대한내과학회지 : 제 90 권제 2 호 2016 http://dx.doi.org/10.3904/kjm.2016.90.2.163 심근및전신의연조직을침범한 Richter 증후군의 1 예 영남대학교의과대학영남대학교의료원 1 혈액종양내과, 2 핵의학과, 3 병리과 구은주 1 김민경 1 공은정 2 고성애 1 구미진 3 정지윤 1 현명수 1 Rare Presentation of Richter s Transformation to Diffuse Large B Cell Lymphoma: a Case Report Eun Joo Goo 1, Min Kyoung Kim 1, Eun Jung Kong 2, Sung Ae Koh 1, Mi Jin Gu 3, Ji Yoon Jung 1, and Myung Soo Hyun 1 Departments of 1 Hematology-Oncology, 2 Nuclear Medicine, and 3 Pathology, Yeungnam University Medical Center, Yeungnam University College of Medicine, Daegu, Korea Richter s syndrome refers to the development of aggressive lymphoma in a patient with chronic lymphocytic leukemia (CLL). It occurs in about 2% to 10% of patients with CLL. The most frequent manifestation of Richter s syndrome is diffuse large B cell lymphoma (DLBCL). Extranodal involvement is rare but can occur. The prognosis of Richter s syndrome is very poor. We herein report a case of a rare presentation of Richter s syndrome. A 42-year-old man diagnosed with CLL 2 years previously developed nodules on the bilateral thighs and buttocks. A positron emission tomography (PET)-CT scan revealed high fluorodeoxyglucose uptake in multiple lymph nodes, skeletal muscles, and the myocardium. An ultrasonography-guided biopsy confirmed Richter s syndrome from CLL to DLBCL. The patient was treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy. After six cycles of chemotherapy, we performed a PET-CT scan that revealed a complete response. However, 3 months later, the syndrome recurred. The patient was undergoing salvage chemotherapy at the time of this writing. (Korean J Med 2016;90:163-168) Keywords: Chronic lymphocytic leukemia; Diffuse large B cell lymphoma 서론 Richter 증후군 (Richter s syndrome or Richter s transformation) 은만성림프구백혈병이공격적인악성종양으로전환되는것을의미하는임상병리학적용어이다 [1-3]. 1928년에 Maurice Richter 에의해만성림프구백혈병이림프종으로전환된예가처음으로보고되었으며, 1966년 Richter 증후군 이라는용어가처음으로사용되었다 [1-3]. 만성림프구백혈병환자의 2-10% 에서 Richter 증후군이발생하는것으로알려져있다 [1]. 광범위큰B세포림프종으로전환되는경우가 90-95% 로가장흔하 Received: 2015. 5. 6 Revised: 2015. 7. 9 Accepted: 2015. 8. 25 Correspondence to Min Kyoung Kim, M.D., Ph.D. Departments of Hematology-Oncology, Yeungnam University Medical Center, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu 42415, Korea Tel: +82-53-620-4683, Fax: +82-53-654-8386, E-mail: kmink21c@hanmail.net Copyright c 2016 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution - 163 - Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
- The Korean Journal of Medicine: Vol. 90, No. 2, 2016 - 며 [1,2], 드물지만호치킨림프종, 전림프구백혈병, 림프모구림프종, 털세포백혈병등으로전환된예가보고되어있다 [3]. Richter 증후군의임상양상은대개갑작스런림프절종대나간비종대등으로발현하며림프절외조직을침범하기도한다. 만성림프구백혈병환자에서고열, lactate dehydrogenase (LDH) 상승, 크기가급격히증가한림프절이나타났다면 Richter 증후군을의심해야하며림프절이나침범된장기의조직검사로확진한다 [3]. 치료로는광범위큰B 세포림프종에준하여 rituximab 을포함한항암화학요법, 동종조혈모세포이식등을시행할수있으나치료반응률이 5-43% 이며평균생존기간이 5-8달로예후가불량한것으로알려져있다 [2,3]. 만성림프구백혈병은미국을비롯한서구의국가들에서는가장흔한백혈병이나 (3.9-6.5명 /100,000명), 국내에서는전체백혈병의 0.4-0.5% 만을차지하는극히드문질환이다 [4]. 따라서 Richter 증후군이국내에서보고된증례는매우드물다. 이에저자들은전신의다발성연조직종괴로발현한 Richter 증후군 1예를경험하였기에문헌고찰과함께보고하는바이다. 증례 42세남자환자로건강검진으로시행한혈액검사에서림프구증가소견을보여본원을방문하였다. 과거력및가족력상특이사항은없었다. 내원당시혈압 120/90 mmhg, 맥박 86회 / 분, 호흡 24회 / 분, 체온 36.8 였다. 신체검사에서비장이촉진되었다. 일반혈액검사에서백혈구 9,110/mm 3 ( 림프구 7,200/mm 3 ), 혈색소 12 g/dl, 혈소판 125 10 3 /mm 3 였다. 일반화학검사에서혈청총단백과알부민은각각 7.13 g/dl, 3.67 g/dl였으며빌리루빈및직접빌리루빈은각각 1 mg/dl, 0.28 mg/dl, AST/ALT 는각각 41 IU/L ( 정상범위 10-35), 68 IU/L ( 정상범위 0-40), 혈청 LDH는 342 IU/L ( 정상범위 150-550) 로 AST/ALT만증가소견을보였다. 간염검사에서 Antihepatitis C virus 양성소견을보였다. 골수흡인도말검사에서작고성숙한림프구가증가되어있었고흐름세포측정에서 CD19, CD20, CD5 양성소견을보였으며면역조직화학염색에서 Cyclin D1은음성소견으로만성림프구백혈병으로진단하였다. 염색체이상은발견되지않았다. 양전자방출단층촬영 (positron emission tomography) 에서전신의골수및비장에광범위한 fluorodeoxyglucose (FDG) 섭취증가와경부, 액와, 서 A B C D Figure 1. (A) Whole-body maximum-intensity projection F-FDG PET and (B-D) fused axial images of the patient revealed increased FDG uptake in the bilateral cervical, axillary, and inguinal lymph nodes. F-FDG PET, fluorodeoxyglucose positron emission tomography. - 164 -
- Eun Joo Goo, et al. Rare presentation of Richter s syndrome - 혜부림프절에 FDG 섭취증가가관찰되었다 (Fig. 1). 만성림프구백혈병 (Rai stage II/Binet stage B) 으로진단하고주기적인경과관찰을시행하였다. 환자는 2년 6개월간진찰및혈액검사에서별다른변화를보이지않던중갑자기양팔, 양쪽허벅지, 왼쪽엉덩이및왼쪽종아리에덩어리가촉진되어내원하였다. 일반혈액검사에서백혈구 3,640/mm 3, 혈색소 12.2 g/dl, 혈소판 170 10 3 /mm 3 였으며혈청 LDH는 473 IU/L 로정상범위였다. 양전자방출단층촬영에서전신의근육, 심장막, 좌심실심근, 복강내부, 왼쪽엉덩이및양쪽회음부의피하조직에강한 FDG 섭취증가를보이는종괴들이관찰되었으며비장및경부, 액와, 복강내림프절에 FDG 섭취증가가관찰되었다 (Fig. 2). 심장초음파검사에서좌심실의외벽, 중격, 심장끝, 대동맥과 우심방쪽의심근에다발성의저에코성종괴가관찰되었다. 양쪽허벅지종괴에대해조직검사를시행하여광범위큰B 세포림프종이확인되었다 (Fig. 3A). 특수염색에서 leukocyte common antigen, CD20, Bcl-2, Mum-1 protein 양성이었다 (Fig. 3B and 3C). International Prognostic Index 점수 2점으로 Low intermediate risk 군에속하였다. 골수조직검사에서는만성림프구백혈병에합당한소견이관찰되었고염색체이상이발견되지않았으며 fluorescence in situ hybridization (FISH) 검사에서 TP53 결실은관찰되지않았다. 환자는만성림프구백혈병에서광범위큰B 세포림프종으로전환된 Richter 증후군으로진단되었고 rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) 항암요법 (rituximab 375 mg/m 2, cyclophosphamide 750 mg/m 2, A B C D E F G Figure 2. (A) Whole-body maximum-intensity projection F-FDG PET, (B, D) fused axial, (C, E) CT axial, (F) fused coronal, and (G) CT coronal images of the patient revealed multiple masses with increased FDG uptake in the myocardium, skeletal muscles, and subcutaneous layer. F-FDG PET, fluorodeoxyglucose positron emission tomography; CT, computed tomography. - 165 -
- 대한내과학회지 : 제 90 권제 2 호통권제 666 호 2016 - A B C Figure 3. Histology of the muscle at the time of the diagnosis of Richter s syndrome. (A) Microscopy showed proliferation of diffuse large pleomorphic lymphoid cells (H&E, 400). (B) Immunohistochemical stain was positive for CD20 ( 400). (C) Immunohistochemical staining was positive for Ki67 ( 400). A B C Figure 4. (A) Whole-body maximum-intensity projection F-FDG PET, (B) fused axial, and (C) CT axial images of the patient showed metabolic remission after six cycles of chemotherapy. F-FDG PET, fluorodeoxyglucose positron emission tomography; CT, computed tomography. doxorubicin 50 mg/m 2, vincristine 2 mg, prednisolone 100 mg D1-5) 을 4주간격으로 6차례투여받았다. 6차례의항암요법을끝내고 2014년 9월시행한양전자방출단층촬영에서환자는완전관해로평가되었다 (Fig. 4). 그러나 3개월뒤경부및양쪽무릎에다시덩어리가발견되어양전자방출단층촬영시행하였으며양쪽오금, 왼쪽횡경막, 오른쪽상복부, 오른쪽엉덩이의피하층과양쪽허벅지의근육및경부림프절에재발이의심되어림프절조직검사를시행하였으며광범위큰 B세포림프종재발로진단되었다. 현재환자는 gemcitabine, cisplatin, dexamethasone 구제항암요법으로치료중이다. 고찰 Richter 증후군의병태생리는아직명확히알려져있지않 다. 다양한면역및유전적소인이 Richter 증후군의발생에영향을줄수있다 [1]. Richter 증후군에특이적인세포유전학적이상및전위로알려진것은없으나 Non-del13q14 이상이 Richter 증후군의위험요인으로생각되고있으며 TP53 파열, c-myc 이상이흔한유전적이상으로발견되었다 [1]. Richter 증후군으로전환된광범위큰B세포림프종은본래의만성림프구백혈병클론과연관되었을수도있고아닐수도있다 [1,3]. Epstein-Barr virus가 Richter 증후군과연관되었다는보고도있으나연관관계는부족하다 [1,5]. 본증례에서는염색체이상이발견되지않았으며 FISH 검사에서 TP53 결실은관찰되지않았다. 만성림프구백혈병환자에서림프절종대, B증상의존재 ( 야간발열, 체중감소및감염의증거가없는발열 ), 림프절외장기침범, 범혈구감소증, LDH 상승등의증상및징후가나 - 166 -
- 구은주외 6 인. Richter 증후군의 1 예 - 타났을때 Richter 증후군을의심하여야한다 [1]. 양전자방출단층촬영은만성림프구백혈병자체의진단에는큰의미가없지만 Richter 증후군의진단에는중요한검사이다. 다양한부위를침범할수있어침범부위확인및조직검사가능한위치의결정과치료후평가에이용될수있다 [1,6,7]. Standardized uptake value 5 이상의 18F-FDG (18-fluorodeoxyglucose) 섭취를보이는경우 Richter 증후군을강하게의심해볼수있다 [1]. 양전자방출단층촬영의민감도, 특이도, 양성예측도및음성예측도는각각 91%, 80%, 53%, 97% 로나타났다 [1,6]. 본증례에서도새로이나타난다리종괴로부터 Richter 증후군을의심하여양전자방출단층촬영을시행하였으며진단에도움이되었고항암치료시행후완전관해되었음을판정할수있었다. Richter 증후군은주로림프절이나골수를침범하지만드물게림프절외장기를침범하기도한다 [3,8]. Richter 증후군의소화기계침범의예가보고되어있으며림프절침범이있는경우보다좋은예후를보였다 [8]. 그외에도유리체, 포도막, 중추신경계, 코, 피부그리고기관지등을침범한예가보고되었다 [8]. 우리나라에서지금까지 4예의 Richter 증후군이보고되었으며국내에서의발생률은아직정확하게알려져있지않다. 본증례는또한주로전신의피하층, 근육및심근을침범하여발현한경우로발현양상이매우독특하여임상적으로의미있는증례로생각된다. 2006년시행된대규모의한연구에서는 Richter 증후군의예후를예측하는 Richter s transformation score를제시하였다. 다섯개의항목 (Zubrod performance status > 1, LDH 의상승 ( 정상치의 1.5배이상 ), 혈소판수치 < 100 10 3 /mm 3, 종양크기 > 5 cm, 2회이상의이전치료력 ) 을각각 1점으로하여위험인자의개수에따라저위험군, 저-중등도위험군, 고-중등도위험군, 고위험군 ( 각각 0-1, 2,3, 4-5점 ) 으로분류하였으며각각의군에서중간생존기간은 1.12, 0.9, 0.33 그리고 0.2 년이었다 [1,2,7]. Richter 증후군의임상양상은매우공격적이어서항암요법에낮은반응률과불량한결과를보이는것으로알려져있으며현재는 rituximab 을포함한복합항암요법이치료의근간을이루고있다 [7]. 현재까지 rituximab 과 Hyper CVXD (cyclophosphamide, vincristine, liposomal daunorubicin, dexamethasone), Rituximab과 HyperCVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone), OFAR (oxaliplatin, fludarabine, cytarabine, rituximab), R-CHOP 요법등에대한연구가있었으나 반응률은 41-50% 이고평균생존기간은 8개월에서 10개월로만족스럽지못한결과를보여주었으며표준치료는아직없는실정이다 [1]. 항암화학요법으로관해유도후강화요법으로동종조혈모세포이식을시행하여생존율을향상시켰다는보고가있다 [1,7]. 그러나 Parikh 등 [9] 의보고에따르면 Richter 증후군으로진단된환자중 95% 가적극적인복합항암요법치료를받았으나그중동종조혈모세포이식까지진행할수있었던환자는 14% 에불과하였다. 관해유도에실패한환자에게구제요법으로자가조혈모세포이식을시행하였다는보고가있으나역할은명확하지않다 [7]. 최근에는새로개발된 human anti-cd20 monoclonal IgG1k antibody인 ofatumumab 과 CHOP의병합요법을이용한유도치료및유지치료에대한임상연구가진행중이다 [1,10]. 본증례에서도광범위큰B 세포림프종에준해 R-CHOP 요법을사용하고완전관해를획득하였음에도불구하고반응지속기간이 3개월밖에되지않았음을볼때앞으로더효과적이고강력한약제의개발이필요할것으로사료된다. 또한이를위해서는 Richter 증후군의병태생리및발생기전에대한규명및표적치료에대해좀더많은연구와논의가필요할것으로생각된다. 요약 Richter 증후군은만성림프구백혈병이공격적인림프종으로전환되는것을의미한다. Richter 증후군의빈도는 2-10% 정도이며, 동아시아에서는만성림프구백혈병의빈도가드물기때문에국내에서 Richter 증후군이보고된경우는매우드물다. Richter 증후군에서는주로림프절과골수의침범을보이며드물게림프절외장기의침범을보인다. 만성림프구백혈병을진단받은 42세남자환자가 2년 6개월후양쪽허벅지와엉덩이에종괴가만져져서병원을방문하였다. 양전자방출단층촬영에서피하, 근육및심근에 FDG 섭취증가를보였으며조직검사결과광범위큰B세포림프종으로전환된 Richter 증후군으로진단되었다. R-CHOP 항암요법을 6회시행후완전관해되었으나 3개월뒤재발하였다. 본환자는만성림프구백혈병에서광범위큰 B세포림프종으로전환된 Richter 증후군으로진단되었으며피하및근육을침범하는드문경과를보였기에문헌고찰과함께보고하는바이다. 중심단어 : 만성림프구백혈병 ; 광범위큰B세포림프종 - 167 -
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