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1 대한안과학회지 2014 년제 55 권제 6 호 J Korean Ophthalmol Soc 2014;55(6): pissn: eissn: Case Report 항암치료를위해사용된표피성장인자수용체억제제로유발된긴속눈썹증 2 예 Paradoxical Trichomegaly of the Eyelashes During Treatment with EGFR Inhibitors: 2 Case Report 나건후 엄영섭 강수연 김효명 송종석 Kun Hoo Na, MD, Young Sub Eom, MD, Su Yeon Kang, MD, Hyo Myung Kim, MD, PhD, Jong Suk Song, MD, PhD 고려대학교의과대학안과학교실 Department of Ophthalmology, Korea University College of Medicine, Seoul, Korea Purpose: To introduce 2 cases of trichomegaly associated with the use of systemic epidermal growth factor receptor (EGFR) inhibitors for the treatment of lung cancer. Case summary: An 82 year old female visited our clinic for ocular pain in both eyes. She was suffering from metastatic lung cancer and was under daily treatment with gefitinib (Iressa, AstraZeneca, London, UK) for 6 months. On ophthalmologic examination, she presented with abnormally elongated eyelashes, hyperemic conjunctiva and dense corneal erosion. A 52 year old male who was diagnosed with non small cell lung cancer 7 months before and treated with erlotinib (Tarceva OSI Pharmaceuticals, Inc., Melville, NY, USA) was referred to our clinic for injection and foreign body sensation in both eyes. Although there were no remarkable changes in eyelashes at the initial visit, long, curly, uneven eyelashes were observed after 3 months. Conclusions: Due to the increased use of EGFR inhibitors in anti cancer treatment, ophthalmologists should be aware of these chemotherapeutics adverse effects. J Korean Ophthalmol Soc 2014;55(6): Key Words: Epidermal growth factor receptor inhibitor, Trichomegaly 속눈썹의변화를일으키는약물로프로스타글란딘제제가알려져있다. 녹내장의치료제인프로스타글란딘제제를장기간점안하는경우눈썹이길어지고두꺼워지며모발색조가짙어지는현상이나타날수있다. 1-3 이러한부작 Received: Revised: Accepted: Address reprint requests to Jong Suk Song, MD, PhD Department of Ophthalmology, Korea University Guro Hospital, #148 Gurodong-ro, Guro-gu, Seoul , Korea Tel: , Fax: crisim@korea.ac.kr * This study was supported by development grants of the Department of Ophthalmology, Korea University College of Medicine. 용을역으로이용하여 Bimatoprost 0.03% (Latisse, Allergan Inc., Irvine, CA, USA) 는미용목적의속눈썹연장제로 2008 년미국식품의약품안전청의승인을받은바있다. 4 표피성장인자수용체 (epidermal growth factor receptor; EGFR) 는티로신인산화효소 (tyrosine kinase) 수용체군의하나로세포의성장과분화를조절한다. 5 최근분자표적치료의도입과함께 EGFR 억제제는기존의항암화학요법에반응하지않는암에대한치료제로서점차그이용이증가하고있으며이에따라 EGFR 억제제의부작용들도다양하게보고되고있다. 6 이중속눈썹의길이가연장되는증례들이드물게보고되었으며대부분의항암제들이빠르게증식하는세포에영향을주어신체각부위의탈모를유발한다는사실과는대조적이다. 국내에서는이에대한보고가없었 c2014 The Korean Ophthalmological Society This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 908

- 나건후외 : 표피성장인자수용체억제제와속눈썹의변화 - 으며이에저자들은폐암의항암치료로 EGFR 억제제를복용하고있는환자에서발생한긴속눈썹증증례에대해보고하고자한다. 증례보고 증례 1 82세여자환자가양안통증을주소로외래방문하였다.

세극등현미경검사에서각막상피미란, 결막미란과화농성분비물이관찰되었다. Levofloxacin 0.5% 와 loteprednol 0.5% 를하루 4회점안후환자의증상과임상소견은호전되었으나 2개월후속눈썹의길이는더욱길어져있었고, 각막과결막을자극하여눈 썹가위로짧게잘라주었다.

초진시세극등현미경검사에서결막충혈, 하부각막상피미란이관찰되었으나속눈썹의특별한변화는보이지않았다 (Fig. 2A). Levofloxacin 0.5% 와 fluorometholone 0.5% 점안액을하루 4회, 무보존제인공누액을하루 2시간마다점안하도록한후 3주뒤환자의증상및임상소견은호전되었다.

(A) Eighty-two-year-old female patient under chemotherapy with gefitinib for metastatic lung cancer shows elongated eyelashes and blepharitis on the upper and lower lids.

2 - 나건후외 : 표피성장인자수용체억제제와속눈썹의변화 - 으며이에저자들은폐암의항암치료로 EGFR 억제제를복용하고있는환자에서발생한긴속눈썹증증례에대해보고하고자한다. 증례보고 증례 1 82세여자환자가양안통증을주소로외래방문하였다. 환자는 5개월전전이성폐암으로진단받고 gefitinib (Iressa, AstraZeneca, London, UK) 을복용중이었다. 초진시양안위아래눈꺼풀의안검염과함께비정상적으로길고구부러진형태의속눈썹이관찰되었으며 (Fig. 1A), 눈을감았을때더욱두드러져보였다 (Fig. 1B). 세극등현미경검사에서각막상피미란, 결막미란과화농성분비물이관찰되었다. Levofloxacin 0.5% 와 loteprednol 0.5% 를하루 4회점안후환자의증상과임상소견은호전되었으나 2개월후속눈썹의길이는더욱길어져있었고, 각막과결막을자극하여눈 썹가위로짧게잘라주었다. 증례 2 52세남자환자가내원두달전부터반복되는양안의충혈과이물감을주소로외래방문하였다. 환자는 3개월전비소세포폐암 4기로진단받고 erlotinib (Tarceva OSI Pharmaceuticals, Inc., Melville, NY, USA) 을아침식전복용하고있었다. 초진시세극등현미경검사에서결막충혈, 하부각막상피미란이관찰되었으나속눈썹의특별한변화는보이지않았다 (Fig. 2A). Levofloxacin 0.5% 와 fluorometholone 0.5% 점안액을하루 4회, 무보존제인공누액을하루 2시간마다점안하도록한후 3주뒤환자의증상및임상소견은호전되었다. 3개월후환자가다시외래로방문하였을때속눈썹의비정상적인변화가관찰되었다. 속눈썹의색조는짙어져있었고비정상적으로길며구부러진형태를보였고속눈썹의일부는결막및각막과닿아있었다 (Fig. 2B). 그러나머리카락등신체다른부위의모발이상은관찰되지않았다. A B Figure 1. (A) Eighty-two-year-old female patient under chemotherapy with gefitinib for metastatic lung cancer shows elongated eyelashes and blepharitis on the upper and lower lids. (B) The elongation of the eyelashes looks prominent when closing eyes. A B Figure 2. (A) Fifty-two-year-old male patient under chemothrerapy with erlotinib for non-small cell lung cancer shows conjunctival injection and superficial punctate keratitis at the initial visit. (B) After 3 months, curly elongated eyelashes are observed. 909

3 - 대한안과학회지 2014 년제 55 권제 6 호 - 고찰 표피성장인자수용체는인간표피성장인자수용체군에속하는세포막의단백질로세포의증식과분화의조절에있어중요한역할을하며, 대장직장암, 두경부편평세포암, 비소세포폐암을비롯한다양한고형암에서과발현되는것으로알려졌다. 7-9 표피성장인자수용체억제제는단클론항체 (monoclonal antibody) 와티로신인산화효소억제제 (tyrosine kinase inhibitor) 로분류된다. 단클론항체에는 EGFR의세포외수용체의리간드결합을방해하여수용체활성화를저해하는 cetuximab, panitumumab 등이있으며 gefitinib, erlotinib과같은티로신인산화효소억제제는 EGFR의 adenosine triphosphate (ATP) 결합부위에경쟁적으로결합하여세포내신호전달체계의활성도를저하시킨다. 9 Panitumumab 은표준적치료에실패한진행성전이성대장암에서쓰이는단독요법으로미국 FDA의승인을받았으며, cetuximab은두경부편평상피암과대장직장암의치료제로허가받았다. Gefitinib과 erlotinib은진행성비소세포폐암의 2차혹은 3 차치료제로서단독요법으로사용되고 EGFR 유전자돌연변이가있는경우단독 1차치료제로사용할수있다. 10 이처럼 EGFR 억제제는분자표적항암제로서효과와부작용면에서기존의항암화학제보다우수한결과를보이고있으며현재그사용이크게증가하고있다. EGFR 억제제는약물의높은특이도로혈액학적합병증과같은전신적부작용은감소하는것으로보이지만 EGFR 은표피의각질형성세포와피지샘, 모낭겉뿌리집 (outer root sheath of the hair follicles) 에분포하고있으며, 이에따라 EGFR의억제는피부독성을나타내게된다. 11,12 여드름양발진은 EGFR 억제제의피부합병증으로흔히나타나며일부에서는긍정적인약물반응과연관된다고보고하였다. 13 다른피부합병증으로피부건조증, 소양증, 조갑주위염등이있으며안와주위피부발진에속발된하안검외반이보고되기도하였다. 12,14 EGFR 억제제가긴속눈썹증을일으키는기전은명확히밝혀지지않았지만 EGFR 억제에따른케라틴유전자의발현조절이상으로모낭상피의성숙과분화에영향을주기때문이라생각한다. 15,16 Vergou et al 17 은 EGFR을통한신호전달체계의억제는모발의생장기 (anagen) 에서휴지기 (telogen) 로의진행을방해하고, 생장기에서퇴행기로전환되는과정을차단하여모발의성장주기가생장기에머물러있게되어모발이연장되는것으로생각하였다. EGFR 억제제의사용에따른속눈썹의변화에대한보고들에서눈썹모발은특징적으로길고, 견고하고구부러진형태를보이며모발의색조와결에도변화를보였다 Dueland et al 16 은 irinotecan과같은항암제로인하여눈썹모발은길어졌으나두피와사지의털이손실되는증례를통하여모발의성장조절은신체의부위마다다른기전이작용할것이라고하였다. 긴속눈썹증은 EGFR 억제제를복용한후 3주에서 8개월사이에발생하며치료중단후저절로소실되는것으로알려졌다 Alexandrescu et al 24 은 EGFR 억제제의복용중나타나는긴속눈썹증은항암제에대한긍정적인반응과연관된다고하였다. 긴속눈썹증은눈썹가위로짧게잘라줌으로써쉽게치료할수있으며전기분해술, 광역학치료, 혹은왁싱등을이용할수있다 녹내장치료제인프로스타글란딘제제의장기적사용으로눈썹이길어지고두꺼워지며색이짙어질수있다. 4 프로스타글란딘제제가속눈썹의변화를일으키는기전은모발의생장기를연장시키고모발내멜라닌의합성을증가시키기때문으로생각한다. 4,28 이번증례보고에서제시한환자들은프로스타글란딘계열의약물을점안하고있지않았다. EGFR은각막과결막의기저상피세포와눈물에도존재하며각막상피결손의치유에있어중요한역할을하고눈의항상성을유지한다. 29,30 EGFR의억제는손상된각막상피가치유되는과정에서상피세포의증식과층화에영향을주게된다. 29 Saint-Jean et al 31 은전신적 EGFR 억제제의부작용으로각막의융해, 천공과같은심각한부작용이발생할수있음을보고하였고반복각막진무름과결막충혈등의부작용이보고되기도하였다. 32 본증례보고의두번째증례에서나타난결막충혈, 점상각막상피미란은이같은기전으로설명해볼수있겠다. EGFR 억제제의사용은안과적부작용을일으킬수있으며이러한부작용은긴속눈썹증과같은경미한것에서부터각막천공과같은심각한합병증에이르기까지다양하다. 속눈썹의연장은시력을저하시키지는않으며이에따라항암제의사용을중단할필요는없다. 항암치료영역에서 EGFR 억제제의사용은점차증가고있으며이에, 발생할수있는안과적합병증에대하여인지하는것이중요하다. REFERENCES 1) Uno H, Zimbric ML, Albert DM, Stjernschantz J. Effect of latanoprost on hair growth in the bald scalp of the stump-tailed macacque: a pilot study. Acta Derm Venereol 2002;82: ) Sugimoto M, Sugimoto M, Uji Y. Quantitative analysis of eyelash lengthening following topical latanoprost therapy. Can J Ophthalmol 2002;37: ) Hart J, Shafranov G. Hypertrichosis of vellus hairs of the malar region after unilateral treatment with bimatoprost. Am J Ophthalmol 910

4 - 나건후외 : 표피성장인자수용체억제제와속눈썹의변화 ;137: ) Woodward DF, Wang JW, Poloso NJ. Recent progress in prostaglandin F2alpha ethanolamide (prostamide F2alpha) research and therapeutics. Pharmacol Rev 2013;65: ) Jost M, Kari C, Rodeck U. The EGF receptor - an essential regulator of multiple epidermal functions. Eur J Dermatol 2000;10: ) Van den Eynde M, Baurain JF, Mazzeo F, Machiels JP. Epidermal growth factor receptor targeted therapies for solid tumours. Acta Clin Belg 2011;66: ) Schneider MR, Wolf E. The epidermal growth factor receptor ligands at a glance. J Cell Physiol 2009;218: ) Herbst RS. Review of epidermal growth factor receptor biology. Int J Radiat Oncol Biol Phys 2004;59: ) Yarden Y, Pines G. The ERBB network: at last, cancer therapy meets systems biology. Nat Rev Cancer 2012;12: ) Cataldo VD, Gibbons DL, Pérez-Soler R, Quintás-Cardama A. Treatment of non-small-cell lung cancer with erlotinib or gefitinib. N Engl J Med 2011;364: ) Alexandrescu DT, Kauffman CL, Dasanu CA. The cutaneous epidermal growth factor network: Can it be translated clinically to stimulate hair growth? Dermatol Online J 2009;15:1. 12) Balagula Y, Garbe C, Myskowski PL, et al. Clinical presentation and management of dermatological toxicities of epidermal growth factor receptor inhibitors. Int J Dermatol 2011;50: ) Mittmann N, Seung SJ. Rash rates with egfr inhibitors: metaanalysis. Curr Oncol 2011;18: ) Methvin AB, Gausas RE. Newly recognized ocular side effects of erlotinib. Ophthal Plast Reconstr Surg 2007;23: ) Hansen LA, Alexander N, Hogan ME, et al. Genetically null mice reveal a central role for epidermal growth factor receptor in the differentiation of the hair follicle and normal hair development. Am J Pathol 1997;150: ) Dueland S, Sauer T, Lund-Johansen F, et al. Epidermal growth factor receptor inhibition induces trichomegaly. Acta Oncol 2003; 42: ) Vergou T, Stratigos AJ, Karapanagiotou EM, et al. Facial hypertrichosis and trichomegaly developing in patients treated with the epidermal growth factor receptor inhibitor erlotinib. J Am Acad Dermatol 2010;63: ) Cohen PR, Escudier SM, Kurzrock R. Cetuximab-associated elongation of the eyelashes: case report and review of eyelash trichomegaly secondary to epidermal growth factor receptor inhibitors. Am J Clin Dermatol 2011;12: ) Fabbrocini G, Panariello L, Cacciapuoti S, et al. Trichomegaly of the eyelashes during therapy with epidermal growth factor receptor inhibitors: report of 3 cases. Dermatitis 2012;23: ) Paul LJ, Cohen PR, Kurzrock R. Eyelash trichomegaly: review of congenital, acquired, and drug-associated etiologies for elongation of the eyelashes. Int J Dermatol 2012;51: ) Braiteh F, Kurzrock R, Johnson FM. Trichomegaly of the eyelashes after lung cancer treatment with the epidermal growth factor receptor inhibitor erlotinib. J Clin Oncol 2008;26: ) Zhang G, Basti S, Jampol LM. Acquired trichomegaly and symptomatic external ocular changes in patients receiving epidermal growth factor receptor inhibitors: case reports and a review of literature. Cornea 2007;26: ) Li T, Perez-Soler R. Skin toxicities associated with epidermal growth factor receptor inhibitors. Target Oncol 2009;4: ) Alexandrescu DT, Kauffman CL, Dasanu CA. Persistent hair growth during treatment with the EGFR inhibitor erlotinib. Dermatol Online J 2009;15:4. 25) Papadopoulos R, Chasapi V, Bachariou A. Trichomegaly induced by erlotinib. Orbit 2008;27: ) Morse L, Calarese P. EGFR-targeted therapy and related skin toxicity. Semin Oncol Nurs 2006;22: ) Osio A, Mateus C, Soria JC, et al. Cutaneous side-effects in patients on long-term treatment with epidermal growth factor receptor inhibitors. Br J Dermatol 2009;161: ) Cohen JL. Enhancing the growth of natural eyelashes: the mechanism of bimatoprost-induced eyelash growth. Dermatol Surg 2010; 36: ) Nakamura Y, Sotozono C, Kinoshita S. The epidermal growth factor receptor (EGFR): role in corneal wound healing and homeostasis. Exp Eye Res 2001;72: ) Wilson SE, He YG, Weng J, et al. Effect of epidermal growth factor, hepatocyte growth factor, and keratinocyte growth factor, on proliferation, motility and differentiation of human corneal epithelial cells. Exp Eye Res 1994;59: ) Saint-Jean A, Sainz de la Maza M, Morral M, et al. Ocular adverse events of systemic inhibitors of the epidermal growth factor receptor: report of 5 cases. Ophthalmology 2012;119: ) Tullo AB, Esmaeli B, Murray PI, et al. Ocular findings in patients with solid tumours treated with the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) in Phase I and II clinical trials. Eye (Lond) 2005;19:

5 - 대한안과학회지 2014 년제 55 권제 6 호 - = 국문초록 = 항암치료를위해사용된표피성장인자수용체억제제로유발된긴속눈썹증 2 예 목적 : 폐암의항암치료로표피성장인자수용체억제제를복용하고있는환자에서발생한긴속눈썹증 2 예를보고하고자한다. 증례요약 : 첫번째증례는 82 세여자환자로양안의통증을주소로내원하였다. 환자는전이성폐암으로진단받고 6 개월전부터 gefitinib (Iressa R, AstraZeneca, London, UK) 을복용하고있었으며, 안과검사에서속눈썹이비정상적으로길어져있었고, 결막충혈과각막상피미란이관찰되었다. 두번째증례는 52 세남자환자로비소세포폐암으로진단받고 7 개월전부터 erlotinib (Tarceva R OSI Pharmaceuticals, Inc., Melville, NY, USA) 을복용하고있었다. 양안의심한충혈과이물감을주소로처음내원하였을때속눈썹의특별한변화를보이지않았으나 3 개월후에는속눈썹이비정상적으로길어져있었고구부러진형태를보였다. 결론 : 항암치료영역에서표피성장인자수용체억제제의사용은증가하고있으며이들이일으킬수있는긴속눈썹증등안과적부작용에대하여주지할필요가있다. < 대한안과학회지 2014;55(6): > 912

<32302D30352D323728B1E8B9CCB1DD2DBFC0C0BAB1D E687770>

<32302D30352D323728B1E8B9CCB1DD2DBFC0C0BAB1D E687770> = 증례보고 = 에를로티닙과라파티닙을사용한환자에서발생한표층점상각막병증 대한안과학회지 2014 년제 55 권제 2 호 J Korean Ophthalmol Soc 2014;55(2):293-297 pissn: 0378-6471 eissn: 2092-9374 http://dx.doi.org/10.3341/jkos.2014.55.2.293 오은규 1,2 조동현 1,2