Classification and management of seeds in retinoblastoma. Ellsworth Lecture Ghent August 24th 2013

Abstract

Retinoblastoma has the unique capacity to accelerate its own intra-ocular propagation by adopting semi-solid or even liquid growth properties through seeding. Until recently, the presence of any degree of seeding was mostly incompatible with successful conservative management, due to the multiresistant nature of the seeds. Surprisingly, this well-recognized retinoblastoma behavior has not undergone any detailed description of seeding patterns and anatomic sites. In this paper, we describe the phenotypic variability of seeds across the four possible intraocular seeding compartments and classify them into three fundamental types: namely dust, spheres, and clouds. We also provide an overview of the different therapeutic strategies developed for seeding, with special attention to intravitreal chemotherapy as the treatment of choice for vitreous and retro-hyaloid seeding. Finally, we propose criteria to enable assessment of the response to treatment by reporting seed regression patterns, as well as a clinical grading system for the retinal toxicity observed following intravitreal melphalan.

Keywords: Classification; intravitreal chemotherapy; retinoblastoma; seeding.

FIGURE 1.

Schematic view of the natural history of intra-ocular retinoblastoma growth with respect to the invasion of five clinically recognizable anatomic sites: (A) retina; (B) retro-hyaloid space; (C) subretinal space; (D) vitreous cavity; (E) posterior and anterior chambers.

FIGURE 2.

Seeding patterns of retinoblastoma: (A) dust following the apical disruption of the ILM/hyaloid complex; (B) spheres resulting either from clonal expansion of dust (or cloud) or (D and E) from sprouting; (C) cloud(s) following massive disruption of the ILM/hyaloid complex. Ophthalmoscopic aspect of vitreous seeds (F–I) white or translucent with a whitish (necrotic upon histopathology and hyper-reflective upon OCT) or translucent center (cystic on OCT, cf. Figure 7E and F). Histopathologic aspect of vitreous seeds (J and K) mono- or multilayered tumor cells surrounding necrotic material.

FIGURE 3.

Characteristics of endophytic seeding into the vitreous cavity: (A and B) fine dust visible around the retinal tumor; (C) dust originating from the upper tumor; (D and E) multiple free-floating spheres growing within the initial dust, (F) sphere formation in the same patient 4 months after focal treatment of the retinal tumors. Note the concentration of localized spheres in the upper quadrant and their migration inferiorly; (G and H) diffuse migration of spheres projecting anterior to the ora serrata, (I) spheres anterior to the ora serrata, masking the corpus ciliaris except the pars plicata and corresponding UBM imaging (J).

FIGURE 4.

Characteristics of prehyaloid seeding, (A–H) partially coalescent seeds attached to the internal face of the posterior hyaloid; (I and J) OCT of prehyaloid seeds (same patient as G and H) showing signs of fragmentation and hyper-reflectivity and progressive hyaloid detachment following intravitreal injections of melphalan.

FIGURE 5.

Localized (A–C) and diffuse (D–F) cloud formation with concomitant clonal growth (F). The cloud can be multiple as a result of iterative translocations of tumor material into the vitreous.

FIGURE 6.

Retro-hyaloid seeding following partial (A–F) or complete (G–H) hyaloid detachment; (I) tumor at presentation with subtotal hyaloid detachment sparing the 6 o’clock meridian. The white arrow indicates the ora serrata and the white asterisks the anterior extension of the hyaloid detachment corresponding to the posterior border of the vitreous base.

FIGURE 7.

Characteristics of subretinal seeding (A–D) partial and total retinal detachment with subretinal seeding showing typical accumulation inferiorly at the ora serrata (Figure 9C white triangles) and tending to coalesce. (G–K) Subretinal cloud with position-dependent ophthalmoscopic contours and spirit level. The white asterisk highlights the limit of cloud extension in lateral decubitus.

FIGURE 8.

Retro-hyaloid seeding: (A–D) free pavementous-like seeds changing position with eye movements within a very shallow retro-hyaloid aqueous space; (F–H) cystic sphere rolling at the posterior pole. See the position of the seed highlighted by the white triangle (E and G) with respect to the vascular bifurcation (white asterisk).

FIGURE 9.

Subretinal seeding. (A and B) free subretinal sphere (white asterisks and triangles show the mobility of the seed). (C and D) Fixed subretinal seeds attached to the external retina as seen by ophthalmoscopy. (D) UBM. The white arrow highlights the oral insertion of the detached retina. (E) OCT showing a seed attached to the external retina. (F and G) OCT showing retinal pigment epithelium attachment of subretinal seeding following retinal reattachment.

FIGURE 10.

(A–H) Retro-hyaloid cloud with typical position-dependent ophthalmoscopic contours and spirit level on ultrasonography (white asterisks: detachment of the posterior hyaloid).

FIGURE 11.

Anterior and posterior chamber seedings. (A and B) spheres in the anterior chamber; (C and D) pseudo-hypopyon (anterior chamber equivalent of a cloud); (E and F) UBM showing spheres invasion of the posterior chamber (E) and spheres and plaque formation in the anterior chamber (F); (G–I) HE staining of seeds in the anterior segment showing spheres and tumor plaques growing at the corneal endothelial surface (G and I).

FIGURE 12.

Regression patterns of vitreous seeding: (A) vitreous seeds prior to IViC, (B) partial response following first IViC characterized by fragmentation of the spheres sometimes accompanied by a pseudo-growth, (C) further fragmentation after additional injections before complete extinction. Complete response can be classified into complete disappearance (type 0), conversion into either (D) calcified seeds (type Ia), (E) crystalline refringent dust (type Ib), (F) amorphous non-spherical (see asterisk) seeds (type II), or (F) a combination of regression types I and II (type III).

FIGURE 13.

Clinical grading system of retinal toxicity: (A) grade I, (B) grade II, (C) grade III, (D) grade IV, (E) grade V.