Cystinosis

Collagen-rich crystalloids, also referred to as collagenous crystalloids, are uncommon findings in benign salivary gland tumors with myoepithelial differentiation and in cutaneous neoplasms. Herein, we report the presence of collagen-rich crystalloids in the scarred, vascularized cornea of a 56-year-old woman. The patient underwent penetrating keratoplasty, and microscopic examination of hematoxylin-eosin-stained sections disclosed large aggregates of refractile material within the corneal stroma. The deposits were partially birefringent when viewed with polarized light and composed of radially arranged columns (long rectangles) with rounded to pointed tips. The deposits had tinctorial properties of collagen using Masson trichrome and the van Gieson method for collagen, and they stained with Alcian blue, pH 2.5, and Verhoeff elastic stain. They did not stain with Gomori methenamine silver, Snook reticulin stain, or tyrosine using the Baker modification of the Millon reaction. This is the first report, to our knowledge, of collagen-rich crystalloids in the cornea. Their presence in the cornea indicates that these structures may occur in the absence of neoplasia.

(Arch Pathol Lab Med. 2005;129:1179-1182)

Corneal deposits have been recognized in many systemic and ocular conditions.1-2 In establishing a differential diagnosis for these deposits, physicians often categorize them on the basis of color, shape, and location within the cornea. Inherited stromal corneal dystrophies include amyloid deposits in lattice corneal dystrophy; protein deposits in granular corneal dystrophy; protein and amyloid deposits in Avellino corneal dystrophy, also referred to as granular corneal dystrophy type II; and glycosaminoglycan in macular corneal dystrophy.3 Stromal crystalline deposits can be secondary to lipids in Schnyder central and Bietti marginal crystalline dystrophies,3 immunoglobulins in systemic diseases that result in excessive immunoglobulin production,2 and cystine deposits in cystinosis.2,4 Band keratopathy secondary to calcium deposition (calcific band keratopathy) may result from chronic ocular disease, repeated ocular trauma, and conditions associated with hypercalcemia or hyperphosphatemia.1,2 Band keratopathy may also be secondary to accumulation of proteinaceous actinic concretions in the condition known variously as chronic actinic keratopathy, climatic droplet keratopathy, and spheroidal degeneration.1,2,5 Herein, we describe unilateral corneal deposits identified as collagen-rich crystalloids that were present in a scarred, vascularized cornea. This is the first report, to our knowledge, of these crystalloids in the cornea.

REPORT OF A CASE

A 56-year-old woman with a medical history significant for hypertension and hyperlipidemia was referred to the Duke University Eye Center for evaluation of unilateral corneal deposits. Her ocular history was significant for what was considered to be band keratopathy in the right eye, first diagnosed approximately 20 years ago. She had a superficial keratectomy with EDTA debridement in the mid-1980s. She had several episodes of recurrent erosions during the 20 years before evaluation at Duke, and for the last several years she had intermittent photophobia. The year before evaluation at Duke, the patient developed a foreignbody sensation in her right eye and was noted to have increased corneal deposits in this eye. She also had a corrected visual acuity of 20/200 OD at the time of referral to Duke, which was a significant change from a best-corrected acuity of 20/50 OD 1 year earlier.

At the time of consultation, the patient noted decreased visual acuity, photophobia, and foreign-body sensation of the right eye. On examination, she had moderate conjunctival injection, diffuse corneal edema, multiple deep round white corneal deposits (Figure 1), and diffuse superficial band keratopathy. She was treated with topical corticosteroids, ofloxacin, and a 5% sodium chloride hypertonic solution (Muro-128). She did not have elevated calcium or phosphate levels in her blood. EDTA chelation was performed to remove the superficial calcium. Five months later, the patient underwent penetrating keratoplasty on the right eye.

RESULTS

Microscopic examination of formalin-fixed, paraffin-embedded sections of the cornea stained with hematoxylineosin revealed irregularly thickened and thinned epithelium that was separated from the Bowman layer by bullae in some areas and fibrovascular pannus in other areas. Anterior stromal scarring was present. There were 3 large aggregates of refractile material, 2 of which were surrounded by scarred, vascularized corneal stroma. The deposits ranged from approximately 80 to 300 µm in maximum diameter and were in all layers of the stroma. They were pink with a light purple tinge in hematoxylin-eosinstained sections, although the smallest deposit in the deep stroma was almost devoid of color. The deposits were composed of radially arranged columns (long rectangles) with rounded to pointed tips (Figure 2). Cells with oval nuclei that had a fibroblastic appearance were within some of the deposits. The deposits were partially birefringent when viewed with polarized light (Figure 3). Small amounts of calcium were in the deposits, as evidenced by a light gray color when stained using the von Kossa method. The deposits had tinctorial properties of collagen using Masson trichrome stain and the van Gieson method for collagen (Figure 4), although the deposits were mostly dissolved using the Masson trichrome procedure. Verhoeff elastic stain turned the deposits gray with black tips (Figure 5), and the deposits stained lightly with Alcian blue stain, pH 2.5 (Figure 6). They did not stain with Gomori methenamine silver, Snook reticulin stain, or tyrosine using the Baker modification of the Millon reaction. Descemet membrane was normal, and there were a reduced number of corneal endothelial cells.

COMMENT

The corneal deposits in this case do not match descriptions of those reported previously in the cornea and do not resemble any we have encountered in the past within the eye. We identified them as collagen-rich crystalloids based on their morphologic features, partial birefringence under polarized light, and histochemical properties,6,7 as well as their lack of similarity to other normal or pathologic birefringent material that occurs in human tissues.8-9 Collagen-rich crystalloids have been previously described mostly within benign salivary gland neoplasms with myoepithelial differentiation6,10,11 and cutaneous tumors.12-14 Campbell and coworkers6 reviewed 294 cases of minor salivary gland tumors and found crystalloids within 6 of 130 cases of pleomorphic adenoma. They identified 2 distinct types of crystalloids: collagen rich and tyrosine rich. The collagen-rich crystalloids were birefringent with polarized light and were composed of radially arranged, eosinophilic fibers with pointed tips, similar to those we found in the cornea. Tyrosine-rich crystalloids lacked birefringence with polarized light,6,7 and they were radially arranged, eosinophilic, petallike structures with blunt ends; our crystalloids do not match those illustrated by Campbell et al.6 Constituents of the collagen-rich crystalloids as determined by histochemical analysis include collagen, glycoprotein, polyanions such as glycosaminoglycans, and carbohydrate.6 More recently, Skalova et al10 identified collagen-rich crystalloids in 12 of 230 cases of benign salivary gland tumors, and they identified collagen types I and III within them.

The staining characteristics of the crystals identified in the cornea and the collagen-rich and tyrosine-rich crystalloids reported by Campbell and coworkers are given in the Table. Although the histochemical properties of the corneal crystals are not identical to either of the crystalloids reported in salivary gland pleomorphic adenomas, they are closer to those of the collagen-rich crystalloids, as are their morphologic features. Of particular importance for our identification of these deposits was their birefringence under polarized light and the presence of collagen demonstrable using Masson trichrome and van Gieson techniques for collagen. The reason why the collagen-rich crystalloids in the cornea mostly dissolved during the Masson trichrome staining procedure is unknown, but this solubility difference emphasizes that the corneal crystals are not identical to those in the salivary gland reported by Campbell et al.6 Unfortunately, we did not have sufficient material to perform transmission electron microscopy, which may have yielded further differences between the corneal collagen-rich crystalloids and those reported in salivary gland and cutaneous tumors.

Collagen-rich crystalloids in neoplasms of the salivary gland and skin are hypothesized to be produced by tumor cells in a fashion analogous to deposition of basement membrane under normal circumstances.14 The reason collagen-rich crystalloids formed in this cornea and not in the innumerable other scarred and vascularized corneas that we have examined clinically and histologically is unknown. We speculate that these collagen-rich crystalloids represent a peculiar manifestation of corneal scarring in this patient. Their presence demonstrates that these structures may form in the absence of neoplasia.

References

1. Kiintworth CK. Degenerations, depositions, and miscellaneous reactions of the ocular anterior segment. In: Garner A, Kiintworth CK, eds. Pathobiology of Ocular Disease: A Dynamic Approach. Part A. 2nd ed. New York, NY: Marcel Dekker lnc; 1994:743-794.

2. Klintworth CK, Font RL. The eye and ocular adnexa. In: Spicer SS, ed. Histochemistry in Pathologic Diagnosis. New York, NY: Marcel Dekker lnc; 1986: 959-1018.

3. Klintworth GK. The molecular genetics of the corneal dystrophies: current status. Front Biosci. 2003;8:687-713.

4. Cogan DG, Kuwabara T, Kinoshita J, Sudarsky D, Ring H. Ocular manifestations of systemic cystinosis. Arch Ophthatmol. 1956;55:36-41.

5. Klintworth GK. The cornea: structure and macromolecules in health and disease: a review. Am J Psthol. 1977;89:718-808.

6. Campbell WG Jr, Priest RE, Weathers DR. Characterization of two types of crystalloids in pleomorphic adenomas of minor salivary glands: a light-microscopic, electron-microscopic, and histochemical study. Am J Pathol. 1985;118: 194-202.

7. Harris BR, Shipkey F. Tyrosine-rich crystalloids in neoplasms and tissues of the head and neck. Arch Pathol Lab Med. 1986;110:709-712.

8. Wolman M. Polarized light microscopy as a tool of diagnostic pathology. J Histochem Cytochem. 1975;23:21-50.

9. Johnson FB. Crystals in pathologic specimens. Pathol Annu. 1972;7:321-344.

10. Skalova A, Leivo I, Michai M, Sakseia E. Analysis of collagen isotypes in crystalloid structures of salivary gland tumors. Hum Pathol. 1992;23:748-754.

11. Skalova A, Michai M. Biphasic myoepithelioma of parotid gland with collagenous crystalloids. Histopathology. 1994;24:583-586.

12. Skalova A, Michai M. Collagenous spher ulosis and collagenous crystalloids. Am J Dermatopathol. 1994; 16:640-642.

13. Zamecnik M, Skalova A, Michai M. Basal cell carcinoma with collagenous crystalloids. Arch Pathol Lab Med. 1996;120:581-582.

14. Zamecnik M, Skalova A, Pelikan K, Leivo I. Basaloid squamous carcinoma with collagenous spherules and crystalloids. Ann Diagn Pathol. 2001;5:233-239.

Natalie A. Afshari, MD; Tarra M. Wright, MD; Thomas J. Cummings, MD; Alan D. Proia, MD, PhD

Accepted for publication April 20, 2005.

From the Departments of Ophthalmology (Drs Afshari, Wright, and Proia) and Pathology (Drs Cummings and Proia), Duke University Medical Center, Durham, NC.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Alan D. Proia, MD, PhD, Department of Pathology, Duke University Medical Center, DUMC 3712, Durham, NC 27710 (e-mail: proia001@mc.duke.edu).

Copyright College of American Pathologists Sep 2005
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