Eye

Retina

Retinoblastoma



Topic Completed: 2 November 2021

Minor changes: 2 November 2021

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PubMed Search: Retinoblastoma [TI] pathology review [PT] free full text [SB]

Riley Lochner, M.D., M.S.
Marta Couce, M.D., Ph.D.
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Cite this page: Lochner R, Couce M. Retinoblastoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/eyeretinaretinoblastoma.html. Accessed December 6th, 2021.
Definition / general
  • Retinoblastoma is the most common intraocular malignancy in children characterized by hyperchromatic small round blue cells with scant cytoplasm arranged in sheets, nests and trabeculae
  • Prognosis dependent on many factors; histopathological evaluation determines metastatic risk, including tumor invasion into anterior chamber, significant invasion into choroid (at least 3 mm) and postlaminar optic nerve invasion
  • Retinoma / retinocytoma is the benign form of retinoblastoma
Essential features
  • Most common intraocular malignancy of childhood (1 in 16,000 - 18,000 births) (Nat Rev Dis Primers 2015;1:15021)
  • Often due to loss or inactivation of both alleles of the retinoblastoma 1 gene (RB1) (Knudson 2 hit hypothesis)
  • Hyperchromatic small round blue cells with scant cytoplasm arranged in sheets, nests and trabeculae, often with calcifications and necrosis
  • Most often has presurgical diagnosis by radiological and clinical features
  • Localized chemotherapy is first line treatment, followed by systemic therapy and surgery
ICD coding
  • ICD-O:
    • 9510/3 - retinoblastoma, NOS
    • 9511/3 - retinoblastoma, differentiated
    • 9512/3 - retinoblastoma, undifferentiated
    • 9513/3 - retinoblastoma, diffuse
    • 9514/1 - retinoblastoma, spontaneously regressed
  • ICD-10: C69.2 - malignant neoplasm of retina
Epidemiology
Sites
  • Sporadic retinoblastoma usually unilateral eye
  • Inherited retinoblastoma often bilateral eyes
    • Can be trilateral (pineoblastoma) or very rarely quadrilateral (pineoblastoma and suprasellar primitive neuroectodermal tumor) (Pediatr Blood Cancer 2010;55:570)
Pathophysiology
  • Loss or inactivation of both alleles of the retinoblastoma 1 gene (RB1)
    • Tumor suppressor gene located at 13q14.2 locus
    • Encodes RB1 protein
  • Knudson 2 hit hypothesis
    • Results from 2 separate mutations:
      • First mutation is somatic or germline
      • Second mutation is somatic
  • Germline mutations in RB1 lead to inherited / familial retinoblastoma
  • Reference: Annu Rev Pathol 2015;10:547
Etiology
  • Inherited germline mutation of RB1
Clinical features
Diagnosis
  • Diagnosis is almost always made clinically and radiologically
  • High resolution MRI used for preoperative planning
  • Can be diagnosed histopathologically post surgery
  • Controversial use of FNA / cytology with concern for tumor seeding
Radiology description
  • Most often diagnosed via imaging
  • Ultrasound:
  • MRI:
    • Modality of choice for pretreatment staging and surgical planning
    • Helps correlate calcifications on ultrasound to confirm diagnosis
    • T2 hypointense compared with surrounding vitreous
    • Variable sensitivity for detecting high risk features (Ophthalmology 2014;121:1109)
    • Optic nerve (59%), choroidal (74%) and scleral invasion (88%)
  • CT:
    • Exposure to radiation not preferred, especially in patients with RB1 germline predisposed to a second malignancy
    • Contrast enhancing retrolental mass with calcifications
Radiology images

Contributed by Marta Couce, M.D., Ph.D. and AFIP
MRI intraocular mass exophytic

MRI, intraocular mass, exophytic

MRI sagittal heterogeneous signal

MRI sagittal, heterogeneous signal

Ovoid retinal tumor

Ovoid retinal tumor

Focal calcification

Focal calcification

Prognostic factors
  • > 95% survival in high income countries and ~30% survival in low income countries (Nat Rev Dis Primers 2015;1:15021, Cancer Lett 2014;351:59, Can J Ophthalmol 2009;44:S1)
  • Risk of metastatic spread evaluated by histology post enucleation
  • International Intraocular Retinoblastoma Classification
    • Classifies tumors into 5 groups based on clinical and radiological features:
      • Group A (tumor ≤ 3 mm away from the fovea and disk)
      • Group B (larger tumor without dissemination)
      • Group C (local tumor dissemination)
      • Group D (diffuse tumor dissemination)
      • Group E (unsalvageable eye)
Case reports
Treatment
  • Evolved significantly from enucleation to vision sparing, localized chemotherapy
  • Intraophthalmic artery / nerve chemotherapy
    • Increased concentration within eye with less systemic effect
    • Cured 85% of group D high risk cases in one trial (PLoS One 2016;11:e0151343)
  • Systemic chemotherapy
    • Second choice following targeted chemotherapy
    • Increased systemic side effects and less effective
    • Adjuvant in very high risk cases treats any micrometastases
  • Role for primary enucleation in some high risk and all very high risk cases and in low income countries (Br J Ophthalmol 2018;102:265, Oncogene 2018;37:1551)
    • Single curative procedure with low recurrence
Clinical images

AFIP images
Leukocoria

Leukocoria

Strabismus without leukocoria

Strabismus without leukocoria

Focal opacified areas

Focal opacified areas

Obscured retinal vessels

Obscured retinal vessels

Retinal tumor invades subretinal space

Retinal tumor invades subretinal space



Images hosted on other servers:
Ultrasound B scan / RetCam

Ultrasound B scan / RetCam

Fundoscopic image demonstrating tumor

Fundoscopic image demonstrating tumor

Gross description
Gross images

Contributed by Marta Couce, M.D., Ph.D. and AFIP
Chalky tumor posterior chamber

Chalky tumor posterior chamber

Exophytic growth, focal hemorrhage

Exophytic growth, focal hemorrhage

Massive extraocular extension

Massive extraocular extension

Destruction of anterior segment

Destruction of anterior segment

Missing Image

Large areas of necrosis


Missing Image

Calcification

3 small retinal tumors

3 small retinal tumors

Choroidal invasion

Choroidal invasion

Total exudative retinal detachment

Total exudative retinal detachment

Optic nerve enlargement

Optic nerve enlargement

Frozen section description
  • Cluster of partially crushed, small round blue cells
  • Touch prep helpful in evaluating optic nerve margin
Microscopic (histologic) description
  • Hyperchromatic small round blue cells with scant cytoplasm arranged in sheets, nests and trabeculae (Ophthalmology 2012;119:850)
  • Variable differentiation
  • Calcification and perivascular ischemic necrosis common
  • Flexner-Wintersteiner rosettes (most common)
    • Central lumen with basally located nuclei
    • Analogous to outer limiting membrane of normal retina
  • Homer Wright rosettes (less common in retinoblastoma)
    • Lack of central lumen
    • Tumor nuclei displaced away from eosinophilic center
  • Fleurettes
    • Tumor cells arranged side by side with central lumen
      • Resembles fleur de lis
  • Photoreceptor differentiation
  • Histological high risk features (tumor involving any of the following structures) (Community Eye Health 2018;31:17)
    • Anterior chamber
    • Iris
    • Trabecular meshwork
    • Schlemm canal
    • Ciliary body
    • Choroid
    • Sclera
    • Extraocular structures
    • Retrolaminar optic nerve
  • Histologic grade:
    • G1: tumor with areas of retinocytoma (fleurettes or neuronal differentiation accounting for more than half of tumor)
    • G2: tumor with many rosettes, Flexner-Wintersteiner or Homer Wright rosettes accounting for more than half of tumor
    • G3: tumor with occasional rosettes, Flexner-Wintersteiner or Homer Wright rosettes accounting for less than half of tumor
    • G4: tumor with poorly differentiated cells without rosettes or with extensive areas of anaplasia
Microscopic (histologic) images

Contributed by Marta Couce, M.D., Ph.D.
Retinoblastoma infiltrating normal retina

Retinoblastoma infiltrating normal retina

Retinoblastoma replacing neurosensory retina

Retinoblastoma replacing neurosensory retina

Intralaminar / postlaminar optic nerve infiltration

Optic nerve infiltration

Extensive tumor necrosis

Extensive tumor necrosis

Flexner-Wintersteiner rosettes

Flexner-Wintersteiner rosettes

Ki67

Ki67



AFIP images
Nodules of tumor cells

Nodules of tumor cells

Anterior chamber involvement

Anterior chamber involvement

Viable tumor cells

Viable tumor cells

Adjacent endophytic tumor

Adjacent endophytic tumor

Sleeve pattern and rosettes Sleeve pattern and rosettes

Sleeve pattern and rosettes


Flexner-Wintersteiner rosettes

Flexner-Wintersteiner rosettes

Homer Wright rosettes

Homer Wright rosettes

Poorly differentiated tumor cells

Poorly differentiated tumor cells

Azzopardi phenomenon

Azzopardi phenomenon

Spindle shaped glia

Spindle shaped glia

Benign cytology

Benign cytology


Benign cytology

Benign cytology

Invasion of optic nerve head

Invasion of optic nerve head

Invasion to lamina cribrosa

Invasion to lamina cribrosa

Invasion of optic nerve parenchyma posterior

Invasion of optic nerve parenchyma posterior

Invasion of full thickness of choroid

Invasion of full thickness of choroid

Whole mount images

AFIP images
Small endophytic tumor

Small endophytic tumor

Total retinal detachment

Total retinal detachment

Extraocular invasion

Extraocular invasion

Bilateral tumor

Bilateral tumor

Cytology description
  • Variably cellular
  • Small round cells with scant cytoplasm
  • Clusters and rosettes
  • PAS positive granules
  • Must have mitosis and apoptosis
  • Reference: J Cytol 2018;35:120
Cytology images

AFIP images
Missing Image

Clumps and individual tumor cells



Images hosted on other servers:
Cluster and rosette formation / PAS positive granules

Cluster and
rosette formation /
PAS positive
granules

Negative stains
  • CD99
  • Negative lymphocyte markers (CD45, CD3, CD20, etc.)
  • GFAP (stains reactive stromal astrocytes in background and peritumoral tissue; negative in tumor cells)
  • Reference: J Cytol 2018;35:120
Electron microscopy images

AFIP images
Bulbous process of fleurette

Bulbous process of fleurette

Molecular / cytogenetics description
  • Recurrent chromosomal abnormalities (Annu Rev Pathol 2015;10:547)
    • Isochromosome 6p (45%)
      • E2F3 and DEK genes
    • Gain of regions of chromosome 1q (44%)
      • zsKIF14 and MDM4 genes
    • Monosomy 16 (18%)
      • CDH11 gene
    • Gain of 1p (13%)
    • Less common - loss of sex chromosomes and alterations in 17 and 19
  • Whole genome sequencing revealed recurrent BCOR mutations in 13% of retinoblastomas (Nature 2012;481:329)
  • Sonic hedgehog signaling proteins (J Clin Pathol 2015;68:6)
    • SHH (98.7%), GLI1 (85.9%) and GLI2 (92.2%) frequently expressed in retinoblastoma
      • 26.6% of 79 cases had strong SHH expression
      • High SHH expression closely related to advanced disease
  • Non-RB1 mutated retinoblastomas (2.7%)
    • Vast majority MYCN mutated
      • Also has role in controlled E2F1, E2F2 and E2F3 genes
      • Frequent gain of 19p, 17p/q and 2p and telomeric end of 9q
    • Very small percentage have RB1 inactivated by chromothriptic event in chromosome 13
Sample pathology report
  • Eye, right, enucleation:
    • Retinoblastoma (follow College of American Pathologists: Protocol for the Examination of Specimens From Patients With Retinoblastoma [Accessed 11 October 2021])
    • Case summary: retinoblastoma
      • AJCC-UICC 8
    • Case summary report
      • No known preoperative therapy
    • Procedure
      • Enucleation
    • Total length of optic nerve
      • Less than 1 mm
    • Tumor sampling for molecular studies
      • Yes
    • Specimen laterality
      • Right
    • Tumor
      • Tumor site (macroscopic examination / transillumination)
        • Superotemporal quadrant of globe
      • Tumor site after sectioning
        • Superotemporal
      • Tumor size after sectioning
        • Greatest basal diameter of tumor
          • Exact measurement: 6 mm
        • Basal diameter at cut edge of tumor
          • Exact measurement: 2 mm
        • Greatest thickness of tumor
          • Exact measurement: 3 mm
        • Percentage of vitreous cavity occupied by tumor
          • Specify percentage: 15%
        • Distance from anterior edge of tumor to limbus at cut edge
          • Exact distance: 7 mm
        • Distance from posterior margin of tumor base to edge of optic disc
          • Exact distance: 6 mm
      • Tumor growth pattern
        • Exophytic
      • Histologic grade
        • G2 (tumor with many rosettes [Flexner-Wintersteiner or Homer Wright rosettes accounting for more than half of tumor])
      • Anaplasia grade
        • Mild
      • Histopathologic features suggesting MYCN amplification
        • Not identified
      • Extent of optic nerve invasion
        • None identified
    • Margins
      • Margin status (select all that apply)
        • All margins negative for tumor
    • Regional lymph nodes
      • Regional lymph node status
        • Not applicable (no regional lymph nodes submitted or found)
    • Pathologic stage classification (pTNM, AJCC 8th edition)
      • TNM descriptors (select all that apply)
        • Not applicable
      • pT category
        • pT1: intraocular tumor without any local invasion, focal choroidal invasion or prelaminar or intralaminar involvement of the optic nerve head
      • pN category
        • pN not assigned (no nodes submitted or found)
      • pM category (required only if confirmed pathologically)
        • Not applicable - pM cannot be determined from the submitted specimen(s)
Differential diagnosis
  • Astrocytoma:
    • Generally not small, round blue cell pattern
    • GFAP positive
  • Leukemia / lymphoma:
    • Calcifications not seen
    • Necrosis rare
    • CD45 positive
    • B cell (e.g. CD19, CD20, PAX5) or T cell (e.g. CD3, CD5, TdT) markers positive
  • Massive retinal gliosis:
    • No rosettes or fleurettes
    • No necrosis or calcifications
Board review style question #1

An 8 year old girl had an enucleation that showed a white, chalky intraocular tumor. A histologic image is shown above. Which of the following statements is true regarding this entity?

  1. Enucleation remains the best initial treatment
  2. Involvement of the optic nerve is not considered a significant prognostic factor
  3. Majority of these tumors have MYCN mutations
  4. Recommended initial treatment paradigm is chemoreduction
  5. Strabismus is never seen in patients with this tumor
Board review style answer #1
D. Recommended initial treatment paradigm is chemoreduction

Comment Here

Reference: Retinoblastoma
Board review style question #2
Retinoblastomas can occur both in sporadic and familial forms. Which of the following features is more indicative of a sporadic tumor?

  1. Bilateral retinoblastomas
  2. Development of subsequent melanoma or osteosarcoma
  3. Early age of onset
  4. Germline mutation of Rb gene
  5. Late age of onset
Board review style answer #2
E. Late age of onset. Familial tumors result from germline mutations in the Rb gene and are more likely to be bilateral or trilateral. They have an early age of onset and are prone to the development of other malignancies, including osteosarcoma, melanoma, sarcoma and breast cancer.

Comment Here

Reference: Retinoblastoma
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