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1 대한내과학회지 : 제 73 권제 6 호 2007 위반지세포암종의내시경소견및임상병리학적특징 울산대학교의과대학강릉아산병원소화기내과 김광석 김영돈 한군희 이세형 김지훈 최혜영 천갑진 =Abstract= Endoscopic findings and clinicopathological characteristics of signet ring cell carcinoma of the stomach Kwang Seok Kim, M.D., Young Don Kim, M.D., Koon Hee Han, M.D., Se Hyung Lee, M.D., Ji Hoon Kim, M.D., Hye Young Choi, M.D. and Gab Jin Cheon, M.D. Department of Gastroenterology, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Korea Background : Signet ring cell carcinoma (SRCC) of the stomach has a young age prevalence and is associated with advanced gastric cancer (AGC) on diagnosis and a poor prognosis. However, the clinical and histopathological characteristics of the disease have been controversial and its endoscopic characteristics are not clear. Thus, we examined the clinical, endoscopic and histopathological characteristics of SRCC of the stomach and analyzed them in comparison with non-signet ring cell carcinoma (NSRCC). Methods : We retrospectively investigated the medical records of cases definitely diagnosed as stomach cancer by upper gastrointestinal endoscopy or radical gastrectomy from March 1996 to May 2006, and statistically analyzed the clinical, endoscopic and histopathological characteristics of the SRCC and NSRCC group selected at random. Results : During the study period, 1,840 patients were diagnosed as stomach cancer, and 117 (6.4%) of the patients were found to have SRCC. Clinically, the SRCC group showed a higher frequency in female (p=0.005), those aged below 60 years (p<0.001), non-smokers (p=0.031) and non-drinkers (p=0.045), and endoscopically the SRCC group was higher in the percentage of lesions located in the body part of stomach (p=0.003), the Helicobacter pylori (H. pylori) infection rate (p<0.001) and the Borrmann 4 type AGC (p=0.003). Significant independent characteristics of SRCC identified through multivariate analysis were an age below 60 years, H. pylori infection and a Borrmann 4 type AGC. Conclusions : The endoscopic and clinicopathological characteristics of SRCC of the stomach are relatively young age on diagnosis, a high H. pylori infection rate, and a high percentage of Borrmann 4 type AGC. (Korean J Med 73: , 2007) Key Words : Stomach cancer, Signet ring cell carcinoma, Helicobacter pylori Received : Accepted : Correspondence to : Gab Jin Cheon, M.D. Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, 415 Bangdong-ri, Sachen-myen, Gangneung , Korea @gnah.co.kr

2 -Kwang Seok Kim, et al : Endoscopic findings and clinicopathological characteristics of signet ring cell carcinoma of the stomach - 서론반지세포암종 (signet ring cell carcinoma) 은대부분위에서발생하며, 유방이나담낭, 췌장, 방광, 대장에서도발생할수있다 1, 2). 위에발생하는반지세포암종은전체위암중적게는일본에서 3.4%, 많게는서구에서 29% 까지보고되고있다 3, 4). 이러한위의반지세포암종의임상적, 조직병리학적특징으로진단당시상대적으로낮은연령과여성에서많이발생한다는점과, 위벽침투력이강하고예후가나쁜점등이알려져있다 5-7). 그러나반지세포암종의임상적, 조직병리학적특징에관해서아직여러논란이있으며, 특히내시경적특징과관련해서는충분한자료가없는실정이다. 이에, 본연구에서는위에발생한반지세포암종의임상적, 내시경적, 조직병리학적특징을연구자료와함께여러문헌들을비교하여파악하고, 비반지세포암종 (non-signet ring cell carcinoma) 군과의차이점을알아보고자하였다. 대상및방법 1. 대상 1996년 3월 1일부터 2006년 5월 31일까지강릉아산병원소화기내과에서상부위장관내시경검사를통한조직검사및근치적위절제술을통해위암으로확진된 1,840명의환자중, 반지세포암종으로진단된 117명 (6.4%) 의환자군과비반지세포암종으로진단된 1,723명중무작위로추출한 296명의대조군을대상으로하였다. 2. 방법반지세포암종은내시경검사를통한생검에서반지세포암종이보이는경우에진단하였고, 생검에서선암으로진단된경우에도수술조직에서반지세포암종이보이는경우에는반지세포암종에포함시켰다. 이후아래와같이환자군와대조군의임상적, 내시경적, 조직병리학적특징을후향적으로비교분석하였다. 임상적특징으로는환자의성별을구분하였으며, 60 세이상과 60세미만으로나이를구분하였다. BMI (25 kg/m 2 ) 를기준으로한비만여부, 위암의가족력유무, 고혈압, 당뇨, 간염, 결핵등의동반질환유무를구분하였으며, 흡연여부, 음주여부를각각조사하였다. 내시경적으로는병변을육안적으로조기위암과진행성위암으로구분하였으며, 조기위암은육안분류법에따라 I, IIa, IIb, IIc, III로세분하였고, 진행성위암은 Borrmann 형에따라 1, 2, 3, 4형으로세분하였다. 병변의크기를 1 cm 미만, 1 cm 이상 2 cm 미만, 2 cm 이상 3 cm 미만, 3 cm 이상으로구분하여각각빈도를알아보았으며, 병변의위치는분문부, 저부, 체부, 전정부로구분하였다. 그리고헬리코박터균의감염여부를판단하기위해위의전정부와체부대만에서각각하나씩두개의조직을얻어 Giemsa stain을시행하였다. 조직병리학적으로는수술한조직을검사하여수술병변의형태를조기위암과진행성위암으로구분하였으며, 암세포의침범깊이를점막층, 점막하층, 고유근층, 장막하층, 장막층으로구분하여조사하였다. 복부 CT 결과를함께참고하여병기를 TNM으로구분하고, 최종병기를알아보았다. 또한, 조기위암과진행성위암에서반지세포암과분화도가좋은선암의발생율의차이를비교분석하였다. 3. 통계적분석환자군의대조군의차이점을분석하기위해통계적으로 Pearson Chi-square test 또는 Fisher's exact test를이용하였고, 통계적유의수준은 p 값이 0.05 미만인경우로하였다. 또한, 단변량변수분석에서유의한인자를대상으로로지스틱다중회귀분석을이용한다변량변수분석을실시하여, 환자군의독립적인특징을알아보았다. 결과 1. 임상적특징환자군과대조군모두남성의비율이높으나, 환자군의여성비율 (42.7%) 이대조군 (28.4%) 보다유의하게높았다 (p=0.005). 또한, 환자군에서 60세미만의낮은연령의환자가유의하게많았다 (54.7%, p<0.001). 비만도 (p= 0.508), 동반질환 (p=0.233), 가족병력유무 (p=0.129) 는두군간의의미있는차이가없었으나, 흡연력과음주력에있어서는환자군에서비흡연자의비율 (62.4%, p=0.031) 과비음주자의비율 (63.2%, p=0.045) 이각각의미있게높았다 ( 표 1)

3 - 대한내과학회지 : 제 73 권제 6 호통권제 568 호 Table 1. Comparison of the clinical characteristics between 차 SRCC and NSRCC of the stomach Variables SRCC (%) NSRCC (%) p value Sex Age Obesity (BMI) Comorbid disorder Family history Smoking Alcohol Male Female < 60 years 60 years < 25 kg/m 2 25 kg/m 2 67 (57.3) 50 (42.7) 64 (54.7) 53 (45.3) 89 (76.1) 28 (23.9) 71 (60.7) 46 (39.3) 108 (92.3) 9 (7.7) 73 (62.4) 44 (37.6) 74 (63.2) 43 (36.8) NSRCC, non signet ring cell carcinoma; SRCC, signet ring cell carcinoma 212 (71.6) 84 (28.4) 88 (29.7) 208 (70.2) 234 (79.1) 62 (20.9) 198 (66.9) 98 (33.1) 284 (95.9) 12 (4.1) 150 (50.7) 146 (49.3) 155 (52.4) 141 (47.6) < Table 2. Comparison of the endoscopic characteristics between SRCC and NSRCC of the stomach Variables SRCC (%) NSRCC (%) p value Gross type EGC type AGC type Size Location H. pylori EGC AGC I IIa IIb IIc III Mixed type Borrmann 1, 2, 3 Borrmann 4 < 1 cm 1 cm, < 2 cm 2 cm, < 3 cm 3 cm Body Other 40 (34.2) 77 (65.8) 0 (0) 1 (2.5) 7 (17.5) 21 (52.5) 3 (7.5) 8 (20.0) 60 (77.9) 17 (22.1) 8 (6.9) 17 (14.7) 12 (10.3) 79 (68.1) 64 (54.7) 53 (45.3) 47 (49.5) 48 (50.5) 81 (27.4) 215 (72.6) 0 (0) 6 (7.5) 8 (10.0) 31 (38.8) 7 (8.7) 28 (35.0) 191 (90.9) 19 (9.1) 12 (4.2) 45 (15.7) 28 (9.7) 202 (70.4) 112 (38.6) 178 (61.4) 165 (71.4) 66 (28.6) < EGC, early gastric cancer; AGC, advanced gastric cancer 2. 내시경적특징 환자군과대조군모두육안적으로조기위암보다진행성위암으로판단되는경우가더많았으나, 두군간의차이는없었다 (p=0.176). 조기위암의형태는두군간에 이를보이지않았으나 (p=0.219), 진행성위암은 Borrmann 4형이의미있게많았다 (p=0.003). 병변의크기는두군모두 3 cm 이상이많은경향을보였으며, 두군간의차이는없었다 (p=0.511). 병변은환자군에서체부에유의

4 - 김광석외 6 인 : 위반지세포암종의내시경소견및임상병리학적특징 - Table 3. Comparison of the pathological characteristics between SRCC and NSRCC of the stomach Variables SRCC (%) NSRCC (%) p value Gross type Depth of invasion Tumor size (T) Lymph node (N) Distant metastasis (M) Cancer stage EGC AGC Mucosa Submucosa Muscularis propria Subserosa Serosa T1 T2 T3 T4 metastasis Metastasis M0 M1 IA IB II IIIA IIIB IV 37 (50.7) 36 (49.3) 25 (34.2) 12 (16.5) 5 (6.9) 15 (20.5) 16 (21.9) 36 (43.9) 25 (30.5) 15 (18.3) 6 (7.3) 52 (63.4) 30 (36.6) 78 (75.7) 25 (24.3) 36 (35.3) 14 (13.8) 13 (12.7) 9 (8.8) 3 (2.9) 27 (26.5) 64 (47.4) 71 (52.6) 30 (22.2) 35 (25.9) 13 (9.6) 23 (17.1) 34 (25.2) 68 (47.5) 30 (21.0) 37 (25.9) 8 (5.6) 72 (50.3) 71 (49.7) 133 (76.4) 41 (23.6) 66 (37.9) 12 (6.9) 23 (13.2) 8 (4.6) 12 (6.9) 53 (30.5) Table 4. Comparison of cancer cell differentiation between EGC and AGC Variables EGC (%) AGC (%) p value Cell differentiation SRCC Adenocarcinoma, WD Adenocarcinoma, MD Adenocarcinoma, PD 40 (34.5) 35 (30.2) 23 (19.8) 18 (15.5) 77 (27.2) 27 (9.6) 79 (27.9) 100 (35.5) <0.001 MD, moderately differentiated; WD, well differentiated; PD, poorly differentiated 하게호발하였으며 (p=0.003), 헬리코박터균감염율도환자군에서유의하게높았다 (p<0.001) ( 표 2). 3. 조직병리학적특징수술병변의형태는두군간의차이가없었으며 (p= 0.652), 암세포의침범깊이도두군간의차이는없었다 (p=0.438). TNM으로병기를구분하였을때, T,N,M 모두두군간의차이를보이지않았으며 (p=0.305, p=0.058, p=0.894), 최종병기역시두군간의차이가없었다 (p=0.512) ( 표 3). 조기위암과진행성위암에서반지세포암종과선암의발생율을분화도에따라비교하였을때, 조기위암에서는반지세포암종 (34.5%) 이, 진행성위암에서는분화도가나쁜선암 (35.5%) 이가장많았으며, 진행성위암의경우, 반지세포암종과분화도가좋은선암만을비교했을때는반지세포암종 (27.2%) 이분화도가좋은선암 (9.6%) 보다많았다 (p=0.004)( 표 4). 4. 다변량분석환자군과대조군을단변량분석으로비교하였을때의미있는특징은여성, 낮은연령, 비흡연자, 비음주자, 진행성위암에서의 Borrmann 4형, 병변의체부발생, 헬리코박터균감염이었다. 각인자들의상호관계를배제하고

5 -The Korean Journal of Medicine : Vol. 73,. 6, Table 5. Multivariate analysis of significantly different factors of SRCC from NSRCC of the stomach Female Age <60 years nsmoker ndrinker Borrmann 4 type Body lesion H. pylori 95% CI, 95% confidence interval Odds ratio (95% CI) ( ) ( ) ( ) ( ) ( ) ( ) ( ) p value 환자군의독립적인특징을알기위해다변량분석을시행하였으며, 반지세포암종의독립적인위험인자는 60세미만의낮은연령, 헬리코박터균감염, 진행성위암에서의 Borrmann 4형으로나타났다 ( 표 5). 고찰위에발생하는반지세포암종은 Lauren에의해미만형 (diffuse type) 선암으로분류되었고, Ming에의해침투형 (infiltrating type) 으로, Nakayama에의해미분화형 (undifferentiated type) 으로, WHO에의해독립적인선암 (independent adenocarcinoma) 으로분류된바있다 6, 8-10). 미만형선암인반지세포암종은화생상피 (metaplastic epithelium) 에서발생하는장형 (intestinal type) 선암과달리, 장상피화생에포함되지않는증식층 (proliferating zone) 의선경부 (glandular neck region) 에국한되어발생하는것으로생각된다 11, 12). 또한, 여러임상적특징, 예후, 조직학적특징이비반지세포암종과차이를보여, 반지세포암종이분명히다른분류의위암이라고제시되기도하였다 1). 우선, 위의반지세포암종은여러연구에서상대적으로여성과젊은연령에서호발하는것으로보고되었다 1, 3, 5). 본연구에서도그러한경향을보였는데, 이는암세포의기능분화상반지세포암종의 80% 이상이 Absorptive and mucusproducing functional differentiation type (AMPFDT) 이라는결과에서그이유를찾을수있다 13). AMPFDT 는에스트로겐수용체를발현하고있어암의성장과침윤이에스트로겐의영향을받기때문에반지세포암종이폐경전의여성에서호발하고에스토로겐이높은수준으로존재하는난소나자궁경부에쉽게전이된다고하였다 13). 또한, 반지세포암종은높은미만성침투력때문에예 후가나쁜것으로흔히알려져있다 6, 7). 그러나반지세포암종의생존률이더높다고보고한예도있는데, 이는이들연구에서반지세포암종의경우비반지세포암종보다조기위암의비율이높았기때문인것으로평가되었으며, 조기위암의경우에는비반지세포암종보다림프절전이가적고생존률이높은것으로나타났다 3, 14). 단, 진행성위암인경우에는비반지세포암종보다암세포의장막침범이많고, 침범깊이가깊으며, 림프절전이도많이발생하여반지세포암종의생존률이낮은것으로보고된바있다 5). 본연구는후향적으로이루어져생존률을분석하지못하였으나, 향후전향적인연구를통한예후의분석이필요하리라생각된다. 암세포의침범깊이에대해두군간의차이가없었다는보고가있으나, 진행성위암에서반지세포암종이장막으로의침범이많다는보고도있다 1, 3, 5). 본연구에서는두군간의의미있는차이는보이지않았다. 림프절전이에대해서는반지세포암종에서비반지세포암종보다림프절전이가적다고보고된바있으며, 특히조기위암의경우반지세포암종의림프절전이가적다고보고된바있다 3, 14, 15). 다만, 반지세포암종이조기위암일경우림프절전이가적으나, 진행성위암일경우에는림프절전이가많다는보고가있다 5). 그러나본연구에서는두군간의의미있는차이를보이지않았다. 암의병기에대해서는두군간의차이가없다고보고된바있다 1, 14). 본연구에서도두군간의의미있는차이는보이지않았다. 여러연구에서반지세포암종은진행성위암보다는조기위암의형태로더많이발견되었다 3, 5, 14). 그러나본연구의내시경적소견으로는두군모두진행성위암의형태가많았고, 두군간의의미있는차이는없었다. 다

6 -Kwang Seok Kim, et al : Endoscopic findings and clinicopathological characteristics of signet ring cell carcinoma of the stomach - 만, 조기위암과진행성위암에서반지세포암종과선암의발생율을분화도에따라각각비교하였을때, 조기위암에서는반지세포암종이진행성위암에서는분화도가나쁜선암의발생율이높았으며, 진행성위암의경우반지세포암종과분화도가좋은선암만을비교했을때는반지세포암종의발생율이분화도가좋은선암보다높았다. 반지세포암종은위벽침투력이강하여 Borrmann 4형의진행성위암이많은것으로보고되었다 1, 5). 본연구에서도진행성위암의경우 Borrmann 4형이의미있게많았다. 병변의크기에대해반지세포암종이비반지세포암종보다크기가작다는보고가있으나, 반지세포암종의크기가더크다고보고한예도있다 1, 3, 5, 14). 본연구에서는두군모두 3 cm 이상이많은경향을보였으나, 두군간의의미있는차이는보이지않았다. 발생부위를보면, 반지세포암종이위의체부에호발한다고보고된바있으며, 위의중간 1/3에서호발한다고보고되기도하였다 3, 5, 14). 본연구에서는반지세포암종이위의체부에호발하는경향을보였다. 헬리코박터균감염을포함한환경적인위험인자는일반적으로미만형위암보다장형위암의발생과정에주로관여한다고알려져왔다 16). 그러나본연구에서는비반지세포암종보다반지세포암종에서헬리코박터균감염률이오히려의미있게높게나타났는데, 최근헬리코박터균감염이장형위암뿐만아니라미만형위암의발생에도동일하게관여한다는여러연구결과들이발표되었으며, 또한현재까지는위의병변중에서헬리코박터균위염 (H. pylori gastritis) 이미만형위암의유일한전구병변으로보고되고있다 17-20). 결론적으로, 반지세포암종의내시경적, 임상병리학적특징은아직여러논란이있으나, 본연구에서반지세포암종의유의한독립적인특징은 60세미만의낮은연령, 높은헬리코박터균감염률, 그리고진행성위암에서 Borrmann 4형의높은비율이었다. 앞으로더많은환자들을대상으로예후와헬리코박터균감염률비교등에대한추가적인연구가필요할것으로생각된다. 요약목적 : 위에발생한반지세포암종 (Signet Ring Cell Carcinoma) 은진단당시연령및병기가낮으며, 또한 예후가불량한것이특징이다. 그러나반지세포암종의임상적, 조직병리학적특징에관하여여러논란이있으며, 내시경적특징에관해서는충분한자료가없는실정이다. 따라서저자들은위에발생한반지세포암종의임상적, 조직병리학적, 내시경적특징을파악하고, 비반지세포암종 (n-signet Ring Cell Carcinoma) 군과의차이점을알아보고자하였다. 방법 :1996년 3월부터 2006년 5월까지강릉아산병원소화기내과에서상부위장관내시경검사를통한조직검사및근치적위절제술을통해위암으로확진된환자들에대해후향적으로의무기록을조사하였고, 반지세포암종환자군과무작위로추출된비반지세포암종환자군사이의임상적특징 ( 나이, 성별, 비만도, 음주력, 흡연력등 ), 내시경적특징 ( 병변크기, 형태, 위치, 헬리코박터균유무등 ), 그리고조직병리학적특징 ( 병변형태, 침범깊이, 병기등 ) 을통계학적으로분석하였다. 결과 : 같은기간동안위암으로확진된환자 1,840명중에서반지세포암종으로진단받은환자는총 117명 (6.4%) 이었다. 임상적으로반지세포암종군에서여자 (p=0.005), 60세미만 (p<0.001), 비흡연자 (p=0.031), 비음주자 (p=0.045) 가더많은경향을보였고, 내시경적으로병변이체부에위치하는비율 (p=0.003) 과헬리코박터균감염율 (p<0.001) 과진행성위암의 Borrmann 4형의비율 (p=0.003) 이높은경향을보였다. 이중다변량분석을통한반지세포암종의유의한독립적인특징은 60세미만의연령, 헬리코박터균감염, 진행성위암에서의 Borrmann 4 형이었다. 결론 : 진단당시상대적으로낮은연령, 높은헬리코박터균감염률, 진행성위암의 Borrmann 4형의높은비율이위반지세포암종의내시경적또는임상병리학적특징이었다. 앞으로더많은환자들을대상으로예후와헬리코박터균감염률등에대한추가적인연구가필요할것으로생각된다. 중심단어 : 위암, 반지세포암종, 헬리코박터 REFERENCES 1) Yokota T, Kunii Y, Teshima S, Yamada Y, Saito T, Kikuchi S, Yamauchi H. Signet ring cell carcinoma of the stomach: a clinicopathological comparison with the other histological types. Tohoku J Exp Med 186: ,

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연하곤란

연하곤란 2015.03.04 부울경소화기내시경지회 Intramucosal gastric cancer: The rate of lymph node metastasis in signet ring cell carcinoma was as low as that in welldifferentiated adenocarcinoma 인제대부산백병원 소화기내과 지삼룡 Signet ring