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   Table of Contents      
CURRENT OPHTHALMOLOGY
Year : 1997  |  Volume : 45  |  Issue : 3  |  Page : 143-161

Current concepts in the management of adult intraocular tumours


Sankara Nethralaya, Medical Research Foundation, Chennai, India

Correspondence Address:
M P Shanmugam
Sankara Nethralaya, Medical Research Foundation, Chennai
India
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Source of Support: None, Conflict of Interest: None


PMID: 9475017

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  Abstract 

The management of intraocular tumours has come a long way since the days when enucleation was the only modality of treatment available to the ophthalmologist. Despite the fact that enucleation is still necessary in certain situations, the emphasis is currently on conservative management, thereby saving the eye and some amount of useful vision wherever possible. This review highlights the current trends in the management of adult intraocular tumours with emphasis on newer diagnostic modalities such as computed tomography, magnetic resonance imaging, and fine needle aspiration biopsy. Only those tumours that are most likely to be seen in clinical practice are included.

Keywords: Adult intraocular tumours, choroidal malignant melanoma, metastatic tumour, choroidal haemangioma, management


How to cite this article:
Shanmugam M P, De Potter P, Gopal L, Biswas J, Bhende M P. Current concepts in the management of adult intraocular tumours. Indian J Ophthalmol 1997;45:143-61

How to cite this URL:
Shanmugam M P, De Potter P, Gopal L, Biswas J, Bhende M P. Current concepts in the management of adult intraocular tumours. Indian J Ophthalmol [serial online] 1997 [cited 2020 Feb 27];45:143-61. Available from: http://www.ijo.in/text.asp?1997/45/3/143/15019



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  I. DIAGNOSTIC AIDS Top


A. Fundus fluorescein angiography (FFA)

FFA studies can provide useful information in the diagnosis and management of intraocular tumours. Fluorescein angioscopy can also be performed in selected cases to further elucidate the diagnosis.

Choroidal malignant melanoma

The choroidal melanoma has no pathognomic FFA features. The FFA can still aid in the diagnosis by differentiating certain pseudomelanomas from the choroidal melanoma. The angiographic appearance of the melanoma depends on the size of the lesion, retinal pigment epithelium (RPE) alterations overlying the mass, degree of pigmentation, and the effect on adjacent structures.

Small choroidal melanomas may not produce any appreciable change in the angiogram due to absence of RPE alterations and tightly packed malignant cells.[1] In the presence of a larger tumour associated with RPE alterations, mottled hyperfluorescence is seen in the arterial and early venous phase [Figure - 1]. The orange pigment associated with the tumour is usually hypofluorescent but may stain in the late phases. There is progressive staining of the lesion in recirculation phase. In large dome shaped lesions, there is intense pin-point fluorescence in the later stages [Figure - 2]. These large tumours may show "double circulation". This is due to simultaneous filling of the large feeder choroidal vessels in the tumour and the overlying retinal vessels in the late arterial and early venous phase. During recirculation phase, the fluorescein in the vessels begin to fade and the hyperfluorescence in the surrounding extravascular tissue, silhouettes the relatively hypofluorescent tumour vessels. Small areas of hyperfluorescence have been found to develop into breaks in the Bruch's membrane subsequently.[2] Late leakage of the fluorescein into the subretinal fluid may be seen. In a study of 15 cases, Edwards et al have found no single angiographic pattern to be common in malignant melanomas.[3] The most frequently found photographic patterns were early phase double circulation, early phase mottling, and late tumour fluorescence. Minimum staining pattern of melanomas may be due to presence of heavy pigmentation, diminished vascularity, overlying subretinal haemorrhage or exudate causing blocked fluorescence.[4],[5]

Choroidal metastasis

FFA has limited value in the diagnosis of choroidal metastasis, as the fluorescein pattern may vary considerably. It is useful though to differentiate metastasis from non-neoplastic conditions such as inflammatory processes, choroidal neovascular membranes, and subretinal organised haemorrhage. The choroidal metastases tend to hyperfluoresce in the venous phase of the angiogram later than the choroidal haemangioma or the melanoma. Pin point areas of fluorescence appear in the late venous phase, persisting into the late phase. Overlying choroidal pigment can mask the hyperfluorescence. There may be late leakage of the dye into the subretinal space. Large choroidal vessels seen in the melanoma or the late multiloculated staining of the haemangioma are absent. It is imperative to remember that considerable variation in the fluorescein pattern may occur.[6],[7] Three patterns of fluorescein have been found to be associated with metastatic carcinomas by Davis and Robertson[6]: early continued progressive fluorescence associated with flat extensive tumours; only late but progressive and diffuse fluorescence in moderately elevated localised tumours; and early fluorescence diminishing later. Absence of patterns such as multilake hyperfluroscence (suggestive of haemangioma) and double circulation (suggestive of melanoma) also suggest the possibility of metastatic carcinoma.

Choroidal haemangioma

The pattern of fluorescence in the haemangioma may be quite variable. This tumour commonly begins to fluoresce in the pre-arterial and early arterial phase [Figure - 3].[8],[9] Linear streaks of fluorescence corresponding to the large choroidal vessels are seen. There is progressive intense fluorescence of the tumour with pinpoint areas of hyperfluorescence and associated late leakage [Figure - 4]. Overlying clumps of pigment may cause blocked fluorescence. Late pictures may show the dye to be pooled within multiloculated areas of cystic spaces in the retina. It begins to fluoresce earlier and shows intense fluorescence with more leakage than the melanoma. The diffuse haemangioma shows similar picture but with more widespread changes.

Angiomatosis retinae

Fluorescein angiography is often confirmatory in diagnosing retinal angiomatosis. In the arterial phase, the tumour fills rapidly through the feeder arteriole and the capillary network within the tumour becomes evident [Figure - 5]. In the venous phase, the lesion shows marked hyperfluorescence due to dye leakage which stains the overlying vitreous in the late stages [Figure - 6]. The presence of dilated feeders are typical of the angioma.


  B. Ultrasonography Top


Ultrasound forms one of the main adjuncts in diagnosis and management of intraocular tumours. Obviously useful in detecting tumours in opaque media, it also has an important role in confirming the diagnosis and assessing the progress of a tumour in clear media [Table - 1]. Ultrasound measurements of tumour size as well as extrascleral extension are valuable in assessing the growth or regression of tumours and the effectiveness of treatment. Though most tumours have typical ultrasound features, variability in both clinical and ultrasound presentations can occur.

A lesion can be detected with certainty by ultrasonography when the following criteria are met[10]:

Minimal thickness or elevation at least 0.8 mm above the surrounding retinochoroidal layer.

Effective quantitative evaluation necessitates a minimal height of 2-3 mm.

Ciliary body tumours need to be larger due to their irregularity and anterior location.

Differentiation between solid and non-solid lesions is usually possible by detecting after-movement of the lesion's surface, which is seen in non-solid lesions (serous/haemorrhagic detachments).

Choroidal melanoma

The typical acoustic properties of choroidal melanoma [Figure - 7] include collar button shape,[10],[11] low to moderate internal reflectivity,[11] regular internal structure, and internal blood flow or vascularity.

Additional findings of importance include sound attenuation,[11] choroidal excavation, associated exudative retinal detachment, changes in internal reflectivity, and status of adjacent scleral/ orbital interface.

Extrascleral extension typically appears as one or more nodules near the sclera, adjacent to the tumour base, and often displayed with high resolution B scans. The minimum size for detection should be 1.0-1.5 mm. In larger nodules, internal reflectivity, blood flow and thickness can be measured. Small areas may be detected but it may be difficult to diagnose them confidently. Serial follow ups can be useful to document growth. Small melanomas can be associated with large extraocular tumour growth. Therefore, it is important to repeat ultrasound at follow-up even if clinically there is no apparent change in size of the intraocular lesion.

Scleral infiltration, with or without extraocular extension can be demonstrated as replacement of a portion of the sclera by tumour tissue. Extension through the sclera within small blood vessels has been observed, as also extension into the orbit via a vortex vein. Congested blood vessels, localized inflammation in Tenon's space and extraocular muscles could simulate an extraocular growth.

Diffuse melanomas are rare lesions which are challenging to detect and diagnose.[10] They are only mildly elevated but can be quite extensive. The surface is irregular and bumpy with indistinct margins. The edges of the base cannot be accurately determined, and also their low elevation may prevent assessment of the internal reflectivity. Reflectivity can vary from low to medium amplitude. Vascularity may also be difficult to assess. These tumours are associated with a high incidence of extrascleral extension. The differential diagnosis includes metastasis to the choroid, Vogt Koyanagi Harada syndrome, and reactive lymphoid hyperplasia. The ultrasonographic differential diagnosis of malignant melanoma is shown in [Table - 1].

Echographic changes following radiation include:

Irregular structure and higher reflectivity as the lesions decrease in size due to necrosis.[10],[11], [12]

Loss of internal vascularity.

Initial enlargement of tumours 3 to 4 weeks after treatment, followed by eventual decrease in size. This is due to irradiation induced edema.

Thickening of adjacent extraocular muscles.

Decreased scleral reflectivity.

Inflammation of Tenon's space corresponding to the location of the plaque can simulate extrascleral extension after it is removed.[13]

It is important to review previous ultrasounds during serial examinations to ensure that there is consistency in measurement.

Correlation between histopathology and ultrasound findings may be useful as the current commercially available instruments do not routinely help to clinically evaluate the prognosis. However, in about 50% of cases histological characteristics influence the amount of reflection in the A mode.[11] Ultrasound spectral analysis is still in the experimental stage that could predict the histologic pattern of the tumour to a certain extent. [14, 15]

Other uses of ultrasound in melanomas include localising tantalum rings which identifies the tumour for charged particle irradiation,[10] and also as an useful adjunct to transillumination to verify the position of the radioactive plaque in relation to the tumour.[10],[16] This is most helpful in tumours near the optic nerve, and also in mushroom shaped tumours with overhang where the entire base cannot be visualized ophthalmoscopically. If the plaque is not well positioned over the tumour it can be moved and ultrasound repeated to ensure adequate coverage. It is reliable in tumours with sloping indistinct borders.

Doppler ultrasonography has also been described as useful in the follow-up of conservatively treated melanomas.[11],[17]

Choroidal metastasis

The typical echographic appearance of choroidal metastasis is diffuse thickening of the ocular coat. The characteristics include:

Mild to moderate elevation.

Rarely highly elevated; irregular bumpy surface contour, often with central excavation.

More extensive echographically than clinically appreciable.

Medium to high internal reflectivity, but structure can be irregular as a result of varied histologic architecture.

Internal vascularity minimal or absent.

Secondary retinal detachment more elevated and extensive than melanomas of similar size.

Simultaneous occurrence of orbital metastases may be noted; rarely have vitreous/subretinal haemorrhage

The atypical presentations include:

Metastatic oat cell carcinoma of lung: low internal reflectivity and internal vascularity.

Metastatic adenocarcinoma: strong acoustic interfaces.

Cutaneous melanoma: cannot be differentiated from primary choroidal melanoma.

Large metastases: bullous choroidal detachment.[18]

Choroidal haemangioma:

Circumscribed haemangiomas [Figure - 8] have the following echographic characteristics:

Dome Shaped, slightly elevated in the posterior pole, usually temporal to optic nerve head.

Associated retinal detachment.

Strongly reflective, nearly concentric widening of the ocular coats

Regular internal structure.

Despite abundant vasculature no significant internal flow due to slow circulation within the cvities of dilated blood vessels.

Calcification is seen occasionally on the surface or within the lesion in long-standing cases; in such cases, ultrasound is not diagnostic.[10]

Diffuse type [Figure - 9] choroidal hemangiomas are less elevated, and may be mistaken for non-specific thickening of the retinochoroid layer.


  C. Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) Top


The diagnosis of intraocular lesions is usually made with assurance by indirect ophthalmoscopy. However, imaging studies are often required tohelp document the lesion, to differentiate it from other similar conditions, and to evaluate the intraocular tissues when opaque media precludes view of the fundus.

The role of CT has been limited in the evaluation of intraocular tumours and simulating lesions due to its poor tissue definition. Because of its safety, soft tissue resolution, and its multiplanar capabilities, MRI appears to be the most helpful and non-invasive imaging study of choice for evaluation of selected intraocular lesions. Information obtained from MR images allows us to identify tissue compounds such as melanin, methemoglobin, deoxyhemoglobin, and proteinaceous fluid. The use of orbital surface coil, gadolinium-DTPA (Gd-DTPA) as contrast agent, and fat suppression techniques are most critical in detecting and evaluating intraocular lesions.


  Ct Top


With CT, uveal melanoma appears as an elevated, solid, moderately dense uveal mass which demonstrates minimal to moderate enhancement after contrast injection. Associated secondary retinal detachment usually appears as a semilunar moderate density which shifts in location with respect to the position of the eye and does not enhance.[19][20][21][22][23] The differential diagnosis between uveal melanoma and other uveal tumours such as choroidal metastasis, choroidal haemangioma, and uveal leiomyoma is almost impossible on CT.[24]Choroidal osteoma appears as a minimally elevated choroidal mass with linear calcification at the level of the choroid and usually without subretinal fluid.[25] Extraocular extension of posterior uveal melanoma may be easily identified on CT if MR studies are contraindicated.


  MRI

Choroidal melanoma
 Top


The MRI characteristics of uveal melanoma have been mainly attributed to the paramagnetic properties of the melanin.[26] Melanin causes enhancement of proton relaxation on MRI that leads to an increase signal intensity on Tl-weighted images. [27,28] Therefore, on Tl-weighted images, choroidal melanoma appears with a hyperintense signal with respect to the hypointense vitreous [Figure - 10]. On T2-weighted images, choroidal melanoma becomes hypointense with respect to the hyperintense vitreous [Figure - 11]. Previous studies have shown that 72-95% of posterior uveal melanomas evaluated at 1.5 Tesla demonstrate these characteristic MRI appearances.[22],[27][28][29][30][31][32] The presence of tumour necrosis containing water (free or in extracellular fluid), the presence of blood or altered blood products (methemoglobin, deoxyhemoglobin, hemosiderin), and iron content may explain the varying combination of signal intensities such as decreased signal on Tl-weighted images and /or increased signal on T2-weighted images.[27],[30][31][32][33] The combination of T1 hyperintensity and T2 hypointensity has also been observed with other intraocular lesions as explained later. Associated serous retinal detachment exhibits hyperintense signal on both T1- and T2-weighted image due to its proteinaceous content.[22],[31][32][33] On Gd-DTPA enhanced Tl-weighted images, posterior uveal melanoma demonstrates moderate to marked enhancement.[30],[31],[34],[35] Larger tumours show more heterogeneous enhancement than smaller tumours.[31] Postcontrast T1-weighted images with fat suppression techniques appear to be most helpful in detecting and delineating small posterior uveal melanoma with a thickness more than 1.8 mm.[30] Because secondary subretinal fluid does not enhance after Gd-DTPA injection, postcontrast T1-weighted images are helpful in differentiating uveal melanomas from retinal detachment.[30],[31],[34],[35] Contrast enhanced MRI with fat suppression technique appears as sensitive as ultrasonography in detecting extraocular extension of posterior uveal melanoma.[27],[8]


  Choroidal metastasis Top


Choroidal metastasis has been reported to demonstrate varying signal intensities such as a combination of T1 and T2 hyperintensities or T1 hyperintensity and T2 hypointensity.[22],[27],[32],[36] Most often, choroidal metastasis shows a hyperintense signal on T1-weighted images and hypointense signal on T2-weighted images with respect to the vitreous.[20][29][30][31],[37] These MRI features suggest caution in differentiating choroidal metastasis from amelanotic choroidal melanoma which exhibits the same MRI characteristics mentioned later.


  Choroidal haemangioma Top


The MRI features of circumscribed choroidal haemangioma are mainly related to the high vascular flow within the lesion. Choroidal haemangioma exhibits an isointense to slightly hyperintense signal on Tl-weighted images with respect to the vitreous. Because of its high content of extracellular free-water (stagnant blood), choroidal haemangioma becomes hyperintense on T2-weighted images and therefore isointense with respect to the vitreous.[20],[22],[29][30][31],[36] Based on our experience, the T1and T2 hyperintensities features of choroidal haemangioma are most helpful in differentiating circumscribed choroidal haemangioma from other amelanotic choroidal tumours. Moreover, choroidal melanoma demonstrates marked enhancement on postcontrast T1-weighted images. The associated exudative T2-weighted images does not enhance after Gd-DTPA injection.[20],[30],[31]

Intraocular lesions with thickness >1.8 mm that can show the combination of T1 hyperintensity and T2 hypointensity on noncontrast MRI include uveal melanoma, uveal metastasis, uveal leiomyoma, uveal melanocytoma, choroidal osteoma, subacute choroidal/ retinal haemorrhagic detachment, retinoblastoma, retinal capillary haemangioma, retinal gliosis (focal), and inflammatory granuloma.[31]


  D. Fine Needle Aspiration Biopsy (FNAB) Top


FNAB was first proposed as an adjunct in the management of intraocular tumours by Jackobiec et al.[38] The advantage of FNAB is that it offers histopathologic correlation to the clinical diagnosis when faced with anatypical presentation of intraocular tumours. It is recommended in (i) cases in which the diagnosis is difficult, distinction between malignant and benign not clear, and where the therapeutic decision will be made based on the cytologic findings; (ii) patients with metastatic disease to the choroid but with no known primary; and (iii) patient refuses recommended therapy until confirmed histopathologically.[39]


  Technique Top


The technique varies with the location of the lesion and the suspected diagnosis. In the anterior segment, free floating cells or a pseudohypopyon can be aspirated by passing a 30 or 27 gauge needle through the clear cornea just inside the limbus into the inferior anterior chamber. For a solid iris tumour, the needle is passed tangentially avoiding the pupil. Posterior segment rumours can be biopsied transvitreally or subretinally depending on the height of associated retinal detachment. A tumour in the ciliary body, retina or choroid with minimal associated retinal detachment is approached through a sclerotomy placed 180 away. The needle is guided through the vitreous into the retina in case of a subretinal tumour under indirect ophthalmoscopic control. When a subretinal mass lesion is associated with a bullous retinal detachment, the needle is guided tangentially through the subretinal space via a suitably placed posterior sclerotomy. In the extremely rare case when FNAB is indicated in a patient of possible retinoblastoma, a clear corneal approach is employed. The needle is guided through a clear corneal wound 2-3 mm within the limbus through the root of the iris, zonules and into the vitreous and the tumour.

A 25 gauge one and a half inch needle attached to a short disposable plastic tubing and a disposable syringe is employed. Once the needle is in the tumour, assistant aided gentle suction is employed to aspirate the cells into the needle. The needle is withdrawn after releasing the suction force and immersed in balanced salt solution and the contents of the needle aspirated into the syringe with the balanced salt solution. Gentle pressure on the globe usually limits the amount of intraocular haemorrhage.

Tumours that have involved the vitreous jelly such as leukemias and reticulum cell sarcoma can be biopsied using the needle technique, or by using a vitreous cutter. This approach is not to be utilized for biopsy of vitreous seeds in friable tumours such as retinoblastoma.

The reported complications of this procedure are intraocular haemorrhage and retinal break formation.[39][40][41] Intraocular haemorrhage as a complication of FNAB occurs virtually in all patients. This haemorrhage is usually of limited quantity and is controlled by gentle pressure on the globe. The haemorrhages clear adequately with time. The retinal breaks created when a subretinal tumour is biopsied transvitreally almost never lead to a rhegmatogenous retinal detachment as they get closed by the blood clot. Even in the presence of minimal subretinal fluid overlying the mass lesion when the break is created, the detachment seldom becomes rhegmatogenous.

The major deterrent to wide use of FNAB is the fear of needle track dissemination of tumour cells. Despite experimental evidence of needle track dissemination, clinical evidence suggests otherwise.[42],[43] Shields et al have not reported any case of needle track dissemination in their large series of 140 patients.[40] The factors which may limit the incidence of tumour dissemination are that the vitreous "wipes" off the tumour cells sticking on to the needle surface, and the prompt treatment of the malignancy with appropriate therapy which usually follows the diagnosis with FNAB.

FNAB is not to be embarked upon without the presence of a skilled cytologist, as a part of the team. Despite the ease of obtaining the specimen, improper interpretation could cause disastrous results. Shields et al have reported that FNAB has a sensitivity rate of 84% and a specificity of 98%, making it a useful adjunct in difficult cases.[40] It is a specialized technique which is not to be used for routine diagnosis of intraocular tumours due to the real risk of tumour dissemination and other potentially vision threatening complications.


  II. Treatment A. Factors influencing treatment choice Top


Malignant melanoma

Eyes with salvageable vision should be conservatively treated. Eyes with severe secondary glaucoma are generally those with large diffuse tumours that rarely respond to conservative methods of management necessitating enucleation.[44],[45]

Small tumours (2mm thick, <10 mm diameter) are generally watched periodically for signs of growth. Medium sized tumours (3-5 mm high, 10-15 mm diameter) can be periodically watched, photocoagulated, treated with plaque therapy, or enucleated based on presence of other clinical features. Large melanomas (5-10 mm high, >15 mm diameter) also need active management. Extra large melanomas (>10 mm high) generally need enucleation.[46][47][48]

Diffusely growing tumours generally will need to be enucleated, while nodular tumours can be conservatively managed depending on other factors. Small degrees of extrascleral extension can also be managed conservatively.[48]

Tumours situated near the equator are likely to benefit from photocoagulation, local resection, or radiotherapy, while in tumours close to the fovea, photocoagulation is best avoided. Circumpapillary tumours will need enucleation.

Dormant tumours can be watched periodically for evidence of activity. Dormant tumours have minimal subretinal fluid, are sessile, and have sparse orange pigment overlying them.[48] Older patients with slow growing tumours are conservatively managed while aggressive tumours in younger patients are more aggressively managed.

Dormant small and medium sized tumours, and slow growing small and medium tumours in sick and one eyed patients are generally observed periodically.[48]

Choroidal metastasis

Chroidal metastasis may be watched periodically, treated with chemotherapy, irradiated or surgically resected, depending on the degree of activity, location, extent, of the tumour, degree of control obtained with chemotherapy, site of the primary, and patient's symptoms.

Some metastatic tumours of the choroid may be inactive, or may have regressed spontaneously following treatment of the primary. They do not have an associated retinal detachment and are flat with pigment clumping. These tumours need periodic observation.

Others

Solitary choroidal haemangiomas that are asymptomatic need be periodically observed until exudative retinal detachment involving the fovea develops. Von Hippel's angiomas may also be watched if there be no exudation or accumulation of subretinal fluid.


  B. Enucleation Top


Choroidal malignant melanoma

Large tumours producing visual loss that cannot be managed by conservative methods, small or medium sized tumours with optic nerve invasion, posterior uveal melanomas with total retinal detachment or severe glaucoma need enucleation. A minimal manipulation enucleation is advised to prevent haematogenous dissemination of the tumour. A "no touch technique" has been advocated as also cannulation of the anterior chamber to avoid sudden fluctuations in the intraocular pressure thereby avoiding egress of tumour cells from the eye.[49][50][51] The current concern is about high rate of mortality following enucleation, despite lack of evidence of metastatic disease at the time of enucleation (30% in the first 5 years following enucleation and 50% within 10 years).[52] The presumed reason for this is that the antitumour antibody levels fall following enucleation, while it increases after local treatment such as photocoagulation or irradiation.[53] This decreased antibody response may not prevent onset of metastatic disease.

Choroidal metastastis

Eyes with large metastatic tumours of the choroid with bullous retinal detachment and intractable painful glaucoma may be difficult to control by any modality other than enucleation.[54] When the ocular tumour is characteristic of metastastic disease, but with no identified primary, and if the involved eye is painful and blind, enucleation of the eye may serve two purposes: relief from pain and diagnosis of the primary site. This is also useful in appropriate treatment of the fellow eye in the presence of bilateral metastasis.


  C. Local resection Top


Ciliary body and choroidal malignant melanoma

Tumours close to the ora not extending more than 4 clock hours of pars plicata and choroidal melanoma not greater than 15 mm in diameter centered at the equator can be considered for partial lamellar sclerouvectomy if the tumour has not involved the retina, and penetrating sclerochorioretinovitrectomy if the retina and sclera are involved.[55],[56]

The technique involves localisation of the tumour on the sclera, partial thickness dissection of the scleral bed, resection of a thin layer of the sclera with the tumour, leaving the overlying retina intact if there is no involvement. Preoperative barrage laser photocoagulation or cryotheraphy 2-3 mm surrounding the tumour is done, if retinal involvement is noted, in an attempt to keep the retina attached postoperatively. In such a situation, the overlying retina is also removed during tumour removal with open sky vitrectomy. The sclera, if involved, is also removed and replaced with donor scleral graft.

Complications of this procedure include retinal detachment, cataract formation, vitreous haemorrhage, expulsive haemorrhage, chronic cystoid macular oedema, anterior segment ischaemia, tumour recurrence, hypotony, wound leak, and preretinal fibrosis. In a large series of 81 posterior uveal melanomas which were resected, 91% were alive at a mean of 4 year follow-up with 26% having 6/9 vision or better following surgery.[48] This group of patients can also be effectively managed by radiotherapy. Resection is generally preferred for anterior tumours with a small base and greater height.

Internal resection is a technique which involves preoperative photocoagulation around the tumour followed by vitrectomy and internal removal of the tumour piece-meal in posteriorly located tumours that are not amenable to lamellar sclerouvectomy.[57] The concern is that of promoting metastasis with this technique. In one study of 23 patients with a variable follow-up, three patients developed metastatic disease in the postoperative period and two patients developed tumour recurrence.[58] Studies with long term results are awaited.

Choroidal metastasis

In selected cases of metastatic tumours from primaries of low malignancy and a probable single metastatic foci, such as bronchial carcinoid, local resection may be considered as in one case of iris and ciliary body metastasis of bronchial carcinoid.[59][60][61]

Capillary angiomas of the retina

Selected cases of Von Hippels angiomas have been subjected to eye wall resection, with attendant decrease in subretinal exudation.[62] Internal resection of these tumours with vitrectomy, endodiathermy, retinectomy, laser photocoagulation, and silicon oil tamponade has also been attempted in a few cases.


  D. Photocoagulation Top


Choroidal malignant melanoma

Photocoagulation has been tried for malignant melanoma of choroid[63] but not with the same success as for retinoblastoma. The classification of choroidal melanoma by the Collaborative Ocular Melanoma Study (COMS)[64] is useful in discussing the role of photocoagulation.

Meyer Schwickerath was the first to use xenon arc photocoagulation for treatment of small malignant melanoma of the choroid.[65] The indications for use of this modality are not clear. Previous reports showed frequent complications such as preretinal fibrosis, macular pucker, tractional retinal detachment, and vitreous haemorrhage. Shields[66] recommended treatment with laser photocoagulation in case of small nasal melanomas and temporal peripheral small melanoma located away from macula outside the arcade. The tumours should be <3 mm in height and 9-10 mm in basal diameter without secondary retinal detachment. They should not be closer than one disc diameter from disc. Some authors feel that argon is less effective compared to xenon or krypton for melanoma of the choroid.[65] Less than 5% of melanomas meet the criteria laid down for use of photocoagulation.

For treatment with xenon,[65] retrobulbar anesthesia is administered. A 6 aperture and green I/II option is used. In the first sitting the tumour is surrounded by 2 rows of burns. This is aimed at preventing rhegmatogenous retinal detachment from spreading if a break occurs during treatment of tumour itself subsequently, reducing the likelihood of marginal miss during treatment, and reducing blood supply to the tumour. In the second sitting, moderate to heavy treatment is given to the entire tumour. This is done approximately 6-8 weeks after the first sitting. The setting in xenon would be green I-IV. Repeat treatment is done if need be up to 4 sessions. If 4-5 sessions do not yield the desired response, other modalities of treatment are opted for.

For treatment with argon or krypton laser,[67] 500 spot size, 0.2 second duration, and 500-1,200 mW power are used. Successful laser treatment is indicated by a flat or depressed gliotic scar with pigmentation. Total obliteration of the tumour may sometimes take up to 2 years. If 4-5 sessions of treatment have failed to achieve any results, one should resort to alternative modes of treatment. Amelanotic tumours are relatively resistant to treatment.

Complications of photocoagulation include retinal break, especially during the subsequent stages of treatment (retreatment), which could cause rhegmatogenous retinal detachment, vitreous haemorrhage during 2nd or 3rd sittings of treatment, choroidoretinovitreal neovascularisation near the edge of treatment, branch retinal vein occlusion, secondary macular edema, and corneal and iris burns.

The combination of tunable dye laser and photoactivated dye has been tried to treat some malignant melanomas.[68] Haemtoporphyrin dye derivative is the most commonly used dye. The efficacy of this treatment has not been well evaluated.

In a rabbit model Chong et al[69] have shown that ICG enhanced diode laser treatment seems to destroy all tumour cells even in the depths of the tumour. The authors implanted green amelanotic melanoma into iris of pigmented rabbits. Incomplete tumour necrosis was seen with only diode laser versus total tumour destruction following ICG enhanced diode laser. The chromophore in the deep blood vessels selectively absorbs diode and facilitates tumour cell destruction in the depths of the tumour. The clinical application of this technique of treatment remains to be evaluated.

Metastatic tumours

There is no role of photocoagulation in the management of metastatic tumours.

Vascular posterior segment tumours

Treatment of angiomatosis retinae can be done with photocoagulation. Large tumours are resistant to photocoagulation treatment. Angiomas located near the optic disc are extremely difficult to treat and eradicate. In general, small tumours of <1.5 mm diameter show little growth and can be watched. Tumours <2.5 mm diameter and <1 mm in elevation can be treated with argon laser or xenon. Slightly thicker lesions may need other modalities of treatment.

In the first sitting, the tumour is surrounded with 500 μ spot size burns of long duration. The burns are placed in contiguous fashion. Multiple sittings may be needed to achieve total destruction of the tumour. In the "feeder vessel technique", heavy intensity 500 burns can be applied to the feeder vessels. This can succeed in closing the vessel and help eradicate the tumour. This technique may work for tumours <2.5 disc diameter in size. The burn diameter must be larger than the vessel diameter to avoid rupture of blood vessel. Temporary occlusion of central retinal artery by raising the intraocular pressure and then coagulating the feeder vessel has also been described.

Johnston et al[70] treated angioma involving temporal aspect of optic disc with photocoagulation along with creation of chorioretinal adhesion to barricade the macula from angioma. The vision has been maintained at 6/6 for 16 years. They recommend early treatment when tumour is still small.

Complications include gliosis that occurs around the tumour following photocoagulation, which may make it difficult to treat subsequently. Vitreous and retinal haemorrhage can occur during feeder vessel technique. As mentioned before, large tumours fail to respond to treatment. Diode laser cannot be used to treat angiomas in view of its lack of absorption by reddish lesions. ICG enhanced diode laser treatment may be a possibility for angiomatous lesions also.

Choroidal haemangioma

Choroidal haemangioma of the localised variety is amenable to treatment [Figure - 12]. If there is no secondary retinal detachment, there is no indication for treatment. Both argon laser and dye yellow laser can be used in the treatment of choroidal haemangioma. The presumed advantage of dye yellow laser is the greater absorption potential by the abnormal tissue of this wave length. It has been found that treatment does not always lead to obliteration of the tumour mass. Treatment of the surface of the tumour leads to resolution of the secondary retinal detachment even when the tumour mass is not destroyed. Hence, the goal of laser therapy is to achieve resolution of secondary retinal detachment. A 500 spot size is useful.


  E. Cryotherapy Top


Von Hippel Lindau disease

Photocoagulation sometimes fails to reach the full thickness of the angioma if it is quite thick. Therefore, cryotherapy can be used as a primary or adjunctive modality of treatment to double freeze thaw the lesion. In general, only small tumours without vitreous and retinal changes do well with this treatment.

Choroidal malignant melanoma

Cryotheraphy has not been very popular in the treatment of malignant melanoma. Klein at al have reported successful treatment of 4 eyes with tumours 1.7-3.8 mm thick and 1.7-11.4 mm in diameter with triple freeze thaw cryoptheraphy.[71]


  F. Radiotherapy Top


Choroidal malignant melanoma

Pre-enucleation external beam radiotherapy had been advocated to decrease mortality rate following enucleation, but it's value is currently debatable.[72] Post-enucleation irradiation to the orbit decreased the mortality in a study but this was not a prospective randomized trial.[73] This issue of benefit of pre-enucleation irradiation is currently being evaluated by the COMS study.[64]

In external beam particle radiotherapy, the charged particle radiation consists of usage of helium ions and protons, and the benefit lies in the fact that relatively large doses can be delivered to the tumour specifically. The high energy charged particles have minimal scatter and a well defined, finite, energy dependent range. The entire tumour can be treated uniformly, and due to the inherent Bragg peak effect, unnecessary radiation to the normal tissue is avoided.[74]

Uveal melanomas up to 24 mm in diameter and 14 mm in height have been treated with charged particle irradiation. Tumours involving the fovea, optic nerve head, those with small extrascleral extension are also manageable. The technique involves localisation of the tumour with transillumination and indirect ophthalmoscopy, and suturing four 2.5 mm tantalum rings as localisation markers. The treatment is then planned using a computer, thereby choosing the correct direction of the beam which entails minimum irradiation to normal structures but also complete treatment of the tumour and 1.5 mm of surrounding normal tissue. Approximately 70 Cobalt-60 gray equivalents are delivered in 5 sittings over 7-10 days.

In one study 58% of the patients treated with protons had 6/36 or better vision at a mean 5.4 year followup,[75] while in another study 55% of helium ion treated patients had 6/60 or better vision at 5.6 year followup.[76] The cumulative probability of developing metastasis is 20% with charged particle radiation.[76],[77] The five year survival rate following proton beam radiation has been reported to be 85%, comparable with that of plaque therapy (82%).[78] Complications include those of the surgery such as transient diplopia and intratumour haemorrhage, and those related to radiation such as epilation, epiphora due to punctal occlusion, dry eye, cataract formation, rubeosis iridis, neovascular glaucoma, radiation vasculopathy, papillopathy, maculopathy, macular oedema, neovascularisation of the retina, and vitreous haemorrhage.

The disadvantage of the current charged particle radiation systems are that they are

expensive to install and maintain.

Choroidal haemangioma

Laser photocoagulation has been advocated in the management of solitary choroidal haemangiomas associated with secondary retinal detachment.[79],[80] In special situations such as juxtapapillary and subfoveal tumours photocoagulation by itself may cause irreversible visual loss. In the presence of a bullous retinal detachment, photocoagulation may not be feasible and may need multiple sessions. Other techniques advocated are drainage of sub retinal fluid followed by laser photocoagulation or vitrectomy with gas tamponade and laser photocoagulation. [79, 80] Diffuse haemangiomas associated with or without Sturge Weber syndrome rarely respond to laser photocoagulation. Low dose external beam radiotherapy has been used successfully in the management of such refractile tumours.[81][82][83]

Solitary and diffuse haemangiomas can be treated with 2,000 cGy to 3,000 cGy of external beam radiation after localising the tumour on a CT or MRI. The largest series of localised and diffuse choroidal haemangioma treated with irradiation is by Alberti and Gerber.[81] Out of the 22 eyes of 21 patients treated, regression of the tumour occurred in all eyes with resorption of the exudative retinal detachment in all the 19 eyes where it was present. Vision improved in 8 eyes, and in the 3 eyes with glaucoma, the intraocular pressure could be brought under control. Cataract and radiation retinopathy as complications of this therapy may occur but are rare due to low dosage of radiation involved. This modality can be employed in eyes that are not suitable for photocoagulation thereby atleast preventing a painful blind eye. Visual recovery is usually small and may not occur in all the eyes, as there would be some degree of amblyopia in the eyes with macular tumours associated with macular degeneration due to long standing retinal detachment.

Choroidal metastasis

The presence of exudative retinal detachment involving the fovea is an indication for radiotherapy. Considering that most of the metastatic tumours involve posterior choroid, irradiation of the posterior segment with a temporal or anteromedial beam is advocated. A dose of 3,000 cGy to 4,000 cGy is delivered over a 4 week period.[84] The technique may have to be modified in the presence of anterior segment involvement or it is advisable to irradiate the whole eye. Some authors advocate adjuvant irradiation for better tumour control even if the tumour responds to chemotherapy.[85] The tumour decreases in thickness with attendant decrease in the associated retinal detachment and improvement in visual acuity. The survival depends on the nature of systemic malignancy and in general have a poor prognosis.


  G. Chemotherapy Top


Choroidal metastasis

In the presence of a known primary that is amenable to chemotherapy, choroidal metastases also respond to the specific treatment of the primary. If the exudative retinal detachment subsides and the patient is asymptomatic, it is a good practice to observe periodically for regrowth or recurrence of the retinal detachment.[86],[87]

Posterior uveal malignant melanoma

There are sporadic reports of treatment of uveal melanomas with various chemotherapeutic agents such as bichloroethyl nitrourea, adjuvant treatment with vinblastine, thiotepa, methotrexate, and deticene, but conclusive proof of benefit is lacking.[88],[89] Experimental studies with fluorouracil are also documented.[90] There has been an attempt at adjuvant chemotherapy with no-touch enucleation with an average follow-up time of 6.75 years. The patients have been treated with hydroxyurea, BCNU and DTIC with reported five year survival rate of 90%. Long term results are awaited.[91]


  H. Brachytherapy Top


Uveal melanoma

The current relative indications for treating a posterior uveal melanoma with plaque radiotherapy are generally as follows: (i) selected small melanomas that are documented to be growing or that show obvious signs of activity on the first visit; (ii) most medium-sized and some large choroidal and ciliary body melanomas in an eye with potential salvageable vision; and (iii) almost all actively growing melanomas that occur in the patient's only useful eye. If a melanoma exceeds 15 mm in diameter and 10 mm in thickness, one should anticipate visual morbidity from radiation therapy, and enucleation should be strongly advised.[92] The surgical technique of radioactive plaque application has been described in detail in the literature.[92],[93] More recently, specially designed notched plaques have been effectively employed to surround the optic nerve and irradiate those tumours with a juxtapapillary location.[92],[93]

The visual outcome of an eye treated with brachytherapy depends mainly on the tumour size and location as well as on the development of radiation retinopathy and papillopathy.[94][95][96] Patients with tumours located near the fovea or optic disc, and patients with larger tumours have the worse visual outcome.[95],[96] In their series of 77 patients with posterior uveal melanoma managed by Cobalt-60 plaque radiotherapy, Cruess et al found that eyes receiving a radiation dose in excess of 5,000 cGy to the fovea and/or optic disc commonly lose a substantial amount of vision within 2-3 years.[97] This toxic dose to these sites is generally given for management of medium and large choroidal melanomas with margins closer than 5 mm to the fovea/optic disc.[97] In a more recent series of 93 patients with choroidal melanoma touching the optic disc, De Potter et al[98] found an incidence of 87% of radiation retinopathy and 52% of radiation papillopathy after a mean interval of 21 and 27 months, respectively, after plaque therapy. The significant predictors of radiation retinopathy were history of diabetes mellitus and the use of notched-designed radioactive plaque. The factors predictive of development of radiation papillopathy were the older age of patient (>45 years old), diabetes mellitus, mushroom-shaped tumour configuration, and nasal location of the tumour. Using life table analysis, the proportion of patients who experienced a decrement of at least three lines of vision was zero by 0-20 months, 22% by 20-30 months, 45% by 30-40 months, and 72% by 50-60 months. These results were also confirmed by Lommatzsch et al that consisted of 106Ru/106Rh plaques for juxtapapillary choroidal melanomas.[99]

Local tumour relapse after plaque radiotherapy has been reported to occur in up to 16% of cases.[95],[96],[98],[99] Local tumour recurrence constitutes an important post-treatment clinical indicator of tumour's greater malignant potential and the patient's increased risk of melanoma-specific mortality.[98] In two series of 93 patients with juxtapapillary choroidal melanoma managed by plaque radiotherapy local tumour recurrence was documented in 14 cases (15%).[98],[99] The younger age of the patient (<35 years old) and the superior and inferior location of the tumour were predictive for local tumour recurrence.[98]

In the published literature there is no statistically significant difference in survival between patients treated with plaque radiotherapy (Cobalt-60, Iodine-125) and those treated with enucleation.[100][101][102][103] De Potter and associates found that in patients younger than 50 years old, the method of treatment (enucleation versus Iodine-125 plaque radiotherapy) did not significantly affect the risk of metastasis. The 5-year survival of relapse-free patients (87%) was significantly better than that of patients whose tumour locally recurred (58%).[98] A rapid local tumour regression behavior has been identified as an unfavorable prognostic sign for survival.[104][105][106]

Combined plaque radiotherapy and laser photocoagulation or thermotheraphy have been used recently to increase the likelihood of complete local tumour destruction particularly in patients with tumour adjacent to the optic disc.[107] Preliminary results have shown that hyperthermia in combination with plaque radiotherapy may decrease the adverse effects of radiation to the retina, optic disc, and choroid.[108] Custom designed plaque radiotherapy appears to be an effective alternative method of controlling non-resectable diffuse iris melanoma.[109] In the series of Shields,[109] 14 patients with non-resectable iris melanoma were treated with Iodine-125 plaque radiotherapy. The mean length of treatment was 96 hours in order to give a mean dose of 29,300 cGy to the base (corneal endothelium) and 10,600 cGy to the apex of the iris melanoma. Tumour control was achieved in 93% of the patients. Despite large dose of radiation given transcorneally, the cornea tolerated it very well without corneal melting. Cataract developed in 6 patients. All but one patient had tumour control and retention of the eye.

Uveal metastasis

Standard external beam radiotherapy in a patient with choroidal metastasis, typically requires 3-4 weeks to complete, which may be a substantial portion of the patient's remaining life expectancy, in contrast to brachytherapy which does not take more than 3-4 days. In a series of 36 patients with uveal metastasis, plaque radiotherapy was used as primary or secondary treatment, after failure of the uveal tumour to respond to external beam radiotherapy, chemotherapy, or hormonal therapy.[110] The mean time for treatment was 86 hours and the mean therapeutic dose was 6,880 cGy to the tumour apex and 23,560 to the tumour base. Regression of the uveal metastasis was documented in 94% of the cases. Plaque radiotherapy salvaged five of the six eyes that had failed prior external beam radiotherapy.[110]

Capillary angioma of the retina

A selected group of solitary angiomas associated with exudative retinal detachment have been treated with local irradiation by application of plaques.[111] There are reports of treating these with charged particle radiation also.


  III. ADVANCES IN PATHOLOGIC INTERPRETATION Top


Choroidal malignant melanoma

In pathologic diagnosis of intraocular tumours mostly routine light microscopy, and occasionally special stain, for example, Fontana-Mason silver stain is needed to identify inconspicuous melanin granules. Most cases of malignant melanoma of the choroid can be diagnosed fairly well by routine light microscopy. Amelanotic melanoma can cause diagnostic dilemma. If definitive diagnosis cannot be established by routine and special stains, a panel of monoclonal antibodies[112] can be used to identify the intraocular tumour [Table - 2]. Immunohistochemistry is needed to differentiate amelanotic melanoma from leiomyoma and peripheral nerve sheath tumours. Positive staining with antibodies against muscle-specific antigen and smooth-muscle antigen, and negative staining with HMB-45 and S-100 protein establishes the diagnosis of leiomyoma. One can distinguish amelanotic melanoma from peripheral nerve sheath tumour using neural marker leu-7 which will be positive, and HMB-45 which will be negative. Positive staining with S-100 and HMB-45 indicates malignant melanoma of the choroid. Histopathologic assessment of prognosis of uveal malignant melanoma can be done by the following features:

Cell type

Callender classified uveal malignant melanoma into six groups which includes spindle A, Spindle B, epithelioid, mixed (mixture of epithelioid and spindle), fascicular, and necrotic. Subsequently, investigators of Armed Force Institute of Pathology (AFIP) simplified Callender's classification by deleting fascicular and necrotic type. Now AFIP classification consists of four types of cells in melanotic tumour [Table - 3]. However, at present controversy exists whether to call an uveal melanoma as epithelia cell type in the presence of few spindle cells as all uveal melanomas contain atleast few spindle cells. Current practice at the AFIP is to designate all epithelia cell melanoma as mixed while assessing the prognosis. Pathology committee of Collaborative Ocular Melanoma Study (COMS) designated a new category: intermediate epithelia cell which are similar to epithelioid cell but often smaller in size and have indistinct borders. Cell type is still considered one of the most important prognostic factors in malignant melanoma of the choroid. In a recent study Seregard et al[113] have found immunoreactivity to a monoclonal antibody PC-10 for proliferating cell nuclear antigen to correlate with the prognosis in uveal melanoma. Ten year survival proportion was 84% for the low PC-10 count group in contrast to 40% for patients having tumour with high PC-10 counts.[113]

Cytomorphometric features

In recent years, Gamel and coworkers[114] have found that the most important prognostic feature in malignant melanoma of the choroid is the size and variability of the nucleolus rather than the shape of the cell as suggested by Callender. They suggested measuring the standard deviation of the area of 200 nucleoli (SDNA) is a reliable and reproducible predictor of prognosis. However, such measurement is time consuming (about half an hour for each case), needs well-trained technical personnel, and a semi-automated image analysis system. Silver staining for nucleolar organizing regions can be done for such evaluation.

Nuclear organising regions (NOR)

NOR are the genes that code for ribosomal RNA. It has been shown that RNA content correlates with prognosis in patients with uveal melanoma. A recent study has indicated that higher mean NOR occurs in uveal melanomas in comparison to benign nevi. A significant correlation between number of NOR in uveal melanoma and computerized cytomorphometric analysis was found.[115]

Tumour size

Tumour size has been found to be an important predictor of prognosis of uveal melanoma. Largest tumour dimension has been found to be the most important prognostic indicator. However, limitations in measuring the size of an irregular tumour exist. Volume of the tumour (length x width) is reported to be strongly associated with the prognostic outcome.[116]

Mitotic activity

Mitotic figures in uveal melanoma are relatively less. One needs to count atleast 40 high power fields using 40x objective. Mitotic activity was found to correlate with prognosis.[117]

Tumour infiltrating lymphocytes

In approximately 5-12% of all uveal melanomas, lymphocytic infiltration are seen and in 74% of the tumours the infiltrating lymphocytes were predominantly T-cells.[118] Lymphocyte infiltration has been found to be associated with higher mortality.[118][119][120] An abnormal ganglioside profile on the surface of the melanoma cells was associated with mixed cell type and lymphocytic infiltration. An immune mechanism caused by antigencity of malignant melanoma has been suggested.[120],[121]

Vascular pattern

Several studies[120],[122],[123] have indicated that microvascular pattern of uveal malignant melanoma is another important indicator of prognosis. Nine vascular patterns seen on 10x objective field of the tumours are: "normal", "silent" with no vessels, "straight" with randomly distributed vessels, "parallel" with oriented straight vessels without cross linking, "parallel with cross linking" between the vessels, "arcs" or incomplete loops, "arcs with branching", "loops" of vessels that completely surround a lobule of tumour, and "networks" composed of atleast three back to back loops. Presence of networks were most strongly related with outcome. But both loops or parallel with cross linking pattern had survival functions similar to that associated with networks. Patients with these patterns have poor survival (40%) compared to their absence (80% survival). In another study of Japanese patients, the prognosis correlated with network pattern and closed loop pattern.[123]

Age and race

In a recent study, the average patient age was found to be younger in the Japanese (55.2 years) than in the white population.[123] Much younger age was been noted by us (unpublished data) in 60 patients of uveal melanoma. In the Kaplan-Meir survival curves comparing younger and older patients, the long term survival rates were similar.

Multivariate statistical analysis of various prognostic factors has been assessed by Mclean et al[117] which indicated best predictor for patient outcome are cell type and largest dimension of the tumour.[124]

Gamel-Boag's log-normal model is a statistical model that can be used to correlate prognostic features to the cure rate and median survival time. Using this model Gamel found larger tumours were associated with a much lower probability of cure and a much shorter median survival time.[124]

Detection of subclinical metastasis is still a challenge in malignant melanoma.[125] Forty percent of patients of uveal melanoma die within 10 years due to metastasis despite enucleation, and in only 1-2% of these casesmetastasis is detected prior to enucleation. In recent years, monoclonal antibodies have been used to detect subclinical metastasis for several cancers like breast carcinoma and uveal melanomas. There are two monoclonal antibodies, Mab8-1H and ME491, which have been found to detect melanoma associated antigen (MAA). Using these antibodies elevated serum MAA levels have been found in patients with documented metastatic choroidal melanoma. Subclinical metastasis of uveal melanoma has also been detected using monoclonal antibody.

Two candidate genes that encode uveal melanoma-specific antigens are currently being investigated.[126],[127] One encodes uveal melanoma associated antigens defined by monoclonal antibody Mab8-1H. The other is the tyrosinase gene which is tissue specific and can detect melanocytes from the peripheral blood. Use of polymerase chain reaction to detect subclinical metastasis in uveal melanoma is under investigation. Detection of malignant melanoma cells in peripheral blood by means of reverse transcriptase and polymerase chain reaction has been done in cutaneous malignant melanoma.

Metastatic tumours

Metastatic tumours to the eye usually involve the choroid. However, less frequently the iris and the ciliary body are involved by metastatic tumours. The most common site of primary in males are the prostate and lungs, in females, the breast. Another common site of primary is the gastrointestinal tract. Routine histology often indicates the morphologic pattern suggestive of the cell of origin of the primary site. Special stains and immunohistochemistry with a panel of primary antibodies, for example, prostate specific antigen can indicate the primary site.

 
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Abstract
I. DIAGNOSTIC AIDS
B. Ultrasonography
Ct
Choroidal metastasis
Technique
B. Enucleation
C. Local resection
D. Photocoagulation
E. Cryotherapy
F. Radiotherapy
G. Chemotherapy
H. Brachytherapy
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