|Year : 2016 | Volume
| Issue : 7 | Page : 485-491
Adult onset retinoblastoma
Sabyasachi Sengupta1, Utsab Pan2, Vikas Khetan3
1 Vitreoretina Services, Aravind Eye Hospital and Post Graduate Institute of Ophthalmology, Puducherry; Vitreoretina Services, Ojas Laser Eye Surgery Center, Mumbai, India
2 Vitreoretina Services, Aravind Eye Hospital and Post Graduate Institute of Ophthalmology, Puducherry, India
3 Vitreoretina Services, Shri Bhagwan Mahavir Vitreoretinal Service, Sankara Nethralaya, Chennai, Tamil Nadu, India
|Date of Submission||19-Aug-2015|
|Date of Acceptance||02-Jun-2016|
|Date of Web Publication||9-Sep-2016|
Sankara Nethralaya, No. 18, College Road, Chennai, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Retinoblastoma (RB) is the most common primary malignant intraocular tumor of childhood presenting usually before 5 years of age. RB in adults older than 20 years is extremely rare. A literature search using PubMed/PubMed Central, Scopus, Google Scholar, EMBASE, and Cochrane databases revealed only 45 cases till date. Over the past decade, there has been a significant increase in the number of such reports, indicating heightened level of suspicion among ophthalmologists. Compared to its pediatric counterpart, adult onset RB poses unique challenges in diagnosis and treatment. This article summarizes available literature on adult onset RB and its clinical and pathologic profile, genetics, association with retinocytoma, diagnostics, treatment, and outcomes.
Keywords: Adult onset retinoblastoma, calcification, enucleation, globe salvage, immunohistochemistry, retinocytoma
|How to cite this article:|
Sengupta S, Pan U, Khetan V. Adult onset retinoblastoma. Indian J Ophthalmol 2016;64:485-91
Retinoblastoma (RB), a tumor originating from the sensory retina, is the most common primary malignant intraocular tumor of childhood with a reported incidence ranging from 1 in 15,000 to 1 in 18,000 live births.  In 90% of cases, the diagnosis is made before 5 years of age.  RB is bilateral in 25-35% of cases with the average age of diagnosis of unilateral cases being 24 months and that of bilateral cases being 12 months. 
Its occurrence in adulthood is rare, and literature on this entity is scarce with majority being anecdotal case reports. There have been around 45 cases reported till date in adults 20 years or older. Ever since the oldest report was presented in 1919 from a 20-year-old white girl,  literature on this demographically rare variety of RB has been building progressively. There has been a flurry of reports in the previous decade with the largest series of eight cases published only recently. 
Adult onset RB can be quite different in presentation compared to its pediatric counterpart. Moreover, due to its rarity, it is usually not considered in the differential diagnosis of a retinal or intraocular mass in an adult  often leading to delayed diagnosis and dismal outcome. An increase in the number of case reports after the previous review article in 2000 and our own experience with such cases prompted us to review the literature again. In this paper, we present a comprehensive review of the historical aspects, clinical manifestations, pathology, pathogenesis, and potential association with retinocytoma, treatment, and outcomes of adult onset RB.
| Historical Background|| |
The first case dates back to 1919 in a 20-year-old girl  followed by another report 10 years later in a 48-year-old gentleman.  Four more cases were reported between 1943 and 1948. ,,, After another quiescence, in the decade between 1959 and 1968, seven cases were documented. ,,,,,, Literature reveals only four more cases in the 1970s and 1980s. ,,, In 2000, Biswas et al. reported three cases and published the first comprehensive review on the subject  where they compiled data from 21 previous cases. ,,,,,,,,,,,,,,,,,,, From 2005 onward, there has been a sudden proliferation of cases where 23 more cases have been published including 16 cases reported in the last 3 years. ,,,,,,,,,,,,,,,
| Pathogenesis|| |
There are two explanations for the late presentation of RB:
- De novo RB without antecedent lesion may be due to persistence of rare embryonal retinal cells which undergo malignant transformation in later life 
- The tumor may also arise from previously undiagnosed, spontaneously regressed/arrested RB often termed retinocytoma or retinoma which have been reactivated by additional oncogenic mutation. 
| Reported Associations of Retinoblastoma with Retinocytoma|| |
Retinocytoma is a rare clinically, well-characterized benign retinal tumor, carrying RB1 gene mutation. Retinocytomas were initially considered a type of spontaneously regressed tumor, but recent evidence suggests that it represents a premalignant lesion. It is frequently associated with cottage cheese calcification and retinal pigment epithelium hyperplasia.  Histopathology shows the presence of fleurettes with benign cytologic features. It is believed that RB arises if the second mutation occurs in immature retinoblasts, whereas retinocytoma is likely if the second event occurs in almost mature retinoblasts. , Another hypothesis states some mutations in RB1 do not inactivate the RB1 protein completely, leading to partial penetrance. 
There is a possibility of malignant transformation of retinocytoma due to genomic instability and unknown stimulus.  Retinocytoma was observed in 1.8-15.6% of patients with childhood RB. , Singh et al. stated that the risk of malignant transformation of a retinocytoma into an RB is 4%.  Among all the cases of adult RB, histological features suggestive of accompanying retinocytoma at the base of malignant cells were reported in three cases. ,, As normal fundi were not previously documented in the majority of reported patients, most authors believe perhaps they did harbor a retinocytoma. In a recent retrospective series of eight cases, Kaliki et al. reported that they did not encounter benign retinocytoma/retinocytoma-like areas on histopathology in any of their cases. Yet, patients with retinocytoma must be kept under follow-up for several years due to the possibility of malignant transformation.
Genetic basis for progression of retinocytoma to retinoblastoma
Genetic studies on retinocytomas have been rarely performed. Sampieri et al. compared genetic mutations in retinocytomas and RBs and demonstrated that some copy number changes thought to belong to early (MDM4 gain) or late stage (MYCN and E2F3 gain) of RB are already present in retinocytoma at the same (for MDM4) or at lower (for MYCN and E2F3) copy number variations.  The authors suggest that MDM4 gain may be involved in the early transition from the normal retina to retinocytoma while MYCN and E2F3 progressive gain may represent driving factors of tumor progression. These results also confirm the premalignant nature of retinocytoma. Dimaras et al. demonstrated similar results and reported that although retinocytomas can remain unchanged throughout life, highly proliferative, clonal and aneuploid RBs commonly emerge, exhibiting altered gene copy number and expression of oncogenes (MYCN, E2F3, DEK, KIF14, and MDM4) and tumor suppressor genes (CDH11, p75NTR), and reduced expression of p16INK4a and p130.  The authors believe that RB1 inactivation in developing retina induces genomic instability, but senescence can block transformation at the stage of retinocytoma. However, stable retinocytoma is rarely clinically observed because progressive genomic instability commonly leads to highly proliferative RB.
There is a lack of genetic studies on adult onset RB specimens; thus, limiting current observations to childhood RB. It may be interesting to note genetic differences between childhood and adult onset RB, once such reports are available.
We suspect that most adult onset RBs harbor underlying retinocytomas and their reactivation much later in life, due to an unknown oncogenic stimulus, may lead to development of adult onset RB. Future publications on adult onset disease will do well to perform genetic analysis and comment on the presence of underlying retinocytoma from the enucleated specimens.
| Histopathology and Immunohistochemistry|| |
In childhood onset RB, it has been reported that well-differentiated tumors occur at an earlier age than poorly differentiated tumor.  This may represent de-differentiation seen in other carcinomas where less severe well-differentiated tumors progress to more severe poorly differentiated tumors.  However, combining all cases of adult onset RB, we did not see any difference in mean age between those with undifferentiated (mean age = 30 years) and poorly differentiated RB (mean age = 32.9 years), suggesting underlying pathogenic and potential genetic differences between childhood and adult onset RB.
Undifferentiated RB may need immunohistochemistry (IHC) for diagnosis.  IHC can help in confirmation of RB by identifying photoreceptors and glial cells. It can also indicate the level of differentiation of RB by identifying red and green cones found in rosettes and fleurettes and blue cones which do not form rosettes and fleurettes. 
There is no specific immunomarker for RB.  Literature shows that the most commonly employed IHC marker employed to confirm the presence of RB cells in adult onset disease was neuron-specific enolase (positive in nine out of ten cases). Other useful markers were synaptophysin (positive in five cases), CD56 (positive in three cases), and glial fibrillary acidic protein (positive in three cases). Other markers such as proliferating cell nuclear antigen, chromogranin A, S-antigen, S-100, vimentin, p53 protein were positive in individual cases only. Although a melanocytic marker, positive staining with S-100 is observed within the reactive stroma. In cases with dilemma, it is important to note that lack of staining with human melanoma black-45 and keratin almost rules out malignant melanoma and metastatic carcinoma. 
| Clinical Features|| |
Age of presentation of adult RB cases ranged from 20 to 74 years. The majority (n = 39) were from 20 to 50 years with only five patients presenting above 50 years. Most common age of presentation was 20-30 years (n = 23) followed by 41-50 years (n = 9). Kaliki et al., in their recent series have reported a mean age at presentation of 30 years and range from 22 to 48 years, very similar to the previous reports. 
No predilection of adult onset RB for any sex was noted. Of the 45 cases, 24 were male, and 21 were female.
All cases of adult RB have been unilateral till date. Among the 19 of 45 cases where data is available, RB affected the right eye in 13 cases and the left eye in 6 cases. The specifics of the eye involved are unavailable from other reports.
Dimness of vision was the most common complaint followed by perception of floaters in the affected eye. Other symptoms were pain and redness. One patient presented with leukocoria and three with proptosis and orbital mass. This is in sharp contrast to childhood RB where leukocoria and strabismus are the most common clinical presentation and vision loss reported in 5% of patients.  Duration of symptoms before diagnosis ranged from 3 days to 100 months with a mean duration of 15.1 months, and the median duration was 6 months in the first 36 cases and median of 12 months in the latest series of 8 cases.  This shows that symptoms of adult onset RB are insidious, and patients wait for a considerable period before seeking ophthalmic consultation.
From available data of 18 cases, visual acuity at presentation ranged from 20/20 to no light perception. Half of the cases had 20/80 or better vision while the other half had 20/400 or worse.
Findings are summarized in [Table 1] and [Table 2]. Solid intraocular mass is the universal presentation in all cases. However, in three cases, it was not identified initially on clinical examination but later confirmed on imaging. , The majority of the eyes (28 out of 45) had a single mass; one had two separate retinal lesions  whereas multiple lesions were noted in two eyes. , Data are not available on 13 cases. Intraocular mass was mostly whitish in color. Single cases of salmon colored  and partially pigmented masses  have been reported. Surprisingly, no cases of diffuse infiltrating variety, which is more common in older children, have been reported in adults. Among available data of 23 cases, anterior segment findings were noted in 11 cases showing keratic precipitates, anterior chamber seeds, iris neovascularization, and pseudohypopyon. Three cases had orbital disease.
|Table 2: Recent reports of cases of adult onset retinoblastoma (1987-2015)|
Click here to view
Grouping of RB in children is done according to the International Intraocular RB Classification (IIRC).  Using the IIRC for adult onset RB has its pitfalls but we, nevertheless, tried to classify eyes based on available data. Grouping of 17 adult RB cases up to 1986 was not possible due to lack of information in the reports. Among subsequent 27 cases, we found only two eyes that could be classified as Group B, 3 as Group C, 8 as Group D, and the majority (n = 12) as Group E. This shows most of the cases were fairly advanced before diagnosis.
Unfortunately, only one of the adult onset RB eyes has been salvaged till date.  Globe was already destroyed in three cases of orbital RB , and others ended up in enucleation. Attempts to salvage the globe with chemo reduction and focal therapy in six cases were unsuccessful. This may be because of delayed presentation with advanced disease in most cases, or recurrences and more aggressive disease than childhood RB. However, with new targeted treatment modalities such as super selective intra-arterial chemotherapy and intravitreal chemotherapy, timely intervention at earliest may make globe salvage a reality in the near future even for adult onset RB.
There was a little hope of salvageable vision at the outset in most cases. The final outcome was dismal as, barring one, all eyes underwent enucleation either as primary management or subsequently due to the failure of conservative methods of treatment.
Extraocular extension, metastasis, and death
Available records from published literature revealed extraocular extension in 5 of 27 cases. Of the 5 cases, 2 had orbital disease but no evidence of metastasis at presentation.  However, follow-up records are not available. Rest of the three cases had distant metastasis and unfortunately expired at 12, 16, and 60 months. ,
| Differential Diagnosis|| |
A diagnostic dilemma often exists as RB in adults is not expected due to its rarity. In the presence of inflammation, cataract or vitreous hemorrhage diagnosis becomes more challenging.  It can be misdiagnosed as:
- Adult onset Coats disease 
- Retinal astrocytoma
- Metastatic carcinoma ,
- Amelanotic melanoma ,,
- Intraocular lymphoma
- Vasoproliferative tumor 
- Endophthalmitis or panophthalmitis
- Fungal granuloma 
- Ocular cystecercosis 
- Retinal inflammatory diseases 
- Intraocular medulloepithelioma
- Neovascular glaucoma (in the presence of anterior segment signs with poor view of fundus). 
| Ancillary Studies|| |
The following ancillary tests can be considered to arrive at the correct diagnosis:
- Ultrasound B-scan
- Computed tomography (CT)
- Magnetic resonance imaging (MRI)
- Fine needle aspiration biopsy (FNAB)
- Metastatic workup.
Ultrasound B-scan is the primary and most important study to confirm the presence of an intraocular mass arising from retina, to measure the dimensions of mass, to detect associated vitreous seeds or retinal detachment, and to exclude optic nerve invasion. It reveals dome-shaped solid mass with high surface reflectivity and variable internal reflectivity. However, an ultrasound scan may or may not reveal intralesional calcification, which is typical of RB in children.  Of 16 cases where ultrasound findings are available, only 5 had calcification confirming that this is not a consistent finding in adult onset RB. In addition, ultrasound B-scan remains invaluable to exclude other differentials.
CT detects extraocular extension and can detect RB associated intracranial tumor-pinealoblastoma, which is extremely rare in an adult.  CT has demonstrated intraocular calcification in only 25% cases (3 out of 12) till date. In two eyes of adult RB, ultrasound and CT gave contradictory results for calcification. 
Magnetic resonance imaging
MRI is specifically indicated if optic nerve invasion or intracranial extension is suspected.  MRI was done in six cases and successfully delineated the intraocular mass, excluded optic nerve, and extraocular spread in five cases and showed orbital apex involvement in one case of orbital RB.  However, MRI does not have specific features typical of RB in T1- or T2-weighted images or other sequences and hence, it is difficult to use MRI to conclusively diagnose the presence of RB. Once there is a good clinical or ultrasound/CT-guided evidence of RB, MRI helps to rule out optic nerve and extraocular/intracranial extension very well.
Diagnostic biopsy or cytology
In atypical cases of intraocular tumors defying accurate clinical diagnosis, sample obtained either by FNAB or from vitrectomy specimens has proved to be a useful adjunct diagnostic tool.  From available reports on adult onset RB, we found that aspiration cytology, biopsy, or vitrectomy samples were obtained in as many as 13 eyes due to diagnostic dilemma. The examination could provide limited information such as the presence of small round malignant cells in ten cases whereas in three cases smear was acellular. Cytology could differentiate nonmalignant masquerades such as Coats disease  or posterior uveitis  but was inconclusive in distinguishing primary and metastatic tumor and lead to delayed diagnosis in one case  and misdiagnosis in another.  In general, preoperative FNAB is not routinely performed in RB for risk of tumor seeding.  Despite the rare use of FNAB in the diagnosis of intraocular tumors, the risk of tumor recurrence in the socket was not increased after enucleation according to the literature. , Shields et al. stated some risks of RB dissemination after vitrectomy in eyes with unsuspected RB, in older pediatric patients.  Zafar et al. reported possible upstaging of tumor due to vitreous tap.  Vitrectomy or vitreous tap in unsuspected RB needs enucleation with chemotherapy or radiotherapy or both without delay to prevent systemic tumor dissemination.  Cases with diagnostic dilemma might benefit from FNAB followed by IHC staining of the specimens.
A patient of RB is always at risk of metastasis. Most metastases are detected within the first 2 years of diagnosis.  The standard metastatic workup for RB includes blood counts, bone marrow biopsy, cerebrospinal fluid cytology, liver function tests, abdominal ultrasound or CT, and chest X-ray or CT thorax. The previous reports also advise performing total body positron emission tomography and 99mTc-methylene diphosphonate whole body bone scan in suspected cases.
| Treatment and Outcomes|| |
Management of RB should be guided by the objectives to save life, retain anatomical integrity of the eye, preserve vision, and obtain good cosmetic results. The treatment option chosen for each individual case depends on the overall situation, including, size and location of the tumor, laterality, visual prognosis, threat of metastatic disease, and systemic status. 
Enucleation with orbital implant was the primary modality of treatment in the majority of reported cases of adult onset RB, due to the advanced stage of tumor and unilateral disease.  Although management of childhood RB has evolved over the past decade and newer modalities such as super selective intra-arterial chemotherapy and intravitreal chemotherapy for residual vitreous seeds favor eye salvage in most instances, there is little literature to support their use in adult onset RB thus far. Of the 17 cases reported up to 1986, no treatment records other than enucleation are available. Among the 27 subsequent cases reported, primary enucleation was done in 14 cases of which 1 case underwent preoperative radiation, 2 required additional postenucleation chemotherapy, , and 1 both chemo and radiotherapy.  Two cases underwent pars plana vitrectomy for retinal detachment with unsuspected RB ending up finally in enucleation. , Seven eyes had to be enucleated after the failure of other treatment modalities. No surgery was needed in one case of orbital RB but exenteration was done in other two. , As mentioned above, newer therapies may make globe salvage a reality in the near future even for adult onset RB.
External beam radiotherapy
External beam radiotherapy (EBRT) was done in total of ten cases. Preoperative EBRT was given in one case before enucleation to prevent seeding.  Postenucleation EBRT even with chemotherapy was unable to control metastasis in one case.  Primary EBRT with subsequent chemotherapy (intra-arterial and intravitreal) and plaque radiotherapy was successful in the only reported case of globe salvage in IIRC Group D tumor (66 months follow-up).  However, EBRT with chemotherapy was only able to temporarily regress another Group D tumor for 18 months  and was unsuccessful in tumor regression in three cases. ,, It controlled local disease in one case of orbital RB  and played a crucial role along with chemotherapy and exenteration in treatment of two other cases. 
Systemic chemotherapy and chemoreduction
Six cycles (1 month apart) of carboplatin 500 mg/m 2 on day 1, vincristine 1.50 mg/m 2 on day 1, and etoposide 150 mg/m 2 on days 1 and 2 was the regime of chemotherapy used in adult RB cases.
Chemotherapy postenucleation was needed in four cases due to microscopic high-risk features. ,,, It controlled orbital disease in three cases. , Chemotherapy with focal therapy (either transpupillary thermotherapy or cryotherapy) was able to induce initial regression in four cases but failed to prevent recurrence. ,,
Focal therapy (plaque brachytherapy, laser therapy, cryotherapy, transpupillary thermotherapy)
RB in adults may be more resistant to focal therapy than RB in children.  Five cases of IIRC Group C and D were treated with various combination of systemic chemotherapy, EBRT, and focal therapy. ,,,, One case was resistant  and others showed initial response but eventually had to be enucleated for recurrence. Khetan et al. reported a patient who underwent 11 cycles of chemotherapy in all combined with multiple treatments of transpupillary thermotherapy, laser using indirect ophthalmoscopy, and transconjunctival cryotherapy but tumor recurred after 2 years finally ending up in enucleation. 
It is important to recognize that out of 13 cases with primary enucleation, only 2 cases recurred with eventual death probably representing aggressive disease. , However, all the five cases with focal therapy recurred (4 within 2 years and 1 at 42 months) indicating either improper case selection for therapy or poor response of adult RB to these modalities. Even after complete regression of a tumor, long follow-up at short intervals and a complete fundus evaluation at every visit is mandatory to detect early recurrences and deliver prompt management. 
Metastatic disease management
In spite of advanced local disease in most cases, metastatic disease has been reported in only three cases thus far. One patient, in spite of whole brain radiotherapy for metastatic suprasellar brain deposit, expired at 16 months.  The remaining two did not receive any treatment for metastasis and eventually died at 1 year and 5 years showing poor outcome. ,
| Conclusion|| |
RB has evolved from a deadly childhood cancer to a largely curable cancer within the past 40 years.  RB should be considered as a possibility in adults with amelanotic whitish mass lesion in the fundus. Ultrasound and CT scan should be the first line of investigation. In case of dilemma, FNAB of the mass with IHC may yield useful results. As of today, globe salvage appears a far cry in eyes with adult onset RB. Early recognition of this entity and trials of appropriate focal therapy and new promising modalities like intraarterial, periocular, or intraocular chemotherapy is warranted for a better outcome. Many questions remain unanswered such as the genetic make-up of adult onset RB and its dependence on retinocytomas, best treatment patterns to allow globe salvage and long-term survival of adults with RB compared with childhood RB.  Long follow-up is required with proper attention to contra lateral eye of the patient and first-degree relatives.
Methods of literature search
PubMed and PubMed Central, Scopus, Google Scholar, EMBASE, Cochrane database for all reports in English using the keywords "Retinoblastoma in Adults," "Adult onset retinoblastoma," and filters such as date (from 1901 onward) and article type (case report, review). Reports in other native languages were translated in English using the "Google Translate" open access service to decipher useful information for this review.
Financial support and sponsorship
Conﬂicts of interest
There are no conflicts of interest.
| References|| |
Bishop JO, Madson EC. Retinoblastoma. Review of the current status. Surv Ophthalmol 1975;19:342-66.
Pendergrass TW, Davis S. Incidence of retinoblastoma in the United States. Arch Ophthalmol 1980;98:1204-10.
Shields JA, Shields CL. Intraocular Tumors: An Atlas and Textbook. 2 nd
Ed. Philadelphia: Lippincott Williams & Wilkins; 2008.
Maghy C. A case of bilateral glioma of the retina in a girl twenty years of age in which the second eye was excised after an interval of nearly eighteen years. Br J Ophthalmol 1919;3:337-40.
Kaliki S, Shields CL, Gupta A, Mishra DK, Das C, Say EA, et al.
Newly diagnosed active retinoblastoma in adults. Retina 2015;35:2483-8.
Mietz H, Hutton WL, Font RL. Unilateral retinoblastoma in an adult: Report of a case and review of the literature. Ophthalmology 1997;104:43-7.
Verhoeff FH. A retinoblastoma in a man aged forty-eight years. Trans Am Ophthalmol Soc 1929;27:176-88.
McCrea WB. Glioma of the retina. A review of twelve cases. Br J Ophthalmol 1943;27:259-73.
Rasmussen K. Retinoblastoma in a man aged forty-eight years. Acta Ophthalmol 1943;21:210-3.
Rychener RO. Retinoblastoma in the adult. Trans Am Ophthalmol Soc 1948;46:318-26.
O'Day K. Two cases of choroidal melanomata with unusual histories. Br J Ophthalmol 1948;32:121.
Arseni C, Opresco I. Unusual anatomo-clinical aspects in a case of retinoblastoma. Ann Anat Pathol (Paris) 1959;4:129-35.
Mehra KS, Hamid S. Retinoblastoma in an adult. Am J Ophthalmol 1961;52:405-6.
Finlay JR, Byron H. Retinoblastoma in the adult: Review of literature and report of a case associated with benign melanoma. Acta XIX Concil Ophthalmol 1962;2:1168-78.
Makley TA Jr. Retinoblastoma in a 52-year-old man. Arch Ophthalmol 1963;69:325-7.
Ohara H, Akatuka S, Akutu S, Matui N. A case of retinoblastoma in an aged woman. Jan J Clin Ophthalmol 1963;17:951-3.
Perz M, Majewski C. A case of retinoblastoma in an adult male. Klin Oczna 1964;34:261-4.
Lasch H. A recurrent retinoblastoma in adult age. Klin Monbl Augenheilkd 1964;144:268-72.
Kremlicka L, Roubková H. Retinoblastoma in an adult (author's transl). Klin Monbl Augenheilkd 1975;167:119-23.
Berkeley JS, Kalita BC. Retinoblastoma in an adult. Lancet 1977;2:508-9.
Takahashi T, Tamura S, Inoue M, Isayama Y, Sashikata T. Retinoblastoma in a 26-year-old adult. Ophthalmology 1983;90:179-83.
Neronova-Kotova LA. Case of retinoblastoma in an adult. Vestn Oftalmol 1986;102:75.
Biswas J, Mani B, Shanmugam MP, Patwardhan D, Kumar KS, Badrinath SS. Retinoblastoma in adults. Report of three cases and review of the literature. Surv Ophthalmol 2000;44:409-14.
Nork TM, Millecchia LL, de Venecia GB, Myers FL, Vogel KA. Immunocytochemical features of retinoblastoma in an adult. Arch Ophthalmol 1996;114:1402-6.
Odashiro AN, Pereira PR, de Souza Filho JP, Cruess SR, Burnier MN Jr. Retinoblastoma in an adult: Case report and literature review. Can J Ophthalmol 2005;40:188-91.
Orellana ME, Brimo F, Auger M, Galic J, Deschenes J, Burnier MN. Cytopathological diagnosis of adult retinoblastoma in a vitrectomy specimen. Diagn Cytopathol 2010;38:59-64.
Shrestha A, Adhikari RC, Saiju R. Retinoblastoma in a 37 years old man in Nepal: A case report. Kathmandu Univ Med J (KUMJ) 2010;8:247-50.
Nandedkar VS, Joshi AR, Kabra N, Deshpande NN. Presentation of retinoblastoma in pregnancy. Indian J Ophthalmol 2010;58:229-32.
Wells JR, Aaberg TM Jr., Shields CL, Comer GM, Grossniklaus HE. Retinoblastoma in a 48-year-old woman. Retin Cases Brief Rep 2011;5:22-5.
Singh SK, Das D, Bhattacharjee H, Biswas J, Kuri G, Bhattacharjee K, et al.
A rare case of adult onset retinoblastoma. Oman J Ophthalmol 2011;4:25-7.
Zhang Z, Shi JT, Wang NL, Ma JM. Retinoblastoma in a young adult mimicking Coats' disease. Int J Ophthalmol 2012;5:625-9.
Khetan V, Mathur G, Kumar SK, Gopal L. Late recurrence of tumor necessitating enucleation in an adult onset retinoblastoma. Ophthalmic Genet 2013;34:87-9.
Zafar SN, Ahmad SQ, Zafar N. Retinoblastoma in an adult. BMC Res Notes 2013;6:304.
Chawla B, Hada M, Kashyap S, Bakhshi S. Orbital retinoblastoma in an adult. Orbit 2013;32:146-8.
Khetan V, Bindu A, Kamat P, Kumar SK. Failure of globe conservation in a case of adult onset retinoblastoma. Middle East Afr J Ophthalmol 2014;21:358-60.
Yousef YA, Istetieh J, Nawaiseh I, Al-Hussaini M, Alrawashdeh K, Jaradat I, et al.
Resistant retinoblastoma in a 23-year-old patient. Oman J Ophthalmol 2014;7:138-40.
Sharifzadeh M, Ghassemi F, Amoli FA, Rahmanikhah E, Tabatabaie SZ. Retinoblastoma in adults: A case report and literature review. J Ophthalmic Vis Res 2014;9:388-91.
Zhang X, Zheng L, Gao F, Dong F. Adult onset retinoblastoma: A case report. Chin Med J (Engl) 2015;128:133-4.
Goel S, Nayaka A, Kamlesh, Rastogi A, Rao S. Retinoblastoma in an adult male: A case report. Delhi J Ophthalmol 2012;23:45-7.
Singh AD, Santos CM, Shields CL, Shields JA, Eagle RC Jr. Observations on 17 patients with retinocytoma. Arch Ophthalmol 2000;118:199-205.
Gallie BL, Ellsworth RM, Abramson DH, Phillips RA. Retinoma: Spontaneous regression of retinoblastoma or benign manifestation of the mutation? Br J Cancer 1982;45:513-21.
Gallie BL, Phillips RA, Ellsworth RM, Abramson DH. Significance of retinoma and phthisis bulbi for retinoblastoma. Ophthalmology 1982;89:1393-9.
Gallie BL, Squire JA, Goddard A, Dunn JM, Canton M, Hinton D, et al.
Mechanism of oncogenesis in retinoblastoma. Lab Invest 1990;62:394-408.
Dimaras H, Khetan V, Halliday W, Orlic M, Prigoda NL, Piovesan B, et al.
Loss of RB1 induces non-proliferative retinoma: Increasing genomic instability correlates with progression to retinoblastoma. Hum Mol Genet 2008;17:1363-72.
Balmer A, Munier F, Gailloud C. Retinocytoma. Case studies. Ophthalmic Paediatr Genet 1991;12:131-7.
Sampieri K, Mencarelli MA, Epistolato MC, Toti P, Lazzi S, Bruttini M, et al.
Genomic differences between retinoma and retinoblastoma. Acta Oncol 2008;47:1483-92.
Madhavan J, Ganesh A, Roy J, Biswas J, Kumaramanickavel G. The relationship between tumor cell differentiation and age at diagnosis in retinoblastoma. J Pediatr Ophthalmol Strabismus 2008;45:22-5.
Santos L, Loo C, Chandraratnam E, Gune S. Anaplastic carcinoma dedifferentiation of solid variant of papillary thyroid carcinoma. Pathology 2004;36:196-211.
Abramson DH, Frank CM, Susman M, Whalen MP, Dunkel IJ, Boyd NW 3 rd
. Presenting signs of retinoblastoma. J Pediatr 1998;132 (3 Pt 1):505-8.
Shields CL, Shields JA. Basic understanding of current classification and management of retinoblastoma. Curr Opin Ophthalmol 2006;17:228-34.
Murthy R, Honavar SG, Naik MN, Reddy VA. Retinoblastoma. In: Dutta LC, editor. Modern Ophthalmology. New Delhi, India: Jaypee Brothers; 2004. p. 849859.
Shields JA, Shields CL, Ehya H, Eagle RC Jr., De Potter P. Fine-needle aspiration biopsy of suspected intraocular tumors. The 1992 Urwick lecture. Ophthalmology 1993;100:1677-84.
Karcioglu ZA, Gordon RA, Karcioglu GL. Tumor seeding in ocular fine needle aspiration biopsy. Ophthalmology 1985;92:1763-7.
Decaussin M, Boran MD, Salle M, Grange JD, Patricot LM, Thivolet-Bejui F. Cytological aspiration of intraocular retinoblastoma in an 11-year-old boy. Diagn Cytopathol 1998;19:190-3.
Shields CL, Honavar S, Shields JA, Demirci H, Meadows AT. Vitrectomy in eyes with unsuspected retinoblastoma. Ophthalmology 2000;107:2250-5.
Goddard AG, Kingston JE, Hungerford JL. Delay in diagnosis of retinoblastoma: Risk factors and treatment outcome. Br J Ophthalmol 1999;83:1320-3.
Shields CL, Shields JA. Diagnosis and management of retinoblastoma. Cancer Control 2004;11:317-27.
Abramson DH, Ellsworth RM, Grumbach N, Kitchin FD. Retinoblastoma: Survival, age at detection and comparison 1914-1958, 1958-1983. J Pediatr Ophthalmol Strabismus 1985;22:246-50.
[Table 1], [Table 2]