06. In-depthreview-351.hwp

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1 대한내과학회지 : 제 93 권제 4 호 In-depth review 골수증식종양의 2017 년 WHO 진단기준주요변경사항의이해 순천향대학교의과대학부천병원진단검사의학과 장미애 Major Changes to the 2017 Revision of the World Health Organization Classification of Myeloproliferative Neoplasms Mi-Ae Jang Department of Laboratory Medicine and Genetics, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea The World Health Organization (WHO) Classification of Tumors of Haematopoietic and Lymphoid Tissues was recently published in a revised fourth edition. The categories of myeloproliferative neoplasms (MPNs) have not significantly changed since the 2008 fourth edition of the classification; however, newly discovered mutations including CALR and CSF3R and improved characterizations and standardizations of morphological features of some entities, particularly BCR-ABL1-negative MPNs, have impacted the diagnostic criteria of disease entities, increasing the reliability and reproducibility of diagnoses. The 2017 revised edition attempts to incorporate new clinical, prognostic, morphologic, and genetic data that have emerged since the last edition. This article reviews the major changes in the classification and their rationale for MPN classification within the revised 2017 WHO system. (Korean J Med 2018;93: ) Keywords: Essential thrombocythemia; Myeloproliferative disorders; Polycythemia vera; Primary myelofibrosis; World Health Organization 서론골수증식종양 (myeloproliferative neoplasms, MPN) 은하나이상의골수세포 ( 과립구계, 적혈구계, 거대핵세포 ) 가과도하게증식하는클론성조혈모세포혈액질환으로, BCR-ABL1 양성만성골수백혈병 (chronic myeloid leukemia), 만성호중 구백혈병 (chronic neutrophilic leukemia), 진성적혈구증가증 (polycythemia vera), 일차골수섬유증 (primary myelofibrosis), 본태혈소판증가증 (essential thrombocythemia), 미범주만성호산구백혈병 (chronic eosinophilic leukemia, not otherwise specified), 미분류골수증식종양 (MPN, unclassifiable) 을포함한총 7개의세부질환이포함되어있다 [1]. 초기에는특별한증 Correspondence to Mi-Ae Jang M.D., Ph.D. Department of Laboratory Medicine and Genetics, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, 170 Jomaru-ro, Wonmi-gu, Bucheon 14584, Korea Tel: , Fax: , miaeyaho@schmc.ac.kr Copyright c 2018 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 - The Korean Journal of Medicine: Vol. 93, No. 4, 상이없고 (insidious onset) 조혈기능증가로인하여말초혈액혈구와골수세포충실도의증가를보이지만, 단계적으로진행하여질환말기에는골수섬유화, 비효과조혈 (ineffective hematopoiesis) 또는급성모세포기 (acute blast phase) 로진행하여골수부전 (marrow failure) 에이르게된다 [1]. 골수증식종양의진단을위해서세계보건기구 (World Health Organization, WHO) 에서발간하는조혈모세포의악성질환과림프구질환에관한진단기준을주로이용하고있으며, 2008년 WHO 4판이후 9년만인 2017년새개정판이발표되었다 [1]. 2017년 WHO 진단기준은이전 4판의분류체계에서크게벗어나지않으면서 2008년이후새롭게밝혀진임상데이터및골수검체의형태학적소견그리고분자진단표지자등이기존내용에추가되었기때문에개정 4판 (revised fourth edition) 버전으로출간되었다. 새롭게포함된주요변화내용을요약하면다음과같다. 만성골수백혈병의 BCR-ABL1 융합유전자와진성적혈구증가증의 JAK2 유전자, 일차골수섬유증과본태혈소판증가증의 MPL 유전자외에최근 CALR 및 CSF3R 유전자등의새로운분자진단표지자가골수증식종양의진단뿐아니라질환의병태생리를이해하고예후를추정하는데유용한것으로검증되어진단기준에새롭게포함되었다 [2,3]. 통상 필라델피아염색체음성 인전형적인골수증식종양 (philadelphia chromosome-negative classical MPN) 으로불리는세질환 ( 진성적혈구증가증, 본태혈소판증가증, 일차골수섬유증 ) 은최근질환별로골수조직의형태학적소견기준이정립이되었는데이를진단시활용하면질환감별뿐아니라반응성골수세포증가를동반할수있는양성질환을배제하는데유용하여 2017년 WHO 개정진단기준에서는주진단기준 (major criteria) 으로포함되어그중요성이강조되었다 [4-8]. WHO 진단기준의기본원칙은질환을분류할때형태학적 (morphologic) 소견뿐아니라혈액학적 (hematologic), 세포유전학 (cytogenetic), 분자유전학 (molecular genetic) 소견등수집가능한모든데이터를통합 (integrated) 하여진단에이용하는것이다. 골수증식종양을대상으로임상적- 병리학적 (clinicopathological) 특성을분석한최근연구결과들에서도이러한통합적인접근방식이진단의정확성과환자의예후예측가능성을높이는것으로검증되어 2008년이후새롭게밝혀진여러정보가이번개정진단기준에도반영이되어있다 [6-12]. 마지막으로, 2008년 WHO 진단기준에서골수증식종양의세부질환으로포함되어있던비만세포증 (mastocytosis) 은 2017년새로운진단기준부터는고유의임상및병리소견을가지는독립적인질환범주로분리되었다 [1]. 최근건강보험심사평가원의자료를이용하여골수증식종양의국내역학조사를시행한연구결과에따르면각질환의발생률은본태성혈소판증가증, 진성적혈구증가증, 일차골수섬유증순서로인구 10만명당각각평균 2.426명, 1.162명, 0.425명으로보고되었다 [13]. 국내골수증식종양의유병률은지난 10년간약 3.8배증가하였고 [13,14] 유전자변이를표적으로한약제가개발되는등골수증식종양에대한관심또한높아지고있으므로이에본종설에서는 2017년 WHO 개정 4판의진단기준의주요변경사항에대하여질환별로소개하고자한다. 질환별 WHO 개정 4판진단기준소개 BCR-ABL1 양성만성골수백혈병 (chronic myeloid leukemia) 만성골수백혈병은골수세포중특히과립구계세포의증식을특징으로하는조혈모세포혈액질환으로특징적인말초혈액소견 ( 여러성숙단계의백혈구증가, 호염기구와호산구증가, 혈소판은정상이거나혹은증가 ) 을보이면서염색체또는분자진단검사를이용하여 t(9;22)(q34.1;q11.2) 또는 BCR-ABL1 융합유전자를확인하는경우진단이가능하다 [1]. 치료하지않으면처음에는증상이없는만성기 (chronic phase) 에이어서가속기 (accelerated phase), 모세포기 (blast phase) 로진행이되지만, 표적항암제인티로신키나아제억제제 (tyrosine-kinase inhibitor) 가도입되면서가속기또는모세포기로진행하는환자의비율이과거에비하여낮아졌다 [1]. 2017년 WHO 개정 4판에서는만성골수백혈병의가속기진단을위하여이전에통용되어오던여러임상적, 검사실적소견들을정리하여표 1과같이보편화된진단기준으로정립하였다. 다음의여덟가지혈액학적또는세포유전학적기준들, 곧 1) 치료에반응하지않는백혈구수증가 (> /L), 2) 치료에반응하지않는비장비대 (splenomegaly) 악화, 3) 치료에반응하지않는지속적인혈소판수증가 (> 1, /L), 4) 치료에반응하지않는지속적인혈소판수감소 (< /L), 5) 호염기구가말초혈액백혈구의 20% 이상, 6) 모세포가말초혈액백혈구또는골수유핵세포의 10-19% 로증가, 7) 진단시필라델피아염색체이외에추가적인클론성염색체이상 (secondary Philadelphia chromosome, trisomy 8, isochromosome 17q, trisomy 19 또는 complex karyotype 또는 3q26.2 부위이상 ) 이발견되는경우, 8) 치료중어떠한클론성염색체이상이라도새롭게발생하는경우중에서하나이상해당되는

3 - Mi-Ae Jang. WHO revised fourth edition for MPNs - 경우가속기로정의한다. 이외에도골수검체를관찰하였을때형태학적소견상거대핵세포가현저히증식하여군집 (cluster) 이나판 (sheet) 을이루고레티큘린이나콜라겐섬유화가동반되는경우만성골수백혈병의질환가속기를추정하는소견 (presumptive evidence) 으로판단할수있다 (Table 1). 그러나연구에따르면혈액학적또는세포유전학적소견만으로는가속기환자들의다양한질환경과나예후를정확히판단할수없기때문에만성골수백혈병치료에대한반응성 (response-to-therapy) 과연관된기준을추가하는것이유용하다고밝히고있다 [15-17]. 따라서, 2017년 WHO 개정 4판에서는티로신키나아제억제제에대한반응성과관련한세가지잠정적인기준들 (provisional criteria) 을다음과같이새롭게추가하였다. 먼저, 1) 티로신키나아제억제제초치료에완전혈액학적반응 (complete hematologic response) 에도달하지않은경우, 2) 두가지티로신키나아제억제제의순차 (sequential) 치료에도불구하고어떠한치료반응 ( 혈액학적, 세포유전학적, 분자유전학적 ) 에도도달하지않은경우, 또는 3) 티로신키나아제억제제치료중 BCR-ABL1 융합유전자에두가지이상돌연변이가발생한경우중하나이상해당되는경우에는만성기 (chronic phase) 환자라할지라도기능면에서는장기적인예후가나쁘 고무진행생존율 (progression-free survival) 이짧은가속기환자일가능성이크다 (Table 1). 모세포기 (blast phase) 의진단은말초혈액또는골수검체에 20% 이상모세포가관찰되거나또는모세포의골수외침범 (extramedullary accumulation) 이관찰되는경우에진단할수있으며, 이는기존의 2008년 WHO 진단기준과동일하다. 만성호중구백혈병 (chronic neutrophilic leukemia) 만성호중구백혈병은말초혈액에지속적인호중구증가와골수세포충실도증가, 간비장종대를특징으로하는드문골수증식종양으로, BCR-ABL1 융합유전자나반응성호중구증가증 (reactive neutrophilia) 을일으킬수있는동반질환이배제되어야한다. 표 2에정리된 2017년 WHO 개정진단기준에따르면만성호중구백혈병은 1) 말초혈액검사상백혈구수가 /L 이상증가하고, 분엽호중구 (segmented neutrophil) 및대상호중구 (banded neutrophil) 가백혈구수의 80% 이상, 미성숙과립구 ( 전골수구, 골수구, 후골수구 ) 가백혈구의 10% 미만, 골수모세포 (myeloblast) 가거의발견되지않으며, 단구 (monocyte) 의수는 < /L개미만이고과립구형성이상 (dysgranulopoiesis) 이없어야한다. 2) 골수생검소견에서는 Table 1. Defining criteria for the accelerated phase (AP) of chronic myeloid leukemia (CML) CML-AP is defined by the presence of 1 of the following hematological/cytogenetic criteria or provisional criteria concerning response to tyrosine kinase inhibitor (TKI) therapy - Hematological/cytogenetic criteria a - Persistent or increasing high white blood cell count (> /L), unresponsive to therapy - Persistent or increasing splenomegaly, unresponsive to therapy - Persistent thrombocytosis (> 1, /L), unresponsive to therapy - Persistent thrombocytopenia (< /L), unrelated to therapy - 20% basophils in peripheral blood % blasts in peripheral blood and/or bone marrow - Additional clonal chromosomal abnormalities in Philadelphia (Ph) chromosome-positive (Ph+) cells at diagnosis, including so-called major route abnormalities (a second Ph chromosome, trisomy 8, isochromosome 17q, trisomy 19), complex karyotype, and abnormalities of 3q Occurrence of new clonal chromosomal abnormalities in Ph+ cells during therapy Provisional response-to-tki criteria - Hematological resistance (or failure to achieve complete hematological response b ) to the first TKI - Any hematological, cytogenetic, or molecular indications of resistance to two sequential TKIs - Occurrence of two or more mutations in the BCR-ABL1 fusion gene during TKI therapy a Large clusters of sheets of small, abnormal megakaryocytes associated with marked reticulin or collagen fibrosis in biopsy specimens may be considered presumptive evidence of AP, although these findings are usually associated with one or more of the criteria listed above. b Complete hematological response is defined as white blood cell count < /L, platelet count < /L, no immature granulocytes in the differential, and spleen not palpable

4 - 대한내과학회지 : 제 93 권제 4 호통권제 683 호 세포충실도가증가하고호중구비율및수의증가를보이지만호중구의성숙단계는정상이고, 골수모세포가전체유핵세포의 5% 미만이어야한다. 3) 앞서기술된 1), 2) 와유사한혈액학적, 형태학적소견을보일수있는다른골수증식종양인 BCR-ABL1 양성만성골수백혈병, 진성적혈구증가증, 본태혈소판증가증, 또는일차골수섬유증이배제되어야하며, 4) PDGFRA, PDGFRB, FGFR1 및 PCM1-JAK2 유전자재배열이음성이어야한다. 마지막으로 5) CSF3R 유전자의 T618I 돌연변이나또다른 CSF3R 유전자변이가검출되는경우또는 3개월이상지속되는만성적인호중구증가증이있지만반응성증가의원인이없는경우진단할수있다. 새롭게진단기준으로포함된분자진단표지자인 CSF3R 은 colony stimulating factor 3 수용체단백을만드는유전자로과립구의성장과분화에중요한역할을담당한다 [18,19]. 기존에 CSF3R 유전자변이는선천성호중구감소증 (severe congenital neutropenia) 환자에서검출되는것으로도잘알려져있는데, 변이의타입이대부분무의미 (nonsense) 또는틀이동 (frameshift) 변이로단백질의미성숙절단 (premature truncation) 을일으키는기능소실돌연변이인경우가대부분이다 [20], 이에비하여, 만성호중구백혈병환자에서검출되는 CSF3R 유전자변이는엑손 14번위치의 extracellular 도메인위치에서아미노산이바뀌는과오변이 (missense) 형태의기 능획득돌연변이로서 JAK-STAT pathway의지속적인활성화를유도하여과립구계세포의증식을일으킨다. 특히 CSF3R 유전자의 618번째코돈인트레오닌 (threonine) 에서이소류신 (isoleucine) 으로바뀌게되는 CSF3R T618I 돌연변이는연구에따라다소차이가있으나만성호중구백혈병환자의 40-83% 에서검출된다고보고되었다 [18,19]. CSF3R 유전자변이와함께 SETBP1 또는 ASXL1 유전자변이가동시에검출이되는경우가있는데 [18,21-23], 특히 ASXL1 유전자변이와동반되는경우예후가좋지않은것으로알려져있다 [24]. 진성적혈구증가증 (polycythemia vera) 정상적인적혈구생성조절기전과는무관하게적혈구생성이증가되는특징을갖는골수증식종양으로거의모든환자에서 JAK2 V617F 돌연변이 (> 95%) 또는이와기능적으로유사한 JAK2 엑손 12번돌연변이 (< 5%) 가발견되며, 적혈구계뿐만아니라과립구계, 거대핵세포계도함께증식하는범혈구증가증 (panmyelosis) 이특징적이다 [1]. 2017년 WHO 개정 4판에따른진성적혈구증가증의진단기준은표 3에제시된바와같다. 2008년진단기준과비교하여주요차이점으로는 1) 혈색소진단기준이낮아지고 ( 남자의경우 18.5 g/dl에서 16.5 g/dl, 여자의경우 16.5 g/dl에서 16.0 g/dl로변경 ), 적혈구용적률 (hematocrit) 기준이추가되었으며 ( 남자의경우 Table WHO revised fourth edition diagnostic criteria for chronic neutrophilic leukemia 1. - Peripheral blood white blood cell count /L - Segmented neutrophils plus banded neutrophils constitute 80% of white blood cells - Neutrophil precursors (promyelocytes, myelocytes, and metamyelocytes) constitute < 10% of white blood cells - Myeloblasts rarely observed - Monocyte count < /L - No dysgranulopoiesis 2. - Hypercellular bone marrow - Neutrophil granulocytes increased in percentage and number - Neutrophil maturation appears normal - Myeloblasts constitute < 5% of nucleated cells 3. Not meeting WHO criteria for BCR-ABL1-positive chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, or primary myelofibrosis 4. No rearrangement of PDGFRA, PDGFRB, or FGFR1, and no PCM1 JAK2 fusion 5. CSF3R T618I or another activating CSF3R mutation OR Persistent neutrophilia ( 3 months), splenomegaly, and no identifiable cause of reactive neutrophilia including absence of a plasma cell neoplasm or, if a plasma cell neoplasm is present, demonstration of clonality in myeloid cells by cytogenetic or molecular studies WHO, World Health Organization

5 - 장미애. 골수증식종양의 WHO 개정진단기준 - > 49%, 여자의경우 > 48%), 2) 골수조직의형태학적소견이기존에부진단기준 (minor criteria) 에서주진단기준 (major criteria) 으로상향조정되었다. 또한, 3) 과거부진단기준에포함되어있던내인성적혈구콜로니형성 (erythroid colony formation in vitro) 은실제의료현장에서거의활용되고있지않고검사법이표준화되지않은등의이유로새로운진단기준에서는삭제되었다 [1,3]. 실제진성적혈구증가증환자임에도불구하고빈혈을동반하거나적혈구증가정도가경미한단계 (initial, pre-polycythemic phase) 의환자에서혈색소수치가 WHO 진단기준에미치지못하여과소진단되는 (underdiagnosed) 경우를통상 masked 진성적혈구증가증이라고한다 [9,25-27]. 또한심한혈소판증가소견을동반한진성적혈구증가증환자에서 JAK2 돌연변이양성본태성혈소판증가증으로잘못진단되는경우도종종있어질환을정확하게감별할수있는최적의혈색소및적혈구용적률의진단기준을마련하기위한연구가진행되었다 [27,28]. 그결과, 혈색소기준을남자 > 16.5 g/dl, 여자 > 16.0 g/dl, 적혈구용적률기준을남자 > 49%, 여자 > 48% 로적용하였을때진성적혈구증가증과본태혈소판증가증을정확하게진단하는비율은남자 95%, 여자 93% 로높은빈도로확인되어 WHO의새로운진단기준으로포함되었다 [3,27,28]. 흔히필라델피아염색체음성골수증식종양으로불리는진성적혈구증가증, 본태혈소판증가증, 일차골수섬유증질환의골수조직소견에대한다양한임상연구들을이뤄졌으며이를바탕으로각질환별형태학적소견이표준화되었다 [29,30]. 진성적혈구증가증은골수조직의세포충실도가 증가되어있고적혈구생성 (erythropoiesis) 은증가하여큰섬 (islets) 또는판 (sheets) 을이루는형태를보인다. 과립구생성 (granulopoiesis) 은증가되어있지만형태학적으로정상이며, 거대핵세포의생성은증가되어있는데밀집된모양보다는느슨한형태의군집을형성하는경우가흔하며, 다형태성 (pleomorphism) 이있어크기가다양하다 (difference in size) (Table 3). 골수조직의형태학적소견은골수증식종양간의감별진단뿐아니라반응성적혈구증가를동반할수있는양성질환을배제하는데유용하다고입증되어 WHO 개정진단기준에서는주진단기준으로중요성이강조되었다 [3,4]. 일차골수섬유증 (primary myelofibrosis) 일차골수섬유증은골수의거대핵세포와과립구계의뚜렷한증식과함께골수외조혈 (extramedullary hematopoiesis) 을동반한심한골수섬유화를특징으로하는골수증식종양이다 [1]. 환자의약 30% 는진단시무증상또는건강검진에서비장비대소견이나혈액검사에서빈혈, 백혈구증가, 혈소판증가가우연히발견되어진단되는경우가있다. 주요증상은피로감, 호흡곤란, 체중감소, 야간발한, 미열, 악액질 (cachexia) 등을보이며, 골수조혈에의한비장비대 (90%) 와간비대 (50%) 동반이흔하다. 골수섬유화정도는질환이진행되면서초기섬유증전단계 (prefibrotic/early stage) 에서섬유화단계 (fibrotic stage) 로점차심해지는데, 진단당시환자들은이미섬유화단계인경우가대부분이다. 2017년 WHO 개정진단기준에따른일차골수섬유증의진단기준은표 4에제시된바와같다. 섬유화단계의골수조직은 grade 2-3 정도의심한레티쿨린또는콜 Table WHO revised fourth edition diagnostic criteria for polycythemia vera The diagnosis of polycythemia vera requires either all three major criteria OR the first two major criteria plus the minor criterion a Major criteria 1. Elevated hemoglobin > 16.5 g/dl in men, 16.0 g/dl in women OR Elevated hematocrit > 49% in men, > 48% in women OR Increased red blood cell mass > 25% above mean normal predicted value 2. Bone marrow biopsy showing age-adjusted hypercellularity with trilineage growth (panmyelosis), including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes (size differences) 3. Presence of JAK2 V617F or JAK2 exon 12 mutation Minor criterion Subnormal serum erythropoietin level WHO, World Health Organization. a Major criterion 2 (bone marrow biopsy) may not be required in patients with sustained absolute erythrocytosis (hemoglobin concentrations of > 18.5 g/dl in men or > 16.5 g/dl in women and hematocrit values of > 55.5% in men or > 49.5% in women), if major criterion 3 and the minor criterion are both met

6 - The Korean Journal of Medicine: Vol. 93, No. 4, 라겐이침착된섬유화소견이관찰되고비정상적인형태의비정형거대핵세포가큰집단 (clusters or sheets) 을이루는특징을보이며, 골경화 (osteosclerosis) 도동반될수있다 [1]. 가장흔히골수외조혈이일어나는장기는비장으로주로비장적수가팽창되고신생혈관생성이증가하며, 간에서도골수외조혈을볼수있다. 특징적인혈액학적소견으로는말초혈액에눈물방울모양의적혈구를동반한대소부동변형적혈구증가증 (anisopoikilocytosis) 과함께미성숙골수전구세포및백적모세포증 (leukoerythroblastosis) 이관찰되고혈청 lactate dehydrogenase가증가한다 [1]. 이에비하여, 초기섬유증전단계에서는혈소판증가이외에다른특별한이상소견이동반되지않는경우가많다. 특히본태혈소판증가증에서관찰될수있는혈소판수의증가정도와유사하기때문에혈액학적소견만으로는두질환을감별하기가어렵다 [1]. 기존연구에의하면, 본태혈소판증가증으로진단받은 438명의환자들을 WHO 기준으로재분류하였을때 162명의실제본태혈소판증가증이외에나머지는일차골수섬유증의전섬유화단계이거나 (184명) 초기섬유화 (137명 ) 단계였다는보고도있다 [31]. 하지만, 일차골수섬유증은본태혈소판증가증에비하여섬유화단계로진행할가 Table WHO revised fourth edition diagnostic criteria for primary myelofibrosis Stage Prefibrotic/early stage a Overt fibrotic stage a Major criteria Minor criteria 1. Megakaryocytic proliferation and atypia, without reticulin fibrosis grade > 1, accompanied by increased age-adjusted bone marrow cellularity, granulocytic proliferation, and (often) decreased erythropoiesis 2. WHO criteria for CML, PV, ET, MDS, or other myeloid neoplasms are not met 3. JAK2, CALR, or MPL mutation OR Presence of another clonal marker b OR Absence of minor reactive bone marrow reticulin fibrosis 1. Anemia 2. Leukocytosis /L 3. Palpable splenomegaly 4. Increased serum LDH level 1. Megakaryocytic proliferation and atypia, accompanied by reticulin and/or collagen fibrosis grades 2 or 3 2. WHO criteria for ET, PV, CML, MDS, or other myeloid neoplasms are not met 3. JAK2, CALR, or MPL mutation OR Presence of another clonal marker b OR Absence of reactive myelofibrosis 1. Anemia 2. Leukocytosis /L 3. Palpable splenomegaly 4. Increased serum LDH level 5. Leukoerythroblastosis WHO, World Health Organization; CML, chronic myeloid leukemia; PV, polycythemia vera; ET, essential thrombocythemia; MDS, myelodysplastic syndrome; LDH, lactate dehydrogenase; PMF, primary myelofibrosis. a Diagnosis of prefibrotic/early or overt PMF requires that all three major criteria and at least one minor criterion are met. b In the absence of any of the three major clonal mutations, a search for other mutations associated with myeloid neoplasms (e.g., ASXL1, EZH2, TET2, IDH1, IDH2, SRSF2, and SF3B1 mutations) may be of help in determining the clonal nature of the disease. Table 5. Morphological features helpful in distinguishing essential thrombocythemia from prefibrotic/early primary myelofibrosis Morphological feature Essential thrombocythemia Prefibrotic/early primary myelofibrosis Cellularity (age-adjusted) Normal Increased Myeloid-to-erythroid ratio Normal Increased Dense megakaryocyte clusters Rare Frequent Megakaryocyte size Large/giant Variable Megakaryocyte nuclear lobulation Hyperlobulated Bulbous/hypolobulated Reticulin fibrosis, grade 1 a Very rare More frequent WHO, World Health Organization According to WHO grading [36]

7 - Mi-Ae Jang. WHO revised fourth edition for MPNs - Table WHO revised fourth edition diagnostic criteria for essential thrombocythemia The diagnosis of essential thrombocythemia requires that either all major criteria or the first three major criteria plus the minor criterion are met. Major criteria Platelet count /L Bone marrow biopsy showing proliferation mainly of the megakaryocytic lineage, with increased numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei; no significant increase or left shift in neutrophil granulopoiesis or erythropoiesis; very rarely a minor (grade 1) increase in reticulin fibers WHO criteria for CML, PV, PMF, or other myeloid neoplasms are not met JAK2, CALR, or MPL mutation Minor criteria Presence of a clonal marker OR Absence of evidence of reactive thrombocytosis WHO, World Health Organization; CML, chronic myeloid leukemia; PV, polycythemia vera; PMF, primary myelofibrosis. 능성이높고생존율이낮으며진단에따른치료전략이달라감별진단이중요하기때문에 [32,33], 골수검사를시행하여형태학적특징비교를통한감별진단을하는것이매우중요하다 (Table 5) [1,29]. 일차골수섬유증초기섬유증전단계는본태혈소판증가증에비하여세포충실도가높고, 주로증식된세포는호중구와비정형거대핵세포이다. 비정형거대핵세포는초기섬유증전단계에서도뚜렷하게관찰되어본태혈소판증가증과중요한감별기준이되며, 심한비정상형태를취하며골수혈관동과뼈잔기둥주위에집단적으로분포하고 grade 0-1정도의섬유화를나타낸다 (Table 4). 이에비하여, 본태혈소판증가증은특징적인과분엽화된핵과풍부한세포질을가진모양의거대핵세포가증가하고호중구및적혈구생성증가나좌방이동 (left shift) 이없다. JAK2 V617F 변이는일차골수섬유증환자의 50-60% 에서나타나고, 기능적으로유사한 CALR 유전자변이가 30%, MPL 유전자변이가 8% 에서검출된다 [2,34]. JAK2, CALR, MPL 세유전자변이가모두발견되지않는경우 (triple-negative 또는 JAK2/CALR/MPL-wild-type) 는전체환자의약 12% 에서확인되는데그렇지않은환자에비하여예후가좋지않은것으로알려져있다 [2,35]. 본태혈소판증가증 (essential thrombocythemia) 일차적으로거대핵세포계가증식하는골수증식종양으로말초혈액에서지속적인 /L 이상의혈소판증가증과함께골수에서크고성숙한거대핵세포의증가소견이관찰된다. 본태혈소판증가증환자들은대부분긴무증상기를보이나일부에서는혈전증이나출혈경향을나타낼수있다 [1]. 말초혈액에증가된혈소판은크기가다양하고, 드물게위 족 (pseudopod) 또는무과립혈소판과같은이상한형태로관찰될수있다. 골수조직검사에서세포충실도는정상또는중등도로증가되어있고, 특징적인형태학적소견으로크기가크고세포질의양이풍부하며핵은깊게패이고과분엽화되어마치사슴뿔모양처럼보이는성숙한거대핵세포가증식된소견이관찰된다 [1]. 분자유전학적이상으로 JAK2 V617F 돌연변이가환자의 50-60% 에서검출되며, 기능적으로유사한 CALR 유전자변이가 30%, MPL 유전자돌연변이가 3% 에서검출된다 [2,34]. 본태혈소판증가증의 2017년 WHO 개정진단기준은표 6에제시된바와같다. 결론골수증식종양의 2017년 WHO 개정진단기준은가장잘알려진분자유전학적이상인 BCR-ABL1 융합유전자, JAK2 V617F 돌연변이이외에도 MPL 유전자, CALR 유전자, CSF3R 유전자돌연변이등의새로운분자진단지표를포함함으로써질환의병태생리를이해하고진단의정확성을높이는데기여하였다. 이와더불어질환별로골수조직의형태학적소견을정립하고표준화함으로써임상적또는혈액학적소견이서로유사한질환들을감별하고판독자사이에진단일치율도높일수있게되었다. 골수생검은침습적인검사이기때문에과거에는주로임상양상을통한감별진단과혈액학적소견등의비특이적인방법으로골수증식종양을진단하는경우가많았다. 그러나 2017년 WHO 개정진단기준에따라임상적, 혈액학적, 유전학적소견등다양한정보를통합하여진단에이용하고골수검사를시행하여정밀한

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