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RETINOBLASTOMAChapter SummaryRetinoblastoma is a childhood cancer that arises from a developing retina due to an abnormality in both alleles of the RB1 gene. The classification of retinoblastoma has evolved significantly since the change in primary treatment from radiation to chemotherapy and focal therapy. Management protocols are changing rapidly in the recent past, including new modes of delivery of chemotherapy and new protocols for treatment of extraocular disease. Most treatment protocols are awaiting large multicenter clinical trials. A robust single classification system is needed to address the outcomes of these trials. Most of the currently used classifications were based on authors’ consensus, awaiting evidence to confirm the validity of the factors chosen by their authors. This chapter has derived its feature descriptions based on the evidence from various retinoblastoma classification systems that are currently used in the management of retinoblastoma. We have defined disease progression with a robust set of criteria that can predict eye and patient survival, and designed the definitions clearly for use in prospective clinical trials for retinoblastoma in the fields of oncology and ophthalmology.Cancers staged using this staging systemRetinoblastoma:Chapter SummaryCancers staged using this staging systemRetinoblastomaCancers not staged using this staging systemThese histopathologic types of cancer…Are staged according to the classification for…And can be found in chapter…Retinocytoma (or Retinocytoma)Not found in AJCC systemRetinocytomaMedulloepitheliomaNot found in AJCC systemSUMMARY OF CHANGES FROM THE 7th EDITIONChangeDetails of ChangeLevel of EvidenceNote the heading, subheading or data element (TNM, Stage Group, prognostic factor) that contains the change.Describe changeNote which of the 8th Edition levels of evidence support this change.cT1 to T4Changes to the definitions of cT1 to cT4 based on evidence from the International Retinoblastoma Classification Survey, the European Retinoblastoma Imaging Collaboration and the International Retinoblastoma Staging Working GroupLevel I EvidenceSuffix ‘g’ to indicate germline diseaseAddition of a new suffix ‘g’ to indicate the possibility of germline disease.Level I EvidencepT1 to T4Changes to the definition of pT1 to pT4 based on evidence from the Children’s Oncology Group, the International Retinoblastoma Classification Survey and the International Retinoblastoma Staging Working GroupLevel I EvidenceN1Changes to the definition of pT1 to pT4 based on evidence from the International Retinoblastoma Staging Working GroupLevel II EvidenceM1Changes to the definition of pT1 to pT4 based on evidence from the International Retinoblastoma Staging Working GroupLevel II EvidenceChangeDetails of ChangeLevel of EvidenceNote the heading, subheading or data element (TNM, Stage Group, prognostic factor) that contains the change.Describe changeNote which of the 8th Edition levels of evidence support this change.ICD-O-3 TOPOGRAPHY CODESCodeDescriptionC69.2RetinaC69.9Eye, NOSICD-O-3 Histology Code Ranges9510–9513/39510/3Retinoblastoma, NOS9511/3Retinoblastoma, differentiated9512/3Retinoblastoma, undifferentiated9513/3Retinoblastoma, diffuseINTRODUCTIONRetinoblastoma is a rare and unique cancer arising in the immature retina. It is the most common intraocular cancer, with India and China having the most new cases per year because of their population growth rate. ADDIN EN.CITE <EndNote><Cite><Author>Dimaras</Author><Year>2015</Year><RecNum>24124</RecNum><DisplayText>[1]</DisplayText><record><rec-number>24124</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1443777748">24124</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dimaras, Helen</author><author>Corson, Timothy W.</author><author>Cobrinik, David</author><author>White, Abby</author><author>Zhao, Junyang</author><author>Munier, Francis L.</author><author>Abramson, David H.</author><author>Shields, Carol L.</author><author>Chantada, Guillermo L.</author><author>Njuguna, Festus</author><author>Gallie, Brenda L.</author></authors></contributors><titles><title>Retinoblastoma</title><secondary-title>Nature Reviews Disease Primers</secondary-title></titles><periodical><full-title>Nature Reviews Disease Primers</full-title></periodical><pages>15021</pages><dates><year>2015</year><pub-dates><date>08/27/online</date></pub-dates></dates><publisher>Macmillan Publishers Limited</publisher><work-type>Primer</work-type><urls><related-urls><url>;[1] Retinoblastoma tumors are caused by the inactivation of both the alleles of the RB1 gene, a tumor suppressor located at chromosome 13q14.2. ADDIN EN.CITE <EndNote><Cite><Author>Friend</Author><Year>1986</Year><RecNum>24139</RecNum><DisplayText>[2]</DisplayText><record><rec-number>24139</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1443777749">24139</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Friend, S. H.</author><author>Bernards, R.</author><author>Rogelj, S.</author><author>Weinberg, R. A.</author><author>Rapaport, J. M.</author><author>Albert, D. M.</author><author>Dryja, T. P.</author></authors></contributors><titles><title>A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma</title><secondary-title>Nature</secondary-title></titles><periodical><full-title>Nature</full-title><abbr-1>Nature</abbr-1></periodical><pages>643-6</pages><volume>323</volume><number>6089</number><keywords><keyword>Chromosome Deletion</keyword><keyword>Chromosome Mapping</keyword><keyword>*Chromosomes, Human, Pair 13</keyword><keyword>Cloning, Molecular</keyword><keyword>DNA/genetics</keyword><keyword>DNA, Neoplasm/genetics</keyword><keyword>Genes, Recessive</keyword><keyword>Human</keyword><keyword>Osteosarcoma/*genetics</keyword><keyword>Polymorphism, Restriction Fragment Length</keyword><keyword>Retina/physiology</keyword><keyword>Retinoblastoma/*genetics</keyword><keyword>Support, Non-U.S. Gov&apos;t</keyword><keyword>Support, U.S. Gov&apos;t, P.H.S.</keyword></keywords><dates><year>1986</year><pub-dates><date>Oct 16-22</date></pub-dates></dates><accession-num>2877398</accession-num><urls><related-urls><url>;[2] Both copies of the RB1 gene are impaired in the tumor, while one copy of the gene is mutant in blood of patients with a germline predisposition to the tumor.This is a cancer from which survival for all affected children is within reach. Children that present early and are treated early demonstrate a better outcome.(Ref: Finger PT, Harbour JW, Karcioglu Z, Survey of Ophthalmology 47:1-16, 2002) The tumors tend toRetinoblastoma remains intraocular through a good period of timeinitially after the most common presenting sign (a white glow from the tumor through the pupil of the eye, termed ‘leukocoria’).leukocoria). Various social and cultural factors however may lead to a delay in diagnosis and impact survival of children, and these factors are complicated to address in clinical classification systems.(Ref: Finger PT, Harbour JW, Karcioglu Z, Survey of Ophthalmology 47:1-16, 2002) If timely diagnosis (the general public and health workers are aware) and treatment is prompt (depending on access to expert care), eye and life salvage are achievable. ADDIN EN.CITE <EndNote><Cite><Author>Dimaras</Author><Year>2015</Year><RecNum>24124</RecNum><DisplayText>[1]</DisplayText><record><rec-number>24124</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1443777748">24124</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dimaras, Helen</author><author>Corson, Timothy W.</author><author>Cobrinik, David</author><author>White, Abby</author><author>Zhao, Junyang</author><author>Munier, Francis L.</author><author>Abramson, David H.</author><author>Shields, Carol L.</author><author>Chantada, Guillermo L.</author><author>Njuguna, Festus</author><author>Gallie, Brenda L.</author></authors></contributors><titles><title>Retinoblastoma</title><secondary-title>Nature Reviews Disease Primers</secondary-title></titles><periodical><full-title>Nature Reviews Disease Primers</full-title></periodical><pages>15021</pages><dates><year>2015</year><pub-dates><date>08/27/online</date></pub-dates></dates><publisher>Macmillan Publishers Limited</publisher><work-type>Primer</work-type><urls><related-urls><url>;[1] Therefore, cancer staging for retinoblastoma must include the features of extent of intraocular tumor that predicts likelihood to salvage the eye (previously called “Group”) and risk for extension from the eye in Tumor (T), in addition to the standard Node (N) and Metastasis (M) fields of TNM Staging. Each eye will have different extent of intraocular tumor, that will be scored separately, but for overall staging, the stage of the worst eye will be counted in TNM Stage.Research and clinical care in retinoblastoma have lagged behind other pediatric cancers, in part because multiple intraocular staging systems have been used worldwide. The first staging system for intraocular retinoblastoma predicted success to salvage an eye with external beam radiation. ADDIN EN.CITE <EndNote><Cite><Author>Reese</Author><Year>1963</Year><RecNum>906</RecNum><DisplayText>[3]</DisplayText><record><rec-number>906</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="0">906</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Reese, A. B.</author><author>Ellsworth, R. M.</author></authors></contributors><titles><title>The evaluation and current concept of retinoblastoma therapy.</title><secondary-title>Trans Am Acad Ophthalmol-Otolaryngol</secondary-title></titles><periodical><full-title>Trans Am Acad Ophthalmol-Otolaryngol</full-title></periodical><pages>164-172</pages><keywords><keyword>RB, treatment</keyword></keywords><dates><year>1963</year></dates><urls></urls></record></Cite></EndNote>[3] External beam radiotherapy is no longer used for primary retinoblastoma. In 2005 the International Intraocular Retinoblastoma Classification was published ADDIN EN.CITE <EndNote><Cite><Author>Murphree</Author><Year>2005</Year><RecNum>22178</RecNum><DisplayText>[4]</DisplayText><record><rec-number>22178</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1428421047">22178</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Murphree, A. L.</author></authors></contributors><titles><title>Intraocular retinoblastoma: the case for a new group classification</title><secondary-title>Ophthalmology Clinics of North America</secondary-title></titles><periodical><full-title>Ophthalmol Clin North Am</full-title><abbr-1>Ophthalmology clinics of North America</abbr-1></periodical><pages>41-53</pages><volume>18</volume><dates><year>2005</year></dates><urls></urls></record></Cite></EndNote>[4] and remains the most accurate predictor of eye salvage and high risk disease (See summary of Survey, below). However, a modification published in 2006 ADDIN EN.CITE <EndNote><Cite><Author>Shields</Author><Year>2006</Year><RecNum>11700</RecNum><DisplayText>[5]</DisplayText><record><rec-number>11700</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1246419839">11700</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shields, C. L.</author><author>Shields, J. A.</author></authors></contributors><auth-address>Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. carol.shields@</auth-address><titles><title>Basic understanding of current classification and management of retinoblastoma</title><secondary-title>Curr Opin Ophthalmol</secondary-title></titles><periodical><full-title>Curr Opin Ophthalmol</full-title></periodical><pages>228-34</pages><volume>17</volume><number>3</number><edition>2006/06/24</edition><keywords><keyword>Antineoplastic Agents/therapeutic use</keyword><keyword>Brachytherapy</keyword><keyword>Cryotherapy</keyword><keyword>Eye Enucleation</keyword><keyword>Humans</keyword><keyword>Laser Therapy</keyword><keyword>Retinal Neoplasms/*classification/pathology/*therapy</keyword><keyword>Retinoblastoma/*classification/pathology/*therapy</keyword></keywords><dates><year>2006</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1040-8738 (Print)</isbn><accession-num>16794434</accession-num><urls><related-urls><url> [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>[5] has been widely used without awareness of the significant differences that change the most important features predicting risk. ADDIN EN.CITE <EndNote><Cite><Author>Dimaras</Author><Year>2015</Year><RecNum>24124</RecNum><DisplayText>[1]</DisplayText><record><rec-number>24124</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1443777748">24124</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dimaras, Helen</author><author>Corson, Timothy W.</author><author>Cobrinik, David</author><author>White, Abby</author><author>Zhao, Junyang</author><author>Munier, Francis L.</author><author>Abramson, David H.</author><author>Shields, Carol L.</author><author>Chantada, Guillermo L.</author><author>Njuguna, Festus</author><author>Gallie, Brenda L.</author></authors></contributors><titles><title>Retinoblastoma</title><secondary-title>Nature Reviews Disease Primers</secondary-title></titles><periodical><full-title>Nature Reviews Disease Primers</full-title></periodical><pages>15021</pages><dates><year>2015</year><pub-dates><date>08/27/online</date></pub-dates></dates><publisher>Macmillan Publishers Limited</publisher><work-type>Primer</work-type><urls><related-urls><url>;[1] Extraocular retinoblastoma staging was published in 2006 ADDIN EN.CITE <EndNote><Cite><Author>Chantada</Author><Year>2006</Year><RecNum>14007</RecNum><DisplayText>[6]</DisplayText><record><rec-number>14007</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1275245296">14007</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chantada, G.</author><author>Doz, F.</author><author>Antoneli, C. B.</author><author>Grundy, R.</author><author>Clare Stannard, F. F.</author><author>Dunkel, I. J.</author><author>Grabowski, E.</author><author>Leal-Leal, C.</author><author>Rodriguez-Galindo, C.</author><author>Schvartzman, E.</author><author>Popovic, M. B.</author><author>Kremens, B.</author><author>Meadows, A. T.</author><author>Zucker, J. M.</author></authors></contributors><auth-address>Department of Hematology-Oncology, Hospital JP Garrahan, Buenos Aires, Argentina. gchantada@.ar</auth-address><titles><title>A proposal for an international retinoblastoma staging system</title><secondary-title>Pediatr Blood Cancer</secondary-title></titles><periodical><full-title>Pediatr Blood Cancer</full-title></periodical><pages>801-5</pages><volume>47</volume><number>6</number><edition>2005/12/17</edition><keywords><keyword>Humans</keyword><keyword>Neoplasm Staging/*standards</keyword><keyword>Retinal Neoplasms/*classification/*diagnosis/pathology</keyword><keyword>Retinoblastoma/*classification/*diagnosis/pathology</keyword></keywords><dates><year>2006</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1545-5009 (Print)&#xD;1545-5009 (Linking)</isbn><accession-num>16358310</accession-num><urls><related-urls><url>;[6] and in the 7th edition of AJCC Staging for Retinoblastoma. The 8th edition stages each eye separately, with the worst eye contributing to the overall T Stage. Data to support the changes in the 8th edition is referenced in published literature and the International Multicenter Classification And Outcomes Survey (See summary of Survey, below). Wide adoption of the 8th edition is an opportunity to replace the present confusion in reporting the outcome of retinoblastoma with a complete intraocular and extraocular staging system, on which high quality multicenter studies can progress to achieve the goal of zero deaths from retinoblastoma.ANATOMYPrimary SiteThe retina is composed of neurons and glial cells. The precursors of the neuronal elements give rise to a retinoblastoma, whereas the glial cells give rise to an astrocytoma. A membrane called the internal limiting membrane separates the retina from the vitreous cavity internally. Externally, it is separated from the choroid by the retinal pigment epithelium (RPE) and Bruch’s membrane, acting as a natural barrier to extension of retinal tumors into the choroid. The continuation of the retina with the optic nerve allows direct extension of retinoblastomas into the optic nerve and then to the subarachnoid space. Because the retina has no lymphatics, spread of retinal tumors is either by direct extension into adjacent structures (uvea, sclera, optic nerve, anterior chamber, orbit and brain) or by distant metastasis through hematogenous routes. Local extension can result in a mass pushing the eye out (proptosis) and/or protruding between the lids and/or soft tissue involvement of the face. Posterior extension results in retinoblastoma extending into the orbit and/or through the optic nerve and into the brain.Regional Lymph NodesThere are no known intraocular lymphatics; this category of staging applies only to extrascleral extraocular extension involving ocular adnexal tissues with lymphatic supply (e.g. conjunctiva).. The regional lymph nodes that could be involved with extraocular retinoblastoma are preauricular (parotid), submandibular and cervical.Metastatic SitesAny retinoblastoma outside the eyeball predicts poor survival. Local extension can result in a mass pushing the eye out (proptosis) and/or protruding between the lids and/or soft tissue involvement of the face. Posterior extension results in retinoblastoma extending into the orbit and/or through the optic nerve and into the brain. Retinoblastomas also metastasize through the hematogenous route to various sites, most commonly to the bone marrow and bone. The tumor might spread from within the optic nerve or subarachnoid space into the intracranial space. The prognosis for central nervous system involvement of retinoblastoma is currently worse than spread to bone marrow, since the blood-brain barrier may inhibit systemic chemotherapy from effectively reaching intracranial tumor cells.CLINICAL DEFINITIONS OF TNM (cTNM)Definition of Primary Tumor (T)cT CategorycT CriteriaEach eye is scored for cT criteria and, in the case of bilateral tumors, the overall staging is based on the most advanced eye.cT0No evidence of intraocular tumorcT1T1: Intra-retinal tumor(s) with sub-retinal fluid not more than 5 mm from the base of any tumor.T1a – Tumors smaller than 3 mm and further than 1.5 mm from the disc and foveaT1b – Tumors larger than 3 mm or closer than 1.5 mm from the disc and foveacT2T2: Intraocular tumor(s) with retinal detachment, vitreous seeding or sub-retinal seedingT2a – Sub-retinal fluid more than 5 mm of the base of any tumorT2b – Tumors with vitreous seeding and/or sub-retinal seedingcT3Advanced intraocular tumor(s)T3a – Hyphema and/or Massive Vitreous HemorrhageT3b – Aseptic Orbital Cellulitis, Phthisis or Pre-phthisisT3c – Intraocular pressure greater than 25 mmHg and/or buphthalmosT3d – Tumor Anterior to Anterior Vitreous Face, and/or Tumor Involvement of Ciliary Body, Iris or Anterior ChambercT4Extraocular tumor(s) involving the orbit, including the optic nerve.T4a – Evidence of optic nerve and/or orbital tissues involvement on contrast enhanced radiological imaging without a clinically obvious mass or proptosis.T4b – Extraocular tumor is clinically evident with proptosis and/or an orbital mass.Suffix ‘g’ for germline disease.The suffix of ‘g’ indicates germline disease: bilateral retinoblastoma, primary intracranial neuro-ectodermal tumor (ie; trilateral retinoblastoma), family history, or molecular evidence of constitutional RB1 mutation.Example: One eye cT1a, other eye cT2b, Overall Stage cT2b(g)Definition of Regional Lymph Node (N)cN CategorycN CriteriacN0No palpable lymph nodecN1Palpable and/or imaging evidence of pre-auricular, submandibular, and cervical lymph node involvement.Definition of Distant Metastasis (M)cM CategorycM CriteriacM0No signs or symptoms of intracranial or distant metastasiscM1aTumor(s) involving any distant site on clinical or radiological tests (such as bone, bone marrow, etc.)cM1bTumor involving the central nervous system on radiological imagingPATHOLOGICAL DEFINITIONS OF TNM (pTNM)Definition of Primary Tumor (T)pT CategorypT CriteriapT0No evidence of intraocular tumorpT1Intraocular tumor(s) with minimalor without isolated partial thickness focal involvement of the choroid (less than 3mm in its largest diameter),involvement of choroid and with or without isolated pre- or intra-laminar minimal involvement of the optic nerve head.pT2Intraocular tumor(s) with some local invasion of special sites:pT2a– Concomitant focal choroidal invasion and pre- or intra-laminar involvement of the optic nerve head.pT2b – Tumor invasion of stroma of iris, and/or trabecular meshwork, and/or Schlemm’s canal.pT3Intraocular tumor(s) with significant local invasion:pT3a – Massive choroidal invasion alone (more than 3 mm) in the largest diameter), or full thickness involvement of the choroid or multiple foci of focal choroidal involvement cumulatively amounting to more than 3mmpT3b – Retro-laminar invasion of optic nerve head, not involving the transected end of the optic nervepT3c– Any partial-thickness involvement of the sclera (without not reaching the outer third).pT4Pathological evidence of extraocular tumor, such as at the transected end of the optic nerve, tumor in the meningeal spaces around the optic nerve, full thickness invasion of sclera or episclera into adjacent adipose tissue, extraocular muscle, bone, conjunctiva or eyelids.Prefix ‘y’ The prefix ‘y’ will indicate histopathologic changes that are present after previous therapy, especially chemotherapy.Definition of Regional Lymph Node (N)pN CategorypN CriteriapN0No pathological evidence of lymph node involvementpN1Histopathology or biopsy evidenced lymph node involvement in the pre-auricular regionDefinition of Distant Metastasis (M)pM CategorypM CriteriapM0No pathological distant metastasispM1aPathological evidence of tumor at any distant site (such as bone marrow, liver, or others)pM1bPathological evidence of tumor the cerebrospinal fluidRULES FOR CLASSIFICATIONClinical ClassificationThe most common signs of retinoblastoma at presentation are a white pupil (leukocoria) and strabismus. ADDIN EN.CITE <EndNote><Cite><Author>Abramson</Author><Year>1998</Year><RecNum>8122</RecNum><DisplayText>[7]</DisplayText><record><rec-number>8122</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="0">8122</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Abramson, D. H.</author><author>Frank, C. M.</author><author>Susman, M.</author><author>Whalen, M. P.</author><author>Dunkel, I. J.</author><author>Boyd, N. W. rd</author></authors></contributors><titles><title>Presenting signs of retinoblastoma</title><secondary-title>J Pediatr</secondary-title></titles><periodical><full-title>J Pediatr</full-title></periodical><pages>505-8</pages><volume>132</volume><number>3 Pt 1</number><keywords><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Female</keyword><keyword>Human</keyword><keyword>Infant</keyword><keyword>Male</keyword><keyword>Retinal Neoplasms/*diagnosis/genetics/physiopathology</keyword><keyword>Retinoblastoma/*diagnosis/genetics/physiopathology</keyword><keyword>Retrospective Studies</keyword></keywords><dates><year>1998</year></dates><urls><related-urls><url>;[7] Small tumors appear as creamy white lesions within the retina. Some very small tumors that are not visible on clinical examination or photography may be detected on imaging the retina with optical coherence tomography, usually in children predicted to be predisposed to retinoblastoma because of a family history of retinoblastoma. Calcification is pathognomonic of retinoblastoma, and contributes to the diagnosis when detected by ultrasonography or radiological imaging. Tumors may be associated with an exudative retinal detachment, allowing the tumor to be described as having an exophytic growth pattern.Retinoblastoma tumors progress to “seeds” that disseminate out of the retina into an exudative retinal detachment. Alternately, tumors breach the inner limiting membrane of the retina to access the vitreous. The morphology of seeds in the vitreous has been described as dust, clouds or pearl-like spheres.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GcmFuY2lzPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48

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ADDIN EN.CITE.DATA [10] The signs of dangerously advanced disease include glaucoma, orbital cellulitis, intraocular hemorrhage, enlargement of the eye and proptosis. Orbital and central nervous system (CNS) involvement may be suspected in clinical examination, that requires imaging confirmation. Pre-treatment brain and orbit imaging is important in all children with cT3 disease.Unique to the 8th edition TNM for retinoblastoma is the indication of germline predisposition, which incurs a high risk for second primary tumors (such as osteosarcoma, melanoma) and impacts overall patient survival.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWNDYXJ0aHk8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFy

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ADDIN EN.CITE.DATA [11] The impact of germline predisposition supports avoidance of unnecessary exposure to diagnostic or therapeutic radiation (including X-rays or computerized tomography scans). We include in the 8th edition a suffix ‘g’ to alert to the evidence of germline RB1 mutation, such as bilateral retinoblastoma, primary intracranial neuro-ectodermal tumor (ie; trilateral retinoblastoma), family history, or molecular test revealing a constitutional RB1 mutation. In a unilateral affected eye, multiple tumors are not good evidence of a germline RB1 mutation, since they can not be reliably distinguished from tumor seeded in the sub-retinal space or vitreous from the primary tumor. ADDIN EN.CITE <EndNote><Cite><Author>Lohmann</Author><Year>2013</Year><RecNum>10173</RecNum><DisplayText>[12]</DisplayText><record><rec-number>10173</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="0">10173</key></foreign-keys><ref-type name="Book Section">5</ref-type><contributors><authors><author>Lohmann, D.</author><author>Gallie, B. L.</author></authors><secondary-authors><author>Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, and Stephens K. </author></secondary-authors></contributors><titles><title>Retinoblastoma</title><secondary-title>GeneReviews? [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2013. Available at : 20301625</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%"></style></url></related-urls></urls></record></Cite></EndNote>[12] In order to define the full clinical extent of disease, all children suspected to have retinoblastoma require a complete clinical examination under anesthesia (EUA). After ascertaining the intraocular pressure in each eye and visualizing the anterior segment (with a hand held slit lamp or operating microscope if available), a detailed fundus examination is performed with the indirect ophthalmoscope with scleral indentation to completely visualize the retina. The pupil requires to be well dilated for a complete examination. The fundus findings are documented using detailed fundus drawings and wide-field fundus photography. Fundus fluorescein angiography is useful to detect subtle iris neovascularization.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaW08L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA [13] Optical coherence tomography (OCT) detects small tumors in the inner nuclear layer of the retina before they are visible to ophthalmoscopy or photography. ADDIN EN.CITE <EndNote><Cite><Author>Rootman</Author><Year>2013</Year><RecNum>549</RecNum><DisplayText>[14]</DisplayText><record><rec-number>549</rec-number><foreign-keys><key app="EN" db-id="tpzsxwxtit9a0qepwxcxpp9wxerd0f50srst" timestamp="1380731466">549</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rootman, Daniel Benson</author><author>Gonzalez, Efren</author><author>Mallipatna, Ashwin</author><author>VandenHoven, Cynthia</author><author>Hampton, Lindsay</author><author>Dimaras, Helen</author><author>Chan, Helen SL</author><author>Gallie, Brenda L</author><author>Heon, Elise</author></authors></contributors><titles><title>Hand-held high-resolution spectral domain optical coherence tomography in retinoblastoma: clinical and morphologic considerations</title><secondary-title>British Journal of Ophthalmology</secondary-title></titles><periodical><full-title>British Journal of Ophthalmology</full-title></periodical><pages>59-65</pages><volume>97</volume><number>1</number><dates><year>2013</year></dates><isbn>1468-2079</isbn><urls></urls></record></Cite></EndNote>[14] This is particularly relevant to children predisposed to retinoblastoma by an RB1 germline mutation, such that treatment of these “invisible” tumors can be initiated very early. OCT is also useful to evaluate tumors abutting the optic nerve margin, differentiating tumors that involve the optic nerve. ADDIN EN.CITE <EndNote><Cite><Author>Mallipatna</Author><Year>2015</Year><RecNum>3337</RecNum><DisplayText>[15]</DisplayText><record><rec-number>3337</rec-number><foreign-keys><key app="EN" db-id="tpzsxwxtit9a0qepwxcxpp9wxerd0f50srst" timestamp="1445478027">3337</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mallipatna, A.</author><author>Vinekar, A.</author><author>Jayadev, C.</author><author>Dabir, S.</author><author>Sivakumar, M.</author><author>Krishnan, N.</author><author>Mehta, P.</author><author>Berendschot, T.</author><author>Yadav, N. K.</author></authors></contributors><auth-address>Department of Pediatric Ophthalmology, Narayana Nethralaya Postgraduate Institute of Ophthalmology, Bengaluru, Karnataka, India.</auth-address><titles><title>The use of handheld spectral domain optical coherence tomography in pediatric ophthalmology practice: Our experience of 975 infants and children</title><secondary-title>Indian J Ophthalmol</secondary-title><alt-title>Indian journal of ophthalmology</alt-title></titles><periodical><full-title>Indian J Ophthalmol</full-title></periodical><pages>586-93</pages><volume>63</volume><number>7</number><edition>2015/10/16</edition><dates><year>2015</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0301-4738</isbn><accession-num>26458476</accession-num><urls><related-urls><url>;[15] The authors acknowledge that while wide-field fundus photography, fluorescein angiography and optical coherence tomography may add value to our clinical assessment and potentially improve clinical decisions and patient survival, they are not considered essential to tumor staging.ImagingThe diagnosis of retinoblastoma relies on a thorough clinical examination. In differentiating retinoblastoma from other diagnoses (such as Coat’s disease), ultrasound can demonstrate the near-pathognomonic calcification of retinoblastoma. Imaging tools are especially useful in diagnosing retinoblastoma with atypical presentations, such as children presenting with buphthalmos, hyphema or orbital cellulitis. These investigations are also required to determine the full extent of retinoblastoma, including optic nerve and intracranial involvement. They also aid detection of primary neuroectodermal tumors, which often arising in the pineal gland (pinealoblastoma) or the para-sellar region. Computerized tomography (CT) scan is no longer recommended for children with a clinical diagnosis retinoblastoma, because the exposure to radiation increases the risk of second primary cancers.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWNDYXJ0aHk8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFy

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ADDIN EN.CITE.DATA [11, 16] Ocular Ultrasonography:A heterogeneous hyper echoic intraocular mass arising from the retina, with highly reflective shadowing suggesting calcification is pathognomonic of retinoblastoma. ADDIN EN.CITE <EndNote><Cite><Author>Marr</Author><Year>2015</Year><RecNum>24106</RecNum><DisplayText>[17]</DisplayText><record><rec-number>24106</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1443762572">24106</key></foreign-keys><ref-type name="Book Section">5</ref-type><contributors><authors><author>Marr, B.P.</author><author>Singh, A.D. </author></authors></contributors><titles><title>Retinoblastoma: Evaluation and Diagnosis</title><secondary-title>Clinical Ophthalmic Oncology</secondary-title></titles><pages>1-11</pages><dates><year>2015</year></dates><publisher>Springer</publisher><urls></urls></record></Cite></EndNote>[17] Ultrasound can determine extent and size of larger tumors, and relationship to the optic nerve. In order to determine optic nerve enlargement, the retrobulbar optic nerve size can be compared to an uninvolved eye. Ultrasound Biomicroscopy biomicroscopy (UBM) can ascertain the anterior extent of the tumor, in relation to the ciliary body, anterior hyaloid face, and posterior surface of the iris. Tumor involvement in the ciliary body may be described as epi-ciliary or intra-ciliary depending on whether the stroma is involved or not.Magnetic Resonance Imaging and Computerized Tomography: Radiological imaging assists to determine of the tumor extent within the orbit and CNS. On MRI, retinoblastoma tumors appear as an intraocular hyper-intense mass in T1-weighted images, and a hypo-intense mass in T2-weighted images. The use of a surface coil can enhance the resolution of orbital sections and gadolinium contrast demonstrates optic nerve involvement.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5kZSBKb25nPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48

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ADDIN EN.CITE.DATA [18-21] Palpable preauricular lymph nodes can be evaluated by imaging the submandibular and cervical lymph nodes to determine the full extent of lymph node involvement. MRI is more sensitive than CT scan to detect extraocular involvement in eyes with retinoblastoma. ADDIN EN.CITE <EndNote><Cite><Author>Schueler</Author><Year>2003</Year><RecNum>9712</RecNum><DisplayText>[22]</DisplayText><record><rec-number>9712</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="0">9712</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Schueler, A. O.</author><author>Hosten, N.</author><author>Bechrakis, N. E.</author><author>Lemke, A. J.</author><author>Foerster, P.</author><author>Felix, R.</author><author>Foerster, M. H.</author><author>Bornfeld, N.</author></authors></contributors><auth-address>Department of Ophthalmology, Universitatsklinikum Essen, Hufelandstrasse 55, 45122 Essen, Germany. andreas.schueler@uni-essen.de</auth-address><titles><title>High resolution magnetic resonance imaging of retinoblastoma</title><secondary-title>Br J Ophthalmol</secondary-title></titles><periodical><full-title>Br J Ophthalmol</full-title></periodical><pages>330-5</pages><volume>87</volume><number>3</number><keywords><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Choroid Neoplasms/diagnosis/pathology</keyword><keyword>Human</keyword><keyword>Infant</keyword><keyword>Magnetic Resonance Imaging/*methods</keyword><keyword>Neoplasm Invasiveness</keyword><keyword>Optic Disk/pathology</keyword><keyword>Optic Nerve/pathology</keyword><keyword>Optic Nerve Neoplasms/diagnosis/pathology</keyword><keyword>Retinal Neoplasms/*diagnosis/pathology</keyword><keyword>Retinoblastoma/*diagnosis/pathology</keyword><keyword>Sclera/pathology</keyword><keyword>Vitreous Body/pathology</keyword></keywords><dates><year>2003</year><pub-dates><date>Mar</date></pub-dates></dates><accession-num>12598449</accession-num><urls><related-urls><url>;[22]Suspected involvement of the optic nerve head in radiological investigations does not always correlate with histopathologic features after enucleation.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaWxzb248L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA [23] The true definition of radiological “high-risk” factors is debated; achieving consensus is further complicated by wide variations in technologies. Radiological features suggesting optic nerve involvement on MRI acquired with surface coils include contrast enhancement of the optic nerve head and asymmetrical optic nerve diameters in the retrobulbar space.Pathologic ClassificationHistopathological features of retinoblastoma are small round cells staining blue on hematoxylin and eosin. The cells are sometimes arranged in rings (rosettes) in regions that are well differentiated. Flexner-Wintersteiner rosettes (typical for retinoblastoma) and Homer-Wright rosettes (characteristic of neuroectodermal tumors) both occur. Tumors with many Flexner-Wintersteiner rosettes are graded as moderately differentiated. Some tumors show photoreceptor-like differentiation (fleurettes) or neuronal differentiation without mitoses or apoptosis that are classified as a premalignant lesion, retinoma.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYWxsaWU8L0F1dGhvcj48WWVhcj4xOTgyPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA [24, 25] A tumor with both retinoma and retinoblastoma elements is graded as well differentiated. Tumors that show no fleurettes or rosettes are graded as poorly differentiated. The nuclei of poorly differentiated tumors may show anaplasia, ADDIN EN.CITE <EndNote><Cite><Author>Mendoza</Author><Year>2015</Year><RecNum>22323</RecNum><DisplayText>[26]</DisplayText><record><rec-number>22323</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1430413532">22323</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mendoza, P. R.</author><author>Specht, C. S.</author><author>Hubbard, G. B.</author><author>Wells, J. R.</author><author>Lynn, M. J.</author><author>Zhang, Q.</author><author>Kong, J.</author><author>Grossniklaus, H. E.</author></authors></contributors><auth-address>Department of Ophthalmology, Emory University, Atlanta, Georgia.&#xD;Department of Pathology, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania.&#xD;Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, Georgia.&#xD;Department of Biomedical Informatics, Emory University, Atlanta, Georgia.&#xD;Department of Ophthalmology, Emory University, Atlanta, Georgia. Electronic address: ophtheg@emory.edu.</auth-address><titles><title>Histopathologic grading of anaplasia in retinoblastoma</title><secondary-title>Am J Ophthalmol</secondary-title></titles><periodical><full-title>Am J Ophthalmol</full-title><abbr-1>American journal of ophthalmology</abbr-1></periodical><pages>764-776 e3</pages><volume>159</volume><number>4</number><dates><year>2015</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1879-1891 (Electronic)&#xD;0002-9394 (Linking)</isbn><accession-num>25528954</accession-num><urls><related-urls><url>;[26] or may be round with prominent multiple nucleoli indicative of MYC-N amplification and normal RB1 alleles.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SdXNobG93PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

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ADDIN EN.CITE.DATA [29]Alternatively, the tumor might spread via the lamina cribrosa into the optic nerve or subarachnoid space, accessing cerebrospinal fluid and the central nervous system. Invasion into the sclera may follow massive choroidal invasion directly or through emissary channels. ADDIN EN.CITE <EndNote><Cite><Author>Chantada</Author><Year>2013</Year><RecNum>18862</RecNum><DisplayText>[30]</DisplayText><record><rec-number>18862</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1364496460">18862</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chantada, G.</author><author>Luna-Fineman, S.</author><author>Sitorus, R. S.</author><author>Kruger, M.</author><author>Israels, T.</author><author>Leal-Leal, C.</author><author>Bakhshi, S.</author><author>Qaddoumi, I.</author><author>Abramson, D. H.</author><author>Doz, F.</author></authors></contributors><auth-address>Hospital de Pediatria SAMIC Prof Dr Juan P Garrahan, Buenos Aires, Argentina; St Jude Children&apos;s Research Hospital, Memphis, Tennessee. gchantada@.</auth-address><titles><title>SIOP-PODC recommendations for graduated-intensity treatment of retinoblastoma in developing countries</title><secondary-title>Pediatr Blood Cancer</secondary-title><alt-title>Pediatric blood &amp; cancer</alt-title></titles><periodical><full-title>Pediatr Blood Cancer</full-title></periodical><pages>719-27</pages><volume>60</volume><number>5</number><edition>2013/01/22</edition><dates><year>2013</year><pub-dates><date>May</date></pub-dates></dates><isbn>1545-5017 (Electronic)&#xD;1545-5009 (Linking)</isbn><accession-num>23335388</accession-num><urls><related-urls><url>;[30] Tumor spreading through sclera can invade into the orbit and result in systemic and pre-auricular lymph node metastasis.After enucleation of the eye, pathologic staging provides information supplemental to the clinical staging. The entire eye should be submitted for histopathologic examination. Although pathology provides histologic verification of retinoblastoma, a clinical diagnosis alone is considered adequate to initiate treatment. Clinicians and pathologists should be warned that pre-enucleation chemotherapy greatly alters the histopathological findings, and may significantly downstage disease severity. ADDIN EN.CITE <EndNote><Cite><Author>Zhao</Author><Year>2011</Year><RecNum>15639</RecNum><DisplayText>[31]</DisplayText><record><rec-number>15639</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1302183192">15639</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Zhao, J.</author><author>Dimaras, H.</author><author>Massey, C.</author><author>Xu, X.</author><author>Huang, D.</author><author>Li, B.</author><author>Chan, H. S.</author><author>Gallie, B. L.</author></authors></contributors><auth-address>Beijing Tongren Eye Centre, Beijing Tongren Hospital, Capital Medical University, Beijing, China.</auth-address><titles><title>Pre-enucleation chemotherapy for eyes severely affected by retinoblastoma masks risk of tumor extension and increases death from metastasis</title><secondary-title>Journal of clinical oncology : official journal of the American Society of Clinical Oncology</secondary-title><alt-title>J Clin Oncol</alt-title></titles><alt-periodical><full-title>J Clin Oncol</full-title></alt-periodical><pages>845-51</pages><volume>29</volume><number>7</number><edition>2011/02/02</edition><dates><year>2011</year><pub-dates><date>Mar 1</date></pub-dates></dates><isbn>1527-7755 (Electronic)&#xD;0732-183X (Linking)</isbn><accession-num>21282531</accession-num><work-type>Research Support, Non-U.S. Gov&apos;t</work-type><urls><related-urls><url>;[31] In order to make that distinction, a prefix ‘y’ should be used indicate histopathologic changes that are present after previous therapy, especially chemotherapy. Processing the Enucleated Retinoblastoma Eye: Processing with Tumor Sampling:PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYXN0cmU8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA [29] Fresh tumor material may be collected from the enucleated eye for genetic testing (and research) prior to formalin fixation. Identification of RB1 mutations and other genetic studies in tumor tissue are difficult with formalin fixed tissue. The enucleated eye is examined in detail, looking for and inking areas that might be of pathological interest, such as areas of scleral thinning or obvious extraocular tumor. The emissary veins are marked to ensure that sections are obtained through that region. The optic nerve and its sheath are gently rolled between the thumb and index finger, looking for palpable lumps or adhesions which will require special attention during sectioning. Prior to opening the eye to collect the fresh tumor sample, the optic nerve is removed to prevent artefactual contamination of the optic nerve with tumor cells. The doctor is advised to first ink the surgical margin of the optic nerve, then cut the optic nerve from the sclera with a sharp razor about 2 mm behind the eyeball. The optic nerve is placed into 10% buffered formaldehyde and kept separate from the eye. A sample of tumor is obtained by opening a sclero-choroidal window adjacent to the tumor near the equator with a 6–8 mm corneal trephine. Alternately, the traditional pupillary-optic nerve section can be made partially, in order to directly visualize the tumor for accurate biopsy to obtain viable tumor tissue. The scleral flap may or may not be closed with suture(s) following the removal of tumor sample, to maintain the overall spherical architecture of the specimen during fixation. The eye is placed in formalin separate from the optic nerve and be is allowed to fixate for at least 24–48 hours.Processing without Tumor Sampling: If there is no need for fresh tissue sampling, the enucleated eyeball is simply fixed in 10% buffered formaldehyde for at least 24-48 h. Careful examination of the enucleated eye is advised, as described previously. If the optic nerve was not previously amputated in the operative room, it should be done now after clearly inking the surgical margin. The surgical margin of the nerve stump should be embedded face down in paraffin for sectioning (i.e., thereby obtaining cross-sections of the nerve, starting at the surgical margin). Then, the eye itself is sectioned. First, a section should be made that extends from one millimeter superior to the optic nerve towards the cornea to include the pupil (the “P-O” section) (Figure 1A), then proceed to cut the other side parallel to the first section (Figure 1B). After cutting the central section, the central portion of this section should contain the intact optic nerve with all the optic nerve structures (optic nerve head, lamina cribrosa, and retro-laminar optic nerve), most of the lens and pupil. Preferably this plane should bisect the largest dimension of the tumor, previously identified by transillumination and during clinical examination. When possible, the plane should avoid the scleral opening if one was made for fresh tumor sampling. The scleral opening should be included in one of the two calottes (cup-shaped sections resulting from obtaining the P-O section)(Figure 1C). The P-O section is critical for evaluation of the optic nerve for tumor invasion. The calottes are then anterior-posteriorly sectioned in a bread loafed manner in at least three segments to evaluate the choroid and sclera for invasion (Figure1D). The P-O section and all the segments of the calottes on edge are then embedded in paraffin in a total of 3 cassettes (one cassette for the P-O and one cassette for each of the calottes) and the cross section of the optic nerve margin as the fourth cassette (Figure1E).) . The embedded P-O calotte is then sectioned every 100–150 ?m (each section being about 5 ?m thick), for a total of about 20–50 sections or until a complete section of the optic nerve is achieved. A complete section of the optic nerve is defined as a section that includes the head of the optic nerve, the lamina cribrosa and the retro-laminar optic nerve all connected and preferably showing the central vessels centrally located. Hematoxylin and eosin staining of every other section is recommended, leaving the sections in between for possible immunohistochemistry or PAS staining. Three levels of the blocks containing the calottes are usually sufficient for examination. In total, four cassettes are submitted: the optic nerve stump, the P-O section, and the two calottes.Figure 1.Palpable lymph nodes require undergoing a fine-needle aspiration biopsy, or an open biopsy to confirm the presence of malignant cells. In order to pathologically stage for distant metastasis, the cerebrospinal fluid and bone marrow analysis are required. Histopathological screening for metastasis should be considered when high-risk features are noted on histopathological examination of the enucleated eye (pT3, pT4). If eye preservation will be attempted, this screening is advised prior to starting chemotherapy as it may downstage the disease. ADDIN EN.CITE <EndNote><Cite><Author>Zhao</Author><Year>2011</Year><RecNum>15639</RecNum><DisplayText>[31]</DisplayText><record><rec-number>15639</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1302183192">15639</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Zhao, J.</author><author>Dimaras, H.</author><author>Massey, C.</author><author>Xu, X.</author><author>Huang, D.</author><author>Li, B.</author><author>Chan, H. S.</author><author>Gallie, B. L.</author></authors></contributors><auth-address>Beijing Tongren Eye Centre, Beijing Tongren Hospital, Capital Medical University, Beijing, China.</auth-address><titles><title>Pre-enucleation chemotherapy for eyes severely affected by retinoblastoma masks risk of tumor extension and increases death from metastasis</title><secondary-title>Journal of clinical oncology : official journal of the American Society of Clinical Oncology</secondary-title><alt-title>J Clin Oncol</alt-title></titles><alt-periodical><full-title>J Clin Oncol</full-title></alt-periodical><pages>845-51</pages><volume>29</volume><number>7</number><edition>2011/02/02</edition><dates><year>2011</year><pub-dates><date>Mar 1</date></pub-dates></dates><isbn>1527-7755 (Electronic)&#xD;0732-183X (Linking)</isbn><accession-num>21282531</accession-num><work-type>Research Support, Non-U.S. Gov&apos;t</work-type><urls><related-urls><url>;[31] Lumbar puncture for analysis of the cerebrospinal fluid is advised if there are any signs of optic nerve involvement or the optic disc can not be visualized on clinical examination. Bone marrow biopsy from bilateral sites is advisable in all children presenting with advanced intraocular disease (cT3) or extraocular disease (cT4).PROGNOSTIC FACTORSPrognostic Factors Required for StagingRB1 Gene Germline Mutation StatusTumor SizeDistance of Tumor from Disc or FoveaRetinal Detachment and Sub-retinal FluidType and Extent of Tumor SeedingSigns of Neovascularization and Intraocular HemorrhageSigns of Current or Previous Ocular InflammationSigns of Increased Intraocular PressureTumor Extension Anterior to the Vitreous FaceRadiological Features of Extraocular Tumor ExtensionSigns of Extraocular Tumor ExtensionSigns of Lymph Node InvolvementHistological Evidence of Micro-metastasis or Extraocular ExtensionSigns of Metastasis through the Hematogenous RouteSigns of Metastasis into the Intracranial SpaceAdditional Prognostic Factors Recommended for Clinical CareAge at Diagnosis and at Treatment InitiationTumor Growth Pattern (Exophytic, Endophytic or Diffused Infiltrative)Vision at Diagnosis and Visual PotentialEmerging Factors for Clinical CareMolecular Constitution of the TumorSocial and Cultural Factors Contributing to SurvivalRegistry Data Collection VariablesNil additionalRISK ASSESSMENT MODELSNoneRECOMMENDATIONS FOR CLINICAL TRIAL STRATIFICATIONNone?Anatomic Stage and Prognostic GroupsWhen T is…And N is…And M is…Then the stage group is…When cT is…When pT is…cT1, cT2pTX (not primarily enucleated)bN0M0-cT1, cT2, cT3pT1, pT2N0M0IcT4apT1, pT2N0M0IcT3pT3, pT4N0M0IIcT4apT3, pT4N0M0IIcT3pTX (not primarily enucleated)N0M0IIcT4bAnyN0M0IIIcT4apTX (not primarily enucleated)N0M0IIIAnyAnyN1M0IIIAnyAnyAnyM1IVHistologic Grade (G)GG Definition1Tumor with areas of retinocytoma (fluorettes or neuronal differentiation)2Tumor with many rosettes (Flexner-Wintersteiner or Homer Wright)3Tumor with occasional rosettes (Flexner-Wintersteiner or Homer Wright)4Tumor with poorly differentiated cells without rosettes and/or with extensive areas (more than half of tumor) of anaplasia.large anaplastic appearing cellsHistopathologic TypeThis classification only applies to retinoblastoma.Survival Tables and ChartsAdd from registry, or wait until after publication?Waiting to add from registry – but since some definitions have changed significantly, the survival tables will look retrospectively at the previous classification systems.BIBLIOGRAPHY:(Need to add: Finger et al, 2002) ADDIN EN.REFLIST 1.Dimaras, H., et al., Retinoblastoma. Nature Reviews Disease Primers, 2015: p. 15021.2.Friend, S.H., et al., A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature, 1986. 323(6089): p. 643-6.3.Reese, A.B. and R.M. Ellsworth, The evaluation and current concept of retinoblastoma therapy. Trans Am Acad Ophthalmol-Otolaryngol, 1963: p. 164-172.4.Murphree, A.L., Intraocular retinoblastoma: the case for a new group classification. Ophthalmology Clinics of North America, 2005. 18: p. 41-53.5.Shields, C.L. and J.A. Shields, Basic understanding of current classification and management of retinoblastoma. Curr Opin Ophthalmol, 2006. 17(3): p. 228-34.6.Chantada, G., et al., A proposal for an international retinoblastoma staging system. Pediatr Blood Cancer, 2006. 47(6): p. 801-5.7.Abramson, D.H., et al., Presenting signs of retinoblastoma. J Pediatr, 1998. 132(3 Pt 1): p. 505-8.8.Francis, J.H., et al., The classification of vitreous seeds in retinoblastoma and response to intravitreal melphalan. Ophthalmology, 2015. 122(6): p. 1173-9.9.Munier, F.L., Classification and management of seeds in retinoblastoma. Ellsworth Lecture Ghent August 24th 2013. Ophthalmic Genet, 2014. 35(4): p. 193-207.10.Chong, E.M., et al., Extensively necrotic retinoblastoma is associated with high-risk prognostic factors. Arch Pathol Lab Med, 2006. 130(11): p. 1669-72.11.MacCarthy, A., et al., Second and subsequent tumours among 1927 retinoblastoma patients diagnosed in Britain 1951-2004. Br J Cancer, 2013. 108(12): p. 2455-63.12.Lohmann, D. and B.L. Gallie, Retinoblastoma, in GeneReviews? [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2013. Available at , A.M. Pagon RA, Bird TD, Dolan CR, Fong C-T, and Stephens K. , Editor. 2013.13.Kim, J.W., et al., Retcam fluorescein angiography findings in eyes with advanced retinoblastoma. Br J Ophthalmol, 2014. 98(12): p. 1666-71.14.Rootman, D.B., et al., Hand-held high-resolution spectral domain optical coherence tomography in retinoblastoma: clinical and morphologic considerations. British Journal of Ophthalmology, 2013. 97(1): p. 59-65.15.Mallipatna, A., et al., The use of handheld spectral domain optical coherence tomography in pediatric ophthalmology practice: Our experience of 975 infants and children. Indian J Ophthalmol, 2015. 63(7): p. 586-93.16.de Jong, M.C., et al., Trilateral retinoblastoma: a systematic review and meta-analysis. Lancet Oncol, 2014. 15(10): p. 1157-67.17.Marr, B.P. and A.D. Singh, Retinoblastoma: Evaluation and Diagnosis, in Clinical Ophthalmic Oncology. 2015, Springer. p. 1-11.18.de Jong, M.C., et al., The potential of 3T high-resolution magnetic resonance imaging for diagnosis, staging, and follow-up of retinoblastoma. Surv Ophthalmol, 2015.19.Brisse, H.J., et al., Assessment of early-stage optic nerve invasion in retinoblastoma using high-resolution 1.5 Tesla MRI with surface coils: a multicentre, prospective accuracy study with histopathological correlation. Eur Radiol, 2015. 25(5): p. 1443-52.20.Sirin, S., et al., High-resolution MRI using orbit surface coils for the evaluation of metastatic risk factors in 143 children with retinoblastoma : Part 2: new vs. old imaging concept. Neuroradiology, 2015. 57(8): p. 815-24.21.Sirin, S., et al., High-resolution MRI using orbit surface coils for the evaluation of metastatic risk factors in 143 children with retinoblastoma : Part 1: MRI vs. histopathology. Neuroradiology, 2015. 57(8): p. 805-14.22.Schueler, A.O., et al., High resolution magnetic resonance imaging of retinoblastoma. Br J Ophthalmol, 2003. 87(3): p. 330-5.23.Wilson, M.W., et al., Lack of correlation between the histologic and magnetic resonance imaging results of optic nerve involvement in eyes primarily enucleated for retinoblastoma. Ophthalmology, 2009. 116(8): p. 1558-63.24.Gallie, B.L., et al., Retinoma: spontaneous regression of retinoblastoma or benign manifestation of the mutation? Br J Cancer, 1982. 45(4): p. 513-21.25.Dimaras, H., et al., Loss of RB1 induces non-proliferative retinoma: increasing genomic instability correlates with progression to retinoblastoma. Hum Mol Genet, 2008. 17(10): p. 1363-72.26.Mendoza, P.R., et al., Histopathologic grading of anaplasia in retinoblastoma. Am J Ophthalmol, 2015. 159(4): p. 764-776 e3.27.Rushlow, D.E., et al., Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies. Lancet Oncol, 2013. 14(4): p. 327-34.28.Chantada, G.L., et al., Retinoblastoma patients with high risk ocular pathological features: who needs adjuvant therapy? Br J Ophthalmol, 2004. 88(8): p. 1069-73.29.Sastre, X., et al., Proceedings of the consensus meetings from the International Retinoblastoma Staging Working Group on the pathology guidelines for the examination of enucleated eyes and evaluation of prognostic risk factors in retinoblastoma. Arch Pathol Lab Med, 2009. 133(8): p. 1199-202.30.Chantada, G., et al., SIOP-PODC recommendations for graduated-intensity treatment of retinoblastoma in developing countries. Pediatr Blood Cancer, 2013. 60(5): p. 719-27.31.Zhao, J., et al., Pre-enucleation chemotherapy for eyes severely affected by retinoblastoma masks risk of tumor extension and increases death from metastasis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2011. 29(7): p. 845-51. ................
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