Clinicopathologic Correlation of Choroidal and Retinal Neovascular Lesions in Age-Related Macular Degeneration




Purpose


To describe histopathologic findings in donor eyes of 3 individuals with neovascular age-related macular degeneration and to correlate with results of clinical and fluorescein angiographic studies performed before death.


Design


Retrospective, observational case series.


Methods


Three eyes of 3 individuals with neovascular age-related macular degeneration were obtained after death and were prepared for histopathologic examination at a tertiary care referral center. Serial sections through the macula and optic nerve were evaluated with light microscopy. Findings were correlated with results of clinical evaluation, including findings of fluorescein angiography performed from 1 week to 5 months before death.


Results


In Case 1, histopathologic examination revealed a thin choroidal neovascular membrane beneath a relatively intact retinal pigment epithelium (type 1 neovascularization). This correlated with an occult choroidal neovascular membrane on fluorescein angiography characterized by a stippled appearance with minimal late leakage, representing possibly the earliest clinically detectable neovascular membrane for which histopathologic correlation is available. In Case 2, histopathologic examination demonstrated subfoveal choroidal neovascularization with distinctly separate subretinal pigment epithelial (type 1) and subretinal (type 2) components, correlating to fluorescein angiographic appearance of a mixed neovascular membrane with corresponding occult and classic features. The histopathologic findings in Case 3 revealed a plexus of blood vessels in the outer retina surrounded by an abundant eosinophiolic extracellular matrix and associated with a pigment epithelial detachment. There was no communication with the choroid. This correlated with clinical findings of retinal angiomatous proliferation.


Conclusions


These 3 in situ clinicopathologic correlative studies add new knowledge of the broad clinical spectrum of neovascular age-related macular degeneration.


Age-related Macular Degeneration (AMD) is a leading cause of visual impairment in the United States and the Western world, with the neovascular form accounting for most cases of legal blindness. Clinicopathologic correlative studies have played an important role in clarifying the clinical manifestations and underlying pathophysiologic features of neovascular AMD. Much knowledge has been gained from case series of surgically removed neovascular membranes studied before surgery with fluorescein angiography and from case reports of donor eyes with in situ active neovascular lesions studied with fluorescein angiography shortly before death.


In this article, we describe additional clinicopathologic correlations of neovascular AMD in 3 donor eyes of 3 individuals in whom clinical evaluation, including fluorescein angiography, was performed shortly before death. Each of the 3 eyes demonstrates findings unique from previously reported cases and represents the spectrum of neovascular lesions commonly seen in clinical practice. The lesions in these 3 eyes comprise early occult choroidal neovascularization (CNV; Case 1), more advanced CNV with both occult and classic components (Case 2), and retinal angiomatous proliferation with pigment epithelial detachment (Case 3).


Methods


Three patients were evaluated at the Casey Eye Institute, a tertiary care referral center that is the ophthalmology department of Oregon Health & Science University. All 3 patients had active neovascular AMD. Each underwent a clinical evaluation that included a complete eye examination, stereoscopic fundus photographs, and stereoscopic fluorescein angiography. All 3 patients died 1 week to 5 months after the last evaluation. The eyes were obtained after death and were fixed in 4% buffered formaldehyde. They then were dehydrated in ethanol, cleared in xylene, and embedded in paraffin. Serial 5-μm sections were prepared in a plane parallel to the pupil, the optic nerve, and the macula. Sections then were stained with hematoxylin and eosin and were evaluated.




Results


Case 1


A 67-year-old woman had been aware of mild visual impairment in both eyes for approximately 2 years. We evaluated her on May 20, 2000. Her past medical history indicated surgery and radiation treatment for breast cancer 11 years earlier. On ophthalmic examination, best-corrected visual acuity was 20/20 in the right eye and 20/25 in the left eye. Intraocular pressure was 19 mm Hg in each eye. Mild nuclear lens changes were present in both eyes. On ophthalmoscopy, large confluent drusen were present in both eyes with no signs of CNV in either eye ( Figure 1 , Top left). Fluorescein angiography showed mild fluorescence of drusen with no signs of CNV in either eye. The patient agreed to participate in the Complications of Age-Related Macular Degeneration Prevention Trial (CAPT) and was randomized to laser grid treatment for the right eye. On May 30, 2000, 60 mild applications of argon green laser at 100-μm spot size, 0.1-second’s duration, and 110 mW of power were applied to the right eye according to the CAPT protocol. She had follow-up examinations 3, 6, and 12 months. At the 12-month visit in June 2001, some drusen resolution had occurred in the right eye, but significant drusen remained. In accordance with the CAPT study protocol, a second session of argon laser photocoagulation was applied using 30 applications of argon green laser. The patient was followed up yearly thereafter until her most recent examination on May 24, 2004. At that time, her visual acuity was recorded as 20/25 in each eye. She noted no change in vision in either eye. On fundus examination, significant drusen resolution had occurred in the treated right eye, and no signs of CNV were noted ( Figure 1 , Top right). A fluorescein angiogram showed a poorly defined area of speckled hyperfluorescence with late leakage supertemporal to the fovea in the right eye ( Figure 1 , Bottom left and Bottom right). On September 1, 2004, 14 weeks after her most recent examination and fluorescein angiographic study, the patient died, and the eyes were obtained for postmortem study.




FIGURE 1


Case 1: fundus photographs and fluorescein angiography demonstrating multiple large drusen and occult choroidal neovascularization in the supertemporal macula of the right eye. (Top left) Fundus photograph of the right eye obtained on May 25, 2000, showing large drusen in the macula. (Top right) Fundus photograph of the right eye obtained in May 2004 showing some regression of macular drusen. (Bottom left) Fluorescein angiogram at 20 seconds showing an early appearance of a poorly defined neovascular membrane in the supertemporal posterior pole (arrow). (Bottom right) Late-phase angiogram at 580 seconds showing late speckled hyperfluorescence and mild staining (arrow).


Histopathologic findings of the right eye ( Figure 2 ) revealed a thin layer of vessels beneath the relatively intact retinal pigment epithelium (RPE). A vascular connection between the choriocapillaris and the sub-RPE neovascularization through a break in the Bruch membrane was evident. The retina was detached artifactitiously, but there was a small defect in the outer nuclear and photoreceptor layer corresponding to a laser burn.




FIGURE 2


Case 1: Photomicrographs showing a histopathologic section through the area of occult choroidal neovascularization in the supertemporal macula of the right eye. (Top) Section through an area of speckled hyperfluorescence in the supertemporal posterior pole of the right eye showing a thin layer of vessels beneath the relatively intact retinal pigment epithelium (arrowhead). A small defect in the outer nuclear and photoreceptor layer of the artifactitiously detached retina corresponds to a laser burn (arrow; hematoxylin and eosin, ×100 magnification). (Bottom) Area showing a break in the Bruch membrane with connection between the choriocapillaris and the subpigment epithelial neovascularization (arrow). Overlying pigment epithelium shows attenuation and pigment clumping (hematoxylin and eosin, ×200 magnification).


Case 2


An 81-year-old man noted decreased vision in his left eye over a 3-week period. He had lost vision in the right eye 9 years earlier. When seen in October 2004, his visual acuity was recorded at 1/200 in the right eye and 20/80 in the left eye. There was a fibrous scar in the macula of the right eye and subretinal fluid in the macula of the left eye. A fluorescein angiogram performed on October 20, 2004, showed an occult subfoveal neovascular lesion in the left eye. Photodynamic therapy (off-label treatment) was recommended and was carried out on November 2, 2004. He returned for follow-up on December 29, 2004. Visual acuity was 20/100 in the left eye and there was subretinal fluid in the macula. A repeat fluorescein angiogram of the treated left eye was carried out on January 5, 2005, and again showed subfoveal CNV. This time, the nasal portion of the lesion consisted of a sharply defined component consistent with classic CNV, whereas the remainder of the lesion was consistent with less well-defined occult CNV ( Figure 3 ). One week later, on January 12, 2005, the patient died, and the eyes were obtained for histopathologic study.




FIGURE 3


Case 2: color fundus photograph and fluorescein angiographic photographs demonstrating a mixed choroidal occult and classic choroidal neovascular membrane in the macula of the left eye. (Top left) Fundus photograph showing fluid, hemorrhage, and exudates in the macula. (Top right) Fluorescein angiogram at 32 seconds showing a classic component of neovascular membrane at the nasal aspect of the lesion (arrow) that fills more rapidly and is seen to be more superficial on stereoscopic viewing, with the more slowly filling and deeper occult component temporally (arrowhead). (Bottom left and right) 126-second and 347-second photographs, respectively, showing late leakage and staining of the entire complex.


Histopathologic findings of left eye ( Figure 4 ) revealed a choroidal neovascular membrane that correlated with the antemortem fluorescein angiographic studies. The temporal portion of the lesion consisted of a fibrovascular membrane interposed between the relatively intact RPE and the elastic portion of the Bruch membrane. On the nasal side of the fovea, a vascular membrane was present in the subretinal space. These vessels were present in a relatively loose extracellular matrix compared with the vessels present in the sub-RPE space. There was a serous detachment of the fovea, and there was partial loss of the photoreceptor layer.




FIGURE 4


Case 2: Photomicrographs showing histopathologic sections through subfoveal choroidal neovascularization, demonstrating both subretinal and subpigment epithelial components in the left eye. (Top) Section through the fovea showing subfoveal choroidal neovascular membrane. The temporal portion consists of a subretinal pigment epithelial fibrovascular membrane (arrowhead). It contains small-caliber vessels and is interposed between the intact retinal pigment epithelium and the Bruch membrane. The nasal portion (arrow) shows a membrane in the subretinal space characterized by larger vessels within a relatively loose extracellular matrix compared with vessels in the temporal portion. There is a serous detachment of the fovea (SD) and partial loss of the photoreceptor layer (P; hematoxylin and eosin, ×100 magnification). (Bottom) Higher-power view of the subpigment epithelial (arrowhead) and subretinal (arrow) portions of the neovascular membrane (hematoxylin and eosin, ×200 magnification).


Case 3


An 87-year-old woman was evaluated on August 16, 1999, for fluctuating, diminished vision in her right eye over the preceding 6 weeks. She had a history of longstanding vision loss in the left eye. Both eyes had previous cataract extraction and glaucoma filtering procedures 3 years earlier. Visual acuity was 20/60 in the right eye and 20/200 in the left eye. In the right eye, there was fluid and prominent intraretinal hemorrhage in the macula along with large drusen and pigment alterations. The fluorescein angiographic and histopathologic findings of this right eye were consistent with retinal angiomatous proliferation and were presented in detail in a previous report. In the left eye, a pigment epithelial detachment (PED) was centered at the fovea, where a focal atrophic lesion approximately 300 μm in diameter was located. Pigment changes were present overlying the PED, and large drusen were present beyond its borders. A few hard exudates were present supertemporal to the PED. No intraretinal hemorrhages were seen. Stereoscopic fluorescein angiographic photographs of the left eye showed pooling of dye beneath the detached pigment epithelium, with an area of persistent and enlarging intense hyperfluorescence located supertemporal to the fovea ( Figure 5 ). There was a sharply circumscribed area of hyperfluorescence consistent with the clinically apparent focal atrophic defect at the fovea. No treatment was applied. The patient died 5 months later on January 23, 2000, and the eyes were obtained for histopathologic study.




FIGURE 5


Case 3: color photograph and fluorescein angiograms of the left eye showing pigment epithelial detachment in the macula with focal leakage at its supertemporal aspect. (Top left) Color fundus photograph of left eye with pigment epithelial detachment centered at the fovea. (Top right) Fluorescein angiogram of the left eye at 73 seconds. The retinal leakage site is at the supertemporal aspect of the pigment epithelial detachment (arrow), and there is a hyperfluorescent window defect corresponding to a focal pigment epithelial atrophic spot at the fovea (A). (Bottom left) Fluorescein angiogram at 188 seconds.


Histopathologic findings of the left eye revealed a plexus of blood vessels in the outer retina, abutting on the elastic portion of the Bruch membrane ( Figure 6 ). These vessels were surrounded by abundant eosinophilic extracellular matrix. In the area of the vessels, the RPE monolayer normally resident on the Bruch membrane was absent. There were scattered pigment-containing cells surrounding the vascular plexus. The outer retinal anatomic features were abnormal in the area of the vascular plexus, with loss of the photoreceptor layer. There was intraretinal edema and scattered intraretinal hemorrhages.




FIGURE 6


Case 3: Photomicrographs showing histopathologic sections through retinal angiomatous proliferation (RAP) lesion, supertemporal to the fovea in the left eye and nasal to fovea in the right eye. (Top left) Blood vessel plexus in the outer retina (arrow) is abutting on the elastic portion of the Bruch membrane. Vessels within the plexus are surrounded by eosinophilic extracellular matrix, and the adjacent pigment epithelial monolayer is absent (arrowhead). The outer retina in the area is disrupted and there is loss of the photoreceptor layer (asterisk). Cystic intraretinal edema and hemorrhages are present. Pigment epithelial detachment is present (PED; hematoxylin and eosin, ×100 magnification). (Top right) Section through another area of the RAP lesion demonstrating decreased patency of vessels within the plexus (arrow; hematoxylin and eosin; ×100 magnification). (Bottom) Section through RAP lesion in the previously reported right eye showing a comparatively denser cellular plexus with less abundant eosinophilic extracellular matrix (arrow; hematoxylin and eosin, ×200 magnification).




Results


Case 1


A 67-year-old woman had been aware of mild visual impairment in both eyes for approximately 2 years. We evaluated her on May 20, 2000. Her past medical history indicated surgery and radiation treatment for breast cancer 11 years earlier. On ophthalmic examination, best-corrected visual acuity was 20/20 in the right eye and 20/25 in the left eye. Intraocular pressure was 19 mm Hg in each eye. Mild nuclear lens changes were present in both eyes. On ophthalmoscopy, large confluent drusen were present in both eyes with no signs of CNV in either eye ( Figure 1 , Top left). Fluorescein angiography showed mild fluorescence of drusen with no signs of CNV in either eye. The patient agreed to participate in the Complications of Age-Related Macular Degeneration Prevention Trial (CAPT) and was randomized to laser grid treatment for the right eye. On May 30, 2000, 60 mild applications of argon green laser at 100-μm spot size, 0.1-second’s duration, and 110 mW of power were applied to the right eye according to the CAPT protocol. She had follow-up examinations 3, 6, and 12 months. At the 12-month visit in June 2001, some drusen resolution had occurred in the right eye, but significant drusen remained. In accordance with the CAPT study protocol, a second session of argon laser photocoagulation was applied using 30 applications of argon green laser. The patient was followed up yearly thereafter until her most recent examination on May 24, 2004. At that time, her visual acuity was recorded as 20/25 in each eye. She noted no change in vision in either eye. On fundus examination, significant drusen resolution had occurred in the treated right eye, and no signs of CNV were noted ( Figure 1 , Top right). A fluorescein angiogram showed a poorly defined area of speckled hyperfluorescence with late leakage supertemporal to the fovea in the right eye ( Figure 1 , Bottom left and Bottom right). On September 1, 2004, 14 weeks after her most recent examination and fluorescein angiographic study, the patient died, and the eyes were obtained for postmortem study.


Jan 16, 2017 | Posted by in OPHTHALMOLOGY | Comments Off on Clinicopathologic Correlation of Choroidal and Retinal Neovascular Lesions in Age-Related Macular Degeneration

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