Challenges in Ophthalmic Pathology: the Vitreoretinal Membrane Biopsy

Challenges in PAUL HISCOTT, DAVID WONG, IAN GRIERSON ophthalmic pathology: The vitreoretinal membrane biopsy Abstract detachment.s Sheets or strands crossing the vitreous are sometimes called transvitreous The introduction of vitreoretinal microsurgery membranes. Anteriorly, membranes can arise has produced a new type of biopsy; that of the in, or be continuous with, the vitreous base and vitreoretinal membrane. This review even extend as far as the posterior iris surface or investigates methods by which these scar-like pupil. tissues are handled in the laboratory and Biopsies of pathological tissue are usually explores the implications of the results of such undertaken to establish a diagnosis. evaluations. The study of vitreoretinal Vitreoretinal biopsies also may be for diagnostic membrane biopsies has provided much purposes as, for example, in the case of information concerning the pathobiology of intraocular lymphoma, but such conditions are the various conditions which may give rise to rare and tend not to produce membranes. the tissue as well as insights into how Conversely, in the conditions which do produce membranes themselves develop. Moreover, membranes the diagnosis is seldom in doubt. the application of new laboratory techniques Why, then, attempt laboratory studies of is expected to enhance our understanding of vitreoretinal membranes? Laboratory findings the formation of vitreoretinal membranes, and from the membranes may have a number of lead to further advances in their surgical and uses, for example providing 'feed-back' to the medical management. surgeon concerning surgical dissection planes Key words Age-related macular degeneration, (see below). However, the principal objective of Epiretinal membrane, Proliferative diabetic these investigations is to improve our retinopathy, Proliferative vitreoretinopathy, understanding of the pathogenesis of P Hiscott D. Wong Retina, Subretinal membrane, Vitreous, vitreoretinal membranes, and of the many I. Grierson disorders which cause them (the most Wound healing Unit of Ophthalmology important of which include proliferative Department of Medicine diabetic retinopathy (PDR), the complication of University of Liverpool It is well over a century since the first rhegmatogenous retinal detachment known as Liverpool, UK descriptions of pathological cellular or proliferative vitreoretinopathy (PVR) and age and connective tissue membranes in the vitreous related macular degeneration (ARMD)). Thus it (e.g. see review by Parsons 1905).1 Until quite St Paul's Eye Unit is anticipated that logical management Royal Liverpool University recently, however, these tissues could generally strategies for vitreoretinal membranes will be Hospital only be observed during the morphological developed. Indeed, previous studies have Liverpool, UK examination of enucleated eyes. The advent of shown that vitreoretinal membrane formation closed} and to a lesser extent 'open-sky',3 P. Hiscott represents an attempt at wound healing, chiefly Department of Pathology vitreoretinal surgery has permitted sampling of by non-neural cells from the retina (see reviews University of Liverpool membranes within the vitreous and also from by Grierson and colleagues).6,7 Nevertheless, Liverpool, UK beneath the neuroretina (including neovascular although the membranes contract like scars Paul Hiscott membranes in conditions such as age-related � (hence causing retinal problems such as folding Unit of Ophthalmology macular degeneration) in patients. Thus a or detachment), they differ from cutaneous Department of Medicine relatively new type of biopsy material has been wounds in that the repair process in University Clinical born. The membranes arising on the inner vitreoretinal membranes is protracted and Departments retinal surface have become known as epiretinal Duncan Building disorganised.s Moreover, although Daulby Street membranes1 (or, if from the macular region, as inflammation probably plays an important part Liverpool L69 3GA, UK 4 epimacular membranes) while those from in initiating membrane formation, the dearth of Tel: +44 (0)151 706 4912 beneath the neuroretina have been called sub inflammatory cells in many established Fax: +44 (0) 151 706 5802 or retro-retinal membranes. Epiretinal membranes suggests that, unlike skin wounds, e-mail: [email protected] membranes may extend within or onto the these cells are not so important in the Received: 11 October 1999 detached posterior vitreous (posterior hyaloid orchestration of subsequent vitreoretinal Accepted without revision: membrane) in the event of a posterior vitreous membrane evolution.9,10 In addition, 10 February 2000 Eye (2000) 14, 549-559 © 2000 Royal College of Ophthalmologists 549 vitreoretinal membranes often are still cellular after in the specimen collection fluid (which may give the months of development. These observations have led to erroneous appearance of a successful transfer of tissue clinical trials with cytotoxic drugs (including from instrument to fluid). daunomycin and 5-fluorouracil) as adjuncts to 2. The specimen is so small and pale that it cannot be membranectomy, with the object of preventing distinguished from debris in the collection fluid. membrane recurrencey,12 Furthermore, a variety of 3. Small specimens are also at risk of drying out if not pep tides and proteins have been described in the tissues quickly placed in fixative or other medium after and some of these molecules have been suggested as removal. Dried-out specimens are easily lost. potential targets for therapeutic intervention 4. The specimen has become lodged in the lid of the (e.g. TGF-beta).13,14 container or between the lid and the top of the By nature, biopsies of these membranes are usually container during transport to the laboratory. much smaller than biopsies obtained from the ocular To improve the success rate in the acquisition of surface or adnexa. Moreover, the membrane tissue tissue, the collection method can be modified in a variety typically is translucent or pale in colour and diaphanous of ways: in nature. Furthermore, some membranes adhere 1. The use of a small bottle (e.g. small glass bottles with tenaciously to almost any surface. Such characteristics screw-on tops) containing only 2-5 ml of collection render the specimens difficult to see and handle in the fluid improves visualisation of the specimen and laboratory. reduces the amount of fluid in which it can hide. Our review aims to explore some of the options 2. The collection fluid may be filtered before use to available in the handling of membrane specimens and to reduce the amount of residual debris. provide examples of the use of these specimens in 3. Ensure that the specimen is placed in fixative or other research and in diagnostic pathology. medium quickly after removal from the eye. 4. Small translucent specimens which have been placed in a fixative for morphological assessment (see below) are sometimes more easily visualised if minute Acquisition of specimens amounts of ink or dye (e.g. Indian ink, methylene blue) The pathologist or researcher new to vitreoretinal are added to the fixative while the membrane is still in membranes initially may find it helpful to observe the fluid. The ink particles or dye often stick to or stain surgical vitreoretinal procedures firsthand before the membrane so that the specimen becomes more handling membrane specimens in the laboratory. The visible. However, it is important to add the ink or dye benefits of such observation include a better in tiny increments so that the fixative fluid remains understanding of the nature of the tissue (which will translucent. 5. If the specimen cannot be seen despite the above assist in the handling of specimens) and an idea of the manoeuvres, check the lid and the gap between sorts of questions likely to be asked of the biopsy. container and lid. Decanting the fluid into a wide Most vitreous and periretinal membrane specimens receptacle, so that the fluid layer becomes very are removed from the eye on the end of one of the shallow, may also help. instruments (e.g. intraocular forceps) used during the If the specimen still cannot be found it was probably vitrectomy and then transferred to a fixative or a too small to provide useful information anyway! transport medium. If a disposable instrument, such as a bent needle, is employed, the surgeon sometimes places the instrument together with attached membrane into the Options in the laboratory investigation of vitreoretinal specimen container. Occasionally, fragmented membrane biopsies membranes are retrieved from the aspirated infusion fluid. There are a number of options available for the Membrane specimens are most often 'lost' between laboratory study of vitreoretinal membrane biopsies their collection in the eye and their arrival in the (Fig. 1) and to some extent the selection depends on the laboratory. Reasons for such a mishap include: question being asked of the tissue. Commonly, inquiries 1. The specimen was not transferred from the surgical arise about either the composition of the specimen or the instrument to the fluid in the specimen container. functional status of the cells in the tissue. Sometimes membranes become dislodged from the forceps as the specimen passes through the sclerotomy at the pars plana (a difficulty which may be evaded by Membrane composition employing modified forceps: e.g. vitreous specimens Vitreoretinal membranes are characteristically can be successfully retrieved with non-crushing heterogeneous in composition: important

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