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고립성폐결절로발현한파종성림프절외변연부 B 세포림프종 1 예 울산대학교병원내과, 1 흉부외과, 2 병리과, 3 진단검사의학과조준현, 정종필 1, 차희정 2, 박창률 1, 김성률 3, 김혁, 박진우, 우순주, 엄은아, 이기영, 제갈양진 A Case Report of Disseminated Extranodal Marginal Zone B-Cell Lymphoma of MALT Manifested by Solitary Pulmonary Nodule Joon Hyun Cho, M.D., Jong Pil Jung. M.D. 1, Hee Jeong Cha, M.D. 2, Chang Ryul Park, M.D. 1, Sung Ryul Kim, M.D. 3, Hawk Kim, M.D., Jin Woo Park, M.D., Soon Joo Woo, M.D., Eun A Eum, M.D., Ki Young Lee, M.D., Yang Jin Jegal, M.D. Department of Internal Medicine, 1 Department of Thoracic and Cardiovascular Surgery, 2 Department of Pathology and 3 Department of Laboratory Medicine. Ulsan University Hospital, Korea. Extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma) is usually indolent. Although it was reported recently that about 20-30% cases of MALT lymphoma presented with a disseminated disease at diagnosis, it was described as a disease localized at diagnosis and remaining stable for a prolonged period. However, only a few cases of MALT lymphoma involved the lung and gastrointestinal tract all at once. We report a case of a 73-year-old man with disseminated MALT lymphoma. He presented with non-productive cough, initial chest radiograph showed a nodule in the right lower lobe. The diagnosis of stage IV MALT lymphoma was made by CT scan, video-assisted thoracoscopic excisional biopy, gastrofiberscopic biopsy and bone marrow biopsy. The lymphoma involved the lung, stomach and bone marrow at the time of diagnosis. Because he refused chemotherapy, he discharged after Helicobacter pylori eradication without chemotherapy. Regular follow-up examination did not show any evidence of disease progression over 22 months. (Tuberc Respir Dis 2006; 61: 171-177) Key words: Extranodal marginal zone B-cell lymphoma of MALT, Disseminated, Solitary pulmonary nodule. 서 MALT 림프종 (extranodal marginal zone B-cell lymphoma of MALT) 은드문질환이기는하지만림프절외림프종의가장흔한형태이다. 이림프종은위장관에서가장흔히발생하는데, 그중 50-60% 가위에서발생하고, 위장관이외에결막, 침샘, 피부, 갑상선, 폐, 신장, 방광, 유방, 간등신체의거의모든장기에발생할수있다 1,2. 임상적으로 MALT림프종은진단당시에는국소적인병변이많고예후도좋은것이일반적인데, 최근약 20-30% 의환자가진단당시에도다발성장기침범혹은파종성병변이있다는보고도있다 3,4. 그러나파종성병변인경우를포함하 론 Address for correspondence : Yangjin Jegal, M.D. Department of Internal Medicine, Ulsan University Hopital, 290-3 Jeonha-dong, Dong-gu, Ulsan 682-714, Korea. Phone : 052-250-8827 Fax : 052-251-8235 E-mail : yjjegal@uuh.ulsan.kr Received : Apr. 18. 2006 Accepted : Jun. 23. 2006 더라도폐와위장관을동시에침범하는경우는드물어소수의증례만이보고되고있고 5-7, 자세한임상경과도잘알려져있지않다. 저자들은흉부단순촬영에서고립성폐결절이발견된 73세남자환자에서위와폐를동시에침범한파종성 MALT림프종을진단하였기에문헌고찰과함께보고하는바이다. 증례환자 : 박 문, 남자, 72세주소 : 기침및객담현병력 : 내원 1년전부터경도의호흡곤란및간헐적으로피곤한증상이있어지역중소병원에 3~4차례입원하였으며내원약 2개월전부터는기침및비화농성객담이동반되어내원하였다. 과거력 : 내원 4년전황달로입원하여간흡충증과알코올성간염을진단받았다. 가족력 : 특이사항없었다. 사회력 : 60갑년의흡연자였고, 음주력은소주1-2 171

JH Cho et al. : The treatment of massive spontaneous subcutaneous emphysema by multiple intravenous catheter Figure 1. Chest radiograph shows a nodule in the right lower lobe 병씩일주일에 3번정도음주하였다. 직업력 : 농부이학적소견 : 내원당시활력징후는혈압 120/70 mmhg, 맥박 80회 / 분, 호흡수 22회 / 분, 체온 36.5 이었고, 전신상태는비교적양호하였다. 결막및공막에빈혈이나황달의소견은없었으며, 경부림프절은촉 지되지않았다. 흉부청진상악설음이나천명음은들리지않았으며, 심음은정상이었다. 복부와사지진찰시장기비대소견이나발진, 자반, 곤봉수지소견등은없었으며, 신경학적검사상특이소견없었다. 안과검진에서도이상소견은보이지않았다. 검사실소견 : 말초혈액검사에서백혈구 5,500/mm 3 Figure 2. Chest CT scan shows a 3.3 1.7cm sized nodule with spiculated margin in anterior basal segment of right lower lobe. 172

Tuberculosis and Respiratory Diseases Vol. 61. No.2, Aug. 2006 Figure 3. Gastrofibroscopy shows 2.0 and 1.5cm sized elevated, central depressed lesions with mucosal irregularity on the great curvature and lesser curvature of the lower body. ( 호중구 52.5%, 림프구 35.5%, 단핵구 6.9%, 호산구 2.3%), 혈색소 13.7 g/dl, 혈구용적 38.1%, 혈소판 163,000/mm 3 이었고, 말초혈액도말검사는정상이었다. 생화학검사에서는총단백 7.3 g/dl, 알부민 4.3 g/dl, 총빌리루빈 0.7 mg/dl, AST 41 IU/L, ALT 24 IU/L, LDH 403 IU/L, 혈액요소질소 30.1 mg/dl, 크레아티닌 1.25 mg/dl 이었다. 객담세포진에서악성세포는발견되지않았다. 폐활량검사에서노력성폐활량 (FVC) 은 2.78L( 예측정상치의 81%), 1초간노력성호기량 (FEV1) 은 1.51L( 예측정상치의 65%) 이고, FEV1/FVC 은 54% 로경증의폐쇄성환기장애소견을보였다. 방사선소견 : 흉부단순촬영상우하엽에약 3cm크기의종괴가관찰되었다 (Figure 1). 흉부전산화단층촬영에서는우하엽의앞바닥구역 (anterior basal segment) 에 3.3 1.7 cm크기의침상형의경계를가지는불규칙한모양의종괴가관찰되었으며내부에공기-기관지음영이일부동반되었다. 양측폐는미만성의중심세엽폐기종소견을보였으며폐문및종격동림프절종대는없었다 (Figure 2). 복부, 골반및 Figure 4. Pathologic findings of the lung nodule (A) The neoplastic lymphoid cells efface pulmonary architecture (H&E x 40). (B) The extranodal marginal zone B cell lymphoma of MALT consists of centrocyte like cells, monocytoid cells and lymphoepithelial lesion (H&E x 100). 173

JH Cho et al. : The treatment of massive spontaneous subcutaneous emphysema by multiple intravenous catheter Figure 5. Immunohistochemical stain of the lung nodule (A) The CK7 stain reveals lymphoepithelial lesion (x 100). (B) The stain for CD20 shows shows strong positive reaction in tumor cells (x 100). 경부전산화단층촬영에서는특이소견없었다. 기관지내시경및위내시경소견 : 기관지내시경에서기관지내병변은없었고, 위내시경상하부체부의대만과소만부에각각 2.0cm, 1.5cm 크기의얕은지도상의미란을동반한약간융기된병변이관찰되어 (Figure 3) 조직검사를시행하였다. 같이시행한 CLO 검사는음성이었다. 수술소견 : 흉강경 (VATS) 으로우하엽의쐐기절제술 (wedge resection) 을시행하였으며, 흉막유착이나비정상흉수는관찰되지않았다. 조직소견 : 폐생검조직의저배율광학현미경소견 은종양세포들이폐간질에광범위하게침윤되어폐포구조를파괴하고있었다 (Figure 4A). 고배율에서는종양세포들이성숙한소림프구보다 4~5배크며핵에균열이있는세포와없는세포가섞여있었고, 종양세포가점막의상피세포로침윤하는림프상피병터 (lymphoepithelial lesion) 가관찰되었다 (Figure 4B). 종양세포는 B-세포표지자인 CD20, CD79a 면역조직화학염색에서세포막에강양성반응을보였고, T 세포표지자인 CD3에음성반응을보였으며, 상피세포표지자인 CK7 염색에서보다저명하게림프상피병터를보여주었다 (Figure 5). 종양세포는 CD5와 Figure 6. Pathologic findings of gastric mucosa. (A) It shows small to medium sized lymphocytes and lymphoepithelial lesion (H&E x 100). (B) Immunohistochemical stain for C79a shows positive reaction in tumor cells (x 100). 174

Tuberculosis and Respiratory Diseases Vol. 61. No.2, Aug. 2006 월후다시시행한위내시경에서병변은호전되었고흰색반흔이남아있었으나조직검사에서는여전히 MALT림프종이남아있었다. 현재 22개월동안외래에서추적관찰중이나별다른증상이나악화의증거는없이비교적건강하게지내고있으며, 경과관찰을위해시행한흉부전산화단층촬영에서도재발의증거는없었다. Figure 7. A tiny nodular mass is seen at the section of bone marrow biopsy with H&E stain (x 100). cyclind1 에도음성반응을보여광학현미경조직소견과면역조직화학염색결과를종합하여 MALT림프종으로진단하였다. 위에서시행한생검의조직학적소견도폐에서보여준소견과동일한 MALT 림프종이었다 (Figure 6). 골수소견 : 조혈세포들이풍부한정세포성골수소견을보이고, 세포성구역에서작은림프구밀집지역이관찰되었다 (Figure 7). 림프구밀집지역의림프구들은 CD20, CD79a에대한면역조직화학염색에서양성반응을보여 (Figure 8), 조직소견에서관찰되었던림프종과동일한종양세포들의골수전이로진단하였다. 세포유전학검사에서비정상클론은관찰되지않았다. 경과 : 환자는위, 폐, 골수를침범한파종성 MALT림프종으로진단되었으나항암화학요법을거부하여 Helicobacter pylori 제균후퇴원하였다. 6개 고찰림프절외변연부 B-세포림프종은 1983년 Isaacson과 Wright 에의하여처음으로 MALT림프종이란용어로기술되었다 8. 이후종양세포의면역학적, 분자생물학적소견에따라 1994년 REAL분류에서는 Marginal zone B-cell lymphoma, extranodal (MALT) type 으로명명되었고 9, 2001년발표된림프구성종양의 WHO 분류에서는 extranodal marginal zone B cell lymphoma of MALT 로분류되었다. 임상적으로 MALT 림프종은매우천천히진행하는병으로약 30% 이상에서다발성장기침범을보고하는것도있지만 4, 진단당시에는국소적인병변이대부분이며, 상당기간동안이러한국소적병변으로남아있는것이일반적인견해이다. 특히위장관의 MALT 림프종은다른장기가원발병소일때보다파종성병변인경우가드물며 4, 그중에서도폐와위장관을동시에침범하는 MALT 림프종은몇개의증례보고만있을뿐이다. 우리나라에서는문등이 Figure 8. Immunohistochemical stain of the bone marrow for CD20(A) & CD79a(B) shows strong positive reaction in tumor cells (x 100). 175

JH Cho et al. : The treatment of massive spontaneous subcutaneous emphysema by multiple intravenous catheter BALT(bronchus-associated lymphoid tissue) 림프종에병발한식도의 MALT림프종을보고하였고 6, 배등이기관과대장에발생한 MALT 림프종을보고하였다 7. Graziadei 등은폐, 위, 혀, 편도와골수를침범한 36세여자환자의증례를보고하면서 3년전에찍은흉부전산화단층촬영에서폐병변이있어폐의 MALT림프종이다발성점막과골수를침범했을것으로결론지었다 5. 본증례의경우비특이적인호흡기증상으로내원하여폐병변이먼저발견되었으나폐병변이원발병소인지, 위병변이원발병소인지, 또는동시에발생하였는지는불분명한것으로생각된다. 본증례의경우진단당시부터위, 폐그리고골수를침범한파종성질환이었는데, Raderer등은 2년동안위의 MALT 림프종으로진단된 24명중 2명이다른장기를침범한반면나머지 11명의위장관외 MALT림프종에서는반수이상 (6명) 이다발성장기침범을하여위장관외의 MALT 림프종이파종성질환이더흔함을보고하였다 3. 우리나라의보고에서도김등의보고에따르면위의 MALT 림프종 57례중 I 기와 II기가 56명이었고, III기는없었으며, IV기는한명 (1.8%)10 으로대부분국소적인질환이었던것에반하여오등은위이외의장기에발생한 MALT림프종 50명중 9명이 IV기라고보고하였다 11. 그러나 MALT림프종의경우파종성질환이라하더라도국소적질환에비하여장기적예후나치료의반응정도가나쁘지않다 4. 본증례의경우도파종성질환이기는하나진단후약 22개월동안악화의증거는없었다. MALT림프종의형태학적특징은정상적인파이어판 (Payer s patch) 의펌프조직을닮아소림프구, marginal zone/monocytoid B세포들이있으며, 형질세포그리고드물지만여포아세포 (centroblast) 와면역아세포 (immuno-blast) 가침윤된다. 병변에는반응성림프여포가있으며, 종양세포가상피조직에서상피를침윤하여소위림프상피병터를만든다. 표면항원으로는 B 세포표지자인 CD19, CD20, CD22, CD79 가양성이며보체수용체인 CD21, CD35도양성이다. 그러나 CD5, CD10, CD23은대개음성인데 8 본증례에서도종양세포들은 CD20, CD79a에양성반응을보 였으며 CD3에는음성이었다. 치료에있어서는위에서발생한 MALT 림프종의경우에는많은수에서 H. pylori에대한반응성 B세포의증식이보이므로국소적병변의초기치료로 H. pylori 의제균을시도하는데장기예후는아직명확하지않으나림프선전이가없는위의저등급악성도 MALT 림프종의 60-92% 에서반응을보이고 12, 직장이나소장의 MALT 림프종의경우에도제균에반응하기도한다. I, II기의국소병변이면서제균치료에듣지않거나 H. pylori가음성인경우에는단독약제를이용한항암치료나방사선치료혹은수술을하면 5년생존율이 90% 를상회한다 13,14. 본증례는파종성병변이므로항암치료를하여야하며 H. pylori를제균하는것은적응증이되지않으나환자가항암치료를거부하여 H. pylori 제균을시도해보았다. 위장관이외장기에서의국소질환인경우에는수술이가장효과적인치료이며, 국소재발을막기위해방사선치료를하기도하며알킬화약물 (Alkylating agent) 이나 fludarabine 을이용한약물치료에대한반응도좋다 10,11,15. 진행된질병인경우약물치료를하지만, 저등급악성도비호치킨림프종은자연경과가길고증상이별로없으므로추적관찰을하는것도한가지방법이다. 이방법의장점으로는치료하지않는기간이길어종양세포가약에노출되지않아내성이생길확률이줄뿐아니라 Horning 등의보고에따르면 23% 의환자에서 1년이상지속되는자연관해를보이기도하므로이런군의환자에서는치료가불필요할수도있다 16. 본증례의경우에도치료를하지않고 20 개월이상추적관찰중이나악화되지않고있다. 요약 MALT 림프종은질병의진행이느리고, 진단당시국소적인병변이대부분이며, 폐와위장관을동시에침범하는경우는매우드물다. 저자들은흉부단순촬영에서고립성폐결절이발견된 73세남자환자에서위, 폐, 골수를침범한파종성 MALT 림프종 1예를경험하였기에문헌고찰과함께보고하는바이다. 176

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