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1 대흉외지 2007;40: 임상연구 원발성폐림프종의임상고찰 김재범 * 박창권 * 박남희 * 금동윤 * 노동섭 * 이재훈 ** 한승범 *** 정혜라 **** Clinical Analysis of Primary Malignant Lymphoma of the Lung JaeBum Kim, M.D.*, Chang-Kwon Park, M.D.*, Nam-Hee Park, M.D.*, Dong-Yoon Kum, M.D.*, Dong-Sub Noh, M.D.*, Jae-Hoon Lee, M.D.**, Seung Bum Han, M.D.***, Hye Ra Jung, M.D.**** Background: Primary malignant lymphoma of the lung is a very rare neoplasm. Although the prognosis of lymphoma is favorable, the clinical features, prognostic factors and management have not been clearly defined. Material and Method: We retrospectively reviewed the records of 8 patients we managed between 1994 and They all had malignant lymphoma on the pathologic examination of the lung with no evidence of mediastinal adenopathy and extrathoracic disease, and no past history of lymphoma. Result: The study group consisted of 3 males and 5 female patients with a mean age of 53.9 years. Three patients were asymtomatic and 5 patients were seen with pulmonary or systemic symptoms. The diagnostic methods were 3 CT needle aspiration biopsies, 1 bronchoscopic biopsy and 4 surgical methods (wedge resection, lobectomy). There were 3 patients with MALT lymphoma, two with diffuse large B-cell lymphoma, two with small lymphocytic lymphom, and one with follicular lymphoma. The 8 patients were treated with a variety of modalities, including surgery, chemotherapy, radiotherapy and combination therapy. The 8 patients have survived for a median follow-up of 38 months. Conclusion: Although this entity of lymphoma appears to have a good prognosis, further clinical experience and long-term follow-up are needed to identify its clinical features, prognostic factors and management. Key words: 1. Lymphoma 2. Pathology 3. Lung neoplasm (Korean J Thorac Cardiovasc Surg 2007;40: ) 서론림프절외조직에서발생하는림프종은모든림프종에서 3 5% 만차지할정도로드물며흔히위장관계통에서발견된다. 원발성폐림프종은매운드문질환으로몸에서 발생하는전체림프종의 0.4% 에서나타난다고알려져있다. 그러나림프종의병력이있는환자에서폐에이차적으로림프종이나타날확률은 25 40% 로보다흔히발견된다 [1]. 원발성폐림프종은점막림프조직에서유래한악성도 * 계명대학교의과대학동산의료원흉부외과학교실 Department of Thoracic and Cardiovascular Surgery, Dongsan Medical Center, Keimyung University School of Medicine ** 울산대학교의과대학서울아산병원흉부외과학교실 Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, University of Ulsan College of Medicine *** 계명대학교의과대학동산의료원내과학교실 Department of Internal Medicine, Dongsan Medical Center, Keimyung University School of Medicine **** 계명대학교의과대학동산의료원병리학교실 Department of Pathology, Dongsan Medical Center, Keimyung University School of Medicine 2006 년제 38 회대한흉부외과학회추계학술대회에서포럼구연으로발표되었음. 논문접수일 :2007 년 3 월 6 일, 심사통과일 :2007 년 4 월 13 일책임저자 : 박창권 ( ) 대구시중구동산동 194 번지, 계명대학교의과대학동산의료원흉부외과 (Tel) , (Fax) , ckpark80@dsmc.or.kr 본논문의저작권및전자매체의지적소유권은대한흉부외과학회에있다. 435

2 대흉외지 2007;40: Table 1. Clinical features n % Age (years)(n=8) Mean (range, SD) 53.88±10.41 (32~66) Sex (n=8) Male Female 4 50 Smoking (n=8) 3 Symptom 2 37 Cough 2 25 Dyspnea 1 25 Chest pain Hemoptysis Fever 1 37 None 17 LDH*>normal (n=6) *LDH=Lactate dehydrogenase. 가낮은 MALT (mucosa-associated lymphoid tissue) 형이가장많은것으로알려져있는데, 기관지점막조직에서발생하는것은만성적인자극으로인한것이며원인으로는흡연이나자가면역질환, 감염으로생각된다. 비록원발성폐림프종의예후는좋으나임상양상이나예후예측요소, 치료에대해서는명확히밝혀져있지않다 [2]. 현재일반적으로추적관찰만하거나수술, 항암치료, 방사선치료를단독혹은병합하여치료하는데아직확실한치료방식은없다. 이연구는계명대학교의과대학동산의료원에서치료받은원발성폐림프종환자를대상으로임상양상과치료방법에대해알아보고자하였다. 대상및방법 1994년부터 2006년사이에치료한원발성폐림프종환자를대상으로후향적연구를진행하였다. 병리적검사에서페에악성림프종으로나타난환자를대상으로하였는데그중종격동림프선비대가없으며복부와골반단층촬영및골수검사에서폐외질병이없는환자로정하였다. 또한과거림프종의병력이없으며최초진단후 6개월이내에폐외질병이나타나지않는경우로하였는데이기준에부합한환자는 8명이었다. 이들환자를대상으로의무기록에의거하여성별, 나이, 과거병력, Table 2. Radiologic features n % Type of image (n=8) Mass 6 75 Consolidation None Site of lesion Right lung 4 50 Left lung 2 25 Both 2 25 흡연여부, 증상, 방사선소견, 진단및치료방법과생존여부에대해조사하였다. 초기에는현미경으로만형태적검사를시행하고면역조직화학검사 (immunohistochemistry) 는필요할경우에만시행하였으나, 2005년부터본원에서검사기계로면역조직화학검사를시도한이후에는모든환자에서면역조직화학검사를시행하였다. 또한명확한진단이어려운경우에는분자생물학적검사 (molecular genetic study) 도시행하였다. 흉부외과에서수술적으로진단한것뿐만아니라내과에서경흉부컴퓨터단층촬영하세침흡입생검 (CT-guided needle aspiration biopsy) 과기관지내시경으로조직검사한악성림프종도포함되었다. 결 남자가 3명, 여자가 5명이었으며연령분포는 32 66세로평균연령은 53.9세였는데 50대에서가장많이발견되었다. 흡연자는 4명이었으며 3명은별다른증상이나타나지않았으나 5명은호흡기및전신증상을가지고있었는데기침이나호흡곤란, 흉통이비교적많이발견되었다 (Table 1). 방사선검사상종괴의형태로나타난것이 6예로가장많았는데오른쪽폐에종양이있는경우가 4예, 왼쪽폐에서발견된경우가 2예있었으며양쪽에서같이발견된경우가 2예있었다 (Table 2). 진단은 3명이경흉부컴퓨터단층촬영하세침흡입생검, 1명이기관지내시경하생검을하였으며수술적으로진행된사람은 4명으로폐쐐기절제술 2예, 폐엽절제술 2 예를시행하였다. 이중기관지내시경으로검사가된환자는각혈을주소로내원하여기관지내시경검사에서 과 436

Yes 47/M 1998/04 B cell, diffuse large Wedge CTx+RTx 6 Yes 56/F 2004/04 B cell, small lymphocytic Broncoscopic Bx No Tx 35 Yes 66/M 2005/10 B cell, MALT* Wedge RTx+CTx 7 Yes 53/F 2005/12 B cell, MALT

3 김재범외원발성폐림프종의임상고찰 Table 3. Diagnostic procedure, pathologic finding and treatment Follow up Age/sex Diagnostic date Pathology Diagnostic procedure Treatment Survival (month) 59/F 1994/07 B cell, small lymphocytic CTNAB CTx 38 Yes 47/M 1998/04 B cell, diffuse large Wedge CTx+RTx 6 Yes 56/F 2004/04 B cell, small lymphocytic Broncoscopic Bx No Tx 35 Yes 66/M 2005/10 B cell, MALT* Wedge RTx+CTx 7 Yes 53/F 2005/12 B cell, MALT CTNAB RTx 14 Yes 60/F 2006/03 B cell, MALT Lobectomy RTx 12 Yes 58/M 2006/05 B cell, follicular Lobectomy CTx 10 Yes 32/F 2006/09 B cell, diffuse large CTNAB CTx+RTx 4 Yes *MALT=Mucosa-associated lymphoid tissue; CTNAB=CT-guided needle aspiration biopsy; CTx=Chemotherapy; RTx= Radiotherapy. Fig. 1. (A) Microscopic finding of MALT lymphoma (H&E stain, 400). Diffuse infiltrate of submucosa by small lymphocystes are noted. These lymphocytes infiltrate overlying bronchial mucosa. (B) Immunohistochemical stain for CD20 of MALT lymphoma. Immunohistochemical stain for CD20 shows cytoplasmic staining pattern in most of lymphocytes which infiltrate the submucosa and bronchial mucosa. 조직검사를시행하여 MALT림프종으로나온환자로이후치료없이외래추적관찰로만지내고있는데별다른증상이나타나지않고있는상태다 (Table 3). 8명중 3명은점막관련림프종 (MALT lymphoma, Fig. 1) 이었으며 2명은큰B세포림프종 (diffuse large B cell lymphoma, Fig. 2), 2명은소림프구림프종 (small lymphocytic lymphoma, Fig. 3) 이었고 1명은여포성림프종 (follicular lymphoma, Fig. 4) 이었다 (Table 3). 이중원발성으로폐에서여포성림프종이발견된것은아주드문경우로면역조직화학검사뿐만아니라분자생물학적검사를시행하여확진할수있었다. 8명의환자들은여러다양한치료를받았는데외래에 서추적관찰만하며지켜보는경우도있고, 수술이나항암화학치료, 방사선치료를단독혹은병합하여치료를일부는받았고일부는받고있는중이다. 8명모두현재생활에별다른불편함없이생존해있으며평균추적관찰기간은 38개월이었다. 정확한진단기법이나타나기전까지 lymphoma는 reactive lymphoid proliferation disease (pseudolymphoma, lymphoid interstitial pneumonitis, lymphomatoid granulomatosis, follicular bronchiolitis) 와병리적으로형태구별이어렵기때문에진단에혼돈이왔던경우가많았던걸로생각된다 [3]. 본병원에서도 2004년이후부터필요할경우면역조직화학검사나분자생물학적검사를사용하여정확한진 437

대흉외지 2007;40:435-440 Fig. 2. Microscopic finding of diffuse large B cell lymphoma (H&E stain, 400). Tumor cells show diffuse growth pattern.

Microscopic finding of small lymphocytic lymphoma (H&E stain, 400). 단과치료를하고있는바대부분의환자가 3년내에발견되어현재모두생존해있는상태다.

Microscopic finding of follicular lymphoma (H&E stain 200). Closely packed follicles are noted. The neoplastic follicles focally shows an almost back-to-back pattern.

4 대흉외지 2007;40: Fig. 2. Microscopic finding of diffuse large B cell lymphoma (H&E stain, 400). Tumor cells show diffuse growth pattern. The tumor cells are medium to large sized and shows oval to round, vesicular nuclei with fine chromatin and 1 2 membrane bound nucleoli. Fig. 3. Microscopic finding of small lymphocytic lymphoma (H&E stain, 400). 단과치료를하고있는바대부분의환자가 3년내에발견되어현재모두생존해있는상태다. 고 원발성폐림프종은폐에정상적으로분포하는기관지주위림프조직 (bronchial-associated lymphoid tissue, BALT) 과폐실질내간질의림프조직, 폐내림프절과같은림프조직의어디에서나발생할수있으며과거에는대부분 B-세포림프종으로만진단하였다. 1973년처음으로폐에 찰 Fig. 4. Microscopic finding of follicular lymphoma (H&E stain 200). Closely packed follicles are noted. The neoplastic follicles focally shows an almost back-to-back pattern. 서의 MALT의존재가알려진후대부분의학자들은 MALT (mucosa associated lymphoid tissue) 가폐의정상적인조직이아니라후천적으로흡연이나자가면역질환, 만성감염과같은발암자극에장기간노출됨으로써이차적으로나타나는것으로믿고있다 [4]. 조직학적악성도는 NCI (National Cancer Institute) 분류에의해저도, 중등도, 고도의세포형태로분류하면서폐악성림프종의경우비교적경한임상증상과악성도가낮은조직소견, 양호한예후등으로인해가성림프종 (pseudolymphoma) 이라는용어로기술되었으므로정확한발생빈도를예측할수없다 [5]. 1994년에개정된 REAL분류법 ( Revised European-American Classification of Lymphoid Neoplasm classification, 1994) 에서는이런것을점막림프조직에서유래한악성도가낮은 B세포악성림프종 (low grade B cell malignant lymphoma), 즉 MALT 종양으로보는경향이있는데 [6] 원발성악성폐림프종은기관지점막의특수한림프조직으로부터유래된이 MALT 림프종의범주에있다고볼수있다 [5]. 1997년 REAL분류를수정한 WHO분류에서는이것을림프절외변연부 B세포림프종 (extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue, MALT lymphoma) 이라고하였는데폐림프종중가장많은부분을차지하고있다 [7]. 본연구에서도 MALT lymphoma가 3명으로 37.5% 정도를차지하여가장많았다. 그외 diffuse large B-cell lymphoma, small lymphocytic lymphoma, anaplastic lage cell lymphoma, small lymphocytic lymphoma가발견되고있는 438

5 김재범외원발성폐림프종의임상고찰 데, 면역조직화학및분자생물학적기법의발달로폐에원발성으로발생한저급의악성림프종을정확히진단내릴수있게되었다 [8]. 고악성도의림프종은매우드물며대부분저급의 MALT 림프종이변형된것이다. T-세포림프종, NK세포림프종, 호즈킨림프종도발생할수있으나매우드물다 [9]. 원발성폐림프종은임상증상에서무증상으로나타나는경우가많으며특히 MALT lymphoma에서두드러지게나타난다. 그외전신증상이나호흡기증상을주소로내원하게되며다른림프종에비해 B-symptom은적게나타나는편으로알려져있는데 [10], 본연구에서도열이나서내원한환자는 1명만발견되었다. 방사선검사에서원발성폐림프종이나타내는소견은작은혹이나종괴가단독혹은여러개가나타나거나경계가불분명한폐침윤소견이나타나는등여러다양한모양을나타내기때문에어떤특별한모양이나타났을때이것을원발성폐림프종이라고지칭하기는어렵다. 이것으로생각해볼때방사선검사상어떤이상소견이나오더라도림프종의가능성을가지고있다고할수있다 [10]. 대부분의원발성폐림프종에서진단을위해수술적시도가요구된다. 많은수의환자에서기관지경이시도되나진단이잘되지않는이유는내강 (endoluminal) 병소가별로없기때문이다. 원발성폐림프종에서수술의역할은절제가가능할경우에는진단을위해충분한조직을얻고또한치료를위해완전절제를하는것이좋다. 그러나절제가불가능하거나양쪽폐에병소가있는경우에는진단을위해충분한조직을얻으려고수술을시행하게된다. 이런환자에서제한적절제술을시행한이후에동결절편검사에서림프종으로나온경우에는병기결정을위해폐문주위와종격동주위의림프절을절제하는것이필요하다 [11]. 비록치료방법은수술이나방사선치료, 항암화학요법의단독혹은병합요법과같이여러방법이있으나표준화된치료방식은아직없다 [2]. 증상이없는 MALT림프종의경우는아주서서히진행하는관계로추적관찰만하는것으로도훌륭한치료방법이될수있다는보고도있다 [12]. 증상을가지고있는 MALT림프종의경우에는 1가지제제의항암화학요법으로도치료가가능하다고알려져있다. 보통 chlorambucil을사용하거나 CVP병합요법 (cyclophosphamide, vincristine, prednisolone) 을사용한다. 이런경우수술적치료의역할은명쾌히규명되어있지 않다 [2,4,12]. 국한된원발성폐림프종 (stage I E or stage II E) 은방사선치료나수술적절제단독으로도완치가가능하나, 수술적절제후에도종양이남아있거나국소재발률이높아비교적예후가불량한비MALT림프종의경우에는추가적인항암요법이나방사선요법이필요하다 [13-15]. 치료후재발률은 50% 정도로매우높게나타난다고알려져있다 [15]. 따라서일부저자는전폐절제술을포함한광범위절제술을추천하기도하였으나 [16] 절제범위정도는생존율을포함한예후에별다른영향을미치지않는다 [11] 고하기도하여아직논란의여지가남아있다. 본연구에서도비록증례가적기는하나절제정도와생존율에서는별다른연관관계를찾을수없었다. Koss 등은주변부림프절전이가나쁜예후를나타내는것은아니라고하였다 [17]. 또한림프종의조직형태에따라생존율에차이가나타나는것은아니라는보고도있다 [11,18]. 그러나다른조직형태와는달리 MALT 림프종은서서히진행하며예후가좋은것으로공통적으로보고되고있다 [11,15,17,18]. 결 원발성폐림프종은매우드문질환으로비특이적인임상증상과방사선소견을보인다. 수술적진단방법이진단과치료에보다더좋은결과를기대할수있으며정확한조직형태를알아내는것이치료방법결정에도움을줄수있다. 림프종은좋은예후를가지고있으나본연구에서는증례가적고추적관찰기간이짦은관계로목표로한예후요소나치료방향설정을제시하기에는어려울걸로생각된다. 좀더긴추적관찰과더많은임상경험이있어야더정확한결과를산출할수있을것으로생각된다. 론 참고문헌 1. L Hoste RT, Filippa DA, Lieberman PH, Bretsky S. Primary pulmonary lymphomas: clinicopathologic analysis of 36 cases. Cancer 1984;54: Ferraro P, Trastek VF, Adlakha H, Deschamps C, Allen MS, Pairolero PC. Primary non-hodgkin s lymphoma of the lung. Ann Thorac Surg 2000;69: Saltzstein SL. Pulmonary malignant lymphomas and pseudolymphomas: classification, therapy and prognosis. Cancer 1963;16:

6 대흉외지 2007;40: Zinzani PL, Tani M, Gabriele A, et al. Extranodal marginal zone B-cell lymphoma of MALT-type of the lung: single-center experience with 12 patients. Leuk Lymphoma 2003;44: Koss MN, Hochholzer L, Nichols PW, et al. Primary non- Hodgkin s lymphoma and pseudolymphoma of lung: a study of 161 patients. Hum Pathol 1983;14: L Hoste RJ, Filippa DA, Lieberman PH, et al. Primary pulmonary lymphomas; a clinicopathologic analysis of 36 cases. Cancer 1984;54: Begueret H, Vergier B, Parrens M, et al. Primary lung small B-cell lymphoma versus lymphoid hyperplasia: evaluation of diagnostic criteria in 26 cases. Am J Surg Pathol 2002; 26: Isaacson PG, Spencer J. Malignant lymphoma of mucosaassociated lymphoid tissue. Histopathology 1987;11: Li G, Hansmann ML, Zwingers T, Lennert K. Primary lymphomas of the lung: morphological, immunohistochemi- cal and clinical features. Histopathology 1990;16: Kim JH, Lee SH, Park J, et al. Primary pulmonary non- Hodgkin s lymphoma. Jpn J Clin Oncol 2004;34: Ferraro P, Trast V, Adlakha H, et al. Primary non-hodgkin s lymphoma of the lung. Ann Thorac Surg 200;69: Cadranel J, Wislez M, Antoine M. Primary pulmonary lymphoma. Eur Respir J 2002;20: Sarna GP, Kagan AR. Extranodal lymphomas. In: Haskell CM, Ed. Cancer treatment. 4th ed. Philadelphia: WB Saumders, 1995: Fisher RI, Dahiberg S, Nathwani BN, Banks PM, Miller TP, Grogan TM. A clinical analysis of two indolent lymphoma entities: mantle cell lymphoma and marginal zone lymphoma (including the mucosa-associated lymphoid tissue and monocytoid B-cell subcategories): a Southwest Oncology Group study. Blood 1995;85: Li G, Hansmann ML, Zwingers T, Lennert K. Primary lymphoma of the lung: morphological, immunohistochemical and clinical features. Histopathology 1990;16: Uppal R, Goldstraw P. Primary pulmonary lymphoma. Lung Cancer 1992;8: Koss MN, Hochholzer L, Nichols PW, Wehunt WD, Lazarus AA. Primary non-hodgkin s lymphoma and pseudolymphoma of lung: a study of 161 patients. Hum Pathol 1983; 14: Kennedy JL, Nathwani BN, Burke JS, Hill LR, Rappaport H. Pulmonary lymphomas and other pulmonary lymphoid lesions: a clinicopathologic and immunologic study of 64 patients. Cancer 1985;56: = 국문초록 = 배경 : 폐에생기는원발성악성림프종은매우드문종양이다. 비록림프종의예후는좋으나임상양상이나예후요소, 치료에대해서는명확히밝혀져있지않다. 대상및방법 : 1994 년부터 2006 년사이에치료한 8 명의환자를대상으로하였다. 병리적검사에서폐에악성림프종으로나타났으며종격동림프선비대가없으며복부와골반단층촬영및골수검사에서폐외질병이없으며과거림프종의병력이없는경우로하였다. 결과 : 남자가 3 명, 여자가 5 명이었으며평균나이는 53.9 세였다. 3 명은무증상이었으며 5 명은폐및전신증상을가지고있었다. 진단은 3 명이흉부컴퓨터단층촬영하세침생검, 1 명이기관지내시경하생검을하였으며수술적으로진행된사람은 4 명으로폐쐐기절제술 2 명과폐엽절제술 2 명을시행하였다. 3 명은점막관련림프종이었으며 2 명은큰 B 세포림프종, 2 명은소림프구림프종이었고한명은여포성림프종이었다. 8 명의환자들은여러다양한치료를받았는데관찰, 수술, 항암화학요법및방사선치료나복합치료를받았다. 8 명모두현재생존해있으며평균추적관찰기간은 38 개월이다. 결론 : 이결과에서도나타나듯폐의원발성악성림프종은좋은예후를가지고있으나임상증상과예후요소, 적절한치료방식을알아내기위해서는더긴기간의추적관찰과더많은임상경험이필요하다. 중심단어 :1. 원발성폐림프종 2. 병리학 3. 폐종양 440

Kaes017.hwp

Kaes017.hwp 갑상선의 Poorly Differentiated (Insular) Carcinoma Insular Carcinoma: An Aggressive Subtype of Differentiated Thyroid Neoplasms Seok-Jin Nam, M.D., Sang-Dal Lee, M.D., Hal-lin Park, M.D., Young-Ryun Oh, M.D.