Retinoblastoma: Understanding Your Pathology Report

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Retinoblastoma is a cancer that develops from immature retinal cells, the light-sensing tissue at the back of the eye. It is the most common eye cancer in children. About 1 child in every 15,000 to 18,000 born is affected. Almost all cases are diagnosed before age 5, and two-thirds before age 2.

Retinoblastoma is diagnosed differently from most other cancers because doctors do not perform an eye biopsy. This article is written for parents and caregivers. It explains why doctors diagnose it without a biopsy, what appears on a pathology report when an eye is removed, and why genetic testing is recommended for every child.

What causes retinoblastoma?

Retinoblastoma develops when both copies of a gene called RB1 stop working inside a cell of the developing retina. RB1 is a tumor suppressor gene, which means its normal job is to stop cells from dividing when they should not. Every cell carries two copies of RB1, one from each parent, and a tumor can only form when both copies are lost in the same cell.

How those two copies are lost divides retinoblastoma into two forms, and the difference matters for the whole family.

Heritable retinoblastoma. About 40 percent of cases. The child is born with one non-working copy of RB1 in every cell of the body. Only one further change is then needed in any retinal cell. Tumors tend to appear early, often in both eyes, and often in more than one place in each eye. In most of these children, the change is new rather than passed down, and neither parent carries it.
Non-heritable retinoblastoma. About 60 percent of cases. Both changes happen inside a single retinal cell after conception. These tumors affect one eye, usually as a single tumor, and there is no increased risk for brothers, sisters, or future children.

Every child with tumors in both eyes has the heritable form, as does every child with a family history. Roughly 15 percent of children with a tumor in one eye also turn out to have it. This is why testing is not limited to children with disease in both eyes. A small number of tumors have working RB1 genes and instead carry many extra copies of a gene called MYCN. These occur in one eye in very young infants and are not inherited.

What are the symptoms of retinoblastoma?

Retinoblastoma usually causes no pain, and a young child cannot describe a vision change. The signs are therefore things a parent or a clinician notices from the outside.

A white pupil. Called leukocoria. The pupil reflects white rather than red, often first noticed in a flash photo. This is the most common sign.
An eye that turns in or out. Called strabismus. This is the second most common sign and happens when the tumor affects vision in that eye.
A red, swollen, or painful eye. Usually a later sign.
Poor vision or an enlarged eye. Also a later sign, and sometimes the reason a child is first examined.

Children in families known to carry an RB1 change are examined from birth on a schedule, and their tumors are usually found before any sign appears.

How is the diagnosis made?

Retinoblastoma is one of the few cancers diagnosed without a biopsy. An eye specialist diagnoses it by examining the retina in detail while the child is under general anesthesia. The instrument uses light and magnification to view the back of the eye. Ultrasound and MRI are used alongside the examination, and calcium deposits within the tumor on imaging strongly support the diagnosis.

A needle or surgical biopsy of the eye is avoided. Passing an instrument through the wall of the eye can carry tumor cells outside it and turn a curable tumor into one that has spread. For this reason, treatment usually begins without a pathology report, unlike almost every other childhood cancer.

A pathology report for retinoblastoma is produced only when an eye is removed, an operation called enucleation. This happens either as the first treatment, when a tumor is too advanced to save the eye, or later, when eye-saving treatments have not worked. The report then describes the tumor and whether it has spread beyond the retina into the other structures of the eye.

What the pathologist examines after the eye is removed

When a retinoblastoma eye is removed, the pathologist examines the whole eye rather than a small sample. The optic nerve, which carries signals from the eye to the brain, is cut during the operation. The cut end is taken and examined first so that the rest of the specimen does not contaminate it.

Under the microscope, retinoblastoma consists of small cells with round nuclei and very little cytoplasm. In many tumor,s the cells form rings around a small space, called Flexner-Wintersteiner rosettes, which show that the cells are trying to become retina. Necrosis (dead tumor tissue) and calcification (calcium deposits) are common and are part of what imaging detects before surgery. Immunohistochemistry, including stains such as CRX and synaptophysin, is used only when the appearance is unclear.

Most of the examination focuses not on the tumor itself but on the surrounding structures. The pathologist looks at the choroid, the layer of blood vessels beneath the retina, the optic nerve, the front of the eye, and the sclera, the tough white outer wall. What is found in those places determines what happens next.

High-risk features on the pathology report

After an eye with retinoblastoma is removed, the pathology report states whether certain features are present. These are called high-risk features, and they identify children in whom tumor cells may have escaped the eye and who therefore benefit from chemotherapy after surgery. At least one is found in roughly a fifth to a quarter of removed eyes.

Massive choroidal invasion. Tumor growing into the choroid, the vessel-rich layer beneath the retina, and measuring 3 millimeters or more. The choroid is rich in blood vessels, which allows tumor cells to reach the rest of the body.
Post-laminar optic nerve invasion. Tumor extending along the optic nerve past a sieve-like plate called the lamina cribrosa. Reports describe invasion as pre-laminar, laminar, or post-laminar, and only post-laminar counts as high risk on its own.
Anterior segment invasion. Tumor in the iris, the ciliary body, or the fluid-filled space at the front of the eye.
Scleral or extrascleral extension. Tumor growing into or through the white outer wall of the eye, meaning it has reached the orbit.
Combined choroidal and optic nerve involvement. Smaller amounts of choroidal invasion together with any optic nerve involvement, which most centers treat as high risk even though neither finding alone would be.

Choroidal invasion of less than 3 millimeters on its own is not considered high risk, and neither is optic nerve involvement that stops before the lamina cribrosa. Chemotherapy is often not needed in those situations. Because these measurements guide treatment, a second pathologist experienced in eye pathology often reviews the slides.

Surgical margin

The margin in a retinoblastoma specimen is the cut end of the optic nerve, the point where the surgeon divided it to remove the eye. The pathologist examines this end for tumor cells and reports the length of nerve that was removed.

A negative margin means no tumor cells were seen at the cut end. A positive margin means tumor reaches the cut end, and tumor may have been left behind in the orbit. This is the most concerning single finding on a retinoblastoma pathology report, and it leads to more intensive treatment, usually chemotherapy together with radiation to the orbit. Surgeons remove as long a segment of optic nerve as they safely can to make this outcome less likely.

Genetic testing and what it means for the family

Genetic testing is recommended for every child diagnosed with retinoblastoma, whatever the number of eyes involved and whether or not anyone else in the family has been affected. Testing looks for a change in the RB1 gene in a blood sample, and often in the tumor as well when an eye has been removed. This is different from tests done on the tumor alone, because it examines the DNA the child was born with.

The result changes what happens next for the child and for relatives.

A germline RB1 change is found. The child has the heritable form. Each of that child’s future children would have a 50 percent chance of inheriting the same change, and siblings may need testing. The child needs continued examination of the remaining eye and imaging of the pineal region of the brain, where a related tumor occasionally develops.
No germline RB1 change is found. The tumor is almost certainly non-heritable. The risk to brothers, sisters, and future children is close to that of the general population, and eye examinations for relatives can usually be stopped.
MYCN amplification with normal RB1. A small group of tumors in very young infants. These are not inherited and carry no risk for other family members.

A genetics service arranges testing, and a genetic counselor explains the results and what they mean for each relative. You can read more in our article What is a hereditary cancer syndrome?

Stage and group

Retinoblastoma is described by more than one system, and several may appear in your child’s record. Each answers a different question.

Group A to E. Applies to an eye that still contains tumor and describes how likely that eye is to be saved with treatment. Group A tumors are small and away from the center of vision. Group E eyes have extensive tumor and are usually removed.
pT stage. Assigned by the pathologist after an eye is removed, based on how far the tumor has grown into the choroid, the optic nerve, and the wall of the eye. This is part of the TNM system used for many cancers.
H category. Unusual to staging, and specific to retinoblastoma. It records whether a germline RB1 change is present, absent, or unknown, because heritability affects lifelong care.
Overall stage. Describes whether the disease is confined to the eye, has reached the orbit, or has spread to distant sites such as the bone marrow or the fluid around the brain.

What is the prognosis?

When retinoblastoma is confined to the eye and treated at an experienced center, more than 95 percent of children survive. This is one of the highest cure rates of any childhood cancer. It reflects both the biology of the tumor and the fact that it is usually found before it leaves the eye.

Outcome depends most on whether the tumor has spread beyond the eye. Disease that has reached the orbit, the optic nerve margin, or distant sites is much harder to treat, and survival falls substantially. Worldwide, survival is far lower than the figures above, because in many countries children reach care only after the tumor has grown outside the eye. Delays in diagnosis, rather than the tumor itself, account for most of that difference.

Survival is a separate question from saving the eye and saving vision. A child can be cured and still lose an eye, and vision in a treated eye depends on where the tumor sat in relation to the center of the retina. Children who lose an eye are fitted with a prosthetic eye and usually adapt well.

Second cancers later in life

Children with the heritable form of retinoblastoma carry the same non-working RB1 gene in every cell of the body. This raises the risk of developing a different cancer later in life. The most common are osteosarcoma and other sarcomas, which together account for about half of these second cancers, followed by melanoma of the skin and, at older ages, other cancers.

Risk depends on treatment. Estimates for children with the heritable form who did not receive radiation to the head are around 20 percent by adulthood. For those treated with external beam radiation, figures have historically reached 40 to 50 percent, which is why that form of radiation is now avoided wherever possible. Children with the non-heritable form carry a risk close to that of the general population.

A risk of this size is high enough to justify lifelong follow-up and low enough that most survivors never develop a second cancer. Practical steps include staying with a survivorship clinic into adulthood, protecting the skin from the sun, and avoiding tobacco. Assess new bone pain or a new lump promptly rather than watch it.

What happens after the diagnosis?

Care for retinoblastoma is planned at a center that treats this tumor regularly. The team usually includes an eye cancer specialist, pediatric oncologist, geneticist, and pathologist. Because the diagnosis is made without a biopsy, the first decisions rest on the examination and imaging rather than on a pathology report.

Several treatments aim to save the eye. Chemotherapy can be delivered through a catheter into the artery supplying the eye, injected into the eye itself for tumor cells floating in the jelly, or given through a vein. Freezing and laser treatments are used for small tumors, and a radioactive plaque can be stitched temporarily to the outside of the eye. Enucleation is used when the tumor is too extensive for these to work or when the eye is already blind and painful.

After an eye is removed, the pathology report determines whether further treatment follows. High-risk features lead to chemotherapy after surgery, and tumor at the optic nerve margin leads to chemotherapy with radiation. Follow-up includes repeated examinations under anesthesia of the remaining eye during the years when new tumors can still form, and genetic testing for the family. For children with the heritable form, follow-up continues into adult life.

Questions to ask your doctor

Is the tumor in one eye or both, and were multiple tumors found?
What group has been assigned, and does that mean the eye can be saved?
Has my child had genetic testing for a change in the RB1 gene, and when will the result be ready?
If a germline change is found, what does it mean for my other children and for future pregnancies?
Do brothers and sisters need eye examinations, and starting at what age?
If an eye was removed, were any high-risk features found on the pathology report?
How much choroidal invasion was present, and how far did the tumor extend along the optic nerve?
Was the optic nerve margin free of tumor?
Were the slides reviewed by a pathologist with experience in eye pathology?
Will chemotherapy or radiation be needed after surgery, and why?
What vision can we expect in the treated eye or the remaining eye?
How often will examinations under anesthesia be needed, and for how long?
What is the long-term plan for monitoring for second cancers?
Is treatment being given on a clinical trial or a standard protocol?