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1 Korean J Hematol Vol. 40, No. 1, March, 2005 Original Article 혈관면역모세포 T- 세포림프종의임상적특징과치료성적 서울대학교의과대학내과학교실 백지연 박숙련 최인실 김상일 김동완 김지현윤성수 박선양 김병국 김노경 허대석 Angioimmunoblastic T-cell Lymphoma: Clinical Characteristics and Treatment Outcomes Ji Yeon Baek, M.D., Sook Ryun Park, M.D., In Sil Choi, M.D., Sang-Il Kim, M.D., Dong-Wan Kim, M.D., Jee Hyun Kim, M.D., Sung-Soo Yoon, M.D., Seonyang Park, M.D., Byoung Kook Kim, M.D., Noe Kyeong Kim, M.D. and Dae Seog Heo, M.D. Department of Internal Medicine, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea Background: An angioimmunoblastic T-cell lymphoma (AITL) is a rare subtype of lymphoma, accounting for only 1 to 2% of studies on non-hodgkin's lymphomas. Because of the rarity of this disease, most studies have been small, including cases of various T-cell Non-Hodgkin's Lymphoma (T-NHL). Those patients diagnosed as AITL, during the last 8 years at a single institution (Seoul National University Hospital), were retrospectively analyzed to determine the clinical features and treatment outcomes of AITL. Methods: All 24 of the patients diagnosed with AITL between February 1995 and February 2003 were included in this retrospective review. Results: The predominant characteristics of the population were: median age 62 years (range, 32~81); M/F=18/6; nodal involvement 24/24 (100%); extranodal involvement, particularly bone marrow 16/20 (80%); skin involvement 6/24 (25%); B-symptoms 18/24 (75%) and advanced disease (stages III and IV) in 20/24 (83%). Twenty-three of the 24 patients received combination chemotherapy, with 8/23 (35%) of patients obtaining a CR. The median CR duration was 18.1 months. With a median follow-up of 40.9 months, the 5-year OS rate was 28%, with median survival of 8.7 months. According to a univariate analysis, an elevated LDH showed a tendency to negatively influence the survival. Conclusion: The prognosis of AITL is poor compared to other NHL, with a low CR rate and short CR duration and OS. From our data, the CR rate after first- or second-line chemotherapy were low (35%), compared with those previously described in Western reports. (Korean J Hematol 2005;40:8-14.) Key Words: Angioimmunoblastic, T-cell lymphoma, Clinical features, Prognosis, Treatment 접수 :2004 년 12 월 20 일, 수정 :2005 년 1 월 7 일승인 :2005 년 1 월 13 일교신저자 : 허대석, 서울시종로구연건동 , 서울대학교의과대학내과학교실 Tel: , Fax: heo1013@snu.ac.kr Correspondence to:dae Seog Heo, M.D. Department of Internal Medicine, Seoul National University College of Medicine 28 Yeongeon-dong, Jongno-gu, Seoul , Korea Tel: , Fax: heo1013@snu.ac.kr 8

2 백지연외 : 혈관면역모세포 T- 세포림프종의임상적특징과치료성적 9 서론혈관면역모세포 T-세포림프종은전신적인림프절종대, 발열과피부발진및다클론고감마글로불린혈증등의특징적인임상상과연관된전신적인질환으로악성비호즈킨림프종의 1~2% 를차지하는흔하지않은조직학적아형이다 (Table 1). 1) 분자유전학적연구와면역조직화학염색기술등의발전으로질환에대한이해가높아지면서 80년대후반에이르러이질환을 T-세포악성림프종으로이해하게되었으며 1989년 modified Kiel 분류 2) 에서는 T-cell lymphoma of angioimmunoblastic type, 1994년 REAL 분류 3) 에서는 Angioimmunoblastic T-cell lymphoma (AILD), 2001년 WHO 분류 4) 에서는 Angioimmunoblastic T-cell lymphoma (AITL) 로명명하였다. 정상림프절구조의부분적인소실및다형의세포침윤과혈관증식이라는특징적인조직학적소견을보이고주로중년층이상의연령에서전신적인림프절종대, 간비종대및발열과피부병변등의임상상을나타내면서빈혈, 호산구혈증, Coombs' test 양성및고감마글로불린혈증등의면역학적이상을수반하는특징을보인다. 혈관면역모세포 T-세포림프종은보고자에따라다소의차이는있으나 5년생존율 30~35%, 중앙생존기간 36개월미만으로비호지킨림프종의다른아형에비해불량한예후를보이는질환이다. 5-7) 위에서언급한대로특징적인조직학적소견이있으나반응결절증식및다른아형의악성림프종과상당한형태학적인중복이있고질환의특징적인표현형또는분자학적표지자가없기때문에진단이지연되거나오진되어조기치료가어려운점도이질환의낮은치료성적과연관이있다. 최근에는이질환의생태에대한이해와다른질환과의조기감별을위한혈관면역모세포 T-세포림프종에서의악성 T-세포의특징적인표지자발현등에대한연구가활발하다. 8) 국내의경우혈관면역모세포 T-세포림프종의낮은질환빈도로말미암아이질환에대한우리나라고유한임상적특성및치료성적, 예후인자등에대한보고가미흡한실정이다. 본연구에서는서울대학교병원에서진단된 24명의혈관면역모세포 T-세포림프종환자를대상으로임상적특성과치료성적, 예후인자에대해알아보고자하였다. Table 1. Relative frequency of histologic subtypes of NHLs according to REAL classification* Study population Korean Korean International (Kang (Ko (NHLCP) 23) et al) 21) et al) 22) (N=1,378) (N=802) (N=1,466) B-cell (total) T-cell (total) Peripheral T-cell Angiocentric Angioimmunoblastic PTCL, NOS Anaplastic large cell *Modified from J Korean Cancer Assoc 1999;31(4): ) 대상및방법 1995년 2월부터 2003년 2월까지서울대학교병원에내원하여조직검사를통해처음으로혈관면역모세포 T-세포림프종으로진단받은치료경력이없는 15세이상의환자를대상으로시행하였다. 면역조직화학염색으로 T-세포기원임이확인되고 REAL 분류법 3) 으로혈관면역모세포 T-세포림프종으로진단된총 24명의환자가연구대상에포함되었으며이들환자의병록지검토를통해임상적특성, 치료에대한반응, 생존율및예후인자들에대해후향적분석을시행하였다. 임상적특성으로는연령, 성별, Ann Arbor 병기, Eastern Cooperative Oncology Group (ECOG) 활동도, B-증상유무, 간비종대유무, 림프절외침범장기의수및국제예후지수 (International Prognostic Index, IPI) 를조사하였고검사실소견으로는혈청헤모글로빈치 (10 g/dl 이상 vs 10g/dL 미만 ) 와호산구혈증 (>500/μL) 및고감마글로불린혈증 (>13g/L) 여부, 혈청 LDH치 ( 정상 vs 증가 ) 를조사하였다. 모든환자에서초기치료로항암화학요법이시행되었으며항암화학요법으로는 CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone), 9) COPBLAM-V (vincristine, bleomycin, cyclophosphamide, doxorubicin, prednisolone, procarbazine), 10) IMEP (ifosfomide, methotrexate, etoposide, prednisolone), CVP (cyclophosphamide, vincristine, prednosolone) 등이사용되었다. 병록지조사와전화, 주소지및본적지조회를통해환자의생사여부를추적하였으며무병생존기간은완전관해에도달한환자를대상으로진단일로부터재발

3 10 Korean J Hematol Vol. 40, No. 1, March, 2005 또는사망일까지의기간으로하였고생존기간은사인에관계없이진단일로부터사망일까지의기간으로하였다. 대상환자군의무병생존율과전체생존율은 Kaplan- Meier 방식을이용하여산출하였고전체생존율에영향을미치는예후인자를알아보기위해 Log-rank test 를이용한단변수분석을시행하였다. 모든통계분석은 SPSS (Version 11.0) 를이용하였다. 결 1. 대상환자의특성 전체 24예혈관면역모세포 T-세포림프종환자의임상적특성을요약하였다 (Table 2). 총 24예의대상환자 Table 2. Clinical characteristics of the AITL patients (N=24) N % Age median: 62yr (32~81) 60yr >60yr Sex Males Females 6 25 Stage I~II 4 17 III~IV Performance status 1~ ~ B-symptoms Present Absent 6 25 LN enlargement Hepatosplenomegaly Skin Rash 5 20 Nodules 1 4 Extranodal involvement Bone marrow 16/20* 80 Pleural effusion 9 38 Ascites 3 13 Cerebrospinal fluid 0 0 IPI Low risk 1 4 Low-intermediate 3 13 High-intermediate 7 29 High *Available for only 20 patients. 과 중남자가 18예 (75%) 였고중앙연령은 62세 ( 범위 32~ 81세 ) 였으며, 60세이상의고연령환자가 14예로전체환자의 58% 를차지하였다. 75% 의환자가 ECOG 활동도 1~2였으며 Ann Arbor 병기는 III/IV기가 20예 (83%) 로진행된병기가대부분이었다. 국제예후지수에따른분류는저위험군이 1예 (4%), 저-중등도위험군이 3예 (13%), 고-중등도위험군이 7예 (29%), 고위험군이 13예 (54%) 였다. B-증상은 18예 (75%) 에서관찰되었고모든예에서림프절종대가있었으며, 림프절외병소로는골수침범이골수조직검사결과가확인된 20명의환자에서 16예 (80%), 악성흉수가 9예 (38%) 였다. 피부병변은 6예에서관찰되었는데붉은반점이 5 예 (20%), 결절양상이 1예 (4%) 에서있었고복부전산단층화촬영에서간종대는 16예 (66%), 비종대는 17예 (71%) 관찰되었다. 검사실소견으로는혈청헤모글로빈치 10g/dL 미만, 고호산구혈증 (>500/μL), 고감마글로불린혈증 (>13g/dL) 이각각전체의 42%, 33%, 67% 비율을보였고혈청 LDH치는정상보다상승된경우가 21예 (88%) 였다 (Table 3). 2. 치료반응및생존율 24명의환자중 23명이항암화학요법치료를받았으며, 완전반응 8예 (33%), 부분반응 4예 (17%) 로전체반응률은 50% 였다. 일차항암화학요법에서완전반응을보인 8예의중앙무병생존기간은 18.1개월이었으며 (Fig. 1) 5예에서재발하여재발률은 62% 였다 (Table 4). 일차항암화학요법치료에서완전반응에도달하지못한 15예중 11예에서이차구제항암화학요법이시 Table 3. Laboratory findings of the AITL patients (N=24) N % Hemoglobin (g/dl) < Hypereosinophilia (>500/μL) 8 33 Polyclonal hypergammoglobulinemia (>13g/dL) 8/12 67* LDH (IU/L) Normal (<225) 3 12 ~ ~ ~ > *Available for only 12 patients.

4 백지연외 : 혈관면역모세포 T- 세포림프종의임상적특징과치료성적 11 행되었고 1예에서완전반응이유도되었다. 중앙추적기간 40.9개월 ( 범위, 3.6~104.5개월 ) 까지생존율을관찰하였을때, 전체환자의 5년생존율은 28% 였고중앙생존기간은 8.7개월 ( 범위, 0.3~ 개월 ) 이었다 (Fig. 2). Probability of DFS Months Fig. 1. Disease-free survival of the 8 patients who achieved complete remission. Probability of survival Months Fig. 2. Overall survival of the 24 patinets with AITL. 3. 예후인자분석 전체 24명의환자를대상으로하여전체생존율에대한단변수분석을시행하였다. 연령 ( 60세 vs >60 세 ), B- 증상유무, Ann Arbor 병기 (I, II vs III, IV), 혈청 LDH 치 ( 300IU/L vs >300IU/L), 혈청헤모글로빈치 ( 10g/dL vs <10g/dL), 림프절외침범유무에따른전체생존율에대한단변수분석을시행한결과혈청 LDH치가통계학적으로의미있는예후인자였다 (P= )(Table 5). 국제예후지수 (0, 1, 2 vs 3, 4, 5) 에따른분석에는 P value=0.1654로통계학적으로의미있 Table 5. Prognostic factors influencing overall survival Prognostic factors (N) Overall P (Log survival (month) rank test) Age 60yrs (10) >60yrs (14) 10.4 B-symptom Absent (18) Present (6) 8.7 Stage I~II (4) III~IV (20) 5.9 IPI L-LI (4) HI-I (20) 5.1 LDH 300IU/L (10) >300IU/L (14) 4.5 Hemoglobin 10g/dL (14) <10g/dL (10) 5.9 Extra-nodal involvement (20) Without involvement (2) Involvement (18) 5.9 Table 4. Response according to initial therapy First-line therapy N Median CR duration Relapse CR PR N (%) N (%) Month N (%) Chemotherapy 23 8 (35) 4 (17%) Anthracycline-based* 16 8 (50) 2 (13%) /8 (62) Others 7 0 (0) 2 (29%) *CHOP (10/16), COPBLAM-V (6/16), IMEP (4/7), CVP (3/7). Abbreviations: CR, complete remission; PR, partial remission.

5 12 Korean J Hematol Vol. 40, No. 1, March, 2005 Table 6. Comparision of patient characteristics and treatment outcomes Study IPI Outcomes No of Median Stage B-sx BM Skin cases age III/IV (+) (+) (+) L-LI HI-H CR 5yr-OS N (yrs) (%) (%) (%) (%) (%) (%) (%) (%) Kang et al. 21) Pautier P et al. 7) Edward RA et al. 24) This study Abbreviations: IPI, international prognostic index; L-LI, low-low intermediate risk; HI-H, high intermediate-high risk; CR, complete remission; 5yr-OS, 5-year overall survival; -, not reported. 는예후인자는아니었으나높은지수일수록불량한예후를나타내는경향성은보였다. 고 혈관면역모세포 T-세포림프종은현재는말초T-세포림프종에속하는조직학적유형으로받아들여지고있으며, 이질환의클론성도 T-세포수용체유전자재배열이나세포유전연구등을통해증명할수있다. 11,12) 더욱이최근에는세포유전학적소견들이혈관면역모세포 T-세포림프종에서예후와관련해서의미가있으며치료방향설정에도움을줄수있다는보고들도있다. 13) 본연구에서혈관면역모세포 T-세포림프종대상환자 24명의임상적특성들을살펴보면중앙연령은 62 세, 남자에서빈도가높았고 (3:1) 양호한전신상태에비해 III기이상의진행된병기를가진환자가전체환자의 83% 였으며대부분의환자에서 B-증상을가지면서모든환자에서림프절종대가관찰되었다. 주로림프절침범을하지만림프절외침범으로는골수침범, 피부병변, 악성흉수 ( 또는흉막침범 ), 복수가각각 80%, 24%, 38%, 13% 를차지하였고중추신경계 ( 연수막파종 ) 침범은관찰되지않았다. 피부병변은발진양상이 5예, 결절양상이 1예였으며 4예에서조직검사가시행되었고이중 3예에서조직학적소견과면역조직화학염색을통해질환과의연관성을확인하였다. 혈관면역모세포 T-세포림프종에서피부병변병발은 40% 정도로보고되고있으나 14) 반점구진성또는구진결절성발진, 전신적인점출혈, 홍색부종, 판등의다양한피부소견을나타내고전형적인조직학적소견이없어양성염증성피부질환이나교원성질환의피부소견과감별이어렵다. 최근에는면역조직화학염색이나 TCRγ- 찰 chain 유전자재배열분석등을통해진단적접근이용이하게되었다. 15) 항암화학요법을받은 23명의환자에서 CHOP, COPBLAM-V, IMEP, CVP 항암제가사용되었으며 1 예에서환자의전신상태가불량하여스테로이드만이사용되었다. 본연구는후향적분석으로첫치료시항암제의무작위배정이아닌, 상대적으로낮은병기의전신상태가양호하였던환자에서 CHOP, COPBLAM- V가사용되었으며완전관해를보인 8명의환자들모두이들군에서유도되었다. 치료성적은항암화학요법을받은 23명의환자중완전관해가 8예 (33%), 부분관해가 4예 (17%) 로전체반응률은 50% 였으며, 완전관해를보인 8예의중앙무병생존기간은 18.1개월이었고전체환자의 5년생존율은 28%, 중앙생존기간은 8.7개월이었다. 서양의경우에서도대체로중앙생존기간 12~24개월로비호즈킨악성림프종의다른아형보다낮은치료성적을보고하고있는데, 5,7,11,16) 본연구에서는진단이늦어지면서상당히진행된병기에서불량한전신상태를보였던몇명의환자가포함되어서양의경우보다중앙생존기간이더낮게보고된것으로생각한다 (Table 6). 사망과관련하여 7예에서심각한감염이합병되었으며동정된원인균은 Pseudomonas, MRSA (methicillin resistant Staphylococcus aureus), Cytomegalovirus, Pneumocystis carinii 등이었다. 연령, 병기, 혈청 LDH치, 골수침범, 림프절외침범, 혈청헤모글로불린치, 세포유전학적소견등이전체생존율과연관된예후인자로보고된바있으며 7,12) 본연구에서는혈청 LDH치만이예후인자로서통계적으로유의하였다 (P=0.0485). 국제예후지수 3점이상의고- 중등도위험군은전체의 83% 를차지하였으나국제예후지수를 0~2점과 3~5점으로분류하여시행한분석결과통계적으로의미있는예후인자는아니었다 (P=

6 백지연외 : 혈관면역모세포 T- 세포림프종의임상적특징과치료성적 ). 다만지수가높을수록불량한예후를나타내는경향성은보였다. 본연구에서의통계분석은대상환자수가적어이에대한해석에는한계가있다. 본연구결과는대상환자수가적어우리나라에서의혈관면역모세포 T-세포림프종의특성과치료성적을반영한다고보기에는한계가있으나기존에서양에서보고된혈관면역모세포 T-세포림프종환자의특성및치료성적과유사함을확인할수있었다. 치료를받은 23명의환자중일차완전관해를보인 8예 (33%) 의경우도중앙무병생존기간이 18.1개월로 1년이내에재발하는경우가많았으며완전관해에도달하지못한 15 예에서의이차완전관해도 1예에서만유도되어완전관해율을높이고관해유지기간을연장시키는새로운치료법에대한연구와시도가필수적일것으로판단된다. 본연구에서전체생존율에대한의미있는예후인자들로는 LDH (P=0.0485), 국제예후지수 (P=0.1654), 병기 (P=0.1742) 등병적요소가비중이있는반면, 완전관해에대한의미있는예후인자들로는 ( 비록통계적으로의미있는예후인자는없었고본문에서언급하지는않았으나 ) 나이 (P=0.242), 혈청헤모글로빈치 (P= 0.242) 등임을살펴보면, 혈관면역모세포 T-세포림프종의호발연령이고령임을고려하여새로운치료법에대한대상환자군의선정또한중요하리라생각한다. 최근에는혈관면역모세포 T-세포림프종을포함한말초혈액 T-세포림프종에서고용량항암제및자가말초혈액조혈모이식후치료성적에대한고무적인결과가보고되고있으며 17-20) 이러한결과가전체생존율의연장에도영향을미칠지는아직장기경과관찰이필요한실정이다. 요약배경 : 혈관면역모세포 T-세포림프종은악성비호지킨림프종의 1~2% 를차지하는흔하지않은조직학적아형이다. 본연구에서는혈관면역모세포 T-세포림프종의임상적특성과치료성적및예후인자에대해알아보고자하였다. 방법 : 1995년 3월부터 2003년 3월까지서울대학교병원에서조직학적으로진단된 24명의혈관면역모세포 T-세포림프종환자를대상으로후향적분석을시행하였다. 결과 : 전체대상환자의중앙연령은 62세 ( 범위, 32~ 81), 남녀비율은 3:1이었다. 모든환자에서림프절종대가관찰되었으며림프절외병소로서골수침범은 16/20예 (80%), 피부병변이동반된경우는 6/24예 (25%) 였다. B-증상은 18/24예 (75%) 에서있었고 Ann Arbor 병기 III기또는 IV기의진행된병기는전체환자의 83% 를차지하였다. 초기치료가시행된 23명의환자에서완전관해율은 35% 이었고중앙무병생존기간은 18.1개월이었다. 중앙추적기간은 40.9개월 ( 범위, 3.6~104.5개월 ) 이었고전체환자의 5년생존율은 28%, 중앙생존기간은 8.7개월이었다. 전체생존율에대한단변수분석에서혈청 LDH치가예후인자로서통계학적으로유의하였다. 결론 : 본연구결과에서도혈관면역모세포 T-세포림프종은악성림프종의다른조직학적아형에비해낮은완전관해율과전체생존율을보이는아형임을확인할수있었다. 임상적특성들은서양의보고들과큰차이는없었으나골수침범의비율이높았고 5년생존율은 28%, 중앙생존기간은 8.7개월이었으며혈청 LDH치만이유의한예후인자로분석되었다. 참고문헌 1) Ganesan TS, Dhaliwal HS, Dorreen MS, Stansfeld AG, Habeshaw JA, Lister TA. Angio-immunoblastic lymphadenopathy: a clinical, immunological and molecular study. Br J Cancer 1987;55: ) Stansfeld AG, Diebold J, Noel H, et al. Updated Kiel classification for lymphomas. Lancet 1988;1: ) Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994;84: ) Harris NL, Jaffe ES, Diebold J, et al. The World Health Organization classification of neoplastic diseases of the haematopoietic and lymphoid tissues: Report of the Clinical Advisory Committee Meeting, Airlie House, Virginia, November Histopathology 2000;36: ) Siegert W, Agthe A, Griesser H, et al. Treatment of angioimmunoblastic lymphadenopathy (AILD)-type T-cell lymphoma using prednisone with or without the COPBLAM/ IMVP-16 regimen. A multicenter study. Kiel Lymphoma Study Group. Ann Intern Med 1992; 117: ) Siegert W, Nerl C, Agthe A, et al. Angioimmunoblastic lymphadenopathy (AILD)-type T-cell lymphoma: prognostic impact of clinical observations and laboratory findings at presentation. The Kiel Lymphoma Study Group. Ann Oncol 1995;6: ) Pautier P, Devidas A, Delmer A, et al. Angioim-

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Jkbcs016(92-97).hwp

Jkbcs016(92-97).hwp Expression of bcl-2 and Apoptosis and Its Relationship to Clinicopathological Prognostic Factors in Breast Cancer - A Study with Long Term Follow-up correlated with the survival rate.(journal of Korean