대한내과학회지 : 제 77 권제 5 호 2009 특집 (Special Review) - 갑상선암의최신지견 갑상선암의초음파, 세포및유전자진단 전남대학교의과대학내과학교실, 화순전남대병원내분비대사내과 강호철 Ultrasonographic, cytologic and genetic diagnosis of thyroid cancers Ho-Cheol Kang, M.D., Ph.D. Department of Internal Medicine, Chonnam National University Medical School, Department of Endocrinology and Metabolism, Chonnam University Hwasun Hospital, Gwangju, Korea Thyroid nodules are very common in adults, but only small fraction of them are malignant. The primary aim in investigating a thyroid nodule is to exclude the possibility of malignancy, which occurs in about 5% of nodules. Thyroid ultrasonography (US) provides not only anatomic details of the nodule, but also features of nodules that increase the likelihood of malignancy. Hypoechogenicity, ill-defined margin, microcalcifications, taller-than-wide shape, and associated pathologic cervical lymphadenopathies are important US features, suggesting thyroid cancer. These findings are helpful in risk stratification of the nodules and in deciding which nodule should be sampled in multinodular goiter. Fine-needle aspiration cytology (FNA) is the most accurate diagnostic test for most thyroid nodules, but the challenge remains in indeterminate cytologic category and inadequate samples. US-guided FNA can improve the diagnostic yield by reducing non-diagnostic specimens, and especially useful in thyroid nodules that are impalpable, posteriorly located, densely-calcified, or mixed solid-cystic. There has been significant progress in biomarkers that could improve the accuracy of FNA and predict disease aggressiveness. Physicians caring for patients with thyroid nodules need to develop a rational, cost-effective approach to ordering and interpreting imaging and diagnostic tests in the evaluation of the thyroid nodule. (Korean J Med 77:543-551, 2009) Key Words: Thyroid nodule; Thyroid cancer; Thyroid ultrasonography; Fine-needle aspiration biopsy; Genetic markers 서론갑상선결절은매우흔하며진단과정에서가장중요한것은악성결절은진단하는것이다. 갑상선초음파 (thyroid ultrasonography, US) 를이용하면전체인구의약 50% 에서결절이발견되며크기에관계없이전체갑상선결절의약 5% 는갑상선암이다 1). 고해상도갑상선초음파는갑상선의해부학적정보를가장예민하게검사할수있는검사법으로갑상선결절의초음파특징을제공하여악성결절을예측하는데도움을주며미세침흡인세포검사 (fine-needle aspiration cytology, FNA) 시초음파유도를제공하여적절한검체를획득하는데도움을준다 1,2). 분자생물학적기법의발달은미량의검체에서다양한생물학적표지자 (biologic marker) 의측정을가능하게했고, 이는미결정형결절에대한진단뿐만아니라갑상선암의예후를예측할수있는영역까지진보하고있다 3). 필자는최근몇몇학회에서출판된권고안과 4-7) 실제임상경험을배경으로갑상선암의진단과정에서갑상선초음파, 미세침흡인세포검사및유전자검사법의역할을정리하고자한다. - 543 -
- The Korean Journal of Medicine: Vol. 77, No. 5, 2009 - 갑상선암의초음파진단갑상선초음파는갑상선결절의크기, 개수, 각결절의초음파특성및경부림프절병증에대한정보를실시간으로제공한다 8). 모든갑상선결절환자에서진단목적의갑상선초음파검사를시행할것이권고되는데 4-7), 이는촉지되는단일결절환자에서도갑상선초음파를시행하면약 20~48% 환자에서검사가필요한추가적인갑상선결절을발견할수있고 9) 갑상선결절에대한자세한정보를제공하여 FNA 시행방법을결정하는데도움을주기때문이다 1,2). 1. 갑상선암을시사하는초음파소견갑상선결절의크기와개수는암의가능성을예측하는데도움이되지않으므로각결절의에코발생도 (echogenicity), 석회화, 경계부위및모양에유념하여관찰해야한다 2,10). 갑 상선암의가능성을높이는초음파소견들로저에코결절 (hypoechogenicity), 불규칙한경계 (irregular or spiculated margin), 미세석회화 (microcalcifications), 둥글지않고긴모양 (tallerthan-wide shape) 및동반되는병적경부림프절비대를들수있다 ( 그림 1) 8,11-13). 결절내에증가된도플러혈관신호가악성의가능성을높인다고알려져있으나 14,15) 작은갑상선유두암종이많은국내환경에서는감별진단에도움이되지않는다 12). 미세석회화이외에거친석회화 (dense or coarse calcifications) 도악성의가능성을높일수있는소견으로 FNA 시행시적절한검체의획득에어려움이있으므로주의한다 16-18). 저에코결절은악성의가능성을높이는중요한소견으로갑상선전면의띠근육 (strap muscle) 에코보다더낮다면악성의가능성이매우높다 ( 그림 1A). 저에코결절소견은갑상선의소포구조가작아지고세포밀도가높아지는경우초음파투과가잘되기때문에발생하는것으로알려져있다 19). A B C Figure 1. Thyroid ultrasonographic features suggesting thyroid cancer. (A) A marked hypoechoic nodule with ill-defined lobulated margin. (B) Multiple microcalcifications in the hypoechoic nodule. (C) A hypoechoic nodule with taller-than-wide shape. (D) A nodule with dense calcifications. All cases were confirmed to be thyroid papillary carcinomas after surgery. D - 544 -
- Ho-Cheol Kang. Ultrasonographic, cytologic and genetic diagnosis of thyroid cancers - A B C Figure 2. A case of cystic colloid nodule with multiple comet-tail artifacts. (A) Multiple comet-tail artifacts are often misinterpreted as microcalcifications (inset). (B) and (C) Old hemorrhagic fluid intermixed with colloid material (arrows) was aspirated using 19 G needle. 종종너무심한저에코소견을보이는결절은낭성결절 (cystic nodule) 로오인할수있는데, 결절후벽의초음파증강 (posterior wall enhancement) 유무를관찰하면오류를피할수있다. 하시모토갑상선염혹은그레이브스병과같이미만성갑상선질환에동반된갑상선결절은실제저에코결절이더라도동일에코 (isoechoic) 로관찰될수있으므로주의한다. 갑상선결절에서불규칙한경계소견은대부분의갑상샘유두암종이피막을형성하지않고침윤성성장을하므로관찰되는소견이다 ( 그림 1A, 1B). 갑상선결절의변연부에보이는저에코의띠 (halo) 가반드시양성결절을의미하지는않으므로 FNA를통해확인해야한다. 결절내의미세석회화는갑상선유두암종에서조직학적으로보이는사종체 (psammomma body) 가그본체로특이도가높은소견이다 ( 그림 1B). 초음파상고에코의점처럼 (punctate) 보이며대개소리그림자를동반하지않는다. 대표적인양성결절인콜로이드낭 (colloid cyst) 에서보이는혜성꼬리허상 (comet-tail artifact) 을미세석회화로오인하는경우가있으므로감별에유의해야한다 13,20). 혜성꼬리허상은콜로이드가탈수되어형성된콜로이드결정때문에보이는현상으로양 성결절을시사하는소견이다 ( 그림 2) 21). 결절의모양이둥글지않고긴소견은암의경우원심성성장을하지만모든방향으로그성장이균일하게이루어지지않기때문이며, 암의진단에특이도가높다 ( 그림 1C) 11,12). 갑상선암을시사하는의심스러운림프절병증의소견들로는크기 8 mm, 둥근모양 (short-to-long axis 0.5), 림프절에코가높음, 점석회화혹은미세석회화, 림프절문이관찰되지않음, 낭성변화및컬러도플러검사상변연부의혈류증가소견을들수있다 22). 초음파검사시흔히보이는반응성림프절병증은저에코의타원형으로중심부에특징적인림프절문이고에코의선상으로관찰된다. 양성결절임을시사하는중요한소견으로동일에코와스폰지모양을들수있는데국내에서시행된다기관연구결과에의하면갑상선결절이동일에코이면서스폰지모양을보인경우 100% 양성결절이었다고한다 12). 2. 갑상선암예측을위한갑상선초음파검사의정확도갑상선암을시사하는각각의단일초음파소견의예민도는낮으나특이도는비교적높으며두가지이상의의심소 - 545 -
- 대한내과학회지 : 제 77 권제 5 호통권제 591 호 2009 - 견을보이는경우약 85~93% 의종양성병변을진단할수있다 2,10). 이는비교적고위험소견을보이는결절을선별하여 FNA가가능함을시사하며갑상선우연종환자에서 FNA의시행여부와다결절성갑상선종환자에서 FNA를시행할결절을결정하는데도움을준다 6,11). 갑상선결절의크기와초음파소견에근거하여선택적 FNA를시행할것을권고하는영상의학과의의견이있으나 6) 1 cm 미만의미세갑상선유두암종이흔한국내의현실에그대로적용시키기는어렵다. 3. 새로운갑상선초음파기술파노라마갑상선초음파 (panoramic thyroid ultrasonography) 기술의등장은과거한영상에갑상선전체의병변을표현할수없었던제한점을해결하였으며갑상선양엽과주변경부림프절을포함하는폭넓은영상을가능하게하였다 ( 그림 2A) 23). 갑상선종이큰경우에도유용하며갑상선및그주변병변을한영상에표현할수있어의료진간의의사소통에도도움을줄수있다. 갑상선결절의단단함정도를초음파기술로표현할수있는갑상선초음파탄성도검사 (thyroid ultrasound elastography) 도임상에도입되었는데, 초음파탐색자로결절을압박시변화되는초음파신호를분석하여결절의단단한정도를색깔로표현해준다 24). 갑상선초음파검사와 FNA 결과미결정형소견을보이는경우수술여부를결정하는데도움이될수있다 25). 세포학적진단갑상선결절의수술적절제여부를결정하는데가장직접적인정보를제공하는것은 FNA이며, 이는임상적소견과초음파검사만으로는양성과악성결절을구별할수없기때문이다 8). 숙련된임상가의시술과갑상선병리에익숙한세포병리학자의판독을전제로한다면약 95% 의정확도를가진신속하며안전한검사법이다 2). 전통적인촉진에근거한 FNA보다초음파유도미세침흡인세포검사 (ultrasound-guided fine needle aspiration biopsy, US-FNA) 가최근더많이이용되는데, 이러한배경에는촉지되지않은갑상선우연종의증가, 다결절성갑상선종에서검사결절의선정, 낭성결절에서낭액으로인한적절한검체획득의문제점등을해결할수있기때문이다 26,27). 연구자에따라차이가있으나약 5% 의위양성과위음성률이알려져있고소포성종양 (follicular neoplasm) 과같은미결정형의문제가있으나, 대부분의갑상선 암이갑상선유두암종인국내상황에서가장큰문제는부적절한검체로인한것이다. 필자는 US-FNA 의적절한술기습득을위한노력이부적절한검체의문제를감소시킬수있다고생각한다. 1. US-FNA 의기본술기환자를눕히고어깨밑에베게를넣어목을신전시키면갑상선을관찰하기쉽다. 미만성갑상선질환유무를관찰하고, 각갑상선결절의특징을면밀하게관찰하여크기에관계없이가장악성의가능성이높은결절에서 US-FNA를시행한다. 1 cm 미만의작은결절에서는위험요인이있을때선택적인 US-FNA가권고되는데그러한소견들로갑상선암의가족력, 두경부방사선치료과거력, 갑상선초음파소견상위험소견을들수있다 4). 다결절성갑상선종의경우두개이상의결절에서 US-FNA를시행하면위음성의가능성을감소시킬수있으나 5) 환자의불편감에대한배려가필요하다. 대부분국소마취가필요하지않지만통증에대한공포감이심한환자혹은검사과정이어려울것으로예견되는경우에는국소마취를미리시행하는것이좋다. 리도카인주사시공기방울이포함되어피하에주사될경우초음파검사에지장을초래하므로주의한다. US-FNA에는 23~27 G 바늘이흔히이용된다 ( 그림 3B). 하지만낭성결절의낭액을배액하기위해서는 18~19 G 바늘이필요할수있고콜로이드성분이많아점도가높은낭액의경우더욱그러하다. 필자는 27 G 바늘을주로사용하는데심한통증없이시술을부드럽게이끌수있고혈액의흡인으로인한부적절한검체의가능성을감소시킬수있기때문이다. 검체를얻는방법에는흡인법과비흡인법이있는데필자는비흡인법을주로사용하며비흡인법만으로충분한검체가얻어지지않는경우흡인법을추가로사용한다. 어떤방법이든시술자에게익숙한검사법이최선이겠으나비흡인법이쉽게배울수있고덜침습적이며작은갑상선결절의검사에유리하다 28-30). 바늘을연필잡듯이엄지와검지로잡고초음파탐색자의중앙에결절이위치하도록초음파유도를하고탐색자중앙의피부를통해약간비스듬하게바늘을진입시키면바늘의끝이결절로진입하는것을실시간으로확인할수있다 ( 그림 3A). 시술과정중바늘끝은항상관찰할수있어야하며바늘의사단 (bevel) 이위를향하도록진입시켜야잘보인다. 결절의다양한부위에서바늘의빠른전후운동과회전운동을시행하면모세관현상에의해검체가바늘의허브 (hub) 부위로올라오는데이때바늘을즉시제거 - 546 -
- 강호철. 갑상선암의초음파, 세포및유전자진단 - A Figure 3. (A) US-guided FNA without suction (capillary technique). (B) Needles used in FNA. A 27 G needle is useful for most nodules and less painful. Large bore needles (18~19 G) are good for removal of thick cystic fluid. B A Figure 4. Tips for difficult US-FNA. (A) A case of cystic papillary carcinoma. FNA should be done in solid portion. (B) A densely calcified nodule. When the calcified nodule cannot be penetrated with the needle, obtain the sample from the interface between the nodule and normal thyroid parenchyme. B 해야혈액으로검체의희석을예방할수있다. 결절의중심부는낭성변화와같은이차변성으로적절한검체를얻기어려우므로결절의주변부에서검사를시행하는것이좋다. 얻어진검체는지체없이주사기를이용하여슬라이드로단번에밀어내고다른슬라이드를이용하여얇게바른다음즉시 95% 에탄올에담가고정해야건조인공물 (dry artifact) 로인한문제를예방할수있다. 한결절당적어도 2~4회 US- FNA를시행하며한번의검체는한장의슬라이드제작에만이용한다. 단번에많은검체를얻으려는노력은부적절한검체의주된요인으로, 많이얻어진검체는대부분혈액이거나낭액이다. 2. 검체획득이어려운결절에서의 US-FNA 낭성결절 (cystic thyroid nodule) 은반복적인낭액의흡인으 로적절한검체를얻기힘들다 27). 초음파유도하에낭액을배액하고남아있는고형부위에서 US-FNA를시행해야한다 ( 그림 4A). 낭성결절에서낭액을흡인하기위해지나친음압을거는경우결절내에출혈을유발하므로완전한배액은피하는것이좋다. 혈관이풍부한결절에서적절한검체를얻는방법은미리도플러초음파를시행하여혈관분포를파악 (vascular mapping) 하는것으로혈관이없는부위에서 US-FNA를시행하면적절한검체를얻을수있다 31). 초음파탐색자로결절을누르면서 US-FNA를시행해볼수도있으나결절혈관이동맥인경우효과는없다. 심한석회화를동반한결절에서도적절한검체를얻기어렵다 18). 난각석회화 (eggshell calcification) 의경우석회화가얇다면바늘의진입이가능하나그렇지않은경우가더흔 - 547 -
- The Korean Journal of Medicine: Vol. 77, No. 5, 2009 - 하다. 석회화된결절과정상갑상선조직의경계부위에서바늘을긁듯이시행하면적절한검체를얻는경우도있으므로시도해본다 ( 그림 4B) 32). 피부에너무근접했거나너무뒤쪽에위치한결절도 US- FNA를시행하기어려운데바늘의진입각도를조절하여해결할수있다. 피부에근접한결절의경우바늘은피부와거의수평이되도록눕혀서진입시키면바늘이잘고정되어시술이용이해지며깊은부위의결절은바늘을거의 90 로세워진입시켜야 US-FNA가가능하다. 2. 세포학적결과에따른의사결정갑상선병리에익숙한유능한세포병리학자의판독은결정적으로중요하다. 문제점은병리학자마다세포학적판독결과를보고하는방식에차이가있다는것으로세포학적판독결과가임상적소견과큰차이를보이는경우에는의사전달과정의문제점을파악해보도록노력한다. 가능하다면 1) 부적절한검체 (inadequate) 2) 양성결절 (benign) 3) 미결정형 (indeterminate) 4) 의심스러운소견 (suspicious) 5) 악성 (malignant) 이란다섯가지범주로표준화하여보고하는체계를구축하면임상가들의의사결정에혼란을감소시킬수있다. 최근미국암센터 (National Cancer Institute, NCI) 주관으로 FNA 표준화를위한회의결과가출판되었는데 ( 표 1) 미결정형의범주를두가지로더세분화하여악성의가능성을평가할것을권고하고있다 33). 미결정형을소포성종양과임상적의의가결정되지않은비정형성병변 (atypia of undetermined significance) 으로세분하였고, 각각 20~30%, 5~ 10% 의암위험도가있으므로소포성종양의경우수술적확진이필요하나임상적의의가결정되지않은소포성병변의경우 3~6개월후 US-FNA를다시시행후동일한비정형 (atypia) 소견을보이거나더나쁜소견이보이는경우수술을시행할것을권고하고있다 33). 분자표지자및유전자진단분자생물학적기법의발전은미량의 FNA 검체에서단백질, RNA 혹은 DNA 분석을가능하게했으며, 이러한생물학적표지자는세포의형태학적소견에근거한 FNA의단점을보완하여보다정확하게갑상선암을진단할뿐만아니라임상적공격성을예측할수있는단계까지진보하고있다 3). 면역조직화학염색법으로 FNA 검체에서 galectin-3, HBME-1 등과같은단백질표지자에대한검사를시행하면갑상선암의진단에도움이될수있어미결정형결절에서의사결정에도움을줄수있다 34,35). 최근소포성병변에서 galectin-3 표지자를이용한전향적연구결과를보면 78% 의예민도와 93% 의특이도를보여 FNA를대체할수는없지만보완적인도구로이용될수있음을보여주었다 34). 갑상선암의 70~80% 에서발견되는유전자돌연변이를이용하여갑상선암을진단하려는노력이이루어지고있고, 그대상은갑상선유두암종에서발견되는 BRAF, RET/PTC, RAS 돌연변이와갑상선소포암종에서보이는 RAS, PAX8/ PPARγ 등이다 36-38). 국내에서이루어진결과에의하면 BRAF (V600E) 돌연변이는갑상선유두암종의약 80% 에서발견되는가장흔한돌연변이로다른지역보다그빈도가높다 38). 실제 FNA의보조적인검사로국내에서도임상에이용되는데진단목적뿐만아니라암의공격성을예측하여수술범위등치료의적극성을결정하기위함이다 39). 이는 BRAF 돌연변이를보이는갑상선유두암종에서림프절전이, 원격전이및재발과같은임상적공격성의지표들이더흔하게관찰 Table 1. NCI thyroid fine-needle aspiration (FNA) guidelines committee IV: The suggested thyroid FNA classification scheme (adopted from reference 33) Suggested category Alternate category Risk of malignancy Benign <1% Atypia of undetermined significance Indeterminate follicular lesions R/O neoplasm Atypical follicular lesion 5~10% Cellular follicular lesion Neoplasm Suspicious for neoplasm 20~30% Suspicious for malignancy 50~75% Malignant 100% Nondiagnostic Unsatisfactory - - 548 -
- Ho-Cheol Kang. Ultrasonographic, cytologic and genetic diagnosis of thyroid cancers - 되기때문이다 36). 다양한돌연변이를 FNA 검체에서동시에검사한다면단일검사보다그정확성을향상시킬수있을것이며, 실제임상적으로문제되는미결정형결절의진단에이용한경우돌연변이가한가지라도발견되는경우갑상선암의가능성은 100% 였다고한다 40). 하지만특정돌연변이를보이지않는갑상선암도있으므로유전자검사만을전적으로신뢰할것은아니며, 유전자검사는 FNA에보완적인도구로발전할것으로생각한다. 결론급증하는갑상선결절환자에서가장중요한것은갑상선암을진단하는것이다. 갑상선초음파검사는갑상선을가장세밀하게관찰할수있는영상진단법으로결절의크기에대한정보뿐만아니라각결절의초음파특성을제공하여암의가능성을예측하는데도움을준다. 저에코, 미세석회화, 불분명한경계, 둥글지않고긴모양, 동반되는병적경부림프절병증은악성결절을시사하는매우중요한초음파소견이지만이를근거로갑상선암을진단할수는없다. 갑상선미세침흡인세포검사는갑상선암진단에있어결정적이며직접적인정보를제공하는안전하며효과적인검사법이지만세포학적미결정형과부적절한검체로인한문제점을가지고있다. 초음파유도미세침흡인세포검사는적절한검체획득의가능성을높일수있는검사법으로검체획득이어려운낭성결절, 촉지되지않는작은결절, 갑상선후방부결절및심한석회화를동반한결절에서유용하며다결절성갑상선결절에서검사할결절을선택하는데도움을준다. 특징적인세포학적소견을보이는갑상선유두암종이갑상선암의대부분인국내상황에서는소포성종양과같은미결정형으로인한문제는적으므로적절한검체의획득은진단에있어결정적이다. 세포병리학자와의소통은중요하며가능하다면세포학적결과보고방식을표준화해야소통과정의오류를감소시킬수있다. 미량의미세침흡인술검체를이용한유전자검사는형태학적소견에근거한세포학적결과를보완할수있는방법으로미결정형결절에서의사결정과정에도움이될수있으며갑상선암의예후에대한정보를제공하여치료의적극성을결정할수있는수준까지진보하고있다. 고해상도영상장비의발전으로갑상선결절이란임상적문제는더욱증가할것이며이를비용- 효율적으로해결하려는임상가의노력은매우중요하다. 갑상선초음파와초음파유도미세침흡인세포검사는매우시술자의존적인검사법 이므로유능한시술자가되려는임상가들의노력은지속되어야하며급격히진보하고있는생물학적표지자에대한연구는이러한검사법들이안고있는단점을보완해나갈것으로기대한다. 중심단어 : 갑상선결절 ; 갑상선암 ; 갑상선초음파 ; 미세침흡인세포검사 ; 유전자검사 REFERENCES 1) Hegedus L. Clinical practice: the thyroid nodule. N Engl J Med 351:1764-1771, 2004 2) Gharib H, Papini E. Thyroid nodules: clinical importance, assessment, and treatment. Endocrinol Metab Clin North Am 36:707-735, vi, 2007 3) Shibru D, Chung KW, Kebebew E. Recent developments in the clinical application of thyroid cancer biomarkers. Curr Opin Oncol 20:13-18, 2008 4) Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Sherman SI, Tuttle RM. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 16:109-142, 2006 5) Gharib H, Papini E, Valcari R, Baskin HJ, Crescenzi A, Dottorini ME, Duick DS, Guglielmi R, Hamilton CR Jr, Zeiger MA, Zini M. American Association of Clinical Endocrinologists and Associazione Medici Endocrinologi medical guidelines for clinical practice for the diagnosis and management of thyroid nodules. Endocr Pract 12:63-102, 2006 6) Frates MC, Benson CB, Charboneau JW, Cibas ES, Clark OH, Coleman BG, Cronan JJ, Doubilet PM, Evans DB, Goellner JR, Hay ID, Hertzberg BS, Intenzo CM, Jeffrey RB, Langer JE, Larsen PR, Mandel SJ, Middleton WD, Reading CC, Sherman SI, Tessler FN. Management of thyroid nodules detected at US: Society of Radiologists in Ultrasound consensus conference statement. Radiology 237:794-800, 2005 7) Kim WB, Kim TW, Kwon HS, Moon WJ, Lee JB, Choi YS, Kim SK, Kim SW, Chung KW, Baeck JH, Kim BI, Park DJ, Na DG, Choe JH, Chung JH, Jung HS, Kim JH, Nam KH, Chang HS, Chung WY, Hong SW, Hong SJ, Lee JH, Yi KH, Jo YS, Kang HC, Song M, Park JW, Yoon JH, Kang SJ, Lee KW. Management guidelines for patients with thyroid nodules and thyroid cancer. J Korean Soc Endocrinol 22:157-187, 2007 8) Hegedus L. Thyroid ultrasound. Endocrinol Metab Clin North Am 30:339-360, viii-ix, 2001 9) Marqusee E, Benson CB, Frates MC, Doubilet PM, Larsen PR, Cibas ES, Mandel SJ. Usefulness of ultrasonography in the management of nodular thyroid disease. Ann Intern Med 133:696-700, 2000 10) Papini E, Guglielmi R, Bianchini A, Crescenzi A, Taccogna S, - 549 -
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