CONJUNCTIVAL PYOGENIC GRANULOMA ASSOCIATED WITH INTRAVITREAL BEVACIZUMAB INJECTION Oded Sagiv, MD, Ilia Piven, MD, Mordechai Rosner, MD
Purpose: To report a case of conjunctival pyogenic granuloma after intravitreal injection of anti–vascular endothelial growth factor, bevacizumab. Methods: A 52-year-old patient after 3 intravitreal bevacizumab injections was found to have a vascular conjunctival nodule at the injection site. A pathologic analysis of the vascular conjunctival nodule was performed after surgical excision. Results: The pathologic analysis revealed a conjunctival pyogenic granuloma. Conclusion: Conjunctival pyogenic granuloma can complicate an otherwise uneventful intravitreal anti–vascular endothelial growth factor injection. RETINAL CASES & BRIEF REPORTS 7:291–293, 2013
gression, posterior vitreous detachment, vitreous hemorrhage, pigment epithelial tear, retinal detachment, subretinal hemorrhage, central retinal artery or vein occlusion, and endophthalmitis. Recently, one case report tied a local conjunctival inflammatory reaction with multiple ranibizumab injections.4 The authors presumed this reaction to be a pyogenic granuloma based on the clinical appearance, anterior segment imaging, and clinical improvement with topical steroid treatment. We hereby report a case of a conjunctival pyogenic granuloma after three intravitreal bevacizumab injections that was excised and diagnosed histologically. To the best of our knowledge, this is the first report of a histologically proven conjunctival pyogenic granuloma after intravitreal injections of anti-VEGF agents.
From the The Goldschleger Eye Institute, Sheba Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel Hashomer, Israel.
B
evacizumab (Avastin; Genentech, San Francisco, CA) is a recombinant humanized antibody common to the different isoforms of vascular endothelial growth factor (VEGF). By inhibiting its activity, it has an antiangiogenic effect. It was approved in 2004 by the Food and Drug Administration for intravenous use in combination with chemotherapy against metastatic colon cancer, and since 2005, it has been widely used off-label in intravitreal injections to treat various retinal diseases such as neovascular age-related macular degeneration, diabetic macular edema, and retinal vein occlusion.1 Several studies evaluated its efficacy and safety and compared it with ranibizumab (Lucentis; Genentech), a recombinant humanized monoclonal G1K isotype antibody Fab that blocks VEGF A. There are several reported adverse reactions to intravitreal anti-VEGF injections,1–3 including subconjunctival hemorrhage, corneal abrasion, elevated intraocular pressure, anterior uveitis, lens injury and cataract pro-
Case Report A 52-year-old woman with uncontrolled diabetes mellitus and hypertension was referred to our retina clinic after complaining of decreased visual acuity. She was diagnosed with bilateral proliferative diabetic retinopathy and cystoid macular edema and treated with a course of 6 intravitreal bevacizumab (0.125 mg/0.05 mL) injections: 3 in each eye, as well as a series of pan-retinal laser photocoagulation treatments in both eyes. Injection technique for all procedures was as follows: a sterile lid speculum and sterile powder-free latex gloves were used. Before the injection, 2 drops of oxybuprocaine hydrochloride 0.4%, 1 drop of 5% Povidone-iodine, and 1 drop of
None of the authors have any financial/conflicts of interest to disclose. Reprint requests: Oded Sagiv, MD, Department of Ophthalmology, The Goldschleger Eye Institute, Sheba Medical Center, Tel Hashomer 52621, Israel; e-mail: [email protected]
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ofloxacin 0.3% were instilled. All injections were administered 4 mm posterior to the limbus in the temporal quadrant using a 32-gauge needle. The injection site was dried with a cotton-tipped sterile applicator before injection. All injections were uneventful. After completing her treatment plan, the cystoid macular edema resolved and she is kept in periodical follow-up at the retina clinic. On a follow-up visit 7 months after the last injection to her left eye, the patient reported left eye pain and redness for the past month. On clinical examination, a hyperemic nodule on the temporal conjunctiva was seen (Figure 1). The rest of the ophthalmic examination of both her eyes was unremarkable in the anterior segment and with no new findings in her vitreous or retina. A possible diagnosis of pyogenic granuloma was suggested. Three weeks later, the patient underwent surgical excision of the nodule under local anesthesia, and cauterization was applied to achieve hemostasis of a conjunctival blood vessel that seemed to supply the nodule (Figure 2). Pathologic examination confirmed the diagnosis of a pyogenic granuloma, composed of capillary proliferation in a typical “spoke-wheel” appearance, infiltrated by acute and chronic inflammatory cells (Figure 3). The patient remains on follow-up, and until this publication, 1 year after the surgery, no recurrence was noted.
Discussion Conjunctival pyogenic granuloma is one of the most common vascular tumors of the conjunctiva. In the largest published series of vascular conjunctival tumors, it was the most common and accounted for 22% of the tumors, followed by lymphangioma (20%) and lymphangiectasis (19%).5 Usually, it presents after an ocular insult and appears as a slowly growing fleshy vascular mass. Macroscopically, it is often pedunculated, with an underlying stalk of feeder blood vessels and connective tissue. Histologically, it is composed of a granulation tissue that contains a mixture of acute and chronic inflammatory cells and proliferating capillaries in a typical “spoke-wheel” pattern. The name is a misnomer as no suppuration or necrosis (as
Fig. 1. Photograph of the patient’s left eye showing the hyperemic conjunctival nodule in the temporal quadrant.
Fig. 2. Photograph of the patient’s left eye taken 1 day after surgical excision of the nodule. Cauterization was used to stop bleeding of a relatively large blood vessel at the base of the nodule located 4 mm from the limbus (arrow).
implies from the term “pyogenic”), and usually, no giant cells (as found in true granulomas) are found. However, giant cells occasionally may be found in pyogenic granulomas that arise after chalazion surgery or after spontaneous drainage of chalazia. It is important to mention that in contrast to ophthalmologists, dermatopathologists apply the same term “pyogenic granuloma” to an entirely different lesion, an acquired capillary hemangioma—capillary hemangioma of the pyogenic granuloma type. Pyogenic granulomas have been classically reported at a traumatic wound site, after a chalazion or after other ocular surgery, such as strabismus (at the muscle insertion), pterygium removal, and enucleation, and at sclerotomy site or after scleral buckling in retinal
Fig. 3. Light microscopy photograph of a cross section of the nodule. A typical fan-shaped capillary proliferation is present as well as a mixture of acute and chronic inflammatory cells (hematoxylin and eosin stain, original magnification: ·100).
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surgery. There are anecdotal reports of pyogenic granuloma associated with foreign bodies.6 Treatment of pyogenic granulomas usually requires surgical excision, although some lesions will respond to treatment with topical steroids. A benefit of surgical excision is the ability to achieve a definitive diagnosis of the lesion. The association between the pyogenic granuloma and the intravitreal anti-VEGF injections in the described case is likely because there is no history of previous ocular trauma or ocular surgery to the reported eye and because the location of the base of the pyogenic granuloma was 4 mm away from the limbus (as demonstrated in Figure 2), correlating with the distance and the quadrant at which all 3 injections were performed. The possibility of idiopathic pyogenic granuloma was also considered. In a large review of 100 pyogenic granulomas of the eye and ocular adnexa,6 there were 11 cases of undetermined cause of which 10 involved the palpebral conjunctiva, 2 involved the cutaneous aspect of the lid, and 1 was found on the cornea. The authors concluded that the lesions in this group were most likely the aftermath of chalazia, although there was neither clinical history nor pathologic signs to support this. We did not find other reports of idiopathic conjunctival pyogenic granuloma and therefore consider this option to be the less likely explanation in the described case. Jung et al reported a case of presumed pyogenic granuloma in a patient after multiple intravitreal ranibizumab injections. The clinical description of the reported case is atypical for a pyogenic granuloma. The inflammatory reaction appeared as soon as 1 week after the injection, which is a rapid time line, and might have not involved the element of chronic inflammation. The nodule is described as subconjunctival, and the patient exhibited an active anterior chamber inflammation. As mentioned by the authors,
the differential diagnosis at presentation included a foreign body reaction in addition to pyogenic granuloma, both of which can improve after treatment with topical steroids. In our opinion, this atypical course and the lack of a definitive histologic diagnosis make the diagnosis of pyogenic granuloma in the reported case questionable. In this report, there is histologic proof that pyogenic granuloma can complicate an otherwise uneventful intravitreal anti-VEGF injection and perhaps raise awareness of physicians in clinical practice to this pathology when a suspicious lesion appears. Several issues that remain elusive are the incidence rate of this adverse reaction and the exact cause that triggers it. Further reports and studies are needed to address these questions. Key words: anti–vascular endothelial growth factor, bevacizumab, conjunctival vascular tumors, intravitreal injection, pyogenic granuloma. References 1. The CATT Research Group, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011;364:1897–1908. 2. Fung AE, Rosenfeld PJ, Reichel E. The International Intravitreal Bevacizumab Safety Survey: using the internet to assess drug safety worldwide. Br J Ophthalmol 2006;90:1344–1349. 3. Schmucker C, Loke YK, Ehlken C, et al. Intravitreal bevacizumab (Avastin) versus ranibizumab (Lucentis) for the treatment of agerelated macular degeneration: a safety review. Br J Ophthalmol 2011;95:308–317. 4. Jung JJ, Della Torre KE, Fell MR, et al. Presumed pyogenic granuloma associated with intravitreal anti-vascular endothelial growth factor therapy. Open Ophthalmol J 2011;5:59–62. 5. Shields JA, Mashayekhi A, Kligman BE, et al. Vascular tumors of the conjunctiva in 140 cases. Ophthalmology 2011;118: 1747–1753. 6. Ferry AP. Pyogenic granulomas of the eye and ocular adnexa: a study of 100 cases. Trans Am Ophthalmol Soc 1989;87: 327–347.
Purpose: To report a case of conjunctival pyogenic granuloma after intravitreal injection of anti–vascular endothelial growth factor, bevacizumab. Methods: A 52-year-old patient after 3 intravitreal bevacizumab injections was found to have a vascular conjunctival nodule at the injection site. A pathologic analysis of the vascular conjunctival nodule was performed after surgical excision. Results: The pathologic analysis revealed a conjunctival pyogenic granuloma. Conclusion: Conjunctival pyogenic granuloma can complicate an otherwise uneventful intravitreal anti–vascular endothelial growth factor injection. RETINAL CASES & BRIEF REPORTS 7:291–293, 2013
gression, posterior vitreous detachment, vitreous hemorrhage, pigment epithelial tear, retinal detachment, subretinal hemorrhage, central retinal artery or vein occlusion, and endophthalmitis. Recently, one case report tied a local conjunctival inflammatory reaction with multiple ranibizumab injections.4 The authors presumed this reaction to be a pyogenic granuloma based on the clinical appearance, anterior segment imaging, and clinical improvement with topical steroid treatment. We hereby report a case of a conjunctival pyogenic granuloma after three intravitreal bevacizumab injections that was excised and diagnosed histologically. To the best of our knowledge, this is the first report of a histologically proven conjunctival pyogenic granuloma after intravitreal injections of anti-VEGF agents.
From the The Goldschleger Eye Institute, Sheba Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel Hashomer, Israel.
B
evacizumab (Avastin; Genentech, San Francisco, CA) is a recombinant humanized antibody common to the different isoforms of vascular endothelial growth factor (VEGF). By inhibiting its activity, it has an antiangiogenic effect. It was approved in 2004 by the Food and Drug Administration for intravenous use in combination with chemotherapy against metastatic colon cancer, and since 2005, it has been widely used off-label in intravitreal injections to treat various retinal diseases such as neovascular age-related macular degeneration, diabetic macular edema, and retinal vein occlusion.1 Several studies evaluated its efficacy and safety and compared it with ranibizumab (Lucentis; Genentech), a recombinant humanized monoclonal G1K isotype antibody Fab that blocks VEGF A. There are several reported adverse reactions to intravitreal anti-VEGF injections,1–3 including subconjunctival hemorrhage, corneal abrasion, elevated intraocular pressure, anterior uveitis, lens injury and cataract pro-
Case Report A 52-year-old woman with uncontrolled diabetes mellitus and hypertension was referred to our retina clinic after complaining of decreased visual acuity. She was diagnosed with bilateral proliferative diabetic retinopathy and cystoid macular edema and treated with a course of 6 intravitreal bevacizumab (0.125 mg/0.05 mL) injections: 3 in each eye, as well as a series of pan-retinal laser photocoagulation treatments in both eyes. Injection technique for all procedures was as follows: a sterile lid speculum and sterile powder-free latex gloves were used. Before the injection, 2 drops of oxybuprocaine hydrochloride 0.4%, 1 drop of 5% Povidone-iodine, and 1 drop of
None of the authors have any financial/conflicts of interest to disclose. Reprint requests: Oded Sagiv, MD, Department of Ophthalmology, The Goldschleger Eye Institute, Sheba Medical Center, Tel Hashomer 52621, Israel; e-mail: [email protected]
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ofloxacin 0.3% were instilled. All injections were administered 4 mm posterior to the limbus in the temporal quadrant using a 32-gauge needle. The injection site was dried with a cotton-tipped sterile applicator before injection. All injections were uneventful. After completing her treatment plan, the cystoid macular edema resolved and she is kept in periodical follow-up at the retina clinic. On a follow-up visit 7 months after the last injection to her left eye, the patient reported left eye pain and redness for the past month. On clinical examination, a hyperemic nodule on the temporal conjunctiva was seen (Figure 1). The rest of the ophthalmic examination of both her eyes was unremarkable in the anterior segment and with no new findings in her vitreous or retina. A possible diagnosis of pyogenic granuloma was suggested. Three weeks later, the patient underwent surgical excision of the nodule under local anesthesia, and cauterization was applied to achieve hemostasis of a conjunctival blood vessel that seemed to supply the nodule (Figure 2). Pathologic examination confirmed the diagnosis of a pyogenic granuloma, composed of capillary proliferation in a typical “spoke-wheel” appearance, infiltrated by acute and chronic inflammatory cells (Figure 3). The patient remains on follow-up, and until this publication, 1 year after the surgery, no recurrence was noted.
Discussion Conjunctival pyogenic granuloma is one of the most common vascular tumors of the conjunctiva. In the largest published series of vascular conjunctival tumors, it was the most common and accounted for 22% of the tumors, followed by lymphangioma (20%) and lymphangiectasis (19%).5 Usually, it presents after an ocular insult and appears as a slowly growing fleshy vascular mass. Macroscopically, it is often pedunculated, with an underlying stalk of feeder blood vessels and connective tissue. Histologically, it is composed of a granulation tissue that contains a mixture of acute and chronic inflammatory cells and proliferating capillaries in a typical “spoke-wheel” pattern. The name is a misnomer as no suppuration or necrosis (as
Fig. 1. Photograph of the patient’s left eye showing the hyperemic conjunctival nodule in the temporal quadrant.
Fig. 2. Photograph of the patient’s left eye taken 1 day after surgical excision of the nodule. Cauterization was used to stop bleeding of a relatively large blood vessel at the base of the nodule located 4 mm from the limbus (arrow).
implies from the term “pyogenic”), and usually, no giant cells (as found in true granulomas) are found. However, giant cells occasionally may be found in pyogenic granulomas that arise after chalazion surgery or after spontaneous drainage of chalazia. It is important to mention that in contrast to ophthalmologists, dermatopathologists apply the same term “pyogenic granuloma” to an entirely different lesion, an acquired capillary hemangioma—capillary hemangioma of the pyogenic granuloma type. Pyogenic granulomas have been classically reported at a traumatic wound site, after a chalazion or after other ocular surgery, such as strabismus (at the muscle insertion), pterygium removal, and enucleation, and at sclerotomy site or after scleral buckling in retinal
Fig. 3. Light microscopy photograph of a cross section of the nodule. A typical fan-shaped capillary proliferation is present as well as a mixture of acute and chronic inflammatory cells (hematoxylin and eosin stain, original magnification: ·100).
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surgery. There are anecdotal reports of pyogenic granuloma associated with foreign bodies.6 Treatment of pyogenic granulomas usually requires surgical excision, although some lesions will respond to treatment with topical steroids. A benefit of surgical excision is the ability to achieve a definitive diagnosis of the lesion. The association between the pyogenic granuloma and the intravitreal anti-VEGF injections in the described case is likely because there is no history of previous ocular trauma or ocular surgery to the reported eye and because the location of the base of the pyogenic granuloma was 4 mm away from the limbus (as demonstrated in Figure 2), correlating with the distance and the quadrant at which all 3 injections were performed. The possibility of idiopathic pyogenic granuloma was also considered. In a large review of 100 pyogenic granulomas of the eye and ocular adnexa,6 there were 11 cases of undetermined cause of which 10 involved the palpebral conjunctiva, 2 involved the cutaneous aspect of the lid, and 1 was found on the cornea. The authors concluded that the lesions in this group were most likely the aftermath of chalazia, although there was neither clinical history nor pathologic signs to support this. We did not find other reports of idiopathic conjunctival pyogenic granuloma and therefore consider this option to be the less likely explanation in the described case. Jung et al reported a case of presumed pyogenic granuloma in a patient after multiple intravitreal ranibizumab injections. The clinical description of the reported case is atypical for a pyogenic granuloma. The inflammatory reaction appeared as soon as 1 week after the injection, which is a rapid time line, and might have not involved the element of chronic inflammation. The nodule is described as subconjunctival, and the patient exhibited an active anterior chamber inflammation. As mentioned by the authors,
the differential diagnosis at presentation included a foreign body reaction in addition to pyogenic granuloma, both of which can improve after treatment with topical steroids. In our opinion, this atypical course and the lack of a definitive histologic diagnosis make the diagnosis of pyogenic granuloma in the reported case questionable. In this report, there is histologic proof that pyogenic granuloma can complicate an otherwise uneventful intravitreal anti-VEGF injection and perhaps raise awareness of physicians in clinical practice to this pathology when a suspicious lesion appears. Several issues that remain elusive are the incidence rate of this adverse reaction and the exact cause that triggers it. Further reports and studies are needed to address these questions. Key words: anti–vascular endothelial growth factor, bevacizumab, conjunctival vascular tumors, intravitreal injection, pyogenic granuloma. References 1. The CATT Research Group, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011;364:1897–1908. 2. Fung AE, Rosenfeld PJ, Reichel E. The International Intravitreal Bevacizumab Safety Survey: using the internet to assess drug safety worldwide. Br J Ophthalmol 2006;90:1344–1349. 3. Schmucker C, Loke YK, Ehlken C, et al. Intravitreal bevacizumab (Avastin) versus ranibizumab (Lucentis) for the treatment of agerelated macular degeneration: a safety review. Br J Ophthalmol 2011;95:308–317. 4. Jung JJ, Della Torre KE, Fell MR, et al. Presumed pyogenic granuloma associated with intravitreal anti-vascular endothelial growth factor therapy. Open Ophthalmol J 2011;5:59–62. 5. Shields JA, Mashayekhi A, Kligman BE, et al. Vascular tumors of the conjunctiva in 140 cases. Ophthalmology 2011;118: 1747–1753. 6. Ferry AP. Pyogenic granulomas of the eye and ocular adnexa: a study of 100 cases. Trans Am Ophthalmol Soc 1989;87: 327–347.
