대한안과학회지 2013 년제 54 권제 8 호 J Korean Ophthalmol Soc 2013;54(8):1157-1164 pissn: 0378-6471 eissn: 2092-9374 http://dx.doi.org/10.3341/jkos.2013.54.8.1157 = 증례보고 = 안와부속기 MALT 림프종환자에서 R-CVP 복합항암화학요법의치료효과 박성진 1 이원식 3 양재욱 1,2 인제대학교의과대학부산백병원안과학교실 1, 안신생혈관질환치료기술개발센터 2, 인제대학교의과대학부산백병원내과학교실 3 목적 : Ocular Adnexal MALT Lymphoma (OAML) 환자에서 Rituximab, Cyclophosphamide, Vincristine, Prednisolone (R-CVP) 항암요법의치료효과를보고하고자한다. 대상과방법 : 2012 년 1 월부터 2012 년 12 월까지 OAML 로확진된 7 명에게 R-CVP 복합항암화학요법을시행하였다. R-CVP 는 3-4 주간격으로총 6 주기를실시한후 Rituximab R 을 3 주간격으로 2 회추가투여하였다. 반응평가는 3 주기 R-CVP 종료 3 주후에 1 차중간종양평가를시행하고, 6 주기 R-CVP 종료후 3 주에 2 차중간종양평가를시행하며 2 차 Rituximab 투여후 3 주에최종종양반응평가를실시하였다. 결과 : R-CVP 환자 7 명 (8 안 ) 모두에서 1 차중간종양평가에서증세의호전및안와 CT 와 MRI 상에서종양의크기가현저하게줄어들었으며, 6 명의환자에서임상적으로완전반응, 1 명의환자에서부분반응에도달하였다. 항암요법투여중호중구감소증및면역글로불린감소등의혈액학적변화는없었으며, 심각한감염은발생하지않았다. 결론 : OAML 환자에서 R-CVP 병합항암화학요법은고식적국소방사선치료와단독항암화학요법의한계점을극복하고관해율을높일수있는효과적이고안전한치료법으로고려해볼수있다. < 대한안과학회지 2013;54(8):1157-1164> 안와의악성림프종은전체비호지킨림프종의 1-2%, 림프절외림프종의 8% 를차지하고있는질환이다. 1 WHO 분류법에의하면, 안와림프종중 MALT 림프종은가장흔한조직학적유형이며, 2 특히한국인에있어서는서양인에비해전체안와림프종중 MALT 림프종이차지하는비율이높은것으로알려졌다. 3-6 안와 MALT 림프종의예후는비교적양호하지만, 높은임상적병기, 비결막성, 림프절침범, 진단당시양측성인경우등은나쁜예후와관계가있다. 1 한편안와 MALT 림프종의예후가전체적으로양호한것으로평가되더라도기존에사용되는국소방사선치료후의재발률은 0-33% 까지다양하게보고되고있다. 7-11 Received: 2012. 12. 29. Revised: 2013. 3. 26. Accepted: 2013. 6. 25. Address reprint requests to Jae Wook Yang, MD, PhD Department of Ophthalmology, Busan Paik Hospital, #75 Bokji-ro, Busanjin-gu, Busan 614-735, Korea Tel: 82-51-890-8710, Fax: 82-51-890-6329 E-mail: oculoplasty@gmail.com * This study was presented as a narration at the 108th Annual Meeting of the Korean Ophthalmology Society 2012. * This study was supported by a grant from the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare Affairs, Republic of Korea (Grant NO. HI12C0005). 재발의위험성이높은경우, 구후나안와에근접한경우, 또는외안근을직접침범하여충분한양의방사선을조사할수없는경우에는국소적방사선치료보다항암화학요법이선호될수있다. 11 Rituximab 은 mouse/human 키메릭 IgG-kappa 단일클론항체로정상적인그리고악성 B 림프구표면에있는 CD20 항원을공격한다. 이와같은원리를바탕으로근래 CD20 양성악성림프종에대한항암화학요법의치료성적은기존항암화학요법에 Rituximab 을추가함으로써많은향상을보여왔다. 12 따라서본연구에서는 CVP 항암화학치료에 Rituximab 을추가한 R-CVP 복합항암화학요법의유효성을알아보고자하였다. 대상과방법 R-CVP 대상군은 2012년 1월부터 2012년 12월까지 AJCC (American Joint Committee on Cancer) 안와림프종 TNM staging에서 T1N0M0 가아닌 Ann Arbor 제1병기, Ann Arbor 제2병기, 양측결막에침범한 bt1n0m0에해당하는총 7명 (8안) 의환자를대상으로하였고, 그중양측결막에침범한 T1b staging이 1명, 안와를침범한 T2 www.ophthalmology.org 1157
- 대한안과학회지 2013 년제 54 권제 8 호 - staging이 4명, 눈꺼풀을침범한 T3 staging이 2명이었으며, 림프절의침범과전이는없었다. 대상환자의선정조건은 WHO 분류에따라조직학적으로확인된안와 MALT 림프종환자중선행하는치료를받지않은만 18세이상, ECOG performance criteria: 0, 1, 2에해당하는적절한조혈기능, 적절한간기능, 적절한신장기능을가지며생존기대치 (life expectancy) 가최소한 6 개월이상, 폐경후 2년이내혹은가임기여성의경우, 혈청및뇨임신반응검사에서음성, 자필고지동의서 (written informed consent) 에동의한자로하였다. 대상환자의제외조건은 MALT 림프종이외의안와림프종, Ann Arbor stage III 또는 IV인환자, 중추신경림프종환자, 임산부또는수유중인환자, 간기능이상, 신장기능이상, 심각하거나조절이되지않는내과적질환을동반한환자, 현성감염환자, Non-melanoma skin tumor 또는 stage 0 (in situ) cervical carcinoma를제외한악성종양을갖고있거나병력이있는환자, 이미알고있는임상시험약제에대한과민반응을가진환자로하였다. R-CVP 요법은 3-4주간격으로 6회실시하고 6주기 R-CVP 투여후 3주, 6주후 Rituximab 단독요법을 2회추가실시하였다. 반응평가는 3주기항암치료이후 3주에 A 1차중간종양평가를시행하고, 6주기항암치료이후 3주에 2차중간종양평가를시행하며, 3주간격으로 2회 Rituximab 투여후 3주후에최종반응평가를실시하였다. 또한시기와상관없이질환의진행이의심되는경우에평가하였다. 치료기간중모든방문은 3일내시행하였다. 이후재평가및추적관찰은최종반응평가후 3, 6, 9, 12, 16, 20, 24, 30, 36개월째시행하였다. 진단후항암화학요법은다음과같이시행하였다. Rituximab은정맥주사로 375 mg/m 2, Cyclophosphamide는정맥주사로 750 mg/m 2, Vincristine 은정맥주사로 1.4 mg/m 2, Prednisolone은경구로 60 mg/m 2 의용량으로투여하였다. 전체반응률은 Cheson et al 13 에따라평가된완전반응 (complete remission, CR) 또는부분반응 (partial remission, PR), SD (stable disease), PD (progressive disease) 환자의비율로정의하였다 (Table 1). 결과남녀의비는남자 6명, 여자 1명의비율을보였다. 평균나이는 43.9세였으며, 증상발현까지의평균기간은 2개월이었다. 양측결막에침범한 T1b staging이 1명, 안와를침 B C D Figure 1. Right eye shows upper lid swelling, proptosis, conjunctival injection and chemosis (A, B). Upper lid swelling, proptosis, conjunctival injection and chemosis, medial gaze limitation in right eye have markedly decreased after R-CVP infusion (C, D). 1158 www.ophthalmology.org
- 박성진외 : 안와부속기 MALT 림프종에서 R CVP 치료효과 - A Pre-treatment B Post-treatment Figure 2. Coronal MRI scans show enhancing mass in medial aspect (involving conal/intraconal/extraconal spaces) of right orbit (postseptal location). (A) It extends to orbital apex, but there is no evidence of tumor invasion into right optic canal or intracranial extension. After R-CVP infusion, size and enhancement of known orbital MALT lymphoma in right postseptal medial area have moderately decreased. (B) In CT scans no enhancing mass was detected (figure not shown). 범한 T2 staging이 4명, 눈꺼풀을침범한 T3 staging이 2 명이었으며, 림프절의침범과전이는없었다. T2 staging이 57.1% 로가장많은비율을차지하였으며, 그다음이 28.6% 의 T3 staging이었다. 반면 T1 staging은 14.3% 로상대적으로예후가더불량한 T2, T3 staging 이전체의 85.7% 를차지하였다. 양측성으로침범한경우는양측결막에침범한 1명이었다. 평균적인경과관찰기간은 6개월이었고, 8안모두에서재발을보이지않았다. 특징적으로각각의증례모두에서 OAML 발생부위가다름을확인할수있었다. 복합항암화학치료에도불구하고호중구감소증및면역글로불린감소등의혈액학적합병증이나심각한감염은발생하지않았다. 증례 1 43세남자가 4개월전부터발생한우안안구돌출을주소로내원하였다. 특이병력은없었으며, 세극등현미경검사에서우안상안검부종과안구돌출을동반하고결막충혈및부종이심하였다. 최대교정시력은우안 0.8, 좌안 1.0 이었으며, 우안안압은 24 mmhg 였고, 3 mm 안구돌출이있었다. MRD1 (Margin Reflex Distance 1) 이 +2 mm, 우안내측에 -3의안구운동장애가있었고복시는없었다. 안와자기공명영상촬영에서조영증강되는우안안구후측의근원추내, 외를포함하는내측의종괴가관찰되었고, 근육만을침범하고시신경을침범하는소견은없었다. 전신검사를통해안와이외엔침범이없음을확인하였다. 절제생검을통 해 extranodal marginal zone B cell lymphoma of MALT Lymphoma로확진후 R-CVP 항암치료를시작하였다. 투여후 1차중간종양평가에서우안상안검부종및안구돌출, 결막충혈및부종이매우호전되었으며, 추적안와자기공명영상촬영에서조영증강되는종괴의크기가상당히감소하였다. 임상적으로 CR state에이르렀다 (Fig. 1, 2). 증례 2 43세남자가 1개월전부터발생한우안안구돌출과결막충혈을주소로내원하였다. 특이병력은없었으며, 세극등현미경검사에서우안안구돌출과결막충혈과부종을동반하였다. 최대교정시력은우안 0.8, 좌안 1.0 이었으며, 우안안압은 19 mmhg 였고, 5 mm 안구돌출이있었고, 우안하측에 -2, 외측에 -1의안구운동장애가있었고복시는없었다. 안와전산화단층촬영에서중등도의균일하게조영증강되는우안안구후측의분명하게경계지어진높은음영의종괴가관찰되었고, 시신경, 뼈등주변조직을침범하는소견은없었다. 전신검사를통해안와이외엔침범이없음을확인하였다. 절제생검을통해 extranodal marginal zone B cell lymphoma of MALT Lymphoma로확진후 R-CVP 항암치료를시작하였다. 투여후 1차중간종양평가에서우안의안구돌출, 결막충혈및부종이매우호전되었으며, 추적안와전산화단층촬영에서조영증강되는종괴의크기가상당히감소하였다. 임상적으로 CR state에이르렀다 (Fig. 3, 4). www.ophthalmology.org 1159
- 대한안과학회지 2013 년제 54 권제 8 호 - A B C D Figure 3. Right eye shows proptosis, conjunctival injection and chemosis. Down and lateral gaze limitation of right eye is prominent (A, B). Proptosis, conjunctival injection and chemosis, down and lateral gaze limitation in right eye have markedly decreased after R-CVP infusion (C, D). A B Figure 4. Coronal CT scans show sharply defined high density mass with moderate homogenous enhancement in retrobulbar space of right orbit (A). No evidence of adjacent bony erosion or intracranial extension. After R-CVP infusion, markedly decreased extent of homogenous enhancing mass in retrobulbar space of right orbit has seen (B). 증례 3 31세남자가정확한발생시기를알수없는우안눈물언덕부위와양안아래눈꺼풀결막충혈과부종을주소로내원하였다. 특이병력은없었으며, 세극등현미경검사에 서우안눈물언덕부위와양안아래눈꺼풀결막충혈과부종을동반하였다. 최대교정시력은우안 1.0, 좌안 1.0 이었으며, 안와전산화단층촬영에서우안의전중격과근원추외, 하사근의전하측구역에종괴가관찰되었고, 시신경, 뼈등주변조직을침범하는소견은없었다. 전신검사 1160 www.ophthalmology.org
- 박성진외 : 안와부속기 MALT 림프종에서 R CVP 치료효과 - A B C D Right eye Left eye Figure 5. Both eyes show lower conjunctival injection and salmon patch appearance mass-like lesion (A, C). Lower conjunctival injection and chemosis in both eye have markedly decreased after R-CVP infusion. In CT and MRI scans, no visualization of discrete mass lesion in both orbits and periorbital (B, D). Table 1. Demographics and clinical characteristics in patients treated with R-CVP diagnosed with ocular adnexal MALT lymphoma Case Sex/ Age Clinical menifestations 1 M/39 Lower lid swelling Conjunctival injection 2 M/43 Proptosis, (3 mm) Upper lid swelling EOM limitation : -3 at medial 3 M/43 Proptosis, (5 mm) EOM limitation : -2 at down, -1 at lateral Laterality Site (lesions) Median period between symptom apprearance and first clinic visit (month) Staging Final response Complications Follow up (month) OS Orbit 1 II CR Peripheral neuropathy (tingling sensation) 9 OD Eyelid 4 III CR URI Sx 7 OD Eyelid 1 III CR Peripheral neuropathy (tingling sensation) 8 OS Orbit 1 II CR - 5 4 M/51 Lower lid swelling Conjunctival injection 5 M/31 Lower conjunctival injection OS Orbit 3 II CR URI Sx 4 Lower lid swelling 6 F/53 Upper lid drooping and swelling OU Conjunctiva 3 I CR - 6 7 M/47 Upper lid swelling OD Orbit 1 II PR - 3 EOM limitation : -1.5 at up, -1 at medial EOM = extraocular muscle; CR = complete remission; PR = partial remission; URI = upper respiratory infection. 를통해안와이외엔침범이없음을확인하였다. 절제생검을통해 extranodal marginal zone B cell lymphoma of MALT Lymphoma로확진후 R-CVP 항암치료를시작하였다. 투여후 1차중간종양평가에서우안결막충혈및부종이매우호전되었으며, 추적안와전산화단층촬영에서조영증강되는종괴의크기가상당히감소하였다. 임상적으로 CR state에이르렀다 (Fig. 5). 고찰 비호지킨림프종 (non-hodgkin s lymphoma, NHL) 은 40% 에서림프절외에서발생하며그중 5-14% 가안와에발생한다. 14 안와의종양중 10-20% 이상이림프구성이며이중림프종이가장흔하다. 15 안와와안와부속기비호지킨림프 종의대부분은 extranodal marginal zone B-cell lymphoma (EMZBL) of the mucosa associated lymphoid tissue (MALT) 이다. 안와부속기 MALT 림프종은눈꺼풀, 안와, 눈물샘또는결막에서기원하여서서히커지는병변으로나타나며, 일반적으로통증을동반하지않고, 안검하수, 안구돌출, 복시등을일으킬정도로크기가커지지않는이상시력저하를야기하지는않는다. 14,16 전신적침범없이국소적이며, 무증상의경과를보이며안와에국한되었을때국소방사선치료로충분히조절될수있고, 이는장기간의효과와함께높은국소적조절능력을제공하였다. 11 그러나방사선치료는흔히중등도의피부반응과결막염, 안구건조증등의급성안과적독성반응뿐만아니라백내장, 허혈성망막병증, 녹내장, 각막궤양, 코눈물길폐쇄등의후기합병증또한일으키며, 환자들의 50% 에서백내장이, www.ophthalmology.org 1161
- 대한안과학회지 2013 년제 54 권제 8 호 - 20-40% 에서안구건조증이발생했다는보고가있었다. 11,17 본원에서시행했던국소방사선치료에대한연구에서도급성합병증으로경미한피부염이가장흔하게발생 (36명) 하였으며, 안구건조증 (10명), 각막미란 (5명) 등도생겼다. 또한만성합병증으로안구건조증 (28명), 눈물소관폐쇄 (17명), 백내장 (8명), 망막병증 (4명), 눈썹소실 (1명) 등이발생하였는데, 특히눈물소관폐쇄는눈물흘림을유발하여 2차적인눈물길수술이필요할수있으며, 젊은시기에빠르게진행하는백내장, 망막병증으로인한시력소실등은환자의삶의질을저하시키는매우심각한합병증으로볼수있다. 그에비해 R-CVP 군에서는이러한급성또는만성합볍증의발생이적었고, 이를통해 R-CVP의치료효과를확인할수있었다. 그동안의연구들은 Ann Arbor staging system을바탕으로하고있는데, 이에따르면안와림프종환자들의 3분의 2가모두 stage IE에속하기때문에해부학적인위치, 주변조직으로의침습여부, 다발성, 양측성등에기초한예후를정확하게평가할수없었다. 18 그결과방사선치료후재발률은논문에따라 0-33%, 6-50% 까지다양하게보고되고있으며특히파종성재발이 17% 의환자에서보고된경우가있었다. 본원연구의경우평균 4500 cgy 의국소방사선치료후 28.6% 의재발률을보였고, 또한비결막조직에침범한경우는재발이높고예후가불량한것으로보고되고있다. 19 방사선치료의재발은높은침범도를가진경우, 구후나안와에근접한경우, 또는외안근을직접침범하는등특히국소적인고용량의방사능조사가힘든경우에높게발생하는것으로나타났다. 이에비해 R-CVP 군에서는재발을보이지않았다. 파종성또는고위험성안와부속기림프종은대부분단독약제또는세포독성복합항암화학요법으로치료되고있다. 19 그러나몇몇시도되고있는항암요법은저위험성안와부속기림프종환자의단지적은일부에게만제한되어사용되었다. 19-21 2008년 Song et al 22 의발표에의하면국소적인안와부속기 EMZBL의 1차치료로 cyclophosphamide, vincristine, prednisolone (CVP) 의병합항암화학요법으로 66.7% 의관해율을보였다. 이결과는 OAML 환자치료의새로운방향성을제공하였고, 방사선치료를대신하여병합항암화학요법이 1차치료로대두될수있는가능성을제시하였다. 그러나 2011년 Paik et al 23 은 24명의비결막성 OAML 환자를대상으로 3종류의병합항암화학요법과방사선치료와의병합및비교연구를통해항암화학요법의결과가방사선치료보다우수하나화학요법만으로는재발이발생하므로새로운치료법에대한추가적인연구가필요하다고하였다. 또한 Jakobiec and Knowles 24 는적절한치료에도불구하고 OAML의발생부위에따라결막, 안와, 눈꺼풀에서각각 20%, 35%, 67% 의재발률을보인다고발표하였다. 24,25 이를비롯한여러연구에서항암화학요법단독으로는국소적재발이흔하게발생하였고, 재발하는경우추가적인방사선치료가요구되는한계점이있었다. Rituximab 은보체와항체의존적세포독성효과를가져세포사멸을유도하는것으로보인다. 표준적항암요법과비교하였을때 Rituximab 은특히혈액학적합병증과감염등이적게발생한다. 투약과연관된반응들은대부분경미하며, 투약횟수가늘어날수록줄어든다. Rituximab 은다양한 indolent 26,27 또는 aggressive B-cell NHL 12,28,29 그리고 B-cell chronic lymphocytic leukemia 30-34 에서효과를증명하였다. 또한항암요법과의병합을통해 aggressive NHL 환자의생존률을향상시키는결과를보였다. 35,36 Conconi et al 37 은 MALT type 의 ENMZL 에서 Rituximab 의임상적활동성에대해발표하였으나, 이연구에는결막의림프종은포함되지않았다. 본연구에서는이결과를바탕으로결막림프종을포함시켰으며, 관해율을높이기위해 CVP 항암화학요법과 Rituximab 과의병합요법을활용하였다. R-CVP 환자 7명 (8안) 모두에서 1차중간종양평가에서증세의호전및안와전산화단층촬영과자기공명영상촬영에서종양의크기가현저하게줄어들었으며, 6명의환자에서임상적으로완전반응, 1명의환자에서부분반응에도달하였다. 항암요법투여호중구감소증및면역글로불린감소등의혈액학적변화는없었으며, 심각한감염은발생하지않았다. R-CVP 복합항암화학요법의치료효과및장점에도불구하고이번연구는몇가지제한점을가진다. 첫째, 방사선치료군에비해 R-CVP 군의환자수가적고, 그경과관찰기간이짧아서환자수가늘어날경우나경과관찰기간이길어질경우재발발생의가능성을배제할수없다는점이다. 둘째, R-CVP 군의선정조건에서양측결막에침범한경우를제외하고는 T1N0M0 staging 의환자를제외시켰다. 이는방사선치료군에서는포함되었으며, 가장많은비율을차지하는 staging이었기때문에방사선치료군과 R-CVP 군의 staging에따른치료효과의정확한비교가어려울수있다. 이와같은한계점에도불구하고 R-CVP 병합요법을 1 차치료로제시할수있는것은고식적방사선치료의한계와재발, 합병증의발생과기존의항암화학요법의재발등의이유때문이다. 또한이전의연구와는다르게본연구에서는결막의림프종까지포함하였으며, OAML 환자에서 Rituximab 과 CVP의병합항암화학요법을새로운 1차치료법으로제시하고자하였다. 이를토대로 R-CVP 병합항암화학요법은고식적국소 1162 www.ophthalmology.org
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- 대한안과학회지 2013 년제 54 권제 8 호 - 33) Lin TS, Lucas MS, Byrd JC. Rituximab in B-cell chronic lymphocytic leukemia. Semin Oncol 2003;30:483-92. 34) Montserrat E. Rituximab in chronic lymphocytic leukemia. Semin Oncol 2003;30(1 Suppl 2):34-9. 35) Coiffier B. Rituximab in combination with CHOP improves survival in elderly patients with aggressive non-hodgkin's lymphoma. Semin Oncol 2002;29(2 Suppl 6):18-22. 36) Czuczman MS, Grillo-López AJ, White CA, et al. Treatment of patients with lowgrade B-cell lymphoma with the combination of chimeric anti-cd20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol 1999;17:268-76. 37) Conconi A, Martinelli G, Thiéblemont C, et al. Clinical activity of rituximab in extranodal marginal zone B-cell lymphoma of MALT type. Blood 2003;102:2741-5. =ABSTRACT= The Effect of Rituximab, Cyclophosphamide, Vincristine, and Prednisolone (R-CVP) Chemotherapy in Patients with Ocular Adnexal Extranodal Marginal Zone B Cell Lymphoma of the Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma Sung Jin Park, MD 1, Won Sik Lee, MD, PhD 3, Jae Wook Yang, MD, PhD 1,2 Department of Ophthalmology, Busan Paik Hospital, Inje University College of Medicine 1, Busan, Korea Ocular Neovascular Disease Research Center 2, Busan, Korea Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine 3, Busan, Korea Purpose: To report the effectiveness of rituximab, cyclophosphamide, vincristine, and prednisolone (R-CVP) combination chemotherapy in patients with ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphoma (OAML). Methods: R-CVP chemotherapy was performed in 7 patients (8 eyes) with a confirmed histopathological diagnosis of OAML from January 2012 to December 2012. A total of 6 cycles were administered at a 3-4 week interval and 2 cycles of rituximab were added at the third week. Response evaluation was performed 3 times, with the first evaluation 3 weeks after the third cycle, the second 3 weeks after the sixth cycle, and the last after the second rituximab cycle. Results: In all 7 patients (8 eyes) with R-CVP, symptoms were improved, and the mass was markedly resolved based on orbit CT and MRI scan at first response evaluation. Clinically complete remission (CR) was achieved in 6 patients and partial response (PR) in 1 patient. At final response assessment, there was no detectable mass on orbit CT or MRI. There were no severe infections or hematologic adverse effects including neutropenia or decreased immunoglobulin during the follow-up period. Conclusions: In OAML, R-CVP combination chemotherapy is considered an effective, safe and important therapeutic approach, reducing the limitations of classic localized radiotherapy and combination chemotherapy and improving the remission rate. J Korean Ophthalmol Soc 2013;54(8):1157-1164 Key Words: Ocular Adnexal MALT Lymphoma, Radiotherapy, R-CVP Address reprint requests to Jae Wook Yang, MD, PhD Department of Ophthalmology, Busan Paik Hospital #75 Bokji-ro, Busanjin-gu, Busan 614-735, Korea Tel: 82-51-890-8710, Fax: 82-51-890-6329, E-mail: oculoplasty@gmail.com 1164 www.ophthalmology.org