Pathology in Practice

Andrew M. Enders Department of Ophthalmology, The Bobst Hospital of the Animal Medical Center, 510 East 62nd St, New York, NY 10065.

Search for other papers by Andrew M. Enders in
Current site
Google Scholar
PubMed
Close
 DVM
,
Taryn A. Donovan Department of Anatomic Pathology, The Bobst Hospital of the Animal Medical Center, 510 East 62nd St, New York, NY 10065.

Search for other papers by Taryn A. Donovan in
Current site
Google Scholar
PubMed
Close
 DVM
, and
Alexandra van der Woerdt Department of Ophthalmology, The Bobst Hospital of the Animal Medical Center, 510 East 62nd St, New York, NY 10065.

Search for other papers by Alexandra van der Woerdt in
Current site
Google Scholar
PubMed
Close
 DVM, MS

History

A 10-year-old 1.13-kg (2.5-lb) spayed female Holland lop rabbit (Oryctolagus cuniculus) was evaluated at The Animal Medical Center Emergency Service because of bilateral ocular and nasal discharge. The owner noted the discharge upon return from a 3-month period away during which the pet-sitter did not report any clinical signs. Past medical history included a cloudy appearance of the eyes 8 months prior, which was presumed by the owner to represent senile cataracts.

Clinical and Gross Findings

On evaluation, the rabbit was mildly under-conditioned with bilateral mucopurulent discharge from the eyes and nares. Auscultation of the thorax revealed wheezes in all fields. The remainder of the physical examination findings were unremarkable.

Ophthalmic abnormalities in the anterior segment of both eyes included mild conjunctival hyperemia, corneal edema, aqueous flare, and mature cataract. Habb striae were present in the left eye.

The irises appeared thickened; moreover, the brown irises were effaced with a white, reflective material associated with neovascularization. Bilaterally, it was not possible to visualize the posterior segment of the eyes. Pupillary light and dazzle reflexes were absent bilaterally. Schirmer tear test values were considered normal1,2 with 7 mm and 4 mm of test strip wetting/min in the right and left eye, respectively. Intraocular pressures measured by applanation tonometry were elevated (right eye, 38 mm Hg; left eye, 42 mm Hg [reference range,1,2 14 to 21 mm Hg]). Given the age of the rabbit and concern for underlying systemic disease, the owner elected euthanasia by means of an IV overdose of pentobarbital, and postmortem evaluation of the ocular tissues was performed.

At postmortem examination, both eyes were enlarged (buphthalmia); however, the left eye was larger than the right. Bilaterally periocular alopecia and adherent mucopurulent discharge were noted. There was variable corneal opacity bilaterally with yellow to tan to white mottling and prominent vascularization of the left iris (Figure 1). The globes were bisected. The left eye contained abundant white material in the anterior and posterior chambers, and the retina was detached. The right eye contained smaller amounts of similar white material in the posterior chamber, and the retina was in place.

Figure 1—
Figure 1—

Photograph of the left eye of a 10-year-old Holland lop rabbit (Oryctolagus cuniculus) that had bilateral ocular and nasal discharge. The owner noted the discharge upon return from a 3-month period away during which the pet-sitter did not report any clinical signs. Notice that the cornea is cloudy and there is a poorly demarcated, vascularized region of iris discoloration (arrow).

Citation: Journal of the American Veterinary Medical Association 253, 8; 10.2460/javma.253.8.991

Formulate differential diagnoses from the history, clinical findings, and Figure 1—then turn the page→

Histopathologic Findings

Two sections from each bisected globe were examined histologically. In the left eye, at the anterior aspect of the iris and extending from the iridocorneal angle to the tip of the iris, there was a focus of osseous metaplasia characterized by mature, lamellar bone with Haversian canals containing osteocytes and multiple marrow spaces lined by osteoblasts. Rare osteoclasts were observed (Figure 2). A pre-iridal fibrovascular membrane was concurrently present at the site of osseous metaplasia, with adherence of the iris to the anterior surface in some sections (ectropion uvea) and multifocal adherence of the iris to the Descemet membrane (anterior synechiae). Small amounts of mineralization and bone formation were observed in the ciliary body, within the stroma at the base of the pars plicata. In the anterior and posterior chambers, there was acellular, homogeneous, lightly eosinophilic material (presumed serum proteins) with scattered macrophages. The retina was detached with regional hypertrophy of retinal pigment epithelial cells. Retinal atrophy was characterized by depletion of the ganglion cell layer, fusion and depletion of the inner and outer nuclear layers, and atrophy of the photoreceptor inner and outer segments (Figure 3). In some regions, the retina was overlain by collagen, within which were small numbers of spindle cells. The optic nerve was markedly depressed (interpreted as marked optic nerve cupping in light of the normal physiologic cupping expected for this species). Rare multinucleated giant cells and cholesterol clefts were observed in the pars plicata of the ciliary body, choroid, and retina. Small populations of lymphocytes and plasma cells were evident in the choroid. The lens fibers at the periphery were rounded and swollen (Morgagnian globules) with large accumulations of acellular, fragmented to round, basophilic material (mineral). In the corneal stroma, small numbers of lymphocytes and plasma cells were accompanied by stromal neovascularization, edema, and rare accumulation of acellular basophilic material (mineralization).

Figure 2—
Figure 2—

Photomicrographs of sections of the left eye (removed after euthanasia) of the rabbit in Figure 1. A—In this view, the cornea is to the right of the image. A section of the globe has well-defined foci of mature lamellar bone (osseous metaplasia) on the anterior surface of the iris (large arrows). H&E stain; bar = 5 mm. B—Higher-magnification view of the iris and ciliary body (area outlined in panel A). The bone is composed of mature lamellar bone. H&E stain; bar = 500 μm. C—High-magnification view of the iris with osseous metaplasia (area outlined in panel B). A pre-iridal fibrovascular membrane is present at the anterior surface of the iris (thin arrow). The osseous metaplasia is characterized by mature, lamellar bone containing osteocytes and multiple marrow spaces lined by osteoblasts. There are rare osteoclasts in the marrow spaces (asterisk). H&E stain; bar = 50 μm.

Citation: Journal of the American Veterinary Medical Association 253, 8; 10.2460/javma.253.8.991

Figure 3—
Figure 3—

Photomicrographs of sections of the left eye of the rabbit in Figure 1. A—Retinal atrophy is characterized by depletion of the ganglion cell layer with few remaining ganglion cells (horizontal large arrow), fusion and depletion of the inner and outer nuclear layers (thin arrow), and atrophy of the photoreceptor inner and outer segments (vertical large arrow). The retina is detached with regional hypertrophy of retinal pigment epithelial cells (asterisk). H&E stain; bar = 20 μm. B—In the pars plicata of the ciliary body, there are multinucleated giant cells (large arrows) and cholesterol clefts (thin arrow). H&E stain; bar = 50 μm. C—In this view, the lens capsule is to the left of the image. Cortical lens fibers are liquefied and replaced by basophilic granular material (mineral [thin arrow]). Scattered Morgagnian globules (large arrow) remain within the liquefied lens fibers. H&E stain; bar = 10 μm.

Citation: Journal of the American Veterinary Medical Association 253, 8; 10.2460/javma.253.8.991

In the rabbit's right eye, minimal scattered lymphocytes and plasma cells had infiltrated the anterior uvea and a pre-iridal fibrovascular membrane lined the anterior iris surface. Multiple sections of the right eye did not reveal osseous metaplasia in the iris or ciliary body. Mild neovascularization, edema, and scattered lymphoplasmacytic infiltrates were observed in the cornea. The lens contained rounded, eosinophilic lens fibers (Morgagnian globules). Marked optic nerve cupping was also present in this eye and was similar to that observed in the left eye. The retina was predominantly intact, but multifocally was detached and atrophied with loss of ganglion cells and mild fusion of the inner and outer nuclear layers.

Sections of each eye were processed with special stains. Staining with Ziehl-Neelsen stain, Gram stain (Brown and Hopps), or Gomori methenamine silver stain did not reveal any evidence of acid-fast bacteria, fungi, or microsporidial parasites.

Morphologic Diagnosis and Case Summary

Morphologic diagnosis: mild chronic, granulomatous, lymphoplasmacytic panuveitis with pre-iridal fibrovascular membrane formation, ectropion uvea, anterior synechiae, iridal osseous metaplasia, ciliary body mineralization, and osseous metaplasia and buphthalmia with optic disc cupping (glaucoma); lenticular cataractous changes with mineralization; retinal detachment and atrophy; anterior and posterior protein accumulation (presumptive serum proteins); and mild lymphoplasmacytic keratitis with corneal neovascularization and rare mineralization of the left eye. Minimal lymphoplasmacytic anterior uveitis with lenticular cataractous changes, mild retinal atrophy and detachment, buphthalmia with optic nerve cupping (glaucoma); and mild lymphoplasmacytic keratitis with corneal neovascularization and edema of the right eye.

Case summary: intraocular osseous metaplasia in a Holland lop rabbit.

Comments

Rabbits are increasingly popular pets and are commonly used as laboratory animals in ophthalmology research. As a species, they are affected by adnexal, ocular surface, and intraocular diseases including dacryocystitis, corneal stromal abscess, uveitis, goniodysgenesis, and retrobulbar disease.1,2 To the authors' knowledge, this was the first report of intraocular osseous metaplasia in a rabbit.

Ocular osteogenesis, also known as osseous metaplasia or heterotopic ossification, can occur in any part of the eyes and has been detected in humans, dogs, cats, horses, guinea pigs, and chickens.3–11 Ocular osteogenesis is considered to represent soft tissue calcification and is classified as either metastatic calcification, dystrophic calcification osseous choristoma, or ectopic mineralization.12,13 Meta-static calcification occurs when circulating calcium and phosphorus concentrations are elevated as a result of systemic disease (eg, renal disease or hypervitaminosis D). Dystrophic calcification occurs with local tissue disease that involves tissue damage or devitalization (eg, trauma or neoplasia).

Osseous metaplasia implies a form of dystrophic calcification wherein local cells differentiate into osteogenic cells in response to a traumatic, neoplastic, or metabolic insult.6 Osseous metaplasia in the ciliary body, choroid, and retina has most often been described, leading to the proposed mechanism that vascular delivery of osteoblasts occurred in tissues with inherent high vascularity.14,15 In the rabbit of the present report, osseous metaplasia was associated with the iris and ciliary body in the left eye. The bone was noted to be at the anteriormost surface, which may reflect osseous metaplasia of the iris stromal cells with subsequent regional atrophy or, alternatively, osseous metaplasia of the cells of the pre-iridal fibrovascular membrane. Heterotopic ossification in other intraocular structures, such as the lens and preretinal membranes in eyes with chronic rhegmatogenous retinal detachment and tears, suggests an alternative mechanism of transdifferentiation of retinal pigmented epithelial cells to mesenchymal phenotypes that then migrate along the back of the retina and through retinal tears.14–16 The retinal pigmented epithelial cells are known to be multipotential cells with the capacity to differentiate into mesenchymal phenotype cells including fibroblasts and bone.14 The induction of this transdifferentiation can be mediated by trauma, inflammation, or anoxia of a detached retina. It has been postulated that inflammatory cell-derived cytokines interleukin-1 or tumor necrosis factor-α stimulate the retinal pigmented epithelial cells to release transforming growth factor β-1, bone morphogenic protein 7, and growth differentiation factor 5 to stimulate osseous metaplasia.15

The geriatric rabbit of the present report had multiple stimuli for the induction of osseous metaplasia including chronic uveitis and retinal detachment as evidenced by the type of inflammation and degenerative changes. The bony lesions were grossly evident in the irises of both eyes, but only examined microscopically in the iris of the left eye. The globes did not have goniodysgenesis, which has been described for New Zealand White rabbits.1,2 In guinea pigs, osseous metaplasia has previously been suggested to predispose older animals to glaucoma17; however, no such association was suggested by histologic findings for the rabbit's eyes in this case. The glaucoma in the rabbit of this report was likely caused by the fibrovascular membrane and synechia formation, which were secondary to inflammation, retinal detachment, or both. The cause of uveitis in this rabbit was unknown, and special staining of ocular tissue sections did not reveal any evidence of acid-fast bacteria, fungi, or microsporidial parasites; however, cataract formation and lens-induced uveitis were still possibilities. Intraocular osseous metaplasia in many species has been described and it can also develop in rabbits.

Acknowledgments

The authors declare that there were no conflicts of interest. The authors thank Drs. Caroline Zeiss and Christopher Reilly for their expertise and opinions on this case.

References

  • 1. Wagner F, Fehr M. Common ophthalmic problems in pet rabbits. J Exot Pet Med 2007;16:158167.

  • 2. Kern TJ. Rabbit and rodent ophthalmology. Semin Avian Exotic Pet Med 1997;6:138145.

  • 3. Buch AC, Chopra YV, Jadhav PS, et al. Intraocular osseous metaplasia. Med J DY Patil Univ 2012;5:7375.

  • 4. Yoon YD, Aaberg TM, Wojno TH, et al. Osseous metaplasia in proliferative vitreoretinopathy. Am J Ophthalmol 1998;125:558559.

  • 5. Ekinci Koktekir B, Karabagli P, Gonul S, et al. Extensive bone formation in a painful blind eye. J Craniofac Surg 2014;25:e562e563.

  • 6. Lynch GL, Scagliotti RH. Osseous metaplasia in the eye of a dog. Vet Pathol 2007;44:222224.

  • 7. Dubielzig RR, Everitt J, Shadduck JA, et al. Clinical and morphologic features of post-traumatic ocular sarcomas in cats. Vet Pathol 1990;27:6265.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8. Donaldson D, Matas M, Stewart J. Osseous metaplasia in the conjunctiva of a horse presenting with recurrent ulcerative keratitis. Equine Vet Educ 2012;24:47.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9. Williams D, Sullivan A. Ocular disease in the guinea pig (Cavia porcellus): a survey of 1000 animals. Vet Ophthalmol 2010;13:5462.

  • 10. Griffith JW, Sassani JW, Bowman TA, et al. Osseous choristoma of the ciliary body in guinea pigs. Vet Pathol 1988;25:100102.

  • 11. Shibuya K, Kinoshita K, Mizutani M, et al. Intraocular ossification in the GSP/pe chicken with imperfect albinism. Vet Pathol 2015;52:688691.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12. Black AS, Kanat IO. A review of soft tissue calcifications. J Foot Surg 1985;24:243250.

  • 13. Seifert G. Heterotopic (extraosseous) calcification (calcinosis) aetiology, pathogenesis and clinical importance. Pathologe 1997;18:430438.

    • Search Google Scholar
    • Export Citation
  • 14. Salero E, Blenkinsop TA, Corneo B, et al. Adult human RPE can be activated into a multipotent stem cell that produces mesenchymal derivatives. Cell Stem Cell 2012;10:8895.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15. Koinzer S, Scharpenack P, Katzke H, et al. Cataracta ossea—ultrastructural and specimen analysis. Ann Anat 2009;191:563567.

  • 16. Grisanti S, Guidry C. Transdifferentiation of retinal pigment epithelial cells from epithelial to mesenchymal phenotype. Invest Ophthalmol Vis Sci 1995;36:391405.

    • Search Google Scholar
    • Export Citation
  • 17. Schaffer EH, Pfeghaar S. Secondary open angle glaucoma from osseous choristoma of the ciliary body in guinea pigs. Tierarztl Prax 1995;23:410414.

    • Search Google Scholar
    • Export Citation

Contributor Notes

Dr. Enders' present address is the Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA 24061.

Address correspondence to Dr. Enders (amenders@vt.edu).
  • Figure 1—

    Photograph of the left eye of a 10-year-old Holland lop rabbit (Oryctolagus cuniculus) that had bilateral ocular and nasal discharge. The owner noted the discharge upon return from a 3-month period away during which the pet-sitter did not report any clinical signs. Notice that the cornea is cloudy and there is a poorly demarcated, vascularized region of iris discoloration (arrow).

  • Figure 2—

    Photomicrographs of sections of the left eye (removed after euthanasia) of the rabbit in Figure 1. A—In this view, the cornea is to the right of the image. A section of the globe has well-defined foci of mature lamellar bone (osseous metaplasia) on the anterior surface of the iris (large arrows). H&E stain; bar = 5 mm. B—Higher-magnification view of the iris and ciliary body (area outlined in panel A). The bone is composed of mature lamellar bone. H&E stain; bar = 500 μm. C—High-magnification view of the iris with osseous metaplasia (area outlined in panel B). A pre-iridal fibrovascular membrane is present at the anterior surface of the iris (thin arrow). The osseous metaplasia is characterized by mature, lamellar bone containing osteocytes and multiple marrow spaces lined by osteoblasts. There are rare osteoclasts in the marrow spaces (asterisk). H&E stain; bar = 50 μm.

  • Figure 3—

    Photomicrographs of sections of the left eye of the rabbit in Figure 1. A—Retinal atrophy is characterized by depletion of the ganglion cell layer with few remaining ganglion cells (horizontal large arrow), fusion and depletion of the inner and outer nuclear layers (thin arrow), and atrophy of the photoreceptor inner and outer segments (vertical large arrow). The retina is detached with regional hypertrophy of retinal pigment epithelial cells (asterisk). H&E stain; bar = 20 μm. B—In the pars plicata of the ciliary body, there are multinucleated giant cells (large arrows) and cholesterol clefts (thin arrow). H&E stain; bar = 50 μm. C—In this view, the lens capsule is to the left of the image. Cortical lens fibers are liquefied and replaced by basophilic granular material (mineral [thin arrow]). Scattered Morgagnian globules (large arrow) remain within the liquefied lens fibers. H&E stain; bar = 10 μm.

  • 1. Wagner F, Fehr M. Common ophthalmic problems in pet rabbits. J Exot Pet Med 2007;16:158167.

  • 2. Kern TJ. Rabbit and rodent ophthalmology. Semin Avian Exotic Pet Med 1997;6:138145.

  • 3. Buch AC, Chopra YV, Jadhav PS, et al. Intraocular osseous metaplasia. Med J DY Patil Univ 2012;5:7375.

  • 4. Yoon YD, Aaberg TM, Wojno TH, et al. Osseous metaplasia in proliferative vitreoretinopathy. Am J Ophthalmol 1998;125:558559.

  • 5. Ekinci Koktekir B, Karabagli P, Gonul S, et al. Extensive bone formation in a painful blind eye. J Craniofac Surg 2014;25:e562e563.

  • 6. Lynch GL, Scagliotti RH. Osseous metaplasia in the eye of a dog. Vet Pathol 2007;44:222224.

  • 7. Dubielzig RR, Everitt J, Shadduck JA, et al. Clinical and morphologic features of post-traumatic ocular sarcomas in cats. Vet Pathol 1990;27:6265.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8. Donaldson D, Matas M, Stewart J. Osseous metaplasia in the conjunctiva of a horse presenting with recurrent ulcerative keratitis. Equine Vet Educ 2012;24:47.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9. Williams D, Sullivan A. Ocular disease in the guinea pig (Cavia porcellus): a survey of 1000 animals. Vet Ophthalmol 2010;13:5462.

  • 10. Griffith JW, Sassani JW, Bowman TA, et al. Osseous choristoma of the ciliary body in guinea pigs. Vet Pathol 1988;25:100102.

  • 11. Shibuya K, Kinoshita K, Mizutani M, et al. Intraocular ossification in the GSP/pe chicken with imperfect albinism. Vet Pathol 2015;52:688691.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12. Black AS, Kanat IO. A review of soft tissue calcifications. J Foot Surg 1985;24:243250.

  • 13. Seifert G. Heterotopic (extraosseous) calcification (calcinosis) aetiology, pathogenesis and clinical importance. Pathologe 1997;18:430438.

    • Search Google Scholar
    • Export Citation
  • 14. Salero E, Blenkinsop TA, Corneo B, et al. Adult human RPE can be activated into a multipotent stem cell that produces mesenchymal derivatives. Cell Stem Cell 2012;10:8895.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15. Koinzer S, Scharpenack P, Katzke H, et al. Cataracta ossea—ultrastructural and specimen analysis. Ann Anat 2009;191:563567.

  • 16. Grisanti S, Guidry C. Transdifferentiation of retinal pigment epithelial cells from epithelial to mesenchymal phenotype. Invest Ophthalmol Vis Sci 1995;36:391405.

    • Search Google Scholar
    • Export Citation
  • 17. Schaffer EH, Pfeghaar S. Secondary open angle glaucoma from osseous choristoma of the ciliary body in guinea pigs. Tierarztl Prax 1995;23:410414.

    • Search Google Scholar
    • Export Citation

Advertisement