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1 Real-time ultrasonography-guided fine needle non aspiration cytology of occult cervical lymphadenopathy in patients with thyroid malignancy without recurrent or residual thyroid cancer: accuracy and impact on clinical decision making Poster No.: C-1672 Congress: ECR 2013 Type: Scientific Exhibit Authors: M. G. Gkeli, M. Milatou, K. Kavvadias ; Athens/GR, SERRES/ GR Keywords: Metastases, Endocrine disorders, Cancer, Sampling, Efficacy studies, Biopsy, Ultrasound-Colour Doppler, Ultrasound, Thyroid / Parathyroids, Lymph nodes, Head and neck DOI: /ecr2013/C Any information contained in this pdf file is automatically generated from digital material submitted to EPOS by third parties in the form of scientific presentations. References to any names, marks, products, or services of third parties or hypertext links to thirdparty sites or information are provided solely as a convenience to you and do not in any way constitute or imply ECR's endorsement, sponsorship or recommendation of the third party, information, product or service. ECR is not responsible for the content of these pages and does not make any representations regarding the content or accuracy of material in this file. As per copyright regulations, any unauthorised use of the material or parts thereof as well as commercial reproduction or multiple distribution by any traditional or electronically based reproduction/publication method ist strictly prohibited. You agree to defend, indemnify, and hold ECR harmless from and against any and all claims, damages, costs, and expenses, including attorneys' fees, arising from or related to your use of these pages. Please note: Links to movies, ppt slideshows and any other multimedia files are not available in the pdf version of presentations. Page 1 of 33

2 Purpose Thyroid cancer is the most common endocrine malignancy. It is classified into well differentiated and undifferentiated carcinomas. The well differentiated thyroid cancer (DTC) derives from follicular epithelial cells and includes papillary, follicular, Hürthle cell and a mixed variety carcinomas. The undifferentiated thyroid cancer includes medullary carcinoma, anaplastic cancer, lymphoma and metastatic tumors. DTC represents more than 90% of primary thyroid cancers and is best treated with total thyroidectomy (TT) and functional lymph node dissection, followed by radioactive iodine ablation therapy and performance of a post treatment whole-body scan, followed by thyroid stimulating hormone (TSH) suppression (L-thyroxine therapy) (1). Thyroid cancer, especially DTC, metastasizes most often to the cervical lymph nodes, and it is not unusual for occult thyroid cancer lymph node metastases to be present at the time of presentation (2). However, prophylactic lymph node dissection for all patients with DTC is controversial. Thus, early detection of metastases is of great clinical importance because it enables more successful surgical results and radiation therapy treatment outcomes (3-5). Ultrasonography is a useful imaging tool for evaluating cervical lymphadenopathy in patients with DTC. Identifying characteristics of cervical lymph nodes, using gray-scale and color and power Doppler U/S, can help to distinguish normal and reactive lymph nodes from potentially metastatic lymph nodes. Round shape ( Fig. 1 on page 5 ), cystic changes ( Fig. 2 on page 5 ), lymph node echogenicity -hypoechogenicity or hyperychogenicity ( Fig. 3 on page 6 ), presence of nodal microcalcifications ( Fig. 4 on page 7 ), peripheral vascularity ( Fig. 5 on page 8 ) and absence of hilus ( Fig. 6 on page 9 ) are the most common features in thyroid cancer lymph node metastases. Page 2 of 33

3 Fig. 4: Gray-scale sonogram of patients with unpalpable metastatic nodes. Image of 23-year-old woman with DTC and associated occult metastatic node in right middle cervical region shows metastatic node that appears hyoechoic with intranodal microcalcifications. These sonographic features are common in metastatic nodes from papillary thyroid carcinoma. References: First Department of Radiology, Anticancer Institute of Athens, Saint Savvas Anticancer Oncological Hospital of Athens - Athens/GR Often, U/S-guided biopsy is needed to identify a cervical lymph node as being metastasis (6-10). After initial treatment, the aim of post-surgical follow-up for DTC is to maintain adequate thyroxine therapy and the early identification of the small proportion of patients who have residual disease or develop a recurrence through the combined use of neck ultrasound (U/S) and serum Tg and (131)I Whole Body Sintigraphy after TSH stimulation. At the same time, highly skilled screening neck U/S can identify a few additional patients with subcentimeter, occult residual, or recurrent neck lymph node metastases not detected by TSH-Tg (11-13). Page 3 of 33

4 The purpose of this study is to determine whether real-time (Rt) ultrasonography-guided (Ug) fine-needle non-aspiration cytology (FNNAC) -Rt-Ug-FNNA- is an effective method for diagnosing non palpable cervical lymphadenopathy in patients with known thyroid malignancy without clinical known recurrent or residual thyroid cancer. Page 4 of 33

5 Images for this section: Fig. 1: Gray-scale sonogram of patients with unpalpable metastatic nodes. Image of 33-year-old man with DTC and associated occult metastatic node in left middle cervical region shows metastatic node which appears round. First Department of Radiology, Anticancer Institute of Athens, Saint Savvas Anticancer Oncological Hospital of Athens - Athens/GR Page 5 of 33

6 Fig. 2: Gray-scale sonogram of patients with unpalpable metastatic nodes. Image of 43year-old woman with DTC and occult metastatic lymph nodes in lower cervical region shows lower cervical node with cystic changes. First Department of Radiology, Anticancer Institute of Athens, Saint Savvas Anticancer Oncological Hospital of Athens - Athens/GR Page 6 of 33

7 Fig. 3: Gray-scale sonograms of patient with unpalpable metastatic nodes. Image of 34year-old woman with DTC and associated occult metastatic node in left central cervical region shows metastatic node which appears hyperechoic when compared with adjacent muscle. These sonographic features are common in metastatic nodes from papillary thyroid carcinoma. First Department of Radiology, Anticancer Institute of Athens, Saint Savvas Anticancer Oncological Hospital of Athens - Athens/GR Page 7 of 33

8 Fig. 4: Gray-scale sonogram of patients with unpalpable metastatic nodes. Image of 23year-old woman with DTC and associated occult metastatic node in right middle cervical region shows metastatic node that appears hyoechoic with intranodal microcalcifications. These sonographic features are common in metastatic nodes from papillary thyroid carcinoma. First Department of Radiology, Anticancer Institute of Athens, Saint Savvas Anticancer Oncological Hospital of Athens - Athens/GR Page 8 of 33

9 Fig. 5: Color Doppler sonogram of a patient with metastatic nodes. Image of 64-year-old woman with DTC and associated metastatic node in right supraclavicular region shows metastatic node that appears hypoechoic,round with peripheral vascularity. First Department of Radiology, Anticancer Institute of Athens, Saint Savvas Anticancer Oncological Hospital of Athens - Athens/GR Page 9 of 33

10 Fig. 6: Gray-scale sonogram of patients with unpalpable metastatic nodes. Image of 32year-old woman with DTC and associated occult metastatic node in left middle cervical region shows metastatic node without hilus. First Department of Radiology, Anticancer Institute of Athens, Saint Savvas Anticancer Oncological Hospital of Athens - Athens/GR Page 10 of 33

11 Methods and Materials During a period of five years ( ), we performed U/S examinations of the neck region in 285 patients (265 women; mean age, 43.2 years; range, years) with known thyroid cancer, looking for potential metastases before surgery as well as in postoperative follow-up, without an already clinical known recurrent or residual thyroid cancer. This was a retrospective study of 365 non palpable cervical lymph nodes detected sonographically and verified by real-time (Rt) ultrasonography-guided (Ug) fine-needle non-aspiration cytology (FNNAC) -Rt-Ug-FNNA(9). Nodes were measured on the screen, and their shape ( Fig. 1 on page 17 ), cystic changes ( Fig. 2 on page 17 ), echogenicity ( Fig. 3 on page 18 ), microcalcifications ( Fig. 4 on page 19 ), vascularity ( Fig. 5 on page 20 ), absence of hilus ( Fig. 6 on page 21 ), size, and location were reported. Informed consent is the communication process between a patient and physician that results in the patient's agreement to undergo a RtUg-FNNAC which was obtained (see Table 1). Table 1. The written informed consent form The consent form was patient friendly and written so that the patient fully understands the procedure. The purpose of the biopsy was discussed with the patient. It was emphasized that a high percentage of cervical nodes are benign and that an adequate tissue sample with RtUg-FNNAC may eliminate the expense and potential morbidity of surgical excision with general anaesthesia. The RtUg-FNNAC procedure, potential risks and complications were described. The possibility of a hematoma, the most frequently occurring complication, was mentioned. Notes were given in case of further complications. For the U/S examination a high-resolution ( MHz) linear-array transducer was used for real-time B-scans of the neck with a sterile cover placed over its head for Rt-UgFNNA. After the target node had been localized on the preprocedural U/S examination, the overlying skin was sterilized with chlohexidine gluconate. Both sides of the neck were checked for the presence of enlarged lymph nodes. All lymph nodes were scanned in the longitudinal plane, and the largest diameter was measured (maximum diameter). Nodes larger than 5 mm in maximum diameter were considered enlarged. Page 11 of 33

12 The lymph nodes were divided into levels according to their location: level I of the neck (the superior third of the neck including submental - region 1 and submandibular nodes - region 2), level II (upper jugular nodes - region 3 and region 4), level III (the mid third of the neck -middle jugular level nodes - region 5), level IV (the inferior third of the neck -including low jugular nodes - region 6), level V (the supraclavicular regions - region 7 and the posterior triangle - region 8) and level VI (midline low neck - central compartment nodes incorporate the Delphian/prelaryngeal, pretracheal, and paratracheal lymph nodes) (15,16) ( Fig. 7 on page 22 ). Fig. 7: The lymph node surgical regions of the neck are divided into levels I through VII: 1) level I nodes are the submental and submandibular nodes; 2) level II are the Page 12 of 33

13 the upper jugular nodes; 3) level III are the midjugular nodes; 4) level IV are the lower jugular nodes; 5) level V are the supraclavicular nodes and posterior triangle; 6) level VI or central compartment nodes incorporate the Delphian/prelaryngeal, pretracheal, and paratracheal lymph nodes; and 7) level VII nodes are those within the superior mediastinum. References: modified from Taylor S. (1975) Surgery of the thyroid gland. In DeGroot LJ, Stanbury JB: The Thyroid and its Diseases, 4th ed. New York, John Wiley & Sons: pp We performed Rt-Ug-FNNA of the most suggestive nodes from the tumor drainage region in one or both sides of the neck. In the case of a solitary node, authors punctured it; in the case of multiple nodes, authors chose 1, 2, or more nodes, depending on their sonographic appearance and position in the neck. Rt-Ug-FNNA was performed by a freehand technique. A plane perpendicular to the ultrasonographic probe for needle insertion was chosen. The puncture was performed with a conventional 23 (or 25) gauge needle without an attached syringe, for cell collection(9) ( Fig. 8 on page 23 ). Page 13 of 33

14 Fig. 8: Freehand biopsy technique without aspiration: the needle is placed just above the transducer without an attached syringe (Rt-Ug-FNNAC). This nonaspirate technique relies on capillary action to draw the sheared cells within the small-caliber needle. References: modified from Gkeli MG et al. (2011) Submandibular ectopic thyroid tissue diagnosed by ultrasound-guided fine needle biopsy. J Oral Sci 53: The patient was placed in a supine position with the neck slightly extended and superimposed on a pillow for his/her convenience. Instead of U/S gel, a topical anaesthetic lidocaine/prilocaine jelly was used during the procedure as it served as a primary coupling agent. The needle was inserted vertically into the target node, centrally in the transverse U/S-image, while the angle of the needle was on a nearly coaxial plane 0 to the axis of transverse image. The used angle was shallow (~60 ) for superficial nodes 0 and steeper (<30 ) for deeper ones. The needle tip was carefully monitored during the procedure. Page 14 of 33

15 Once the needle was entered into the node, it was oscillated gently back and forth in various positions and directions without aspiration under real time U/S attendance for a few seconds only by movement of the operator's wrist ( Fig. 9 on page 24 ). Fig. 9: Gray-scale sonogram of patient with unpalpable metastatic node. Image of 34year-old woman with DTC and associated occult metastatic node in left central cervical region shows the needle tip (arrow) inside the node. References: First Department of Radiology, Anticancer Institute of Athens, Saint Savvas Anticancer Oncological Hospital of Athens - Athens/GR When a small amount of material filled the hub of the needle, the needle was withdrawn and the puncture site on the skin was compressed for a few minutes. This nonaspirate technique relies on capillary action to draw the sheared cells within the small-caliber needle. Smears were stained by Quick Giemsa stain and Pap-method and the ultimate diagnoses were made by cytopathologists. In the case of smears with inadequate material for reliable cytologic diagnosis (4.8%), we repeated the Rt-Ug-FNNA to obtain adequate material. Page 15 of 33

16 Final diagnoses were determined by the histologic examination from excision biopsy when performed or by the clinical (monitoring of thyroglobulin -Tg- and antithyroglobulin antibody levels) and U/S follow-up for more than 12 months (to 36 months). All cytologically verified malignant nodes were confirmed histologically after surgical removal. When a lymph node diagnosed as benign by Rt-Ug-FNNAC was unchanged or regressed spontaneously on U/S follow up and there was not any detectable Tg, the diagnosis made by the Rt-Ug-FNNAC was considered correct. When a lymph node diagnosed as benign by Rt-Ug-FNNAC increased in size with subsequent management or became palpable at clinical follow up or there was detectable Tg without already clinical known recurrent or residual thyroid cancer, excisional biopsy was performed. Patients with clinical known recurrent or residual thyroid cancer were excluded from this study. Diagnostic yield, sensitivity, specificity, accuracy, and complications of Rt-Ug-FNNAC were evaluated. Page 16 of 33

17 Images for this section: Fig. 1: Gray-scale sonogram of patients with unpalpable metastatic nodes. Image of 33-year-old man with DTC and associated occult metastatic node in left middle cervical region shows metastatic node which appears round. First Department of Radiology, Anticancer Institute of Athens, Saint Savvas Anticancer Oncological Hospital of Athens - Athens/GR Page 17 of 33

18 Fig. 2: Gray-scale sonogram of patients with unpalpable metastatic nodes. Image of 43year-old woman with DTC and occult metastatic lymph nodes in lower cervical region shows lower cervical node with cystic changes. First Department of Radiology, Anticancer Institute of Athens, Saint Savvas Anticancer Oncological Hospital of Athens - Athens/GR Page 18 of 33

19 Fig. 3: Gray-scale sonograms of patient with unpalpable metastatic nodes. Image of 34year-old woman with DTC and associated occult metastatic node in left central cervical region shows metastatic node which appears hyperechoic when compared with adjacent muscle. These sonographic features are common in metastatic nodes from papillary thyroid carcinoma. First Department of Radiology, Anticancer Institute of Athens, Saint Savvas Anticancer Oncological Hospital of Athens - Athens/GR Page 19 of 33

20 Fig. 4: Gray-scale sonogram of patients with unpalpable metastatic nodes. Image of 23year-old woman with DTC and associated occult metastatic node in right middle cervical region shows metastatic node that appears hyoechoic with intranodal microcalcifications. These sonographic features are common in metastatic nodes from papillary thyroid carcinoma. First Department of Radiology, Anticancer Institute of Athens, Saint Savvas Anticancer Oncological Hospital of Athens - Athens/GR Page 20 of 33

21 Fig. 5: Color Doppler sonogram of a patient with metastatic nodes. Image of 64-year-old woman with DTC and associated metastatic node in right supraclavicular region shows metastatic node that appears hypoechoic,round with peripheral vascularity. First Department of Radiology, Anticancer Institute of Athens, Saint Savvas Anticancer Oncological Hospital of Athens - Athens/GR Page 21 of 33

22 Fig. 6: Gray-scale sonogram of patients with unpalpable metastatic nodes. Image of 32year-old woman with DTC and associated occult metastatic node in left middle cervical region shows metastatic node without hilus. First Department of Radiology, Anticancer Institute of Athens, Saint Savvas Anticancer Oncological Hospital of Athens - Athens/GR Page 22 of 33

23 Fig. 7: The lymph node surgical regions of the neck are divided into levels I through VII: 1) level I nodes are the submental and submandibular nodes; 2) level II are the the upper jugular nodes; 3) level III are the midjugular nodes; 4) level IV are the lower jugular nodes; 5) level V are the supraclavicular nodes and posterior triangle; 6) level VI or central compartment nodes incorporate the Delphian/prelaryngeal, pretracheal, and paratracheal lymph nodes; and 7) level VII nodes are those within the superior mediastinum. modified from Taylor S. (1975) Surgery of the thyroid gland. In DeGroot LJ, Stanbury JB: The Thyroid and its Diseases, 4th ed. New York, John Wiley & Sons: pp Page 23 of 33

24 Fig. 8: Freehand biopsy technique without aspiration: the needle is placed just above the transducer without an attached syringe (Rt-Ug-FNNAC). This nonaspirate technique relies on capillary action to draw the sheared cells within the small-caliber needle. modified from Gkeli MG et al. (2011) Submandibular ectopic thyroid tissue diagnosed by ultrasound-guided fine needle biopsy. J Oral Sci 53: Page 24 of 33

25 Fig. 9: Gray-scale sonogram of patient with unpalpable metastatic node. Image of 34year-old woman with DTC and associated occult metastatic node in left central cervical region shows the needle tip (arrow) inside the node. First Department of Radiology, Anticancer Institute of Athens, Saint Savvas Anticancer Oncological Hospital of Athens - Athens/GR Page 25 of 33

26 Results All the 285 patients had a known thyroid malignancy, which was included in the DTC group. 55% of the patients were in the phase of primary staging and treatment of a preoperatively diagnosed DTC ( Fig. 10 on page 28, Fig. 11 on page 28 ) and 45% had undergone TT with or without central neck dissection for DTC, without a clinical known residual or recurrent thyroid cancer. Cytological diagnosis could be made by Rt-Ug-FNNAC in 282 of the 285 patients yielding a diagnostic rate of 98.9%. 365 cervical lymph nodes underwent Rt-Ug-FNNAC. The cytological diagnoses were metastasis in 176 nodes, and benign findings in 189 nodes (see Table 2). Cytological Results Rt-Ug-FNNAC (n) Metastases 176 Reactive Hyperplasia 144 Tuberculosis 2 Toxoplasmosis 1 Normal 42 Total 365 Table 2. Rt-Ug-FNNAC of cervical lymph nodes and Cytological results All 176 malignant nodes underwent surgery, 115 nodes under initially TT and lymph node dissection and 61 nodes under reoperative lymph node dissection. False positive results were not mentioned. From the 189 cytologically benign nodes, 42 nodes underwent surgery under an initial TT and lymph node dissection and 6 nodes underwent an excisional biopsy, because of increase of their size or the presence of detectable Tg and the clinical suspicion of residual or recurrent thyroid cancer. False negative results were not mentioned. The rest 141 cytologically benign lymph nodes were unchanged or regressed spontaneously on U/S follow up and there was not any detectable Tg, for a total of 36- Page 26 of 33

27 month monitoring period and the diagnosis made by the Rt-Ug-FNNAC was considered correct. In summary, no false negative cytological results were referred. In differentiation of benign from metastatic thyroid disease, Rt-Ug-FNNAC had a sensitivity, specificity, and diagnostic accuracy of 100%. Rt-Ug-FNNAC had positive and negative predictive values of 100% in the diagnosis of metastatic thyroid lymph node malignancy. There were no procedure-related complications. Page 27 of 33

28 Images for this section: Fig. 10: Gray-scale sonogram of patients with unpalpable metastatic nodes. Image of 23-year-old woman with DTC in right thyroid lobe that appears hyoechoic with intranodal microcalcifications. These sonographic features are common in papillary thyroid carcinoma. First Department of Radiology, Anticancer Institute of Athens, Saint Savvas Anticancer Oncological Hospital of Athens - Athens/GR Page 28 of 33

29 Fig. 11: Gray-scale sonogram of patients with unpalpable metastatic nodes. Image of 23year-old woman with DTC and associated occult metastatic node in right middle cervical region shows metastatic node that appears hyoechoic with intranodal microcalcifications. These sonographic features are common in metastatic nodes from papillary thyroid carcinoma. Note the same appearance of the thyroid nodule and the lymph node. First Department of Radiology, Anticancer Institute of Athens, Saint Savvas Anticancer Oncological Hospital of Athens - Athens/GR Page 29 of 33

30 Conclusion Early detection of metastatic lymph nodes is of great clinical importance because it enables more successful surgical results and radiation therapy treatment outcomes in a balanced decision between the need for achieving local radical excision, correct disease staging, and reducing the risk of complications (2-5, 14). Sonography itself cannot distinguish benign from malignant nodes in patients with thyroid malignancy, especially if the nodes are small and unpalpable. However, U/S appearance suggests malignancy and helps in the selection of the node for Rt-Ug-FNNAC, which is crucial for a final diagnosis (6-8, 15). Therefore, patients with the diagnosis of DTC need preoperative Rt-Ug-FNNAC of suspicious nodes to avoid under-treating cases scheduled for TT (10). Furthermore, for the postoperative follow up of patients with treated DTC, U/S evaluation of the neck in conjunction with Rt-Ug-FNNAC of suspicious nodes is recommended (11, 13, 14). Rt-Ug-FNNAC is a safe and efficient tool for diagnosing the presence of occult metastatic cervical lymphadenopathy in patients with thyroid malignancy either preoperatively or postoperatively even in cases without clinical known recurrent or residual thyroid cancer and may obviate either unnecessary radical lymph node dissection or an excisional biopsy. Page 30 of 33

31 References Kloos RT. Papillary thyroid cancer: medical management and follow-up. Curr Treat Options Oncol 2005; 6: Wada N, Duh QY, Sugino K, et al. Lymph node metastasis from 259 papillary thyroid microcarcinomas: frequency, pattern of occurrence and recurrence, and optimal strategy for neck dissection. Ann Surg 2003; 237: Palestini N, Borasi A, Cestino L, et al. Is central neck dissection a safe procedure in the treatment of papillary thyroid cancer? Our experience. Langenbecks Arch Surg 2008; 393: Shan CX, Zhang W, Jiang DZ, et al. Routine central neck dissection in differentiated thyroid carcinoma: a systematic review and meta-analysis. Laryngoscope 2012; 122: Pisello F, Geraci G, Lo Nigro C, et al. Neck node dissection in thyroid cancer. A review. G Chir 2010; 31: Chan JM, Shin LK, Jeffrey RB. Ultrasonography of abnormal neck lymph nodes. Ultrasound Q 2007; 23: Ahuja A, Ying M. Sonography of neck lymph nodes. Part II: abnormal lymph nodes. Clin Radiol 2003; 58: Kuna SK, Bracic I, Tesic V, et al. Ultrasonographic Differentiation of Benign From Malignant Neck Lymphadenopathy in Thyroid Cancer. J Ultrasound Med 2006; 25: Gkeli MG, Daskalopoulou D. Real-time ultrasound-guided fine needle cytology of the thyroid gland by capillary action. A modified technique without aspiration. Journal of BUON 2011; 16: Ariba# BK, Arda K, Cileda# N, et al. Fine-needle aspiration biopsy of cervical lymph nodes: factors in predicting malignant diagnosis. Neoplasma 2011; 58: Pagano L, Klain M, Pulcrano M, et al. Follow-up of differentiated thyroid carcinoma. Curr Treat Options Oncol 2012; 13:1-10. Cisco RM, Shen WT, Gosnell JE. Extent of surgery for papillary thyroid cancer: preoperative imaging and role of prophylactic and therapeutic neck dissection. Curr Treat Options Oncol 2012; 13: Sutton RT, Reading CC, Charboneau JW, et al. US-guided biopsy of neck masses in postoperative management of patients with thyroid cancer. Radiology 1988; 168: Stack BC Jr, Ferris RL, Goldenberg D, et al; American Thyroid Association Surgical Affairs Committee. American Thyroid Association consensus review and statement regarding the anatomy, terminology, and rationale for lateral neck dissection in differentiated thyroid cancer. Thyroid 2012; 22: Ahuja AT, Ying M. Sonographic Evaluation of Cervical Lymph Nodes. AJR 2005; 184: Page 31 of 33

32 16. Taylor S: Surgery of the thyroid gland. In DeGroot LJ, Stanbury JB: The Thyroid and its Diseases, 4th ed. New York, John Wiley & Sons, 1975, pp Page 32 of 33

33 Personal Information M.G. Gkeli, M. Milatou, K. Kavvadias. First Department of Radiology, Anticancer Oncological Hospital of Athens, Alexandras Avenue 171, 11522, Athens, GREECE. mail to: Page 33 of 33