Korean Journal of HBP Surgery Vol. 11, No 3, September 원 저 복강경담낭절제술후발견된담낭암에대한고찰 Gallbladder Carcinomas found after a Laparoscopic Cholecystectomy Purpose: An laparoscopic cholecystectomy (LC) is being increasingly performed for benign gallbladder disease. Accordingly, gallbladder carcinomas have been increasingly reported in patients after undergoing an LC. This study aims to reveal the clinicopathological features and prognosis of gallbladder carcinomas found after an LC. Methods: Between April 1994 and March 2007, 2714 patients underwent an LC and 1.5% of the patients were diagnosed histologically as having a gallbladder carcinoma. We retrospectively evaluated the clinicopathological features and long-term survival of the patients. Results: There were 19 male patients and 21 female patients, with a mean age of 60.7 ±12.3 years. The indications for LC included acute calculous cholecystitis, chronic calculous cholecystitis and polypoid lesions of the gallbladder (PLGs). An LC only was performed in 26 patients (13 pt1a, 7 pt1b and 6 pt2 cases) while additional surgery including gallbladder bed resection and lymph node dissection was performed in 14 patients (2 pt1a, 2 pt1b, 8 pt2 and 2 pt3 cases). The patients with a carcinoma associated with PLGs were younger, had more incidence of pt1a and had well differentiated carcinomas and a better 5-year survival rate as compared to patients with a non-polypoid carcinoma. Whereas no recurrences or deaths occurred for the 24 pt1 patients, two of the 14 pt2 patients had a recurrence. Both pt3 patients had a recurrence despite additional surgery. In patients with pt2 or more, additional surgery did not improve survival (p = 0.82). Conclusion: The polypoid morphology of gallbladder carcinoma, but not additional surgery, favorably affects survival of gallbladder carcinoma patients following an LC. However, a further multi-institutional study may be needed to determine the benefit of additional surgery. Key Words: Gallbladder Carcinomas, Laparoscopic Cholecystectomy 중심단어 : 담낭암, 복강경담낭절제술 정혜연, 장수근, 김종렬, 김상걸, 황윤진, 윤영국 경북대학교의과대학외과학교실 Hye Yeon Jeong M.D, Su Kurn Chang M.D, Jong Yeol Kim M.D, Sang Geol Kim M.D, Yun Jin Hwang M.D, Ph.D., Young Kook Yun M.D, Ph.D. Department of surgery, Kyoung Pook National University College of Medicine, 책임저자 윤영국대구중구삼덕동 2 가 50 번지경북대학교병원외과 Tel: 053-420-5615 Fax: 053-421-0510 E-mail: ykyun@knu.ac.kr 이논문은제 22 차한국간담췌외과학회춘계학술대회에서구연되었음. 서론 복강경담낭절제술은최소침습, 수술후빠른회복과사회복귀등의장점으로인하여급만성결석성담낭염, 급성비결석성담낭염, 담낭의용종성질환등의담낭질환에대한표준적인수술로보편화되고그적용이증가하고있다. 1 이에따라복강경담낭절제술후우연히발견되는담낭암과담낭의용종성질환에서담낭암이진단되는경우가빈번히보고되고있다. 2,3 수술전영상학적소견에담낭암을시사하는소견은없지만우연히담낭암이발견되는빈도는 0.3% 1.5% 로다양하게보고되고있고담낭의용종성질환에서담낭암이발견되는빈도는더많으며 10% 내외로보고되고있다. 4 담낭암의발생초기에는증상이없으며대부분의경우에영상학적방법으로수술전진단은불가능하여양성담낭질환에대해복강경담낭절제수술을시행할때담낭암에대 한의증을가지고수술에임하는경우는드물다. 이러한이유로복강경담낭절제술을시행시특별한주의를기울이지않는경우가많으며이에따라담낭천공, 담낭암종괴박리로인한복강내혹은투관침삽입부에암세포파종과담낭관잔존암의가능성이있으며또한복강내이산화탄소가스가담낭암세포성장에영향을미칠수있다. 5-10 더욱이임파절곽청술이불가능하기때문에정확한병기를알수없으며환자의예후에좋지않은영향을미칠수있다. 복강경담낭절제술후발견된담낭암에대한치료방침은담낭암의침윤깊이, 환자의전신상태등을고려하여결정되지만담낭암의형태적특성과추가수술의시행여부, 방법, 시기가예후에미치는영향은잘알려져있지않으므로이러한환자의임상적특성과예후인자를이해하는것이향후치료방침을결정하는데필수적이라고할수있다. 이에저자등은양성담낭질환으로복강경담낭절제술을시행한후병리조직학적 1
정혜연외 : 복강경담낭절제술후발견된담낭암에대한고찰 으로담낭암이진단된환자의임상및병리학적특성, 수술방법, 종양의침윤깊이에따른예후를연구하여복강경담낭절제술후진단된담낭암의치료에도움이되고자하였다. 방법 1994년 4월에서 2007년 3월까지 13년간경북대학교병원에서담석증, 급성담낭염, 만성담낭염, 담낭용종등의담낭질환에대해복강경담낭절제술을시행하였던 2,714명중복강경으로담낭을절제한후담낭암으로진단되었던 40명의담낭암환자를대상으로하였으며복강경으로관찰후개복전환한경우는연구대상에서제외하였다. 환자의성별, 나이, 증상및수술적응증등의임상적특성, 수술소견, CEA, CA19-9, 종양의침윤깊이, 임파절전이, 조직학적분류등 과같은병리학적특성에대해병력지검토를통한후향적방법으로연구하였다. 수술적응증은급성담낭염, 만성결석성담낭염, 담낭종증, 담낭용종과담석증이동반된경우등으로수술전영상학적으로양성담낭질환이의심된경우였다. 복강경담낭절제술은이산화탄소가스를이용한기복법을이용하였고절제후비닐백을이용하여담낭을체외로제거하였다. 복강경담낭절제술후담낭암이발견된경우에담낭암의침윤깊이가 T2이상인경우에추가수술을시행하는것을원칙으로하였다. 그러나 pt1인경우라도환자가젊거나보호자가원하는경우에는추가수술을시행하였고 pt2에서도고령, 신체상태가좋지않을경우에는추가적수술을시행하지않았다. 재발및생존은장기추적관찰을통해조사하였고평균추적기간은 87개월이였다. pt2이상의진행성담낭암에대해추가수술시행여부에따라재발및생존률을비교하였다. 각군의임상지표의비교는 Fisher Exact Test와 student T-test를사용하였고생존율은 Kaplan-Meier법을사용하여 log-rank법으로비교하였다. Table 1. Clinicopathological characteristics LC * only LC with additional surgery p-value (N=26) (N=14) Age (yrs) 60.8 60.59 NS Sex (Male : Female) 15:11 4:10 NS Indications of LC NS Acute calculous cholecystitis 15.4%(4/26) 35.7%(5/14) Chroinc calculous cholecystitis 15.4%(4/26) 21.4%(3/14) Polyoid lesons of gallbladder 50.0%(13/26) 35.7%(5/14) Polyp Combined with stones 19.2%(5/26) 7.1%(1/14) Elective vs Emergency 88.5%(23:3) 92.9%(13:1) NS Preop CEA (Mean) 1.98±1.8 1.97±1.8 NS Preop CA19-9 (Mean) 8.02±6.8 7.8±1.8 NS Depth of Invasion pt1a 50%(13/26) 14.3%(2/14) 0.01 p 1b 26.9%(7/26) 14.3%(2/14) p 2 23.1%(6/26) 57.1%(8/14) p 3 0%(0/26) 14.3%(2/14) Size of tumor (cm) 1.89±1.1 2.59±1.2 NS Histologic Differentiation 0.03 Well 95.5%(21/22) 61.5%(8/13) Moderate 18.2%(1/22) 30.85%(4/13) Mucinous 0 7.7%(1/13) *LC=laparoscopic cholecystectomy NS=Not Statistically Significant 2
한국간담췌외과학회지 : 제 11 권제 3 호 2007 Table 2. Comparison between PLGs and NPLGs PLGs* NPLGs p-value (N=27) (N=13) Age (yrs) 57.1 68.1 NS Sex (Male : Female) 12:14 7:7 NS Preoperative Diagnosis 0.000 Acute calculous cholecystitis 0%(0/27) 69.2%(9/13) Chroinc calculous cholecystitis 11.1%(3/27) 30.8%(4/13) Polyoid lesons of gallbladder 66.7%(18/27) 0%(0/13) Combined polyp with stones 22.2%(6/27) 0%(0/13) LC vs. LC with additional surgery 19:8 7:6 NS Preop CEA (Mean) 1.2±0.28 2.07±1.2 NS Preop CA19-9 (Mean) 14.0±11.9 6.9±6.5 NS Depth of Invasion pt1a 51.9%(14/27) 7.7%(1/13) 0.008 pt1b 22.2%(6/27) 23.7%(3/13) pt2 25.9%(7/27) 53.8%(7/13) pt3 0%(0/27) 15.4%(2/13) Size of tumor (cm) 2.09±1.1 2.19±1.2 NS Histologic Differentiation 0.034 Well 95.5%(21/22) 61.5%(8/13) Moderate 4.5%(1/22) 30.8%(4/13) Mucinous 0%(0/22) 7.7%(1/13) *PLGs=Polypdoid gallbladder lesions; NPLGs=Non-polypdoid gallbladder lesions; Three additional cases were diagnosed as having gallbladder polyps with chronic calculous cholecystitis after surgery. 결과 1. 복강경담낭절제술후발견된담낭암의빈도와임상병리학적특성복강경담낭절제수술을받은전체 2,714례중에서수술후확진된담낭암의빈도는 1.47% (40/2,714) 이었다. 담낭암의빈도는비용종성담낭질환에서 0.5%(13/2,446), 용종성담낭질환에서 10.1%(27/268) 례로용종성담낭질환에서유의하게높았다 (p<0.0001). 복강경담낭절제술후담낭암으로진단된 40명중남자는 19명, 여자는 21명이었고평균나이는 60.7±12.3세이었다. 복강경담낭절제수술의적응증은급성결석성담낭염 9명, 만성결석성담낭염 7명, 용종성담낭질환 18명, 용종성담낭질환과담석증이동반된경우 6명이었다. 계획수술을시행한경우는 36례이며응급수술을시행한경우는 4례이었다.Table 1에서보여진바와같이복강경담낭절제술만시행한환자군 (26명) 과추가수술을시행한환자군 (14명) 간에수술전 CEA 과 CA19-9 평균치의차이는없었다. 양군에서담낭암의침윤깊이는복강경담낭절제수술로치료를종료한군보다근치적절제술을추 가한군에서 pt2 이상의진행암이더많았다 (P=0.01). 담낭암은모두선암이었으며고분화함의빈도는복강경담낭절제수술만시행한군에서 95.5% 로추가수술을시행한군보다유의하게높았다 (P=0.03). 담낭암의크기는양군간에차이는없었으며 (1.89cm vs. 2.59cm) 추가수술을시행한군에서임파절전이가있었던경우는 1례이었다. 2. 수술후결과, 재발및장기생존률분석복강경담낭절제술만을시행한경우는 26례이며추가수술을시행한경우는 14례이었다. 추가수술의시기는복강경담낭절제수술직후, 일주일째, 1 개월이내가각각 9례, 1례, 4례이었다. 복강경담낭절제술중담낭벽이천공된경우는 1 례이었으며담낭암종괴가 박리된경우는없었다. 복강경담낭절제수술로수술을종료한군과추가수술을시행한군모두에서수술후합병증례와사망례는없었다. 평균추적관찰기간은 87개월이었으며관찰기간중 pt1환자 24명 (pt1a:15명, pt1b:8명 ) 중추적관찰이가능했던 23 명은추가수술시행여부와관계없이재발이없었으며복강경수술을한 pt1b 1명이폐암으로사망한한것을제외 3
정혜연외 : 복강경담낭절제술후발견된담낭암에대한고찰 환자 2명은모두추가적으로근치적임파절곽청술과간상부절제술을시행하였으나각각수술후 40개월과 2개월에간내재발을하였고모두사망하였다. 복강경수술군과추가수술군간의생존률비교에서복강경군에서 pt1의빈도가많았지만두군간에생존률은차이가없었다. 한편 pt2이상의환자 16명에서추가수술의효과를알아보기위하여비교한결과 ( 복강경군 6명, 추가수술군 10명 ) 두군간의유의한생존률의차이는없었다 (p=0.82) (Fig. 1). Fig. 1. Comparison of 5 year survival rate between LC only group(n=6) and Additional surgery group(n=10) in pt2 or more advanced gallbladder carcinoma 3. 비용종성담낭암환자군과용종성담낭암환자군의비교비용종성담낭암환자군 13명과용종성담낭암환자군 27 명의임상양상을비교한결과용종성담낭암환자는비용종성담낭암환자보다연령이낮고 담낭암이점막에국한된 pt1a의빈도가더높았으며조직학적으로고분화암인경우가더많았다 (Table 2). 수술중담낭의천공이발생한경우 1례는비용종성담낭암환자에서발생하였다. 수술후두군간의생존률을비교한결과용종성담낭암환자는암의재발및사망례가한례도없었던반면비용종성담낭암환자군 13명은 5년생존률이 69.3% 였다 (p=0.01) (Fig. 2). 한편, 비용종성담낭암환자군과용종성담낭암환자군에서 pt2환자는각각 7명이었으며이환자들에국한하여생존률을비교한결과역시용종성담낭암환자의수술후 5년생존이양호한것을보여주었다 (71.4 % vs. 100%, p=0.11). 고 찰 Fig. 2. Comparison of 5 year survival rate between PLGs and NPLGs 하고모두생존하였다. pt2 환자 14명중복강경담낭절제수술로종료한군 (8명) 과추가적수술을시행한군 (6명) 에서각각 1례씩 31개월과 8개월째재발하였는데전자는복강내의파종, 후자는투관침삽입부의재발과간내재발이있었으며모두수술후 33개월, 10개월에 사망하였다. pt3 영상학적소견이담낭암을강력히시사하는경우에는이미진행된담낭암이대부분이며환자의생존률증가를위해개복근치적담낭절제술이우선적으로시행될것이다. 그러나담낭암의소견이명확하지않은급만성담낭염이나크지않은용종성담낭질환이있는경우에암의빈도가낮으며담낭암이있다하더라도조기담낭암이많으므로많은수술자들은복강경담낭절제술을우선적으로선택한다. 11-13 복강경담낭절제술후담낭암이발견되는빈도는환자의나이, 수술의적응증과조기담낭암의수술방법에대한술자의태도등에의해다양하게보고되고있다. 급만성담낭염으로복강경담낭절제술시행한후담낭암이발견되는경우는매우드물며대부분우연히발견되지만담낭의용종성질환으로복강경담낭절제술을시행한후에는담낭암의발견이 4
한국간담췌외과학회지 : 제 11 권제 3 호 2007 보다빈번하며담낭암의가능성을어느정도예견할수있는경우가많다. Yeh 등 14 은복강경담낭절제술을시행한담낭의용종성질환을가진환자의 5.7% 에서담낭암이병존하며그빈도는크기에따라증가한다고주장하였다. 본연구에서도다른연구자들의보고와유사하게 복강경담낭절제수술후확진된담낭암의빈도는 1.47% (40/2714) 이었으며비용종성담낭질환에서는 0.5% (13/2446), 용종성담낭질환에서는 10.1%(27/268) 에서담낭암이발견되었다. 담낭암의가능성이어느정도예견되는담낭의용종성질환에대해복강경담낭절제술을시행할것인지에관해서는저자들에따라견해가상이하다. Frauenschuh 등 15 은복강경담낭절제술을절제생검개념으로시행하고병리조직학적인침윤도에따라치료방침을제시하였다. 이치료방침이적절한방법으로받아들여지기위해서는복강경술식이담낭암의예후에나쁜영향을미치지않으며또한추가수술을시행함으로개복근치적절제술과다르지않은결과를얻을수있다는증거가있어야만할것이다. 복강경담낭절제수술후담낭암이발견되었을때추가수술의적용에가장중요한요소는담낭암의침윤깊이이며추가수술이생존률에미치는영향에대한평가는향후적절한치료방침을세우는데매우중요하다. ptis와 pt1a병변은임파절전이가거의없기때문에복강경담낭절제술만으로충분하다. 16, 17 그러나 pt1b의경우 13-15% 에서임파절전이가보고되어있어복강경담낭절제술만으로는진단및치료를위한임파절곽청이불가능하여복강경담낭절제술이충분한수술인지에대해서는논란의여지가많다. 17,18 pt2 이상의진행암은복강경술식시암종괴박리, 담낭천공에의한암성담즙의유출등에의한암세포의파종, 투관침삽입부전이로인해환자의예후에좋지않은영향을미칠수있기때문에공격적인근치적임파절곽청술과확대절제가환자의예후에도움이된다고보고되고있다. 19-22 Toshifumi 등 20 은 28명의 pt2 담낭남에서복강경담낭절제술후추가적근치적인절제술을시행한환자 7명의 5년생존율은 100% 인반면복강경절제술만시행한환자 6명의 5년생존율은 50% 임을보고하며근치적절제술이생존율향상시킨다고보고하였다. Ouchi 등 21 은일본전역을대상으로담낭암환자 498명을추적관찰한결과 pt2암에서는추가수술이환자의생존률을높이는경향이있으나 pt3 암에서생존률의이득이미미함을보여주었고한편복강경담낭절제술시담낭천공은환자의예후에좋지않은영향을미친다는것을보여주었다. 그러나추가수술이생존률을향상에미치는영향이대규모의전향적인연구에의해증명된적은없다. 본연구는단일기관으로가지는소규모의대상환자와후향적연구라는제한성을가지고있으나이러한제한성을염두에두고결과를고찰해보면 pt1a 환자 15명과 pt1b 환자 9명중에서추가수술을받은환자는각각 2명씩모두 4 명이었으며모든예에서임파절전이는없었고 pt1 환자는추가수술의적용과관계없이모두재발없이생존하였다. 한편 pt2 환자 14명중복강경수술로종료한군과추가적수술을시행한군에서각각 1례씩 31개월과 8개월째재발하였는데전자는복강경담낭절제수술후 31개월째 CT상복강내의파종이발견되었고후자는추가수술시행후임파절전이가확인된경우이며추가수술후 8개월째투관침삽입부의파종과간내재발이발생하였으며 2례모두사망하였다. pt3 환자 2명중 1명은근치적임파절곽청술과간상부절제술을시행하였으며절제간및절제연에병리학적으로암침윤은없었고, 1명은병리학적인절단면암침윤은없었지만수술소견상간내암침윤이심하고간십이지장인대에도침윤이되어근치적절제술이불가능하였다. 각각 40 개월, 2개월에간내재발을하여모두사망하였다. pt2이상의환자 16명에서복강경담낭절제수술군 6명과추가수술군 10명간의유의한생존율의차이는없었다 (p=0.82). 근치적임파절곽청술과확대절제가환자의예후에도움이된다는것과상이한결과는상대적으로적은환자군과짧은추적기간에의한것으로사료되며복강경담낭절제수술후에추가적근치적수술의생존율증가를증명하기위해서는향후보다많은연구기관에서더많은환자를대상으로하여장기적추적관찰을통해연구해야할것으로생각된다. 한편수술전관찰된담낭의형태에따른수술후생존률은큰차이를보였는데용종성담낭암환자는암의재발및사망례가한례도없었던반면비용종성담낭암환자군 13명은 5년생존률이 69.3% 였다 (p=0.01). 또한, 비용종성담낭암환자군과용종성담낭암환자군에서 pt2환자만을선택하여비교한결과역시용종성담낭암환자의 5년생존이양호한것을보여주었다 (71.4% vs. 100 %). 이는개복근치적절제술을적용했을때도용종성담낭암이비용종성담낭암보다좋은예후를보이는보고와유사하며또한비용종성담낭질환에서는담낭암을의심하지않는경우가많은반면용종성담낭질환에서는담낭암을의심하기때문에수술중천공, 종괴박리, 제거등의과정에서더욱주의하게되는것과관련이있을것으로사료된다. 결론 용종성담낭암과담낭암이고유근층까지도달한경우에예 5
정혜연외 : 복강경담낭절제술후발견된담낭암에대한고찰 후가좋았다. 한편, 대상환자수가적고전향적무작위적연구방법이아니므로추가수술이생존률에미치는영향에대한평가는제한적이지만본연구결과에서는추가수술에따른생존율의향상이관찰되지않았다. 향후추가수술의의의를결정하기위해서는다기관연구를통해더많은환자를대상으로한연구가필요할것으로사료된다. 참고문헌 1. Legorreta AP, Silber JH, Costantino GN, Kobylinski RW, Zatz SL. Increased cholecystectomy rate after the introduction of laparoscopic cholecystectomy. JAMA 1993;270:1429 1432. 2. Fong Y, Brennan MF, Turnbull A, Colt DG, Blumgart LH. Gallbladder cancer discovered during laparoscopic surgery. Arch Surg 1993;128:1054 1056. 3. Gornish AL, Averbach D, Schwartz MR. Carcinoma of the gallbladder found during laparoscopic cholecystectomy : a case report and review of the literature. J Laparoendosc Surg 1991;1:361 367. 4. Yeh CN, Jan YY, Chen MF. Management of unsuspected gallbladder carcinoma discovered during or following laparoscopic cholecystectomy. Am Surg 2004;70:256-258. 5. Suzuki K, Kimura T, Ogawa H. Is laparoscopic cholecystectomy hazardous for gallbladder cancer. Surgery 1999;123:311-314. 6. Shirai Y, Ohtani T, Hatakeyama K. Is laparoscopic cholecystectomy indicated for early gallbladder cancer. Surgery 1997;122:120-121. 7. Braghetto I, Bastias J. Csendes A, Choing H, Compan A, Valladares H, et al. Gallbladder carcinoma during laparoscopic cholecystectomy: is it associated with bad prognosis. Int Surg 1999;84:344-349. 8. Wysocki A, Bobryzynski A, Krzywon J, Budzynski A. Laparoscopic cholecystectomy and gallbladder cancer. Surg Endosc 1999;13:899-900. 9. Ricardo AE, Feig BW, Ellis LM. Gallbladder cancer and trocar site recurrences. Am J Surg 1997;174:619-623. 10. Tanaka N, Nobori M, Suzuki Y. Does bile spillage during an operation present a risk for peritoneal metastasis in bile duct carcinoma. Surg Today 1997;27:1010-1014. 11. Wibbenmeyer LA, Wade TP, Chen RC, Meyer RC, Turgeon RP, Andrus CH. Laparoscopic cholecystectomy can disseminate in situ carcinoma of the gallbladder. J Am Coll Surg 1995;181:504-510. 12. Donohue JH, Stewart AK, Menck HR. The National Cancer Data Base report on carcinoma of the gallbladder, 1989 1995. Cancer 1998;83:2618-2628. 13. Suzuki K, Kimura T, Ogawa H. Long-term prognosis of gallbladder cancer diagnosed after laparoscopic cholecystectomy. Surg Endosc 2000;14:712 716. 14. Yeh CN, Jan YY, Chao TC, Chen MF. Laparoscopic clinicopathologic study. Surg Laparosc Endosc Percutan Tech. 2001;11:176-181. 15. Frauenschuh D, Greim R, Krase E. How to proceed in patients with carcinoma detected after laparoscopic cholecystectomy. Langenbecks Arch Surg 2000;385:495-500. 16. Tsukada K, Kurosaki I, Uchida K, Shirai Y, Oohashi Y,Yokoyama N, et al. Lymph node spread from carcinoma of the gallbladder. Cancer 1997;80:661-667. 17. Nevin JE, Moran TJ, Kay S, King R. Carcinoma of the gall bladder. Staging, treatment, and prognosis. Cancer 1976;37:141-148. 18. Nagakura S, Shirai Y, Yokoyama N, Hatakeyama K. Clinical significance of lymph node micrometastasis in gallbladder carcinoma. Surgery 2001;129:704-713. 19. Hwang S, Lee SG, Lee YJ, Park KM, Min PC. Result of extended resection in advanced gallbladder cancers. Korean J Gastroenterol 1997;30:379-389. 20. Toshifumi W, Yoshio S, Katsuyoshi H. Radical second resection provides survival benefit for patients with T2 gallbladder carcinoma first discovered after laparoscopic cholecystectomy. World J Surg 2002;26:867-871. 21. Ouchi K, Mikuni J, Kakugawa Y, et al. Laparoscopic cholecystectomy for gallbladder carcinoma: results of a Japanese survey of 498 patients. J Hepatobiliary Pancreat Surg 2002;9:256-260. 22. Nduka CC, Monson JRT, Menzies-Gow N, et al. Abdominal wall metastases following laparoscopy. Br J Surg 1994;81:648-652. 6