76 유수진 강수경 서을주외 3 인 증 례 증례 년 3월부터 2001년 3월까지서울중앙병원에서 acml로진단된 4예의현병력, 치료및경과는다음과같으며, 그들의임상소견, 말초혈액및골수검사결과는 Table 2 및 Table 3과같다. Table 1. The per

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1 대한임상병리학회지 : 제 22 권제 2 호 2002 Korean J Clin Pathol 2002; 22: 75-9 진단혈액학 비전형만성골수성백혈병 4 예 유수진 강수경 서을주 박찬정 이규형 * 지현숙 울산대학교의과대학서울중앙병원임상병리학교실, 내과학교실 * Four Cases of Atypical Chronic Myeloid Leukemia Soo Jin Yoo, M.D., Su Gyoung Kang, M.D., Eul Ju Seo, M.D., Chan Jeoung Park, M.D., Kyoo-Hyung Lee, M.D.,* and Hyun Sook Chi, M.D. Departments of Clinical Pathology and Internal Medicine,* University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea Four cases of atypical chronic myeloid leukemia (acml), which were compatible with the FAB guideline for the classification of chronic myeloid leukemia (CML), are presented. All 4 patients showed the onset in old age, leukocytosis with an increase in the number of immature granulocytes, monocytosis, a low basophil count, and a dysgranulopoiesis in the peripheral blood, a negativity of the bcr-abl gene rearrangement, and a hypercellular marrow with marked granulocytic hyperplasia and dyshemopoietic features. Two patients died within 3 months and the other 2 are currently under observation after a partial response to hydroxyurea. acml is known to have a poor therapeutic response and outcome without a blastic crisis. A greater deal of concern regarding acml is required for an accurate diagnosis and classification. (Korean J Clin Pathol 2002; 22: 75-9) Key words : Atypical chronic myeloid leukemia, FAB guideline, bcr-abl negative chronic myeloid leukemia 서 특정원인없이지속적으로말초혈액과골수에서현저한과립구증식및미성숙과립구의증가를보이며전형적인만성골수성백혈병 (chronic myeloid leukemia, CML) 과임상적, 혈액학적소견이유사하지만, bcr-abl 융합유전자를검출할수없는질환군 (bcr-abl(-) CML) 이 5% 내외로존재하는것으로알려져있으며 [1], 이들은여러가지질환군을포함하는것으로생각되어왔다. 접 수 : 2001년 12월 19일 접수번호 : KJCP1557 수정본접수 : 2002년 3월 5일 교신저자 : 박찬정 우 서울시송파구풍납동 서울중앙병원임상병리과 전화 : , Fax: cjpark@amc.seoul.kr 론 FAB group은 Philadelphia염색체및 bcr-abl 융합유전자를나타내며미성숙과립구와호염기구가증가한전형적인만성과립구성백혈병 (chronic granulocytic leukemia, CGL), 호염기구증가가없고, 과립구이형성, 단구증가등을특징으로하는비전형만성골수성백혈병 (atypical chronic myeloid leukemia, acml), 미성숙과립구증가가적으며, 단구증가가저명한만성골수단구성백혈병 (chronic myelomonocytic leukemia, CMML) 의세가지를말초혈액의감별계산, 형태학적차이와골수의적혈구계백분율을이용하여감별하는기준을제시한바있으며 (Table 1)[2, 3], 최근 WHO에서는 acml, CMML, 연소성골수단핵구성백혈병 (juvenile myelomonocytic leukemia, JMML) 의세질환을묶어서골수이형성 / 골수증식성질환 (myelodysplastic/myeloproliferative disorder, MDS/MPD) 으로분류하였다 [4]. 국내에는아직 acml에대한보고가없는바, 본원에서 FAB 기준에준하여 acml에합당한 4예를경험하였기에이를보고하는바이다. 75

2 76 유수진 강수경 서을주외 3 인 증 례 증례 년 3월부터 2001년 3월까지서울중앙병원에서 acml로진단된 4예의현병력, 치료및경과는다음과같으며, 그들의임상소견, 말초혈액및골수검사결과는 Table 2 및 Table 3과같다. Table 1. The peripheral blood and marrow erythroid findings in chronic myeloid leukemia[2] CGL acml CMML Basophil 2% <2% <2% Monocyte <3% 3-10% 3-10% (usually >10%) Granulocytic dysplasia Immature granulocytes* >20% 10-20% 10% Blasts 2% >2% <2% Marrow erythroid cells (usually 15%) *promyelocytes, myelocytes, and metamyelocytes. Abbreviations: CGL, chronic granulocytic leukemia; acml, atypical chronic myeloid leukemia; CMML, chronic myelomonocytic leukemia. 현병력 : 65세여자로 4년전부터항인지질항체증후군으로경구항응고제로치료받던중호흡곤란, 체중감소, 간비종대및백혈구증가증이관찰되었다. 치료및경과 : Hydroxyurea 투여후혈액검사상호전을보이다가, hydroxyurea 용량감소시혈액검사상백혈구수가증가하는양상을보이며, 현재외래에서간헐적인적혈구수혈과 hydroxyurea 치료를지속하며, 부분관해상태를유지한상태로 30개월간추적관찰중이다 (Fig. 1, 2). 증례 2 현병력 : 80세여자로내원 4개월전시행한복부단층촬영상비종대및좌측위혈관주위림프절종대가관찰되었으나치료없이지내던중좌상복부불편감이악화되어비장제거술을받았다. 수술후말초혈액에지속적인백혈구증가와미성숙과립구의출현으로골수검사를시행하였다. Table 2. Clinical and peripheral blood findings and molecular studies of four patients with atypical CML Cases Age (year)/sex 65/F 80/F 49/F 82/M Hepatomegaly Splenomegaly at diagnosis 2 FB* 20 cm 2 FB* 15 cm and the therapeutic response not palpated splenectomy not palpated expired after chemotherapy after chemotherapy Lymphadenopathy Hemoglobin (g/dl) Anisopoikilocytosis Mild Moderate Mild Marked Normoblast (/100 leukocytes) Platelet ( 10 3 / L) Abnormal platelet morphology agranular form giant and agranular form giant and agranular form agranular form Leukocyte (/ L) 50,500 80,900 75,980 78,200 Neutrophils with band form (%) Lymphocyte (%) Monocyte (%) Eosinophil (%) Basophil (%) Immature granulocyte (%) Blast (%) Dysgranulopoiesis (%) Chromosome study with marrow aspirate 46,XX 46,XX 46,XX not tested RT-PCR for BCR/ABL gene rearrangement FISH for BCR/ABL gene rearrangement not tested 500 leukocytes are counted from peripheral blood smear for differential count. *2 finger breath palpated below right costal margin; diameter in sonography; promyelocyte, myelocytes, and metamyelocytes; the proportion of granulocytic cells with hypogranulation and/or bilobed neutrophils from promyelocytes, myelocytes, metamyelocytes, band neutrophils, and segmented neutrophils; Nested reverse transcriptase polymerase chain reaction was performed with marrow aspirates in case 1, 2, and 3 and with peripheral blood cells in case 4; Fluorescence in situ hybridization was performed with bcr/abl dual color probe (Vysis, Downers Grove, IL, USA) on marrow aspirates. 200 interphase cells examined were negative of fusion signal.

비전형만성골수성백혈병 4 예 77 Table 3. The bone marrow findings of 3 patients with atypical CML Cases 1 2 3 Cellularity (%) 100 95 100 M:E ratio 11.2:1 15.7:1 5.8:1 Monocytic series (%) 6.2 4.8 2.

0 Morphology of megakaryocytes Increased Increased Clustered increased micromegakaryocytes micromegakaryocytes and micromegakaryocytes and mononuclear forms mononuclear forms Extent of fibrosis

3 비전형만성골수성백혈병 4 예 77 Table 3. The bone marrow findings of 3 patients with atypical CML Cases Cellularity (%) M:E ratio 11.2:1 15.7:1 5.8:1 Monocytic series (%) Eosinophil (%) Basophil (%) Marrow erythroid cells (%) Megakaryocytes/HPF ( 400) Morphology of megakaryocytes Increased Increased Clustered increased micromegakaryocytes micromegakaryocytes and micromegakaryocytes and mononuclear forms mononuclear forms Extent of fibrosis diffuse focal focal Grade of fibrosis* II I II Dysgranulopoiesis Dyserythropoiesis Dysmegakaryopoiesis *I: a few interstitial fibers, II: intermediate degree between I and III, III: obliterative fibrosis; hypogranularion and abnormal nuclear shape; basophilic stippling, Howell-Jolly bodies, nuclear lobulation, binucleation, and multinucleation; mononuclear form and separated nuclei. Fig. 1. Monocytosis and dysplastic granulocytes in peripheral blood of Case 1 (Wright-Giemsa, 1,000). Fig. 2. Granulocytic hyperplasia with dysgranulopoietic features such as hypogranulation and increased monocytic series in bone marrow aspirate of Case 1 (Wright-Giemsa, 1,000). 치료및경과 : Hydroxyurea 투여로혈액검사상부분관해소견을보였다. Hydroxyurea 투여용량에반비례하는백혈구수증감을보이며현재 20개월간추적관찰중이다. 증례 3 현병력 : 49세여자로 10년전갑상선기능저하진단하에호르몬치료를받다가갑상선호르몬이정상화되어치료를중단하고지내던중, 건강검진상백혈구증가를보여내원하였다. 치료및경과 : Hydroxyurea투여로혈액검사상완전관해소견을보였으나, 골수이식을기다리던중, 진단후 3개월에발생한뇌출혈로사망하였다. 증례 4 현병력 : 82세남자로특이한과거력없이지내던중현기증과피로감을주소로내원하였다. 치료및경과 : 환자및보호자의거부로골수검사및항암화학요법을시행하지못하였고, 지속되는백혈구증가, 빈혈, 혈소판감소및발열, 신부전증상을보이다진단 2개월후사망하였다. 고찰 Costello 등 [5] 의보고에의하면 bcr-abl(-) 인 acml 환자군

4 78 유수진 강수경 서을주외 3 인 은 bcr-abl(+) CML 환자군과비교하여볼때간비종대와림프절종대의빈도, 평균혈색소, 중성구 alkaline phosphatase 값은차이가없으며, 평균발병연령이더높고, 혈액검사상백혈구증가증및미성숙과립구증가가모든환자에서관찰되나, 그수치가더낮고, 호염기구의수는평균 2% 이하로낮은것으로알려져있다. 동일기간본원에서골수검사를시행하여 bcr-abl(+) CML로진단된신환 35예의경우, 진단당시연령이평균 41.1세 (13-73세) 이며, 말초혈액검사상백혈구증가증과함께호염기구가평균 8.2% (1-29%) 로증가되고, 단구는평균 2.2% (0-12%) 이었다. 이에반해, acml로진단된본증례에서는발병연령이 3예가 65세이상, 1예가 49세로더높았고, 4예모두호염기구는 1% 정도로높지않았으며, 단구는 5-13% 로증가되어있었다. 그리고, 4예모두백혈구증가증을보이나말초혈액백혈구수가 50,000-80,900/L로 100,000/L을넘지않아기존의보고와일치하였다 (Table 2)[6]. 말초혈액에서단구는 5-13% 로 bcr-abl (+) CML 35예에서평균 2.2% 인데비해증가되어있었으나, CMML 환자군과달리미성숙과립구증가가현저하였다 [2]. 증례 2의경우말초혈액의미성숙과립구가 4.6% 이고, 아구가 1.0% 로 FAB group이제시한 acml 진단기준에미흡하였다. 이는환자가비장제거술직후여서독성변화를보이는과립구가증가하는등수술후보이는호중구증가증소견이백혈구감별계산결과를변화시킨것으로여겨진다. 골수검사를시행한 3예모두세포충실도와미성숙과립구가증가한면이 bcr-abl(+) CML과유사하였으나, 호염기구의증가가없고, 단구계의증식이있다는점에서차이를보였다. 한편, 3 예에서모두골수의단구가 10% 미만, 적아구가 15% 미만으로 CMML에서의전형적인소견과는다른소견을보였다. 또세환자의골수에서모든세포계열에이형성변화가관찰되어기존의보고와일치하였다 [6]. acml은 Ph염색체외에다른염색체동반빈도가 20-87% 까지높은것으로보고되고있으나, 본원에서골수천자로시행한염색체검사상 3예모두정상핵형만이관찰되었다 [6]. 여러문헌에서 acml의임상적경과는 bcr(+) CML에비해치료에대한반응이나쁘고, 생존기간이짧은것으로보고된바있다 [5, 6]. 많은환자들이 hydroxyurea치료에완전관해보다는부분관해를보이며, 아주드물게아세포기를나타내지만, 대부분은지속적인백혈구증가증과동반된빈혈, 혈소판감소증, 감염, 뇌출혈등으로사망한다고한다 [7-9]. 본증례가운데증례 3과증례 4가각각진단 3개월내에뇌출혈과발열및혈액학적이상소견을보이다가사망하였다. 전형적인 CML과유사하나, bcr-abl 융합유전자가검출되지않는만성골수증식성질환일경우 acml과같은혈액학적소견을보이지않는지면밀히관찰하고이를별도의질환군으로분류하여, 이들의임상적양상및예후에대한고찰이지속적으로이루어져야할것으로생각된다. 요약저자들은 FAB의만성골수성백혈병분류에대한기준에서비전형만성골수성백혈병에합당한 4예를경험하였기에보고하는바이다. 네환자모두고연령에서진단되었으며, 혈액검사에서백혈구수및미성숙과립구의증가와단구증가, 과립구이형성소견을보였으며호염기구의증가가없었고, bcr-abl 융합유전자검사상음성이었으며, 골수검사상 95% 이상의세포충실도를보이고현저한과립구계증식및조혈세포이형성소견을보였다. 두환자는 3개월이내에사망하였으며, 두환자는 hydroxyurea에부분관해소견을보이며추적관찰중이다. 비전형만성골수성백혈병은항암화학요법에반응이저조하고, 생존기간도짧으나, 아세포기의빈도는아주낮아다른임상경과를보이는것으로알려져있다. 앞으로이질환의정확한진단과임상양상의고찰을위하여말초혈액도말및골수검사판독시주의를기울여야할것으로사료된다. 참고문헌 1. 신수, 박성섭, 조한익, 허미나. 중합효소연쇄반응을이용한 bcr-abl 융합유전자의절단위치분석. 대한임상병리학회지 1999; 19: Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick H, et al. The chronic myeloid leukaemias: guidelines for distinguishing chronic granulocytic, atypical chronic myeloid, and chronic myelomonocytic leukaemia. Proposals by the French-American-British Cooperative Leukaemia Group. Bri J Haematol 1994; 87: Oscier DG. Atypical chronic myeloid leukaemia, a distinct clinical entity related to the myelodysplastic syndrome? Brit J Haematol 1996; 92: Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-airlie House, Virginia, November J Clin Oncol 1999; 17: Costello R, Sainty D, Lafage-Pochitaloff M, Gabert J. Clinical and biological aspects of Philadelphia-negative/BCR-negative chronic myeloid leukemia. Leuk Lymphoma 1997; 25: Hernandez JM, del Canizo MC, Cuneo A, Garcia JL, Gutierrez NC, Gonzalez M, et al. Clinical, hematological and cytogenetic characteristics of atypical chronic myeloid leukemia. Ann Oncol 2000; 11: Kurzrock R, Kantarjian HM, Shtalrid M, Gutterman JU, Talpaz M. Philadelphia chromosome-negative chronic myelogenous leukemia without breakpoint cluster region rearrangement: a chronic myeloid leukemia with a distinct clinical course. Blood 1990; 75: Montefusco E, Alimena G, Lo Coco F, De Cuia MR, Wang YZ, Aloe Spiriti MA, et al. Ph-negative and bcr-negative atypical chronic myeloge-

5 비전형만성골수성백혈병 4 예 79 nous leukemia: biological features and clinical outcome. Ann Hematol 1992; 65: Kurzrock R, Bueso-Ramos CE, Kantarjian H, Freireich E, Tucker SL, Siciliano M, et al. BCR rearrangement-negative chronic myelogenous leukemia revisited. J Clin Oncol 2001; 19:

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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