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Chapter 1

General introduction


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Chapter 1


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Introduction

Introduction

Retinoblastoma (Rb) is a rare, but very aggressive malignant eye tumour seen in young children.1 Worldwide, it affects 8000 children per year; the incidence in the Netherlands is 10-15 patients.2,3 Rb is a life threatening disease, but improved diagnostic facilities and an ever-growing range of therapeutic options have changed the perspective of the Rb-patient dramatically. Surgical removal of the affected eye(s), called enucleation, is the oldest treatment for Rb and till present one of the most frequently applied treatment modalities.4 There is a tendency towards less invasive interventions, in developed countries treatment for advanced tumours (accounting for almost 80% of all Rb-patients5) is progressing by eye and vision saving modalities whereas these tumours were previously enucleated. However, enucleation remains a valid treatment option depending on the clinical setting, tumour extend, judgement of ophthalmologist and expectations of parents. Primary enucleation remains the treatment of choice for group E eyes6 as it appeared to be highly effective and a definite cure for Rb restricted to the eye.7 Enucleation, however, is an invasive and definitive procedure with the loss of a child’s eye. Rehabilitative procedures, such as insertion of an orbital implant, have been developed to minimize mutilating aspects and aim to offer the Rb-patient a life as good as can be. In contrast to most other aspects of Rb such as pathogenesis, genetics and survival, the role and functional and cosmetic outcome of enucleation in Rb-patients has received little attention so far.

In this thesis, we evaluate the consequences of enucleation in survivors of Rb.

Inheritance, Pathogenesis and PresentationRb is almost always caused by bi-allelic mutation of the RB1 suppressor gene, located on chromosome 13q14.8 In sporadic or non-familial cases there has been no prior manifestation of the disease in the family. This accounts for 90% of the patients with retinoblastoma. When a mutation is limited to the somatic cells of the retina tumour, the RB1 mutation will not be passed on to the offspring. If, however, the mutation also involves the germline cells, the disease becomes heritable and will be passed to the offspring in 50% of the cases because Rb has an autosomal dominant inheritance pattern with > 90% penetrance.9 We therefore distinguish heritable and non-heritable cases with Rb. Whether one is suffering from an heritable form of Rb, can be assessed by RB1 germline mutation testing.10

If one eye is affected and no family members are affected, there is a 15% chance of a heritable form; if both eyes are affected, the chance of an heritable form is almost 100%.9 In 75% of the patients with Rb, only one eye is affected.

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Chapter 1

In heritable patients (40% of all Rb-patients), the first mutation in the germline cells can be inherited (familial heritable Rb) or occur ‘de novo’ (non-familial heritable Rb). The second inactivation of RB1 occurs in the developing retina cells. In non-heritable Rb (unilateral cases) both mutations occur in the somatic cells. The RB1 suppressor gene prevents excessive cell growth. When the RB1 gene has been mutated, its function as a suppressor gets lost, allowing uncontrollable cell division and genomic instability, which finally leads to malignant retinoblastoma formation.11,12 In 1% of the Rb-patients no RB1 gene mutations in the tumour can be found. Recently, it was shown that in these patients the oncogene ‘MYC-N’ is amplificated (28-121 DNA copies instead of the normal 2 copies), which also initiates Rb.10 Patients with Rb due to MYC-N amplification are only unilaterally affected.10 This form is presumably not heritable. Rb originates from mutated retinoblasts, the precursor cells of the retina. Blasts start differentiating into retina cells before birth; by the age of five, the retina is fully developed, which explains why Rb is hardly ever seen in patients older than 5 years of age.

In addition to bilateral Rb, a tumour -histopathological very closely resembling Rb- can be seen in locations outside the eyes, namely in the pineal gland or in the suprasellar cistern.13 This condition is called trilateral Rb or intracranial midline primitive neuroectodermal tumour.

Rb is suspected in young children with leukocoria (white pupillary reflex) and/or strabismus. In more advanced cases nystagmus, photophobia, pain, orbital cellulitis, proptosis, buphthalmos and glaucoma may be present.14 A diagnosis of Rb is made upon funduscopic examination under anaesthesia and on ultrasonography. A complemented MRI is performed to visualize the extensiveness of the tumour(s), which indicates metastatic risk and to assess potential intracranial tumours.

SurvivalIn developed countries the overall 5-year survival rate is 95-100%.13,15 Diagnosis delay combined with inadequate treatment leads to tumour extension in orbit, brain, liquor and distant metastasis, lowering the survival rates to 30% in under developed countries.13,15 Patients with the hereditary form have an increased risk of second primary malignancies including osteogenic sarcoma, soft tissue sarcomas, and malignant melanoma.16,17 This is nowadays the main reason of death in hereditary retinoblastoma survivors.

Staging & Treatment The choice of treatment, as well as the prognosis, depends on the stage of the tumour at presentation. Tumour stage, - foci, - size, - location, - seedings


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Introduction

(tumour cells floating within the vitreous cavity or in the anterior chamber), - growth pattern (endofytic, exofytic, diffuse or combined), intra- and extraocular disruptions (retinal detachment, glaucoma, haemorrhages, phtisis bulbi, orbital cellulitis) and risk factors assessed by histopathology are features predictive of the outcome. At present, multiple staging systems are used.18,19 The most recent and complete staging system is the 2017 TNMH staging system, which is based on an international consensus.20 Today, many different treatment modalities for Rb are available. A small retinoblastoma can be treated with cryotherapy (Rb < 3 mm, located in the retinal periphery). Lasertherapy is an option for tumours of < 3 mm located in the centre of the eye, but excluding the macular area and optic nerve head. Brachytherapy is applied for middle-sized tumours (> 3 mm) or recurrent tumours. These treatments can be combined with systemic chemotherapy to increase the susceptibility of the lesion and to induce tumour shrinkage. Intra vitreal chemotherapeutic injections can achieve adequate therapeutic levels to treat seedings of the (prior or simultaneously treated) primary tumour.21 Treatment options for the advanced stages (concerning 80% of the cases5) are enucleation, intra-arterial chemotherapy (IAC) and external beam radiation therapy (EBRT). Systemic chemotherapy is given as adjuvant treatment in patients with identified high risk factors for metastasis. The latest development, IAC, is a technique allowing the administration of highly concentrated cytostatics directly into the ophthalmic artery. This is a very promising technique, which ultimately may make enucleation superfluously. At present, however, the efficacy and long-term sequels of IAC are insufficiently known. EBRT was the first introduced treatment modality for retinoblastoma to preserve vision and to save the eyeball in 1950.22 It has been performed on a large scale to treat small and larger Rbs until the mid-nineties. EBRT appeared to be effective, but did not replace enucleation in the long run. The use of this treatment for Rb significantly decreased when the long term sequelae were learned. Apart from irradiation retinopathy, inhibition of tear production and cataract, radiotherapy-related toxicity was seen in skull and teeth development.23,24 In children younger than six months of age radiation arrested healthy bony cell-growth, leading to extensive disfigurement of the face.23 Moreover, it increased the chance of a second primary malignant tumour.24

Although irradiation techniques have been improved from a two-way field orthovoltage irradiation to a D-shaped field megavoltage technique and nowadays to proton beam radiation, the risk of severe late complications has not been eliminated and today EBRT is only considered as last treatment option in bilateral Rb-patients unresponsive to other therapy to preserve at least one eye with some residual vision.

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Chapter 1

EnucleationJohannes Lang, in 1555, was the first to report on an enucleation.25 Enucleation refers to the complete removal of the globe and is an effective procedure for intra-ocular tumours as retinoblastoma. The technique is also used for other malignant intraocular tumours for which other treatment modalities offer an insufficient survival perspective. Enucleation is also performed in patients with a painful, blind eye without tumour, although there is a tendency to perform an evisceration in these cases.26 The procedure is almost always performed under general anaesthesia (recommended in children) and the original technique is as follows: the conjunctiva is opened around the limbus and detached from the globe. The ocular muscles are detached from the globe and the largest possible portion of the optic nerve is transected with a special pair of scissors or with a metal sling. The conjunctival edges are sued together. The orbital socket, thus, loses the volume of the globe, which is about 7 cc. After healing of the wound, a prosthesis can be placed in the cavity.27

Federico da Montefeltro (1422-1482) (Figure 1) lost his right eye as a result of trauma. This person, a famous representative of the beau monde of the Renaissance in Italy, only wanted the left side of his face to be painted. Apparently, -during his life- a satisfying solution to rehabilitate his appearance was never found. Although even in those days, one realized that a prosthesis would help to restore the original appearance.

The first artificial eyes (stone, metal, silver or gold) were made by the Babylonian and Sumerian civilizations for their mummies and statues.

Ambroise Paré (1510-1590) has been the pioneer of the modern prosthesis, the first who manufactured both glass and porcelain eyes.28,29 Shortage of material to make glass led to the use of methyl methacrylate (dental acryl) during the Second World War.27 Today both glass and poly methyl methacrylate eyes are manufactured.

Even with a well fitted prosthesis, there is a serious risk for development of the so-called ‘Postenucleation Socket Syndrome’ (PESS), described by Tyers and Collin.30 The classic PESS phenomena: enophthalmos, deepening of the superior sulcus, ptosis and lower lid laxity (resulting in sagging of the lower lid and possible ec- or entropion), shortening of the inferior fornix with subsequent malpositioning or ill-fitting of the prosthesis (tilted, looking upwards) and lagophthalmos were described as symptoms in anophthalmic patients without orbital implants.30,31 All these phenomena can also occur isolated. A prosthesis equalling the size of the removed eye is rather heavy and tends to rotate the remaining orbital tissues in a backward fashion in the sagittal plane as described by Smit et al.32 This backward rotation and volume loss can be prevented by inserting an artificial volume into


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Introduction

the socket, over which the muscles, tenon and conjunctiva are closed. Using this technique a much thinner and thus lower weight prosthesis is needed, provoking less PESS.32 At present, a large number of different implants to compensate for the volume loss after enucleation are available. Mostly, the implant needs a covering sheet (wrapping), to which the muscles can be attached and which may prevent extrusion of the orbital implant. Again, many different wrapping materials are used. Apart, from substitution of the lost volume, the implant and prosthesis, ideally, should suggest the presence of a real eye, that moves in conjunction with the fellow eye and of which the pupil size may even change like the natural light-induced pupillary reaction. All these differences may lead to different cosmetic results. For over a decade, new implant shapes (with and anterior ring (Allen

Figure 1. Federico da Montefeltro di Piero della Francesca.* although he seemed to care for his cosmesis, he removed a part of his nose bridge to increase his field of view.

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Chapter 1

Implant), tunnels or holes (Castroviejo and Medpor SST) to facilitate muscle attachment)) and new implant materials (allowing for fibrovascular integration) have been introduced to improve the motility of the implant itself. Also, attempts have been made to connect the implant with the prosthesis in order to reinforce artificial eye motility. These attempts include magnetic coupling of the implant and prosthesis, direct coupling via a peg, and indirect coupling (using ‘the lock and key’ mechanism) via a quasi-integrated implant with an irregular shaped anterior side (Iowa, Universal and quad motility implant) and a prosthesis resembling the negative (at the posterior side) of the irregular anterior shape of the implant.

However, problems encountered due to the altered shapes and surfaces were tilting of the implant and erosion of the overlying conjunctiva. Magnetic coupling seemed promising but in cases where the magnet was to strong, conjunctival compression could lead to exposure. More importantly a local toxicity due to accumulation of iron ions in the conjunctiva led to tissue necrosis and rusting of the magnet was seen with subsequent tissue response and exposure. Also, as with all metallic implants, MR imaging was contraindicated.33 Alternatively, pegging of the implant was too frequent subject of insufficient reepithelialisation of the conjunctiva over the drilled hole (exposure) followed by infection and extrusion of the pin that connected the implant with the prosthesis. The postulations that the porous implants would also achieve better motility -without an additional motility peg- than the non-porous implant was nullified in a study of Colen et al.34

Today it is believed that the translation of the orbital motility to the prosthesis is best using a large implant filling up the entire socket in combination with a connected fit of a thin and light weighted prosthesis.

In young children, enucleation evokes another problem: for the growth of the orbit, indeed for the whole half of the ipsilateral face, the presence of an eye or substitute stimulates the surrounding tissues to grow. In the study of Oatts et al.35 the detrimental effect of enucleation with orbital implant insertion on the symmetry of the face was shown significant in children enucleated below the age of three. Choiniak et al.36 found that patients abnormal orbital development was greater in patients additionally treated with EBRT. Also 2-fold greater orbital asymmetry was registered in patients without an implant.

Age at time of enucleation influences the options for reconstructive measurements such as the size of an implant that can fit in the socket. Furthermore, the ongoing growth of the contralateral eye and total face in these young children influences the facial proportions. Growth retardation is thus a sequel of enucleation to reckon with.

Even after successful enucleation, patients may be bothered with discharge from the socket, from displacement of the implant resulting in prostheses fitting


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Introduction

problems, from exposure or extrusion of the implant needing subsequent surgery, from postoperative persisting pain complaints and from dissatisfaction with the cosmetic result.

In this thesis we evaluate eyesocket-related problems and cosmetic effects in patients enucleated or irradiated for retinoblastoma at young age, and assess potential adjustable factors. Questions we like to address are the following: how often do we see socket-related functional and cosmetic problems in this patient group? Can we relate these issues to surgery techniques or materials? Which interventions are successful or can be advised? How can we improve cosmetic outcome and reduce socket related complaints?

Aims & Outline of the thesis This thesis focusses on the outcome in Rb-patients treated with enucleation (and/or EBRT), representing the majority of the current retinoblastoma survivors. Today many enucleation techniques and materials exist. Studies reporting cosmetic and functional outcome of these different techniques are scarce and comparison of the different techniques has not been done. In the treatment of Rb we aim for a save technique with the lowest risk of complications. The clinician should be aware of (potential) effects on short and long term when considering different treatment options. In this thesis we will evaluate our own experiences of the treatment with enucleation and/or external beam radiation therapy and compare these with the literature. The aim of this thesis is to provide the clinician with relevant information and advice regarding enucleation and EBRT. Initially an inventory of used surgery techniques, use of different orbital implants and documented major complications in our own cohort of 216 retinoblastoma patients was done and compared with the results in the literature. Results will be described in chapter 2. In order to gain insight in techniques and materials that are currently used worldwide, another inventory was carried out and discussed in chapter 3. In chapter 4 we call for a return of the use of acrylic (non-porous) orbital implants. Different implants and surgery techniques are designed for several reasons, one being prosthetic eye motility. However, since an easy -in children applicable- objective and reproducible prosthetic eye motility measurement method was lacking, we implemented a new technique. This technique was readily applied to compare the motility of porous and non-porous implants as well as different sized implants. This novel technique and results of the comparison are presented in chapter 5. From 195 treated patients in our cohort we actively tested the outcome focussing on both the cosmetic part and functional problems following enucleation and/or radiation in this patient group. The relation between variable factors such as implant type and size

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Chapter 1

and outcome of cosmetics (eyelid positioning, symmetry, volume, artificial eye motility) were tested. Satisfaction of patients and/or parents was evaluated using questionnaires. Experience of pain and occurrence of phantom vision were also evaluated by means of questionnaires. This cross-sectional study is presented in chapter 6. Socket discharge was separately investigated in a small cohort including bacterial testing. Results and suggestions for the management of this problem are described in chapter 7. In chapter 8 we address another socket related problem ‘persistent socket pain’ by systematically reviewing the literature. Intervention to intolerable problems such as chronic pain or continuous socket related infections are described in chapter 9. In chapter 10 we present a special conformer designed and printed three-dimensionally to improve rehabilitation and lining of complex sockets post dermis-fat insertion. The results of the thesis are discussed in chapter 11, together with implications for the clinic and forthcoming studies.


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Introduction

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and death. Br J Ophthalmol. 2009;93(9):1129-1131. 3. Moll AC, Kuik DJ, Bouter LM, et al. Incidence and survival of retinoblastoma in the Netherlands : a register

based study 1862 – 1995. Br J Ophthalmol. 1997;81:559-562.4. Chawla B, Singh R. Recent advances and challenges in the management of retinoblastoma. Indian J

Ophthalmol. 2017;65(2):133. 5. Kim J-Y, Park Y. Treatment of Retinoblastoma: The Role of External Beam Radiotherapy. Yonsei Med J.

2015;56(6):1478-1491. 6. Fabian ID, Onadim Z, Karaa E, et al. The management of retinoblastoma. Oncogene. January 2018. 7. Zhao J, Dimaras H, Massey C, et al. Pre-enucleation chemotherapy for eyes severely affected by

retinoblastoma masks risk of tumour extension and increases death from metastasis. J Clin Oncol. 2011;29(7):845-851.

8. Friend SH, Bernards R, Rogelj S, et al. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature. 1986;323(6089):643-646.

9. Soliman SE, Racher H, Zhang C, MacDonald H, Gallie BL. Genetics and Molecular Diagnostics in Retinoblastoma—An Update. Asia-Pacific J Ophthalmol. 2017;6(2):197-207.

10. Rushlow DE, Mol BM, Kennett JY, et al. Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies. Lancet Oncol. 2013;14(4):327-334.

11. Dimaras H, Khetan V, Halliday W, et al. Loss of RB1 induces non-proliferative retinoma: increasing genomic instability correlates with progression to retinoblastoma. Hum Mol Genet. 2008;17(10):1363-1372.

12. Corson TW, Gallie BL. One hit, two hits, three hits, more? Genomic changes in the development of retinoblastoma. Genes, Chromosom Cancer. 2007;46(7):617-634.

13. Jakobiec FA, Tso MOM, Zimmerman LE, Danis P. Retinoblastoma and intracranial malignancy. Cancer. 1977;39(5):2048-2058.

14. Dimaras H, Kimani K, Dimba EA, et al. Retinoblastoma. Lancet. 2012;379(9824):1436-1446. 15. Broaddus E, Topham A, Singh AD. Survival with retinoblastoma in the USA: 1975-2004. Br J Ophthalmol.

2009;93(1):24-27. 16. Dommering CJ, Garvelink MM, Moll AC, et al. Reproductive behavior of individuals with increased risk of

having a child with retinoblastoma. Clin Genet. 2012;81(3):216-223. 17. Moll AC, Imhof SM, Meeteren AYNS-V, Boers M. At what age could screening for familial retinoblastoma

be stopped? A register based study 1945–98. Br J Ophthalmol . 2000;84(10):1170-1172. 18. Kim J-Y, Park Y. Treatment of Retinoblastoma: The Role of External Beam Radiotherapy. Yonsei Med J.

2015;56(6):1478. 19. Abramson DH, Fabius AWM, Issa R, et al. Advanced Unilateral Retinoblastoma: The Impact of

Ophthalmic Artery Chemosurgery on Enucleation Rate and Patient Survival at MSKCC. PLoS One. 2015;10(12):e0145436.

20. Mallipatna A, Gallie BL, Chévez-Barrios P et al. Retinoblastoma. In: Amin MB, Edge SB, Greene FL, Eds. AJCC Cancer Staging Manual. 8th Ed. New York, NY: Springer; 2017.

21. Shields CL, Douglass AM, Beggache M, Say EAT, Shields JA. Intravitreous chemotherapy for active vitreous seeding fro retinoblastoma: Outcomes After 192 Consecutive Injections. The 2015 Howard Naquin Lecture. Retina. December 2015.

22. Stallard HB. Irradiation of retinoblastoma (Glioma retinae). Lancet. 1952;259(6717):1046-1049. 23. Imhof SM, Mourits MP, Hofman P, et al. Quantification of Orbital and Mid-facial Growth Retardation

after Megavoltage External Beam Irradiation in Children with Retinoblastoma. Ophthalmology. 1996;103(2):263-268.

24. Imhof SM, Moll AC, Hofman P, Mourits MP, Schipper J, Tan KE. Second primary tumours in hereditary- and nonhereditary retinoblastoma patients treated with megavoltage external beam irradiation. Doc Ophthalmol. 1997;93(4):337-344.

25. Smit T, Koorneef L, Groet E, Otto AJ. Honderd jaar intra-orbitale implantaten na enucleatie. Ned Tijdschr Geneeskd. 1990;134:274-277.

26. Viswanathan P, Sagoo MS, Olver JM. UK national survey of enucleation, evisceration and orbital implant trends. Br J Ophthalmol. 2007;91(5):616-619.

27. Moshfeghi DM, Moshfeghi AA, Finger PT. Enucleation. Surv Ophthalmol. 2000;44(4):277-301. 28. McCord CP. Artificial eyes: the early history of ocular prostheses.J Occup Med. 1965;7:61-68. 29. Raizada K, Rani D. Ocular prosthesis. Contact Lens Anterior Eye. 2007;30(3):152-162.

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30. Tyers AG, Collin JR. Orbital implants and postenucleation socket syndrome. Trans Ophthalmol Soc U K. 1982;102 (Pt 1)(Pt 1):90-92.

31. Vistnes LM. Mechanism of upper lid ptosis in the anophthalmic orbit. Plast Reconstr Surg. 1976;58(5):539-545.

32. Smit TJ, Koornneef L, Zonneveld FW, Groet E, Otto AJ. Computed tomography in the assessment of the postenucleation socket syndrome. Ophthalmology. 1990;97(10):1347-1351.

33. Baino F, Perero S, Ferraris S, et al. Biomaterials for orbital implants and ocular prostheses: overview and future prospects. Acta Biomater. 2014;10(3):1064-1087.

34. Colen TP, Paridaens DA, Lemij HG, Mourits MP, van Den Bosch WA. Comparison of artificial eye amplitudes with acrylic and hydroxyapatite spherical enucleation implants. Ophthalmology. 2000;107(10):1889-1894.

35. Oatts JT, Robbins JA, de Alba Campomanes AG. The effect of enucleation on orbital growth in patients with retinoblastoma. J Am Assoc Pediatr Ophthalmol Strabismus. 2017;21(4):309-312.

36. Chojniak, Martha Maria Motono MD, PhD*; Chojniak, Rubens MD, PhD†; Testa, Maria Luiza MD†; Min, Tjioe Tjia MD†; Guimarães, Marcos Duarte MD†; Barbosa e Silva, Andréa Maria MD†; Antoneli, Célia Beatriz Gianotti MD P. Abnormal Orbital Growth in Children Submitted to Enucleation for Retinoblastoma Treatment. J Pediatr Hematol / Oncol. 2012;3(34):e102–e105.


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