Malignant Tumours of the Eye and Ocular Adnexae

A Photo-Essay for Health Professionals

 

John G. O'Shea MD, Robert B. Harvey FRCSE

 

Introduction, Ocular malignancies in Western Communities

Cancer is a leading cause of morbidity and the second leading cause of mortality. The eye and adnexa are potential foci of neoplastic disease, either as primary sites or as sites of metastatic carcinoma. The most frequent anatomical site of ocular cancer is the eye itself, followed by the orbit, the conjunctiva, and the lacrimal gland. The majority of ophthalmic malignancies are included within three histologic groupings: melanomas (70.4%), retinoblastomas (9.8%), and squamous cell carcinomas (9.2%). (1)

 

This article reviews the principal tumours involving the eye and also emphases the detection and treatment of basal cell carcinoma, the commonest eyelid tumour.

 

The average annual age-adjusted incidence of ocular cancer varies between 0.6 per 100,000 and 0.9 per 100,000 for the male population and between 0.5 per 100,000 and 0.8 per 100,000 for the female population. (1) The distribution of eye cancer risk by age is bimodal, with peaks occurring during early childhood and again during adulthood. Retinoblastoma is the most common ocular malignancy in children, and uveal melanoma is the most common ocular malignancy in adults. (2)

  Retinoblastoma, if treated, has a favourable prognosis, with a relative five year survival rate of more than 90%. However, visual morbidity, although improving, remains poor for bilateral disease. (1,2,3,4)

 

Retinoblastoma - a tumour of childhood  with genetic determinants

 Retinoblastoma is the most common intraocular malignancy of childhood.  It is an undifferentiated,  neuroblastic tumour.  (4)

  

Table 1 RETINOBLASTOMA

 

The commonest intraocular malignancy in children

 

INCIDENCE

1/20000, M=F

1/3 bilateral (genetic)

2/3 unilateral (25% genetic, 75% sporadic)                            (1,2,3)

 

________________________________________________________________________

 

The disease is bilateral in approximately 30% of cases. The average age at diagnosis is 18 months and 90% of patients are diagnosed before the age of  3 years. Less than 10%  of retinoblastoma suffers have a family history of the disorder,  90% of cases are sporadic. Of the sporadic cases,  the responsible mutation is in a germ cell in 25% of cases and in a somatic cell in 75% of cases.  (1,5)

 In total therefore, about 40 % of retinoblastomas are due to a germinal mutation. Those whose tumor is due to a germ cell mutation may actually pass the disorder to their offspring. Approximately 50% of offspring are affected, the disease being transmitted as a dominant trait. The hereditary form of the disease usually presents earlier and tumours are more likely to be both bilateral and multifocal.

 

The ‘two hit hypothesis’ of Knudson states that two mutational  events  are necessary  for tumour formation to occur and explains observed differences in the behavior of tumours in hereditary and non hereditary cases. (5)

 

Table 2- GENETICS

Retinoblastoma gene is a recessive oncogene of 180,000 kilobases.

Located chromosome- 13q14

Knudson two hit hypothesis:-

Germinal cells have one defective and one normal RB gene.

A somatic mutation results in loss of the normal RB gene and hence retinoblastoma develops (somatic mutations occur frequently enough in the developing retina, therefore lesions usually affect both eyes)

 

In addition, the first child of a parent who had had a unilateral retinoblastoma  has  a 4% chance of developing the disease.

___________________________________________(2,5,6)_______________________

 

Two mutational events are needed in a retinal cell for a tumour to occur. In patients with a germinal mutation all retinal cells will carry the mutation and only one further mutation is necessary, hence multiple tumours may occur.  In somatic mutations it is unlikely that the chances of these events occurring in several loci is relatively small, hence tumours are typically unilateral and unifocal. 

 

Chromosomal abnormalities are not typically found but partial deletion of the long arm of chromosome 13 ( q14 deletion) is well described and is occasionally found. Retinoblastoma patients with these deletions characteristically have reduced levels of the enzyme Esterase D.

 

________________________________________________________________________

 

Table 3- CLINICAL MANIFESTATIONS

Leukocoria (60%)  

Strabismus (20%)

 

OTHER- Uveitis, Orbital cellulitis, Hyphaema, Heterochromia, Glaucoma, Bupthalmos (2)

________________________________________________________________________

 

In hereditary retinoblastoma there is also an increased risk of developing a second, non ocular malignancy.

 

Parental  age,  exposure to ionising radiation and their  possible influence upon the development of  retinoblastoma 

 

Does parental  age, exposure to ionising radiation or other external events influence the incidence of retinoblastoma in human populations ?  Matsunaga et al. performed statistical analysis of parental age data from 225 sporadic cases of bilateral retinoblastoma, plus ten sporadic cases of chromosome deletion or translocation involving 13q14 that was identified as of paternal origin, revealed no evidence of paternal or maternal age effect. (7) Parental exposure to ionizing radiation or chemical mutagens, the effect of which is accumulated with advancing age, does not seem to play a major role in the production of germinal mutations at the responsible (RB) locus.

Furthermore, analysis of variation in the month of birth of 753 children with sporadic unilateral retinoblastoma did not show any significant deviation from the controls or a cyclic trend. (7)

 

________________________________________________________________________

 

Table 4  PATHOLOGY

 

Arise in primitive photoreceptor cells.

Characteristic histology:

Retinoblastomas are composed of poorly differentiated neuroblastic cells with scanty cytoplasm and prominent basophilic nuclei.

The tumour proliferates rapidly, with a tendency to outgrow its blood supply and undergo spontaneous necrosis. Necrotic tumour being eosinophilic stain pink.

Characteristic Flexner-Wintersteiner rosettes represent an attempt at retinal differentiation.  Histologically, a ring of cuboidal cells is seen surrounding a central lumen. Cuboidal tumour cells with basally oriented nuclei arranged around a central lumen.

 

Calcification is another feature of retinoblastomas, usually occurring in necrotic areas. Calcium stains with H&E.  It is worth identifying calcium in suspect eyes by ultrasound, or CT scan to differentiate retinoblastomas from other tumours.

(2,3)

________________________________________________________________________

 

The occurrence of nonheritable retinoblastoma is not likely to be associated with certain viruses such as human adenovirus 12 whose activity varies markedly with season. Their results, together with the fairly uniform pattern in the incidence of this tumor among different populations, suggested that most cases of sporadic retinoblastoma are caused by intrinsic biological mechanisms rather than by environmental mutagens that may vary with respect to time and place. (7,8)

Amemiya, Takano and Choshi  studied the effect of atomic bomb radiation in Nagasaki and Hiroshima on the incidence of retinoblastoma by examining the history of exposure to atomic bomb radiation among the grandparents and parents of retinoblastoma patients in Nagasaki and Hiroshima. Of 85 patients born in Nagasaki Prefecture from 1965 to 1986 and in Hiroshima Prefecture from 1966 to 1986, 42 had records to whether or not their grandparents and parents had been exposed to atomic bomb radiation. Seven had parents or grandparents exposed to atomic bomb radiation. (8)

   

Table 5 INVESTIGATION AND MANAGEMENT OF RETINOBLASTOMA

 

INVESTIGATION

 

EUA

CT head and orbits

Bone marrow

Lumbar Puncture

All should ideally be done during the same anaesthetic.

   

MANAGEMENT

EMPIRICAL GENETIC COUNSELLING

ENUCLEATION

unilateral, poor visual prognosis

PLAQUE

4-12mm +/- vitreous seeding

EXTERNAL BEAM

>12mm, multiple foci, only eye

LASER

consider- indirect, xenon arc

cryotherapy if <2dd in size

CHEMOTHERAPY

if intracranial extension

 

(orbital growth affected by enucleation and external beam up to 5yrs, external beam has a worse effect and also hastens onset of osteosarcoma and other second tumours )

 

FOLLOW UP

one month

3 monthly for 2 years

6 monthly for 5yrs

annually for >5yrs

                                                           ( 2,9,10,11,12 )

________________________________________________________________________


These patients showed neither a high incidence of bilateral retinoblastoma nor a family history of retinoblastoma, although a higher incidence of cancer in the family history was found in the exposed group. Exposure to radiation showed no correlation with the onset of retinoblastoma. (8)

 

Course and Outcomes

 

As many as 45% of eyes treated initially by one form or another of eye-preserving therapy, eventually require some subsequent therapy by the same or another modality because of the development of new or recurrent intraocular tumours . In spite of the need for secondary treatments of a sequential type, the great majority of eyes that have small-to-medium sized tumours and no vitreous seeding are salvaged with useful vision. (2,9,10,11,12)

 

 Following treatment of retinoblastoma, the child must be re-examined within about 2-4 weeks to assess treatment efficacy, and supplemental local treatment is performed if the prior therapy appears inadequate. Once treatment appears to have eradicated all intraocular tumors totally, children are monitored about every 3 months for at least 2 years post-treatment. Thereafter, children should probably be followed at about 6-month intervals until they are at least 6 years of age, after which children should be followed at yearly intervals.(2)

 

Some children have substantial orbital extension of tumor at the time of their initial diagnosis and treatment, and others develop orbital recurrence after enucleation. Although such cases were almost invariably fatal in the past, current evidence suggests that at least some of these children now may be saved by an aggressive regimen of tumor debulking, supplemental orbital irradiation, and systemic multidrug chemotherapy. Unfortunately, the prognosis for children who have intracranial extension or widespread metastasis remains dismal at this point in time.(6,9)

 

Untreated children who have retinoblastoma almost always die of intracranial extension or widely disseminated disease within approximately 2 years of the date of tumour detection. Recognized clinical prognostic factors for mortality include age at detection and diagnosis (more advanced cases tend to be detected earlier), unilaterality or bilaterality of the disease (unilateral cases tend to be detected later), extent of the intraocular tumor, and, most importantly, evidence of retrobulbar or extraocular tumor extension on computed tomography or other imaging studies. (10,11)

 

The 5 year survival rate for both unilaterally and bilaterally affected children who have retinoblastoma in developed countries is 90-95%. (1,2,3)

 

Unfortunately, children who have genetic retinoblastoma and survive their primary intraocular cancer have a substantially increased risk of death from one or more nonretinoblastoma malignancies over the course of their lifetimes, up to 35% of children who have had a bliateral retinoblastoma and external beam radiation therapy will develop a second cancer by age 25 years.  (2,13)


Uveal  Malignant Melanoma

 

Malignant melanoma of the uvea, the vascular coat of the eye,  is the most common primary intraocular tumour in adults. Certain lesions such as ocular or oculodermal melanosis increase the risk of ocular melanoma.  (1,2)

 

__________________________________________________________________

 

Table 6-CHOROIDAL MELANOMA

 

The commonest primary intraocular tumour in adults

 

INCIDENCE

6/1,000,000/year

Peak incidence at 60yrs,

Whites >> blacks

 

RISK FACTORS

Oculodermal and ocular melanocytosis, neurofibromatosis

Choroidal naevi

Light irides

Genetic predisposition

Monosomy Chromosome 3

                                                                          (2,14,15,16,17)

_______________________________________________________________________

 

 

There is no clear reported relationship to UV-B in adult malignant melanoma of the eye.  (The paediatric cindition is extremely rare. )The average age of patients is 50 years, the tumour is also extremely rare in Afro- Caribbeans. The posterior pole of the eye is the commonest site followed by ciliary body, iris lesions are relatively rare. (2,16,18)

   

 

Table 7- CLINICAL FEATURES

 

Dilated episcleral sentinel vessels

Pigmented or amelanotic mass

Lipofuscin pigmentation

Serous detachment

Uveitis, Cataract

Rubeosis

Disciform lesion

Haemorrhage is uncommon.       (2,18)

       

Maligant Melanoma of Choroid

 

Associations of Ocular melanoma with other tumours

 

Swerdlow, Storm, and Sasieni  (14) report risks of 2nd primary cancer assessed in all patients with cutaneous melanoma (12,460) and all patients with ocular melanoma (2,018) incident in Denmark from 1943 to 1989 and followed for totals of 88,667 person-years and 16,045 person-years, respectively. After cutaneous melanoma, 972 2nd cancers occurred. The risk of non-melanoma skin cancer was significantly raised in each sex. Risk of all non-skin cancers was not raised for all ages but was significantly increased for patients with the primary melanoma incident at ages under 50 years (standardised incidence ratio [SIR], i.e., ratio of observed to expected cancer incidence, multiplied by 100 = 117; 95% confidence interval [CI] 101-134). There were significantly increased risks of chronic lymphocytic leukaemia in males and both sexes combined, brain and nervous system cancers in females and both sexes combined and oropharyngeal cancer in both sexes combined. Risk of pancreatic cancer was not raised, suggesting that cutaneous melanoma patients generally do not share the diathesis for this malignancy which has been observed in certain families with atypical naevi and melanoma.

 

After ocular melanoma, 216 2nd cancers occurred. There was a significantly increased risk of 2nd cancer overall in males but not females and a significantly increased risk of liver cancer in each sex. Risk of non-melanoma skin cancer (NMSC) was not raised, which suggests that the aetiology of ocular melanoma is not mainly dependent on UV exposure, at least of the type causing NMSC. (14)

 

Relationship of Uveal Tract Melanoma to Cutaneous Moles and hereditary premalignant conditions.

 

Bataille and co-workers (15)  set up a case-control study  to assess the risk of eye melanoma in relation to the number and type of cutaneous melanocytic naevi and pigmented lesions of the iris. Cases comprised 211 unselected ocular melanoma patients attending the Ocular Oncology Clinic at Moorfields Eye Hospital, London, during November 1990 to October 1991 and diagnosed after August 1986. Hospital and general practice controls (416) were recruited in the North East Thames Region of the UK. Cutaneous naevi greater than or equal to 2 mm in diameter were counted on the skin. Clinically atypical and congenital naevi were recorded separately. Pigmented lesions of the iris were counted. The relative risk for ocular melanoma increased with numbers of atypical naevi and numbers of common naevi. Ten percent of cases but 3% of controls had at least 100 naevi of 2 mm or greater diameter. Seven percent of cases and 0.4% of controls had 4 or more atypical naevi. Pigmented lesions of the iris were significantly more common in cases than controls. Nine percent of cases had the Atypical Mole syndrome (AMS) phenotype compared with 1% of controls. Six cases had concurrent cutaneous melanoma primaries. They concluded that atypical and iris naevi are important risk factors for eye melanoma and that patients with eye melanoma are at increased risk of cutaneous melanoma. Dermatological examination for the AMS phenotype and cutaneous melanoma should be recommended in eye melanoma patients with large numbers of pigmented lesions of the skin or family history of melanoma.


________________________________________________________________________

 

Table 8- PATHOLOGY

 

PATHOLOGY

The majority of choroidal melanomata in fair skinned people are amelonotic, the ­ pigmentation seen clinically is due to increased thickness of the RPE.

NODULAR

Common, grows through Bruch's membrane like a mushroom

DIFFUSE

Rare, serous detachment

Extrascleral spread common

Poorer prognosis

 

Basal diameter usually 2x thickness

small = 3mm, medium = 5mm, large = 10mm, huge = >10mm

 

CELLTYPE

SPINDLE A- bipolar cells with thin tapering nuclei 5% 5yr mortality

 

SPINDLE B-common, plump nucleus with prominent nucleolus, 15% 5yr mortality

MIXED- commonest, 50% 5yr mortality

NECROTIC- 50% 5yr mortality

EPITHELIOID- large pleomorphic cells with coarse chromatin and large nucleoli, 70% 5yr mortality    (2,18,18,20)

   

 

The naevus of  Ota is another hereditary pre-malignant condition associated with ocular melanomas.(18)  In the literature surveyed adult uveal  malignant melanomas are not convincingly linked to UV-B exposure, indeed very little UVR is transmitted to the posterior pole of the adult  eye. There are well described dermatological pre-malignant markers for melanomas of the uveal tract. (13,15)

   

Pemalignant melanosis of the conjunctiva and UVR

 

Paridaens , McCartney and  Hungerford report neoplastic changes in sunlight-exposed areas of the skin and eyes which may be related to the impaired replication of ultraviolet radiation-damaged DNA.  

Iris malignant melanoma

A 38-year-old Greek woman was reported with a mild form of xeroderma pigmentosum and primary acquired melanosis with atypia of her right limbal conjunctiva and cornea. The development of this precursor of conjunctival malignant melanoma in a xeroderma pigmentosum patient may support the putative role of sunlight exposure in malignant transformation of conjunctival melanocytes. (17)

 


_______________________________________________________________________

 

Table 9- DIAGNOSIS

 

PERIODIC OBSERVATION

With indirect examination

Transpupillary illumination (Welch Allen transilluminator) for pre-equatorial tumours

 

ULTRASOUND                    

A scan - high initial spike,low to medium internal reflectivity

B scan - acoustic hollowness, due to areas of homogeneity within the tumour (see image above)choroidal excavation and orbital shadowing

determination of tumour thickness >3mm (malignant), <2mm (probably benign)

 

FLUORESCEIN ANGIOGRAM: Differentiates tumours from disciform lesions etc. Double circulation with retinal and choroidal circulation may be seen Hyperfluoresence is due to secondary changes in the RPE.

 

CT SCAN- extrascleral extension, scan lungs and liver if abnormal CXR, LFT's

MRI SCAN Gadolinium enhancement may allow detection of optic nerve extension

FIELD ANALYSIS Can help in differentiating a naevus (normal field) from a MM.

CXR, ECG, LFT's (metastasis: liver, lungs, subcutaneous tissue, bone)

Biopsy of amelanotic tumours may be inconclusive due to histochemical markers trans-scleral if large RD overlying or trans-vitreous if no retinal detachment. (2,21,22)

________________________________________________________________________

 

Treatment

 

Many therapeutic options are currently available for choroidal and ciliary body melanomas  Factors that influence the therapeutic decision for a patient who has such a tumor include the size and extent of the intraocular tumour, the location of the tumor within the eye, the presence or absence of extrascleral tumour extension, the presence or absence of clinically detectable metastasis of the tumour to other bodily organs, the visual status of the affected eye, the visual status of the unaffected eye, the age and general health of the patient, availability of the various treatments, and personal preferences and biases of the patient and physician. (2,21)

   

Observation

Observation without intervention is an appropriate option for patients in whom the differentiation between nevus and melanoma cannot be made with reasonable certainty and almost certainly is advisable for those persons who have a serious coexistent life-threatening medical condition that precludes any surgical intervention, even under local anesthesia.  Observation currently is not advisable for most patients who have an unequivocal, undisseminated ocular malignant melanoma. (23,24)

________________________________________________________________________

Table 10- TREATMENT   

AIM- to preserve life, eye and sight.

 

OBSERVATION                 

Small tumours with equivocal diagnosis or systemic metastases present.

See 3/12 then 6/12

 

RADIOTHERAPY                                       

BRACHYTHERAPY Tumours up to 15mm in size especially if salvageable vision. Ruthenium plaque-Radiation penetration is limited so there are fewer ocular complications

                       

TELETHERAPY                    

Proton beam- Clatterbridge, Merseyside, UK Useful for small tumours within 2-3 mm of the disc or fovea. 

Large tumours may result in severe exudative retinal detachment and anterior segment / lid complications.

                       

TRANS-SCLERAL LOCAL RESECTION 

Hypotensive anaesthesia required for 1-3hours. May be suitable if the tumour is less than 16mm in diameter and not perforating the retina. MM should not involve >1/3 of the ciliary body. Long term visual results are good if the tumour does not extend within 2 DD of the disc or fovea. Adjunctive laser or plaque brachytherapy reduces recurrence from local seedlings. Retinal detachment / dialysis occurs after iridocyclochoroidectomy.  Inferior iridectomy causes glare - (a painted contact lens may be useful).

 

THERMOTHERAPY- Uses diode laser to heat lesion and produce necrosis, supersedes argon laser photocoagulation in many Western centres.

 

ENUCLEATION                 

Consider if-  Large tumour with poor visual potential or cosmesis or discomfort.(e.g. total retinal detachment, secondary glaucoma, optic nerve invasion, elderly patient.) If the patient cannot psychologically tolerate leaving the tumour in situ. If prolonged follow up is impracticable. Radiotherapy prior to enucleation has not yet been shown to be advantageous.  

(2,22,25-31)

____________________________________________________________________


 

Enucleation

 

Enucleation of the eye that contains the tumor is still one of the more commonly employed therapeutic methods for patients who have a choroidal or ciliary body melanoma. Enucleation is an aggressive treatment designed to rid the body of the cancer. It has been used longer than any of the alternative treatments, and it is certainly the simplest and probably the least expensive of the available treatments. (25,26)

 

However, virtually no convincing evidence exists at this time that enucleation improves the survival prognosis of affected patients compared with no treatment at all.

 

Although all patients who have a choroidal or ciliary body melanoma can be managed by enucleation, this method of treatment is most strongly indicated for patients who have a tumour that causes the eye to be blind and painful, an extremely large intraocular tumour, or a tumour that surrounds or invades the optic disc. (2,22)

   

 

Table 11- PROGNOSIS OF CHOROIDAL MELANOMA

Factors associated with a poorer prognosis

Tumour size

Cell type- inverse of standard deviation of nucleolar area

The number of epithelioid cells per high power field  

Monosomy chromosome 3 equals poor prognosis

 

Lymphocytic infiltration

Presence of closed microvascular loops

Extrascleral extension

Ciliary body involvement

Location (anterior do worse than posterior)

Rapid tumour regression after radiotherapy

Age- older do more poorly

 

5 year mortality figures (Diener-West meta-analysis):16 %  for tumours  <10 mm 32%  for tumours  10-15 mm 32%  for tumours  > 15 mm

 

Enucleation -Approximately one-half of all patients who have a choroidal or ciliary body melanoma treated by enucleation will eventually die of metastatic melanoma. Cosmetic results with an ocular prosthesis currently are quite satisfactory. Most patients adapt well to their monocular status within a few months. (2,21,22)

________________________________________________________________________

 

Pre-enucleation radiation has been employed as 'adjuvant therapy' designed to improve the patient's survival probability and reduce the risk of postenucleation orbital tumor recurrence. (22,27)

 

This method of treatment now is under investigation in a multi-centre randomized clinical trial , but current evidence from several nonrandomized comparative survival studies indicates that a substantial improvement in survival with this combined surgical-irradiation method as compared with enucleation alone does not occur. (22,27)

 

Microscopic metastasis cannot be detected reliably by currently available methods. Consequently, failure of baseline medical tests to show metastatic disease before enucleation does not guarantee that metastasis will not develop in the future. (22,27,28,29)

 

Unfortunately, approximately one-half of all patients who have a choroidal or ciliary body melanoma treated by enucleation will eventually die of metastatic melanoma. Cosmetic results with an ocular prosthesis currently are quite satisfactory. Most patients adapt well to their monocular status within a few months. (2,22,27,28,29)

 

To summarise, a substantial body of evidence obtained from analysis of the survival distributions of enucleation patients who have a choroidal or ciliary body melanoma suggest that enucleation will not improve a patient's prognosis for survival. (25)

 

Radiation Therapy

 

Radiation therapy is probably the most commonly employed method of management for choroidal and ciliary body melanomas today. Two principal methods of irradiation are currently in use for such tumors. In plaque radiotherapy, a radioactive plaque is sutured to the episcleral surface of the eye directly exterior to the tumor. The radioisotope used most commonly in episcleral plaques at the time of writing is ruthenium-l06.

 

A plaque that is generally at least 3mm larger in diameter than the measured maximal basal diameter of the tumor is selected for the treatment. Plaques are constructed in such a way that they can deliver a radiation dose of 80-100Gy to the apex of the tumor during a treatment interval of about 3-7 days. Implantation and removal of the radioactive plaque generally can be performed under local anesthesia

 

 The second method of local tumor irradiation currently in use is charged particle beam radiotherapy, usually in the form of proton beam irradiation. This treatment modality is currently much less widely available than plaque radiotherapy. Charged particle beam radiotherapy consists of surgical localization of the tumor base, suturing of radio-opaque markers  to the sclera around the tumor base, computer-assisted treatment simulation and, finally, tumor treatment with the charged particle beam while the eye is maintained in a stable direction of gaze. (2,18,22)


The treatment generally is given in about four or five equivalent fractions over 4-7 days starting several days after the placement of the tantalum rings. Each fraction is delivered in about 30-90 seconds. The standard target dose is in the range of 50-70Gy.

 

Melanoma before and after radiotherapy.

Plaque and charged particle beam radiation therapy appear to be most appropriate for patients who have a relatively small tumor (preferably less than 15mm at greatest diameter and less than 8mm in thickness) that is located 3mm or more from the optic disc and fovea. Older patients are more likely to be advised to undergo treatment by plaque or charged particle beam radiotherapy than are younger patients. (29,30,31)

 

Chemotherapy

 

Chemotherapy is not currently advocated as treatment for patients who have a choroidal or ciliary body melanoma confined to the eye, no currently available regimen has produced consistently demonstrable clinical regression of the intraocular tumor.  Patients who develop clinical metastatic disease are likely to be advised about various alternative chemotherapy regimens and approaches that might be used in an attempt to control the disease. At present, no chemotherapeutic regimens appear able to eradicate malignant melanoma totally once it has metastasised. (2,22)

 

Ocular  epithelial malignancies

 

The proposed role of  ultraviolet radiation  in the development of  ocular  epithelial malignancy

 

Acute and cumulative ultraviolet radiation (UVR) and visible light exposure has been proposed as an important causative factor in the development of a whole spectrum of eye diseases. The sun is the main UVR source on earth, and it is beyond scientific doubt that the cornea can be harmed by both acute and cumulative ambient exposures. There is also powerful epidemiological support for an association between chronic UVR exposure and the formation of cataracts and pterygia. (32,33) The evidence in support of UVR linkage to pinguecula, ocular neoplasms and retinal changes is weaker--in part because there are fewer studies reported in the literature. (34)

 

The cornea is sensitive to the effects of ultraviolet (UV) light and can suffer both acute and chronic toxicity. Ultraviolet keratitis is associated with relatively short exposures to light sources such as welding arcs or tanning lamps. The corneal effects are seen within a few hours following exposure and typically will resolve within 72 hours. Chronic exposure to environmental UV light may lead to a variety of ocular surface abnormalities that rarely resolve in the absence of therapy.  (35)

 

Phenotypic susceptibility to UVR. There appears to be a wide range of susceptibility to the effects of sunlight based upon genetic phenotype.  Dark skinned people have more melanin and absorb light with less damage. (36,37)  Queensland, Australia for example, was originally peopled by those from fair skinned Celtic backgrounds, has a high rate of skin cancer and cancer of the ocular adnexae. . (36,37) 
An extreme example of susceptibility to skin tumours is  the inherited disorder Xeroderma Pigmentosum,  those suffering from this disorder are prone to ocular surface neoplasia. Recently, the precise mechanism of defective DNA repair has been elucidated. (38)

 

Ocular Protection.

Fortunately, effective protection in the form of UV-blocking lenses and headgear  is  now available to wearers.

 

UV‑B is reflected from the whole sky by the Rayleigh phenomenon. (39,40,41) Ambient levels are determined by the proportion of the 360° hemisphere of the sky that the individual is exposed to. Ambient levels are increased by reflection of UV‑B, and this varies quite markedly from one surface to another. Ambient UV‑B levels also vary by geographic location, time of day and  season of year. . (39,40,41)

 

The eye is protected from ambient UV‑B by its anatomical location -being shielded by the brow and eye lids, and by its horizontal orientation.  Only a Small proportion of ambient UV‑B reaches the eye. This has been called the ocular ambient exposure ratio by Rosenthal and colleagues, and was measured as being approximately 5 percent of UV             B exposure over land. . (39,40,41)

Ocular exposure to UV‑B can be reduced by almost half by wearing a hat with a brim.. Further studies are needed to quantify the protection provided by headgear used in diverse cultures.  Corrective spectacles have a variable effect in reducing ocular UV‑B exposure that depends on lens type and spectacle design. Glass lenses may transmit high levels of UV‑B,  CR39 resin lenses absorb UVR more effectively than glass. UV‑B blocking coatings and lenses may reduce transmission to almost zero.  Close fitting wrap‑around lenses  with UVR coatings may give nearly total protection when worn.  (41)

However, approximately 4 percent of ambient UV‑B will still reach the eye by coming around the side of regular spectacle frames. Small frames or those worn away from the eyes will let even more UV‑B reach the eye even if they have UV‑B absorbing material in the lenses.

Best protection is provided by avoiding exposure to ambient UV‑B during the middle of the day, especially in summer. If one has to go outdoors at this time a hat and close‑fitting sunglasses or spectacles with UV‑B absorbing lenses can be used.(41)

 

Ocular surface squamous neoplasia (OSSN)

 

Ocular surface squamous neoplasia (OSSN) presents as a spectrum from simple dysplasia to carcinoma in situ to invasive squamous cell carcinoma involving the conjunctiva as well as the cornea. (36,37,42)


It is a distinct clinical entity, although it has been known by a variety of different names throughout the literature. Most commonly it arises in the limbal region, occurring particularly in elderly males who have lived in geographic areas exposed to high levels of ultraviolet-B radiation. Symptoms range from none to severe pain and visual loss. . (36,37,42)

 

Clinical Presentation of OSSN

 

The lesions are difficult to distinguish on appearances alone. They are described as being slightly elevated variably shaped and sharply demarcated from surrounding tissues. they may be accompanied by feeding blood vessels, they may be Bowenoid,  papilloform or leukoplakic. (36)

 

The development of preoperative diagnostic techniques, such as impression cytology, are of value in clinical decision making and follow-up management. Simple excision with adequate margins is currently the best established form of treatment despite trials of other modalities. The course of this disease may be evanescent, but is more frequently slowly progressive and may require exenteration and occasionally may lead to death. . (36,37,42)

 

OSSN typically occurs in older males the average age being 56 years the youngest age being in a 13 year old Caucasian female. The average age of carcinoma in situ patients is 5-9 years younger than squamous cell carcinoma patients which may represent the time taken to progress from dysplasia to carcinoma. . (36)

 

OSSN occurs not infrequently in widely differing populations, constituting 25% of malignant eye tumours in Madras, India. (42) A review of ocular surface neoplasia in a Western population was published in 1995 in Survey of Ophthalmology by Lee and Hirst of Brisbane. (10) In the study conducted in Metropolitan Brisbane between 1980 -1989  the authors estimated an incidence of 1.9/100000- the rate was lower than for squamous cell carcinoma of the skin  600/100000 occurring in the  same geographic area.  (36,37)

 

Factors related to the development of  OSSN

 

The following are factors which Lee and Hirst  consider as aetiological or predisposing conditions to OSSN. (36)

 

Ultraviolet Light

 

Lee and Hirst review the literature relating OSSN to UV-B radiation.They cite a study undertaken in the Sudan which shows a linear distribution of the frequency of the tumour in direct relation to UVB dosage. The authors themselves performed a case control study and noted the following as risk factors. (36,37)


  1. Phenotypic features, pale skin, pale iris, and propensity to sunburn.

  2. Living closer to the equator than 30 degrees latitude.

  3. History of actinic lesions such as squamous cell carcinoma or solar keratoses

  4. Spending > 50% of life outdoors in the first six years of life. (36)

 

Basal Cell Carcinoma

 

Basal cell carcinoma is the most common eyelid malignancy and accounts for approximately 90% of malignant tumors of the eyelid. The tumour is also strongly related to exposure to ultraviloet light.  Squamous cell carcinoma, sebaceous cell carcinoma, and cutaneous melanoma are other neoplasms that involve the eyelids.

_______________________________________________________________________

 

Table 12- BASAL CELL CARCINOMA (BCC)

 

The commonest form of lid neoplasia.

Most commonly occur on the lower lid.

Metastases do not occur but local spread occurs.

Medial canthal BCCs are more likely to go deep thereby involving orbital structures.

Basal Cell Naevus syndrome causes multifocal BCCs

Xeroderma pigmentosa (autosomal recessive) predisposes BCC SCC and melanoma.

 

CLINICAL

Nodular and nodular-ulcerative type:

Typical nodules and telangiectasia ± ulceration.

Cystic type:     

May resemble a benign epithelial inclusion cyst.

Sclerosing / Fibrosing / Morpheic type:

Easily missed.  May present as loss of lashes, ectropion, lid notching etc. Requires wider excision and follow-up.

                       

 

MANAGEMENT

Excision: is the ideal treatment which can be backed up by histology.

Radiotherapy: useful in selected cases but it can result in long term complications such as skin atrophy and canalicular stenosis.   (2,18,43,44)

 

________________________________________________________________________

 

Small tumors not involving the eyelid margin may be excised without preceding biopsy. More extensive tumors, particularly those that involve the eyelid margin, should be biopsied prior to excision and repair.

  

Basal cell carcinoma

Mohs' micrographic surgery could be considered for recurrent lesions, for tumors characterized by a sclerosing or morpheaform tumor pattern, and for extensive tumors where margins are uncertain. All malignant neoplasms of the eyelid or canthus should have surgical margins monitored at the time of tumor removal. (43,44)

 

Nodular Basal cell carcinoma

 

Metastatic Ocular Carcinoma

 

The eye may not infrequently be the site of tumour metastases, the most frequent primary site is the breast in females and the bronchus in males, often these secondaries metastasize to the choroid. Other less common sites include kidney, testis, gastrointestinal tract.  (45) The prostate is a rare primary site. Weiss and Kanski note that the uveal tract is a highly favoured site for metastases. (18,45)The incidence of metastases to the uvea is compared with that in eight other (extraocular) target sites, in patients with metastatic primary carcinomas of the breast, colorectum, and lungs. ()When the incidence of intraocular metastases  was viewed in relation to the calculated numbers of cancer cells delivered via the arterial route, the uveal tract is the most highly favoured target site for the development of metastases per unit of delivered cancer cells. (2,18,45,46)

   

TABLE 13- SUPPORT GROUPS

 

Ocular cancer is an extremely disturbing diagnosis, best practice involves prompt referral to an ocular oncologist without delay. Support groups for patients with ocular tumours inlude:

 

Cancer of the Eye Link Line ( CELL)

PO BOX 2586, Radstock, Bath BA3 2YP

 

HELPLINE: 01761-411 055

________________________________________________________________________

 

Summary

 

This  review has emphasised environmental factors which may precipiate cancer in the eye. Cancer risk by age is bimodal, with peaks occurring during early childhood and again during adulthood. (46)The majority of ophthalmic malignancies are included within three histologic groupings: melanomas (70.4%), retinoblastomas (9.8%), and squamous cell carcinomas (9.2%).Retinoblastoma is the most common ocular malignancy in children, and uveal melanoma is the most common ocular malignancy in adults. (1,12)

 

Sunlight, and in particular UV-B, has been postulated to be an important factor in the development of epithelial malignancies of the ocular adnexae such as basal cell carcinoma. (2,3,8,10) Methods of ocular protection against the harmful effects of ultraviolet radiation were also discussed.

Contact Us

Author : John G. O'Shea MD

  Illustrations: Robert Harvey FRCSEd (from Practical Ophthalmology,  2002 Palmtrees Publishing)

Webmaster:  David Kinschuck FRCS

      

     

    

    

Correspondence-

Birmingham and Midland Eye Centre, Dudley Rd,  Birmingham B18 7QH,  U.K.

  References

1. Mahoney MC; Burnett WS; Majerovics A ; Tanenbaum H The epidemiology of ophthalmic malignancies in New York State. Ophthalmology. 1990 97: 1143-7

 

2. Harvey RB, Practical Ophthalmology- CD ROM 1999 Birmingham;  Palmtrees Publishing.

 

3. Sanders BM, Draper GJ, Kingston JE. Retinoblastoma in Great Britain 1969-80: incidence, treatment and survival. Br J Ophthalmol. 1988;72:576-83

 

4. Khelfaoui F, Validire P, Auperin A, et al. Histopathologic risk factors in retinoblastoma. A retrospective study of 172 patients treated in a single institution. Cancer. 1996;77:1206-13.

 

5. Smith BJ, O'Brien JM. The genetics of retinoblastoma and current diagnostic testing. J Pediatr Ophthalmol Strabismus. 1996;33:120-3.

 

6. Moore A,  Retinoblastoma in Taylor D,  (Editor ) Pediatric Ophthalmology London, Blackwell Scientific 1990 ;  348-365

 

7. Matsunaga E; Minoda K; Sasaki MS Parental age and seasonal variation in the births of children with sporadic retinoblastoma: a mutation- epidemiologic study.Hum Genet. 1990  84: 155-8

 

8. Amemiya T; Takano J; Choshi K Did atomic bomb radiation influence the incidence of retinoblastoma in Nagasaki and Hiroshima? Ophthalmic-Paediatr-Genet. 1993 ; 14(2): 75-9

 

9 . Karcioglu ZA, Al-Mesfer SA, Abboud E, et al. Workup for metastatic retinoblastoma. A review of 261 patients. Ophthalmology. 1997;104:307-12.

 

10. Hungerford JL, Toma NMG, Plowman PN, Kingston JE. External beam radiotherapy for retinoblastoma: I. Whole eye technique. Br J Ophthalmol. 1995;79:109-11.

 

11 .Egbert PR, Donaldson SS, Moazed K, et al. Visual results and ocular complications following radiotherapy for retinoblastoma. Arch Ophthalmol. 1978;96:1826-30.

 

12. Shields CL, Shields JA, De Potter P, et al. Plaque radiotherapy in the management of retinoblastoma. Use as a primary and secondary treatment. Ophthalmology. 1993;100:216-24.

 

13.Amoaku WMK, Willshaw HE, Parkes SE, Shah KJ, Mann JR. Trilateral retinoblastoma. A report of five patients. Cancer. 1996;78;858-63.

14. Swerdlow AJ; Storm HH; Sasieni PD Risks of second primary malignancy in patients with cutaneous and ocular melanoma in Denmark, 1943-1989. Int J Cancer. 1995 61: 773-9

 

15 . Bataille V; Sasieni P; Cuzick J; Hungerford JL; Swerdlow A; Bishop JA Risk of ocular melanoma in relation to cutaneous and iris naevi. Int J Cancer. 1995  60: 610-22.

 

16 .  Vagero D; Swerdlow AJ; Beral V Occupation and malignant melanoma: a study based on cancer registration data in England and Wales and in Sweden.

Br J Ind Med. 1990 47: 317-24

 

17. Paridaens AD;  McCartney AC; Hungerford JL Premalignant melanosis of the conjunctiva and the cornea in xeroderma pigmentosum. : Br. J Ophthalmol. 1992; 76: 120-2

 

18. Kanski J; Clinical Ophthalmology 2nd Edition, London Butterworth 1989 ; 390-400

 

19. Augsburger JJ, Gamel JW. Clinical prognostic factors in patients with posterior uveal malignant melanoma. Cancer. 1990;66:1596-1600.

 

20. Gamel JW, McCurdy JB, McLean IW. A comparison of prognostic covariates for uveal melanoma. Invest Ophthalmol Vis Sci. 1992;33:1919-22.

 

20. McLean IW, Foster WD, Zimmerman LE, Gamel JW. Modifications of Callender's classification of uveal melanoma at the Armed Forces Institute of Pathology. Am J Ophthalmol. 1983;96:502-9.

 

21. Albert DM, Niffenegger AS, Willson JKV. Treatment of metastatic uveal melanoma: review and recommendations. Surv Ophthalmol. 1992;36:429-38.

 

22. Rankin SJA, Johnston PB. Metastatic disease from untreated choroidal and ciliary body melanomas. Int Ophthalmol. 1991;15:75-8.

 

23. Augsburger JJ. Is observation really appropriate for small choroidal melanomas? Trans Am Ophthalmol Soc 1994;91:147-68.

 

24. Gass JDM. Observation of suspected choroidal and ciliary body melanomas for evidence of growth prior to enucleation. Ophthalmology. 1980;87:523-8.

 

25. Zimmerman LE, McLean IW, Foster WD. Does enucleation of the eye containing a malignant melanoma prevent or accelerate the dissemination of tumour cells? Br J Ophthalmol. 1978;62:420-5.

26. Straatsma BR, Fine SL, Earle JD, et al. Enucleation versus plaque irradiation for choroidal melanoma. Ophthalmology. 1988;95:1000-4.

 

27. Char DH, Phillips TL. The potential for adjuvant radiotherapy in choroidal melanoma. Arch Ophthalmol. 1982;100:247-8.

28. Kersten RC, Tse T, Anderson RL, et al. The role of orbital exenteration in choroidal melanoma with extrascleral extension. Ophthalmology. 1985;92:436-43.

29. Augsburger JJ, Gamel JW. Clinical prognostic factors in patients with posterior uveal malignant melanoma. Cancer. 1990;66:1596-1600.

 

30. Damato BE, Paul J, Foulds WS. Predictive factors of visual outcome after local resection of choroidal melanoma. Br J Ophthalmol. 1993;77:616-25.

 

31. Foulds WS, Damato BE, Burton RL. Local resection versus enucleation in the management of choroidal melanoma. Eye 1987;1:676-9.

 

32. Bergmanson JP; Soderberg  PG  The significance of ultraviolet radiation for eye diseases. A review with comments on the efficacy of UV-blocking contact lenses. Ophthalmic Physiol Opt. 1995 15: 83-91

 

33.  Taylor HR; West S; Munoz B; Rosenthal FS; Bressler SB; Bressler NM

The long-term effects of visible light on the eye Arch-Ophthalmol. 1992  110: 99-104

 

34. Taylor HR Ocular Effects of UV-B Exposure Documenta Ophthalmologica (1995) 88 285-2935.

 

35. Schein , OD  Phototoxicity and the cornea J. Natl. Med. Assoc. 1992 84: 579-83

 

36. Lee GA; Hirst LW: Ocular surface squamous neoplasia.

Surv Ophthalmol. 199 39: 429-50

 

37. Lee GA; Hirst LW Incidence of ocular surface epithelial dysplasia in metropolitan Brisbane. A 10-year survey. Arch. Ophthalmol. 1992 110: 525-7


38.  Wries A; van Oostrom CT; Hofhuis FM; Dortant PM; Berg RJ; de Gruijl  FR; Wester PW; van Kreijl CF; Capel PJ; van Steeg H; et al  Increased susceptibility to ultraviolet-B and carcinogens of mice lacking the DNA excision repair gene XPA. Nature. 1995 377: 169-73

 

  39. Rosen ES Filtration of non ionising radiation through the ocular media In Cronly-Dillon J ,Editor ,Hazards of Light,Myths and Realities New York,  Pergamon Press (1985) 145-152

 

40. Hillenkamp F;  Biophysical mechanisms of damage induced by light

In Cronly-Dillon J, editor  Hazards of Light, Myths and Realities New York , Pergamon Press (1985) 21-32

 

41. Gibbons L, Symposium on ultraviolet radiation-related diseases: a risk management approach. Can J. Ophthalmol. 1992 47: 268

 

42. Sunderraj P,  Malignant tumours of the eye and adnexa. Indian-J-Ophthalmol. 1991  39: 6-8

 

43. JRO Collin,  A Manual of Systematic Eyelid Surgery Second Edition, London, Churchill Livingston  1989

 

44. Demorest BH, Ophthalmic Plastic and Reconstructive Surgery San Francisco, American Academy of Ohthamology  1984

 

45. Weiss L,  Analysis of the incidence of intraocular metastasis. Br J. Ophthalmol. 1993 77: 149-51

 

46. O’Shea JG, Environmental  factors in  the epidemiology and aetiology of malignant tumours of the eye  Clinical and Experimental Optometry 1996 79;  177-185