Letters
to be associated with HPV 16. Higher-weight cytokeratins are encountered in the epidermis as opposed to mucous membranes.2,3 The 2 major differential diagnoses were sebaceous and mucoepidermoid carcinomas.4 Sebaceous carcinoma was excluded by oil red O cytoplasmic negativity and immunohistochemical stains that demonstrated negativity for both adipophilin (except for faint focal positivity in necrotic zones) and androgen receptors.5,6 Sebaceous carcinomas are 100% positive for androgen receptors.6 Mucoepidermoid carcinoma was excluded by negative Alcian blue and mucicarmine stains.4 Cutaneous squamous cell carcinomas of epidermal origin are 100% androgen receptor negative, but conjunctival dysplasias may rarely be focally positive.6 Immunohistochemistry can therefore be helpful in distinguishing clear-cell squamous carcinoma from sebaceous cell carcinoma. Our findings should also help to resolve the controversy over whether sebaceous carcinoma can arise primarily in the conjunctival epithelium. Previous reports of this entity may in fact have been examples of clear-cell squamous carcinomas in situ. Accurate early diagnosis separating intraepithelial clear-cell squamous and sebaceous carcinomas should lead to improved clinical management of these disparate conditions. Alia Rashid, MBChB Frederick A. Jakobiec, MD, DSc John T. Mandeville, MD Author Affiliations: David G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston (Rashid, Jakobiec); Eye Health Services, Quincy, Massachusetts (Mandeville). Corresponding Author: Frederick A. Jakobiec, MD, DSc, David G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, 243 Charles St, Boston, MA 02114 ([email protected]). Published Online: May 22, 2014. doi:10.1001/jamaophthalmol.2014.971. Author Contributions: Dr Jakobiec had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Jakobiec, Mandeville. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Rashid, Jakobiec. Critical revision of the manuscript for important intellectual content: All authors. Administrative, technical, or material support: All authors. Study supervision: Jakobiec. Conflict of Interest Disclosures: None reported.
Effect of Topical Rebamipide on Human Conjunctival Goblet Cells The conjunctival epithelium contains mucin-secreting goblet cells, which are essential for maintenance of a healthy ocular surface.1 It has been demonstrated that topical administration of rebamipide, an antiulcer agent, increases the mucin level of the tear film and improves the ocular surface in dry eye syndrome.2 Indeed, rebamipide increased the number of goblet cells in rabbit and murine conjunctivas in vivo.3,4 Ríos et al demonstrated that rebamipide led to proliferation of cultured rat conjunctival goblet cells,5 subsequently stimulating secretion from the cells.6 However, there has been no evidence that rebamipide exerts a strong action on human goblet cell behavior. This is the first report, to our knowledge, showing markedly increased goblet cells after administration of topic al rebamipide in a patient with conjunctival dysplasia. Report of a Case | A man in his late 70s had conjunctival hyperemia in the left eye. He was referred to our hospital because a conjunctival tumor was initially observed at a clinic. His visual acuity was 20/25 OS and his intraocular pressure was normal. Slitlamp examination revealed a pinkish tumor located in the nasal bulbar conjunctiva (Figure 1A). Indocyanine green angiography of the anterior segment demonstrated a markedly stained lesion corresponding to the tumor (Figure 1B). Dilated vessels associated with the tumor extended to the cornea (Figure 1B). The right eye was healthy. Because carcinoma in situ was initially suspected, the conjunctival tumor and the
Figure 1. Slitlamp Examination and Indocyanine Green Angiographic Findings in a Patient With Conjunctival Tumor Before and After Topical Rebamipide Treatment A
B
C
D
1. Kuo T. Clear cell carcinoma of the skin: a variant of the squamous cell carcinoma that simulates sebaceous carcinoma. Am J Surg Pathol. 1980;4(6): 573-583. 2. Ansai S, Arase S, Kawana S, Kimura T. Immunohistochemical findings of sebaceous carcinoma and sebaceoma: retrieval of cytokeratin expression by a panel of anti-cytokeratin monoclonal antibodies. J Dermatol. 2011;38(10):951-958. 3. Jakobiec FA, Mendoza PR, Colby KA. Clinicopathologic and immunohistochemical studies of conjunctival large cell acanthoma, epidermoid dysplasia, and squamous papilloma. Am J Ophthalmol. 2013;156(4):830-846. 4. Rankin JK, Jakobiec FA, Zakka FR, Foster CS. An improved approach to diagnosing and treating conjunctival mucoepidermoid carcinoma. Surv Ophthalmol. 2012;57(4):337-346. 5. Jakobiec FA, Mendoza PR. Eyelid sebaceous carcinoma: clinicopathologic and multiparametric immunohistochemical analysis that includes adipophilin. Am J Ophthalmol. 2014;157(1):186-208, e2. 6. Jakobiec FA, Werdich X. Androgen receptor identification in the diagnosis of eyelid sebaceous carcinomas. Am J Ophthalmol. 2014;157(3):687-696, e1-e2.
A, Slitlamp examination before topical rebamipide treatment shows a pinkish tumor located in the nasal bulbar conjunctiva with abnormal vessels. B, Indocyanine green angiography of the anterior segment before topical rebamipide treatment displays a markedly stained lesion corresponding to the tumor. Abnormal dilated vessels associated with the tumor extend to the cornea (arrowheads). C, Slitlamp examination 3 months after starting topical rebamipide treatment demonstrates mild hyperemia without tumor formation in the left eye. D, Indocyanine green angiography 3 months after starting topical rebamipide treatment shows no staining in the conjunctiva.
jamaophthalmology.com
JAMA Ophthalmology August 2014 Volume 132, Number 8
Copyright 2014 American Medical Association. All rights reserved.
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1021
Letters
Figure 2. Histological Findings of the Bulbar Conjunctiva Before and After Rebamipide Treatment A
B
that its effectiveness would last for at least 2 weeks after the end of treatment.2 Careful observation is mandatory to ensure the safety of topical rebamipide. Also, the conjunctiva of the fellow eye was not available in this study. Further studies are needed to verify the goblet cells in the conjunctival tissues of human eyes that have not undergone surgery. Satoru Kase, MD Toshiya Shinohara, MD Manabu Kase, MD
C
Author Affiliations: Department of Ophthalmology, Teine Keijinkai Hospital, Teine-ku, Sapporo, Japan (S. Kase, M. Kase); Department of Surgical Pathology, Teine Keijinkai Hospital, Teine-ku, Sapporo, Japan (Shinohara).
A, Before rebamipide treatment, the initial lesion shows acanthosis with mild nuclear atypia (asterisk) as well as conjunctival dysplasia. Noncancerous epithelium is noted in the surgical margin (arrowhead) (hematoxylin-eosin, original magnification ×200). B, Goblet cells (arrowheads) are hardly noted in the adjacent normal conjunctiva (2/high-power field) before rebamipide treatment (hematoxylin-eosin, original magnification ×400). C, After topical rebamipide treatment, the conjunctival epithelium shows a smooth surface with an increased number of goblet cells (25/high-power field) (hematoxylin-eosin, original magnification ×400).
associated corneal epithelial lesion were excised with a 3-mm surgical margin after obtaining written informed consent. The conjunctival deficit was completely reconstructed using a rotation flap. Histologically, the conjunctival tumor showed mild dysplasia (Figure 2A). The lesion of the dysplasia was located at the site 2 mm nasal to the corneal limbus. The adjacent noncancerous conjunctiva contained a few goblet cells (2/highpower field) (Figure 2B). Surgical margins were free of dysplasia cells. The patient used topical rebamipide eyedrops 4 times a day for 3 months without other topical agents to support healing of the postoperative corneal erosion. Slitlamp examination demonstrated smooth bulbar conjunctiva of the left eye (Figure 1C) 3 months after starting treatment with rebamipide. Indocyanine green angiography showed no staining or dilated vessels in the conjunctiva (Figure 1D). After oral informed consent was obtained, a biopsy was performed at the bulbar conjunctiva 2 mm nasal to the corneal limbus to evaluate how the epithelial atypia changed. Histologically, the conjunctival epithelium contained an increased number of goblet cells (25/high-power field) without cellular atypia (Figure 2C). After 6 months’ follow-up, the patient is well without recurrence of the tumor. Discussion | Rebamipide is considered to increase the number of goblet cells of the tissues in rabbit and mouse models.3,4 For the first time, to our knowledge, our study has demonstrated that use of rebamipide alone for 3 months resulted in a markedly increased number of goblet cells in the conjunctival epithelium of a human. The results also verify in vitro evidence that rebamipide led to an increased number of goblet cells of the rat conjunctiva.5,6 A limitation of this study is its short follow-up time. A previous article demonstrated that topical rebamipide could be safely used for 4 weeks in patients with dry eye syndrome and 1022
Corresponding Author: Satoru Kase, MD, Department of Ophthalmology, Teine Keijinkai Hospital, Maeda 1-12, Teine-ku, Sapporo 006-0811, Japan (kaseron @keijinkai.or.jp). Author Contributions: Dr S. Kase had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: S. Kase, M. Kase. Acquisition, analysis, or interpretation of data: Shinohara. Drafting of the manuscript: S. Kase. Critical revision of the manuscript for important intellectual content: Shinohara, M. Kase. Statistical analysis: S. Kase. Obtained funding: S. Kase, Shinohara. Administrative, technical, or material support: S. Kase. Study supervision: Shinohara, M. Kase. Conflict of Interest Disclosures: None reported. 1. Le QH, Wang WT, Hong JX, et al. An in vivo confocal microscopy and impression cytology analysis of goblet cells in patients with chemical burns. Invest Ophthalmol Vis Sci. 2010;51(3):1397-1400. 2. Kinoshita S, Awamura S, Oshiden K, Nakamichi N, Suzuki H, Yokoi N; Rebamipide Ophthalmic Suspension Phase II Study Group. Rebamipide (OPC-12759) in the treatment of dry eye: a randomized, double-masked, multicenter, placebo-controlled phase II study. Ophthalmology. 2012;119(12): 2471-2478. 3. Urashima H, Takeji Y, Okamoto T, Fujisawa S, Shinohara H. Rebamipide increases mucin-like substance contents and periodic acid Schiff reagent-positive cells density in normal rabbits. J Ocul Pharmacol Ther. 2012;28 (3):264-270. 4. Ohguchi T, Kojima T, Ibrahim OM, et al. The effects of 2% rebamipide ophthalmic solution on the tear functions and ocular surface of the superoxide dismutase-1 (Sod1) knockout mice. Invest Ophthalmol Vis Sci. 2013;54(12):77937802. 5. Ríos JD, Shatos M, Urashima H, Tran H, Dartt DA. OPC-12759 increases proliferation of cultured rat conjunctival goblet cells. Cornea. 2006;25(5):573581. 6. Ríos JD, Shatos MA, Urashima H, Dartt DA. Effect of OPC-12759 on EGF receptor activation, p44/p42 MAPK activity, and secretion in conjunctival goblet cells. Exp Eye Res. 2008;86(4):629-636.
Adalimumab for Pediatric Sympathetic Ophthalmia Sympathetic ophthalmia (SO) is an autoimmune, bilateral, granulomatous panuveitis occurring after accidental or surgical trauma to the eye.1 Systemic corticosteroids are firstline therapy for SO, with immunomodulatory therapy used for corticosteroid-sparing immunosuppression and chronic, refractory cases. Biological response modifiers are a class of therapeutics that target specific cytokines mediating inflammation, and tumor necrosis factor α (TNF-α)– antagonist biological response modifiers have shown prom-
JAMA Ophthalmology August 2014 Volume 132, Number 8
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a Purdue University User on 05/20/2015
jamaophthalmology.com
to be associated with HPV 16. Higher-weight cytokeratins are encountered in the epidermis as opposed to mucous membranes.2,3 The 2 major differential diagnoses were sebaceous and mucoepidermoid carcinomas.4 Sebaceous carcinoma was excluded by oil red O cytoplasmic negativity and immunohistochemical stains that demonstrated negativity for both adipophilin (except for faint focal positivity in necrotic zones) and androgen receptors.5,6 Sebaceous carcinomas are 100% positive for androgen receptors.6 Mucoepidermoid carcinoma was excluded by negative Alcian blue and mucicarmine stains.4 Cutaneous squamous cell carcinomas of epidermal origin are 100% androgen receptor negative, but conjunctival dysplasias may rarely be focally positive.6 Immunohistochemistry can therefore be helpful in distinguishing clear-cell squamous carcinoma from sebaceous cell carcinoma. Our findings should also help to resolve the controversy over whether sebaceous carcinoma can arise primarily in the conjunctival epithelium. Previous reports of this entity may in fact have been examples of clear-cell squamous carcinomas in situ. Accurate early diagnosis separating intraepithelial clear-cell squamous and sebaceous carcinomas should lead to improved clinical management of these disparate conditions. Alia Rashid, MBChB Frederick A. Jakobiec, MD, DSc John T. Mandeville, MD Author Affiliations: David G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston (Rashid, Jakobiec); Eye Health Services, Quincy, Massachusetts (Mandeville). Corresponding Author: Frederick A. Jakobiec, MD, DSc, David G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, 243 Charles St, Boston, MA 02114 ([email protected]). Published Online: May 22, 2014. doi:10.1001/jamaophthalmol.2014.971. Author Contributions: Dr Jakobiec had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Jakobiec, Mandeville. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Rashid, Jakobiec. Critical revision of the manuscript for important intellectual content: All authors. Administrative, technical, or material support: All authors. Study supervision: Jakobiec. Conflict of Interest Disclosures: None reported.
Effect of Topical Rebamipide on Human Conjunctival Goblet Cells The conjunctival epithelium contains mucin-secreting goblet cells, which are essential for maintenance of a healthy ocular surface.1 It has been demonstrated that topical administration of rebamipide, an antiulcer agent, increases the mucin level of the tear film and improves the ocular surface in dry eye syndrome.2 Indeed, rebamipide increased the number of goblet cells in rabbit and murine conjunctivas in vivo.3,4 Ríos et al demonstrated that rebamipide led to proliferation of cultured rat conjunctival goblet cells,5 subsequently stimulating secretion from the cells.6 However, there has been no evidence that rebamipide exerts a strong action on human goblet cell behavior. This is the first report, to our knowledge, showing markedly increased goblet cells after administration of topic al rebamipide in a patient with conjunctival dysplasia. Report of a Case | A man in his late 70s had conjunctival hyperemia in the left eye. He was referred to our hospital because a conjunctival tumor was initially observed at a clinic. His visual acuity was 20/25 OS and his intraocular pressure was normal. Slitlamp examination revealed a pinkish tumor located in the nasal bulbar conjunctiva (Figure 1A). Indocyanine green angiography of the anterior segment demonstrated a markedly stained lesion corresponding to the tumor (Figure 1B). Dilated vessels associated with the tumor extended to the cornea (Figure 1B). The right eye was healthy. Because carcinoma in situ was initially suspected, the conjunctival tumor and the
Figure 1. Slitlamp Examination and Indocyanine Green Angiographic Findings in a Patient With Conjunctival Tumor Before and After Topical Rebamipide Treatment A
B
C
D
1. Kuo T. Clear cell carcinoma of the skin: a variant of the squamous cell carcinoma that simulates sebaceous carcinoma. Am J Surg Pathol. 1980;4(6): 573-583. 2. Ansai S, Arase S, Kawana S, Kimura T. Immunohistochemical findings of sebaceous carcinoma and sebaceoma: retrieval of cytokeratin expression by a panel of anti-cytokeratin monoclonal antibodies. J Dermatol. 2011;38(10):951-958. 3. Jakobiec FA, Mendoza PR, Colby KA. Clinicopathologic and immunohistochemical studies of conjunctival large cell acanthoma, epidermoid dysplasia, and squamous papilloma. Am J Ophthalmol. 2013;156(4):830-846. 4. Rankin JK, Jakobiec FA, Zakka FR, Foster CS. An improved approach to diagnosing and treating conjunctival mucoepidermoid carcinoma. Surv Ophthalmol. 2012;57(4):337-346. 5. Jakobiec FA, Mendoza PR. Eyelid sebaceous carcinoma: clinicopathologic and multiparametric immunohistochemical analysis that includes adipophilin. Am J Ophthalmol. 2014;157(1):186-208, e2. 6. Jakobiec FA, Werdich X. Androgen receptor identification in the diagnosis of eyelid sebaceous carcinomas. Am J Ophthalmol. 2014;157(3):687-696, e1-e2.
A, Slitlamp examination before topical rebamipide treatment shows a pinkish tumor located in the nasal bulbar conjunctiva with abnormal vessels. B, Indocyanine green angiography of the anterior segment before topical rebamipide treatment displays a markedly stained lesion corresponding to the tumor. Abnormal dilated vessels associated with the tumor extend to the cornea (arrowheads). C, Slitlamp examination 3 months after starting topical rebamipide treatment demonstrates mild hyperemia without tumor formation in the left eye. D, Indocyanine green angiography 3 months after starting topical rebamipide treatment shows no staining in the conjunctiva.
jamaophthalmology.com
JAMA Ophthalmology August 2014 Volume 132, Number 8
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a Purdue University User on 05/20/2015
1021
Letters
Figure 2. Histological Findings of the Bulbar Conjunctiva Before and After Rebamipide Treatment A
B
that its effectiveness would last for at least 2 weeks after the end of treatment.2 Careful observation is mandatory to ensure the safety of topical rebamipide. Also, the conjunctiva of the fellow eye was not available in this study. Further studies are needed to verify the goblet cells in the conjunctival tissues of human eyes that have not undergone surgery. Satoru Kase, MD Toshiya Shinohara, MD Manabu Kase, MD
C
Author Affiliations: Department of Ophthalmology, Teine Keijinkai Hospital, Teine-ku, Sapporo, Japan (S. Kase, M. Kase); Department of Surgical Pathology, Teine Keijinkai Hospital, Teine-ku, Sapporo, Japan (Shinohara).
A, Before rebamipide treatment, the initial lesion shows acanthosis with mild nuclear atypia (asterisk) as well as conjunctival dysplasia. Noncancerous epithelium is noted in the surgical margin (arrowhead) (hematoxylin-eosin, original magnification ×200). B, Goblet cells (arrowheads) are hardly noted in the adjacent normal conjunctiva (2/high-power field) before rebamipide treatment (hematoxylin-eosin, original magnification ×400). C, After topical rebamipide treatment, the conjunctival epithelium shows a smooth surface with an increased number of goblet cells (25/high-power field) (hematoxylin-eosin, original magnification ×400).
associated corneal epithelial lesion were excised with a 3-mm surgical margin after obtaining written informed consent. The conjunctival deficit was completely reconstructed using a rotation flap. Histologically, the conjunctival tumor showed mild dysplasia (Figure 2A). The lesion of the dysplasia was located at the site 2 mm nasal to the corneal limbus. The adjacent noncancerous conjunctiva contained a few goblet cells (2/highpower field) (Figure 2B). Surgical margins were free of dysplasia cells. The patient used topical rebamipide eyedrops 4 times a day for 3 months without other topical agents to support healing of the postoperative corneal erosion. Slitlamp examination demonstrated smooth bulbar conjunctiva of the left eye (Figure 1C) 3 months after starting treatment with rebamipide. Indocyanine green angiography showed no staining or dilated vessels in the conjunctiva (Figure 1D). After oral informed consent was obtained, a biopsy was performed at the bulbar conjunctiva 2 mm nasal to the corneal limbus to evaluate how the epithelial atypia changed. Histologically, the conjunctival epithelium contained an increased number of goblet cells (25/high-power field) without cellular atypia (Figure 2C). After 6 months’ follow-up, the patient is well without recurrence of the tumor. Discussion | Rebamipide is considered to increase the number of goblet cells of the tissues in rabbit and mouse models.3,4 For the first time, to our knowledge, our study has demonstrated that use of rebamipide alone for 3 months resulted in a markedly increased number of goblet cells in the conjunctival epithelium of a human. The results also verify in vitro evidence that rebamipide led to an increased number of goblet cells of the rat conjunctiva.5,6 A limitation of this study is its short follow-up time. A previous article demonstrated that topical rebamipide could be safely used for 4 weeks in patients with dry eye syndrome and 1022
Corresponding Author: Satoru Kase, MD, Department of Ophthalmology, Teine Keijinkai Hospital, Maeda 1-12, Teine-ku, Sapporo 006-0811, Japan (kaseron @keijinkai.or.jp). Author Contributions: Dr S. Kase had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: S. Kase, M. Kase. Acquisition, analysis, or interpretation of data: Shinohara. Drafting of the manuscript: S. Kase. Critical revision of the manuscript for important intellectual content: Shinohara, M. Kase. Statistical analysis: S. Kase. Obtained funding: S. Kase, Shinohara. Administrative, technical, or material support: S. Kase. Study supervision: Shinohara, M. Kase. Conflict of Interest Disclosures: None reported. 1. Le QH, Wang WT, Hong JX, et al. An in vivo confocal microscopy and impression cytology analysis of goblet cells in patients with chemical burns. Invest Ophthalmol Vis Sci. 2010;51(3):1397-1400. 2. Kinoshita S, Awamura S, Oshiden K, Nakamichi N, Suzuki H, Yokoi N; Rebamipide Ophthalmic Suspension Phase II Study Group. Rebamipide (OPC-12759) in the treatment of dry eye: a randomized, double-masked, multicenter, placebo-controlled phase II study. Ophthalmology. 2012;119(12): 2471-2478. 3. Urashima H, Takeji Y, Okamoto T, Fujisawa S, Shinohara H. Rebamipide increases mucin-like substance contents and periodic acid Schiff reagent-positive cells density in normal rabbits. J Ocul Pharmacol Ther. 2012;28 (3):264-270. 4. Ohguchi T, Kojima T, Ibrahim OM, et al. The effects of 2% rebamipide ophthalmic solution on the tear functions and ocular surface of the superoxide dismutase-1 (Sod1) knockout mice. Invest Ophthalmol Vis Sci. 2013;54(12):77937802. 5. Ríos JD, Shatos M, Urashima H, Tran H, Dartt DA. OPC-12759 increases proliferation of cultured rat conjunctival goblet cells. Cornea. 2006;25(5):573581. 6. Ríos JD, Shatos MA, Urashima H, Dartt DA. Effect of OPC-12759 on EGF receptor activation, p44/p42 MAPK activity, and secretion in conjunctival goblet cells. Exp Eye Res. 2008;86(4):629-636.
Adalimumab for Pediatric Sympathetic Ophthalmia Sympathetic ophthalmia (SO) is an autoimmune, bilateral, granulomatous panuveitis occurring after accidental or surgical trauma to the eye.1 Systemic corticosteroids are firstline therapy for SO, with immunomodulatory therapy used for corticosteroid-sparing immunosuppression and chronic, refractory cases. Biological response modifiers are a class of therapeutics that target specific cytokines mediating inflammation, and tumor necrosis factor α (TNF-α)– antagonist biological response modifiers have shown prom-
JAMA Ophthalmology August 2014 Volume 132, Number 8
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a Purdue University User on 05/20/2015
jamaophthalmology.com
