Ординатура / Офтальмология / Английские материалы / Ocular Oncology_Albert, Polans_2003

Figure 2 Endophytic retinoblastoma. Tumor grows from inner surface of retina into the vitreous. Well-defined sleeve pattern with cuffs of retinoblasts surrounding blood vessels.

I.PATHOLOGICAL FEATURES

The gross features of intraocular retinoblastoma are dependent on the growth pattern of the tumor. Five growth patterns are recognized in retinoblastomas, which explain certain variations in clinical presentation as well as differences in intraocular and extraocular spread:

A.Endophytic Retinoblastomas

Endophytic retinoblastomas (Figs. 2 and 3) grow from the inner surface of the retina into the vitreous. Thus, on ophthalmoscopic examination, the tumor is viewed directly. Retinal vessels are typically lost from view as they enter the tumor (Fig. 4). As endophytic tumors grow large and become friable, tumor cells tend to be shed from the tumor into the vitreous, where they grow into separate tiny spheroidal masses that appear as fluff balls or cotton balls. These spheroidal masses of tumor can mimic inflammatory conditions such as mycotic or nematodal endophthalmitis. Tumor cells in the vitreous may seed onto the inner surface of the retina (Fig. 3), where they may invade the retina, making it very difficult to distinguish histologically between seeding and multicentricity.

It is important to distinguish multicentric retinoblastoma (Fig. 4) from retinal seeding (Fig. 3), because the presence of multiple tumors indicates a germinal mutation and the heritable form of retinoblastoma. This distinction is impossible once there is extensive vitreous seeding. Tumors that lie mainly on the inner surface

Figure 3 Endophytic retinoblastoma. Seeding of retinoblasts on the inner surface of the retina.

of the retina rather than within it or consist of clusters of tumor cell within the vitreous are tumors in which retinal seeding is more likely than multifocality.

Tumor cells in the vitreous may invade posteriorly into the optic nerve and spread to the brain. They may spread anteriorly into the posterior chamber and then into the anterior chamber by aqueous flow. Secondary deposits on the lens, zonular fibers, ciliary epithelium, iris, corneal endothelium, and trabecular meshwork may be observed, and tumor cells may clog the aqueous outflow pathways, causing glaucoma. In such cases, the anterior segment changes may be misinterpreted clinically as those of granulomatous iridocyclitis.

B.Exophytic Retinoblastomas

Exophytic retinoblastomas (Figs. 4 and 5) grow from the outer retinal surface toward the choroid, producing a retinal detachment. On ophthalmoscopic examination, the tumor is viewed through the retina and the retinal vessels course over the tumor. As the tumor grows larger, causing subretinal exudation, tumor cells may escape into the subretinal exudate. Secondary implants may then develop on the outer retinal surface, where they can invade the retina or the inner surface of the retinal pigment epithelium. These implants may replace the pigment epithelium and eventually infiltrate through Bruch’s membrane into the choroid. From the choroid, tumor cells may escape along ciliary vessels and nerves into the orbit and conjunctiva. From the orbit and conjunctiva, they can gain access to blood vessels and lymphatics and metastasize.

D.Diffuse Infiltrating Retinoblastomas

Diffuse infiltrating retinoblastomas (Figs. 6 and 7) are the least common and often give rise to the greatest difficulty in clinical diagnosis [11–13]. It occurs later in life than other forms of retinoblastoma, with a mean age of 6 years, compared to 1.5 years for other forms of retinoblastoma. These tumors grow diffusely within the peripheral retina without greatly thickening it. Tumor cells are discharged into the vitreous, often with seeding of the anterior chamber producing a pseudohypopion. Because of the absence of a retinal mass, this type of retinoblastoma masquerades as a vitritis or Toxocara endophthalmitis. With anterior chamber involvement, hyperacute iritis with hypopyon, juvenile xanthogranuloma, or tuberculosis may be suspected [13].

E.Complete Spontaneous Regression

Complete spontaneous regression (Figs. 8 and 9) is believed to occur more frequently in retinoblastoma than in any other malignant neoplasm [7]. Typically, there is a severe inflammatory reaction followed by phthisis bulbi [14]. The mechanism or mechanisms by which regression occurs are unknown. In several cases of bilateral retinoblastoma from the American Registry of Ophthalmic Pathology there was total necrosis and phthisis bulbi on one side, while, on the other, a viable tumor massively filled the eye and invaded the orbit [14]. Such cases would seem to exclude the possibility of a systemic mechanism for tumor necrosis. The cells of a retinoblastoma have not only a high growth fraction but also a high death rate. If

Figure 6 Diffuse infiltrating retinoblastoma. Retinoblasts have infiltrated the iris and ciliary body, occluded the chamber angle, and seeded the corneal endothelium.

Figure 9 Spontaneously regressed retinoblastoma. There is bone formation and clumps of necrotic ossified retinoblasts.

for some reason the growth rate is slowed down, then the high death rate gets the upper hand and total necrosis occurs. Extraocular extension is important in determining this outcome, because once the tumor reaches the vascular supply to the orbit, the retinoblastoma, if left untreated, will grow rapidly until it kills the patient.

F.Histopathology

Retinoblastomas are malignant neuroblastic tumors. The predominant cell has a large basophilic nucleus of variable size and shape and scanty cytoplasm. Mitotic figures are typically numerous. The tumor cells have a striking tendency to outgrow their blood supply. Characteristically, especially in large tumors, sleeves of viable cells are present, cuffing dilated blood vessels (Figs. 2 and 10). As the tumor cells become displaced more than 90–110 mm away from the vessel, they undergo ischemic coagulative necrosis [15,16]. Although this is a relatively constant finding from one tumor to the next, the thickness of the sleeves is dependent on the metabolic activity of the cells within the cuff. Burnier et al. [16] demonstrated an inverse relationship between the thickness of the cuff and the mitotic activity within the cuff. A cuff thickness of 100 mm represents the approximate distance that oxygen can diffuse before it is completely consumed in rapidly growing neoplasms.

When viable tumor cells are shed into the vitreous or into subretinal fluid, they may grow into spheroidal aggregates with diameters that rarely exceed 1 mm [15]. Within the spheroids, the more peripherally situated cells derive their nutrition from the vitreous or subretinal fluid and the more central cells undergo necrosis. This

neoplasms in which Flexner-Wintersteiner rosettes have been observed. The FlexnerWintersteiner rosette represents photoreceptor differentiation by the tumor, but the cells of the rosettes are not benign. Characteristically Flexner-Wintersteiner rosettes are found within areas of undifferentiated malignant cells exhibiting mitotic activity, and the cells that form the rosettes may also contain mitotic figures. Some rosettes are incompletely formed and the cells blend with the surrounding undifferentiated cells.

The typical Flexner-Wintersteiner rosette (Fig. 12) is lined by columnar cells that circumscribe an apical lumen. The basal ends of the cells that form the rosettes contain the nuclei. The apical ends of the columnar cells are held together by terminal bars and the cells may have apical cytoplasmic projections into the lumen of the rosette. Electron microscopy has demonstrated that these projections represent primitive inner and outer segments. In the lumens of the rosettes, Alcian blue and colloidal iron stains reveal a coating of hyaluronidase-resistant acid mucopolysaccharide that has similar staining characteristics to the glycosaminogycan matrix that surrounds the rod and cones of the retina [18]. Tso and coworkers [19] described several additional ultrastructural features that the cells forming Flexner-Winter- steiner rosettes share with retinal photoreceptors: zonula occludens that form a luminal limiting membrane analogous to the cellular junctions that form the outer limiting membrane of the retina, cytoplasmic microtubules, cilia with the 9 þ 0 pattern of microtubules, and lamellated membranous structures resembling the discs of rod outer segments. Immunohistochemical and lectin histochemical studies have also supported the concept that retinoblastomas are composed of neuroblastic cells that may differentiate into photoreceptor-like cells [20–22].

Homer Wright rosettes (Fig. 13) are much less commonly seen in retinoblastomas than Flexner-Wintersteiner rosettes. Because they are found in a variety of neuroblastic tumors, they are less specific for retinoblastoma. These rosettes do not contain photoreceptor elements, and Wright first described this rosette in a neuroblastoma of the adrenal gland. They are also highly characteristic of cerebellar medulloblastomas [23]. The cells in these rosettes are not arranged about a lumen but, instead, send out neurofibrillary processes that form a tangle within the center of the rosette. Therefore, Homer White rosettes represent differentiation toward neurons similar to the retinal bipolar cells.

In 1970, Tso and coworkers [4] reported that in 18 of 300 retinoblastomas (6%) treated by enucleation, there were foci of cytologically benign cells that had features of photoreceptors (Figs. 1, 14, and 15). In most of these 18 tumors, the areas exhibiting photoreceptor differentiation could easily be spotted at low magnification as discrete, comparatively eosinophilic islands standing out in contrast to the much more intensely basophilic portions of the tumor. The tumor cells that exhibited photoreceptor differentiation had more abundant cytoplasm and smaller, less basophilic nuclei. In these areas, mitotic figures were uncommon and necrosis was absent, but scattered deposits of calcium were occasionally present. This calcification differed from that in the undifferentiated areas because it was not associated with necrosis. Scattered among the differentiated cells were individual cells and clusters of cells with long cytoplasmic processes that stained brightly with eosin. The cytoplasmic processes project through a fenestrated membrane and, when present in a cluster, tended to fan out like a bouquet of flowers (hence the name fleurette) (Figs. 1 and 14). Electron microscopy has revealed that the cells of the fleurettes