대한내분비외과학회지 : 제10권제4호 Vol. 10, No. 4, December 2010 원저 Bethesda Classification 에의거한갑상선세침흡인검사결과분석및 Atypical Cells of Undetermined Significance 의임상적의의에대한고찰 연세대학교원주의과대학외과학교실, 1 병리학교실 장정택ㆍ김광민ㆍ박준범ㆍ배금석ㆍ조미연 1 ㆍ강성준 Analysis of Cytopathology of Fine Needle Aspiration Biopsy of the Thyroid according to Bethesda Classification and Clinical Implication of Atypical Cells of Undetermined Significance Joung-teak Jang, M.D., Kwang-Min Kim, M.D., Joon- Beom Park, M.D., Keum-Seok Bae, M.D., Mee-Yon Cho, M.D. 1 and Sung-Joon Kang, M.D. 책임저자 : 강성준, 강원도원주시일산동 162 번지 220-701, 연세대학교원주의과대학외과학교실 Tel: 033-741-0573, Fax: 033-742-1815 E-mail: mdkang@yonsei.ac.kr 접수일 :2010 년 9 월 18 일, 게재승인일 :2010 년 10 월 14 일 Purpose: The frequency of diagnosis of each nodule category under the Bethesda classification was studied, and the differences in the results between cytopathologic and histopathologic analyses of same patients were assessed. Special attention was paid to the atypical cells of undetermined significance (ACUS), which is an intermediate category. The histopathology of ACUS specimens was confirmed to examine the clinical implication. Methods: Patients (n=417) who underwent thyroid ultrasonography and fine needle aspiration of the thyroid since the application of Bethesda classification (November 2009 to August 2010) in this institution was enrolled in the study. Results: According to the Bethesda criteria, of the 640 nodules there were 56 cases (8.8%) of ACUS, 14 cases (2.2%) of follicular neoplasm, 13 cases (2.0%) were suspicious for malignancy, and 37 cases (5.8%) were positive of malignancy. A total of 102 surgically-excised specimens were obtained, of which 40 specimens were previously categorized cytopathologically as ACUS. Of these 40 specimens, 16 cases (40%) were found to be malignant. Conclusion: A precise understanding of each diagnostic category seems to be necessary, which may help with treatment of patients with thyroid mass. This is especially true for ACUS, which was previously understood as an intermediate specimen, but which is actually a heterogeneous mix of benign specimen, benign specimen with various atypia, and malignancy. In case of ACUS, an extensive and accurate diagnostic approach utilizing various examination methods may be beneficial for the patient treatment. (Korean J Endocrine Surg 2010;10:240-244) Key Words: Fine needle aspiration cytology, Bethesda classification, Atypical cells of undetermined significance 중심단어 : 세침흡인세포검사, 베데스다분류법, 의미미결정비정형편평세포 Departments of Surgery and 1 Pathology, Wonju College of Medicine, Yonsei University, Wonju, Korea 서 갑상선결절은매우흔한질환으로일부의보고에서는 4 7% 정도의유병률을나타낸다고하며,(1,2) 미국에서 14 명의성인중 1명이갑상선결절을가지고있다고보고하고있다.(3) 이런갑상선결절의유병률은증가추세를나타내며, 이는질환의실제증가보다는갑상선초음파, 갑상선스캔, 컴퓨터단층촬영등의진단장비및건강검진의보편화등의기술적사회적현상에기인한다고볼수있겠다.(4,5) 갑상선세침흡인검사는갑상선결절의정확한진단을위해널리이용되는진단방법이다.(6-8) 이세침흡인검사의가장중요한의미는수술이필요한갑상선결절을분류하여수술을결정하는외과의사에게도움을주는것이라고볼수있겠다. 따라서검체를해석하고진단하는세포병리의사와검사결과를받고치료를결정하는외과의사간의정보의전달및공유가중요하다고볼수있겠다. 이전에갑상선세침흡인검사의진단시사용하는용어는각기관마다상당히달라서종종혼란을주는경우도있었다.(9-11) 이러한용어의재정비및진단기준의확립을위해 National Cancer 론 240
장정택외 :Bethesda Classification 에의거한갑상선세침흡인검사결과분석및 ACUS 의임상적의의에대한고찰 241 Institute (NCI) 가주관하여 2007년 10월 NCI Thyroid Fine Needle Aspiration State of the Science Conference. 를개최하였고검체의정확성과진단기준, 결과보고형식에대한권고안인 Bethesda classification을발표하였다.(12) 이새로운권고안은 6개의진단분류를사용하고있다. 이권고안을적용하여검체의각분류의진단빈도및수술한환자의조직병리검사와세포병리검사간의차이점에대해조사하고특히 Bethesda classification에서 Atypical cells of undetermined significance (ACUS) 로정해진중간형검체의최종조직검사결과를분석하여새로운 classification을적용하였을때각각의범주의빈도와각범주의악성도에대해알아보고자하였다. 방법본원에서 Bethesda classification을적용하기시작한 2009 년 11월부터 2010년 8월까지본원외과에서갑상선초음파및세침흡인검사를시행받은환자 417명을대상으로하였다. 초음파검사시행후신경두경부영상의학회산하갑상선연구회및기타외국에발표한세침흡인세포검사의지침에따라목표를정하였다. 환자목을신전시킨뒤검사부위에 0.5% chlorhexidine gluconate 로처지한뒤, 21 G needle이부착된주사기를흡입자에연결하여세침흡인하였다. 흡인후검체는액상세포검사를위한시약병에담아병리과의세포병리파트에의뢰하였다. 각검체는 6개의진단분류를통하여 Nondiagnostic or Unsatisfactory (ND), Benign, Atypical cells of undetermined significance or follicular lesion of undetermined significance, Follicular neoplasm or Suspicious for a Follicular neoplasm (FN), Suspicious for malignancy (SM), Positive for malignancy (PM) 로나누었다. Nondiagnostic or Unsatisfactory (ND) 로분류되는검체는 Cyst fluid only (CFO), Virtually acellular specimen (VAS), Other (obscuring blood, clotting artifact, etc) 로세분하였고, Benign으로분류되는검체는 consistent with a benign follicular nodule (BFN), consistent with lymphocytic (Hashimoto) thyroiditis (HT), consistent with granulomatous (subacute) thyroiditis (ST) 로세분하였다. Follicular neoplasm or suspicious for a Follicular neoplasm (FN) 으로분류되는경우에특히 H?rthle cell (oncocytic) type (HN) 으로세분하였고 Suspicious for malignancy는 papillary carcinoma (SPC), medullary carcinoma, metastatic carcinoma, lymphoma의조직유형에따라세분하였다. Positive for malignancy인경우는 papillary carcinoma (PC), Poorly differentiated carcinoma, Medullary thyroid carcinoma, Undifferentiated (anaplastic) carcinoma, squamous cell carcinoma, carcinoma with mixed features, metastatic carcinoma, Non-Hodgkin lymphoma로세분하였다. 대상환자를각검사결과에따라빈도분석을시행하였 고, 이중수술을시행하였던환자를따로구분하여세침흡인세포검사결과와비교하였다. 본원에서는세침흡인세포검사에서악성이보고되지는않았지만, 영상의학적검사와이학적검사상악성이의심되는환자는수술을시행하였다. 특히 ACUS로진단내려진환자에대한분석을위해 2008년 1월 1일부터 2009년 11월까지갑상선절제술을시행하였던환자들중세침흡인검사결과를다시검토하여 Bethesda classification을적용하였을때 ACUS로진단된환자군을포함하여최종조직검사와비교해보았다. 결 총환자수는 417명이었고세침흡인검사를시행하였던갑상선결절의수는 640개였다. 남자가 37명이었고여자가 380명이었으며, 평균연령은 50.9세였다. 갑상선결절에대한세침흡인검사결과의빈도분석을시행해보았을때 ND이며 CFO로세분된경우가 38예 (5.9%), VAC인경우가 63예 (9.9%) 였다. BFN인경우는 370 예 (57.8%), HT는 45예 (7.0%), ST는 4예 (0.6%) 였으며, ACUS 인경우는 56예 (8.8%) 로나타났으며, FN은 14예 (2.2%) 로나타났다. SPC는 13예 (2.0%) 였으며, PC는 37예 (5.8%) 였다 (Table 1). 총 417명의환자중갑상선절제술을시행하였던환자는총 72명이었으며, 최종조직검사와비교할수있는결절의수는총 102예였다. 수술전시행한세침흡인검사와최종조직검사와비교해봤을때세침검사에서 CFO로나왔던경우 4예중최종조직검사에서샘종과다형성 2예, 여포상선종 (FA) 2예였다. VAS인경우최종조직검사에서샘종과다형성으로결과나왔던경우가 6예, 이중구형석회화 Table 1. Frequency of categories according to Bethesda classifications of FNAB results Cytology category Nondiagnostic or Unsatisfactory Cyst fluid only Virtually acellular specimen Benign Consistent with a benign follicular nodule Consistent with Hashimoto thyroiditis Consistent with subacute thyroiditis By nodules 101 (15.8%) 38 (5.9%) 63 (9.9%) 419 (65.5%) 370 (57.8%) 45 (7.0%) 4 (0.6%) Atypical cells of undetermined significance 56 (8.8%) Follicular neoplasmor suspicious for a 14 (2.2%) follicular neoplasm Suspicious for malignancy 13 (2.0%) Suspicious for papillary carcinoma 13 (2.0%) Positive for malignancy 37 (5.8%) Papillary thyroid carcinoma 37 (5.8%) Total 640 과
242 대한내분비외과학회지 : 제 10 권제 4 호 2010 가동반된 AH인경우가 2예였으며, 하시모토갑상선염인경우가 1예가있었다. BFN인경우최종조직검사결과는샘종과다형성인경우가 30예, 하시모토갑상선염인경우가 1예, 미세유두상갑상선암으로결과보고된예가 1예가있었으며, 세침흡인검사에서 ACUS로결과보고된경우에서는유두상갑상선암이 9예, 샘종과다형성이 7예, 이중미세석회화가동반된경우가 4예, 여포상암인경우 1예, 아급성갑상선염으로결과보고된예가 1예, 휘틀세포선종으로결과보고되었던경우가 1예가있었다. FN인경우는최종조직검사에서샘종과다형성으로결과보고되었던경우가 4예, 여포상선종이 1예였다. SPC로진단되었던 7예중최종조직검사에서 5예는갑상선유두상암이었으며, 샘종과다형성이 1예, 아급성갑상선염이 1예가있었다. PC로진단되었던 27예는최종조직검사에서모두유두상갑상선암으로진단되었다 (Table 2). 대상기간동안의 specimen 개수의제한이있어 2008년 1월 1일부터 2010년 8월까지갑상선절제술을시행하였던환자중세포병리슬라이드를다시분석하여 Bethesda classification을적용하였을때 ACUS로진단된 40예의최종조직검사결과를분석하였다. 샘종과다형성으로진단된경우가 7예, 샘종과다형성과석회화가동반되었던경우가 5 예, 호산과립세포변화 (oncocytic change) 가동반된경우가 5예, 석회화와호산과립세포변화가동반된경우가 2예였다. 갑상선유두상암이었던경우가 11예, 소포변이유두상갑상선암이 2예, 여포상선종이 3예, 여포상암이 3예, 하시모토갑상선염이 2예였다 (Table 3). 고찰갑상선결절의진단에있어서초음파가이드하에세침흡인세포검사는외래에서도간단하고안전하게시행할수있는장점을지니고있으므로, 현재일차적검사로많이이용되고있는실정이며, The American Thyroid Association 의지침에서도갑상선결절에대한검사법중비용적으로효율성이높고가장정확한방법으로추천된다.(13) 검체의정확성을높이고진단기준, 결과보고형식을단일화하기위해제창된권고안인 Bethesda classification을이용하여검체를분류한다른연구를살펴보았을때, ND인경우 11.1% 로보고하는경우도있었으며,(14) 타연구에서는 ND의범주에 2 20% 정도의검체가포함될수있으나대식세포만가득한즉 CFO의범주에들어가는검체를제외하였을때, 10% 이내의 ND범주의검체결과가나오는것이이상적이라고주장하고있다.(6,15,16) 또한 ND범주에들어가는 CFO의비율은 15 30% 정도된다고주장한연구 Table 2. Histologic correspondences according to FNAB results Cytology category Histologic follow-up AH HT ST FA PTC FC Total Cyst fluid only 2 0 0 2 0 0 4 Virtually acellular specimen 6 1 0 0 0 0 7 Consistent with a benign follicular nodule 30 1 0 0 1 0 32 Consistent with Hashimoto thyroiditis 0 1 0 0 0 0 1 Atypical cells of undetermined significance 7 0 1 1 9 1 19 Follicular neoplasm or suspicious for a Follicular neoplasm 4 0 0 1 0 0 5 Suspicious for papillary carcinoma 1 0 1 0 5 0 7 Papillary thyroid carcinoma 0 0 0 0 27 0 27 Total 50 3 2 4 42 1 102 AH = adenomatous hyperplasia; HT = hashimoto thyroiditis; ST = subacute thyroiditis; FA = follicular and Hurthle cell adenoma; PTC = papillary thyroid carcinoma; FC = follicular and Hurthle cell carcinoma. Table 3. Final surgical pathology of ACUS (n=40) Surgical pathology Histologic follow-up AH AHC AHO AHCO HT FA PTC PCF FC Total ACUS (%) 7 (17.5) 5 (12.5) 5 (12.5) 2 (5) 2 (5) 3 (7.5) 11 (27.5) 2 (5) 3 (7.5) 40 (100) ACUS = atypical cells of undetermined significance; AH = adenomatous hyperplasia; AHC = adenomatous hyperplasia with calcification; AHO = adenomatous hyperplasia with oncocystic change; AHCO = adenomatous hyperplasia with calcification with oncocystic change; HT = hashimoto thyroiditis; FA = follicular and Hurthle cell adenoma; PTC = papillary thyroid carcinoma; PCF = papillary carcinoma with follicular variant; FC = follicular and Hurthle cell carcinoma.
장정택외 :Bethesda Classification 에의거한갑상선세침흡인검사결과분석및 ACUS 의임상적의의에대한고찰 243 도있었다.(16,17) 본연구에서는 ND 전체가 15.7%, CFO가 5.9%, VAS이 9.8% 를차지하였고 CFO는 ND범주의 37.6% 를차지하여, 이전연구와비교시 CFO의비율이약간높은것으로나타났다. Benign으로분류되는검체는타연구에의하면 60 73.8% 정도를차지한다고보고하고있다.(12,14) 본연구에서는 419예로 65% 를차지하여이전의연구와크게다르지않음을알수있었다. 은등 (18) 의연구에서 ACUS는 1.1%, FN는 0.4%, SM은 1.4%, PM은 6.8% 의결과를나타냈으며, Theoharis 등 (14) 의연구에서는 ACUS 는 3.0%, FN은 5.5%, SM은 1.3%, PM은 5.2% 의결과를보고한바있다. ACUS인경우는 56예 (8.8%), FN은 14예 (2.2%), SPC 는 13예 (2.0%) 였으며, PC는 37예 (5.8%) 였다. 연구마다차이는있지만비슷한비율을이루고있음을알수있었으며, 특히 ACUS인경우갑상선세침흡인검사결과의 3 6% 를차지하며적어도 7% 이내의진단률이가장적절하다고알려져있다.(6,17) Layfield 등 (19) 의연구에의하면 28명의병리의사가진단한 6,872예의세침흡인검사결과를분석하였을때, ACUS의비율은 2.5 28.6% 까지다양하게나타났으며, 평균적으로는 12.1% 의진단률을나타내었다. 세침흡인검사에서 CFO 및 VAS로결과보고되었던예에서수술시행하였을때, 본원결과에서최종조직검사결과양성갑상선종양으로결론이났다. 타연구를참고하였을때 CFO인경우갑상선절제술시행시에악성종양으로보고될수있는비율은대략 4% 정도, CFO를제외한 ND검체인경우갑상선절제술시행시에악성보고비율은 1 4% 정도로보고하고있다.(6,15,16) 본원결과에서 CFO인경우악성결절인경우는없었지만, 갑상선결절중 90% 이상이낭성부분을갖는결절인경우악성의빈도는매우드물지만종종갑상선유두상암에서낭성부분을함께가지고있는부분이있어고형부분이동반된낭성결절인경우세침흡인검사에서 CFO라고결론이나도초음파소견을참고하여수술결정을하여야할것으로생각된다.(20) 또한 ND, VAS인경우둘레석회화를가지고있는결절인경우가 2예가있었다. 이런경우경험적으로결절내부로바늘이통과되기어렵기때문에이런결과가나올수있다고생각하며, Alexander 등 (20) 의보고에의하면비진단적검체가발생하는경우는낭성결절, 혈성검체, 섬유화석회화가동반된결절인경우에서흔히발생한다고주장하고있다. 둘레석회화를보이는경우 44.1% 가악성, 55.9% 가양성결절로알려져있다.(21) 따라서둘레석회화가있는경우 VAS로결과가나와도초음파소견을참고하여수술적접근이이루어져야할것으로사료된다. BFN인경우에최종조직검사에서악성의결과가나올확률은 0 3% 정도로보고되고있다.(17,22) 본원에서는 32 예중 1예 (3.1%) 에서악성이보고된바있다. 이는양성결절내에미세유두상갑상선암이포함되어있는경우였다. 이 러한검체획득의오차를줄이기위해검체를시행할갑상선결절의다른부위에서 2 5회정도의바늘투과를시행하여야한다고보고한연구도있다.(23) 은등 (18) 의보고에서초기세침흡인검사에서 Benign으로진단되었던예중추적관찰하며다시미세침흡인검사를시행하였을때 3.1% 에서유의하게진단이바꾼예가있었다. 따라서 Benign으로진단되었다고하여도정기적인외래추적관찰및초음파, 세침흡인검사가필요할것으로사료된다. ACUS는보통다량의미세여포 (microfollicle) 가관찰되나 FN의진단기준을충족시키기엔부족한경우, 즉이런경우병리의사들은양성, 샘종과다형성의진단명을선호하는편이나이런경우여포상암종이완전히배재되지못하는경우로볼수있겠다. 적은양의교질을동반하고있으며, 비교적적은세포가분포하고있으며, 이세포의대부분이휘틀세포인경우, 검체의인공적인영향으로비전형여포세포로생각되는세포군집이자세히보이지않는경우, 하시모토갑상선염과같이중등도, 고도로세포가많이나왔으나세포가대부분휘틀세포인경우이면서임상적으로양상휘틀세포종이의심되는경우, 국소적인비전형세포의특징-예로써, 불규칙한핵막과창백한크로마틴 (pale chromatin) 을가진비대해진핵-을가진검체도 ACUS로분류하며, 이경우악성변화특이유두상암을완전히배재할수가없으며, 이런경우방사선동위원소치료나카비마졸등의약물등을사용하였을경우에서도이런변화를일으킬수있는것으로알려져있다.(12,18) 일부의보고에서세포병리검사에서 ACUS로진단된검체의최종조직검사에서악성갑상선결절을나타냈던예는 20 25% 로보고하고있다.(6,17) Theoharis 등 (14) 의보고에서는총 27예의 ACUS에서샘종과다형성및하시모토갑상선염이 7예, 여포상선종이 7예, 갑상선유두상암이 11예 (40.1%), 여포상암이 2예로보고한바있으며, 은등 (18) 의보고에서는 7예의 ACUS에서샘종과다형성이 2예, 여포상선종이 2예, 갑상선유두상암 5예 (71.4%) 로보고하고있다. Layfield 등 (19) 의보고에서는 127예의 ACUS 검체중최종조직검사에서악성갑상선결절이나온경우는 36예로 28.3% 를차지하였다. 앞서서술한대로본원에서의 ACUS 진단비율은 8.8% 정도였으며, 40예중 16예 (40%) 에서악성갑상선결절이보고되었다. 다른보고나본원의보고를참고하였을때 ACUS인경우악성의빈도를무시할수없으므로초음파나경부컴퓨터촬영등의영상의학적검사 (24) 및진찰소견을참고하여조직학적확진을위해수술을시행하거나단기간내에세침흡인검사를시행하는것이도움이될것이라생각한다. 결론병원과병원간의그리고원내에서의병리의사와임상의
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