Making Choices: A Multi-institutional, Longitudinal Cohort Study Assessing Changes in Treatment Outcome Valuation for Low-Risk Thyroid Cancer.

OBJECTIVE: To evaluate the relative importance of treatment outcomes to patients with low-risk thyroid cancer (TC). SUMMARY BACKGROUND DATA: Overuse of total thyroidectomy (TT) for low-risk TC is common. Emotions from a cancer diagnosis may lead patients to choose TT resulting in outcomes that do not align with their preferences. METHODS: Adults with clinically low-risk TC enrolled in a prospective, multi-institutional, longitudinal cohort study from 11/2019-6/2021. Participants rated treatment outcomes at the time of their surgical decision and again 9 months later by allocating 100 points amongst 10 outcomes. T-tests and Hotelling's T 2 statistic compared outcome valuation within and between subjects based on chosen extent of surgery (TT vs. lobectomy). RESULTS: Of 177 eligible patients, 125 participated (70.6% response) and 114 completed the 9-month follow-up (91.2% retention). At the time of the treatment decision, patients choosing TT valued the risk of recurrence more than those choosing lobectomy and the need to take thyroid hormone less ( P <0.05). At repeat valuation, all patients assigned fewer points to cancer being removed and the impact of treatment on their voice, and more points to energy levels ( P <0.05). The importance of the risk of recurrence increased for those who chose lobectomy and decreased for those choosing TT ( P <0.05). CONCLUSION: The relative importance of treatment outcomes changes for patients with low-risk TC once the outcome has been experienced to favor quality of life over emotion-related outcomes. Surgeons can use this information to discuss the potential for asthenia or changes in energy levels associated with total thyroidectomy.

From Bench-to-Bedside: How Artificial Intelligence is Changing Thyroid Nodule Diagnostics, a Systematic Review.

CONTEXT: Use of artificial intelligence (AI) to predict clinical outcomes in thyroid nodule diagnostics has grown exponentially over the past decade. The greatest challenge is in understanding the best model to apply to one's own patient population, and how to operationalize such a model in practice. EVIDENCE ACQUISITION: A literature search of PubMed and IEEE Xplore was conducted for English-language publications between January 1, 2015 and January 1, 2023, studying diagnostic tests on suspected thyroid nodules that used AI. We excluded articles without prospective or external validation, nonprimary literature, duplicates, focused on nonnodular thyroid conditions, not using AI, and those incidentally using AI in support of an experimental diagnostic outside standard clinical practice. Quality was graded by Oxford level of evidence. EVIDENCE SYNTHESIS: A total of 61 studies were identified; all performed external validation, 16 studies were prospective, and 33 compared a model to physician prediction of ground truth. Statistical validation was reported in 50 papers. A diagnostic pipeline was abstracted, yielding 5 high-level outcomes: (1) nodule localization, (2) ultrasound (US) risk score, (3) molecular status, (4) malignancy, and (5) long-term prognosis. Seven prospective studies validated a single commercial AI; strengths included automating nodule feature assessment from US and assisting the physician in predicting malignancy risk, while weaknesses included automated margin prediction and interobserver variability. CONCLUSION: Models predominantly used US images to predict malignancy. Of 4 Food and Drug Administration-approved products, only S-Detect was extensively validated. Implementing an AI model locally requires data sanitization and revalidation to ensure appropriate clinical performance.

Outcomes of cytologically indeterminate thyroid nodules managed with Genomic Sequencing Classifier.

CONTEXT: Molecular testing can refine the risk of malignancy in thyroid nodules with indeterminate cytology to decrease unnecessary diagnostic surgery. OBJECTIVE: This study was performed to evaluate the outcomes of cytologically indeterminate thyroid nodules managed with Afirma genomic sequencing classifier (GSC) testing. DESIGN, SETTING, PATIENTS, AND INTERVENTION: Adult patients who underwent a biopsy at three major academic centers between July 2017 and June 2021 with Bethesda III or IV cytology were included. All patients had surgery or minimum follow-up of 1 year ultrasound surveillance. MAIN OUTCOME MEASURES: The primary outcomes were the sensitivity, specificity, PPV, and NPV of GSC in Bethesda III and IV nodules. RESULTS: The median nodule size of the 834 indeterminate nodules was 2.1 cm and the median follow-up was 23 months. GSC's sensitivity, specificity, PPV, and NPV across all institutions were 95%, 81%, 50%, and 99% for Bethesda III nodules and 94%, 82%, 65%, and 98% for Bethesda IV nodules, respectively. The overall false negative rate was 2%. The NPV of GSC in thyroid nodules with oncocytic predominance was 100% in Bethesda III nodules and 98% in Bethesda IV nodules. However, the PPV of oncocytic nodules was low (17% in Bethesda III nodules and 45% in Bethesda IV nodules). Only 22% of thyroid nodules with benign GSC results grew during surveillance. CONCLUSIONS: GSC is a key tool for managing patients with indeterminate cytology, including the higher-risk Bethesda IV category. GSC benign thyroid nodules can be observed similarly to thyroid nodules with benign cytology.

Extent of Surgery for Medullary Thyroid Cancer and Prevalence of Occult Contralateral Foci.

Importance: Standard treatment for patients with medullary thyroid cancer (MTC) consists of total thyroidectomy with central neck dissection, but the rationale for bilateral surgery in patients with unilateral disease on ultrasonography remains unclear. Objective: To determine the presence of occult contralateral disease (lesions not seen on preoperative ultrasonography) in patients with MTC as a rationale for total thyroidectomy. Design, Setting, and Participants: This multi-institutional, retrospective cohort study was conducted from September 1998 to April 2022 in academic medical centers and included patients with MTC who underwent thyroidectomy with preoperative imaging. Main Outcomes and Measures: The primary end point was the prevalence of sonographically occult foci of MTC in the contralateral lobe among patients with sporadic MTC. Results: The cohort comprised 176 patients with a median age at diagnosis of 55 years (range, 2-87 years), 69 (57.6%) of whom were female. Genetic testing was performed in 109 patients (61.9%), 48 (27.5%) of whom carried germline RET variants. Initial surgical management consisted of total thyroidectomy (161 [91.0%]), lobectomy followed by completion thyroidectomy (7 [4.0%]), and lobectomy alone (8 [4.5%]). Central and lateral neck dissections were performed as part of initial therapy for 146 patients (83.1%). In the entire cohort of 176 patients, 46 (26.0%) had contralateral foci disease and 9 (5.1%) had occult contralateral foci that were not identified on preoperative ultrasonography. Among 109 patients who underwent genetic testing, 38 (34.9%) had contralateral disease, 8 (7.3%) of whom had occult contralateral disease not seen on preoperative ultrasonography. Patients with sporadic MTC experienced a 95.7% reduction in the odds of having a focus of MTC in the contralateral lobe compared with patients with a germline RET variant (odds ratio, 0.043; 95% CI, 0.013-0.123). When adjusting for age, sex, tumor size, and lymph node involvement, the odds ratio of having contralateral MTC in patients with sporadic disease was 0.034 (95% CI, 0.007-0.116). Among patients who underwent lobectomy alone with postoperative calcitonin levels, 5 of 12 (41.7%) achieved undetectable calcitonin levels (<2.0 pg/mL; to convert to pmol/L, multiply by 0.292). Conclusions and Relevance: The results of this cohort study suggest that a staged approach involving initial thyroid lobectomy could be considered in patients with sporadic MTC and no contralateral ultrasonography findings, with no further surgery if calcitonin levels became undetectable. Further work using prospective randomized clinical trials to evaluate lobectomy as a biochemical cure in patients presenting with unilateral disease is warranted.

Histopathology of telomerase reverse transcriptase promoter (TERT) mutated indeterminate thyroid nodules.

Objective: The objective of this study was to analyze the risk of malignancy and the histopathology of telomerase reverse transcriptase promoter (TERT) mutated cytologically indeterminate thyroid nodules (ITN). Methods: A PUBMED search of molecularly tested ITN was conducted and data on TERT mutated ITN with histopathology correlation were extracted. Results: Twenty-six manuscripts (published between 2014 and 2022) reported on 77 TERT mutated ITN. Sixty-five nodules were malignant (84 %), with 16 (25 %) described with high-risk histopathology, 5 (8 %) described as low-risk, and most without any description. Isolated TERT mutations were malignant in 26/30 ITNs (87 %) with 9 (35 %) described as high risk and none described as low risk. TERT + RAS mutated ITNs were malignant in 29/34 ITNs (85 %) with 3 (10 %) described as high risk and 4 (14 %) described as low risk. Finally, all 5 TERT + BRAFV600E mutated nodules were malignant and 3/5 (60 %) were described as high risk. Conclusion: TERT mutated ITNs have a high risk of malignancy (84 %), and the current data does not show a difference in malignancy rate between isolated TERT mutations and TERT + RAS co-mutated ITNs. When described, TERT + RAS co-mutated ITNs did not have a higher rate of high-risk histopathology as compared to isolated TERT mutated lesions. Most TERT mutated ITNs did not have a description of histopathology risk and the oncologic outcomes, including rate of recurrence, metastases, and disease specific survival, are unknown. Further data is needed to determine if TERT mutated ITNs should be subjected to aggressive initial treatment.

Diagnostic performance of molecular testing in indeterminate (Bethesda III and IV) thyroid nodules with Hürthle cell cytology.

BACKGROUND: Indeterminate thyroid nodules with Hürthle cell cytology remain a diagnostic challenge. The low benign call rate and positive predictive value of first-generation molecular tests precluded their use to rule out malignancy. We examined the diagnostic performance of current tests. METHOD: This subset analysis of our prospective randomized trial compared the benign call rate and positive predictive value of Afirma Gene Sequencing Classifier and Thyroseq v3 in Bethesda III and IV nodules with Hürthle cell cytology. Molecular test samples were obtained at initial fine-needle aspiration (8/2017-7/2022) and reflexively sent for processing. RESULTS: Molecular testing was performed on 140 Hürthle cell nodules. Of 79 nodules tested with the Afirma Gene Sequencing Classifier, the benign call rate was 84% (66/79). Nine of 66 nodules with benign results were resected, with no malignancies. Twelve of 13 nodules with suspicious results were resected, revealing 3 malignancies-2 papillary thyroid carcinomas and one Hürthle cell carcinoma (positive predictive value 25%). Of 61 nodules tested with Thyroseq v3, the benign call rate was 56% (34/61; (P < .01 versus Afirma Gene Sequencing Classifier). Five of 34 nodules with negative results were resected, with no malignancies. Nineteen of 27 nodules with positive results were resected, revealing 3 malignancies-2 papillary thyroid carcinomas and 1 Hürthle cell carcinoma (positive predictive value 16%). CONCLUSION: The high benign call rate of current molecular tests in Hürthle cell nodules strengthens their value in enabling patients to avoid surgery.