대한내과학회지 : 제 76 권제 6 호 2009 증례 08-183 제균치료에반응하지않은유전자전좌를동반한 MALT 위림프종 1예 울산대학교의과대학서울아산병원소화기내과 이욱진 정훈용 윤덕현 최기돈송호준 이진혁 김진호 A case of an API2-MALT1 translocation-positive gastric MALT lymphoma resistant to Helicobacter pylori eradication Wook Jin Lee, M.D., Hwoon-Yong Jung, M.D., Dok Hyun Yoon, M.D., Kee Don Choi, M.D., Ho June Song, M.D., Gin-Hyug Lee, M.D. and Jin Ho Kim, M.D. Department of Internal Medicine, Ulsan University College of Medicine, Asan Medical Center, Seoul, Korea About 90% of low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphomas are strongly related to Helicobacter pylori infection. The eradication of the H. pylori by antibiotics leads to complete regression of the gastric MALT lymphoma in 80% of cases, and this is currently recommended as the first-line treatment for this tumor. However, no standard treatment for H. pylori-negative and H. pylori-eradication-resistant gastric MALT lymphomas has yet been devised. The association between H. pylori-negative MALT lymphoma and the t(11;18)(q21;q21) translocation, resulting in an API2-MALT1 chimera gene, was reported, and is now considered one of the possible causes of and a reliable predictive marker for unresponsiveness to H. pylori-eradication treatment in patients with low-grade gastric MALT lymphoma. We report a case of H. pylori-eradication-treatment-resistant low-grade gastric MALT lymphoma that was treated successfully with radiotherapy after recognizing the API2-MALT1 chimera gene. (Korean J Med 76:737-741, 2009) Key Words: MALT Lymphoma; Helicobacter pylori; API2-MALT1 translocation 서론저위도위점막연관림프조직형 (mucosa-associated lymphoid tissue, MALT) 림프종은 H. pylori 의감염과 90% 이상관련되어있다. 따라서일차치료로 H. plylori 제균요법이추천되 고있으며, 임상에서도환자의 80% 가제균치료후완전관해에이른다 1,2). 하지만 H. pylori 감염이발견되지않은위 MALT 림프종과제균치료후관해에이르지못하는림프종의경우에는치료방법이정립되어있지않다 3). H. pylori 음성인위 MALT 림프종의원인에대해서는 t(11;18)(q21;q21) Received: 2008. 6. 24 Accepted: 2008. 7. 14 Correspondence to Hwoon-Yong Jung, M.D., Division of Gastroenterology, Departments of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, 388-1 Pungnap-2-dong, Songpa-gu, Seoul 138-736, Korea E-mail: hyjung@amc.seoul.kr - 737 -
- The Korean Journal of Medicine: Vol. 76, No. 6, 2009 - 과의연관성이보고되었고, 그기전이 API2 유전자와 MALT1 유전자의전좌에의한융합으로 chimera 유전자가형성되는것으로밝혀지면서 API2-MALT1 chimera 유전자이상유무는제균치료의중요한예측인자로받아들여지고있다 4). 저자들은 H. pylori 제균치료에반응하지않은위 MALT 림프종환자의조직에서 API2-MALT1 chimera 유전자검사를시행하여방사선치료로관해된위 MALT 림프종 1예를경험하여문헌고찰과함께보고하는바이다. 증례환자 : 황 덕, 여자 65세주소 : 상복부통증현병력 : 평소건강하던 65세여자환자로내원 1달전부터악화된명치부위의통증으로내원하였다. 과거력 : 내원 1달전고혈압을진단받았으며당뇨병, 간염, 결핵의병력은없었다. 가족력 : 특이소견없었다. 사회력 : 술, 담배와같은사회력은없었다. 신체검사소견 : 내원당시혈압 116/67 mmhg, 맥박수 85 회 / 분, 호흡수 18회 / 분, 체온 ( 고막 ) 37.0 였다. 청진에서심음과폐음은정상이었으며복부진찰상간과비장은만져지지않았고, 림프절종대도관찰되지않았다. 가벼운심와부압통이있었으나, 다른부위의압통및반발통은없었다. 검사실소견 : 말초혈액검사상백혈구 6,000/mm 3, 혈색소 13.3 g/dl, 혈소판 281,000/mm 3 이었고, 혈청생화학검사상총단백 7.2 g/dl, 알부민 4.5 g/dl, AST 27 IU/L, ALT 14 IU/L, ALP 113 IU/L, LDH 174 IU/L 이었다. 전해질검사와요검사는정상범위였다. 방사선소견 : 흉부단순촬영, 복부및흉부전산화단층촬영 A B C Figure 1. The initial endoscopic and pathological findings. (A) Small multiple ulcerations and edematous mucosa are seen at the lesser curvature of the midbody. (B) A monomorphic lymphocytic infiltration and lymphoepithelial lesions are noted (H&E, 100). (C) PCR was positive for the IgH rearrangement (M, marker; P, positive control; N, negative control; S, sample). - 738 -
- Wook Jin Lee, et al. A case of API2-MALT1 translocation-positive gastric MALT lymphoma - 은정상소견이었다. 내시경및조직검사소견 : 상부위장관내시경검사상분문부에서부터체부의소만쪽에미만성위축성변화가관찰되었고, 다발성의궤양및점막결절이보였다. 조직검사에서중심구유사 (centrocyte-like) 세포증식및특징적인림프상피병변 (lymphoepithelial lesion) 이관찰되었으며 B형세포의면역글로불린중사슬 (IgH) 유전자재배열양성으로단클론을증명하여위 MALT 림프종으로진단하였다 ( 그림 1). H. Figure 2. Genetic translocation analysis of API2-MALT1 from biopsy samples using fluorescence in situ hybridization. The cells show a red and green fusion signal pattern. pylori 감염은조직검사, CLO 검사및균배양검사모두에서음성으로확인하였다. 초음파내시경검사상병소는점막이두꺼워져있었으며점막하층으로의침범소견이있었다. 궤양주변부외측으로 4~6 mm의림프절이수개관찰되었으나림프절전이를강하게시사하는소견은보이지않았다골수천자및생검소견 : 림프종의침범은관찰되지않았다. 임상경과및치료 : 환자는점막하층의침윤을동반한 1기위 MALT 림프종으로진단되었으며, H. pylori 음성이었지만병변이미만성으로진행하면서균의존재진단에어려움이있을수있음에착안하여, 일차적으로제균요법을시행하기로하였다. 환자는 14일간 3제 (rabeprazole 20 mg bid, amoxicillin 1,000 mg bid, clarithromycin 500 mg bid) 로 H. pylori 제균치료를받았다. H. pylori 제균후시행한추적검사상부분적인관해만을얻을수있었다. 1년째검사에서도잔존병소가완전소실되지않아치료전의조직을이용하여 API2-MALT1 유전자전좌유무를 FISH (Fluorescence in situ hybridization) 방법으로검사하였다. 200개의간기세포를분석한결과 103개 (51.5%) 의세포가 API2-MALT1 유전자재배열을가지고있어 t(11;18)(q21;q21) 양성으로진단하였다 ( 그림 2). 환자는추가적으로방사선치료를받기로결정하였으며, 총 3,060 cgy 용량의방사선치료를시행받았다. 그후시행한위내시경검사및조직검사상완전관해되어현재외래에서추적관찰중이다 ( 그림 3). Figure 3. Follow-up endoscopy after H. pylori eradication and radiotherapy. (A) After H. pylori eradication, whitish atrophy with persistent mucosal nodularities is noted. (B) After radiation therapy, there is extensive atrophic change with several whitish ulcer scars. - 739 -
- 대한내과학회지 : 제 76 권제 6 호통권제 586 호 2009 - 고찰저위도위 MALT 림프종의 90% 이상에서 H. pylori 감염이증명되어있으며제균치료후저위도위 MALT 림프종의 80% 가관해된다고보고된다 5). 반면에약 10% 의저위도위 MALT 림프종은 H. pylori 음성이며제균치료에잘반응하지않는다 6). 저위도위 MALT 림프종의치료는비록 H. pylori 가발견되지않더라도항생제요법의시도를권유하고있으며, 그이유는항생제치료가비교적저렴하고부작용이없기때문이며 7), 또한, 과거감염을완전히배제할수없기때문이다. 일부증례보고에서 H. pylori 음성인위 MALT 림프종및직장 MALT 림프종환자를대상으로제균치료후관해에도달하였음을보고하였지만대부분의보고에서는비판적이며, 따라서제균치료에저항성이있다고판단된경우에는적절한이차치료가빨리이루어져야한다는주장이있다 8). 특히관해에실패한저위도위 MALT 림프종에서 t(11;18)(q21; q21) 의존재는제균치료실패를예측할수있는유용한지표로입증되었다 4,9). t(11;18)(q21;q21) 염색체전좌의기전은 11q21 염색체의절단점에존재하는세포자연사억제기능을소유한 API2 유전자와 MALT1 유전자의전좌에의한융합으로 chimera 유전자가형성되기때문이다 10). 임상에서도 Liu 등 11) 에의하면 API2-MALT1 전좌가있는위 MALT 림프종의경우 75% 에서제균요법에반응하지않았으며제균요법에반응이있었던환자군에서는 chimera 유전자가발견되지않았다. t(11;18)(q21;q21) 를보인위 MALT 림프종은 H. pylori 의존재유무와관계없이보다진행된병기를보였으며제균치료에저항성을가지므로, 진단당시에항암화학요법, 방사선치료, 수술적치료등을고려해야한다는주장이있다 11). 하지만 H. pylori 음성및 API2-MALT1 chimera 유전자양성인위 MALT 림프종의경우도전반적인위 MALT 림프종의예후및경과에비하여나쁘다는보고는없었다 12). 본증례에서는초음파내시경을통하여위벽의침범이점막하층에국한되었고, 조직검사상저위도의병변을보였기때문에 H. pylori 음성이었지만제균요법을시도해볼수있었다. 제균요법후조직관해까지소요되는시간은평균 5개월정도이나실제로는 4주에서 14개월까지다양한것으로알려져있으며 5) 본증례에서도 12개월간추적관찰후관해를보이지않아, API2-MALT1 chimera 유전자검사를시행한후양성결과를확인하여이차치료를시행하였다. 제균요법으로관해를보이지않은림프종은방사선치료, 수술, 항암화학요법을시도해볼수있으며최근의보고에따르면세가지방법의치료성적모두높은관해율을보였으나대규모의전향적인비교연구가없어현재까지확정적인치료지침이없는상태이다 13). 하지만 MALT 림프종이방사선치료에예민하여높은완전관해율을보인다는점과방사선치료가수술에비교하여장기보전적이라는점을감안하여본증례에서는방사선치료를시행하였고, 치료후완전관해에도달하였다 14). 현재까지의대다수보고에서 API2-MALT1 chimera 유전자의존재는 H. pylori 제균요법의중요한예측인자로판단되므로저위도위 MALT 림프종의경우진단시반드시유전자전좌여부를검사해야하며, 유전자의변이가관찰될경우제균요법보다는방사선치료, 수술, 항암화학요법을시행해야한다는일부주장이있다 15). 그러나모든증례에서유전자변이검사를실시하는것에대해서는회의적이다. 다만, 본증례처럼제균치료에저항성을보일것으로예측되면추후치료방침을결정하기위하여실시할수있을것이다. 저자들은 H. pylori 제균치료에반응하지않은 API2- MALT1 유전자전좌를동반한위 MALT 림프종 1예를경험하였기에문헌고찰과함께보고한다. 요 H. pylori 음성인위 MALT 림프종의치료는확립되어있지않으며제균치료의효과도예측하기어렵다. 최근 API2- MALT1 키메라유전자의존재가제균치료의유효한예측인자로밝혀졌고, 이에따라새로운치료방법을고려해야한다는주장이제기되고있다. 저자들은 H. pylori 제균치료에반응하지않은 API2-MALT1 유전자전좌를동반한위 MALT 림프종 1예를경험하였기에문헌고찰과함께보고한다. 중심단어 : 헬리코박터 ; 위림프종 ; API2-MALT; 유전자전좌 약 REFERENCES 1) Issacson PG, Wright DH. Malignant lymphoma of mucosa-associated lymphoid tissue: a distinctive type of B-cell lymphoma. Cancer 52:1410-1416, 1983 2) Montalban C, Manzanal A, Boixeda D, Redondo C, Alvarez I, - 740 -
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