Luth): a 15 Year Review

REVIEW OF MANAGEMENT OF ORBITO-OCULAR MALIGNANCIES IN LAGOS UNIVERSITY TEACHING HOSPITAL (LUTH): A 15 YEAR REVIEW

DR. ADEWUMI OLABIMPE ALABI (MBBS, IBADAN) AF/012/11/002/554

A PART II DISSERTATION SUBMITTED IN PARTIAL FULFILMENT OF THE AWARD OF FELLOWSHIP IN RADIOTHERAPY, FACULTY OF RADIOLOGY, NATIONAL POSTGRADUATE MEDICAL COLLEGE OF NIGERIA.

NOVEMBER, 2015 1

DECLARATION

I declare that this study titled “REVIEW OF MANAGEMENT OF ORBITO- OCULAR MALIGNANCIES IN LAGOS UNIVERSITY TEACHING HOSPITAL (LUTH): A 15 YEAR REVIEW” was carried out by me and to the best of my knowledge contains no material previously published or written by another person, nor material which has been submitted or accepted for the award of any degree or Fellowship except where due acknowledgement has been made in the text.

______DR. ADEWUMI OLABIMPE ALABI (MBBS, IBADAN)

CERTIFICATION

This is to certify that this research project “REVIEW OF MANAGEMENT OF ORBITO- OCULAR MALIGNANCIES IN LAGOS UNIVERSITY TEACHING HOSPITAL (LUTH) : A 15 YEAR REVIEW” was conducted in the Departments of Radiotherapy and Ophthalmology (Guinness Eye Centre), LUTH, Idi-araba, Lagos and Supervised by:

Professor A. T. Ajekigbe Head, Department of Radiotherapy/Consultant Clinical & Radiation oncologist, Lagos University Teaching Hospital, Idi-araba, Lagos.

Signature/Date: ______

Professor (Mrs) F. B. Akinsola Head,

Department of Ophthalmology/Consultant Ophthalmologist, Guinness Eye Centre, Lagos University Teaching Hospital, Idi-araba, Lagos.

Signature/Date: ______

Department of Radiotherapy, Lagos University Teaching Hospital, Idi – araba, Lagos state. 2nd of August, 2015.

This is to certify that this research project “REVIEW OF MANAGEMENT OF ORBITO-

OCULAR MALIGNANCIES IN LAGOS UNIVERSITY TEACHING HOSPITAL (LUTH) : A 15 YEAR

REVIEW” by Dr Alabi, Adewumi Olabimpe of the Department Of Radiotherapy, LUTH was

conducted in the Departments of Radiotherapy and Ophthalmology (Guinness Eye

Centre), LUTH, Idi-araba, Lagos State.

Professor A. T. Ajekigbe (B.pharm (Hons), MBBS, DMRT, FWACS, FMCR) Head, 4

Department of Radiotherapy/Consultant Clinical & Radiation Oncologist, Lagos University Teaching Hospital/College of Medicine, Idi-araba, Lagos.

DEDICATION

This book is dedicated to God Almighty for His grace and favour and to my late Father Engr. Ganiyu Toye Layioye for laying a good foundation.

ACKNOWLEDGEMENTS

I wish to acknowledge the Department of Radiotherapy, Lagos University Teaching

Hospital, Idi -araba, Lagos for the privilege to undergo my training in Radiation Oncology.

My Teachers and Consultants at Lagos University Teaching Hospital namely Prof K.K.

Ketiku, Prof. F.A. Durosinmi-Etti, Prof A.T. Ajekigbe, Dr A.C. Sowunmi and Dr M.Y.M.

Habeebu for their immeasurable contributions and inspiration. You gave me the best of your wealth of knowledge and time.

Prof (Mrs) F. B. Akinsola for supervising the project and the motherly role you have played in my home. To my Teachers and Consultants in other Institutions namely Prof. O. B

Campbell, Dr A.A. Adenipekun, Dr R.A. Oyesegun, Dr T.N. Elumelu-Kupoluyi, Dr A.A.

Abdussalam, Dr A.I. Ntekim, Dr A.M. Folasire, Dr O. Ogunnorin, Dr Igbinoba, Dr N.Y.

Okunnuga, Dr O. Iyare, Dr O. Salako and Prof M.A. Aweda. I say thank you for your

contributions to my training. You are all highly appreciated. I thank my colleagues and other members of the Department both medical and non-medical for their support and assistance during my period of study.

My appreciation also goes to my darling husband (Dr Adegboyega Alabi) for his untiring love, support and encouragements all the way, my adorable sons: Timi and Temi, thank you for understanding and the sacrifices you made during the period of my study and to my wonderful Mother for always being there.

Finally to the Almighty God without whom all this would have been impossible, you are

Highly Honored.

TABLE OF CONTENTS

TITLE PAGE i

DECLARATION ii

CERTIFICATION iii

DEDICATION v

ACKNOWLEDGEMENTS vi

TABLE OF CONTENTS vii

SUMMARY viii

INTRODUCTION 1

AIM AND OBJECTIVES 4

LITERATURE REVIEW 5

MATERIALS AND METHODS 43

RESULTS 47

DISCUSSION 57

LIMITATIONS 60

CONCLUSION 61

RECOMMENDATIONS 62

REFERENCES 63

APPENDIX 68

SUMMARY

Introduction: Orbito-ocular malignancies (OOM) generally are rare tumours1 with age adjusted incidence rate of 0.8per 100,000 per year in the United States2. Most ocular tumours are seen in adults with some peculiar to the paediatric age group. Uveal melanomas are the most common primary intraocular malignancies in adult in the United

States and Europe3,4. Retinoblastoma is the commonest malignant intraocular tumour in

childhood with a potential for curative intent3,4. Studies in Nigeria, have shown prevalence of Squamous cell carcinoma in adults and retinoblastoma as the commonest ocular malignancy and commonest orbital cancer in children5,6. The main goals of treatment for

Orbito-ocular tumours (OOT) in order of importance include: to save life, to save the eye and preserve vision7.

Aim and Objectives: To review the management of orbito-ocular malignancies in the

Departments of Radiotherapy and Ophthalmology, Lagos University Teaching Hospital, between January 1997 and December 2011 in comparison to previous and recent studies globally.

Methodology: This is a retrospective study of Orbito-ocular malignancies seen at the

Departments of Radiotherapy and Ophthalmology, LUTH from 1997 to 2011. Case files and treatment cards were retrieved through the record departments and the information required was extracted with the aid of a data extraction form.

Results: A total of 98 cases with histologically confirmed orbito-ocular malignancies seen during the 15 year study period were analyzed. The age range was to <1 – 83years, mean of

22.94years (SD 24.64years). Majority, 54 were children accounting for <10years of age.

Retinoblastoma (52.0%) was the commonest histological type seen in children while

Squamous cell carcinoma (25.5%) was the commonest in adult. The most common presenting complaints were proptosis seen in 47 patients followed by leucokoria seen in 20 patients. 17 patients had a combination of Radiotherapy, Surgery and Chemotherapy. 91

patients had surgery, 31% had enucleation while 34% had exenteration. 36 patients had

Chemotherapy. 44 patients benefited from radiotherapy, radical treatment was offered to

24 patients. Total radical treatment dose was 35-65Gy in 20-35 fractions over 4-7weeks. 84 patients were lost to follow up. 5 died from disease progression and 4 are still alive and are seen in the clinic on follow up.

Conclusion: This study showed that the use of multimodality treatment was implemented but did not improve survival because majority of patients presented late. The need for a collaborative effort in early detection and prompt referral for treatment of cancer cases cannot be overemphasized.

INTRODUCTION

Orbito-ocular malignancies (OOM) generally are rare tumours1,4 with age adjusted incidence rate of 0.8per 100,000 per year in the United States2. Most ocular tumours are seen in adults with some specific to the paediatric age group. These tumours are limited to malignancies developing from the eye, orbit or the lids. The eye consists of various anatomic and functional elements including the Conjunctiva, Cornea, Uvea, Lens, Vitreous,

Retina and Optic nerve. All these structures can form malignancies with pathologic processes4. Secondary ocular malignancies are rare but are commoner than primary malignancies of the eye4.

Uveal melanomas are the most common primary intraocular malignancies in adult3 in the

United States and Europe with incidence estimated at 7 per million per year1,4.

Retinoblastoma is the most common malignant intraocular tumour in childhood with a potential for curative intent1. Its incidence is 1 in 15,000-20,000 live births1,2,4. It usually presents before 3 years of age1. A Nigeria based study by Annunobi et al showed that retinoblastoma is the most common ocular malignancy in all age groups5. It accounts for

85% of all Orbito-Ocular Tumours (OOT) in the South Western part of Nigeria5. It also showed Rhabdomyosarcoma as the most common orbital malignancy occurring in childhood in the South Western part of Nigeria5. In adults, Squamous cell carcinoma was the most common malignant conjunctiva lesion with a mean age of 45 years5.

The age adjusted incidence rate for Orbito-Ocular malignancies from 2005-2009 was 0.8 per 100,000 men and women per year in the United States2. Overall 5 year survival rate was 83.1% and the life time risk was 0.08% (1 in 1256 persons)2.

There is an increase in incidence of both primary and secondary malignancies in both pediatric and adult tumours owing to better diagnosis and increase awareness6. Better treatment options are now available which has helped in proffering better treatment outcomes. The main goals of treatment for OOM in order of importance include: to save life, to save the eye and preserve vision7. In retinoblastoma, cure can be achieved8.

The awareness and knowledge of Orbito-Ocular malignancies in developing countries such as Nigeria is low due to suboptimal awareness programmes, poor health seeking attitudes, faith healing belief and etc. These had led to patients seeking alternative traditional

treatment thus increasing the number of patients presenting with advanced stage of the disease6,9.

Various treatment modalities are available for different stages of disease. These include

Surgery, Radiotherapy (External Beam Radiotherapy or Brachytherapy), Focal ophthalmic therapies (Laser photocoagulation, Cryotherapy, Thermotherapy), Chemotherapy,

Chemoradiation and Induction chemotherapy.

In Lagos University Teaching Hospital (LUTH) a multidisciplinary approach is in place involving the Ophthalmologist, Neurosurgeon, Pathologist, Radiation Oncologist, Clinical

Oncologist, Pediatric Oncologist, Oncology nurses, Palliative care specialist and others.

The challenges of management of patients with OOM are enormous. These include late presentation with advanced disease, inappropriate or wrong diagnosis, delayed referral to the Ophthalmologists, lack of expertise and facilities for early intervention, poverty, fear of losing their vision and challenges with preserving vision. A carefully co-ordinated treatment program helps to ensure that the right decisions are taken. These will help to reduce the increasing morbidity and mortality rate of the disease.

AIM AND OBJECTIVES

AIM

To review the management of Orbito-Ocular malignancies (OOM) in the Departments of

Radiotherapy and Ophthalmology (Guinness Eye Centre), Lagos University Teaching

Hospital (LUTH) over a fifteen year period from January 1997 to December 2011.

OBJECTIVES

1. To determine the prevalence and socio-demographic characteristics of patients

with Orbito–Ocular malignancies in the Departments of Radiotherapy and

Ophthalmology, LUTH.

2. To determine the histologic types of Orbito-Ocular malignancies in the Departments

of Radiotherapy and Ophthalmology, LUTH.

3. To determine the management and outcome of Orbito-Ocular malignancies in

LUTH.

LITERATURE REVIEW

Orbito-Ocular malignancies are malignancies of the eyeball, orbit and adnexea. The ocular adnexea includes the Eyelids, Cilia, Lacrimal glands, Lacrimal drainage apparatus and

Orbit10. The eye consists of various anatomic and functional structures including the

Conjunctiva, Cornea, Uvea, Lens, Vitreous, Retina and Optic nerve4 and within the orbit lays fat and muscle10. The orbit is formed by fusion of several bones all these structures have propensity to form malignancies10. Secondary malignancies also occur through metastasis

from distant organs to the eye likewise from adjacent contiguous sites such as the sinuses, eyelids and nasopharynx4.

EPIDEMIOLOGY

Orbito-ocular Malignancies (OOM) generally are rare tumours1,3,4 with age adjusted incidence rate of 0.8per 100,000 per year in the United States3. They are more common in

Africans than in Caucasians11. These tumours are usually classified as intraocular and extraocular tumours with most OOM occuring in adults while some are peculiar to paediatric age group. Secondary ocular tumours are rare arising from malignancies of the breast, lungs and gastrointestinal tract1. Breast cancer is considered to be the most prevalent metastatic ocular tumour to the orbit accounting for 29-70% of all metastasis12 and most often it metastasizes to the uvea causing choroidal melanoma1,3,11,12. Ocular malignancies also arise from local spread from contiguous sites such as paranasal sinuses, eyelids and nasopharynx4.

OCULAR MELANOMAS

Intraocular melanomas constitute the most common primary ocular malignancy in whites4.

Melanomas can occur on the skin of the eyelid, conjunctiva, uvea and even within the orbit1,4. The annual incidence of non-skin melanomas is 0.7 per 100,000 populations constituting about one eighth that of melanomas of the skin in the United States1,4,13.

Ocular tumours constitute 80% of all non-cutaneous melanomas and the risk of ocular melanoma in whites is eight fold higher than in blacks4.

Uveal melanoma is rare, incidence in the United States is estimated as 7 cases per million per year which is less than 10% the incidence of lung cancer1,14. Conjunctiva melanoma is also relatively rare, accounting for 2% of all ocular malignancies1,15. Primary nevi and malignant melanomas arise from melanocytes which are pigments found in the epithelium1. The pigments may protect from the development of uveal tumours because uveal melanomas occur most often in individuals with blue eyes and is rare in heavily pigmented individuals1,15-17. Nevi constitute the benign end of the biologic spectrum of melanocytic neoplasms and hence transformation of nevi into malignant melanomas does occur1. The overall risk of malignant transformation of conjunctiva naevus is 1%15.

Melanomas arising from pre-existing naevus are seen in 20% of cases15. Uveal melanomas are associated with congenital melanocytic naevus18.

Uveal melanomas are relatively more common in North America and Europe which may be attributed to geographical differences1. This suggests environmental factors being involved in disease prevalence as it is less common in Latin and Native Americans1,12,18. It usually occurs in older persons3 who tend to have larger tumours and are more likely to die from disseminated melanomas due to enucleation1. Collaborative Ocular Melanoma Study

(COMS) indicated that Uveal Melanoma affects both sexes equally1,19 with fewer than 0.8% of cases occurring in patients younger than 20 years of age1,20-22.

Choroidal melanoma accounts for 80% of all uveal melanomas while Iris and ciliary body melanomas are seen in 8% and 12% of uveal melanomas respectively15,23. Iris melanoma is 16

extremely rare in blacks and affects both sexes equally16. They affect individuals in the 5th-

6th decade, a decade earlier than that of ciliary body and choroidal melanomas15.

Uveal metastasis arises from breast and lung cancers in women and in men from lung and gastrointestinal tract tumours15. They are often unifocal, they can also occur as multifocal or bilateral tumours23-25. They arise as precocious metastasis in 15 per cent of cases, synchronous in 4 per cent and metachronous in most of the remaining except for 8 per cent of cases in which appropriate parameters cannot be established23. 90% of uveal metastasis is found in the choroid followed by the iris and ciliary body15. Other less common primary sites to the uvea are the kidney and skin melanoma while it is extremely rare in prostate cancer15.

RETINOBLASTOMA

Retinoblastoma (Rb) is the most common malignant tumour of childhood1,4,5,26. It is worldwide in distribution and affects all racial group with a frequency of approximately 1 in

17,000 live births1,4,9,11,15. It accounts for 3% of all childhood tumours15.

Rb was first recognized by Pawius in 165727 and is responsible for 1% of all deaths from cancer in the age group of newborns to 15 years4. It is of significant importance in clinical oncology because of its high curability without significant loss of vision28. Modern treatment in the early stage of the disease also offers good treatment outcome. 17

It constitutes majority of childhood tumours of studies done in Nigeria29-31. It has no sex predilection4. It usually presents before 3 years of age (mean 13-15months in Bilateral and

24 months in Unilateral cases) with median age of presentation at 18months23. Rb studied in Nigeria showed a median age of 3.2 years29. Cases with tumours present at birth are not exceptions23. A study done by Olurin et al in Southwest Nigeria showed that Rb was the most common orbito-ocular tumour11. It was restricted to children as no tumour was seen in adults11. Mohammed et al showed a prevalence of 40.3% for Rb in a study done on malignant Orbito-ocular tumours in Northern Nigeria31.

Retinoblastoma can arise in hereditary and non-hereditary forms4,15,28. The gene predisposing to Rb is located on the long arm of chromosome 1315. It is heritable (germline) in 40 per cent of cases and non-heritable (somatic) in 60per cent of cases15,28. 10per cent of patients diagnosed with Rb have a family history while the remaining 90per cent of cases are sporadic23. 70-80per cent of sporadic cases are unilateral while 20-30% are bilateral and heritable23.

Most cases of hereditary Rb have tumours affecting both eyes (bilateral Rb) 4,15 while 15% of hereditary Rb have unilateral involvement15. Tumours can also arise from either the pineal gland, suprasellar or parasellar region as trilateral Rb 4,23. In 60% of cases abnormality affects only the eye and in 40% of cases abnormality is in all cells of the body which may account for the risk of developing second malignancies such as osteosarcoma, fibrosarcoma, leiomyosarcoma, squamous cell carcinoma, renal cell carcinoma,

medulloblastoma and leukemia15. The risk of having a second malignancy is 6% and the risk further increases within the irradiated field to five fold if external beam irradiation has been used to treat the primary tumour15.

The mutation is transmitted in 50% of cases but because of incomplete penetrance only

40% of offspring will be affected15. The risk to siblings is 2% in heritable Rb if the parents are healthy and the risk increases to 40% for unhealthy parents15.

RHABDOMYOSARCOMA

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children32 with an incidence of 50% to 60% of all soft tissue sarcomas32. Orbital RMS account for 10 -20 per cent of all RMS1,23 with approximately 35 new cases per year in the United States33. They usually occur in children below 16 years of age with a mean age of onset of 5-7 years old34,35. Case reports have shown newborns and elderly with orbital RMS23. About 35% to

40% of RMS arises in the head and neck15. It accounts for about 3-8% of childhood malignancies15. RMS is the most prevalent extraocular orbital malignancy in children, although it is only one tenth as common as retinoblastoma3.

The male to female ratio is 5:3 with a slight male predominance35. There is no racial predilection. It can primarily involve the orbits, eyelid, conjunctiva and rarely the uveal tract(76% orbit, 3% eyelid, 12% conjunctiva, 9% uveal tract)35. Secondarily it can occur via direct extension from the paranasal sinuses or nasopharynx and rarely from distant sites23.

There are multiple associations with genetic syndromes such as Li-Fraumeni,

Neurofibromatosis Type 1 and Beckwith Wiedemann Syndrome23. Neurofibromatosis Type

1 (NF 1) previously called von Recklinghausen disease is a relatively common autosomal dominant disorder that affects cell growth of neural tissues36. It has three major features: mulitiple neural tumours (neurofibromas), numerous pigmented skin lesions (café au lait spots) and pigmented iris harmatoma (Lisch nodules)36. Individuals with NF 1 have an increased risk of developing other tumours such as Wilms’ tumour, meningiomas, optic nerve gliomas, pheochromocytomas and chronic myeloid leukemia in children36.

Li-Fraumeni syndrome is a hereditary cancer predisposition syndrome36. It is extremely rare and is also an autosomal dominant disorder36,37. Individuals affected have an increased risk of developing several other malignancies. The most common of such tumours include sarcomas, breast cancer, leukemias, brain tumours and others36. Such individuals are diagnosed with a malignancy by age 5036.

Beckwith-Wiedemann Syndrome is a congenital disorder that is characterized by overgrowth, tumour predisposition and congenital malformations34. Clinical findings include large body size, large organs such as the tongue (macroglossia) and umbilical hernia or defect38. There is also an increased rate of developing Wilms’ tumour, Adrenal tumours,

Rhabdomyosarcoma and Neuroblastoma38,39. It is often due to a chromosomal abnormality on chromosome 1136.

SQUAMOUS CELL CARCINOMA (SCC)/BASAL CELL CARCINOMA (BCC)

They are both epithelial lesions affecting individuals with a history of chronic sun exposure.

They are common in albinos and rare in blacks4,15. BCC is the most common eyelid malignancy which accounts for 90 per cent of malignant eyelid tumours1. It is the most common malignancy in caucassians1. SCC accounts for the commonest orbital malignancy in adults in Western Nigeria40. Incidence of SCC is 14 per 100,000 populations per year in white American and higher rate in other countries1,41. It affects older men and women greater than 50 years of age and is common in fair complexioned individuals1. It rarely metastasizes but has a tendency to cause significant morbidity and mortality because of its invasive and destructive ability. It occurs predominantly in the medial and lateral canthi via direct extension1.

SCC is approximately 10 per cent of orbital cancers, it accounts for 2-9% of eyelid malignancies1,23. It occurs as an invasive lesion or carcinoma in situ. It is usually seen in older individuals with a predilection for Caucassians males who have a history of exposure to ultraviolet radiation23. It is also seen in individuals who are immunocompromised1. The lower eyelid is frequently affected1,23.

SCC is locally invasive and rarely metastasizes to regional or distant lymph nodes1. When it spreads it could be as direct spread, metastases to distant sites or via perineural spread.

SCC of the conjunctiva is the most common ocular malignancy, usually involving the bulbar conjunctiva23.

SEBACEOUS CARCINOMA

They are relatively rare glandular lesions arising from the meibomian glands, glands of Zeis or sebaceous gland23. In Caucasians it accounts for 6per cent of all malignant eyelid tumours affecting individuals in the 6th and 7th decade of life1,15,23,27. It affects women more than men. It is seen in younger individuals who are immunocompromised or who have received radiation treatment1,23. It is common in the upper lid and lower lid probably because there are more meibomian glands than in the upper lid1. Orbital invasion occurs in about 6per cent of cases1.

LYMPHOMAS

Malignant lymphoma is the most common orbital tumor in the elderly age group with a median age of presentation greater than 60 years3,23. It accounts for 24% of cases in the

United States23. Incidence generally increases with advancing age23. There is no sex predilection23, however in cases of intraocular lymphoma women are known to have twice incidence than men. Likewise orbital lymphoma has female preponderance1,23.

Non-Hodgkin’s Lymphoma (NHL) is the most common type of ocular lymphoma23.

Hodgkin’s Lymphoma rarely causes ocular disease. Orbital Lymphoma can be intraocular, orbital or adnexal. They are usually indolent tumours3 and Intraocular Lymphoma is said to be rare3. There are two main types of intraocular lymphoma: Primary Central Nervous

System involvement (PCNSL) and Primary Central Nervous System lymphoma with ocular involvement (PCNSLO)23. PCNSLO is usually bilateral and does not involve the central 22

nervous system. It is seen in immunocompromised individuals with median age of 50-60yrs of age3. About 56-86% of orbital lymphomas are PCNSL while 15-25% are PCNSLO23.

OPTIC NERVE GLIOMAS

These are tumours of the optic nerve usually seen in children under 15 years of age23. They are now classified as juvenile pilocytic astrocytoma which may occur in the optic nerve or chiasm23. They account for 1% of all central nervous system tumours23. They are slow indolent tumours which may extend into the brain causing reduced or permanent visual loss23. Optic nerve gliomas are associated with Neurofibromatosis in 40% of individuals and have a female preponderance23.

VASCULAR LESIONS OF THE ORBIT

Hemangiomas/Angiosarcomas

They are rare mesenchymal tumour of vascular origin which may arise primarily in the orbit or secondarily invading the orbit from adjacent sinuses or metastasis from a distant site23.

In adults cavernous hemangioma is one of the most common primary orbital tumour15,23. It usually presents in middle aged women and the lesions tend to be solitary which may be associated with skin or central nervous system vascular lesions as part of an inherited neuro-oculocutaneous syndrome23.

Choroidal hemangiomas grow slowly with mainly two types: diffuse and circumscribed23.

The circumscribed type has no systemic abnormalities, it may be dormant or give rise to symptoms when there is exudative retinal detachment23. It is seen in the 2nd - 4th decade of

life23. Diffuse choroidal hemangioma is usually seen in the 2nd decade of life and may be present at birth23. It is usually associated with vascular abnormality of the skin and central nervous system as part of Sturge-Weber syndrome23.

RISK FACTORS

Age: Some malignancies are more common in the paediatric age group (eg. retinoblastoma, rhabdomyosarcoma) while some are more in adults (eg. squamous cell carcinoma of the conjunctiva, uveal melanomas).

Sex: Most OOT have no sex predilection however squamous cell carcinoma has a slightly greater predilection for males25.

Race: There is a risk of uveal melanomas in Europeans who have blue or lightly pigmented eyes1,16. Also the risk in Non-Hispanic white was 72 times that in black men23. Individual with different eye colour of blue, grey or green eyes are more likely to develop melanoma than those with brown eyes1,19 likewise individuals with abnormal brown spots

(pigmentation) on their uvea called oculodermal melanocytosis(nevus of ota) are at an increased risk of malignant melanoma1. Also individuals with moles, numerous cutaneous naevi, dysplastic nevus syndrome, are at higher risk1.

Familial: Familial Retinoblastoma accounts for 40% of all Retinoblastomas and are due to an inherited faulty gene1. Familial cutaneous naevi also predisposes to uveal melanomas1.

Immunosuppression: Immunosuppressed individuals with human immunodeficiency virus are at a higher risk of squamous cell carcinoma of the eye, lymphoma and Kaposi sarcoma because of the effect of the virus on their immune systems28. Also individuals with organ 24

transplant on immunosuppressant drugs could develop a lymphoma or squamous cell carcinoma of the eye1 while those with human papilloma virus (type 6) are at risk of squamous cell carcinoma1,23.

Exposure to sunlight and ultraviolet radiation in some workers (welders) causes an increase in risk for developing melanomas23. Squamous cell carcinoma of the eye is common in areas where sunlight is more23.

Exposure to radiation and chemical carcinogens may also increase the risk of retinoblastoma and an increased incidence of uveal melanomas was seen in a group of chemical workers3.

Genetic syndromes: Patients with Von Recklinghansen Neurofibromatosis Type 1 are at risk of uveal melanomas15,23. Others are Beckwith Weidemann and Li Fraumeni syndromes.

ANATOMY10

Orbit and Eye

The eye is located within the orbit together with the extraocular muscles which move the eye, nerves, vessels, lacrimal gland, fascia and fat. The optic nerve enters the orbit through the optic canal. Superiorly is the anterior cranial fossa with the meninges and the frontal lobe of the cerebral hemisphere. Medially are the nasal cavity, ethmoidal sinus and the sphenoid sinus with the maxillary sinus below. Posterolaterally are the infratemporal fossa and the middle cranial fossa.

Eyelids

There are two eyelids, the upper and lower eyelids which meet at medial and lateral canthi

(angles). They are covered in front with loose skin and behind with adherent conjunctiva.

The orbicularis oculi muscle lies in front of the septum. The tarsal glands (meibomian) are modified sebaceous glands embedded within the substance of the tarsal plates.

Conjunctiva

It is a transparent membrane attached to the sclera at the margins of the cornea with which it blends. It has stratified columnar epithelium except near the eyelid margins where it changes to non-keratinized stratified squamous epithelium. It also has mucus secreting goblet cells scattered in the epithelium and small accessory lacrimal glands scattered in the sub-conjunctiva.

Blood supply: Medial palpebral branches of the ophthalmic artery and lacrimal palpebral branches of the lacrimal artery branch of ophthalmic supplies the eyelids. The palpebral conjunctiva is highly vascularised while the bulbar conjunctiva is only slightly vascular hence its transparency. Venous drainage is to the ophthalmic and angular veins.

Lymphatic Drainage: The lymphatic drainage of the lateral two thirds of lids is to the preauricular nodes and the medial third drains to the submandibular nodes.

Nerve Supply: Upper Lid is the lacrimal, supraorbital, supratrochlear and infraorbital nerves while the Lower lid is the infraorbital nerve.

Lacrimal Apparatus: This consists of the lacrimal gland, lacrimal cannaliculi, lacrimal sac and nasolacrimal duct which all function for the production of tears and removal of excess tears.

Lacrimal Gland: Serous gland with a large orbital and a small palpebral part. It produces tears that are spread across the eye for lubrication and excessive tears convey in a tiny canal the lacrimal cannaliculus via a minute lacrimal punctum.

Lacrimal Sac: This lies in the lacrimal groove formed by the maxilla and lacrimal bones.

Nasolacrimal Duct: This is a 2cm duct which slopes downwards, backwards and laterally to open in the anterior part of the inferior meatus 2cm behind the nostril. The duct and sac are lined by ciliated columnar epithelium.

MUSCLES OF THE ORBIT

The eyeball is moved by extrinsic or extraocular muscles including four recti (superior, inferior, medial and lateral) and two obliques (superior and inferior) muscles. The orbit also consists of the levator palpebrae superioris for moving the upper lid. The ocular muscles come from the apex of the orbit at the back of the medial wall and pass forward and laterally to their ocular attachment. They function to produce various movements of the eyes.

rd th th NERVE SUPPLY: The nerve supplies are from 3 , 4 and 6 cranial nerves (LR6SO4). This is a pneumonic used to describe the innervation of the muscles of the orbit, the Lateral rectus 27

is supplied by Cranial nerve VI and the superior oblique muscle is by Cranial nerve IV while all the other muscles are supplied by the third (oculomotor) cranial nerve.

NERVES OF THE ORBIT

Optic nerve enters the orbit through the optic canal at the apex of the orbit and is an extension of the white matter of the brain covered by pia, arachnoid and dura mata as far back as the back of the eye. Its length in the orbit is 25mm. The continuation of the subarachnoid space around the nerve accounts for appearance of papilloedema in increased intracranial pressure.

STRUCTURE OF THE EYE

The Eye contains the cornea, sclera, aqueous humour, lens, vitreous, uveal tract, retina and optic nerve. Its wall is made of 3 coats:

Outer coat is fibrous; it consists of sclera and cornea. The Sclera is an expansion of dural sheath of the optic nerve. The cornea is a transparent membrane and conical in shape.

Middle coat is the vascular coat, consisting of uveal tract: the choroid, ciliary body and iris which intervene between the outermost and the innermost nervous coat (the retina).

Choroid an expansion of arachnoid and pia, the ciliary muscles lies behind the iris and consists of smooth muscle which enables the eye to focus the lens for near vision. The sphincter pupillae are a circular band of smooth muscle lying in the stroma of the iris at the margin of the pupil.

Inner coat is the retina and its analogs, an expansion of brain substance through the optic nerve.

PATHOLOGY

EPITHELIAL TUMOURS

Epithelial malignancies of the lids are similar to those in other skin surfaces while those of the conjunctiva may be closely related to changes in other mucous membranes. Common epithelial malignancies of the lids include basal cell carcinoma, squamous cell carcinoma, sebaceous carcinoma and melanoma4.

Squamous cell carcinoma shows features of carcinoma in-situ, but there is also invasion by the tumor cells through the epithelial basement membrane into the superficial connective tissues4. Most squamous cell carcinoma of the conjunctiva only shows superficial invasion and deep invasion and metastases are rare4. Carcinoma composed of the mucus secreting cells and squamous cells of the conjunctiva epithelium (mucoepidermoid carcinoma) and melanoma of the conjunctiva also occur4. Conjunctiva Carcinoma in situ appears clinically either as an opaque, white, shiny lesion (leukoplakia) or as a fleshy mass4.

MELANOMAS

These differ significantly in their biologic behavior from cutaenous melanomas1. They occur on the skin of the lid, conjunctiva and even within the orbit. Uveal melanocytes are second population of pigmented cells which are of neural crest cells origin and possess long dendritic like processes emanating from the centre of the cell body4. They do not undergo reactive hyperplasia but are the origin of malignant melanomas of the eye4.

Melanomas arise in the posterior choroid and they may spread laterally between the sclera and retina or may produce bulbous masses projecting into the vitreous cavity and pushing the retina ahead of them4. The cellular classification relates histology to prognosis4.

Callender's Classification of Uveal Melanoma23

1. Spindle A cell (the most benign)

2. Spindle B cell

3. Pure epithelioid cell (most aggressive)

4. Mixed cell

Spindle A Melanomas have cohesive tumour cells with small, spindle-shaped nuclei containing a central dark strip23. They have a good prognosis23. Nucleoli are inconspicuous, the cytoplasm is scanty and cell borders are difficult to identify4. Because of the frequent late metastases, 5 year cure rate are less useful prognostic parameters in ocular melanomas1,4. Spindle B Melanomas are composed of cohesive cells having distinct spindle shaped nuclei with prominent nucleoli and they tend to be oval and plumper1,4. The cells contain more cytoplasm than those in A lesion and cell borders are difficult to discern by light microscopy4.

Epitheloid melanomas are composed of poorly cohesive large cells with round nuclei and prominent nucleoli, abundant eosinophillic cytoplasm and well demarcated cell borders, it is the rarest type with poor prognosis4. Mixed cell types usually have spindle cell (usually B) together with a significant epitheloid population4. It is the most common type of ciliary body and choroidal Melanoma4.

TNM Classification of Uveal Melanoma (International Union Against Cancer UICC)23 T1 <10 mm greatest dimension, <3 mm thickness

T1 A <8 mm greatest dimension, <2 mm thickness

T1 B >8 to 10 mm greatest dimension, >2-3 mm thickness

T2 10-15 mm greatest dimension, 3-5 mm thickness

T3 >15 mm greatest dimension, >5 mm thickness

T4 Extr aocular extension

N1 All sites, regional

M Metastasis

American Joint Committee on Cancer (AJCC) Stage Grouping for Uveal Melanoma23

Stage IA T1A N0 M0

Stage IB T1B N0 M0

Stage II T2 N0 M0

Stage III T3 N0 M0

Stage IVA T4 N0 M0

Stage IVB Any T N1 M0 Any T Any N M1

RETINOBLASTOMA

Retinoblastoma is worldwide in distribution and affects all racial groups15. It is the commonest malignant intraocular tumour in childhood and is second only to choroidal melanoma in all ages4. The tumour is composed of small basophilic cells (retinoblasts) having large hyperchromatic nuclei and scanty cytoplasm15. All retinoblasts are terminally differentiated by age 2.5 years4. Retinoblastoma presents as grossly friable chalky white mass with dense foci of calcification and necrosis4. Its growth pattern may be endophytic

(into the vitreous) or exophytic (into the subretinal space) or diffuse infiltration of the retina or optic nerve invasion or metastatic spread to distant sites15.

Retinoblastomas are usually undifferentiated cells with varying degree of differentiation characterized by rosettes4. Three of such are known: Flexner – Wintersteiner a single row of columnar cells that surrounds a central lumen, the nuclei of the cells lies away from the

lumen4,15. It is highly specific but could be seen in cases of medulloblastoma4. Homer–

Wright (‘pseudorosettes’) is seen as radial arrangements of tumour cells around a tangle of fibrils4. Occasionally seen are Fleurettes which is an expression of photoreceptor differentiation of the retinoblastoma cells4,15.

A new classification of retinoblastoma was introduced and is referred to as the

International Classification of Retinoblastoma23. More recently, two staging systems, the

American Joint Committee on Cancer (AJCC) and the St. Jude's System have been developed to include extraocular extension and metastasis, which determine survival after treatment28. Reese Ellsworth classification is based on tumour size, number of location and vitreous involvement4.

International Classification of Retinoblastoma23

A Small tumor Retinoblastoma ≤3 mm in size B Larger tumor Retinoblastoma >3 mm in size C Focal seeds Retinoblastoma with Subretinal seeds ≤3 mm from retinoblastoma Vitreous seeds ≤3 mm from retinoblastoma Both subretinal and vitreous seeds ≤3 mm from retinoblastoma D Diffuse seeds Retinoblastoma with Subretinal seeds >3 mm from retinoblastoma Vitreous seeds >3 mm from retinoblastoma Both subretinal and vitreous seeds >3 mm from retinoblastom E Extensive retinoblastoma It occupies >50% globe or Neovascular glaucoma Opaque media from hemorrhage in anterior chamber, vitreous, or subretinal space Invasion of

postlaminar optic nerve, choroid (>2 mm), sclera, orbit and anterior Chamber23.

American Joint Committee on Cancer Tumor Staging System for RB23

REESE ELLSWORTH CLASSIFICATION23

Group I: Single or multiple tumours less than 4 disc diameters at or behind the equator

(1 optic disc diameter1.5 mm)

Group IIA: Solitary lesion 4–10 disc diameters at or behind the equator

Group IIB: Solitary lesion larger than 10 disc diameters

Group III: Lesions anterior to the equator

Group IVA: Multiple tumours, some larger than 10 disc diameters

Group IVB: Any lesion extending anteriorly beyond the limits of ophthalmoscopy

Group VA: Massive tumours

Group VB: Vitreous seedlings

RHABDOMYOSARCOMA

The classification of rhabdomyosarcoma used by the Intergroup Rhabdomyosarcoma Study investigators consists of four histologic subtypes: embryonal, botryoid subtype of embryonal, alveolar, and pleomorphic4,23. Other variants considered include; a subtype of alveolar rhabdomyosarcoma, a spindle cell subtype of embryonal rhabdomyosarcoma, and a diffuse anaplastic variant23. The embryonal histology is found most commonly in the orbit, head and neck, and genitourinary sites23. The botryoid tumors are usually non-

invasive and localized and occur in mucosal-lined organs such as the vagina, urinary bladder, middle ear, biliary tree, and nasopharynx23. The botryoid and spindle cell group have a favorable prognosis of 88-95%23.

ORBITAL LYMPHOMAS

Most lesions are low grade B-cell lymphomas23. The commonest histology is extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT)23. There are different staging systems, Ann Arbor staging system, REAL classification and the AJCC.

AJCC/ANN ARBOR STAGING SYSTEM23

STAGE INVOLVEMENT

I Single lymph node region (1) or one extralymphatic site (1E)

II Two or more lymph node regions, same side of the diaphragm (2) or local

extralymphatic extension plus one or more lymph node regions same side of the

diaphragm (2E).

III Lymph node regions on both side of the diaphragm (3) which may be accompanied

by local extralymphatic extension (3E)

IV Diffuse involvement of one or more extralymphatic organs or sites

B Unexplained weight loss (>10% in 6months prior to diagnosis), unexplained fever >380C, drenching night sweats E Extranodal disease X Bulky (>10cm, or for mediastinal mass >1/3 intrathoracic diameter)

CATEGORIES OF ORBITAL AND OCULAR MALIGNANCIES23

Eyelids and lacrimal drainage systems

Premalignant and malignant tumors of surface epithelium of eyelids

Nevoid basal cell carcinoma syndrome

Squamous cell carcinoma

Glandular and adnexal tumors of eyelids

Sebaceous gland carcinoma

Sweat gland and hair follicle tumors

Melanocytic tumors of eyelids

Malignant melanoma

Vascular tumors of eyelids

Capillary hemangiomas

Xanthomatous tumors of eyelids

Metastatic tumors to eyelids

Tumors of lacrimal drainage system

Conjunctiva

Congenital tumors

Premalignant/malignant lesions of surface epithelium

Dysplasia

Carcinoma in situ

Invasive squamous cell carcinoma

Melanocytic tumors

Nevus

Malignant melanoma

Other conjunctival tumors

Systemic hamartomatoses

Tuberous sclerosis

Neurofibromatosis

Retinocerebellar capillary hemangiomatosis (von Hippel - Lindau syndrome)

Encephalofacial cavernous hemangiomatosis (Sturge-Weber syndrome)

Racemose hemangiomatosis (Wyburn-Mason syndrome)

Retinal cavernous hemangiomatosis with cutaneous and central nervous system involvement

Intraocular tumors

Melanocytic tumors of the iris

Malignant melanoma

Tumors of iris pigment epithelium

Melanocytic tumors of the posterior uvea

Ciliary body melanoma

Choroidal melanoma

Other uveal tumors

Circumscribed choroidal hemangioma

Metastatic carcinoma

Medulloepithelioma (diktyoma)

Choroidal osteoma

Choroidal neurilemoma

Other uveal tumors

Tumors of the retina and optic disk

Tumors and related lesions of the retinal pigmented epithelium

Adenoma and adenocarcinoma

Retinoblastoma

Acquired nonfamilial retinal hemangioma

Glial tumors of retina and optic disk

Astrocytoma

Melanocytoma of optic nerve

Intraocular lymphoid tumors and leukemias

Histiocytic lymphoma (reticulum cell sarcoma)

Leukemias

Orbital tumors

Juvenile pilocytic astrocytoma

Meningioma

Fibrous histiocytoma

Fibro-osseous tumors

Peripheral nerve tumors

Neurofibroma

Neurilemoma

Rhabdomyosarcoma

Lymphoid tumors

Leukeamia

Metastatic tumors to orbit

Lacrimal gland tumors

MODE OF SPREAD

Tumour spreads via direct extension to adjacent structures and via hematogenous route28.

Lymphatic spread occurs when there is extraocular extension of the tumour since there is no lymphatic drainage in the orbit23. Retinoblastoma spreads directly causing vitreous seedlings and then spreads into the choroid, sclera, orbit, optic nerve and brain23. Tumours can invade or grow into the middle cranial fossa through the superior orbital fissure and optic canal or into the pterygoid fossa10. They can also grow through the inferior wall of the orbit causing trismus23.

Hematogenous spread usually follows the involvement of uveal tissues which are highly vascularised to distant sites23. Spread to the preauricular and cervical lymph nodes occur following extraocular spread23. Distant metastasis occur to the Liver in more than 90% of cases1,3. Other common sites of metastasis include lung and bone in 24% and 16% of cases 39

respectively1. Other sites are Central nervous system, skull and lymph nodes3. Multiple sites are found in 87% of cases and brain metastases are rare1,3.

CLINICAL FEATURES

Most commonly seen signs and symptoms include reduced visual acuity, epiphora, orbital swelling, proptosis, salmon coloured patches on the sclera (conjunctiva lymphoma) or fleshy mass on the conjunctiva for conjunctiva lesions1,15,28. Retinoblastoma usually presents with Leucokoria (cat eye reflex/red reflex) which is the most common presentation seen in 60% of cases while strabismus is the second most common presentation seen in 20% of cases15,42. Several Studies done in Nigeria have confirmed that proptosis and chemosis were the commonest presentation of Rb owing to late presentations9,43. Likewise, Studies done in some other developing countries showed that proptosis and chemosis were also the commonest presentations44,45. Other clinical features include glaucoma, intraocular inflammation, pseudohypopyon, Squint and red eye44.

Features of metastasis and raised intracranial pressure such as severe headaches, projectile vomiting without nausea and papillodema can also be seen44.

Cranial nerve (CN) palsies involving CN II, III, IV, VI) and extraocular muscle involvement are seen when there is spread through the superior orbital fissure and the patient presents with trismus when there is spread through the inferior orbital fissure28.

In Melanomas four characteristic stages are seen, there is a relatively asymptomatic stage, a symptomatic stage marked by glaucoma and or infiltration, a stage of extra-ocular growth 40

and a stage of distant metastasis4. Individuals with iris melanoma present with visible pigmented mass with distortion of the pupil4. Cilliary body melanomas present with episcleral vascular injection and may cause a localized cataract4. Choroidal melanoma is usually seen on routine ophthalmoscopy examination and may produce symptoms of retinal detachment, macular oedema or choroidal hemorrhage4. Uveal melanomas on clinical examination present with visual distortion, field loss, floaters, scotomas, flashing lights, unilateral cataract and pain3. Distant metastasis can occur to the Liver and this is seen in 95% of patients with metastatic uveal melanoma4.

INVESTIGATIONS/DIAGNOSTIC WORK-UP

It is important to properly ascertain the extent of disease and make proper diagnosis.

Baseline investigations include: Full blood count, Electrolyte, Urea and creatinine which are important in evaluating patients prior to treatment3. Liver function tests to determine any spread to the liver. Lactate dehydrogenase is a tumour marker useful in monitoring disease progression. Binocular Indirect Ophthalmoscopy for examination of the retina3. Fundal

Fluorescein Angiography is useful in diagnosing vascular tumours3. Ocular Ultrasonography

(A&B mode)3 is an important diagnostic tool for orbital tumours as it identifies cystic and solid masses. It is also useful in measuring tumour dimensions.

Head and Neck Computer Tomography (CT)/Magnetic Resonance Imaging(MRI) is used to determine extent of disease and involvement of other vital structures. It helps in effective planning and delineation of tumour. It identifies and shows lymph node involvement47. MRI

is better for soft tissue imaging while CT Scan shows bony involvement of disease. Chest X- ray/Computer Tomography Scan is used in evaluating patients with metastasis to the lungs.

Abdomino-pelvic Ultrasound/Computer Tomography Scan is used in evaluating abdominal metastasis.

Bone marrow aspirate, Peripheral blood smears and cerebrospinal fluid examinations are useful in assessing extent of spread of disease4. Immunohistochemistry has been useful in identification and classification of tumours arising from T and B lymphocytes and from mononuclear- phagocytic cells. Mature B cells express CD19 and CD20 positivity. This is useful in offering better treatment options with monoclonal antibody(Rituximab)23,28.

Tissue Biopsies are useful for histopathological diagnosis and grading.

MANAGEMENT

SURGERY

The role of surgery in the management of OOM plays an important role in treatment. This can be in form of biopsy to confirm diagnosis or surgical resection for cure or for debulking of tumour to reduce mass effect prior to other forms of therapy. Surgery aims at complete surgical eradication of tumour and when the tumour cannot be completely removed a wide tumor-free margin of 3-4mm is allowed to prevent tumour recurrence28. Adjuvant therapy such as radiotherapy or chemotherapy may be indicated thereafter. The goal of therapy includes preserving vision hence decisions taken should favour surgery options15.

Surgical options available include: Enucleation which involves removal of the globe. It is indicated in lesions involving more than 50% of globe, optic nerve invasion, and extensive involvement of the ciliary body or angle and in cases of Alternative Treatment Failure15. It is also for Unilateral Tumours with no visual potential15. It is usually complicated by haemorrhage and infection15. Orbital implants and prosthesis are required after surgery15.

Adjunctive therapy may then follow treatment3.

Individuals with Iris Melanomas are often kept under observation since most of them are of the spindle cell A variety which tends to have good prognosis and low potential for malignancy4. Enucleation is considerd when there is intraocular spread3,23. For ciliary body and choroidal Melanomas enucleation is the treatment of choice for medium sized (10-

15mm in diameter) and large (>15mm) tumours15,23.

Exenteration involves total removal of the contents of the bony orbit. It could be total which involves removal of the eyelids or subtotal with lid sparing. Indications include orbital recurrence after therapy and extraocular spread15. Its Complications are hemorrhage, Sunken Orbit, facial asymmetry and less satisfactory cosmesis15. Orbital implants and ocular prostheses are used by the surgeon to restore a more natural appearance. It is followed up by radiotherapy and/or chemotherapy. It is rarely indicated in the developed world where patients present with early disease.

Eviseration is defined as removal of the contents of the globe in cases when the extraorbital structures are not involved. The gold standard for management of most ocular

tumours is Surgery either for curative or palliative intent. A successful treatment depends principally on the absolute eradication of tumor cells from the ocular surface prior to other adjunctive treatment.

Lymph node neck dissection is done for individuals with solitary or multiple discrete cervical lymphadenopathy15,23.

CHEMOTHERAPY

Chemotherapy is indicated for neoadjuvant or adjuvant form of treatment. It is used in cases of orbital invasion, recurrent tumour, adverse histology following enucleation and retrolaminar invasion of the optic nerve with or without involvement of the resection margin. It can also be as chemoreduction in cases where the primary tumour is too large or too close to the optic nerve or macular or as chemoradiation (concurrent chemotherapy with radiation treatment) and also for metastatic disease23. It is indicated in individuals with Rb who have high incidence of second malignancies to prevent systemic disease23.

Some tumours such as lymphomas will benefit from chemotherapy because they are chemosensitive. Mucosal associated lymphoid tissue (MALT) of the conjunctiva can be treated with topical chemotherapy or intralesional interferon47 or kept on close observation23.

The effect of induction chemotherapy with 1 or 2 courses of chemotherapy prior to radiotherapy has also been useful in down staging disease and preventing distant spread46.

Several chemotherapeutic options are available which are given at 2/3 weekly intervals.

Also different histological types of tumour respond to different chemotherapy agents23.

Examples of chemotherapeutic agents used and their regimen includes: Intravenous

Vincristine, Actinomycin-D and Cyclophosphamide (VAC), Intravenous Vincristine,

Adriamycin, Actinomycin–D and Cyclophosphamide (Adria-VAC), or Etoposide with

Cisplatin(EC), Intravenous Vincristine, Adriamycin and Cisplatin(VACis), Intravenous

Vincristine and Cyclphosphamide(VC), Intravenous Cyclophosphamide, Adriamycin

(Hydroxy Doxorubicin), Vincristine(Oncovin) and Oral Prednisolone. Others include

Cisplatin/Carboplatin, 5 Fluorouracil and Intrathecal Metothrexate23. Chemotherapy can also be administered locally. Several new methods of administration are now being used and these include sub-conjunctival Carboplatin, Selective Ophthalmic Arterial Infusion therapy (SOAI) or direct Intra-arterial Chemotherapy and Photodynamic therapy23.

RADIOTHERAPY

Radiotherapy could be External beam radiotherapy, Brachytherapy or Beta irradiation.

External Beam Radiotherapy46

External Beam Radiotherapy (EBRT) can be with either 3D-conformal radiotherapy,

Intensity Modulated Radiotherapy (IMRT) or Image Guided Radiotherapy (IGRT). EBRT to the orbit involves assessment of the disease using radiological imaging with Computer

Tomography Scan or Magnetic Resonance Imaging to define the target volume for delineation; this includes the primary tumour and draining lymph nodes.

Several critical organs in the head and neck makes treatment difficult hence immobilization and reproducibility is important. The patient is immoblised using a persplex shell / custom made thermoplastic and head rest. The patient lies supine with the chin in neutral position.

The patient is simulated using a CT simulation and the target volume is localised. The superior border of the field is the superior orbital ridge while the inferior orbital ridge is the lower border, the medial wall of the orbit medially and the lateral edge laterally. Centre of field is in line with the pupil. A 3mm isotropic margin is allowed around the primary tumour to produce a planning treatment volume which encompasses the disease and subclinical disease to prevent recurrence. Beam is angled posteriorly by 50 to avoid contralateral lens.

The eye is treated with the eye open to minimize dose to the lens. The Organs at risk are the optic nerve, chiasm, lenses, retina, lacrimal gland and pituitary. These are contoured using a simulator to prevent excess radiation getting to them. It is also important to monitor radiation dose received by these organs.

Conventional radiotherapy for stage I & II disease is 60Gray (Gy) over 6weeks using an anterior and lateral wedge pair technique with 30-450 usual field sizes of 4x4cm. 3D conformal radiotherapy has enabled dose to be increased to as high as 70Gy to the tumour with minimal side effects. IMRT, IGRT and proton therapy produce more conformal dose distribution than standard EBRT. Other beam arrangements are superior and inferior wedge beams in the sagittal plane with the aim of sparing the cornea anteriorly but the lacrimal gland is difficult to avoid. A standard dose of 56Gy in 4 fractions of proton or charged particles with local control can also be used3.

Bilateral choroidal metastasis are treated using opposing beams angled 50 posteriorly with doses of 20Gy in 5 fractions of 4Gy given in 1 week. For Conjunctiva lymphomas 30Gy in

15daily fractions given over 3weeks while orbital lymphomas is 40Gy in 20 daily fractions

(no chemotherapy) or 30-36Gy in 15-18 fractions following chemotherapy. Post-operative radiotherapy dose for sarcomas, carcinomas and melanomas is 60Gy in 30 daily fractions given over 6weeks. In orbital lymphomas radiotherapy is indicated as the primary treatment for stage 1 disease or it may follow chemotherapy. Primary lacrimal gland carcinoma and orbital sarcomas, surgical excision can be followed with post-operative radiotherapy. BCC and SCC of the skin and lower eyelid are treated with superficial photons/electrons especially in early disease. In cases with advanced disease EBRT is used as an alternative to exenteration or after exenteration if the resection margins are positive for malignant cells.

Complications of radiotherapy treatment include uveitis, dry eye, cataract, eyelid damage, corneal ulceration and radiation retinopathy. Other complications are bone and soft tissue hypoplasia in children and increased incidence of secondary tumour in the individual.

Fractionated doses of more than 10Gy result in cataract formation which occurs as a late effect and can be treated surgically23. Lacrimal gland damage occurs when doses over 32Gy are used resulting in dry eye. Corneal ulceration can be prevented with the eyes open to prevent dose build up effect caused by overlying eyelid and is usually seen at doses greater than 48Gy. Optic nerve and chiasm doses should not exceed 55Gy and retinopathy is seen

when greater than 50Gy is used. Care should be taken to avoid exceeding tolerance doses of contralateral orbital structures. Thermo-luminescence dosimeter can be used to verify dose to contralateral eye.

Special instructions are given to provide care for the eye which includes lubricating eye drops to prevent keratitis. Patients are asked to keep their eyes open and look directly at the beam to spare the front of the eye. Frequent ophthalmic review is required to detect early reactions such as conjunctivitis and corneal damage so as to institute treatment early to prevent permanent damage to the eyes.

BRACHYTHERAPY

Plaque therapy aims at conserving vision and is used in early stage disease or for small tumours15. Brachytherapy (episcleral plaque) is temporarily sutured to the sclera using

Iodine 125 implanted seeds or ruthenium 10615. The indication for brachytherapy includes small sized lesions in which there is a good potential of salvaging vision. The I125 radioactive seeds are placed in gold plaque and sown unto the outside of the eye in a surgical procedure and left in place for 5-7 days15. Doses of 400Gray to the base of the tumour and

80-100Gray to the apex can be achieved using a dose rate of 0.7-1.0Gy/hr3,46. Patient is usually discharged in 24hrs and returns for plaque removal in 4-7days46. Radiation retinopathy or cataract occurs from excessive irradiation leading to loss of useful vision15,46.

Other problems which can occur include macular oedema, retinal hard exudates, serous retinal detachment and neovascular glaucoma15.

Several factors influence the therapeutic options in the management of OOM and these include tumour size, activity, location, grade, growth pattern, patients age, performance status of the patient, status of the opposite eye and comorbidity3,15.

Melanomas

Small melanomas of <5mm in diameter, <3mm in thickness are usually asymptomatic and difficult to differentiate from benign lesions15. They are observed or treated with plaque brachytherapy with I125 or ruthenium106 or protons or other local treatment

(photocoagulation or surgical excision)3,46.

High risk Melanomas are commonly treated with Laser photocoagulation, Thermotherapy, plaque brachytherapy and external beam radiotherapy15. Local resection may also be indicated.

Medium sized uveal melanomas (3-8mm thickness,10-15m in diameter) are treated with plaque brachytherapy, external beam radiotherapy, local resection or enucleation1,46 .

Large tumours (>8mm in thickness, >15mm in diameter) are treated with local resection, plaque brachytherapy46. Enucleation and post-operative radiotherapy is preferred for tumours with extrascleral extension2,46 or tumours that are diffuse and have fast growth pattern45.

Melanomas that have caused secondary glaucoma are treated with enucleation15.

Brachytherapy is indicated for less extensive disease. Pre-operative Radiotherapy does not

improve cure rate46. Iris melanoma is treated with excision, plaque therapy or enucleation15. Ciliary body and Choroidal Melanoma are treated either by plaque brachytherapy or excision15. The closer the tumour is to the optic disc or fovea the higher the risk of irreversible visual impairment15. Patients with Posterior uveal melanoma who are treated with enucleation tend to have worse prognosis than untreated individuals because distant micrometastasis is more in those with enucleation46.

COMS were designed to compare survival in patients treated with either brachytherapy or enucleation46. Their study showed that mortality rates after I125 plaque therapy and enucleation are similar46. The study also showed that pre-enucleation EBRT of large choroidal melanoma does not improve survival46.

Non-Hodgkins Lymphomas are characterized into low grade, limited disease and intermediate/ high grade or systemic disease with orbital involvement15. Individuals with low grade, limited disease are best treated with radiotherapy alone using EBRT 30-30.6Gy in 1.5-1.8Gy fractions while those with intermediate/high grade or systemic disease with orbital involvement are treated with combined chemotherapy CHOP Regimen(intravenous cyclophosphamide, hydroxyurea, oncovine and oral prednisolone) and EBRT to the orbit(40Gy)46. Monoclonal antibody Rituximab is added to patients who have CD20+3.

Lesions involving the eyelid or bulbar conjunctiva are treated with electron beam therapy using 6-8Mev with 0.5-1cm bolus to allow for even dose penetration of the tumour46.

Monoclonal Antibodies: are targeted therapy treatments useful in treatment of specific malignancies because of their specificity and ability to bind preferentially to tumour- specific antigens without causing significant side effects compared with conventional cytotoxic drugs3,28.

Antibodies raised against CD20 on the surface of B cells (e.g. Rituximab) have emerged as major components of Non-Hogdkins lymphoma treatment23,47,48. Cetuximab is also used to treat epidermal growth factor (EGF) receptor overexpressing malignancies such as

Squamous cell carcinoma23,28.

PROGNOSIS

Tumour size is the most important prognostic factor23. Other prognostic factors include optic nerve invasion, orbital invasion, vitreous seedlings, extrascleral extension, undifferentiated histology, heritable retinoblastoma, bilateral or multifocal retinoblastoma and choroidal extension23,28,49. All these confer poor prognosis23.

Prognostic factors for increased metastasis in patients with uveal melanomas include mixed or epitheloid type, large tumour size, ciliary body invasion, monosomy of chromosome 3, scleral penetration, high mitotic rate, ki-67, optic nerve invasion and vascular networks of closed vascular loops3.

Survival rates tend to be better for earlier than for later-stage cancers. Accurate survival rates for eye melanomas and lymphomas based on a specific stage are hard to determine

because these cancers are fairly rare23. Intraocular tumours of more than 90% have 5 years disease survival while extraocular tumours less than 10% have 5 years disease survival rate23. Death usually occurs within 2 years23. Slightly less than 50% of ciliary body and choroidal malignant melanoma are of spindle cell variety with good prognosis of 73% survival rate at 15 years4. A little more than 50% are of non-spindle cell type, with a prognosis of 35% survival rate at 15 years4.

The overall 5-year relative survival for 18 SEER geographic areas was 81.7% from 2003-

20092. Five-year relative survival by race and sex was: 81.2% for white men; 81.5% for white women; 75.5% for black men; 83.4% for black women2. Survival prognosis correlates with clinical stage of the disease, histologic grade and genetic type50.

MATERIALS AND METHODS

This was a retrospective study of patients with histologically confirmed Orbito - ocular malignancies seen in the Departments of Radiotherapy and Ophthalmology (Guinness Eye

Centre) of the Lagos University Teaching Hospital, Lagos State between January 1997 and

December 2011.

The study included all patients presenting or being referred for the treatment of Orbito- ocular malignancies within LUTH or from State hospitals, Private health Institutions as well as those referred from other Teaching Hospitals and other referral centres all over the country during the study period for Surgical, Chemotherapy, Radiotherapy or other forms of treatment.

INCLUSION AND EXCLUSION CRITERIA

Inclusion Criteria

1. All patients who have been managed for histologically confirmed Orbito-ocular

malignancies in the Departments of Radiotherapy and Ophthalmology (Guinness Eye

Centre) LUTH from January 1997 to December 2011.

2. Those with metastatic diseases, the primary disease were histologically confirmed.

3. All patients with OOM whose data could be retrieved from the medical records.

4. Patients who had adequate data in their case notes which included detailed clerking

and examination, detailed investigations reports and detailed documentation of

treatment the patient received.

5. Patients who received treatment and were adequately followed up till the period of

the end of the study or those who were seen till their demise or defaulted from the

Clinics.

Exclusion Criteria

1. Patients whose data could not be retrieved from the medical records during the

period of study.

2. Patients who did not have histopathological result in their case notes.

3. Patients who had insufficient data regarding details of presentation, investigations

and treatment in their case notes.

DATA COLLECTION TOOLS AND TECHNIQUE

The data for this research were obtained from the case notes of the patients retrieved from the Medical Records Department using a questionnaire (Appendix 1). The questionnaire consisted of two sections; Section A were of questions on socio-demographic characteristics of the patients. Section B consisted of questions used to assess complaints, signs and symptoms, investigations and management modalities offered.

The data analyzed included the following:

1. Hospital number

2. Age of patient at presentation

3. Sex

4. Occupation

5. Ethnic Group

6. Marital Status

7. Family History

8. Presenting Complaints

9. Left or right or both eyes

10. Referral Centre

11. Visual Acuity at presentation

12. Histology

13. Clinical Stage

14. Management Modalities offered

15. Follow – Up till discharge/demise.

DATA ANALYSIS

The data were entered into a computer and analyzed using EPI info (2008) and Winpepi

(2008) Statistical Software package. Analyzed data was presented in the form of frequency tables, charts and cross tabulations.

ETHICAL CONSIDERATION

Ethical approval was obtained from the Ethical and Research committee of Lagos University

Teaching Hospital, Lagos State where the study was conducted.

RESULTS

There were one hundred and seven (107) cases available for review however only ninety eight (98) cases were eligible for the study based on the inclusion criteria, these were analyzed (Table 1.0). Nine patients could not be used because three of the patients had no histologic diagnosis while six of them had insufficient data in their case notes. Patients were referred from all over Nigeria to the department of Radiotherapy and Ophthalmology in LUTH for treatment.

Table 1.0: Yearly distribution of Orbito-ocular malignancies seen in the Departments.

Years Frequency Percentage (%) 1997 3 3.1 1998 2 2.0 1999 4 4.1 2000 3 3.1 2001 10 10.2 2002 8 8.2 2003 10 10.2 2004 7 7.1

2005 11 11.2 2006 4 4.1 2007 8 8.2 2008 5 5.1 2009 7 7.1 2010 10 10.2 2011 6 6.1

Total 98 100

Table 2.0: Age and Sex distribution of Orbito-ocular malignancies.

Age range(years) Male Female Frequency Percentage (%) 0-9 34 20 54 55.1 10-19 1 0 1 1.0 20-29 3 2 5 5.1 30-39 6 5 11 11.2 40-49 7 3 10 10.2 50-59 2 2 4 4.1 60-69 5 7 12 12.3 ≥70 0 1 1 1.0 Total 58 40 98 100

Majority (55.1%) of the patients were children less than 10yrs of age. 21 and 13patients were of ages 2 and 3 years respectively. Ten patients were ≤ 1year of age. 12 patients were between the ages of 60-69years. Only 1 patient was above 70years. The study showed that 58 patients were males and 40 females (M:F=1.5:1). The age range was 8months to 83years with a mean of 22.94years (SD 24.64years). (Table 2.0)

Table 3.0: The Socio-demographic characteristics of Patients.

Frequency Percentage (%) Marital status Married 36 36.7 Single 61 62.3 Widowed 1 1.0 Separated 0 0 Divorced 0 0 Ethnicity Yoruba 51 52.0 Igbo 25 25.6 Hausa 2 2.0 Others 20 20.4

Sixty one (62.3%) patients were single while thirty-six (36.7%) were married and only one (1%) was widowed. They were predominantly Yoruba, 51(52.0%) by tribe while 25(25.6%) were Igbos, 2 were Hausas and 20 from the minority (Table 3.0).

Figure 1.0: Frequency of Affected Eye

The right eye was affected in 46(46.94%) individuals while 42(42.86%) had the left eye involved. 8 (8.16%) had bilateral involvement of both eyes, in 2 (2.04%) cases the site(s) affected was not mentioned (Figure 1.0).

Table 4.0: Orbito - ocular malignancies in the Departments (1997 – 2011).

Retinoblastoma 51 Squamous Cell Carcinoma 25 Melanoma 4 Rhabdomyosarcoma 3 -Embryonal 3 Non-Hodgkin’s Lymphoma 2 Adenoid Cystic Carcinoma 1 Kaposi Sarcoma 1 Sebaceous Carcinoma 1 Optic Nerve Meningioma 1 Squamous Papilloma with severe Dysplasia 1 Intraorbital Neoplasia 1 Lymphoid Pseudotumour 1 Epithelial Salivary Gland Neoplasm 1 Metastasis 2

Total 98

Retinoblastoma was the commonest histologic variant seen in 51(52.0%) of the patients followed by squamous cell carcinoma also seen in 25(25.5%) of the patients. Rhabdomyosarcoma was seen in 6 (6.1%) patients of whom the embryonal type was seen in 3 of them; the other 3 patients were not specified. Melanoma was found in 4 (4.1%) patients. The various histologic types are as shown above(Table 4.0).

Table 5.0: Common signs and symptoms of orbito-ocular malignancies.

Leucokoria 20

Red eye 7

Cornea opacity 1

Conjunctiva swelling 2

Lower eye lid swelling 11

Loss of vision 3

Proptosis 47

Pain in the eye 1

The most common presenting complaints was proptosis seen in 47, Leucokoria 20, Lower eyelid swelling in 11 and red eye in 7patients (Table 5.0). Other symptoms includes fungating eye mass seen in four patients, swelling in the mandible and or maxilla. Ptosis was seen in two patients.

Percentage (%)

Chemotherapy alone 1.1

Radiotherapy alone 3.1

Surgery alone 32.7

Percentage (%) Surgery/Chemotherapy 18.5

Surgery/Radiotherapy 24.5

Surgery/Chemotherapy/Radiotherapy 17.3

0 5 10 15 20 25 30 35

Figure 2.0: Treatment modalities used for management of patients. 17(17.4%) patients had a combination of Surgery, Chemotherapy and Radiotherapy. 24(24.5%) had a combination of Surgery and Radiotherapy, 18(18.5%) had a combination of Surgery and Chemotherapy while 32(32.7%) had surgery alone. 1(1.1%) and 3(3.1) patients received only Chemotherapy and Radiotherapy respectively (Figure 2.0).

Figure 3.0: Types of Surgeries Performed.

Ninety-one patients had surgery. 30(33%) patients had Enucleation while 33(36%) had

Exenteration. 22 (24%) had excisional biopsy while 6 (7%) had incisional biopsy. 7 patients had no surgery (Figure 3.0).

Table 6.0: Chemotherapy regimen

VAC VACis VC CHOP CAPECITABINE TOTAL

Retinoblastoma 13 10 - - 23 Non-Hodgkin’s - - 2 - 2 Lymphoma Squamous Cell - 5 - - 1 6 Carcinoma Rhabdomyosarcoma 4 - - - 4 Metastasis 1 - - - 1 Total 18 5 10 2 1 36

36 patients had Chemotherapy, the chemotherapy regimen used are as shown in Table 6.0 above.

Table 7.0: Outcome of Treatment in Patients. Frequency Percentage (%) Complete Response 4 4.1 Recurrence 5 5.1 Dead 5 5.1 Lost to follow up 84 85.7 Total 98 100

Majority 84 (85.7%) of the patients were lost to follow up. 4 had complete response and are still alive and are seen in the clinic on follow up. 5 had recurrence and received further treatment, 5 died from disease progression within 2years following treatment (Table 7.0).

DISCUSSION

Orbito-ocular malignancies though rare are a common cause of morbidity and mortality. The rarity accounts for the low incidence seen over the period of study. Several Nigerian based studies from Zaria, Benin, Ilorin and Ibadan have reported incidence of 40.3%31, 22.8%51, 57.3%43 and 51.5%40 of OOM among OOT respectively. These results are contrary to previous perception on the rarity of the disease in Africa52. Low number of cases seen during the early period of the study may be due to lack of radiotherapy machine or machine break down or facility shut down during strike action of health workers. Lack of awareness could also have been a contributing factor to the low number of cases. It was evident that several patients treated during this period had radiotherapy at nearby facilities and still came back to continue treatment at the clinic. In this study OOM occurred more in males than females in a ratio of 1.5:1, this is similar to findings on pattern of ocular tumours in Ibadan, Lagos, Ilorin, Kaduna and Ghana but at variance with a study done in Enugu where females outnumbered male subjects (M:F of 1:1.4) 5,6,40,43,53,54. The study identified three most common OOT as retinoblastoma 52.0%, Squamous cell carcinoma 25.5% and melanoma 4.1% which were similar to other findings from Nigeria but different from findings in the Western World of retinoblastoma 53.6%, melanoma 19.2%, and 11.2% of SCC in Singapore26 while New York State reported 70.4% melanoma, 9.8% retinoblastoma, and 9.2% SCC55. The relative frequencies of histologic types seen in each of these studies varied widely in order of occurrence but were also the most common OOT found in these areas. Squamous cell carcinoma (SCC) was the most common in adults and affected both sex equally similar to findings in Lagos, Ibadan and Ilorin. SCC is reported as the most common conjunctival lesion in Nigeria and the most common ocular malignancy in adulthood 67

supported by earlier studies5,38,51. Previous report from Ibadan has concluded that the carcinoma is common in the tropics and strongly associated with HIV/AIDS40. Five individuals with SCC had HIV in this study though the patients were not all screened. Uveal melanoma is rare in Africa as reported in this study and others51,52 this is in contrast to incidence in the United States America and Europe where it accounts for the commonest primary intraocular malignancy in adults1,3,4. Rhabdomyosarcoma was seen in 6(6.1%) patients and was of embryonal origin in three of them; it is the commonest primary orbital malignancy of childhood15. Kaposi sarcoma was associated with Human Immunodeficiency virus infection and seen in only one patient. Lymphoma were rare in this study, only two patients had NHL which is in contrast to studies reported by Chuka-Okosa et al and Ajaiyeoba et al in Eastern and Western Nigeria respectively which showed lymphomas as the most common orbital tumour including Burkitt’s Lymphoma30,54. Despite the relationship between AIDS related pandemic and OOM, there has not been significant association in the incidence of OOM in this environment. The study showed a high prevalence of orbital cancers in children with retinoblastoma accounting for 50% of the study population. Annunobi et al and Umar et al in Nigeria also reported high prevalence rates of 85% and 44.5% respectively, however this is in variance to studies done by Owoeye who reported low incidence of 33.3%5,56,43. Studies done in Singapore and New York also showed incidences of 53.6% and 9.8% respectively26,55. The differences in frequencies may suggest that environmental factors have a role to play in the etiology of these malignancies. The age range was 8months to 6years with mean of 2.53years, modal 2years. The mean age of retinoblastoma in this study is similar to that of 2.65years reported by Bekibele et al and 2.42years by Owoeye et al in South West Nigeria40,53 this is in variance with 18months in Western Countries57. The variation in age incidence could be attributed to late presentation in developing countries while environmental factors may be related to variations in geographic incidence of these malignancies. Most often, early stage OOM is asymptomatic, patients usually present with symptoms of leucokoria, proptosis, red eye, eye lid swelling and bone pain in late or advanced stages. 68

The commonest complaints were those of proptosis and leucokoria seen in 47 and 20 patients respectively. Proptosis was also the commonest presentation at Ilorin (84.6)% followed by leucokoria (61.5%)43. Majority of the patients in developing countries present with proptosis a fact which validates the late presentation for treatment52. The delay in presentation is attributed to poverty and ignorance on the part of the patient, lack of adequate treatment facilities and incompetence of some primary physicians in suspecting the disease and effecting early referral. The stage, age and histology are considered the most important prognostic factor in OOM1. Management of orbito-ocular malignancies has changed dramatically over recent decades and continues to evolve. It now includes a wide range of different techniques that can achieve good tumour control when used alone or in combination with other treatment modalities. Within the study period, the most common modality of treatment in LUTH was a combination of Surgery, Radiotherapy and Chemotherapy. In this study, 44 patients had radiotherapy for mostly adjuvant treatment (radical treatment dose of 35-65Gy in 20-35 fractions over 4-7weeks using a LINAC), neoadjuvant and for palliation (doses varying from 18-30Gy in 10fractions over 2weeks) of symptoms. External beam radiotherapy was avoided in children because of the risk of secondary malignancies and craniofacial asymmetry. However, because of late presentation children above the age of 3years received it frequently as adjuvant treatment following surgery or chemotherapy. High radiation doses could not be delivered because of acute side effects and complications following treatment because there was no facility for 3D conformal radiotherapy. Enucleation and exenteration were a major form of surgery for intraocular cancers because most patients present in advance cases where the likelihood of salvaging vision is low. Patients who are identified early are also offered enucleation as there is no other means of proper excision of the tumour. A review of orbital exenterations by Ackuaku-Dogbe revealed that this is the surgical procedure most often done in developing countries for neglected periorbital and ocular surface malignancies which may have resulted in fungating tumours which are no longer salvageable58.

Primary systemic neoadjuvant and adjuvant chemotherapy were widely used with VAC, VC, and Chemoradiation with Capecitabine or intravenous Cisplatin. Chemothermotherapy has been shown to improve tumour control in several studies in selected cases of retinoblastoma59. Tumour regression was obtained in 96% of lesions and relapse was observed in 6.8% of treated tumours following the use of chemothermotherapy59. Visual acuity was supposed to be an endpoint in the study however sufficient data was not made available for it to be assessed. Several management policy guidelines have been put in place to ensure better treatment outcome and a universal approach to treatment. Majority of the patients presented in late stages and many were lost to follow up. Early diagnosis and appropriate treatment will improve overall survival and quality of life.

LIMITATIONS • It was a retrospective study and some case notes were not available for study. Some informations were not supplied in the case notes for analysis.

• Majority of patients in the study had advanced disease at presentation and majority of them were also lost to follow up making it difficult to determine the disease free survival and overall survival of the patients.

• There were incessant breakdowns of the radiotherapy machine during the period of study which necessitated patient’s referral to other nearby radiotherapy centres for treatment.

CONCLUSION

The burden of OOM has been linked to its rate of morbidity and mortality. Retinoblastoma and Squamous Cell Carcinoma both accounted for three quarters of this disease with children predominantly affected. There is no defined protocol or algorithm for treatment of OOM in the country and so majority of the patients were referred to the specialists in late stages mostly for palliative care. Radiation therapy was limited to external beam radiotherapy as there is no facility for brachytherapy or cryotherapy for OOM. This makes treatment options inadequate for localized disease. Several patients had palliative radiotherapy to control pain, for treatment of locally advanced fungating tumours and bone metastasis. Major Prognostic factors in this study were stage at presentation and histological type. Inadequate staging of the disease is still a challenge as several patients were not staged. This is a significant prognostic index. Late presentation, irregular follow ups and poverty contributed to the poor outcome seen in most cases. Late presentation is still a dilemma in developing countries and the need for a collaborative effort between the government (in creating enlightenment programmes to aid early presentation) and the healthcare givers is imperative.

RECOMMENDATIONS  There should be improvement in cancer research and national guideline policy to set standard treatment protocols that are realistic and such that will fit into our environment.  There is a need to collate figures and improve education and knowledge. Most studies done on OOM did not review the management of the disease. They were based on epidemiological studies.  Joint Oncology meetings should be established in all hospitals so that experts involved in the management of OOM can exchange knowledge on how to incorporate International guidelines in our Institutions for better treatment outcomes.  Social workers, religious leaders and the community should be involved in patient care, to help reduce the rate at which patients are lost to follow up.  Government should make health care affordable and accessible by providing more equipped National Cancer Centers. These Centers should be well equipped with adequate diagnostic tools and Modern Radiotherapy equipment for patient care, likewise providing adequate manpower for training and patient care.

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APPENDIX A

REVIEW ON MANAGEMENT OF ORBITO OCULAR MALIGNANCIES IN THE DEPARTMENT OF RADIOTHERAPY AND OPHTHALMOLOGY, LAGOS UNIVERSITY TEACHING HOSPITAL (1997 – 2011).

DATA EXTRACTION FORM SECTION A QUESTIONNAIRE

SECTION A

1. HOSPITAL NO. ______

2. AGE AT PRESENTATION ______

3. AGE GROUP (A)0-9yrs___ (B)10-19yrs___ (C)20-29yrs___ (D)30-39yrs___ (E)40-

49yrs___ (F)50- 59yrs___(G)60-69yrs___ (H)≥70

4. SEX (A) MALE_____ (B) FEMALE_____

5. OCCUPATION ______

6. ETHNIC GROUP: Yoruba______Igbo ______Hausa______

7. MARITAL STATUS:(A)Married (B)Single (C)Divorced (D)Separated (E)Widow

8. FAMILY HISTORY (of malignancy) (A)YES ___(B)NO ____

SECTION B

9. TIME OF PRESENTATION______

10. PRESENTING COMPLAINTS______

11. PRESENTATION OF TUMOUR 10 OR 20 ______

11a. IF METASTATIC TYPE OF PRIMARY (A) Breast (B) Lungs(C) Others

12. EYE (A) LEFT (B) RIGHT (C) BOTH

13. VISUAL ACUITY______

14. ABILITY TO SEE/INABILITY

15. STAGE AT PRESENTATION (A)1 (B)2 (C)3 (D)4

16. HISTOLOGIC TYPE ______

17. TREATMENT OPTION (A)Surgery (B) Chemotherapy (C) Radiotherapy

(D) Chemoradiation (E) Others specify______

18. TYPE OF SURGERY (A)Excisional (B)Incisional (C) Exenteration (D)

Enucleation (E) Others ______

19. TYPE OF CHEMOTHERAPY (A)Induction (B) Chemoradiation (C) Others

______

20. AIM OF RADIOTHERAPY (A) Radical (B)Palliative

21. RADIOTHERAPY (A) External Beam Radiotherapy (B) Brachytherapy

22. TYPE OF RADIOTHERAPY MACHINE (A) LINAC (B)Cobalt 60 (C)Others

23. OUTCOME OF TREATMENT (A)Complete response (B)Partial response (C) No response

24. FOLLOW UP (A)Absence of new complaints (B)Presentation of new complaints

(C)Recurrence (D)Lost to follow up

25. (A) ALIVE (B) DEAD