Thyroid nodules are common clinical findings, with a

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1 Fine-Needle Aspiration Versus Frozen Section in the Evaluation of Malignant Thyroid Nodules in Patients With the Diagnosis of Suspicious for Malignancy or Malignancy by Fine-Needle Aspiration Qin Ye, MD; Jennifer S. Woo, MD; Qunzi Zhao, MD; Ping Wang, MD; Pintong Huang, MD; Lirong Chen, MD; Xin Li, MS; Kanlun Xu, MD; Ying Yong, CT; Stephanie (Sung-Eun) Yang, MD; Jianyu Rao, MD Context. The Bethesda System for Reporting Thyroid Cytopathology recommends against the use of intraoperative frozen section (FS) during lobectomy of a thyroid nodule with a fine-needle aspiration (FNA) diagnosis of malignant. Bethesda recommendations for FS in the FNA category of suspicious for malignancy (SFM) is less welldefined. In some institutions in China, FS examination is performed during lobectomy even for FNA-proven malignant cases. Objective. To compare the efficacy of FNA versus FS in the evaluation of malignant thyroid lesions. Design. A 3-year retrospective analysis from a single institution was performed on cases with an FNA diagnosis of SFM or malignant with subsequent FS examination during thyroidectomy. The results of FNA and FS findings were compared to the final thyroidectomy pathology. Results. A total of 5832 thyroidectomy procedures were performed: 1265 cases had FNA and FS results available. Fine-needle aspiration gave a diagnosis of SFM to 306 cases and a diagnosis of malignant to 821 cases. Of the SFM cases, 10.5% (32 of 306) had benign/indeterminate, 4.6% (14 of 306) suspicious, and 84.9% (260 of 306) malignant FS results. Final pathology showed 56.3% (18 of 32), 64.3% (9 of 14), and 100% (260 of 260) malignancy rates, respectively. For the malignant FNA group, 10.0% (82 of 821) had benign/indeterminate, 4.4% (36 of 821) suspicious, and 85.6% (703 of 821) malignant FS results. The final pathology showed 96.4% (79 of 82), 97.2% (35 of 36), and 99.9% (702 of 703) malignancy rates, respectively. Conclusions. Frozen section should not be performed for the malignant FNA category because FS evaluation may result in 10% falsely negative findings. Performing FS for SFM may be better justified; however, more than half of FS cases read as benign in this category had malignant final pathology. Therefore, caution should be taken for FS results even in the SFM group. (Arch Pathol Lab Med. 2017;141: ; doi: / arpa oa) Thyroid nodules are common clinical findings, with a reported prevalence of 4% to 7% in the general population. 1 They are more common in women and are seen more frequently with increasing age and decreasing iodine intake. 2 The most frequent thyroid carcinoma is papillary thyroid carcinoma (PTC), which comprises 80% to 85% of thyroid malignancies. 3 Fine-needle aspiration (FNA) is considered the most reliable and cost-effective test for the diagnosis of malignant thyroid nodules, with excellent sensitivity and specificity. 4 Accepted for publication September 20, From the Departments of Pathology (Drs Ye, Chen, and Xu, and Ms Li), Surgery (Drs Zhao and Wang), and Ultrasonography (Dr Huang), Second Affiliate Hospital, Zhejiang University, Hangzhou, China; and the Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California (Drs Woo, Yang, and Rao, and Mr Yong). The authors have no relevant financial interest in the products or companies described in this article. Reprints: Jianyu Rao, MD, David Geffen School of Medicine at UCLA, Ronald Reagan Medical Center, Le Conte Ave, Los Angeles, CA ( jrao@mednet.ucla.edu). Currently, the reporting of thyroid FNA is based on the Bethesda Criteria for Reporting Thyroid Cytopathology, which organizes thyroid lesions into 6 general diagnostic categories, including nondiagnostic/unsatisfactory, benign, atypia/follicular lesion of undetermined significance (AUS/ FLUS), follicular neoplasm/suspicion for a follicular neoplasm (FN/SFN), suspicious for malignancy (SFM), and malignant. 5 Each diagnostic category implies its own risk for malignancy and clinical management guidelines. The diagnosis of malignancy includes that of PTC, the most common malignant neoplasm of the thyroid. The diagnosis of PTC is rendered in the presence of distinctive cytologic features, including nuclear enlargement, nuclear pallor, powdery chromatin, longitudinal nuclear grooves, and intranuclear cytoplasmic pseudoinclusions. 6 According to the American Thyroid Association, treatment of PTC includes total or near total thyroidectomy if any of the following is present: contralateral thyroid nodules, regional or distant metastases, personal history of head and neck radiation, or a first-degree family history of thyroid cancer. 7 With preoperative FNA diagnosis of PTC, the use of intraoperative frozen section (FS) is not recommended. 684 Arch Pathol Lab Med Vol 141, May 2017 FNA Versus Frozen Section in Thyroid Nodules Ye et al

2 Table 1. Age Distribution of All Patients With Thyroidectomy (n ¼ 5832; From January 2011 to January 2014): Male ¼ 1532 (26.27%) and Female ¼ 4300 (73.73%) Age, y No. (%) (0.50) (6.90) (17.40) (26.80) (28.30) (15.60) (4.03) (0.43) Although clinical management is straightforward with an FNA diagnosis of PTC, management is less definitive with the SFM, suspicious for papillary thyroid carcinoma category. Although the diagnosis of SFM is an indication for surgery, surgical management includes either lobectomy or total thyroidectomy, with or without intraoperative FS. The utility of intraoperative FS for cases with diagnostic SFM by FNA is unclear; however, when compared with FS, FNA has shown to have a comparable sensitivity and positive predictive value for PTC. 8,9 Current American Thyroid Association guidelines do not address a definitive role for FS in the evaluation of these lesions, therefore highlighting a need to elucidate the utility of FS on thyroid nodules with a previous FNA of SFM. In late 2010, as a part of broad collaboration project between a large academic hospital in the United States and a large academic hospital in China, thyroid FNA was first introduced as a standard of care at the Chinese institution. American pathologists traveled to China to help train Chinese staff, including pathologists and endocrinologists. However, Chinese surgeons felt uncomfortable relying entirely on FNA diagnosis, because of a lack of experience with thyroid FNA. Therefore, FS examination is still requested routinely, even for FNA-proven malignant cases. Although not recommended by the American Thyroid Association guidelines, this scenario nevertheless provides a unique opportunity to compare the efficacy of FNA versus FS in evaluating malignant thyroid lesions, including the diagnosis of SFM. In this retrospective analysis, we compared the results of cases with both FNA and FS to the final pathology of thyroidectomy specimens during a 3- year period, to address the efficacy of FNA versus FS modalities in the evaluation of thyroid nodules. MATERIALS AND METHODS Patient Cohort and Data Extraction The study was conducted at Second Affiliate Hospital of Zhejiang University, Hangzhou, Zhejiang, China, which has more than 2000 hospital beds. This was a retrospective study of 5832 consecutive patients who underwent total thyroidectomy during a period of 3 years (2011 to 2013). Complete clinical data, including demographics, radiologic findings, clinical presentation, and treatment history, were obtained through chart review, and were entered into a clinical database manually. The results of preoperative FNA diagnosis, intraoperative FS examination, and final pathology were obtained from the pathology department and linked to the established clinical database. Of the 5832 cases, 1265 (22%) had both FNA and FS results. These patients were the focus of the current study. Ethics approval was waived by the Institutional Review Board because the study only involves a retrospective review of anonymous data collected for routine medical activities. Table 2. Fine-Needle Aspiration (FNA) Results of Cases With Both FNA and Frozen Section Diagnosis (n ¼ 1265) Category No. (%) Malignancy Rate, No. (%) 1. Nondiagnostic/ unsatisfactory 56 (4.4) 30 (53.6) 2. Benign 30 (2.4) 9 (30) 3. AUS/FLUS 36 (2.8) 18 (50) 4. FN/SFN 16 (1.3) 8 (50) 5. SFM 306 (24.2) 287 (93.8) 6. Malignant 821 (64.9) 816 (99.4) Abbreviations: AUS/FLUS, atypia of undetermined significance/follicular lesion of undetermined significance; FN/SFN, follicular neoplasm/ suspicious for follicular neoplasm; SFM, suspicious for malignancy. Definitions and Diagnostic Categories for FNA and FS The FNA diagnosis follows the Bethesda Criteria for Reporting Thyroid Cytopathology, which includes 6 general diagnostic categories, including nondiagnostic/unsatisfactory, benign, AUS/ FLUS, FN/SFN, SFM, and malignant. 5 Frozen section diagnosis was grouped into 3 categories, including benign/indeterminate, suspicious, and malignant. Statistical Analysis The primary outcome measure of the study was the rate of malignancy defined by the final pathology of thyroidectomy specimens. We used the Fisher exact test to compare the malignancy rate of each group. All of the analyses were performed using SAS computer software (SAS Institute Inc, Cary, North Carolina). RESULTS A total of 5832 patients underwent thyroidectomy from 2011 to 2013 (inclusive). There were 4300 female (73.73%) and 1532 male (26.27%) patients. The ages ranged from 10 to 90 years. The age distribution is listed in Table 1. Of 5832 total patients, 1265 patients (22%) had both preoperative FNA diagnosis by the Bethesda Criteria and FS examination at time of surgery. By FNA, there were 326 patients (24.2%) with a diagnosis of SFM and 821 patients (64.9%) with a diagnosis of malignancy. The remaining patients had a diagnosis of either nondiagnostic/unsatisfactory (n ¼ 56; 4.4%), benign (n ¼ 30; 2.4%), AUS/FLUS (n ¼ 36; 2.8%), or FN/SFN (n ¼ 16; 1.3%; Table 2). In the SFM category, the final pathology was malignant in 287 of 306 patients (93.8%). In the malignant category, the final pathology was malignant in 816 of 821 patients (99.4%). Of the FNA cases with a diagnosis of SFM, 32 (10.5%) had benign or indeterminate FS results, 14 (4.6%) were read as suspicious, and 260 (84.9%) were read as malignant (Figure 1). Final pathology showed 56.3% (18 of 32), 64.3% (9 of 14), and 100% (260 of 260) malignancy rates, respectively (P ¼.02 by Fisher exact test; Figure 2). For the malignant FNA group, 82 (10.0%) had benign or indeterminate FS results, 36 (4.4%) were read as suspicious, and 703 (85.6%) were read as malignant (Figure 1). The final pathology showed 96.4% (79 of 82), 97.2% (35 of 36), and 99.9% (702 of 703) malignancy rates, respectively (P ¼.10 by Fisher exact test; Figure 3). Additionally, clinicopathologic features, including age and thyroid nodule size, were examined for all patients who underwent FS analysis (Table 3). Patients with falsenegative FS results (n ¼ 186) had an average nodule size Arch Pathol Lab Med Vol 141, May 2017 FNA Versus Frozen Section in Thyroid Nodules Ye et al 685

3 Figure 1. Distribution of frozen section (FS) cases by fine-needle aspiration (FNA) category of either suspicious for malignancy (SFM) or malignant. of cm, whereas patients with true-positive FS results (n ¼ 2617) had an average nodule size of cm (P ¼.001). Patients with false-negative FS results had an average age of years, whereas patients with true-positive FS results had an average age of years (P ¼.06). DISCUSSION In the United States, thyroid carcinoma comprises about 1% of all cancers, accounting for 0.2% of cancer deaths. 10,11 During the past 30 years, the overall incidence of thyroid carcinoma has increased 3-fold. 12 In women, the ageadjusted incidence has seen the most rapid increase among malignancies, with an increase of 4.3% per year from 1992 through Thyroid carcinoma in China has shown similar increases, with a rise of 49.5% from 2005 to The increased incidence in thyroid carcinoma is thought to be at least partially attributed to increased detection of thyroid nodules secondary to widespread use of neck ultrasonography and other imaging modalities. 15 Although the incidence of thyroid carcinoma is on the rise, most thyroid carcinomas are indolent and demonstrate excellent prognosis (survival rates of.95% at 25 years). 3 Figure 2. Suspicious for malignancy (SFM) fine-needle aspiration (FNA) category: comparison of distribution of frozen section (FS) cases (left) with final malignancy rate (right). 686 Arch Pathol Lab Med Vol 141, May 2017 FNA Versus Frozen Section in Thyroid Nodules Ye et al

4 Figure 3. Malignant fine-needle aspiration (FNA) category: comparison of distribution of frozen section (FS) cases (left) with final malignancy rate (right). Fine-needle aspiration is considered the most reliable, cost-effective, and minimally invasive test for the diagnosis of malignant thyroid nodules. Reasonable indications for FNA include family history of thyroid carcinoma, history of exposure to previous head/neck irradiation, thyroid nodule size (.1 cm), increasing nodule size on clinical follow-up, and thyroid nodule ultrasound characteristics, including microcalcifications and increased central vascularity. 16 Fineneedle aspiration has previously been shown to have both excellent sensitivity and specificity 4 ; however, pitfalls to FNA include variable specimen adequacy, sampling techniques, experience of the pathologist, and overlapping cytologic features between benign and malignant follicular neoplasms. 17 Use of preoperative FNA has been shown to improve surgical outcomes in patients with thyroid cancer, especially among patients with a preoperative diagnosis of malignancy. 18 Surgical management is straightforward with a preoperative FNA diagnosis of malignancy, where total or near total thyroidectomy is indicated. Performing FS in the setting of FNA-proven malignancy has been shown to have little added benefit in clinical management of patients with thyroid nodules in smaller studies Our study benefits from a large sample size of patients with both preoperative FNA diagnosis and FS examination at time of surgery. In our study, we demonstrate that with an FNA diagnosis of malignancy, there is a 99.4% rate of malignancy, similar to rates seen previously. 5 When FS is performed on cases with FNA diagnosis of malignancy, 10% of cases are read as benign on FS, which may potentially lead to clinical mismanagement (ie, performing lobectomy when total thyroidectomy is actually warranted). Reasons for false-negative FS may include sampling error, especially for small nodules (Figure 4). Indeed, further analysis showed there was a statistically significant difference in size between false-negative and true-positive FS, with smaller nodules being associated with falsely negative FS. This particular finding raises the issue of inappropriate sampling at time of FS, because the sampling of subcentimeter lesions may exhaust tissue and adversely affect the pathologist s ability to render a complete and accurate diagnosis on formalin-fixed, paraffin-embedded tissue. Another issue that is raised with FS sampling is the pathologist s ability to render the diagnosis of noninvasive follicular thyroid neoplasm with papillary-like features. The category of noninvasive follicular thyroid neoplasm with papillary-like features, although nonexistent at the time of this series, requires the complete assessment of the lesion in question, thereby suggesting that intraoperative consultation may be detrimental in these instances. Another possibility for false-negative FS is that no touch imprint was performed at the time of FS, thereby limiting the pathologist s interpretation at the time of FS. Overall, our study further validates the recommendation that FS is not helpful with a preoperative FNA diagnosis of malignancy. We also suggest that FS may be harmful to patients because of the potential risk of undertreating patients in the event of a benign FS diagnosis, and for adversely affecting tissue available for a final diagnosis after formalin fixation. In contrast to the FNA diagnosis of malignancy, the clinical management of patients with an FNA diagnosis of SFM is less well-defined. Because the diagnosis of SFM entails a high risk of malignancy, with recent reports citing a Table 3. Clinicopathologic Features in Patients With False-Negative and True-Positive Frozen Sections Clinicopathologic Features False-Negative Frozen Section (n ¼ 186) True-Positive Frozen Section (n ¼ 2617) P Value Age, y Size, cm ,.001 Arch Pathol Lab Med Vol 141, May 2017 FNA Versus Frozen Section in Thyroid Nodules Ye et al 687

5 Figure 4. a, Fine-needle aspiration (FNA) of thyroid nodule with a diagnosis of category 6, papillary thyroid carcinoma. b, Frozen section of the same patient during thyroidectomy. c, Final pathology of the thyroid nodule (Papanicolaou stain, original magnification 3400 [a]; hematoxylin-eosin, original magnifications 340 [b] and 3400 [c]). positive predictive value ranging from 72% to 90%, surgical management by either lobectomy or total thyroidectomy is recommended. In the United States, many institutions proceed with lobectomy with intraoperative evaluation to confirm the diagnosis of papillary carcinoma. Once confirmed, the surgeon may proceed with a concurrent completion thyroidectomy. However, the clinical utility of FS with a preoperative FNA diagnosis of SFM is not consistent. Previous studies have reported no clinical usefulness of FS with previous FNA biopsies showing SFM. 26 Additionally, some institutions perform thyroid procedures based on prognostic factors and intraoperative findings regardless of previous FNA results. 20 The diagnosis of SFM is a relatively infrequent diagnosis among the 6 Bethesda categories (,5% of total FNA cases). 27 Interestingly, our study shows that the diagnosis of SFM accounts for a rather large percentage of FNAs (24.4% of total cases with both FNA and FS diagnosis), thereby providing another unique glimpse into the utility of FS with a previous FNA diagnosis of SFM. The reason for relatively high SFM diagnosis might be due to the fact that the cytologist at the institution where this study was conducted has been more cautious in making a definitive malignant diagnosis. Our findings demonstrate that FS may be helpful in confirming the diagnosis of malignancy, because 100% of SFM cases with malignant FS findings were malignant on final histopathologic exam. However, when FS was read as benign, more than half of cases (56.3%) were malignant on the final pathology. This suggests that FS cannot be used to exclude the diagnosis of malignancy. When comparing FNA alone versus FS alone, our findings also demonstrate that the diagnosis of SFM by FNA is more likely to be malignant than FS read as suspicious (P ¼.02 by Fisher exact test). The malignancy rates for malignant FNA and malignant FS were not statistically significant (P ¼.10 by Fisher exact test). Our institutional experience therefore suggests that an FNA with the diagnosis of SFM may be more informative for the surgeon in terms of management. Although our study benefits from a large sample size, there are several limiting factors to our investigation. The study is not prospective or randomized into FNA and FS cohorts; therefore, we are unable to fully comment on the superiority of one modality over the other. Additionally, our FNA results showed high malignancy rates across all Bethesda categories, including that of SFM (93.8% risk for malignancy), which are higher than most institutions. CONCLUSIONS In conclusion, we demonstrate that an FNA diagnosis of malignant corresponds to a diagnosis of malignancy on final pathology in more than 96% of cases regardless of FS diagnosis. Frozen section should not be performed with a previous FNA diagnosis of malignancy because as many as 10% of cases may be read as benign during the time of FS. With an FNA diagnosis of SFM, FS may be helpful to confirm the diagnosis of malignancy. However, a benign FS does not entirely exclude the possibility of malignancy, because more than half of benign FSs show malignancy on final pathologic exam. 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