eMedicine Specialties > Ophthalmology > Retina

Retinoblastoma: Differential Diagnoses & Workup

Author: Marichelle Aventura Isidro, MD, Consulting Staff, Department of Ophthalmology, Santo Tomas University Hospital of Manila, Philippine Heart Center
Coauthor(s): Manolette R Roque, MD, MBA, DPBO, FPAO, President and CEO, Chief of Service, Ocular Immunology and Uveitis, Consulting Staff, Cornea and Refractive Surgery, Eye Republic Ophthalmology Clinic; General Manager, Ophthalmic Consultants Philippines Co; Consulting Staff, CME Liaison, Section Chief of Ocular Immunology and Uveitis, Department of Ophthalmology, Asian Hospital and Medical Center; Thomas M Aaberg, Jr, MD, Clinical Assistant Professor, Department of Surgery, Michigan State University College of Human Medicine; Consulting Staff, Department of Ophthalmology, Associated Retinal Consultants; Barbara L Roque, MD, Full Partner, Ophthalmic Consultants Philippines Co, Chief of Service, Pediatric Ophthalmology and Strabismus, Consulting Staff, Orbit and Eye Plastics, Eye Republic Ophthalmology Clinic
Contributor Information and Disclosures

Updated: Jan 21, 2009

Differential Diagnoses

Cataract, Congenital
Hemorrhage, Vitreous
Retinal Detachment, Exudative
Retinopathy of Prematurity
Tuberculosis
Uveitis, Anterior, Childhood

Other Problems to Be Considered

Persistent hyperplastic primary vitreous
Toxocariasis
Nematode endophthalmitis
Colobomas of choroid and disc
Uveitis
Congenital retinal fold
Retinal dysplasia
Retinal astrocytic hamartomas
Retinal capillary hemangiomatosis
Tumors other than retinoblastoma

To assist the clinician in coming up with a differential diagnosis cheat sheet, the following diseases have been categorized by presenting tumor:

Diseases presenting as an exophytic tumor

Coats disease
Toxocariasis
Choroiditis
Exudative retinitis
Choroidal hemangioma
Angiomatosis retinae
Retinal pigment epithelium proliferation

Diseases presenting as an endophytic tumor

Retinal hamartomas
Astrocytomas
Myelinated nerve fibers
Retinochoroiditis
Metastatic endophthalmitis

Diseases presenting with leukocoria

Cicatricial retinopathy of prematurity
Persistent hyperplastic primary vitreous
Retinal dysplasia
Toxocariasis
Pseudogliomas
Coats disease
Medulloepitheliomas
Retinal detachments
Late-stage vitreous hemorrhage

Workup

Laboratory Studies

  • Blood counts and electrolyte determination as well as urinalysis and liver function tests are useful in excluding other conditions confused with retinoblastoma.
  • Blood specimens should be taken not only from the patient but also from the parents and any siblings for DNA analysis, which could aid in genetic counseling.
    • There are direct and indirect methods in the analysis of the retinoblastoma gene. The direct method aims to find the initial mutation that precipitated the development of the tumor; then, it is determined whether that mutation is in the germline of the affected patient. Indirect methods can be used in cases where the initial mutation cannot be located or it is uncertain whether it exists.
    • Sources of DNA to be evaluated directly are either from tumor cells or leukocytes.
    • Deletions or rearrangements of the retinoblastoma gene can be detected by either karyotyping or Southern blotting techniques.
    • Point mutations in the retinoblastoma gene can be detected by the following techniques: ribonuclease protection, denaturing gradient gel electrophoresis, single-strand conformation polymorphism, or direct DNA sequencing amplified by the polymerase chain reaction.
    • Retinoblastomas also may arise by hypermethylation of the promoter region of the retinoblastoma gene, which deactivates this gene but does not alter the DNA sequence. This also can be detected by Southern blot analysis.
    • Indirect methods of analysis of the retinoblastoma gene rely on DNA polymorphisms within this gene.
  • Assays of aqueous humor enzyme levels could offer useful information to patients with suspected retinoblastoma. Lactate dehydrogenase (LDH) is a glycolytic enzyme that uses glucose as an energy source. It is present in high concentrations within metabolically active cells. Normally, its concentration in serum and aqueous humor is low and the ratio of aqueous humor to serum LDH is less than 1.0 in patients with ocular disease other than retinoblastoma. However, aqueous humor for eyes with retinoblastoma exhibits increased LDH activity expressed as an aqueous humor/LDH ratio of greater than 1.0.

Imaging Studies

  • Cranial and orbital computerized tomography provides a sensitive method for diagnosis and detecting intraocular calcification and shows intraocular extent of the tumor even in the absence of calcification. This neuroimaging technique is also invaluable in assessing the CNS anatomy, including the optic nerve, for possible extension of retinoblastoma.
  • Ultrasonography is useful in distinguishing retinoblastomas from non-neoplastic conditions. It is also useful in detecting calcifications.
  • MRI
    • MRI may be beneficial in estimating the degree of differentiation of retinoblastomas but is not as specific as computerized tomography because of its lack of sensitivity in detecting calcium.
    • Studies show that on T1-weighted images, the tumors usually have a low intensity and are usually difficult to distinguish from surrounding vitreous, but, on T2-weighted images, retinoblastoma tumors demonstrate very low intensity compared to vitreous. Calcification is more pronounced on T2 sequences.
    • MRI also is useful in identifying any associated hemorrhagic or exudative retinal detachment. This is seen as a localized subretinal area of higher signal intensity compared to vitreous on both T1- and T2-weighted sequences.
  • X-ray studies: In areas of the world where ultrasonography and computerized tomography are not available, x-ray studies may be the only means of identifying intraocular calcium in patients with opaque media.

Other Tests

  • Immunohistopathologic staining
    • The aim of immunohistochemical studies is to decide whether retinoblastomas come from a common progenitor cell capable of differentiation into either glial or neuronal cells or from neuron-committed cells.
    • Numerous variables alter the results in these studies. These variables include tissue fixation, staining procedures, specific areas taken into consideration, tumor cell differentiation, antigen expressivity, and age of tumor.
    • Caution is required when interpreting most immunohistochemical results because of the related controversies associated with these tests. An experienced immunopathologist is required to provide worthwhile results.
    • Immunohistochemical and biochemical studies show an S-antigen detected in well-differentiated retinoblastomas using immunoperoxidase staining of paraffin sections. Felberg and Donoso have performed several related studies.11
    • Bridges and colleagues performed biochemical assays and showed interphotoreceptor retinoid-binding protein (IRBP) in retinoblastoma. These findings suggested an embryonic origin of the cells.
    • Numerous contradictory studies providing evidence for a neuronal nature and differentiation exist.
  • Transmission electron microscopy
    • Ultrastructural investigations have paved the way for more definitive descriptions of retinoblastoma. Research using this technology provided evidence of the presence of photoreceptor cell elements in retinoblastoma, and a strong evidence of retinoblastoma to human fetal retina has been demonstrated.
    • The ultrastructural findings of retinoblastoma investigations have been described previously.

Procedures

  • Patients noted to have presenting signs of retinoblastoma should undergo prompt office examination.
    • Complete eye examination should be performed including an estimation of the patient's visual acuity for both eyes.
    • A dilated fundus examination with indirect ophthalmoscopy should be completed since ancillary diagnostic studies play only a secondary role when the fundus can be visualized clearly.
  • Bone marrow aspiration and biopsy
    • A bone marrow aspiration and biopsy could be performed as well as lumbar puncture with cytocentrifuge examination for tumor cells. These may prove useful in the early diagnosis of distant spread since the primary mode of spread of retinoblastoma is hematogenous to the bone marrow and back through the optic nerve into the cerebrospinal fluid (CSF).
    • Results of a study by Moscinski et al recommends performing bone marrow and CSF evaluations only in patients with clinical, histologic, or radiologic evidence of local or systemic extension or in patients presenting with 1 R-E group V eye with retrolaminar or extrascleral extension of their tumor. They also recommend limiting follow-up bone marrow and CSF determinations to those patients who develop objective signs and symptoms of metastasis or recurrence.12

Histologic Findings

The classic histologic findings of retinoblastoma are Flexner-Wintersteiner rosettes and less commonly fleurettes. A Homer-Wright rosette can be encountered, but they are also seen in other neuroblastic tumors.

Considerable variability exists in the histologic features. Some neoplasms display marked necrosis and prominent foci of calcification. Few show areas of glial differentiation.

Note: In an enucleated eye that is being prepared for gross examination and fixation for histopathologic examination, it is essential that adequate fixation is attained (fixation is usually complete within 48 h). Thorough fixation is especially important for eyes removed for retinoblastoma because the tumor is friable and may be spilled into the uvea or outside of the eye when the eye is sectioned, thereby confusing the assessment of the confinement of tumor to the interior of the eye (a feature that is important for the assessment of survival).

Staging

The staging of retinoblastoma is currently in flux. The Reese-Ellsworth classification system was the most useful system when external beam radiation therapy (EBRT) was the standard of treatment for eye salvage. However, now that chemotherapy has supplanted radiation, this classification system is not as predictive of outcome and survival. A Linn Murphree and colleagues have developed (and are in the process of refining) a new classification system. These classification systems are listed in Image 11.

Reese-Ellsworth classification of retinoblastoma

Reese-Ellsworth classification of retinoblastoma

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Reese-Ellsworth classification of retinoblastoma

Reese-Ellsworth classification of retinoblastoma


More on Retinoblastoma

Overview: Retinoblastoma
Differential Diagnoses & Workup: Retinoblastoma
Treatment & Medication: Retinoblastoma
Follow-up: Retinoblastoma
Multimedia: Retinoblastoma
References
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Further Reading

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Keywords

intraocular cancer, intraocular childhood malignancy, eye tumor, ocular tumor, ocular malignancy, RB gene, retinoblastoma gene, childhood cancer, eye cancer

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Contributor Information and Disclosures

Author

Marichelle Aventura Isidro, MD, Consulting Staff, Department of Ophthalmology, Santo Tomas University Hospital of Manila, Philippine Heart Center
Marichelle Aventura Isidro, MD is a member of the following medical societies: American Academy of Ophthalmology and International Society of Refractive Surgery
Disclosure: Nothing to disclose.

Coauthor(s)

Manolette R Roque, MD, MBA, DPBO, FPAO, President and CEO, Chief of Service, Ocular Immunology and Uveitis, Consulting Staff, Cornea and Refractive Surgery, Eye Republic Ophthalmology Clinic; General Manager, Ophthalmic Consultants Philippines Co; Consulting Staff, CME Liaison, Section Chief of Ocular Immunology and Uveitis, Department of Ophthalmology, Asian Hospital and Medical Center
Manolette R Roque, MD, MBA, DPBO, FPAO is a member of the following medical societies: American Academy of Ophthalmic Executives, American Academy of Ophthalmology, American Society of Cataract and Refractive Surgery, American Society of Ophthalmic Administrators, American Uveitis Society, International Ocular Inflammation Society, Philippine Medical Association, Philippine Ocular Inflammation Society, and Philippine Society of Cataract and Refractive Surgery
Disclosure: Nothing to disclose.

Thomas M Aaberg, Jr, MD, Clinical Assistant Professor, Department of Surgery, Michigan State University College of Human Medicine; Consulting Staff, Department of Ophthalmology, Associated Retinal Consultants
Thomas M Aaberg, Jr, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Ophthalmology, American Medical Association, American Society of Retina Specialists, Michigan Society of Eye Physicians & Surgeons, and Retina Society
Disclosure: Novartis Consulting fee Consulting

Barbara L Roque, MD, Full Partner, Ophthalmic Consultants Philippines Co, Chief of Service, Pediatric Ophthalmology and Strabismus, Consulting Staff, Orbit and Eye Plastics, Eye Republic Ophthalmology Clinic
Disclosure: Nothing to disclose.

Medical Editor

Gerhard W Cibis, MD, Clinical Professor, Director of Pediatric Ophthalmology Service, Department of Ophthalmology, University of Kansas, Kansas City
Gerhard W Cibis, MD is a member of the following medical societies: American Academy of Ophthalmology, American Association for Pediatric Ophthalmology and Strabismus, and American Ophthalmological Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Steve Charles, MD, Director of Charles Retina Institute; Clinical Professor, Department of Ophthalmology, University of Tennessee College of Medicine
Steve Charles, MD is a member of the following medical societies: American Academy of Ophthalmology, American Society of Retina Specialists, Club Jules Gonin, Macula Society, and Retina Society
Disclosure: Alcon Laboratories Consulting fee Consulting; OptiMedica Ownership interest Consulting

CME Editor

Lance L Brown, OD, MD, Ophthalmologist, Affiliated With Freeman Hospital and St John's Hospital, Regional Eye Center, Joplin, Missouri
Disclosure: Nothing to disclose.

Chief Editor

Hampton Roy Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences
Hampton Roy Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, and Pan-American Association of Ophthalmology
Disclosure: Nothing to disclose.

 
 
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