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1 대한내분비외과학회지 : 제9권제2호 Vol. 9, No. 2, June 2009 원저 유두갑상선미세암의수술적치료 관동대학교의과대학제일병원외과학교실 임라주ㆍ이숙현ㆍ윤찬석ㆍ고승상ㆍ허민희ㆍ강성수ㆍ이해경 The Surgical Management of Papillary Thyroid Microcarcinoma Ra Joo Lim, M.D., Sook Hyun Lee, M.D., Chan Seok Yoon, M.D., Ph.D., Seung Sang Ko, M.D., Ph.D., Min Hee Hur, M.D., Ph.D., Sung Soo Kang, M.D., Ph.D. and Hae Kyung Lee, M.D., Ph.D. 책임저자 : 이해경, 서울시중구묵정동 , 제일병원외과 Tel: , Fax: haelee67@kobi.com 게재승인일 :2009 년 6 월 7 일본논문은 2009 년춘계내분비외과학회에서구연되었음. Purpose: There has been a rapid rise in the incidence of thyroid cancer, particularly papillary thyroid microcarcinoma (PTMC). However, there is a lack of consensus of treatment guidelines or follow-up strategies. Methods: A retrospective analysis of 606 patients who underwent operation due to thyroid cancer from March 2000 to December 2008 was conducted. Of these patients, 587 with pure papillary carcinomas were studied, of whom 392 (67%) presented with PTMC. Results: Only 23% of patients were symptomatic, but 75% of patients were positive using the imaging techniques ultrasonography or positron emission tomography. When the microcarcinoma patient group (G1) was compared with the group of remaining patients (G2), less aggressive operations were chosen for G1. A lobectomy was performed in 63.8% of G1 versus in 14% of G2, and the central compartment neck dissection was omitted in 30% of G1 versus 16% of G2. During the follow-up period (mean 37.9±25.2 months), there were 11 recurrences. Two patients developed contralateral cancers 42 and 49 months after lobectomy. One patient had recurrences on central compartment lymph nodes 34 months post-operatively. Eight patients had lateral neck lymph nodes metastases months postoperatively. Three of these eight patients had concomitant central neck lymph node metastases. Conclusion: Less aggressive treatments can be chosen for PTMC patients compared to non-ptmc patients. To clarify these results, longer follow up and larger and multi-institutional data are needed. (Korean J Endocrine Surg 2009; 9:74-78) Key Words: Thyroid cancer, Papillary thyroid microcarcinoma, Less aggressive operation 중심단어 : 갑상선암, 유두갑상선미세암, 최소침습적수술 Department of General Surgery, Cheil General Hospital, Kwandong University College of Medicine, Seoul, Korea 서 최근고해상도초음파검사와세침흡인생검술의발달, 병리학적진단의진보로인해갑상선암의진단이증가하고있으며,(1-3) 그중많은원인이 1 cm 미만의유두미세암의진단율역시급증에기인하고있다.(2) 과거에유두갑상선미세암은부검이나수술중우연히발견되는경우가많아서잠재적 (occult) 또는우연종 (incidental) 으로명명되어왔으나 (4,5) 최근진단의증가로개념이모호해지면서 WHO 에서 1 cm 미만의유두갑상선암으로정의하여통용되고있다.(6,7) 현재이러한작은암의발견율이높아졌고예후가좋다고알려져있지만보다큰갑상선암에비해특별한치료지침이나추적검사방법등에대한논의가부족한것이현실이다. 이를반영하듯 2차병원인본연구기관에서도의사에따라각기다른수술과치료가시행되고있다. 이러한미세암은대체적으로예후가좋은것은사실이나가끔재발이나원격전이등도보이며심지어는이로인해사망에이르기도한다.(8-10) 이에본연구를통해갑상선유두미세암의임상적, 병리적특성을살펴보고재발에관련된예후인자를예측하여수술에대한계획이나치료지침을세우는데도움이되고자한다. 방 2000년 3월부터 2008년 12월까지 8년 9개월간관동대학교의과대학제일병원외과에서갑상선암으로수술받은 606명을대상으로후향적분석을시행하였다. 606명중 5명은이미타병원에서갑상선암으로 1차수술을시행받은병 론 법 74

2 임라주외 : 유두갑상선미세암의수술적치료 75 력이있었으며, 9명은여포암, 1명은미분화암, 4명은두종류의갑상선암이동반되어발생하여제외하였고, 순수한유두암환자 587명을대상으로분석하였다. 587명중 67% 인 392명이유두미세암환자였다. 평균추적관찰기간은 38개월이었고, 이기간동안 11명이재발하였으며이중 7명이유두미세암이었다. 크기를기준으로 G1 (<1 cm; PTMC) 와 G2 (>1 cm의 large PTC) 로나누어 G1/G2의각연도별비율, 수술방법의차이, 조직병리학적차이, 수술후방사성요오드치료유무등을비교하였다. 결과증상이있거나의료진에의해발견된경우가 133명으로 23% 에해당하였고, 수술에서우연히발견된경우가 9명, 초음파검사나양전자단층촬영술등영상진단법으로발견된경우가 445명이었고이중초음파검사가 443명으로전체환자의 75.4% 를차지하였다. 각연도별전체유두갑상선암중, 유두갑상선미세암의비율은 50% 정도에서점차증가하여평균 67% 에달했다 (Fig. 1). 본원에서시행한유두갑상선미세암의수술적치료방법으로는일엽절제술, 최소침습적일엽절제술, 내시경적일엽절제술등의일엽절제술과갑상선전절제술, 갑상선아전절제술등이시행되었으며, 이중일엽절제술이 236명 (60.2%) 으로가장많았다. G1에서 142명 (36.2%) 에서갑상선전절제술을시행한반면, 나머지 250명 (63.8%) 에서일엽절제술과아전절제술을시행하였다. 특히일엽절제술을시행한경우를비교하였을때, G1에서 60% 인반면, G2에서단지 14% 에서만시행하였다. 중심부림프절곽청술의경우, G2에서는 16% 에서생략한반면 G1 에서는 118명 (29.9%) 에서생략하여두군에서차이를보였다. 종양의크기를 1 cm 기준으로하여 G1과 G2에서조직병리학적소견을비교하였을때갑상선주변침습 (P<0.001), 다발성병변 (P=0.001), 양측성병변 (P=0.001), 중심부임파선전이 (P<0.001), 외측림프절전이 (P<0.001) 에서통계학적유의성을보였다 (Table 1). 종양의크기에따른수술방법을 G1과 G2에서비교하였을때, 갑상선전절제술 (P<0.001) 과중심부림프절곽청술 (P=0.002) 에서통계학적유의성을보였다 (Table 2). 수술후방사성요오드치료의경우, G2에서는 123명 (69.1%) 에서방사성요오드치료를하였고, 55명 (30.9%) 에서만생략한반면, G1중 123명 (32.6%) 에서시행하였고, 254명 (67.4%) 에서생략하였다 (Fig. 2). 평균추적관찰기간 38개월중 84% 에서규칙적관찰이가능하였으며 11명에서재발하여 1.9% 의재발율을보였다. 11명중 6명은갑상선전절제술과중심부림프절곽청술을시행받았었고 5 명은일엽절제술만시행받았다. 11명중 G2에서 4명이재발하여 2.3% 의재발율을보였으며, 미세암인 G1에서 7명이재발하여 1.8% 의재발율을보였다. 이중 2명은반대편갑상선에발생한유두암이었고 1차수술당시에는발견되지않았었다. 1명은중심부림프절의재발, 8명이외측경부림프절의재발로가장많았는데, 8명중 3명은중심부림프절 Fig. 1. Frequency and proportion of PTMC/PTC per each year. Table 1. Histopathologic findings according to tumor size Perithyroidal extension Multifocal Bilateral LN metastasis-central LN metastasisposterolateral Size>1 cm PTMC P value 126/195 (64.9%) 167/392 (42.6%) < /195 (40.5%) 106/392 (27%) /195 (29.7%) 68/392 (17.3%) /195 (46.7%) 73/392 (18.6%) < /195 (8.2%) 5/392 (1.3%) <0.001 Fig. 2. Postoperative radioactive iodine treatment for PTC including PTMC. Table 2. Surgical procedures according to tumor size Size>1 cm PTMC P value Total thyroidectomy 167/195 (85.6%) 188/392 (48%) <0.001 Cetral compartment 163/195 (83.6%) 121/392 (30.9%) LN dissection

3 76 대한내분비외과학회지 : 제 9 권제 2 호 2009 Table 3. Review of recurred patients after operation for PTC Sex/Age Size Initial operation Recurred time/site 2nd operation State 1 F/56 2 cm TT+CCND RI 16 mon/ln (L) Loss 2 F/ cm TT+CCND RI 40 mon/ln (L) MRND, both 51 mon/ned 3 F/ cm TT+CCND+MRND, both RI 13 mon/ln (L) Loss 4 F/ cm Unilateral lobectomy 27 mon/ln (C+L) CT+CND+MRND 71 mon/ned TT = total thyroidectomy; CCND = central compartment lymph node dissection; RI = radioactive iodine; L = lateral; C = central; MRND = modified radical neck dissection; NED = no evidence of disease; CT = completion thyroidectomy. Table 4. Reviews of recurred patients after operation for PTMC Sex/Age Size Initial operation Recurred time/site 2nd operation State 1 F/ cm Unilateral lobectomy 42 mon/contralateral CT+CCND 92 mon/ned 2 F/ cm Endoscopic lobectomy 49 mon/contralateral CT+CCND 64 mon/ned 3 F/ cm TT+CCND RI 34 mon/ln(c) Loss 4 F/27 1 cm Lobectomy+CCND 52 mon/ln(l) CT+MRND 66 mon/ned 5 F/27 1 cm Lobectomy+CCND 14 mon/ln(l) Loss 6 F/ cm TT+CCND 32 mon/ln(l) MRND 32 mon/ned 7 F/ cm TT+CCND 34 mon/ln(c+l) MRND 53 mon/ned TT = total thyroidectomy; CCND = central compartment lymph node dissection; RI = radioactive iodine; L = lateral; C = central; MRND = modified radical neck dissection; NED = no evidence of disease; CT = completion thyroidectomy. 과함께재발을보였다. 추적기간중원격전이나사망한예는없었으며, 모두국소림프절전이에해당하였다. G2에서재발한 4명을고찰하였을때크기는 cm 사이였고, 4명모두외측경부림프절의재발을보였고그중 1명은중심부림프절에서함께재발하였다 (Table 3). G1에서재발한 7명을고찰하였을때모두 0.5 cm 이상이었고대부분 1 cm 에가까운크기를보였다. 크기가작더라도다발성병변이거나림프절전이소견이많았다 (Table 4). 고찰유두갑상선미세암은약 85% 로갑상선에발생하는암중가장많다.(11) 최근고해상도초음파검사의발달로인해 1 2 mm 결절까지발견이가능해지고 (12) 세침흡인생검술을통해 3 mm 크기의결절까지조직검사가가능해지면서 (13) 과거에수술중우연히발견되거나부검중발견되던유두미세암진단의급증이최근갑상선암의발생빈도급증에주원인을제공하고있다.(2,14) 유두미세암의유병율은부검에서 6 36% 정도보고되고있고 (5) 수술중우연히발견된경우에도 2 24% 로보고되었다.(15) 유두암중유두미세암의비율은 30% 로알려져있고 (14,16) Noguchi 등 (17) 은 42.8%, 이등 (18) 은 50% 로보고하였다. 본연구에서도 67% 로유두미세암의비율이높았으며이는초음파 screening의높은비중이원인으로생각된다. 대개유두미세암은예후가매우양호하며재발및원격전이가드 물고 (2,3,15,16,19) 대부분주변부림프절이나수술기저부에서발생하는국부적인전이를보인다.(9,20) 본연구에서도재발율은 1.9% 였고그중유두미세암의재발율은 1.8% 였으며원격전이는없었다. 대부분예후가좋지만드물게원격전이나재발로인한사망에이를수있기때문에재발을예측하는것이무엇보다중요하다.(8-10) Mayo clinic의연구에서도재발율 6 8% 였고 (10) 그중 80% 이상이경부림프절전이였고, 0.3% 에서원격전이로사망한 3예에대해보고하였다.(10) 또한다발성병변과림프절전이가재발에영향을미치는것으로나타났다.(10) 김등 (19) 은 5% 의재발율을보고하였고림프절전이여부, 특히외측림프절전이와성별이재발에영향을미쳤고수술방법의차이는재발과연관이없었다. 특히림프절전이는다발성병변인경우와혈관또는피막침습이있는경우와연관성이많다.(8,9,21) 유두미세암의재발에영향을미치는인자로는림프절전이여부, 다발성병변, 갑상선주변침습등으로알려져있고 (2,3,10,19,22) 종양의크기, 성별, 나이, 갑상선의자가면역성질환등에대한연관성도제기되지만명확하게재발을예측할수있는확립된인자는없다.(9,19,23,24) 한편 Kasai와 Sakamoto(25) 는 5 mm를기준으로림프절전이및갑상선주변침습의차이를보였기때문에유두미세암의크기를더욱세분화하자는주장을하였고 5 mm를기준으로 5 10 mm를 소 (tiny) 미세암, 5 mm 이하를 미소 (minute) 미세암으로분류하였다. 물론크기만으로재발을예측할수있는단독인자는아니지만본연구에서도유두

4 임라주외 : 유두갑상선미세암의수술적치료 77 미세암환자중재발한 7명이모두 5 mm 이상의크기였고 1 cm에가까운경우가많았다. 이외에도 p53, EGFR, Ki-67, COX-2, RET/ PTC1 rearrangement 등면역조직학적표지자의연구 (26,27) 및양전자단층촬영술의표준흡수값 (SUV) 과갑상선주변침습과의연관성,(28) 수술전후의싸이로글로불린 (Tg) 수치와의연관성에대한연구도진행되고있다.(2,29) 높은유병율에도좋은예후를가진유두미세암이지만수술범위에대해서는여전히논란이많다.(2,10) 유두미세암이 20 46% 로비교적높은비율의다발성병변을가지며 (5,20) 또한재발이나전이의가능성을없애기위해갑상선전절제술및림프절곽청술을제안하기도한다.(2,22) 그러나최근더공격적인치료가치료결과를향상시키지못하고예후가매우좋으므로일엽절제술로충분하다는의견이많다.(17,19,30-32) 심지어는수술을하지않고관찰만한연구에서 70% 이상의환자는변화가없거나오히려크기가줄어들었기때문에저자는명백한진행의증거가있을때수술을해도늦지않는다고주장을하기도한다.(16) 갑상선전절제술이일엽절제술에비해재발을현저히낮춘다는보고도있지만 (22) Hay 등 (1) 은수술방법과재발율사이에차이점이없다고주장하였다. 이러한관점은최근더욱부각되고있는데 America Thyroid Association (ATA) 치료지침에서도경부림프절전이가없는작고저위험군의갑상선내부에국한된유두미세암인경우일엽절제술만으로충분하다고하였고, 다발성이거나림프절전이가있는유두미세암의경우에갑상선전절제술을권유하고있다. 수술후방사선성요오드의추가치료에대해서도고위험군의선택된환자에한해서권유하고있다.(30) 그리고 British Thyroid Association (BTA) 이나유럽에서도비슷한치료지침을권장하고있다.(31,32) 물론불필요하게과다치료를해서는안되겠지만재발이나전이의가능성이높은환자를과소치료해서도안된다는사실을염두에두어야한다.(2,19) 이러한이유로수술전의초음파는단순히갑상선암의확진뿐아니라수술범위및추가치료결정을위한임파선전이여부나다발성여부를알기위해선행되어야하며매우중요한역할을한다.(19,22) 본연구에서도유두미세암의수술적치료로 63.8% 에서갑상선전절제술을시행했고 30% 에서중심부림프절곽청술을생략하였으며 67.4% 에서방사성요오드치료를생략하는등최소침습적인치료를하였으며재발율은 1.8% 였고사망률은없었다. 환자군이적고추적관찰기간이짧고재발환자가적은것이본연구의제한점이며좀더긴추적관찰자료를가진다기관의연구가필요할것으로생각한다. 결론유두갑상선미세암은드물게재발이나원격전이등공격적인성향을보이기도하지만대개는매우양호한예후 를보이는암이다. 이러한이유로과거갑상선전절제술및림프절곽청술이표준치료로시행되어왔지만최근치료지침들은덜침습적인치료를권유하고있다. 재발부위는대부분외측경부림프절이었고유두미세암의재발에관련된인자로림프절전이나다발성병변, 갑상선주위침습, 크기등이중요하다. 이러한예후인자들을고려하여선택된유두갑상선미세암환자군에서좀더덜침습적인치료를시행할수있다. 재발을예측할수있는다른인자나방법에대해서도연구가더욱진행되어야할것이며앞으로좀더긴추적관찰자료를가진다기관의연구가필요할것으로생각한다. REFERENCES 1) Mazzaferri EL. Long-term outcome of patients with differentiated thyroid carcinoma: effect of therapy. Endocri Pract 2000;6: ) Sakorafas G, Giotakis J, Stafyla V. Papillary thyroid microcarcinoma: a Surgical perspective. Cancer Treat Rev 2005;31: ) Grodski S, Delbridge L. An update on papillary microcarcinoma. Curr Opin Oncol 2008;21:1-4. 4) Nasir A, Chaudhry AZ, Gillespie J, Kaiser HE. Papillary microcaricnoma of the thyroid: a clinicopathologic and prognostic review. In Vivo 2000;14: ) Harach HR, Franssila KO, Wasenius VM. Occult papillary carcinoma of the thyroid: A normal finding in Finland. A systemic autopsy study. Cancer 1985;56: ) Salvadori B, Del Bo R, Pilotti S, Grassi M, Cusumano F. Occult papillary carcinoma of the thyroid: a questionable entity. Eur J Cancer 1993;29A: ) Lloyd R, De Lellis R, Heitz P, Eng C. World Health Organization Classification of Tumors: Pathology and Genetics of Tumors of the Endocrine Organs. Lyon, France: IARC Press; ) Rodriguez JM, Moreno A, Parrilla P, Sola J, Soria T, Tebar FJ. Papillary thyroid microcarcinoma: clinical study and prognosis. Eur J Surg 1997;163: ) Hay ID, Grant CS, van Heerden JA, Goellner JR, Ebersold JR, Bergstralh EJ. Papillary thyroid microcarcinoma: a study of 535 cases observed in a 50-year period. Surgery 1992;112: ) Hay ID, Hutchinsin ME, Gonzalez-Losada T, Mclever B, Reinalda ME, Grant CS, et al. Papillary thyroid microcarcinoma: a study of 900 cases observed in a 60-year period. Surgery 2008;144: ) Degroot LJ, Kaplan EL, McCormick M, Straus FH. Natural history, treatment, and course of papillary thyroid carcinoma. J Clin Endocrinol Metab 1990;71: ) Senchenkov A, Staren ED. Ultrasound in head and neck

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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.