AN INVESTIGATION OF NON-DIAGNOSTIC RESULTS OF ULTRASOUND GUIDED FNA OF THYROID NODULES IN AN OUTPATIENT RADIOLOGY DEPARTMENT by Cydnee Andersen A thesis submitted in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE IN RADIOLOGIC SCIENCES WEBER STATE UNIVERSITY Ogden, Utah December 10, 2020 Approved ______________________________ Dr. Laurie Coburn, Ed.D. R.R.A., RT (R)(CV)(ARRT), RPA (CBRPA) Committee Chairperson ______________________________ Dr. Robert J. Walker, PhD R.T. (R)(CT)(MR)(QM)(ARRT), FASRT Committee Member ______________________________ Dr. Tanya Nolan, EdD R.T. (R)(ARRT), ARDMS Committee Member Thyroid FNA Research 2 Acknowledgements I would like to acknowledge and express gratitude to the many people who have helped me accomplish the goals of my educational and professional career thus far. I would also like to thank my husband for his support and encouragement, my mother and father for instilling the importance of education in me, and my rambunctious children for making me smile throughout the process. Thyroid FNA Research 3 Tables of Contents Abstract……………………………………………………………………………...…………………………...……......4 Literature Review Introduction.………………………………………..…………………………………………….…………...5 Conclusion………………………………………………..………………………………..…………….……11 Methods……………………………………………….……...………………………………………..…………….…..13 Results……………………………………………….………………….………………………………………..…...….14 Discussion/Conclusion…………………………….………….………………..……………...……………...….17 References…………………………………………...……………….……………………………………...……....…19 Thyroid FNA Research 4 Abstract Non-diagnostic results from ultrasound (US) guided fine needle aspiration (FNA) of thyroid nodules are unsatisfying for patients, referring providers, and performing clinicians. Non-diagnostic pathology results cost patients and radiology departments additional time and resources since the procedure is frequently repeated. Although it can be frustrating the American Thyroid Association recommends FNA as the procedure of choice in the evaluation of thyroid nodules if the nodule meets suggested criteria (Haugen, 2016). This research is a retrospective analysis of data from one radiology department in Utah with two radiologists performing the procedure. 731 ultrasound guided FNA’s were reviewed, from January 2017 - December 2019, with 98 (13.41%) samples having non-diagnostic results. Other published research has reported non-diagnostic rates from 2%-36% (Gill, Amdur, & Joshi, 2017)(Isaac et al., 2014). This department's non-diagnostic rate is within range compared to others performing the same procedure. Thyroid FNA Research 5 Literature Review Introduction Thyroid nodules are common among the population. The American Thyroid Association reported thyroid nodules are present on thyroid ultrasound 19%–68% of the time in randomly selected individuals (Haugen, 2016). FNA biopsy is the most accurate way to screen thyroid nodules for malignancy (Popoveniuc & Jonklaas, 2012). In one Utah radiology department, thyroid FNA’s are performed by two full time radiologists. Despite their 23 years combined experience, some pathology results return as non-diagnostic samples. Non-diagnostic pathology results are an added cost for patients and require additional resources from the departments to repeat the procedure. Another consequence is delay in treatment if malignancy is found on repeat biopsy. Unfortunately, potential for non-diagnostic results is considered one of the limitations with this procedure. Research has identified similar trends with this specific limitation. The nature of this study is to make certain the biopsies performed in this Utah radiology department meet the national standards of quality. This study was a retrospective review of all adult patients who underwent a thyroid FNA between January 2017 and December 2019 in one Utah radiology department. The goal of this study was to determine the rate of non-diagnostic results in radiologist performed US guided FNA of thyroid nodules. It is anticipated the non-diagnostic percentage for this procedure at this facility follows the trend of other providers offering the same procedure.Thyroid FNA Research 6 To ensure quality for the department, it was confirmed through a review of literature that FNA biopsy is the most accurate way to screen thyroid nodules. After collecting a large number of articles and data about thyroid nodules, Popoveniuc and Jonklaas (2012) reported thyroid FNA biopsy is the most accurate and reliable tool for diagnosing thyroid malignancy and selecting candidates for surgery. In their own research almost 20% of FNA results are non-diagnostic, because of sampling error or poor preparation technique. Even if the biopsy comes back as benign Popoveniuc and Jonklaas (2012) suggested further long-term follow-up because of the risk of false-negative results after initial FNA. False negative results occur about 5% of the time. Serial ultrasound from 6 to 18 months from the initial FNA is the recommended investigation for the follow-up examination of thyroid nodules. This time frame can accurately detect significant changes in size or discover changes in appearance. They reported it is considered reasonable to repeat the FNA if there is a 50% increase in the volume of a previously biopsied thyroid nodule. Management of thyroid nodules can be difficult for providers. Thyroid nodules are often discovered in several ways. Fisher and Perrier (2018) studied incidental thyroid nodules (ITN) and their management after the nodules have been found. The primary goal in managing ITNs is to differentiate malignant lesions from benign conditions. It is not advisable to perform FNA on all nodules detected by imaging. Langer, Baloch, McGrath, Loevner, and Mandel (2012) explained thyroid nodules are commonly detected on a wide variety of imaging examinations. Nodules noted in at least 16% of patients undergoing neck computed tomography and magnetic resonance imaging. Thyroid FNA Research 7 Regardless of how thyroid nodules are discovered a further workup with a thyroid ultrasound is warranted. Chaikhoutdinov, Mitzner, and Goldenburg (2014) examined patients with incidentally discovered thyroid nodules (IDTNs) and focused on identification, evaluation, surgical intervention, and rates of malignancy. Chaikhoutdinov et al. (2014) revealed a malignancy rate of at least 13.3% in IDTNs which gives support that IDTNs should be further investigated. Thyroid cancer is on the rise. Simard, Ward, Siegel and Jemal (2012) reviewed population‐based incidence data compiled by the North American Association of Central Cancer Registries and used the data to examine trends of incident rates of cancers from 1999 through 2008. Despite the decline of most common cancers, some cancers had increased. Cancers of the pancreas, liver, thyroid, kidney, melanoma of the skin, esophageal adenocarcinoma and certain subsets of oropharyngeal cancer associated with human papillomavirus (HPV) infection had all increased. The specific section pertaining to thyroid cancer was reviewed. For thyroid cancer Simard et al. (2012) reported rates increased for men and women of all ages, most notably for women ages 55 to 64 years. Thyroid cancer incidence rates (per 100,000 population) for all races combined were 3‐fold higher among women (21.0) versus men (7.0) from 2004 to 2008. From 2000 to 2007, 5‐year survival rates for thyroid cancer were 99.8% for localized tumors, 97.0% for regional staged tumors, and 57.3% for distant staged tumors. There is importance of standardization in thyroid FNA reporting to ensure clarity and uniformity of reporting. In 2007, a system was introduced to standardize terminology Thyroid FNA Research 8 used in reporting thyroid cytology. Cibas and Ali (2017) discussed the need and implementation for the Bethesda System for Reporting Thyroid Cytopathology (BSRTC). Cibas and Ali (2017) also discussed the categories for the classifications and the criteria. In 2017, there was a revision that echoes every thyroid FNA report should begin with 1 of 6 diagnostic categories, the names of which remain unchanged since they were first introduced: (1) Nondiagnostic or Unsatisfactory; (2) Benign; (3) Atypia of Undetermined Significance (AUS) or Follicular Lesion of Undetermined Significance (FLUS); (4) Follicular Neoplasm or Suspicious for a Follicular Neoplasm; (5) Suspicious for Malignancy; and (6) Malignant. The BSRTC is the reporting system used in this research and is a very useful standardized system. Alshaikh, Harb, Aljufairi, and Almahari, (2018) talked about their experience using TBSRTC . It was concluded the BSRTC improves the quality of reporting by reducing the diagnostic discrepancies. Sameen, Abbas, and Sarfraz (2014) reported thyroid FNA cytology by the Bethesda system is a highly sensitive and specific method for differentiating benign from malignant thyroid nodules. Their research was performed in Pakistan. Sameen et al. (2014) recognized the Bethesda system is widely accepted in the United States and Europe. Other geographical areas noted while preparing this literature review were Turkey, Saudi Arabia, and Korea that indicated their use with the Bethesda system. There has been research to help lower the incidence of non-diagnostic samples. Gill, Amdur, Joshi (2017) goal was to identify potential involvements that may lower the high non-diagnostic rates associated with US FNA biopsy of thyroid nodules. Retrospectively a 164 thyroid nodule US-guided FNA’s were studied. The following variables were analyzed in regard to diagnostic and non-diagnostic sampling: patient age, gender, size of nodule, Thyroid FNA Research 9 biopsy technique (capillary vs. aspiration), needle gauge (23 vs. 25), and physician experience. After their data analysis, they discovered a statistically significant decrease in non-diagnostic rates with the use of capillary action compared to aspiration technique. Kim et al. (2008) reported the results of FNA biopsy are operator dependent. Also, the results may be affected by the lesion characteristics, the method of guidance, the number of aspirated samples, the needle gauge, the aspiration technique, and the presence or absence of on-site facilities for immediate cytologic examination. This article suggested in order to maintain the necessary level of staff expertise in an institution, the number of staff members who perform aspiration biopsies should be kept small. It was recommended each staff member who performs FNA biopsies to complete at least 1–5 procedures per month. There are predictive factors of non-diagnostic samples. Isaac et al. (2014) research was to determine the rate and factors predictive of non-diagnostic FNA in surgeon performed US-guided FNA of thyroid nodules. Isaac et al. (2014) also compared the rates of surgeon and non surgeon performed US-guided FNA of thyroid nodules. They conducted a retrospective review of all adult patients who underwent thyroid FNA by a staff, fellow, or resident Otolaryngologist at the University of Alberta between January 2011 and June 2013. In their retrospective research they analyzed data from 131 patients (180 nodules). They discovered nodules with predominantly cystic components, that were less than 1 cm, and resident performed FNA were associated with non-diagnostic cytology. A cystic nodule was the only independent predictor of non-diagnostic FNA on their multivariate analysis. It was concluded that the rate of non-diagnostic thyroid FNA performed by a surgeon or other clinicians is similar with ultrasound guidance. Their non-diagnostic rate was 23%. Thyroid FNA Research 10 A complete thyroid ultrasound should be performed on suspected thyroid nodules. The American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer serves as guidelines for clinicians, patients, researchers, and health policy makers on published evidence involving the diagnosis and management of thyroid nodules, and differentiated thyroid cancer. One of this publications’ strong recommendations suggests thyroid ultrasound, with survey of the cervical lymph nodes, be performed in all patients with known or suspected thyroid nodules (Haugen et al., 2016). Performing an ultrasound of the thyroid can answer many questions. Another recommendation from this publication is, when clinically indicated, FNA is the procedure of choice in the evaluation of thyroid nodules if the nodule meets suggested criteria. Their recommendations for a nodule with an initial non-diagnostic cytology result is to repeat the FNA with US guidance and, if available, on-site cytologic evaluation. Although FNA of the thyroid nodule is considered the gold standard, ultrasound can provide supporting information. Park et al. (2018) research was to evaluate the malignancy rate of nodules with non-diagnostic cytologic results based on the American Thyroid Association ultrasound characteristics. Another goal from their research was to suggest management guidelines for these types of nodules. Among their total 191 nodules, 20 (10.5%) were malignant. The characteristics they used for this category were solid composition, marked hypoechogenicity, microlobulated or irregular margins, microcalcifications, and taller-than-wide shape. These characteristics were more frequently seen in malignant nodules. The malignancy rate of nodules with very low suspicion characteristics of malignancy was 0% (0/58); low, 0% (0/45); intermediate, 10.3% (6/58); and high, 46.7% (14/30). Park et al. (2018) concluded if ultrasound findings Thyroid FNA Research 11 of thyroid nodules are assessed according to the 2015 ATA guidelines, non-diagnostic thyroid nodules with very-low- or low-suspicion ultrasound patterns can be followed up with ultrasound. Non-diagnostic nodules with intermediate or highly suspicious ultrasound patterns should be evaluated with repeat ultrasound guided FNA biopsy. Non-diagnostic biopsies need follow up, better sooner than later. Deniwar et al. (2017) described in cases of a non-diagnostic thyroid FNA biopsy results, guidelines from the Bethesda system recommend repeat thyroid FNA after 3 months. This guideline was to prevent false-positive results. Deniwar et al. (2017) examined their institutional data to determine whether the 3-month period affects the diagnostic yield of repeat biopsies. It was found that a less than 3-month period did not affect the diagnostic yield of the subsequent sample. The shortened biopsy gap would alleviate stress on patients with benign nodules and aid in faster surgical intervention in patients with malignancy. There may be a connection between papillary thyroid carcinoma diagnosis among insured individuals. Patients in this research were insured and open to further testing on their thyroid nodules. Altekruse, Das, Cho, Petkov, and Yu (2015) found a relationship between thyroid cancer incidence, insurance, and census tract socioeconomic status during a three-year period through population-based cancer registries. Altekruse et al. (2015) concluded there is a >2.5-fold increase in risk of papillary thyroid carcinoma diagnosis among insured individuals associated with high socioeconomic status. Conclusion Research has seen an increase in the rate of thyroid cancer (Simard, Ward, Siegel & Jemal, 2012). Ultrasound guided FNA’s are an important step in the exclusion of Thyroid FNA Research 12 malignancy. Given the high frequency of nodules combined with the impracticality of surgically removing all nodules, FNA plays an important role as a screening procedure. Departments should review their non-diagnostic rates regularly to ensure quality work. Research supporting the work up of incidental thyroid nodules strongly recommends these nodules have further testing. With a malignancy rate as high as 13.3% this gives support that all thyroid nodules, regardless of how they are found, should have further testing if they fit the criteria for such (Chaikhoutdinov et al., 2014). Patients with health insurance may have a higher incidence of thyroid cancer (Altekruse et al., 2015). FNA is the most accurate and cost-effective method for diagnostic evaluation of thyroid nodules (Kim et al., 2008). Thyroid FNA Research 13 Methods A retrospective analysis of US guided thyroid FNA’s completed in a radiology department at a Utah clinic. Information from the years 2017, 2018 and 2019 were analyzed. The information of interest was the non-diagnostic data. In 2017, 237 US guided FNA’s were performed. In 2018, 235 US guided FNA’s were performed. In 2019, 259 US guided FNA’s were performed. This research included 552 female participants and 110 male participants. All participants in this study were between the ages 18-98. In years 2018 and 2019, one minor was excluded each year. An IRB was approved by Weber State University and permission was granted from the researched institution. The US guided thyroid FNA’s performed have been completed by two full time radiologists. Each Radiologist was assigned an anonymous name and will be known as Radiologist A and Radiologist B. The questions this review sought to answer are: 1. Are the percentages of non-diagnostic US guided thyroid FNA’s performed at this facility within acceptable range as a whole? 2. Are the percentages of non-diagnostic US guided thyroid FNA’s performed by each individual radiologist at this facility within acceptable range? The data was entered into an excel spreadsheet by year (2017/2018/2019). Number of total studies for that year. Number of non-diagnostic results and the Department or Radiologist A or Radiologist B. The number of non-diagnostic cases were divided by the total number of exams. To gain a percentage, the sum was multiplied by 100. A 2 sample T-Test for unequal variance was performed with the means of the three years (2017, 2018, and 2019) and the means of 2 other research groups. Thyroid FNA Research 14 Results The study consisted of 662 patients with 731 thyroid FNA biopsies performed over the three-year period with 98 (13.41%) considered non-diagnostic. In 2017, 237 US FNA biopsies were performed with 36 (15.18%) of these samples considered non-diagnostic. In 2018, 235 US FNA biopsies were performed with 25 (10.60%) of these samples considered non-diagnostic. In 2019, 259 US FNA biopsies were performed with 37 (14.28%) of these samples considered non-diagnostic (Table 1). Table 1 Radiology Department Non-Diagnostic Rates Year(s) Total Samples Non-Dx % 2017 237 36 15.18% 2018 235 25 10.60% 2019 259 37 14.48% 2017-2019 731 98 13.41% Note. Non-Dx=Non-Diagnostic. %=Percentage In 2017, 94 US FNA biopsies were performed by Radiologist A with 9 (9.57%) of these samples considered non-diagnostic. In 2018, 132 US FNA biopsies were performed by Radiologist A with 12 (9.09%) of these samples considered non-diagnostic. In 2019, 134 US FNA biopsies were performed by Radiologist A with 10 (7.46%) of these samples Thyroid FNA Research 15 considered non-diagnostic. In the three-year period 360 US FNA biopsies were performed by Radiologist A with 31 (8.61%) considered non-diagnostic (Table 2). Table 2 Radiologist A Non-Diagnostic Rates Year(s) Total Samples Non-Dx % 2017 94 9 9.57% 2018 132 12 9.09% 2019 134 10 7.46% 2017-2019 360 31 8.61% Note. Non-Dx=Non-Diagnostic. %=Percentage In 2017, 143 US FNA biopsies were performed by Radiologist B with 27 (18.88%) of these samples considered non-diagnostic. In 2018, 103 US FNA biopsies were performed by Radiologist B with 13 (12.62%) of these samples considered non-diagnostic. In 2019, 125 US FNA biopsies were performed by Radiologist B with 27 (21.60%) of these samples considered non-diagnostic. In the three-year period 371 US FNA biopsies were performed by Radiologist B with 67 (18.05%) considered non-diagnostic (Table 3). Thyroid FNA Research 16 Table 3 Radiologist B Non-Diagnostic Rates Year(s) Total Samples Non-Dx % 2017 143 27 18.88% 2018 103 13 12.62% 2019 125 27 21.60% 2017-2019 371 67 18.05% Note. Non-Dx=Non-Diagnostic. %=Percentage An independent sample T-Test was performed on the data obtained. The test identified that means between the studied radiology department and reporting groups were not equivalent. Therefore, a future study would be more robust if randomized equal sample sizes were obtained. Despite this finding, it would appear that results identified for the quality study are similar to published results. Thyroid FNA Research 17 Discussion/Conclusion The years 2017 with a non-diagnostic rate of 15.18%, 2018 with a non-diagnostic rate of 10.60%, and 2019 with a non-diagnostic rate of 14.34% are all within range of others published non-diagnostic rates as well as the three-year non-diagnostic rate of 13.41%. Radiologist A and Radiologist B each had non-diagnostic rates within range compared to others research. Issac et al. (2014) had a reported 23% non-diagnostic rate for their total of 180 thyroid FNA biopsies. Gill et al. (2017) had reported a 26.8% non-diagnostic rate for their total of 164 thyroid FNA biopsies. Limitations of this study included a sample population deriving from a similar geographical area and sample size. Due to the large differences between sample sizes, the administration of a t-test for the statistical comparison of means may increase the rate of Type I errors. Therefore, it is recommended that for future research a random and equal sample be selected from both sets of data, large enough to suffice the requirements of statistical power, as to determine acceptance or rejection of the null hypothesis. Further, a suggestion for potential research could be to study US guided FNA non-diagnostic rates and their associations with nodular sizes. FNA is a cost-effective, safe and a highly reliable method for differentiating benign and malignant thyroid nodules (Park et al. 2018). As with any procedure US guided FNA has limitations, such as non-diagnostic, or unsatisfactory results. This is unsatisfying for the patient as well as the radiologists who performed the procedure. This research benefits patients and any department performing US guided FNA of the thyroid. To ensure the high standards of quality non-diagnostic rates for departments Thyroid FNA Research 18 should be recorded. It is suggested if a proceduralist's attempts at FNA repeatedly result in unsatisfactory specimens, the staff member be identified. Kim et al. 2008 suggested doing more training or decreasing the number of staff who perform the procedure. Both suggestions have been found to help lower the rate of non-diagnostic studies. The value of this research will allow departments to determine if more training should be implemented or if different aspiration techniques should be performed. A major focus in healthcare today is providing cost-effective, minimally invasive care. Having better non-diagnostic rates offer patients a better service and are more satisfying for the clinician who performs the procedure. Thyroid FNA Research 19 References Alshaikh, S., Harb, Z., Aljufairi, E., & Almahari, S. (2018). Classification of thyroid fine-needle aspiration cytology into Bethesda categories: An institutional experience and review of the literature. Cytojournal, 15, 4. doi: 10.4103/cytojournal.cytojournal_32_17 Altekruse S, Das A, Cho H, Petkov V, Yu M. Do US thyroid cancer incidence rates increase with socioeconomic status among people with health insurance? An observational study using SEER population-based data. BMJ Journals. https://bmjopen.bmj.com/content/5/12/e009843. Published 2015. Accessed January 19, 2020. Chaikhoutdinov I, Mitzner R, Goldenburg D. Incidental Thyroid Nodules: Incidence, Evaluation, and Outcome. - PubMed - NCBI. Ncbi.nlm.nih.gov. https://www.ncbi.nlm.nih.gov/pubmed/24618501. Published 2014. Accessed January 13, 2020. Cibas E, Ali S. The 2017 Bethesda System for Reporting Thyroid Cytopathology. 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