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1 대한내과학회지 : 제 93 권제 1 호 Omalizumab 투여로호전된반복적아나필락시스를보인전신비만세포증 1예 1 서울대학교의과대학서울대학교병원내과, 2 서울대학교알레르기및임상면역연구소, 3 서울대학교의과대학서울대학교병원진단검사의학과 문홍란 1 ㆍ장희준 1 ㆍ이춘근 1 ㆍ김영찬 1,2 ㆍ유신혜 1 ㆍ이동순 3 ㆍ강혜련 1,2 Successful Remission of Recurrent Anaphylaxis after Omalizumab Administration in a Patient with Systemic Mastocytosis Hongran Moon 1, Hee Joon Jang 1, Choon Geun Lee 1, Young-Chan Kim 1,2, Shin Hye Yoo 1, Dong Soon Lee 3, and Hye-Ryun Kang 1,2 1 Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul; 2 Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul; 3 Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea Mastocytosis is a disorder characterized by abnormal mast cell proliferation and accumulation in one or more tissues. It presents in two major variants: cutaneous mastocytosis and systemic mastocytosis. Because the symptoms are related to mast cells, histamine receptor antagonists and leukotriene receptor antagonists are recommended as therapeutic options. Here, we report a 54-year-old male patient with a history of urticaria pigmentosa who presented with recurrent anaphylaxis. His serum tryptase level was 31.7 ng/ml and mast cell infiltration was observed in his bone marrow. He had frequent attacks of anaphylaxis despite treatment with ketotifen, levocetirizine, and montelukast. Symptoms related to systemic mastocytosis were controlled and the patient exhibited no recurrence of anaphylaxis following the introduction of monthly omalizumab injection. Omalizumab can be considered as a treatment option in patients with systemic mastocytosis unresponsive to conventional oral medications. (Korean J Med 2018;93:68-73) Keywords: Mastocytosis, Systemic; Anaphylaxis; Omalizumab 서 비만세포증 (mastocytosis) 은피부를비롯한여러장기에서 론 비만세포의비정상적인증식을보이는질환으로십만명당 3-13명정도발견되는드문질병이다 [1]. 모든인종에서보고되고있지만백인에서보다많이보고되고있다. 우리나라의 Received: Revised: Accepted: Correspondence to Hye-Ryun Kang, M.D., Ph.D. Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea Tel: , Fax: , helenmed@snu.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 - Hongran Moon, et al. Omalizumab for systemic mastocytosis - 경우일부증례보고가있으나정확한유병률은알려져있지않다. 비만세포증의정확한발생기전은알려져있지않으며, 보통주로피부에국한된피부비만세포증 (cutaneous mastocytosis) 과피부외하나이상의장기를침범하는전신비만세포증 (systemic mastocytosis) 으로분류한다. 전신비만세포증은임상경과에따라서서히진행하는비활동성전신비만세포증 (indolent systemic mastocytosis), 혈액계신생물과관련된전신비만세포증 (systemic mastocytosis with associated hematologic neoplasm), 공격성전신비만세포증 (aggressive systemic mastocytosis), 비만세포백혈병 (mast cell leukemia) 으로분류된다 [2]. 전신비만세포증은아직까지완치법이알려져있지않아대증치료를기반으로하는데, 비만세포를활성화시키는상황을피하고, 히스타민수용체길항제, 크로몰린, 항류코트리엔제등을단독혹은병용투여하여비만세포활성화산물에의한증상을조절한다. 전신비만세포증의경우비만세포활성화에따른알레르기증상이나타날수있는데, 아나필락시스로나타날수있으므로이에대비하여휴대용에피네프린을지참하도록교육해야한다 [3]. 국내에서는피부비만세포증및공격성전신비만세포증은보고되었던바있으나, 비활동성전신비만세포증은아직보고된적이없다 [4-6]. 저자들은반복적인아나필락시스로나타난비활동성전신비만세포증을한국인에서최초로확인하였으며치료를위해경구항히스타민제, 항류코트린엔제와휴대에피네프린을처방하였으나반복적으로아나필락시스를보여 omalizumab 을투여하였고아나필락시스발생을효과적으로예방한사례를경험하였기에, 문헌고찰과함께보고하는바이다. 과거력 : 13년전목에발생한다수의반점에대해색소성두드러기 (urticaria pigmentosa) 로진단받았으나별다른증상이없어치료를하지않았다. 5개월전벌에쏘인후실신하였던적이있다. 가족력및사회력 : 알레르기질환가족력은없었고, 음주및흡연력도없었다. 진찰소견 : 응급실도착당시혈압 82/26 mmhg, 맥박 73회 / 분, 호흡수 18회 / 분, 체온 35.6 였으며급성병색을보였고, 의식상태는부르면대답하는정도였다. 호흡음은명료하였으며복부는부드러웠고하지부종은관찰되지않았다. 목에다수의갈색반점이관찰되었으나다리에징후 (Darier s sign) 는나타나지않았다. 검사실소견 : 말초혈액검사에서백혈구 6,550/mm 3, 혈색소 13.6 g/dl, 혈소판 223,000/mm 3, 알칼리인산분해효소 67 IU/L, 아스파르테이트아미노전이효소 / 알라닌아미노전이효소 15/13 IU/L, 칼륨 3.3 mmol/l였다. 혈청트립신분해효소 (tryptase) 는 31.7 ng/ml ( 정상치 < 11.0 ng/ml) 로증가소견을보였다. 갑상선기능검사, 부신피질자극호르몬검사에서특이소견은없었고, 심장초음파검사에서정상심장기능이확인되었다. 벌독알레르기확인을위해시행한혈청특이 IgE 검사에서꿀벌, 호박벌, 말벌에대해양성반응을보였으며 (Table 1), 이밖에다양한알레르겐에대한특이 IgE 항체양성반응을나타내었다 (Table 2). 골수검사및조직면역화학검사 : 피부조직검사에서혈관주위에경도의림프구와호산구침윤이관찰되었으며, CD117 양성인비만세포가관찰되었다. 골수흡인검사에서비만세포가 1.4% 로증가해있었다. 골수조직검사에서악성소견은확인되지않았으며다세포성비만세포군집이확인되었고, 면역화학검사에서 CD25, CD117 양성으로전신비만세포증에 증례환자 : 54세남성주소 : 복통및의식저하현병력 : 집에서갑작스런복통과함께변의를느껴화장실에가던중의식저하를보여응급실로이송되었다. 도착당시아나필락시스로진단하고급속수액공급과함께에피네프린 0.3 mg을근주하였으나혈압이정상화되지않아, 에피네프린 0.3 mg을추가로근주하고생리식염수 2.8 L를급속주입하면서혈압및의식이회복되어 3일후퇴원하였다. Table 1. ImmunoCAP test results for serum specific IgE to bee venom allergens Allergen kua/l Class Honey bee Bumble bee Hornet Wasp Paper wasp Wheat Gluten Omega 5 Gliadin < Apple

- 대한내과학회지 : 제 93 권제 1 호통권제 680 호 2018 - Table 2.

3 - 대한내과학회지 : 제 93 권제 1 호통권제 680 호 Table 2. Multiple Allergen Simultaneous Test (MAST ) results for serum specific immunoglobulin E to common allergens A B Allergen LU/mL Class Total IgE Soy 33 1 Milk 0 0 Egg white 0 0 Crab 7 0 Shrimp 11 0 Peach > Acacia > Ash 52 1 Birch > Willow > Hazel > Japanese cedar > Oak > Poplar > Plane Bermuda > Orchard > Timothy > Rye > Goldenrod > Pigweed > Russian thistle > Dandelion > Mugwort > Ragweed > Alternaria 15 0 Aspergillus 3 0 Cladosporium 5 0 Penicillium 1 0 Cat 0 0 Dog 3 0 Cockroach > House dust mite 3 0 Dermatophagoides farinae 6 0 Dermatophagoides pteronyssinus 0 0 합당한소견을나타내었다 (Fig. 1). KIT 유전자 exon 9, 11, 13, 17에서의미있는돌연변이는검출되지않았다. 치료및경과 : 색소성두드러기에서서서히이행된전신비만세포증으로진단하고휴대용에피네프린, ketotifen 1.38 mg 1일 2회, levocetirizine 5 mg 1일 1회, ranitidine 150 mg 1일 2회경구복용을시작하였다. 이후 3개월동안별다른증상을보이지않아 ketotifen 1.38 mg 단독으로줄였으나한달후벌에쏘인후심한어지러움발생하여응급실을방문하였다. 이후다시 ketotifen, levocetirizine, ranitidine 을유지하였 C Figure 1. Histological findings on bone marrow sections. Multifocal, sharply demarcated infiltrates consisting of a central core of lymphocytes surrounded by mast cells were observed. (A) Hematoxylin and eosin staining, 200. (B) Hematoxylin and eosin staining, 100. (C) Infiltration of spindle-shaped CD25 + mast cells (immunohistochemical staining for CD25, 200). (D) Infiltration of mast cells with CD117 positivity (immunohistochemical staining for CD117, 200). 나, 의식소실을동반한아나필락시스를반복적으로경험하여항류코트리엔제 (montelukast 10 mg 1일 1회 ) 를추가하였다. 그러나이후에도두차례더아나필락시스가발생하여 4개월간네차례아나필락시스성쇼크를경험하였다. 아나필락시스발생전사과, 돈가스, 성분미상의감기약등을먹은병력이있으나, 별다른유발인자없이증상이발생한적도있었다. 평상시밀가루음식을섭취하였을때별다른증상은없었다. 아나필락시스발생횟수가증가하여전신비만세포증의아형이비활동성에서공격성으로이행되었을가능성고려하여골수검사를재시행하였으나악성을시사하는소견은관찰되지않았다. 혈중트립신분해효소수치는이후증상이없는상태에서시행한추적검사에서도 33.7 ng/ml로지속적으로증가되어있었으며항히스타민제, 루코트리엔수용체길항체투여에도불구하고생명을위협하는아나필락시스성쇼크가반복적으로발생하여, 증상예방을위해 omalizumab 투여를결정하였다. 이후 omalizumab 150 mg을월 1회투약하면서 12개월째아나필락시스를포함한비만세포관련증상없이양호한경과를보이고있다. D

4 - 문홍란외 6 인. Omalizumab 으로치료한전신비만세포증 - 고찰비만세포는주로점막에위치하는면역세포로, 한가지이상의조직에과도한비만세포가축적되는비만세포증은어린이들에게서는주로피부에국한되어나타나고청소년기에접어들면저절로소실되지만, 성인의경우전신으로발현되어평생지속되는경우가많다 [7]. 전신비만세포증은가려움증, 구토, 설사, 복통및저혈압을유발할수있으나, 비특이적증상을나타내므로진단이쉽지않아보통증상발생후진단이되기까지 10년이상소요된다 [8,9]. 피부를비롯하여위장관, 림프절, 간, 비장, 골수및골격계가증상발생과관련되어있다. 피부병변은다양한형태로나타날수있는데, 색소성두드러기는비활동성전신비만세포증의 90% 에서관찰된다. 색소성두드러기는작고햇빛에그을린듯한갈색반점이나구진으로나타나는데압력을가해문지를경우병변주위에두드러기와홍반이발생하는다리에징후를보이는것이특징적이다. 이밖에골격계침범으로인한전신통증이나주의력감소, 기억력장애, 짜증 (irritability) 등신경정신증상으로나타나기도한다. 간과비장은흔히침범하나호흡기나내분비계장기, 신장침범은상대적으로드물다. 전신비만세포증환자들은알코올, 아스피린, 곤충자상, 감염또는요오드화조영제에노출되면저혈압을보일수있으므로주의를요한다 [3]. 그러나세균, 곰팡이, 바이러스감염위험은증가하지않는다. 비만세포증의발생은전암유전자 (proto-oncogene) 로비만세포수용체인 KIT (CD117) 의변이와관련이있는데, 소아 의경우에는다양한 KIT 변이가보고되었으나성인전신비만세포증환자에서는대부분 c-kit 유전자의 exon 17번의점돌연변이 (point mutation, D816V) 의유전변형을보이며, 최근에는 RAS 변이도보고된바가있다 [6]. 전신비만세포증은 WHO 진단기준의주진단 1개, 부진단 1개이상에합당하거나, 부진단 3개이상에합당한경우에진단이가능하다 (Table 3). 피부병변에서조직학적으로비만세포증이확인되면골수검사를하여전신비만세포증을감별해야하며, 피부병변이없더라도비만세포관련증상이뚜렷하게있는경우혈청트립신분해효소수치를우선확인하여전신비만세포증의가능성을평가해야한다. 말초혈액에서의 KIT D816V 를확인하는것도전신비만세포증의진단에도움이되며, 골수절편에서 CD117, CD25를발현하는비만세포군집이확인되면진단이가능하다 [10]. 본증례는반복된비만세포관련증상을경험한환자에서기저트립신분해효소수치의상승과골수에서비만세포군집이확인되어전신비만세포증으로확진하였다. 최근벌독 (hymenoptera) 에대한전신과민반응과비만세포증의관련성에대한연구결과들이보고되고있다. 벌독알레르기는벌독항원에대한특이 IgE 형성결과나타나는전형적인 I형과민반응으로알려져있으나, 전신비만세포증환자의경우정상인보다벌독알레르기의빈도가높은것으로알려져있어벌독에의한반복적인아나필락시스를보이는경우비만세포증동반여부를감별해야한다. 379명의벌독에대한전신반응환자를대상으로한연구에서 11.6% 가혈청트립신분해효소기저치의증가소견을보였으며, 이중 65% 에서비만세포의골수침입이관찰되었고, 54.8% 에서 Table 3. WHO criteria for systemic mastocytosis a Major criteria Multifocal, dense infiltrates of mast cells ( 15 in aggregates) detected in sections of bone marrow and/or another extracutaneous organ and confirmed by tryptase immunohistochemistry or other special stains Minor criteria a. In biopsy sections of bone marrow or other extracutaneous organs, more than 25% of the mast cells in the infiltrate are spindle-shaped or have atypical morphology, or of all mast cells in bone marrow aspirates smears, more than 25% are immature or atypical mast cells. b. Detection of an activating point mutation at codon 816 of KIT in bone marrow, blood, or another extracutaneous organ. c. Mast cells in bone marrow, blood, or another extracutaneous organ express CD117 with CD2 and/or CD25. d. Serum total tryptase persistently greater than 20 ng/ml in the absence of an associated clonal myeloid disorder. WHO, World Health Organization. a Diagnosis may be rendered if one major plus one minor or three minor criteria are fulfilled

5 - The Korean Journal of Medicine: Vol. 93, No. 1, KIT 돌연변이가확인된바있다 [3]. 피부증상이없고혈청트립신분해효소기저치가정상이었던벌독아나필락시스성쇼크환자 22명을대상으로한연구에서는 77.3% 가골수에서비만세포증에합당한소견을보였음이보고된바있다 [11]. 본증례의환자또한반복적으로벌독에의한과민반응을보인바있으며, 혈청에서벌독특이 IgE가확인되었다 (Table 1). 벌독아나필락시스환자의경우재발예방을위해벌독면역치료를적극적으로고려해보아야한다. 그러나본증례와같이반복적인벌독아나필락시스를보이는경우기저질환으로전신비만세포증이있는지의심해보아야하겠다. 전신비만세포증은다양한혈액암과감별진단이필요한데, 말초혈액에서혈구감소 (cytopenia) 와트립신분해효소수치의상승이함께확인될경우골수형성이상증후군 (myelodysplastic syndrome), 급성골수성백혈병 (acute myeloid leukemia), 일차성골수섬유증 (primary myelofibrosis) 등의악성혈액질환의가능성을고려해야하며, 호산구증가증이동반될경우에는만성호산구성백혈병 (chronic eosinophilic leukemia) 을감별해야한다 [12]. 서서히진행하는비활동성전신비만세포증은빠른진행을보이는공격성전신비만세포증으로이행할가능성이있다 [7]. 골격계침범소견은피부외장기침범중에서가장흔하게관찰되는데골수침범이가장많으며주요침범부위는늑골, 골반, 대퇴골, 상완골그리고두개골이다. 흔한골격계이상은비만세포에서분비하는물질에의한골다공증 (osteoporosis) 병변이며골경화성 (osteosclerosis) 병변도관찰될수있어매년정기적인골밀도검사를권고한다. 전신비만세포증으로진단된환자일지라도수년간무증상인환자들도다수있다. 히스타민관련증상이있을경우 H1 수용체길항제를투여해볼수있다. 장기간써야하므로졸림이없는 2세대항히스타민제를유지요법으로선호한다. 위장관증상이있는경우 H2 수용체길항제인 ranitidine, cimetidine, famotidine 등을써볼수있다. 또한항류코트리엔제인 montelukast도항히스타민제에추가해볼수있다. 이밖에 FcεRI의교차결합 (cross-linking) 을막아비만세포의활성화를억제하는 cromoglycate가주요치료제로추천되지만 [10] 국내에서는처방이불가능하며, 대신 1세대항히스타민제중비만세포안정화효과를가진 ketotifen 을써볼수있다. 본증례에서 ketotifen, levocetirizine, montelukast 를비롯하여휴대용에피네프린펜을처방하였음에도불구하고생명을위협하는아나필락시스가 4개월동안네차례나반복적 으로발생하여추가치료로 omalizumab을투약하게되었다. Omalizumab은인간 IgE에선택적으로결합하는단클론성항체로알레르기천식치료제로승인된약물이며, 비만세포와호염기구에서의 FCεRI의발현을줄이기도한다 [13]. 따라서 omalizumab은비만세포의활성을줄이며, 히스타민분비를줄여만성두드러기치료에활용이되고있다. 장기침범을보이며 KIT-D816V (Exon17) mutation이없는공격성전신비만세포증의경우, imatinib과같은티로신인산화효소억제제 (tyrosine kinase inhibitor) 혹은세포감소치료제 (cytoreductive agent) 투약을고려해볼수있으나 [14] 본증례와같은비활동성전신비만세포증의경우급격한경과를보이지않기때문에이러한치료제들보다는 omalizumab 으로알레르기증상을조절하는치료를우선적으로고려해볼수있겠다. 전신비만세포증환자에서 omalizumab의치료효과는잘알려져있지않으나반복적인아나필락시스성쇼크가발생한비만세포활성화증후군 (mast cell activation syndrome) 환자에서 omalizumab 치료후완전관해된증례가보고된바있으며 [13], 본증례환자역시 omalizumab 투약후아나필락시스를더이상경험하지않았다. Omalizumab은현재전신비만세포증에승인된치료법은아니지만, 본증례를비롯하여 omalizumab 투약으로증상조절된다수의증례들이보고된바있어 cromoglycate나항히스타민제로조절되지않는전신비만세포증의경우치료약제로 omalizumab을고려해볼수있겠다. 요 저자들은빈번한아나필락시스를보이는환자에서비활동성비만세포증을확진하였으며, omalizumab 으로효과적으로치료하였기에문헌고찰과함께보고하는바이다. 중심단어 : 전신비만세포증 ; 아나필락시스 ; Omalizumab 약 REFERENCES 1. Bonadonna P, Perbellini O, Passalacqua G, et al. Clonal mast cell disorders in patients with systemic reactions to Hymenoptera stings and increased serum tryptase levels. J Allergy Clin Immunol 2009;123: Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid ne

6 - Hongran Moon, et al. Omalizumab for systemic mastocytosis - oplasms and acute leukemia. Blood 2016;127: Bonadonna P, Zanotti R, Müller U. Mastocytosis and insect venom allergy. Curr Opin Allergy Clin Immunol 2010;10: Bae MH, Kim HK, Park CJ, et al. A case of systemic mastocytosis associated with acute myeloid leukemia terminating as aleukemic mast cell leukemia after allogeneic hematopoietic stem cell transplantation. Ann Lab Med 2013;33: Huh EJ, Park SY, Choi SR, et al. Aggressive systemic mastocytosis following ovarian germ cell tumor. Korean J Hematol 2005;40: Park MN, Kim GA, Chey MG, Shim GH. A case of diffuse cutaneous mastocytosis in a newborn. Korean J Perinatol 2014;25: Pardanani A. Systemic mastocytosis in adults: 2017 update on diagnosis, risk stratification, and management. Am J Hematol 2016;91: Valent P. Mastocytosis: a paradigmatic example of a rare disease with complex biology and pathology. Am J Cancer Res 2013;3: Spector MS, Iossifov I, Kritharis A, et al. Mast-cell leukemia exome sequencing reveals a mutation in the IgE mast-cell receptor beta chain and KIT V654A. Leukemia 2012;26: Valent P, Akin C, Escribano L, et al. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest 2007;37: Zanotti R, Lombardo C, Passalacqua G, et al. Clonal mast cell disorders in patients with severe Hymenoptera venom allergy and normal serum tryptase levels. J Allergy Clin Immunol 2015;136: Arredondo AR, Gotlib J, Shier L, et al. Myelomastocytic leukemia versus mast cell leukemia versus systemic mastocytosis associated with acute myeloid leukemia: a diagnostic challenge. Am J Hematol 2010;85: Bell MC, Jackson DJ. Prevention of anaphylaxis related to mast cell activation syndrome with omalizumab. Ann Allergy Asthma Immunol 2012;108: Cardet JC, Akin C, Lee MJ. Mastocytosis: update on pharmacotherapy and future directions. Expert Opin Pharmacother 2013;14:

김범수

김범수 Analysis of Outcomes after Resection of Sarcomatous Hepatocellular Carcinoma Purpose: Sarcomatous hepatocellular carcinoma (HCC) is rare. Therefore, the clinicopathologic characteristics and prognosis