대한초음파의학회지 2011; 30(1) 한눈에보는베데스다갑상선세포병리보고체계 문희정 곽진영 김은경 연세대학교의과대학영상의학과 A Glance at the Bethesda System for Reporting Thyroid Cytopathology Hee Jung Moon, MD, Jin Young Kwak, MD, Eun-Kyung Kim, MD Department of Radiology, Research Institute of Radiological Science, Yonsei University College of Medicine J Korean Soc Ultrasound Med 2011; 30: 1-6 Received October 26, 2010; Revised October 29, 2010; Accepted January 19, 2011. Address for reprints : Eun-Kyung Kim, MD, Department of Radiology, Research Institute of Radiological Science, Yonsei University College of Medicine, 250 Seongsan-no, Seodaemun-gu, Seoul 120-752, Korea. Tel. 82-2-2228-7400 Fax. 82-2-393-3035 E-mail: ekkim@yuhs.ac Fine needle aspiration biopsy (FNAB) is an accurate and cost effective diagnostic tool for differentiating malignant and benign thyroid nodules. Despite the efforts of the Papanicolaou group to standardize thyroid cytopathology reporting, no universal standard reporting system exists to date. Pathologists believe that clinicians sufficiently understand FNAB cytological reports. However, this is not necessarily the case. There is often a significant gap between pathologists beliefs and the clinicians understanding. As a result, we propose The Bethesda System for Reporting Thyroid Cytopathology by the National Cancer Institute. In this editorial, we briefly introduce the Bethesda System for Reporting Thyroid Cytopathology. Key words : Thyroid; Ultrasound (US); Fine needle aspiration biopsy; Bethesda System 서론 화성에서온임상의사, 금성에서온병리의사, 이는 Powsner 등이발표한논문의제목이다 [1]. 이제목만으로도병리의사가의미하는판독결과와그것을보는임상의사사이에괴리가얼마나큰지짐작할수있다. 왜병리의사와임상의사사이에소통의문제가있는것일까? 세침흡입생검 (fine needle aspiration biopsy) 은갑상선결절의양성과악성을구별하는데정확한검사이며, 이검사가널리쓰인후불필요한수술을많이줄일수있었다 [2-7]. 세침흡입생검이갑상선결절의진단과치료에핵심역할을하나, 생검의결과를보고하는양식은매우다양하였다. 1997년, Papanicolaou 등은세침흡입생검결과를양성 (benign), 비정형세포의존재 (atypical cell present), 악성의심 (suspicious for malignancy), 악성 (malignant), 불충분검체 (inadequate or unsatisfactory) 의 5가지로분류, 보고하는지침서를발표하였다 [8]. 이들은비정형세포의존재는독립적인진단명으 로사용할수없으며, 반드시임상소견과비교하여다른권고가있어야한다고명시하였다 [8]. Baloch와 LiVolsi 등은양성, 임상의미를정확히알수없슴 (indeterminate), 악성의심, 악성, 불충분검체의 5가지로분류하는권고안을발표하였다 [9]. Baloch 등은악성의심은소포변형유두암 (follicular variant of papillary thyroid carcinoma) 에사용해야한다고명시하였다 [9]. 이처럼저자들마다세침흡입생검의결과를보고하는용어가다르고, 같은용어를사용하더라고다른정의를내리고있다. 같은기관에근무하는병리의사들조차도서로각기다른권고안을사용하며, 심지어는결론이없이소견만을기술한결과보고도있다 [10, 11]. 양성, 악성의결과는논란의여지가적으나, 비정형세포의존재, 악성의심, 임상의미를정확히알수없슴등의결과는임상의사들을혼란스럽게하며, 때로는병리의사가말하고자하는바를임상의사가정확히인지하지못하는경우도있다 [10, 11]. 불충분검체와임상의미를알수없슴을혼돈하는경우도있다 [10, 11]. 병리의사들은임상의사가자신이보고한결과를잘이해하고있을것이라고믿지만 [1, 11], Powsner 등의연구에의하면약 30% 의 - 1-
대한초음파의학회지 2011;30(1) 임상의사들이병리결과를보고병리의사가의도한것과는다른결과로생각을하였다 [1]. 특히경험이적은의사들에서더빈번하였으니, 전공의에게결과를듣는전문의가있는기관들이많으니문제가아닐수없다 [1]. 이런문제를조금이라도줄여보고자 2009년 The Bethesda System for Reporting Thyroid Cytopathology 를발표하였다 [12]. 이에 Bethesda system이무엇인지소개하고자한다. 1. The Bethesda System for Reporting Thyroid Cytopathology 세침흡입생검결과보고에대한용어와다른이슈들을논의하기위해 2007년 10월 22, 23일에걸쳐미국의국립암센터 (National Cancer Institute, NCI) 주도로회의를열었다. 회의가개최되기 18개월전에 PubMed의영어논문들을검색, 고찰, 정리하여초안을완성하였다. 완성된초안을웹사이트에올려다양한전공을가지고있는의사들이웹사이트를통해많은논의를하였다. 웹사이트를통한토의과정중초안이여러번수정되었고, 마지막으로수정된안을논의하기위해 2007 년 10월미국국립암센터주도로 Bethesda에서회의를개최하였다. 이회의에서다시한번심도깊은논의를하였고이를바탕으로권고안을발표하였다. 개최지인 Bethesda 도시의이름을따서 Betheda system, 혹은국립암센터의권고안 (NCI classification) 으로명명하였다 [12]. Bethesda system은갑상선결절의세침흡입생검결과를 6개의범주로분류하였는데, 일부범주는 2개의이름이있다 (Table 1). 각범주별악성의위험도를예측할수있을뿐아니라진료권고안을제공하고있다 (Table 2). 1) 불충분검체 (Nondiagnostic or Unsatisfactory) 여러가지이유로세침흡입생검의결과를도출할수없는경우의범주다. 먼저도말의질적인문제로인해판독이어려운경우로, 검체에너무많은피가섞이거나너무두껍게도말된경우, 혹은알코올로고정시킨검체가말라서판독이어려울때이에해당한다 [13]. 다음으로양적인문제로세포수가적어결과를도출하기어려운경우이다 [14, 15]. 소포세포 (follicular cell) 수가 10개이상인그룹이최소 6개가되지못하는경우불충분검체로분류한다 [15, 16]. 이범주는전체세침흡입생검중 2-20% 까지발생한다고보고되었으나, 10% 를넘지않도록유의해야한다 [16, 17]. 세포수가적더라도불충분검체로분류되면안되는예외가있다. 비정형세포가있는경우에세포수가 10개이상인그룹이최소 6개가되지않더라도비정형세포의존재 (atypical cell present) 라는범주로분류하는것이원칙이다. 또한 10개이상인그룹이최소 6개가되지못하는경우라도콜로이드가많고거대소포결절 (macrofollicular nodule) 이면양성으로분류할수있다. 낭성흡인만된경우 (cytic fluid only) 라는것은세침 흡입생검시행시검체에소포세포는없고대식세포 (macrophage) 만포함된경우이다. 이결과까지불충분검체로분류한다면범주 1은무려 30% 에이른다 [17-20]. 일부기관들에서는낭성흡인만된경우더라도위음성이적기때문에불충분검체로분류하지않고양성으로분류하기도한다 [18, 21]. 그러나 Bethesda system에서는낭성흡인만된경우를범주 1, 불충분검체로분류하였다. 왜냐하면이경우악성율은 4% 로불충분검체의악성율, 1-4% 와비슷하기때문이다 [17, 21]. 낭성흡인만된경우를불충분검체로포함하였지만, 초음파소견이악성의심소견이없고결절의대부분이낭성성분이라면임상의사는이를양성으로간주할수있다는조항을함께명시하여초음파소견과의비교를강조하였다. 첫번째생검에서불충분검체로진단된경우다시한번초음파유도하재생검시 88% 까지진단적결과를얻을수있었다 [15, 17, 20, 22]. 그러나일부결절은여전히불충분검체의결과를얻으며, 이경우악성율이 10% 이기때문에수술을권유한다 [22]. 기존의세침흡입생검결과를 Bethesda system으로재분류한연구들이있다 [23, 24]. 이연구들에서는낭성흡인만된경우를불충분검체로분류하였고, 범주 1은전체생검중 11.1%, Table 1. The Bethesda System for Reporting Thyroid Cytopathology: Recommended Diagnostic Categories [12] I. Nondiganotic or Unsatisfactory Cyst fluid only Vritually acellular specimen Other (obscuring blood, clotting artifact, etc) II. Benign Consistent with a benign follicular nodule (includes adenomatoid nodule, colloid nodule, etc) Consistent with lymphocytic (Hashimoto) thyroiditis in the proper clinical context Consistent with granulomatous (subacute) thyroiditis III. Atypia of Undetermoned Significance or Follicular Lesion of Undetermined Significance IV. Follicular Neoplasm or Suspicious for a Follicular Neoplasm Specify if Hurthle cell (oncocytic) type V. Suspicious for Malignancy Suspicious for papillary carcinoma Suspicious for medullary carcinoma Suspicious for metastatic carcinoma Suspicious for lymphoma VI. Malignant Papillary thyroid carcinoma Poorly differentiated carcinoma Medullary thyroid carcinoma Undifferentiated (abaplastic) carcinoma Squamous cell carcinoma Carcinoma with mixed features (specify) Metastatic carcinoma Non-Hodgkin lymphoma Other - 2-
문희정외 : 한눈에보는베데스다갑상선세포병리보고체계 18.8% 를차지했다 [23, 24]. 권고안인 10% 보다는조금높은수치이나이는낭성흡인만된경우를포함했기때문이다. 이범주의악성율은 8.9%, 32% 였다 [23, 24]. Theoharis 등의연구에서 32% 의높은악성율을보인이유는수술한환자를대상으로악성율을계산하였기때문인데, 전체 230명의불충분검체의결과를보인환자중, 25명만이수술을받았다 [24]. 2) 양성 (Benign) 세침흡입생검을시행하는결절중 60-70% 가양성의결과를얻는다. 양성의결과는범주 2, 양성으로명명하며위음성율은 0-3% 로낮다 [19, 20, 25]. 임프구성갑상선염 (lymphocytic thyroiditis), 아급성육아종성갑상선염 (subacute granulomatous thyroiditis) 도양성범주에속한다. Theoharis 등과 Jo 등의연구에서양성범주는전체생검중 73.8%, 59% 였다 [23, 24]. 위음성율은 Jo 등의연구에서는 1.1% 로낮았으나 Theoharis 등의연구에서는 9.8% 로높았다 [23, 24]. Theoharis 등의연구는수술한결절만을포함했을때문이며, 양성의결과를얻은결절중수술하지않은경우도포함한경우악성율은 0.4% 로낮았다 [24]. 곽등의연구에서도세침흡입생검상양성의결과를보인결절의위음성율은 1.9% 로낮았다 [25]. 일반적으로세포검사에서양성으로진단된결절은추적검사만을권하고있으나, 세포검사에서양성의결과를보였더라도초음파상악성이의심되는결절의악성율은 20.4% 로그렇지않은결절의악성율, 0.6% 에비해유의하게높았다 [25]. 따라서초음파상악성이의심되면생검의결과가양성이어도재생검을권유해야한다 [25, 26]. 3) 임상의미를알수없는비정형세포의존재, 임상의미를알수없는소포병변 (Atypia of Undetermoned Significance or Follicular Lesion of Undetermined Significance) 세침흡입생검의결과가양성, 악성의심, 악성중어느범주에도속하지않을때이범주로분류하며, 6개의범주중가장논란이되는범주다. Bethesda system이나오기전에도양성, 악성의경우보다는양성, 악성으로분류할수없는경우에많은논란이있었다. Bethesda 회의에서도이범주의존재에대해많은논란이있었지만많은의사들이이범주를남겨두기 를원해채택되었다. 어떤결절을이범주로분류해야하는지많은논의를하였고다음의결절들을이범주로분류할수있을것으로생각하였다. A. 콜로이드는적고많은미세소포가보이나소포신생물, 소포신생물의심을진단하기에는미약한경우 B. 소포세포도적고콜로이드도적으나존재하는세포가대부분 Hurthle 세포인경우 C. 건조나응고에의한인공물로인해소포세포의비정형유무를알기어려운경우 D. 임상적으로 Hurthle세포결절이아님에도불구하고 Hurthle세포로이루어진결절일경우 ( 임파구성갑상선염, 다결절갑상선종대 ) E. 검체중극히일부가유두암에합당한모양을보이나대부분은양성일경우 F. 낭종을이루는세포중일부가핵고랑 (nuclear grooves), 두드러진핵소체 (prominent nucleoli), 길어진핵과세포질 (elogated nuclei and cytoplasm), 세포질봉합체 (internuclear cytoplasmic inclusions) 모양을보이나대부분은양성인경우 G. 일부의세포에서만핵크기증가, 두드러진핵소체가보이는경우 1) 방사선요오드, carbimazole, 다른약제를사용한경력이있는환자 2) 갑상선결절이낭성변화나출혈로인한퇴행성변화에서회복된경우 H. 비정형림프구침윤이있으나, 비정형의정도가악성의심에는미치지못하는경우 I. 어느범주에도속하지않는경우이범주는반드시임상적중요도를평가할수없는비정형세포가있는경우에만사용되어야한다. 6개의진단범주중가장나중에생각해야하는범주이며, 전체생검의 7% 를넘으면안된다. Bethesda system이나오기전의연구들에서, 이범주는전체세침흡입생검의 3-6% 를차지했다 [20, 21]. Bethesda system을이용한후향적연구인 Theoharis와 Jo 등의연구에있어서도전체생검의 3.6%, 3.4% 를차지하여권고안인 7% 미만이었다 [23, 24]. 이범주로진단된결절은수술보다는재 Table 2. The Bethesda System for Reporting Thyroid Cytopathology: Implied Risk of Malignancy and Recommended Clinical Management [12] Diagnostic Category Risk of Malignancy (%) Usual Management Nondiagnostic or Unsatisfactory 01-4 Repeat FNA with US guidance Benign 00-3 Clinical follow-up Atypia of Undetermoned Significance or Follicular Lesion of 05-15 Repeat FNA Undetermined Significance Follicular Neoplasm or Suspicious for a Follicular Neoplasm 15-30 Surgical lobectomy Suspicious for Malignancy 60-75 Near-total thyroidectomy or surgical lobectomy Malignant 97-99 Near-total thyroidectomy - 3-
대한초음파의학회지 2011;30(1) 생검을권한다. 대부분의경우재생검을시행하면진단적결과를얻을수있다. 그러나약 20% 정도에서는여전히임상의미를알수없는비정형세포의존재, 임상의미를알수없는소포병변의결과를얻었다 [20]. 이경우초음파결과, 임상소견을고려하여재생검보다는수술이나추적검사를시행할수있다. 이범주의악성율은 5-15% 를유지하도록권한다. 이범주에속하는모든결절에대해수술을시행하지않아정확한악성율을알기는어려우나, Jo 등의연구에서 104 결절중 53개가수술을받아이범주의결절들중가장많이수술을하였고, 악성율을 17% 로보고하였다 [23]. 4) 소포신생물혹은소포신생물의심 (Follicular Neoplasm or Suspicious for a Follicular Neoplasm) 일부기관에서는소포신생물 (follicular neoplasm) 보다소포신생물의심 (suspicious for a follicular neoplasm) 이라는용어를더선호한다. 왜냐하면이범주의결절중, 35% 는신생물이아니라단순한증식증 (hyperplasia) 이기때문이다 [21, 27-30]. 따라서두가지용어를모두사용하기로하였다. 세침흡입생검으로는소포선종과소포암 (follicular adenoma or follicular carcinoma), Hurthle세포선종과 Hurthle세포암 (Hurthle cell adenoma or carcinoma) 을구별할수없기때문에이범주는소포암과 Hurthle세포암을찾기위한스크리닝범주다. 이범주의결절은재생검이의미가없고, 진단을위해수술을시행해야한다. 검체에포함된세포가많고, 세포들이미세소포혹은지주배열 (microfollicular or trabecular arrangement) 을하고있으나콜로이드는적을때이범주로진단을할수있다. 유두암의소견에서보이는핵의모양을보이는경우이범주로진단하면안된다. 이범주의 15-30% 는악성으로최종진단된다 [19-21, 27]. 이범주의악성결절중많은부분을소포암이차지하기는하나상당부분은소포변종유두암이다 [18, 20, 27]. 나머지이범주의 70% 정도는소포선종이나증식증으로진단된다. 세계보건기구의분류에따르면 Hurthle세포선종, Hurthle 세포암은소포선종, 소포암의호산성변종이라고명시하였다 [31]. 그러나몇몇의연구에서소포신생물과 Hurthle세포생물은유전적으로다른종양으로보고를하였다 [32, 33]. 또한세포학적으로도다른모양을보이기때문에 Hurthle세포신생물인경우판독에명시할것을권하고있다. Hurthle세포신생물또한 16-25% 는신생물이아니라증식증으로최종진단이된다 [34, 35]. 나머지신생물의 15-45% 는악성으로, 나머지는 Hurthle세포선종으로최종진단된다 [19, 34, 35]. Theoharis 등과 Jo 등은이범주의모든결절을수술을하지않았으나, 악성율을 34.3%, 25.4% 로보고를하였다 [23, 24]. 5) 악성의심 (Suspicious for Malignancy) 유두암이의심되나세침흡입생검의검체가불충분하거나, 충분하더라도유두암을진단하는특징적인소견중일부만보이는경우이범주에속하게된다 [36]. 일부저자들은악성의심의범주에속하는결절의대부분이소포변종유두암이라고하였다 [36]. 유두암뿐아니라다른악성을의심할수있는결절들도이범주로분류한다 (Table 1). 이범주에속하는결절은수술로진단을해야한다. 그러나림프종, 전이가의심되는경우에는수술을하지않기때문에, 정확한진단을위해다른검사들을시도해볼수있다 [32]. 림프종이의심되는경우는면역화학염색등을할수있고, 수질암이의심되는경우칼시토닌, CEA, 크로모그라닌등의검사를시행하면진단에도움이될수있다 [32]. 유두암의심의경우 70-85% 정도에서악성으로진단된다 [19-21, 23, 24, 37-40]. 악성율이연구마다다른이유는모든결절에대해수술을시행하지않고, 포함된환자들의기준이다르고, 많은병리의사의판독이포함되었기때문이다. 6) 악성 (Malignant) 갑상선결절중악성은 3-7% 를차지하며이경우 97-99% 가악성으로진단된다 [18, 19, 21]. Theoharis와 Jo 등의연구에서이범주의악성율은 100%, 98.1% 였다 [23, 24]. 대부분의악성으로진단된결절은수술을시행하는것이원칙이나, 전이암, 비호지킨림프종, 미분화암의경우예외이다. 결론세침흡입생검의결과는다양한권고안들이있었고, 각권고안들마다다른범주로분류를하였다. 또한같은용어를사용하는범주라도다른정의를내려병리의사뿐아니라임상의사에게도혼란이있었다. 이에 Bethesda System이발표되었다. 물론이것이완벽한것은아닐것이다. 특히범주 3, 임상의미를알수없는비정형세포의존재, 임상의미를알수없는소포병변은논란의여지가많이있다. 아직많은연구가이루어지지는않았으나, Bethesda System을바탕으로한일부후향적연구들은각범주가의미하는악성율과진료권고안을실제진료에서적용할수있다고하였다 [23, 24]. Bethesda System 을많이이용하고, 병리의사와임상의사간의소통이원활해지면현재 Bethesda System이가지고있는문제를해결할수있을것으로생각된다. 금성출신의병리의사와화성출신의임상의사가지구에서원활한소통을할수있는날이오기를기대한다. - 4-
문희정외 : 한눈에보는베데스다갑상선세포병리보고체계 요 갑상선결절의세포학적진단이증가함에따라공통된용어와일관된대처방안이필요하다. 이에본종설에서는갑상선세포진단의베데스다체계를소개하고자한다. 약 References 1. Powsner SM, Costa J, Homer RJ. Clinicians are from Mars and pathologists are from Venus. Arch Pathol Lab Med 2000;124:1040-1046 2. Asp AA, Georgitis W, Waldron EJ, Sims JE, Kidd GS. Fine needle aspiration of the thyroid. Use in an average health care facility. Am J Med 1987;83:489-493 3. Castro MR, Gharib H. Thyroid fine-needle aspiration biopsy: progress, practice, and pitfalls. Endocr Pract 2003;9:128-136 4. Castro MR, Gharib H. Continuing controversies in the management of thyroid nodules. Ann Intern Med 2005;142:926-931 5. Hamburger JI. Consistency of sequential needle biopsy findings for thyroid nodules. Management implications. Arch Intern Med 1987;147:97-99 6. Pepper GM, Zwickler D, Rosen Y. Fine-needle aspiration biopsy of the thyroid nodule. Results of a start-up project in a general teaching hospital setting. Arch Intern Med 1989;149:594-596 7. 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