COMPANION MEETING OPHTHALMIC. Meeting Room: Bayside Room 106 Time: 5:15 7:00

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Australasian Division of the International Academy of Pathology Limited ABN 73 008 593 815 36 TH Annual Scientific Meeting Darling Harbour Convention Centre, Sydney, Australia June 3-5, 2011

1 Australasian Division of the International Academy of Pathology Limited ABN TH Annual Scientific Meeting Darling Harbour Convention Centre, Sydney, Australia June 3-5, 2011 COMPANION MEETING OPHTHALMIC Meeting Room: Bayside Room 106 Time: 5:15 7:00 Convenors: A/Prof Sonya Klebe, SA Pathology/Flinders University, SA and Dr Jeanne Tomlinson, ICPMR, Westmead Hospital, NSW Lecture 1: A/Prof. Sonya Klebe An Approach to the Handling and Interpretation of Corneal Specimens Lecture 2: Dr Jeanne Tomlinson Tumours of the Eyelid

2 Common corneal pathology- clinical and pathological aspects (Sonja Klebe, Dept Anatomical Pathology, Flinders Medical Centre, Bedford Park, SA 5042, Australia) Corneal specimens are unpopular in most laboratories. This is in part due to the small size of many of these specimens, but also due the use of incomprehensible clinical abbreviations, and an unusual pathological jargon, which developed because these specimens were traditionally assessed by ophthalmologists rather than pathologists (Table 1). Corneal specimens include corneal discs and corneal biopsies. Corneal discs removed for penetrating keratoplasty are virtually never urgent, as definitive treatment has been undertaken, whereas small partial thickness corneal biopsies are mostly undertaken for culture-negative keratitis and require urgent diagnosis, since destruction of the cornea may occur within hours 1. Anatomy and physiology The key to correct diagnosis is an understanding of the anatomy and physiology of the cornea. This is well covered in the standard textbooks 2-4 and only briefly recapitulated here. The cornea must maintain shape and transparency, which depends on an undisturbed ultrastructure and low hydration. The cornea is divided into five layers. 1. epithelium, 2. Bowman s layer, 3. stroma 4. Descemet s membrane 5. endothelium. The epithelium is of non-keratinising stratified squamous type and 5-6 cells thick. Bowman s layer is the compressed outer layer of the corneal stroma (NOT a basement membrane) and ends at the limbus. It is not well seen in H&E stained sections, but PAS stains will demonstrate it well. The stroma consists of regularly arranged connective tissue fibrils, extracellular matrix and keratocytes. Descemet s membrane is constantly being added to by the corneal endothelium, which it supports. The corneal endothelium consists of a monolayer of post mitotic cells and controls the hydration of the corneal stroma, with a relatively dehydrated state being imperative for corneal clarity 5. Vessels or inflammatory cells are not present within the normal central cornea. Systematic assessment of these layers will help in reaching the correct diagnosis.

3 General considerations Consider sending tissue for microbiology if a fresh biopsy has been sent (acanthamoeba or fungi!). Wrap small tissue portions and ink them. They may be better off on a short cycle 6. We routinely cut 3 H&E levels, and PAS. Add to this, AB/PASD, silver, Gram, Giemsa, and Ziehl Neelsen. To look for acanthamoeba, calcufluor white is very useful, particularly in smears. Communication with the clinician is important. For example, a diagnosis of keratoconus is made clinically, and the histology may not show any abnormality. However, this is still consistent with the clinical diagnosis. In addition, the age and ethnic origin of the patient are important. Macular corneal dystrophy is rare in Australia 7, but it is the most common cause for corneal grafting in Saudi Arabia and Iceland, and Fuchs dystrophy is unlikely to affect a young patient. Common conditions Pterygia are triangular sheets of fibrovascular tissue which originate from the conjunctiva, but by definition, involve the cornea. They comprise conjunctival epithelium, often with squamous metaplasia, with underlying vascular stroma showing solar elastosis. Unless corneal tissue is visible in the sections, distinction form a pingueculum is impossible. Often, there is some atypia of the epithelium, and ocular squamous neoplasia may originate from a pterygium. Keratoconus is the most common indication for grafting in Australia. Ideally, there are breaks in the irregular Bowman s layer and pannus formation, but a normal endothelium. In advanced cases, a descemetocele may be present. However, keratoconus is defined by clinical criteria, and a normal histology does not exclude the diagnosis. Pellucid degeneration resembles keratoconus, but affects the corneal periphery. Bullous keratopathy is a clinical term and corresponds to the histological features of endothelial failure. It commonly follows cataract extraction (pseudophakic or aphakic bullous keratopathy) or graft rejection. The bullae are painful, and rupture of the bullae predisposed to infections. Edema can be prominent in the stroma, characterized by clefting, smudged stromal lamellae and a frothy appearance of the stroma. However, processing artifacts may result in similar appearances, and the appearances of the basal cell layer of the epithelium has proven more reliable to diagnose corneal edema, since basal vacuolation (basal edema) is a good indicator of endothelial cell failure. Corneal endothelial failure and long-standing corneal edema will often result in pannus formation. These changes are non-

4 specific and indicate only that the endothelium is severely damaged, but the term endothelial cell failure describes only the symptom, and the underlying cause must be found. Corneal dystrophies, as understood in the clinical jargon, are bilateral inherited conditions divided into I. epithelial, II. stromal and III. endothelial dystrophies (Table 2). Sometimes, the term dystrophy is also used for degenerative conditions, such as Salzmann s nodular dystrophy. Pigmentation of the cornea may affect the epithelium (iron deposition with Hudson-Stahli, Fleischer, Stocker, Ferry lines), the stroma (hemosiderin after anterior chamber hemorrhage, argyrosis), Descemet s (copper in Wilson s disease, Kayser-Fleicher ring) or the endothelium (melanin deposition within endothelial cells in pigmentary glaucoma). Infections are mostly of bacterial origin and easily identified. Therefore, uncommon organisms are the rule rather then the exception in biopsy specimens- if an infection responds to therapy, would not usually be biopsied 8. If a full-thickness specimen is provided, a comment should be made if organisms are present on the endothelium and therefore, in the anterior chamber. Do not mistake uveal pigment for bacteria- particularly if there was an episode of inflammation, pigment is released from the uvea and may present as small dark granules adherent to the endothelium. Infection with gram-positive cocci may result in crystalline stromal deposits comprising dead or avirulent bacteria (often streptococci) forming large interlamellar colonies that have a crystalloid appearance clinically (infectious (pseudo) crystalline keratopathy). This not associated with stromal inflammation. Fungal organisms reside deeply within the stroma and are therefore not reached by superficial scrapings. Acanthamoeba are difficult to see on H&E stains and may mimic keratocytes, and Giemsa and calcufluor white are useful stains. Viral ulcers are not usually biopsied, but may be grafted after acute perforation and characteristic giant cells adjacent to Descemet s membrane may be seen in HSV infections. Sterile ulcers are isolated phenomena in Mooren s peripheral ulcer or may be associated with systemic disease, in particular rheumatoid arthritis. They are treated with topical steroids, and biopsy may be done to exclude infection. Systemic diseases affect the cornea in many ways. For example, systemic medication may cause corneal opacities (e.g. amiodarone) and cystine crystals may be deposited in cystinosis. These crystals can be demonstrated by polarization of an unstained section. Crystalloidal keratopathy may precede the onset of systemic symptoms in protein dyscrasias, such as multiple myeloma 9.

5 Other opacities include scars after trauma or complications of refractive surgery 10 or infection, deep band keratopathy, secondary corneal amyloidosis and, rarely, primary tumors Corneal transplantation is most commonly performed as full-thickness penetrating keratoplasty. This involves excising a full-thickness corneal disc and replacing it with tissue obtained from a donor. Recently, lamellar keratoplasty has been successfully used for conditions where it is primarily the endothelium that is diseased. In this procedure, only the inner third of the corneal stroma, including Descemet s and the endothelium, are excised and replaced by donor tissue. Corneal grafting is usually performed for visual disturbance, such as corneal edema secondary to endothelial failure, or corneal opacity due a corneal dystrophy. Sometimes, a graft is performed if the curvature of the cornea shows aberrations of its shape that cannot be corrected by optical aids, such as glasses or contact lenses, and in this case, the corneal may appear histologically normal. Despite being an avascular structure situated in an immunoprivileged site, rejection of corneal grafts may occur 11,12. If it does, it results in destruction of the endothelial cell layer and thus endothelial failure, and is in itself a common indication for corneal grafting. In summary, pathologists can provide important information to the clinician upon examination of corneal specimens, since reaching a correct diagnosis may sometimes save the patient s sight.

6 Table 1. Glossary of terms and common abbreviations ABK A chaud ALK Anterior synechia Band keratopathy Basal edema Bullous keratopathy CHED CL Clefting CR DALK Descemeto-cele DSAEK DSEK DLEK DMEK Dystrophy Endothelial failure Epithelial edema Epithelial ingrowth Facet Hassal-Henle warts IK Interstitial keratitis ICE IOL IOP KP LASIK Mooren s OSSN PAM Pannus PBK Pinguecu-lum PK PRK Pterygium Retrocorneal membrane Aphakic bullous keratopathy- cataract surgery has been done, IOL in place Surgery, usually keratoplasty, into inflamed graft bed, does not imply a specific cause of inflammation, could be infection, or rejection Anterior lamellar keratoplasty Adhesion of iris tissue to endothelium, may result in endothelial failure or raised IOP = Calcific band keratopathy, band-like area of dystrophic calcification on cornea, usually treated with debridement, rarely grafted Edema of epithelial basal layer - small intracytoplasmic vacuoles Clinical sign of endothelial failure, resulting in basal edema and bullae between epithelium and Bowman s layer Congenital hereditary endothelial dystrophy Contact lens Stromal discohesion, usually artefactual Conductive keratoplasty Deep anterior lamellar keratoplasty Extreme thinning of stroma with bulging of Descemet s through stroma, may result in acute endothelial failure, often in keratoconus Descemet s stripping automated endothelial keratoplasty Descemet s stripping endothelial keratoplasty Deep lamellar endokeratoplasty Decemet s membrane endokeratoplasty May refer to a specific corneal dystrophy, usually a bilateral, inherited condition (see Table 2) or to a degenerative process (e.g. calcific band keratopathy) End-result of any condition with loss/lack of endothelial cells, characterized by epithelial edema, stromal edema Small vacuoles in the basal cell layer of the epithelium, sign of endothelial cell failure Epithelial cells deep to Bowman s, suggestive of previous trauma, e.g. surgical tract may epithelialise Epithelial thickening often associated with irregularity/defect in Bowman s layer, suggestive of previous trauma Focal thickening of Descemet s, may be seen in the periphery of elderly corneas, if in central cornea, suggestive of Fuchs Interstitial keratitis Classically, congenital lues affecting the cornea, but may also denote any keratitis involving the corneal stroma Iridocorneal endothelial syndrome, corneal edema, glaucoma and iris abnormalities Intraocular lens Intraocular pressure Keratic precipitates (part of graft rejection) Laser assisted stromal in situ keratomileusis Sterile peripheral corneal ulcer Ocular surface squamous neoplasia Primary acquired melanosis Break in Bowman s with anterior stroma coming to lay between Bowman s and epithelium and directly abutting epithelium Pseudophakic bullous keratopathy- cataract surgery with lens replacement in situ Degenerative condition with fibrous proliferation and solar damage, affecting conjunctiva Penetrating keratoplasty Photorefractive keratectomy As pingueculum, but involves cornea Organising fibrin adherent to endothelium, may result in endothelial cell failure or raised IOP

7 RK Salzmann s SPK Radial keratotomy Corneal degeneration characterized by massive localized pannus Superficial punctate keratitis Dystrophy Epithelial Stromal Endothelial Reis-Bücklers dystrophy Thiel-Behnke dystrophy Macular, lattice and granular Schnyder s crystalline Congenital hereditary Fuchs Histology Irregular epithelium overlying thick pannus containing eosinophilic material, distinction by the appearances of deposits: Reis-Bücklers resembles superficial variant of granular dystrophy, subepithelial deposits in Thiel- Behnke more amorphous, curly filaments on electron microscopy Light microscopy Macular Granular MPS deposits PAS, AB+ve, anterior stroma, within keratocytes Lattice Anterior + middle stroma central cornea web-like amyloid, CR, PAS +ve Granular Granular hyaline (Rock candy) central stroma, Trichrome+ve +/- amyloid anterior stroma Schnyder s Cholesterolcrystals anterior stroma Congenital/ Normal hereditary endothelium, stromal oedema Electron microscopy Filamentous and granular deposits in RER Extracellular amyloid fibrils Dense rod-shaped and trapezoid crystalloidal material Thinned stromal collagen fibers Hassal-Henle bodies in the central cornea thickened and laminated Descemet s Table 2. Summary of the most common corneal dystrophies Abbreviations: AB, Alcian blue, CR Congo red MPS, mucopolysaccharide, PAS, periodic acid Schiff, RER, rough endoplasmatic reticulum Bibliography 1. Lee P, Green R. Corneal biopsy. Ophthalmology 1990;97: Apple D, Rabb M. Ocular Pathology. St Louis: Mosby Year Book, Eagle R. Eye Pathology. Philadelphia: W.B. Saunders Company, Yanoff M, Fine BS. Ocular Pathology. Philadelphia: Harper and Rows, Tuft SJ, Coster DJ. The corneal endothelium. [Review] [455 refs]. Eye 1990;4: Klebe S, Coster D, Rozenbilds M. A practical approach to interpretation of corneal specimens. Adv Anat Pathol 2004;in press. 7. Williams KA, Muehlberg SM, Bartlett C, Esterman A, Coster DJ. The Australian corneal graft registry report. Adelaide: Snap Printing 2000, Badenoch P. Expecting the unexpected: intersting eye infections and their diagnosis. Australian J of Med Science 2001;22: Henderson DW, Stirling JW, Lipsett J, Rozenbilds MA, Roberts-Thomson PJ, Coster DJ. Paraproteinemic crystalloidal keratopathy: an ultrastructural study of two cases, including immunoelectron microscopy. [Review] [61 refs]. Ultrastructural Pathology 1993;17: Apple DJ, Werner L. Complications of cataract and refractive surgery: a clinicopathological documentation. Trans Am Ophthalmol Soc 2001;99:95-107; discussion Rocha G, Deschenes J, Rowsey JJ. The immunology of corneal graft rejection. Critical Reviews in Immunology 1998;18:

8 12. Williams KA, Coster DJ. Rethinking immunological privilege: implications for corneal and limbal stem cell transplantation. [Review] [44 refs]. Molecular Medicine Today 1997;3:

Corneal specimens that influence clinical decisions

Corneal specimens that influence clinical decisions Refractive surgery Corneal dystrophies Microbial infections J. Douglas Cameron, MD Chief, Ophthalmic Pathology Division Neuropathology Department Armed