The iFS analysis has been historically proposed as a tool for tailoring surgical extension of thyroidectomies. In the last decade, FNAB has become the most useful method to assess preoperative malignancy risk in thyroid nodules. Due to increasing thyroid cancer screening and diagnosis rates, we depend on reliable pre and intraoperative histological data to avoid overtreatment of nodular thyroid disease. In this context, we assessed the iFS performance among all BC nodules to evaluate its potential role in the surgical management of thyroid nodules. We demonstrated that the iFS accuracy is 97% in BC II, V, and VI nodules, however, when it is compared to an FNAB accuracy (94.1%), the iFS performance in BC III and IV nodules is lower, showing low sensitivity (25%) to detect malignant disease in these categories.
Studies report FNAB sensitivity ranging from 36–89% and specificity ranging from 94–99%, presenting an accuracy from 84–94% when considering all BC categories[20, 21]. However, most studies focus on cytologically indeterminate lesions (BC III and IV)  and include only cases in which clinical judgment guided the referral to iFS, rendering a biased selection in most analysis[22, 23]. We investigated routine iFS performed in our institution (94.5% of cases of nodular disease), generating a non-biased analysis concerning the iFS performance in thyroid nodules. As expected for a tertiary referral center, our cohort presents higher malignancy rates (26.6%), showing 10.2% and 19.5% of malignancy rates in BC III and IV categories. Similarly to other studies , the iFS accuracy was 94.9% when considering all BC nodules, a value that decreased to 88.7% in BC III and IV nodules (Table 2). Recently, Huang et al. reported an iFS accuracy rate ranging from 90-91.4% in BC I, II, V and VI nodules, but 87.9% in BC III and IV nodules. However, the cohort's malignancy rate was 84%, with most nodules in BC V and VI, which limits the interpretation of the results due to a high pre-test probability .
Indeed, the related iFS performed in BC III and IV nodules rendered the lowest sensitivity among the distinct BCs (25%), although showing 100% of specificity. Cotton et al. also described iFS low sensitivity, primarily for BC III and IV nodules (S = 20%) , which was also evident for follicular lesions in a meta-analysis. In BC III and IV nodules, we can observe high deferral rates in other studies (up to 68% and 84%, respectively). The iFS test for BC III and IV was classified as having low utility by the Yuden's index analysis. Since deferred cases were classified as benign nodules (per intention diagnosis), we have a higher rate of misdiagnosed nodules in these categories (5.1% and 17%, respectively). In a recent meta-analysis that evaluated the iFS performance in follicular lesions, its sensitivity was also low (43%), proposing a limited utility for this test in these BC .
In BC V nodules, iFS misdiagnosed two malignant nodules (5.2%), whereas the Bethesda system also misclassified two nodules whose final histology was benign. Obtaining intraoperative consultation for this nodule category does not justify surgical time delay, as iFS did not change the conduct in most cases as already demonstrated by other studies . In Bethesda VI nodules, the iFS test was perfect. However, the high accuracy of FNAB does not support an intraoperative procedure for surgical guidance.
Although the number of patients with BC I nodules was low (n = 21), iFS had a high accuracy in this group (95.2%, Table 2). Since preoperative information to determine surgery extent in this group is usually limited, the information provided by iFS could significantly help guide intraoperative management of BC nodules.
Eleven incidental papillary thyroid microcarcinomas not related to the index nodule were diagnosed in the study population. Nevertheless, according to current guidelines, thyroid lobectomy may be sufficient for the very low-risk papillary or follicular carcinomas, precluding the necessity of a complementary thyroidectomy. Therefore, even in this context, iFS would not significantly add information to surgical decision.
The strength of the present study is that iFS was performed in almost all nodules submitted to surgical procedure, rendering a non-biased selection analysis. As a limitation, our study could not calculate the impact of iFS on surgery time due to a lack of registered data. This calculation would be essential for cost-effectiveness analysis. A recent study evaluated the iFS cost-effectiveness for nodules with atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS), when its specificity was 100%, demonstrating that total thyroidectomy was avoided in one out of every 24 cases, resulting in savings of $80 per surgery in this population . In another analysis of BC V nodules that considered a surgical approach based on ATA 2015 guidelines, a small percentage of cases would have been converted to total thyroidectomy based on iFS. However, routine iFS would still be cost-effective if the method specificity were 100% , similarly for BC IV nodules, according to other studies [27, 28]. Nevertheless, most of the cost-effectiveness analysis does not consider operative and postoperative costs associated with unnecessary total thyroidectomies and management of complications (hypoparathyroidism, recurrent laryngeal nerve palsy), which can occur in up to 20% of the cases . In our study, 11.2% of patients in BC III and IV would have been submitted to unnecessary total thyroidectomy (false positive), which could significantly influence postoperative complications and their associated costs.