Screening for Familial Retinoblastoma and Related Second Primary Cancers

Monday September 16, 2024

Familial retinoblastoma affects more than one person in a family, and individuals with a heritable RB1 gene mutation have increased cancer risk throughout life. Finding cancer early is vital for the best treatment and outcomes. Revisiting blogs from ocular oncologist Alison Skalet M.D. PhD, and WE C Hope CEO / Rb Survivor, Abby White, we explore screening for high-risk individuals at all stages of life.

View along a vast valley under a dramatic sky. On the left, rocks are strewn in the foreground, and steep rugged hills lie in shadow. Sunlight breaks through dark clouds above, illuminating the verdant valley floor and rolling green hills beyond. A lush oak tree stands prominently in the foreground, its canopy festooned with childhood cancer gold ribbons. A meandering path leads up to the tree and continues into the distance, following the contours of the hills into the misty brightening distance.

Cancer Care From Birth, Throughout Life

Recent decades have brought huge advances in treatment for retinoblastoma. In high income countries, most children survive and retain vision in at least one eye. Tumor location and size influence vision outcome. Yet better outcomes and less intensive treatment regimens may be possible when children are diagnosed when tumors are small. In Low and Middle Income Countries (LMICs), early diagnosis is remains critical for life-saving care, and increasingly improves vision-saving outcomes.

Most children without a family history of retinoblastoma are diagnosed only after they develop a relatively large tumor that affects vision and causes signs like strabismus (turned eye) or leukocoria (a white glow in the pupil). However, children with a family history of retinoblastoma may be at higher risk for developing the cancer. Frequent dilated eye examination of these children can detect tumors before they cause obvious signs or symptoms.

Carriers of a heritable RB1 mutation have a lifelong increased risk of developing certain cancers in addition to retinoblastoma. As with retinoblastoma, early diagnosis of a second primary cancer significantly increases chance of cure and reduced treatment burden. However, there is no agreed routine screening protocol for RB1-carriers, despite copious evidence of the high cancer risk and evolution of survivorship care.

Below, we revisit two previous blogs to explore screening for familial retinoblastoma and second primary cancers, with several family stories and survivor insights. The original blog is linked from the end of each related section.

Jaylen and Ayla’s Story

Genetic Testing Empowers Screening.

Jaylen’s mother was curious when he developed a squint shortly after birth. Several months later, she began noticing both eyes glowing in iPhone photos. Though she asked the pediatrician repeatedly about these signs, he saw nothing wrong and explained that Jaylen’s eye would grow out of this developmental phase. Like many new parents, she trusted the doctor’s reassuring words.

Jaylen’s four month exam was delayed as the pediatrician refused to see him without an interpreter for his mother, who is deaf. Rather than wait another two weeks, Jaylen’s mother found a new doctor, who immediately referred Jaylen to an ophthalmologist. That crucial referral led to Jaylen’s diagnosis of bilateral retinoblastoma, and urgent treatment in Houston, Texas.

When cancer affects both eyes, doctors knew the child has the heritable form of retinoblastoma. About 15% of children diagnosed with unilateral retinoblastoma also have this form of eye cancer, but genetic testing is the only way to identify these children. Genetic testing forms a key part of medical care for all children and their families, whether one or both eyes are affected.

Jaylen’s genetic testing revealed that his father carries a damaged copy of the RB1 gene that initiates retinoblastoma, but had never developed eye cancer himself. The results were shocking for the family, but also empower them to advocate for better healthcare for Jaylen, his dad, and future children.

When Jaylen’s sister, Ayla, was born, genetic testing of her cord blood confirmed her risk for retinoblastoma, and at a screening eye exam soon after, she was diagnosed with cancer in both eyes. Her early diagnosis created the best opportunities for sight-saving care, and demonstrates the value of genetic knowledge and regular eye exams when there is a family history of retinoblastoma.

Read Jaylen and Ayla’s story at KnowTheGlow

Jaylen and Ayla

Hope

Cameron and Hope’s Story

Genetic Counselling Empowers Screening.

Sylvia had unilateral retinoblastoma as a young child in South Africa. Like many survivors with cancer in only one eye, she grew up with no knowledge of RB1 genetics and the potential risk to her children. Her first child, Cameron, had a life-threatening late diagnosis of bilateral retinoblastoma, though his life was ultimately saved with intensive chemotherapy.

Sylvia received genetic counselling as part of Cameron’s medical care. Although she could not afford the cost of genetic testing, she understood the importance of regular eye exams from birth for all her future children. So when her second child was born, Sylvia brought her baby to the hospital for an eye exam at two weeks old.

Like her older brother, Hope was diagnosed with cancer in both eyes, but this time, Sylvia’s crucial genetic knowledge empowered her daughter’s screening, early diagnosis and sight-saving care.

Read Cameron and Hope’s story

Screening When Retinoblastoma Runs in the Family

Familial retinoblastoma affects multiple family members, and usually both eyes. Diagnosing children early provides the best opportunities for life and sight-saving care. In April 2019, Alison Skalet, ocular oncologist and director of the Rb service at Casey Eye Institute, Oregon Health & Science University, wrote for our blog, examining early diagnosis strategies when there is a family history of childhood eye cancer. We republished the article in July 2023 as part of our year-long Rb Research series.

Dr. Skalet highlighted some retinoblastoma research presented at the 2019 International Society of Ocular Oncology (ISOO) meeting in Los Angeles, California, and explored a variety of screening strategies for familial retinoblastoma in the United States and around the world. These include the first national guidelines for screening children for familial retinoblastoma in the United States.

She concluded with the compelling story of how one mother has translated her diagnosis experience of worry and overwhelm into proactive clinical researcher. Ivana shows how our broad community of parents and survivors have a growing role in shaping research focus, approaches, and outcomes for all affected by retinoblastoma throughout life.

Dr. Skalet examines a child under anesthesia using an indirect ophthalmoscope.

Dr. Skalet examines a child under anesthesia. Published with permission.

Development of U.S. National Retinoblastoma Screening Guidelines

Most children do not inherit retinoblastoma, but when there is a family history, the child benefits from methodical screening, including genetic testing and dilated eye exams by an ophthalmologist familiar with examining children’s eyes.

It is important families and health care professionals know that children in families with retinoblastoma benefit from early screening for tumors by an ophthalmologist.

In the United States, the first national guidelines for retinoblastoma screening were published in 2018. They aim to increase awareness and provide a systematic approach to screening for at-risk children that is accessible to pediatricians and ophthalmologists caring for these children.

Despite its importance in guiding care, and the proven cost-benefit, genetic testing has not been available to all at-risk children in the U.S. due to lack of insurance coverage. The published guidelines support advocacy to improve industry-wide insurance coverage for screening examinations and genetic testing.

There are a variety of approaches to screening exams, shaped by individual circumstances, local resources, and physician preferences. So the U.S. guidelines do not recommend a specific approach. They emphasize the need for a clear, systematic screening for every child with a family history of retinoblastoma, including:

Dilated eye exams by an ophthalmologist for children with a family history of Rb.
All children with a family history of Rb benefit from genetic counseling and testing to clarify their risk.
Children are stratified into high, intermediate, and low risk categories. Frequency of examinations recommended varies based on a child’s age and level of risk, decreasing in frequency for all children as they grow older.
Children may benefit from exams under anesthesia (EUA), and many medical groups prefer this approach for children in higher risk categories. EUA gives the doctors a more thorough view of the eye with less distress to the very young child.
Specific care decisions regarding screening, including whether to choose an awake exam in clinic or an EUA, are best made in consultation with the child’s family; however anesthesia is strongly recommended for a child unable to participate in an awake exam.
Examinations are continued until a child is 7 years of age, or has tested negative for their relative’s known RB1

Father and son team Dr. Nakul Singh and Dr. Arun Singh developed a web-based application to help clinicians identify the best screening pathway for their patients, using the U.S. screening guidelines. Together with their collaborators, the Singhs aim to improve care by making these care guidelines more easily accessible to paediatricians and local ophthalmologists, most of whom are unfamiliar with retinoblastoma. .

An Ongoing Discussion

The U.S. guidelines provide a useful structured approach to familial retinoblastoma screening, but they are not the only valid strategy. Specialists may recommend a different approach based on their clinical experience, perspective, and resources.

Discussions continue – enriched by solid research and the insight of parent and survivor advocates who live with familial retinoblastoma and its impacts. The best approach is the one that identifies the child’s true risk and allows for the earliest diagnosis, tailored to the child’s specific circumstances and available resources.

Areas of Agreement

While there are areas of disagreement regarding screening approaches, retinoblastoma experts do agree on several things:

Serial dilated eye exams for children with family history of retinoblastoma are recommended, unless the child is known to not have inherited the familial RB1
Examinations are recommended frequently during early infancy, when most children with familial retinoblastoma develop the disease.
Genetic testing, when available, improves care.

Diverse Screening Strategies

At ISOO 2019, Dr. Skalet discussed retinoblastoma screening strategies with colleagues from around the world. They all emphasized the importance of combining public education and outreach with a structured exam strategy. Individual countries adopt various strategies for outreach and screening based on their resources, challenges, and strength. For example:

The Netherlands follows a rigorous schedule of exams under anesthesia until age 3.
Israel screens children at regular intervals, tailored to individual risk factors.
Brazil starts screening before birth and follows the U.S. guidelines, despite logistical challenges.
Pakistan emphasizes strict follow-up, but faces challenges in convincing families about the benefits of screening and early diagnosis.

Read Dr. Skalet’s full article: Familial Retinoblastoma Screening: When Eye Cancer Runs in the Family

The statue of Dr. Martin Luther King Jr. stands tall over the group of 16 Rb survivors of all ages.

Survivors gather at the Martin Luther King Memorial in Washington D.C. during WE C Hope USA’s Mid-Atlantic Rb Family Weekend in March 2023.

Screening for Second Primary Cancers

Carriers of a heritable RB1 mutation have a lifelong risk of developing cancers in addition to retinoblastoma, even if they did not develop cancer in either eye.

Reported incidence of second primary cancer varies widely, but increases over time, rising to roughly 33% risk by age 50, compared to approximately 3% risk at age 50 in the general population. Radiation increases risk, and is highest if radiotherapy was given before one year old. People with a mosaic RB1 mutation have theoretically lower risk, as the mutation affects fewer cells throughout their body.

Second primary cancers include common adult cancers like lung, breast, and lymphoma. Common second primary cancers in RB1 mutation carriers, especially those treated with radiotherapy, are:

Soft tissue sarcomas (cancers that develop in the muscle, tendons and ligaments, and fatty tissue)
Osteosarcoma (a type of bone cancer)
Cancers in the mouth or nose
Malignant Melanoma (a type of skin cancer).
Brain tumours (glioblastoma multiforme, astrocytoma, and meningioma)

Parents, adults with known or suspected RB1 mutation, and their medical team should be aware of the risks and second primary cancer symptoms to advocate early investigation when concerns arise. Like retinoblastoma, early diagnosis of a second primary cancer has better chance of cure.

Lifelong Follow-Up Care

Lifelong oncology follow-up care is important for all carriers of an RB1 mutation, whether they had retinoblastoma or not.

Many oncology centres in developed countries have established late effects clinics or survivorship programs. They offer ongoing care to cancer survivors, and to individuals at risk of developing cancer due to inherited cancer syndromes.

The ideal program caring for retinoblastoma survivors will coordinate routine tests, and order investigations if symptoms arise, or liaise with the primary physician and referral centre to advocate for these. However, there is no agreed routine screening protocol for RB1-related second primary cancers, despite copious published evidence of the high cancer risk and evolution of survivorship care.

Individuals with RB1 mutation are advised to avoid routine CT, x-ray and bone scans, as radiation exposure increases cancer risk. Retinoblastoma specialists propose that effective Whole Body MRI screening would require multiple scans per year, rendering it impractical and too costly. They also advise that frequent scanning increases the possibility of identifying concerns that require further investigation and will likely prove to be of no consequence (also known as a false positive).

Yet individuals worldwide with Li-Fraumeni Syndrome – whose cancer risk is similar to the profile of RB1 mutation, are increasingly screened with annual rapid scan Whole Body MRI and brain MRI, following nationally and internationally agreed Li-Fraumeni protocols that also recognise the need for psychosocial research and care.

If a Li-Fraumeni protocol can be established, why is it so impossible to offer the same screening for we survivors whose lives are threatened and mutilated by RB1?

“I have lost family members and friends to second cancers, and that could be me. I have smoke detectors in my house for early warning – I wouldn’t wait until I’m coughing to take action. Routine scans would help me feel much less anxious about the possible wildfire inside me. I’d rather they find more things that are nothing than miss the one thing that could kill me because no one looked for it.”

SurvivorCanada

Imaging Scans are vital to our lives, but for most of us, totally chaotic. RB1 mutation carriers should avoid routine x-rays due to second cancer risk. Most doctors don’t know this and we have to fight for alternatives to CT, mammogram etc. Some of us have regular MRI to screen for second cancers, most don’t – but we wish we did. Fighting for scans we know we need is demoralising and draining. Image to the right of the text shows an MRI scanner.

Letter I from our 2019 Alphabet of Hope – #LifeBeyondRb

Annual Screening – A Survivor’s Unique Perspective

The following contribution from a US survivor was updated in 2024 from the original 2021 blog.

I am a genetic counselor and a retinoblastoma survivor. Part of my motivation to become a genetic counselor was to help people like me understand and be empowered by genetic knowledge.

Imagine my surprise when I sat down with my survivorship team to discuss second cancer risks, and they sadly told me that the main things they could offer were to remind me to stay out of the sun (I had already had burn after burn as a child who loved to swim) and to not smoke (done). I would just have to hope for the best with the other cancers, which seemed incredibly scary and frustrating.

Over time my team followed advances in whole body MRI for Li-Fraumeni syndrome (LFS) patients. First children were receiving whole body MRI, then over time, adults were being screened too. My team decided to model my screening after the LFS screening protocol since no other recommendations existed.

My screening protocol is as follows:

Annual physical exam with neurology exam.
Annual full body dermatologic exam.
Breast MRI every other year in High-Risk Breast Clinic.
Annual Whole body MRI.
Annual brain and orbits MRI (full head and orbits imaging is especially important for survivors whose retinoblastoma was treated with radiotherapy).
Report any persistent, unexplained symptoms that last more than two weeks.

This plan requires extra time and paperwork – my doctors have to do a special phone call called a peer-to-peer review to get the screening authorized by my insurance company. This used to take four hours but now it’s definitely less. I have been screening this way for almost eight years. Recent data also prompted re-review of my case at tumor board and I am now also on a BRCA1/2 type breast screening protocol.

There was no data to support whole body MRI in LFS patients until people started doing this screening and catching tumors early. At risk patients like myself struggle to understand why the lack of data (not data disproving utility) would keep our care teams from looking for new cancers at least yearly. The American Cancer Society writes:

Children with the heritable form of retinoblastoma have a much higher risk of developing other types of cancer throughout their lives. This is because each cell in the body has an abnormal RB1 tumor suppressor gene, which if it were normal would help stop some of these cancers from forming.

The risk for these cancers is even higher in any parts of the body that got radiation during treatment for retinoblastoma.

Most of these cancers are very treatable if detected early, which is why it’s very important that these children are followed closely throughout their lives.

Without safe and effective whole body MRI, how can our care teams say they have followed us closely? Have we done our best to catch things early? Most survivors struggle to find survivorship care at all, let alone MRI screening. As a community, we have lost too many dear friends to soft tissue sarcomas, especially in the field of radiation, time and time again. At the very least, irradiated survivors should receive yearly head and neck MRIs.

Genereviews (an excellent genetics resource continually updated by experts) states:

“Total-body MRI at regular intervals is under investigation to determine when the technology will be specific and sensitive enough for screening for second cancers in persons with a heterozygous germline RB1 pathogenic variant.”

But I don’t know of a single survivor, besides myself, who is receiving this surveillance. I know of no study recruiting patients to look at the efficacy of whole body MRI, and if there were, would it be ethical to have a no surveillance arm to the study? If whole body MRI is “specific and sensitive” enough for LFS, why not retinoblastoma?

As a survivor, I am immensely grateful to my clinicians who spend hours fighting for insurance coverage for me in the US which allows me to have my yearly whole body MRI. Until we have the data disproving utility, I believe we should follow in the footsteps of LFS and support RB1 mutation carriers as we continue to fight cancers throughout our lifetimes.

Too many brilliant survivors’ lives have been cut short by second malignancies. I believe we owe it to our survivors to empower them with the knowledge and the screening to help catch second malignancies as early as possible.

BRCA1/2 patients are screened with rotating mammograms and MRIs, alternating every 6 months, and patients are made aware of the potential for false positives. Retinoblastoma patients may also have scares and biopsies; I’ve had a few already myself, but I would rather keep checking. I’ve been poked and prodded all my life, and I’ll take as many more pokes as it takes to stick around for my children as long as I can.

Survivor, USA.

Bright lights reflect on the floor of a long, empty hospital corridor, with many open doors. The floor is painted pale green, the walls cream, and the doors a pale purple-blue periwinkle. At the end of the corridor, large double doors are painted dark green.

The Impact of Lifelong Risk

Retinoblastoma is rare, and the associated second cancer risks rarer still. While scientific knowledge and understanding of the risk is growing, individuals living with RB1 mutation see little practical change in medical care. Most of us have no ongoing oncology care, and when we do, it often does not reflect our specific RB1 risks and needs. We continue to lose relatives and friends due to late diagnosis of second primary cancers, and we live with the knowledge of this, our risk.

We need better routine lifelong care – specifically routine screening for second primary cancers.

“I get irritated by all the messaging that early diagnosis of retinoblastoma saves lives, while no effort is made to improve screening and early diagnosis for survivors with second cancer risk. The cancers may be less easy to spot, but they can still be found early. We matter just as much as the little children we once were, and we have families and loves and friends, and careers and adventures and dreams, and precious children of our own we passionately want to continue living for.”

SurvivorU.K.

Read the full two-part article: Living with the Retinoblastoma Cancer Syndrome

Help Secure Effective Lifelong Screening

Effective referral processes aid early diagnosis, support effective care, and improve outcomes for children with retinoblastoma and survivors at risk of second cancers. Healthcare professionals, researchers, families, and survivors can work together to develop and advocate for the best referral processes for diverse settings around the world.

Join us at the 7^th One Rb World meeting this October in Honolulu, Hawaii to explore referral and early diagnosis worldwide, along with many other aspects of retinoblastoma. Your voice matters at this unique global forum.

Find Out More and Register Today!

About the Authors

Abby’s father was diagnosed with bilateral retinoblastoma in Kenya in 1946. Abby was also born with cancer in both eyes. She has an artificial eye and limited vision in her left eye that is now failing due to late effects of radiotherapy in infancy.

Abby studied geography at university, with emphasis on development in sub-Saharan Africa. She co-founded WE C Hope with Brenda Gallie, responding to the needs of one child and the desire to help many in developing countries. After receiving many requests for help from American families and adult survivors, she co-founded the US chapter to bring hope and encourage action across the country.

Abby enjoys listening to audio books, creative writing, open water swimming and long country walks.

Abby is wearing a blue and white patterned top, dark pink collared cardigan, and light blue patterned skirt, and a heart necklace. She is pictured with her black German shepherd - golden retriever guide dog, who is wearing a pink collar with guide dor tag showing. Both are smiling broadly. The background is a bed of bright orange marigolds, a low hedge and tall trees.

Read the story of how WE C Hope began.

Dr. Alison Skalet, MD PhD is an ocular oncologist, Associate Professor of Ophthalmology and Adjunct Associate Professor of Radiation Medicine at the Oregon Health & Science University’s Casey Eye Institute in Portland, Oregon, USA, where she directs the retinoblastoma service. She combines a busy clinical practice with clinical and translational research.

Dr. Skalet has enjoyed serving on multiple national and international subspecialty committees for the American Academy of Ophthalmology, American Board of Ophthalmology, American Association of Ophthalmic Oncologists and Pathologists, and the International Society of Ocular Oncology.

Dr. Skalet was the lead author of the U.S. guidelines, “Screening Children at Risk for Retinoblastoma: Consensus Report from the American Association of Ophthalmic Oncologists and Pathologists.”

Screening for Familial Retinoblastoma and Related Second Primary Cancers

Cancer Care From Birth, Throughout Life