Eye Cancer Survivorship Follow-Up Questions

"Eye cancer" in adults usually means uveal melanoma. That is melanoma of the iris, ciliary body, or choroid. In children it usually means retinoblastoma. The follow-up questions barely overlap. So it is worth knowing which one this is.

Uveal melanoma is rare. It is still the most common primary cancer inside the adult eye. The mean age-adjusted incidence in the United States is about 4.3 new cases per million people a year. That is 4.9 per million in men and 3.7 in women. Incidence rises with age and peaks near 70. It has been stable since at least the early 1970s.

Retinoblastoma is a childhood tumor, and it comes in two forms. Heritable retinoblastoma accounts for 25% to 30% of cases, nonheritable for 70% to 75%. That split governs everything that follows.

The uveal tract has blood vessels but no lymph channels. So spread happens by local growth and through the bloodstream. It does not happen through lymph nodes. Nodal spread is rare enough that sentinel node biopsy is not part of staging.

Where it goes is specific. The first site found is usually the liver. Lung, bone, and sites under the skin are also common. The Collaborative Ocular Melanoma Study trials put numbers on it. Among patients whose spread was reported during follow-up or at death, the liver was the only site found in 46%. Another 43% had liver plus other sites. That is roughly nine in ten involving the liver.

So the practical follow-up question is blunt. What liver surveillance is planned, by what method, at what interval, and for how long? The PDQ also notes the reverse case. In someone with a history of ocular melanoma who turns up with liver metastases of unknown origin, metastatic melanoma belongs in the differential diagnosis.

Two reassurances sit in the same section. Choroidal melanoma of any size invading the optic nerve or its meninges is particularly unusual. And spread to the choroid of the other eye is rare.

For uveal melanoma the PDQ names five leading prognostic factors. Cell type. Tumor size. The location of the tumor front edge. The degree of ciliary body involvement. And growth outside the eye. Three more microscopic features can matter: mitotic activity, lymphocytic infiltration, and possibly fibrovascular loops.

Cell type is the most commonly used predictor of outcome after enucleation, meaning removal of the eye. The revised Callender classification sorts cells four ways: spindle-A, spindle-B, epithelioid, and intermediate. Spindle-A melanomas carry the best prognosis. Epithelioid melanomas carry the least favorable. Pure epithelioid tumors are uncommon, about 3% of cases. In the Collaborative Ocular Melanoma Study, mixed-cell melanomas made up 86%. The PDQ is candid about a gap here. There is no clear consensus on what share of epithelioid cells makes a tumor "mixed" rather than "epithelioid." That is a fair thing to ask about when reading a report.

Size has defined boundaries too, taken from the COMS trials:

• Small: 1.0 to 3.0 mm apical height, largest basal diameter 5.0 to 16.0 mm.
• Medium: 3.1 to 8.0 mm apical height, basal diameter no more than 16.0 mm.
• Large: more than 8.0 mm apical height, or basal diameter over 16.0 mm when apical height is at least 2.0 mm.

About 5% grow in a flat, spread-out pattern instead. Their thickness is roughly 20% or less of the greatest basal width. That uncommon variant appears to carry a poorer prognosis. The risk is higher with a large diameter and poorly defined margins.

Location within the uvea matters as well. Iris melanomas tend to be smaller, slower growing, and relatively quiet. They rarely spread. Tumors at the back of the eye, in the ciliary body and choroid, generally look more malignant under the microscope. They are also found later and spread more often. The 5-year mortality rate with spread from ciliary body or choroidal melanoma is approximately 30%. For iris melanoma it is 2% to 3%.

Uveal melanoma often causes nothing at all at first. As a tumor grows, the effects depend on where it sits. Iris melanoma can distort the pupil. Ciliary body melanoma can blur vision. Choroidal melanoma can sharply reduce visual acuity, through a secondary retinal detachment. Serous retinal detachment can occur. If that detachment is extensive, secondary angle-closure glaucoma occasionally develops.

Those are the mechanisms to ask about for the treated eye. Is detachment being watched? Is eye pressure being watched? And what symptoms would prompt a same-day call? Ophthalmic ultrasonography has one job here beyond measurement. It detects extrascleral extension, meaning growth outside the wall of the eye. That carries a poor prognosis. The PDQ says plainly that growth outside the eye, recurrence, and distant spread all carry an extremely poor prognosis.

Heritable retinoblastoma is defined by a germline pathogenic variant in the RB1 gene. In 25% of cases the variant came from an affected parent. In 75% it arose in a germ cell before conception, or in early embryonic development. All children with disease in both eyes are presumed to have the heritable form. So are roughly 15% of children with disease in one eye. Only 25% have an affected parent.

Age at diagnosis shifts the odds substantially. In a series of 482 children with unilateral retinoblastoma, germline pathogenic variants were found in 33% of infants under 12 months, 6% of children aged 12 to 24 months, and 7% aged 24 to 39 months.

Subsequent neoplasms, meaning second cancers, are the most common cause of death in retinoblastoma. They contribute about 50% of deaths among people with both bilateral disease and genetically defined heritable disease. The numbers are stark, and worth having in hand.

• Cumulative incidence of second cancers by 50 years after diagnosis was 26% in patients not given radiation, and 58% in those who were. That is roughly 1% per year.
• Cohorts treated with more modern radiation planning report about 9.4% in nonirradiated and about 30.4% in irradiated patients.
• In one nonrandomized comparison, the 10-year cumulative incidence of radiation-induced second cancers was 0% with proton therapy versus 14% with photon therapy.
• The most common second cancer is sarcoma. Osteosarcoma comes first, then soft tissue sarcoma, then melanoma. In survivors given radiation, two-thirds of second cancers arise inside the treated tissue and one-third outside it.

Risk of second cancers is markedly increased in heritable retinoblastoma, whether or not radiation was given. Adults with heritable disease also face risk of epithelial cancers later in life. Increased mortality has been described from lung, bladder, and other epithelial cancers.

Family screening has published risk figures. Take a child affected in both eyes. The pretest chance a relative carries the mutant RB1 allele is 50% for an infant offspring, 5% for a parent, and 2.5% for a sibling. Where the affected child had one eye involved, those figures become 7.5%, 0.8%, and 0.4%. General population risk is 0.007%. Infants born to affected parents get a dilated eye examination under anesthesia as soon as possible in the first month of life, plus genetic evaluation. Infants with a positive genetic test are examined under anesthesia every month.

One more figure belongs on a survivorship list. The Retinoblastoma Survivor Study followed 470 survivors, at a mean age of 43, with median follow-up of 42 years. Of those, 87% had at least one medical condition. And 71% had a severe or life-threatening condition.

Related pages: cancer staging for the TNM framework, what a survivorship care plan is for how this gets written down, and fear of recurrence for the part that surveillance does not address.

• NCI PDQ — Intraocular (Uveal) Melanoma Treatment, health professional version
• NCI PDQ — Retinoblastoma Treatment, health professional version