Indeterminate thyroid cytology (Bethesda III and IV) corresponds to follicular-patterned benign and malignant lesions, which are particularly difficult to differentiate on cytology alone. As approximately 25% of these nodules harbor malignancy, diagnostic hemithyroidectomy is still custom. However, advanced preoperative diagnostics are rapidly evolving. This review provides an overview of additional molecular and imaging diagnostics for indeterminate thyroid nodules in a pre-operative clinical setting, including considerations regarding cost-effectiveness, availability, and feasibility of combining techniques. Addressed diagnostics include gene mutation analysis, microRNA, immunocytochemistry, ultrasonography, elastosonography, CT, sestamibi scintigraphy, FDG-PET and diffusion-weighted MRI. The best rule-out tests for malignancy were the Afirma® GEC and FDG-PET. The most accurate rule-in test was sole BRAF mutation analysis. No diagnostic had both near-perfect sensitivity and specificity, and estimated cost-effectiveness. Molecular techniques are rapidly advancing. However, given the currently available techniques a multimodality stepwise approach likely offers the most accurate diagnosis, sequentially applying one sensitive rule-out test and one specific rule-in test. Geographical variations in cytology (e.g. Hürthle cell neoplasms) and tumor genetics strongly influence local test performance and clinical utility. Multidisciplinary collaboration and implementation studies can aid the local decision for one or more eligible diagnostics.

Objective: Nondiagnostic cytology is the most important limitation of thyroid ultrasound-guided fine-needle aspiration (US-FNA). This study aimed to identify factors associated with the adequacy rate of thyroid US-FNA. Study Design: Consecutive thyroid US-FNAs (2006-2013) were retrospectively included. Attending radiologists, radiology fellows and radiology residents performed US-FNA, usually involving 2-3 needle passes. In more recent years, rapid on-site adequacy assessment (ROSAA) was performed to ensure specimen adequacy. US characteristics, procedural variations and cytology results were extracted from US and pathology reports and statistically evaluated. Results: Diagnostic cytology was obtained in 64.6% of 1,381 thyroid US-FNAs. Factors associated with nondiagnostic cytology were ROSAA (74.6% diagnostic cytology, OR 0.55, 95% CI 0.42-0.71), ≥3 clinic visits for US-FNA of the same thyroid nodule (54.7%, OR 1.56, 95% CI 1.16-2.10) and increased intranodular vascularization (51.8%, OR 1.73, 95% CI 1.17-2.57). With ROSAA, an increasing number of needle passes demonstrated improving adequacy rates. The adequacy rate was not operator-dependent. Conclusion: This study demonstrates that ROSAA improves the adequacy rate of thyroid US-FNA. Without ROSAA, we recommend performing at least 3 needle passes. Less diagnostic cytology is obtained from nodules with increased intranodular vascularization or from those undergoing US-FNA ≥3 times.

Purpose: To assess the impact of an [¹⁸F]FDG-PET/CT-driven diagnostic workup to rule out malignancy, avoid futile diagnostic surgeries, and improve patient outcomes in thyroid nodules with indeterminate cytology. Methods: In this double-blinded, randomised controlled multicentre trial, 132 adult euthyroid patients with scheduled diagnostic surgery for a Bethesda III or IV thyroid nodule underwent [¹⁸F]FDG-PET/CT and were randomised to an [¹⁸F]FDG-PET/CT-driven or diagnostic surgery group. In the [¹⁸F]FDG-PET/CT-driven group, management was based on the [¹⁸F]FDG-PET/CT result: when the index nodule was visually [¹⁸F]FDG-positive, diagnostic surgery was advised; when [¹⁸F]FDG-negative, active surveillance was recommended. The nodule was presumed benign when it remained unchanged on ultrasound surveillance. In the diagnostic surgery group, all patients were advised to proceed to the scheduled surgery, according to current guidelines. The primary outcome was the fraction of unbeneficial patient management in one year, i.e., diagnostic surgery for benign nodules and active surveillance for malignant/borderline nodules. Intention-to-treat analysis was performed. Subgroup analyses were performed for non-Hürthle cell and Hürthle cell nodules. Results: Patient management was unbeneficial in 42% (38/91 [95% confidence interval [CI], 32–53%]) of patients in the [¹⁸F]FDG-PET/CT-driven group, as compared to 83% (34/41 [95% CI, 68–93%]) in the diagnostic surgery group (p < 0.001). [¹⁸F]FDG-PET/CT-driven management avoided 40% (25/63 [95% CI, 28–53%]) diagnostic surgeries for benign nodules: 48% (23/48 [95% CI, 33–63%]) in non-Hürthle cell and 13% (2/15 [95% CI, 2–40%]) in Hürthle cell nodules (p = 0.02). No malignant or borderline tumours were observed in patients under surveillance. Sensitivity, specificity, negative and positive predictive value, and benign call rate (95% CI) of [¹⁸F]FDG-PET/CT were 94.1% (80.3–99.3%), 39.8% (30.0–50.2%), 95.1% (83.5–99.4%), 35.2% (25.4–45.9%), and 31.1% (23.3–39.7%), respectively. Conclusion: An [¹⁸F]FDG-PET/CT-driven diagnostic workup of indeterminate thyroid nodules leads to practice changing management, accurately and oncologically safely reducing futile surgeries by 40%. For optimal therapeutic yield, application should be limited to non-Hürthle cell nodules. Trial registration number: This trial is registered with ClinicalTrials.gov: NCT02208544 (5 August 2014), https://clinicaltrials.gov/ct2/show/NCT02208544.

Aim: The aims of this study were to determine the role of ¹⁸F-FDG PET/CT in vulvar cancer patients and to extract summary estimates of its diagnostic performance for preoperative lymph node staging. Patients and Methods: PubMed/Medline and Embase databases were searched to identify studies evaluating ¹⁸F-FDG PET/CT in vulvar cancer patients. The assessment of methodological quality of the included articles was performed. Per-patient and per-groin pooled estimates, with 95% confidence intervals (CIs), of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic odds ratio (DOR) were calculated. Results: Ten articles were included in the systematic review, 7 among which evaluated the diagnostic performance of preoperative ¹⁸F-FDG PET/CT for lymph node staging. Qualitative per-patient analysis (72 patients from 4 studies) resulted in estimated pooled sensitivity, specificity, PPV, NPV, and DOR of 0.70 (95% CI, 0.44–0.95), 0.90 (95% CI, 0.76–1.04), 0.86 (95% CI, 0.66–1.06), 0.77 (95% CI, 0.56–0.97), and 10.49 (95% CI, 1.68–65.50), respectively. Qualitative per-groin analysis (245 groins from 5 studies) resulted in estimated pooled sensitivity, specificity, PPV, NPV, and DOR of 0.76 (95% CI, 0.57–0.94), 0.88 (95% CI, 0.82–0.94), 0.70 (95% CI, 0.55–0.85), 0.92 (95% CI, 0.86–0.97), and 19.43 (95% CI, 6.40–58.95), respectively. Conclusions: Despite limited literature data, this systematic review and meta-analysis revealed that a negative preoperative PET/CT scan may exclude groin metastases in at least early-stage vulvar cancer patients currently unfit for sentinel node biopsy and select those eligible for a less invasive surgical treatment. A positive PET/CT result should otherwise be interpreted with caution. Larger prospective studies are needed to confirm these results and to evaluate the diagnostic value of standardized semiquantitative analysis compared with the qualitative one.

Purpose: To evaluate whether quantitative [¹⁸F]FDG-PET/CT assessment, including radiomic analysis of [¹⁸F]FDG-positive thyroid nodules, improved the preoperative differentiation of indeterminate thyroid nodules of non-Hürthle cell and Hürthle cell cytology. Methods: Prospectively included patients with a Bethesda III or IV thyroid nodule underwent [¹⁸F]FDG-PET/CT imaging. Receiver operating characteristic (ROC) curve analysis was performed for standardised uptake values (SUV) and SUV-ratios, including assessment of SUV cut-offs at which a malignant/borderline neoplasm was reliably ruled out (≥ 95% sensitivity). [¹⁸F]FDG-positive scans were included in radiomic analysis. After segmentation at 50% of SUV_peak, 107 radiomic features were extracted from [¹⁸F]FDG-PET and low-dose CT images. Elastic net regression classifiers were trained in a 20-times repeated random split. Dimensionality reduction was incorporated into the splits. Predictive performance of radiomics was presented as mean area under the ROC curve (AUC) across the test sets. Results: Of 123 included patients, 84 (68%) index nodules were visually [¹⁸F]FDG-positive. The malignant/borderline rate was 27% (33/123). SUV-metrices showed AUCs ranging from 0.705 (95% CI, 0.601–0.810) to 0.729 (0.633–0.824), 0.708 (0.580–0.835) to 0.757 (0.650–0.864), and 0.533 (0.320–0.747) to 0.700 (0.502–0.898) in all (n = 123), non-Hürthle (n = 94), and Hürthle cell (n = 29) nodules, respectively. At SUV_max, SUV_peak, SUV_max-ratio, and SUV_peak-ratio cut-offs of 2.1 g/mL, 1.6 g/mL, 1.2, and 0.9, respectively, sensitivity of [¹⁸F]FDG-PET/CT was 95.8% (95% CI, 78.9–99.9%) in non-Hürthle cell nodules. In Hürthle cell nodules, cut-offs of 5.2 g/mL, 4.7 g/mL, 3.4, and 2.8, respectively, resulted in 100% sensitivity (95% CI, 66.4–100%). Radiomic analysis of 84 (68%) [¹⁸F]FDG-positive nodules showed a mean test set AUC of 0.445 (95% CI, 0.290–0.600) for the PET model. Conclusion: Quantitative [¹⁸F]FDG-PET/CT assessment ruled out malignancy in indeterminate thyroid nodules. Distinctive, higher SUV cut-offs should be applied in Hürthle cell nodules to optimize rule-out ability. Radiomic analysis did not contribute to the additional differentiation of [¹⁸F]FDG-positive nodules. Trial registration number: This trial is registered with ClinicalTrials.gov: NCT02208544 (5 August 2014), https://clinicaltrials.gov/ct2/show/NCT02208544.

Purpose: To evaluate cost-effectiveness of an [¹⁸F]FDG-PET/CT-driven diagnostic workup as compared to diagnostic surgery, for thyroid nodules with Bethesda III/IV cytology. [¹⁸F]FDG-PET/CT avoids 40% of futile diagnostic surgeries for benign Bethesda III/IV nodules. Methods: Lifelong societal costs and quality-adjusted life years (QALYs) were assessed for 132 patients participating in a randomised controlled multicentre trial comparing [¹⁸F]FDG-PET/CT to diagnostic surgery. The observed 1-year trial results were extrapolated using a Markov model. The probability of cost-effectiveness was estimated using cost-effectiveness acceptability curves, taking uncertainty about sampling, imputation, and parameters into account. Results: The observed 1-year cost difference of [¹⁸F]FDG-PET/CT as compared to diagnostic surgery was − €1000 (95% CI: − €2100 to €0) for thyroid nodule–related care (p = 0.06). From the broader societal perspective, the 1-year difference in total societal costs was − €4500 (− €9200 to €150) (p = 0.06). Over the modelled lifelong period, the cost difference was − €9900 (− €23,100 to €3200) (p = 0.14). The difference in QALYs was 0.019 (− 0.045 to 0.083) at 1 year (p = 0.57) and 0.402 (− 0.581 to 1.385) over the lifelong period (p = 0.42). For a willingness to pay of €50,000 per QALY, an [¹⁸F]FDG-PET/CT-driven work-up was the cost-effective strategy with 84% certainty. Conclusion: Following the observed reduction in diagnostic surgery, an [¹⁸F]FDG-PET/CT-driven diagnostic workup reduced the 1-year thyroid nodule–related and societal costs while sustaining quality of life. It is very likely cost-effective as compared to diagnostic surgery for Bethesda III/IV nodules. Trial registration number: This trial is registered with ClinicalTrials.gov: NCT02208544 (5 August 2014), https://clinicaltrials.gov/ct2/show/NCT02208544.