What's in the Case?
What is our patient's name and age?
What was the initial presentation noticed, and what are other symptoms of retinoblastoma?
Leukocoria "Cat's Eye Reflex"
-loss of vision
-bulging eye
-lazy eye
-pain
Autosomal dominant inheritance of Rb1 gene (8-10% of cases)
De novo germline mutation (25-35%)
Non-hereditary "sporadic" mutation (65%)
Bonus: amplification of MYCN oncogene independent of Rb1 gene, not well understood
Describe the dangers of self-diagnosis.
Unnecessary panic leading to excessive self-prescribed treatments (essential oils, medications, illicit drugs, diet changes) which actually cause more damage.
Define oncogene and identify a potential oncogene in the case. How is this different than proto oncogene?
Oncogene- gene that is typically involved in normal cell growth that has become mutated to cause uncontrolled growth and proliferation. Mutations caused by genetics or environment.
Cyclin D1 is potentially an oncogene
Proto oncogene refers to a normal gene that has not yet mutated
List the providers involved in the patient's care and briefly mention their contributions.
Pediatrician-initial referral to ophthalmologist (PCP important)!
Ophthalmologist- performs imaging to confirm diagnosis and most likely performed the enucleation
Oncologist- initiates treatment (chemotherapy)
Genetic counselor- elucidates hereditary pattern
Provide 3 reasons why a biopsy is not performed. Are there exceptions?
Not needed for accurate diagnosis after PE and imaging
High risk of damage and loss of vision
Risk of spreading cancer outside of the eye
Very rare cases where it cannot be confirmed fine needle aspiration cytology may be used and has 99.9% specificity
Explain the recommendations for genetic testing and the reasoning behind each family member either getting tested or not tested (parents, siblings)
Positive retinoblastoma warrants a genetic test of both parents to determine hereditary status. Because neither sibling manifested symptoms and they are both too old, they must be given the autonomy to decide if they would like to be tested to see if they are carriers.
Propose an advantage of a media campaign for screenings.
When information is scientifically backed and distributed, it can be extremely beneficial in areas where medical literacy is low. A study in Brazil (where prevalence of RB is 2-6x as high as USA) showed increased early detection of RB after a campaign regarding the signs of RB was run.
Define tumor suppressor gene. What is the TSG here, what protein does it code for, and how is it functioning abnormally?
In charge of inhibiting cell proliferation and tumor development by acting as a "checkpoint" in the cell cycle. Loss of function leads to unchecked growth. RB1 controls pRB expression which has lost function and is allowing cell to progress into S phase unchecked
Where did the family go on vacation and what activity were they participating in when the infamous photo was taken?
Big Bend, night walk with rangers
Describe the two critical diagnostic tests done. Why was T1 selected as the weighting? What are other imaging options?
Ophthalmic exam is generally done under anesthesia to numb the eye and allow the doctor to properly observe the eye; lids are clipped back and the doctor uses various light tools and magnifying lenses to observe the retina
A likely diagnosis after physical exam then merits imaging such as MRI; ultrasounds are also possible though they are not as detailed as MRI; CT scans can be used to see if spread to bony structures has occurred, though generally avoided to prevent radiation exposure to child; T1 used to show hyperintensity of tumor in vitreous fluid due to increased globulin as well as some calcification
Pinpoint the patient's mutation type and describe why. Are his siblings at risk, and are his children at risk?
De novo mutation. Tumors bilaterally are a big indicator confirming hereditary aspect. Parents are not carriers so did not pass on a mutated gene. Theoretically the siblings could also have de novo mutations that never manifested due to two-hit theory. Patient has a 50% chance of passing on mutated allele
Briefly outline the epidemiology of retinoblastoma. Discuss the disparities between developed and developing nations in terms of mortality, and propose reasons why this pattern occurs.
In USA, 250-300 cases a year. Developed nations have a high prognosis with 95% survival rate.
Worldwide there are 16,000-18,000 cases a year and survival rate ranges between 35-50% in developing countries.
Lack of medical access and decreased medical literacy have major impact on mortality.
List the top 3 pediatric cancers and their approximate percentages. What percentage of pediatric cancers are retinoblastomas?
Leukemia by far the most common accounting for 30% of cases
Brain and spinal cord tumors next with 26%
Neuroblastomas are 6%
Retinoblastomas account for 2-4%
What are the patient's siblings' names and ages? Why is there no concern for pediatric retinoblastoma?
Vanetta-13
Patrick-17
Average age of diagnosis is 2, and beyond 6 years old is rare.
Outline the mechanism of action for each of the following:
Carboplatin
Vincristine
Etoposide
Carboplatin- heavy metal compound given intravenously that inhibits synthesis of RNA, DNA, and proteins in cells resulting in prevention of proliferation
Vincristine- inhibits proper mitotic spindle formation which prevents cell separation; also given IV
Etoposide- inhibits topoisomerase II which is necessary for proper "unkinking" of DNA for replication; may also cause breaks in DNA; taken orally
Describe compounded heterozygosity. Where are the patient's mutations, and what type of mutations are they?
Refers to two different mutant alleles for a gene having mutations at different loci. One allele has a nonsense mutation at 320th codon, other allele has a nonsense mutation at 556th codon.
Discuss challenges associated with a cancer diagnosis for each of the following:
Child (patient)
Parents
Siblings
Child may begin to consider own mortality and ask questions about death. May miss out on social and educational progression. Experience side effects of treatments
Parents often go through guilt, shock, denial, anxiety. Should rely on counselors and social workers and ask questions of nurses and doctors. Need to maintain a balance in life and feel empowered to make decisions. There is often a financial burden as well as issues with spirituality, nutrition, health, and other accommodations.
Siblings cannot become secondary to child with diagnosis. Critical to monitor changes in sibling behavior, allow them to ask questions, validate their feelings, and affirm love.
Define the two-hit hypothesis. Who introduced it, and how does it apply to the case?
Alfred Knudson proposed that both copies of a tumor suppressor gene must become mutated for manifestation of symptoms to occur. This is critical because it supports the notion that unaffected parents who are carriers can have children with disease. Also helps explain the 3 mutation types.
Outline the patient's specific treatment plan in the correct order and the circumstances that led to each decision.
1. Chemotherapy started initially
2. Genetic counselor consulted and sample taken for testing
3. Genetic counselor reports findings
4. Enucleation because cancer progressing too quickly in left eye
5. Tumor biopsied
6. Radiation started to save right eye
7. Enrolled in long term surveillance program due to higher risk of recurrence
Priorities are removal of cancer and preserve the eye/vision if possible
-Chemotherapy generally the first step in an attempt to save the eye; can target via intra-arterial chemotherapy
-Enucleation warranted if cancer progressing too quickly or vision lost
-Radiation can be used to destroy remaining cancer cells or if cancer has spread **raises risk of recurrence in hereditary patients
-Cryotherapy can be used if tumor is small and towards front of eye
-Laser therapy with angio ablation can be used if tumor is small and towards back of eye
What is the approximate size, in base pairs, of the Rb1 gene? What is it's chromosomal location in correct nomenclature?
180,000 base pairs
13q.14.2
Discuss the role of the internet, celebrities, and social media influencers on self-diagnosis. How do computer algorithms help lead to unnecessary panic?
Social media is notorious for allowing misinformation and disinformation (intentionally misleading someone) to flourish because posts are not critically vetted. Celebrities and influencers, despite having minority opinions, have platforms that allow them to amplify incorrect information.
Study found that search engines are more likely to put the most serious ailments at the top of a search result (brain tumor vs caffeine withdrawal for headache) for the sake of page hits and views
Define trilateral retinoblastoma. What organ is this referring to, which type of mutation is this linked to, and what other organ systems are at high risk of tumor development?
Pineal gland tumor due to similarities between pineal cells and retinal cells. Skin, bone, muscular tissue, bladder, breast, and lung tumors have been identified. This must be a germline mutation.