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1 REVIEW ARTICLE ISSN (Print) ISSN (Online) Korean J Endocr Surg 2015;15:1-5 The Korean Journal of Endocrine Surgery 갑상선결절의미세침흡입세포검사에대한권고안들의고찰 아주대학교의과대학외과학교실이정훈ㆍ소의영 Current Guidelines for Fine Needle Aspiration of Thyroid dules Thyroid cancer is a hot issue in Korea because there is debate on screening and diagnosis of thyroid cancer. Therefore, we reviewed the guidelines for the management of thyroid nodules of other countries. Western countries accepted the criteria of fine needle aspiration including the tumor size of thyroid nodules, although ultrasonographic morphologic characteristics are more important to diagnose the thyroid cancer than tumor size. This recommendation is based on good prognosis of papillary thyroid microcarcinoma. However, small subset of papillary thyroid microcarcinoma has aggressive behavior, which we cannot discern from those with benign behavior before operation. Therefore, further researches are necessary to resolve these problems and improve the management of papillary thyroid cancer avoiding overtreatment and mismanagement. Key Words: Thyroid nodule, Thyroid cancer, Fine needle aspiration 중심단어 : 갑상선결절, 갑상선암, 미세침흡입세포검사 Jeonghun Lee, Euy Young Soh Department of Surgery, Ajou University School of Medicine, Suwon, Korea Received February 19, 2015, Revised March 2, 2015, Accepted March 19, 2015 Correspondence: Euy Young Soh Department of Surgery, Ajou University School of Medicine, 164 Worldcup-ro, Yongtong-gu, Suwon , Korea Tel: Fax: sohey@ajou.ac.kr 서론 초음파와미세침검사는갑상선암을진단하고치료방침을정하기위한중요한술전검사이다. 그러나 1982년에는초음파는미세침검사보다암을진단하는데더특이적이지못하다는보고로갑상선암진단에잘활용되지않았고, 2004년까지도초음파에대한이해의부족과내분비의사들의초음파에대한잘못된인식으로인하여널리사용되지못하였다.(1) 그러나, 1990년대이후로초음파기계의발전과더불어, 갑상선암의초음파의영상학적특징이활발히연구되었고, 이를바탕으로 2000년대후반에는초음파가갑상선암진단에보편적으로사용되었다. 이러한변화와함께갑상선암의발생률은전세계적으로증가하는추세를보였고, 특히우리나라의경우에는다른나라와달리발생률의증가속도가더빨라서, 2008년도에는미국 ( 조발생률 19.7) 에비해서우리나라의발생률은 ( 조발생률 80.9) 4배많았다.(2,3) 이러한발생률의증가에는여러가지원인들이있으나, 무엇보다초음파의보급으로인한과잉진료가가장큰원인으로지목이되었다. 그래서몇몇나라들의갑상선암권고안에는초음파와미세침검사에대한권고안을두고있다. 본연구에서는우리나라와다른나라들의초음파와미세침흡입세포검사 (fine needle aspiration cytology, FNA) 에대한권고안및이와관련된사항들을비교하여보고자하였다. 최근에발표된권고안들로는, 2014년에미국 National comprehensive cancer network (NCCN) 에발표한 Thyroid guideline version 2, 2014년에영국의 British Thyroid Association (BTA) 의 The management of thyroid nodule, 2010년에 Japanese Association of Endocrine Surgeons & Japanese Society of Thyroid Surgeons (JTA) 이발표한 Treatment of thyroid tumor, 2010년에대한갑상선학회에서발표한 갑상선결절과갑상선암진료권고안 2011년 The Copyright 2015 Korean Association of Thyroid and Endocrine Surgeons; KATES. All Rights Reserved. cc This is an Open Access article distributed under the terms of the Creative Commons Attribution n-commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 2 Korean J Endocr Surg 2015;15:1-5 journal.kates.or.kr Thyroid Study of The Korean Society of Radiology에서발표한 Ultrasonography and the ultrasound-based management of thyroid nodules: Consensus statement and recommendations, 2010년 American Association of Clinical Endocrinologists (AACE), Associazione Medici Endocrinologi (AME, Italy), and European Thyroid Association (ETA) 에서발표한 consensus 등이있다. 본론 2014년에발표된 NCCN guideline에서는갑상선결절이발견되거나의심되는경우먼저, 갑상선자극호르몬검사를시행하도록하였다. 갑상선자극호로몬수치가정상이거나증가된경우, 또는갑상선호르몬이낮으나 radioiodine scan을시행하였을때 cold nodule인경우에초음파를시행하여초음파소견과종양의크기에따라 FNA을시행하도록하였다 (Table 1).(4) 암이의심되는초음파소견들로는 hypoechoic, microcalcification, increased central vascularity, infiltrative margin, taller than wide in transverse plane로정의하였다. NCCN 권고안에서는이러한소견이있을경우이고결절의크기가 1 cm 이상인경우 FNA을시행하도록하였다. 그러나크기가더작은경우라도임상적으로고위험요인이있는경우에는 FNA를시행할수있다고하였고, 임상적으로고위험군으로는어릴때방사선에노출되었거나, 부모나형제중에갑상선암을가지고있는경우, PET scan상 FDG uptake가있는경우, MEN2, FAP (familial adenomatous polyposis, Carney complex, Cowden syndrome, 갑상선암으로엽절제술을받은과거력이있는경우들로정의하였다. 이렇듯 2014 NCCN guideline에서는 FNA를갑상선자극호르몬, 초음파검사및임상적위험성을고려하여결정을하도록권고하고있다. NCCN panel에서는종양의크기를포함한 FNA의권고안을채택하는데중요한근거로는첫째 로, 갑상선결절의크기가증가할수록비선형적으로갑상선암의가능성이높아진다는연구인데, 이논문에선 cm, cm, cm, 4 cm 네군에서암빈도는각각 10.5%, 14%, 16%, 15% 였고, 2 cm의문턱값을기준으로갑상선암가능성이통계학적으로의미있게높아진다고했다.(5) 둘째로는크기가 1 cm 이하인경우 FNA의위음성률 (false negative value) 이 15.8%, 크기가 1 cm 이상인경우 % 로, 크기가 1 cm 이하인경우갑상선암에대한 FNA의정확성이낮았다 (6) 는논문을근거로종양의크기를 FNA 시행기준으로추가하였다. NCCN panel 구성원들중 50 85% 에는이기준에찬성하였고종양크기의척도는암이의심되는초음파소견들과함께중요한역할을할것이라고기술하고있다. 그러나, Kim 등 (7) 은 5 mm, 6 10 mm, >10 mm 세군에서각각위음성률은 3.9%, 0.9%, 0% 로 5 mm인경우에위음성률이증가하지만 6 mm 이상의군에서는차이가없다고하였다. 그러므로, FNA는크기에따라정확성은시행하는자따라차이가있다. 미국에서이전에보고된 2009년도에 American Thyroid Association에발표한 Revised American Thyroid Association Management Guidelines for patients with thyroid nodules and differentiated thyroid cancer ( 이하 2009 ATA 권고안 ) 에서도 FNA에대한비슷한권고안을가지고있다 ATA 권고안에서는 5 mm 이상이고, hypoechoic echogenicity 와 microcalcification을가지고있는경우에는일부에서는림프절전이가발생할수있으나, 1 cm 이하이고, 림프절전이, 방사선피폭의과거력, 갑상선암의가족력이없는경우는 morbidity나 mortality가거의없고이러한갑상선결절을진단하기위한노력은비용대비효과를측면에서수술의위험성이유용성보다더높다고하여 1 cm 이하의결절은고위험군이아니면하지않도록하였다 (Table 2).(8) 그리고고위험군에서는 0.5 cm 이상이 Table 2. FNA recommendation by American Thyroid Association (2009) Table 1. NCCN guidelines, version 2. thyroid carcinoma (2014) Ultrasonographic features Solid nodule Mixed cystic-solid nodule Spongiform nodule Simple cyst Suspicious cervical lymph node Threshold for FNA 1.0 cm 1.5 cm cm t indicated FNA node±fna thyroid nodule Ultrasonographic features High-risk history dule with suspicious US features dule without suspicious US features Abnormal cervical lymph nodes Microcalicifications present in nodule Solid nodule With hypoechic Without iso- or hyperechoic Mixed cystic-solid nodule Spongiform nodule Simple cyst Threshold for FNA >0.5 cm >0.5 cm All 1 cm 1.0 cm cm cm t indicated

3 이정훈ㆍ소의영 : 갑상선결절의미세침흡입세포검사에대한권고안들의고찰 3 면서초음파상암이의심되는경우에 FNA를시행하도록하여고위험군에서도크기의기준을명확히하고있으나, 고위험군이아닌경우는 2014 NCCN권고안에서처럼 1 cm의크기를두고있었다. 그러나, 2011년에 The Thyroid Study of The Korean Society of Radiology 에서발표한 Ultrasonography and the ultrasound-based management of thyoid nodules: Consensus statement and recommendations 에서는종양의크기는암과양성종양을구분하는데도움이되지않으며, 종양을추적관찰하기위한잣대로사용하도록하였으며, 6 10 mm의종양에서도암이의심되는병변에서는 FNA가가능할때에는 FNA를시행하고, <6 mm 종양은고위험군인경우에숙련된영상의학전문의경우에시행할수있다고하였다. 그리고, 다른근거로는 5 mm, >5 mm 이상의갑상선암의재발률이각각 3%, 14% 로 >5 mm에서는재발가능성이높으므로 FNA가필요하다고하였다.(9) 2014년 British Thyroid Association에서발표한 Guidelines for the management of thyroid cancer 에서는초음파소견들을바탕으로갑상선결절들을 5가지의분류로구분하여불필요한 FNA를줄이고자하였다 (Table 3).(10) 이권고안에서는갑상선결절의크기는암을감별하는데비특이적이며, 믿을만한잣대가되지못한다고하였으며, 크기보다는초음파상의 morphology 가더중요하다고하였다. 그리고 1 cm 이하의종양에대해서 FNA 시행여부는 extrathyroidal extension이나, lymph node metastasis유무에따라결정하는것이좋을것으로기술하였다. 그리고초음파소견을바탕으로한분류체계상 U3-5일경우에는 FNA을시행할것을권고하였고, U1-2에서는고위험군이아 니라면시행하지않도록하였다. 2014년 BTA 권고안은 2014년 NCCN 권고안에비해서 FNA을시행할때, 크기보다는 morphology의중요성을더강조하는차이점을보인다. 그러나영국갑상선학회의권고안은몇가지특이한점이있다. 첫째로갑상선결절은진단하고치료하는데현실적으로크기의기준을가지고있다. 2014년 BTA에서는우연히발견된 1 cm 미만의갑상선결절이나만져지는갑상선결절이라도몇년동안촉진상크기변화가없고, 어른이며, 방사선피폭과거력, 갑상선암가족력, 경부림프절종대및목소리변화가없으면상급병원으로전원하지않고일차진료의가추적관찰하도록하였다 (3.2. Symptoms and signs that warrant investigation). 그러나, 2010 JTA 권고안에의하면갑상선결절이 1.6 cm 이상일경우 80% 에서만져지지만 1 cm 이하인경우는 7% 에서만만져지는것으로보고하였다. 이를고려할경우, BTA 권고안에서는 1.6 cm보다더크고, 자라는경우에만상급병원으로전원하므로현실적으로는 FNA의크기기준을두고있는것이다. 둘째로일차진료의가초음파를사용하는것은진단을지연시키므로하지않도록권고하였다 (3.4. Appropriate investigations pending hospital appointment).(11) BTA 에서는갑상선결절이만져지더라도고위험군이아니면초음파와 FNA을시행하지않고추적관찰을하고추적관찰시크기가증가하면상급병원으로전원하여초음파와 FNA를시행하도록한것이다. 이에대한근거로대부분의갑상선결절 (95%) 들이양성결절이기때문이라고설명하였다. 그리고일차진료의는환자를상급병원으로전원시중한정도에따라전원시기를달리하였는데, non-urgent referral해야할경우로는갑상선기능이상인경우, 갑상선결절내출혈로갑자기커 Table 3. The management of thyroid cancer, British Thyroid Association (2014) Grade BTA US features Consider biopsy U5 malignancy U4 Suspicious U3 Indeterminate/equivocal U2 Benign U1 rmal 1. Solid, hypo-, lobulated/irregualr, microcalicification (PTC) 2. Solid, hypo-, lobulated/irregular, globular calcification (MTC) 3. Intra-nodular vascularity 4. Taller than wide 5. lymphadenopathy 1. Solid, hypo-echoid 2. Solid, very hypo- 3. Disrupted peripheral calcification, hypo-echoic 4. Lobulated margin 1. Homogenous, iso-/hyper, solid, halo (follicular lesion) 2. Hypo-, equivocal echogenic foci, cystic change 3. Mixed central vascularity 1. Halo, hyper-/iso- 2. Cystic chagne+/- ring down sign (colloid) 3. Micro-cystic/spongioform 4. Peripheral egg shell calcification 5. Peripheral vascularity (yes, if high risk history)

4 4 Korean J Endocr Surg 2015;15:1-5 journal.kates.or.kr 지는경우로정의하였고, urgent referral (2-week rule) 해야할경우는목소리변화가있는경우, 어린아이에서생긴갑상선결절, 갑상선결절을동반한림프절종대가있는경우, 몇주사이에크기가증가하면서통증이없는갑상선결절인경우 (anaplastic thyroid cancer, lymphoma 등 ) 로권고하였다. 그리고, immediate referral (same day) 해야할경우는갑상선결절을동반한 stridor가있는경우로권유하였다. 그외, 갑상선가족력, 방사선피폭의기왕력이없고, 수년동안자라지않은경우는전원하지않고증상과촉진등의임상소견만으로추적관찰하도록하였다. 영국의 BTA 권고안에따르면 FNA을받기위해서는상급병원전원기준에합당해야하므로, 실질적으로 1.6 cm 이상의크기이거나, 진행성갑상선암인경우등으로초음파와 FNA가미국보다더제한적으로시행된다 JTA 권고안에서는 FNA 시행시미국처럼크기의규정을두거나영국처럼초음파의시행에대해서권고안을두고있지는않다. 다만, 갑상선암의진단을위한방법으로신체검진시에시행하는촉진은초음파보다민감도가낮고, 초음파가갑상선암을진단하는데가장유용한방법으로기술하여민감도 %, 특이도 66 93% 로보고하였다. 그리고일본에서도다른나라들처럼공공의료에서갑상선암검진을시행하지않고, 개인이일정부분의비용 (50, ,000 JPY) 을지불하는 ningen dock 에의해서갑상선암에대한검진이이루어지고있어서이는우리나라나미국의의료현실과비슷한양상이다. 2000대후반에는이외에도다양한권고안들이발표되었다. American Association of Clinical Endocrinologists (AACE), Associazione Medici Endocrinologi (AME, Italy), and European Thyroid Association (ETA) 는이러한여러권고안들마다의차이점을줄이고자, 2010년에공동으로 consensus를발표하였다. 이 consensus에서는 FNA가필요한경우로는크기가 1 cm 이상에는결절로초음파상 solid, hypoechic한경우, 크기가 1 cm 이하인경우에는 extracapsular growth 또는림프절전이가있는경우, 임상적으로고위험군 ( 방사선노출, 유두암, 수질암, MEN2 등의가족력, calcitonin이증가한경우 ), 초음파상에서암의심소견들이있는경우로정의하였으며, 특히초음파상두개이상의암의심소견이있는경우에는암가능성높아진다고하였다 (Table 4).(12) 그러나 0.5 cm 이하인우연종인경우에는공격적인양상을보이는경우는드물기때문에초음파만으로추적관찰할수있다고하였다. 이러한기준은 2009년 ATA 와비슷하다. 그러나이권고안에서는만져지지않은갑상선결절의암빈도 ( %) 와만져지는결절의암빈도 ( %) 가차이가나지않으므로암위험성에대한임의적인크기기준은옳지않고 1 cm 이하의암의심되는병변에서도 FNA를시행할것을권유하였다. 우리나라에서는대한갑상선학회에서 2010년에 대한갑상선학회갑상선결절및암진료권고암개정안 (2010년 KTA) 을발표하였다. 2010년 KTA 에서는일반적으로 1 cm 이상인결정이임상적으로의미있는암의위험이있으므로 FNA을시행하고, 1 cm 미만이더라도두경부및전신방사선조사기왕력, 갑상선암가족력, 갑상선암으로엽절제술을받은과거력, FDG-PET 양성, MEN2/FMTC와연관된 RET 유전자변이, 혈정칼시토닌 100 pg/ml인고위험군과초음파상악성을시사하는경우에는 1 cm 미만의결절에서도검사가필요하다고하였다. 그리고 1 Table 4. American Association of Clinical Endocrinologists (AACE), Associazione Medici Endocrinologi (AME), and European Thyroid Association (ETA) (2010) FNA guideline dule(s) >1 cm Solid and hypoechoic Any size Extracapsular growth or metastatic cervical lymph nodes Any size History of neck irradiation in childhood or adolescence PTC, MTC, or MEN 2 in first-degree relatives Increased calcitonin levels in the absence of interfering factors <1 cm Coexistence of 2 or more suspicious US findings Hot nodules in scintigraphy MNG Selected on the basis of previously described criteria t biopsy hot areas Biopsy both LN and nodule in presence of suspicious cervical LN Solid-cystic Sample the solid compoenent of the lesion by UGFNA biopsy Submit both FNA biopsy specimen and drained fluid for cytologic examination Incidentaloma Should be managed according to previously described criteria US evaluation before consideration for UGFNA biopsy Hot nodule on PET should be undergo US evaluation plus UGFNA biopsy UGFNA = Ultrasound-guided fine needle aspiration; MNG = multinodular goiter; PTC = papillary thyroid cancer; MTC = medullary thyroid cancer; MEN 2 = multiple endocrine neoplasia type 2.

5 이정훈ㆍ소의영 : 갑상선결절의미세침흡입세포검사에대한권고안들의고찰 5 cm 미만의갑상선결절에서 FNA의시행여부는각개인의위험인자와초음파검사소견을고려하여결정하되, 대부분 0.5 cm 이하의갑상선암은예후가양호하고, 0.5 cm 이하의결절에서 FNA를시행할때에부적절한검체의빈도가높은점을고려하여, 고위험군이거나초음파검사상악성을시사하는소견을보이는경우 0.5 cm 보다큰경우에만 FNA를시행할것을권고하되, 다만악성이의심되는경부림프절종대가동반된경우에는크기에관계없이 FNA를시행할것을권유하고있다. 결론 결론적으로여러나라들의권고안에서 FNA를위한크기기준에대해서는다른입장을보이지만, 고위험군이아닌경우 1 cm 이상의갑상선결절들은초음파상소견에따라 FNA를시행해야할것이고, cm 미만의우연종에대해서는, 고위험군에서는 FNA을초음파소견에따라시행하고, 고위험군이아닌경우에는 extrathyroidal invasion이나림프절전이가의심되는경우에 FNA를시행하는것이좋을것이다. 그러나, 이러한갑상선결절과갑상선암의진료지침은다양한예후인자를가진여러병기분류체제들과장기생존으로인한전향적연구의어려움으로인해차이를보인다. 그러므로향후확실한권고안을위해서는이에대한연구가필요하며, 또한 FNA를시행할때에는이러한차이들에대해서환자들에게충분한설명과동의가필요할것이다. REFERENCES 1. Baskin HJ. Thyroid ultrasound-just do it. Thyroid 2004;14: Park K YH, Nam EJ. Cancer Facts & Figures 2014, Seoul. Ministry of Health and Welfare Howlader NA, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, et al. SEER Stat Fact Sheets: Thyroid Cancer. National Cancer Institute Tuttle M, Haddad R, Ball DW, Byrd D, Dickson P, Duh DY, et al. NCCN Clinical Practice Guidelines in Oncology. Thyroid cancer Kamran SC, Marqusee E, Kim MI, Frates MC, Ritner J, Peters H, et al. Thyroid nodule size and prediction of cancer. J Clin Endocrinol Metab 2013;98: Shrestha M, Crothers BA, Burch HB. The impact of thyroid nodule size on the risk of malignancy and accuracy of fine-needle aspiration: a 10-year study from a single institution. Thyroid 2012;22: Kim DW, Lee EJ, Kim SH, Kim TH, Lee SH, Kim DH, et al. Ultrasound-guided fine-needle aspiration biopsy of thyroid nodules: comparison in efficacy according to nodule size. Thyroid 2009;19: American Thyroid Association (ATA) Guidelines Taskforce on Thyroid dules and Differentiated Thyroid Cancer, Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009;19: Moon WJ, Baek JH, Jung SL, Kim DW, Kim EK, Kim JY, et al; Korean Society of Thyroid Radiology (KSThR); Korean Society of Radiology. Ultrasonography and the ultrasound-based management of thyroid nodules: consensus statement and recommendations. Korean J Radiol 2011;12: Perros P, Boelaert K, Colley S, Evans C, Evans RM, Gerrad G, et al. Guidelines for the management of thyroid cancer Suzuki S, Fukunari N, Kameyama K, Miyakawa M, Tanaka K, Hibi Y. Treatment of Thyroid Tumor. Tokyo Heidelberg New York Dordrecht London, Springer Gharib H, Papini E, Paschke R, Duick DS, Valcavi R, Hegedüs L, et al; AACE/AME/ETA Task Force on Thyroid dules. American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association Medical guidelines for clinical practice for the diagnosis and management of thyroid nodules: executive summary of recommendations. Endocr Pract 2010;16:

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Kaes017.hwp 갑상선의 Poorly Differentiated (Insular) Carcinoma Insular Carcinoma: An Aggressive Subtype of Differentiated Thyroid Neoplasms Seok-Jin Nam, M.D., Sang-Dal Lee, M.D., Hal-lin Park, M.D., Young-Ryun Oh, M.D.