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Clinical Sciences |

Clinicopathologic Correlation of Retinal Angiomatous Proliferation FREE

Dinelli M. Monson, MD; Justine R. Smith, MBBS, PhD; Michael L. Klein, MD; David J. Wilson, MD
[+] Author Affiliations

Author Affiliations: Casey Eye Institute, Portland, Oregon.


Arch Ophthalmol. 2008;126(12):1664-1668. doi:10.1001/archopht.126.12.1664.
Text Size: A A A
Published online

Objectives  To correlate clinical and histopathologic features of an eye with retinal angiomatous proliferation (RAP) secondary to age-related macular degeneration and to investigate the expression of von Willebrand factor (VWF) and vascular endothelial growth factor (VEGF) in this condition.

Methods  Histopathologic features from serial sections through the globe of an 87-year-old woman with RAP were studied and compared with fluorescein angiography and color fundus photographs obtained 4 months before death. Commercially available anti bodies were used to detect expression of VWF and VEGF in tissue sections.

Results  The pathologic correlate of RAP was a circumscribed intraretinal angiomatous complex within the outer part of the neurosensory retina overlying a large pigment epithelial detachment. There were no breaks in the Bruch membrane. No choroidal neovascularization was present. Endothelial cells within the RAP lesion immunostained positively for VWF and VEGF. The Bruch membrane expressed VWF adjacent to the RAP.

Conclusions  Fundus examination and fluorescein angiography images of RAP in a patient with age-related macular degeneration correlated histopathologically with a neovascular intraretinal angiomatous complex, without the presence of sub–retinal pigment epithelial neovascularization. Immunostaining demonstrated that RAP expresses VWF and VEGF.

Figures in this Article

Retinal angiomatous proliferation (RAP) is a term used to describe intraretinal neovascularization in patients with age-related macular degeneration (ARMD). This condition was first described by Hartnett et al1,2 in 1992 as deep retinal vascular anomalous complexes. Retinal angiomatous proliferation is a distinct form of neovascular ARMD, and the term RAP was coined by Yannuzzi et al3 in 2001.

An RAP is characterized by the early appearance of an intraretinal vascular complex, often associated with adjoining telangiectatic vessels. Retinal choroidal anastomosis is variable and is considered to be a late feature.3 In a recent prospective multicenter consecutive series of patients with newly diagnosed exudative ARMD, 15% of 205 eyes were diagnosed with RAP.4 There is a tendency toward bilateral involvement. In the series of 108 patients of Yannuzzi et al,3 there were 56 bilateral cases. Prior to the introduction of intravitreal antiangiogenic drug therapy, treatment outcomes were generally poor and most patients declined to a visual acuity of 20/200 or worse secondary to disciform scar formation.5

Prior to proposal of the concept of RAP, in 2000, Lafaut et al6 histologically examined neovascular membranes obtained during foveal translocation surgery from 6 patients who had angiographic features of RAP. In 2007, Shimada et al7 also examined neovascular membranes from 9 eyes with RAP, after excision of neovascularization. However, to our knowledge, there are no reports of histologic studies in whole eyes, and in the absence of a definitive histopathologic study, RAP has been defined primarily by its clinical features. In this study, we report the first clinicopathologic correlation of RAP in a whole eye.

An 87-year-old white woman complained of the recent onset of blurred vision in the right eye. The vision in the patient's left eye had been poor due to long-standing exudative ARMD. The patient's ocular history was also significant for glaucoma and cataract surgery in both eyes and left Nd:YAG capsulotomy for posterior capsular opacification.

At presentation, best-corrected visual acuity was 20/60 OD and 20/200 OS. Examination of the right fundus disclosed fluid in the macula accompanied by intraretinal hemorrhages located in the fovea and just nasal. Large drusen and retinal pigment epithelial (RPE) changes were most prominent in the temporal macula (Figure 1). Funduscopic examination of the left eye revealed a large pigment epithelial detachment (PED) centered at the fovea with a few surrounding large drusen. Hyperpigmentation was present overlying the PED, and there was a focal, sharply demarcated area of pigmentary atrophy at the fovea (eFigure 1).

Place holder to copy figure label and caption
Figure 1.

Color fundus photograph, right eye, taken 4 months prior to death. Intraretinal hemorrhages are located in the fovea and just nasal. Boxed area includes the approximate area studied in slides 140 through 180. Large drusen and retinal pigment epithelial changes were most prominent in the temporal macula.

Graphic Jump Location

Stereoscopic fluorescein angiography (FA) of the right eye in the early frames revealed telangiectatic vessels in the superficial retina at the nasal aspect of the fovea. There was focal hyperfluorescence and leakage deep to these vessels consistent with a neovascular lesion in communication with the retinal vasculature. Superior and nasal to the fovea were small areas of intraretinal blocked fluorescence corresponding to hemorrhage seen clinically (Figure 2A). In the later frames of the FA, there was further fluorescein leakage and late staining centered nasal to the fovea with small superficial cystic accumulations of dye (Figure 2B). Inferonasal to the fovea was an irregular circumscribed area of hyperfluorescence that did not leak and was consistent with a pigment epithelial window defect. Stereoscopic FA of the left eye revealed fluorescein pooling beneath a large PED involving the fovea with hyperfluorescence of the focal pigment epithelial atrophic defect at the fovea.

Place holder to copy figure label and caption
Figure 2.

Early- and late-stage fluorescein angiography. A, Early-stage (25.2 seconds) fluorescein angiography, right eye, taken at the same time as the photograph shown in Figure 1. Telangiectatic vessels are present in the superficial retina at the nasal aspect of the fovea (thin arrow).There is focal hyperfluorescence of vessels. Superior and nasal to the fovea are small areas of intraretinal blocked fluorescence (thick arrow). Inferonasal to the fovea is an irregular circumscribed area of hyperfluorescence (asterisk). B, Late-stage (520.9 seconds) fluorescein angiography, right eye, taken at the same time as the photograph shown in Figure 1. There is leakage of fluorescein in the area of the focal hyperfluorescence and telangiectatic vessels (arrow). Inferonasal to the fovea is the irregular circumscribed area of hyperfluorescence in part A, with no leakage, consistent with a pigment epithelial window defect (asterisk).

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HISTOLOGIC PREPARATION OF THE GLOBE

The eyes were enucleated post mortem and immediately fixed in 10% neutral buffered formalin. The globe was opened horizontally. Opening the globe revealed a posterior chamber lens implant and mild asteroid hyalosis, but the vitreous was otherwise normal. When compared with the final color photographs taken 4 months prior to death, there were no gross changes noted. The globe was dehydrated in graded ethanol solutions, cleared in xylene, and embedded in paraffin. The globe was sectioned serially at a thickness of 5 μm, in a plane parallel to the pupil, optic nerve, and macula. Each section was numbered, from 1 to 674, and each number section represented a width of 5 μm. The sections were then stained with hematoxylin-eosin, and the histopathologic features were reviewed by light microscopy.

IMMUNOHISTOCHEMICAL ANALYSIS

Five-micron formalin-fixed, paraffin-embedded ocular sections were stained according to a previously published indirect immunohistochemical method that included antigen retrieval by boiling in citrate buffer.8 Primary polyclonal antibodies raised in rabbit against human von Willebrand factor (VWF) (catalog number A0082; DAKO, Glostrup, Denmark) and human vascular endothelial growth factor (VEGF) (catalog number sc-152; Santa Cruz Biotechnology, Santa Cruz, California) were used. Rabbit IgG (Vector Laboratories, Burlingame, California) was used as a negative control antibody. Sections including the RAP were stained to detect VWF and VEGF. Because of the limited number of ocular sections containing the lesion, an additional section cut remote from the lesion, but from the same eye, was stained with rabbit IgG in place of specific primary antibodies.

The histopathologic features of serial section 180 are illustrated in Figure 3A and B. An intraretinal vascular complex is present in the outer part of the neurosensory retina. This complex consists of a circumscribed mass of endothelial cells. This vascular core is surrounded by eosinophilic fibrous material. This vascular tissue is adjacent to the inner portion of the Bruch membrane. The RPE cells containing pigment epithelial granules are seen enveloping the lesion. This angiomatous lesion is nasal to the fovea, and evidence of the lesion is present in section 170 through section 200. Intraretinal hemorrhages are present. In the parafoveal area there are multiple telangiectatic vessels extending into the outer neurosensory retina (eFigure 2). The angiomatous complex, and associated telangiectatic vessels, corresponds to the FA image of a hyperfluorescent intraretinal vascular complex seen nasal to the fovea with associated telangiectatic vessels (Figure 2A). The intraretinal hemorrhages observed microscopically corresponded to the areas of intraretinal blocked fluorescence seen superior and nasal to the fovea.

Place holder to copy figure label and caption
Figure 3.

Serial section 180. A, Serial section 180 shows an intraretinal vascular complex present in the outer part of the neurosensory retina (arrow). This retinal angiomatous proliferation lesion lies over a large pigment epithelial detachment (asterisk). The Bruch membrane is separated along the length of this pigment epithelial detachment. There is no subretinal neovascularization. Intraretinal hemorrhages are adjacent to the vascular complex. Diffuse retinal thickening with cystic spaces is present with associated intraretinal exudates. Vitreous and choroid are indicated (hematoxylin-eosin, original magnification ×10 before reduction). B, The intraretinal vascular complex consists of a circumscribed mass of endothelial cells. The central area contains vascular spaces with a small number of red blood cells. This vascular core is surrounded by an eosinophilic fibrous material. This core appears adherent to the inner portion of the Bruch membrane. Retinal pigment epithelial cells containing pigment epithelial granules (arrows) are seen enveloping the lesion (hematoxylin-eosin, original magnification ×20 before reduction).

Graphic Jump Location

Figure 3A and B also illustrates that the RAP lies over a broad, shallow PED. The Bruch membrane is separated along the length of this PED into its inner and outer components, as is often seen in PEDs.9,10 The RPE cells are adherent to the inner part of the Bruch membrane and associated basal laminar deposits; the outer, elastic part of the Bruch membrane is adherent to the choriocapillaris. There is no evidence of subretinal neovascularization in any of the serial sections.

Diffuse retinal thickening with cystic spaces is illustrated in Figure 3A, along with associated intraretinal exudates. This corresponds to the intraretinal accumulation of fluorescein in a petalloid pattern on FA. Section 230 corresponds to an area of focal atrophic RPE and scarring. This corresponds to an area of staining seen on the FA inferonasal to the fovea.

Vascular structures within the retina stain positively for VWF. Cells within the RAP also express VWF, confirming their endothelial identity. In addition, the Bruch membrane in this area is strongly VWF positive (Figure 4). Cells of the RAP also demonstrate positive immunoreactivity to VEGF, although not as strongly as the adjacent neurosensory retina (eFigure 3A). Expression of VEGF by the neurosensory retina has been previously reported.1114 The RPE is strongly positive for VEGF, and the choroid exhibits little immunoreactivity (not shown). No positive staining in the retina is observed for the control section immunostained with rabbit IgG in place of the primary antibody (eFigure 3B).

Place holder to copy figure label and caption
Figure 4.

Serial section 185 shows that vascular structures within the retina stain positively for von Willebrand factor (VWF). Cells within the retinal angiomatous proliferation also express VWF. The inner portion of the Bruch membrane (arrow) in this area is strongly VWF positive (anti-VWF antibody counterstained with fast red, original magnification ×400 before reduction).

Graphic Jump Location

Based on this case, we confirm that RAP is a distinct form of neovascular ARMD. In RAP, there is intraretinal neovascularization with angiomatous proliferation of capillaries within the retina. There was no subretinal neovascularization present in our case. The surgically excised lesions studied by Lafaut et al6 and Shimada et al7 were felt clinically to have some component of subretinal neovascularization or choroidal neovascularization. In 2001, it was hypothesized by Yannuzzi et al3 that RAP originated as a retinal proliferation that could progress posteriorly into the subretinal space. In 2003, Gass et al15 hypothesized that RAP originated on the choroidal side of the Bruch membrane with anterior progression. It seems plausible to us that neovascularization could develop on either side of the RPE, possibly based on perturbations of the balance of VEGF and pigment epithelium–derived factor in this microenvironment.16

The Bruch membrane in the area of RAP stained strongly with VWF, though in other locations the Bruch membrane did not stain positively. von Willebrand factor is a large multimeric glycoprotein made by endothelial cells. Each monomer contains a number of domains, with known specific binding capabilities, though the physiologic significance of every domain is not known. Domain A3 is known to bind to collagen. von Willebrand factor binds specifically to several collagens including I, II, III, IV, V, and VI.17 Collagens I, III, IV, and V are known components of the Bruch membrane.18,19

A small comparative cross-sectional study conducted by Lip et al20 demonstrated that VWF levels are elevated in patients with ARMD. In this study, VWF levels were compared in “dry” ARMD, “exudative” ARMD, and normal controls. The VWF levels were elevated in both ARMD groups, regardless of the presence of neovascular disease. Hence, Lip et al hypothesized that VWF may not just be an indicator of disease but may contribute to the pathogenesis of ARMD.

Inflammation may play a role in the pathogenesis of ARMD.21,22 Pendu et al23 hypothesized that VWF may contribute to inflammation and showed that neutrophils and monocytes may adhere directly to VWF. Though a causal relationship has not been identified between ARMD and VWF, the specific pattern of VWF staining in our case may support an association.

Although previous treatment methods for RAP, including laser photocoagulation and photodynamic therapy, had not been particularly effective in altering the course of the disease, the use of intravitreal bevacizumab has been recently investigated in a small cohort of patients, showing some benefit.24,25 Detection of VEGF in the RAP lesion from our patient suggests that treatments that block the actions of VEGF may have a role to play in the treatment of RAP. Interestingly, intravitreous injections of VEGF in the eyes of adult primates produce concentric layers of proliferating endothelial cells that are similar to the RAP lesion we have described.26

In conclusion, fundus examination and FA images of a RAP lesion in a patient with ARMD correlate histopathologically to a neovascular intraretinal angiomatous complex, without the presence of sub-RPE neovascularization. Immunostaining demonstrates that RAP expresses VWF and VEGF.

Correspondence: David J. Wilson, MD, Casey Eye Institute, 3375 SW Terwilliger Blvd, Portland, OR 97239-4197 (wilsonda@ohsu.edu).

Submitted for Publication: May 29, 2008; final revision received July 16, 2008; accepted July 18, 2008.

Financial Disclosure: None reported.

Funding/Support: This work was supported in part by Research to Prevent Blindness, New York, NY (Career Development Award to Dr Smith and unrestricted grant to Casey Eye Institute).

Previous Presentations: This work was presented in part at the Association for Research in Vision and Ophthalmology Annual Meeting; April, 29, 2008; Fort Lauderdale, Florida.

Additional Contributions: Thea Burke and Timothy Chipps provided technical assistance.

Hartnett  MEWeiter  JJGarsd  AJalkh  AE Classification of retinal pigment epithelial detachments associated with drusen. Graefes Arch Clin Exp Ophthalmol 1992;230 (1) 11- 19
PubMed Link to Article
Hartnett  MEWeiter  JJStaurenghi  GElsner  AE Deep retinal vascular anomalous complexes in advanced age-related macular degeneration. Ophthalmology 1996;103 (12) 2042- 2053
PubMed Link to Article
Yannuzzi  LANegrao  SIida  T  et al.  Retinal angiomatous proliferation in age-related macular degeneration. Retina 2001;21 (5) 416- 434
PubMed Link to Article
Cohen  SYCreuzot-Garcher  CDarmon  J  et al.  Types of choroidal neovascularisation in newly diagnosed exudative age-related macular degeneration. Br J Ophthalmol 2007;91 (9) 1173- 1176
PubMed Link to Article
Bottoni  FMassacesi  ACigada  MViola  FMusicco  IStaurenghi  G Treatment of retinal angiomatous proliferation in age-related macular degeneration. Arch Ophthalmol 2005;123 (12) 1644- 1650
PubMed Link to Article
Lafaut  BAAisenbrey  SVanden Broecke  CBartz-Schmidt  KU Clinicopathological correlation of deep retinal vascular anomalous complex in age related macular degeneration. Br J Ophthalmol 2000;84 (11) 1269- 1274
PubMed Link to Article
Shimada  HKawamura  AMori  RYuzawa  M Clinicopathological findings of retinal angiomatous proliferation. Graefes Arch Clin Exp Ophthalmol 2007;245 (2) 295- 300
PubMed Link to Article
Smith  JRLanier  VBBraziel  RMFalkenhagen  KMWhite  CRosenbaum  JT Expression of vascular endothelial growth factor and its receptors in rosacea. Br J Ophthalmol 2007;91 (2) 226- 229
PubMed Link to Article
Holz  FGPauleikhoff  DSpaide  RFBird  AC Histopathology. Age-Related Macular Degeneration New York Springer-Verlag New York LLC2003;60
Green  WR McDonnell  PJYeo  JH Pathologic features of senile macular degeneration. Ophthalmology 1985;92 (5) 615- 627
PubMed Link to Article
Gerhardinger  CBrown  LFRoy  SMizutani  MZucker  CLLorenzi  M Expression of vascular endothelial growth factor in the human retina and in nonproliferative diabetic retinopathy. Am J Pathol 1998;152 (6) 1453- 1462
PubMed
Stitt  AWSimpson  DACBoocock  CGardiner  TAMurphy  GMArcher  DB Expression of vascular endothelial growth factor (VEGF) and its receptors is regulated in eyes with intra-ocular tumours. J Pathol 1998;186 (3) 306- 312
PubMed Link to Article
Kim  IRyan  AMRohan  R  et al.  Constitutive expression of VEGF, VEGFR-1 and VEGFR-2 in normal eyes. Invest Ophthalmol Vis Sci 1999;40 (9) 2115- 2121
PubMed
Lutty  GAMcLeod  DSMerges  CDiggs  APlouet  J Localization of vascular endothelial growth factor in human retina and choroid. Arch Ophthalmol 1996;114 (8) 971- 977
PubMed Link to Article
Gass  JDMAgarwal  ALavina  AMTawansy  KA Focal inner retinal hemorrhages in patients with drusen: an early sign of occult choroidal neovascularization and chorioretinal anastomosis. Retina 2003;23 (6) 741- 751
PubMed Link to Article
Holz  FGPauleikhoff  DKlein  RBird  AC Pathogenesis of lesions in late age-related macular disease. Am J Ophthalmol 2004;137 (3) 504- 510
PubMed Link to Article
Sadler  JE Biochemistry and genetics of von Willebrand factor. Annu Rev Biochem 1998;67395- 424
PubMed Link to Article
Marshall  GEKonstas  AGPReid  GGEdwards  JGLee  WR Type IV collagen and laminin in Bruch's membrane and basal linear deposit in the human macula. Br J Ophthalmol 1992;76 (10) 607- 614
PubMed Link to Article
Karwatowski  WSSJeffries  TEDuance  VCAlbon  JBailey  AJEasty  DL Preparation of Bruch's membrane and analysis of the age-related changes in the structural collagens. Br J Ophthalmol 1995;79 (10) 944- 952
PubMed Link to Article
Lip  PLBlann  ADHope-Ross  MGibson  JMLip  GYH Age-related macular degeneration is associated with increased vascular endothelial growth factor, hemorheology, and endothelial dysfunction. Ophthalmology 2001;108 (4) 705- 710
PubMed Link to Article
Barouch  FCMiller  JW The role of inflammation and infection in age-related macular degeneration. Int Ophthalmol Clin 2007;47 (2) 185- 197
PubMed Link to Article
Zarbin  MA Current concepts in the pathogenesis of age-related macular degeneration. Arch Ophthalmol 2004;122 (4) 598- 614
PubMed Link to Article
Pendu  RTerraube  VChristophe  OD  et al.  P-selectin glycoprotein 1 ligand (PSGL-1) and {beta}2-integrins cooperate in adhesion of leukocytes to von Willebrand factor. Blood 2006;108 (12) 3746- 3752
PubMed Link to Article
Costagliola  CRomano  MRDell’Oma  RCipollone  UPolisena  P Intravitreal bevacizumab for the treatment of retinal angiomatous proliferation. Am J Ophthalmol 2007;144 (3) 449- 451
PubMed Link to Article
Joeres  SHeussen  FMTreziak  T  et al.  Bevacizumab (Avastin) treatment in patients with retinal angiomatous proliferation. Graefes Arch Clin Exp Ophthalmol 2007;245 (11) 1597- 1602
PubMed Link to Article
Tolentino  MJMiller  JWGragoudas  ES  et al.  Intravitreous injections of VEGF produce retinal ischemia and microangiopathy in an adult primate. Ophthalmology 1996;103 (11) 1820- 1828
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Color fundus photograph, right eye, taken 4 months prior to death. Intraretinal hemorrhages are located in the fovea and just nasal. Boxed area includes the approximate area studied in slides 140 through 180. Large drusen and retinal pigment epithelial changes were most prominent in the temporal macula.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Early- and late-stage fluorescein angiography. A, Early-stage (25.2 seconds) fluorescein angiography, right eye, taken at the same time as the photograph shown in Figure 1. Telangiectatic vessels are present in the superficial retina at the nasal aspect of the fovea (thin arrow).There is focal hyperfluorescence of vessels. Superior and nasal to the fovea are small areas of intraretinal blocked fluorescence (thick arrow). Inferonasal to the fovea is an irregular circumscribed area of hyperfluorescence (asterisk). B, Late-stage (520.9 seconds) fluorescein angiography, right eye, taken at the same time as the photograph shown in Figure 1. There is leakage of fluorescein in the area of the focal hyperfluorescence and telangiectatic vessels (arrow). Inferonasal to the fovea is the irregular circumscribed area of hyperfluorescence in part A, with no leakage, consistent with a pigment epithelial window defect (asterisk).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Serial section 180. A, Serial section 180 shows an intraretinal vascular complex present in the outer part of the neurosensory retina (arrow). This retinal angiomatous proliferation lesion lies over a large pigment epithelial detachment (asterisk). The Bruch membrane is separated along the length of this pigment epithelial detachment. There is no subretinal neovascularization. Intraretinal hemorrhages are adjacent to the vascular complex. Diffuse retinal thickening with cystic spaces is present with associated intraretinal exudates. Vitreous and choroid are indicated (hematoxylin-eosin, original magnification ×10 before reduction). B, The intraretinal vascular complex consists of a circumscribed mass of endothelial cells. The central area contains vascular spaces with a small number of red blood cells. This vascular core is surrounded by an eosinophilic fibrous material. This core appears adherent to the inner portion of the Bruch membrane. Retinal pigment epithelial cells containing pigment epithelial granules (arrows) are seen enveloping the lesion (hematoxylin-eosin, original magnification ×20 before reduction).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Serial section 185 shows that vascular structures within the retina stain positively for von Willebrand factor (VWF). Cells within the retinal angiomatous proliferation also express VWF. The inner portion of the Bruch membrane (arrow) in this area is strongly VWF positive (anti-VWF antibody counterstained with fast red, original magnification ×400 before reduction).

Graphic Jump Location

Tables

References

Hartnett  MEWeiter  JJGarsd  AJalkh  AE Classification of retinal pigment epithelial detachments associated with drusen. Graefes Arch Clin Exp Ophthalmol 1992;230 (1) 11- 19
PubMed Link to Article
Hartnett  MEWeiter  JJStaurenghi  GElsner  AE Deep retinal vascular anomalous complexes in advanced age-related macular degeneration. Ophthalmology 1996;103 (12) 2042- 2053
PubMed Link to Article
Yannuzzi  LANegrao  SIida  T  et al.  Retinal angiomatous proliferation in age-related macular degeneration. Retina 2001;21 (5) 416- 434
PubMed Link to Article
Cohen  SYCreuzot-Garcher  CDarmon  J  et al.  Types of choroidal neovascularisation in newly diagnosed exudative age-related macular degeneration. Br J Ophthalmol 2007;91 (9) 1173- 1176
PubMed Link to Article
Bottoni  FMassacesi  ACigada  MViola  FMusicco  IStaurenghi  G Treatment of retinal angiomatous proliferation in age-related macular degeneration. Arch Ophthalmol 2005;123 (12) 1644- 1650
PubMed Link to Article
Lafaut  BAAisenbrey  SVanden Broecke  CBartz-Schmidt  KU Clinicopathological correlation of deep retinal vascular anomalous complex in age related macular degeneration. Br J Ophthalmol 2000;84 (11) 1269- 1274
PubMed Link to Article
Shimada  HKawamura  AMori  RYuzawa  M Clinicopathological findings of retinal angiomatous proliferation. Graefes Arch Clin Exp Ophthalmol 2007;245 (2) 295- 300
PubMed Link to Article
Smith  JRLanier  VBBraziel  RMFalkenhagen  KMWhite  CRosenbaum  JT Expression of vascular endothelial growth factor and its receptors in rosacea. Br J Ophthalmol 2007;91 (2) 226- 229
PubMed Link to Article
Holz  FGPauleikhoff  DSpaide  RFBird  AC Histopathology. Age-Related Macular Degeneration New York Springer-Verlag New York LLC2003;60
Green  WR McDonnell  PJYeo  JH Pathologic features of senile macular degeneration. Ophthalmology 1985;92 (5) 615- 627
PubMed Link to Article
Gerhardinger  CBrown  LFRoy  SMizutani  MZucker  CLLorenzi  M Expression of vascular endothelial growth factor in the human retina and in nonproliferative diabetic retinopathy. Am J Pathol 1998;152 (6) 1453- 1462
PubMed
Stitt  AWSimpson  DACBoocock  CGardiner  TAMurphy  GMArcher  DB Expression of vascular endothelial growth factor (VEGF) and its receptors is regulated in eyes with intra-ocular tumours. J Pathol 1998;186 (3) 306- 312
PubMed Link to Article
Kim  IRyan  AMRohan  R  et al.  Constitutive expression of VEGF, VEGFR-1 and VEGFR-2 in normal eyes. Invest Ophthalmol Vis Sci 1999;40 (9) 2115- 2121
PubMed
Lutty  GAMcLeod  DSMerges  CDiggs  APlouet  J Localization of vascular endothelial growth factor in human retina and choroid. Arch Ophthalmol 1996;114 (8) 971- 977
PubMed Link to Article
Gass  JDMAgarwal  ALavina  AMTawansy  KA Focal inner retinal hemorrhages in patients with drusen: an early sign of occult choroidal neovascularization and chorioretinal anastomosis. Retina 2003;23 (6) 741- 751
PubMed Link to Article
Holz  FGPauleikhoff  DKlein  RBird  AC Pathogenesis of lesions in late age-related macular disease. Am J Ophthalmol 2004;137 (3) 504- 510
PubMed Link to Article
Sadler  JE Biochemistry and genetics of von Willebrand factor. Annu Rev Biochem 1998;67395- 424
PubMed Link to Article
Marshall  GEKonstas  AGPReid  GGEdwards  JGLee  WR Type IV collagen and laminin in Bruch's membrane and basal linear deposit in the human macula. Br J Ophthalmol 1992;76 (10) 607- 614
PubMed Link to Article
Karwatowski  WSSJeffries  TEDuance  VCAlbon  JBailey  AJEasty  DL Preparation of Bruch's membrane and analysis of the age-related changes in the structural collagens. Br J Ophthalmol 1995;79 (10) 944- 952
PubMed Link to Article
Lip  PLBlann  ADHope-Ross  MGibson  JMLip  GYH Age-related macular degeneration is associated with increased vascular endothelial growth factor, hemorheology, and endothelial dysfunction. Ophthalmology 2001;108 (4) 705- 710
PubMed Link to Article
Barouch  FCMiller  JW The role of inflammation and infection in age-related macular degeneration. Int Ophthalmol Clin 2007;47 (2) 185- 197
PubMed Link to Article
Zarbin  MA Current concepts in the pathogenesis of age-related macular degeneration. Arch Ophthalmol 2004;122 (4) 598- 614
PubMed Link to Article
Pendu  RTerraube  VChristophe  OD  et al.  P-selectin glycoprotein 1 ligand (PSGL-1) and {beta}2-integrins cooperate in adhesion of leukocytes to von Willebrand factor. Blood 2006;108 (12) 3746- 3752
PubMed Link to Article
Costagliola  CRomano  MRDell’Oma  RCipollone  UPolisena  P Intravitreal bevacizumab for the treatment of retinal angiomatous proliferation. Am J Ophthalmol 2007;144 (3) 449- 451
PubMed Link to Article
Joeres  SHeussen  FMTreziak  T  et al.  Bevacizumab (Avastin) treatment in patients with retinal angiomatous proliferation. Graefes Arch Clin Exp Ophthalmol 2007;245 (11) 1597- 1602
PubMed Link to Article
Tolentino  MJMiller  JWGragoudas  ES  et al.  Intravitreous injections of VEGF produce retinal ischemia and microangiopathy in an adult primate. Ophthalmology 1996;103 (11) 1820- 1828
PubMed Link to Article

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Clinicopathologic Correlation of Retinal Angiomatous Proliferation
Arch Ophthalmol.2008;126(12):1664-1668.eFigures

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