Korean J Lab Med 2010;30:244-8 DOI /kjlm Case Report Diagnostic Hematology Acquired Amegakaryocytic Thrombocytopenia after Thymec

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1 Korean J Lab Med 21;3:244-8 DOI /kjlm Case Report Diagnostic Hematology Acquired Amegakaryocytic Thrombocytopenia after Thymectomy in a Case of Pure Red Cell Aplasia Associated with Thymoma Ah Ra Cho, M.D. 1, Young Joo Cha, M.D. 1, Hye Ryoun Kim, M.D. 1, Eun Kyung Park, M.D. 2, and Eun-Jong Cha, Ph.D. 3 Departments of Laboratory Medicine 1 and Internal Medicine 2, College of Medicine, Chung-Ang University, Seoul; Personalized Tumor Engineering Research Center (PTERC) 3, College of Medicine, Chungbuk National University, Cheongju, Korea The association of thymoma with pure red cell aplasia has been well documented, but amegakaryocytic thrombocytopenia is not a recognized paraneoplastic syndrome complicating thymoma. We report a case of thymoma-complicated pure red cell aplasia and amegakaryocytic thrombocytopenia in a 73-yr-old woman. Pure red cell aplasia was diagnosed seven months after the detection of thymoma. One year after the diagnosis of pure red cell aplasia and seven months after thymectomy, bone marrow aspiration and biopsy showed an absence of megakaryocytes, marked erythroid hypoplasia with normal myeloid series. A diagnosis of amegakaryocytic thrombocytopenia and pure red cell aplasia was made. Oral steroid maintenance therapy resulted in recovery of platelet count. She has still transfusion-dependant anemia but platelet and neutrophil counts had been maintained in normal range for more than five months, until the last follow-up. We think that autoreactive T cells may induce a clinical autoimmune response even after eradication of thymoma, and aplastic anemia as a late complication following thymectomy was described in previous cases. This patient also has to be under a close observation because of the possibility to evolve into aplastic anemia. (Korean J Lab Med 21;3:244-8) Key Words : Thymoma, Pure red cell aplasia, Amegakaryocytic thrombocytopenia 서 흉선종은종격전부 (anterior mediastinum) 에서발생하는가장흔한종양으로, 발생원인에대하여서는아직잘알려져있지않으며, 중증근육무력증 (myasthenia gravis) 을비롯한여러종류의자가면역과관련된부종양증후군이잘동반되는것이특징적이다 [1, 2]. Received : December 28, 29 Manuscript No : KJLM1-3 Revision received : March 22, 21 Accepted : April 3, 21 Corresponding author : Young Joo Cha, M.D. Department of Laboratory Medicine, Chung-Ang University College of Medicine, Heukseok-dong, Dongjak-gu, Seoul , Korea Tel : , Fax : chayoung@cau.ac.kr *This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( ). ISSN 론 The Korean Society for Laboratory Medicine 순적혈구빈혈은흉선종의부종양증후군으로약 5% 이하의빈도를보이나무거핵구성혈소판감소증 (amegakaryocytic thrombocytopenia) 은흉선종환자에게매우드물며 [3, 4] 특히순적혈구빈혈과무거핵구성혈소판감소증이함께동반된흉선종은국내에서보고된바없다. 최근 73 세여자환자에서흉선종에동반된순적혈구빈혈과함께흉선절제술이후무거핵구성혈소판감소증이발생한증례를경험하였기에문헌고찰과함께보고하는바이다. 증례 73세여자환자가호흡곤란을주소로호흡기내과에내원하였다. 환자는간질성폐질환 (interstitial pulmonary disease) 을진단받았으며이때시행한흉부전산화단층촬영에서우연히흉선종을발견하였다. 일반혈액검사는혈색소 11.8 g/dl, 적혈구용적 35.2%, 총백혈구수 6,35/mL, 혈소판수 418,/mL 로비교적정상수치를보였다. 환자는프레드니솔론용량 4 mg/day 244

Cho AR, et al., Acquired Amegakaryocytic Thrombocytopenia and PRCA with Thymoma 245 로간질성폐질환치료를시작하였으며흉선종은상태가안정화된이후절제하기로하였다. 7개월이후운동성호흡곤란으로응급실에내원하였으며, 일반혈액검사에서혈색소 3.6 g/dl, 적혈구용적 1.

조혈세포계의이형성증은관찰되지않았으며골수로시행한염색체검사는 46, XX로정상이었다. Parvovirus B19 항체검사에서 IgM 음성, IgG 양성이었으며중합효소연쇄반응검사는음성이었다. 간접면역형광법으로시행한항핵항체 (ANA), dsdna는음성이었다. 환자는프레드니솔론 4 mg/day에서 8 mg/day로점차감량시켜복용하고있었으며다른투약복용력은없었다.

2 Cho AR, et al., Acquired Amegakaryocytic Thrombocytopenia and PRCA with Thymoma 245 로간질성폐질환치료를시작하였으며흉선종은상태가안정화된이후절제하기로하였다. 7개월이후운동성호흡곤란으로응급실에내원하였으며, 일반혈액검사에서혈색소 3.6 g/dl, 적혈구용적 1.3%, 총백혈구수 5,49/mL, 혈소판수 253,/mL, 망상적혈구수와교정망상적혈구수는각각.12% 와.3% 로과거와비교하여심한빈혈소견을보였다. 골수검사에서적혈모구계세포는거의관찰되지않았으며과립구계와거핵구계세포는정상적인분포를보였고, 1-2% 의낮은세포충실도를보였다 (Fig. 1A). 조혈세포계의이형성증은관찰되지않았으며골수로시행한염색체검사는 46, XX로정상이었다. Parvovirus B19 항체검사에서 IgM 음성, IgG 양성이었으며중합효소연쇄반응검사는음성이었다. 간접면역형광법으로시행한항핵항체 (ANA), dsdna는음성이었다. 환자는프레드니솔론 4 mg/day에서 8 mg/day로점차감량시켜복용하고있었으며다른투약복용력은없었다. 환자는흉선종과연관된순적혈구빈혈로진단하여흉선종발견 1년만에흉선제거술을실시하였다. 조직소견은흉선상피세포의증식과림프구의침윤이혼재하는 WHO 분류 type AB, Masaoka 임상병기 1기에해당하였으며이후추가치료는시행하지않았다 [5, 6]. 흉선종절제이후에도빈혈의회복은이루어지지않아적혈구수혈로혈색소수치유지하면서외래추적관찰하였다. 순적혈구빈혈발병일년, 흉선종제거 7개월이후말초혈액검사에서혈색소 5.4 g/dl, 적혈구용적 16.1%, 총백혈구수 3,68/ ml, 호중구수 1,44/mL, 혈소판수 46,/mL 로빈혈외에도그전에비해경도의호중구감소증, 저혈소판증이관찰되었다. 골수검사에서는세포충실도는여전히 1-2% 로감소되었으며과립구계세포는정상분포를보였으나적혈모구와거핵구는심하 게감소되었다. 환자는폐렴소견으로항생제 (ceftriaxone, clarithromycin) 를투여하였으며내원 8일째총백혈구수 2,39/ ml, 호중구수 227/mL, 혈소판수 2,/mL 로호중구감소증과저혈소판증은더욱악화되었다. 이후항생제투여이외에다른치료없이혈구감소증은호전되어내원 25일째혈색소 1.2 g/dl, 총백혈구수 4,29/mL, 호중구수 2,883/mL, 혈소판수 161,/mL 로정상화되어환자는퇴원하였다. 퇴원 21일째외래에서시행한일반혈액검사상혈색소 7.5 g/dl, 총백혈구수 3,47/mL, 호중구수 1,711/mL, 혈소판수치 13,/mL 로다시혈소판감소증이보였다. 골수검사상이전과큰변화없이낮은세포충실도 (1-2%) 를보였으며적혈모구계와거핵구는거의관찰할수없었으나과립구계는정상분포를보였다. 환자는순적혈구빈혈외에무거핵구성혈소판감소증을진단할수있었다 (Fig. 1B). 유세포분석으로시행한말초혈액림프구아형검사에서총림프구 (1,239/mL), CD4 T-림프구 (37.4%, 463/mL), CD8 T-림프구 (49.6%, 615/mL) 였으며 CD4/CD8 비율은.75로감소하였다. 면역억제요법으로프레드니솔론 5 mg/day를시작한이후혈소판수치는회복되기시작하여치료 14일에는 141,/mL로회복되었다. 림프구아형검사에서총림프구 (1,469/mL), CD4 T-림프구 (46.6%, 685/mL), CD8 T-림프구 (44.8%, 658/mL) 였고 CD4/CD8 비율은 1.4로증가되었다. 이후 5개월동안혈소판감소증은재발하지않았다. 상기환자는현재프레드니솔론 15 mg/day으로면역억제요법을시행하고있으며적혈구수혈로혈색소수치유지하고있으나호중구와혈소판수치는정상을유지하고있다. 환자의임상경과에따른혈구수변화는 Fig. 2와같다. A B Fig. 1. Bone marrow findings. (A) Hypocellular marrow with erythroid aplasia and adequate megakaryocytes at the diagnosis of pure red cell aplasia (hematoxylin and eosin stain, 4). (B) Hypocellular marrow with erythroid aplasia and megakaryocytic aplasia at the seven months after thymectomy (hematoxylin and eosin stain, 4).

3 246 Korean J Lab Med 21;3:244-8 Prednisolone 4 mg/day 8 mg/day Red cell transfusion 5 mg/day 15 mg/day Thymoma detection Leukocyte 15, 1, 5, /ml Hemoglobin g/dl Platelet /ml PRCA Thymomectomy Months Fig. 2. Peripheral blood findings according to the clinical course. Abbreviation: PRCA, pure red cell aplasia. 고 흉선은흉선상피세포와림프구로이루어졌으며 T-림프구전구세포의분화과정이이루어지는기관이다. 흉선에서대부분의림프구는파괴되나일부는성숙 T-림프구로분화되어혈중이나조직으로이동하게된다 [7]. T-림프구의 CD4, CD8 발현과정중흉선상피세포의자기주조직적합복합체-자기펩티드복합체를강하게인식하는 T-림프구는음성선택 (negative selection) 에의해서제거되며, 복합체를적당한친화력 (affinity) 으로인지하는세포만이양성선택 (positive selection) 되어말초 T-림프구로분화하는과정을거친다 [7]. 흉선종에서는비정상적인흉선상피세포증식으로인한미세환경의변화로림프구- 상피세포상호작용에이상이생기게되며정상적으로는제거되어야할자가항원을공격하는 T-림프구가선택되어분화하게된다 [8]. 비정상적인자가반응 T-림프구의활성화는흉선종의부종양증후군인중증근육무력증, 저감마글로불린혈증, 순적혈구빈혈등의기전으로제시되고있다 [3, 9]. 순적혈구빈혈은골수에서과립구계및거핵구계의성숙이나수에는이상이없이적혈구계의선택적인심한결핍을나타내는혈액질환이며흉선종환자에서약 5% 이하의빈도를보인다 [3]. 그외원인으로서전신홍반루푸스, 류마티스관절염, 혼합결합조직병, 쇼그렌증후군등다양한자가면역질환, 만성림프구성백혈병, 림프종, 파르보바이러스B19 감염, 약물, 적혈구생성인자 (erythropoietin) 의장기간투여등이있다 [3, 9]. 찰 Prednisolone Amegakaryocytic thrombocytopenia 무거핵구성혈소판감소증은골수에서선택적인거핵구의결핍으로인하여혈소판감소증을보이는질환으로서순적혈구빈혈에비해그빈도가매우낮다 [1]. 재생불량빈혈이나골수이형성증후군같은혈액질환에선행되어생기거나자가면역질환, 댕귀열, 선천성풍진, 알코올중독, 비타민B12결핍등과연관되어나타난다 [1]. 흉선종환자에게서는매우드물게보고되며단독, 혹은순적혈구빈혈이선행되어발생하기도한다 [3, 4, 11, 12]. 이러한흉선종과연관된조혈세포감소증의병태생리로가장유력하게제시되는것은앞에서언급한바와같이자가면역기전이다. 활성화된자가반응 T-림프구가조절이잘되지않아골수에서여러단계의조혈세포 ( 조혈줄기세포, 적혈구및거핵구전구세포등 ) 를공격하며, 체외연구에서도적혈구세포군 (erythroid colony) 의생성을방해하는 T-림프구의역할이밝혀진바있다 [9, 11, 13]. 순적혈구빈혈및재생불량빈혈에서말초혈액및골수에서 CD8 림프구증가와 CD4/CD8 비율의감소를보이며면역치료이후에세포수의회복과함께 CD8 림프구의감소, CD4/CD8 비율이다시정상화된보고들은자가면역기전을더욱뒷받침해준다 [13, 14]. 본증례에서도 CD4/CD8 비율은.75로감소하였다가프레드니솔론치료이후 1.4로정상화되는소견을보였다. 이런세포성면역외에도조혈전구세포자체가자가항체의표적이되거나적혈구생성인자, 혈소판생성인자 (thrombopoietin) 등조혈생성인자에관한자가항체등체액성면역또한제시되고있다 [15, 16]. 역시면역치료를함으로서세포수의회복, 항체역가의감소, 조혈생성인자수치의정상화를관찰할수있으며흉선종환자의부검결과다계열조혈방해인자가발견된보고도있다 [3]. 자가면역기전이원인으로생각되는조혈세포감소증에서약물이나바이러스감염에의한경우는면역억제치료가끝난이후에쉽게관해상태를유지하지만흉선종환자는계속적인면역억제를필요로하며또한치료도중이나이후잦은재발을일으킨다 [11]. 혈구감소증의회복은흉선종을제거하더라도 2-3% 에서만일어난다. 흉선종에서이미생성된자가반응 T-림프구가말초로이동하여계속적으로존재하며활성화되기때문이며 [13], 이는면역억제치료에잘듣지않고잦은재발의원인으로생각된다. 흉선종환자에게순적혈구빈혈이아닌다른세포계의감소증은드물며또한일부에서흉선종제거이후늦은합병증으로보고된다 [3, 4, 9, 12]. 순적혈구빈혈이빈도가높은것은자가면역기전에대해적혈구계세포의취약성때문이며이후계속되는자가반응 T-림프구의자극으로인해흉선제거이후에도일부환자에게거핵구또는과립구계감소증이생기는것으로생

4 Cho AR, et al., Acquired Amegakaryocytic Thrombocytopenia and PRCA with Thymoma 247 각된다. 본증례에서도순적혈구빈혈이먼저발병하고흉선제거이후거핵구감소증이생겼으며또한실제흉선종에서재생불량빈혈은흉선제거이후발병한보고들이있어이후재생불량빈혈로진행될가능성또한배제할수없다 [3, 11-14]. 본증례의환자는흉선종제거 7개월째혈소판감소증과호중구감소증을보였고세포충실도가낮아재생불량빈혈의진단기준에합당하였으나이후항생제치료로호전되어다시나타나지않았기때문에순적혈구빈혈과무거핵구성혈소판감소증만을진단하였다. 흉선종과연관된조혈세포감소증치료의표준적요법은정립되어있지않으며수혈, 흉선제거, 면역억제요법, 동종골수이식등이시도되고있다 [11, 12, 17]. 흉선제거나스테로이드, 면역글로불린등일반적인면역억제치료는잘듣지않으며항흉선세포글로불린, 시클로스포린, 시클로포스파마이드등강화된면역억제병합요법이비교적좋은예후를보여준다 [11]. 본증례는흉선종과동반된순적혈구빈혈환자에게흉선종제거이후무거핵구성혈소판감소증이나타난예로스테로이드치료만으로혈소판수치가회복되었다. 환자는간질성폐질환으로인해스테로이드치료를시작하여이후감량시기가순적혈구빈혈발병과일치하여, 우연일지모르나간질성폐질환의면역억제요법이순적혈구빈혈의발병을늦출수있었던하나의요인으로생각된다. 이렇게흉선종에서순적혈구빈혈과무거핵구성혈소판감소증이동반된경우는매우드물며다양한예후를보여준다. 강화된면역억제병합요법으로치료된경우도있으며재생불량빈혈로진행하기도한다 [4, 11, 14]. 본증례는항흉선글로불린, 시클로스포린등강화된면역억제요법없이스테로이드만으로혈소판수치는유지가되고있으나발병도중생긴호중구감소증, 그리고이전사례들을고려해볼때추후재생불량빈혈로진행가능성을생각하여면밀한관찰이필요할것으로사료된다. 요약흉선종환자에게순적혈구빈혈은잘알려진부종양증후군이나무거핵구성혈소판감소증은매우드물게나타난다. 저자들은최근 73세여자환자에서흉선종에동반된순적혈구빈혈과함께흉선절제술이후무거핵구성혈소판감소증이발생한증례를경험하였기에보고하는바이다. 환자는흉선종발견 7개월째순적혈구빈혈이발병하였으며이후흉선종을제거하였다. 순적혈구빈혈발병 1년, 흉선종제거 7개월이후골수에서과립구계는정상분포를보였으나적혈모구와거핵구는거의관찰되지않아 순적혈구빈혈과함께무거핵구성혈소판감소증을진단하였다. 스테로이드치료이후혈소판감소증은호전되었으며현재적혈구수치는수혈로유지되나호중구와혈소판수치는지속적으로정상소견을보이고있다. 흉선종을제거한후에도자가반응 T- 림프구의지속적인자극으로인해조혈세포계의감소증이일어나는것으로생각되며, 흉선종제거이후재생불량빈혈이늦은합병증으로나타난이전보고들이있다. 환자는추후재생불량빈혈로진행가능성을고려하여적극적관찰이필요할것으로사료된다. 감사논문작성에도움을주신박찬정교수님께깊은감사를드립니다. 참고문헌 1. Thomas CR, Wright CD, Loehrer PJ. Thymoma: state of the art. J Clin Oncol 1999;17: Johnson SB, Eng TY, Giaccone G, Thomas CR Jr. Thymoma: update for the new millennium. Oncologist 21;6: Coplu L, Selcuk ZT, Haznedaroglu IC, Dogan R, Gungen Y. Aplastic pancytopenia associated with thymoma. Ann Hematol 2;79: Maslovsky I, Gefel D, Uriev L, Ben Dor D, Lugassy G. Malignant thymoma complicated by amegakaryocytic thrombocytopenic purpura. Eur J Intern Med 25;16: Rosai J, Sobin LH, et al. eds. World Health Organization. Histological typing of tumors of the thymus. 2nd ed. Berlin: Springer-Verlag, 1999: (International histological classification of tumors). 6. Masaoka A, Monden Y, Nakahara K, Tanioka T. Follow-up study of thymomas with special reference to their clinical stages. Cancer 1981;48: Jameson SC, Hogquist KA, Bevan MJ. Positive selection of thymocytes. Annu Rev Immunol 1995;13: Muller-Hermelink HK, Wilisch A, Schultz A, Marx A. Characterization of the human thymic microenvironment: lymphoepithelial interaction in normal thymus and thymoma. Arch Histol Cytol 1997; 6: Ritchie DS, Underhill C, Grigg AP. Aplastic anemia as a late complication of thymoma in remission. Eur J Haematol 22;68: Tristano AG. Acquired amegakaryocytic thrombocytopenic purpura:

5 248 Korean J Lab Med 21;3:244-8 review of a not very well-defined disorder. Eur J Intern Med 25; 16: Ueda K, Matsubara A, Kizuki N, Sato Y, Oka Y, Hosaka T. Successful treatment of acquired pure red cell aplasia and acquired amegakaryocytic thrombocytopenia with anti-thymocyte globulin. Am J Hematol 21;66: Azuno Y and Yaga K. Successful cyclosporin A therapy for acquired amegakaryocytic thrombocytopenic purpura. Am J Hematol 22; 69: Hoffacker V, Schultz A, Tiesinga JJ, Gold R, Schalke B, Nix W, et al. Thymomas alter the T-cell subset composition in the blood: a potential mechanism for thymoma-associated autoimmune disease. Blood 2;96: Spath-Schwalbe E, Arnold R, Flath B, Possinger K. Red cell aplasia and megakaryocytic hypoplasia with elevated counts of CD8-positive lymphocytes after resection of a thymoma responding to cyclosporine. Ann Hematol 1998;76: Nara N. Pure red cell aplasia as an autoimmune-mediated disorder. Intern Med 22;41: Shiozaki H, Miyawaki S, Kuwaki T, Hagiwara T, Kato T, Miyazaki H. Autoantibodies neutralizing thrombopoietin in a patient with amegakaryocytic thrombocytopenic purpura. Blood 2;95: Trisal V, Nademanee A, Lau SK, Grannis FW Jr. Thymoma-associated severe aplastic anemia treated with surgical resection followed by allogeneic stem-cell transplantation. J Clin Oncol 27;25:

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7.Æ¯Áýb71ÎÀ¯È« š J KMA Special Issue Myelodysplastic Syndrome June Won Cheong, MD Yoo Hong Min, MD Department of Internal Medicine, Yonsei University College of Medicine E mail : jwcheong70@yumc.yonsei.ac.kr minbrmmd@yumc.yonsei.ac.kr