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Retinoblastoma

Authors: Riley Lochner, M.D., M.S., Marta Couce, M.D., Ph.D.

Editorial Board Member: Molly Housley Smith, D.M.D.

Deputy Editor-in-Chief: Kelly Magliocca, D.D.S., M.P.H.

Last author update: 2 November 2021

Last staff update: 2 June 2022

Copyright: 2004-2024, PathologyOutlines.com, Inc.

PubMed Search: Retinoblastoma pathology

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Table of Contents

Cite this page: Lochner R, Couce M. Retinoblastoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/eyeretinaretinoblastoma.html. Accessed April 19th, 2024.

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

Most common intraocular malignancy of childhood (1 in 16,000 - 18,000 births) (Nat Rev Dis Primers 2015;1:15021)
> 40% of cases are located in 6 countries in Asia-Pacific region (Eye (Lond) 2019;33:87)
Approximately 90% in middle and low income countries (Nat Rev Dis Primers 2015;1:15021)

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
- Earlier age of onset (J Neurosci Res 2019;97:29)
- Often bilateral involvement but can be trilateral or quadrilateral (Pediatr Blood Cancer 2010;55:570)
- Predisposes to development of other malignancies including osteosarcoma and melanoma (Pneumologie 1990;44:327)
Reference: Annu Rev Pathol 2015;10:547

Etiology

Inherited germline mutation of RB1

Clinical features

Leukocoria (white reflex) of affected eye (late presenting sign) (J Neurosci Res 2019;97:29, J Ophthalmol 2020;2020:9315784)
Glaucoma
Strabismus (second most common sign)
Eye pain
Decreased visual acuity
Retinal detachment

Diagnosis

Diagnosis is almost always made clinically and radiologically
High resolution MRI used for preoperative planning
- Can reliably detect optic nerve invasion, choroid and extrascleral invasion (Egypt J Radiol Nucl Med 2020;51:28)
Can be diagnosed histopathologically post surgery
Controversial use of FNA / cytology with concern for tumor seeding
- Can be done safely in select cases where imaging is not definitive (Int J Ophthalmol 2016;9:1233)

Radiology description

Most often diagnosed via imaging
Ultrasound:
- Does not require sedation or exposure to radiation
- Can visualize tumor calcification (J Neurosci Res 2019;97:29)
- Variably heterogeneous, echogenic soft tissue mass (AJR Am J Roentgenol 2000;175:495)
- Helps monitor tumor in treatment
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 images

MRI, intraocular mass, exophytic

MRI sagittal, heterogeneous signal

Ovoid retinal tumor

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
- High risk histopathological features
  - Involvement of optic nerve, choroid or anterior ocular structures (Oncogene 2018;37:1551, Arch Ophthalmol 2011;129:1422)
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

23 year old man treated with primary intra-arterial and intravitreal chemotherapy (Oman J Ophthalmol 2019;12:119)
55 year old woman with late stage intraocular mass, diagnosed with FNA (J Cytol 2018;35:120)
3 sets of twins with retinoblastoma discordance (Indian J Ophthalmol 2019;67:436)

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

Strabismus without leukocoria

Focal opacified areas

Obscured retinal vessels

Retinal tumor invades subretinal space

Images hosted on other servers:

Ultrasound B scan / RetCam

Fundoscopic image demonstrating tumor

Gross description

Creamy white with chalky areas of calcification and yellow necrotic areas
May grow inward (endophytic) or outward toward choroid (exophytic)
Rarely are diffusely infiltrative; typically seeds intraocularly
References: Int J Ophthalmol 2018;11:2011, Turk Patoloji Derg 2015;31:45

Gross images

Contributed by Marta Couce, M.D., Ph.D. and AFIP images

Chalky tumor posterior chamber

Exophytic growth, focal hemorrhage

Massive extraocular extension

Destruction of anterior segment

Large areas of necrosis

Calcification

3 small retinal tumors

Choroidal invasion

Total exudative retinal detachment

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 replacing neurosensory retina

Optic nerve infiltration

Extensive tumor necrosis

Flexner-Wintersteiner rosettes

Ki67

AFIP images

Nodules of tumor cells

Anterior chamber involvement

Viable tumor cells

Adjacent endophytic tumor

Sleeve pattern and rosettes

Flexner-Wintersteiner rosettes

Homer Wright rosettes

Poorly differentiated tumor cells

Azzopardi phenomenon

Spindle shaped glia

Benign cytology

Invasion of optic nerve head

Invasion to lamina cribrosa

Invasion of optic nerve parenchyma posterior

Invasion of full thickness of choroid

Whole mount images

AFIP images

Small endophytic tumor

Total retinal detachment

Extraocular invasion

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

Clumps and individual tumor cells

Images hosted on other servers:

Cluster and
rosette formation /
PAS positive
granules

Positive stains

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

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?

Enucleation remains the best initial treatment
Involvement of the optic nerve is not considered a significant prognostic factor
Majority of these tumors have MYCN mutations
Recommended initial treatment paradigm is chemoreduction
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?

Bilateral retinoblastomas
Development of subsequent melanoma or osteosarcoma
Early age of onset
Germline mutation of Rb gene
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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