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Subconjunctival injection of bevacizumab for recurrent conjunctival papilloma: a case report
CASE REPORT Subconjunctival injection of bevacizumab for recurrent conjunctival papilloma: a case report Conjunctival papilloma is an acquired benign neoplasm of the conjunctiva and is caused by human papillomavirus, which mostly develops in middle-aged males and often appears as sessile or pedunculated lesions.1–3. The recurrence of conjunctival papilloma is common and has a recurrence rate of 410%.1–3 The conventional therapeutic options include surgical excision and cryotherapy for eradication, but usually conjunctival papilloma recurs, and repeated excisions may lead to ocular surface damage.4,5 Topical interferon, topical mitomycin C, and oral cimetidine are therefore used as adjuvant treatments.2,3,6–8 However, the cytotoxicity of mitomycin C may cause severe side effects, such as dry eyes, corneal melt, and punctual stenosis,2 and it takes a relatively long period for interferon to reach clinical resolution.6 Although no significant side effects have been reported with the use of cimetidine, secondary surgical interventions are often needed to reach better outcomes.8 Previously, bevacizumab (Avastin), a humanized anti– vascular endothelial growth factor monoclonal antibody, was shown to be effective in the treatment of various advanced neoplasms, such as colorectal, lung, and breast cancers.9 Recently, administration of bevacizumab in the treatment of respiratory papillomatosis was reported. In one study, bevacizumab, with a mean dose of 30 mg total per treatment, with or without a potassium titanyl phosphate laser (KTP laser), was used to treat recurrent respiratory papillomatosis, and no recurrences or complications were recorded.10 In another study, bevacizumab was used as concurrent therapy with a KTP laser to treat glottal papillomatosis; regression was noted in most cases, but no complications were found.11 In addition, systemic bevacizumab treatment has been proven to be effective in the treatment for recurrent respiratory papillomatosis.12 Notably, no significant local or systemic complications were detected in these studies.10–12
Currently, there are no reports on the use of bevacizumab as an adjuvant therapy for recurrent conjunctival papilloma. Here, we report a case of a young patient who had recurrent conjunctival papilloma and was treated successfully by simple excision with a concomitant subconjunctival injection of bevacizumab; this patient showed no recurrence for 37 months.
CASE PRESENTATION A 29-year-old Han Taiwanese man without any systemic disease or family history of ocular disorder presented with a conjunctival mass in the right eye. Within 6 months of treatment at another location, the tumor had been resected 3 times, with recurrence after each simple excision. On examination, a pedunculated papillomatous lesion with a mulberry surface was seen arising from the inferior surface of the right palpebral conjunctiva (Fig. 1A). His visual acuity was 20/20 in both eyes, and the remaining ophthalmic examinations showed normal results, except for mild bilateral conjunctival injection. To prevent further recurrences and minimize the possible side effects of conventional therapies, we chose to inject a single dose of bevacizumab (0.2 mL, 25 mg/mL; Roche Diagnostics GmbH, Mannheim, Germany) intraoperatively after excisional biopsy as an adjuvant therapy. The subsequent histopathologic examination revealed fibrovascular cores surrounded by an acanthotic epithelium with nonspecific inflammation (Fig. 2A). Koilocytosis (Fig. 2B, arrowheads), squamous hyperplasia, and mild dysplasia with an elevated nuclear/cytoplasm ratio (Fig. 2B) were observed within the high-power fields of the same specimen. Thus, recurrent conjunctival papilloma was clinically and pathologically diagnosed. Six months after the surgery and concurrent injection, the fornix was free of recurrence, and only topical fluorometholone (0.1%; Winston Medical Supply Co., Ltd., Tainan, Taiwan) was used to treat mild and localized occasional inflammation. At the latest visit 37 months postoperatively, there were still no signs of recurrences or complications (Fig. 1B).
Fig. 1 — Clinical appearance of recurrent conjunctival papilloma before and after treatment. A, The pedunculated papillomatous lesion with a mulberry surface at the inferior palpebral conjunctiva. B, There were no signs of recurrence 37 months after surgical excision with the subconjunctival injection of bevacizumab. CAN J OPHTHALMOL — VOL. ], NO. ], ] 2017
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Case Report
Fig. 2 — Histopathology of the specimens from recurrent conjunctival papilloma. A, Hematoxylin and eosin (H&E) staining showing the acanthotic epithelium encircling fibrovascular cores (100). Magnification of the bracketed area is shown in the insert (400). B, H&E staining indicating koilocytosis (arrowheads), mild dysplasia, squamous hyperplasia, and elevated nuclear/cytoplasm ratio (100). Magnification of the bracketed area is shown in the insert (400).
DISCUSSION Instead of considering simple excision combined with the use of the mitomycin, interferon, cimetidine, or other medications to treat conjunctival papilloma, we adopted the method of local injection of bevacizumab intraoperatively, which was safe and effective for nearly 3 years after the fourth surgical excision. We adopted bevacizumab as a concomitant treatment for the treatment of recurrent conjunctival papilloma for several reasons. First, bevacizumab is a vascular endothelial growth factor inhibitor and has been used as an effective adjuvant therapy for many types of advanced and recurrent tumors.9,13 Theoretically, bevacizumab should be effective for recurrent conjunctival papilloma, which was vascular-rich2 and recurred 3 times in our patient. Second, Best et al. and Zeitels et al. used a sublesional injection of bevacizumab both before and after KTP laser to treat respiratory papillomatosis without significant complications.10,11 No recurrence was reported by Best et al.; and, as reported by Zeitels et al., 17 of the 20 patients who had residual diseases after a treatment period of 6 months had less disease compared with the control subjects.10,11 Therefore, it is reasonable to treat conjunctival papilloma with a similar fashion of subconjunctival injection with bevacizumab because respiratory papillomatosis and conjunctival papilloma are both characterized by vascular growth.3,10 Third, although complications, such as gastrointestinal perforation, arterial thromboembolic events, proteinuria, and hypertension, are observed among patients treated with bevacizumab,14,15 our patient was a healthy young male, who was not among the high-risk group for an arterial thromboembolic event.15 Moreover, in our study, the total dose of bevacizumab injected was much lower than the systemic doses used in other studies,14 and thus the risk of such side effects was reduced. Despite obtaining successful results in the use of bevacizumab for recurrent conjunctival papilloma, the optimal dosage for this drug and its long-term toxicity
2
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remain unclear and thus merit further research. Although the small, but effective, dose that we used should not have caused systemic toxicity, this is still an off-label use of bevacizumab for a benign ocular surface tumor. Further well-designed, prospective studies with larger patient populations and longer follow-up periods are required to justify the current novel adjuvant therapy for recurrent conjunctival papilloma.
CONCLUSIONS In summary, intraoperative subconjunctival injection of bevacizumab can be an effective and safe adjuvant therapy for recurrent conjunctivae papilloma.
Disclosure: The authors have no proprietary or commercial interest in any materials discussed in this article. This study was supported by the Chang Gung Memorial Hospital CMRPG3F1471∼2 and CMRPG3G0031∼3 and the Ministry of Science and Technology (MOST 104-2314-B-182A007-) to Chen HC. The funding organization had no role in the design or conduct of this research, the collection, management, analysis, and interpretation of the data, the preparation, review, or approval of the manuscript, and the decision to submit the manuscript for publication. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. All procedures performed in our study involving human participants adhered to the 1964 Declaration of Helsinki and its later amendments. Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
Chia-Yi Lee, MD,* Hung-Chi Chen, MD, PhD,†,‡,§ Yaa-Jyuhn James Meir, PhD,‖ David Hui-Kang Ma, MD, PhD,†,§,¶ Wei-Chi Wu, MD, PhD†,‡
Case Report *Department
of Ophthalmology, Show Chwan Memorial Hospital, Changhua, Taiwan; †Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou, Taiwan; ‡ Department of Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan; §Center for Tissue Engineering, Chang Gung Memorial Hospital, Linkou, Taiwan; ‖Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; ¶Department of Chinese Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan. Correspondence to: Hung-Chi Chen, MD, PhD: [email protected]
REFERENCES 1. Sjö N, Heegaard S, Prause JU. Conjunctival papilloma. A histopathologically based retrospective study. Acta Ophthalmol Scand. 2000;78:663-6. 2. Shields CL, Shields JA. Tumors of the conjunctiva and cornea. Surv Ophthalmol. 2004;49:3-24. 3. Verma V, Shen D, Sieving PC, Chan CC. The role of infectious agents in the etiology of ocular adnexal neoplasia. Surv Ophthalmol. 2008;53:312-31. 4. Tseng SH. Conjunctival papilloma. Ophthalmology. 2009;116:1013. e1. 5. Hawkins AS, Yu J, Hamming NA, Rubenstein JB. Treatment of recurrent conjunctival papillomatosis with mitomycin C. Am J Ophthalmol. 1999;128:638-40. 6. de Keizer RJ, de Wolff-Rouendaal D. Topical alpha-interferon in recurrent conjunctival papilloma. Acta Ophthalmol Scand. 2003;81:193-6.
7. Yuen HK, Yeung EF, Chan NR, Chi SC, Lam DS. The use of postoperative topical mitomycin C in the treatment of recurrent conjunctival papilloma. Cornea. 2002;21:838-9. 8. Chang SW, Huang ZL. Oral cimetidine adjuvant therapy for recalcitrant, diffuse conjunctival papillomatosis. Cornea. 2006;25: 687-90. 9. Braghiroli MI, Sabbaga J, Hoff PM. Bevacizumab: overview of the literature. Expert Rev Anticancer Ther. 2012;12:567-80. 10. Best SR, Friedman AD, Landau-Zemer T, et al. Safety and dosing of bevacizumab (Avastin) for the treatment of recurrent respiratory papillomatosis. Ann Otol Rhinol Laryngol. 2012;121:587-93. 11. Zeitels SM, Barbu AM, Landau-Zemer T, et al. Local injection of bevacizumab (Avastin) and angiolytic KTP laser treatment of recurrent respiratory papillomatosis of the vocal folds: a prospective study. Ann Otol Rhinol Laryngol. 2011;120:627-34. 12. Mohr M, Schliemann C, Biermann C, et al. Rapid response to systemic bevacizumab therapy in recurrent respiratory papillomatosis. Oncol Lett. 2014;8:1912-8. 13. Komatsu Y, Yuki S, Sogabe S, et al. Phase II study of combined chemotherapy with irinotecan and S-1 (IRIS) plus bevacizumab in patients with inoperable recurrent or advanced colorectal cancer. Acta Oncol. 2012;51:867-72. 14. Keating GM. Bevacizumab: a review of its use in advanced cancer. Drugs. 2014;74:1891-925. 15. Scappaticci FA, Skillings JR, Holden SN, et al. Arterial thromboembolic events in patients with metastatic carcinoma treated with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst. 2007;99:1232-9. Can J Ophthalmol 2017;]:]]]–]]] 0008-4182/17/$-see front matter & 2017 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcjo.2017.03.011
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Currently, there are no reports on the use of bevacizumab as an adjuvant therapy for recurrent conjunctival papilloma. Here, we report a case of a young patient who had recurrent conjunctival papilloma and was treated successfully by simple excision with a concomitant subconjunctival injection of bevacizumab; this patient showed no recurrence for 37 months.
CASE PRESENTATION A 29-year-old Han Taiwanese man without any systemic disease or family history of ocular disorder presented with a conjunctival mass in the right eye. Within 6 months of treatment at another location, the tumor had been resected 3 times, with recurrence after each simple excision. On examination, a pedunculated papillomatous lesion with a mulberry surface was seen arising from the inferior surface of the right palpebral conjunctiva (Fig. 1A). His visual acuity was 20/20 in both eyes, and the remaining ophthalmic examinations showed normal results, except for mild bilateral conjunctival injection. To prevent further recurrences and minimize the possible side effects of conventional therapies, we chose to inject a single dose of bevacizumab (0.2 mL, 25 mg/mL; Roche Diagnostics GmbH, Mannheim, Germany) intraoperatively after excisional biopsy as an adjuvant therapy. The subsequent histopathologic examination revealed fibrovascular cores surrounded by an acanthotic epithelium with nonspecific inflammation (Fig. 2A). Koilocytosis (Fig. 2B, arrowheads), squamous hyperplasia, and mild dysplasia with an elevated nuclear/cytoplasm ratio (Fig. 2B) were observed within the high-power fields of the same specimen. Thus, recurrent conjunctival papilloma was clinically and pathologically diagnosed. Six months after the surgery and concurrent injection, the fornix was free of recurrence, and only topical fluorometholone (0.1%; Winston Medical Supply Co., Ltd., Tainan, Taiwan) was used to treat mild and localized occasional inflammation. At the latest visit 37 months postoperatively, there were still no signs of recurrences or complications (Fig. 1B).
Fig. 1 — Clinical appearance of recurrent conjunctival papilloma before and after treatment. A, The pedunculated papillomatous lesion with a mulberry surface at the inferior palpebral conjunctiva. B, There were no signs of recurrence 37 months after surgical excision with the subconjunctival injection of bevacizumab. CAN J OPHTHALMOL — VOL. ], NO. ], ] 2017
1
Case Report
Fig. 2 — Histopathology of the specimens from recurrent conjunctival papilloma. A, Hematoxylin and eosin (H&E) staining showing the acanthotic epithelium encircling fibrovascular cores (100). Magnification of the bracketed area is shown in the insert (400). B, H&E staining indicating koilocytosis (arrowheads), mild dysplasia, squamous hyperplasia, and elevated nuclear/cytoplasm ratio (100). Magnification of the bracketed area is shown in the insert (400).
DISCUSSION Instead of considering simple excision combined with the use of the mitomycin, interferon, cimetidine, or other medications to treat conjunctival papilloma, we adopted the method of local injection of bevacizumab intraoperatively, which was safe and effective for nearly 3 years after the fourth surgical excision. We adopted bevacizumab as a concomitant treatment for the treatment of recurrent conjunctival papilloma for several reasons. First, bevacizumab is a vascular endothelial growth factor inhibitor and has been used as an effective adjuvant therapy for many types of advanced and recurrent tumors.9,13 Theoretically, bevacizumab should be effective for recurrent conjunctival papilloma, which was vascular-rich2 and recurred 3 times in our patient. Second, Best et al. and Zeitels et al. used a sublesional injection of bevacizumab both before and after KTP laser to treat respiratory papillomatosis without significant complications.10,11 No recurrence was reported by Best et al.; and, as reported by Zeitels et al., 17 of the 20 patients who had residual diseases after a treatment period of 6 months had less disease compared with the control subjects.10,11 Therefore, it is reasonable to treat conjunctival papilloma with a similar fashion of subconjunctival injection with bevacizumab because respiratory papillomatosis and conjunctival papilloma are both characterized by vascular growth.3,10 Third, although complications, such as gastrointestinal perforation, arterial thromboembolic events, proteinuria, and hypertension, are observed among patients treated with bevacizumab,14,15 our patient was a healthy young male, who was not among the high-risk group for an arterial thromboembolic event.15 Moreover, in our study, the total dose of bevacizumab injected was much lower than the systemic doses used in other studies,14 and thus the risk of such side effects was reduced. Despite obtaining successful results in the use of bevacizumab for recurrent conjunctival papilloma, the optimal dosage for this drug and its long-term toxicity
2
CAN J OPHTHALMOL — VOL. ], NO. ], ] 2017
remain unclear and thus merit further research. Although the small, but effective, dose that we used should not have caused systemic toxicity, this is still an off-label use of bevacizumab for a benign ocular surface tumor. Further well-designed, prospective studies with larger patient populations and longer follow-up periods are required to justify the current novel adjuvant therapy for recurrent conjunctival papilloma.
CONCLUSIONS In summary, intraoperative subconjunctival injection of bevacizumab can be an effective and safe adjuvant therapy for recurrent conjunctivae papilloma.
Disclosure: The authors have no proprietary or commercial interest in any materials discussed in this article. This study was supported by the Chang Gung Memorial Hospital CMRPG3F1471∼2 and CMRPG3G0031∼3 and the Ministry of Science and Technology (MOST 104-2314-B-182A007-) to Chen HC. The funding organization had no role in the design or conduct of this research, the collection, management, analysis, and interpretation of the data, the preparation, review, or approval of the manuscript, and the decision to submit the manuscript for publication. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. All procedures performed in our study involving human participants adhered to the 1964 Declaration of Helsinki and its later amendments. Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
Chia-Yi Lee, MD,* Hung-Chi Chen, MD, PhD,†,‡,§ Yaa-Jyuhn James Meir, PhD,‖ David Hui-Kang Ma, MD, PhD,†,§,¶ Wei-Chi Wu, MD, PhD†,‡
Case Report *Department
of Ophthalmology, Show Chwan Memorial Hospital, Changhua, Taiwan; †Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou, Taiwan; ‡ Department of Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan; §Center for Tissue Engineering, Chang Gung Memorial Hospital, Linkou, Taiwan; ‖Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; ¶Department of Chinese Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan. Correspondence to: Hung-Chi Chen, MD, PhD: [email protected]
REFERENCES 1. Sjö N, Heegaard S, Prause JU. Conjunctival papilloma. A histopathologically based retrospective study. Acta Ophthalmol Scand. 2000;78:663-6. 2. Shields CL, Shields JA. Tumors of the conjunctiva and cornea. Surv Ophthalmol. 2004;49:3-24. 3. Verma V, Shen D, Sieving PC, Chan CC. The role of infectious agents in the etiology of ocular adnexal neoplasia. Surv Ophthalmol. 2008;53:312-31. 4. Tseng SH. Conjunctival papilloma. Ophthalmology. 2009;116:1013. e1. 5. Hawkins AS, Yu J, Hamming NA, Rubenstein JB. Treatment of recurrent conjunctival papillomatosis with mitomycin C. Am J Ophthalmol. 1999;128:638-40. 6. de Keizer RJ, de Wolff-Rouendaal D. Topical alpha-interferon in recurrent conjunctival papilloma. Acta Ophthalmol Scand. 2003;81:193-6.
7. Yuen HK, Yeung EF, Chan NR, Chi SC, Lam DS. The use of postoperative topical mitomycin C in the treatment of recurrent conjunctival papilloma. Cornea. 2002;21:838-9. 8. Chang SW, Huang ZL. Oral cimetidine adjuvant therapy for recalcitrant, diffuse conjunctival papillomatosis. Cornea. 2006;25: 687-90. 9. Braghiroli MI, Sabbaga J, Hoff PM. Bevacizumab: overview of the literature. Expert Rev Anticancer Ther. 2012;12:567-80. 10. Best SR, Friedman AD, Landau-Zemer T, et al. Safety and dosing of bevacizumab (Avastin) for the treatment of recurrent respiratory papillomatosis. Ann Otol Rhinol Laryngol. 2012;121:587-93. 11. Zeitels SM, Barbu AM, Landau-Zemer T, et al. Local injection of bevacizumab (Avastin) and angiolytic KTP laser treatment of recurrent respiratory papillomatosis of the vocal folds: a prospective study. Ann Otol Rhinol Laryngol. 2011;120:627-34. 12. Mohr M, Schliemann C, Biermann C, et al. Rapid response to systemic bevacizumab therapy in recurrent respiratory papillomatosis. Oncol Lett. 2014;8:1912-8. 13. Komatsu Y, Yuki S, Sogabe S, et al. Phase II study of combined chemotherapy with irinotecan and S-1 (IRIS) plus bevacizumab in patients with inoperable recurrent or advanced colorectal cancer. Acta Oncol. 2012;51:867-72. 14. Keating GM. Bevacizumab: a review of its use in advanced cancer. Drugs. 2014;74:1891-925. 15. Scappaticci FA, Skillings JR, Holden SN, et al. Arterial thromboembolic events in patients with metastatic carcinoma treated with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst. 2007;99:1232-9. Can J Ophthalmol 2017;]:]]]–]]] 0008-4182/17/$-see front matter & 2017 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcjo.2017.03.011
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