Ocular Melanoma

Ocular melanoma is the most common malignant tumor in adults after cutaneous melanoma. There is a wide clinical spectrum depending upon the location of the tumor. The various predispositions, risk factors, tumor classification, and treatment modalities are discussed. Choroidal melanoma is the most common type of ocular melanoma. Its management has evolved over the years. The Collaborative Ocular Melanoma Study (COMS) has helped to precisely classify choroidal melanoma and standardize its treatment. The future lies in the genetics which can help prognosticate and provide adjuvant treatment to patients at risk.


Introduction
The incidence of melanoma continues to rise globally with significant mortality in spite of modern treatment protocols [1]. Ocular melanoma is the most common type of melanoma in adults after the cutaneous melanoma. It constitutes 3.7% of all melanomas [2]. It results due to the abnormal proliferation of the melanocytes in the eye. Based on the location, the ocular melanoma can be broadly classified as follows: 4. Episcleral plaque brachytherapy if base is involved for more than 3 clock hours. Plaque rotation can be customized depending on the tumor extent.
5. Interferon and interleukin-2 in combination can be administered in disseminated melanoma [8]. 6. Sentinel lymphangiography is indicated in tumors more than 2 mm and helps in complete removal of the lymph nodes.

Histopathology
Abnormal proliferation of the melanocytes, spindle, or the epitheloid cells.

Prognosis
1. Metastasis to ipsilateral facial lymph nodes, brain, lung, skin, bone, and liver are the most common.

Uveal melanoma
It is the most common primary intraocular malignancy in adults. The earlier detection and prompt treatment has decreased the morbidity to some extent over the years.

Definition of regional lymph nodes (N)
NX Regional lymph nodes cannot be assessed N0 Regional lymph node metastasis absent N1 Regional lymph node metastasis present

Epidemiology
Iris melanoma constitutes about 4% of uveal melanomas [14]. The mean age at presentation is 40-47 years. It is very rarely seen in the pediatric age group. Males and females are equally affected. It is most commonly seen in Caucasians (97.8%) [15].

Clinical presentation
Nodular pigmented lesion usually seen in the inferior iris. It is usually associated with tumor seeding in the adjacent iris or trabecular meshwork and secondary glaucoma.   [14] Prognosis is better than ciliary body or choroidal melanoma with a 10-year metastasis of 7% as compared to 25% in choroidal melanoma and 34% for ciliary body melanoma.

Ciliary body melanoma
It is relatively a rare uveal tumor and is reported in one of 10 cases of all intraocular melanomas [18,19].

Clinical presentation
1. Diminution of vision due to astigmatism or lens dislocation 2. Painless visual field loss or pain due to acute glaucoma 3. Episcleral sentinel vessels 4. Unexplained relatively low intraocular pressure Management options include local resection, plaque brachytherapy, proton beam radiation, and enucleation.

Metastasis
Hematogenous metastasis is faster in ciliary body melanoma as a result of continuous contractions of the ciliary muscle and rich vascularization.

T1-Tumor limited to the iris
T1a-Tumor limited to the iris, not more than 3 clock hours in size T1b-Tumor limited to the iris, more than 3 clock hours in size T1c-Tumor limited to the iris with secondary glaucoma T2-Tumor confluent with or extending into the ciliary body, choroid, or both T2a-Tumor confluent with or extending into the ciliary body, without secondary glaucoma T2b-Tumor confluent with or extending into the ciliary body and choroid, without secondary glaucoma T2c-Tumor confluent with or extending into the ciliary body, choroid, or both with secondary glaucoma T3-Tumor confluent with or extending into the ciliary body, choroid, or both, with scleral extension T4-Tumor with extrascleral extension T4a-Tumor with extrascleral extension ≤5 mm in largest diameter T4b-Tumor with extrascleral extension >5 mm in largest diameter

G Category and criteria
GX-Grade cannot be assessed G1-Spindle cell melanoma (>90% spindle cells) G2-Mixed cell melanoma (>10% epitheloid cells and < 90% spindle cells) G3-Epitheloid cell melanoma (>90% epitheloid cells) N Category and criteria N1-Regional lymph node metastasis or discrete tumor deposits in the orbit N1a-Metastasis in one or more regional lymph node(s) N1b-No regional lymph nodes are positive, but there are discrete tumor deposits in the orbit that are not contiguous to the eye

Prognosis
The prognostic factors are listed in Table 3.

Choroidal melanoma
Choroidal melanoma is the most common uveal melanoma and constitutes about 90% of all uveal melanomas. This is usually seen in an elderly age group at around 60 years and there is no gross gender predilection. It is seen predominantly in Caucasians (98%), as compared to other races. It has a pronounced tendency to metastasize resulting in high mortality [21]. Predisposing factors are listed in Table 4.

Clinical presentation
It can be incidentally detected in asymptomatic patients on routine ocular examination. Most of the patients, however, manifest with diminution of vision, floaters, photopsia, visual field loss, or pain due to impingement of posterior ciliary nerve or angle closure glaucoma. It can metastasize to liver (89%), lung (29%), and bone (17%). Median survival after metastasis is 6-12 months [22]. Males have a poor prognosis than females. The lower metastatic rate in females can be explained due to the inhibitory action of estrogen on the growth of micrometastases within the liver [23,24].

Classification
Choroidal melanoma can be broadly classified into diffuse (Figure 2) and circumscribed (Figure 3). The circumscribed variant can either be dome-shaped (75%) or mushroom-shaped (20%). Diffuse choroidal melanoma is seen in 3-17% cases and has a substantial risk of metastasis despite its flat appearance. The poor prognostic factors include delayed diagnosis, greater proportion of epitheloid cells, and a tendency for extraocular extension [25].
AJCC Classification has already been mentioned under the section of iris melanoma (  Table 3.
The prognostic factors for ciliary body melanoma.

Host factors Environment factors
Light colored eyes Fair skinned Intermittent ultraviolet exposure to arc welding Chronic UV exposure Occupational sunlight exposure Table 4. Predisposing factors.
The most common precursor lesion for choroidal melanoma is the preexisting choroidal nevus (Figure 4), followed by oculodermal melanocytosis.
The following are used to differentiate a choroidal nevus from a melanoma (pneumonic: to find small ocular melanoma using helpful hints daily): 1. Thickness > 2 mm 2. Fluid

Fundus fluorescein angiography
Small melanoma: Hypofluorescence (blocked fluorescence) Large melanoma: Patchy pattern of early hypofluorescence and hyperfluorescence followed by late intense staining. Double circulation-internal vascularity

Ultrasound biomicroscopy
It helps to differentiate anterior tumors from those of ciliary body origin. Although the tumor margins and extent is well delineated by UBM, the resolution of internal tumor details is limited.

Optical coherence tomography
Dome-shaped choroidal mass with overlying outer retinal thickening and subretinal fluid.
Optical coherence tomography angiography shows reduced capillary density in the affected eye.

Magnetic resonance imaging
Pigmented melanomas can be seen as T1 Hyperdense and T2 hypodense intraocular masses.

Fine needle aspiration cytology
Although reliable, it is technically challenging and requires expertise.

Management
The most common treatment modality is the episceral plaque brachytherapy. Plaque brachytherapy is suitable for tumors up to 16 mm in diameter and up to 6 mm thickness with Ruthenium-106 and up to 8 mm thickness with Iodine-125. The dose to the tumor apex should be 10,000 cGy and almost up to 90% tumor control can be achieved. Enucleation is an option for tumors beyond the scope of plaque brachytherapy. Orbital exenteration might be required in tumors with orbital invasion. The proton beam irradiation has a higher chance of eye salvage but the availability and affordability are the considerable limitations. The other treatment modalities include laser photocoagulation, transpupillary thermotherapy, chemotherapy, and immunotherapy.

Metastasis
The risk factors for metastasis include ( Table 7) The presence of four risk factors has a metastatic rate of 20% but the absence of risk factors has only <1% risk of systemic metastasis. Also, each millimeter increase in thickness adds 5% risk for metastasis at 10 years and a hazard ratio of 1.08 [27]. Doubling time of untreated metastases ranged from 34 to 220 days (median, 63 days). The metastasis from tumors as small as 3 Â 3 Â 1.5 mm has been noted in a study [28]. Based on the estimated growth rates, a rational follow-up interval to detect metastatic uveal melanoma would be 4-6 months. Primary uveal melanomas that develop clinically detectable metastasis after conservative therapy may have micrometastasized several years before treatment.
Damato's classification of metastasis [26]: 1. Metastasizing melanomas, which have already metastasized by the time of ocular treatment even though the metastases may not be detectable.  2. Pre-metastasizing melanomas, which develop metastatic capability and disseminate if treatment is delayed.
3. Non-metastasizing melanomas, which do not metastasize even if never treated.

Colloborative ocular melanoma study
This is the largest study ever to be performed in Ocular oncology with 43 participating centers and more than 2000 patients [29,30].
Objectives of the study: 1. To evaluate the therapeutic interventions for patients with choroidal melanoma 2. To determine which of the two, enucleation or brachytherapy prolongs the lifetime of an individual, and if both have a similar survival, then which offers the longer cancer-free survival and better prognosis for vision.
Inclusion and exclusion criteria: • Primary choroidal melanoma in one eye 1. Pre-enucleation EBRT for large melanoma has no advantage over enucleation group. Five-year Kaplan-Meier estimates for survival were 57% for the enucleation group and 62% for the pre enucleation radiation group.
2. Enucleation versus brachytherapy for medium melanoma were comparable. The cumulative all-cause mortality at 12 years was 43% for patient in the plaque radiotherapy group versus 41% for those in enucleation group.
3. The small tumor trial showed that small choroidal melanomas managed by observation showed tumor growth in 21% by 2 years and 31% by 5 years. Observation for small melanoma is not acceptable now and is treated appropriately.
Based on gene expression prolifes (GEP), uveal melanoma is now classified into three prognostic categories for metastasis ( Table 6).
The GEPs are playing a major role at present in prognosticating the risk of metastasis. The tumor as such is constantly evolving at the genetic and molecular level which is described as intratumoral genetic heterogeneity. The term cresendo malignancy is described which explains the transformation of a small tumor which is slow growing over years but acquires Class 2 genetic changes over time ( Table 6).

Follow-up
A periodic follow-up with systemic investigations is mandatory in view of high metastatic rates of choroidal melanoma. An annual PET-CT scan is ideal, however, the monitoring of the liver function tests, ultrasonography of the abdomen and the chest X-Ray are reasonably good.

Conclusion
Ocular melanoma is being effectively managed currently. A protocol-based management of the patient can lead to good local tumor control and careful systemic monitoring can decrease the morbidity and mortality to a great extent. The ongoing research in genetics will probably help us understand and prognosticate ocular melanoma in a better way. Large >8 mm >50% 58% Table 7.