J Korean Surg Soc 2010;78:298-304 DOI: 10.4174/jkss.2010.78.5.298 원 저 직장암에서전층절편조직검사를통한직장간막미세종양결절과측방절제연에관한임상연구 국민건강보험공단일산병원외과, 1 병리과 김서전ㆍ최윤정 1 ㆍ강중구 Clinicopathologic Analysis of Mesorectal Spread of Rectal Cancer with Whole Mount Section Seo-Jeon Kim, M.D., Yoon-Jung Choi, M.D. 1, Jung-Gu Kang, M.D. Departments of Surgery and 1 Pathology, National Health Insurance Corporation Ilsan Hospital, Goyang, Korea Purpose: Total mesorectal excision (TME) has been widely accepted as the principal method in rectal cancer surgery and demonstrates good oncologic and functional outcome. The recurrence rate of mid-low rectal cancer surgery with TME is reported as 5 6%. Concerning local recurrence, remaining microscopic nodules in mesorectum are a major issue. In this study, we investigated mesorectal spread of tumors and exact lateral resection margin using whole mount section (WMS) to obtain correlations with other clinico-pathological variables. Methods: 63 rectal cancer patients underwent surgery with TME and WMS at National Health Insurance Corporation Ilsan Hospital between December 2005 and October 2008. Preoperative study was made by computed tomography (CT), magnetic resonance imaging (MRI). We measured the distance from the largest cut section of the primary tumor to the nearest circumferential margin using MRI and compared them to lateral resection margins in WMS. Results: Among 63 patients, the sex ratio was 1:1.17 and the median age was 62.7 years. There were 34 patients in TNM stage III (54.0%), 21 patients in stage II (33.3%) and 8 patients in stage I (12.7%). Lateral margin involvement was predicted in 4 cases pre-operatively and confirmed in 3 cases with WMS. Micrometastasis in mesorectum was detected in 6 patients (9.5%) and all were in stage III. N stage was statistically correlated with micrometastasis (P=0.016). Conclusion: WMS offers precise lateral resection margin and mesorectal spread of microscopic tumor nodules. WMS is best considered in stage III cancer to evaluate mesorectal micrometastasis. The mid-low rectal cancer cases with predicted lateral margin involvements using MRI should be operated on with great care. (J Korean Surg Soc 2010;78:298-304) Key Words: Whole mount section, Total mesorectal excision, Circumferential resection margin 중심단어 : 전층절편조직검사, 전직장간막절제술, 측방절제연 서 론 책임저자 : 강중구, 경기도고양시일산동구백석동 1232 411-719, 국민건강보험공단일산병원외과 Tel: 031-900-0216, Fax: 031-900-0343 E-mail: kangski1004@yahoo.co.kr 접수일 :2009 년 11 월 5 일, 게재승인일 :2010 년 2 월 1 일 직장암에있어수술후에발생하는국소재발은전직장간막절제술이보급되기이전까지일반적으로 30% 이상으로 (Dukes B, C) 보고되고있다.(1,2) Heald 등은직장암수술에 298
Seo-Jeon Kim, et al:clinicopathologic Analysis of Mesorectal Spread of Rectal Cancer with Whole Mount Section 299 있어주요병변보다원위부의직장간막에서도미세종양결절이발견되므로전직장간막절제술을통해미세종양결절을전부제거하는것이국소재발을줄이는데중요한것으로보고하였으며, 현재는직장암의표준술식으로널리받아들여지고있다.(3,4) 전직장간막절제술을통한중하부직장암의국소재발률은 5 6% 정도로보고되고있는데이는원위부절제연하방의미세종양결절및충분치않은전직장간막절제술, 측방절제연의종양침습등에기인한다.(5-8) 일부전층절편조직검사를통한직장간막의미세종양결절에관한연구가진행되면서측방절제연확보를위한정확한절제연까지의거리, 원위부절제연의결정및충분한원위부절제연확보시의괄약근보존의어려움등이논란이되고있으며,(9-12) 국내에서도여러연구가수행되어왔으나아직까지전층절편조직검사를통한연구가보고된적은없다. 저자들은본연구에서전직장간막절제술을통해얻은직장암수술조직으로전층절편조직검사를시행하고, 이를통하여직장간막의미세종양결절의유무및전이양상과정확한측방절제연을확인하고, 또한이결과를수술전시행한영상의학검사결과및임상지표등과관련하여통계학적상관관계가있는지를확인하고자한다. 방법 2005년 12월부터 2008년 10월까지 35개월동안국민건강보험공단일산병원외과에서조직학적으로직장암으로진단받고, 수술을시행한 139명의환자들중에서전직장간막절제술및수술검체의전층절편조직검사를시행한 63명의환자들을대상으로하였다. 63명의환자들모두에서수술전혈액검사, 복부전산화단층촬영, 흉부전산화단층촬영, 자기공명영상촬영을시행하였고, 진행성병변에서양전자방사촬영 (PET scan) 을선택적으로시행하였다. 수술전영상의학검사를통하여측방절제연이침습된경우와근접된경우, 주위장기침습여부를예측하였으며수술후, 전층절편조직검사를통하여직장간막내의미세종양결절유무와측방절제연까지의거리를확인하여비교하였다. 수술전측방절제연까지의거리측정은자기공명영상촬영을활용하였으며, 주요병변의최대단면적과최대침습깊이를나타내는단면영상에서, 병변의최외측과직장고유근막까지의거리를측정하여측방절제연거리로정하였다 (Fig. 1). 침습깊이의차이로인하여측방절제연까지 의거리가더작게측정되는경우에는그거리를최소측방절제연거리로설정하였다. 63명의환자들중에서저위전방절제술을시행한경우가 53예로가장많았고초저위전방절제술및문합부보호를위한일시적회장루조성술을시행한경우가 5예였으며, 나머지 5예에서복회음절제술을시행하였다. 절제연침습이예측되는환자들중에서침습정도가깊고원격전이가동반되는경우는없었으며수술을통하여치료가가능할것으로판단되는경우여서수술전항암방사선치료를시행한경우는없었다. 전층절편조직검사방법은수술직후검체를절개하지않고병리과로이송하여 10% 포르말린용액으로 24 48시간동안 1차고정하였고 (Fig. 2A), 5 mm 간격으로장축에수직으로자른후에 2차고정하였다 (Fig. 2B). 전층절편검체를전부포함하는슬라이드를제작하였고이후 Hematoxylin and Eosin (H&E) 염색을시행하였다. 완성된슬라이드들을검토하여종양의분화, 침윤, 림프절전이및직장간막의미세종양결절등을확인하였고종양과측방절제연까지의거리는화상분석기 (Image Pro R Plus) 를이용하여측정하였다 (Fig. 3). 측방절제연침습은여러문헌에서제안하는바와같이 1 mm 이하를절제연양성으로정의하였다.(7-9) 통계학적검증은 SPSS 11.0 for Windows를사용하였으며전직장간막의미세종양결절과기타변수의단변량분석은 Chi-square test, Fisher s exact test를사용하였고다변량분석은 binary logistic regression test를사용하였다. P값은 0.05 미 Fig. 1. MRI measurement: The image shows measurement of the closest circumferential distance between tumor and rectal proper fascia.
300 J Korean Surg Soc. Vol. 78, No. 5 Fig. 2. Preparation of whole mount section specimen. (A) The total mesorectal excision (TME) specimen was fixed in formalin without cutting. (B) After 1st fixation, the TME specimen was cut vertically along the long-axis evenly at 5 mm each. Table 1. Patients demographics and clinical characteristics Fig. 3. Whole mount section slide: The H&E stained slide shows main tumor mass, depth of tumor invasion, regional lymph node and discontinuous micrometastasis in mesorectum (black arrow = primary tumor; green double-arrow, the closest distance between tumor and CRM; blank arrow = discontinuous microscopic tumor nodule in mesorectum; blank arrow head, posterior wall of uterus). Age (range, mean) No. of patients (%) (n=63) 37 84 62.7 years Micrometastasis in mesorectum P-value Sex * Male 29 (46.0) 4 Female 34 (54.0) 2 Location of the primary tumor Mid rectum 33 (52.4) 4 Low rectum 30 (47.6) 2 Largest diameter of the primary tumor (cm) <5 19 (30.2) 2 5 44 (69.8) 4 CEA (mg/dl) <5 44 (69.8) 4 5 19 (30.2) 2 * = not specific statistically between groups; CEA = carcino-embryonic antigen, range (0.3 73.3). 만을통계학적으로유의한것으로처리하였다. 결과 총 63명의환자들중에서남자가 29예, 여자가 34예로남녀비는 1:1.2였으며연령분포는 37세에서 84세로평균연령은 62.7세였다. 63명의환자들중주요병변이중간직장에위치한경우가 33예 (52.4%), 하부직장에위치한경우가 30예 (47.6%) 였다. 주요병변의최대직경은 5 cm 미만이 19 예 (30.2%), 5 cm 이상이 44예 (69.8%) 였다. 연령, 성별, 주요병변의위치및크기는각각의변수가고르게분포하였으며연령대별, 남녀간및병변의위치에따른통계학적상관 관계는없었다 (Table 1). 수술전모든환자에서 CEA 검사를시행하였으며 5 mg/dl 미만인경우가 44예 (69.8%), 5 mg/dl 이상인경우가 19예 (30.2%) 였으며두집단간의직장간막미세종양결절유무와통계학적의의는없었다 (Table 1). 수술전자기공명영상촬영상의측방절제연침습은 1 mm 이하로정하였으며본연구에서는 4예 (6.4%) 가예측되었다. 자기공명영상촬영상주요병변과측방절제연까지의거리는 1 mm 이하가 4예 (6.4%), 1 mm 초과 2 mm 이하는 2예 (3.2%) 였으며, 2 mm 초과가 57예 (90.4%) 로대부분을차지하였다. 전층절편조직조직검사를통해확인한측방절제연측정에서는이중 3예만이 1 mm 이하로확인되었다. 수술전영상의학검사상주변장기침습이 5예 (7.9%) 에서
Seo-Jeon Kim, et al:clinicopathologic Analysis of Mesorectal Spread of Rectal Cancer with Whole Mount Section 301 Table 2. Comparison between imaging study and pathologic report (n=63) Distance* (mm) Pre-operative MRI (%) Pathologic report by WMS (%) 1 4 (6.4) 3 (4.8) >1, 2 2 (3.2) 4 (6.4) >2, 3 4 (6.4) 0 (0.0) >3 53 (84.0) 56 (88.8) *Distance from primary tumor to lateral margin; WMS = whole mount section. 예측되었다. 따라서수술전측방절제연침습은 4예에서예측되었으나수술후전층절편조직검사를통해확인된경우는 3예로수술전영상의학검사와비교하여 75% 의진단적정확도를보였다. 이 3예중 2예에서직장간막미세종양결절이발견되었으며직장간막의미세종양결절은측방절제연 2 mm 이하에서 3예 (50.0%) 가발견되었다. 통계학적으로측방절제연까지의거리, 침습과직장간막의미세종양결절유무와는유의한상관관계를보이지는않았으나 2 mm 이하의측방절제연이예측되는경우에는특별히완전한전직장간막절제술이되도록주의해야할것으로생각된다 (Table 2). 원위부절제연까지의거리는 3 cm 초과가 20예 (31.7%), 2 cm 이상 3 cm 미만이 10예 (15.9%), 1 cm 이상 2 cm 미만이 15예 (23.8%) 그리고 1 cm 이하가 18예 (28.6%) 였으며직장간막의미세종양결절유무와통계학적유의성은없었다 (Table 3). 조직학적분화도는고분화도가 13예 (20.6%), 중등도분화도가 45예 (71.4%) 로가장많았고저분화도가 2예 (3.2%), 점액성인경우가 3예 (4.8%) 에서관찰되었다. TNM 병기는 Stage III가 34예 (54.0%) 로가장많았으며이중 IIIA가 4예, Stage IIIB가 14예, Stage IIIC가 16예로나타났다. 그밖에 Stage IIA가 20예 (31.7%), Stage IIB가 1예 (1.6%), Stage I이 8예 (12.7%) 로확인되었다. 림프관및혈관침습은주요한예후인자중하나로본연구에서 19예 (30.2%) 에서양성이었으나전층절편조직조직검사상의미세종양결절과의통계학적연관성은보이지않았다. 주변장기로의침습이예측된경우는 5예로침습장기는자궁이 2예, 방광이 1예, 난소와자궁이각각 1예였다. 실제 4예에서수술시확인되어동시절제가시행되었고 80% 의진단적정확도를보였다. 전층절편조직검사를통한직장간막의미세종양결절이확인된예는 6예 (9.5%) 였다. 6예모두원격전이가없었으 Table 3. Pathologic results (n=63) No. of Micrometastasis P-value patients (%) (%*) Differenciation of tumor Well 13 (20.6) 2 (5.4) Moderately 45 (71.4) 2 (4.4) Poorly 2 (3.2) 1 (50) Mucinous type 3 (4.8) 1 (33.3) TNM staging I 8 (12.7) 0 (0) IIA 20 (31.7) 0 (0) IIB 1 (1.6) 0 (0) IIIA 4 (6.4) 0 (0) IIIB 14 (22.2) 2 (14.3) IIIC 16 (25.4) 4 (25) N staging 0.016 0 29 (46) 0 (0) 1 18 (28.6) 2 (11.1) 2 16 (25.4) 4 (25) Distal resection margin (cm) 1 18 (28.6) 1 (5.5) >1, 2 15 (23.8) 1 (6.7) >2, 3 10 (15.9) 1 (10) >3 20 (31.7) 3 (15) Lateral margin involvement with tumor (pathologic report, mm) 1 3 (4.8) 2 (66.7) >1, 2 4 (6.4) 1 (25) >2, 3 0 (0) 0 (0) >3 56 (88.8) 3 (5.3) Lymphovascular permeation Positive 19 (30.2) 2 (10.5) Negative 44 (69.8) 4 (9.1) *Number of micrometastasis in mesorectum 100/number of cases; = not specific statistically between groups. 며수술전항암방사선치료를시행하지않은경우였다. 직장간막의미세종양결절이발견된 6예전부 TNM 병기상 Stage III 였고, Stage IIIC에서 4예, Stage IIIB에서 2예가발견되었다. 미세종양결절의분포에대하여 Stage 별로 Chisquare test를실시하였으나각군간통계학적유의성을발견하지못하였다. 그러나림프절전이가양성인경우, 미세종양결절유무와통계학적연관성을나타냄을확인하였다 (Table 3). 직장간막미세종양결절이발견된 6예에서조직학적분화도는고분화가 2예, 중등도분화가 2예, 저분화가 1예, 점액성이 1예였고림프-혈관침습은 6예중 2예에서관찰되었다. 조직학적분화도및림프-혈관침습또한직장간막의미세종양결절과통계학적유의성은없었다. 본연구에서는직장간막의미세종양결절이발견된 6 명
302 J Korean Surg Soc. Vol. 78, No. 5 Table 4. Summary of micrometastasis in mesorectum by whole mount section (n=6) Case No. Age Sex Location of tumor Differenciation TNM staging CRM* (mm) DRM (cm) Recurrence 1 69 M Mid-Low Well IIIB 1 4.5 No 2 80 M Mid-Low Well+Mucinous IIIC 3.1 1.0 No 3 55 M Mid-Low Moderate IIIB 8 3 No 4 70 M Mid-Low Moderate IIIC 10 2.2 No 5 71 F Low Mucinous IIIC 2 0.6 No 6 70 F Low Poor IIIC 0.8 3.1 Liver *CRM = distance between tumor and circumferential resection margin; DRM = distance between tumor and distal resection margin; M = male; F = female; Recurred after 19 months, without local recurrence, treated with radio-frequency ablation and intravenous chemotherapy (5-FU and Leucovorine), survived until October, 2009. 에대하여 2009년 10월까지추적관찰하였으며추적중앙값은 42.8개월, 범위는 38 47개월이었다. 1명의환자에서수술후 19개월째국소재발없이간전이가단독으로발견되어 radiofrequency ablation 치료후에 5-FU, Leucovorine 항암화학치료를시행하였고, 이후의추적검사상간전이의재성장은보이지않았으며 2009년 10월까지외래에서추적진료중이다 (Table 4). 고찰 전직장간막절제술은국소재발감소에종양학적으로유의한의미를가지며생존율향상에기여하고있다.(1-5) 중하부직장암의수술적인치료에있어서전직장간막절제술은기본적이고중요하나원위부절제연을설정함에있어항문고유기능을유지하는방향으로술식이발전하고있으며적절한원위부절제연까지의거리에관하여논란의여지가남아있다.(13-15) 전층절편조직검사는직장암의수술후정확한직장간막의미세종양결절의확인과측방절제연까지의정확한거리를측정하기위해활용되며그외다양하고유용한정보를제공할수있다.(16,17) 특히직장암수술에있어서직장간막의미세종양결절에관한정보는전층절편조직검사이외의방법으로는알기어렵다. 더욱이전층절편조직검사를통해서원위부의직장간막에존재하는미세종양결절을확인할수있으며, 이를근거로정확한원위부절제연까지의거리를정하는데임상지침으로활용할수있다.(10-12) 본연구에서원위부절제연의미세종양결절을확인하지못하였으나추가적인연구를통하여원위부절제연에관한자료가추가되어야하겠다. 또한본연구에서통계학적의의는없었으나직장간막의미세전 이가보고된 6예모두 TNM병기가 Stage III 이상이었으며특히, N 병기는직장간막의미세종양결절유무와통계학적유의성을보였으므로병기가진행된것으로추정되는경우직장간막의미세전이를예상할수있어국소재발과림프절전이를줄이기위한더욱정교하고온전한전직장간막절제술을시행해야할것으로생각된다. 또한본연구에서수술전시행한자기공명영상촬영상의측방절제연침습유무는전층절편조직검사상 75% 의정확도를나타내었으며, 측방절제연까지의거리또한 1 mm 이내의편차로예측이가능하였다. 이는수술전 T병기설정에도움을줄수있으며일부고해상도장비를이용한연구에서는측방절제연침습을 88% 까지예측가능한것으로보고한바있다. 수술시불완전한조작으로직장간막의손상이동반된경우골반강내에미세종양결절이남게되는경우가발생할수있으며이런경우국소재발로이어질수있다.(18,19) 통상적인수술에서측방절제연침습은약 27% 로보고되며전직장간막절제술을시행한경우에는 6.5 8.1% 까지줄어들수있다.(20,21) 본연구에서도전직장간막절제술을시행한 63명의환자에서측방절제연침습은단지 3예에서만관찰되었다. 전층절편조직검사의연구를통한측방절제연측정은수술전예측할수있는영상의학검사보다정확한결과를제시하며 (16,22) 수술전측방절제연의침습이예측된경우충분한절제연확보를고려한더욱정교한수술을계획할수있을것으로생각된다. 또한실제절제연양성인경우골반강내측부림프절절제와수술후방사선치료를고려해야할것으로생각된다. 절제연하방의원위부직장간막의미세종양결절은문헌에따라 5 64% 까지보고되며 (10-12,19,21,23) 불연속적인직장간막의미세종양결절전이는주요병변에서 5 cm 원위부에서도발견된
Seo-Jeon Kim, et al:clinicopathologic Analysis of Mesorectal Spread of Rectal Cancer with Whole Mount Section 303 다.(1-3) 이와같은절제연하방의미세전이는국소재발로이어질수있어예후에나쁜영향을미친다.(14,23,24) 따라서적절한직장간막원위부절제연을확보하는것이중요하며문헌에따라 3 cm 이상, 4 cm 이상등다양한의견이제시되고있으나 (6,9-12) 4 cm 이상을확보하는것이임상적으로유리한것으로받아들여지고있다.(12,16,19) 추가적인원위부직장간막의전층절편조직연구를통하여미세종양결절을확인하는방법이야말로정확한원위부절제연의적절한길이를제시할수있을것으로생각된다.(10-12) 수술후 4 mm 이상의종양결절이골반강내에남아있게되는경우나쁜예후를보이는것으로보고되고있으나비교적큰종양결절은육안상으로확인될수있으며오히려그보다작은종양결절들이남아서국소재발을일으킬수있으므로주의를요한다.(10,11,18,25) 최근연구에서수술전방사선치료가직장간막의미세종양결절을줄여수술후국소재발률을유의하게떨어뜨린다고보고하였으나상대적으로짧은추적관찰기간으로인하여생존율과의상관관계는아직까지보고되지않았다.(26,27) 전직장간막절제술의범위를넘어광범위한절제술을시행하는수술은일본에서시행되어생존율연장에도움이되는것으로보고되었으나기능적인장애, 제한적인적응증등으로일반적으로받아들여지기에는논란의여지가있다.(15,28,29) 전층절편조직검사는시간이많이걸리며비용및인력등의시행상난점이있어모든경우에적용하기어렵다. 특히초기병변을제외한진행성병변에서더많은이점을얻을수있으므로선택적인적용이필요하며, 향후보다많은대상군을통하여장기적으로전층절편조직검사를통한연구를진행하여, 원위부절제연에대한개념정립을위해노력한다면더욱합리적이고타당한기준을제시할수있을것으로기대한다. 또한이러한증례들의추적관찰을통하여재발률과생존율에관한연구가추가된다면전층절편조직검사의의의가더욱커질것으로생각된다. 결론 직장암의수술에서전직장간막절제술후검체의전층절편조직검사를통하여측방절제연의정확한측정이가능하며수술전영상의학검사상으로예측된측방절제연의침습은실제수술후전층절편조직검사결과와 75% 의정확도를보이므로수술시측방절제연확보를위한적절한 술기의고려가필요하다. 전층절편조직검사상직장간막의미세종양결절은 9.5% 에서확인되었으며모두 TNM 병기상 Stage III 이상에서관찰되었으므로수술전진행된병기가예측되는경우직장간막의손상없이충분한원위부절제연확보를위한술식이필요할것으로생각된다. 또한 N 병기가미세종양결절의유무와통계학적유의성을나타냈으므로수술시정교한전직장간막절제술과림프절절제가되도록주의를기울여야할것으로생각된다. REFERENCES 1) Reynolds JV, Joyce WP, Dolan J, Sheahan K, Hyland JM. Pathological evidence in support of total mesorectal excision in the management of rectal cancer. Br J Surg 1996;83:1112-5. 2) Soreide O, Norstein J. Local recurrence after operative treatment of rectal carcinoma: a strategy for change. J Am Coll Surg 1997;184:84-92. 3) Heald RJ, Husband EM, Ryall RD. The mesorectum in rectal cancer surgery--the clue to pelvic recurrence? Br J Surg 1982;69:613-6. 4) Heald RJ, Ryall RD. Recurrence and survival after total mesorectal excision for rectal cancer. Lancet 1986;1:1479-82. 5) Lee KY, Kim SM, Kim NK, Park JK, Sohn SK, Min JS. Pattern of recurrence after curative resection for rectal cancer. J Korean Surg Soc 2001;61:588-92. 6) Andreola S, Leo E, Belli F, Gallino G, Sirizzotti G, Sampietro G. Adenocarcinoma of the lower third of the rectum: metastases in lymph nodes smaller than 5 mm and occult micrometastases; preliminary results on early tumor recurrence. Ann Surg Oncol 2001;8:413-7. 7) Baik SH, Kim NK, Lee KY, Sohn SK, Cho CH, Kim HG, et al. Prognostic significance of circumferential resection margin following a total mesorectal excision in rectal cancer. J Korean Soc Coloproctol 2005;21:307-13. 8) Lee SH, Hernandez de Anda E, Finne CO, Madoff RD, Garcia-Aguilar J. The effect of circumferential tumor location in clinical outcomes of rectal cancer patients treated with total mesorectal excision. Dis Colon Rectum 2005;48:2249-57. 9) Nagtegaal ID, Quirke P. What is the role for the circumferential margin in the modern treatment of rectal cancer? J Clin Oncol 2008;26:303-12. 10) Ono C, Yoshinaga K, Enomoto M, Sugihara K. Discontinuous rectal cancer spread in the mesorectum and the optimal distal clearance margin in situ. Dis Colon Rectum 2002;45:744-9. 11) Wang Z, Zhou ZG, Wang C, Zhao GP, Chen YD, Gao HK, et al. Microscopic spread of low rectal cancer in regions of mesorectum: pathologic assessment with whole-mount sections. World J Gastroenterol 2004;10:2949-53.
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