The following signs and symptoms present in patients with retinoblastoma:

• Eye redness or injection: This is due to the irritation of the sclera when the tumor encroaches from within the vitreous humor to affect the outer eye.
• Eye swelling: The eye orbit may enlarge or swell due to an enlarging tumorous growth. The eyes lymphatic and venous drainage may be blocked by tumor seeding in exophytic cancer growth in the retina.
• Eyes gazing at the wrong direction: Tumor seeding of the ciliary nerves may affect the orbital musculature causing strabismus in some cases.
• Leukocoria: White opacities reflected on the pupils during pupillary reflex testing. This reflects the white opacity formed during retinal encroachment of the retinoblastoma.

• Asymptomatic

  Urgent ophthalmological evaluation revealed an asymptomatic retinoblastoma of the left eye, leading to early treatment. CONCLUSION: This is the first case report of infantile spasms specifically associated with a chromosome 13q deletion. [ncbi.nlm.nih.gov]

  Some mutations have a low penetrance (asymptomatic carriers or unilateral RB). Some rare unilateral retinoblastoma cases may arise without RB1 gene mutation but with somatic NMYC amplification. Monosomy 13q14 also causes RB. [orpha.net]

• Chills

  Case 2 A 31-year-old woman presented with a 2-d history of right hypochondrial pain that radiated to the back and right shoulder tip, fever with chills, and vomiting. She also complained of foul-smelling urine and vaginal discharge. [ncbi.nlm.nih.gov]

• Macula

  A significantly thickened total macula, GCL, GCC, and pRNFL in study group (I) compared to study group (II). Thickened pRNFL was significantly correlated to standard automated perimetry pattern deviations. [ncbi.nlm.nih.gov]

  Tumors in group A occupied a mean of 71% of the macula, and those in group B occupied 74% of the macula. [doi.org]

  If the tumor is at the center of the retina (on the macula), sharp detailed vision and central vision will be significantly impaired. Of course, if one or both eyes are removed (enucleated), no vision from the removed eye(s) will remain. [afb.org]

• Pigmented Scar

  If you’re interested in treating or taking preventive measures for wrinkles, fine lines, pigmentation, scarring, and more, then your late 20s or early 30s is a great age to start with an over-the-counter retinol or even prescription-strength tretinoin [healthline.com]

  A successfully treated retinoblastoma appears as a flat, well-delineated variably pigmented scar with no signs of viable tumor. [djo.harvard.edu]

• Strabismus

  The most common signs and symptoms are leukokoria and strabismus and sometimes, red eye, glaucoma and orbital cellulitis. [symptoma.com]

  For the differential diagnosis of strabismus in childhood see ocular motility disorders and strabismus. Strabismus is normal until three months after birth! Strabismus that persists after three months should be evaluated by an ophthalmologist! [amboss.com]

  The presence of a squint, or strabismus, is found in 20% of children with retinoblastoma. [news-medical.net]

  Leukocoria (white pupil) and misaligned eyes (strabismus) are the most common signs of retinoblastoma. In other cases, the child may have developed neovascular glaucoma and may be in pain. [eyecancer.com]

• Eye Pain

  Six months postoperatively, the pain and lid swelling persisted; hence, the painful near absolute eye was enucleated. The histopathology revealed small round blue cells with necrosis consistent with retinoblastoma. [ncbi.nlm.nih.gov]

  Other possible signs and symptoms Less common signs and symptoms of retinoblastoma include: Vision problems Eye pain Redness of the white part of the eye Bleeding in the front part of the eye Bulging of the eye A pupil that doesn’t get smaller when exposed [cancer.org]

  “Other signs and symptoms of retinoblastoma include crossed eyes or eyes that do not point in the same direction; persistent eye pain, redness, or irritation; and blindness or poor vision in the affected eye.” [ibtimes.com]

  Blood vessels in the back of the eye will normally reflect red. The eyes might not move or focus in the same direction. There might be eye pain. The pupil is constantly dilated. The eye(s) might be red. [my.clevelandclinic.org]

  Other symptoms can include: Crossed eyes Double vision Eyes that do not align Eye pain and redness Poor vision Differing iris colors in each eye If the cancer has spread, bone pain and other symptoms may occur. [medlineplus.gov]

• Visual Impairment

  In order to learn how your child uses any remaining vision, your child’s teacher of students with visual impairments should perform a functional vision assessment. [afb.org]

  RB is most often painless and children rarely complain of visual impairment despite its rapid progression towards loss of vision in the affected eye. [orpha.net]

  They include parents of visually impaired children, visually impaired children themselves, Community Paediatricians, Ophthalmologists, Educationalists and Psychologists. [ssc.education.ed.ac.uk]

  Symptoms Leukocoria, visual impairment, blindness, and enlargement of the eye orbit occur. Diagnosis Retinoblastoma is diagnosed by direct ophthalmologic eye examination and confirmed through biopsy or imaging modalities. [symptoma.com]

• Visual Impairment

  In order to learn how your child uses any remaining vision, your child’s teacher of students with visual impairments should perform a functional vision assessment. [afb.org]

  RB is most often painless and children rarely complain of visual impairment despite its rapid progression towards loss of vision in the affected eye. [orpha.net]

  They include parents of visually impaired children, visually impaired children themselves, Community Paediatricians, Ophthalmologists, Educationalists and Psychologists. [ssc.education.ed.ac.uk]

  Symptoms Leukocoria, visual impairment, blindness, and enlargement of the eye orbit occur. Diagnosis Retinoblastoma is diagnosed by direct ophthalmologic eye examination and confirmed through biopsy or imaging modalities. [symptoma.com]

• Retinal Lesion

  We report the case of a 23-month-old girl with bilateral retinoblastoma that demonstrated absence of retinal lesions in one eye but had an isolated white tumor in the posterior chamber. [ncbi.nlm.nih.gov]

  In under 50% of the cases, retinoblastoma affects both eyes (bilateral retinoblastoma: the child is affected by several independent retinal lesions. [retinostop.org]

  Retinomas are non-progressive retinal lesions which may be benign precursors to Rb. Rarely, they remain benign and do not progress. [patient.info]

• Aggressive Behavior

  The objective of this study was to determine whether reduced expression of RB and/or overexpression of hyperphosphorylated RB predict MTC aggressive behavior. [ncbi.nlm.nih.gov]

  On The aggressive behavior of pineoblastoma in patients with an inherited mutation of the RB1 gene. Clin Oncol (R Coll Radiol). 2004;16:244–247. [CrossRef] [PubMed] 43 BlachLE, McCormickB, AbramsonDH, EllsworthRM. [iovs.arvojournals.org]

• Nystagmus

  The child may present with nystagmus, or jerky oscillations of the eyeballs. Systemic Symptoms Systemic symptoms associated with retinoblastomas include bone pain due to metastasis or concurrent osteosarcomas. [news-medical.net]

  References:[1][2] Clinical features Leukocoria (“cat's eye pupil”) Strabismus A painful, red eye Loss of vision Retinal detachment (later stages) Rarely: orbital cellulitis, nystagmus, proptosis References:[1][2][3] Diagnostics Evaluation of the retinoblastoma [amboss.com]

  An abnormal pupil reflex (leukokoria); NYSTAGMUS, PATHOLOGIC; STRABISMUS; and visual loss represent common clinical characteristics of this condition. [fpnotebook.com]

  Other presenting features include a squint, nystagmus and defective vision. The growth patterns of retinoblastoma can be classified into intraretinal, endophytic, and exophytic. [lecturio.com]

  Nystagmus. Parental history of Rb - children of an affected parent who has Rb should be screened from birth. Parental concern over vision or eye appearance. [patient.info]

The following tests are done to confirm and assess the extent of spread of the cancer in retinoblastoma among patients:

• Eye examination: Screening tests for retinoblastoma.
• Head and eye echoencephalogram: May demonstrate masses between the eyes and the skull .
• CT scan and High resolution MRI of the head: This will detect the actual size and location of the tumor as well as its metastatic locations [6].
• Bone marrow biopsy: This will elucidate metastasis to the hematopoietic tissues of the bone.
• Cerebrospinal fluid cytology: For aggressive and metastatic tumors.

The treatment option available for retinoblastoma varies on the size, location and spread of the tumor. The following common treatment modalities are available for the treatment of primary and metastatic forms of Retinoblastoma:

• Laser and Cryotherapy are ideal for small non-aggressive tumors that are detected early.
• Radiation therapy is implored for small and large local tumors of the eye and retina.
• Chemotherapy is used for cases with extraocular metastasis using carboplatin, vincristine and etoposide [7]. The preferred routes for chemotherapy includes intravenous route, intra-arterial, intravitreal, and periocular routes to effectively reach the carcinoma [8].
• Surgical enucleating is the last recourse for refractory cases or may be the first recourse if tumor spread is to be avoided.
• Combination therapy is the use of chemotherapy (vincristine, etoposide and carboplatin) followed by cryotherapy, photocoagulation, and plaque treatment with (I 125) which has been arbitrarily used for advanced cases of retinoblastoma to improve vision and to do away from the unnecessary enucleating of the eye [9].

Intraocular retinoblastoma which is treated early may garner a 90% survival rating. However, extraocular metastasis in retinoblastoma carries a poorer prognosis.

Patients with the inherited gene mutation have a higher likelihood to develop a second cancer in the affected eye and the irradiated region. Within a 30 year period from diagnosis, second cancers may develop in up to 70% of patients who survive. The more common second cancer observed are malignant melanoma and sarcomas.

Complications

The following clinical conditions may complicate from the primary retinoblastoma and from its post-radiation condition:

•  Blindness: A dysfunctional orbit may be enucleated.
•  Optic nerve neuroma
•  Metastasis to the brain, lungs and bones
•  Sarcoma 
•  Malignant melanoma 
• Unilateral retinoblastoma may complicate and affect the other eye [5]

Retinoblastoma evolves from a gene mutation that triggers an uncontrolled cell division in the retina attributing for its carcinogenesis.

A modifier gene called MDM2 has been discovered to increase the catabolism of p53 and pRB in the chromosome 13 band [2]. In half of retinoblastoma cases, patients may have family members with the gene mutation that presents with this type of eye cancer. Parents with retinoblastoma mutation gene increase the risk of their siblings to develop the cancer many folds over.

Retinoblastoma has an incidence rating of 0.5 to 1 case per 30,000 live births representing 3% of all cancers in childhood. It is commonly diagnosed among children from the age of 1 to 2 years old.

The worldwide occurrence scores at 11 cases per million children population occurring before the age of 5 years old representing 90% of all cases of retinoblastoma. In the United States, an estimated 250 to 500 new cases of retinoblastoma is diagnosed per year. Survival rating ranges from 86-92% but may subsequently drop with age. There is no predilection to either sex.

The pathophysiology of retinoblastoma revolves around its origin as a multi-potential precursor cell that may develop to either the inner or the outer endothelium of the retina. Theories postulates that the carcinogenesis in retinoblastoma arises from the photoreceptor cell layer of the retina [3]. In retinoblastoma, gene mutations are identified in the locus of the long arm of chromosome 13 band 13q14.

Leading theories points to either endophytic spread of tumorous growth where it invades towards the vitreous humor by seeding, or by exophytic spread involving the backside of the retina spreading through the vessels and ciliary nerves. A diffuse infiltrating spread within the retina may rarely occur where only an infiltrating whitish discoloration is observed instead of an infiltrating mass.

As of 2007, studies conducted in St. Jude’s Research Hospital, Minnesota revealed that the progenitors of the retinoblastoma tumor may arise from matured horizontal interneuron cells explaining the rare pathology that may still express during adulthood [4].

The origin of retinoblastoma is still unclear and being currently researched; thus, actual prevention by modifiable factors in lifestyle isn’t possible yet. However, the genetic correlations found in retinoblastoma enables one to do genetic screening very early.

Massive drives of genetic screening may be performed amongst children to screen early detection of retinoblastoma and prevent the formation of the second cancer [10]. Families with high risk of gene mutation may have their children’s eyes checked very early to spot the retinoblastoma at an early stage to afford excellent cure rate and save the normal vision of the affected eye.

Retinoblastoma is a common carcinoma of the eye that originates from the immature retina lining. Retinoblastoma usually affects young children but may rarely occur in adults. It may arise singly from one eye but it can simultaneously affect both concurrently.

Patients usually present with strabismus, inflammatory pain, impaired vision and leukocoria (white reflex in the pupils). Its occurrence is generally rare but it is known as the most common eye carcinoma. Retinoblastoma may spread to contiguous structures like the optic nerve and the brain, and may later metastasize to distant parts of the body [1].

Definition

Retinoblastoma is the most common eye cancer in childhood. It evolves from the immature linings of the retina and may spread to contiguous structures or metastasize to distant body organs.

Cause

Retinoblastoma is a gene mutation in chromosome 13 that causes uncontrolled cell division in the retina.

Symptoms

Leukocoria, visual impairment, blindness, and enlargement of the eye orbit occur.

Diagnosis

Retinoblastoma is diagnosed by direct ophthalmologic eye examination and confirmed through biopsy or imaging modalities.

Treatment and follow up

Small and early neoplasms may be treated with laser or cryosurgery. Extensive ones are subjected to a combination of chemotherapy and radiation therapy. Surgical enucleating of the eye orbit may be done when everything else fail. Patients should lookout for signs of metastasis after the treatments and report them immediately to their family eye doctor.

1. Wardrop J. Observations on the fungus haematodes. Edinburgh: Constable; 1809.
2. Castera L, Sabbagh A, Dehainault C, et al. MDM2 as a modifier gene in retinoblastoma. J Natl Cancer Inst. Dec 1 2010; 102(23):1805-8. 
3. Tso MO, Zimmerman LE, Fine BS. The nature of retinoblastoma, I: photoreceptor differentiation: a clinical and histopathological study. Am J Ophthalmol. 1970; 69:339-49.
4. Science Daily. St. Jude Children's Research Hospital (2007, October 21). Specific Cell That Causes Eye Cancer Identified, Disproving Long-held Theory. sciencedaily.com. 
5. Viehmann A, Biewald E, Lohmann DR, Temming P. Sporadic unilateral retinoblastoma or first sign of bilateral disease? Br J Ophthalmol. 2013; 97(4):475-80 
6. Rauschecker AM, Patel CV, Yeom KW, Eisenhut CA, Gawande RS et al. High-resolution MR imaging of the orbit in patients with retinoblastoma. Radiographics; 2012 Sep-Oct;32(5):1307-26
7. Kingston JE, Hungerford JL, Madreperla SA, et al. Results of combined chemotherapy and radiotherapy for advanced intraocular retinoblastoma. Arch Ophthalmol. Nov 1996; 114(11):1339-43.
8. Fulco EM, Arias JD, Alarcon C, Pellegrini M, Rishi P, Kaliki S, Bianciotto CG, Shields JA. Retinoblastoma frontiers with intravenous, intra-arterial, periocular, and intravitreal chemotherapy. Eye (Lond). 2013; 27(2):253-64 
9. Shields CL, Shields JA, Needle M, et al. Combined chemoreduction and adjuvant treatment for intraocular retinoblastoma. Ophthalmology. Dec 1997; 104(12):2101-11.
10. Temming P, Lohmann D, Bornfeld N, Sauerwein W, Goericke SL, Eggert A. Current concepts for diagnosis and treatment of retinoblastoma in Germany: aiming for safe tumor control and vision preservation. Klin Padiatr. 2012; 224(6):339-47 (ISSN: 1439-3824)