- Email: [email protected]
Secondary corneal amyloidosis after perforating corneal trauma: A series of 5 cases and review of the literature
s u r v e y o f o p h t h a l m o l o g y 6 0 ( 2 0 1 5 ) 5 9 0 e5 9 5
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/survophthal
Clinical pathologic reviews
Secondary corneal amyloidosis after perforating corneal trauma: A series of 5 cases and review of the literature Solin Saleh, MDa,b, Seymour Brownstein, MDa,b,*, Joshua S. Manusow, MDa,b, Andre´ Jastrzebski, MDa,b, Kay Lam, MDa,b, Joseph W. Sassani, MDc,d, George Mintsioulis, MDa, Steven M. Gilberg, MDa a
Department of Ophthalmology, The Ottawa Hospital, Ottawa, Ontario, Canada Department of Pathology, The Ottawa Hospital, Ottawa, Ontario, Canada c Department of Ophthalmology, Milton S. Hershey Medical Centre, Pennsylvania State University, Hershey, Pennsylvania, USA d Department of Pathology, Milton S. Hershey Medical Centre, Pennsylvania State University, Hershey, Pennsylvania, USA b
article info
abstract
Article history:
We retrospectively reviewed the clinical and surgical histories of 5 patients with traumatic
Received 5 May 2015
secondary corneal amyloidosis, a relatively rare sequela of nonsurgical and surgical
Received in revised form
perforating corneal trauma. Four had history of nonsurgical trauma, and 1 had surgical
25 June 2015
trauma to the cornea. Three specimens were obtained by penetrating keratoplasties and 2
Accepted 17 July 2015
by excision of the cornea during evisceration of the ocular contents. All the corneal
Available online 4 August 2015
specimens showed full-thickness scars of a prior perforating wound with congophilic
Stefan Seregard and Hans
amyloid deposits that exhibited apple-green birefringence under polarized light and
Grossniklaus, Editors
dichroism. All cases had variable degrees of predominantly chronic nongranulomatous inflammation. Ultrastructural examination in 1 patient disclosed 8-nm diameter fibrils in
Keywords:
disarray, consistent with amyloid. Amyloid P immunostaining was positive in all 3 patients
cornea
tested for this protein.
amyloid
ª 2015 Elsevier Inc. All rights reserved.
secondary corneal amyloidosis perforating corneal trauma corneal degeneration pathology
* Corresponding author: Seymour Brownstein, MD, Department of Ophthalmology, The Ottawa Hospital, 501 Smyth Road, Suite W6213, Ottawa, Ontario K1H 8L6, Canada. E-mail address: [email protected] (S. Brownstein). 0039-6257/$ e see front matter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.survophthal.2015.07.004
591
s u r v e y o f o p h t h a l m o l o g y 6 0 ( 2 0 1 5 ) 5 9 0 e5 9 5
1.
Introduction
2.2.
Corneal amyloidosis is an infrequent condition that occurs when normally soluble autologous proteins are deposited in tissues as abnormal insoluble fibrils.2 Amyloidosis may be classified into 2 main groups, primary and secondary, each of which is further divided into systemic or localized.47 Secondary localized amyloidosis is uncommon, and secondary amyloid deposition following corneal trauma and wound healing is rarely reported. We present 5 cases of secondary corneal amyloidosis after surgical and nonsurgical perforating trauma (Table 1) and suggest a pathogenesis of this uncommon condition.
2.
Case reports
2.1.
Case 1
A 35-year-old man underwent a left corneal transplant for a scar sustained from a corneal laceration at age 6 years, which also resulted in amblyopia in that eye. On examination, the visual acuity was 20/200 with pinhole improvement to 20/80 in the left eye, and there was no maculopathy. Histopathologic examination of the excised cornea disclosed a full-thickness scar displaying mild chronic nongranulomatous inflammation. Anterior to the adjacent, residual Bowman layer, there was a large accumulation of congophilic, amorphous material that exhibited apple-green birefringence and dichroism under polarized light. Immunohistochemical studies for amyloid A (AA) and amyloid L (AL) proteins were negative; amyloid P (AP) protein testing was not performed in this case. The diagnosis was secondary localized corneal amyloidosis after nonsurgical perforating trauma.
2.3.
A 31-year-old man sustained nonsurgical trauma to his right cornea 20 years previously that was managed at the time with a keratoplasty. The ocular history also included 2 retinal detachment surgeries, and the past medical history was otherwise unremarkable. He had no light perception and corneal opacification in the right eye (Fig. 1A). The left eye was normal. He underwent evisceration and placement of an orbital implant for a phthisical, blind, painful right eye. Histopathologic examination of the excised cornea showed a full-thickness scar with subepithelial deposits of an amorphous, eosinophilic material (Fig. 2A) that exhibited Congo red positivity with apple-green birefringence (Fig. 2B) and dichroism (Figs. 2C and D). A mild chronic nongranulomatous inflammatory infiltrate was present adjacent to the corneal scar. The diagnosis was secondary localized corneal amyloidosis after surgical perforating trauma.
Case 2
Case 3
A 37-year-old woman underwent a right corneal transplant for a corneal scar sustained at age 18 months from a nonsurgical perforating wound caused by glass (Fig. 1B). On ocular examination, she had a best-corrected visual acuity of counting fingers in the right eye, and there was no maculopathy. The left eye was normal. Histopathologic examination demonstrated a full-thickness scar in the excised left cornea with mild chronic nongranulomatous inflammation and subepithelial deposits of amorphous, homogenous, congophilic material. Immunohistochemical studies showed AP protein deposits, but no AA or AL proteins were detected. Secondary localized corneal amyloidosis after nonsurgical perforating trauma was diagnosed.
2.4.
Case 4
A 54-year-old man sustained a corneoscleral laceration by a screwdriver at age 34, following which he developed a
Table 1 e Clinical and immunohistochemical features of reported cases of secondary corneal amyloidosis following nonsurgical and surgical perforating corneal trauma Reference
Age (years)
Sex
Case 1
31
M
Case 2
35
M
Case 3
37
F
Case 4
54
M
Case 5
52
M
Javadi et al16 Yamada et al18
33 30
M F
History and timeline of injury Nonsurgical trauma and PK and 20 years previously Corneal laceration and 29 years previously Corneal penetration by glass and 36 years previously Corneoscleral laceration by screwdriver and 20 years previously Corneal penetration by arrow and 45 years previously Mustard gas keratitis Keratoconus, PK, subsequent hard contact lens wear
Clinical description
Source of specimen
Immunohistochemistry
Corneal opacification
Evisceration
Not available
Full-thickness central corneal scar Fibrovascular central corneal scar Thin, scarred cornea and band keratopathy
PK
AP (not available), AA, AL
PK
APþ, AA, AL
Evisceration
APþ, AA, AL
Fibrovascular corneal scar
PK
APþ, AA, AL
Corneal scar Nodular gray-white opacities in subepithelial zone of graft
LK Superficial keratectomy
NR NR
M, male; F, female; PK, penetrating keratoplasty; AP, amyloid P protein; AA, amyloid A protein; AL, AL protein; NR, not reported; LK, lamellar keratoplasty.
592
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AL proteins. The diagnosis was secondary corneal amyloidosis with band keratopathy after nonsurgical perforating trauma.
2.5.
Case 5
A 52-year-old man sustained an arrow injury to his left eye at age 7 years that left him with an extensive central corneal fibrovascular scar (Fig. 1C). The management was a corneal graft and insertion of an anterior chamber intraocular lens. There was no maculopathy on fundus examination. Histopathologic examination of the excised cornea disclosed irregularly thickened and thinned epithelium overlying prominent, full-thickness scars. There were focal deposits of amorphous, homogenous material subepithelialy focally replacing Bowman layer. The deposits were congophilic with apple-green birefringence under polarized light. The underlying stroma was extensively scarred, edematous and vascularized and disclosed a mild chronic nongranulomatous inflammatory infiltrate. Descemet membrane was thickened and fragmented and the endothelium was only focally present. Immunohistochemical evaluation demonstrated positive staining of the deposits for AP protein (Fig. 2G), and negative staining for AA protein (Fig. 2H) and AL protein. Transmission electron microscopic examination disclosed subepithelial deposits of disorganized filaments 8 nm in diameter consistent with amyloid (Fig. 3). The diagnosis was secondary corneal amyloidosis resulting from nonsurgical perforating trauma. The immunohistochemical analyses of these formalinfixed, paraffin-embedded corneal specimens involved staining with rabbit polyclonal antibodies against AP protein, mouse monoclonal antibodies against AA protein, and rabbit monoclonal antibodies against AL protein, which is comprised of kappa and lambda immunoglobulin light chains.
3.
Fig. 1 e Clinical findings in 3 cases (1, 3, and 5). A: Opacification of the right cornea in case 1. B: White, central corneal scar in case 3. C: White, central corneal scar with vascularization in case 5. funnel-shaped retinal detachment and proliferative retinopathy. The eye became phthisical and underwent evisceration. Histopathologic examination of the excised cornea disclosed a full-thickness scar displaying mild to moderate chronic nongranulomatous inflammation with a focus of plasma cells (Figs. 2E and F) and subepithelial, congophilic, amorphous material that exhibited apple-green birefringence under polarized light and dichroism. Focal calcifications were present within and adjacent to the fragmented Bowman’s layer. Immunohistochemical studies showed AP, but no AA or
Discussion
On histopathologic examination, corneal amyloid generally appears as amorphous, pale, eosinophilic hyaline deposits within the corneal stroma on hematoxylin and eosin staining. This substance is congophilic, with apple-green birefringence with polarized light, and exhibits dichroism. Birefringence refers to the change in refractive index of light polarized in different directions through a substance,47 using polarizing lenses, with one fixed above the specimen in the microscope and the other rotated by the pathologist to produce the applegreen color in the amyloid deposit. In contrast, dichroism, a change in color of a substance that varies with the plane of polarized light,47 is characterized by a change in the intensity of redness of the amyloid deposit stained with Congo red using one polarizing lens that also is rotated by the pathologist as the amyloid itself acts as the second polarizer. Ultrastructural studies have demonstrated that amyloid filaments have a diameter of approximately 7e11 nm and can be arranged in an ordered or, more commonly, disordered fashion.9,47 Corneal amyloidosis may be classified into 2 main groupsdprimary and secondarydand may be localized or be part of a systemic deposition involving multiple tissues throughout the body.12 Primary corneal amyloidosis includes autosomal dominant entities such as lattice type 1 and combined
s u r v e y o f o p h t h a l m o l o g y 6 0 ( 2 0 1 5 ) 5 9 0 e5 9 5
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Fig. 2 e Histopathologic and immunohistochemical findings in 3 cases (1, 4, and 5). A: Prominent full-thickness corneal scar (chevron) and pale, amorphous, eosinophilic amyloid (black arrows) deposited in the subepithelial space (hematoxylin-eosin, original magnification, 100 X). B: The amyloid exhibits apple-green birefringence under polarized light (Congo red, original magnification, 100 X). C and D: Amyloid stains positively with Congo red and displays dichroism. Note that the dark pink area (black arrow) in C becomes light pink (transparent arrow) in D and vice-versa from D to C in the adjacent area (Congo red, original magnification, 100 X). E: Moderate chronic nongranulomatous inflammation is present adjacent to the amyloid deposits (hematoxylin-eosin, original magnification, 50 X). F: The inflammatory infiltrate in this case consists predominantly of plasma cells (hematoxylin-eosin, original magnification, 400 X). G: Positive staining of the amyloid deposits for Amyloid P protein (original magnification, 50 X). H: Negative staining of the amyloid deposits for Amyloid A protein (original magnification, 50 X).
granular-lattice (Avellino) corneal dystrophies, which are linked to missense mutations in the big-h3 gene (transforming growth factor b-induced gene) on chromosome 5q31,24,37 and the autosomal recessive gelatinous droplike corneal dystrophy, which is associated with mutations in the M1S1 gene located on the short arm of chromosome 1.42 Meretoja syndrome, a primary hereditary form of corneal amyloidosis, is characterized by systemic amyloidosis with latticelike corneal amyloid deposits caused by mutations in the GSN gene on chromosome 9q32-34.11,24,29 Secondary localized corneal amyloidosis is an uncommon condition in which amyloid deposition occurs following
chronic ocular surface inflammation and degeneration and may present as posterior polymorphous amyloid degeneration.20 Secondary localized corneal amyloidosis has also been associated with ocular trauma,22,30 trichiasis,2,5,6,15,23,25,45 keratoconus,4,30,36,39,41 and ocular inflammatory and degenerative conditions including interstitial keratitis,12 phlyctenular keratoconjunctivitis,30 syphilis,17 herpes keratitis,7,40 trachoma,16 congenital glaucoma,43 spheroidal elastotic (climatic droplet) keratopathy,26,28,34 pellucid marginal degeneration,18 and various corneal dystrophies including Fuchs’ endothelial dystrophy38 and congenital hereditary endothelial dystrophy.26,27,44 There currently is no
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s u r v e y o f o p h t h a l m o l o g y 6 0 ( 2 0 1 5 ) 5 9 0 e5 9 5
in addition to these 2 cases with perforating nonsurgical and surgical corneal trauma, our 5 cases represent, to our knowledge, the only other reported examples of secondary corneal amyloidosis following nonsurgical and surgical perforating corneal trauma in the English literature.
4.
Fig. 3 e Electron microscopic findings of amyloid in case 5. Organized and disorganized filaments approximately 8 nm in size (original magnification, 30,000 X).
consensus on the mechanism of amyloid deposition in secondary localized corneal amyloidosis, though some hypotheses have been put forth. It has been suggested that altered transforming growth factor b-induced protein produced by injured keratocytes may result in amyloid fibril deposition.39 Lactoferrin from the tear film3 and keratoepithelin from the corneal epithelium38 also have been proposed as precursor proteins of amyloid in the cornea. Amyloid deposition has been reported in other ocular structures, including the orbit,33 eyelids,31 lacrimal gland,32 conjunctiva,35 extraocular muscles, sclera, ciliary body, iris, the lens surface, trabecular meshwork, Schlemm canal, choroid, optic nerve,14 vitreous, and retina.1 AP protein is present in all of the amyloidoses and may be bound to amyloid fibrils.47 The amyloid filaments of primary systemic amyloidosis are termed AL protein, which consists of portions of kappa and lambda immunoglobulin light chains. Alternatively, the amyloid filaments of secondary systemic amyloidosis are termed AA protein and are related to a nonimmunoglobulin serum protein that may be deposited in chronic inflammatory infectious and noninfectious diseases.47 Three of our corneal cases that were tested for AP protein were positive, and all 4 of our cases that were tested for AL and AA proteins were negative. Similarly, Gorevic and colleagues were unable to demonstrate AA amyloid positivity using multiple techniques in the corneal stromal amyloid deposits of patients with polymorphous amyloid degeneration and lattice corneal dystrophy.13 There have been many previous reports of corneal amyloid deposition associated with nonperforating trauma and wound healing,2,3,5,6,15,19,23,25,38,45,46 with trichiasis2,5,6,15,23,25,45 being the most common mechanism of injury in these cases. We found only 2 reports describing secondary corneal amyloidosis following perforating trauma. Javadi and colleagues collected 48 cases of mustard gas keratitis in survivors of Iraqi chemical warfare, of which 21 (43.8%) had corneal amyloid deposits.19 Of these, only one also had a corneal perforation (Table 1). Yamada and colleagues reported a case of secondary amyloidosis in a failed corneal graft in a 30-year-old woman with keratoconus who had underwent penetrating keratoplasty at age 17.46 It could not be determined, however, whether it was prolonged use of hard contact lenses or the surgical trauma that led to the amyloid deposition. Therefore,
Conclusion
Over a period of 10 years, our laboratory received 3,070 ophthalmic specimens, of which 1,058 were penetrating keratoplasties and 222 were eviscerations, with only 5 corneal specimens demonstrating secondary posttraumatic localized amyloidosis. Of these 5 cases, 3 were penetrating keratoplasties and 2 were from evisceration procedures (Table 1). This observation, coupled with the fact that there are few reports of secondary corneal amyloidosis from perforating trauma in the literature, suggests that secondary localized corneal amyloidosis is a rare condition. Other degenerative conditions have been reported in patients with perforating corneal trauma, including corneal elastotic degeneration,10 corneal fibromatosis (keloid),21 and corneal myxoma.8 Chronic inflammation may play a role in amyloid deposition, as previously suggested.25 All of our 5 corneal cases displayed mild to moderate chronic nongranulomatous inflammation adjacent to areas of amyloid deposition. We hypothesize that the type of corneal degeneration occurring following trauma associated with chronic inflammation, whether it is amyloid, elastotic, fibromatous, myxomatous, or of another type, may be determined by a patient’s genetic predisposition.
5.
Method of literature search
A search of the PubMed (1974e2015) database was conducted using the search phrases: secondary corneal amyloidosis and corneal amyloidosis. A search of the Medline (1940e2015) database was performed using the Ovid interface. The search was conducted using the key words: secondary and corneal amyloidosis. Articles in languages other than English were not included.
6.
Disclosure
The authors have no financial or proprietary disclosure in relation to this article.
references
1. Alberto R, Luigi S, Ambrogio F, et al. Bilateral optic neuropathy and intraretinal deposits after pars plana vitrectomy in amyloidosis. Indian J Ophthalmol. 2015;63(1):72e4 2. Aldave AJ, Principe AH, Lin DY, et al. Lattice dystrophy-like localized amyloidosis of the cornea secondary to trichiasis. Cornea. 2005;24(1):112e5
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3. Araki-Sasaki K, Ando Y, Nakamura M, et al. Lactoferrin Glu561Asp facilitates secondary amyloidosis in the cornea. Br J Ophthalmol. 2005;89(6):684e8 4. Araki-Sasaki K, Hirano K, Osakabe Y, et al. Classification of secondary corneal amyloidosis and involvement of lactoferrin. Ophthalmology. 2013;120(6):1166e72 5. Araki-Sasaki K, Osakabe Y, Fukuoka H, et al. Findings of secondary corneal amyloidosis with ultrahigh-resolution optical coherence tomography. Clin Ophthalmol. 2014;8(14):2115e9 6. Aso K, Wakakura M. Corneal amyloidosis complicated by trichiasis: immunohistochemical identification of the amyloid light chain protein. Jpn J Ophthalmol. 2000;44(2):191 7. Bell JA. Corneal amyloidosis. Br J Ophthalmol. 1990;74(5):320 8. Belliveau MJ, Liao WN, Brownstein S, et al. Myxomatous corneal degeneration: a clinicopathological study of six cases and a review of the literature. Surv Ophthalmol. 2012;57(3):264e71 9. Benjamin M, Brownstein S, Bao W, et al. Unusual superficial variant of granular corneal dystrophy with amyloid deposition. Arch Ophthalmol. 2003;121(2):269e71 10. Brownstein S, Rodrigues MM, Fine BS, Albert EN. The elastotic nature of hyaline corneal deposits. Am J Ophthalmol. 1973;75(5):799e809 11. Carrwik C, Stenevi U. Lattice corneal dystrophy, gelsolin type (Meretoja’s syndrome). Acta Ophthalmol. 2009;87(8):813e9 12. Dutt S, Elner VM, Soong HK, et al. Secondary localized amyloidosis in interstitial keratitis: clinicopathologic findings. Ophthalmology. 1992;99(5):817e23 13. Gorevic PD, Rodrigues MM, Krachmer JH, et al. Lack of evidence for protein AA reactivity in amyloid deposits of lattice corneal dystrophy and amyloid corneal degeneration. Am J Ophthalmol. 1984;98(2):216e24 14. Haraoka K, Ando Y, Ando E, et al. Amyloid deposition in ocular tissues of patients with familial amyloidotic polyneuropathy (FAP). Amyloid. 2002;9(3):183e9 15. Hayasaka S, Setogawa T, Ohmura M. Secondary localized amyloidosis of the cornea caused by trichiasis. Ophthalmologica. 1987;194(2-3):77e81 16. Hidayat AA, Risco JM. Amyloidosis of corneal stroma in patients with trachoma: a clinicopathologic study of 62 cases. Ophthalmology. 1989;96(8):1203e11 17. Hill JC, Maske R, Bowen RM. Secondary localized amyloidosis of the cornea associated with tertiary syphilis. Cornea. 1990;9(2):98e101 18. Hsu HY, Phillips NJ, Harocopos GJ. Secondary amyloidosis in the hydrops lesion of a patient with pellucid marginal degeneration. Cornea. 2007;26(8):992e4 19. Javadi MA, Yazdani S, Sajjadi H, et al. Chronic and delayedonset mustard gas keratitis: report of 48 patients and review of literature. Ophthalmology. 2005;112(4):617e25 20. Jiang K, Brownstein S, Lam K, et al. Posterior polymorphous amyloid degeneration. JAMA Ophthalmol. 2014;132(6):736 21. Jung JJ, Wojno TH, Grossniklaus HE. Giant corneal keloid: case report and review of the literature. Cornea. 2010;29(12):1455e8 22. Khalifa YM, Bloomer MM, Margolis TP. Secondary localized sectoral keratoconjunctival amyloidosis from ocular trauma. Cornea. 2010;29(11):1328e9 23. Klemen UM, Kulnig W, Radda TM. Secondary corneal amyloidosis: clinical and pathohistological examinations. Graefes Arch Clin Exp Ophthalmol. 1983;220(3):130e8 24. Klintworth GK. Advances in the molecular genetics of corneal dystrophies. Am J Ophthalmol. 1999;128(6):747e54 25. Lin PY, Kao SC, Hsueh KF, et al. Localized amyloidosis of the cornea secondary to trichiasis: clinical course and pathogenesis. Cornea. 2003;22(5):491e4
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26. Loeffler KU, Edward DP, Tso MOM. An immunohistochemical study of gelsolin immunoreactivity in corneal amyloidosis. Am J Ophthalmol. 1992;113(5):546e54 27. Mahmood MA, Teichmann KD. Corneal amyloidosis associated with congenital hereditary endothelial dystrophy. Cornea. 2000;19(4):570e3 28. Matta CS, Tabbara KF, Cameron JA, et al. Climatic droplet keratopathy with corneal amyloidosis. Ophthalmology. 1991;98(2):192e5 29. Mattila JS, Krootila K, Kivela¨ T, Holopainen JM. Penetrating keratoplasty for corneal amyloidosis in Familial Amyloidosis, Finnish Type. Ophthalmology. 2015;122(3):457e63 30. McPherson SD, Kiffney GT, Freed CC. Corneal amyloidosis. Am J Ophthalmol. 1966;62(6):1025e33 31. Nair AG, Mukherjee B, Krishnakumar S, Biswas J, Mehta RA. Unilateral primary cutaneous amyloidosis of the eyelid masquerading as a chalazion. Can J Ophthalmol. 2014;49(5):e112e4 32. Prabhakaran VC, Babu K, Mahadevan A, Murthy SR. Amyloidosis of lacrimal gland. Indian J Ophthalmol. 2009;57(6):461e3 33. Rawlings NG, Brownstein S, Robinson JW, Jordan DR. Solitary osseous plasmacytoma of the orbit with amyloidosis. Ophthal Plast Reconstr Surg. 2007;23(1):79e80 34. Santo RM, Yamaguchi T, Kanai A. Spheroidal keratopathy associated with subepithelial corneal amyloidosis: a clinicopathologic case report and a proposed new classification for spheroidal keratopathy. Ophthalmology. 1993;100(10):1455e61 35. Spitellie PH, Jordan DR, Gooi P, Brownstein S, Burns BF. Primary localized conjunctival amyloidosis simulating a lymphoproliferative disorder. Ophthal Plast Reconstr Surg. 2008;24(5):417e9 36. Stern GA, Knap A, Hood I. Corneal amyloidosis associated with keratoconus. Ophthalmology. 1988;95(1):52e5 37. Streeten BW, Qi Y, Klintworth GK, et al. Immunolocalization of big-h3 protein in 5q31-linked corneal dystrophies and normal corneas. Arch Ophthalmol. 1999;117(1):67e75 38. Suesskind D, Auw-Haedrich C, Schorderet DF, et al. Keratoepithelin in secondary corneal amyloidosis. Graefes Arch Clin Exp Ophthalmol. 2006;244(6):725e31 39. Tai TYT, Damani MR, Vo R, et al. Keratoconus associated with corneal stromal amyloid deposition containing TGFBIp. Cornea. 2009;28(5):589e93 40. Tejwani D, Azuara-Blanco A. Localised corneal amyloidosis associated with herpetic keratitis. Br J Ophthalmol. 2003;87(8):1049 41. Trikha S, Sahu D, Jeffry M, Boase D. Secondary corneal amyloidosis in keratoconus. Cornea. 2011;30(6):716e7 42. Tsujikawa M, Kurahashi H, Tanaka T, et al. Identification of the gene responsible for gelatinous drop-like corneal dystrophy. Nat Genet. 1999;21(4):420e3 43. Vemuganti GK, Mandal AK. Subepithelial corneal amyloid deposits in a case of congenital glaucoma: a case report. Cornea. 2002;21(3):315e7 44. Vemuganti GK, Sridhar MS, Edward DP, Singh S. Subepithelial amyloid deposits in congenital hereditary endothelial dystrophy: a histopathologic study of five cases. Cornea. 2002;21(5):524e9 45. Watts J, Frank H. Corneal amyloidosis. Br J Ophthalmol. 1989;73(8):674e6 46. Yamada M, Nishiyama T, Konishi M, Mashima Y. Secondary amyloidosis in a corneal graft. Jpn J Ophthalmol. 2002;46(3):305e7 47. Yanoff M, Sassani JW. Ocular Pathology. China, Elsevier; 6th ed, 2009, pp 238e40, 283.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/survophthal
Clinical pathologic reviews
Secondary corneal amyloidosis after perforating corneal trauma: A series of 5 cases and review of the literature Solin Saleh, MDa,b, Seymour Brownstein, MDa,b,*, Joshua S. Manusow, MDa,b, Andre´ Jastrzebski, MDa,b, Kay Lam, MDa,b, Joseph W. Sassani, MDc,d, George Mintsioulis, MDa, Steven M. Gilberg, MDa a
Department of Ophthalmology, The Ottawa Hospital, Ottawa, Ontario, Canada Department of Pathology, The Ottawa Hospital, Ottawa, Ontario, Canada c Department of Ophthalmology, Milton S. Hershey Medical Centre, Pennsylvania State University, Hershey, Pennsylvania, USA d Department of Pathology, Milton S. Hershey Medical Centre, Pennsylvania State University, Hershey, Pennsylvania, USA b
article info
abstract
Article history:
We retrospectively reviewed the clinical and surgical histories of 5 patients with traumatic
Received 5 May 2015
secondary corneal amyloidosis, a relatively rare sequela of nonsurgical and surgical
Received in revised form
perforating corneal trauma. Four had history of nonsurgical trauma, and 1 had surgical
25 June 2015
trauma to the cornea. Three specimens were obtained by penetrating keratoplasties and 2
Accepted 17 July 2015
by excision of the cornea during evisceration of the ocular contents. All the corneal
Available online 4 August 2015
specimens showed full-thickness scars of a prior perforating wound with congophilic
Stefan Seregard and Hans
amyloid deposits that exhibited apple-green birefringence under polarized light and
Grossniklaus, Editors
dichroism. All cases had variable degrees of predominantly chronic nongranulomatous inflammation. Ultrastructural examination in 1 patient disclosed 8-nm diameter fibrils in
Keywords:
disarray, consistent with amyloid. Amyloid P immunostaining was positive in all 3 patients
cornea
tested for this protein.
amyloid
ª 2015 Elsevier Inc. All rights reserved.
secondary corneal amyloidosis perforating corneal trauma corneal degeneration pathology
* Corresponding author: Seymour Brownstein, MD, Department of Ophthalmology, The Ottawa Hospital, 501 Smyth Road, Suite W6213, Ottawa, Ontario K1H 8L6, Canada. E-mail address: [email protected] (S. Brownstein). 0039-6257/$ e see front matter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.survophthal.2015.07.004
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s u r v e y o f o p h t h a l m o l o g y 6 0 ( 2 0 1 5 ) 5 9 0 e5 9 5
1.
Introduction
2.2.
Corneal amyloidosis is an infrequent condition that occurs when normally soluble autologous proteins are deposited in tissues as abnormal insoluble fibrils.2 Amyloidosis may be classified into 2 main groups, primary and secondary, each of which is further divided into systemic or localized.47 Secondary localized amyloidosis is uncommon, and secondary amyloid deposition following corneal trauma and wound healing is rarely reported. We present 5 cases of secondary corneal amyloidosis after surgical and nonsurgical perforating trauma (Table 1) and suggest a pathogenesis of this uncommon condition.
2.
Case reports
2.1.
Case 1
A 35-year-old man underwent a left corneal transplant for a scar sustained from a corneal laceration at age 6 years, which also resulted in amblyopia in that eye. On examination, the visual acuity was 20/200 with pinhole improvement to 20/80 in the left eye, and there was no maculopathy. Histopathologic examination of the excised cornea disclosed a full-thickness scar displaying mild chronic nongranulomatous inflammation. Anterior to the adjacent, residual Bowman layer, there was a large accumulation of congophilic, amorphous material that exhibited apple-green birefringence and dichroism under polarized light. Immunohistochemical studies for amyloid A (AA) and amyloid L (AL) proteins were negative; amyloid P (AP) protein testing was not performed in this case. The diagnosis was secondary localized corneal amyloidosis after nonsurgical perforating trauma.
2.3.
A 31-year-old man sustained nonsurgical trauma to his right cornea 20 years previously that was managed at the time with a keratoplasty. The ocular history also included 2 retinal detachment surgeries, and the past medical history was otherwise unremarkable. He had no light perception and corneal opacification in the right eye (Fig. 1A). The left eye was normal. He underwent evisceration and placement of an orbital implant for a phthisical, blind, painful right eye. Histopathologic examination of the excised cornea showed a full-thickness scar with subepithelial deposits of an amorphous, eosinophilic material (Fig. 2A) that exhibited Congo red positivity with apple-green birefringence (Fig. 2B) and dichroism (Figs. 2C and D). A mild chronic nongranulomatous inflammatory infiltrate was present adjacent to the corneal scar. The diagnosis was secondary localized corneal amyloidosis after surgical perforating trauma.
Case 2
Case 3
A 37-year-old woman underwent a right corneal transplant for a corneal scar sustained at age 18 months from a nonsurgical perforating wound caused by glass (Fig. 1B). On ocular examination, she had a best-corrected visual acuity of counting fingers in the right eye, and there was no maculopathy. The left eye was normal. Histopathologic examination demonstrated a full-thickness scar in the excised left cornea with mild chronic nongranulomatous inflammation and subepithelial deposits of amorphous, homogenous, congophilic material. Immunohistochemical studies showed AP protein deposits, but no AA or AL proteins were detected. Secondary localized corneal amyloidosis after nonsurgical perforating trauma was diagnosed.
2.4.
Case 4
A 54-year-old man sustained a corneoscleral laceration by a screwdriver at age 34, following which he developed a
Table 1 e Clinical and immunohistochemical features of reported cases of secondary corneal amyloidosis following nonsurgical and surgical perforating corneal trauma Reference
Age (years)
Sex
Case 1
31
M
Case 2
35
M
Case 3
37
F
Case 4
54
M
Case 5
52
M
Javadi et al16 Yamada et al18
33 30
M F
History and timeline of injury Nonsurgical trauma and PK and 20 years previously Corneal laceration and 29 years previously Corneal penetration by glass and 36 years previously Corneoscleral laceration by screwdriver and 20 years previously Corneal penetration by arrow and 45 years previously Mustard gas keratitis Keratoconus, PK, subsequent hard contact lens wear
Clinical description
Source of specimen
Immunohistochemistry
Corneal opacification
Evisceration
Not available
Full-thickness central corneal scar Fibrovascular central corneal scar Thin, scarred cornea and band keratopathy
PK
AP (not available), AA, AL
PK
APþ, AA, AL
Evisceration
APþ, AA, AL
Fibrovascular corneal scar
PK
APþ, AA, AL
Corneal scar Nodular gray-white opacities in subepithelial zone of graft
LK Superficial keratectomy
NR NR
M, male; F, female; PK, penetrating keratoplasty; AP, amyloid P protein; AA, amyloid A protein; AL, AL protein; NR, not reported; LK, lamellar keratoplasty.
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AL proteins. The diagnosis was secondary corneal amyloidosis with band keratopathy after nonsurgical perforating trauma.
2.5.
Case 5
A 52-year-old man sustained an arrow injury to his left eye at age 7 years that left him with an extensive central corneal fibrovascular scar (Fig. 1C). The management was a corneal graft and insertion of an anterior chamber intraocular lens. There was no maculopathy on fundus examination. Histopathologic examination of the excised cornea disclosed irregularly thickened and thinned epithelium overlying prominent, full-thickness scars. There were focal deposits of amorphous, homogenous material subepithelialy focally replacing Bowman layer. The deposits were congophilic with apple-green birefringence under polarized light. The underlying stroma was extensively scarred, edematous and vascularized and disclosed a mild chronic nongranulomatous inflammatory infiltrate. Descemet membrane was thickened and fragmented and the endothelium was only focally present. Immunohistochemical evaluation demonstrated positive staining of the deposits for AP protein (Fig. 2G), and negative staining for AA protein (Fig. 2H) and AL protein. Transmission electron microscopic examination disclosed subepithelial deposits of disorganized filaments 8 nm in diameter consistent with amyloid (Fig. 3). The diagnosis was secondary corneal amyloidosis resulting from nonsurgical perforating trauma. The immunohistochemical analyses of these formalinfixed, paraffin-embedded corneal specimens involved staining with rabbit polyclonal antibodies against AP protein, mouse monoclonal antibodies against AA protein, and rabbit monoclonal antibodies against AL protein, which is comprised of kappa and lambda immunoglobulin light chains.
3.
Fig. 1 e Clinical findings in 3 cases (1, 3, and 5). A: Opacification of the right cornea in case 1. B: White, central corneal scar in case 3. C: White, central corneal scar with vascularization in case 5. funnel-shaped retinal detachment and proliferative retinopathy. The eye became phthisical and underwent evisceration. Histopathologic examination of the excised cornea disclosed a full-thickness scar displaying mild to moderate chronic nongranulomatous inflammation with a focus of plasma cells (Figs. 2E and F) and subepithelial, congophilic, amorphous material that exhibited apple-green birefringence under polarized light and dichroism. Focal calcifications were present within and adjacent to the fragmented Bowman’s layer. Immunohistochemical studies showed AP, but no AA or
Discussion
On histopathologic examination, corneal amyloid generally appears as amorphous, pale, eosinophilic hyaline deposits within the corneal stroma on hematoxylin and eosin staining. This substance is congophilic, with apple-green birefringence with polarized light, and exhibits dichroism. Birefringence refers to the change in refractive index of light polarized in different directions through a substance,47 using polarizing lenses, with one fixed above the specimen in the microscope and the other rotated by the pathologist to produce the applegreen color in the amyloid deposit. In contrast, dichroism, a change in color of a substance that varies with the plane of polarized light,47 is characterized by a change in the intensity of redness of the amyloid deposit stained with Congo red using one polarizing lens that also is rotated by the pathologist as the amyloid itself acts as the second polarizer. Ultrastructural studies have demonstrated that amyloid filaments have a diameter of approximately 7e11 nm and can be arranged in an ordered or, more commonly, disordered fashion.9,47 Corneal amyloidosis may be classified into 2 main groupsdprimary and secondarydand may be localized or be part of a systemic deposition involving multiple tissues throughout the body.12 Primary corneal amyloidosis includes autosomal dominant entities such as lattice type 1 and combined
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Fig. 2 e Histopathologic and immunohistochemical findings in 3 cases (1, 4, and 5). A: Prominent full-thickness corneal scar (chevron) and pale, amorphous, eosinophilic amyloid (black arrows) deposited in the subepithelial space (hematoxylin-eosin, original magnification, 100 X). B: The amyloid exhibits apple-green birefringence under polarized light (Congo red, original magnification, 100 X). C and D: Amyloid stains positively with Congo red and displays dichroism. Note that the dark pink area (black arrow) in C becomes light pink (transparent arrow) in D and vice-versa from D to C in the adjacent area (Congo red, original magnification, 100 X). E: Moderate chronic nongranulomatous inflammation is present adjacent to the amyloid deposits (hematoxylin-eosin, original magnification, 50 X). F: The inflammatory infiltrate in this case consists predominantly of plasma cells (hematoxylin-eosin, original magnification, 400 X). G: Positive staining of the amyloid deposits for Amyloid P protein (original magnification, 50 X). H: Negative staining of the amyloid deposits for Amyloid A protein (original magnification, 50 X).
granular-lattice (Avellino) corneal dystrophies, which are linked to missense mutations in the big-h3 gene (transforming growth factor b-induced gene) on chromosome 5q31,24,37 and the autosomal recessive gelatinous droplike corneal dystrophy, which is associated with mutations in the M1S1 gene located on the short arm of chromosome 1.42 Meretoja syndrome, a primary hereditary form of corneal amyloidosis, is characterized by systemic amyloidosis with latticelike corneal amyloid deposits caused by mutations in the GSN gene on chromosome 9q32-34.11,24,29 Secondary localized corneal amyloidosis is an uncommon condition in which amyloid deposition occurs following
chronic ocular surface inflammation and degeneration and may present as posterior polymorphous amyloid degeneration.20 Secondary localized corneal amyloidosis has also been associated with ocular trauma,22,30 trichiasis,2,5,6,15,23,25,45 keratoconus,4,30,36,39,41 and ocular inflammatory and degenerative conditions including interstitial keratitis,12 phlyctenular keratoconjunctivitis,30 syphilis,17 herpes keratitis,7,40 trachoma,16 congenital glaucoma,43 spheroidal elastotic (climatic droplet) keratopathy,26,28,34 pellucid marginal degeneration,18 and various corneal dystrophies including Fuchs’ endothelial dystrophy38 and congenital hereditary endothelial dystrophy.26,27,44 There currently is no
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in addition to these 2 cases with perforating nonsurgical and surgical corneal trauma, our 5 cases represent, to our knowledge, the only other reported examples of secondary corneal amyloidosis following nonsurgical and surgical perforating corneal trauma in the English literature.
4.
Fig. 3 e Electron microscopic findings of amyloid in case 5. Organized and disorganized filaments approximately 8 nm in size (original magnification, 30,000 X).
consensus on the mechanism of amyloid deposition in secondary localized corneal amyloidosis, though some hypotheses have been put forth. It has been suggested that altered transforming growth factor b-induced protein produced by injured keratocytes may result in amyloid fibril deposition.39 Lactoferrin from the tear film3 and keratoepithelin from the corneal epithelium38 also have been proposed as precursor proteins of amyloid in the cornea. Amyloid deposition has been reported in other ocular structures, including the orbit,33 eyelids,31 lacrimal gland,32 conjunctiva,35 extraocular muscles, sclera, ciliary body, iris, the lens surface, trabecular meshwork, Schlemm canal, choroid, optic nerve,14 vitreous, and retina.1 AP protein is present in all of the amyloidoses and may be bound to amyloid fibrils.47 The amyloid filaments of primary systemic amyloidosis are termed AL protein, which consists of portions of kappa and lambda immunoglobulin light chains. Alternatively, the amyloid filaments of secondary systemic amyloidosis are termed AA protein and are related to a nonimmunoglobulin serum protein that may be deposited in chronic inflammatory infectious and noninfectious diseases.47 Three of our corneal cases that were tested for AP protein were positive, and all 4 of our cases that were tested for AL and AA proteins were negative. Similarly, Gorevic and colleagues were unable to demonstrate AA amyloid positivity using multiple techniques in the corneal stromal amyloid deposits of patients with polymorphous amyloid degeneration and lattice corneal dystrophy.13 There have been many previous reports of corneal amyloid deposition associated with nonperforating trauma and wound healing,2,3,5,6,15,19,23,25,38,45,46 with trichiasis2,5,6,15,23,25,45 being the most common mechanism of injury in these cases. We found only 2 reports describing secondary corneal amyloidosis following perforating trauma. Javadi and colleagues collected 48 cases of mustard gas keratitis in survivors of Iraqi chemical warfare, of which 21 (43.8%) had corneal amyloid deposits.19 Of these, only one also had a corneal perforation (Table 1). Yamada and colleagues reported a case of secondary amyloidosis in a failed corneal graft in a 30-year-old woman with keratoconus who had underwent penetrating keratoplasty at age 17.46 It could not be determined, however, whether it was prolonged use of hard contact lenses or the surgical trauma that led to the amyloid deposition. Therefore,
Conclusion
Over a period of 10 years, our laboratory received 3,070 ophthalmic specimens, of which 1,058 were penetrating keratoplasties and 222 were eviscerations, with only 5 corneal specimens demonstrating secondary posttraumatic localized amyloidosis. Of these 5 cases, 3 were penetrating keratoplasties and 2 were from evisceration procedures (Table 1). This observation, coupled with the fact that there are few reports of secondary corneal amyloidosis from perforating trauma in the literature, suggests that secondary localized corneal amyloidosis is a rare condition. Other degenerative conditions have been reported in patients with perforating corneal trauma, including corneal elastotic degeneration,10 corneal fibromatosis (keloid),21 and corneal myxoma.8 Chronic inflammation may play a role in amyloid deposition, as previously suggested.25 All of our 5 corneal cases displayed mild to moderate chronic nongranulomatous inflammation adjacent to areas of amyloid deposition. We hypothesize that the type of corneal degeneration occurring following trauma associated with chronic inflammation, whether it is amyloid, elastotic, fibromatous, myxomatous, or of another type, may be determined by a patient’s genetic predisposition.
5.
Method of literature search
A search of the PubMed (1974e2015) database was conducted using the search phrases: secondary corneal amyloidosis and corneal amyloidosis. A search of the Medline (1940e2015) database was performed using the Ovid interface. The search was conducted using the key words: secondary and corneal amyloidosis. Articles in languages other than English were not included.
6.
Disclosure
The authors have no financial or proprietary disclosure in relation to this article.
references
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