**2.2 Uveal melanoma**

*Melanoma*

with genetic results.

term endurance cannot be normal [2].

and photodynamic treatment.

(SRS) by linear accelerator [2–5].

**2. Uvea and uveal tumors**

Prognosis can be influenced by number of factors. The most important are the histopathologic type of cells, the size of tumor, tumor volume, the margins of the tumor, karyotype and grading and staging by TNM Classification (e.g. extraocular extension). Cell type, however, remains the most often used predictor of outcome

The treatment relies upon the site of birthplace (choroid, ciliary body or iris), the size, volume and area of the injury, the general statis of the patient, age of the patient and whether extraocular attack, repeat or metastasis has happened. Extraocular augmentation, repeat, and metastasis are related with a very helpless guess and long -

Elective therapy modalities have been proposed as of late including extremist careful evacuation of the eye globe (enucleation), nearby resection, light procedures: plaque brachytherapy, charged-molecule radiotherapy, stereotactic photon bar illumination treatment or in start of the tumor transpupillary thermotherapy

Over the past 3–4 decades diagnostic methods have improved and radiotherapy (external beam, charged particle or brachytherapy) has become the preferred treatment for most of the patients with uveal melanoma. The aim of the treatment is to improve survival and preserve eye globe anatomically with aim to preserve the best vision in patients with uveal melanoma. Different radiation modalities are currently in use in treatment of posterior uveal melanoma in many Ophthalmology Centers. One of the methods of "conservative" approach is the stereotactic radiosurgery

The uveal parcel frames the center layer (or "vasculo-strong" coat) mass of the eyeball. Uvea layer is a combination of veins, pigmented cells and muscles, woven together by connective tissue. It has a nutritive capacity of the eye globe. The uveal parcel comprises of three anatomical parts, all profoundly vascular and pigmented. The noticeable part in front is the iris (part of the foremost portion of the eye) and it makes the shade of the eye globe. The iris consolidates in reverse into the ciliary body, and the ciliary body offers path to the choroid, to the back fragment of the eye globe, which is such a vascular undercoat between the sclera and the shade retina. It is substantial pigmented, along these lines engrossing light which has gone through

The pigmented cells (the melanocytes) - are derived from the neural crests which have migrated to the skin and mucous membranes. Melanocytes synthesize a special organelle called a melanosome – this is responsible for the characteristic color of the skin in different races. Melanosis (melanocytosis) refers to increased

Changes in melanocytes usually cause melanomas. Melanocytes produce melanin, which is responsible for skin and hair tone. It can show up on ordinary skin or it might start as a mole or other territory that has changed in appearance. A few moles that are available upon entering the world may form into melanomas during the

Benign tumor composed of nevus cells or melanocytes is nevus. In nevi cells contain melanosomes and are therefore capable of producing pigment melanin [1].

pigmentation caused by hyperplasia or hypertrophy of melanocytes.

**12**

adulthood.

the retina.

**2.1 Uvea layer**

Melanoma is a malignant tumor resulting from a transformation of melanocytes or nevus cells. It may be pigmented or non-pigmented. Melanoma is caused mainly by intense, occasional UV exposure (frequently leading to sunburn), especially in those who are genetically predisposed to the disease. Most melanomas are dark or earthy colored, however they can likewise be skin-shaded, pink, red, purple, blue or white. In the event that melanoma is perceived and treated early, it is quite often reparable, however on the off chance that it is not, the tumor can progress and spread to different pieces of the body, particularly liver, where it turns out to be difficult to treat and can be deadly. Melanomas frequently metastasize widely and the regional lymph nodes, liver, lungs and brain are likely to be involved.

Intraocular melanoma is the most common primary ocular malignant tumor in adults and develops from uvea. Intraocular tumors might be benign or malignant.

Intraocular melanoma is a quite rare type of tumor and it occurs most often in elderly people. There is lot of cases when ophthalmologists detected intraocular melanoma during a routine eye examination. The chance of recovery is depending on factors such as the size, localization and cell type of the tumor. Extraocular extension is the term used to describe the intraocular melanoma which spreads to the optic nerve or nearby tissue of the eye socket and is the sign of the advanced stage of the tumor [6].

Intraocular melanoma of the ciliary body and choroid (structures together called the posterior uvea), is the most common primary ocular malignant tumor in adults. Iris melanomas are a subset of uveal melanomas that tend to have a more benign course, in comparison with posterior uveal melanomas. Anterior segment melanomas have a lower incidence of metastases when compared to ciliary body and choroidal melanomas. Anterior segment melanomas account for about 15% of all uveal melanomas. The incidence of uveal melanoma increases with age and reaches a maximum between the 6th and 7th decade of life. It is more common in males and is uncommon or rare in kids and darker looking people. Uveal melanomas are infrequently two-sided. Be that as it may, the quantity of patients with two-sided inclusion is more noteworthy than would be anticipated by chance alone, subsequently inferring a potential hereditary inclination.

As mentioned before, choroidal melanoma represents the most common primary intraocular tumor in adults. Peak incidence is in the early 60s representing about 7.5 cases per one million populations. Incidence is rare in younger adults under 30 years of age with an estimated peak incidence of about six cases per one hundred million. Caucasians are 8 times more likely to develop the melanoma than Africans or Afro-Americans and 3 times more likely than Asians. Intraocular melanoma is arising from choroid in more than 75% of all the cases. Whether some environmental exposure triggers the development of uveal melanoma remains an open question. Sunlight has been proposed as an environmental risk factor for melanoma generally. Unlike cutaneous melanoma, incidence rates for uveal melanoma have not increased over time and last decades and it does not vary by latitude [7, 8].

#### **2.3 Diagnostic method of uveal melanoma**

The first step to diagnose uveal melanoma is patient's history. Patients with uveal melanoma may present with complaints of visual acuity reduction, but many can be without symptoms and the condition is discovered on routine ocular examination or by glasses prescription. In eyes with clear optic media, the diagnosis of posterior uveal melanoma can be made by indirect ophthalmoscopy.

a.ophthalmoscopy, fundus photography,

b.transillumination,

c.perimetry,

d.fluorescein angiography, indocyanine green angiography,

e.ultrasonography (A and B modes),

f. ultrasound biomicroscopy - UBM,

g.optical coherence tomography - OCT,

h.computed tomography - CT,

i. magnetic resonance imaging - MRI,

j. fine-needle biopsy

k.whole body PET/CT to distinguish metastasis.

Depending on their site of growth, posterior uveal melanomas differ in their symptoms, clinical presentation and appearance. A ciliary body melanoma can attain a large size, volume, before it is clinically recognized. It can be seen in association with one or more dilated episcleral blood vessels, it can present itself as an epibulbar pigmented lesion if there is transscleral extension of the tumor. Also, cataract, and/or lens subluxation or secondary glaucoma due to infiltration of the trabecular meshwork in the angle of the eye can be present. The tumor can be envisioned clinically through a broadly enlarged understudy by cut light assessment as an arch formed collection in the area or it can have a diffuse circumferential development design known as "ring melanoma". It can develop anteriorly into the front chamber – iridocorneal point and iris (iridociliary melanoma) or back into the choroid (ciliochoroidal melanoma).

A melanoma of choroid ordinarily presents as a sessile or curve formed collection arranged under the retina. Initial step analytic techniques can be aberrant ophthalmoscopy, ultrasound and fluorescein angiography. Surface orange color at the degree of the retinal shade epithelium can be imagined clinically, particularly in more modest back melanomas. Retinal separations can be seen auxiliary to the tumor development just as Bruch membrane rupture (cellar layer bellow the retinal shade epithelium). We can divide melanoma of chodoid into two groups the first is melanoma with pigment and the second one is melanoma withou pigment and can likewise accept a spread development design with just negligible tumor diameter under 3 mm.

Melanoma of ciliary body and melanomas of choroidea may develop cataracts, extraocular extension, secondary glaucoma. Orbital infiltration can be seen usually when the tumor has large volume, higher stage and they therefore have a worse prognosis [9].

Due to the huge range of clinical, morphologic and cytological changes and an absence of discrete stages it is hard to foresee clinical result in singular instances of uveal melanoma based on intraocular tumor size. His size and volume is perhaps the best boundary used to foresee metastatic infection.

**15**

*Uveal Melanoma*

*DOI: http://dx.doi.org/10.5772/intechopen.95321*

thickness and in excess of 15 mm in breadth.

appetite, difficulty with breathing or fatigue.

examination, when a liver or skin metastasis is suspected.

**2.4 Survival modeling of intraocular melanoma**

the five-year endurance rate is about 15%.

*2.4.1 Prognostic factors for uveal melanoma*

bility to metastases with a diameter of less than 10–20 mm [10–13].

A little tumor - melanoma - is characterized as estimating 3 mm or less in thickness and under 10 mm in breadth because of TNM plot. A tumor is delegated medium-sized in the event that it measures between 3 to 5 mm in thickness and between 10 to 15 mm in width. A huge tumor is more prominent than 5 mm in

Patients, who are diagnosed with a primary choroidal "intraocular" melanoma,

Patients who have metastatic choroidal melanoma, as mentioned above, seem to have no symptoms. For this reason, they should have periodic medical examinations, physical examinations, blood tests and radiographic imaging tests as X-ray, MRI, CT or PET/CT. Later on, patients may have symptoms like loss of their

The highest percentage of metastatic choroidal melanoma is likely to be found in the liver. Metastases in this area of the body can be discovered by blood tests or abdominal imaging studies even in cases when patients are asymptomatic. Besides this, other organs also can be affected, e.g. subcutaneous lymph nodes, lung, bone and brain. A needle biopsy can be used to aspirate tumor cells for cytopathologic

The liver is the known site of metastasing of choroidal melanoma. Hepatic enzyme levels are tested in all patients with melanoma of uvea. The most sensitive tests of liver capacity are serum antacid phosphate levels, glutamate oxaloacetic transaminase, lactate dehydrogenase and gamma-glutamyl transpeptidase. These test results are negative at closure hour in the majority of patients with choroidal melanoma. If any of the results of these research devices is anomalous, ultrasonography and CT of the liver are displayed. Both imaging modalities have low suscepti-

Endurance displaying gives a sign of guess. Likewise, it empowers exceptional measures to be focused just as it improves the assessment of clinical methodology. Endurance rates give a more precise system so as to depict the visualization for patients with a specific stage and type of disease. These rates are frequently founded on past results of huge quantities of individuals who had the sickness, however they cannot anticipate what will occur in a specific patient's case. In patients whose malignancy is bound to the eye, the five-year endurance rate is about 80%. This is as opposed to melanomas that have spread to inaccessible pieces of the body, where

Pigmented choroidal lessions that are somewhat raised might be called vague sores and present a test concerning determination and the board. Given the dangers

have usually no signs or symptoms of metastatic tumor. Even with total body positron emission tomography/computed tomography (PET/CT) imaging, very few patients are found to have their melanomas spread to other parts of their body. Others may be found to have metastasis over the following years. The overall percentage of the patients diagnosed for choroidal melanoma does not develop metastatic melanoma. The size of the tumor is one of the very important factors to predict the risk for metastatic spreading. Treatments that limit tumors ability to enlarge will decrease the chance of metastasis because removing the eye tumor is the best method to prevent future spread from that tumor. It is very important for the patients to have periodic general medical examinations because the treatment itself does not affect micrometastasis that can be already present at the time the treatment occurs.

#### *Uveal Melanoma DOI: http://dx.doi.org/10.5772/intechopen.95321*

*Melanoma*

b.transillumination,

c.perimetry,

a.ophthalmoscopy, fundus photography,

e.ultrasonography (A and B modes),

f. ultrasound biomicroscopy - UBM,

h.computed tomography - CT,

choroid (ciliochoroidal melanoma).

best boundary used to foresee metastatic infection.

j. fine-needle biopsy

g.optical coherence tomography - OCT,

i. magnetic resonance imaging - MRI,

k.whole body PET/CT to distinguish metastasis.

Depending on their site of growth, posterior uveal melanomas differ in their symptoms, clinical presentation and appearance. A ciliary body melanoma can attain a large size, volume, before it is clinically recognized. It can be seen in association with one or more dilated episcleral blood vessels, it can present itself as an epibulbar pigmented lesion if there is transscleral extension of the tumor. Also, cataract, and/or lens subluxation or secondary glaucoma due to infiltration of the trabecular meshwork in the angle of the eye can be present. The tumor can be envisioned clinically through a broadly enlarged understudy by cut light assessment as an arch formed collection in the area or it can have a diffuse circumferential development design known as "ring melanoma". It can develop anteriorly into the front chamber – iridocorneal point and iris (iridociliary melanoma) or back into the

A melanoma of choroid ordinarily presents as a sessile or curve formed collection arranged under the retina. Initial step analytic techniques can be aberrant ophthalmoscopy, ultrasound and fluorescein angiography. Surface orange color at the degree of the retinal shade epithelium can be imagined clinically, particularly in more modest back melanomas. Retinal separations can be seen auxiliary to the tumor development just as Bruch membrane rupture (cellar layer bellow the retinal shade epithelium). We can divide melanoma of chodoid into two groups the first is melanoma with pigment and the second one is melanoma withou pigment and can likewise accept a spread development design with just negligible tumor diameter

Melanoma of ciliary body and melanomas of choroidea may develop cataracts, extraocular extension, secondary glaucoma. Orbital infiltration can be seen usually when the tumor has large volume, higher stage and they therefore have a worse

Due to the huge range of clinical, morphologic and cytological changes and an absence of discrete stages it is hard to foresee clinical result in singular instances of uveal melanoma based on intraocular tumor size. His size and volume is perhaps the

d.fluorescein angiography, indocyanine green angiography,

**14**

under 3 mm.

prognosis [9].

A little tumor - melanoma - is characterized as estimating 3 mm or less in thickness and under 10 mm in breadth because of TNM plot. A tumor is delegated medium-sized in the event that it measures between 3 to 5 mm in thickness and between 10 to 15 mm in width. A huge tumor is more prominent than 5 mm in thickness and in excess of 15 mm in breadth.

Patients, who are diagnosed with a primary choroidal "intraocular" melanoma, have usually no signs or symptoms of metastatic tumor. Even with total body positron emission tomography/computed tomography (PET/CT) imaging, very few patients are found to have their melanomas spread to other parts of their body. Others may be found to have metastasis over the following years. The overall percentage of the patients diagnosed for choroidal melanoma does not develop metastatic melanoma. The size of the tumor is one of the very important factors to predict the risk for metastatic spreading. Treatments that limit tumors ability to enlarge will decrease the chance of metastasis because removing the eye tumor is the best method to prevent future spread from that tumor. It is very important for the patients to have periodic general medical examinations because the treatment itself does not affect micrometastasis that can be already present at the time the treatment occurs.

Patients who have metastatic choroidal melanoma, as mentioned above, seem to have no symptoms. For this reason, they should have periodic medical examinations, physical examinations, blood tests and radiographic imaging tests as X-ray, MRI, CT or PET/CT. Later on, patients may have symptoms like loss of their appetite, difficulty with breathing or fatigue.

The highest percentage of metastatic choroidal melanoma is likely to be found in the liver. Metastases in this area of the body can be discovered by blood tests or abdominal imaging studies even in cases when patients are asymptomatic. Besides this, other organs also can be affected, e.g. subcutaneous lymph nodes, lung, bone and brain. A needle biopsy can be used to aspirate tumor cells for cytopathologic examination, when a liver or skin metastasis is suspected.

The liver is the known site of metastasing of choroidal melanoma. Hepatic enzyme levels are tested in all patients with melanoma of uvea. The most sensitive tests of liver capacity are serum antacid phosphate levels, glutamate oxaloacetic transaminase, lactate dehydrogenase and gamma-glutamyl transpeptidase. These test results are negative at closure hour in the majority of patients with choroidal melanoma. If any of the results of these research devices is anomalous, ultrasonography and CT of the liver are displayed. Both imaging modalities have low susceptibility to metastases with a diameter of less than 10–20 mm [10–13].

### **2.4 Survival modeling of intraocular melanoma**

Endurance displaying gives a sign of guess. Likewise, it empowers exceptional measures to be focused just as it improves the assessment of clinical methodology.

Endurance rates give a more precise system so as to depict the visualization for patients with a specific stage and type of disease. These rates are frequently founded on past results of huge quantities of individuals who had the sickness, however they cannot anticipate what will occur in a specific patient's case. In patients whose malignancy is bound to the eye, the five-year endurance rate is about 80%. This is as opposed to melanomas that have spread to inaccessible pieces of the body, where the five-year endurance rate is about 15%.

#### *2.4.1 Prognostic factors for uveal melanoma*

Pigmented choroidal lessions that are somewhat raised might be called vague sores and present a test concerning determination and the board. Given the dangers

#### *Melanoma*

and restrictions regarding getting histological affirmation of harm, ophthalmologists need to depend on clinical qualities recognized as prescient of development and metastasis so as to separate little melanomas from raised choroidal melanocytic tumors that are likely kindhearted. Shields et al. distinguished five components related with danger of development of little choroidal melanocytic lessions under 3 mm in diameter using examinations retrospectively of around 1300 patients [14].

These factors were:


3.tumor thickness bigger than 2.0 mm;

4. subretinal fluid;

5.orange pigment.

In 4 percent of patients was observed growth of lesion with none of risk factor, in 36 percent of patients was present one risk factor, and three or more factors were present in more than 50 percent of patients.

Clinical factors associated with an increased risk of metastasis included:

1.growth documentation;

2.increased tumor diameter (bigger than/equal to 1.1 mm);

3.posterior margin touching the disc.

The small-tumor observational study conducted by the COMS Group identified similar risk factors associated with tumor growth; namely

1. apical tumor thickness was greater,

2.initial basal diameter was larger,

3.orange pigment was present,

4.there were no drusen,

5. retinal pigment epithelial change adjacent to the tumor was absent.

Prognostic factors for uveal melanoma can be subdivided into three categories: clinical, histopathological and genetical. Clinical predictive factors have been extensively described. Location of the tumor, its thickness and diameter are clinical factors predicting tumor growth. In addition, age at time of treatment, male gender and secondary glaucoma were prognostic relevant. Shields constructed a mnemonic "TFSOM" "to find small ocular melanoma" (thickness greater than 2 mm, subretinal fluid, symptoms, orange pigment and margin at the disc) to assist in identifying small choroidal melanoma at risk for growth. The most important histopathological markers predicting clinical behavior are the presence of epithelioid cells, largest tumor diameter, sclera invasion, and presence of vascular loops. Other valuable prognostic factors are the presence of mitotic figures and tumor-infiltrating

**17**

*Uveal Melanoma*

endurance [15].

the tumor mass.

endurance.

the advantage of this sort of treatment.

*DOI: http://dx.doi.org/10.5772/intechopen.95321*

lymphocytes. The cell sort of uveal melanoma is identified with guess. Patients with tumors made out of unadulterated axle cells have a more ideal guess, and those with a part of epithelioid cells (blended or epithelioid-cell types) have a more awful visualization. Melanomas with a low mitotic movement show a superior anticipation. Tumor invasion by lymphocytes has been related with diminished

These days there are a lot greater treatment choices other than enucleation, which was the main alternative for a large portion of a century ago. The more moderate treatment choices mean to save the influenced eye and hold vision. Treatment of uveal melanoma relies upon different variables including age of the patients, foundational strength of the patient, state of the contrary eye, tumor size and area. Neverthesess, metastases cannot be prevented. Based on the theoretical models, clinically manifest metastases are likely to occour 5 or 6 years onset of the systemic dissemination. By the time we diagnosis uveal melanoma, micrometastases may have been spread as of now. Along these lines, metastatic sickness happening after therapy is not unprecedented. Roughly 50% of the patients will kick the bucket from the sickness inside 10 to 15 years of enucleation. When a metastasis is found the endurance is under 7 months. In the event that a metastasis emerges as a lone injury in the liver, expanded endurance might be acquired by nearby resection of

Tumor area and size are considered to be two of the primary factors in deciding on the treatment of ocular melanoma. There is no reason to save the eye if a small melanoma in a necessary place completely destroyed vision. It is important to remember this - patients who have undergone enucleation and individuals who have undergone radiation treatment respond appropriately when they receive information about the nature of their patients after treatment. The most important for them was tumor

Treatment using radiation is a typical therapy for intraocular melanoma that utilizes high energy radiation to kill tumor cells. Radiation treatment can regularly safeguard some vision, albeit once in a while this is lost at any rate since radiation harms different pieces of the eye. The structure of the eye is saved and this is mainly

Radiation treetment can be divided into two categories. External radiation treatment that utilizes a machine outside the body to send radiation toward the tumor, and the second type is inside radiation treatment that utilizes a radioactive substance fixed in needles, seeds, wires, or catheters that are set legitimately into or close to the tumor. The manner in which the radiation treatment is given relies upon the sort and phase of the tumor being dealt with. In ophthalmooncology field we

The metastatic free survival rate, the local control and the late toxicity were studied in patients that underwent fractionated Stereotactic Radiation Therapy (fSRT) for uveal melanoma. These patients had a median follow-up 32 months and were given five fractions of 10 Gy. The results showed that fSRT is an effective treatment for uveal melanoma with a good local control. There were performed 15 enucleations after irradiation mainly because of neurovascular glaucoma [16].

Plaque therapy is the most often utilized framework for delivering radiation The other methods are Gamma Knife or methods that include proton beam. Radiation plaque treatment which offers great tumor control, can frequently safeguard helpful vision, and has a fundamental visualization that is practically identical to that of

utilize both photon pillar light and furthermore proton beam irradiation.

**3. Overview of methods of treatment of uveal melanoma**

#### *Uveal Melanoma DOI: http://dx.doi.org/10.5772/intechopen.95321*

*Melanoma*

These factors were:

2.visual symptoms;

4. subretinal fluid;

5.orange pigment.

1.growth documentation;

1.posterior tumor margin touching the disc;

3.tumor thickness bigger than 2.0 mm;

present in more than 50 percent of patients.

3.posterior margin touching the disc.

1. apical tumor thickness was greater,

2.initial basal diameter was larger,

3.orange pigment was present,

4.there were no drusen,

and restrictions regarding getting histological affirmation of harm, ophthalmologists need to depend on clinical qualities recognized as prescient of development and metastasis so as to separate little melanomas from raised choroidal melanocytic tumors that are likely kindhearted. Shields et al. distinguished five components related with danger of development of little choroidal melanocytic lessions under 3 mm in diameter using examinations retrospectively of around 1300 patients [14].

In 4 percent of patients was observed growth of lesion with none of risk factor, in 36 percent of patients was present one risk factor, and three or more factors were

The small-tumor observational study conducted by the COMS Group identified

5. retinal pigment epithelial change adjacent to the tumor was absent.

clinical, histopathological and genetical. Clinical predictive factors have been extensively described. Location of the tumor, its thickness and diameter are clinical factors predicting tumor growth. In addition, age at time of treatment, male gender and secondary glaucoma were prognostic relevant. Shields constructed a mnemonic "TFSOM" "to find small ocular melanoma" (thickness greater than 2 mm, subretinal fluid, symptoms, orange pigment and margin at the disc) to assist in identifying small choroidal melanoma at risk for growth. The most important histopathological markers predicting clinical behavior are the presence of epithelioid cells, largest tumor diameter, sclera invasion, and presence of vascular loops. Other valuable prognostic factors are the presence of mitotic figures and tumor-infiltrating

Prognostic factors for uveal melanoma can be subdivided into three categories:

Clinical factors associated with an increased risk of metastasis included:

2.increased tumor diameter (bigger than/equal to 1.1 mm);

similar risk factors associated with tumor growth; namely

**16**

lymphocytes. The cell sort of uveal melanoma is identified with guess. Patients with tumors made out of unadulterated axle cells have a more ideal guess, and those with a part of epithelioid cells (blended or epithelioid-cell types) have a more awful visualization. Melanomas with a low mitotic movement show a superior anticipation. Tumor invasion by lymphocytes has been related with diminished endurance [15].
