Uveal melanoma and retinoblastoma

Uveal Melanoma: Epidemiology & Clinical Features

Uveal melanoma represents the most common primary intraocular malignancy in adults, with an annual incidence in European populations of approximately 5 to 7 cases per million. Arising from neuroectodermal melanocytes within the uveal tract, its anatomical distribution is:

• Choroid (85-90%): Most frequent site.
• Ciliary Body (5-8%): Diagnosed later due to hidden location behind the iris; associated with poorer prognosis.
• Iris (3-5%): Diagnosed earliest; carries the most favorable prognosis.

Risk Stratification: Choroidal Nevus versus Melanoma

The contemporary imaging mnemonic TFSOM-DIM highlights thickness over 2 mm on ultrasound, subretinal fluid on OCT, symptoms with acuity 20/50 or worse, orange pigment on autofluorescence, melanoma acoustic hollowness and diameter over 5 mm on photography. These risk features help referral and surveillance; they are not a histological diagnosis or the same as older clinical mnemonics. Compare serial size, fluid and symptoms, and seek ocular-oncology assessment when suspicious.

Multimodal Ophthalmic Imaging Hallmarks

1. B-Scan Ultrasonography:
   • Tumour Shape: Typically dome-shaped in early stages. Rupture of the tumor through Bruch's membrane produces the characteristic collar-button (mushroom) configuration with a narrow neck and expanded apical head.
   • Acoustic Hollowness: The dense, homogeneous cellular composition of melanoma causes progressive acoustic attenuation, manifesting as internal acoustic hollowness (hyporeflective tumor parenchyma).
   • Choroidal Excavation: Apparent backward bowing or indentation of the underlying scleral contour due to replacement of the normal highly reflective choroid by hyporeflective tumor tissue.
2. A-Scan Ultrasonography:
   • Demonstrates a high initial surface spike followed by low-to-medium regular internal reflectivity (characteristically $<40-60\%$, usually $10-40\%$) with a distinctive declining acoustic gradient ("kappa angle"), reflecting acoustic absorption.
3. Optical Coherence Tomography (OCT):
   • Visualizes subretinal fluid, elongated "shaggy" photoreceptor outer segments, and intraretinal cystoid spaces.
4. Fluorescein Angiography (FFA):
   • In collar-button tumors, reveals the "double circulation" pattern: simultaneous visualization of the superficial retinal capillary network and the deeper, intrinsic tumor vasculature.

Landmark COMS Trial Findings & Genetic Prognostication

The multicentre Collaborative Ocular Melanoma Study (COMS) established modern treatment paradigms:

1. COMS eligibility: The medium-tumour trial included height 2.5–10 mm (up to 8 mm near the disc) and largest basal diameter no more than 16 mm. Use the actual trial eligibility rather than a fabricated universal size table.
2. The Medium Tumour Trial (Brachytherapy vs. Enucleation):
   • Randomized patients with medium-sized choroidal melanoma to either Iodine-125 ($^{125}\text{I}$) plaque brachytherapy or primary enucleation.
   • Landmark Conclusion: No statistically significant difference in 5-, 10-, or 12-year all-cause or melanoma-specific mortality between plaque brachytherapy and enucleation (5-year survival ~81-82% in both cohorts). This landmark trial validated eye-preserving plaque radiotherapy as the international standard of care.
3. The Large Tumour Trial (Pre-Enucleation Radiation):
   • Randomized patients with large choroidal melanoma to enucleation alone versus external beam radiation therapy (20 Gy) prior to enucleation.
   • Conclusion: Pre-enucleation radiation conferred no survival benefit, establishing standard enucleation alone as the definitive surgical therapy for large intraocular tumors.

Molecular and Cytogenetic Prognostication

GNAQ/GNA11 pathway mutations are common initiating drivers; monosomy 3, 8q changes, BAP1 loss and gene-expression profiles provide prognostic information. These are different roles. Prognosis also depends on stage, tumour size and other molecular findings; neither disomy 3 nor a class label guarantees a fixed risk. Consider PRAME and contemporary validated panels in specialist counselling.

Somatic BAP1 loss does not establish a germline BAP1 tumour-predisposition syndrome. Family/personal history and appropriate germline testing guide that assessment. Coordinate liver and systemic surveillance according to risk and oncology policy. Tebentafusp is an option for appropriate HLA-A*02:01-positive adults with unresectable/metastatic uveal melanoma; treatment eligibility is not determined by tumour pigmentation.

Retinoblastoma (RB)

Retinoblastoma is the most common primary malignant intraocular neoplasm of infancy and childhood, affecting approximately 1 in 15,000 to 18,000 live births. Arising from developing neuroectodermal retinal cells (cone precursor origin), 95% of cases are diagnosed before the age of 5 years.

Knudson's "Two-Hit" Hypothesis & Genetics

Tumorigenesis requires the functional inactivation of both alleles of the RB1 tumor suppressor gene, located on chromosome 13q14.2. The RB1 gene encodes the retinoblastoma protein ($pRb$), a critical nuclear phosphoprotein that regulates the $G_1$ to $S$ cell cycle checkpoint by binding and inactivating E2F transcription factors:

1. Heritable Retinoblastoma (~40% of cases):
   • First Hit: Germline mutation present in all somatic cells (inherited from an affected parent in ~10%, or a de novo constitutional variant in many of the remaining cases, with mosaicism considered).
   • Second Hit: Somatic mutation occurring in a developing retinal progenitor cell.
   • Phenotype: Often bilateral or multifocal and earlier in onset; a confirmed constitutional heterozygous RB1 variant has a 50% transmission probability, with phenotype and penetrance considered in counselling.
   • Second Primary Cancers: Survivors harbor an exceptionally high lifetime risk of second non-ocular malignant neoplasms (principally osteosarcoma, soft tissue sarcomas, and cutaneous melanoma). External beam radiation therapy markedly compounds this risk and is now avoided.
   • Trilateral Retinoblastoma: An intracranial midline embryonal tumour associated with heritable retinoblastoma, which can accompany unilateral or bilateral ocular disease, most commonly a pineoblastoma (or suprasellar primitive neuroectodermal tumor).
2. Non-Heritable Retinoblastoma (~60% of cases):
   • Both mutational "hits" occur somatically within a single developing retinal cell.
   • Phenotype: Usually unilateral; clinical appearance alone cannot establish non-heritable status. Genetic testing and counselling clarify the risk; no family history; very low transmission risk when absence of a germline variant is confirmed; no predisposition to second non-ocular cancers.

Clinical Presentation & Staging

• Leukocoria (60%): A white pupillary reflex ("amaurotic cat's eye") is the most frequent presenting sign, caused by light reflection off the white, elevated intraocular tumor mass.
• Strabismus (20%): Second most common presentation; sensory esotropia or exotropia resulting from macular involvement by the tumor.
• Secondary Features: Secondary neovascular glaucoma with buphthalmos, pseudohypopyon (clumps of necrotic tumor cells floating in the anterior chamber mimicking endophthalmitis), vitreous haemorrhage, and aseptic orbital cellulitis.

Diagnostic Imaging: The Calcium Hallmark

• B-Scan Ultrasonography: Highly reflective intraocular mass with prominent acoustic shadowing, representing intra-tumoural calcification (present in $>90\%$ of retinoblastomas).
• MRI of Brain and Orbits: The imaging modality of choice. Evaluates: 1) Optic nerve invasion (enhancement of the retrobulbar optic nerve), 2) Extraocular scleral extension, and 3) The pineal gland (to assess current intracranial disease; a normal scan cannot exclude future occurrence). On MRI, retinoblastoma appears moderately hyperintense on T1-weighted images and hypointense on T2-weighted images. (Note: CT readily demonstrates calcification, but is strictly minimized in germline RB patients to avoid ionizing radiation-induced second malignancies).

International Intraocular Retinoblastoma Classification (IIRC)

• Group A: Small intraretinal tumors ($\le 3\text{ mm}$) located $>3\text{ mm}$ from fovea and $>1.5\text{ mm}$ from disc; no subretinal or vitreous seeds.
• Group B: Larger tumors or tumors located near fovea/disc; subretinal fluid $\le 5\text{ mm}$ from tumor base; no seeding.
• Group C: Discrete tumors with localized subretinal or vitreous seeds $\le 3\text{ mm}$ from tumor.
• Group D: Diffuse disease with massive, widespread subretinal or vitreous seeds ($>3\text{ mm}$ from tumor).
• Group E: Very advanced intraocular disease destroying functional potential (tumor touching lens, anterior chamber involvement, neovascular glaucoma, phthisis bulbi, or opaque media).

Modern Management Paradigms

1. Intravenous Chemoreduction (IVC): VEC protocol (Vincristine, Etoposide, Carboplatin), standardly administered for 6 cycles to reduce tumor volume, followed by focal consolidation with transpupillary thermotherapy (TTT) or cryotherapy.
2. Intra-Arterial Chemotherapy (IAC / Superselective Ophthalmic Artery Infusion): Microcatheterization via the femoral artery directly into the ostium of the ophthalmic artery, infusing Melphalan ($\pm$ topotecan or carboplatin). Has transformed the management of Groups C and D retinoblastoma, achieving high rates of globe salvage.
3. Intravitreal Chemotherapy: Direct injection of low-dose melphalan into the vitreous cavity for refractory vitreous seeding, performed with strict safety precautions (cryotherapy to injection site, hypotensive globe, avoid anterior chamber contamination).
4. Enucleation is often appropriate for advanced poorly seeing eyes, but decisions consider bilateral disease, spread risk and available salvage. Suspected extraocular/retrobulbar extension requires multidisciplinary staging and treatment planning. Obtain an adequate safe optic-nerve margin for histology; no fixed stump length guarantees clearance.

Retinocytoma and oncological staging

Retinocytoma/retinoma is a differentiated retinal lesion related to the retinoblastoma pathway. A translucent or pale retinal mass with calcification, surrounding pigment epithelial change and chorioretinal atrophy can suggest it. These features are variable, so the diagnosis belongs with an ocular-oncology assessment rather than an isolated photograph. Document thickness, extent and serial imaging. Enlargement or new active features need urgent reassessment for retinoblastoma; an apparently stable lesion is not a reason to stop surveillance. Primary clinical observations and long-term follow-up show that malignant transformation is possible. Offer RB1-related genetic counselling and appropriate family assessment: a benign-appearing ocular lesion does not exclude a constitutional cancer-predisposition variant.

Stage describes anatomical extent; grade describes histological differentiation/aggressiveness. In a TNM framework, T concerns primary tumour extent, N regional lymph nodes and M distant metastasis. Use the tumour-specific current system rather than one ocular size cutoff. Uveal melanoma staging considers dimensions, ciliary-body involvement and extraocular extension, while its metastatic assessment particularly considers the liver. Conjunctival melanoma also requires attention to regional lymphatic spread. Molecular prognostic markers add risk information without replacing anatomical staging or guaranteeing an individual outcome. For retinoblastoma, globe-salvage groupings and cancer staging answer different questions; optic-nerve or choroidal high-risk histology affects further multidisciplinary treatment even after the eye is removed.