Bishop Jo Madsen Ec Ratinoblastoma Review of Current Status Surv Opthalmol 197519342-66

Retinoblastoma: A comprehensive review

^one Section of Pediatric Retina and Ocular Oncology, Aravind Centre Hospital and Postgraduate Institute of Ophthalmology, Coimbatore, Tamil Nadu, India
² Section of Physiology, Karpagam Faculty of Medical Sciences and Research, Coimbatore, Tamil Nadu, India

Date of Web Publication

ii-May-2017

Correspondence Address:
Dr. Parag M Shah
Department of Pediatric Retina and Ocular Oncology, Aravind Middle Hospital, Avinashi Road, Coimbatore - 641 014, Tamil Nadu
India

Source of Support: None, Conflict of Interest: None

DOI: ten.4103/kjo.kjo_11_17

Retinoblastoma is the most common intraocular malignancy in childhood. It usually presents earlier 3 years of historic period and can be germinal or nongerminal. There has been a prototype shift in the classification and management of retinoblastoma. This review provide the international retinoblastoma nomenclature, latest classification of vitreous seeds, and current and newer handling modalities such every bit intra-arterial and intravitreal chemotherapy.

Keywords: International classification, intra-arterial chemotherapy, intravitreal chemotherapy, retinoblastoma, vitreous seeds

How to cite this commodity:
Naik As, Jyothi Due south, Shah PK. Retinoblastoma: A comprehensive review. Kerala J Ophthalmol 2016;28:164-seventy

Introduction

Retinoblastoma is the well-nigh common intraocular malignancy in children, with a reported incidence ranging from 1 in 15000 to 1 in 18000 alive births.^[ane] There is no racial or gender predisposition in the incidence of retinoblastoma. It is bilateral in approximately 25–35% of the cases. The average age at diagnosis is xviii months, unilateral cases being diagnosed at approximately 24 months and bilateral cases before 12 months.^[2] Pawius described retinoblastoma as early on equally in 1597. In 1809, Wardrop referred to the tumor as fungus hematodes and suggested enucleation as the primary mode of direction. The discovery of ophthalmoloscope in 1851 facilitated recognition of specific clinical features of retinoblastoma. Initially thought to be derived from the glial cells, it was called a glioma of the retina past Virchow.^[three] Flexner (1891) and Wintersteiner (1897) believed it to be a neuroepithelioma because of the presence of rosettes.^[3] Later, at that place was a consensus that the tumor originated from the retinoblasts, and the American Ophthalmological Society officially accepted the term retinoblastoma in 1926.^[iv] There has been a epitome shift in the management of retinoblastoma since then. Information technology is now known as a curable cancer.^[five] Amidst the most important objectives in the management of a child with retinoblastoma is survival followed by preservation of the globe, and focus on visual vigil comes concluding. Therapy is customized to each individual instance and is based on the overall anatomical situation, including threat of metastatic disease, laterality, the number, size and location of the tumor(southward), evidence of subretinal fluid, localized or lengthened vitreous seeding, risks for secondary tumors, systemic status, and estimated visual prognosis.^[vi]

Genetics of Retinoblastoma

It is caused by a mutation long arm of chromosome 13, band fourteen (13q14).^[7] RB1 gene is a tumor-suppressor cistron, and both the genes have to exist mutated to cause this disease. When both the mutations involve only the retinal cells (somatic cells), the child develops a nongerminal type of disease, which is nonheritable. Yet, when 1 mutation involves the germinal jail cell, the kid develops the germinal blazon of disease, which is transmittable to the adjacent generation.^[v] Out of the newly diagnosed cases of retinoblastoma, only 6% are familial whereas 94% are sporadic.^{[2],[half-dozen]} Bilateral retinoblastomas involve germinal mutations in all cases. Approximately fifteen% of unilateral sporadic retinoblastoma is caused by germinal mutations affecting just one heart whereas 85% are sporadic.^[2]

In 1971, Knudson proposed the two-striking hypothesis. He stated that, for retinoblastoma to develop, two chromosomal mutations are needed. In hereditary retinoblastoma, the initial hit is a germinal mutation, which is inherited and is found in all the cells. The 2nd hit develops in the somatic retinal cells leading to the development of retinoblastoma. Therefore, hereditary cases are predisposed to the development of nonocular tumors such as osteosarcoma. In unilateral sporadic retinoblastoma, both the hits occur during the development of the retina and are somatic mutations. Therefore there is no adventure of 2nd nonocular tumors.^[viii]

Genetic counseling is an important aspect in the management of retinoblastoma. In patients with a positive family history, 40% of the siblings would exist at risk of developing retinoblastoma and twoscore% of the offspring of the affected patient may develop retinoblastoma. In patients with no family unit history of retinoblastoma, if the affected kid has unilateral retinoblastoma, 1% of the siblings are at risk and eight% of the offspring may develop retinoblastoma. In cases of bilateral retinoblastoma with no positive family unit history, 6% of the siblings and 40% of the offspring take a hazard of developing retinoblastoma.^[2]

Apart from empiric genetic counseling, as described to a higher place, the current trend is to identify the mutation and compute specific antenatal adventure.^[ix] Knowledge of the full range of mutations can aid in the design of screening tests for individuals at risk.^[10]

Histopathology of Retinoblastoma

On low magnification, basophilic areas of tumor are seen along with eosinophilic areas of necrosis and more basophilic areas of calcification within the tumor. Poorly-differentiated tumors consist of small-to-medium sized round cells with large hyperchromatic nuclei and scanty cytoplasm with mitotic figures. Well-differentiated tumors show the presence of rosettes and fleurettes. These can be of various types. Flexner Wintersteiner rosettes consist of columnar cells arranged around a cardinal lumen. This is highly characteristic of retinoblastoma, and is likewise seen in medulloepithelioma. Homer Wright rosettes consist of cells arranged around a central neuromuscular tangle. This is besides institute in neuroblastomas, medulloblastomas, and medulloepitheliomas. Pseudorosette refers to the organisation of tumor cells effectually blood vessels. They are non signs of good differentiation. Fleurettes are eosinophilic structures composed of tumor cells with pear-shaped eosinophilic processes projecting through a fenestrated membrane. Rosettes and fleurettes betoken that the tumor cells show photoreceptor differentiation. In improver, basophilic deposits (precipitated DNA released after tumor necrosis) can exist found in the walls of the lumen of blood vessels.^[ii],[5]

Clinical Manifestations of Retinoblastoma

Leucocoria is the nearly common presenting feature of retinoblastoma, followed by strabismus, painful bullheaded eye, and loss of vision.^[5] [Tabular array one] lists the common presenting signs and symptoms of retinoblastoma.^[11] The clinical presentation of retinoblastoma depends on the stage of the illness. 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 kid may present with strabismus if the tumor involves the macula or with reduced visual acuity.^[12]

There are three types of clinical presentations. 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 normally occurs and retinal vessels are seen over the tumor. Diffuse infiltrating tumor in which the tumor diffusely involves the retina causing only a placoid thickness of the retina and not a mass. This is generally seen in older children and usually in that location is a delay in the diagnosis.^[5]

Advanced tumors manifest with proptosis secondary to optic nerve extension or orbital extension and systemic metastasis.^[12] Retinoblastoma can spread through the optic nervus with relative ease, especially once the lamina cribrosa is breached. Orbital extension may present with proptosis and is nearly likely to occur at the site of the scleral emissary veins. Systemic metastasis occurs to the brain, skull, distant bones, and lymph nodes.^[12] Some of the atypical manifestations of retinoblastoma include pseudohypopyon, spontaneous hyphema, vitreous hemorrhage, phthisis bulbi, and preseptal or orbital cellulitis.

Classification

The classification currently used for staging and grouping retinoblastoma is "The International Nomenclature of Retinoblastoma." Information technology has replaced the older Reese Ellsworth classification, as information technology could not be applied to current handling modalities.

This classification consists of two parts:

1. Staging for the patient
2. Grouping for each eye.

Staging for patient equally a whole

There are five stages:^[13]

Stage 0: When the child presents with intraocular retinoblastoma with no regional or systemic metastasis, and no enucleation has been performed.

Stage one: When enucleation has been washed in one eye. High-risk pathology features may exist nowadays in the enucleated specimen. It may be nowadays in the other center.

Stage two: When residual orbital tumor is seen at the cut end of the optic nerve during enucleation.

Stage 3: When at that place is an overt orbital extension with involvement of preauricular or cervical lymph nodes.

Stage 4: Distant metastasis. Information technology is subdivided into:

1. Phase 4a: Non-key nervous system (CNS) spread
2. Stage 4b: CNS spread.

Grouping for each heart

This also has five groups:^[14]

1. Group A: Small-scale tumors which are <3 mm in size and should be located at to the lowest degree 3 mm from the fovea and one.v mm from the optic disc
2. Group B: Any tumor >3 mm in size (except smaller tumors which are very close to fovea and optic disc every bit specified in group A). Cuff of exudative retinal detachment <5 mm from the tumor base or <1 quadrant is allowed
3. Group C: Any tumor with localized tumor dissemination, i.e., vitreous seeds or subretinal seeds, which are <iii mm from the tumor surface
4. Grouping D: Whatever tumor with lengthened vitreous or subretinal seeds
5. Group Due east: End-stage disease.

For case:

1. Neovascular glaucoma
2. Tumor or retinal detachment touching the lens
3. Anterior segment involvement
4. Aseptic orbital cellulitis, etc.

Diagnosis

A thorough clinical evaluation with careful attention to details, aided by ultrasonography

B browse helps in the diagnosis. Computed tomography is usually avoided to reduce radiations exposure, which tin trigger second cancers in children with germinal mutation. Magnetic resonance imaging (MRI) is the preferred modality for diagnosis and to dominion out extraocular or intracranial "trilateral" retinoblastoma. A child with suspected retinoblastoma necessarily needs complete ophthalmic evaluation including a dilated fundus examination under anesthesia.^[12]

The intraocular pressure is measured and the anterior segment is examined for neovascularization, pseudohypopyon, hyphema, and signs of inflammation. Bilateral fundus examination with 360-caste scleral depression is mandatory. Direct visualization of the tumor by an indirect ophthalmoscope is diagnostic of retinoblastoma in over 90% of the cases. RetCam is a wideangle fundus camera useful in accurately documenting retinoblastoma and monitoring response to therapy. Ultrasonography B browse shows a rounded or irregular intraocular mass with high internal reflectivity representing typical intralesional calcification. On fluorescein angiography, smaller retinoblastoma shows minimally dilated feeding vessels in the arterial phase, blotchy hyperfluorescence in the venous phase, and tardily staining. Paw-held spectral domain optical coherence Tomography (HH SD-OCT) imaging has dramatically improved the sensitivity to discover early tumors, recurrences, and complications in focal therapy management of retinoblastoma patients. Overall, indirect ophthalmoscopy remains the aureate standard for the diagnosis and handling of active retinoblastoma. Lumbar puncture and os marrow aspiration for distant staging is done only when there are features of extraocular spread.^[15],[16]

Management of Retinoblastoma

The primary goal of management of retinoblastoma is to salvage life. Salve of the organ (eye) and function (vision) are the secondary and tertiary goals, respectively. The management of retinoblastoma needs a multidisciplinary team arroyo including an ocular oncologist, pediatric oncologist, radiation oncologist, radiation physicist, genetist and an ophthalmic oncopathologist. The management strategy depends on the stage of the disease – intraocular retinoblastoma, retinoblastoma with high run a risk characteristics, orbital retinoblastoma, and metastatic retinoblastoma. Management of retinoblastoma is highly individualized and is based on several considerations including historic period at presentation, laterality, tumor location, tumor staging, visual prognosis, systemic status, and family unit and societal perception, and, to a certain extent, the overall prognosis and cost effectiveness of the treatment in a given economical situation.^[5]

Treatment of Intraocular Retinoblastoma

A bulk of children with retinoblastoma manifest at the phase when the tumor is confined to the centre. Approximately 90–95% of the children in developed countries present with intraocular retinoblastoma, whereas 60–70% present at this stage in the developing world. Diagnosis of retinoblastoma at this stage and advisable management are crucial for life, center, and possible vision relieve.

There are several options for the treatment of retinoblastoma, and the ocular oncologist should be thoroughly familiar with the indications, technique, and expected results of all treatment methods besides equally the expected systemic and visual problems.^[6]

Various methods to manage intraocular retinoblastoma are focal (cryotherapy, laser photocoagulation, transpupillary thermotherapy, transcleral thermotherapy, plaque brachytherapy), local (external beam radiotherapy, enucleation), and systemic (chemotherapy). While primary focal measures are mainly reserved for minor tumors, local and systemic modalities are used to treat advanced retinoblastoma.^[5],[12]

Grouping A

Only focal treatment in the form of cryotherapy, light amplification by stimulated emission of radiation photocoagulation, or thermotherapy.

1. Cryotherapy involves freezing the tumor till its apex with a cryoprobe and thawing it for 1 min. This is done thrice and is called triple freeze thaw cryotherapy. This handling is preferred for anterior tumors. The disadvantage is that the scar formed is much bigger than the tumor size ^[17]
2. Light amplification by stimulated emission of radiation photocoagulation involves surrounding the tumor with ii to iii rows of greenish laser (532 nm). This cuts off the claret supply and leads to regression of the tumor. This is preferred for posterior tumors. However, here also the scar formed is much bigger than the initial tumor and high power if used on tumor surface can cause iatrogenic vitreous seeding ^[18],[19]
3. Transpupillary thermotherapy (TTT) is a method of applying localized heat to tissue that is below the coagulative threshold, and thus sparing the retinal vessels from photocoagulation. The goal is to evangelize a temperature of 42–60°C using a diode infrared (810 nm) laser system and induce tumor necrosis. The reward of TTT is that the scar formed is not bigger than the tumor size.^[20]

Group B

Here, in addition to local therapy, the tumor needs to exist reduced in size with the help of chemotherapy. Hither, at least iii cycles of chemotherapy (carboplatin, vincristine with or without etoposide) are needed along with local therapy earlier every wheel. Primary episcleral brachytherapy using either Ru 106 or I 125 seeds is besides an option.^[6]

Group C

Almost retinoblastoma centers now prefer a protocol of three-amanuensis chemotherapy using vincristine (0.05 mg/kg), etoposide (v mg/kg), and carboplatin (18.6 mg/kg) (VEC) delivered 3 weekly over six cycles to allow for adequate tumor reduction along with local therapy before each cycle. In addition to this, ii ml of sub-tenon carboplatin (STC) can exist given to tackle the avascular vitreous or subretinal seeds on the day of chemocycles ii, 3, and 4. However, it causes lot of periocular inflammation and might crusade a frozen orbit. STC should exist avoided along with cryotherapy as this combination can lead to rhegmatogenous retinal disengagement.^[21] A strikingly fewer numbers of trilateral retinoblastoma were noted in children who were treated with chemotherapy, and hence, Shields concluded that chemotherapy might exist protecting confronting the highly fatal intracranial neuroblastic tumors.^[22] This observation is especially important in children with bilateral or familial retinoblastoma who are at greatest gamble for this encephalon tumor.

Grouping D

In addition to the treatment described above for group C, a reduced dose of 36 Gy of whole-globe EBRT (standard dose is 46 Gy) would exist required if reactivation of tumor is seen. EBRT may induce a second cancer among patients with familial illness. Babies who are younger than 12 months of age accept a greater adventure for second cancers than patients over 12 months of historic period in the field of irradiation.^[23] The 30-year cumulative incidence for second cancers in bilateral retinoblastoma (germinal mutation) has been reported at 35% for patients who received radiation therapy compared with 6% for those who did not receive radiation.^[24] This was found to be dependent on patient age at the time of irradiation as well as other factors. Primary enucleation is all the same an option in unilateral grouping D cases.

Group E

The ideal treatment option for this group is enucleation. The thought is to gently remove the intact heart without seeding the malignancy into the orbit.^[25] Orbital implants are routinely placed in children at the time of initial surgery and give splendid cosmetic results with improved prosthesis motility.^[26],[27] After enucleation, on histopathology, if high-risk pathology features are nowadays, the child will require six cycles of adjuvant chemotherapy to foreclose distant metastasis.

Histopathologic high-take a chance features are:

1. Massive choroidal invasion
2. Involvement of tumor past the lamina cribrosa of optic nerve
3. Tumor invading into the sclera
4. Anterior chamber involvement
5. Iris invasion.

In rare cases of bilateral group E, treatment as specified in group D should be attempted. On the basis of the International Classification of Retinoblastoma, handling success was establish in 100% of group A optics, 93% of grouping B eyes, and 90% of grouping C optics.^[28] Group D eyes showed 48% success, however, more recently, these eyes have been managed with additional focal chemotherapy (intra-arterial and intravitreal) to amend control.

Tumor Regression Patterns

The interpretation of tumor regression tin exist challenging as retinoblastoma tin regress in one of several patterns including type 0 (no remnant visible), type 1 (calcified remnant), blazon 2 (noncalcified or fish flesh remnant), type 3 (partially calcified with fish flesh remnant), and type 4 (flat scar).^[29] These regression patterns are defined mail EBRT. However postal service chemotherapy, types two and 3 patterns should be closely watched as they have a high chance of reactivation.

Intra-arterial chemotherapy

This was first described equally early as 1954 by Reese.^[30] Later, the Japanese revisited this delivery technique in 1993,^[31] followed by the Americans.^[32] In this procedure, chemotherapy is given directly in the ophthalmic artery with the help of an interventional radiologist. The benefit is that it allows a high concentration of the drug to the center (and to the cancer), with far lower concentrations when given systemically. This modality was successful in sparing enucleation in seven out of 9 children with avant-garde retinoblastoma, with acceptable ocular toxicity and minimal systemic toxicity, and that many treated eyes could retain or even improve retinal function.^[33] In a 3-twelvemonth experience with this technique on advanced retinoblastoma, only 1 of 28 eyes required enucleation and none required adjuvant systemic chemotherapy or radiations.^[34]

The drugs that tin be used are melphalan (about common) with or without topotecan hydrochloride or carboplatin. Drug dosage is five mg for melphalan, 0.three mg for topotecan, and 30 mg for carboplatin. The decision to apply 1 or 2 drugs is based on clinical judgment with eyes that were more than extensively involved (especially widespread seeding) receiving two agents at one time.^[34] Melphalan is diluted with saline to obtain a volume of 30 ml of solution, which is injected manually by repeated pocket-sized bolus (pulsatile injection) at a rate of 1 ml/min. After drug commitment, the catheter is removed and hemostasis of the femoral artery is obtained with transmission compression. Efficacy and toxicity are judged during the examination under anesthesia performed 3–4 weeks after each treatment. Efficacy is judged on tumor shrinkage and regression, disappearance or calcifications of vitreous and subretinal seeds, and absence of new tumor growth. Toxicity is estimated with electroretinograph study. The mild short-term effects included eyelid edema, blepharoptosis, and orbital congestion, sometimes with temporary dysmotility.^[35] The more serious ocular adverse events include arterial occlusion, retinal haemorrhage, and orbital inflammation in the early phase, and chorioretinal atrophy and ischemic chorioretinopathy in the late phase.^[36] Another drawback of this therapy is that, even if enucleation is avoided in some advanced grouping E eyes, there is a chance of afar metastasis every bit that child would have received prophylactic chemotherapy if high-gamble pathology features were seen on enuleated specimen.^[35] There could also be a risk of inducing 2d cancers in patients with germinal mutation if repeated fluoroscopy was done for this procedure.

Intravitreal chemotherapy

Intravitreal assistants of chemotherapy for vitreous illness offers the opportunity of delivering the desired tumoricidal drug concentration within the vitreous crenel, however, information technology is associated with the risk of tumor spread. The use of intravitreal melphalan for vitreous seeding was first introduced in the 1990s by Kaneko and Suzuki, who treated 41 eyes with eight mg melphalan and simultaneous hyperthermia using a Lagendijk applicator.^[37]

Munier et al.^[38] described the eligibility criteria for intravitreal chemotherapy injection in retinoblastoma, and described a safety-enhanced technique for intravitreal injection using an antireflux procedure followed by sterilization of the needle rails. Eligibility criteria for IViC as assessed past ultrasonic biomicroscopy (UBM) were every bit follows: (one) absenteeism of invasion of the anterior and posterior bedroom; (2) absence of anterior hyaloid detachment; (iii) absence of retinal detachment at the entry site; (iv) absenteeism of tumor at the entry site; and (5) absenteeism of vitreous seeds at the entry site.^[39]

The current literature on retinoblastoma emphasizes vitreous seeding as the chief reason for treatment failure and loss of the eye.^[40] In fact, vitreous seeds have been recognized every bit the defining feature for failure by the Reese and Ellsworth classification group (Vb)^[41] and the International Classification of Retinoblastoma group (D).^[14] With increased adoption of intravitreal melphalan, salve rates for optics with vitreous seeds are surpassing all historical data. Munier also proposed a classification scheme ^[42] for the vitreous seeds to aid in the interpretation of disease and raise reporting in the literature. This classification system is based on morphologic features of seeds and divides vitreous seeds into 3 groups: dust (grade 1), spheres (class two), and clouds (class 3).^[42] He likewise proposed seed regression pattern (type 0 = non visible, blazon 1 = calcific, blazon 2 = baggy, type 3 = types 1 and two).^[42]

Dust results from a deportation of tumor cells into the vitreous appears as minor granules of vitreous opacities, and can be seen as a vitreous brume overlying the tumor. They respond to the to the lowest degree amount of time to intravitreal melphalan and required significantly fewer injections (median, 3) earlier regression is noted. Grit typically regressed into a blazon 0 pattern, implying that it was non detectable via ophthalmoscopy.

Spheres result from the translocation of tumor cells into the vitreous, which then undergo clonal expansion into spheres. They are spherical opacities inside the vitreous, and dust may be present effectually them. They tin exist homogeneously opaque and have a translucent outer beat with a relatively transparent or whitish heart. The median number of injections required for regression is v. Following the injections, they initially disperse and eventually disappear on ophthalmoscopy or became calcific (regression blazon I), or baggy in shape (regression blazon II), or even a mixture of these 2 (regression type Iii).

Clouds consequence from massive transference of tumor cells into the vitreous and are typically visualized as a dense collection of punctate vitreous opacities. They tin can appear as a sail or globule of seed granules and often with wispy edges, and dust and spheres are sometimes too visible. They responded to intravitreal melphalan in a significantly prolonged fashion, with a median of eight injections. They typically regress to calcific or baggy granules, and over time, some slowly became undetectable to ophthalmoscopy. Special precaution should be taken while giving intravitreal chemotherpy for retinoblastoma.^[43]

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Conflicts of interest

In that location are no conflicts of interest.

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  [Table 1]

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Source: https://www.kjophthal.com/article.asp?issn=0976-6677;year=2016;volume=28;issue=3;spage=164;epage=170;aulast=Naik

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