대한내분비외과학회지 : 제10권제1호 Vol. 10, No. 1, March 2010 원저 다발성유두상갑상선암의임상병리학적특성분석 인제대학교의과대학부산백병원외과학교실 이민욱ㆍ하태권ㆍ유성목ㆍ김상효 Analysis of the Clinicopathologic Characteristics of Multifocal Papillary Thyroid Carcinoma Min Wuk Lee, M.D., Tae Kwun Ha, M.D., Sung Mock Ryu, M.D. and Sang Hyo Kim, M.D. 책임저자 : 김상효, 부산시진구개금동 633-165 614-735, 인제대학교부산백병원외과 Tel: 051-890-6347, Fax: 051-898-9427 E-mail: hnkim80@hotmail.com 게재승인일 :2010 년 2 월 12 일본논문의요지는 2009 년대한외과학회추계학술대회에서구연발표되었음. Purpose: Papillary thyroid carcinoma (PTC) is the most common malignancy that develops from the thyroid gland and its prognosis is quite excellent. One of the characteristic behaviors of PTC is that it often occurs at multiple foci. The purpose of this study was to investigate the clinicopathologic features and risk factors of multifocal papillary thyroid cancer. Methods: A retrospective review was carried out on 624 patients with PTC and who underwent surgery from January 2005 to December 2007. Two hundred twenty-nine of them were found to have multiple tumor foci ( 2 foci). The risk factors that included gender, age at diagnosis, tumor size, capsular invasion, extrathyroidal extension (ETE), cervical lymph node (LN) involvement, the TNM classification, local recurrence and distant metastasis were comparatively analyzed between the solitary PTC and multifocal PTC groups. Results: The enrolled patients were 59 male and 565 females. The mean age was 46 years (range: 15 77 years). Age (P=0.025), tumor size (P=0.027), capsular invasion (P<0.001), ETE (P<0.001) and cervical LN metastasis (P=0.002) were the significantly related factors for multifocal papillary thyroid cancer. However, gender was not significantly related with multifocality. Conclusion: The results of this study showed that multifocal tumors were significantly associated with age, tumors size, capsular invasion, ETE and cervical LN metastasis in patients with PTC. LN metastasis was mostly influenced by multifocality in the PTC patients. It seems certain that total thyroidectomy and formal central node dissection with postoperative adjuvant therapy are essential treatment for these patients, and closely surveying the nodal status is needed on the follow up of patients with multifocal PTC. (Korean J Endocrine Surg 2010;10:24-28) Key Words: Papillary thyroid carcinoma, Multifocality, Lymph node metastasis 중심단어 : 유두상갑상선암, 다발성, 림프절전이 Department of Surgery, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea 서 유두상갑상선암은갑상선에서발생하는암중가장흔하며, 수술후의생존율이 90% 이상에이를정도로비교적양호한예후를갖는다.(1) 흔히국소림프절에전이를일으키는것으로알려져있으며, 갑상선의결절이나계통적전이에의한림프절병소로발견된다.(2) 또한, 갑상선각엽에다발성종양을가지는것이특징중의하나이다. 수술이후발견되는이러한종양의다발성빈도는 22 80% 에이르며, 양쪽엽에서동시에발견되는다발성병소는 33 60% 이상인것으로기관마다다양한보고를하고있다.(3-6) 갑상선유두상암의다발성은국소림프절전이및원격전이의발생위험을증가시킬뿐만아니라, 분화갑상선암에서 3개이상의병소가있을경우사망률을증가시킨다는보고도있으나,(7,8) 갑상선위험인자분류에포함되어있지않는등, 국소재발이나예후와는연관성이없다는주장도있어임상적의의에대한다른견해들이있다.(9,10) 이에저자들은본병원수술예의고찰을통하여다발성유두상갑상선암의임상적특징을알아보고자하였다. 방 2005년 1월부터 2007년 12월까지인제대학교부산백병원외과에서갑상선암으로수술을시행받고조직학적으로유두상갑상선암으로진단된 624명의환자를대상으로의무기록을조사하여후향적연구분석을하였다. 수술후병리 론 법 24
이민욱외 : 다발성유두상갑상선암의임상병리학적특성분석 25 적진단에따라암병소가 1개인경우를단일성, 암병소가 2개이상인경우에, 병소가포함된갑상선엽과는관계없이다발성으로정의하였으며, 229명 (36.7%) 의환자에서다발성유두상암이확인되었다. 추적관찰기간의중앙값은 34 개월 ( 범위 : 1 56) 이었고이들의남녀성비, 종양크기 (1 cm 이상혹은이하 ), 병리보고에서피막침범, 갑상선외침범, TNM 분류, 국소재발및전신전이등을단일성및다발성그룹으로분류하여각각의그룹과관련된연관인자들을분석하였다. 진단시연령은 AJCC (American Joint Committee on Cancer) 의 TNM (6 th edition) 분류에따라 45세를기준으로구분하였다. 통계분석은단변량분석은 Chi-square test를, 다변량분석은 multiple logistic regression analysis를시행하였으며, P값이 0.05 미만인경우통계적으로유의한것으로판정하였다. 결과 1) 단일성, 다발성유두상갑상선암의임상적특징성별에따른환자수는여자 565예, 남자 59예였으며, 평균연령은 46세 (15 77세) 였다. 종양의크기는평균 1.15 cm였다. 종양크기에따른다발성암종의발생빈도는최대원발종양의크기를 1 cm를기준으로분류하였을때, 다발성그룹에서종양의크기가커질수록발생빈도가증가함을알수있었다 (P=0.027). 다발성그룹에서피막침범을보인예는 27예 (11.8%), 주변구조물까지침범한경우는 80예 (34.9%) 이었으며, 침범빈도는갑상선주변연부조직, 근육, 기관순이었다. TNM stage로두그룹을분류하였을때, 다발성군에서높은병기의빈도비율이증가하였으며, 통계적으로유의하였다 (P=0.004). 획득된경부림프절의수는 1 27개로다양하였으며, 평균절제된림프절수는 5.82개였다. 다발성과관련하여통계적으로유의한연관인자로는연령 (P=0.025), 종양의크기 (P=0.027), 피막침범 (P<0.001), 갑상선외침범 (P<0.001), 경부림프절전이 (P=0.002) 등이었다. 성별은다발성과통계적유의성을가지지못하는것으로나타났다 (Table 1). 단변량분석에서통계적으로유의한인자를가지고시행한다변량분석에서다발성에가장유의한연관인자는경부림프절전이 (OR=1.782, P=0.024) 였으며, 연령 (OR=1.565, P=0.01) 과갑상선외침범 (OR=1.518, P= 0.005) 또한다발성에있어서통계적으로유의한연관인자였다 (Table 2). Table 2. Multivariate analysis of related factors between solitary and multifocal papillary thyroid carcinoma Odds ratio P value Lymph node metastasis 1.782 0.024 Age (45 ) 1.565 0.01 Extrathyroidal extension 1.518 0.005 Tumor size 1.201 0.303 Capsular invasion 1.183 0.535 Table 1. Clinicopathologic characteristics of 624 patients with solitary & multifocal papillary thyroid carcinoma Total (n=624) Solitary (n=395) Multifocal (n=229) P value Gender Female 565 (90.5%) 359 (90.9%) 206 (90.0%) Male 59 (9.5%) 36 (9.1%) 23 (10.0%) 0.702 Mean age 46 44.66 48.26 <45 294 (47.1%) 205 (51.9%) 89 (38.9%) 45 330 (52.9%) 190 (48.1%) 140 (61.1%) 0.025 Tumor size mean 1.15 cm 1.11 cm 1.22 cm 1 cm 317 (50.8%) 214 (54.2%) 103 (45.0%) >1 cm 307 (49.2%) 181 (45.8%) 126 (55.0%) 0.027 Capsular invasion 72 (11.5%) 45 (11.4%) 27 (11.8%) <0.001 ETE 161 (25.8%) 81 (20.5%) 80 (34.9%) <0.001 Cervical lymph node metastasis 226 (36.2%) 125 (31.6%) 101 (44.1%) 0.002 TNM (SI/SII/SIII/SIV) 312/2/69/12 144/3/71/11 0.004 Local recurrence 12 (1.9%) 4 (1.01%) 8 (3.5%) 0.03 Distant metastasis 0 0 0 Dissected lymph node 5.82±5.55 5.27±4.99 6.78±6.33 Surgery TT/CND 361 (57.8%) 205 (51.9%) 156 (68.1%) TT/MND 46 (7.4%) 23 (5.8%) 23 (10.0%) Lobectomy/CND 217 (34.8%) 167 (42.3%) 50 (21.9%) ETE = extra-thyroidal extension; TNM = Tumor-Node-Metastasis; SI = stage I; SII = stage II; SIII = stage III; SIV = stage IV; TT = total thyroidectomy; CND = central neck dissection; MND = modified neck dissection.
26 대한내분비외과학회지 : 제 10 권제 1 호 2010 Table 3. Comparison of cervical lymph node metastasis between solitary and multifocal papillary thyroid carcinoma Cervical lymph node metastasis Cervical lymph node metastasis (n=226) P value P value LN ( ) LN (+) N1a N1b Solitary 270/395 (68.4%) 125/395 (31.6%) 102/125 (81.6%) 23/125 (18.4%) 0.002 0.517 Multifocal 128/229 (55.9%) 101/229 (44.1%) 78/101 (77.2%) 23/101 (22.8%) LN = lymph node; N1a = metastasis to level VI (pretracheal, paratracheal, and prelaryngeal/delphian lymph nodes); N1b = metastasis to unilateral, bilateral, or contralateral cervical or superior mediastinal lymph nodes. Table 4. Characteristics of patients with recurrence Tumor size Tumor Time to recurrence Gender Age (yr) Initial op Re op Recurrence site (cm) foci (month) Case 1 M 41 1.2 2 TT/CND B.MND 31 B.level III Case 2 M 37 1.4 2 TT/CND B.MND 12 B.level III, IV Case 3 F 58 2.5 2 TT/CND I.MND 9 Level III Case 4 F 57 0.9 1 RL/CND Completion/CND 56 Level VI Case 5 F 22 3 2 TT/CND I.MND 25 Level IV Case 6 F 35 2.2 2 TT/CND I.MND 15 Level III, IV Case 7 F 36 0.8 2 TT/CND I.MND 18 Level II, III Case 8 F 42 1.6 2 TT/CND I.MND 18 Level III, IV Case 9 F 25 2.0 1 RL/CND Completion/CND 35 Level VI Case 10 F 44 1.9 1 LL/CND Completion/CND 23 Level VI Case 11 F 42 0.8 1 RL/CND Completion/CND 19 Level VI Case 12 F 21 2.6 2 TT/CND I.MND 11 Level IV TT = total thyroidectomy; RL = right lobectomy; LL = left lobectomy; CND = central neck dissection; B.MND = both modified neck dissection; I.MND = ipsilateral modified neck dissection. 로재발을확인한다음재수술을시행하였다 (Table 4). 2) 경부림프절전이경부림프절전이가있는경우는전체 624예중 226예 (36.2%) 였고, 단일병소에서림프절전이가있는경우는 31.6% (125/395), 다발성병소에서 44.1% (101/229) 로다발성병소에서경부림프절전이의빈도비율이더높았으며통계적으로유의하였다 (P=0.002) (Table 3). 경부림프절전이가있는 226예중측경부림프절전이가확인된 46예에서다발성그룹에서의발생비율은 22.8% (23/101) 로단일성그룹의 18.4% (23/125) 에비해높은전이비율을보여주고있으나, 다발성이측경부림프절전이에미치는영향은통계적으로유의하지않았다 (P=0.517) (Table 3). 3) 국소재발과원격전이국소재발은다발성과단일성에서각각 3.5% (8/229), 1% (4/395) 의비율을보였으며 (P=0.03), 원격전이는발견되지않았다. 재발까지의평균추적기간은 22.7개월이었으며, 추적기간동안경부초음파를시행한후세침흡입세포검사 고찰갑상선유두상암에서다발성은흔히보여진다. 문헌적보고에따르면다발성암종에대한상대적빈도는 22 80% 까지이르는것으로나와있으며, 조직학적으로는다양성을나타낸다. 병소의발생에대하여서로다른암종들이단일악성종양에서연속적인선내전이를통한것인지, 아니면독립적인암종인지에대한이견이존재한다. Park 등 (11) 과 Giannini 등 (12) 은 BRAF 돌연변이율을조사하여다발성암종은각각독립적으로발생한다고하였고, Sugg 등 (13) 은 ret/ptc 재배열의다른분류를통해개별적인암종의발생이다발성을이룬다고보고하였으며, Shattuck 등 (14) 은 X 염색체의비활성화형태가서로이질적임을보임으로병소가독립적인기원에서발생한다고하였다. 이러한주장들은갑상선절제술이후남아있는갑상선조직이재발을유발할수있는병소를함유하고있음을암시하고있다. 이에반하여 McCarthy 등 (15) 은 X-염색체의비활성화와이질성소실의분석을통하여종양의클론형성능을평가한후
이민욱외 : 다발성유두상갑상선암의임상병리학적특성분석 27 동시에존재하는암종은같은클론에서유래하였음을주장하여선내전이가암종의전파와다발성유발에중요한역할을한다고제안하였다. 이처럼유전적변화분석을통해얻은결론들이차이를보임은향후종양의발생과정을밝히는데더많은부가적인분석이추가되어야함을시사한다. 다발성이있는갑상선암에서반대쪽에병소를가지는빈도는두엽사이에해부학적구분이없으므로더높은것으로알려져있으며, 이러한양측성이나타나는비율은약 10 62% 에이른다.(16,17) 특히, 갑상선미세유두상암이진단되었을때반대쪽엽에서암종이발견될가능성은 47 83% 에이른다고보고되고있다.(18,19) 갑상선암의수술이후예후는매우좋은것으로알려져있다. 그러나, 현재유두상갑상선암의수술시절제범위에대해서는아직도논란의대상이다. 갑상선다발성병소의발생기원에대해분자생물학적으로다른견해들이존재한다하더라도두이론의치료에대한결론은양측갑상선절제와방사능동위원소치료를통한잔여조직의완전한제거이다. 그러나최근초음파이용의증가와미세침흡입술의기술적향상으로인한갑상선암의조기발견으로인해, 저위험군환자에대한축소수술뿐만아니라장기적인추적관찰만이필요하다는주장도있다. 갑상선암의위험인자분류체계로 AGES (age, grade, extent, size), AMES (age, metastasis, extent, size), MACIS (metastasis, age, completeness of resection, local invasion, tumor size), TNM (tumor, node, metastasis) 등이일반적으로분화갑상선암환자의예후를결정하는데사용되어지지만, 다발성갑상선암의종양학적잠재성등이명확하게밝혀져있지않으므로인해서대부분의문헌보고에서는다발성과예후와의관계에관한보고등이없으나, Mazzaferri 등 (8) 은분화갑상선암에서 3개이상의병소를가진환자에게서사망률이증가한다고주장하였다. 본원의연구에서는다발성유두상갑상선암의임상병리학적분석을통하여연령, 종양의크기, 피막침범, 갑상선외침범, 경부림프절전이등이다발성과통계적으로의미있는연관인자였다. 또한수술이후분석을통하여 TNM stage 및국소재발도다발성과유의한관계가있는것으로밝혀졌다. 연령은 45세를기준으로병기와예후가달라진다고 TNM 분류에서알려지고있으며, 유두상갑상선암환자의연령이 45세이하인경우에생존율이높다고 Handahl 등 (20) 은보고하였다. 본연구에서는 45세이상의연령대가전체의 52.9% 를차지할뿐만아니라, 다발성그룹에서 61.1% 로 48.1% 인단일성그룹보다높은비율을보여연령이증가할수록다발성비율이증가하는것으로나타났다. Kasai 등 (21) 은종양의크기를더욱세분화하여크기에따라공격성이다름을주장하였고, 다른연구에서는원발 종양의크기에따른공격성을분석하여임상양상의차이를제시하였다.(22) 본연구에서도종양의크기가커질수록다발성의빈도가높은비율로나타남을보이고있다. 갑상선외침범은수술후갑상선암의재발에중요한위험인자이며 3배이상증가된재발과사망률을보인다고하였으며, 그비율은 15.9 33.3% 에이른다고보고되고있다.(9,23) 전체대상환자의 25.8% 에서갑상선외침범이있었으며다발성과관련된경우는 34.9% 였다. 갑상선주변연부조직, 근육, 기관순으로의침범빈도를보였다. 이는다발성암종의국소적침습성을시사한다하겠다. 다발성그룹의갑상선피막침범은 11.8% 로 11.4% 를보인단일성그룹과비교하여빈도비율에서큰차이가나지는않았으나, 갑상선외침범과연속과정임을고려할때국소재발및원격전이에중요한요인이라할수있다. 분화갑상선암에서경부림프절의전이는약 20 50% 까지다양한결과들이알려져있다.(24) 본연구에서다발성그룹의경부림프절전이는 229예중 101예 (44.1%) 의빈도를보이며, 분화갑상선암경부림프절전이의다른보고들과비슷한결과를보였을뿐만아니라발생비율에서통계적유효성을가짐으로다발성은종양의공격성으로써의미를부여할수있겠다. 반대측혹은양측의림프절에전이를나타내는 N1b의빈도는다발성군에서빈도비율이높았으나, 단일성군과비교하여통계적으로의의를가지는차이가없었다. TNM system은분화갑상선암환자에서환자의예후를결정하는중요한요인중의하나로알려져있으며,(25,26) 다발성에서단일성보다높은병기의빈도가증가하였다. 국소재발은다발성그룹에서 3.5% 발생하여통계적유의하게나왔으나, 재발의발생기간이긴갑상선암의특성을고려할때, 본연구의환자추적기간이길지않아다발성의국소재발및원격전이와의관련여부는결론을내기가어려웠으며, 장기간의관찰과추후지속적인연구가필요할것으로생각된다. 결론본연구에서유두상갑상선암의다발성은연령, 종양의크기, 피막침범, 갑상선외침범, 경부림프절전이와연관이있으며, 이중경부림프절전이가다발성에가장유의한연관이있는것으로나왔다. 다발성은예후및국소재발을나타내는위험인자분류에는포함되지않음에도불구하고단일성보다중앙경부림프절전이에높은연관성을가졌다. 다발성유두상갑상선암이진단되었을경우, 기본적으로갑상선전절제술및예방적중앙경부림프절청소술을시행하여야하며, 재발에대한세밀한추적관찰이필요할것으로생각한다.
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