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Retinoblastoma Treatment (PDQ®)

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Staging and Grouping Systems for Retinoblastoma

The staging of patients with retinoblastoma requires close coordination of radiologists, pediatric oncologists, and ophthalmologists. Several staging and grouping systems have been proposed for retinoblastoma.[1] Overall assessment of retinoblastoma extension is documented by staging systems; intraocular extension, which is relevant for ocular salvage, is documented by grouping systems. For treatment purposes, retinoblastoma is categorized into intraocular and extraocular disease.

Intraocular Retinoblastoma

Intraocular retinoblastoma is localized to the eye and may be confined to the retina or may extend to involve other structures such as the choroid, ciliary body, anterior chamber, and optic nerve head. Intraocular retinoblastoma, however, does not extend beyond the eye into the tissues around the eye or to other parts of the body.

Extraocular Retinoblastoma

Extraocular retinoblastoma has extended beyond the eye. It may be confined to the tissues around the eye (orbital retinoblastoma); it may have spread to the central nervous system (CNS); or, it may have spread systemically to the bone marrow or lymph nodes (metastatic retinoblastoma). Magnetic resonance imaging (MRI) can be useful in the evaluation of extrascleral and extraocular disease in children with advanced intraocular retinoblastoma. Optic nerve enhancement by MRI does not necessarily indicate involvement and cautious interpretation is needed.[2] The detection of the synthetase of ganglioside GD2 mRNA by reverse transcriptase-polymerase chain reaction in the cerebrospinal fluid at the time of diagnosis may be a marker for CNS disease.[3]

Staging Systems

AJCC staging system

Several staging systems have been proposed over the years. The AJCC clinical and pathological classifications represent a consensus opinion around which a common language is used.

Clinical classification system
Table 1. Primary Tumor (T)a
aReprinted with permission from AJCC: Retinoblastoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 562–63.
TXPrimary tumor cannot be assessed.
T0No evidence of primary tumor.
T1Tumors no more than 2/3 the volume of the eye with no vitreous or subretinal seeding.
T1aNo tumor in the either eye is greater than 3 mm in largest dimension or located closer than 1.5 mm to the optic nerve or fovea.
T1bAt least one tumor is greater than 3 mm in largest dimension or located closer than 1.5 mm to the optic nerve or fovea. No retinal detachment or subretinal fluid beyond 5 mm from above the base of the tumor.
T1cAt least one tumor is greater than 3 mm in largest dimension or located closer than 1.5 mm to the optic nerve or fovea, with retinal detachment or subretinal fluid beyond 5 mm from the base of the tumor.
T2Tumors no more than 2/3 the volume of the eye with vitreous or subretinal seeding. Can have retinal detachment.
T2aFocal vitreous and/or subretinal seeding of fine aggregates of tumor cells is present, but no large clumps or "snowballs" of tumor cells.
T2bMassive vitreous and/or subretinal seeding is present, defined as diffuse clumps or "snowballs" of tumor cells.
T3Severe intraocular disease.
T3aTumor fills more than 2/3 of the eye.
T3bOne or more complications present, which may include tumor-associated neovascular or angle closure glaucoma, tumor extension into the anterior segment, hyphema, vitreous hemorrhage, or orbital cellulitis.
T4Extraocular disease detected by imaging studies.
T4aInvasion of optic nerve.
T4bInvasion of the orbit.
T4cIntracranial extension not past chiasm.
T4dIntracranial extension past chiasm.
Table 2. Regional Lymph Nodes (N)a
aReprinted with permission from AJCC: Retinoblastoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 562–63.
NXRegional lymph nodes cannot be assessed.
N0No regional lymph node involvement.
N1Regional lymph node involvement (preauricular, cervical, submandibular).
N2Distant lymph node involvement.
Table 3. Metastasis (M)a
CNS = central nervous system; CSF = cerebrospinal fluid.
aReprinted with permission from AJCC: Retinoblastoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 562–63.
M0No metastasis.
M1Systemic metastasis.
M1aSingle lesion to sites other than CNS.
M1bMultiple lesions to sites other than CNS.
M1cPrechiasmatic CNS lesion(s).
M1dPostchiasmatic CNS lesion(s).
M1eLeptomeningeal and/or CSF involvement.
Pathologic classification system
Table 4. Primary Tumor (pT)a
aReprinted with permission from AJCC: Retinoblastoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 562–63.
pTxPrimary tumor cannot be assessed.
pT0No evidence of primary tumor.
pT1Tumor confined to eye with no optic nerve or choroidal invasion.
pT2Tumor with minimal optic nerve and/or choroidal invasion.
pT2aTumor superficially invades optic nerve head but does not extend past lamina cribrosa or tumor exhibits focal choroidal invasion.
pT2bTumor superficially invades optic nerve head but does not extend past lamina cribrosa and exhibits focal choroidal invasion.
pT3Tumor with significant optic nerve and/or choroidal invasion.
pT3aTumor invades optic nerve past lamina cribrosa but not to surgical resection line or tumor exhibits massive choroidal invasion.
pT3bTumor invades optic nerve past lamina cribrosa but not to surgical resection line and exhibits massive choroidal invasion.
pT4Tumor invades optic nerve to resection line or exhibits extra-ocular extension elsewhere.
pT4aTumor invades optic nerve to resection line but no extra-ocular extension identified.
pT4bTumor invades optic nerve to resection line and extra-ocular extension identified.
Table 5. Regional Lymph Nodes (pN)a
aReprinted with permission from AJCC: Retinoblastoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 562–63.
pNXRegional lymph nodes cannot be assessed.
pN0No regional lymph node involvement.
pN1Regional lymph node involvement (preauricular, cervical).
N2Distant lymph node involvement.
Table 6. Metastasis (pM)a
CNS = central nervous system; CSF = cerebrospinal fluid.
aReprinted with permission from AJCC: Retinoblastoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 562–63.
cM0No metastasis.
pM1Metastasis to sites other than CNS.
pM1aSingle lesion.
pM1bMultiple lesions.
pM1cCNS metastasis.
pM1dDiscrete mass(es) without leptomeningeal and/or CSF involvement.
pM1eLeptomeningeal and/or CSF involvement.

International Retinoblastoma Staging System

The more simplified International Retinoblastoma Staging System has been proposed by an international consortium of ophthalmologists and pediatric oncologists.[4] It is more widely used in the clinical setting than the AJCC staging system.

Table 7. International Retinoblastoma Staging System
StageDescription
CNS = central nervous system; CSF = cerebrospinal fluid.
Stage 0Eye has not been enucleated and no dissemination of disease (refer to the International Classification of Retinoblastoma section of this summary for more information).
Stage IEye enucleated, completely resected histologically
Stage IIEye enucleated, microscopic residual tumor
Stage IIIRegional extensiona. Overt orbital disease
  b. Preauricular or cervical lymph node extension
Stage IVMetastatic diseasea. Hematogenous metastasis (without CNS involvement)
 1. Single lesion
2. Multiple lesions
  b. CNS extension (with or without any other site of regional or metastatic disease)
 1. Prechiasmatic lesion
2. CNS mass
3. Leptomeningeal and CSF disease

Grouping Systems

Grouping systems are relevant for assessment of intraocular disease extension and are helpful predictors of ocular salvage.

Reese-Ellsworth Classification for Intraocular Tumors

Reese and Ellsworth developed a classification system for intraocular retinoblastoma that has been shown to have prognostic significance for maintenance of sight and control of local disease at a time when surgery and external-beam radiation therapy (EBRT) were the primary treatment options. However, developments in the conservative management of intraocular retinoblastoma have made the Reese-Ellsworth grouping system less predictive for eye salvage and less helpful in guiding treatment.[5] This grouping system is seldom used.

Group I: Very favorable for maintenance of sight

  1. Solitary tumor, smaller than 4 disc diameters (DD), tumor at or behind the equator.
  2. Multiple tumors, none larger than 4 DD, all tumors at or behind the equator.

Group II: Favorable for maintenance of sight

  1. Solitary tumor, 4 to 10 DD, tumor at or behind the equator.
  2. Multiple tumors, 4 to 10 DD, all tumors behind the equator.

Group III: Possible for maintenance of sight

  1. Any lesion anterior to the equator.
  2. Solitary tumor, larger than 10 DD, tumor behind the equator.

Group IV: Unfavorable for maintenance of sight

  1. Multiple tumors, some larger than 10 DD.
  2. Any lesion extending anteriorly to the ora serrata.

Group V: Very unfavorable for maintenance of sight

  1. Massive tumors involving more than one-half of the retina.
  2. Vitreous seeding.

International Classification of Retinoblastoma

The new International Classification of Retinoblastoma staging system has been developed with the goal of providing a simpler, more user-friendly classification that is more applicable to current therapies. This new system is based on the extent of tumor seeding within the vitreous cavity and subretinal space, rather than on tumor size and location, and this system seems to be a better predictor of treatment success.[5-8] This classification system may also help predict high-risk histopathology. In a study of over 500 patients with retinoblastoma, histopathologic evidence of high-risk disease was noted in 17% of Group D and 24% of Group E eyes. Such predication can be helpful in counseling parents regarding the potential need for postoperative systemic therapy.[9]

  • Group A: Small intraretinal tumors away from foveola and disc.
    • All tumors are 3 mm or smaller in greatest dimension, confined to the retina and
    • All tumors are located further than 3 mm from the foveola and 1.5 mm from the optic disc.
  • Group B: All remaining discrete tumors confined to the retina.
    • All other tumors confined to the retina not in Group A.
    • Tumor-associated subretinal fluid less than 3 mm from the tumor with no subretinal seeding.
  • Group C: Discrete local disease with minimal subretinal or vitreous seeding.
    • Tumor(s) are discrete.
    • Subretinal fluid, present or past, without seeding involving up to one-fourth of the retina.
    • Local fine vitreous seeding may be present close to discrete tumor.
    • Local subretinal seeding less than 3 mm (2 DD) from the tumor.
  • Group D: Diffuse disease with significant vitreous or subretinal seeding.
    • Tumor(s) may be massive or diffuse.
    • Subretinal fluid present or past without seeding, involving up to total retinal detachment.
    • Diffuse or massive vitreous disease may include “greasy” seeds or avascular tumor masses.
    • Diffuse subretinal seeding may include subretinal plaques or tumor nodules.
  • Group E: Presence of any one or more of the following poor prognosis features.
    • Tumor touching the lens.
    • Tumor anterior to anterior vitreous face involving ciliary body or anterior segment.
    • Diffuse infiltrating retinoblastoma.
    • Neovascular glaucoma.
    • Opaque media from hemorrhage.
    • Tumor necrosis with aseptic orbital cellulites.
    • Phthisis bulbi.

References

  1. Chantada GL, Sampor C, Bosaleh A, et al.: Comparison of staging systems for extraocular retinoblastoma: analysis of 533 patients. JAMA Ophthalmol 131 (9): 1127-34, 2013. [PUBMED Abstract]
  2. Khurana A, Eisenhut CA, Wan W, et al.: Comparison of the diagnostic value of MR imaging and ophthalmoscopy for the staging of retinoblastoma. Eur Radiol 23 (5): 1271-80, 2013. [PUBMED Abstract]
  3. Laurent VE, Sampor C, Solernou V, et al.: Detection of minimally disseminated disease in the cerebrospinal fluid of children with high-risk retinoblastoma by reverse transcriptase-polymerase chain reaction for GD2 synthase mRNA. Eur J Cancer 49 (13): 2892-9, 2013. [PUBMED Abstract]
  4. Chantada G, Doz F, Antoneli CB, et al.: A proposal for an international retinoblastoma staging system. Pediatr Blood Cancer 47 (6): 801-5, 2006. [PUBMED Abstract]
  5. Shields CL, Mashayekhi A, Au AK, et al.: The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology 113 (12): 2276-80, 2006. [PUBMED Abstract]
  6. Murphree L: Staging and grouping of retinoblastoma. In: Singh A, Damato B: Clinical Ophthalmic Oncology. Philadelphia, Pa: Saunders Elsevier, 2007, pp 422-7.
  7. Zage PE, Reitman AJ, Seshadri R, et al.: Outcomes of a two-drug chemotherapy regimen for intraocular retinoblastoma. Pediatr Blood Cancer 50 (3): 567-72, 2008. [PUBMED Abstract]
  8. Novetsky DE, Abramson DH, Kim JW, et al.: Published international classification of retinoblastoma (ICRB) definitions contain inconsistencies--an analysis of impact. Ophthalmic Genet 30 (1): 40-4, 2009. [PUBMED Abstract]
  9. Kaliki S, Shields CL, Rojanaporn D, et al.: High-risk retinoblastoma based on international classification of retinoblastoma: analysis of 519 enucleated eyes. Ophthalmology 120 (5): 997-1003, 2013. [PUBMED Abstract]
  • Updated: October 24, 2014