Clinical performance and utility of Afirma GEC in a community hospital practice

Transcription

1 Clinical performance and utility of Afirma GEC in a community hospital practice Michael Traynor, Jacob Torrison, Faculty: Hallanger-Johnson JE, Newman DW, and Beal JR PURPOSE: To assess the performance of the Veracyte s Afirma Gene Expression Classifier (GEC) in a large community hospital setting. BACKGROUND: Molecular markers are increasingly employed as an adjunct to fine needle aspiration (FNA) cytology in nodules with indeterminate classification. It is has been recommended that nodules read as Atypia of Undetermined Significance or Follicular Lesion of Undetermined Significance (AUS/FLUS), Follicular or Hürthle Cell Neoplasm (FN/HCN) have such testing. METHOD: Retrospective review of medical records of patients who underwent FNA of thyroid nodules from April 1, 2012 to October 31, 2014 at Sanford Health, Fargo, North Dakota. Analyzed patients who underwent Afirma GEC testing. Nodule and patient characteristics, FNA cytology, Afirma GEC results, and subsequent clinical or surgical follow-up were obtained for 70 patients of 831 patients. RESULTS: Sixty-six patients had Afirma GEC clinically actionable results available for analysis (48 AUS/FLUS; 13 SFN; and 5 HCN). Thirty-seven of 66 patients had benign GEC results (56.1%), whereas 29 patients (43.9%) had suspicious results. One patient avoided surgery for every two GEC tests run as 35 of 37 patients with benign GEC profile elected conservative follow-up. Twenty-six of 29 patients with Afirma suspicious results underwent surgery with final pathologic diagnosis (rate of malignancy in GECsuspicious nodules was 42.3%). CONCLUSION: Though FNA classification is variable across institutions, the implementation of the Afirma GEC leads to a significant reduction in unnecessary thyroid surgery when applied to a population at a large community medical center. The results of benign calls by the Afirma GEC and malignancy rate within GEC-suspicious nodules is in line with previous results published and purported Veracyte.

2 INTRODUCTION Thyroid nodules account for an increasing number of annual visits to endocrinology clinics, more than 525,000 endocrinology visits each year in the United States are for concerns related to a new palpable thyroid nodule or nodule detected via imaging. 1 Studies based on autopsy and ultrasound estimate that up to one in two women and one in five men over age 50 have thyroid nodules detectable by ultrasound. Large scale studies, such as the Framingham study, estimate that the incidence of new palpable thyroid nodules in the United States is approximately 300,000 anually. 2 Increased usage of ultrasound and computed tomography scans detects a significant number of thyroid incidentalomas. Using high resolution ultrasound, one prospective study detected thyroid nodules in 2 out of every 3 patients studied with only 21% of those nodules being palpable. 3 When these nodules are detected via physical exam or incidental imaging, the need to exclude cancer is of prime clinical concern. Thyroid cancer presents most frequently as a nodule; but a mere 4 to 6.5 percent of all thyroid nodules are cancerous according to studies in non-surgical populations. 4,5 Selecting nodules to biopsy based on suspicious ultrasound features increases the yield of malignancies only to an estimated 10-15%. 6 Guidelines for the management of thyroid nodules are standardized across the United States and Europe. The American Thyroid Association (ATA), American Association of Clinical Endocrinologists (AACE), Associazione Medicie Endocrinologi, and the European Thyroid Association recommend a multistep process for evaluation: clinical assessment, measurement of thyroid-stimulating hormone (TSH), ultrasound evaluation, and Fine Needle Aspiration (FNA) or biopsy of nodules selected according to size and ultrasound characteristics. 5 For biopsied nodules, FNA cytology classifies a majority of nodules as benign (72%: range 62-85%) and approximately 5% (range 1-8%) of nodules as cytologically malignant. 7 Performance of FNA cytologic classification via the Bethesda System is superb in malignant lesions with one study estimating that 98.1% of lesions identified as malignant on cytology have confirmed malignancy following surgery. 8 Still FNA classification has its limitations, with an estimated 10-30% of biopsied thyroid nodules falling under indeterminate cytological categories. 9 These categories include: Atypia of Undetermined Significance or Follicular Lesion of Undetermined Significance (AUS/FLUS); (Suspicious for) Follicular or Hürthle Cell Neoplasm (FN/HCN); and Suspicious for Malignancy. When nodules fall into these categories, current consensus guidelines recommend surgery for definitive pathologic diagnosis. Though repeat biopsy is considered appropriate for patients with AUS/FLUS when such a classification is driven by characteristics other than nuclear atypia. 10 For those patients with indeterminate nodules who undergo surgery, more than half have benign final histology. 6 These patients often undergo diagnostic lobectomies (arguably too much surgery for a benign diagnosis and too little surgery for the 15-30% who have malignant disease). To address the shortcomings of FNA cytology in nodules classified as indeterminate, molecular analysis of aspiration has been employed as a tool for further evaluation. The

3 Afirma assay, a commercially available molecular marker, purports to improve the diagnostic yield in thyroid FNA via measurement of the expression of 167 gene transcripts. The test is offered at a single CLIA-certified laboratory and classifies nodules as either benign or suspicious. The assay has been validated by a prospective, multicenter, and blinded trail. In nodules with FNA classifications of AUS/FLUS or FN/HCN that are characterized as benign by the assay, there is a reported 5-6% post-test probability of malignancy. 11 The assay s performance in thyroid nodules with AUS/FLUS or FN/HCN that are benign by GEC is comparable to benign cytologic results; and therefore, the National Cancer Cooperative Network along with others have recommended that patients with such nodules be treated non-surgically. A study in 2012 supports observation or ultrasound follow-up over thyroid lobectomy in patients with cytologically indeterminate-afirma benign nodules. 12 Clinical performance of the Afirma assay has been more variable than validation studies would suggest. The NCCN recommendation of observation for follow up in cytologically indeterminate-afirma benign nodules is based upon a single study with a sample of 81 FN/HCN and 120 AUS/FLUS nodules. In this study, the assay had an estimated positive predictive value (PPV) of 47% (95% C.I %) and negative predictive value (NPV) of 93% (95% C.I of 86-97%) across nodules deemed indeterminate by FNA cytology with a known pretest probability of malignancy. 11 Three subsequent studies in clinical settings have reported varied positive predictive values (16, 54, and 57%, respectively) and lower implied negative predictive values (75, 92, 90, respectively) It should be noted, however, that NPV estimates in these studies are from small sample sizes where the NPV cannot be directly measured given that few patients with benign GEC results undergo thyroid surgery. Given the disparate results between McIver et al. 13 and the two studies by Alexander et al. 14 and Harrel and Bimston 15, it is unclear what value the Afirma assay has in tertiary-referral community medical centers. The Afirma GEC has two primary clinical goals when employed at large tertiary referral community medical centers. First, it aims to rule out cancer in nodules with indeterminate FNA cytology. Second, it hopes to decrease the number of diagnostic lobectomies among patients with cytologically indeterminate-histopathologically benign nodules. On the one hand, two previous clinical studies, one multicenter trial 14 and one trial at a specialized thyroid clinic operating from a community hospital setting, 15 have supported the GEC s efficacy in these clinical outcomes. On the other hand, one more recent study at a large academic center found that the GEC had a lower than expected rate of benign calls, thus limiting its ability to achieve its second clinical goal. 13 While their results were significant, larger sample sizes would lend power to the studies and help to further inform current clinical practice. This study will correlate the histopathology of surgical specimens from both benign and suspicious test results with histologic diagnosis following surgery. In doing so, this study will evaluate the efficacy of the Afirma GEC when offered to patients with cytologically indeterminate nodules presenting to a large community medical center. METHODS

4 The study consisted of a retrospective medical records review of patients who underwent fine needle aspiration of thyroid nodules (ICD 9 code 10022) that were obtained from the Sanford Medical Center in Fargo, North Dakota. This cohort included patients that underwent an FNA of a thyroid nodule between April 1 st, 2012 and September 30 th, GEC was offered to whose cytology was reported as suspicious for follicular neoplasm (FN), suspicious for Hürthle Cell neoplasm, (HCN) atypia of undetermined significance, (AUS) or follicular lesion of undetermined significance (FLUS). Currently published guidelines for the evaluation of thyroid nodules recommend the following: clinical assessment, ultrasound evaluation, measurement of thyroid stimulating hormone (TSH), and biopsy of select nodules dependent upon ultrasound findings and nodule size. 5,16 Our study additionally retrospectively analyzed patient age and TSH as it correlated with malignancy. The tertiary community medical center from which the data was obtained follows up to date guidelines regarding indeterminate nodules by FNA cytology. Therefore, if a patient during the above time period biopsy results were read as AUS/FLUS or suspicious for FN/HCN, the center recommended that the Afirma GEC assay be offered in an attempt to guide clinical reasoning. Practice guidelines at this center dictates that patients with indeterminate pathology that had additional risk factors for thyroid cancer, compressive symptoms or otherwise symptomatic nodules, those with ultrasounds associated with poor prognosis and/or worrisome imaging features, or those in which there was a clinical or patient-driven decision to undergo surgery not be offered the GEC assay as surgery would be the recommended decision regardless of GEC results in these cases. Patients whose biopsies were read as definitively benign or malignant were not offered the GEC assay. Patients whose GEC resulted as benign were recommended to be closely followed clinically with serial ultrasound and physical examination at time intervals based on provider and patient preference. Those with malignant biopsies were offered surgical intervention if the provider felt the patient was an appropriate candidate for surgery. SPSS 21.0 for Windows was used to analyze demographic and clinical characteristics of patients. Frequencies and relative percentages were computed for each categorical variable. We performed Chi-square tests or Fisher s exact tests to determine which categories were significantly different from one another, and t-test and/or ANOVA were used to compare continuous variables. All p-values are two-sided, and p-value < 0.05 will be considered significant. Missing data was excluded from analysis. RESULTS As illustrated in figure 1, 1383 nodules were sampled via fine needle aspiration in the 873 patients that met criteria during the designated time period. Of these, 105 (7.6%) nodules

5 were determined to be cytopathologically indeterminate. Of these indeterminate nodules, 81 (5.9%) were read as AUS/FLUS and 24 (1.7%) as suspicious for FN/HCN. TSH was also measured to ascertain if there was any correlation between a hypothyroid, euthyroid or hyperthyroid state and malignancy. As demonstrated in Table 1, euthyroid states were by far the most prevalent in this population with 675 patients (87.8%) in the euthyroid lab range. A euthyroid state also therefore correlated with the largest percentage of malignant nodules with 95 out of the 114 total (83.3%). The amount of patients in a clinically hyperthyroid (39, 5.1%) state and hypothyroid (55, 7.2%) state were a much smaller proportion of the cohort and had comparable malignancy rates with regards to the overall number of hyperthyroid (10 patients, 8.8% of malignancies) or hypothyroid (9 patients, 7.9% of malignancies) patients. No statistically significant difference between benign, indeterminate, malignant can be seen based on TSH in this study. Figure 1 is a summary of the results organized by initial cytology results and final histopathology. It shows that of these 105 indeterminate nodules, 35 had no GEC submitted. Twenty-eight of those with no GEC submitted underwent thyroid lobectomy due to a combination of physician-driven clinical decision making and/or patient preference. Of these 28, 12 opted for surgical intervention because the patient or physician were concerned to the point that they felt an operation was necessary, four because of a highly suspicious ultrasound, six because of compressive symptoms, three because of concurrent primary hyperparathyroidism and three because of a positive pet scan or other evidence of metastatic cancer. Seven of this cohort of 35 did not undergo thyroid lobectomy as two were lost to follow up, four of the nodules were read as benign on a subsequent FNA, and one patient elected not to further pursue the indeterminate nodule due to concurrent metastatic breast cancer. Seventy remaining nodules were available and sent for GEC analysis. Of these 70, four samples were deemed insufficient for analysis and a result of Benign or Suspicious was thus not determined. Therefore a total of 66 patients that met criteria of this study had GEC analysis completed. Of these, 37 (56.1%) were reported to be Benign and 29 (43.9%) were reported to be Suspicious. The 37 patients with benign results were offered close follow up with serial ultrasound as an alternative to a diagnostic surgical procedure given the GEC assay s strong (>95%) 4 negative predictive value. Of those with benign GEC results 35 elected for observation with serial ultrasound and two elected to have surgery. One patient with cytology consisting of AUS/FLUS but a benign GEC profile elected to undergo surgery as a result of worsening compressive symptoms, and the other surgery was performed due to patient concern for malignancy (cytology SFN, GEC benign). The former s thyroid was found to be a follicular adenoma and the latter was found to have an incidental 0.5 cm papillary microcarcinoma in the left lobe, whereas the isthmus that correlated with the GEC was benign. Finally, a third patient in the remaining 35 patients that remained under surveillance underwent a total thyroidectomy 18 months after the GEC assay was obtained due to increasingly compressive symptoms. This patient was found to have

6 benign thyroid tissue. For the purposes of this study all three of these would correlate with a benign pathological diagnosis as the benign GEC result correctly identified the nodule in question as benign. The remaining 34 patients are continuing to be closely monitored with clinical examination and ultrasound and have been actively monitored for a mean of 21.4 months Of the 29 who had a suspicious GEC results, 26 (89.7%) elected to have surgery and 3 opted against surgery despite recommendation for surgical intervention. Two of these patients were lost to follow up. The remaining patient elected to follow with serial ultrasound, and a follow up ultrasound showed a decreasing nodule size and a subsequent biopsy result was determined to be chronic lymphocytic thyroiditis. Within the cohort of 26 patients with suspicious GEC results that underwent surgery, 12 had evidence of malignancy. However, one of these malignant nodules was incidentally found on the opposite lobe that GEC analysis was conducted and was a papillary microcarcinoma. Therefore, those with suspicious GEC results had a malignancy in the nodule sampled at a rate of 11/26, correlating with a post-test probability of cancer of 42.3%. Those with pathological evidence of malignancy in nodules sampled for GEC were represented by six with papillary carcinoma follicular variant, four with papillary carcinoma (including one incidental microcarcinoma arising from a follicular nodule), and one with Hürthle Cell carcinoma. The correspondence of cytology, GEC result, and final histopathology is represented in Table 2. Zero of four patients (0%) with initial cytology of SFN and suspicious GEC had malignant findings at final diagnosis. One of two patients (50%) with initial cytology of SHCN and suspicious GEC had a Hürthle cell carcinoma with nodal metastasis at final diagnosis. Ten of twenty patients (50%) with initial cytology of AUS/FLUS and suspicious GEC had malignant findings at final diagnosis. Malignancies found in these patients included 6 with papillary carcinoma follicular variant, 3 with classical papillary carcinoma, and 1 micro-papillary thyroid carcinoma arising out a follicular nodule. DISCUSSION Molecular markers have become an important tool in the evaluation of cytologically indeterminate thyroid nodules. The Afirma GEC has been validated in laboratory settings with negative predictive values akin to cytologically benign results. Less clear, however, is the clinical utility of the Afirma assay when applied to heterogeneous patient populations. The clinical data is limited to three studies with disparate results in settings of specialized clinics or academic medical centers. Relatively little is known about the clinical utility of the Afirma GEC in community medical centers. Our study reviewed 105 patients with indeterminate thyroid nodules. Seventy of these patients had samples sent for GEC analysis. Four samples were deemed insufficient for analysis and a result of Benign or Suspicious was thus not determined. A total of 66 patients had GEC results available for clinical decision-making. Of these, 37 (56.1%) were reported to be

7 Benign and 29 (43.9%) were reported to be Suspicious. Thirty-five of the 37 Afirma benign patients (94.5%) elected for follow-up with serial ultrasound over diagnostic thyroid surgery a rate similar to patients with Afirma benign results in previous studies. 12,14 For comparison, 88% of patients with Afirma benign results in a study by McIver et al. and 75% of patients with Afirma benign results in a study by Harrell and Bimston were managed conservatively. 13,15 Our study demonstrates that use of the Afirma GEC in patients with indeterminate nodules presenting to community medical centers decreases the number of unnecessary thyroid surgeries and significantly alters management for such patients. The rates of surgery avoidance in this study support the results of previous studies and the use of the Afirma GEC for surgery avoidance and cost savings in such settings. Veracyte reports that, based on their experience thusfar, approximately one in two samples submitted to GEC will have benign results. Such results have bolstered Veracyte s claim that almost 50,000 patients per year could benefit (i.e. avoid surgery) from GEC implementation throughout the United States. 12 Our data would support such claims and reflects a similar rate of benign GEC profiles (56.1%). In our study, approximately one in every two patients avoided surgery for every two tests run, a rate similar to Alexander et al., in which 52% of nodules that were AUS/FLUS and SFN/SHCN were Afirma benign. 14 Rates of surgery avoidance, however, have not been consistent across studies. Notably, lower reported rates of GEC benign results have been reported in the literature. A prospective study by McIver et al. reported only 28% of samples receiving benign GEC results. 13 Harrell and Bimston (34% of nodules that were AUS/FLUS and SFN/SHCN were Afirma benign) also reported lower than expected rates of benign GEC profiles. A comparison of this study to other clinical studies (both prospective and retrospective) demonstrates variability in the cytology of nodules available for Afirma GEC. In total, 66 nodules had GEC results available from Veracyte for analysis: 20 were suspicious for FN (SFN) (30.3%), 11 were suspicious for HCN (SHCN) (16.7%), and 35 were characterized as AUS/FLUS (53.0%). The percentage of AUS/FLUS versus FN/HCN differed significantly when compared to other analagous studies 12,13 which displayed significantly higher amounts of FN/HCN interpretations. The problem of variability in cytological ratings has been previously demonstrated 17,18 and specifically noted by the multi-center retrospective study by Alexander et al. 14 Inter- and Intra-observer comparisons regarding FNA cytology note that follicular lesions in particular have a high rate of discordance with one study showing that 18 (78.3%) of a total of 23 discordant cases were follicular lesions (either FLUS versus FCN). 18 Our cytopathologists stress that they have begun to rate indeterminate nodules as AUS/FLUS more frequently in smaller nodules. Lesions that are small (around 1 cm), with low cellularity, scant colloid, often display hemodilution, clotting artifact and "architectural atypia" in the form of microfollicular architecture. While one could argue that some of these nodules should be placed in the suspicious-for-follicular-neoplasm category, our cytopathologists assess the risk of malignancy to be very low in many of these lesions since many specimens have low cellularity and architectural features distorted by fibrin clot. The vast majority of such lesions will be adenomatoid nodules with microfollicular architecture, and our

8 pathologists rate such nodules as FLUS. Such practices explain the discrepancies in FNA classification between our study institution and others. Those lesions that had suspicious GEC profiles were compared with final histological diagnoses. Eleven patients out of 26 (42.3%) with suspicious GEC results had confirmed malignancies within the nodules sampled. While this positive-predictive value of malignancy is in line with results published by Alexander et al. in the original validation (38%), 11 the PPV of the Afirma assay has varied across studies from 15.6% 13 to 57%. 15 It has been suggested that such variability could be due to reported variability in the specificity of the Afirma GEC across institutions. 11,13 Our study did not report any false negative results from the Afirma GEC, though only 3 patients with Afirma-benign (8.1%) results underwent surgery. As in all subsequent clinical studies of the Afirma GEC, our study did not operate on all patients with Afirma-benign results and thus is unable to directly calculate the sensitivity, specificity, and negative predictive value a notable but shared limitation. This study has some notable limitations. We acknowledge that the retrospective nature of the study may have led to bother referral and sample bias, though these factors are controlled somewhat by the standardized NCCN guidelines regarding indeterminate thyroid nodules. The retrospective nature of the study also allows a fairly accurate assessment of the clinical utility of the Afirma GEC in such community hospital settings. Our analysis does not account for all outcomes. A mere 8.1% of patients with benign GEC and 90% of patients with suspicious results have had final surgical diagnoses, while the remaining patients have either been followed with serial ultrasound or managed conservatively. Such a limitation interferes with our ability to precisely assess the specificity, sensitivity, and negative predictive value of the GEC in our clinical practice. Future investigations could examine the performance of the Afirma assay in a prospective manner as demonstrated in McIver et al. 13 Such studies could also explore whether Afirma versus careful clinical selection of patients for surgery significantly decreases the number of thyroid surgeries. At the heart of this study is the problem of both costs and harms associated with unnecessary thyroid surgery. More research is needed to determine the rate of benign GEC results that balances sufficient patient and financial benefits with the financial costs of GEC implementation. Looking forward, newer molecular markers will no doubt challenge the effectiveness and validity of Afirma; and future studies should compare the Afirma GEC to newer diagnostic tools. CONCLUSION In summary, these data analyze the clinical utility of the Afirma GEC in a communitybased hospital practice. Despite variability in FNA classification and the varied sensitivity and specificity of the Afirma GEC across institutions, our study shows that the Afirma GEC appears to avoid unnecessary surgery in a significant number of patients with cytologically indeterminate nodules (AUS/FLUS, FN, HCN). Analysis shows a PPV and rate of benign calls similar to that of the initial blinded validation and supports the implementation of the GEC in centers with similar clinical settings. Compared to prior

9 studies, notable variation in FNA interpretation exists, and further supports the use of molecular diagnostics in clinical decision-making.

10 REFERENCES 1. Sosa JA, Hanna JW, Robinson KA, Lanman RB. Increases in thyroid nodule fineneedle aspirations, operations, and diagnoses of thyroid cancer in the United States. Surgery. 2013;154(6): ; discussion doi: /j.surg Dean DS, Gharib H. Epidemiology of thyroid nodules. Best Pract Res Clin Endocrinol Metab. 2008;22(6): doi: /j.beem Ezzat S, Sarti DA, Cain DR, Braunstein GD. Thyroid incidentalomas: Prevalence by palpation and ultrasonography. Arch Intern Med. 1994;154(16): doi: /archinte Jo VY, Stelow EB, Dustin SM, Hanley KZ. Malignancy risk for fine-needle aspiration of thyroid lesions according to the Bethesda System for Reporting Thyroid Cytopathology. Am J Clin Pathol. 2010;134(3): doi: /ajcp5n4mthpafxfb. 5. Gharib H, Papini E, Paschke R, et al. American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and EuropeanThyroid Association Medical Guidelines for Clinical Practice for the Diagnosis and Management of Thyroid Nodules. Endocr Pract Off J Am Coll Endocrinol Am Assoc Clin Endocrinol. 2010;16 Suppl 1:1-43. doi: /10024.gl. 6. Yassa L, Cibas ES, Benson CB, et al. Long-term assessment of a multidisciplinary approach to thyroid nodule diagnostic evaluation. Cancer. 2007;111(6): doi: /cncr Gharib H, Goellner JR. Fine-needle aspiration biopsy of the thyroid: an appraisal. Ann Intern Med. 1993;118(4): Jo VY, Stelow EB, Dustin SM, Hanley KZ. Malignancy risk for fine-needle aspiration of thyroid lesions according to the Bethesda System for Reporting Thyroid Cytopathology. Am J Clin Pathol. 2010;134(3): doi: /ajcp5n4mthpafxfb. 9. Cibas ES, Ali SZ. The Bethesda System for Reporting Thyroid Cytopathology. Am J Clin Pathol. 2009;132(5): doi: /ajcpphlwmi3jv4la. 10. Horne MJ, Chhieng DC, Theoharis C, et al. Thyroid follicular lesion of undetermined significance: Evaluation of the risk of malignancy using the two-tier subclassification. Diagn Cytopathol. 2012;40(5): doi: /dc Alexander EK, Kennedy GC, Baloch ZW, et al. Preoperative diagnosis of benign thyroid nodules with indeterminate cytology. N Engl J Med. 2012;367(8): doi: /nejmoa

11 12. Duick DS, Klopper JP, Diggans JC, et al. The impact of benign gene expression classifier test results on the endocrinologist-patient decision to operate on patients with thyroid nodules with indeterminate fine-needle aspiration cytopathology. Thyroid Off J Am Thyroid Assoc. 2012;22(10): doi: /thy McIver B, Castro MR, Morris JC, et al. An Independent Study of a Gene Expression Classifier (Afirma TM ) in the Evaluation of Cytologically Indeterminate Thyroid Nodules. J Clin Endocrinol Metab. April 2014:jc doi: /jc Alexander EK, Schorr M, Klopper J, et al. Multicenter clinical experience with the Afirma gene expression classifier. J Clin Endocrinol Metab. 2014;99(1): doi: /jc Harrell RM, Bimston DN. Surgical utility of Afirma: effects of high cancer prevalence and oncocytic cell types in patients with indeterminate thyroid cytology. Endocr Pract Off J Am Coll Endocrinol Am Assoc Clin Endocrinol. 2014;20(4): doi: /ep13330.or. 16. Cooper DS, Doherty GM, Haugen BR, et al. Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2009;19(11): doi: /thy Elsheikh TM, Asa SL, Chan JKC, et al. Interobserver and intraobserver variation among experts in the diagnosis of thyroid follicular lesions with borderline nuclear features of papillary carcinoma. Am J Clin Pathol. 2008;130(5): doi: /ajcpkp2quvn4rccp. 18. Gerhard R, da Cunha Santos G. Inter- and intraobserver reproducibility of thyroid fine needle aspiration cytology: an analysis of discrepant cases. Cytopathol Off J Br Soc Clin Cytol. 2007;18(2): doi: /j x.

12 1383 Nodules 873 Patients 11 Patients Nondiagnostic FNA 133 Patients Malignant FNA 624 Patients Benign FNA 105 #Indeterminate Results 81 Atypia/FLUS 24 FN/HCN 70 Patients GEC Attempted 35 No GEC Submitted 66 with GEC results 4 With Insufficent Sample 7 No Sample Collected 28 Surgery 37 Benign 29 Suspicious 8 Malignant 2 PTC 4 PTC FV 1 FCa 1HCCa 35 Observation 2 Surgery 26 Surgery 15 Benign 3 No Surgery 20 Benign 1 Surgery during post GEC surveillance 1 Benign 2 Benign 1 Incidental Micropapillary thryoid carcinoma 1 Follicular Adenoma 11 Malignant 3 PTC 1 Micropapillary thyroid carcinoma arising from follicular nodule 6 PTC FV4 1 HCCa 2 Lost To F/U 1 F/U Serial Ultrasound

13 Table 1:

14 Table 2: Results of GEC According to final histopathology for indeterminate nodules/gec suspicious nodules that underwent surgery

15