Diagnostic Approach for Evaluation of Lymph Node Metastasis From Thyroid Cancer Using Ultrasound and Fine-Needle Aspiration Biopsy

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1 Neuroradiology/Head and Neck Imaging Original Research Sohn et al. Ultrasound and FNAB of Lymph Node Metastasis Neuroradiology/Head and Neck Imaging Original Research FOCUS ON: Yu-Mee Sohn 1,2 Jin Young Kwak 1 Eun-Kyung Kim 1 Hee Jung Moon 1 Soo Jin Kim 1 Min Jung Kim 1 Sohn YM, Kwak JY, Kim EK, Moon HJ, Kim SJ, Kim MJ Keywords: fine-needle aspiration biopsy, lymph node metastasis, ultrasound DOI: /AJR Received June 3, 2009; accepted after revision July 2, Department of Radiology, Research Institute of Radiological Science, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul , South Korea. Address correspondence to J. Y. Kwak (docjin@yuhs.ac). 2 Department of Radiology, Kyung Hee University Medical Center, Seoul, South Korea. AJR 2010; 194: X/10/ American Roentgen Ray Society Diagnostic Approach for Evaluation of Lymph Node Metastasis From Thyroid Cancer Using Ultrasound and Fine-Needle Aspiration Biopsy OBJECTIVE. The purpose of our study was to investigate ultrasound criteria to determine the most accurate criterion to differentiate metastatic from benign lymph nodes on ultrasound and to evaluate the frequency of metastasis according to the cytology results. MATERIALS AND METHODS. One hundred eighteen consecutive patients with thyroid malignancy underwent fine-needle biopsy of suspicious lymph nodes. We investigated the diagnostic performance of each ultrasound feature (loss of fatty hilum, presence of cystic change or calcification, hyperechogenicity, and round shape) and ultrasound criteria 1 and 2. We considered criterion 1 to be if one of the aforementioned malignant ultrasound findings was present and criterion 2 to be if one of the aforementioned malignant ultrasound findings, excluding the loss of fatty hilum, was present. Cytology results were divided into metastasis, macrophages without malignant cells, cell paucity, and negative for malignancy, and we evaluated the frequency of metastasis. RESULTS. There were 91 metastatic and 27 benign nodes. The area under the receiver operating characteristic curve value of criterion 2 was significantly higher than that of criterion 1. The frequency of metastasis was highest with a cytologic result of metastasis (95.8%), followed by macrophages without malignant cells (87.5%), cell paucity (71.4%), and negative for malignancy (34.4%). CONCLUSION. The most accurate ultrasound criterion to differentiate metastatic from benign lymph nodes was ultrasound criterion 2 (any suspicious ultrasound features except for loss of fatty hilum), and we should not neglect lymph nodes with suspicious ultrasound features, even if they do not contain malignant cells on cytology. T hyroid cancer often metastasizes to cervical lymph nodes, and early detection of metastasis is important for planning surgery and management of patients [1]. Ultrasound is the imaging method of choice for detecting and characterizing cervical lymph nodes in thyroid cancer and providing guidance for fineneedle aspiration biopsy (FNAB) [1]. Ultrasound and ultrasound-guided FNAB are the main diagnostic tools for detecting cervical metastasis of thyroid cancer by preoperative cytologic analysis and recurrence after thyroid surgery [2 5]. Numerous previous reports have described the ultrasound characteristics of metastatic lymph nodes of papillary thyroid cancer, such as the presence of calcification [1, 3, 5 10], cystic change [1, 3, 5 12], loss of an echogenic fatty hilum [3, 5 10, 13 15], hyperechogenicity [3, 6, 8 10], round shape [3, 5 10, 13, 14], and abnormal vascu- larity on color Doppler images [3, 6, 8, 9, 14]. Recent studies have shown excellent diagnostic performance using a combination of various ultrasound characteristics [3, 7 10]. However, loss of fatty hilum as a diagnostic ultrasound criterion of metastatic lymph nodes has been the subject of debate [16 19]. The cytology results of metastatic thyroid cancer in cervical lymph nodes displayed a higher frequency of foamy macrophages (38.5%) and cystic degeneration (44.7%), even though no malignant cells were found on cytology [20]. However, to the best of our knowledge, the frequency of metastasis according to each cytology result of lymph nodes has not been reported. Therefore, in this study we investigated the most accurate criteria to differentiate metastatic from benign lymph nodes on ultrasound and evaluated the frequency of metastasis according to the cytology results. 38 AJR:194, January 2010

2 Ultrasound and FNAB of Lymph Node Metastasis TABLE 1: Aspirated Lymph Nodes in 118 Patients Levels of Aspirated Lymph Nodes Materials and Methods Patients The institutional review board approved this retrospective observational study and required neither patient approval nor patient informed consent for the review of images and records. Informed consent was obtained from all patients before FNAB. From January 2003 to December 2005, 135 consecutive patients at our institution underwent FNAB due to suspicious metastatic cervical lymph nodes of papillary thyroid carcinoma. During the study period, we considered a lymph node to be suspicious when it had one of following features: loss of fatty hilum, cystic change, calcification, hyperechogenicity (higher echogenicity than the surrounding muscles), and round shape (long to transverse diameter ratio < 1.5). Doppler ultrasound was not routinely performed. Eight lymph nodes in eight patients were excluded because there was no subsequent surgical excision or longterm imaging follow-up for at least 2 years. Nine patients also were excluded because ultrasound examinations were unavailable. Ultimately, 118 lymph nodes in 118 patients were included in this analysis. Forty-eight patients had already undergone surgery for thyroid papillary carcinoma, and the remaining 70 had no prior surgery for cytologically confirmed papillary carcinoma (Table 1). Imaging and Image Analyses Ultrasound evaluation of cervical lymph nodes was undertaken using a 7-15 MHz linear-array transducer (HDI 5000, Philips Healthcare) and 8-15 MHz linear-array transducer (Acuson Sequoia, Siemens Healthcare). Compound imaging was performed in all cases using the HDI 5000 machine, and lymph node sizes were measured along the longest diameter on transverse scans. Two radiologists with 2 and 8 years of experience with thyroid imaging retrospectively reviewed the thyroid ultrasound examinations in consensus. They had no knowledge of the clinical history or cytopathologic results of the patients while performing the consensus reading. Suspicious ultrasound features of lymph nodes were the following: loss of fatty hilum, cystic change, No. of Patients Initial Surgery (n = 70) Postsurgery (n = 48) I 1 II 4 8 III IV V 7 4 VI 2 calcification, hyperechogenicity (higher echogenicity than the surrounding muscles), and round shape (long to transverse diameter ratio < 1.5) (Figs. 1 3). The ultrasound results were grouped as positive (suspicious) and negative (benign), and lymph nodes were considered positive if one of the malignant sonographic findings was present on ultrasound (criterion 1) [1, 3, 5 10]. Lymph nodes were also considered positive if one of the malignant sonographic findings was present, excluding loss of fatty hilum (criterion 2), on ultrasound [16 19]. Preoperative Evaluation of Lymph Nodes At our institution, we performed ultrasoundguided FNAB on lymph nodes with suspicious ultrasound features. However, we did not perform ultrasound-guided FNAB on central lymph nodes with suspicious ultrasound features in patients who were scheduled for thyroidectomy because routine central lymph node dissections were performed at the time of thyroidectomy. Lymph nodes were considered suspicious during the study period when one of the suspicious ultrasound findings (loss of fatty hilum, calcifications, cystic change, hyperechogenicity, and round shape) was present. Ultrasound-guided FNAB was performed by one of three radiologists who had 4, 6, and 10 years of experience with thyroid imaging. They Fig year-old woman with level IV metastatic lymph node in left neck. Ultrasound image shows loss of fatty hilum, microcalcification, and hyperechogenicity in lymph node (arrows). Cytology results confirmed lymph node metastasis. were aware of the patients clinical histories. Ultrasound-guided FNAB was performed with a 23-gauge needle attached to a 20-mL disposable plastic syringe and aspirator. Materials obtained from FNAB were smeared on glass slides. All smears were placed in 95% alcohol for Papanicolau staining, and the remaining material was rinsed in saline to be processed as a cell block. The cytopathologist was not on site during the biopsy. Cytopathologic Evaluation One of five cytopathologists interpreted the ultrasound-guided FNAB according to their schedules. They were blinded with respect to the ultrasound diagnosis. At our institution, cytology results were divided into one of the following four categories: metastasis, macrophages without malignant cells, cell paucity, and negative for malignancy. Metastasis was defined as positive for metastatic thyroid carcinoma [3], macrophages without malignant cells were reported when cytology showed foamy macrophages with no malignant cells [20], cell paucity was assigned in cases with insufficient material [3], and negative for malignancy included reactive lymph nodes or other benign lymphadenitis [3]. We used the initial cytologic report for the cytopathologic evaluations. Surgical Protocol and Histopathologic Analyses When cytology results revealed malignant cells in lymph nodes, unilateral modified neck dissection was performed as the initial thyroid surgery. However, selective frozen sectioning was performed as the initial thyroid surgery in patients with lymph nodes with suspicious ultrasound features but no definite malignant cells on cytology. Selective dissection was performed in patients who had already undergone thyroid surgery. We evaluated the final results of aspirated lymph nodes in level-by-level analyses and compared them to pathology reports. AJR:194, January

3 Sohn et al. Fig year-old woman with level IV metastatic lymph nodes in right neck. Ultrasound image shows microcalcification (arrow), loss of fatty hilum, and round shape in lymph nodes (arrowheads). Cytology results confirmed lymph node metastasis. Statistical Analyses A reference standard was set by pathology results from lymph node dissections or long-term imaging follow-up for at least 2 years with no subsequent surgical excision. Categorical data were summarized using frequencies and percentages. The Student s t test was used to determine differences between metastatic and benign lymph nodes according to age and lymph node size on ultrasound. The chi-square test was performed to evaluate the differences between benign and malignant groups by sex. Diagnostic performance, including sensitivity, specificity, accuracy, positive predictive value (), and negative predictive value (NPV), was calculated according to the ultrasound findings. We also examined diagnostic performance by ultrasound grouping (criteria 1 and 2). The chisquare test or Fisher s exact test was used to compare each ultrasound finding to standard results. Receiver operating characteristic (ROC) curve analysis was performed to compare the two ultrasound criteria to differentiate metastatic from benign lymph nodes. We evaluated the frequency of metastasis according to cytology results. Statistical significance was assumed when the p value was less than Results This study included 23 men and 95 women with a mean age of 51 ± 13.4 years. The mean size of lymph nodes was 13.8 ± 8.5 mm. Pathologic confirmations were obtained from 115 patients. There were 91 malignant and 24 benign results on pathology. Three patients who did not undergo surgery had nodes that decreased in size during the long-term imaging follow-up duration of at least 2 years. Therefore, this study consisted of 91 malignant and 27 benign lymph nodes. There was no significant difference between metastatic and benign lymph nodes according to TABLE 2: Diagnostic Accuracy of Each Ultrasound Feature Ultrasound Feature TP TN FP FN Fig year-old woman with level II metastatic lymph nodes in left neck. Ultrasound image shows loss of fatty hilum and cystic change. Cytology results confirmed macrophages without malignant cells. age (p = 0.765) and sex (p = 0.071). The mean longest diameter of metastatic lymph nodes (14.5 mm ± 9 mm) was significantly larger than that of benign nodes (11.4 mm ± 5.8 mm) (p = 0.042). The diagnostic performance of each ultrasound finding in this study is shown in Table 2. Ultrasound criteria 1 and 2 as well as each suspicious ultrasound feature had statistical significance with metastasis. Most ultrasound features had high specificity and but low sensitivity and NPV. However, loss of fatty hilum had the highest sensitivity and NPV but showed lower specificity than other ultrasound features. When each ultrasound feature and ultrasound criteria 1 and 2 were compared, criterion 2 had the highest accuracy. The area under the ROC curve value (0.83; 95% CI, ] of criterion 2 was significantly higher than that (0.704; 95% CI, ) of criterion 1 (p = 0.006) (Fig. 4). Accuracy NPV Loss of fatty hilum (91/91) 48 (13/27) 88 (104/118) 87 (91/105) 100 (13/13) Cystic change (31/91) 96 (26/27) 48 (57/118) 97 (31/32) 30 (26/86) Presence of calcification (41/91) 93 (25/27) 56 (66/118) 95 (41/43) 33 (25/75) Hyperechogenicity (54/91) 85 (23/27) 65 (77/118) 93 (54/58) 38 (23/60) Round shape (50/91) 89 (24/27) 63 (74/118) 94 (50/58) 37 (24/65) Any suspicious ultrasound feature (criterion 1) (91/91) 41 (11/27) 86 (102/118) 85 (91/107) 100 (11/11) Any suspicious ultrasound feature, excluding loss of fatty hilum (criterion 2) (87/91) 70 (19/27) 89 (106/118) 92 (87/95) 83 (19/23) Note Data in parentheses are number of cases. TP = true-positive, TN = true-negative, FP = false-positive, FN = false-negative, = positive predictive value, NPV = negative predictive value. 40 AJR:194, January 2010

4 Ultrasound and FNAB of Lymph Node Metastasis The frequency of metastasis was highest with a cytology reading of metastasis (68/71, 95.8%), followed by macrophages without malignant cells (7/8, 87.5%), cell paucity (5/7, 71.4%), and negative for malignancy (11/32, 34.4%). Discussion Ultrasound characteristics of metastatic lymph nodes of thyroid cancer have been reported by several investigators [1, 5, 6, 11]. Major ultrasound characteristics suggesting metastasis of thyroid cancer included the presence of calcification [1, 3, 5 10], cystic change [1, 3, 5 12], loss of echogenic fatty hilum [3, 5 10, 13 15], hyperechogenicity [3, 6, 8 10], round shape [3, 5 10, 13, 14], and abnormal vascularity [3, 6, 8, 9, 14]. The results of previous studies [5, 7 11] that examined diagnostic performance of each ultrasound characteristic are shown in Table 3. The frequency of metastasis was % in lymph nodes with absent hilum [5, 7 10], % in those with round shapes [7 10], % in those with hyperechogenicity [8 10], % in those with calcification [5, 7 11], % in those with cystic change [5, 7, 9 11], and % in those with abnormal vascularity [8, 9]. Of these ultrasound characteristics, several studies have shown that calcification and cystic change have 100% specificity and [10, 11] and that they are not observed in normal or reactive lymph nodes [10]. Calcifications in metastatic lymph nodes are shown in punctate microcalcifications on ultrasound, and these calcifications are laminated, calcified, spherical bodies on cytology that are called psammoma bodies [21]. Psammoma bodies were reported to be formed by calcification of intravascular tumor thrombi or infarcted tips of malignant papillae, and their presence is considered to be diagnostic of malignancy [22]. Some investigators have reported that cystic degeneration of lymph nodes was highly suggestive of metastasis in Fig. 4 Graph shows receiver operating characteristic curve of two ultrasound criteria to differentiate metastatic from benign lymph nodes. Area under ROC curve value (0.83) of criterion 2 (dashed line) was significantly higher than that of criterion 1 (0.704) (solid line). thyroid cancer [1, 11, 23] and squamous cell carcinoma of the head and neck [23]. Thyroid papillary carcinoma most commonly showed cystic formation in lymph node metastasis, and the incidence of cystic change of lymph nodes in thyroid cancer was reported in 10 25% of cases [23]. This cystic change is the result of liquefaction necrosis [12] or spontaneous or postradiotherapeutic central breakdown of keratin, which gives the node a pseudocystic appearance [24]. Cystic changes are shown on ultrasound as small solitary cystic areas, multiple peripheral cystic areas, or almost complete replacement of the node by cystic formation [11]. Another study [12] reported that pure cystic change was mostly found in young adults. These ultrasound findings were explained by the increased aggressiveness of tumors at a young age, which caused extensive necrosis [24]. In the current study, cystic change also had high specificity and as diagnostic ultrasound features. Several investigators revealed good results on preoperative staging when the criterion involving one suspicious finding was present on ultrasound [9, 17, 25, 26]. In this study, we evaluated diagnostic performance in the diagnosis of metastasis with combined ultrasound criteria (1 and 2) as well as suspicious ultrasound findings, such as loss of fatty hilum, calcification, cystic change, hyperechogenicity, and round shape. Most ultrasound features had high specificity and but low sensitivity and NPV. However, loss of fatty hilum had the highest sensitivity and NPV but lower specificity than other ultrasound features. This result is consistent with previous reports [16 19] that loss of fatty hilum is not a definite criterion for differentiation between malignant and benign lymph nodes. When each ultrasound feature and ultrasound criteria 1 and 2 were compared, criterion 2 had the highest accuracy, with a significantly higher area under the curve value than criterion 1. The results correspond to those of previous studies that loss of fatty hilum is not a specific ultrasound feature for malignancy [16 19]. Until now, malignant cells on cytology have been considered suggestive of metastasis, prompting surgical management. However, the frequency of metastasis has been reported rarely on other cytologic results of suspicious lymph nodes on ultrasound, to the best of our knowledge. Cytology results of metastatic thyroid cancer in cervical lymph nodes displayed a higher frequency of foamy macrophages (38.5%), even if no malignant cells were found on cytology [20, 23]. In this study, we categorized cytologic results as metastasis, presence of macrophages without malignant cells, cell paucity, and negative for malignancy. The inclusion of macrophages in this criterion was supported by a previous report [20]. The frequency of metastasis was the highest in lymph nodes with suspicious ultrasound features having malignant cells (95.8%), followed by macrophages without malignant cells (87.5%), cell paucity (71.4%), and negative for malignancy (34.4%). When metastatic lymph nodes were diagnosed on cytology, functional compartment en bloc dissection was preferred over selective dissection ( berry picking ) because of improved mortality [27 30]. However, we cannot neglect a lymph node with a suspicious ultrasound feature, even when it does not have malignant cells on cytology. A recent study [31] reported an effective method of preoperative ultrasound-guided tattooing using charcoal suspension for localizing nonpalpable cervical recurrent lymph nodes after thyroidectomy. This method can be applied to suspicious lymph nodes on ultrasound as a preoperative ultrasound marking for sampling with frozen sectioning and determining further surgical treatment. Therefore, we suggest that frozen sampling with preoperative ultrasound marking should be performed for pathologic confirmation of a lymph node with a suspicious ultrasound feature to prevent undertreatment of patients. In addition to FNAB, several studies [3, 4, 17, 32 34] have reported the detection of thyroglobulin (Tg) in FNAB washout fluid. FNAB-Tg identified metastasis and recurrence of the neck with excellent sensitivity and specificity, especially cystic metastatic lymph nodes, which can show a higher incidence of false-negative findings on cytology than metastatic lymph nodes without cystic change [3, 23, 32, 33]. Moreover, the FNAB- Tg test and the combination of FNAB-Tg and AJR:194, January

5 TABLE 3: Previous Reports of Diagnostic Values According to Ultrasound Criteria to Differentiate Metastatic From Benign Lymph Nodes Short-to-Long Axis Diameter Ratio > 0.5 Abnormal Echogenicity Calcification Cystic Change Absent Hilum Peripheral Vascularity No. of Metastatic Lymph Nodes Total No. of Lymph Nodes Study [Reference No.] Lyshchik et al. [8] NA NA NA Kessler et al. [11] NA NA NA NA NA NA 30 NA NA 70 NA NA NA NA NA NA NA NA Takashima et al. [5] NA NA NA NA NA NA NA NA NA Park et al. [9] Kuna et al. [7] NA NA NA NA NA 5.4 NA NA 21.3 NA NA 99.5 NA NA NA NA NA Rosario et al. [10] NA NA NA This study NA NA NA Note = positive predictive value, NA = not applicable. Sohn et al. FNAB cytology have been shown to be more sensitive and accurate than FNAB cytology alone [3, 32, 34]. However, the current study was a retrospective study, and additional Tg data could not be obtained. The first limitation of the current study is that it is retrospective and included only patients who underwent ultrasound-guided FNAB and thyroid surgery or imaging follow-up for at least 2 years. Therefore, selection bias does exist. Second, the high percentage of included lymph nodes with metastasis with suspicious features on initial ultrasound resulted in incomplete examination of the most accurate criterion to differentiate malignant from benign lymph nodes. This was another form of selection bias. Third, abnormal vascularity of lymph nodes was not included, and inclusion was not possible because of the retrospective design. Fourth, we used the initial cytologic results of the lymph nodes. In the study period, five cytopathologists interpreted the FNAB slides at our institution. This was a limitation of the study because of the possibility of interobserver variability in cytologic interpretations. Fifth, we could not perform a node-by-node analysis of all lymph nodes and instead, a levelby-level analysis was performed. Lastly, the study included a relatively small number of patients. Further prospective study will be necessary to resolve these issues. In conclusion, the most accurate ultrasound criterion to differentiate metastatic from benign lymph nodes was ultrasound criterion 2 (any suspicious ultrasound features except loss of fatty hilum), and we should not neglect lymph nodes with suspicious ultrasound features, even if they do not contain malignant cells on cytology. Acknowledgments The authors are grateful to Kyung Hwa Han, biostatistician, Department of Research Affairs, Yonsei University College of Medicine, Seoul, Korea, for her help with the statistics in this study. References 1. Miseikyte-Kaubriene E, Trakymas M, Ulys A. Cystic lymph node metastasis in papillary thyroid carcinoma. 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