Reactive retinal astrocytic tumors (so-called vasoproliferative tumors): histopathologic, immunohistochemical, and genetic studies of four cases

Abstract

Purpose: To evaluate the cellular nature of and diagnostic terminology used in connection with acquired retinal "vasoproliferative tumors."

Design: Retrospective clinicopathologic study.

Methods: Clinical records and microscopic slides of 4 enucleated globes were reviewed. Special stains and immunohistochemical probes for CD31, CD34, p53, glial fibrillary acidic protein (GFAP), CD163, and Ki67 (cell replication) were employed; ultrastructural and fluorescence in situ hybridization (FISH) analyses were performed.

Results: Tumors were located inferotemporally in middle-aged patients. They were uniformly composed of compacted elongated, GFAP-positive spindle cells (due to intermediate filaments identified ultrastructurally) with a Ki67 index of less than 1%. Rosenthal fibers and eosinophilic granular bodies were observed. Hyalinized periodic acid-Schiff-positive vessels were widely separated. CD31 and CD34 revealed a sparse microvasculature. Tumor-associated exudate spread predominantly subretinally. The retinal pigment epithelium had undergone extensive placoid fibrous metaplasia with focal ossification. P53 upregulation, BRAF-KIAA gene rearrangement, and IDH1R132H mutation typically associated with low-grade astrocytic neoplasms were absent.

Conclusions: Retinal "vasoproliferative" tumors have been mischaracterized, because they actually display a paucity of microvessels. Proliferating fibrous astrocytes with a very low proliferation index predominate, without immunohistochemical or genetic evidence favoring a neoplasm. Subretinal exudate appeared capable of provoking widespread fibrous metaplasia of the pigment epithelium that was mainly responsible for secondary retinal damage. The term "reactive retinal astrocytic tumor" is proposed as more appropriate for this entity. In carefully selected progressive lesions, consideration should be given to earlier surgical intervention before extensive subretinal exudate accumulates and pigment epithelial proliferation with fibrous metaplasia ensues.

Figure 1

Clinical features of reactive retinal astrocytic tumor. (Top) Photomontage of right fundus: appearance of an elevated lesion in the far retinal periphery (arrow) with extensive surrounding exudate including in the inferonasal quadrant. Note that there are no large feeding and draining vessels, in contrast to a von Hippel lesion (hemangioblastoma). (Bottom left) Somewhat blurred view (due to difficulty in focusing on peripheral lesion) of pink-yellow to orange retinal lesion toward the left. (Bottom right) B-scan ultrasonogram displays a well-circumscribed retinal mass that measured5 mm in elevation without choroidal or scleral acoustic excavation. The superimposed A-mode ultrasonogram shows moderate and uniform intralesional internal acoustic reflectivity without spikes that might suggest calcification.

Figure 2

Histopathologic features of reactive retinal astrocytic tumors. (Top left) Enucleated globe containing inferotemporal moderately elevated tumor (crossed arrow) with eosinophilic exudate present in the vitreous cavity (arrows). A large intraretinal cyst (C) is present immediately posterior to the mass. (Top right) Another example of a reactive astrocytic tumor (crossed arrow) with an area of apical necrosis. Contralateral to the tumor is an area of diffuse placoid fibrous thickening in the subretinal space (arrows) corresponding to areas of metaplasia of the retinal pigment epithelium. (Middle left) There is no inflammation within the necrotic area of the tumor present in the top right panel. Ghost-like vascular outlines (crossed arrows) are clearly identifiable. At the bottom is the interface with viable tumor showing massively sclerotic vessels with barely discernible lumens (arrows). (Middle right) All of the tumors were composed of interweaving bundles of bipolar spindle cells with regularly spaced sclerotic vessels (arrows), shown in a small cluster in the inset. (Bottom left) Glial fibrillary acidic protein (GFAP) intensely and diffusely immunostains the highly elongated (pilocytic) fibrous astrocytes composing the lesions. (Bottom right) Top panel: Two of the lesions displayed cells with mildly atypical nuclei consisting of hypochromasia, more rounded than elongated nuclear forms, and occasional nucleoli. Bottom panel: In 1 tumor there was an area at the periphery abutting the adjacent retina with honeycombed cells having clear cytoplasm and resembling oligodendroglial cells. Some of these cells were synaptophysin- and neurofilament-positive, indicating that they were probably persistent entrapped elements of the preexisting retina being replaced by the tumor. (Top left and Top right, hematoxylineosin [H&E], ×7; Middle left, H&E, ×7; Middle right, H&E, ×100, inset ×100; Bottom left, immunoperoxidase reaction, diaminobenzidine chromogen, ×200; Bottom right, H&E, top panel ×500, bottom panel ×400.)

Figure 3

Histopathologic figures of reactive retinal astrocytic tumors. (Top left) A homogeneous eosinophilic intracytoplasmic inclusion (arrow), called a Rosenthal fiber, is present in this more loosely textured field. The crossed arrow indicates a mildly sclerotic blood vessel. (Top right) Numerous collections of eosinophilic granular bodies (arrows) are distributed among the astrocytic cells. (Middle left) Ki67 stains a minimal number of cells (fewer than 1%) within the tumors. (Middle right) The tumors feature widely spaced sclerotic vessels, which are endowed with periodic acid–Schiff (PAS)-positive, thickened walls. The inset depicts the trichrome positivity signifying collagen in the vascular walls. (Bottom left) Rare cluster of proliferating blood vessels within the tumors. Note the eosinophilic granular bodies on the left. (Bottom right) CD31 immunostains a sparsity of microvessels within the tumor (arrows). (Top left, hematoxylineosin [H&E], ×500; Top right, H&E, ×400; Middle left, immunoperoxidase reaction, diaminobenzidine chromogen, ×100; Middle right, PAS, ×100, inset, Masson trichrome, ×200; Bottom left, H&E, ×400; Bottom right, immunoperoxidase reaction, ×100.)

Figure 4

Histopathologic features of reactive retinal astrocytic tumors. (Top left) The left panel illustrates a hemangioblastoma (von Hippel lesion) with lipidized interstitial cells (IC). The right panel shows CD31 immunostaining of a rich background microvasculature, in contrast to the minimal microvasculature of reactive retinal glial astrocytic tumors (see Figure 3, Bottom right). (Top right) Osseous metaplasia of the retinal pigment epithelium (arrows) underlies a reactive astrocytic tumor (S, sclera). (Middle left) Diffuse placoid fibrous metaplasia of the retinal pigment epithelium in a zone contralateral to where the astrocytic tumor was located. On the surface of the fibrous plaque (FP) is a layer of loosely adherent histiocytic cells (arrows). The overlying retina shows a preretinal gliotic membrane (closed arrows), disorganization, loss of ganglionic and photoreceptor cells, and mild intraretinal gliosis. The underlying choroid exhibits a moderately intense lymphocytic infiltrate (IN). The inset in the upper right demonstrates a monolayer of epithelioid histiocytes (arrows) on the surface of the fibrous plaque. The inset on the bottom left demonstrates entrapped multi-nucleated and mononucleated epithelioid histiocytes within the plaque. (Middle right) There are myriad mononucleated and multi-nucleated granulomatous cells in the subretinal space above the pigment epithelium (crossed arrows) engulfing cholesterol clefts (arrows). The inset displays intense periodic acid–Schiff (PAS) positivity in the cytoplasm of the histiocytes, mimicking the appearance of Whipple cells. (Bottom left) Pseudoadenomatous proliferation where the pigment epithelium (arrows and inset) begins to undergo metaplasia into a fibrous plague. In the choroid there are masses of cholesterol clefts (C) and a collection of fully lipidized xanthoma cells (XC). (Bottom right) A blood vessel is present in the deep retina (arrow), having originated from the choroid and migrated through a break in the metaplastic fibrous plaque (FP). The vessel is surrounded by xanthoma cells (XC), which are also present in the retina above. (S, sclera.) The inset displays intralamellar histiocytes within the sclera. (Top left, left panel, hematoxylineosin [H&E], ×200, right panel, immunoperoxidase reaction, diaminobenzidine chromogen, ×200; Top right, H&E, ×20; Middle left, H&E, ×100, insets ×200 and ×400; Middle right, H&E, ×200, inset, PAS, ×400; Bottom left, H&E, ×100, inset ×100; Bottom right, H&E, ×100, inset ×400.)

Figure 5

Ultrastructural and genetic features of reactive retinal astrocytic tumors. (Top) Transmission electron micrograph of a tumor cell reveals short profiles of rough-surfaced endoplasmic reticulum (rer) in the perikaryon region. The cell has straight borders without basement membranes. Adjacent small cellular processes (P), some of which contain lysosomes (Ly), are clustered toward the bottom left and upper left. The inset highlights intermediate cytoplasmic filaments that correspond to the glial fibrillary acid protein positivity of the tumor cells. There are no villous processes suggestive of Müller cells. (Bottom) Fluorescence in situ hybridization analysis failed to reveal a BRAF-KIAA fusion because probes BRAF (red) and KIAA (green) were nonoverlapping. (Top, ×11 000, inset ×15 000; Bottom, ×1000.)