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%.
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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
- 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
If mets occurs, usually within 1-2 years following 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.
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.
- 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.
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