Korean J Lab Med 2010;30: DOI /kjlm Original Article Diagnostic Hematology Myelodysplastic Syndrome Mimicking Idiopathic Th

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1 Korean J Lab Med 2010;30: DOI /kjlm Original Article Diagnostic Hematology Myelodysplastic Syndrome Mimicking Idiopathic Thrombocytopenic Purpura Yusun Hwang, M.D. 1, Jung-Won Huh, M.D. 1, Yeung-Chul Mun, M.D. 2, Chu-Myong Seong, M.D. 2, and Wha Soon Chung, M.D. 1 Department of Laboratory Medicine 1, Division of Hematology-Oncology, Department of Internal Medicine 2, Ewha Womans University School of Medicine, Seoul, Korea Background : In patients with isolated thrombocytopenia, but without significant dysplasia, diagnosis of idiopathic thrombocytopenic purpura (ITP) rather than myelodysplastic syndrome (MDS) may be taken into account. It is important to make an accurate diagnosis because different treatments are used for ITP and MDS. The purpose of this study was to investigate the clinical and hematologic features of patients who were initially diagnosed as ITP but had cytogenetic abnormalities. Methods : We retrospectively reviewed cytogenetic studies of 100 patients who were diagnosed as ITP from 2004 to 2009 at Mokdong Hospital of Ewha Womans University based on clinical features and hematologic studies. Bone marrow pathology was re-evaluated based on 2008 WHO classification. Cytogenetic analysis was performed by hr culture of bone marrow aspirates without using mitogens and 20 metaphases were analyzed. Results : Of the 100 patients diagnosed as ITP initially, three patients (3%) had cytogenetic abnormalities. They had no thrombocytopenia-related symptoms and thrombocytopenia was found accidentally. The numbers of megakaryocytes in bone marrow were increased and dysplasia was not found in megakaryocyte, erythroid, and myeloid cell lineages. The proportion of blasts was within normal limits. Clonal chromosomal abnormalities found were der(1;7)(q10;p10), add(9)(q12), or t(7;11)(p22;q12). Presumptive diagnosis of MDS or diagnosis of idiopathic cytopenia of undetermined significance (ICUS) was made according to 2008 WHO classification. During the follow up, disease progression was not found. Conclusions : In patients with suspected ITP, cytogenetic analysis should be done. If specific clonal chromosomal abnormality is found, presumptive diagnosis of MDS has to be considered and close follow up is needed. (Korean J Lab Med 2010;30:105-10) Key Words : Thrombocytopenia, ITP, MDS, Cytogenetics, WHO 서 골수형성이상증후군 (myelodysplastic syndrome, MDS) 은골수계세포들의형성이상 (dysplasia) 과비효율적인조혈로혈구감소증을특징으로하는클론성줄기세포질환이다 [1, 2]. 골수형성이상증후군은말초혈액과골수의모세포비율, 형성이상의정도및형성이상이관찰되는세포계열의수, 환상철적모세포비율등에의해진단하고분류할수있다. 반면, 특발혈소판 Received : June 23, 2009 Manuscript No : KJLM Revision received : February 10, 2010 Accepted : February 10, 2010 Corresponding author : Jung-Won Huh, M.D. Department of Laboratory Medicine, Mokdong Hospital, Ewha Womans University School of Medicine, Mok-dong, Yangcheon-gu, Seoul , Korea Tel : , Fax : JungWonH@ewha.ac.kr 론 감소자색반병 (idiopathic thrombocytopenic purpura) 은면역기전에의해혈소판의파괴가증가되어혈소판감소를초래하며, 골수에서는거대핵세포의수가정상이거나증가되어있고, 각세포계열의형성이상은뚜렷하게관찰되지않는다 [3, 4]. 따라서혈소판감소증환자에서거대핵세포를포함한다른골수계세포들의형성이상이뚜렷하지않은경우는골수형성이상증후군보다는특발혈소판감소자색반병을더의심하게된다. 골수형성이상증후군과특발혈소판감소자색반병은치료방침이서로다르므로두질환을감별진단하는것이중요하며, 특히골수형성이상증후군환자의일부는급성골수백혈병으로진행될수있어조기에정확히진단해야한다. 골수형성이상증후군은 French-American-British (FAB) 에의해처음분류된이후, WHO 2001 분류 [1] 에의해이전의진단기준이여러면에서보완되었지만, 골수형성이상증후군을 105

2 106 Yusun Hwang, Jung-Won Huh, Yeung-Chul Mun, et al. Table 1. Recurring chromosomal abnormalities in the MDS at diagnosis Unbalanced *The presence of these abnormalities as the sole cytogenetic abnormality in the absence of morphologic criteria is not considered definitive evidence for MDS. In the setting of persistent cytopenias of undetermined origin, the other abnormalities shown are considered presumptive evidence of MDS in the absence of definitive morphologic features [2]. 진단하는데여전히어려운경우가있었다. 예를들면, 말초혈액에서혈소판감소증을비롯한혈구감소증은있으나모세포가관찰되지않고골수에서도모세포가 5% 미만이며형성이상이뚜렷하지않을경우골수형성이상증후군을진단하는데어려움이있을수있다. WHO 2008 분류에따르면이와같은환자에서 -5, del(5q), -7, del(7q) 등의특정한염색체이상이동반된경우는추정골수형성이상증후군 (presumptive diagnosis of MDS) 으로진단할수있고, 이외의염색체이상이동반된경우는미결정특발혈구감소증 (idiopathic cytopenia of undetermined significance, ICUS) 으로정의하였다 (Table 1) [2]. 본연구에서는특발혈소판감소자색반병이의심되었으나염색체이상이동반되어골수형성이상증후군으로추정진단하거나미결정특발혈구감소증으로진단한환자들의임상및혈액학적검사소견을알아보고자하였다. 1. 대상 대상및방법 2004년부터 2008년까지이대목동병원에내원한환자의임상소견과혈액학적검사에서특발혈소판감소자색반병이의심되었던 100명의환자의염색체검사를후향적으로검토하였다. 2. 방법 Balanced +8* t(11;16)(q23;p13.3) -7 or del(7q) t(3;21)(q26.2;q22.1) -5 or del(5q) t(1;3)(p36.3;q21.2) del(20q)* t(2;11)(p21;q23) -Y* inv(3)(q21q26.2) i(17q) or t(17p) t(6;9)(p23;q34) -13 or del(13q) del(11q) del(12p) or t(12p) del(9q) idic(x)(q13) 일반혈액검사는 SYSMEX XE-2100 (Sysmex, Kobe, Japan) 을이용하였다. 골수검사는흡인과생검을모두시행하였다. 세포충실도는생검을기준으로판정하였으며, 골수의감별계산은유핵세포 500개를대상으로관찰하였다. 각세포계열의형성이상은 WHO 2008 분류 [3] 에근거하여관찰하였으며, 진단검사의학과의사 2명이판독하여최종판정하였다. 클론성염색체이상을알아보기위한염색체검사는골수흡입액에분열촉진물질 (mitogen) 을첨가하지않고 24-48시간배양후, G- 분염법으로염색하여 20개중기세포를분석하였다. 체질성염색체이상유무를확인하기위해서는말초혈액에 phytohemagglutinin을첨가한후 72 시간배양하여분석하였다. 클론성염색체이상의기준과핵형표기는 International System for Human Cytogenetic Nomenclature 2009 [5] 를따랐다. 결과 1. 빈도임상소견및혈액학적검사에서특발혈소판감소자색반병이의심되었던 100명환자중, 각세포계열의형성이상이뚜렷하지않고염색체이상이관찰된환자는 3명 (3%) 이었다. 2. 임상및혈액학적소견 (Table 2, 3) 1) 증례 1 67세남자 (case No. 1) 가만성폐쇄성폐질환과당뇨로치료받던중혈소판감소증이우연히발견되었다. 혈소판수치가 /ml 정도로유지되었고특별한증상이없어 2년간치료없이지냈다. 항혈소판항체는음성이었고, 골수의형태학적검사에서는거대핵세포의수가증가된것외에특이한소견은관찰되지않았으나 +1,der(1;7)(q10;p10) 염색체이상이관찰되었다. 이는 1q의세염색체증 (trisomy) 과 7q 의결실 (deletion) 을초래하는염색체이상이므로 WHO 2008 분류기준 [2](Table 1) 에의하여, 최종적으로추정골수형성이상증후군으로진단하였다. 혈소판감소증에대한치료없이지냈으며, 12개월뒤빈혈과백혈구감소증이생겼고혈소판감소는더심해졌지만이로인한특별한문제는발생하지않았다. 이후췌장암이발견되었는데더이상추적관찰하지못하였다. 2) 증례 2 58세여자 (case No. 2) 에서우연히혈소판감소증이발견되

3 MDS Mimicking ITP 107 Table 2. Clinical and CBC data in patients with presumptive diagnosis of MDS or ICUS No. Date* Age Sex WBC case (months) (yr) ( 10 9 /L) Differential (%) N L M E B Hb Hct MCV MCH MCHC RDW Plt Blast (g/l) (%) (fl) (pg) (%) (%) ( 10 9 /L) (%) M F M *Months after initial bone marrow study. Abbreviations: ICUS, idiopathic cytopenia of undetermined significance; WBC, white blood cell; N, neutrophil; L, lymphocyte; M, monocyte; E, eosinophil; B, basophil; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; RDW, red cell distribution width; Plt, platelet. Table 3. Bone marrow findings and cytogenetics in patients with presumptive diagnosis or ICUS No. Date case (months) BM cellularity (%) BM blast (%) M:E ratio BM dysplasia E M MK N of megakaryocyte* (/LPF) Fibrosis IPSS Cytogenetics INT-1 46,XY,+1,der(1;7)(q10;p10)[6]/46,XY[14] INT-1 47,XX,+add(9)(q12)[16]/46,XX[4] INT-1 47,XX,+add(9)(q12)[7]/46,XX[6] INT-1 47,XX,+add(9)(q12)[8]/46,XX[12] INT-1 46,XY,t(7;11)(p22;q12)[5]/46,XY[15] * Numbers of megakaryocytes in bone marrow biopsy by low power field microscopy ( 100). Abbreviations: ICUS, idiopathic cytopenia of undetermined significance; BM, bone marrow; M:E ratio, myeloid:erythroid ratio; E, erythroid cell lineage; M, myeloid cell lineage; MK, megakaryocyte lineage; IPSS, International Prognostic Scoring System; INT-1, intermediate-1. 었고, 특발혈소판감소자색반병을의심하여시행한골수검사는이에합당한소견이관찰되었다. 그러나골수의염색체검사에서 +add(9)(q12) 가관찰되었고, 말초혈액염색체검사결과는정상핵형이었으므로, 골수에서클론성염색체이상이관찰된것으로판단하였다. 이는 9p 부위의세염색체증 (trisomy) 을초래하는염색체이상이며, WHO 2008 분류기준 [2](Table 1) 에의하여, 미결정특발혈구감소증으로진단하였다. 9개월후에도골수검사와염색체검사에서는전과동일한소견이관찰되었고특별한증상이없어치료없이지냈다. 이후혈색소수치가 117 g/l로감소하여 10개월부터 danazol 치료를시작하였으며, 18 개월에는혈색소 130 g/l, 혈소판 /L, 백혈구 /L 를유지하고있다. 3) 증례 3 39세남자 (case No. 3) 가기저질환은없었으나 3년전혈소 판수치가낮다는얘기를들은적이있었다. 그동안특별한증상없이지내다가, 소라를먹은후어지럼증이발생하여보존적치료후퇴원하였다. 내원당시에도혈소판감소증이관찰되었고, 항혈소판항체검사는음성이었다. 평균적혈구용적 (mean corpuscular volume) 이증가된것외에말초혈액에특이소견은없었다. 골수의형태학적검사에서는세포충실도가 20% 로나이에비해감소되어있었고, 거대핵세포의수가증가된것외에다른비정상적인소견은관찰되지않아특발혈소판감소자색반병에합당하다고생각하였다. 그러나골수의염색체검사에서 t(7;11)(p22;q12) 비정상핵형이관찰되었다. 체질성염색체이상을배제하기위한말초혈액염색체결과는 46, XY 정상핵형이었다. 따라서환자의골수에서관찰된염색체이상은클론성이상으로판단하였으며, WHO 2008 분류기준 [2] (Table 1) 에의하여미결정특발혈구감소증으로진단하였다. 환자는임상적으로특별한증상이나문제가

4 108 Yusun Hwang, Jung-Won Huh, Yeung-Chul Mun, et al. 없어혈소판감소증에대한치료없이 36개월동안추적관찰중에있다. 고찰혈소판감소증환자에서빈혈이나백혈구감소증이동반되어있지않고, 골수에서각세포계열의형성이상이뚜렷하지않은경우는특발혈소판감소자색반병을의심하게된다. 본연구의환자들에서도골수의형태학적소견만으로는특발혈소판감소자색반병으로생각되었으나, 염색체검사에서클론성을가진비정상핵형이관찰되었다. 단독혈소판감소증과함께거대핵세포의형성이상이 10% 이상관찰되었다면 WHO 2008 기준 [2] 에의하여불응성혈소판감소증을의심할수있다. 그러나본연구에포함된환자들은거대핵세포의형성이상이없었으므로 WHO 2008 진단기준에따라서추정골수형성이상증후군또는미결정특발혈소판감소증으로진단하는것이더합당한것으로생각되었다. 다른연구자들의결과를살펴보면, 골수형성이상증후군으로진단된환자중빈혈이나백혈구감소증없이혈소판감소증이단독으로관찰된환자는 % 로보고하였고, 특히이들환자중 15-27% 는처음에골수형성이상증후군으로진단하지못 하고특발혈소판감소자색반병으로진단하였으며, 비장절제술까지시행한환자들도있었다 [6-8]. 본연구에서는처음에특발혈소판감소자색반병이의심되었던환자의 1% (1/100) 는추정골수형성이상증후군으로진단내릴수있었고, 2% (2/100) 는미결정특발혈구감소증으로진단하였다. 일반적으로특발혈소판감소자색반병인경우여자에서호발하는것으로알려져있는데본연구와다른연구에서특발혈소판감소자색반병과유사하게발병한골수형성이상증후군환자들은남자가더많은경향이있었다 (Table 4). 본연구에서한명환자의경우 (Table 2, case 3) 빈혈은관찰되지않았으나평균적혈구용적이증가된소견을보였는데, 다른증례들에서는평균적혈구용적의증가가뚜렷하지않았다. 다른연구결과에서도특발혈소판감소자색반병처럼발병하는골수형성이상증후군은평균적혈구용적이증가되어있는경향이있다고하였다 [7] (Table 4). 또한다른보고에서는항혈소판항체가양성인경우가흔했는데, 본연구에서는검사를시행한 2명에서모두음성이었다 [8] (Table 4). 항혈소판항체는골수형성이상증후군에서도양성을나타낼수있고, 특발혈소판감소자색반병에서는음성을나타낼수도있으므로, 항혈소판항체의유무로두질환을감별하기는어려울것으로생각한다. 본연구결과에서골수의형태학적검사에서뚜렷한형성이상은관찰되지않았지만, 세 Table 4. Reported cases with MDS mimicking ITP* Case No. Date (months) Age Sex WBC ( 10 9 /L) Hb (g/l) MCV (fl) Plt ( 10 9 /L) Cytogenetics PAIgG IPSS Leukemic transformation Ours M ,XY,+1,der(1;7)(q10;p10) - INT-1 No F ,XX,+add(9)(q12) NT INT-1 No M ,XY,t(7;11)(p22;q12) - INT-1 No Ref F ,XX - Low No M ,XY - Low No M ,XY - Low No F NT 41 46,XX NT Low No NT 55 46,XX,20q M ,XY + INT-1 No ,XY Ref M ,XY + Low No M ,XY,+8 + INT-1 No M ,XY ± Low No *Clonality was demonstrated by cytogenetics, abnormal DNA ploidy of megakaryocytes and skewed pattern of human androgen receptor (HUMARA). Abbreviations: ITP, idiopathic thrombocytopenic purpura; WBC, white blood cell; MCV, mean corpuscular volume; Plt, platelet; PAIgG, platelet-associated IgG; IPSS, International Prognostic Scoring System; INT-1, intermediate-1; NT, not tested.

5 MDS Mimicking ITP 109 포충실도가 20% 정도로연령에비해낮은경향이있었는데, 다른연구에서도세포충실도가낮은경향이있다고하였다 [7]. 이와같이혈소판감소증만있고형성이상이뚜렷하지않은경우, 임상양상이나혈액학적검사만으로는특발혈소판감소자색반병과감별진단이어렵다. 특발혈소판감소자색반병은비클론성의양성혈액질환이고골수형성이상증후군은클론성질환이므로, 클론성이상을검출할수있는세포유전학검사가감별진단하는데도움이될수있다. 한연구결과에따르면, 특발혈소판감소자색반병환자에서염색체이상이관찰되지않는점외에, 다른혈액학적소견은두질환에서유의한차이가없다고보고하였다 [8]. 특발혈소판감소자색반병과비슷한형태로발병하는골수형성이상증후군환자들은주로정상핵형이가장많았고, 8번염색체세염색체증 (trisomy 8) 과 20q 결실이관찰되었던경우도있었다 [7-9] (Table 4). 이들연구에서정상핵형이었던환자들은거대핵세포의비정상적인 DNA ploidy, human androgen receptor (HUMARA) 의비정상결과로클론성이있음을증명하였거나, 골수의추적검사를통해최종적으로골수형성이상증후군으로진단하였다 [7, 8]. 한연구에따르면 20q 결실을단독염색체이상으로가지고있는환자에서혈소판감소증을호소하면서골수검사에서는형성이상이뚜렷하게관찰되지않았으며세포충실도, 거대핵세포수및형성이상이특발혈소판감소자색반병과비교하여차이가없었다고보고하였다 [9]. 따라서 20q 결실을단독염색체이상으로가지고있는환자에서는특발혈소판감소자색반병과비슷한소견을나타낼수있다는점을고려할필요가있다. 특발혈소판감소자색반병과비슷하게발병하는골수형성이상증후군환자의경과나예후에대해서는확실히밝혀져있지않다. 본연구와다른연구의추적관찰결과를살펴보면, 일부환자에서시간이경과됨에따라혈소판감소증외에빈혈과백혈구감소증이추가로발생하였다 [7, 8] (Table 4). 이들환자의 international prognostic scoring system (IPSS) 점수는주로 intermediate-1 (INT-1) 에속하였고백혈병으로진행된환자가드문점으로미루어보아, 불량한예후를보이지는않을것으로추측되나, 더많은환자들을대상으로연구가진행되어야할것이다. 결론적으로특발혈소판감소자색반병이의심되는환자에서도세포유전학결과를확인해야하고, 특이한클론성염색체이상이있는경우는추정골수형성이상증후군진단을고려해야하며, 세심한추적관찰이필요하다. 요약배경 : 단독혈소판감소증환자에서형성이상이뚜렷하지않은경우는골수형성이상증후군보다는특발혈소판감소자색반병을더의심하게되는데, 두질환은치료방침이서로다르므로감별진단하는것이중요하다. 본연구에서는특발혈소판감소자색반병이의심되었으나염색체이상이동반되었던증례들의임상및혈액학적검사소견을알아보고자하였다. 방법 : 2004년부터 2008년까지이대목동병원에서임상소견, 골수의형태학적검사를포함하는혈액학적검사에서, 특발혈소판감소자색반병으로진단되었던 100명환자의염색체검사를후향적으로검토하였다. 골수의병리학소견은 WHO 2008 기준에근거하여다시검토하였고염색체검사는골수흡인액에분열촉진물질을첨가하지않고 24-48시간배양후 20 개중기세포를분석하였다. 결과 : 특발혈소판감소자색반병이의심되었던환자중염색체이상이관찰된환자는 3% (3/100) 이었다. 3명의환자는모두우연히혈소판감소증이발견되었고, 이와연관된임상증상은없었다. 또한골수의형태학적검사에서거대핵세포의형성이상은관찰되지않았고수는증가되어있었다. 그외적혈구계와백혈구계세포의형성이상은관찰되지않았고모세포의비율도정상범위였다. 이들환자는 der(1;7)(q10;p10), add(9)(q12), t(7;11)(p22;q12) 와같은클론성염색체이상이각각관찰되었으며, 최종적으로 WHO 2008 분류기준에의해추정골수형성이상증후군및미결정특발혈구감소증으로진단하였다. 이들환자의추적관찰기간중질환의진행은관찰되지않았다. 결론 : 특발혈소판감소자색반병이의심되는환자에서도세포유전학결과를확인하고, 특이한클론성염색체이상이있는경우추정골수형성이상증후군진단을고려해야하며이후세심한추적관찰이필요하다. 참고문헌 1. Jaffe ES, Harris NL, et al. eds. World Health Organization classification of tumours. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. Lyon: IARC Press, 2001: Swerdlow SH, Campo E, et al. eds. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon: IARC, 2008: Rodeghiero F. Idiopathic thrombocytopenic purpura: an old disease revisited in the era of evidence-based medicine. Haematologi-

6 110 Yusun Hwang, Jung-Won Huh, Yeung-Chul Mun, et al. ca 2003;88: Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D, Arnold DM, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood 2009;113: Shaffer LG and Tommerup N, eds. ISCN 2009: an international system for human cytogenetic nomenclature (2009): recommendations of the International Standing Committee on Human Cytogenetic Nomenclature. Basel: Karger, Menke DM, Colon-Otero G, Cockerill KJ, Jenkins RB, Noel P, Pierre RV. Refractory thrombocytopenia. A myelodysplastic syndrome that may mimic immune thrombocytopenic purpura. Am J Clin Pathol 1992;98: Kuroda J, Kimura S, Kobayashi Y, Wada K, Uoshima N, Yoshikawa T. Unusual myelodysplastic syndrome with the initial presentation mimicking idiopathic thrombocytopenic purpura. Acta Haematol 2002;108: Sashida G, Takaku TI, Shoji N, Nishimaki J, Ito Y, Miyazawa K, et al. Clinico-hematologic features of myelodysplastic syndrome presenting as isolated thrombocytopenia: an entity with a relatively favorable prognosis. Leuk Lymphoma 2003;44: Gupta R, Soupir CP, Johari V, Hasserjian RP. Myelodysplastic syndrome with isolated deletion of chromosome 20q: an indolent disease with minimal morphological dysplasia and frequent thrombocytopenic presentation. Br J Haematol 2007;139:265-8.

7.Æ¯Áýb71ÎÀ¯È« š

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