Retinoma: An overview

Abstract

Retinoma, also referred to as retinocytoma, is a benign manifestation of biallelic retinoblastoma gene (RB1) inactivation. Genetic or epigenetic loss of retinoblastoma protein in maturing cone precursors induces genomic instability which leads to upregulation of senescence-associated p16^INK4a and p130, resulting in non-proliferative retinoma. When senescence pathways fail and genetic instability accumulates to a critical level through altered gene copies of oncogenes and tumor suppression genes, transformation into RB1 ^-/- retinoblastoma occurs. Thus, the management of retinoma involves frequent ophthalmic examination and imaging to monitor the size and characteristics of the tumor, ensure stability, and rule out malignant transformation. Key ophthalmoscopic features of retinoma often include a translucent whitish-gray retinal mass, calcification, retinal pigment epithelial alterations with well-defined margins, located typically around the lesion, as well as a zone of chorioretinal atrophy. This review aims to provide a comprehensive overview of this non-malignant tumor drawing from current understanding of its molecular genetics, clinical characteristics, diagnostic modalities, differential diagnosis, management, and prognosis. A deeper understanding of retinoma could offer valuable insights into how retinoblastoma develops and oncogenesis more broadly, paving the way for improved strategies to prevent and treat this malignant tumor.

Keywords: Ocular oncology; Retinal tumor; Retinoblastoma; Retinocytoma; Retinoma.

FIGURE 1

Clinical presentation of patients with retinoma. Fundus photo (A) and optical coherence tomography (OCT) image (B) of retinoma in a 43‐year‐old father identified incidentally after his son was diagnosed with retinoblastoma, showing a grey translucent elevated mass in the middle of a retinal scar. Fundus photo (C) and OCT image (D) of retinoma in a 9‐year‐old girl under surveillance, showing grey translucent elevated mass with calcification. Fundus photo (E) and OCT image (F) of a 10‐month‐old child with retinoblastoma treated by chemotherapy and enucleated for reactivation. (G) Histopathology demonstrated active retinoblastoma (white arrows) adjacent to retinoma (black arrows).

FIGURE 2

Function of the retinoblastoma protein (pRB) in the control of the G1 checkpoint. A core function of pRB is to prevent the progression from the G1 to the S phase of the cell cycle by binding to and inhibiting E2F family transcription factors, which drive the cell into the S phase. Cell cycle progression occurs through the inactivation of pRB, catalyzed by cyclin‐dependent kinases (CDKs). Specifically, CDK4 and CDK6 are activated in response to the accumulation of D‐type cyclins (CycD) due to mitogenic signaling, initiating the phosphorylation (P) of pRB. This kinase activity is counterbalanced by factors including the CDK4/6 inhibitor p16^ΙΝΚ4Α. Typically, p16^ΙΝΚ4Α is present at low levels in cells, but it can be upregulated in response to oncogenic stress or DNA damage to suppress CDK4/6 activity.

FIGURE 3

Genetics of Retinoblastoma. (A) The first two ‘hits’ to RB1 (M1 and M2) occur in somatic cells. (B) M1 is found in all germline cells, resulting from either de novo or inherited from a parent (in this case example, the father). Consequently, the genotype of the affected individual is heterozygous, carrying one pathogenic variant in germline cells (RB1 ^+/−). The M2 arises after a somatic mutational event in a retinal cell. Distinct second pathogenic variants in separate retinal cells give rise to independent tumor foci. (C) In some individuals, M1 occurs during embryonic development, resulting in somatic mosaicism. The M2 can then occur in retinal cells that harbor the M1, leading to tumor initiation. Heritable disease results from pathways depicted in pathways B and C. Both M1 and M2 are present in retinoma.

FIGURE 4

Retinoma pathogenesis. In human retinas, the loss of pRB promotes the proliferation of maturing (ARR3+) cone precursor cells (CPs) through MYCN‐dependent cell‐cycle activation and MDM2‐mediated inhibition of apoptosis. Most of these cells exit the cell cycle, exhibiting high levels of p16^INK4a and p130, which leads to the formation of indolent premalignant lesions. Within these lesions, a small number of cells maintain a proliferative dynamic, ultimately giving rise to quiescent retinomas. Some cells evade this regulatory mechanism, leading to the development of highly proliferative masses that express cone cell markers typical of retinoblastoma. While the majority of retinomas remain benign throughout an individual's lifetime and do not progress to retinoblastoma, transformation into RB1^−/− retinoblastoma may occur when senescence pathways fail and genetic instability reaches a critical threshold. M1, first hit; M2, second hit; Mn, n^th hit.