year 2 resident

1. Common childhood ophthalmic malignancy
Elias T - R-II
JUDO, June 2021
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2. Out lines
• Introduction
• Retinoblastoma
• Rhabdomyosarcoma
• Neuroblastoma
• Capillary hemangioma
• Others to discus
• References
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3. Introduction
Several benign and malignant ocular tumors can occur in childhood
Tumors in the ocular region can lead to loss of vision, loss of the eye
In the case of malignant neoplasms - loss of life
It is important to recognize childhood ocular tumors early
To have diagnostic studies done and manage appropriately
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“If most solid tumors of childhood
are indeed correctly
attributable to mutations in germ
and/or somatic cells …
then childhood cancer cannot be
prevented. … the main
effort against childhood cancer
must be that of early
diagnosis and treatment”
A. G. Knudson Jr, 1976

5. Retinoblastoma
• The most common primary intraocular malignancy in childhood.
• Accounts for about 3% of all childhood cancers
• Incidence: 1 in 14, 000 to 1 in 20, 000 live births.
• Bilateral in 30-40% of cases.
• 40% of the case is heritable.
• No gender or racial variation
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6. Cont.…
• Occurs equally in right and left eyes
• 90% occurs before 3 years.
• Eighth most common childhood cancer
• Mean age at diagnosis depends on family history and the laterality
– patients with a known family history of retinoblastoma: 8 months
– patients with bilateral disease: 12 months
– patients with unilateral disease: 24 months
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7. Genetic Counseling
• Mutation in the RB1 located on the long arm of chromosome 13 at locus 14
(13q14).
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8. Cont.…
• Protein (pRB) that binds various cellular proteins to suppress cell
growth
• RB1 is a recessive oncogene at cellular level
• Mutations of RB1 alleles result in cancer only in developing retina; other
cell types die by apoptosis in absence of RB1
• Primitive retinal cells disappear within first few years of life so RB is
seldom seen after 3 or 4 years of age
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9. Pathogenesis of RB
• Arises from undifferentiated retinoblasts of inner layer of optic cup
• Before its differentiation to PHR
• Immunohistochemistry - neuron-specific enolase, ROS specific S-
antigen & rhodopsin. IPRrBP – Secreted by tumor cell
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10. Hereditary
• One of Knudson’s 2 hits occur prior to conception
• 40% of RB is hereditary type of RB
• The risk of the Knudson’s second hit/new mutation is extremely
high (therefore RB is inherited as AD trait with 90% penetrance)
• There is risk of bilateral RB (as all cells have inherited one mutant
allele)
• There is risk of non-ocular malignancies elsewhere (as all cells
have one mutant allele)
• Age of presentation: 12 months
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11. Non-hereditary
• Both of Knudson’s 2 hits occur after conception
• Both alleles are normal after fertilization, but two or more
subsequent spontaneous mutations inactivate both alleles
• 60% of RB is nonhereditary type of RB
• No risk of bilateral RB
• No risk of non-ocular malignancies elsewhere
• Age of presentation: 24 months
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12. Clinical Features
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13. In Ethiopia
presentation Percentage (%)
proptosis 53.7
Leukocoria 22
Ocular inflammation 9
Strabismus 7.3
Glaucoma 2.4
Loss of vision 2.4
hyphemia 2.4
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Presenting sign of retinoblastoma at a tertiary level teaching hospital In Ethiopia ,Jemal Zeberga Shifa and Alemayew
mekonin gezmu , 2017
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20. DDx
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21. Evaluation
• Complete physical examination
• EUA
• The intraocular pressure and corneal diameter of both eyes should
be measured
• The location of all tumors in each eye should be clearly documented
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22. Cont.…
• A funduscopic examination is performed with indirect
ophthalmoscopy and gentle scleral depression to the ora serrata.
• Small retinoblastoma lesions may appear as translucent flat or
dome shaped lesions
• As the tumors increase in size, they often take on a white or
off-white, chalky color
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23. Morphologic feature
• Early retinoblastoma is a solitary or multifocal, well-circumscribed,
translucent intraretinal mass
• As the disease advances,
• Tumor becomes more pink in color,
• With dilated feeding blood vessels,
• Exhibit one of three main growth patterns
• Exophytic ,endophytic and diffuse infiltrating retinoblastoma
• Trilateral retinoblastoma??
• SPONTANEOUSLY ARRESTED&REGRESSED TUMORS and RETINOCYTOMA??
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25. Histopathology
 Composed of small basophilic cells (Retinoblasts) with large hyperchromatic
nuclei and scanty cytoplasm
 Many retinoblastomas are undifferentiated but varying degrees of differentiation
are characterized by the formation of rosettes
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26. Histology feature
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27. Table summery
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28. Investigation
• US
• CT
• MRI – (T1- Weighted hyperintense, T2-weighted hypointense to vitreous)
• Wide-field photography
• Systemic assessment
• Genetic studies
• Esterase D - linked marker
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29. Classification
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30. Treatment
• Aims of management
• First goal to save life
• Second goal to save eye
• Third goal to maximize vision
• Oncologists, pediatric ophthalmologists, geneticists, genetic
counselors, pediatric oncologists, and radiation oncologists
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31. Treatment methods
• Enucleation
• External beam radiotherapy
• Chemotherapy (e.g. chemoreduction, systemic chemotherapy,
subconjunctival chemoreduction, intrathecal cytosine arabinoside)
• Focal therapy (e.g. laser, cryotherapy, radioactive plaque,
thermotherapy)
• Orbital exenteration
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32. Enucleation
• The tumor involves more than 50% of the globe
• Orbital or optic nerve involvement is suspected
• Anterior segment involvement is present
• Neovascular glaucoma is present
• The affected eye has limited vision potential
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33. Laser Therapy
• Argon 532um
• Power 250-300mw and duration 300-500ms.
Cryotherapy
• Destruction of the cellular membranes during freeze-thaw cycle
• Vaso-occulsion
• Laser is chosen for posterior tumors, cryoablation for more anterior
tumors.
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34. External Beam Radiotherapy
• In the mid-1900s, EBRT became the main alternative to enucleation for
salvaging eyes with RB
• EBRT is associated with second cancers, mainly in the field of
irradiation and with facial cosmetic problems
• In recent years, there has been a trend toward avoiding both
enucleation and EBRT when possible
• Because RB tumors are responsive to radiation, EBRT has become a
salvage technique, when chemotherapy has failed
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35. Chemo treatment from INCTR-03-05 RB protocol
• Based on PE, diagnostic work-up, consider the following scenarios:
– Intraocular disease without buphthalmos
– Intraocular disease with buphthalmos
– Extraocular/orbital disease
– Extraorbital (metastatic) disease
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36. .
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• Intraocular Disease without Buphthalmos
– Upfront enucleation – removing 0.8 to 1 cm of ON
– Review of pathology
– Risk factors: involvement of choroid (massive), sclera
or episcleral vessels, optic nerve beyond lamina
cribrosa, anterior chamber/ciliary body
– If NO risk histology – no additional therapy
– If YES risk histology – adjuvant chemotherapy
• 3 courses of VCE and 3 courses (VCyD)
or
• 6 courses of VCyD if carboplatinum and etoposide are not
available.
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37. ‘
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• Intraocular Disease with Buphthalmos
– Delay enucleation to avoid rupture and suboptimal optic
nerve resection
– Preoperative chemotherapy:
• 2 courses of VCE or
• 2 courses of VCyD if VCE not available
– Enucleation
– Postoperative chemotherapy
• To complete a total of 6 courses ;3 courses of VCE and 3
courses of VCR/CYC/DOX (VCyD) or
• 6 courses of VCyD if carboplatinum and etoposide are not
available
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38. .
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• Extraocular/Orbital Disease
– Treatment ; chemotherapy+ enucleation+ orbital irradiation
if possible.
• Chemotherapy 4 courses VCE and 4 courses VCyD for a total of 8
cycles (4 VCE and 4 VCyD).
– Start chemotherapy with standard regimen: give 2 or 3
courses of VCE (or VCyD if VCE not available).
– If good response, proceed with enucleation.
– Complete postoperative chemotherapy for a total of 8
courses.
• Consolidate with orbital Radiation Therapy (45 Gy) to orbit up to
optic chiasm if RT is available
• Extraorbital (metastatic) disease;Palliation
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Chemotherapy Regimens
• If carboplatin is available , standard regimen ;VCE(
vincristine, carboplatin&etoposide)
• If carboplatin is not available , can use VCyD( vincristine
,cyclophosphamide & doxorubicin)instead,
• Cycles can be given every 21 or 28 days
• Cotrimoxazole -5 mg /kg orally daily for 3 consecutive
days per week through entire chemotherapy protocol and
for 12 weeks after the end of therapy
• Criteria for initiation of each cycle
1. ANC > 750/mm3and recovering
2. Platelets > 75,000/mm3 and recovering
3. Normal serum creatinine for age
5. SGPT/SGOT < 2.5 times upper limit of normal
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40. Follow-up
• Patients with treated RB and siblings at risk need to be followed
• After initial treatment, re-examine patient 3–6 weeks later:
• Active tumor on treatment requires follow-up every 3 weeks
• If tumor is obliterated, follow-up 6–12 weeks later
• 3-monthly until 2 years post-treatment, then 6 monthly until 6 years of
age, then yearly for life
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41. Prognosis
• Location (most important factor):
• 95% 5-year survival if intraocular tumor
• Less than 50% 5-year survival with extraocular
extension/optic nerve involvement
• Tumor size and grade
• Iris rubeosis
• Bilateral tumors (risk of second malignancy)
• Age of patient (older is worse)
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42. Second cancer in RB patients
• Osteogenic sarcoma is the most common cancer
• Pineoblastoma, ectopic intracranial RB (trilateral RB) is common up to 2 years
after diagnosis of RB
• Beyond 2 years after diagnosis of RB
• Bony and soft tissue sarcomas (Ewing’s tumor, chondrosarcoma,
rhabdomyosarcoma)
• Skin tumors (malignant melanoma, sebaceous cell CA, squamous cell CA)
• Neuroblastoma, medulloblastoma, leukemia
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43. Natural history of RB
• Intra-retinal tumor
• Angiogenesis with feeder artery and draining vein.
• Loss of cellular adhesion and begin to seed into the vitreous (endophytic)
and subretinal spaces (exophytic with RD)
• Invasion of the choroid and optic nerves and into the brain Continued
growth may induce glaucoma
• Ruptures the globe and see into the orbit or periorbital tissue.
• Distant metastasis is rare nowadays.
• Spontaneous regression in 5%
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44. Orbital Rhabdomyosarcoma
• The most common primary orbital malignant tumor in children
• Rhabdomyosarcomas arise from undifferentiated pluripotential
mesenchymal cell not from extraocular muscle
• 3.4 % of all childhood malignancies
• The average age of onset is 7-8 years, but it can occur at any age.
• No racial predisposition
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45. Cont.…
• The orbit is the origin of 10% of RMS;
• 25% of these tumors arise elsewhere in the head and neck,
• 90% diagnosed before age 16 yrs
• RMS in infancy is more aggressive and carries a poorer prognosis
• Can primarily involve orbit, eyelid, conjunctiva & uveal tract
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46. Histopathological classification
• Embryonal
• Alveolar
• Pleomorphic
• botryoid
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47. Embryonal RMS
• Most common (85 %) & good prognosis.
• Elongated cell with centrally located hyperchromatic nucleus
surrounded by eosinophilic cytoplasm.
• Cross-striations are seen in 50- 60%.
• Commonly arise in superior nasal quadrants
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48. Alveolar RMS
• Least common & carries worst prognosis.
• Consists of eosinophilic rhabdomyoblasts that are loosely adherent
within thin hyalinized CT septa.
• Only 30% show cross striations.
• Usually originates within inferior orbit.
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49. Botyroid RMS
• Considered as variant of embryonal RMS
• Appears as fleshy grape-like or papillomatous mass
• It is not found in the orbit as a primary tumor
• Occurs as a secondary invader from the PNS or from the conjunctiva
• Cluster of tumor cells arranged in a loose syncytium
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50. Pleomorphic RMS
• Very rare & common in adult.
• Has best prognosis
• Cells are straplike or rounded, and cross-striations are easily
visualized with trichrome stain.
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51. Clinical feature
• Acute, rapidly progressive proptosis with an absence of pain – typical
CF
• Proptosis (80%–100%)
• Globe displacement (80%)
• Blepharoptosis (30%–50%)
• Conjunctival and eyelid swelling (60%)
• Palpable mass (25%)
• Pain (10%)
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52. Work up
• US - well circumscribed, heterogenous, irregular mass with low to medium echogenicity
• CT- well circumscribed, homogenous, soft tissue mass isodense as compared to muscles calcification
• MRI - T1 weighted – Isointense to EOM & hypointense to orbital fat
T2 weighted - Hyperintense to orbital fat & EOM
• Immunohistochemical –Ab to desmin, actin,myoD1,myoglobin, vimentin
• Biopsy
• Systemic evaluation
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53. .
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Treatment
• Ultimate diagnosis of RMS requires biopsy for histopathologic
evaluation
• Treatment modalities
• surgery,
• irradiation and
• Chemotherapy
IRSG postsurgical staging system
• Group I: localized disease, completely resected (excisional biopsy)
• Group II: microscopic disease remaining after biopsy
• Group III: gross residual disease remaining after biopsy
• Group IV: distant metastasis present at onset
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• Group I ;chemotherapy only: VA (vincristine and actinomycin)
• Group II; chemotherapy(vincristine + actinomycin D) & radiotherapy
• Group III; chemotherapy (vincristine + actinomycin D
+cyclophosphamide /ifosfamide / etoposide) & radiotherapy
• Group IV - palliative care
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55. Prognosis
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• 94% and 74% ; 5-year survival for embryonal & alveolar
variants respectively
• Infants - more aggressive & survival rates of 54%
• Confined to orbit - survival rate is 90%
• Bone destruction & extension beyond orbit →survival rate
65%
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56. Follow up
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• Look for side effects of radiotherapy, recurrence & secondary
tumors
• MRI - at 3mo intervals, with decreasing frequency until 5
years after treatment
• Ocular examination - every 3–4 months & after first year
every 4–6 months for several years and then yearly
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57. Metastatic tumor
• Metastatic neoplasms to orbit
• Predominated by small, round, blue-cell tumors.
• Neuroblastoma
• Ewing’s sarcoma
• Wilms tumor
• Leukemia
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58. Neuroblastoma
• Neuroblastoma is one of the most common childhood cancers
• The most frequent source of childhood orbital metastasis (89% of cases).
• Arise from primitive neural cells (neural crest cells)
• Adrenal gland or the sympathetic ganglion chain in the retroperitoneum or
mediastinum.
• 20% of all patients with neuroblastoma show clinical evidence of orbital
involvement,
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59. Cont…
• Incidence  1 per 1000 live births
• Accounts for 10% of all pediatric malignancy.
• The mean age at diagnosis - 2 years
• 90% are diagnosed by 5 years of age.
• Inherited as AD
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60. Histopathology
• Soft, friable, bluish mass; small round cells that resemble lymphocytes
• Specks of calcium and areas of necrosis are seen.
• Disproportionately large darkly staining nuclei & scanty cytoplasm.
• Electron microscopy reveals neurosecretory tubules
• In 1° tumors there is differentiating neuroblasts with a rosette
formations is seen (Homer Wright rosettes).
• Once tumor metastasizes - neural differentiation lost
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61. • Immunohistochemical markers
• NB84, neuron-specific enolase (NSE), S-100, Synaptophysin &
Chromogranin.
• >90% of affected children excrete catecholamine by products.
• Homovanillic acid (HVA)
• Vanillylmandelic acid (VMA) in urine.
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62. CLINICAL PRESENTATION
• Blueberry muffin baby
• Unilateral or bilateral proptosis
• Raccoon eyes, Eyelid swelling
• Motility disturbances
• Horner syndrome
• Abdominal fullness & pain
• Bone pain
• Edema(venous obstruction)
• HTN (renal involvement)
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63. Investigation
• UA - Homovanillic acid (HVA) and Vanillylmandelic acid (VMA)
• US
• Plain abd XR and CXR
• CT
• MRI
• CBC, RFT,LFT
• BMA and Biopsy
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64. Staging by INSS
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65. Treatment
• Stage 1,2 & 4-S
– Surgery alone
– Chemotherapy indicated
• Reccurence
• Unfavorable histology
• Stage 3 & 4
– Neoadjuvant chemotherapy
– Followed by surgery
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66. Chemo agent
• Combination of drugs :
– Cyclophosphamide (Cy)
– Carboplatin(C)
– Cisplatin
– Vincristine (V)
– Doxorubicin (D)
– Etoposide(E)
– Topotecan(T)
• Most common combination used – (CCyDE)
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67. RT
• 1500cGy in children & 4000cGy in patients older than 10years.
• Used for localized tumor
• Shrink tumors before surgery.
• As treatment regimen (along with high-dose chemotherapy) before
a stem cell transplant.
• Relieves pain
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68. • Stage 1 - 5 year survival rate >98%
• Stage 2 & 3 - 5 year survival rate 90 to 95%
• Stage 4 - 5 year survival rate 40 to 50%
• Stage 4-S - 5 year survival rate >90%
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69. Leukemia
• Acute in 95%
• ALL>AML
• Responsible for 30% all childhood malignancy
• Most common ocular manifestation is leukemic retinopathy ( retinal hg)
• Ocular involvement highly corelate CNS involvement
• Anterior segment - HI, KPs, hyphemia, pseudo hypopyon, glaucoma
• Choroid ……..
• Optic nerve …..
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70. References
• Pediatric Ophthalmology & Strabismus, BCSC, Section 6, 2019-2020
• Ryan’s retina 6th edition (2017)
• Duane`s Ophthalmology, 2012
• Yanoff & Duker Ophthalmology, 5th ed
• J.J. Kanski. Clinical Ophthalmology, A Systematic Approach, 8th ed.
• INCTR-USA protocol for the treatment of children with
Retinoblastoma in Ethiopia
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71. Thank you
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