TNM Staging System for Retinoblastoma


Monday June 10, 2019


Retinoblastoma is staged to help doctors describe the extent of cancer in a child’s body, define potential for cure, vision and eye salvage, identify the best treatments, and compare impact of different therapies. Dr. Ashwin Mallipatna explains the TNM Staging System for Retinoblastoma and why it is the best approach for patient care.

An African doctor looks on as another uses a handheld digital camera to visualise a child's eyes during an exam under anaesthesia.

Dr. Kahaki Kimani thoroughly assesses a child’s eye using a Retcam during an Exam Under Anaesthesia in Nairobi, Kenya.

How Is Retinoblastoma Staged?

Our current understanding of retinoblastoma tells us that every tumour starts in a child’s eye from an abnormal RB1 gene in an immature retinal cell. In some children, this mutation could be inherited from parents, and in others it is sporadic and occurs for an unknown reason.

.The tumour then develops in stages, from a few malignant cells within the immature retina in a young child, to an aggressive cancer spreading outside the eye and into the vital organs (such as the brain) as the child grows. It is important for us to know which stage the cancer is in so we can predict the outcome and identify the most appropriate treatments for children with retinoblastoma.

Working with the American Joint Committee on Cancer (AJCC), we have published a 2018 consensus about the stages in which this cancer grows. This new TNM staging system for retinoblastoma is designed to predict the outcome for each eye and our ability to save the child’s life. Leaving a child’s retinoblastoma untreated could result in the tumour growing from one stage to the next. Treatment is expected to halt the tumour at a stage at which the cancer has grown to. Progression despite treatment is usually considered ominous.

To stage retinoblastoma, eye doctors need to examine each of the child’s eyes in detail under anaesthesia, and use information obtained from an MRI scan of the head and other lab tests to look for areas of tumour spread. Genetics lab tests have become essential in predicting the long-term outcome of children with retinoblastoma, especially adding value to those children who do not have both eyes involved with this cancer.

We look for four categories to stage the child:

  1. {T) Tumour Stage: how much of the eye is involved, especially in the worse eye?
  2. {N} Lymph Nodes: has the tumour involved the child’s lymph nodes?
  3. {M} Metastasis: are there any signs that the tumour has spread into other organs, like the brain or bones?
  4. {H} Heritability: is the child at risk for cancers from their genetic build?

What Do The Different Stages Mean?

Clinically, how much an eye is involved is judged by a careful and detailed examination of both eyeballs. Additional information is sought from scanning the eye with an ultrasound scan and scanning the head with an MRI scan (or sometimes a CT scan if an MRI is not possible). Each eye will be in one of the following stages:

Tumour Stage

Stage 0

After a proper examination, there is no evidence that an eye has retinoblastoma.

Stage 1

One or more retinoblastoma tumours occupy the retina, and may affect vision, either because of their size or location

Stage 2

A retinoblastoma tumour causes the retina to detach or a tumour is found to be “Seeding” (a sign of spread within the eye, making the eye more challenging to treat).

Stage 3

The eye shows signs of uncontrolled tumour spread (spreading beyond the retina or causing an eye to bleed or be inflamed) but the tumour still seems confined to inside the eyeball.

Stage 4

MRI scans indicate that the tumour has spread beyond the confines of the eyeball (“extraocular”), into the optic nerve or other tissues surrounding the eyeball.

Lymph Nodes

At the time of diagnosis, the presence of swelling lymph nodes around the eye should alert the ophthalmologist to the possibility that tumour has spread beyond the eye. This is especially important in determining the outcome of a child when a tumour is deemed to be stage 4 (or having spread outside the eyeball).

Metastasis

At the time of diagnosis, every child must undergo a scan of the brain, where available, and an examination by the oncologist to determine if the brain or other organs have been involved by retinoblastoma or a related tumour. Sometimes, tests involve taking a sample of spinal fluid or bone marrow to look at its cells under a microscope.

Heritability

We have strong evidence to show that looking for an abnormality in a child’s RB1 gene can predict a child’s survival. A child with an abnormal RB1 gene can develop new retinoblastoma tumours in the eye, and second primary tumours in sites away from the eyeball even after retinoblastoma is cured. Their children also have a risk to develop retinoblastoma. Therefore, we suggest looking for an abnormal RB1 gene in the blood of all children with retinoblastoma, and providing early screening for those who show an abnormal RB1 gene.

A graphic showing six images of eyes at different stages of retinoblastoma progression (cT1a, cT1b, cT2a, seeding at cT2b, orbital cellulitis at cT3 and advanced extraocular disease at cT4.

A visual progression of retinoblastoma through the TNM Staging System.

Which Stages Indicate Risk To My Child’s Life?

The higher the stage, the greater the risk to a child’s life. With appropriate treatment, Tumour Stages 1 and 2 respond well to current treatment modalities and are generally not a threat to the child’s life. Tumour Stage 3 has a moderate risk, and Stage 4 has higher risk of death from retinoblastoma despite treatment. As this new staging system is used more, we will begin to gain clear evidence and learn more about the exact survival rates of each stage of cancer.

Is This Staging System Useful After Enucleation?

Yes. We can also stage the risk of a child developing a tumour in distant vital organs (like the brain and bones) after an eyeball filled with tumour has been removed. The American Joint Committee on Cancer has published a consensus about how to look for microscopic tumour spread, and therefore determine the risk for retinoblastoma developing outside the eyeball. The pathological stage of the eyeball determines whether the child receives adjuvant chemotherapy after the removal of an eye with tumour.

What Other Systems Classify Retinoblastoma?

Retinoblastoma has historically been staged and classified in different ways:

The International Retinoblastoma Staging System:

This system proposed in 2006 is probably one of the more successful methods of staging each child with retinoblastoma. This was improved going into the new TNM staging system approved by the American Joint Committee on Cancer.

The “A..B..C system” (International Intraocular Retinoblastoma Classification):

This seems to be the most common classification system for retinoblastoma. It pertains to intraocular retinoblastoma and was designed to predict vision and eye survival. Unfortunately, two versions of this classification were published by different authorities, resulting in differing definitions of Group D and Group E retinoblastoma. The working group of the American Joint Committee on Cancer has made its consensus based on the commonalities of both systems, and the most evidence based system for clinical trials.

The Reese-Ellsworth staging system

The Reese-Ellsworth system (developed in the 1960’s) was designed to predict which eyes have a favourable outcome with external beam radiation therapy (EBRT) as the primary treatment. EBRT is no longer a primary treatment, therefore this system fails to predict the outcome of a child with retinoblastoma. Most doctors treating retinoblastoma have therefore decided not to use this system of classification.

A segment of a table comparing the TNMH Staging System with the IIRC, ICRB and IRSS Systems.

Extract of a summary comparison chart showing TNM staging and other retinoblastoma staging systems used today.  Download the full PDF Summary document.

How Can I Help My Child?

When retinoblastoma is confined to the eye and treated appropriately, and the child has regular, frequent examination of both eyes, the chance of cure is excellent.

A range of modern therapies are used today to treat retinoblastoma with the goal of saving eyes and sight.  Understanding each and assessing their appropriateness is vital to protect the child’s life and wellbeing, and ensure the best outcome.  This can only be done when both eyes have been staged using a system designed to monitor and predict outcome from current therapies.

Ask your child’s doctor how their cancer has been staged, with what system, and what the stage means for potential to save sight and risk to life.  If you aren’t sure about anything that has already been explained, ask for more clarification until you clearly understand.  This will help you to be more effectively involved in discussions, ask more specific questions, make informed decisions about treatment, and advocate more proactively about your child’s care.

Watch the Diagnosis and Staging Session at One Rb World 2017, co-led by Dr. Mallipatna.

The following session was recorded during One Retinoblastoma World 2017 in Washington D.C.  Dr. Mallipatna opened with a detailed explanation of retinoblastoma staging and several examples of diagnosed children.  The session also included a breakout activity in which doctors, scientists, parents and survivors collaboratively discussed different patient presentations and their TNM staging.

Reference

Mallipatna, A., Gallie, B. L., Chévez-Barrios, P., Lumbroso-Le Rouic, L., Chantada, G. L., Doz, F., Brisse, H. J., Munier, F. L., Albert, D. M., Català-Mora, J., Desjardin, L., Suzuki, S., Carroll, W. L., Coupland, S. E. & Finger, P. T. Retinoblastoma. In: Amin MB, Edge SB, Greene FL, et al., eds. AJCC Cancer Staging Manual. 8th ed. New York: Springer; 2017: Ch. 68, 819-831.

About the Author

Dr Ashwin Mallipatna is a paediatric ophthalmologist and an expert in the management of retinoblastoma. His recent work on standardising the TNM staging of retinoblastoma with the American Joint Committee on Cancer is making an impact on the management of retinoblastoma worldwide by allowing for international treatment protocols to be tested on the same platform. As the publication’s lead author, he consolidated and analysed published and unpublished evidence to provide the only evidence-based staging system for retinoblastoma.

In addition, this chapter is the first staging system to include the Stage Group “H” indicating the prognostic importance of “Heritable” disease. He has been recognised for his significant and enduring contribution to the 8th Edition of the AJCC Cancer Staging Manual.