Referral for Possible Retinoblastoma or Second Primary Cancer

Monday September 02, 2024

Many parents and survivors report signs and symptoms of retinoblastoma and related second cancers to primary care providers. Prompt referral is vital for timely diagnosis and optimal treatment. WE C Hope CEO Abby White explores who needs referral and when, and the key elements of an effective referral process – for children with possible eye cancer, and survivors throughout life.

Referral Delays Harm Patients and Their Families

Melissa sensed that something was wrong with her son soon after Jude was born, but multiple trips to the doctor failed to explain his repeated rashes and high fevers. When Jude was four months old, Melissa asked the doctor for an eye exam as she had noticed a “white spot” in his pupil during a bath, though no one else in her family saw it.

After looking casually at Jude’s eyes, the paediatrician told Melissa the glow was nothing to worry about. A fundal (red) reflex exam, the key primary care eye exam when children present with white pupil or turned eye, was not done.

A nagging concern would not go away, and increased when Jude’s eye began turning inwards. Another paediatrician in the practice listened patiently to Melissa, but dismissed the turned eye as normal development of infant eyes. Again, no fundal (red) reflex test was done.

Jude was now six months old, and the family joyfully prepared for his first Holiday season. They took many Christmas pictures, and the photos taken with a flash clearly captured Jude’s white glow for all to see. Melissa had now searched enough online to know this glow could indicate retinoblastoma. She shared the information with her husband, who was instantly concerned.

Returning to the doctor, Melissa requested referral to a paediatric ophthalmologist, but the proposed appointment was several weeks later. Unwilling to wait, she reached out directly to multiple ophthalmologists in the region. One doctor responded, suggesting she send photos for review.

On seeing Jude’s photos, the ophthalmologist asked Melissa to bring him in to the eye clinic for immediate assessment. Finally, at this appointment, aged 7 months, Jude was tentatively diagnosed with retinoblastoma and sent directly to Memorial Sloan Kettering Cancer Center.

Jude’s cancer was already threatening his life at diagnosis – removing his eye was the only safe option to save his life. Yet Melissa had asked for an eye exam repeatedly for three months, and requested an urgent referral to ophthalmology due to concerns about both a white glow and turned eye.

Read Jude’s Story

Prompt referral is critical to the early diagnosis and effective treatment of retinoblastoma and second primary cancers. Swift action and timely care can be the difference between life and death, between removing an eye to save a child’s life, and potential to safely save the eye and sight.

Primary care providers are pivotal in this process. They are usually the first point of contact for parents and survivors who are concerned about potential signs and symptoms; their quick, informed decisions enable early intervention.

Below, we explore who needs referral and when, and the key elements of an effective referral pathway – for both children with possible eye cancer, and survivors at risk of second primary cancers. By understanding the need and implementing effective referral systems, healthcare providers can significantly improve outcomes for all affected by retinoblastoma, throughout life.

A smiling woman and a young child, both retinoblastoma survivors, stand in front of a curved solid wall next to a vast fountain at the World War II Memorial in Washington D.C. The woman holds the child on her hip with her left arm, and an Elli plush toy in her right hand. The child’s white t-shirt says “One Retinoblastoma World”. The fountain is circled by water jets and a row of white pillars, under a clear blue sky.

Who Is At Risk

Risk of Developing Retinoblastoma

Retinoblastoma is rare, affecting about one in 15,000 children. The eye cancer typically develops in the first few years of life, and babies can be born with tumours already formed. Most children are under five years old at diagnosis, but older children, even young teenagers, are occasionally diagnosed.

Children tend to be older at diagnosis in Low and Middle Income Countries (LMICs) due to less awareness of cancer signs and slower access to primary and specialist medical care. Globally, older children typically have more advanced disease at diagnosis, with poorer prognosis for their vision, and higher risk to life

Children with a family history of retinoblastoma may have a considerably higher than population risk for developing the cancer (<1% - 50% versus 0.007%). About 40% of retinoblastoma cases are caused by changes on the RB1 gene that can be inherited. If a parent carries this gene change, each child has a 50% chance of inheriting it.

Siblings of a diagnosed child have varying risk, depending on the child’s diagnosis and family history.

A child who carries an RB1 gene change has a greater than 90% chance of developing eye cancer. All children with a known or suspected risk of heritable retinoblastoma should be closely monitored with regular eye exams by a health professional who is familiar with retinoblastoma diagnosis and treatment.

Precise genetic testing can now identify who is at risk in a family, and eliminate invasive surveillance procedures for most children. However, genetic testing is not always available, or recommended to families when it is available. Access is particularly limited in LMICs. Genetic counselling is important for all parents to ensure they know and understand their individual risks so they can advocate for effective healthcare.

Genetic testing has been available and informing care for several decades. However, many survivors have not had any genetic testing or counselling, while others had testing that used earlier technology.

Rb specialists strongly recommend all retinoblastoma survivors be re-referred to a retinoblastoma treating centre when planning a family or if already expecting a child. The baby’s genetic risk can be re-evaluated or clarified, and appropriate screening recommended.

Risk of Developing Second Primary Cancers

Many retinoblastoma survivors face an increased risk of developing second primary cancers, especially if they have the heritable form described above.

Genetic Risk

The RB1 cancer syndrome predisposes individuals to retinoblastoma, and increases their lifetime risk for other cancers. RB1 is a tumour-suppressor gene. When a gene change occurs in RB1, the body loses its natural ability to control cell division, leaving the person vulnerable to certain cancers for life.

Carriers of an RB1 pathogenic allele are at risk for certain cancers, whether they had retinoblastoma as a child or not. They need ongoing care and prompt referral to investigate any concerning symptoms.

Cancer Treatment History

Radiotherapy was the primary eye-salvage treatment for retinoblastoma until the mid-1990s when chemotherapy began to replace it. Both therapies increase the risk of developing second primary cancers.

Survivors with the RB1 cancer syndrome who were treated with radiation, particularly before one year old, have a significantly higher than average risk for certain cancers, including osteosarcoma, soft tissue sarcomas, melanoma, and certain brain tumours. Generally, this risk increases throughout life.

These high-risk survivors are advised to avoid radiation exposure from medical imaging wherever possible, throughout life. For example, routine dental x-rays are not recommended, MRI is preferable to CT, and ultrasound is preferable to mammogram.

The combination of radiotherapy and chemotherapy increases risk for a range of cancers. Without radiation, certain types of chemotherapy and the way they are given increase the risk of leukaemia for up-to five years after treatment.

Survivors and Referral to Survivorship Care

For individuals who are known or suspected to have the RB1 cancer syndrome, lifelong survivorship care is crucial. Ongoing care supports patient education, monitoring for second primary cancers, and holistic care. Rb survivorship programs can ensure survivors receive care tailored to the specific increased cancer risks and impacts of retinoblastoma.

Despite its importance, access to survivorship care is limited worldwide, and Rb-specific survivorship programs are rare. Most child and adult survivors lack access to specialized programs that address their unique needs. This scarcity of tailored care is compounded by the absence of agreed Rb-specific follow-up or screening recommendations.

Without consensus guidelines, survivors routinely struggle to advocate for themselves, and their doctors struggle to know what to do for the best. These gaps can lead to unnecessary delays in vital care.

The primary care provider is likely to be the first healthcare contact when a survivor has concerning symptoms. Their swift referral is key to early diagnosis, especially when the patient has no effective retinoblastoma survivorship care.

A young girl with blond hair and wearing a Minnie mouse dress is standing on a small round trampoline, holding on to the arched handle. She has a white pupil glow in one eye, and her other eye is turned outwards.

Children with leukocoria (white pupil) and strabismus (turned eye), occurring independently or in combination, should be referred for a thorough eye exam by a specialist experienced in examining children’s eyes and diagnosing retinoblastoma.

When to Refer

Retinoblastoma

Each of the following indicates possible eye cancer or a potentially blinding eye condition, and should trigger urgent referral to paediatric ophthalmology for a thorough fundal (red) reflex eye exam and other investigations. Ideally, the child will be seen for the specialist eye exam within 48 hours.

Parent-reported white pupil, absence of red-reflex in flash photos, or misaligned eyes, even if transient and not evident on office exam.
Abnormal fundal (red) reflex in one or both eyes on exam.
Misaligned eyes (strabismus), regardless of age.
Different coloured irises.
A red or swollen eye.
Unequal or misshapen pupils.
Watering eye with sensitivity to light and pain.
New vision loss (this may be indicated by changes in behaviour such as reluctance to crawl or walk, fear of descending steps, clumsiness).

Second Primary Cancers

Any unexplained symptoms lasting more than two weeks, or one week if neurological, warrant immediate referral for investigation.

Below are symptoms of the most common second primary cancers linked to the RB1 cancer syndrome and/or retinoblastoma treatment.

While many of these signs and symptoms can be caused by other diseases, as with retinoblastoma itself, the cancer risk should be prioritized. Investigate all symptoms promptly and thoroughly. Early diagnosis saves lives.

Osteosarcoma (a type of bone cancer)

The most common locations in are limbs and orbits. Symptoms depend on the cancer’s location, and include:

Limb

Persistent bone pain or tenderness.
A lump or swelling under the skin that may be red and feel warm.
Increased pain with lifting (if an arm is affected).
Limping and pain on walking (if a leg is affected).
Limited range of movement (if a joint is affected).
Broken bone (especially arising from a simple movement).
Unexplained fever (this may indicate infection in the bone).

Orbit

Numbness, tingling, pressure or pain around the eye.
Pain around or behind the eye.
Swelling and/or visible deformity around the eye.
Painful protrusion of the eyeball, or poorly fitting prosthetic eye.
Changing or decreasing vision.
Loss of previous ability to move both eyes in sync.
Swollen or drooping eyelid.

Soft Tissue Sarcoma (cancers that develop in the muscle, tendons and ligaments, and fatty tissue)

Symptoms depend on the cancer’s location, and include:

Painless or uncomfortable swelling.
Any painful or tender lump that is bigger than 5cm (2in).

Specific symptoms by common location include:

Bladder

Visible blood in your urine.
Increased need to urinate.
Abdominal pain.
Painful or difficult urination.

Uterus

Post-menopausal bleeding, or bleeding/spotting between periods.
Abnormal vaginal discharge.
Pressure or pain in the pelvis or abdomen.
A mass in the pelvis or abdomen.

Abdomen

Bloating in the abdomen.
Stomach-ache.
Black-coloured stools or blood in the stool.
Loss of appetite and/or unexplained weight loss.
Nausea and vomiting.
Vomiting blood.
Unexplained upper-back/shoulder pain (referred pain).

Lung

Persistent or worsening cough.
Recurring chest infections.
Chest pain when breathing or coughing.
Persistent breathlessness.
Coughing up blood or blood-stained mucus.
Persistent fatigue and lack of energy.

Jaw

Increasing numbness, tingling, pressure or pain around the jaw.
Visible swelling around the jaw or inside the mouth.
A lump in the roof of the mouth or along the gumline that may or may not be painful.
Loose teeth or teeth moving position.
Unexplained toothache.
Difficulty moving the jaw and trouble chewing.

Orbit

Painless growth on one of the eyelids or in the tissues around the eye.
Painless protrusion of the eyeball, or poorly fitting prosthetic eye.
Discharge from the eye or eye socket.
Increasing numbness, tingling, pressure or pain around the eye.
Changing or decreasing vision.
Loss of previous ability to move both eyes in sync.
Swollen or drooping eyelid.

Malignant Melanoma (skin cancer)

Look for changes in the size, shape or colour of a mole or freckle. Warning signs include:

Irregular shape.
Uneven colour.
More than 6mm diameter (larger than the blunt end of a pencil).
Unusual skin marks that last more than a few weeks.
Tingling, itching, crusting or bleeding of a mole.
Something growing under a nail or a new pigmented line in a nail.

Oral Cavity (mouth) and Oropharyngeal (throat) Cancers

A sore on the lip or in the mouth that doesn’t heal.
Pain in the mouth that doesn’t go away.
A lump or thickening in the lips, mouth, or cheek.
A white or red patch on the gums, tongue, tonsil, or lining of the mouth.
A persistent sore throat or feeling that something is caught in your throat.
Trouble chewing or swallowing
Trouble moving the jaw or tongue.
Numbness of the tongue, lip, or other area of the mouth.
Swelling or pain in the jaw.
Dentures that start to fit poorly or become uncomfortable.
Loose teeth or pain around the teeth.
Voice changes.
A small lump on one or both sides of the neck, towards the back.
Pain in the ear.

Nasopharyngeal Cancer (cancers that occur in the nose)

A painless small lump on one or both sides of the neck, towards the back.
Hearing loss, ringing in the ear, pain, or feeling of fullness in the ear (especially one-sided).
Recurring ear infections.
Nasal blockage or stuffiness.
Nosebleeds.
Headaches.
Facial pain or numbness.
Trouble opening the mouth.
Blurred or double vision.
Trouble breathing or talking.

Brain Tumours

Symptoms vary widely. They arise because the tumour puts pressure on the brain, or because it disrupts function of the structures where it is located.

Symptoms of increased pressure include:

Headache: usually associated with nausea and vomiting. Pain and nausea are worst in the morning, easing throughout the day. Coughing, sneezing, leaning forward or exercise can increase the pain, and vomiting may reduce it.
Drowsiness – sleeping or “dropping off” excessively.
New blurred vision, ‘floating objects’ and tunnel vision.
Balance problems.
Confusion.

Survivors should see their doctor urgently if any of these symptoms persist for more than a week.

Symptoms caused by location include:

Frontal lobe: altered personality or intellect; uncoordinated gait; weakness on one side of the body; loss of smell; occasional speech impairment.
Parietal lobe: difficulty speaking or understanding words; problems with writing; reading or simple calculation; poor coordination; numbness on one side of the body.
Occipital lobe: loss of vision.
Temporal lobe: Speech and memory problems; seizures that may cause a feeling of fear, familiarity (déjà vu) or strange smells.
Cerebellum: Unsteady gait; poor articulation (speech); flickering involuntary movement of the eyes; vomiting; stiff neck.
Brain stem: Unsteady gait; a one-sided smile; drooping eyelid; double vision; difficulty speaking and swallowing.

These symptoms may be caused by other conditions. However, survivors should be referred for prompt investigation if individual symptoms persist for more than two weeks, or if a cluster of symptoms persist for more than one week.

Leukaemia and Myelodysplastic Syndrome

Acute Myeloid Leukemia (AML) is the most common blood cancer in Rb survivors, Acute Lymphoblastic Leukaemia (ALL) and Myelodysplastic Syndrome (MDS) are less common.

Symptoms of these conditions are the same. Most occur due to damaged bone marrow. The main symptoms are:

Pale skin, fatigue and breathlessness (low red cells).
Increased infection (low white cells).
Easy bruising, bleeding gums, frequent nosebleeds (low platelets).
A rash of tiny, flat red spots on the legs or in the mouth (petechiae).
Aching bones (caused by too many immature cells in bone marrow).
Blue-purple bumps under the skin (leukaemia cells in the skin).
Swollen gums (leukaemia cells in the gums).

A black and silver compass tipped on its side facing the camera. The compass is sitting on top of an open paper map that extends out behind it out of focus.

Planning an Effective Referral Pathway

A well-structured referral pathway is crucial for timely diagnosis, effective treatment, and optimal outcomes for the patient and family. The best referral pathway ensures clear communication, minimizes delays, and addresses potential barriers. Here are six key elements to consider for a supportive, efficient, and lifesaving referral.

1. Urgent Referral Timeline

For suspected retinoblastoma, an “urgent” referral means an eye exam within 48 hours. This is a fast-growing cancer; rapid assessment by an ophthalmologist familiar with examining young children’s eyes is crucial to find and treat tumours as quickly as possible.

Referral for possible second cancer should also be treated as urgent, even if the primary care provider does not see anything amiss.

2. Communication with Referral Centre

The quality of communication between the primary care provider and the referral centre can significantly impact care. Effective communication includes sharing:

All relevant patient information.
Parent/survivor-reported observations and concerns.
PCP diagnostic findings.
Suspicion of retinoblastoma or second primary cancer.
Recommendation to avoid radiation exposure for individuals with a known or suspected RB1 pathogenic allele.

Emails and faxes are too easily lost or not read by the appropriate person. Establishing a direct line of communication with a telephone call can streamline the process and ensure the referral is understood and prioritized.

3. Information to, and Communication with, the Family/Survivor

Clear, compassionate discussion with the family or survivor is paramount. Providing detailed information about the referral process – why it is needed, what to expect, and the importance of timely action – helps reduce anxiety and empowers parents/patients to be effective self-advocates. Both the primary care provider and the referral centre can support this process.

4. Identifying Barriers to Referral Completion

Families and survivors worldwide face diverse barriers that reduce their ability to complete the referral. These include logistical issues such as lack of transport; financial constraints such as inability to pay medical bills, or loss of income due to time off work for the medical care; and psychosocial concerns such as stigma or fear of cancer.

Open communication with the family/survivor is the best way to help understand and identify these potential barriers before they occur. Addressing them early with empathy and compassion allows the patient family, primary care provider, specialist doctors, and support professionals to develop solutions that promote a swift, successful referral.

5. Signposting to Local Support Services

Providing information about local support services can help alleviate some of the stress patient families experience as they navigate the referral process. Services might include financial aid; logistical help with transport, hospital housing, and other practical needs; and emotional support. Service providers may include hospital social workers, cancer care charities, and vision rehabilitation programs.

When patients and families know where to turn for help, they are often able to navigate the healthcare system and their own experiences with more ease and confidence, as stronger self-advocates.

6. Supporting International Care When Needed

Around the world, children with suspected or diagnosed retinoblastoma are referred internationally for care, particularly from LMICs. Sometimes, these referrals begin at the point of primary care, even when appropriate, affordable specialist care is available much closer to home.

Clear discussion is vital between the family, local doctors, and international centre about finances, logistics, and potential impacts on the family. Discussion should include:

Available specialist care options locally.
Potential treatment costs and duration of care.
Costs, logistics, need for, and duration of follow-up.
Funding, who is financially responsible, and realities of fundraising.
Accommodation and cost of living at the international centre.
Visa requirements and travel arrangements.
Risk and impact of delays in care.
Impacts on separated families.

These are uncomfortable conversations, but collaborative planning can ensure the best decisions and care for the child and their family. This minimizes delays to the start of treatment, reduces the risk of a future breakdown in follow-up care, and limits the stress and impact on the family.

Resources for Families and Survivors

Eye Exam Guide: Discover what to expect and what a Fundal (Red) Reflex Test involves.
Diagnosis and Staging: Information and practical tips for parents.
One Rb World Map: Find and connect with retinoblastoma specialist teams around the world.
International Care: Practical guidance on contacting doctors, finances and fundraising, travel and housing, and key questions to ensure optimal care.
10 Ways to Support Your Child Through EUA (blog): Guidance from WE C Hope’s Child Life Specialist.
Child Life Guidance for Procedure Support: Practical tips for the best preparation and minimal stress during medical procedures for the child, parents, and medical professionals.
Reduce Your Stress. 45 tips to help parents, survivors, and professionals soothe body and mind – many tips recommended by members of our community.
Retinoblastoma Support Organizations – list of orgs worldwide.
Rb Communities on Social Media.
Childhood Cancer International: find local childhood cancer support groups worldwide.

Quarter view of a compass. Its gold pin points to the word SURVIVORSHIP arcing around the edge of the compass.

Influence of the Healthcare System

Health systems differ around the world, with advantages and challenges in achieving timely referral and diagnosis. These differences can impact patient care, outcomes, and overall healthcare efficiency. Some approaches to referral also differ between countries, even between communities within the same country, impacting potential for fast, effective care.

Rapid Referral Supports Optimal Care

Poppy Joy was 3.5 weeks old when her mum, Rhiannon, noticed a “moon-like” reflection in her right eye while breastfeeding. When she was in any other position, her eyes looked perfectly normal, but Rhiannon knew instinctively that something was wrong.

She remembered in the distant past reading a story of a little girl whose eye cancer was only discovered because of a glow in flash photos. She hoped this wasn’t the case as she could see Poppy’s glow with her own eyes, but the memory of that story helped her recognise the glow as something significant.

Rhiannon took Poppy straight to an optometrist who specialized in children. After examining both her eyes, including the use of dilating eye drops, he advised the family to head straight to emergency – he would phone ahead with the referral.

The Queensland Children’s Hospital emergency department were quick to send Poppy through to ophthalmology, where she was diagnosed with retinoblastoma. Initially, she had one large tumour in her right eye, but soon after diagnosis, she developed several new tumours in her left eye.

Rhiannon’s early detection and the optometrist’s swift referral meant those small tumours could be treated with minimally invasive therapy, increasing the potential to save sight in Poppy’s left eye, without risk to her life, and with less trauma to her growing body, mind, and spirit.

Read Poppy’s story.

A newborn baby has a round face with a soft, smooth complexion. Her eyes are open, revealing a bright glow in her right eye.

A young toddler our about 1 year old smiles widely, showing a few small teeth. Her eyes are bright and expressive. She is wearing a pastel outfit and is surrounded by soft, warm lighting.

Help Secure Effective Early Care For All

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 Author

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.

Referral for Possible Retinoblastoma or Second Primary Cancer

Referral Delays Harm Patients and Their Families