FNA has become the predominant method for preoperative diagnosis of thyroid nodules with the risk of malignancy according to Thyroid Imaging Reporting and Data System (TI-RADS) classification. FNA were performed, and then the cytology results were graded according to Bethesda System for Reporting Thyroid Cytopathology. The cytology reporting system had good coherence in large groups of patients, with 89%– 95% of samples being acceptable; 55%– 74% of samples were benign, and 2%– 5% were malignant. However, the false negative rate for benign thyroid nodules in cytology is still as high as 5%. The risk of malignancy (0–3%) also exists, even for cytology benign nodules (class II), especially if the nodule had suspicious malignant features. Similarly, twenty of 534 cytology benign nodules were pathologically confirmed malignancy in our study and the false negative rate accounted for 3.7%. Under the guidance of the current FNA strategy, these malignant nodules with benign cytological results might be missed without further treatment.
The combined FNA and BRAF V600E tests were well known to effectively improve the diagnostic accuracy, especially for predicting the results of atypia or follicular lesion of undetermined significance (AUS/FLUS) cytology samples and had a high specificity. The BRAF V600E test was proposed to refine the risk of malignancy, and surgical management would change based on the presence of positive results. In a meta-analysis, the findings suggested that better risk stratification and treatment options were possible for MPTC with BRAF V600E mutations than those without BRAF V600E mutations. For thyroid nodules found to be benign with FNA cytology, it was unpractical and did not meeting the ATA guideline to do BRAF V600E test. However, thirty-six nodules of 534 nodules with benign FNA results were confirmed as positive results of BRAF V600E in our data, and the application of the BRAF(V600E) test is expensive and not available in clinical. How to find out the suspicious nodules in the cytological benign nodules and reduce the false negative rate of FNA before operation is an important problem. Our study retrospectively analyzed whether SWE and CUS features can be used to improve to find out suspicious nodules with benign cytology results and then combined BRAF V600E mutation results to reduce the number of preoperative missed diagnosis.
SWE, an available noninvasive method, has been widely used for qualitative and quantitative analysis. Throughout the years that SWE was in development, Carmela Asteria already reported that US elastography was promising for identifying potentially malignant thyroid nodules. Many subsequent prospective and retrospective studies had interpreted the diagnostic efficacy of elastic assessments for benign and malignant thyroid nodules with both qualitative and quantitative modes and two-dimensional and three-dimensional techniques. Elastography of ARFI also showed the special diagnostic superiority in thyroid nodules less than 10 mm. To date, few research has assessed the diagnostic value of SWE in identifying thyroid nodules with benign cytology and positive BRAF V600E results. Based on our study, we concluded that SWE parameter with E max ratio > 1.49 was significant factor for malignancy in thyroid nodules with benign cytology. It was consistent with previous researches that the ratio of elastic parameters (VTI area ratio) can be used to predict the malignancy of thyroid and also consistent with our results. However, there is no statistical difference (p = 0.214) in benign and malignant nodules although the elastic value with SWE max of malignant nodules is higher than that of benign nodules (35.59 ± 16.71vs26. 56 ± 6.74) and the results was conflict with previous researches which confirmed that SWE max was an important predictor of benign and malignant nodules.
In our study, 22 (85%) nodules had a maximum diameter less than 10 mm, and the number of nodules with a maximum diameter less than 10 mm was not significant between benign and malignant nodules (83% vs 86%). The part of the reason for the FNA misdiagnosis might be that several cells of the thyroid nodule cytology sample were unable to reflect the morphology of the nodule tissue and that of the adjacent to the surrounding tissues. Nodule size may also be one of the factors that account for the accuracy of FNA. Additionally, the pathological results showed that 18 of 20 PTCs were MPTCs, which was considered an FNA omission due to the small diameter of the cancer. Although there were missing positive results with FNA, the thyroid nodules with suspicious US features were recommended for genetic tests since the mutation of BRAF V600E might be a prognostic factor of MPTC. According to the ATA guidelines, nodules with class III or IV cytology results cannot be classified. Several studies had been reported that the malignancy of thyroid nodules with AUS/FLUS could be predicted by suspicious US features (irregular margins, taller-than-wide shape, marked hypo echogenicity or microcalcification), which increased the cancer risk to 60–90%. Moreover, the number of suspicious US features can predict the malignancy of thyroid nodules that had benign FNA results but were pathologically proven to be malignant. In our research, suspicious US features with undefined boundary and microcalcification can be suggestive of malignancy, therefore BRAF V600E gene detection is necessary for these thyroid nodules with above malignant features, even if the cytological results were benign.
There were two patients with benign cytology and preoperative BRAF V600E mutations, but the histology results were benign. Both nodules in these two patients showed a solid component. one nodule had an undefined boundary, and the other nodule extended from the isthmus but had a clear boundary. There were two reasons for this situation in the analysis, one was that the FNA BRAF V600E test was false positive before surgery; the other was that the nodule gene was mutated, but the cellular tissue morphology had not changed significantly and cannot be diagnosed malignant by histology.
There were some limitations in our study. First, the sample of this retrospective study was relatively small and only 26 thyroid nodules were included. There are fewer cases to make it unclear that the p value of E max ratio was 0.066. Second, of the 10 patients who were lost to follow-up, 8 patients could not be contacted and 2 patients could not be operated because of failed cardiac function assessment. the loss of 10 thyroid nodules may influence the accuracy of the risk-stratification assessment. Third, the small diameters with 85% nodules that were less than 10 mm were important factors for the false negative results of FNA and SWE parameter although no significant differences of elastic diagnostic efficacy between nodule size in other research. However, we need more cases and prospective studies to verify our results especially the performances of SWE in future studies.