대한외과학회지 : 제74권제2호 Vol. 74, No. 2, February, 2008 원 저 갑상선휘틀세포암 (Hurthle Cell Carcinoma) 의임상적특징및예후인자 : 순수소포상갑상선암과의비교 1 아주대학교의과대학외과학교실, 2 연세대학교의과대학외과학교실 이잔디 1 ㆍ이승환 1 ㆍ최수윤 1 ㆍ남기현 2 ㆍ정웅윤 2 ㆍ소의영 1 ㆍ박정수 2 Hurthle Cell Carcinoma of the Thyroid Gland: Clinicopathologic Features and Treatment Outcome Compared with Pure Follicular Thyroid Carcinoma Jandee Lee, M.D. 1, Seong Hwan Lee, M.D. 1, Su-Yun Choi, M.D. 1, Kee-Hyun Nam, M.D. 2, Woong Youn Chung, M.D. 2, Eui-Young Soh, M.D. 1 and Cheong Soo Park, M.D. 2 1 Department of Surgery, College of Medicine, Ajou University, Suwon, 2 Department of Surgery, Yonsei University College of Medicine, Seoul, Korea 책임저자 : 박정수, 서울시서대문구신촌동 134 번지 120-752, 연세대학교의과대학외과학교실 Tel: 02-2019-3376, Fax: 031-219-5755 E-mail: ysurg@yuhs.ac 접수일 :2007 년 8 월 13 일, 게재승인일 :2007 년 11 월 13 일중심단어 : 휘틀세포암, 순수소포상암, 예후인자, 치료범위 91 Purpose: Hurthle cell carcinoma (HCC) of the thyroid gland is a rare disease that represents 3% of all thyroid carcinomas. HCC has been known as a more aggressive disease than the usual differentiated thyroid carcinoma. However, the biologic behavior and optimal treatment have come under considerable debate in recent years. This study was performed to evaluate the clinicopathologic features and treatment outcome of HCC. Methods: From April 1986 to August 2006, 18 patients with HCC and 216 patients with pure follicular carcinoma (PFC) underwent thyroidectomy at our institutions with a mean follow-up of 114 (range: 6 253) months. The clinicopathologic characteristics and treatment outcome of each group were compared, and the prognostic factors for disease-free survival were analyzed. Results: There were 14 women and 4 men with a mean age of 50 (range: 26 76) years. Compared with PFC patients, all of clinicopathologic features of HCC patients were different (gender, age, tumor size, multifocality, angioinvaion, invasion to adjacent structures, the subclassification and initial distant metastasis), but the high incidence of bilaterality was similar to the PFC patients (P<0.0001). The causespecific survival (CSS) rates at 10 years were 83.4% in the HCC patients and 89.3% in the PFC patients (P=0.702). Older age (greater than 45) (P=0.0125) and initial distant metastasis (P<0.0001) in the HCC patients, and an older age (P<0.0001), male gender (P=0.0039), angioinvasion (P= 0.0122), invasion to adjacent structures (P<0.0001), a widely invasive type (P=0.004) and initial distant metastasis (P<0.0001) in the PCC patients were independent prognostic factors for survival. Conclusion: After accounting for important biologic behaviors, patients with HCC had similar clinicopathologic characteristics and prognosis compared with that of the PFC patients. Therefore, HCC should be managed using the same treatment strategy as PFC. (J Korean Surg Soc 2008;74:91-97) Key Words: Hurthle cell carcinoma, Pure follicular carcinoma, Prognostic factors, Proper management 서 휘틀세포암 (Hurthle cell carcinoma) 은전체분화갑상선암의약 3% 내외의빈도를보이는소포상갑상선암의드문아형이다.(1) 병리조직검사상 75% 이상의휘틀세포 (Hurthle cell) 로구성되고이들이섬유상 (trabecular) 혹은소포상 (follicular) 군집을이루는특징을보이며, 피막침습이나혈관침습유무에따라악성여부가결정된다.(2) 휘틀세포암은순수소포상암 (pure follicular carcinoma) 에비해여성및고령에서호발하고더공격적인성향을보인다고알려져있다. 즉, 다발성, 국소림프절전이및원격전이의빈도가높으며전신스캔상요오드흡착정도가낮아방사성요오드치료효과가떨어진다.(3-5) 예후는재발률 7 53%, 10년생존율이 45 80% 등으로다양하게보고되어논란이많으나, 순수소포상암에비해비교적불량한경과를보인다고알려져왔다.(6-9) 하지만, 최근에는환자의연령및암종의병기를동일한조건에서비교하였을때순수소포상암과공격성향및예 론
92 J Korean Surg Soc. Vol. 74, No. 2 후에서큰차이가없다고보고되고있다.(10-12) 즉, 동일한조건의순수소포상암과임상병리적특징및예후인자에차이가없으므로, 순수소포상암과같은치료지침이적용될수있다는주장이다.(11-13) 하지만, 휘틀세포암은발생빈도가드물고발표된사례가적어, 현재까지도임상상과예후에대한논란이계속되고있다. 우리나라에서는요오드섭취가풍부한지역적특성때문에소포상암이서구에비해매우드물게발생하며나아가휘틀세포암에대한보고는거의없는실정이다. 저자들은진단방법, 수술술기, 추적관찰방법이동일한세군데의 3 차의료기관에서경험한휘틀세포암을순수소포상갑상선암과비교하여특징적인임상상과적절한치료범위에대해알아보고자하였다. 방법 1986년 4월부터 2006년 8월까지신촌세브란스병원 (172예) 및아주대학교병원 (62예) 에서수술적치료를받은순수소 포상갑상선암 (216예) 과휘틀세포암 (18예) 을대상으로의무기록을통한후향적조사를하였다. 최종조직검사상순수소포상갑상선암 (pure follicular carcinoma) 과휘틀세포암으로진단된경우만을대상군으로한정하였고, 저분화 (poorly-differentiated) 형태가포함된경우, 휘틀세포변이유두상갑상선암 (Hurthle cell variant papillary carcinoma), 및유두갑상선우연암 (incidentaloma) 이동시에발견된경우등은대상군에서제외하였다. 대상군은최종병리검사상피막침범정도에따라미세침윤형 (minimally invasive type) 과광범위침윤형 (widely invasive type) 으로분류하였으며, 각각에서혈관침습 (vascular invasion) 유무를확인하였다. 휘틀세포아형을포함한소포상암은술전세침흡인검사및술중동결절편검사로양성과악성의구분이되지않는경우가대부분이므로, 최종조직검사에서악성으로판명되면예후인자를고려하여추가적인수술여부를결정하였다. 즉, 갑상선엽절제술또는아전절제술후최종조직검사상광범위침윤형이나혈관침습등의불량한예후 Table 1. Comparison of clinicopathologic characteristics between HCC and PFC Characteristics HCC* (%) (n=18) PFC (%) (n=216) P-value Age (years) 45 9 (50.0) 61 (28.2) <45 9 (50.0) 155 (71.8) 0.053 Sex Male 4 (22.2) 42 (19.4) Female 14 (77.8) 174 (80.6) 0.776 Size 5 cm 1 (5.6) 21 (9.7) <5 cm 17 (94.4) 195 (90.3) 0.561 Multifocality Yes 5 (27.8) 31 (14.4) No 13 (72.2) 185 (85.6) 0.129 Bilaterality Yes 5 (27.8) 12 (5.6) No 3 (16.6) 64 (29.6) <0.0001 Unknown 10 (55.6) 140 (64.8) Angioinvasion Yes 6 (33.3) 83 (38.4) No 3 (16.7) 70 (32.4) 0.355 Unknown 9 (50.0) 63 (29.2) Invasion to adjacent structure Yes 0 (0) 8 (3.7) No 18 (100) 208 (96.3) 0.522 Subclassification Widely invasive type 2 (11.1) 28 (13.0) Minimally invasive type 16 (88.9) 188 (87.0) 0.587 Initial distant metastasis Yes 1 (5.6) 11 (5.1) No 17 (94.4) 205 (94.9) 0.627 *HCC = hurthle cell carcinoma; PFC = pure follicular carcinoma.
Jandee Lee, et al:hurthle Cell Carcinoma of the Thyroid Gland 93 인자가확인된경우에는완결절제술을추가하였다. 또한, 갑상선전절제술을받은대상군에서는방사성요오드 ( 131 I) 를잔여조직소멸또는치료목적으로투여하였으며, 치료후방사성요오드전신촬영을시행하였다. 대상환자들은수술후 6개월간격으로재발검사 ( 이학적검사, 영상학적검사및혈액학적검사 ) 를시행하였다. 이학적, 영상학적및혈청티로글로불린및안티티로글로불린항체수치에서재발의증거가없는경우를무병생존으로분류하였으며, 국소재발이나원격전이의증거가있거나의심되는경우를유병생존으로분류하였다. 또한, 휘틀세포암과순수소포상암사이에임상병리적특징과예후인자에차이가있는지를조사하였다. 평균추적기간은 114 (6 253) 개월이었다. 통계학적분석은 SPSS 12.0 (2003 SPSS Inc. Chicago, Illinois, USA) 을이용하였다. 추적기간동안의전체생존율및질병특이생존율은 Kaplan-meier 방법, 두군간의임상병리적특징에대한비교는 Fisher's exact test와 Mann- Whitnney test를이용하였고, 예후인자들의다변량분석은 Cox의비례위험모델 (proportional hazards regression model) 을이용하였으며, 단변량분석에서유의하다고판정된예후인자들을다시다변량분석으로검증하였다. P<0.05인경우를유의한것으로정하였다. 결과휘틀세포암환자의평균연령은 50 (27 76) 세였으며, 남녀비는 4:14였다. 순수소포상암의경우평균연령은 41 (4 87) 세, 남녀비는 42:174였다. 휘틀세포암환자에서주소가갑상선종괴인경우가 15예 (83.3%), 영상학적검사상우연히발견된우연암의경우가 2예 (11.1%), 및최초원격폐전이증상 ( 기침 ) 으로발견된경우가 1예 (5.6%) 였다. 병리검사상휘틀세포암종괴의크기는평균 3.0 (0.4 5.5) cm였다. 미세피막침윤형이 16예 (88.9%), 광범위피막침윤형이 2예 (11.1%) 였으며, 혈관침습을보인경우는 6예 (33.3%) 였다. 다발성 5예 (27.8%) 및양측성 5예 (27.8%) 로비교적높은빈도를보였다. 중앙구획림프절절제술을시행한 8예중 4예 (50%) 에서림프절전이를보였으며, 측경부림프절전이는 2예 (11.1%) 에서관찰되었다. 휘틀세포암과순수소포상암의임상병리적특징을비교하였을때, 성별 (P=0.776), 연령 (P=0.053), 종괴의크기 (P= 0.561), 다발성 (P=0.129), 혈관침습여부 (P=0.355), 주위조직침범 (P=0.522), 피막침범정도 (P=0.587), 및최초원격전이 (P=0.571) 등은차이가없었으나, 양측성 (P<0.0001) 의빈도만휘틀세포암에서유의하게높았다 (Table 1). 휘틀세포암에서최초에갑상선전절제술을시행한경우는 5예 (27.8%) 였고, 엽절제술후최종조직검사확인후완결절제술을시행한경우는 3예 (16.7%) 였다. 엽절제술혹은아전절제술을시행한경우는 10예 (55.6%) 였다. 전절제술이시행된 8예 (44.5%) 중 5예에서는저용량 (30 mci), 3예에서는고용량 (150 400 mci) 방사성요오드치료를추가하였다. 순수소포상암의경우에는엽절제술후최종조직검사결과에따라완결절제술이시행되어진 34예를포함하여 76 예 (35.2%) 에서갑상선전절제술이시행되었고, 나머지 140 예 (64.8%) 에서엽절제술혹은아전절제술이시행되었다. 수술후방사성요오드치료를받은경우는저용량 (30 mci) 은 29예, 고용량 (150 630 mci) 은 32예로모두 61예 (28.2%) 였다 (Table 2). 휘틀세포암의경우추적기간동안국소재발을보인경우는 1예로측경부림프절에서재발을보였고, 원격전이 1 예는견갑골및늑골의다발성골전이를보였으며, 영상학적재발의증거는없으나혈액검사상혈청티로글로불린의상승을보인경우가 1예있었다. 추적기간동안질병관련사망은없었다. 10년전체생존율및무병생존율은각각 100%, 83.4% 였다. 순수소포상암의경우국소재발이 9예, Table 2. Treatment of HCC and PFC Treatment HCC* (n=18) PFC (n=216) Extent of surgery Total thyroidectomy 8 (44.4%) 6 (35.2%) Lobectomy or Subtotal thyroidectomy 10 (55.6%) 140 (64.8%) Radioactive iodine therapy Low-dose 5 (27.8%) 29 (13.4%) High-dose 3 (16.7%) 32 (14.8%) Unknown 10 (55.6%) 155 (71.8%) *HCC = hurthle cell carcinoma; PFC = pure follicular carcinoma. Fig. 1. Comparison of cause-specific survival (CSS) in patients with HCC and PFC: CSS rates between HCC (89.3%) and PFC (89.3%) were not significantly different (P=0.702).
94 J Korean Surg Soc. Vol. 74, No. 2 원격전이가 2예, 국소재발및원격전이를동시에보인경우가 6예였으며, 질병관련사망이 8예였다. 10년전체및무병생존율은각각 95.4%, 89.3% 였다. 휘틀세포암및순수소포상암의예후를비교하였을때, 10년무병생존율이각각 83.4% 및 89.3% 로통계학적으로유의한차이를보이지않았다 (P=0.702)(Fig. 1). 휘틀세포암에서예후예측인자는 45세이상의연령 (P=0.0125) 및최초원격전이 (P<0.0001) 였다. 순수소포상암의경우에는 45세이상의연령 (P<0.0001), 남성 (P= 0.0039), 혈관침습 (P=0.0122), 주위조직침범 (P<0.0001), 광범위침윤형 (P<0.0001), 및최초원격전이 (P<0.0001) 등이재발을예측하는유의한지표였다 (Table 3). 고찰휘틀세포 (Hurthle cell) 는커다란다선상 (polygonal) 소포성상피세포로세포질내미토콘드리아가풍부하여헤마톡실린 (hematoxylin) 및에오신 (eosin) 에염색되어호산성과립형태를보이는특징이있다. 이러한휘틀세포는하시모토갑상선염, 그레이브스병, 선종양및고분화갑상선암에서 Table 3. Comparison of prognostic factors for cause-specific survival (CSS) in patients with HCC* and PFC HCC* PFC Variables 10-years DFS (n=15) (%) P-value 10-years DFS (n=197) (%) P-value Age (years) 45 4/9 (44.5) 46/61 (70.1) <45 9/9 (100.0) 0.0125 151/155 (96.7) <0.0001 Sex Male 3/4 (75.0) 34/42 (73.1) Female 12/14 (82.1) 0.6431 163/174 (92.5) 0.0039 Size (cm) 4 5/6 (75.0) 69/80 (83.5) <4 10/12 (81.8) 0.9125 128/136 (93.1) 0.0539 Angioinvasion (n=9) (n=139) Yes 4/6 (66.7) 72/83 (82.7) No 3/3 (100.0) 0.2945 67/70 (95.6) 0.0122 Invasion to adjacent structure Yes 0/1 (0.0) 2/8 (15.6) No 15/17 (80.2) 0.5273 195/208 (92.2) <0.0001 Subclassification Widely invasive type 1/2 (50.0) 16/28 (52.4) Minimally invasive type 14/16 (84.4) 0.2027 181/188 (95.3) <0.0001 Initial distant metastasis Yes 0/1(0.0) 3/11 (16.4) No 15/17(80.2) <0.0001 194/205 (93.4) <0.0001 *HCC = hurthle cell carcinoma; PFC = pure follicular carcinoma; DHS = disease free survival. Fig. 2. (A) A Hurthle cell is characterised by larger polygonal follicular epithelial cells with distinct borders and abundance of mitochondria in the cytoplasm (B) which often appear as eosinophilc granule with large hyperchromatic nucleus ( cherry pink ) on hematoxylin and eosin staining.
Jandee Lee, et al:hurthle Cell Carcinoma of the Thyroid Gland 95 도비특이적으로발견될수있지만, 휘틀세포가 75% 이상을차지하여특징적인군집형태로피막내하나의종물을형성한경우에휘틀세포종양 (Hurthle cell neoplasm) 이라고진단한다 (Fig. 2).(1,14,15) 순수소포상암과마찬가지로, 휘틀세포종양중최종조직검사상피막침범이있거나, 혈관침범을보이는경우를휘틀세포암으로정의하며, 피막침범정도에따라서광범위침윤형과미세침윤형으로구분된다.(2) 휘틀세포암은 1928년 Ewing에의해최초로알려진후 80 여년간전세계적으로약 400예정도보고되었고, 전체분화갑상선암의약 3% 내외로드물게발생한다.(13,16) 2004 년 WHO (World Health Organization) 에서최초로휘틀세포암이소포상갑상선암의변이이며, 독특한특징을가지고있는별개의질병으로분류하였으며, 갑상선자극호르몬 (thyrotropin stimulating hormone) 수용체및티로글로불린면역반응력 (immunoactivity) 체계에서소포상암과동일하다는점이알려져있다.(17,18) 그외에도분자생물학적접근법을이용한조직미소배열 (tissue microarray) 에서이두군간의유전자지도 (molecular profiling) 가유사하다는것도이를뒷받침해주고있다.(17,19) 임상적특징을살펴보면순수소포상암이 40대의비교적젊은연령에호발하고, 남녀비율이 1:3 정도로다른갑상선암에비해여성의비율이상대적으로덜높은데비해, 휘틀세포암은 50대이후의연령및여성에서주로발생한다는점에서양군간에차이가있다.(4,6,8) 휘틀세포암의병리적특징에서주위조직침범 (5 34%), 다발성 (33 70%), 및림프절전이 (2.7 56%) 등공격성향은다양하게보고되고있지만, 양측성의경우는약 40 70% 로공통적으로높은빈도로보고된다.(20-25) 그외휘틀세포암이순수소포상암과마찬가지로림프절을통한전이보다는혈액성경로를통한원격전이의발생률이높다는사실은이미알려져있다.(6) 또한, 대부분의휘틀세포암은방사성요오드흡착능이다른분화갑상선암에비해떨어지므로방사성요오드치료는크게효과적이지않다는보고도있지만, 일부에서는차이가없다는주장도있다.(6,7,20,23) 저자들의경우에도휘틀세포암의평균연령이 50세로순수소포상암이평균 41세인것과비교하여고령에빈발함을알수있었다. 하지만, 성별에있어서는휘틀세포암의남성비율이 22% 로순수소포상암 19.5% 와비교하여여성에서호발하는양상은관찰되지않았다. 또한, 기존의보고들과마찬가지로양군간의임상병리적특징및공격성향은차이가없었으나, 양측성의빈도만이휘틀세포암이높았다. 과거에는휘틀세포암이순수소포상암에비해불량한예후를보여, 재발률 50% 이상, 10년생존율 50% 미만이라는보고도있었다.(6-9) 하지만, 최근에는휘틀세포암과순수소포상암을연령별, 병기별로동일조건에서비교한결과, 양군의공격성과예후에는차이가없다는주장이우세하 다. 이러한결론은대부분의휘틀세포암이고령에흔히발생한다는특성때문에연령을고려하지않고양군을비교하였을때휘틀세포암의예후가불량한것을근본적인질병특성의차이로오인한것으로해석되고있다.(8,20,26) 예후예측인자는순수소포상암의예후인자인피막침범정도, 혈관침습유무, 연령, 암종의크기, 원격전이등이휘틀세포암에도동일하게적용된다고알려져있지만, 일부논란이되는부분도있다.(10-12) 저자들의경우에도휘틀세포암과순수소포암의 10년무병생존율은차이가없었다. 하지만, 예후예측인자의경우순수소포암이연령, 성별, 주위조직침범, 광범위침윤형, 혈관침습, 및최초원격전이등을보이는반면, 휘틀세포암은최초원격전이만이유일하게의미있는요인이었다. 이러한결과는휘틀세포암의대상군이부족하기때문으로해석되며, 순수소포상암의예후인자와의비교는향후대상군이충분히수집되었을때가능할것으로생각한다. 최근에는병리조직검사상더정밀한추가적인검사를통해휘틀세포암의예후인자를규명하고자하는노력들이있다. 일부에서는혈관침습유무가주요한예후예측인자로알려지면서, 기존의피막침범정도를기준으로광범위침윤형과미세침윤형외에도혈관침습여부를추가하여중간침윤형 (moderately invasive subtype) 의다른아형으로분류하고자하는시도가있다.(6,10-13,22,23) 그외병리조직검사상휘틀세포암의혈관침습정도를다시세분하여현미경상 4초점 (foci) 이상의혈관침습을보이는경우높은재발율을보인다는연구결과도있다.(27) 또한, 분자생물학적접근으로휘틀세포암을포함한소포상암에서조직미소배열을통해단백질의발현형태를통해암종의임상상과공격성을알아보려는시도도진행되고있다. 즉, Ki-67 발현정도가휘틀세포암의재발여부및암관련사망률과관계있다는보고가있는가하면, Bcl-2의하향조절 (down regulation) 과휘틀세포암의공격성과밀접한관계가있다는보고도있다.(28) 수술범위결정기준으로순수소포상암의경우광범위침윤형혹은혈관침습을보이는경우갑상선전절제술 ( 완결절제술을포함 ) 이상의광범위한절제가필요하지만, 혈관침습등의위험요인이없는미세침윤형의경우에는엽절제술혹은아전절제술로충분하다는것이현재까지수술경향이다.(6-8,29,30) 휘틀세포암의경우과거에는순수소포상암보다공격적인성향을보인다고알려져광범위절제술이주장되었지만, 최근에는공격성및예후인자에차이가없으므로순수소포상암과동일한치료방침을따르자는주장이우세하다.(6-9,22-26) 저자들의경우에도휘틀세포암과순수소포상암의예후에차이가없으며, 공격적인성향에도차이가없음을확인하였다. 대상군이부족하여아직정확한결론을내리기는어렵지만, 본연구결과를바탕으로하여휘틀세포암은기
96 J Korean Surg Soc. Vol. 74, No. 2 존의전형적인여포상암과마찬가지로광범위침윤형및혈관침습을보이는경우에는갑상선전절제술이상의광범위절제가필요하며, 다른위험요인이없는미세침윤형의경우에는엽절제술만으로충분한치료가될수있을것으로판단된다. 하지만, 휘틀세포암에서는특징적으로양측성의빈도가높은점을염두에두어반대측병소가능성을충분히검토해야할것이다. 향후대상군이추가된다면적절한치료범위에대한정확한지침이마련될수있을것이며, 병리조직검사의정밀한분석및분자생물학적암종의공격성에대한연구가도움이될수있을것이다. 결 휘틀세포암은양측성을제외한임상병리적특징이순수소포상암과유사하며, 공격성을나타내는요인및예후에도큰차이가없었다. 따라서, 휘틀세포암의경우기존의소포상암과동일한치료원칙이적용되어, 다른위험요인이없는미세침윤형의경우엽절제술로충분하지만, 광범위침윤형과혈관침습이있는경우에는갑상선전절제술이상의적극적인치료를결정해야할것이다. 하지만, 수술범위결정시양측성의빈도가높음을고려하여가능성있는반대측병소에대한충분한검토는필요할것으로생각한다. 론 REFERENCES 1) Hundahl SA, Fleming ID, Fremgen AM, Mench HR. A national cancer database report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995. Cancer 1998;82:2638-48. 2) Rosai J, Carcangiu ML, De Lellis RA. Tumors of the thyroid gland. In: Rosai J, Sobin LH, editors. Atlas of Tumor Pathology. 3rd series, fascicle 5. Washington(DC): Armed Forces Institute of Pathology; 1992. p.49-62. 3) Watson RG, Brennan MD, Goellner JR, van Heerden JA, McConahey WM, Taylor WF. Invasive Hurthle cell carcinoma of the thyroid: natural history and management. Mayo Clin Proc 1984;59:851-5. 4) Brennan MD, Bergstralh EJ, van Heerden JA, McConahey WM. Follicular thyroid carcinoma treated at the Mayo Clinic, 1946 through 1970: initial manifestations, pathologic findings, therapy and outcome. Mayo Clin Proc 1991;66:11-22. 5) Stojadinovic A, Ghossein RA, Hoos A, Urist MJ, Spiro RH, Shah JP, et al. Hurthle cell carcinoma: a critical histopathologic appraisal. J Clin Oncol 2001;19:2616-25. 6) Phitayakorn R, McHenry CR. Follicular and Hurthle cell carcinoma of the thyroid gland. Surg Oncol Clin N Am 2006; 15:603-23. 7) Mai KT, Thomas J, Yazdi HM, Commons AS, Lamba M, Stinson AW. Pathologic study and clinical significance of Hurthle cell papillary thyroid carcinoma. Appl Immunohistochem Mol Morphol 2004;12:329-37. 8) Lopez-Penabad L, Chiu AC, Hoff AO, Schultz P, Gaztambide S, Ordonez NG, et al. Prognostic factors in patients with Hurthle cell neoplasm of the thyroid. Cancer 2003;97:1186-94. 9) Ryan JJ, Hay ID, Grant CS, Rainwater LM, Farrow GM, Goellner JR. Flow cytometric DNA measurements in benign and malignant Hurthle cell tumors of the thyroid. World J Surg 1988;12:482-7. 10) Khafif A, Khafif RA, Attie JN. Hurthle cell carcinoma; a malignancy of low-grade potential. Head Neck 1999;21:506-11. 11) Bhattacharyya N. Survival and prognosis in Hurthle cell carcinoma of the thyroid gland. Arch Otol Head Neck Surg 2003;129:207-10. 12) Kucuk NO, Kulak H, Tokmak E, Tari P, Ibis E, Aras G. Hurthle cell carcinoma: a clinicopathological study of thirteen cases. Nucl Med Commun 2006;27:377-9. 13) Ewing J. Neoplastic Disease. 2nd ed. Philadelphia: Saunders; 1928. p.952-3. 14) Bondeson L, Bondeson AG, Ljungberg O, Tibblin S. Oxyphil tumors of the thyroid: follow-up of 42 surgical cases. Ann Surg 1981;194:677-80. 15) Johnson TL, Lloyd RV, Burney RE, Thompson NW. Hurthle cell thyroid tumors: an immunohistochemical study. Cancer 1987;59:107-12. 16) Grossman RF, Clark OH. Hurthle cell carcinoma. Cancer Control 1997;4:13-7. 17) Clark OH, Gerend PL. Thyrotropin receptor-adenylate cyclase system in Hurthle cell neoplasm. J Clin Endocrinol Metab 1985;61:773-8. 18) Sobrino SM. Follicular carcinoma. In: Delellis RA, Lloyd RV, Heitz PU, Eng C, editors. WHO Classification of Tumors: Pathology and Genetics: Tumors of Endocrine Organs. Lyon (France): IARC Press; 2004. p.67-76. 19) Finley DJ, Zhu B, Fahey TJ 3rd. Molecular analysis of Hurthle cell neoplasms by gene profiling. Surgery 2004;136:1160-8. 20) Sanders LE, Silverman M. Follicular and Hurthle cell carcinoma: predicting outcome and directing therapy. Surgery 1998; 124:967-74. 21) Stojadinovic A, Hoos A, Ghossein RA, Urist MJ, Leung DH, Spiro RH, et al. Hurthle cell carcinoma: a 60-year experience. Ann Surg Oncol 2002;9:197-203. 22) Bhattacharyya N. Survival and prognosis in Hurthle cell carcinoma of the thyroid gland. Arch Otolaryngol Head Neck Surg 2003;129:207-10. 23) Maxwell EL, Palme CE, Freeman J. Hurthle cell tumors: applying molecular markers to define a new management algorithm. Arch Otolaryngol Head Neck Surg 2006;132:54-8. 24) Gundry SR, Burney RE, Thompson NW, Lloyd R. Total thyroidectomy for Hurthle cell neoplasm of the thyroid. Arch Surg 1983;118:529-32. 25) Arganini M, Behar R, Wu TC, Straus F 2nd, McCormick M, DeGroot LJ, et al. Hurthle cell tumors: a twenty-five-year experience. Surgery 1986;100:1108-15.
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