#153: Say Cheese! Eye Spy Retinoblastoma

September 24, 2025 | By Sam Masur

Audio

Join us this week for an eye-opening conversation about Retinoblastoma with Dr. Basil Williams, a combined Ocular Oncologist and Vitreoretinal Disease specialist at the renowned Bascom Palmer Eye Institute in Miami, FL. In this episode, Dr. Williams walks us through the pathophysiology of just how Retinoblastoma develops, how our iPhones can help Retinoblastoma come to clinical attention, and new advancements in treatment methods. Don’t blink or you might miss something!

Retinoblastoma Clinical Pearls

1. Evaluate the red reflex at every well-child check starting at birth! 
2. Most cases of Retinoblastoma are diagnosed before age 2. Nearly 95% of all cases are diagnosed before age 5.
3. The most common presenting symptom is leukocoria (‘the white reflex’ instead of the normal ‘red reflex’) and should be considered Retinoblastoma until proven otherwise.
4. Ask parents to see a picture of their children if you are suspicious of Retinoblastoma – often times flash photos will show a glimpse of the white reflex that can help with diagnosis!
5. CT scans are a contraindication in children with Retinoblastoma (specifically the heritable form) as it increases the risks of radiation-induced malignancy in these children who are already at a higher risk of second cancers as adults. 
6. When identified early, long-term visual potential and survivorship (~95%) are still very favorable.

Retinoblastoma Show Notes 

Pathophysiology of Retinoblastoma

Retinoblastoma is a type of eye cancer that develops in the retina, the tissue that lines the back of our eyes and promotes vision. It is the most common primary intraocular malignancy in children and is caused by either sporadic or inherited mutations of the retinoblastoma gene.

The retinoblastoma (RB1) gene is located on chromosome 13 and normally functions as a tumor suppressor gene. How? The RB1 gene encodes the production of the Retinoblastoma protein (Rb), a protein that plays a very important role in regulating the cell cycle (specifically the G1/S checkpoint). Under normal conditions, the Rb protein inhibits the cell cycle by binding to the E2F transcription factors, thus stopping entry into the S-phase and inhibiting uncontrolled cell growth and division.

When the RB1 gene is mutated, there is decreased (or even absent) synthesis of the Rb protein, leading to loss of cell cycle control. 

When the Rb protein is absent (or dysfunctional), the E2F transcription factor is unrestrained, leading to uncontrolled cell growth and division.

In summary: Retinoblastoma (the eye cancer) is associated with loss of function of the retinoblastoma gene (RB1) located on chromosome 13, which prevents production of the tumor suppressor retinoblastoma protein (Rb), leading to uncontrolled cell growth and division.

Heritable retinoblastoma (the “two-hit hypothesis”) typically affects both eyes and is inherited in an autosomal dominant fashion. The “two-hit hypothesis” describes how there must be two mutational “events” that inactivate both alleles of the RB1 tumor suppressor gene for Retinoblastoma (the eye cancer) to develop. 

• The “first hit” is an inherited, germline mutation (germline meaning it occurs in the egg or sperm cells themselves, thereby affecting every cell in the human body) mutation that occurs at conception. In summary: the first hit is when someone inherits a defective RB1 gene from a parent. A child born to a parent who has had a heritable Retinoblastoma has a 50% chance of acquiring the mutated Rb allele! 
• The “second hit” is a random, spontaneous somatic mutation (meaning it occurs in non-reproductive cells, such as the cells of the retina) that occurs sometime in a person’s life, most commonly in early childhood (when the eye cancer Retinoblastoma is discovered). To summarize: the second hit is not-inherited, but a random event that is the final blow to the RB1 gene, rendering it completely ineffective. 
• These children are at an increased risk for developing other cancers as they age into adulthood.
• In summary: Heritable Retinoblastoma = 1 germline mutation + 1 somatic mutation. It occurs when the first hit is present in all cells from birth, so only one other random, spontaneous somatic mutation of a retinal cell is needed in order for cancer to develop. This is why heritable (bilateral) Retinoblastoma has an earlier onset and affects both eyes.

Sporadic  (Non-heritable) Retinoblastoma (the “one-hit hypothesis”) typically affects one eye. It is not inherited and instead describes how there must be two somatic mutations within the same retinal cell (a statistically more rare event) for Retinoblastoma (the eye cancer) to occur.

• Just ‘one-hit’/mutation to the RB1 gene does not cause cancer as the remaining RB1 allele is still able to function and produce the Rb protein, maintaining cell cycle control.

• When the ‘second hit’/mutation to the RB1 gene occurs in the same retinal cell, both RB1 alleles are now nonfunctional so no Rb protein is produced, and the cell cycle progresses unchecked, leading to uncontrolled growth and division and development of Retinoblastoma (the eye cancer).
• Expert opinion from Dr. Williams: Just because you have unilateral disease does not guarantee that it is a non-hereditary form. About 15% of people with germline mutations will have unilateral disease!
• In summary: Sporadic Retinoblastoma = 2 somatic mutations (of the same retinal cell). It occurs when there are two, random, subsequent somatic mutations in the same retinal cell (a more statistically rare event). This is why sporadic Retinoblastoma has a little later onset (still in childhood) and affects one eye.

Epidemiology

Retinoblastoma is the most common intraocular malignancy of childhood but is still relatively rare!

• There is a global incidence of approximately 1 in 16,000-20,000 live births.
• It primarily affects children.
• 95% of cases are diagnosed before the age of 5.
• Two-thirds of cases are diagnosed before the age of 2.
• Retinoblastoma accounts for ~11% of cancers in the first year of life.

According to a study published in JAMA Pediatrics (Truong, 2015), there are approximately 300 cases diagnosed each year in the United States with ~9,000 cases diagnosed yearly worldwide.. 

As mentioned in the episode by Dr. Williams, of the cases diagnosed in the United States, there is no increased predilection of Retinoblastoma based on sex, ethnicity, race or socioeconomic status that we have been able to identify. 

Risk Factors

The largest risk factor for development of Retinoblastoma is family history! If a parent has the hereditary form of Retinoblastoma, their child has a 50% change of inheriting the same mutation and developing Retinoblastoma themselves. 

Presenting Symptoms

The most common presenting symptom of Retinoblastoma is leukocoria (“white pupil”), which describes an abnormal white reflection from the retina, causing the pupil (which is typically black) to instead appear white. In Retinoblastoma, when you see white, you are actually visualizing the tumor itself in the back of the eye. As opposed to when you see the normal red reflex, you are visualizing the normal blood vessels that line the back of the eye. 

The way you diagnose leukocoria on a physical exam is by utilizing the ophthalmoscope to evaluate for the red reflex. Because the red reflex is a standard portion of every single well-child check in newborns, Retinoblastoma is typically identified by the Pediatrician.

• The ‘red reflex’ is the normal red/orange-colored reflection of light emitted from both eyes when light from an ophthalmoscope is shone into the eyes.
• The ‘white reflex’ is the abnormal red reflex and describes the abnormal white-colored reflection of light from one or both eyes when light from an ophthalmoscope is shone into the eyes.

Expert opinion from Dr. Williams: The presence of a white reflex is Retinoblastoma until proven otherwise!

Other, less common presenting symptoms include: 

• Strabismus (“eye misalignment”, when the eye turns inwards or outwards)
• Proptosis (the anterior protrusion/bulging of the eye)
• Buphthalmos (enlargement of the eyeball itself)
• Poor vision! This is a tricky symptom given young children will not be able to verbalize their vision is changed. Additionally,  if the tumor is only in one eye, the opposite eye will generally work very hard to compensate for vision so they may not even notice their vision has decreased. Also, vision can be subjective depending on where the tumor is in the back of the eye. If the tumor is in the macula (the center most part of our retina that is responsible for sharp, detailed vision) then their vision will be poor. However, if the tumor is in the periphery of the eye (which doesn’t do the fine, detailed seeing), then their vision may actually be excellent. 
• In more advanced/later stages: a painful, red eye (caused when the tumor has outgrown its own blood supply and releases a lot of inflammatory debris in the eye), orbital cellulitis (rarely), retinal detachment.

To perform the red reflex: you should hold the direct ophthalmoscope close to the patient’s eye with the lens power set to “0”. While standing ~18 inches away from the patient’s face, the ophthalmoscope light should be projected onto both eyes of the patient at the same time. You should normally see a red, symmetric color from both eyes. If it is white (the ‘white reflex’), asymmetric, or there is a significant color variation (darker in one eye, much lighter in the other), refer emergently to a Pediatric Ophthalmologist! If there is any second guessing about your exam findings, it is better to send the patient to the Ophthalmologist to be sure.

Retinoblastoma is rapidly dividing – in fact, it has a doubling time of about 2 weeks. So once identified, refer quickly! 

Pro-tip: it is easier to observe the red reflex in a darkened room! Refer to the American Academy of Pediatrics guide to the red reflex examination for help practicing your exam!

Refer to ‘Know the Glow’, an organization dedicated to raising awareness about Retinoblastoma and other conditions causing leukocoria: https://knowtheglow.org/.

Diagnosis

Differential Diagnosis

As mentioned before, an abnormal red reflex should be considered Retinoblastoma until proven otherwise. However, there are other things (though much less common) that can cause a white reflex.  The differential diagnosis of leukocoria includes cataracts (congenital or acquired), intraocular infections or uveitis, persistent hyperplastic primary vitreous (PHPV), vitreous hemorrhage, retinal detachment, Coats’ Disease, Brown Syndrome and Familial Exudative Vitreoretinopathy (FEVR) amongst other etiologies. 

Diagnosis

Expert advice from Dr. Williams: In almost every scenario when you see cancer, you want a tissue diagnosis. That is NOT the case in Retinoblastoma! If you were to obtain a tissue specimen from a patient with Retinoblastoma, you would actually increase the risk of seeding of the tumor and it extending outside of the eye. This decreases survival rates!

To make the diagnosis of Retinoblastoma, urgent referral to a Pediatric Ophthalmologist is required for a dilated eye examination (often done under anesthesia given kids will seldom cooperate for an in-depth eye exam). 

In many forms of cancer, we also think of MRI as the go to test for helping us with diagnosis. That is NOT the case for Retinoblastoma. While MRI is helpful in identifying extraocular extension of the tumor, it is not great for making the diagnosis. The most important test for making the diagnosis is actually an ocular ultrasound (“B-scan”)! It is just like prenatal ultrasounds but instead of over the abdomen, it is performed over a patient’s closed eye. It allows the Ophthalmologist to see if there are calcium deposits in the retina. According to Dr. Williams: “If you see a lesion that has calcium in the retina, that is pretty much Retinoblastoma 99 times out of 100.” 

Expert Point: CT scans are a contraindication for children with Retinoblastoma. Children with heritable Retinoblastoma have a germline mutation that puts them at higher risk for second cancers as an adult. CT increases radiation exposure, generating even higher risks of developing second cancer later in life. 

Although rare, fetal ultrasounds can sometimes detect Retinoblastoma! If you have a known family history and positive in-utero genetic testing (either chorionic villus sampling or amniocentesis), you can do regular ultrasounds specifically looking for a mass or intraocular calcifications. 

Patients often undergo genetic testing as well to identify any genetic variants that are present (often their families will too!).

Management and Treatment

Management and treatment options vary based on laterality (heritable vs nonheritable), initial size and staging (Classification and Staging of Retinoblastoma), as well as long-term visual potential and survivorship. The first objective is to preserve life then preserve vision if able. It is often a multidisciplinary team treating children with Retinoblastoma (Ophthalmology, Oncology, Pathology, Genetics, IR, etc). 

There are a few options when it comes to treatment management (Shields, 2014).

(1) Intra-arterial Chemotherapy – delivers chemotherapy directly to the ophthalmic artery (by way of the femoral artery) and only more recently became popular. Generally used for sporadic/non-germline (unilateral) Retinoblastoma

• This method allows us to deliver high concentrations of chemotherapy locally, directly accessing the desired location of treatment while minimizing systemic side effects.
• Expert opinion: Dr. Williams estimates that about 80% of his Retinoblastoma patients are treated with intra-arterial chemotherapy.
• While the chemotherapy regimen may vary by center, the typical intraarterial chemotherapy regimen includes some combination of Melphalan, Topotecan and/or Carboplatin. 

(2) Intravenous (IV) Chemotherapy – delivers chemotherapy systemically throughout the body and became popular in the 1990s. Generally used for germline mutations (bilateral or familial Retinoblastoma).

• Benefits: if you were concerned about extraocular extension (metastasis), IV chemotherapy will circulate throughout the entire body so might be the better treatment regimen.
• Downsides: because it is systemic, there are more side effects associated with this regimen.
• The IV chemotherapy regimen has been standardized by the Children’s Oncology Group and includes Vincristine, Etoposide and Carboplatin (typically requires ~6 sessions) amongst others

(3) Enucleation (removal of the eye) – was historically the most common treatment form though less so now. 

• Expert opinion: Dr. Williams says that only about 5% or less of his patients with Retinoblastoma require enucleation. 
• However: this option may still be appropriate, especially if disease is very advanced (so advanced that the prognosis for long term visual potential is poor).
• What is an enucleation? It is when an ophthalmologist surgically removes the eye, places an implant inside of the orbit, and then attaches the extraocular muscles to this implant. On top of that implant, there can be a prosthesis made and placed. This prosthesis is typically made of acrylic and can be painted to look just like any other eye (it will have a colored iris and everything!).  The prosthesis can be easily placed in and out of the eye multiple times per day.  

(4) Radiation – this was used in the early 1900s given Retinoblastoma is a very radiosensitive condition. However, external beam radiotherapy is typically used as a last resort given the increased risk of secondary malignancies into adulthood. 

(5) Local therapies such as cryotherapy and laser photocoagulation can be used for small, localized tumors.

Most children require intermittent prolonged hospitalizations for induction and maintenance chemotherapy regimens. Typically, they have eye examinations done under anesthesia around every 4 weeks which they attempt to time so it lines up with their next session for chemo. According to Dr. Williams, because Retinoblastoma is so fast growing, there are some studies that show that waiting 35 days or more in between chemotherapy sessions actually increases your risk of recurrence. 

According to a review published in the International Ophthalmology Clinics journal, “the rates of new tumor development following all types of primary [chemotherapy] treatment range from 6% to 45%.”  

Remember: Retinoblastoma is often contained in the retina (unless it’s in advanced disease), but our eyes are filled with a jelly-like material called the aqueous humor. You can think of the aqueous humor of the eye to air within a soccer ball. A potential complication during treatment is what is called ‘vitreous seeding’. This is when small pieces of tumor break away from the main tumor (in the retina) and float into the vitreous cavity. What makes this difficult is that these small pieces of tumor are no longer connected to the blood supply – they are floating in the jelly. Thus, these areas may not respond as well (if at all) to chemotherapy (since it’s not reaching these areas!). If that were the case, it may require intravitreal chemotherapy chemotherapy (a process where there is an injection directly into the eye itself) and enucleation..

Survivorship and Prognosis

Retinoblastoma, when caught early, generally has a favorable treatment prognosis! According to an article published in The Lancet Global Health, the 3-year survival rate was around 99% for children from high-income countries, around 91% for children from upper-middle-income countries, around 80% for children from lower-middle-income countries, and around 57% for children from low-income countries. 

Expert opinion: Per Dr. Williams, when the tumor is contained in the eye, the survival rate is around 98% (however, if it reaches the optic nerve or extends outside of the eye, the survival rate can decrease to about 50%).

As mentioned in the episode by Dr. Williams, “A lot of future, long-term vision potential is dependent on where the tumor is located. If the tumor is located directly in the center of vision, it is likely that they are going to have some level of decreased vision in that eye. If the tumor is located in the periphery and away from the center part of the vision, the vast majority of the time, they end up having pretty good vision. If an eye has to be removed and that is the only eye that was involved, they are able to live completely normal lives, see extremely well, drive, do almost every activity that everyone else can do except maybe be a fighter pilot!”

Education, Monitoring and Surveillance

• Check the red reflex at every well child check!
• If the patient is difficult to examine, ask the parents if they take pictures of the child or their eyes and evaluate any difference between the two eyes – many cases of Retinoblastoma are diagnosed because a parent notices an abnormal eye color in a flash photo!
• These patients should have eye exams once per year for life! While the vast majority of recurrences happen within the first 3 years of completing treatment, they can recur at any time!
• There are very few centers that take care of patients with Retinoblastoma. Patients will often travel very far to see their Ophthalmologists and when they are done with the active treatment phase, they may try to transition care back closer to home and get lost to follow-up. But – they will still follow-up with their Pediatrician! It’s important for the Pediatrician to ensure that they continue their follow-ups. Even if they don’t want to travel far away, ensuring they have regular eye exams by Ophthalmology is critical.
• Talk to your patient about reproductive potential when they are around the age where it would benefit. This conversation should occur at the time of diagnosis and then continuously and repeatedly as the child grows up.
• You should be having conversations about radiation and the risk for second primary malignancies (ie, Osteosarcoma, epithelial tumors) with your patient! 
• If a child has one eye that is affected by Retinoblastoma, they should be wearing protective glasses at all times! This is to prevent any random accident or trauma that could damage their other eye and leave them without any sight. 
• Children receiving chemotherapy or other immunosuppressive treatments may require a modified vaccine schedule. Encourage families to speak with their Pediatrician and Oncologist for what is best for them!

Future Innovations

New innovations in the world of Retinoblastoma include the development of liquid biopsy – a test developed by CHLA which involves obtaining a sample from the aqueous humor of the eye (the front part of the eye where there is no tumor present) to help determine if specific biomarkers are present, indicating a more severe or aggressive cancer. To read more about it, refer to this article in the American Journal of Ophthalmology!

Citations

1. Truong B, Green AL, Friedrich P, Ribeiro KB, Rodriguez-Galindo C. Ethnic, Racial, and Socioeconomic Disparities in Retinoblastoma. JAMA Pediatr. 2015;169(12):1096–1104. doi:10.1001/jamapediatrics.2015.2360.
2. American Academy of Pediatrics, Section on Ophthalmology, American Association for Pediatric Ophthalmology and Strabismus, American Academy of Ophthalmology, American Association of Certified Orthoptists; Red Reflex Examination in Neonates, Infants, and Children. Pediatrics December 2008; 122 (6): 1401–1404. 10.1542/peds.2008-2624
3. Fabian ID, Reddy A, Sagoo MS. Classification and staging of retinoblastoma. Community Eye Health. 2018;31(101):11-13.
4. Shields CL, Lally SE, Leahey AM, Jabbour PM, Caywood EH, Schwendeman R, Shields JA. Targeted retinoblastoma management: when to use intravenous, intra-arterial, periocular, and intravitreal chemotherapy. Curr Opin Ophthalmol. 2014 Sep;25(5):374-85.
5. Berry JL, Kogachi K, Murphree AL, Jubran R, Kim JW. A Review of Recurrent Retinoblastoma: Children’s Hospital Los Angeles Classification and Treatment Guidelines. Int Ophthalmol Clin. 2019 Spring;59(2):65-75. 
6. Fabian, Ido Didi et al. The Global Retinoblastoma Outcome Study: a prospective, cluster-based analysis of 4064 patients from 149 countries. The Lancet Global Health, August 2022; Volume 10, Issue 8, e1128 – e1140.
7. Berry, J. et al. Aqueous Humor Liquid Biopsy as a Companion Diagnostic for Retinoblastoma: Implications for Diagnosis, Prognosis, and Therapeutic Options: Five Years of Progress. American Journal of Ophthalmology, July 2024; Volume 263, 188-205.

Goal

Listeners will be able to explain the basic pathophysiology, diagnosis, management, and common treatment options of pediatric Retinoblastoma.

Learning Objectives

After listening to this episode listeners will…  

1. Recall the basic pathophysiology of Retinoblastoma development, including both heritable and non-heritable forms. 
2. Be familiar with the most common presenting signs and symptoms of Retinoblastoma.
3. Learn how to diagnose Retinoblastoma and the best next steps in management of a new or suspected diagnosis.
4. Be familiar with common treatment methods including intra-arterial chemotherapy, radiation, and enucleation. 
5. Recognize the importance of continued surveillance given the risk of recurrence.
6. Describe best topic points for counseling newly diagnosed or previously treated patients regarding long-term vision potential, increased risk of second primary malignancies, and reproductive potential.  

Disclosures

Dr. Williams reports consulting for AbbVie, Alcon, Alimera, Astellas, DORC International, EyePoint, Genentech, Immunocore and Regeneron Pharmaceuticals as well as working with Lumata Health. The Cribsiders report no relevant financial disclosures.

Citation

Hogue T, Williams B, Berk J, Chiu C, Masur S. “#153: Say Cheese! Eye Spy Retinoblastoma”. The Cribsiders Pediatric Podcast. https:/www.thecribsiders.com/ September 24, 2025.