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1 대한내분비외과학회지 : 제10권제3호 Vol. 10, No. 3, September 2010 원저 갑상선미세유두암에서종양크기의구분에따른임상병리학적특징의분석 가톨릭대학교의과대학대전성모병원외과학교실 조윤정ㆍ이동호ㆍ이상철ㆍ김세준ㆍ김정구ㆍ안창준ㆍ이관주 Analysis of Clinicopathologic Features of Papillary Thyroid Microcarcinoma According to Cut-off of Tumor Size Yun-Jung Cho, M.D., Dong-Ho Lee, M.D., Sang-Chul Lee, M.D., Say-Jun Kim, M.D., Jung-Koo Kim, M.D., Chang-Joon Ahn, M.D. and Kwan-Ju Lee, M.D. Purpose: Although the detected incidence of papillary thyroid microcarcinoma (PTMC) has increased with development of ultrasonography and fine-needle aspiration biopsy, the best treatment has not yet been established. Treatment decisions require information on many factors including lymph node metastasis, extrathyroidal extension, and bilaterality. With this aim, the present study analyzed clinicopathologic features of PTMC according to cut-off of tumor size. Methods: The clinicopathologic features of patients with PTMC between January 2007 and December 2009 were reviewed retrospectively from medical records. Patients were divided according to tumors lesser than or equal to cut-off (Group I) and tumors exceeding cut-off (Group II). Results: Both capsule invasion and lymphovascular invasion were significantly different at all cut-off diameters (5 9 mm). Central node metastasis revealed a difference in all cut-off values except 8 mm. Extrathyroidal extension differed at all cut-off values except 5 mm. Bilaterality displayed a statistically significantdifference only at the 8 mm cut-off. Conclusion: A cut-off of 5 mm represents a safe value to discriminate less aggressive from aggressive treatment for PTMC. (Korean J Endocrine Surg 2010;10: ) Key Words: Papillary thyroid microcarcinoma, Tumor size, Cut-off 중심단어 : 갑상선미세유두암, 종양크기, 크기기준 Department of Surgery, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon, Korea 서 갑상선미세유두암은세계보건기구 (WHO) 에서종양의크기가 1 cm 이하인갑상선유두암으로정의하고있다. 최근초음파진단의발달및미세침흡인검사의발달로갑상선유두암내에서미세유두암의비율이증가되고있지만치료에있어서차별화되어있지는않은상태이다. 사실상유두암의치료에있어서수술을하지않고지켜보자는의견부터 (1) 일측엽수술및갑상선전절제술과더불어방사성요오드치료에이르기까지다양한치료가적용되어왔다.(2) 이러한치료의결정을위해연령, 종양의크기, 림프절전이, 갑상선외침범, 양측성등의특징들을고려하게된다. 갑상선미세유두암의치료를덜공격적으로시행해도된다면일측엽만절제하는수술또는중앙경부림프절의절제를생략하는수술을고려할수있겠다. 이에저자들은갑상선미세유두암중에서도덜공격적인수술방법을적용시키기위하여양측성이적게발견되며, 림프절전이가적은적절한종양의크기기준을찾아보기로하였다. 갑상선미세유두암을 5 mm에서 10 mm까지종양의크기에따라 1 mm 간격으로나누고두군으로나누어임상병리학적특징들을비교하였고통계적으로의미있는크기기준을결정하고자하였다. 방 론 법 책임저자 : 이관주, 대전시중구대흥동 , 가톨릭대학교대전성모병원외과 Tel: , Fax: leekj@catholic.ac.kr 접수일 :2010 년 7 월 13 일, 게재승인일 :2010 년 8 월 16 일 2007년 1월부터 2009년 12월까지대전성모병원에서갑상선미세유두암으로치료받은환자 318명을대상으로후향적연구를진행하였다. 수술방법은일측엽절제술또는갑상선전절제술이시행되었고모든환자들은병변의동측 152

2 조윤정외 : 갑상선미세유두암에서종양크기의구분에따른임상병리학적특징의분석 153 또는양측의중앙경부림프절절제술을같이시행받았다. 수술전초음파에서갑상선외침범의소견이보이지않고임상적으로림프절전이가의심되지않는, 나이가 45세이전의환자를위주로일측엽절제술을적용시켰고이때중앙경부림프절절제술은동측에서시행했다. 수술전측경부의림프절전이가확진되었거나의심되는경우측경부림프절절제술을중앙경부림프절절제와함께시행받았고연구대상에포함되었다. 갑상선암이아닌수술을시행받고유두암을진단받은환자는제외되었다. 종양의크기는 5, 6, 7, 8, 9 mm를기준으로나누었고환자들을각크기이하의군 (group I) 과그크기를초과하는군 (group II) 으로나누어성별, 45세기준의나이, 중앙경부림프절전이, 피막침범, 갑상선외침범, 혈관-림프관침범, 수술의방법, 양측성, 다발성에대해비교분석하였다. 양측성은갑상선의양측엽에모두종양이존재하는경우로정의하였고다발성은위치와상관없이개수가 2개이상인경우로정의하였다. 통계처리는 Chi-square, Fisher s exact test 를이용하였고 가 0.05 미만인경우를통계학적인의미가있다고판단하였다. 결과총 318명의환자중남성은 18명 (5.7%), 여성은 300명 (94.3%) 이었다. 피막침범은 120명인 37.7% 에서관찰되었고갑상선외침범은 79명 (24.8%) 에서관찰되었다. 중앙경 부림프절전이는 113명인 35.5% 에서혈관-림프관침범은 112명 (35.2%), 양측성은 62명 (19.5%), 다발성은 102명 (32.1%), 수술은갑상선전절제가 252명 (79.2%) 에게시행되었다 (Table 1). Table 2와 Table 3은종양의각크기에따른임상-병리학적특징의분석결과를보여준다. 남녀성별의차이는어느크기에서도보이지않았다. 45세를기준으로환자를나눈경우, 5 mm 이하의군에서보다 5 mm를초과하는크기의종양을갖는군에서 45세이상의환자가통계적으로많았 Table 1. Clinicopathologic features of papillary thyroid microcarcinoma Gender Male 18 (5.7) Female 300 (94.3) Capsule invasion 120 (37.7) Extrathyroidal extension 79 (24.8) Central node metastasis 113 (35.5) Lymphovascular invasion 112 (35.2) Type of surgery Lobectomy 66 (20.8) Total thyroidectomy 252 (79.2) Bilaterality 62 (19.5) Multifocality 102 (32.1) Table 2. Analysis of clinicopathologic features of papillary thyroid microcarcinoma according to 5 mm, 6 mm, and 7 mm cut-off 5 mm cut-off 6 mm cut-off 7 mm cut-off Group I Group II Group I Group II Group I Group II Gender Male 8 (6.1) 10 (5.4) 11 (6.2) 7 (5.0) 14 (6.3) 4 (4.2) Female 124 (93.9) 176 (94.6) 167 (93.8) 133 (95.0) 208 (93.7) 92 (95.8) Age (years) <45 57 (43.2) 57 (30.6) 71 (39.9) 43 (30.7) 84 (37.8) 30 (31.3) 45s 75 (56.8) 129 (69.4) 107 (60.1) 97 (69.3) 138 (62.2) 66 (68.8) Capsule invasion 35 (26.5) 85 (45.7) (28.1) 70 (50.0) < (31.5) 50 (52.1) ETE* 27 (20.5) 52 (28.0) (18.5) 46 (32.9) (20.7) 33 (34.4) 0.01 CN metastasis 37 (28.0) 76 (40.9) (29.2) 61 (43.6) (31.5) 43 (44.8) LV invasion 37 (29.8) 75 (41.7) (29.8) 62 (45.6) (33.0) 43 (45.3) 0.04 Type of surgery < Lobectomy 41 (31.1) 25 (13.4) 48 (27.0) 18 (12.9) 56 (25.2) 10 (10.4) Total thyroidectomy 91 (68.9) 161 (86.6) 130 (73.0) 122 (87.1) 166 (74.8) 86 (89.6) Bilaterality 18 (19.8) 44 (27.3) (22.3) 33 (27.0) (22.3) 25 (29.1) Multifocality 33 (25.0) 69 (37.1) (29.2) 50 (35.7) (29.3) 37 (38.5) *Extrathyroidal extension; Central node; Lymphvascular; The case that was not described about lymphovascular invasion was excluded; The patients who underwent lobecotmy were excluded.

3 154 대한내분비외과학회지 : 제 10 권제 3 호 2010 Table 3. Analysis of clinicopathologic features of papillary thyroid microcarcinoma according to 8 mm and 9 mm cut-off 8 mm cut-off 9 mm cut-off Group I Group II Group I Group II Gender Male 16 (6.2) 2 (3.4) 17 (6.2) 1 (2.2) Female 244 (93.8) 56 (96.6) 256 (93.8) 44 (97.8) Age (years) <45 95 (36.5) 19 (32.8) 101 (37.0) 13 (28.9) 45s 165 (63.5) 39 (67.2) 172 (63.0) 32 (71.1) Capsule invasion 88 (33.8) 32 (55.2) (35.2) 24 (53.3) 0.02 ETE* 57 (21.9) 22 (37.9) (22.7) 17 (37.8) 0.03 CN metastasis 87 (33.5) 26 (44.8) (33.3) 22 (48.9) 0.04 LV invasion 84 (34.0) 28 (49.1) (34.6) 22 (50.0) 0.05 Type of surgery < Lobectomy 64 (24.6) 2 (3.4) 64 (23.4) 2 (4.4) Total thyroidectomy 196 (75.4) 56 (96.6) 209 (76.6) 43 (95.6) Bilaterality 42 (21.4) 20 (35.7) (23.0) 14 (32.6) 0.18 Multifocality 74 (28.5) 28 (48.3) (29.7) 21 (46.7) *Extrathyroidal extension; Central node; Lymphvascular; The case that was not described about lymphovascular invasion was excluded; The patients who underwent lobecotmy were excluded. 다 (P=0.02). 5 mm를제외한나머지크기를기준으로한경우에서는 45세를기준으로한나이의차이를보이지않았다. 피막침범의경우는모든크기에서그크기의이하군과초과하는군에서통계적차이를보였다. 갑상선외침범의경우, 5 mm 이하군과초과군에서 는 0.12로통계적유의성은없었고 6, 7, 8, 9 mm에서는 가각각 미만, 0.001, 0.011, 0.03으로통계적유의성을보였다. 중앙경부림프절전이는 5, 6, 7, 9 mm에서그이하군과초과군에서통계적유의성으로보였으나 8 mm 기준인경우 P value가 0.102로통계적의의가없었다. 혈관-림프관침범은모든크기의기준에서그이하군과초과군에서통계적차이를보였다. 양측성은 8 mm 크기가기준일경우만그이하군보다초과군에서많이관찰되었다 (P=0.029). 다발성은 5, 8, 9 mm 기준일경우 가각각 0.023, 0.003, 0.024로그이하군보다초과군에서더많은빈도를보였다. 고찰초음파및초음파를이용한미세침흡인검사법이널리이용되면서갑상선유두암, 특히갑상선미세유두암의진단은증가되고있다.(3) 갑상선미세유두암에대한관심이높아지면서이러한질환의치료를기존의갑상선유두암과동일하게시행해야하는가에대한논란이있어왔다. 갑상선미세유두암의치료에있어서기존의유두암과동일하게치료해야한다는의견부터즉각적수술없이추적 관찰을하자는의견까지다양하다. Arora 등 (2) 은갑상선미세유두암에서림프절전이와갑상선외침범과같은좋지않은특징이기존의갑상선유두암에서보이는것과비슷하다고보고하였고재발률에있어서도큰차이가없다고 (16.7% vs. 21.3%) 보고하였으며미세유두암을기존의유두암과동일하게치료해야한다고주장하였다. 반면, Ito 등 (1) 은기도와가깝게위치한종양, 갑상선의뒤쪽 (dorsal surface) 에위치한종양, 미세침흡인검사에서조직등급이높은경우, 임상적림프절전이가있는경우를좋지않은특징이라정의하며이러한특징을갖지않는종양은진단당시즉각적수술을시행하지않고추적관찰할수있다고보고하였다. 이저자들은 340명의환자들을평균 74개월동안추적관찰하였고경과관찰 5년후와 10년후종양의크기증가를보인경우는각각 6.4% 와 15.9% 였고림프절의전이를보인경우는각각 1.4% 와 3.4% 라고보고하였다. 종양의공격성과관련하여몇몇연구에서는갑상선미세유두암은기존의유두암보다공격성이적다고보고하였으며 (4-6) 일부연구들은갑상선미세유두암이기존의유두암이갖는공격성과비슷한특징을갖는다고보고하였다.(2,7,8) Hay 등 (9) 은갑상선미세유두암을갖는 900명의환자를 60년동안추적관찰한결과매우좋은예후를갖는다고보고하였다. 질환과관련된사망률은 0.3% 로보고하였고진단시림프절전이가있었던경우재발률이림프절전이가없었던경우보다높게관찰되었다 (16% vs. 0.8%). 그외재발에영향을주는인자로다발성, 양측성을언급하였다. 하지만일

4 조윤정외 : 갑상선미세유두암에서종양크기의구분에따른임상병리학적특징의분석 155 측엽절제를받는경우와전절제를시행받은경우재발은차이가없다고보고하였다. 본연구에서갑상선미세유두암에서중앙경부림프절전이는 318명중 113명으로 35.5% 에서관찰되었다. 이러한빈도는저자들이이전에발표한논문에서의빈도인 33.8% 와큰차이가없었고 (10) Hay 등 (9) 이보고한 30% 와도큰차이가없지만이등 (11) 이보고한 26.3% 보다는높다. 림프절전이의빈도는종양의크기가클수록높아진다.(10) 본연구에서도 8 mm 기준인경우를제외하고모두크기가큰군에서림프절전이의빈도가높았다. 8 mm 기준인경우림프절전이의차이가없는이유에대해서저자들은특별한이유를찾지못했다. 이러한림프절전이는생존율에영향을주지는않지만국소재발및원격전이에영향을줄수있다.(9,12) 수술전중앙경부림프절전이를진단할수있다면치료에도움이되겠지만그예측은어렵다.(11) Ito 등 (13) 도초음파를통한진단의민감도를 10% 정도로보고하였다. Ito 등 (14) 은갑상선미세유두암을갖는환자를 7 mm 기준으로나누었을때 7 mm 미만의군에서보다 7 mm 이상의군에서림프절전이가더많았다고보고했다. 이는본연구에서 6 mm 기준으로나눈경우에해당한다. 본연구에서의결과로는크기가클수록림프절전이가많았기에연구결과만으로림프절절제술을생략해도될크기의기준을정하기는어려웠다. 갑상선의수술에서일측엽절제술을선택한경우남겨진반대쪽엽에서의재발이문제가될수있다. 신등 (15) 이보고한연구에의하면갑상선유두암에서양측성은 35.7% 의환자에서관찰되었고이환자들중 66% 에서는수술전반대쪽유두암이확인되지않은상태로전절제술를시행받았다. 그리고양측성은종양의크기가클수록관련이있었다. 본연구에서양측성은 19.5% 에서관찰되었다. 다발성및양측성이갑상선유두암에서국소재발과관련이있다는보고들이있다.(16,17) Giordano 등 (18) 은양측성은단변량, 다변량분석에서모두종양의재발과통계적유의성을보였다고보고하였다. 본연구에서종양의크기를 8 mm 기준으로구분했던경우양측성이통계적의미를보였기에종양의크기가 9 mm, 10 mm인갑상선미세유두암에서는반대쪽갑상선에대한종양의유무에대해주의깊은관찰이필요하다고생각한다. 따라서일측엽절제술을고려할경우 8 mm 이하의종양에서고려하는것이좋겠다. 저자들은본연구가갑상선미세유두암을 1 mm 간격의크기로임상병리학적특징을분석했다는점에서의의가있다고생각하지만, 후향적분석이라는점과장기간의추적관찰에따른재발률이다루어지지않았다는점에서더많은환자들에대한장기간의전향적연구로각종양의크기에따른재발률및생존율을분석한다면더좋은결과를얻으리라생각한다. 결 갑상선미세유두암을 5 mm 부터 10 mm까지 1 mm 간격으로구분하고각각의크기를기준으로임상병리학적특징을분석한결과, 전반적으로림프절전이, 피막침범, 갑상선외침범및혈관-림프관침범은크기가증가될수록빈도가증가되었고양측성은 8 mm를기준으로한경우통계적의미를보였다. 만약갑상선미세유두암에서덜공격적인치료로일측엽절제술을고려한다면수술전초음파에서반대쪽병변이관찰되지않는최소한 8 mm 이하의종양에서고려하는것이좋겠다. 하지만중앙경부림프절절제술의생략을결정하는경우는그기준을정하기는어렵고종양의크기가작을수록안전하다하겠다. 저자들은모든결과를고려할경우덜공격적인치료를고려하는경우종양의크기를 5 mm 기준으로하는것이안전하다고생각한다. 론 REFERENCES 1) Ito Y, Miyauchi A, Inoue H, Fukushima M, Kihara M, Higashiyama T, et al. An observational trial for papillary thyroid microcarcinoma in Japanese patients. World J Surg 2010;34: ) Arora N, Turbendian HK, Kato MA, Moo TA, Zarnegar R, Fahey TJ 3rd. Papillary thyroid carcinoma and microcarcinoma: is there a need to distinguish the two? Thyroid 2009; 19: ) Mazzaferri EL, Sipos J. Should all patients with subcentimeter thyroid nodules undergo fine-needle aspiration biopsy and preoperative neck ultrasonography to define the extent of tumor invasion. Thyroid 2008;18: ) Ito Y, Uruno T, Nakano K, Takamura Y, Miya A, Kobayashi K, et al. An observation trial without surgical treatment in patients with papillary microcarcinoma of the thyroid. Thyroid 2003;13: ) Roti E, degli Uberti EC, Bondanelli M, Braverman LE. Thyroid papillary microcarcinoma: a descriptive and metaanalysis study. Eur J Endocrinol 2008;159: ) Ito Y, Higashiyama T, Takamura Y, Miya A, Kobayashi K, Matsuzuka F, et al. Prognosis of patients with benign thyroid diseases accompanied by incidental papillary carcinoma undetectable on preoperative imaging tests. World J Surg 2007; 31: ) Lo CY, Chan WF, Lang BH, Lam KY, Wan KY. Papillary microcarcinoma: is there any difference between clinically overt and occult tumors? World J Surg 2006;30: ) Pelizzo MR, Boschin IM, Toniato A, Piotto A, Bernante P, Pagetta C, et al. Papillary thyroid microcarcinoma (PTMC): prognostic factors, management and outcome in 403 patients.

5 156 대한내분비외과학회지 : 제 10 권제 3 호 2010 Eur J Surg Oncol 2006;32: ) Hay ID, Hutchinson ME, Gonzalez-Losada T, McIver B, Reinalda ME, Grant CS, et al. Papillary thyroid microcarcinoma: a study of 900 cases observed in a 60-year period. Surgery 2008;144:980-7; discussion ) Lee KJ, Kim HR, Kim SJ, Lee SC, Kim JG, Sung GY, et al. Analysis of the relationship between central cervical lymph node metastasis from papillary thyroid carcinoma and the associated factors according to the tumor size. J Korean Surg Soc 2008;75: ) Lee NS, Bae JS, Jeong SR, Jung CK, Lim DJ, Park WC, et al. Risk factors of lymph node metastasis in papillary thyroid microcarcinoma. J Korean Surg Soc 2010;78: ) Harwood J, Clark OH, Dunphy JE. Significance of lymph node metastasis in differentiated thyroid cancer. Am J Surg 1978;136: ) Ito Y, Tomoda C, Uruno T, Takamura Y, Miya A, Kobayashi K, et al. Clinical significance of metastasis to the central compartment from papillary microcarcinoma of the thyroid. World J Surg 2006;30: ) Ito Y, Tomoda C, Uruno T, Takamura Y, Miya A, Kobayashi K, et al. Papillary microcarcinoma of the thyroid: how should it be treated? World J Surg 2004;28: ) Shin IY, Lee KJ, Kim HR, Kim SJ, KIM JG, Lee DH, et al. Analysis of the relationship between bilaterality and other clinicopathological factors in papillary thyroid carcinoma. Korean J Endocrine Surg 2008;8: ) Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 1994;97: ) Baudin E, Travagli JP, Ropers J, Mancusi F, Bruno-Bossio G, Caillou B, et al. Microcarcinoma of the thyroid gland: the Gustave-Roussy Institute experience. Cancer 1998;83: ) Giordano D, Gradoni P, Oretti G, Molina E, Ferri T. Treatment and prognostic factors of papillary thyroid microcarcinoma. Clin Otolaryngol 2010;35:

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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.