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Retinoblastoma is a cancer of the retina. It is caused by a mutation in the Rb-1 protein. It occurs mostly in younger children and accounts for about 3% of the cancers occurring in children younger than 15 years. The estimated annual incidence is approximately 4 per million children . more...

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The tumor may begin in one or both eyes. Retinoblastoma is usually confined to the eye but can spread to the brain via the optic nerve.


Retinoblastoma may be hereditary (genetically inherited) or nonhereditary. The hereditary form may be in one or both eyes, and generally affects younger children. Retinoblastoma occurring in only one eye is often not hereditary and is more prevalent in older children. When the disease occurs in both eyes, it is always hereditary. Because of the hereditary factor, patients and their brothers and sisters should have periodic examinations, including genetic counseling, to determine their risk for developing the disease.

A statistical study by Dr Alfred G. Knudson in 1971 led to a hypothesis (later known as the Knudson hypothesis) about why some retinablastomas are hereditary and others occur by chance. This hypothesis led to the first identification of a tumor suppressor gene by a team led by Dr Thaddeus P. Dryja in 1986. Knudson won the 1998 Albert Lasker Medical Research Award for this work.

Hereditary retinoblastoma is caused by an inherited mutation in a single copy of the Rb1 gene. The remaining functional copy prevents most retinal cells from becoming cancerous. However, one or more cells in the retina are likely to undergo a spontaneous loss of this functional copy, causing those cells to transform into cancer. This loss of the second copy of Rb1 is termed loss of heterozygosity, a frequent event in cancer for which retinoblastoma is the canonical example.


The patient's choice of treatment depends on the extent of the disease within and beyond the eye. Smaller tumors can be removed with laser surgery, thermo-, or cryotherapy. Larger tumors may require enucleation.

Genetic testing can identify the mutation that lead to the development of retinoblastoma. Testing in unilateral cases can identify the 15% of unilateral cases with a germline mutation, indicating risk in future children. Testing amniotic cells in an at-risk pregnancy can identify a fetus with the mutation, which can then be delivered early before retinal cells have fully developed and before tumors arise. This early treatment can lead to a fully sighted bilaterally affected patient.


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Protocol for the examination of specimens from patients with retinoblastoma: A basis for checklists
From Archives of Pathology & Laboratory Medicine, 9/1/01 by Albert, Daniel

A Basis for Checklists

This protocol is intended to assist pathologists in providing clinically useful and relevant information as a result of the examination of surgical specimens. Use of this protocol is intended to be entirely voluntary. If equally valid protocols or similar documents are applicable, the pathologist is, of course, free to follow those authorities. Indeed, the ultimate judgment regarding the propriety of any specific procedure must be made by the physician in light of the individual circumstances presented by a specific patient or specimen.

It should be understood that adherence to this protocol will not guarantee a successful result. Nevertheless, pathologists are urged to familiarize themselves with the document. Should a physician choose to deviate from the protocol based on the circumstances of a particular patient or specimen, the physician is advised to make a contemporaneous written notation of the reason for the procedure followed.

The College recognizes that this document may be used by hospitals, attorneys, managed care organizations, insurance carriers, and other payers. However, the document was developed solely as a tool to assist pathologists in the diagnostic process by providing information that reflects the state of relevant medical knowledge at the time the protocol was first published. It was not developed for credentialing, litigation, or reimbursement purposes. The College cautions that any uses of the protocol for these purposes involve considerations that are beyond the scope of this document.


A: Cytology/Biopsy.-Cytologic and biopsy specimens are rarely obtained from eyes with suspected retinoblastoma owing to the potential risk of tumor seeding. An anterior chamber paracentesis may be performed if indicated by clinical findings and is not associated with risk of tumor seeding.1,2

B: Fixation.-The minimum recommended fixation time for whole globes with intraocular tumors is 48 hours. The globe should be fixed in an adequate volume of fixative; a 10:1 ratio of fixative volume to specimen volume is recommended. Incisions or windows in the globe are not necessary for adequate penetration of fixative and are not recommended. Injection of fixative into the globe is also not recommended.

C: Additional Studies.-Genetic studies may be requested on neoplastic tissue, and specimens should be harvested prior to fixation? The surgical margin of the optic nerve should be obtained prior to opening the globe (note G). Once tissue is harvested for genetic studies, the globe can be fixed prior to completing macroscopic examination. The appropriate materials/medium required by the laboratory performing genetic testing should be obtained prior to the procedure.

D: Histologic Features.-Typical histologic features include cells with large basophilic nuclei and scant cytoplasm. Mitoses are generally frequent. Calcification and necrosis are common, with sleeves of viable cells typically surrounding blood vessels (pseudorosettes). Apoptotic cells may be seen. The extent of differentiation may be judged based on the presence and type of rosettes. Homer Wright rosettes similar to those seen in neuroblastoma or medulloblastoma may be seen and are not a sign of significant differentiation. Flexner-Wintersteiner rosettes are evidence of higher differentiation. Fleurettes are considered the most differentiated form of rosette found in the tumor. A benign variant of retinoblastoma termed retinocytoma or retinoma has been described. This tumor consists entirely of benign, well-differentiated cells often with associated calcification. The cells have smaller, less hyperchromatic nuclei and abundant cytoplasm. Necrosis is typically absent and mitotic figures are rare." Retinoblastomas may arise in multicentric foci.

E: Histologic Features of Prognostic Significance.-- Histologic features with prognostic significance for survival include the following: invasion of optic nerve, particularly if tumor is present at the surgical margin (most important feature); invasion of sclera; invasion of choroid; tumor size; basophilic staining of tumor vessels; seeding of vitreous; degree of differentiation; involvement of anterior segment; and growth pattern.10-16 This list should not be confused with the Reese-Ellsworth classification, which is intended as a predictor for visual outcome, not survival.17

F: Orientation of Globe.-The orientation of a globe may be determined by identifying extraocular muscle insertions, optic nerve, and other landmarks as illustrated in Figure 1. The terms temporal and nasal are generally used in place of lateral and medial with reference to ocular anatomy.

G: Sectioning the Globe.-The globe is generally sectioned in the horizontal or vertical plane with care to include the pupil and optic nerve in the cassette to be submitted for microscopic examination. If the mass cannot be included with horizontal or vertical sectioning, the globe is sectioned obliquely to include tumor, pupil, and optic nerve (Figure 2). The surgical margin of the optic nerve should be sectioned and submitted prior to sectioning the globe to ensure that intraocular malignant cells do not contaminate this important surgical margin.3 Retinoblastoma is an extremely friable tumor.

H: Sections Submitted for Microscopic Examination.-Multiple sections should be examined with special attention to sections containing optic nerve and tumor. The nerve should be sectioned along the various levels to determine tumor extension.

I: Growth Pattern.-Endophytic growth pattern indicates growth from the inner retinal surface into the vitreous cavity. Exophytic tumors grow primarily from the outer surface of the retina into the subretinal space toward the choroid. Mixed growth pattern exhibits features of both endophytic and exophytic growth. Diffuse infiltrating tumors grow laterally within the retina without significant thickening.


1. Karcioglu ZA, Gordon RA, Karcioglu GL. Tumor seeding in ocular fine needle aspiration biopsy. Ophthalmology. 1985;92:1763-1767.

2. Stevenson KE, Hungerford J, Garner A. Local extraocular extension of retinoblastoma following intraocular surgery. Br Ophthalmol. 1989;73:739-742.

3. Shields JA, Shields CL, DePotter P. Enucleation technique for children with retinoblastoma. J Pediatr Ophthalmol Strabismus. 1992;29:213-215.

4. Zimmerman LE. Retinoblastoma and retinocytoma. In: Spencer WH, ed. Ophthalmic Pathology: An Atlas and Textbook. 3rd ed. Philadelphia, Pa: WB Saunders Co; 1986:1292-1351.

5. Tso MOM, Fine BS, Zimmerman LE. The Flexner-Wintersteiner rosettes in retinoblastoma. Arch Pathol. 1969;88:665-671.

6. Tso MOM, Fine BS, Zimmerman LE. The nature of retinoblastoma, I: photoreceptor differentiation: a clinical and histologic study. Am JOphthalmol. 1970; 69:339-350.

7. Tso MOM, Fine BS, Zimmerman LE. The nature of retinoblastoma, II: photoreceptor differentiation: an electron microscopic study. Am J Ophthalmol. 1970; 69:350-359.

8. Margo C, Hidayat A, Kopelman J, Zimmerman LE. Retinocytoma: a benign variant of retinoblastoma. Arch Ophthalmol. 1983;101:1519-1531.

9. Gallie BL, Ellsworth RM, Abramson DH, Phillips RA. Retinoma: spontaneous regression of retinoblastoma or benign manifestation of the mutation? Br J Cancer, 1982;45:513-521.

10. Redler LD, Ellsworth RM. Prognostic importance of choroidal invasion in retinoblastoma. Arch Ophthalmol. 1973;90:294-296.

11. Kopelman JE, McLean IW. Multivariate analysis of clinical and histological risk factors for metastasis in retinoblastoma [abstract]. Invest Ophthalmol Vis Sci. 1983;24(ARVO suppl):50.

12. Kopelman JE, McLean IW. Multivariate analysis of risk factors for metastasis in retinoblastoma treated by enucleation. Ophthalmology. 1987;94:371-377.

13. Haik BG, Dunleavy SA, Cooke C, et al. Retinoblastoma with anterior chamber extension. Ophthalmology. 1987;94:367-370.

14. Magramm I, Abramson DH, Ellsworth RM. Optic nerve involvement in retinoblastoma. Ophthalmology. 1989;96:217-222.

15. Shields CL, Shields )A, Baez KA, Cater J, DePotter PV. Choroidal invasion of retinoblastoma: metastatic potential and clinical risk factors. BrJ OphthalmoL 1993;77:544-548.

16. Shields CL, Shields JA, Baez K, Cater JR, DePotter P. Optic nerve invasion of retinoblastoma: metastatic potential and clinical risk factors. Cancer. 1994;73: 692-698.

17. Reese AB, Ellsworth RM. The evaluation and current concept of retinoblastoma therapy. Trans Am Acad Ophthalmol Otolaryngol. 1963;67:164-172. 18. Fleming ID, Cooper JS, Henson DE, et al, eds. AICC Manual for Staging of Cancer. Sth ed. Philadelphia, Pa: Lippincott Raven; 1997.


Albert DM. Principles of pathology. In: Albert DM, Jakobiec FA, eds. Principles and Practice of Ophthalmology, Vol 4. Philadelphia, Pa: WB Saunders Co; 1994:2101-2126.

Albert DM, Dryja TP.The eye. In: Cotran RS, Kumar V, Robbins SL, eds. Pathologic Basis of Disease. 6th ed. Philadelphia, Pa: WB Saunders Co; 1998.

Sahel JA, Brini A, Albert DM. Pathology of the retina and vitreous. In: Albert DM, jakobiec FA, eds. Principles and Practice of Ophthalmology. Vol 4. Philadelphia, Pa: WB Saunders Co; 1994:2239-2280.

Yanoff MF, Fine BS. Ocular Pathology: A Text and Atlas. 3rd ed. Philadelphia, Pa: JB Lippincott Co; 1989;684-694.

Zimmerman LE. Retinoblastoma and retinocytoma. In: Spencer WH, ed. Ophthalmic Pathology: An Atlas and Textbook 3rd ed. Philadelphia, Pa: WB Saunders Co; 1986:1292-1351.

Daniel Albert, MD; Nasreen Syed, MD; for the Members of the Cancer Committee, College of American Pathologists

Accepted for publication May 10, 2001.

From the Department of Ophthalmology, University of Wisconsin Hospital, Madison, Wis (Dr Albert); and the Departments of Ophthalmology and Pathology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pa (Dr Syed).

This protocol was developed by the Cancer Committee of the College of American Pathologists and submitted for editorial review and publication. It represents the views of the Cancer Committee and is not the official policy of the College of American Pathologists.

Reprints: See Archives of Pathology & Laboratory Medicine Web site at

Copyright College of American Pathologists Sep 2001
Provided by ProQuest Information and Learning Company. All rights Reserved

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