Accepted 11 April 2013 Published online 25 April 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed.23371

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1 ORIGINAL ARTICLE Optimal indication of thyroglobulin measurement in fine-needle aspiration for detecting lateral metastatic lymph nodes in patients with papillary thyroid carcinoma Jin Chung, MD, 1 Eun Kyung Kim, MD, PhD, 2 Hyunsun Lim, PhD, 3 Eun Ju Son, MD, PhD, 2 Jung Hyun Yoon, MD, 4 Ji Hyun Youk, MD, PhD, 2 Jeong-Ah Kim, MD, PhD, 2 Hee Jung Moon, MD, PhD, 2 Jin Young Kwak, MD, PhD 2* 1 Department of Radiology, Ewha Womans University, School of Medicine, Seoul, Korea, 2 Department of Radiology, Research Institute of Radiological Science, Yonsei University, College of Medicine, Seoul, Korea, 3 Department of Biostatistics Collaboration Unit, Gangnam Severance Hospital, Biomedical Research Center, Yonsei University, College of Medicine, Seoul, Korea, 4 Department of Radiology, CHA Bundang Medical Center, CHA University, College of Medicine, Sungnam, Korea. Accepted 11 April 2013 Published online 25 April 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. The purpose of this study was to evaluate optimal indication of thyroglobulin (Tg) measurement in fine-needle aspiration (FNA) for detecting lateral metastatic lymph nodes in patients with papillary thyroid carcinoma (PTC). Methods. We performed a retrospective study of 241 lymph nodes of 220 patients who underwent ultrasound-guided FNA with Tg in FNA (FNA-Tg) washout fluid measurements for suspicious lymph nodes. Results. On multivariate analysis, hyperechogenicity, cystic change, presence of calcifications, and peripheral vascularity were independent factors predictive of lymph node metastasis. After adding FNA-Tg, sensitivity and accuracy were significantly increased when the lymph node had 1 or 2 suspicious ultrasound features. However, sensitivity and accuracy were not significantly increased when the lymph node had multiple suspicious ultrasound features. Conclusion. Additional FNA-Tg can help diagnose a metastatic lymph node with 1 or 2 suspicious ultrasound features. However, additional FNA-Tg is not beneficial in lymph nodes with highly suspicious ultrasound features, in which FNA alone is sufficient for diagnosis of predictive of lymph node. VC 2013 Wiley Periodicals, Inc. Head Neck 36: , 2014 KEY WORDS: papillary thyroid carcinoma, lymph node metastasis, thyroglobulin, ultrasound, fine-needle aspiration INTRODUCTION Papillary thyroid carcinoma (PTC) accounts for 80% of all differentiated thyroid cancer and the prognosis of PTC is usually favorable. 1,2 The frequency of lateral lymph node metastasis in PTC is reported to be 4.1% to 42.6% depending on the study, with central lymph node metastasis presenting in 23% to 62.2% of patients with PTC Although mortality related to lymph node metastasis still remains controversial, previous studies have reported that extrathyroidal invasion of PTC and lymph node metastasis are independent risk factors of tumor recurrence According to the American Thyroid Association guidelines, therapeutic central and lateral compartment node dissection are recommended with fair evidence. 17,18 Although prophylactic central compartment node dissection has been performed by experienced surgeons in some institutions with low morbidity, it can result in recurrent laryngeal nerve injury and transient hypoparathyroidism by less experienced hands. 9,19,20 In comparison, the more extensive dissection required for lateral lymph node metastasis is associated with longer operation time, a wide *Corresponding author: J. Y. Kwak, Department of Radiology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemoon-gu, Seoul , South Korea. docjin@yuhs.ac incision, a higher potential for nerve injury, hemorrhage, and chyle leakage. 9,19 22 Preoperative ultrasound is the diagnostic method recommended by the American Thyroid Association guidelines for evaluation of primary thyroid cancer and lymph node status. 17 When metastatic lymph nodes are suspected on preoperative ultrasound, ultrasound-guided fine-needle aspiration (FNA) is beneficial to the surgeon s planning of thyroid surgery. The additional detection of thyroglobulin in FNA (FNA-Tg) washout fluid can help identify PTC metastases of the neck with higher sensitivity and accuracy than FNA alone However, it is unclear whether FNA-Tg measurements should be routinely accompanied by ultrasound-guided FNA for the diagnosis of lymph node metastasis in patients with PTC considering cost-effectiveness. The purpose of this study was to evaluate the optimal indication of thyroglobulin (Tg) measurement in FNA for detecting lateral lymph node metastasis s in patients with PTC. PATIENTS AND METHODS Patients The institutional review board at our institution approved this retrospective study and required neither patient approval nor informed consent for review of images and records. Informed consent was obtained HEAD & NECK DOI /HED JUNE

2 CHUNG ET AL. FIGURE 1. Diagram of study selection and standard reference. The gray box represents final inclusion and standard reference. FNA, fine-needle aspiration; PTC, papillary thyroid carcinoma; Tg, thyroglobulin; LND, lymph node dissection; ftg/stg, FNA-Tg/serum-Tg; RI, radioiodine. from all patients before they underwent ultrasoundguided FNA. From April 2009 to April 2010, 711 ultrasound-guided FNAs for lateral cervical lymph nodes were performed in Severance Hospital. A consecutive series of 616 patients with single or multiple suspicious cervical lymph nodes underwent ultrasound-guided FNA with measurement of Tg levels from the needle washouts (FNA-Tg). Serum Tg levels of all patients were also measured. Patients with primary thyroid cancer with metastasis were only included in this study. Three hundred eighty-nine FNAs were excluded because of underlying malignancies other than PTC. Twenty-seven lymph nodes were excluded because they were recurrent lymph nodes and 54 lymph nodes were excluded because of lack of FNA-Tg measurements. Finally, 241 lateral cervical lymph nodes of 220 patients with PTC were included in this study (Figure 1). Clinicopathologic characteristics of patients, primary tumors, and lymph nodes are summarized in Table 1. This study included 170 women (77.3%) and 50 men (22.7%). Patients ages ranged from 13 to 76 years (mean, 44 years). Aspirated lymph nodes were located at level II (n 5 19), level III (n 5 84), level IV (n 5 131), and level V (n 5 7). Two hundred twenty-two lymph nodes (92.1%) were located ipsilaterally, whereas the remaining 19 (17.9%) were located contralateral to the primary thyroid cancer. Sixty-three patients with 68 lymph nodes had bilateral thyroid cancers. Bilateral neck nodes with bilateral cancers were considered as ipsilateral lymph nodes for each side. Ultrasound and ultrasound-guided fine-needle aspiration Ultrasound examinations and ultrasound-guided FNA were performed by 1 of 7 board-certified radiologists with 1 to 15 years of experience in thyroid imaging, using a 5 to 12 MHz linear probe (iu22, Philips Medical Systems, Bothell, WA) and 6 to 13 MHz linear probe (Hitachi Medical, Tokyo, Japan). When using the iu22 machine, compound imaging was performed in all ultrasound examinations. All radiologists were aware of the patients clinical histories. Ultrasound-guided FNA was performed on lateral cervical lymph nodes with suspicious ultrasound features in our institution. Suspicious ultrasound features of lymph nodes were as follows: irregular margin, a round shape (long/transverse diameter ratio of <1.5), loss of fatty hilum, hyperechogenicity (higher echogenicity than the surrounding muscles), cystic change, calcifications, and peripheral or chaotic vascularity. 6,27 36 If one or more of the above-mentioned suspicious ultrasound features were present, lymph nodes were considered as suspicious. Ultrasound interpretations were prospectively entered into a computer database for clinical use. However, 32 of 241 lymph nodes (13.3%) without a suspicious ultrasound feature described, also had FNA performed in our study, because of suspicious enhancement on CT (n 5 15) and clinical suspicion or the anxiety of patients (n 5 17). Ultrasound-guided FNA was performed using a 23-gauge needle connected to a 2-mL syringe with the free-hand technique. Each lesion was aspirated at least twice. Immediately after the first aspiration, samples were 796 HEAD & NECK DOI /HED JUNE 2014

3 PTC WITH METASTATIC NODES TABLE 1. Association between clinicopathologic characteristics and lateral lymph node metastases. Characteristics Value p value Total patients 220 Total lymph nodes 241 Age Age at diagnosis, y * Groups, <45 y/45 y 111/ Sex Male 50 (22.7%) Female 170 (77.3%) Primary tumor Pathologic size, mm * Multifocality 91 (37.6%) 0.05 Extracapsular invasion 156 (64.5%) 0.04 Lateral lymph node Location 1, right/left 109/ Location 2, levels 2/3/4/5 19/84/131/ Location 3, ipsilateral/contralateral 222/ Number, 1/2 4/more than 5 115/102/ Long size on axial view of ultrasound, mm Short size on axial view of ultrasound, mm *Mean 6 SD. By 2-sample t test. By chi-square test. By Fisher exact test. expelled onto glass slides for cytological examination and smeared. The same needle and syringe were rinsed with 1 ml of normal saline, and the washout was submitted for Tg measurement (FNA-Tg). After smearing the sample from the second aspiration, the remainder of the material was rinsed in saline for processing as a cellblock. All smears were placed immediately in 95% alcohol for Papanicolaou staining. The cytologists were not on site during the aspiration. The interpretation of FNA was made by 1 of 5 cytopathologists, specializing in thyroid cytology. The cytology results were grouped into 2 categories according to the cytology report. FNA results with metastases from thyroid carcinoma and mention of foamy macrophages but without the mention of metastasis were considered positive. 37,38 Negative diagnoses included reactive hyperplasia, nondiagnostic because of insufficient material, and benign diagnoses such as tuberculosis. Thyroglobulin assessment Tg was measured with a monoclonal antibody immunoradiometric assay (CIS Bio International, Gif-sur- Yvette, France). Analytical sensitivity, defined as the smallest detectable concentration different from zero with a probability of 95%, is 0.2 ng/ml. Functional sensitivity, calculated with the imprecision profile for a coefficient of variation equal to 20%, was 0.7 ng/ml. FNA washout samples were not assayed for Tg antibodies because it has been shown that FNA-Tg measurements are unaffected by serum Tg antibodies. 39 Subjects with no anti-tg antibodies were only included in this study. When measured FNA-Tg/serum Tg ratio was >1, we assumed that the lymph node was positive for metastasis from PTC, otherwise, it was negative. 39 Surgical protocol and histopathologic analyses When cytology results revealed malignant cells in lymph nodes, or when the value of FNA-Tg levels were higher than 100 ng/ml in the negative cytology cases, unilateral modified neck dissection was performed as initial thyroid surgery. 39 However, selective frozen section biopsy was performed as the initial thyroid surgery in patients with lymph nodes with suspicious ultrasound findings, but FNA-Tg levels <100 ng/ml or no definite malignant cells on cytology. We evaluated the final results of aspirated lymph nodes in level-by-level analyses, comparing them to pathology reports. Statistical analyses Baseline characteristic data were summarized into frequencies and percentages. The chi-square test or Fisher exact test was used to determine differences between benign and metastatic lymph nodes according to categorical variables. The 2-sample t test was performed to evaluate the differences between benign and metastatic lymph nodes according to continuous variables. Univariate analysis was performed for ultrasound features in predicting lymph node metastasis. Multivariate logistic regression analysis was also performed to assess for independent associations of all factors to lymph node metastasis. The rate of lymph node metastasis was evaluated using total numbers of statistically significant suspicious ultrasound features. The Fisher exact test was used to analyze the association of cystic change in a lymph node with nondiagnostic results in FNA. Diagnostic performances of FNA and FNA-Tg were evaluated with respect to sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy. For comparing the difference of diagnostic performance between FNA alone and FNA-Tg groups, we used the McNemar test (comparison of sensitivity, specificity, and accuracy), and generalized estimating equation (comparison for PPV and NPV). Statistical significance was determined when the p value was <.05. All reported p values are 2-sided. Analysis was performed by SAS software (version 9.2; SAS Institute, Cary, NC). RESULTS There were 116 metastatic (48.1%) and 125 benign (51.9%) lymph nodes at final cytopathology (Figure 1). Results of FNA and standard reference are summarized in Table 2 and Figure 1. One hundred sixteen metastatic and 32 benign lymph nodes were surgically confirmed (61.4%). A standard reference was set by the surgical pathologic results from selective frozen sectioning (n 5 58) and lymph node dissection (n 5 90; Figure 1). The lymph nodes without surgery were considered benign (n 5 93) if FNA-Tg/serum-Tg ratio was <1, with benign results at FNAs (n 5 93). One lymph node was benign at FNA; however, FNA-Tg/serum-Tg ratio was 1.3. This HEAD & NECK DOI /HED JUNE

4 CHUNG ET AL. TABLE 2. Results of ultrasound-guided fine-needle aspiration and standard reference of the 241 lymph nodes. FNA results Standard reference Metastasis (n 5 116) Benign (n 5 125) Rate of metastases, % Metastasis (n 5 92) Foamy macrophage (n 5 1) Nondiagnostic (n 5 16) Benign (n 5 132) Abbreviation: FNA, fine-needle aspiration. lymph node showed no uptake on radioiodine scan with 30 mci and disappeared on 17-month follow-up ultrasound scan. We also considered this lymph node as a benign lymph node. Extracapsular invasion of primary thyroid cancer was significantly associated with lateral lymph node metastasis (p 5.040; Table 1). On univariate analysis, lateral lymph node metastasis was significantly associated with irregular margin, round shape, absence of fatty hilum, hyperechogenicity, cystic change, presence of calcifications, and peripheral vascularity on ultrasound (all ultrasound features p <.001, except irregular margin p and round shape p 5.005; Table 3). On multivariate analysis, hyperechogenicity, cystic change, presence of calcifications, and peripheral vascularity were independent factors predictive of lymph node metastasis (all FIGURE 2. A 64-year-old male patient had a suspicious lymph node in the left neck. Ultrasound revealed a lymph node with 3 suspicious ultrasound features; hyperechogenicity, cystic change (thick arrows), calcifications (thin arrows). Results of fine-needle aspiration (FNA) for this lymph node was metastasis and the level of thyroglobulin (Tg) in FNA washout fluid (FNA-Tg) and serum Tg were 500 ng/ml and 95 ng/ml, respectively. This patient underwent lymph node dissection and the final surgical pathology also revealed metastasis for this lymph node. ultrasound features p <.001, except presence of calcifications (p 5.023; Table 3; Figure 2). The value of FNA-Tg ranged from 0.7 to 500 ng/ml in metastatic lymph nodes (mean, ng/ml) and 0.2 to ng/ml in benign lymph nodes (mean, 6.1 ng/ml). Among the 153 surgically confirmed lymph nodes, the TABLE 3. Association between sonographic findings and lateral lymph node metastases. Univariate analysis Multivariate analysis Metastasis (%) Benign (%) Total number OR (95% CI) p value * OR (95% CI) p value Margin Well 104 (45.8) 123 (54.2) 1 Irregular 12 (85.7) 2 (14.3) ( ) 5.2 ( ) Shape Oval 104 (46.6) 119 (53.4) 1 Round 12 (66.7) 6 (33.3) 3.9 ( ) 1.6 ( ).465 Hilum <0.001 Absence 106 (55.5) 85 (44.5) 4.9 ( ) 2.1 ( ) Presence 10 (20) 40 (80) 1 Echogenicity <0.001 Hyperechogenicity 61 (73.5) 22 (26.5) 5.2 ( ) 4.1 ( ) <0.001 Isoechogenicity or hypoechogenicity 55 (34.8) 103 (65.2) 1 Cystic change <0.001 Yes 37 (82.2) 8 (17.8) 6.9 ( ) 7.6 ( ) <0.001 No 79 (40.3) 117 (59.7) 1 Calcifications <0.001 Presence 38 (79.2) 10 (20.8) 5.7 ( ) 2.9 ( ) Absence 78 (40.4) 115 (59.6) 1 Vascularity <0.001 Peripheral 48 (80) 12 (20) 6.7 ( ) 5.5 ( ) <0.001 Central or no 68 (37.6) 113 (62.4) 1 Abbreviations: OR, odds ratio; CI, confidence interval. *By Chi-square test. By logistic regression analysis. Note: Data are number of nodules. 798 HEAD & NECK DOI /HED JUNE 2014

5 PTC WITH METASTATIC NODES TABLE 4. Diagnostic performances of fine-needle aspiration and fine-needle aspiration with thyroglobulin measurement for predicting lymph node metastases using suspicious sonographic features. Diagnostic performance Total number of suspicious ultrasound features Any suspicious ultrasound features Sensitivity (%) FNA 11/18 (61.1) 27/38 (71.1) 35/39 (89.7) 16/17 (94.1) 4/4 (100) 82/98 (83.7) FNA1Tg 15/18 (83.3) 36/38 (94.7) 39/39 (100) 17/17 (100) 4/4 (100) 96/98 (98.0) p value NA.001 Specificity (%) FNA 81/81 (100) 36/36 (100) 7/7 (100) 1/1 (100) 0/0 (NA) 44/44 (100) FNA1Tg 81/81 (100) 36/36 (100) 7/7 (100) 1/1 (100) 0/0 (NA) 44/44 (100) p value NA NA NA NA NA NA PPV (%) FNA 11/11 (100) 27/27 (100) 35/35 (100) 16/16 (100) 4/4 (100) 82/82 (100) FNA1Tg 15/15 (100) 36/36 (100) 35/35 (100) 17/17 (100) 4/4 (100) 96/96 (100) p value NA NA NA NA NA NA NPV (%) FNA 81/88 (92.1) 36/47 (76.6) 7/11 (63.6) 1/2 (50) 0/0 (NA) 44/60 (73.3) FNA1Tg 81/84 (96.4) 36/38 (94.7) 7/7 (100) 1/1 (100) 0/0 (NA) 44/46 (95.7) p value NA NA NA.002 Accuracy (%) FNA 92/99 (92.9) 63/74 (85.1) 42/26 (91.3) 17/18 (94.4) 4/4 (100) 126/142 (88.7) FNA1Tg 96/99 (97) 72/74 (97.3) 46/46 (100) 18/18 (100) 4/4 (100) 140/142 (98.6) p value NA.001 Rate of metastasis (%) 18/99 (18.2) 38/74 (51.4) 39/46 (84.8) 17/18 (94.4) 4/4 (100) 98/142 (69) Abbreviations: FNA, fine-needle aspiration; FNA1Tg, thyroglobulin levels in FNA; PPV, positive predictive value; NPV, negative predictive value; NA, not applicable. mean FNA-Tg value was measured as ng/ml in metastatic lymph nodes and in benign lymph nodes. There was a significant association between cystic lymph nodes and nondiagnostic results in FNA (p <. 001). In addition, cystic changes of lymph nodes showed a significant association with washout-serum Tg levels (p <. 001; in lymph nodes with cystic change; in lymph nodes without cystic change). FIGURE 3. Ultrasound scan shows a lateral lymph node with a focal cystic change (arrows). This lymph node was nondiagnostic at fineneedle aspiration (FNA). Thyroglobulin (Tg) with FNA washout fluid (FNA-Tg) was measured 500 ng/ml and serum Tg was checked 29 ng/ml. After lymph node dissection, this lymph node finally confirmed as metastasis. The rate of metastasis was calculated according to the number of suspicious ultrasound features in Table 4. The rate of metastasis was exponentially increased with the number of suspicious ultrasound features (Table 4). The sensitivity, specificity, PPV, NPV, and accuracy, according to the number of suspicious ultrasound features, are summarized in Table 4. Diagnostic performances of FNA and FNA-Tg were also compared (Table 4). After adding FNA-Tg, sensitivity and accuracy were significantly increased when the lymph node had 1 or 2 suspicious ultrasound features (Figures 2 and 3). Regardless of total numbers of suspicious ultrasound features, specificity and PPV were not increased with additional FNA-Tg (Table 4). After adding FNA-Tg, NPV was increased when the lymph node had 1, 2, or 3 suspicious ultrasound features. However, sensitivity and accuracy were not significantly increased when the lymph node had 3 or more suspicious ultrasound features. DISCUSSION Preoperative lymph node evaluation for patients with PTC is essential for planning the extent of surgery. Preoperative ultrasound and ultrasound-guided FNA are widely used and are the most popular diagnostic methods for evaluation of primary thyroid lesions and nodal status. Numerous studies have reported the various ultrasound features of metastatic lymph nodes of PTC, such as irregular margin, round shape, loss of fatty hilum, hyperechogenicity, cystic change, presence of calcifications, and abnormal vascularity. 6,27 36 However, some investigators have reported that loss of fatty hilum was not a significant finding in predicting lymph node metastasis. 28,40 HEAD & NECK DOI /HED JUNE

6 CHUNG ET AL. Like the previous studies, the multivariate analysis of this study showed that the loss of fatty hilum was not an independent factor for predicting lymph node metastasis. In our study, hyperechogenicity, cystic change, presence of calcifications, and abnormal vascularity were independent ultrasound features associated with lymph node metastasis. We investigated the rate of metastasis according to the number of suspicious ultrasound features, and results showed exponential increase according to the increased number of suspicious features. When 4 of the suspicious ultrasound features mentioned above were present, the rate of metastasis was 100%. FNA is a useful and easy method in the diagnosis of lymph node metastasis at suspicious lymph nodes on ultrasound in patients with PTC. However, FNA has diagnostic limitations, and 5% to 10% of samples are nondiagnostic with 6% to 8% of false-negative results. 23,41 In our study, 6.6% of the samples were nondiagnostic, and 5.8% showed false-negative results. Among them, 56.3% of the nondiagnostic and 10.6% of the benign lymph nodes were finally proved metastatic (Table 2). Similar to previous studies, all lymph nodes with metastasis or foamy macrophages on FNA were surgically proved metastases in our study (Table 2). 28,38 Cystic appearance of lymph nodes is a characteristic of metastatic PTC. 25,28,29,35,36 However, frequent nondiagnostic cytologic results and high false-negative rates for FNA are reported in cystic metastatic lymph nodes. 25,35,36 Our study also showed that cystic lymph nodes were significantly related with nondiagnostic FNA results (p <.001). Additional Tg measurement in FNA is useful, especially for cystic lymph nodes. 25,35,36 In our study, 16 of 241 lymph nodes (6.6%) showed nondiagnostic FNA results and, among them, 9 lymph nodes had cystic change. These 9 lymph nodes were finally proven to be 5 metastatic and 4 benign lymph nodes. Additional Tg measurement in FNA was useful for all of these cystic lymph nodes with nondiagnostic cytologic results. To overcome the limitations of FNA, such as nondiagnostic or false-negative results, numerous studies reported that adding FNA-Tg to FNA increased the sensitivity and accuracy in detecting lymph node metastasis in patients with PTC However, applying FNA-Tg measurement in all aspirated lymph nodes is an unverified method when considering cost-effectiveness. Therefore, we tried to find the optimal indications for FNA-Tg measurement in detecting metastatic lymph nodes in patients with PTC. When we evaluated the diagnostic performances of FNA and combination of FNA with FNA-Tg according to the total number of suspicious ultrasound features, our results demonstrated that if lymph nodes have 3 or more suspicious ultrasound features, adding FNA-Tg had no benefit in the diagnosis of lymph node metastasis. However, adding FNA-Tg showed significantly increased sensitivity, NPV, and accuracy in lymph nodes showing 1 or 2 suspicious ultrasound features. Considering the higher malignancy rate as well as the higher diagnostic performance of FNA at a lymph node with 3 or more suspicious ultrasound features, additional FNA-Tg measurements may be beneficial to lymph nodes with small numbers of suspicious ultrasound features. There are several limitations in our study. First, 7 radiologists with various experiences in thyroid imaging were enrolled in ultrasound evaluation, and interobserver variability regarding the multiple suspicious ultrasound features was not considered. 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