Retinoblastoma

This is the most common intraocular tumor of childhood. These tumors have a fascinating molecular biology which has opened the doors to understanding the mechanisms of cancer in many organs. In spite of the remarkable success in treating these once uniformly fatal tumors, patients with inherited form of the disease who survive the tumor are at increased risk to develop other malignancies. Thus lifelong surveillance is necessary. Before eye care was routine, patients may present with advanced tumor with a fungating mass causing proptosis of the eyeball. Today, most patients present with pupil abnormalities such as leukocoria or a white pupil (90%). Strabismus is present in 35%.

OUTLINE

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/ Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGY	CHARACTERIZATION
INCIDENCE	1/23,000 live births in England 1/20,000 live births in Japan 1/16,000 live births in Holland
AGE RANGE-MEDIAN	Incidence decreases with age Majority of cases <3 years Rare in adults
SEX (M:F)	Equal
GEOGRAPHY	Worldwide

DISEASE ASSOCIATIONS	CHARACTERIZATION
Development of secondary malignancies in heritable cases	30 year cummulative incidence for non-ocular tumors was 26%
	Radiation treatment increases to 35% vs. 6% who did not receive radiation
	Sarcomas were most common tumors occurring both within and outside the radiation fields
Osteosarcoma	Osteosarcoma of lower extremities occurs at a 500 fold increase in survivors of bilateral tumors than in non-carriers
Intracranial tumors	Frequent in pineal or parasellar regions, often resembling retinoblastomas Termed trilateral retinoblastoma

PATHOGENESIS	CHARACTERIZATION
May result from germinal (heritable) mutation or somatic mutation	If multiple, usually from germinal mutation Two hit hypothesis of Knudsen stated that the development of these tumors required two complementary tumor-inducing events to convert a normal retinal cell into neoplastic Heritable cases have a first germline mutation, the first hit. The second hit occurs in the somatic cell In non-heritable cases, both hits must occur in the same somatic cell, this is supported by the fact that these tumors occur in an older age group
	Only 5-10% of patients who are carriers will not develop a retinoblastoma
Autosomal dominant inheritance but recessive at cellular level	13q14 chromosome mutation Gene normally producesa phosphoprotein (RB protein) which regulates cell division by binding to DNA Adenovirus and SV40 virus transform cultured cells by binding and inactivating the normal RB protein
Chromosomal deletion retinoblastoma	Heritable form with measurable defect in on the long arms of chromosome 13 involving q14 band Associated somatic and mental developmental abnormalities

GROSS APPEARANCE/CLINICAL VARIANTS	CHARACTERIZATION
General	If patient carries the mutation, likelihood that they will develop the tumor
No tumor	5-10%
Unilateral	25-35%
Bilateral	60-75%
VARIANTS
Endophytic
Exophytic
Mixed endophytic-exophytic
Diffuse infiltrating
Complete spontaneous regression

HISTOLOGICAL TYPES	CHARACTERIZATION
General	Small round blue cell tumor with increased vascularity
Flexner-Wintersteiner rosettes	Usually found in undifferentiated malignant cells with mitotic activity Lined by tall cuboidal cells that circumscribe an apical lumen Only pineoblastomas and medulloepitheliomas have these as well
Homer-Wright rosettes	Cells are not arranged about a lumen but send out cytoplasmic processes that form a tangle within the center of the rosette Less common than the former Also present in cerebellar medulloblastomas
Fleurettes	Cells with photoreceptor characteristics with cytoplasmic processes that project through a fenestrated membrane and fan out like a flower bouquet
VARIANTS

PROGNOSIS AND TREATMENT	CHARACTERIZATION
Prognostic Factors	Extent of invasion most important prognostic factor Extent of invasion into optic nerve and throught the ocular coats most important predictors of outcome Bilateral tumors worse prognosis
Extensively necrotic retinoblastoma is associated with high-risk prognostic factors. Chong EM, Coffee RE, Chintagumpala M, Hurwitz RL, Hurwitz MY, Chevez-Barrios P. Department of Ophthalmology, Baylor College of Medicine, Houston, Tex, USA.	Arch Pathol Lab Med. 2006 Nov;130(11):1669-72 Abstract quote CONTEXT: Retinoblastoma is the most common malignant intraocular tumor in children. It has been shown that adjuvant therapy following enucleation in patients with high-risk histopathologic features significantly decreases the mortality. We describe the association of extensive necrosis of tumor and intraocular structures with 2 of the major risk factors: optic nerve invasion and choroidal invasion. This may alert the pathologist who makes the observation of extensive necrosis to carefully search for histologic features associated with adverse outcome. OBJECTIVE: To determine whether extensively necrotic retinoblastoma is associated with high-risk histologic prognostic factors for metastatic disease and patient survival. DESIGN: Retrospective case series. Forty-three eyes of 43 patients with retinoblastoma who underwent enucleation between 1990 and 2001 were evaluated. Medical records, histopathology specimens, pathology reports, and clinical photographs were reviewed. Tumors were designated as exhibiting extensive necrosis if more than 95% of tumor cells and intraocular tissues were necrotic. The main outcome measure was the association of extensive tumor necrosis with 3 high-risk histopathologic features: extraocular extension, optic nerve invasion, or choroidal invasion. Metastatic disease, patient survival, and associations with pathologic findings were also analyzed. RESULTS: Optic nerve head invasion (P < .001), post-lamina-cribrosal invasion (P < .001), and choroidal invasion by tumor (P = .004) were observed more frequently in eyes with extensive necrosis compared with eyes without extensive necrosis. Two of the 11 patients with extensively necrotic intraocular retinoblastoma died from metastatic disease (P = .06). None of the 32 patients without extensive necrosis developed metastatic disease or died. CONCLUSIONS: Extensive ocular tissue and tumor necrosis is associated with histologic high-risk prognostic factors for tumor metastasis and mortality.
Recurrence	Almost always from incomplete treatment
Metastasis	Spreads by invasion through the optic disc into the optic nerve May extend into the subarachnoid space and to CSF Usually about 6 months elapses from initial symptoms to invasion outside the eye Direct invasion Dispersion Hematogenous dissemination Lymphatic spread If mets occurs, usually within 1-2 years following treatment
Treatment	Dependent upon the age, tumor stage, and whether bilateral tumors are present Enucleation most common treatment but for smaller tumors, photocoagulation and cryotherapy have been used Medium tumors use plaque irradiation or external beam irradiation Large tumors-enucleation with radiation and chemotherapy
Evaluation of chemoprophylaxis in patients with unilateral retinoblastoma with high-risk features on histopathologic examination. Uusitalo MS, Van Quill KR, Scott IU, Matthay KK, Murray TG, O'Brien JM. Division of Ocular Oncology, Department of Ophthalmology, University of California, San Francisco, 10 Kirkham St, San Francisco, CA 94143-0730.	Arch Ophthalmol. 2001 Jan;119(1):41-8. Abstract quote OBJECTIVES: To identify risk factors for metastatic disease on histopathologic specimens of enucleated eyes from patients with unilateral retinoblastoma, and to evaluate the value of chemoprophylaxis in preventing disease dissemination. METHODS: Medical records from patients with unilateral retinoblastoma who underwent primary enucleation were reviewed at the University of California, San Francisco (1977-1998) and Bascom Palmer Eye Institute, University of Miami, Miami, Fla (1991-1998). All routine histopathologic specimens were reexamined. The extent of tumor invasion into the optic nerve or ocular coats and the prescribed chemoprophylactic regimen were recorded. RESULTS: This retrospective study included 129 patients followed for a median of 54 months. Three patients had tumor invading the sclera. The optic nerve was involved to some extent in 82 patients, 11 of whom had tumor extension beyond the lamina cribrosa. The surgical margin of the optic nerve was involved in an additional 4 patients. The choroid was involved in 43 patients, and was considered massively affected in 12 patients. Anterior segment involvement was observed in 10 patients. Postenucleation chemoprophylaxis was administered to 4 of 4 patients who had tumor cells at the surgical margin of the optic nerve and to 7 of 11 patients with postlaminar disease, all of whom had at least 1 mm of postlaminar tumor extension. External beam radiotherapy was administered to 3/4 and 1/11 of these patients, respectively. Chemoprophylaxis was not administered to patients with choroidal or anterior chamber involvement unless the optic nerve was also involved beyond the lamina cribrosa. One patient with tumor extending to the surgical margin of the optic nerve died of metastatic disease. CONCLUSIONS: Chemoprophylaxis is necessary for patients with tumor extending to the surgical margin of the optic nerve and is likely to be beneficial in preventing metastases in patients with tumor extending beyond the lamina cribrosa. We did not offer chemoprophylaxis to patients with prelaminar optic nerve disease or isolated choroidal involvement, and these patients remained free of disseminated disease.
ADJUVANT
Postenucleation adjuvant therapy in high-risk retinoblastoma. Honavar SG, Singh AD, Shields CL, Meadows AT, Demirci H, Cater J, Shields JA. Oncology Service, Wills Eye Hospital, 900 Walnut St, Philadelphia, PA 19107, USA.	Arch Ophthalmol. 2002 Jul;120(7):923-31 Abstract quote PURPOSE: The main purpose of this study was to determine the efficacy of postenucleation adjuvant therapy in preventing metastasis in cases of high-risk retinoblastoma. METHODS: This was a retrospective, nonrandomized comparative study. Of 1020 consecutive patients with retinoblastoma had were managed at a referral center between January 1974 and December 1999, 80 (8%) of those analyzed had unilateral sporadic cases that were treated by primary enucleation and that had high-risk characteristics for metastasis on histopathology reports (anterior chamber seeding, iris infiltration, ciliary body infiltration, massive choroidal infiltration, invasion of optic nerve lamina cribrosa, retrolaminar optic nerve invasion, invasion of optic nerve transection, scleral infiltration, and extrascleral extension). The main outcome measure was the development of metastasis at a minimum follow-up period of 12 months. RESULTS: There were 44 male and 36 female patients, with age ranging from 1 day to 16 years (median, 33 months). A single histopathologic high-risk characteristic was present in 50 patients (62.5%). Thirty patients (37.5%) manifested 2 or more high-risk characteristics. Forty-six patients (58%) had received postenucleation adjuvant therapy (chemotherapy with or without orbital external beam radiotherapy). Adjuvant therapy was not administered in 34 patients (42%). Metastasis occurred in 10 patients (13%) at a median of 9 months (range, 6-57 months) following enucleation. Eight (80%) of those who developed metastasis had not received adjuvant therapy. A significant difference (P =.02) was found in the incidence of metastasis between the group that had received adjuvant therapy (4%; 2/46) and the group that had not (24%; 8/34). The beneficial effect of adjuvant therapy was statistically significant in subgroups of patients with massive choroidal infiltration (P =.04) or retrolaminar optic nerve invasion (P =.04). There were no adjuvant therapy-related serious systemic complications. CONCLUSION: Postenucleation adjuvant therapy is safe and effective in significantly reducing the occurrence of metastasis in patients with retinoblastoma manifesting histopathologic high-risk characteristics.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.