Molecular fine-needle aspiration (FNA) cytology diagnostics has the potential to address the inherent limitation of FNA cytology which is an indeterminate (atypia of undetermined significance/follicular lesion of undetermined significance follicular neoplasm) cytology. Because of the emerging role of molecular FNA cytology diagnostics, the European Thyroid Association convened a panel of international experts to review methodological aspects, indications, results, and limitations of molecular FNA cytology diagnostics. The panel reviewed the evidence for the diagnostic value of mutation panel assessment (including at least BRAF, NRAS, HRAS, KRAS, PAX8/PPARG, RET/PTC) of targeted next generation sequencing and of a microarray gene expression classifier (GEC) test in the diagnostic assessment of an indeterminate cytology thyroid nodule. Moreover, possible surgical consequences of molecular FNA diagnostic results of thyroid nodules and the evidence that analysis of a molecular FNA diagnostic panel of somatic mutations or a microarray GEC test can alter the follow-up were reviewed. Molecular tests may help clinicians to drive patient care and the surgical decision if the analysis is performed in specialized laboratories. These molecular tests require standardization of performance characteristics and appropriate calibration as well as analytic validation before clinical interpretation.
Ralf Paschke, Silvia Cantara, Anna Crescenzi, Barbara Jarzab, Thomas J. Musholt, and Manuel Sobrinho Simoes
Luisa Paschke, Thomas Lincke, Katja Sibylle Mühlberg, Wolfram J. Jabs, Tom H. Lindner, and Ralf Paschke
Cabozantinib and lenvatinib have been approved for the treatment of progressive medullary thyroid cancer and radioiodine-resistant thyroid cancer, respectively. Both phase III trials of cabozantinib and lenvatinib reported that renal adverse events (AEs) rarely occurred. The cabozantinib phase III study reported no AEs related to renal toxicity. In the lenvatinib phase III trial grade 3 (CTCAE), proteinuria (urinary protein ≥3.5 g/24 h) was found in 10.0% of the lenvatinib and 0.0% of the placebo patients. We report a 23-year-old patient with metastatic medullary thyroid cancer who was enrolled in the phase III trial, comparing cabozantinib to placebo and a 67-year-old patient with metastatic, papillary thyroid carcinoma who was undergoing treatment with lenvatinib during his enrollment in the phase III trial. The first patient had a normal kidney function initially, but developed end-stage chronic kidney disease unexpectedly on cabozantinib and additional zoledronate infusion. Whereas the second patient suffered from a dramatic aggravation of his known mild chronic renal insufficiency (KDOQI stage 2) due to long standing hypertension and atherosclerosis during the treatment with lenvatinib. These severe AEs due to anti-VEGF tyrosine kinase inhibitor treatment were unknown so far. In conclusion, these 2 cases argue for increased awareness for the possibility of renal failure as a consequence of anti-VEFG treatment. Predisposing conditions like known mild chronic renal insufficiency with only mild proteinuria and with atherosclerosis or precipitating co-medications like zoledronate infusion need to be accounted for to prevent these severe AEs.
Xun Yang Hu, Jiahui Wu, Paula Seal, Sana Ghaznavi, Christopher John Symonds, Susan Elizabeth Kinnear, and Ralf Paschke
Objectives: There has been slow adoption of thyroid ultrasound guidelines with adherence rates as low as 30% and no population-based studies investigating adherence to guideline-based malignancy risk assessment. We therefore evaluated the impact of adherence to the 2015 ATA guidelines or 2017 ACR-TIRADS guidelines on the quality of thyroid ultrasound reports in our healthcare region.
Methods: We reviewed 899 thyroid ultrasound reports of patients who received fine needle aspiration biopsy and were diagnosed with Bethesda III or IV nodules or thyroid cancer. Ultrasounds were reported by radiology group 1, group 2, or other groups, and were divided into pre-2018 (before guideline adherence) or 2018-onwards. Reports were given a utility score (0 to 6) based on how many relevant nodule characteristics were included.
Results: Group 1 had a pre-2018 utility score of 3.62 and 39.4% classification reporting rate, improving to 5.77 and 97.0% among 2018-onwards reports. Group 2 had a pre-2018 score of 2.8 and reporting rate of 11.5%, improving to 5.58 and 93.3%. Other radiology groups had a pre-2018 score of 2.49 and reporting rate of 32.2%, improving to 3.28 and 61.8%. Groups 1 and 2 had significantly higher utility scores and reporting rates in their 2018-onward reports when compared to other groups’ 2018-onward reports, pre-2018 group 1 reports, and pre-2018 group 2 reports.
Conclusions: Dedicated adherence to published thyroid ultrasound reporting guidelines can lead to improvements in report quality. This will reduce diagnostic ambiguity and improve clinician’s decision-making, leading to overall reductions in unnecessary FNA biopsy and diagnostic surgery.
Markus Eszlinger, Paul Stewardson, John B McIntyre, Adrian Box, Moosa Khalil, Martin Hyrcza, Konstantin Koro, Dean Ruether, Jiahui Wu, and Ralf Paschke
The aim of the study was to identify patients with NTRK fusion-positive or RET fusion/mutation-positive thyroid cancers, who could benefit from neurotrophic tyrosine kinase receptor (NTRK) or receptor tyrosine kinase (RET) inhibitors.
Patients were identified in the Calgary prospective thyroid cancer database (N= 482). Patients were ‘pre-screened’ with clinically available MassARRAY® BRAF test, Colon Panel, Melanoma Panel, or ThyroSPEC™. Mutation-negative tumors were ‘screened’ for NTRK fusions and RET fusions/mutations with the Oncomine™ Comprehensive Assay v3 (OCAv3).
A total of 86 patients were included in 1 of 2 separate analyses. Analysis A included 42 patients with radioactive iodine (RAI)-resistant distant metastases. After pre-screening, 20 BRAF and RAS mutation-negative patients underwent OCAv3 screening, resulting in the detection of 4 patients with NTRKfusions and 4 patients with RET fusions (8/20, 40% of analyzed patients). Analysis B included 44 patients, 42 with American Thyroid Association (ATA) high and intermediate risk of recurrence and 2 with medullary thyroid carcinoma. During pre-screening, 1 patient with an NTRK fusion, 1 patient with a RET fusion, and 30 patients with BRAF mutations were identified. The remaining 9 patients received OCAv3 screening, resulting in detection of 1 patient with an NTRKfusion and 1 with a RET fusion (4/11, 36% of analyzed patients).
Our findings indicate a higher rate of NTRK fusions and RETfusions in patients with thyroid cancer with RAI-resistant distant metastases and ATA high or intermediate risk of recurrence. This highlights the importance of early screening to enable intervention with a NTRK or RET inhibitor.