. 2.4 ± 3.0 cm3, p < 0.001). Volume reduction ratios at 6-12 months (mean: 10.1 months) after RFA were 73.3% ± 17.7%. One patient presented with vocal cord palsy and recovered within 3 months after RFA. No postprocedural hypothyroidism occurred in the RFA patients. CONCLUSIONS: By using PET/CT, we can select patients with low SUV follicular neoplasm. RFA offers a safe and feasible alternative treatment option for patients unsuitable or unwilling to undergo surgery.KEY POINTSBy using positron emission tomography-computed tomography, we can distinguish low SUV follicular neoplasm for radiofrequency ablation.For low SUV follicular neoplasm, RF ablation offers a safe and effective alternative treatment option for patients unsuitable or unwilling to undergo surgery.

Diagnostic Role of Cell-free DNA Integrity in Thyroid Cancer Particularly for Bethesda IV Cytology.

BACKGROUND: The cell-free DNA integrity index (cfDI) is promising for the differentiation between malignant and benign tumors, but little data has been reported on thyroid cancer (TC). We explored its diagnostic role in TC, mainly in cases of Bethesda category IV. METHODS: cfDI was evaluated by quantitative real-time polymerase chain reaction using 2 primer sets to identify cell-free DNAs (cfDNAs) Alu83 and Alu244. Blood samples were collected from 85 patients with thyroid nodules (18 papillary [PTC], 21 follicular [FTC], 21 medullary, and 25 benign thyroid nodules [BTN]) before fine-needle aspiration cytology and surgical treatment and also from 25 patients with autoimmune thyroid disease (ATD) and 25 healthy subjects (HS). RESULTS: cfDNA Alu244 concentration ≥6.95 ng/mL and cfDI ≥0.3 were excellent sensitive and specific tests to discriminate TC particularly cytologically indeterminate thyroid nodules (Bethesda IV) from the control groups (BTN, ATD, and HS). The levels of both cfDNA Alu83 and Alu244 were decreased while cfDI was increased significantly in medullary compared with FTC and PTC, with a nonsignificant difference between the latter subgroups. There was a significantly positive correlation between both cfDNA Alu83 and Alu244 with the T-classification of TNM staging and capsular invasion among PTC and FTC patients and between cfDI with Bethesda categories. Additionally, ATD had significantly higher cfDNA Alu83 and lower cfDI than HS. CONCLUSION: cfDI is a useful noninvasive molecular biomarker in TC that correlates with the Bethesda classification and histopathology. Tumor size and capsular invasion were correlated with quantitative cfDNA among PTC and FTC.

Clinicopathological features of in situ follicular neoplasm and relations with follicular lymphoma in Japan.

This study aims to investigate the clinicopathological features of in situ follicular neoplasm (ISFN) in Japan. ISFN is a rare condition formerly considered as an early precursor of follicular lymphoma (FL). This is a first original report of ISFN from Asian country. We reviewed 19 biopsy samples of ISFN. ISFNs were categorized into two groups: (1) ISFN, consisting of ISFN with strong positivity for BCL-2 immunohistochemical staining (IHC), and obvious translocation of BCL-2; and (2) ISFN-like FL, featuring cases without obvious translocation but having morphological features and characteristic IHC findings of ISFN. As control, we adopted obvious FL. For some cases showing coexisting ISFN and FL lesions in the same lymph node, we could conduct further clonality analysis for each lesion. Nine of the 19 cases of ISFN coexisted with FL or had a history of overt B- or T-cell lymphoma including FL. Statistical comparison among ISFN-like FL and FL showed no significant differences in pathological features. Molecular analysis suggested that ISFN lesion and FL lesion in the same lymph node each have a different clonality. ISFN coexists or associates with other overt lymphomas frequently.

Lobectomy may not be suitable for patients with follicular neoplasm cytology

Background/aim: The most appropriate surgical management of follicular neoplasm/suspicious for follicular neoplasm (FN) lesions is still contradictory. We aimed to evaluate the data of our patients with follicular neoplasm treated with thyroidectomy. Materials and methods: We retrospectively analyzed the data of 74 patients who were diagnosed with follicular neoplasm cytology (FN cytology) by fine needle aspiration biopsy (FNAB) and had undergone total thyroidectomy or lobectomy with isthmectomy (LwI). Results: We examined a total of 74 patients, of which 64 (83.7%) were female and 10 (16.3%) were male. The malignancy rate in the pathological examinations of these patients was 31/74 (41.9%). The most common cancer among the patients with malignancy was papillary thyroid carcinomas (PTC) (20/31, 65%). Among the subtypes of PTCs, 11 were classical PTC, 5 were a follicular variant of PTC, 2 were the oncocytic variant of PTC, 1 was the diffuse sclerosing variant, and 1 was a columnar cell variant of PTC. Conclusion: Since most FN cytology has been pathologically diagnosed with papillary cancer and some papillary cancer subtypes have been unfavorable pathologically, total thyroidectomy should be the most suitable treatment option in this group. Lobectomy with LwI is not suitable for patients with FNAB-proven FN cytology.

[Risk factors of malignancy in patients with fine needle aspiration biopsy results interpreted as "suspicious for follicular neoplasm"].

OBJECTIVE: Introduction: Approximately 10% of fine needle aspiration biopsy (FNAB) of thyroid nodules may be verified as "suspicious for follicular neoplasm"; this category involves follicular adenoma, follicular carcinoma, follicular variants of papillary carcinoma and subclass "suspicious for Hurthle cell neoplasm". At present, there is no diagnostic tool to discriminate between follicular adenoma and cancer. Most patients are required surgery to exclude malignant process. The aim: To define factors correlating with risk of malignancy in patients with FNAB of thyroid focal lesions and nodules verified as Bethesda tier IV. PATIENTS AND METHODS: Materials and Methods: In this study 110 consecutive patients were included. All patients were operated because of FNAB result "suspicious for follicular neoplasm" of thyroid gland at a single institution from January 2016 until March 2020. From this set, six specific categories were defined and the clinical records for patients were collected: sex, age, presence of oxyphilic cells, diameter of the tumour, presence of Hashimoto disease, aggregate amount of clinical and ultrasonographic features of malignancy according to ATA. RESULTS: Results: In 18 patients (16,3%) thyroid cancer occurred. Most frequent subtype turned out to be papillary cancer (66,6%). In group of benign lesion (92 patients) predominance of follicular adenoma was disclosed - (49%). Age, gender, tumour diameter, aggregate amount of clinical and ultrasonografic factors, presence of Hashimoto disease and fine needle aspiration biopsy result suspicious for Hurthle cell neoplasm did not correspond to increased risk of malignancy. CONCLUSION: Conclusions: In patients with FNAB results classified as Bethesda tier IV there are no reliable clinical features associated with low risk of malignancy and surgery should be consider in every case as most appropriate manner to exclude thyroid cancer .

Outcomes of Bethesda categories III and IV thyroid nodules over 5 years and performance of the Afirma gene expression classifier: A single-institution study.

OBJECTIVE: The second edition Bethesda System for Reporting Thyroid Cytology estimates 6%-18% malignancy rate of category III (B3) and 10%-40% for category IV (B4) nodules; however, reported malignancy rates have considerable variability among institutions. Use of molecular classifiers (including Afirma Gene Expression Classifier, GEC) can be utilized in management of thyroid nodules. Our objective was to analyse malignancy rates of B3 and B4 nodules and determine clinical outcomes of GEC Benign nodules. METHODS: A retrospective analysis of 2019 thyroid FNAs was performed at the University of Colorado from 2011 to 2015, including molecular, surgical and clinical follow-up. RESULTS: Of 2019 FNAs analysed, 231 (11.4%) were diagnosed as B3 and 80 (4.0%) as B4. GEC was obtained in 54.1% of B3 cases, with nearly half (48.8%) having a Benign result. Surgery was performed in 40.7% B3 cases with a 24.5% malignancy rate, ranging 8%-38% by year. In the B4 group, 52.5% underwent molecular testing with 28.6% as GEC Benign. About 68.8% of B4 cases underwent surgery with a 20% malignancy rate, ranging 0%-42% by year. Seventy-three GEC Benign cases were reviewed: 5 (6.8%) underwent surgery, with none demonstrating malignancy in the target nodule. Size remained stable for most GEC Benign nodules: 75.9% (B3) and 71.4% (B4) with no malignancy on repeat FNA. CONCLUSIONS: Our 5-year review demonstrated that malignancy rates of B3 and B4 nodules showed year-to-year variability. We suggest that clinicians use a multi-year average of their institution's malignancy rates to optimally manage patients. Follow-up for GEC Benign cases thus far supports their indolent nature.

PET/CT and prediction of thyroid cancer in patients with follicular neoplasm or atypia.

PURPOSE: To examine whether addition of 18F-fluoro-deoxy-glucose positron emission tomography/computed tomography (FDG-PET/CT) to fine needle aspiration biopsy (FNAB) would improve prediction of thyroid cancer in patients with FNAB-derived follicular neoplasm or atypia, classified according to focal, multifocal, diffuse, or no FDG uptake. MATERIALS AND METHODS: Consecutive patients with FNAB-derived follicular neoplasm or atypia planned for surgery from September 2013 to March 2016 were prospectively included and considered for analysis. All patients underwent preoperative PET/CT and a clinical head and neck examination, including ultrasound of the neck and the thyroid gland. Patients with obvious signs of thyroid malignancy were excluded from the study. Histology of the surgical specimen was used as reference standard for statistical analysis. RESULTS: Of the 108 patients included (85 women, median age 53.4 years), 31 (29%) had a thyroid nodule that was histologically verified as malignant. Sensitivity and specificity for PET/CT in detection of thyroid cancer was 79 and 32%, respectively, including a derived positive predictive value (PPV) of 31%, and a negative predictive value (NPV) of 79%. Univariate and multivariate analyses showed no significant increase in the risk of thyroid cancer among patients with focal or multifocal FDG uptake compared to patients with no FDG uptake. CONCLUSION: Addition of PET/CT to FNAB did not improve prediction of thyroid cancer in patients with FNAB-derived follicular neoplasm or atypia.

Eosinophil-rich trichoblastic carcinoma with aggressive clinical course in a young man.

We present the case of a 35-year-old man who developed a follicular differentiated cutaneous carcinoma with an eosinophil-rich infiltrate and an aggressive clinical behavior. After an in-depth histopathological investigation the diagnosis of trichoblastic carcinoma was made. Over the course of the disease the patient developed a cutaneous in-transit metastasis as well as an axillary lymph node metastasis 18 months after the excision of the primary tumor on his back. Based on a literature review we discuss the different concepts behind the term "trichoblastic carcinoma" and we summarize the clinical and histological details of previously reported cases. Furthermore, we focus on the phenomenon of tumor-associated eosinophilia.

Intra-institutional second opinion diagnosis can reduce unnecessary surgery for indeterminate thyroid FNA: A preliminary report on 34 cases.

INTRODUCTION: Indeterminate diagnoses are rendered on 15%-30% of thyroid fine-needle aspirates (FNA). Thus, a second diagnostic opinion given by an outside expert pathologist is a common practice that facilitates a more appropriate clinical management. Conversely, the role of an intra-institutional second opinion diagnosis (iSOD), which is usually informally performed in-house, has not been well established. METHODS: To assess the contribution of iSOD, a retrospective series of 34 thyroid FNA diagnosed as follicular neoplasm/suspicious follicular neoplasm (FN/SFN) with matched histological follow-up and a malignancy rate of 17.6% was selected and independently reviewed by two cytopathologists (CYT1 and 2). Cases with discrepant diagnoses were referred to a third in-house senior cytopathologist for the iSOD. The malignancy rates (MR) obtained after single independent reviews and iSOD were compared. RESULTS: MR obtained after CYT1 and CYT2 re-screening was similar (14.28% and 19.04%, respectively) and did not improve the original MR (17.64%). Conversely, after the iSOD of discrepant diagnoses, the overall malignancy rate increased up to the 27.27%, potentially sparing unnecessary surgical procedures. CONCLUSIONS: Intra-institutional second opinion practice for "indeterminate" thyroid FNA avoids unnecessary surgeries and maximises the detection of malignant cases diagnosed as FN/SFN.

Preoperative serum thyroglobulin and changes in serum thyroglobulin during TSH suppression independently predict follicular thyroid carcinoma in thyroid nodules with a cytological diagnosis of follicular lesion.

BACKGROUND: Fine-needle aspiration biopsy (FNAB) cannot distinguish a follicular thyroid carcinoma (FTC) from a follicular adenoma in follicular lesions. We designed this study to determine whether the preoperative thyroglobulin (Tg) and change in serum Tg during thyroid-stimulating hormone (TSH) suppression can predict FTC in thyroid nodules with a cytological diagnosis of follicular lesion. METHODS: Among 854 patients who underwent thyroid surgery, the 198 patients who presented with thyroid nodules with a cytological diagnosis of follicular lesion were analyzed. Predictive factors for malignancy were evaluated using multivariate logistic regression models. Subgroup analyses of patients with TSH suppression therapy by levothyroxine were also conducted. RESULTS: Thirty-two patients (16%) had FTC, and 166 patients had confirmed benign nodules. The median preoperative serum Tg levels were significantly higher in patients with FTC compared to those with benign pathology (449 vs. 34 ng/mL, p < 0.001). The serum Tg (odds ratios (OR) 10.311, p < 0.001) and tumor volume (OR 4.500, p = 0.035) were found to be independent predictors for FTC in all patients with a cytological diagnosis of follicular lesion. Forty-eight patients received TSH suppression therapy. When we performed subgroup analyses on the patients with TSH suppression therapy, decrease less than 15% in serum Tg during TSH suppression was found to be an independent predictor of FTC (OR 13.918, p = 0.018). CONCLUSION: Preoperative serum Tg and changes in serum Tg during TSH suppression independently predict FTC in thyroid nodules with a cytological diagnosis of follicular lesion.

Frozen section analysis in the post-Bethesda era.

BACKGROUND: The utility of frozen section (FS) for indeterminate thyroid nodules is controversial. In 2009, the Bethesda System for Reporting Thyroid Cytopathology was established to further subcategorize indeterminate fine-needle aspiration results (follicular lesions, FL) into Bethesda category 3 (BC3) and Bethesda category 4 (BC4). We hypothesize that FS will have less utility in the evaluation of BC3 lesions when compared to BC4. MATERIALS AND METHODS: A total of 479 patients who underwent thyroid lobectomy from January 2008 to July 2014 were retrospectively reviewed. Patients without appropriate Bethesda categorization were excluded. A total of 135 patients (65 FL, 45 BC3, 25 BC4) comprised the study groups. The sensitivity and specificity of FS within these three categories were determined. RESULTS: In the FL group, 6 of 65 patients were found to have thyroid cancer. Three were identified on frozen section (FS) resulting in a sensitivity and specificity of 50% and 100%, respectively. Thus, FS changed the operation in 3 of 65 cases (4.6%). In the BC3 group, 5 of 45 patients were found to have cancer. One was identified on FS resulting in a sensitivity and specificity of 20% and 100%, respectively. Thus, FS changed the operation in 1 of 45 patients (2.2%). In the BC4 group, 4 of 25 patients were found to have cancer. Two were identified on FS resulting in a sensitivity and specificity of 50% and 100% respectively. Thus, FS changed the operation in 2 of 25 patients (8%). CONCLUSIONS: There is improved utility of FS in BC 4 patients as 8% avoided reoperation. However, this benefit hinges on surgeon practice regarding the management of differentiated thyroid cancer >1 cm and <4 cm.

Carbonic anhydrase 4 and crystallin α-B immunoreactivity may distinguish benign from malignant thyroid nodules in patients with indeterminate thyroid cytology.

BACKGROUND: Thyroid nodules are present in 19%-67% of the population and carry a 5%-10% risk of malignancy. Unfortunately, fine-needle aspiration biopsies are indeterminate in 20%-30% of patients, often necessitating thyroid surgery for diagnosis. Numerous DNA microarray studies including a recently commercialized molecular classifier have helped to better distinguish benign from malignant thyroid nodules. Unfortunately, these assays often require probes for >100 genes, are expensive, and only available at a few laboratories. We sought to validate these DNA microarray assays at the protein level and determine whether simple and widely available immunohistochemical biomarkers alone could distinguish benign from malignant thyroid nodules. METHODS: A tissue microarray (TMA) composed of 26 follicular thyroid carcinomas (FTCs) and 53 follicular adenomas (FAs) from patients with indeterminate thyroid nodules was stained with 17 immunohistochemical biomarkers selected based on prior DNA microarray studies. Antibodies used included galectin 3, growth and differentiation factor 15, protein convertase 2, cluster of differentiation 44 (CD44), glutamic oxaloacetic transaminase 1 (GOT1), trefoil factor 3 (TFF3), Friedreich Ataxia gene (X123), fibroblast growth factor 13 (FGF13), carbonic anhydrase 4 (CA4), crystallin alpha-B (CRYAB), peptidylprolyl isomerase F (PPIF), asparagine synthase (ASNS), sodium channel, non-voltage gated, 1 alpha subunit (SCNN1A), frizzled homolog 1 (FZD1), tyrosine related protein 1 (TYRP1), E cadherin, type 1 (ECAD), and thyroid hormone receptor associated protein 220 (TRAP220). Of note, two of these biomarkers (GOT1 and CD44) are now used in the Afirma classifier assay. We chose to compare specifically FTC versus FA rather than include all histologic categories to create a more uniform immunohistochemical comparison. In addition, we have found that most papillary thyroid carcinoma could often be reasonably distinguished from benign disease by morphological cytology findings alone. RESULTS: Increased immunoreactivity of CRYAB was associated with thyroid malignancy (c-statistic, 0.644; negative predictive value [NPV], 0.90) and loss of immunoreactivity of CA4 was also associated with malignancy (c-statistic, 0.715; NPV, 0.90) in indeterminate thyroid specimens. The combination of CA4 and CRYAB for discriminating FTC from FA resulted in a better c-statistic of 0.75, sensitivity of 0.76, specificity of 0.59, positive predictive value (PPV) of 0.32, and NPV of 0.91. When comparing widely angioinvasive FTC from FA, the resultant c-statistic improved to 0.84, sensitivity of 0.75, specificity of 0.76, PPV of 0.11, and NPV of 0.99. CONCLUSIONS: Loss of CA4 and increase in CRYAB immunoreactivity distinguish FTC from FA in indeterminate thyroid nodules on a thyroid TMA with an NPV of 91%. Further studies in preoperative patient fine needle aspiration (FNAs) are needed to validate these results.

Malignancy Risk of Follicular Neoplasm (Bethesda IV) With Variable Cutoffs of Tumor Size: A Systemic Review and Meta-Analysis.

CONTEXT: The decision on diagnostic lobectomy for follicular neoplasms (FN) is challenging. OBJECTIVE: This meta-analysis investigates whether an appropriate size cutoff exists for recommending surgery for thyroid nodules diagnosed as FN by fine needle aspiration. METHODS: The Ovid-Medline, EMBASE, Cochrane, and KoreaMed databases were searched for studies reporting the malignancy rate of FN/suspicious for FN (FN/SFN) according to tumor size, using search terms "fine needle aspiration," "follicular neoplasm," "lobectomy," "surgery," and "thyroidectomy." RESULTS: Fourteen observational studies comprising 2016 FN/SFN nodules with postsurgical pathologic reports were included, and 2 studies included malignancy rates with various tumor sizes. The pooled malignancy risk of FN/SFN nodules according to size was: odds ratio (OR) 2.29 (95% CI, 1.68-3.11) with cutoff of 4 cm (9 studies), OR 2.39 (95% CI, 1.45-3.95) with cutoff of 3 cm (3 studies), and OR 1.81 (95% CI, 0.94-3.50) with cutoff of 2 cm (5 studies). However, tumors ≥2 cm also showed a higher risk (OR 2.43; 95% CI, 1.54-3.82) based on the leave-one-out meta-analysis after removal of 1 influence study. When each cutoff size was evaluated by summary receiver operating characteristic (sROC) curves, the cutoff of 4 cm showed the highest summary area under the curve (sAUC, 0.645) compared to other cutoffs (sAUC, 0.58 with 2 cm, and 0.62 with 3 cm), although there was no significant difference. CONCLUSION: Although the risk of malignancy increases with increasing tumor size, the risk remains significant at all tumor sizes and no cutoff limit can be recommended as a decision-making parameter for diagnostic surgery in Bethesda IV thyroid nodules.

Prediction of Follicular Thyroid Neoplasm and Malignancy of Follicular Thyroid Neoplasm Using Multiparametric MRI.

The study aims to evaluate multiparametric magnetic resonance imaging (MRI) for differentiating Follicular thyroid neoplasm (FTN) from non-FTN and malignant FTN (MFTN) from benign FTN (BFTN). We retrospectively analyzed 702 postoperatively confirmed thyroid nodules, and divided them into training (n = 482) and validation (n = 220) cohorts. The 133 FTNs were further split into BFTN (n = 116) and MFTN (n = 17) groups. Employing univariate and multivariate logistic regression, we identified independent predictors of FTN and MFTN, and subsequently develop a nomogram for FTN and a risk score system (RSS) for MFTN prediction. We assessed performance of nomogram through its discrimination, calibration, and clinical utility. The diagnostic performance of the RSS for MFTN was further compared with the performance of the Thyroid Imaging Reporting and Data System (TIRADS). The nomogram, integrating independent predictors, demonstrated robust discrimination and calibration in differentiating FTN from non-FTN in both training cohort (AUC = 0.947, Hosmer-Lemeshow P = 0.698) and validation cohort (AUC = 0.927, Hosmer-Lemeshow P = 0.088). Key risk factors for differentiating MFTN from BFTN included tumor size, restricted diffusion, and cystic degeneration. The AUC of the RSS for MFTN prediction was 0.902 (95% CI 0.798-0.971), outperforming five TIRADS with a sensitivity of 73.3%, specificity of 95.1%, accuracy of 92.4%, and positive and negative predictive values of 68.8% and 96.1%, respectively, at the optimal cutoff. MRI-based models demonstrate excellent diagnostic performance for preoperative predicting of FTN and MFTN, potentially guiding clinicians in optimizing therapeutic decision-making.

A case series of thyroid fine needle aspiration biopsies diagnosed as follicular neoplasm with oncocytic features.

Oncocytic lesions of the thyroid are a heterogeneous group encompassing nonneoplastic and neoplastic entities ranging from benign to malignant and have traditionally been classified as separate entities in thyroid pathology. To illustrate the diversity of these thyroid lesions, we describe three cases of fine needle aspiration biopsies (FNAB) diagnosed as Bethesda Category IV: Follicular neoplasm, oncocytic type, under the 2017 Bethesda System for Reporting Thyroid Cytopathology (TBSRTC), with ThyroSeq v3 molecular testing and subsequent surgical excision.

Risk stratification of ThyroSeq results in indeterminate thyroid lesions: A single-institution experience of clinicopathologic correlation with cytologic findings.

BACKGROUND: ThyroSeq offers the opportunity to stratify the risk of malignancy (ROM) in the characterization of indeterminate thyroid nodules, especially those categorized as atypia of undetermined significance (AUS). However, whether ThyroSeq interpretations correlate with cytologic features, management, and surgical outcome remains unclear. METHODS: Thyroid fine-needle aspiration specimens categorized as AUS and follicular neoplasm (FN) from 2017 to 2021 were identified from a cytology database search. Patient clinical information and ThyroSeq results were collected and correlated with resection diagnosis if available. RESULTS: A total of 520 cases were classified as AUS and 111 cases were classified as FN. Within the AUS lesions, 190 cases (36.5%) were subcategorized as cytologic atypia (III-C), 109 cases (21.0%) as architectural atypia (III-A), 138 cases (26.5%) as both cytologic and architectural atypia (III-CA), and 69 cases (13.0%) as oncocytic cell aspirate (III-O). Category III-C showed the highest malignancy rate (16.7%; p = .29), and a higher ThyroSeq-defined probability of cancer or noninvasive follicular thyroid neoplasms with papillary-like nuclear features. Notably, within III-C, intermediate-risk mutations led to a significantly higher malignancy rate (46.7%; p = .0012). Conversely, III-A had the lowest malignancy rate (9.7%) but this was significantly increased by concurrent high-risk mutations (62.5%). BRAFV600E-like mutations were frequently associated with III-C and classical papillary thyroid carcinoma in histology. RAS-like mutations were the most common alterations across all subcategories, and were frequently associated with follicular-patterned lesions. CONCLUSIONS: Atypia subcategories have differential ThyroSeq-defined ROMs and histologic outcomes. Combining atypia subcategory interpretation, ThyroSeq-defined ROMs and molecular results aids in optimal clinical management for indeterminate thyroid lesions.