Received: 14 June 2000Revised: 4 September 2000Accepted: 13 September 2000

Abstract Purpose: To report the pa-thology of surgically removed sub-macular tissue in recurrent choroidalneovascularization after laser photo-coagulation of classic choroidal neo-vascularization in age-related macu-lar degeneration. Methods: A recur-rent subfoveal choroidal neovascularmembrane was surgically removedin two patients. The recurrence wasidentified as a classic membrane onfluorescein angiography at the fovealborder of the laser scar. A net wasvisualized in the early venous phaseof the indocyanine green angiogram,with associated late hyperfluores-cence. Both patients had undergonelaser photocoagulation for a classicinterpapillomacular choroidal neo-vascular membrane about 1 1/2 yearsearlier. The specimens were seriallysectioned and stained with hematox-ylin–eosin, periodic acid–Schiff,Masson trichrome and phosphotung-stic acid–hematoxylin. Results: Thetwo specimens consisted of subreti-nal fibrovascular tissue with fibrin

exudation. Fibrovascular tissue bor-dered subretinal fibrous tissue adher-ent to Bruch’s membrane and rem-nants of the choroid in one patient.The fibrovascular portion most like-ly corresponded to the recurrence,whereas the fibrous portion repre-sented the original membrane, beingobliterated after photocoagulation.Some peripapillary tissue was addi-tionally removed in the other patient.The latter lesion was invisible onfluorescein angiography but stainedin the late phase of indocyaninegreen angiography and correspondedhistopathologically to poorly vascu-larized intra-Bruch’s fibrovasculartissue. Granular deposits, periodicacid–Schiff positive and metachro-matically purple on Masson tri-chrome stain, representing diffusedrusen (basal laminar/linear depos-its), were identified in the three spec-imens. Conclusion: A subretinal fi-brovascular membrane correspondedwith the classic recurrent choroidalneovascularization.

Graefe’s Arch Clin Exp Ophthalmol (2001)239:5–11 © Springer-Verlag 2001 C L I N I C A L I N V E S T I G AT I O N

B.A. LafautS. AisenbreyC. Vanden BroeckeF. Di TizioK.U. Bartz-Schmidt

Clinicopathological correlation in exudativeage-related macular degeneration: recurrent choroidal neovascularization

Introduction

The Macular Photocoagulation Study Group (MPS) trialshave determined that patients with extra- or juxtafovealchoroidal neovascularization in age-related macular de-generation clearly benefit from laser photocoagulationcompared with untreated controls [15, 17, 18]. Lasertreatment of eyes with an entirely classic membrane wasof greater benefit than for the entire group with juxtafo-veal choroidal neovascularization [19]. Persistence or re-

currence was observed in 54% of cases of treated extra-foveal choroidal neovascularization and in 45% of pa-tients with treated juxtafoveal choroidal neovasculariza-tion by the end of a 5-year follow-up period, the largemajority of instances occurring within 1 year after pho-tocoagulation [17, 18]. Recurrence had a devastating ef-fect on visual acuity [17, 18].

Several clinicopathological correlations after laserphotocoagulation for choroidal neovascularization inage-related macular degeneration have been reported [3,

B.A. Lafaut · S. Aisenbrey · F. Di TizioK.U. Bartz-SchmidtUniversity Eye Clinic, Joseph-Stelzmann-Strasse 9, 50931 Cologne, Germany

B.A. Lafaut (✉ )Department of Ophthalmology, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgiume-mail: bart.lafaut@rug.ac.beFax: +32-9-2404963

C. Vanden BroeckeDepartment of Pathology, Ghent University Hospital, Ghent, Belgium

5, 6, 10, 13, 22, 26]. Grossniklaus et al. [12] reported thehistologic features of surgically excised choroidal neo-vascularization in age-related macular degeneration, in-cluding some recurrences for the Submacular SurgeryTrials Research Group, but no clinicopathological corre-lation of surgically removed recurrent choroidal neovas-cularization is yet available. We report the histoarchitec-ture of surgically removed submacular tissue in two pa-tients in whom a subfoveal recurrence occurred 1 1/2 yearsafter laser photocoagulation of an interpapillomacularclassic extrafoveal choroidal neovascular membrane.

Materials and methods

The cases of two patients with recurrent choroidal neovasculariza-tion who underwent membrane extraction with subsequent fovealtranslocation are reported. The preoperative examinations includ-ed binocular funduscopy and both fluorescein and indocyaninegreen angiography. The files and fluorescein angiograms werestudied to confirm the earlier presence of a primary classic choroi-dal neovascularization due to age-related macular degenerationand the initial success of laser treatment according to the MPSguidelines [15–19].

The surgical specimens were immediately fixed in 10% neu-trally buffered formalin and embedded in paraffin for light micros-copy. The membrane was serially sectioned and stained in astepped fashion with hematoxylin–eosin, Masson trichrome(MTC) and periodic acid–Schiff (PAS). Multiple sections werestained with phosphotungstic acid–hematoxylin histochemicalstain for fibrin (PTAH). Several PAS-stained sections were studiedwith fluorescence microscopy to identify melanolipofuscin.

Case reports

Patient 1

A 78-year-old man was referred because of visual loss in the righteye. He had undergone argon green laser photocoagulation of anextrafoveal classic choroidal neovascular membrane (dimension:1/2 disc diameter) located in the interpapillomacular bundle 17 months earlier. His visual acuity was 0.1 in the right eye. Theright eye presented a serous sensory macular detachment. A green-grayish subretinal neovascular membrane with retinal hemorrhag-es was seen immediately temporal to the laser scar. Fluoresceinangiography confirmed the presence of a well-demarcated recur-rent neovascular net adjacent to the laser scar (dimensions: hori-zontal, 1/2 disc diameter; vertical, 1 disc diameter) (Fig. 1A). In-docyanine green angiography showed the presence of a recur-rence: a neovascular net was seen in the venous phase (Fig. 1B)that became a hyperfluorescent sickle temporal to the hypofluores-cent laser scar in the late phase (Fig. 1C). A disciform scar wasseen in the left macula. The recurrent membrane was surgically re-moved.

Microscopic findings. The specimen consisted of a thick fibrovas-cular membrane, entirely located on the retinal side of the retinalpigment epithelium (RPE) (Fig. 2A). The fibrovascular membranewas composed of two parts; one was densely collagenized and al-most avascular, while the other was vascularized and less collage-nized. The latter portion contained several fibroblasts, some in-flammatory cells (predominantly lymphocytes ) and was partiallybordered by remains of outer segments and fibrin deposition.Some choroidal stroma was found to be adherent to the outer, cho-

roidal border of the fibrous part of the fibrovascular membrane.The RPE layer was discontinuous as no RPE cells could be identi-fied centrally in the fibrous area where collagenous tissue directlycontacted PAS-positive, MTC metachromatically purple granulardeposits, corresponding with diffuse drusen (the inner part ofBruch’s membrane) (Fig. 2B). A homogeneous PAS-positivemembrane, corresponding with the remainder of Bruch’s mem-brane (the outer part of Bruch’s membrane) as well as some cho-roidal stroma, that did not contain choriocapillaris, lay at the cho-roidal side of the diffuse drusen. Metaplastic RPE cells were pres-ent in the vascularized part of the membrane complex (Fig. 2C).Fibrin deposition was found surrounding these RPE cells, whichwere separated from the choroidal stroma by a layer of diffusedrusen. Here, the choroidal stroma contained at least some chorio-capillaris. Melanosomes from pigmented cells embedded in thechoroidal stroma did not autofluoresce, in contrast to melanolipo-fuscin granules within RPE or melanophages on the retinal side ofthe diffuse drusen.

Patient 2

A 77-year-old man consulted us because of visual loss of recentonset, 14 months after argon green laser photocoagulation of anextrafoveal classic choroidal neovascular membrane (dimension:2/3 disc diameter) located in the interpapillomacular region. Hisvisual acuity was 0.05 in the right eye. A green-grayish subretinalneovascular membrane growing from the laser scar, extendingsubfoveally, was ophthalmoscopically identified as well as a hel-icoidal peripapillary area of pigmentary changes and mild chorio-retinal atrophy. A neovascular net stemming from the scar wasidentified in the early phase of the fluorescein angiogram withleakage in the late phase (dimension: 1/2 disc diameter) (Fig. 2A).The peripapillary area of mild atrophy showed irregular pigmenta-ry changes. Indocyanine green angiography confirmed the pres-ence of the recurrence and identified in addition a peripapillaryplaque superotemporal to the disc (Fig. 1F, G). In the left eye adisciform scar was found.

The subfoveal classic recurrent membrane was surgically re-moved as well as the peripapillary occult membrane (separatespecimen).

Microscopic findings. The subfoveal specimen contained fibrovas-cular tissue that corresponded with the recurrent choroidal neovas-cularization (Fig. 2D). This specimen was richly vascularized.Many fibroblasts were identified but only scarce lymphocyteswere seen. The membrane was bordered by metaplastic RPE anddiffuse drusen (PAS positive, MTC metachromatically purplegranular deposits) on its choroidal side. There was a striking fibrindeposition around metaplastic RPE. Sub-RPE fibrovascular tissueor choroidal stroma was not found. On the retinal side the mem-brane was covered by outer segments and fibrin deposition in itsouter perimeter, while centrally it was covered by more amor-phous debris that contained dense fibrin and degenerating redblood cells. The peripapillary specimen consisted of a rather fi-brous fibrovascular membrane containing only very few capillar-ies, entirely located at the choroidal side of the RPE and the dif-fuse drusen.

Discussion

Subfoveal choroidal neovascularization is an importantcause of visual loss in age-related macular degeneration.Many authors have reported the histologic characteristicsof primary choroidal neovascularization in age-relatedmacular degeneration [1, 2, 4, 7, 8, 12, 20, 21, 23]. Cho-

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Fig. 1A–D Patient 1: A venousphase fluorescein angiogram; B venous phase indocyaninegreen angiogram; C late phaseindocyanine green angiogram;D schematic drawing of the le-sion: open circle laser scar,filled circle recurrence. E–H Patient 2: E venous phasefluorescein angiogram; F latephase fluorescein angiogram;G late phase indocyanine greenangiogram; H schematic draw-ing of the lesion: open circlerepresents laser scar, closedcircle recurrence, gray area theplaque visualized by indocya-nine green angiography

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Fig. 2A–C Patient 1: A Histo-pathological overview of therecurrent neovascular mem-brane, MTC. Single arrow fi-brovascular subretinal compo-nent, double arrow fibrocellu-lar subretinal component, triplearrow scarred choroid. B Detail, center of previouslyphotocoagulated area: retinalpigment epithelium and chorio-capillaris in adherent choroidalstroma have disappeared,MTC. C Detail, recurrent neo-vascular membrane itself: sub-retinal fibrovascular tissue bor-dered by retinal pigment epi-thelium, MTC. The arrow in C and D points at the diffusedrusen. D, E Patient 2: D His-topathological overview of therecurrence: subretinal fibrovas-cular tissue bordered by retinalpigment epithelium and diffusedrusen on its choroidal side anddeposition of amorphous mate-rial containing fibrin on its reti-nal side, MTC. The single ar-row points at the diffuse drus-en, and the double arrow at re-mains of the outer segments in-terspersed with fibrin. E Sche-matic drawing summarizing thehistoarchitecture of the well-demarcated recurrence. Thelarger dashed green pentagoncorresponds with the specimenin the first patient, and thesmaller pentagon with thespecimen in the second patient.The neovascular complex is fi-brous in the area of the laserscar, adherent to underlyingscarred choroid with absentchoriocapillaris.

roidal neovascularization is generally considered to growunder the RPE [1, 2, 4, 7, 8, 9, 11, 14, 20, 21, 23]. Morerecently, it was recognized that choroidal neovascular-ization in age-related macular degeneration may be acombination of sub-RPE and subretinal fibrovascular tis-sue [9, 11, 12, 14]. Persistent or recurrent choroidal neo-vascularization was found to be a major cause of severevisual loss after laser treatment for juxta- or extrafovealmembranes [17, 18]. The histopathology of these recur-rent lesions is still not well understood.

In 1985, Sorenson et al. [24] suggested a classifica-tion of recurrent choroidal neovascularization based onfluorescein angiographic appearance. They defined re-current neovascularization as neovascularization notedclinically and angiographically within 250 µm of the la-ser burn appearing 2 weeks or later after photocoagula-tion. Several patterns of marginal recurrence were identi-fied: rim recurrence was vessel proliferation stretchedalong the border of the photocoagulation burn without anobvious feeding vessel; contiguous recurrence was morefocal vessel proliferation directly from the edge into theadjacent retina; satellite recurrence was neovasculariza-tion within 250 µm but not in contact with the border ofthe laser scar; feeder recurrence was new vessels thatcould be traced to a feeder vessel within the photocoagu-lation scar. Our first patient had a rim recurrence, where-as the second patient had a contiguous recurrence. Thesetwo types of marginal recurrence are rather similar, asboth are in direct contact with the laser scar withoutidentifiable feeder vessels. The definition of recurrencewas modified by the MPS group: fluorescein dye leakagenoted on the periphery of the laser scar within 6 weeksafter photocoagulation was classified as persistence,while marginal fluorescein dye leakage appearing laterthan 6 weeks was termed recurrence [16]. Recurrenceswere not further subdivided on the basis of fluoresceinangiographic morphology. Both patients had recurrentchoroidal neovascularization, using the MPS terminolo-gy.

We used light microscopy for this analysis, as the ma-jor cellular components (RPE, vascular endothelium, fi-brocytes, macrophages and photoreceptors) as well asextracellular components (collagen, diffuse drusen andfibrin) can be correctly identified by light microscopyalone [11, 25]. Diffuse drusen is a light-microscopicterm corresponding with basal laminar/linear deposits inelectron-microscopic terminology [7, 25]. Diffuse drus-en, characteristic for age-related macular degeneration,are seen as an extra layer between the RPE and the outerBruch’s membrane (here defined as Bruch’s membrane),which is a granular, PAS-positive deposition that stainsmetachromatically blue-purple on MTC. It can be differ-entiated from Bruch’s membrane itself, which is a homo-geneous linear PAS-positive layer.

Both specimens contained a fibrovascular membranelocated between the neurosensory retina and the diffuse

drusen, in other words entirely subretinal (Fig. 3). In thefirst case the fibrovascular portion was adjacent to a fi-brous avascular portion which was also entirely subreti-nal. This latter component, adherent to scarred innerchoroidal tissue, probably corresponded to the laser scaritself, as the native RPE as well as the choriocapillarishad disappeared. Obvious breaks in Bruch’s membranewere not identified, and the subretinal vascularizationcould therefore not be traced with certainty to the chor-oid. It can be deduced that the original juxtafoveal clas-sic membrane and the recurrence in case 1 was entirelysubretinal, as no remaining fibrous or fibrovascular com-ponent was found between the diffuse drusen and the re-mainder of Bruch’s membrane. The location of the pri-mary membrane in case 2 is unknown, as a fibrotic scarwas not identified in the removed submacular tissue.

The postmortem morphological findings after laserphotocoagulation for choroidal neovascularization inage-related macular degeneration have been reported ineight eyes [3, 5, 6, 9, 13, 22, 26], unfortunately oftenwith a rather long interval between clinical and patho-logical examination. These findings are reviewed in Ta-ble 1 with regard to the location of the fibrous or fibro-vascular component. Three photocoagulated membraneswere entirely subretinal (nos. 2, 7, 8), four others (nos. 1,3, 5, 6) were on both sides of the diffuse drusen, and forthe remaining eye (no. 4) the location of the fibrousmembrane versus the diffuse drusen was not indicated.Three of five clinically atrophic scars (no. 4, 7, 8) provedto be avascular; in two of these three eyes, however, dis-tant subclinical choroidal neovascularization was ob-served (nos. 4, 8), while in the remaining two eyes (nos.1, 3) clinically atrophic scars harbored patent vessels. Intwo of three eyes with clinical recurrence, fibrovasculartissue extending far beyond the area of the original pho-tocoagulation was identified 6 and 7 months after treat-ment (no. 6 and no. 5 respectively). Clinically unsuspect-ed choroidal neovascularization was identified in foureyes, either adjacent to the scar (nos. 1, 3) or at a distantlocation (nos. 4, 8). This observation is not really sur-prising; as early as 1973, Sarks [20] indicated the pres-ence of clinically unsuspected choroidal neovasculariza-tion in a large proportion of postmortem eyes with age-related macular degeneration. Whole-eye studies usuallyreveal several fibrovascular connections between the fi-brovascular membrane and the choroidal stroma, where-as such bridges are only rarely identified on surgicallyremoved neovascular membranes.

We found in a previous study that 8 of 18 surgicallyremoved primary classic choroidal neovascular mem-branes in age-related macular degeneration were entirelylocated in the subretinal space; however, we could notexclude the possibility that the membrane was only par-tially removed [14]. The first case reported here, togeth-er with postmortem histopathological studies of laserscars [3, 6,22, 26], strongly suggests that classic choroi-

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dal neovascularization in age-related macular degenera-tion can be entirely located in the subretinal space.

In conclusion, two clinicopathological correlations inrecurrent choroidal neovascularization are presented.The well-demarcated recurrence consisted of a subretinalfibrovascular membrane, bordered by a rim of outer seg-

ments interspersed with fibrin. In primary or recurrentclassic choroidal neovascularization the fibrovasculartissue may be entirely located subretinally.

Acknowledgement The authors express their appreciation toProf. Jean-Jacques De Laey for reviewing the manuscript.

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Table 1 Review of postmortem correlations of laser photocoagu-lation for exudative age-related macular degeneration with atten-tion to the location of the fibrovascular tissue versus the diffusedrusen. Columns: 1 number of published cases and reference(s), 2age at first treatment session, 3 type of primary choroidal neovas-

cularization, 4 number of laser sessions, 5 clinical status of the la-ser scar at last examination, 6 interval from first laser treatment todeath / interval from last clinical evaluation to death, 7 presence ofa subretinal component, 8 presence of a sub-RPE component, 9 in-dication of communicating vascular bed

1 2 3 4 5 6 7 8 9No. [ref.] Age Primary Laser Last First treatment/ Subretinal Sub- Feeding

(years) CNV exam. last exam. component RPE componentto death

1 [5, 6] 69 Mixed 1 Atrophic scar 1 1/2 years / Fibrovascular Fibrovascular, From choroid; 5 months (scar) more extensive two Bruch’s breaksa

2 [6, 26] 75 Extrafoveal 1 Questionable 5 1/2 months / Fibrous (scar) – From retinab;classic recurrence 2 1/2 months + fibrovascular nine Bruch’s

(neighboring) breaksc

3 [6, 13] 79 Subfoveal 4 Atrophic scar 3 1/2 years / Fibrous (scar) Fibrovascular, –4 months more extensive

4 [6, 10] 76 Juxtafoveal 2 Atrophic scar 10 months / Fibrousd (scar) –8 months Fibrovasculard

(distant)

5 [6] 89 Juxtafoveal 1 Recurrence 1 year / Fibro(vascular) Fibrovascular From choroid; threeclassic 7 months Bruch’s breakse

6 [6] 72 Peripapillary 4 Recurrence 3 years / Fibro(vascular) Fibrovascular From choroid; 6 months two Bruch’s breaksf

7 [3] 66 Extrafoveal 2 Atrophic scar 3 years / Fibrous (scar) – –;classic 4 months one Bruch’s breakg

8 [22] 71 Extrafoveal 1 Atrophic scar 54 days / Fibrous (scar) Fibrovascular >From choroid;classic 12 days mounds, distant 13 Bruch’s breaksh

a One avascular break inside laser scar and one vascularized breakoutsideb Two abnormal, dilated, tortuous vessels interpreted as possibleresidual or new chorioretinal anastomoses; histologic demonstra-tion of retinal feeder vesselsc Nine avascular breaks within laser scard Location of fibrous scar and fibrovascular membrane versus dif-fuse drusen is not mentioned

e Two avascular breaks within laser scar and one vascularizedbreak outsidef One avascular break within laser scar and one vascularized breakat its edgeg One avascular break within laser scarh Two avascular breaks within scar and 11 distant vascularizedbreaks

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