**6. Staging**

There are two main staging systems for UM, both based on tumor thickness and maximal basal diameter. The first staging system was formulated by the Collaborative Ocular Melanoma Study Group (COMS) [37], and the second was the TNM staging system proposed by the American Joint Committee on Cancer (AJCC) in 1968 [38]. In COMS staging, tumors are classified according to their thickness and largest basal diameter as small (1.5–2.4 mm thickness with the largest basal diameter 5–16 mm), medium (2.5–10.0 mm thickness with the largest base ≤16 mm in diameter), and large (thickness > 10.0 mm or maximal basal diameter > 16 mm). In TNM staging, tumors are classified into T1, T2, T3, and T4 stages, where "T" indicates the characteristics of the primary tumor, including tumor volume and its infiltrating relationship with surrounding tissues; "N" indicates the degree and scope of regional lymph node involvement; and "M" indicates distant metastasis of the tumor. There is partial overlap between small and medium tumors in the COMS staging and T1 and T2 in the TNM staging, and between large tumors in the COMS staging and T3 and T4 in the TNM staging. In the 8th edition of the TNM staging system launched by AJCC in 2018, more detailed staging was carried out for iris melanoma and the extrascleral extension of the tumor. The primary tumor is divided into T1-T4 stages according to clinical features, T1 stage is tumor limited to iris; T2 stage is tumor invaded ciliary body and (or) choroid; T3 stage is tumor invaded ciliary body and (or) choroid, with scleral infiltration; T4 stage is tumor with extrascleral extension. For ciliary body and choroidal melanoma staging, the eighth edition of the TNM staging system was also updated (**Table 1**).

UM is divided into N0 stage without lymph node involvement and N1 stage with lymph node involvement; M0 stage without metastasis; and M1 stage with metastasis, and is divided into M1a ~ M1c stage according to the size of metastatic lesions.

AJCC assessed the prognosis of patients according to TNM staging, and divided patients into 7 categories according to the assessed prognosis (**Table 2**) [39, 40].

#### T1 tumors:

T1a: The T1-size tumor is not growing into the ciliary body or growing outside the eyeball.

T1b: The T1-size tumor is growing into the ciliary body.

T1c: The T1-size tumor is not growing into the ciliary body but is growing outside of the eyeball. The part of the tumor that is outside the eyeball is 5 mm (about 1/5 of an inch) or less across.

T1d: The T1-size tumor is growing into the ciliary body and also outside of the eyeball. The part of the tumor that is outside the eyeball is 5 mm (about 1/5 of an inch) or less across.

#### T2 tumors:

T2a: The T2-size tumor is not growing into the ciliary body or growing outside the eyeball.

T2b: The T2-size tumor is growing into the ciliary body.

T2c: The T2-size tumor is not growing into the ciliary body but is growing outside the eyeball. The part of the tumor that is outside the eyeball is 5 mm (about 1/5 of an inch) or less across.

T2d: The T2-size tumor is growing into the ciliary body and also outside the eyeball. The part of the tumor that is outside the eyeball is 5 mm (about 1/5 of an inch) or less across.

#### T3 tumors:

T3a: The T3-size tumor is not growing into the ciliary body and is not growing outside the eyeball.

T3b: The T3-size tumor is growing into the ciliary body.

T3c: The T3-size tumor is not growing into the ciliary body but is growing outside the eyeball. The part of the tumor that is outside the eyeball is 5 mm (about 1/5 of an inch) or less across.

T3d: The T3-size tumor is growing into the ciliary body and also outside the eyeball. The part of the tumor that is outside the eyeball is 5 mm (about 1/5 of an inch) or less across.

#### T4 tumors:

T4a: The T4-size tumor is not growing into the ciliary body or growing outside the eyeball.

T4b: The T4-size tumor is growing into the ciliary body.

T4c: The T4-size tumor is not growing into the ciliary body but is growing outside the eyeball. The part of the tumor that is outside the eyeball is 5 mm (about 1/5 of an inch) or less across.

T4d: The T4-size tumor is growing into the ciliary body and also outside the eyeball. The part of the tumor that is outside the eyeball is 5 mm (about 1/5 of an inch) or less across.

T4e: The tumor can be any size. It is growing outside the eyeball and the part of the tumor that is outside the eyeball is greater than 5 mm across.

#### **Table 1.**

*AJCC TNM staging system (T categories for ciliary body and choroidal melanoma [39]).*


**Table 2.**

*AJCC stage grouping.*

#### **7. Treatment**

The individualized and comprehensive treatment should be applied to UM patients. The appropriate methods or a combination of multiple methods should be selected according to tumor size, location, shape, growth rate, visual acuity of the affected eye and fellow eye, and general conditions. Given that UM is not sensitive

*Basis, Diagnosis, and Treatment of Uveal Melanoma DOI: http://dx.doi.org/10.5772/intechopen.110329*

to traditional radiochemotherapy (referred to as radiochemotherapy), enucleation was the only and effective treatment, but this operation has caused great damage to the patient's physiology and psychology, seriously affecting the quality of life. With the advancement of science and technology, new types of radiotherapy such as patch radiotherapy and particle radiotherapy can not only effectively kill tumors and preserve eyeballs, but also preserve part of effective vision. Compared with traditional radiotherapy, the local control rate is higher and complications are fewer. Therefore, eye protection therapy represented by patch radiotherapy and particle radiotherapy has become the first-line treatment for UM. Other treatments include transpupillary thermotherapy (TTT), photodynamic therapy (PDT), local resection of ocular tumors, enucleation, orbital content extraction, and immunotherapy.

#### **7.1 Adhesive radiation therapy**

Brachytherapy is a type of radiotherapy in which the radiation source is located next to the treatment target. It is the preferred treatment method for small and medium tumors in UM (the maximal diameter of the tumor base is ≤18 mm and the thickness is ≤10 mm). The goal is to deliver a higher localized radiation dose to the tumor with less damage to surrounding tissue. Currently, the radioactive isotopes commonly used in ophthalmology are 106 ruthenium, 125 iodine, 103 palladium, and 131 cesium [41, 42]. Brachytherapy can continue to give a lower radiation dose, and its radiation dose attenuates with distance (radiation dose = 1/(radiation distance)<sup>2</sup> ), so the dose distribution is roughly decreasing from the base of the tumor (adjacent to the applicator) to the apex of the tumor [43]. After radiation exposure, tumor cell DNA breaks, cell membrane permeability increases, cell division cycle arrests, cell proliferation decreases, and necrosis and apoptosis occur [44]. The 5-year and 12-year survival rates of the plaster treatment group for medium-volume (thickness 2.5–10 mm and maximal tumor base diameter < 16 mm) tumors reported by the famous Collaborative Ocular Melanoma Study Group (COMS) were 82% and 57% [45], which were no different from those in the enucleation group; at the same time, the 5-year cumulative local recurrence rate and enucleation rate were only 10.3% and 12.5% [46], and 1/3 of the patients could still retain better vision [47]. The main complications of patch radiotherapy are cataract, retinal detachment, glaucoma, radiation retinopathy, radiation optic neuropathy, etc.

#### **7.2 Particle radiation therapy**

Unlike previous photon radiotherapy (including X-rays, alpha, beta, and gamma rays released by isotopes, etc.), particle radiotherapy is a radiation therapy that uses charged particles as radiation sources, including protons, carbon ions, helium ions, etc. Particle radiotherapy has the characteristics of the Bragg peak; that is, after the particle beam obtains energy through the accelerator, it is injected into the human body under precise control and the energy is concentratedly released to the lesion, killing the lesion cells, and at the same time, the energy decays sharply and falls back, forming the Bragg peak [48]. Therefore, particle radiation therapy has little damage to surrounding normal tissues. Due to its good targeting, and uniform dose distribution, it becomes the first choice for UM radiation therapy. It is reported that the eye protection rate of proton radiotherapy is above 85%, the 5-year survival rate is above 80% [49–51], and the 5-year local control rate and disease-related survival rate after heavy ion therapy are 92.8% and 82.2% [52]. It is more suitable for the treatment of difficult

tumors near the macula or optic disc [53, 54]. Compared with patch radiotherapy, particle radiotherapy represented by protons and heavy ions has a higher local tumor suppression rate and a lower tumor recurrence rate, which provides an important reference for clinicians to choose treatment in the future. Common complications of particle radiotherapy include cataract, retinal detachment, ocular surface changes, glaucoma, macular degeneration, and radiation-induced fundus lesions.

#### **7.3 Transpupillary thermotherapy (TTT)**

TTT is a non-invasive treatment. The 810 nm infrared diode laser is delivered to the inside of the choroidal tumor through the pupil, raising the temperature of the tumor to 45–60°C, resulting in vascular occlusion and tumor necrosis in the tumor. The maximal penetration depth of TTT is 4 mm. It is suitable for small tumors with a thickness of <4 mm that are located outside the optic disc and macula or local recurrence after vitrectomy of the entire tumor. It is more effective for choroidal melanoma with a thickness of <2.5 mm. Tumors with a thickness > 3 mm should be treated with patch radiation therapy combined with TTT, that is, "sandwich" therapy. The advantages of TTT include the precise focus of the laser, which can cause immediate necrosis of the tumor and less damage to the surrounding normal choroid. It is easy to operate. The treatment can be completed in an outpatient clinic, and the treatment can be repeated. The disadvantage of TTT is that it is more likely to recur, and potential complications include occlusion of epiretinal membrane and branch retinal vein, retinal stretch, and secondary rhegmatogenous retinal detachment.

#### **7.4 Photodynamic therapy (PDT)**

PDT is a non-thermal laser that activates a photosensitizing dye (verteporfin) to induce vascular closure, tumor necrosis, and cell apoptosis, and can be used to treat small choroidal melanoma [55]. However, tumor pigmentation can affect the effectiveness of PDT, so PDT is mainly used in the treatment of small amelanotic choroidal melanoma, adjuvant treatment of radiotherapy, and supplementary treatment after radiotherapy failure.

#### **7.5 Local tumor resection**

Local tumor resection was first used for the residual tumor after radiotherapy, and later it was also reported as the first choice for the treatment of UM [56]. There are two types of surgery to remove the entire tumor through an incision in the sclera (excision) and to remove the entire tumor through the vitreous (endectomy). External resection is suitable for iris, ciliary body, and peripheral choroidal melanoma; internal resection is suitable for choroidal melanoma located retroequatorially. Local tumor resection can provide fresh tissue samples for histopathological diagnosis and genetic testing, and preserve the eyeball and vision. During local excision of the tumor, if there is residual tumor on the scleral surface or the tumor is close to the edge of the surgical resection area, radiotherapy can also be supplemented to prevent tumor recurrence. The effect of local tumor resection is usually ideal, but it is difficult and requires high surgical experience and technical requirements for the surgeon.

At present, the routine surgical indications for clinical UM local resection: (a) The maximal diameter of the tumor base is ≤15 mm; (b) the tumor has no local invasion,

or involvement of the sclera and orbit; (c) the tumor has no systemic metastasis. Contraindications to surgery: (a) extraocular invasion or distant metastasis of the tumor; (b) general conditions that cannot tolerate surgery; (c) flat diffuse tumors. The main complications of local tumor resection include retinal detachment, proliferative vitreoretinopathy, and hemorrhage.

#### **7.6 Enucleation**

Enucleation is required for large and advanced UM (maximal diameter of tumor base >20 mm or thickness > 12 mm), optic nerve involvement or orbital involvement, and/or secondary glaucoma [57].

#### **7.7 Removal of orbital contents**

For UM that invaded the orbit, orbital content extraction was used, and the eyelids were preserved as much as possible during the operation to facilitate rapid healing.

#### **7.8 Immunotherapy**

In recent years, with the rapid development of immunotherapy, the tumor microenvironment plays a pivotal role in cancer progression and treatment response. A study of the UM tumor microenvironment based on a public database found that people with high-risk UM risk scores were more sensitive to anti-programmed death receptor 1 immunotherapy [58]. Prostaglandin endoperoxide synthase can be used as an immunotherapy target for UM, and its inhibitor, celecoxib, can effectively inhibit UM cell growth and promote tumor cell apoptosis [59].

#### **8. Prognosis**

The 20 to 50% of patients with UM eventually die of tumor metastasis. Tumors metastasize through the blood circulation, with the liver taking the first place (64.86%), followed by the skin, stomach, lung, and bone.

Factors affecting the prognosis of patients with UM include: (1) Patient age. Those over 50 years old have a poor prognosis, which may be related to their reduced immune function. Reduced immune defenses in patients may contribute to tumor metastasis. (2) The largest basal diameter of the tumor. The prognosis of tumor base diameter ≤ 12 mm is better than that of >12 mm. The larger the tumor base, the greater the possibility of destroying blood vessels, the greater the contact area with the sclera, the greater the possibility of spreading outside the eyeball, leading to an increased risk of tumor metastasis. (3) The maximal height of the tumor. The prognosis of tumors whose maximal height exceeds 12 mm is significantly worse than that of those less than 12 mm. (4) The location of the tumor. If the front edge of the tumor is located in front of the equator, the prognosis is worse than that in the back of the equator; if the tumor invades the ciliary body further forward, the prognosis is even worse. (5) With or without ball spread. If the tumor invades the scleral duct and scleral wall tissue, its prognosis is poor. (6) Tumor cell type. Cell type is the most important factor influencing the prognosis of UM. The prognosis of the spindle cell type is better, and the prognosis of mixed cell type and epithelioid cell type is poor. Small tumors are often of spindle cell type, while epithelioid and mixed types are dominant in large tumors.
