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Retinoblastoma: Standard Treatment Guidelines


Retinoblastoma:  Standard Treatment Guidelines

Retinoblastoma is the most common intraocular malignancy of childhood. It is second only to uveal melanoma in the frequency of occurrence of malignant intraocular tumors. Although it is highly malignant, it is eminently curable. The recent advances such as identification of genetic mutations, replacement of external beam radiotherapy by chemoreduction as the primary management modality, use of chemoreduction to minimize the size of regression scar with consequent optimization of visual potential, identification of histopathologic high-risk factors following enucleation and provision of adjuvant therapy to reduce the incidence of systemic metastasis, protocol-based management of retinoblastoma with accidental perforation or intraocular surgery and aggressive multimodal therapy in the management of orbital retinoblastoma have contributed to improved outcome in terms of better survival, improved eye salvage and potential for optimal visual recovery. Life salvage has improved from 30% in the 1930s to nearly 95% now. Early diagnosis and appropriate referral are the keys to better outcome.

The Ministry of Health and Family Welfare has issued the Standard Treatment Guidelines for Retinoblastoma  treatment in children. Following are the major recommendations:

Case definition:

Retinoblastoma is a malignant tumor arising from the retinal progenitor cell or the retinal stem cell during the period of retinal development and occurs predominantly in children under 3 years of age.

INCIDENCE OF THE CONDITION IN OUR COUNTRY

The reported incidence of retinoblastoma ranges from 1 in 10,000 to 1 in 20,000 live births. There are no good epidemiological studies that provide the accurate data on incidence of retinoblastoma in India. It is estimated that 1500 new cases of retinoblastoma occur in India every year. The ICMR Indian Retinoblastoma Registry has recorded 1019 cases from 8 treatment centers between April 2009 to December 2010. There is no racial or gender predisposition in the incidence of retinoblastoma. Retinoblastoma is bilateral in about 25 to 35% of cases. The average age at diagnosis is 18 months, unilateral cases being diagnosed at around 24 months and bilateral cases before 12 months.

DIFFERENTIAL DIAGNOSIS

The typical clinical manifestation of retinoblastoma is leucocoria. There are several other causes for leucocoria in children that may clinically mimic retinoblastoma in children. Some of the common differential diagnosis are:

1. Coats’ Disease

2. Persistent Hyperplastic Primary Vitreous

3. Toxocara Retinal Granuloma

4. Congenital or Developmental Cataract

5. Endogenous Endophthalmitis

6. Retinal Dysplasia

7. Astrocytic Hamartoma

A good history regarding the time of onset and course of the disease, comprehensive ophthalmic examination often under anesthesia,ultrasonography B-scan and computed tomography scan can reliably help differentiate retinoblastoma from pseudoretinoblastomas.

PREVENTION AND COUNSELING

Out of the newly diagnosed cases of retinoblastoma only 6% are familial while 94% are sporadic. Bilateral retinoblastomas involve germinal mutations in all cases. Approximately 15% of unilateral sporadic retinoblastoma is caused by germinal mutations affecting only one eye while the 85% are sporadic.

Genetic counseling is an important aspect in the management of retinoblastoma. In patients with a positive family history, 40% of the siblings would be at risk of developing retinoblastoma and 40% of the offspring of the affected patient may develop retinoblastoma. In patients with no family history of retinoblastoma, if the affected child has unilateral retinoblastoma, 1% of the siblings are at risk and 8% of the offspring may develop retinoblastoma. In cases of bilateral retinoblastoma with no positive family history, 6% of the siblings and 40% of the offspring have a chance of developing retinoblastoma. The families are counseled to have every future sibling screened for retinoblastoma within 3 weeks after birth and periodically thereafter until at least 3 years of age. Apart from empiric genetic counseling as described above, the current trend is to identify the mutation and compute specific antenatal risk.
The most important aspect in the management of retinoblastoma is early diagnosis. Early diagnosis can be achieved by increasing public awareness about the most common obvious signs (white reflex as seen externally or on a photograph of the child or squint) of retinoblastoma so that the parents bring the child to medical attention. Concurrent sensitization of the medical community, specifically the pediatricians, pediatric health care workers and general ophthalmologists about the possible signs of retinoblastoma and the need for early initiation of management can not be overemphasized.

OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA
Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited

a) Clinical Diagnosis:

A good history eliciting specific symptoms and also a family history of retinoblastoma are essential. Leucocoria is the most common presenting feature of retinoblastoma, followed by strabismus, painful blind eye and loss of vision. The clinical presentation of retinoblastoma depends on the stage of the disease. Early lesions are likely to be missed, unless an indirect ophthalmoscopy is performed. The tumor appears as a translucent or white fluffy retinal mass. The child may present with strabismus if the tumor involves the macula or with reduced visual acuity.

Moderately advanced lesions usually present with leucocoria due to the reflection of light by the white mass in the fundus.

Advanced tumors manifest with proptosis secondary to optic nerve extension or orbital extension and systemic metastasis. Retinoblastoma can spread through the optic nerve with relative ease especially once the lamina cribrosa is breached. Orbital extension may present with proptosis and is most likely to occur at the site of the scleral emissary veins. Systemic metastasis occurs to the brain, skull, distant bones and the lymph nodes.
Some of the atypical manifestations of retinoblastoma include pseudohypopyon, spontaneous hyphema, vitreous hemorrhage, phthisis bulbi and preseptal or orbital cellulites.

Examination: The ocular examination includes estimation of vision by age-appropriate means, an external examination, distant direct ophthalmoscopy, examination of the eye under good illumination and magnification, direct ophthalmoscopy and indirect ophthalmoscopy. A child with suspected retinoblastoma necessarily needs examination under anesthesia. The intraocular pressure is measured and the anterior segment and fundus are examined. Direct visualization of the tumor by an indirect ophthalmoscope is diagnostic of retinoblastoma in over 90% of cases.

Visual acuity measurement: Visual acuity assessment in children is difficult. A 3-12 month old child can only be assessed by fixation and following responses and by determining if one eye is preferred. A child in the age range of 12 months to 36 months can be dynamically assessed using familiar toys. An older verbal child can be assessed by using picture chart and alphabets.

External examination

1. Regional enlargement of lymph nodes

2. Eyelid and periocular edema

3. Proptosis and displacement

Slit-lamp Biomicroscopy (Handheld slit-lamp in younger children) or Examination under illumination and magnification

1. Conjunctival congestion, circumciliary congestion

2. Anterior extraocular extension

3. Corneal horizontal diameter and clarity

4. Depth of anterior chamber, presence of tumor hypopyon

5. Iris neovascularization

6. Cataract

Fundus Evaluation

1. Bilateral fundus examination with 360 degree scleral depression

2. Tumor location, size, morphology, vascularity

3. Extent and location of subretinal fluid, subretinal seeds and vitreous seeds

b) Investigations:

Ultrasonography B-scan helps in confirming the clinical diagnosis when in doubt or if the tumor is not directly visible because of media haze. CT-scan is reserved only to rule out suspected extraocular extension and MRI to rule out optic nerve or intracranial extension and pinealoblastoma. Fundus fluorescein angiography is rarely performed. Bone marrow biopsy is performed to rule out systemic metastasis in cases with clinical or histopathological risk factors and CSF cytology to rule out intracranial extension or CNS metastasis.

Management:

Classification

International Classification of Intraocular Retinoblastoma

Group A Small tumors (< 3 mm) outside macula

Group B Bigger tumors (> 3 mm) or any tumor in macula or any tumor with subretinal fluid

Group C Localized seeds (subretinal or vitreous)

Group D Diffuse seeds (subretinal or vitreous)

Group E Tumor touching the lens, Neovascular glaucoma, Tumor anterior to anterior vitreous face involving ciliary body or anterior segment, Diffuse infiltrating retinoblastoma, Opaque media from hemorrhage, Tumor necrosis with aseptic orbital cellulitis, and Phthisis bulbi

International Staging System for Retinoblastoma

Stage 0

No enucleation (one or both eyes may have intraocular disease)

Stage I

Enucleation, tumor completely resected

Stage II

Enucleation with microscopic residual tumor

Stage III Regional extension
A Overt orbital disease

B Preauricular or cervical lymph node extension

Stage IV Metastatic disease
A Hematogenous metastasis
1 Single lesion
2 Multiple lesions

B CNS Extension
1 Prechiasmatic lesion
2 CNS mass
3 Leptomeningeal disease

C)Treatment

A. Intraocular tumor, International Classification Group A to C, Unilateral or Bilateral

Refer to retinoblastoma treatment center
B. Intraocular tumor, International Classification Group D, Unilateral or Bilateral Refer to retinoblastoma treatment center

C. Intraocular tumor, International Classification Group E, Unilateral or Bilateral

1. Primary enucleation with PMMA orbital implant Special considerations for enucleation in retinoblastoma

• Minimal manipulation

• Avoid perforation of the eye

• Harvest long (> 15 mm) optic nerve stump

• Inspect the enucleated eye for macroscopic extraocular extension and optic nerve involvement

• Harvest fresh tissue for genetic studies

• Avoid biointegrated implant if postoperative radiotherapy is necessary
2. Send specimen for histopathology and high risk factors predictive of metastasis

• Anterior chamber seeding

• Iris infiltration

• Ciliary body infiltration

• Massive choroidal infiltration

• Invasion of the optic nerve lamina cribrosa

• Retrolaminar optic nerve invasion

• Invasion of optic nerve transection

• Scleral infiltration

• Extrascleral extension
D. High risk factors on histopathology, International Staging, Stage II Refer to retinoblastoma treatment center

E. Extraocular tumor, International Staging, Stage IIIA Refer to retinoblastoma treatment center

F. Regional Lymph Node Metastasis, International Staging, Stage IIIB Refer to retinoblastoma treatment center

G. Hematogenous or Central Nervous System Metastasis, International Staging, Stage IV

Refer to retinoblastoma treatment center

Standard Operating Procedure

a. In-Patient :Admit patients for enucleation

b. Out Patient: All older children who can cooperate for examination

c. Day Care: All children undergoing examination under anesthesia
c) Referral criteria:

a) Intraocular tumor, International Classification Group A to C, Unilateral or Bilateral

b) Intraocular tumor, International Classification Group D, Unilateral or Bilateral

c) High risk factors on histopathology, International Staging, Stage II

d) Extraocular tumor, International Staging, Stage IIIA

e) Regional Lymph Node Metastasis, International Staging, Stage IIIB

f) Hematogenous or Central Nervous System Metastasis, International Staging, Stage IV

Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available
a) Clinical Diagnosis:

A good history eliciting specific symptoms and also a family history of retinoblastoma are essential. Leucocoria is the most common presenting feature of retinoblastoma, followed by strabismus, painful blind eye and loss of vision. The clinical presentation of retinoblastoma depends on the stage of the disease. Early lesions are likely to be missed, unless an indirect ophthalmoscopy is performed. The tumor appears as a translucent or white fluffy retinal mass. The child may present with strabismus if the tumor involves the macula or with reduced visual acuity.
Moderately advanced lesions usually present with leucocoria due to the reflection of light by the white mass in the fundus. As the tumor grows further, three patterns are usually seen:

• Endophytic, in which the tumor grows into the vitreous cavity. A yellow white mass progressively fills the entire vitreous cavity and vitreous seeds occur. The retinal vessels are not seen on the tumor surface.

• Exophytic, in which the tumor grows towards the subretinal space. Retinal detachment usually occurs and retinal vessels are seen over the tumor.
• Diffuse infiltrating tumor, in which the tumor diffusely involves the retina causing just a placoid thickness of the retina and not a mass. This is generally seen in older children and usually there is a delay in the diagnosis.
Advanced tumors manifest with proptosis secondary to optic nerve extension or orbital extension and systemic metastasis. Retinoblastoma can spread through the optic nerve with relative ease especially once the lamina cribrosa is breached. Orbital extension may present with proptosis and is most likely to occur at the site of the scleral emissary veins. Systemic metastasis occurs to the brain, skull, distant bones and the lymph nodes.
Some of the atypical manifestations of retinoblastoma include pseudohypopyon, spontaneous hyphema, vitreous hemorrhage, phthisis bulbi and preseptal or orbital cellulites.

Examination: The ocular examination includes estimation of vision by age-appropriate means, an external examination, distant direct ophthalmoscopy, examination of the eye under good illumination and magnification, direct ophthalmoscopy and indirect ophthalmoscopy. A child with suspected retinoblastoma necessarily needs examination under anaesthesia. The intraocular pressure is measured and the anterior segment and fundus are examined. Direct visualization of the tumor by an indirect ophthalmoscope is diagnostic of retinoblastoma in over 90% of cases.

Visual acuity measurement: Visual acuity assessment in children is difficult. A 3-12 month old child can only be assessed by fixation and following responses and by determining if one eye is preferred. A child in the age range of 12 months to 36 months can be dynamically assessed using familiar toys. An older verbal child can be assessed by using picture chart and alphabets.

External examination

1. Regional enlargement of lymph nodes

2. Eyelid and periocular edema

3.Proptosis and displacement
Slit-lamp Biomicroscopy (Handheld slit-lamp in younger children) or Examination under illumination and magnification

1.Conjunctival congestion, circumciliary congestion

2.Anterior extraocular extension

3.Corneal horizontal diameter and clarity

4..Depth of anterior chamber, presence of tumor hypopyon

5.Iris neovascularization

6.Cataract

Fundus Evaluation

1. Bilateral fundus examination with 360 degree scleral depression

2.Tumor location, size, morphology, vascularity

3. Extent and location of subretinal fluid, subretinal seeds and vitreous seeds
b) Investigations:

Ultrasonography B-scan helps in confirming the clinical diagnosis when in doubt or if the tumor is not directly visible because of media haze. CT-scan is reserved only to rule out suspected extraocular extension and MRI to rule out optic nerve or intracranial extension and pinealoblastoma. Fundus fluorescein angiography is rarely performed. Bone marrow biopsy is performed to rule out systemic metastasis in cases with clinical or histopathological risk factors and CSF cytology to rule out intracranial extension or CNS metastasis.

Management:

A. Intraocular tumor, International Classification Group A to C, Unilateral or Bilateral

1. Focal therapy (cryotherapy or transpupillary thermotherapy) alone for smaller tumors (< 3mm diameter and height) located in visually noncrucial areas

2. Standard 6 cycle chemoreduction and sequential aggressive focal therapy for larger tumors and those located in visually crucial areas

3. Defer focal therapy until 6 cycles for tumors located in the macular and juxtapapillary areas. Transpupillary thermotherapy or plaque brachytherapy for residual tumor >6 cycles.

4. Focal therapy for small residual tumor, and plaque brachytherapy/external beam radiotherapy (>12 months age) for large residual tumor if bilateral, and enucleation if unilateral.

B. Intraocular tumor, International Classification Group D, Unilateral or Bilateral

1. High dose chemotherapy and sequential aggressive focal therapy

2. Periocular carboplatin for vitreous seeds

3. Consider primary enucleation if unilateral specially in eyes with no visual prognosis

C. Intraocular tumor, International Classification Group E, Unilateral or Bilateral

1. Primary enucleation with PMMA orbital implant Special considerations for enucleation in retinoblastoma

• Minimal manipulation

• Avoid perforation of the eye

• Harvest long (> 15 mm) optic nerve stump

• Inspect the enucleated eye for macroscopic extraocular extension and optic nerve involvement

• Harvest fresh tissue for genetic studies

• Avoid biointegrated implant if postoperative radiotherapy is necessary
2. Send specimen for histopathology and high risk factors predictive of metastasis

• Anterior chamber seeding

• Iris infiltration

• Ciliary body infiltration

• Massive choroidal infiltration

• Invasion of the optic nerve lamina cribrosa

• Retrolaminar optic nerve invasion

• Invasion of optic nerve transection

• Scleral infiltration

• Extrascleral extension

D. High risk factors on histopathology, International Staging, Stage II

1. Standard 6 cycle adjuvant chemotherapy

2. High dose adjuvant chemotherapy and orbital external beam radiotherapy in patients with scleral infiltration, extraocular extension, and optic nerve extension to transection.

E. Extraocular tumor, International Staging, Stage IIIA

1. Baseline systemic evaluation for metastasis
2. High dose chemotherapy for 3-6 cycles, followed by enucleation or extended enucleation, external beam radiotherapy, and continued chemotherapy for 12 cycles

F. Regional Lymph Node Metastasis, International Staging, Stage IIIB

1. Baseline evaluation for systemic metastasis
2. Neck dissection, high dose chemotherapy for 6 cycles, followed by external beam radiotherapy, and continued chemotherapy for 12 cycles
G. Hematogenous or Central Nervous System Metastasis, International Staging, Stage IV

Palliative therapy in discussion with the family

Standard Operating Procedure

a. In-Patient :

• Admit patients for surgery and chemotherapy

• Admit patients with complications following chemotherapy

b. Out Patient: All older children who can cooperate for examination

c. Day Care: All children undergoing examination under anesthesia and focal treatment.

c) Referral criteria: not applicable

VI. WHO DOES WHAT? AND TIMELINES

a. Doctor :

• Patient history is taken and a clinical examination performed

• Documenting the medical record

• Plan treatment guidelines and perform surgery if necessary.

• Awareness of public and medical personnel

b. Nurse/Technician:

• Perform lab tests

• To monitor the patients who are admitted

• To maintain separate inpatient and outpatient record

• To administer medications as prescribed by the Physician

Situation HUMAN RESOURCES INVESTIGATION DRUGS &
CONSUMABLES
EQUIPMENT
1) Secondary
level
• 1 Ophthalmologist
• 1 OP Nurse
• 1 IP Nurse
• 1 Medicosocial
worker
• Ultrasound B-
scan
• Surgical set for
enucleation
• Facility for
general
• anesthesia
Topical
antibiotics,
topical steroids,
oral anti-
inflammatory
drugs, oral
antibiotics
• Slit-lamp
• Perkins
applanation
• tonometer
Direct
ophthalmoscope
• Indirect
ophthalmoscope
2) Tertiary level • 3 Ocular
Oncologist or
Ophthalmic Plastic
Surgeon or Retinal
Surgeon
• 3 OP Nurse
• 3 IP Nurse
• 2 Medicosocial
worker
• Ultrasound B-
scan
• CT-scan
• MRI
• Pathology
Laboratory
• Surgical set for
enucleation and
orbital
• exenteration
Cryotherapy
• Transpupillary
Thermotherapy
• Plaque
Brachytherapy
• EBRT
• Facility for
Chemotherapy
• Facility for
general
anesthesia
• Topical
antibiotics,
topical steroids,
oral anti-
inflammatory
drugs, oral
antibiotics
• Slit-lamp
• Perkins
applanation
tonometer
• Direct
ophthalmoscope
• Indirect
ophthalmoscope
• Wide-field
fundus imaging
• Fundus
fluorescein
angiography

Guideline of Ministry of Health & Family Welfare Govt. of India.

Group Head Coordinator of Development Team

Dr. Venkatesh Prajna Chief- Dept of Medical Education,

Aravind Eye Hospitals, Madurai

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savita thakur

savita thakur

Studied at Indraprastha College for Women (Delhi University), completed in 2014. Currently working with Medical Dialogues, a online Medical news paper dedicated for healthcare Professionals.
Source: self

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