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1 Korean J Hematol Vol. 44, No. 3, September, 2009 Case Report 원발성자가면역골수섬유증 1 예 가천의과학대학교길병원 1 진단검사의학과, 2 혈약종양내과 박순호 1 ㆍ서일혜 1 ㆍ박필환 1 ㆍ안정열 1 ㆍ송영희 1 ㆍ김정은 1 ㆍ박진희 2 ㆍ김경희 1 A Case of Primary Autoimmune Myelofibrosis Soon-Ho Park, M.D. 1, Yiel-Hea Seo, M.D. 1, Pil-Hwan Park, M.D. 1, Jeong-Yeal Ahn, M.D. 1, Young-Hee Song, M.D. 1, Jung-Eun Kim, M.D. 1, Jinny Park, M.D. 2 and Kyung-Hee Kim, M.D. 1 Departments of 1 Laboratory Medicine, 2 Internal Medicine, Gachon University Gil Hospital, Incheon, Korea Myelofibrosis is usually observed in association with hematologic malignancies or metastatic solid tumors, but it has rarely been reported in patients who suffer with autoimmune disorders. Autoimmune myelofibrosis is a distinct clinicopathologic entity and it can occur alone or in association with autoimmune disorders, and the final result is chronic peripheral cytopenia. Primary autoimmune myelofibrosis, in which the autoimmune myelofibrosis is not preceded by a well-defined autoimmune disease, has recently been defined as a distinct clinicopathologic syndrome. We report here on a case of an 18-year-old woman who was diagnosed with primary autoimmune myelofibrosis, and she manifested peripheral pancytopenia, positivity for autoantibodies and Grade III myelofibrosis without having any preceding autoimmune or hematologic disorders. (Korean J Hematol 2009;44: ) Key Words: Myelofibrosis, Primary, Autoimmune disorder 서론골수섬유증 (myelofibrosis) 은종양세포혹은반응성세포에서합성된섬유소생성시토카인 (cytokine) 에의해골수기질의섬유모세포 (fibroblast) 가자극됨으로써유발되는질병으로서, 1) 골수증식성종양외에급ㆍ만성골수성혈액종양, 림프구성혈액종양및고형종양의골수내전이등을포함한종양성원인에의해일차적혹은이차적으로발생할수있고, 자가면역질환, 바이러스감염등의비종양성원인에의해이차적으로유발될수있다. 2) 비종양성원인중자가면역골수섬유증 (autoimmune myelofibrosis) 은대부분전신홍반루푸스 (systemic lupus erythematosus, SLE) 와같이잘알려진 자가면역질환이나드물게쇼그렌증후군, 피부근염에의해이차적으로발생하며, 원발성골수섬유증 (primary myelofibrosis) 과달리비장종대나클론성염색체이상은나타나지않고, 스테로이드치료에대한반응과예후가좋다고알려져있다. 3-6) 최근 SLE와같은잘알려진자가면역질환의선행없이자가면역골수섬유증이발생하는경우를원발성자가면역골수섬유증 (primary autoimmune myelofibrosis) 이라고하며구별되는임상적, 병리학적특징을갖는증후군으로평가되고있다. 7,9) 저자들은선행자가면역질환이없는환자에서자가면역골수섬유증을경험하였기에간단한문헌고찰과함께보고하고자한다. 접수 :2009 년 6 월 19 일, 수정 :2009 년 9 월 11 일승인 :2009 년 9 월 11 일교신저자 : 김경희, 인천시남동구구월동 1198 번지 , 가천의과학대학교길병원진단검사의학과 Tel: , Fax: khkim74@gilhospital.com Correspondence to:kyung-hee Kim, M.D. Department of Laboratory Medicine, Gachon University Gil Hospital 1198, Guwol-dong, Namdong-gu, Incheon , Korea Tel: , Fax: khkim74@gilhospital.com 157

2 158 Korean J Hematol Vol. 44, No. 3, September, 2009 증례환자 : 18세, 여자주소 : 월경과다, 잇몸출혈과거력및현병력 : 환자는멍이자주드는외에특이병력없었으며내원전약물복용력은없었다. 1개월전월경과다로타병원에서실시한혈액검사에서빈혈, 혈소판감소증이관찰되었고내원하루전부터잇몸출혈이멈추지않아본원응급실을통하여입원하였다. 신체검사 : 결막은창백하였고황달이나두경부림프절종대는없었다. 흉부청진상심음과폐음은정상이었고복부진찰에서간비종대소견은없었고사지에서자반은관찰되지않았다. 검사소견 : 복부컴퓨터단층촬영에서간비종대관찰되지않았고 PET-CT와위내시경검사에서특이소견없었다. 내원당시일반혈액검사에서혈색소 5.7 g/dl, 백혈구 2,860/μL, 혈소판 4,000/μL, 교정망상적혈구수 4.19% 였다 (Table 1). 말초혈액도말검사에서정구성정색소성빈혈과적혈구부동증, 눈물방울적혈구 (tear drop cell), 구상적혈구가관찰되는변형적혈구증및유핵적혈구와골수세포 (myelocyte) 가출현한백적아구증 (leukoerythroblastosis) 이관찰되었고 (Fig. 1A, B) 호산구증가증이나호염기구증가증은관찰되지않았다. 혈청검사에서항카디오리핀항체 (anti-cardiolipin antibody) IgG와 IgM 양성, platelet associated antibody IgG 양성이었고, 류마티스인자 (rheumatoid factor) 는 6.7 IU/mL로정상, 항핵항체와루푸스항응고인자 (lupus anticoagulant) 및항인지질항체 (anti-phospholipid antibody) 는음성이었다 (Table 2). 직접항글로불린검사 (direct antiglobulin test) 양성, LDH 811/IU, CA-125와 CEA 종양표지자검사음성, 유세포분석을이용한발작 야간혈색뇨증검사에서정상소견이었다. 골수검사에서세포충실도정상이면서 (60 90%) 적혈구계와거대핵세포 (megakaryocyte) 증식을보였으나거대핵세포무리나골수이형성은관찰되지않았으며, 림프구증가증이나종양성림프구의침윤은보이지않았다 (Fig. 1C, D). 골수생검에대한레티쿨린 (reticulin) 염색에서산재된거친섬유를동반한미만성섬유망이관찰되고 Masson s trichrome 염색에서아교질 (collagen) 음성으로서 (Fig. 1E, F), modified Bauermeister scale 8) 에따라 Grade 3의골수섬유증으로판단하였다. 골수염색체검사결과정상핵형이었다. 임상경과 : 프레드니솔론 3 mg/kg로치료 40일후일반혈액검사에서혈색소와백혈구수치가정상화되고혈소판수치가호전되었으며, 말초혈액도말에서관찰되던변형적혈구증도감소하였다 (Table 1, Fig. 2A, C). 혈청검사에서항카디오리핀항체 IgG와 IgM 및 platelet associated antibody IgG가음성화되었으나, 직접항글로불린검사는양성이었다 (Table 2). 추적골수검사에서각각 Grade 2 ( 치료 40일째 ) 와 Grade 1 ( 치료 4개월째 ) 의골수섬유증을보였다 (Table 1, Fig. 2B, D). 지속적스테로이드치료 13개월후현재혈액검사소견상진단시보다호전된양상보이며외래추적관찰중이다 (Table 1). 고 골수섬유증은 1879년 Heuck 등에의해처음소개된이래다양한질환과의연관성이알려져있고, 1) 원인은크게종양성과비종양성질환으로나눌수있다. 종양성질환에는급성골수성종양, 골수와연관된림프구성종양, 형질세포질환과악성종양의골수침범등이있다. 2,10) 비종양성원인에는 SLE외에드물게쇼그렌증 찰 Table 1. The changes of CBC, blood smear findings and bone marrow fibrosis after steroid treatment Pretreatment After 40 days After 4 M After 13 M Hgb (g/dl) Hct (%) WBC (/μl) 2,860 4,280 8,480 10,180 Platelet (10 3 /μl) Tear drop cells/hpf* Spherocytes/HPF Leukoerythroblastosis + BM fibrosis Grade 3 Grade 2 Grade 1 NA Abbreviations: M, months; BM, bone marrow; NA, not available. *Under 1,000 magnification, Modified Bauermeister scale.

박순호 외: 원발성자가면역골수섬유증 1예 후군, 피부근염, 원발성담즙성간경변, 궤양성대장염, 3-6,11) 결절성다발동맥염 같은

골수섬유증의 가장 흔한 원인은 골수증식성종양의 하나인 원발성골수섬유증(primary myelofibrosis)으로 Fig. 1.

(A, B) Peripheral blood smears showed marked anisopoikilocytosis with tear

(arrow) and a myelocyte (arrowhead) (Wright-Giemsa stain, 1,000).

myelodysplastic features (W right-giemsa stain, 1,000).

megakaryocytic hyperplasia (Hematoxylin & eosin stain, 400).

3 박순호 외: 원발성자가면역골수섬유증 1예 후군, 피부근염, 원발성담즙성간경변, 궤양성대장염, 3-6,11) 결절성다발동맥염 같은 자가면역질환과 그외바 이러스감염, 신성골이영양증, 비타민D결핍증, 갑상선 159 2,12) 기능이상과도 연관되어 있다고 알려져 있다. 골수섬유증의 가장 흔한 원인은 골수증식성종양의 하나인 원발성골수섬유증(primary myelofibrosis)으로 Fig. 1. Blood and bone marrow findings of the patient at diagnosis. (A, B) Peripheral blood smears showed marked anisopoikilocytosis with tear drop cells and spherocytes, and leukoerythroblastosis with a nucleated RBC (arrow) and a myelocyte (arrowhead) (Wright-Giemsa stain, 1,000). (C) The touch print smear showed erythroid hyperplasia without myelodysplastic features (W right-giemsa stain, 1,000). (D) The bone marrow biopsy section showed normocellularity with erythroid and megakaryocytic hyperplasia (Hematoxylin & eosin stain, 400). (E) The reticulin stain showed diffuse reticulin fiber network with scattered coarse fibers (Reticulin silver stain, 400). (F) trichrome stain (Masson s trichrome stain, 400).

160 Korean J Hematol Vol. 44, No. 3, September, 2009 Table 2.

associated Ab IgG Direct antiglobulin test Rheumatoid factor (IU/mL) Antinuclear antibody Lupus anticoagulant Anti-phospholipid Ab IgG, IgM (U/mL)

4 0 10 Abbreviation: Ab, antibody. Fig. 2.

(A) Mild poikilocytosis with tear drop cells. (B) Fine fiber network throughout most of the section and no coarse fibers.

4 160 Korean J Hematol Vol. 44, No. 3, September, 2009 Table 2. The changes of the results of autoantibodies after steroid treatment Anti-cardiolipin Ab IgG Anti-cardiolipin Ab IgA Anti-cardiolipin IgM Platelet associated Ab IgG Direct antiglobulin test Rheumatoid factor (IU/mL) Antinuclear antibody Lupus anticoagulant Anti-phospholipid Ab IgG, IgM (U/mL) Pretreatment After 40 days Normal value Positive Positive , Positive , Abbreviation: Ab, antibody. Fig. 2. Findings of blood smears and the reticulin stain of bone marrow biopsy in 40 days (A, B) and in 4 months (C, D) after treatment. (A) Mild poikilocytosis with tear drop cells. (B) Fine fiber network throughout most of the section and no coarse fibers. (C) More decreased tear drop cells than those observed in Fig. 2A. (D) Occasional fine individual fibers and foci of a fine fiber network. (A and C, Wright-Giemsa stain, 1,000; B and D, Reticulin silver stain, 400). 종양성 거대핵세포가 platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), basic fibroblast growth factor와 vascular endothelial growth factor (VEGF) 등을 생성하여 골수 기질의 섬 1) 유아세포를 자극하여 발생하며, 환자의 1/3에서 무증 상이고, 증상이 있는 경우에도 피로, 미열, 야간발한,

5 박순호외 : 원발성자가면역골수섬유증 1 예 161 체중감소, 가려움증등비특이적증상을호소하는경우가대부분이다. 그러므로대개우연히시행한일반혈액검사에서이상소견이나말초혈액도말검사에서미성숙과립구와유핵적혈구, 눈물방울적혈구를보이거나신체검사상비장종대를보여추가로시행한확진검사를통해진단되는경우가많다. 13) 자가면역골수섬유증은 1994년 Paquette 등이처음소개하였으며, 골수의섬유화는자가면역질환진행의한양상으로알려져왔다. 자가면역골수섬유증은원발성골수섬유증과비교하여, 조혈장애와더불어특징적인 reticulin과 collagen 다발의증가는있지만, 골수의세포충실도는다양하고거대핵세포무리나골수구계, 적혈구계와거대핵세포의이형성은관찰되지않으며, 호산구증가증이나호염기구증가증도없다. 혈액도말에서눈물방울적혈구나백적아구증이보이기는하나비교적드문편이다. 또한자가면역골수섬유증으로진단하려면골수외조혈과연관된비장비대와골수섬유증의원인이될수있는다른질환은배제되면서, 자가면역질환과연관된혈청학적검사는양성을보여야한다. 14) 2003년 Pullarkat 등 9) 은 SLE나다른자가면역질환의선행없이발생하는자가면역골수섬유증에대해서독립적인임상병리적증후군으로평가하였으며 7개의증례를통하여다음의특징적기준을제시하였다 : (1) Grade 3 또는 4의골수섬유증이있고 (2) 거대핵세포무리나이형성이없으며 (3) 골수구계나적혈구계의이형성이나호산구증가증, 호염기구증가증이없고 (4) 골수의림프구침윤이있으며 (5) 골경화증의증거가없고 (6) 비장종대가없거나경하며 (7) 자가항체가존재하고 (8) 골수섬유증의원인으로알려진다른선행질환이없어야한다. 본증례는선행자가면역질환이없는환자에서범혈구감소증과함께 Grade 3의 reticulin 골수섬유증이관찰되었고거대핵세포와적혈구의증식은있었지만거대핵세포무리나골수이형성을보이지는않았으며, 호산구증가증과호염기구증가증은없었고, 림프구의골수침윤은뚜렷하지않았으며골경화증은관찰되지않았다. 신체검사에서촉지되는림프절이나비장종대가없었고컴퓨터단층좔영에서도비장종대나종양은없었으며 PET-CT에서다른원발성종양의증거가없었다. 환자는 anti-cardiolipin antibody IgG와 IgM, platelet associated antibody IgG, 직접항글로불린검사에서양성을보여 Pullarkat 등이제시한원발성자가면역골수섬유증의기준에서, 림프구침윤을제외한나머지특징 에모두부합하는소견을보였다. 자가면역골수섬유증에서골수섬유화의원인으로자가항체에의해자극을받은반응성골수침윤림프구에서분비된사이토카인을들고있으며, 따라서 Pullarkat 등은원발성자가면역골수섬유증에서도비종양성림프구의골수침윤을특징적양상으로보고진단기준에포함시켰다. 그러나골수섬유증을일으키는사이토카인은림프구뿐만아니라반응성또는종양성거핵구, 혈소판, 단핵구등여러혈액세포에의해서분비되며아직자가면역골수섬유증에서골수섬유화의확실한면역병리학적기전은밝혀지지않은상태이다. 1,8) 본증례에서림프구의침윤은뚜렷하지않았으나, 종양성거핵구증식과는달리이형성이나무리를이루고있지않은반응성거핵구의증가가있었으며이로인해골수섬유증이유발될수있으므로원발성자가면역골수섬유증에합당한것으로보인다. 본증례와비슷한임상및검사소견을보이는질환으로자가항체에의한면역성용혈성빈혈과면역성혈소판감소증을특징으로하는에반증후군 (Evans syndrome) 에서드물게골수섬유증이동반되는경우가있지만, 대부분기저질환으로자가면역질환특히 SLE가동반되며, 용혈성빈혈과혈소판감소증그리고골수섬유증은 SLE의임상경과의한양상으로나타난다. 4) SLE 등의기저질환이없는에반증후군도아주드물게있지만골수섬유증이같이있는보고는없었다. 에반증후군은특정한기전을통해진단하는질환이아니라증상과다른질환을배제하여내리는진단이므로 15) 기저자가면역질환없이골수섬유증이동반된에반증후군은원발성자가면역골수섬유증진단을고려하여야할것이다. 원발성자가면역골수섬유증의치료는코르티코스테로이드에잘반응하며, 불응성이거나부분반응을보일경우면역억제제가치료에사용될수있다. Pullarkat 등이발표한일곱증례에서치료는프레드니솔론 1 mg/kg으로시작하여 1 3개월에걸쳐천천히줄여일곱환자중여섯증례에서일반혈액검사결과가정상화되었으며, 한증례에서는스테로이드에부분반응을보여면역억제제를추가하여좋은효과를보였다. 9) 원발성골수섬유증은특별한치료가없으며증상에따라비장절제술이나화학요법등을시행할수있으나치료의반응과예후가불량하고, SLE와관련된골수섬유증은코르티코스테로이드에잘반응하지않거나고용량의스테로이드나면역억제제에만반응한다고알려져있는것에비해원발성자가면역골수섬유증은보다적은용량의스테로이드치료에도반응이양호함을알

6 162 Korean J Hematol Vol. 44, No. 3, September, 2009 수있다. 본증례는프레드니솔론 3 mg/kg으로치료를시작한지 40일째검사에서혈색소와백혈구수가정상화되었고혈소판수역시진단시보다상승하였으며골수검사에서 Grade 2의골수섬유증으로서진단시보다호전을보여스테로이드에대한치료반응이우수하였으며면역억제제사용은필요하지않았다. 원발성자가면역골수섬유증은현재까지확실한명칭이나진단기준이없고혈액질환의독립적인범주로정립되어있지않은드문질환이며국내에 SLE나류마티스관절염에의한골수섬유증의증례는있으나기저질환이없이발병한경우는보고된적이없다. 본증례와같이골수섬유증이있는환자에서중등도이상의비장종대가없으면서위에서언급한특징적소견을보일경우원발성자가면역골수섬유증을고려하여다른혈액질환, 특히원발성골수섬유증이나 SLE에의한골수섬유증과의감별을통해조기에보다적은용량의코르티코스테로이드를사용함으로써양호한임상반응을기대할수있을것이다. 요 골수섬유증은혈액종양이나전이성고형종양에서주로나타나며자가면역질환에서는드물게나타난다. 자가면역골수섬유증은종양성골수섬유증과는별개의임상적, 병리학적범주로서, 단독으로혹은자가면역질환과연관되어발생하며결과적으로말초혈액의혈구감소증을보인다. 최근자가면역질환의선행없이자가면역골수섬유증이발생하는경우를원발성자가면역골수섬유증이라고하며구별되는임상적-병리학적특징을갖는증후군으로평가되고있다. 저자들은 18 세여자가선행자가면역질환이나혈액질환없이범혈구감소증과자가항체양성을보이며 Grade 3의골수섬유증이관찰되어원발성자가면역골수섬유증으로진단하였기에보고하는바이다. 약 참고문헌 1) Tefferi A. Pathogenesis of myelofibrosis with myeloid metaplasia. J Clin Oncol 2005;23: ) McCarthy DM. Fibrosis of the bone marrow: content and causes. Br J Haematol 1985;59:1-7. 3) Kiss E, Gál I, Simkovics E, et al. Myelofibrosis in systemic lupus erythematosus. Leuk Lymphoma 2000; 39: ) Ramakrishna R, Kyle PW, Day PJ, Manoharan A. Evans' syndrome, myelofibrosis and systemic lupus erythematosus: role of procollagens in myelofibrosis. Pathology 1995;27: ) Marie I, Levesque H, Cailleux N, et al. An uncommon association: Sjögren s syndrome and autoimmune myelofibrosis. Rheumatology 1999;38: ) Muslimani A, Ahluwalia MS, Palaparty P, Daw HA. Idiopathic myelofibrosis associated with dermatomyositis. Am J hematol 2006;81: ) Bass RD, Pullarkat V, Feinstein DI, Kaul A, Winberg CD, Brynes RK. Pathology of autoimmune myelofibrosis. A report of three cases and a review of the literature. Am J Clin Pathol 2001;116: ) Kuter DJ, Bain B, Mufti G, Bagg A, Hasserjian RP. Bone marrow fibrosis: pathophysiology and clinical significance of increased bone marrow stromal fibres. Br J Haematol 2007;139: ) Pullarkat V, Bass RD, Gong JZ, Feinstein DI, Brynes RK. Primary autoimmune myelofibrosis: definition of a distinct clincopathologic syndrome. Am J Hematol 2003;72: ) Kasahara S, Tsurumi H, Yoshikawa T, et al. Plasma cell leukemia with myelofibrosis. J Clin Exp Hematopathol 2008;48: ) Arellano-Rodrigo E, Esteve J, Giné E, Panés J, Cervantes F. Idiopathic myelofibrosis associated with ulcerative colitis. Leuk Lymphoma 2002;43: ) Stéphan JL, Galambrun C, Dutour A, Freycon F. Myelofibrosis: an unusual presentation of vitamin D-deficient rickets. Eur J Pediatr 1999;158: ) Mesa RA, Schwager S, Radia D, et al. The myelofibrosis symptom assessment form (MFSAF): an evidence-based brief inventory to measure quality of life and symptomatic response to treatment in myelofibrosis. Leuk Res 2009;26: ) Paquette RL, Meshkinpour A, Rosen PJ. Autoimmune myelofibrosis. A steroid responsive cause of bone marrow fibrosis associated with systemic lupus erythematosus. Medicine (Baltimore) 1994;73: ) Norton A, Roberts I. Management of Evans syndrome. Br J Haematol 2006;132:

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Jksvs019(8-15).hwp Grade I Grade II Grade III 12 대한혈관외과학회지 : 제 20 권 제 1 호 2004 Control Group A Group B Fig. 4. Microscopic findings of vein wall in control, group A and group B on the day of 7 after venous occlusion. The