Repeat fine-needle aspiration cytology refines selection of nodules for thyroidectomy
Limiting molecular testing to people with thyroid nodules that are Bethesda category III or IV on repeat fine-needle aspiration, or FNA, cytology can reduce the rate of surgery of histologically benign nodules, according to study data.
“This is the first study to our knowledge that provides data about the role of repeat FNA cytology in selecting nodules for molecular testing,” Michiya Nishino, MD, PhD, an assistant professor of pathology at Beth Israel Deaconess Medical Center, and colleagues wrote in a study published in Thyroid. “The different cytologic criteria for selecting nodules for Afirma gene expression classifier testing present trade-offs between sensitivity and specificity for detecting noninvasive follicular thyroid neoplasm with papillary-like nuclear features and cancer. Reflex testing does not involve a repeat biopsy. This strategy, as well as the relatively permissive semi-restrictive testing strategy, detected rare cases of noninvasive follicular thyroid neoplasm with papillary-like nuclear features and low-risk cancer that would not have undergone Afirma testing under the restrictive testing approach. However, the higher sensitivity of these permissive testing strategies is offset by their lower specificity.”
Researchers obtained thyroid FNA samples from Beth Israel Deaconess Medical Center that were submitted for Afirma gene expression classifier (GEC) testing between June 2013 and October 2017. Researchers compared data on GEC testing, surveillance of unresected nodules and histopathologic diagnoses of thyroidectomies using three testing strategies. The reflex approach sends nodules for molecular testing based on an initial Bethesda III or IV classification, the semi-restrictive approach calls for molecular testing for nodules that are classified as Bethesda category I through IV in repeat FNA, and the restrictive approach calls for molecular testing for nodules only in Bethesda category III or IV in repeat FNA.
There were 363 nodules included in the study, of which 59% were classified as benign and 41% as suspicious in Afirma GEC testing. Of nodules with follow-up data available, 86% of suspicious nodules were resected vs. 15% of benign nodules (P < .0001). Twenty-five of the 28 resected benign nodules were histologically benign, one was noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), and two were carcinomas. Of 115 suspicious resected nodules, 80 were benign, 15 were NIFTP and 20 were carcinomas.
After applying nodules to each of the three surveillance approaches, the restrictive approach would have missed four cancers and three NIFTP cases that would have been detected in the semi-restrictive and reflex approaches. All four cancers were considered low risk for structural disease recurrence. The reflex and semi-restrictive models would have led to 42 cases of diagnostic surgery performed for histologically benign tumors. The restrictive strategy was found to be more specific and less sensitive than the reflex and semi-restrictive approaches in detecting NIFTP or cancer.
“The restrictive strategy would have averted diagnostic surgeries, otherwise prompted by GEC-suspicious results in the reflex and semi-restrictive approaches, in up to 42 histologically benign nodules,” the researchers wrote. “Given the low but nontrivial risks of thyroidectomy, we conclude that this benefit of the restrictive strategy disproportionately outweighs both the potential harms of missing rare, low-risk tumors as well as the uncertainty that may be caused by disparate initial and repeat FNA cytology interpretations.”
Perspective
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Fine-needle aspiration cytology of thyroid nodules and classification by the Bethesda system is used worldwide for evaluation of thyroid nodules. Molecular testing has reduced the need for diagnostic surgery in cases of indeterminate (Bethesda III/IV) thyroid nodules. Most institutions have an algorithm of how molecular testing is incorporated in their workflow, with some adopting a reflex-testing approach where all indeterminate samples are sent for molecular testing and others use a two-step approach, where repeat FNA with indeterminate testing is sent for molecular analysis.
This study by Nishino and colleagues attempted to look at algorithms comparing GEC testing using different strategies. Restrictive testing, utilizing a two-step approach, whereby molecular testing was done on repeat FNA samples reported indeterminate, was more specific in comparison to the reflex testing arm and missed only rare low-risk tumors. Reflex testing of all indeterminate samples was more sensitive but led to unwarranted diagnostic surgeries of benign nodules.
This study presents an alternative algorithm to reflex molecular testing and decreases the number of unnecessary surgeries. However, the cost-effectiveness of this approach will need to be evaluated. With the advent of Afirma GSC, with a higher test performance, and incorporation of ultrasound features as a tool for selecting nodules for molecular testing, the two-step approach needs further validation.
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