Uveal Melanoma

From EyeWiki
Article initiated by:
Adam R. Sweeney, MD, Divakar Gupta, MD
All authors and contributors:
Divakar Gupta, MD, Adam R. Sweeney, MD, Jill Wells, MD, Constance Fry, MD, Andrew W. Stacey
Assigned editor:
Benjamin King, MD
Review:
Assigned status Update Pending
 by Constance Fry, MD on February 26, 2021.


Uveal Melanoma
DiseasesDB
2614
ICD-10
[1]69.3
OMIM
155720
MedlinePlus
001022
MeSH
D014604


Uveal melanoma is a rare disease, but the most common primary ocular malignancy. While recent advancements are improving treatment options and supporting more accurate prognoses, the risk for metastasis and mortality remains unchanged.

Disease Entity

Uveal melanoma

Disease

Uveal melanoma is the most common primary intraocular malignancy in adults. The age-adjusted incidence of this rare malignancy has been reported as 5.1 per million and has remained stable since at least the early 1970’s.[1] These tumors most commonly arise unilaterally in Caucasians during the fifth to sixth decade of life.[1]

Etiology

This malignancy arises from melanocytes in the choroid, ciliary body, or iris. The choroid posterior to the equator, hereafter referred to as the posterior choroid, is the most common site involved with approximately 85% of cases localized to this region.[2] Anterior uveal melanoma refers to the involvement of the iris, ciliary body, and/or choroid anterior to the equator and comprises 9-15% of uveal melanomas.[2] Melanoma localized to the iris encompasses 2-4% of uveal melanoma cases and is associated with the earliest detection and overall best prognosis.[3] Associated with the worst prognosis, tumors localize to the ciliary body makeup 4-7% of uveal melanomas. Often described as an especially bleak malignancy, 50% of patients diagnosed with uveal melanoma will develop metastasis, despite treatment, with survival time after metastasis averaging 6 months to 1 year.[4] [5]

Risk Factors

While development of uveal melanoma is largely considered to be a sporadic event, certain risk factors including light iris color, light skin color, ability to tan, northern European ancestry, and rarely a family history of uveal melanoma have been reported to predispose individuals to uveal melanoma.[6] [7] [8] Other conditions with an increased incidence of uveal melanoma include dysplastic nevi and Nevus of Ota (estimated that 1:400 will develop uveal melanoma. Though ocular nevi have been suggested to be a risk factor, the estimated rate of transformation into melanoma is approximately 1/8845.[9]

Pathophysiology

The pathophysiology of uveal melanoma is currently not well understood. There have been several advances in the molecular mechanisms involved in this malignancy. Monosomy 3 has long been known to be associated with development of aggressive uveal melanoma. More recently, specific abnormalities in loci associated with high-risk melanoma have been identified including 3p and 1p losses and 8q gain.[10] Currently, numerous genetic mutations have been demonstrated to be highly conserved in the clonal proliferation of uveal melanocytes.[11] Downstream signaling pathways are known to be involved are the retinoblastoma pathway, p53 pathway, P13K/AKT and MAPK pathway. No evidence for a common molecular pathway has yet been found. However, at the cellular level, the molecular expression for metastasis is heavily biased towards only one of the three cell types that make up uveal melanoma tumors.

The three cell types classically comprising almost all uveal melanoma tumors are

  • type A
  • type B oblong spindle-shaped cells
  • Large, polygonal shaped epitheloid cells.[12][13] These epitheloid cells appear to have an intrinsic affinity for metastasis and are considered to be the make up more high-risk lesion, however, 87% of primary tumors have a mixture of all three cell types.[12][14] [15]

Diagnosis

History

The history for any ocular neoplasm should include assessment for risk factors, family history, onset of visual abnormalities and extent of visual disturbance.

Symptoms

The clinical presentation of malignant uveal melanoma is characterized by nonspecific findings associated with the location of the tumor. The more common posterior choroidal tumors may present with decreased visual acuity, floaters, photopsia, and visual field defects. Ciliary body tumors present later as symptoms develop later. They may present with visual field defects, decreased visual acuity, and in advanced cases secondary glaucoma. Tumors involving the iris are often found incidentally on an ophthalmologic evaluation. They may present with the patient complaining of iris color changes. Very rarely an advanced case of iris melanoma may present with a secondary glaucoma due to tumor extension into the angle and pigment-laden macrophages causing blockage of the trabecular meshwork or neovascularization.[16]· 

Cilary Body/Ciliochoroidal melanoma

Melanomas of the ciliary bodychoroidal and ciliary body melanoma are often relatively large when they present. They have the same characteristics as choroidal melanoma but more frequently have a sentinel vessel (dilated tortuous episcleral vessel overlying the tumor). Additionally, these tumors are more likely to present with anterior displacement of the lens-iris diaphragm and a secondary angle closure glaucoma.

Iris melanoma

Iris melanomas are often asymptomatic and detected on routine ocular evaluation. They may be brown or tanish (tapioca) in color. They may be associated with corectopia, ectropion iridis,

Clinical diagnosis

Choriodal melanoma

Collar button mushroom configuration of melanoma. (Image courtesy of Constance L. Fry, M.D.)

Posterior uveal melanomas typically present as a unilateral elevated domed-shaped gray-brown colored mass of the choroid with irregular margins. Less commonly, a melanoma may be amelanotic. About 20% of the time the tumor will break through Brüch membrane and the appearance will be of the classic mushroom-shaped (or collar button) configuration. Melanomas should be differentiated from nonmalignant pigmented solid lesions, most commonly choroidal nevus, indeterminant nevi and congenital hypertrophy of the retinal pigment epithelium (CHRPE) as well as metastasis and blood.

Ultrasound of a collar button mushroom configuration of melanoma. (Image courtesy of Constance L. Fry, M.D.)

A useful approach to choroidal pigmented lesions as described by Kanski[17] and Eichhorn-Mulligan et al[18] is to classify lesions into one of three groups: nevi, indeterminant and melanoma. Nevi are typically flat elevated, have overlying drusen, which suggests chronicity, and may have a halo of depigmentation surrounding the pigmented portion. Indeterminant nevi often are mildly elevated (<2.5mm) and have 1 or 2 other features of melanoma but do not meet enough of the criteria to be certain of their malignant potential. Another possible disorder is CHRPE which is very, very well circumscribed and may have internal lacunae.

Clinical features and symptoms of melanoma include:

  • Thickness >2mm
  • Fluid - subretinal fluid due to an exudative detachment of the retina or RPE
  • Symptoms-decreased vision, flashes or floaters
  • Orange pigment - lipofuscin accumulation in RPE overlying the melanoma
  • Margin within 3 disc diameters of the optic nerve head
  • Acoustic hollowness on ultrasonography


Cilary Body/Ciliochoroidal melanoma

Melanomas of the ciliary body are often relatively large when they present. They have the same characteristics as choroidal melanoma but more frequently have a sentinel vessel (dilated tortuous episcleral vessel overlying the tumor). Additionally, these tumors are more likely to present with anterior displacement of the lens-iris diaphragm and a secondary angle closure glaucoma.

Iris melanoma

Most pigmented iris tumors are nevi according to a histopathologic study by Jakobiec in 1981. Iris melanomas are often asymptomatic and detected on routine ocular evaluation. They may be brown or tanish (tapioca) in color. They may be associated with corectopia, ectropion iridis, and cataract. The risk of an iris nevus transforming into an iris melanoma in a tertiary referral center was 11% in 20 years (Shields 2013). Risk factors for transformation create the ABCDEF mnemonic:

  • Age </= 40 at presentation
  • Blood - spontaneous hyphema*
  • Clock hour - inferior 4:00-9:00*
  • Diffuse involving the entire iris*
  • Ectropion uveae
  • Feathery edges


*The hazard ratio for each of these features predicting malignant transformation is substantially higher than the other three characteristics.

Melanoma picture.jpg

Diagnostic procedures

Diagnosing uveal melanoma often requires the utility of several resources. Serial fundus photography is imperative in the screening and follow-up of suspicious lesions. Factors seen on fundus photography are the addition of the suspicious features mentioned above, development of scattered plaques, and lateral extension seen over time.

Other critical tools to aid in the evaluation and diagnosis of uveal melanoma or suspected uveal melanoma are A and B scan ultrasonography. Together these evaluate the lesion looking for low to medium internal echogenicity, choroidal excavation and orbital shadowing—signs found to be consistent with choroidal melanoma.[17] Additionally, these modalities allow the dimensions of the tumor to be assessed, functioning as a valuable tool in following lesions, identifying scleral/extra-scleral extension, and planning treatment.

2013-07-05 17-26-43 10.jpg

As pinpoint measurements in this disease process are vital to the classification and management of uveal melanoma, limitations in the quality of description with gonioscopy and A and B scan ultrasonography may be supplemented by ultrasound biomicroscopy, which offers better resolution and is often utilized to fully characterize iris and ciliary body melanoma.[12] Shields et al[16] suggested a diagnostic criteria for iris melanoma using ultrasound biomicroscopy to include melanotic and amelanotic lesions of at least 1 mm in height and 3 mm in base diameter that replace the iris stroma with at least three of the following five features: prominent vasculature, ectropion iridis, secondary cataract, secondary glaucoma (intraocular pressure >24), and documented growth.

A newer, innovative visual approach to the characterization of questionable lesions is optical coherence tomography via enhanced depth imaging. This allows a more accurate characterization of the thickness and quality of choroidal lesions--assisting in differentiating superficial nevi from melanoma.[19] The role of this modality and objective clinical superiority, however, has yet to be fully assessed.

Fluorescein angiography is also used to characterize lesions suspicious for melanoma. Fluorescein angiography is best used to identify acute, high-risk features including areas of fluorescein dye leakage and irregular vessels located in and around the lesion.[12] This test will also help to recognize the neovascularization on the surface of the lesion, characteristic of low-risk lesions.


Differential diagnosis

While the above symptoms have been shown to be the first features of this malignancy, uveal melanoma is most frequently caught as an incidental finding on routine ophthalmoscopic examination. It is most commonly seen as a raised, sub-retinal lesion in the posterior pole. The differential such lesions includes benign nevus, metastatic lesions, hemangioma, hamartoma of the retina and retinal pigment epithelium, congenital hypertrophy or reactive hyperplasia of the retinal pigment epithelium, diffuse melanocytic proliferation, and detachment of the pigment epithelium, retina, or choroid.[20] The differential diagnosis for iris lesions suspected of being melanoma should include the findings and frequency of iris pseudomelanomas reported by Shields et al: primary iris cyst (38%), iris nevus (31%), essential iris atrophy (5.7%), iris foreign body (4.5%), peripheral anterior synechia (2.5%), and iris metastasis (2.5%).[21] Ciliary body melanomas are generally detected secondary to other signs and symptoms, however the differential for a pigmented mass on the ciliary body should include: iridociliary epithelial cyst, Intraocular foreign body granuloma, melanocytic nevus, melanocytoma, leiomyoma, Fuchs adenoma, sarcoid nodule, or a metastatic tumor.

Management

Once a clinician has considerable suspicion for uveal melanoma, the decision to treat rests on several subjective and objective features. Observation of lesions is justified for small tumors where ancillary studies, not including biopsy, have failed to establish a definitive diagnosis. Additionally, smaller lesions with tumor doubling time less than 10 years may be observed if the patient is elderly and/or if the patient is satisfied with a conservative approach. Additionally, when the lifespan of the patient is estimated to be less than 5 years, the decision to observe may be justified. Finally, for very small tumors in the patient’s only remaining eye, observation for development of high-risk indicators is reasonable. Observation of lesions less than 3 mm in thickness should include preliminary fundus photos, fluorescein angiography, and A and B scan ultrasonography. After first diagnosis, this should be repeated at a 3-4 month follow-up. If no change in the lesions has been identified, the minimum follow-up should be fundus photography every 6-12 months for the remainder of the patient’s life.

While the above diagnostics can provide sufficient evidence for the clinical classification of uveal melanoma, biopsy of the lesion is the only way to definitively yield the diagnosing. This can, of course, be done after enucleation, however, for patients wishing to keep the affected eye, fine needle aspiration biopsy followed by histological examination and cytopathological analysis can accurately identify uveal melanoma. This has been advocated by many authorities to increase the specificity of noninvasive testing, to save patients from unnecessary treatment side-effects, to better advise patient decisions, and to conserve treatment finances when unnecessary.[22] Fine needle aspiration, when performed by an experienced ophthalmologist, has been proven to be safe by several researchers.[23] This procedure can be done in the operating room with real time diagnosis by a present cytopathologist before initiating an intraocular incision for the use of radiotherapy. Alternatively, fine needle aspiration biopsy may be done before treatment is discussed to provide an accurate diagnosis and prognosis to better manage potential therapy. A transvitreal approach is used to biopsy tumors posterior to the equator, while a direct transscleral approach is used to access anterior tumors. The prognostic implications of various tests using fine needle aspiration biopsy will be discussed later.

Most ophthalmologists use clinical indicators to predict the likelihood of a borderline lesion growing and thus differentiating a benign lesion from malignant melanoma, thus guiding the workup and treatment. If one of the high-risk indicators, mentioned previously is found, there is reasonable evidence for potential growth and many authorities recommend advancing the workup and obtaining a biopsy.

General treatment

The primary goal of treatment for uveal melanomas is to prevent metastasis. Historically, this as best accomplished for all uveal melanomas by enucleation, which provided a histological diagnosis and also guided further treatment, when necessary. In the late 1970’s advances in the field of radiation oncology opened the door to eye conserving radiotherapy for uveal melanoma. Radiotherapy treatment outcomes reported in the literature with the use of brachytherapy in the early 1980’s and charged particle radiation therapy in the early 1990’s were found to offer promising results by ophthalmologists trained in ocular oncology.[24]

Brachytherapy as a treatment for uveal melanoma was led in its infancy by Packer[25], who described sewing a customized plaque containing a radioisotope, in his study iodine-125, over the region affected by the tumor. With numerous ophthalmologists subsequently borrowing this mode of therapy, the techniques of brachytherapy were refined and skills were improved to allow ophthalmologists proficient in radiotherapy management to suggest treatment superiority.

Despite promising findings early in the history of brachytherapy, apprehension held by many ophthalmologists regarding the possibility for recurrence and metastasis in eye conserving therapy delayed its utilization.[26] In 2001, the Collaborative Ocular Melanoma Study (COMS), a large, multicenter, randomized control trial studying 1317 patients over 12 years concluded that there was no significant difference in mortality for iodine-125 brachytherapy compared to enucleation for choroidal melanomas.[9] The results of this COMS report, in addition to subsequent COMS publications confirming this finding ,have bolstered the use of radiotherapy to become the standard of treatment today for uncomplicated uveal melanomas.

Today the procedure is similar to that described by Packer, however, the specifications have been standardized. The American Brachytherapy Society currently recommends 3D tumor planning either with a multi-modality reconstruction program or with MRI to clearly demonstrate the size and location of the tumor before treatment.[27] The planning of the dosage of the radioisotope plaque is often a collaborative effort between an ophthalmologist and an oncologist. The American Brachytherapy Society recommends using iodine-125 at a dosage of 0.60-1.05 Gy/h over 3 to 7 consecutive days.[27] This amount has been carefully chosen after the COMS and other researchers reported that dose rates of less than 0.60 Gy/h allowed lower tumor control rates.[28] With a well constructed 3D model of the tumor, the application of the radioisotope plaque to the apex of the tumor is performed by an ophthalmologist. Using this modality, great success has been reported in providing a lethal dose of radiation to a confined area with attenuated, dose-related tissue toxicity a function of distance from the site of the plaque. Currently, the most common isotope used in brachytherapy for uveal melanoma in the United States is iodine-125. This is largely a result of the well-established documentation of the isotope’s efficacy in the COMS trials. Other radioisotopes such cobalt-60, iridium-192, palladium-103, ruthenium-106 have also been used. The limitations of brachytherapy are generally governed by the experience of the ophthalmologists, however general guidelines for use are for tumors less than 18-mm in diameter, tumors not involving the macula, and tumors not involving or proximal to the optic disc.

While brachytherapy has been a well-established and accepted modality for eye conserving radiotherapy, charged particle radiation therapy, notably proton beam radiotherapy, has becoming a novel and attractive alternative. Proton beam radiotherapy is an extraocular application of large charged particles with specified kinetic energy aimed at the exact location of interest-generally the tumor apex. This treatment precisely localizes radiation due to the quick deceleration of large mass particles and the ability of the treating ophthalmologist-oncologist to modify the kinetic energy of the beam. This treatment boasts a high degree of precision and is now referred by many trained in this technique as equal if not superior to brachytherapy in terms of tumor reduction and decreased recurrence.[29] Proton beam radiotherapy also has the ability to treat larger choroidal melanomas and melanomas closer to the optic disc.

Subsequent publications following the COMS initial reports studying the efficacy of brachytherapy or proton beam therapy in melanoma anterior to the equator reported similarly positive findings.[29] The decision to use brachytherapy vs. proton beam therapy is now largely made in regard to the size and location of the tumor and patient preference.

For small tumors, other less commonly used treatment options are available. These include transpupillary thermotherapy, photocoagulation, photodynamic therapy, and local resection. Transpupillary thermotherapy uses infrared radiation over several treatments to cause local necrosis to the tumor, leaving a chorioretinal scar.[30] Photocoagulation and photodynamic therapy take advantage of the popularized laser techniques to provide local destruction to the tumor.[31] [32] Local resection attempts to avoid enucleation and the frequent complications of radiotherapy, but little has been reported on the recurrence and long-term outcomes of this treatment.[33] All of these therapies have had much less reported regarding their respective efficacies, however, it is generally suggested that these therapies be reserved for small tumors with more anterior locations.

Enucleation is warranted for large tumors, tumors involving the optic nerve, unrecoverable total vision loss, and patient specific indicators, particularly patient preference. All enucleations involving active uveal melanoma must pay considerable attention to minimizing the potential for seeding. Several authors state that this is most successful when i.) occlusion of the bloodstream is performed as early as possible and ii.) close attention to maintaining a puncture free globe when dissecting Tenon’s tissue and severing the extraocular muscles.[34] [35]

Complications

The complications associated with brachytherapy are associated with the necessity of 2 invasive operations requiring anesthesia and radiotoxic effects on healthy ocular tissue. As posterior choroidal tumors are the most common uveal melanomas, extraocular muscle removal is typically required for both placement and removal of the plaque. Both dissections carry with them the risk of inducing diplopia. Radiation induced complications after brachytherapy are numerous and may depend on the tumor size, tumor location, dose of radiation use, and rate of use. Radiation complications are often delayed; indeed, these are seemingly becoming more frequent following documentation of trials with longer follow-up times. Complications of brachytherapy to the adnexa and anterior segment include cataract, symptomatic dry eye, iris neovascularization, and secondary glaucoma. Posterior segment complications of brachytherapy include retinal detachment, cystoid macular edema, optic neuropathy, and hemorrhage of the vitreous, retina, choroid, or a combination of these structures. The most common posterior segment complication, however, is radiation retinopathy[36], with greater than 75% of individuals experiencing this complication following brachytherapy in some reports.[37] The mechanism of injury in radiation retinopathy is hypothesized to be secondary to free radical damage to the vascular endothelial cells leading to occlusion of the capillary beds, microaneurysm formation and retinal ischemia.[38] This can further lead to areas of retinal nonperfusion causing macular edema, neovascularization, and tractional retinal detachment.

Proton beam radiotherapy has several recognized complications including cataract, chronic uveitis, hyphema, macula edema, retinal detachment, corneal melting, scleral atrophy and secondary glaucoma. Indeed the incidence of glaucoma following proton beam radiotherapy has been reported to be as high as 53%.[39] [40] Secondary glaucoma is also the leading complication necessitating subsequent enucleation.

Follow up

Regardless of treatment, monitoring for metastasis should be performed regularly and patient compliance with follow-up should be stressed. Regular dilated fundus examination, liver function test, and CT or right upper quadrant ultrasound assessing liver metastasis is the follow-up performed by most ophthalmologists. The frequency of follow-up is recommended to be based on the demonstrated risk of the tumor, as discussed below, with visits every 3-4 months suggested for patient’s with the highest risk tumors.[41]

Prognosis

Prognostic variables for uveal melanoma have been reported by several authors since the first description of the malignancy. Generally accepted variables estimating the prognosis for uveal melanoma include: the patient’s age, the size of the tumor, the cell type seen on histology (spindle A cells associated with the best prognosis and epithelial cells the worst), histological characteristics (meiotic activity, lymphocytic infiltration, fibrovascular loops) the location of the tumor (with melanomas involving the ciliary body conferring the highest risk of metastasis), and the extent of metastasis.[12] While the cellular makeup of biopsied tumors remains very useful, recent discoveries in tumor cytology, gene expression profiling, and identification of circulating tumors cells have given more influence to cutting edge prognostic indicators.

It has been well established that there exists an association of uveal melanoma with monosomy 3.[42] A retrospective study analyzing tumors in enucleated specimens demonstrated that no individuals with two copies of chromosomes 3 developed metastatic disease, however, 57% of those with monosomy 3 developed metastatic disease with a 3 year survival rate of 50%.[43] With this finding, direct tissue biopsy obtained via fine needle aspiration increased in popularity to offer screening for patients during therapeutic procedures for high-risk of metastasis. Patients found to have evidence for monosomy 3 were selected for adjuvant therapy or closer monitoring.

Only In the last several years have specific genes causing the down-regulation of key tumor suppressors on chromosome 3 and the up-regulation of multiple genes on chromosome 8q been isolated that predict risk for metastasis.[44] [45] Current genes considered to be candidates for the promotion of dissemination of uveal melanoma cells include GNAQ, GNA11, LZTS1 (8p22), DDEF1 (8q24.21), PTP4A3 (8q24.3),TCEB1 (8q21.11), and NOTCH signaling.[46] [47] [48] Harbour et al[49] described the influential role of the gene BAP1 in regulating the metastasis of uveal melanoma as it does in other cancers involving the lung, breast, and kidney. The BAP1 gene codes for a deubiquitinating enzyme that binds to BRCA1 and BARD1 to create a heterodimeric tumor suppressor complex. Inactivation of this gene has been described in up to 84% of class 2 uveal melanomas.[50] As BAP1 is mapped to chromosome 3p21.31-p21.2, a loss of this region, as in monosomy 3, could predispose an individual to uveal melanoma via the classic mechanism underlying other tumor suppressor genes.

While multiple genes are likely involved in the development of metastatic uveal melanoma, Onken et al[44] has been the leader in translating this research into an applicable clinical test. Onken observed that monosomy 3 had limited ability in prognosis for uveal melanoma. Onken thereafter identified 12 genes found to be predictive of metastasis in uveal melanoma. Using a 15 gene microarray assay, including 3 control genes, Onken found this test to very accurately discriminate between low-grade (class 1A and class 1B) and high-grade (class 2) uveal melanoma. Both fine needle aspirate biopsies and formalin fixed, paraffin embedded tumor tissue provide adequate supply of tumor cells while being safe and technically simple.[45] This technique, termed multi-gene expression profiling, has been compared against the other various prognostic indicators for accuracy in predicting risk of metastasis and was found to be superior to all previous prognostic indicators.[11][51] [52] [53] Multi-gene expression assay were initially offered in 2009 and have since become an important tool for clinicians to provide more accurate prognoses.

After 3 years of international use of multi-gene expression profiling, the Collaborative Ocular Oncology Group led by Onken[11] published a follow-up prospective study demonstrating the reliable utility of this technique. It was found that the accuracy of producing interpretable results using the fine needle aspiration biopsy far outperformed cytogenetic competitors. Additionally, the 12 genes chosen for the assay were validated with over half of patients diagnosed with a class 2 tumor found to develop detectable metastatic uveal melanoma by 3 years after this testing. The foreseeable future of gene expression profiling is to continue to add to or substitute the current genes represented on the assay with identified genes that are both more sensitive and specific for tumor metastasis. One gene currently not incorporated in the assay that has recently been shown to be strongly associated with class 2 tumors is BAP1 gene. Incorporation of this gene will surely increase the utility of the gene expression profile assay currently available and offer more precise diagnoses to patients.

Another, less commonly utilized, modality involved in the workup and prognosis of uveal melanoma is peripheral blood cytology. It has been hypothesized that most uveal melanoma has already metastasized to some extent by the time of diagnosis. Researchers looking into this found that indeed, there was evidence for cells with specific tumor markers for malignant uveal melanoma in the peripheral blood. Callejo et al[54] have demonstrated that peripheral cytology can predict, if not determine, metastasis of uveal melanoma. The strengths of this developing test are to catch metastasis as early as possible and to assist in distinguishing high-risk melanoma from lower risk lesions.

Recurrence and Metastasis

Local recurrence of uveal melanoma following eye-conserving therapy varies widely between institutions and between therapies used. A recent review found the following rates of treatment failure: proton/helium beam radiation: 4.2%, brachytherapy 9.5%, surgical: 18.6%, laser therapies: 20.8%.[55] While some advocate proton beam therapy for small, well localized recurrence,[56] many authorities advocate that recurrence as an indication for enucleation.

Recurrence of uveal melanoma after Baerveldt implant following brachytherapy for ciliary body melanoma

Even with early diagnosis, appropriate treatment, and close follow-up, an estimated 40-50% of all patients will eventually die of metastatic disease.[4] Metastasis generally occurs via local extension or though infiltrating into the circulating system. Systemic metastasis is most commonly found in the liver with 80%-90% of initial extra-scleral tumors identified at this site. Kath et al described the distant sites of metastasis in patient’s with disseminated uveal melanoma and reported the following sites of metastases: liver (87%), lung (46%), bone (29%), and skin (17%).[57]

Eskelin et al[58] was the first to calculate the rate of growth for tumors affecting the uveal tract. He measured the doubling time using a standardized tumor growth formula to find that the range of time required for untreated uveal melanoma tumors was between 34 and 220 days. Two thirds of these lesions were found to have a doubling time of less than 80 days if left untreated. Eskelin et al also described the rate of growth for treated tumors finding that the median tumor doubling time was 255 days, however some patients were found to have treated tumors doubling as long as 2619 days, indicating that some patients may respond much more favorably to the same treatment. In this study, no correlation between tumor doubling time and the age of tumor detection was found. Based on the reported rate of growth however, patients treated for uveal melanoma should be followed every 4-6 months.

Metastasis of uveal melanoma is associated with a median survival time of less than 1 year[59] with patients less than 50 years of age having significantly greater relapse-free survival time—up to 54 months reported in one study.[57] Unfortunately, patients with liver involvement at diagnosis of metastasis have a much worse prognosis. Kath et al[57] found the median survival time after detection of metastatic lesions to the liver was 7 months and was unchanged if other organs were involved along with the liver. Patients with metastasis to other organs without evidence for liver involvement have a much more favorable survival times with average lifespan being 10-31 months.[57]

If aggressive treatment for metastatic uveal melanoma is desired by the patient, a discussion of the benefits and risks is indicated. Common systemic chemotherapy regimens include decarbazine, fotemustine, and immunotherapy. If patients desiring full treatment are found to have isolated liver metastasis, various aggressive modalities must be used to ensure complete destruction of that lesion. Such treatments include chemoembolization, surgery, and intra-arterial chemotherapy. Reports of intra-arterial application of fotemustine or carboplatin along with chemoembolization with cisplatin have shown to have a response in up to 40% of patients.[60] When full treatment is used to battle metastatic uveal melanoma, the median overall survival is still very limited, only increasing to 14-15 months.[61]

While the most aggressive measure have found some, yet limited, improvement in survival, the physical and emotional burden of such treatments along with the financial encumbrance is significant. With this in mind, most clinicians fully educate patients of the risks and benefits of treatment while carefully presenting the option of comfort care.

References

  1. ↑ 1.0 1.1 Singh AD, Turell ME, Topham AK. Uveal melanoma: trends in incidence, treatment, and survival. Ophthalmology. 2011 Sep;118(9):1881-5.
  2. ↑ 2.0 2.1 Shields CL, Kaliki S, Furuta M, Mashayekhi A, Shields JA. Clinical spectrum and prognosis of uveal melanoma based on age at presentation in 8,033 cases. Retina. 2012 Jul;32(7):1363-72.
  3. ↑ Shields CL, Kaliki S, Shah SU, Luo W, Furuta M, Shields JA. Iris melanoma: features and prognosis in 317 children and adults. J AAPOS. 2012 Feb;16(1):10-6.
  4. ↑ 4.0 4.1 Kujala E, Makitie T, Kivela T (2003) Very Long-Term Prognosis of Patients with Malignant Uveal Melanoma. Investigative Ophthalmology and Visual Science 44: 4651-4659.
  5. ↑ Diener-West M, Earle JD, Fine SL, Hawkins BS, Moy CS, Reynolds SM, Schachat AP, Straatsma BR; Collaborative Ocular Melanoma Study Group. The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma, III: initial mortality findings. COMS Report No. 18. Arch Ophthalmol. 2001 Jul;119(7):969-82.
  6. ↑ Ezekiel Weis, MD, MPH, Chirag P. Shah, MD, MPH, Martin Lajous, MD, Jerry A. Shields, MD, Carol L. Shields, MD. The Association Between Host Susceptibility Factors and Uveal Melanoma: A Meta-analysis. Arch Ophthalmol. 2006;124(1):54-60.
  7. ↑ Johanna M. Seddon, MD; Evangelos S. Gragoudas, MD; Robert J. Glynn, ScD; Kathleen M. Egan, MPH; Daniel M. Albert, MD; Peter H. Blitzer, MD. Host Factors, UV Radiation, and Risk of Uveal Melanoma. Arch Ophthalmol. 1990;108(9):1274-1280.
  8. ↑ Smith J.H., Padnick-Silver L., Newlin A.,et al. Genetic study of familial uveal melanoma: association of uveal and cutaneous melanoma with cutaneous and ocular nevi. Ophthalmology 2007; 114: 774-779
  9. ↑ 9.0 9.1 Singh AD, Kalyani P, Topham A. Estimating the risk of malignant transformation of a choroidal nevus. Ophthalmology. 2005 Oct;112(10):1784-9.
  10. ↑ Sisley K, Rennie IG, Parsons MA, Jacques R, Hammond DW, Bell SM, Potter AM, Rees RC. Abnormalities of chromosomes 3 and 8 in posterior uveal melanoma correlate with prognosis. Genes Chromosomes Cancer. 1997 May;19(1):22-8.
  11. ↑ 11.0 11.1 11.2 Onken MD, Worley LA, Char DH, Augsburger JJ, Correa ZM, Nudleman E et al. Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma. Ophthalmology 2012; 119(8): 1596–1603.
  12. ↑ 12.0 12.1 12.2 12.3 12.4 Pavan-Langston, Deborah. Manual of Ocular Diagnosis and Therapy: 6th edition. Lippincott Williams & Wilkins. Philadelphia; 2008.
  13. ↑ Collaborative Ocular Melanoma Study Group. Histopathologic characteristics of uveal melanomas in eyes enucleated from the Collaborative Ocular Melanoma Study. COMS report no. 6. Am J Ophthalmol. 1998 Jun;125(6):745-66.
  14. ↑ Shammas HF, Blodi FC. Prognostic factors in choroidal and ciliary body melanomas. Arch Ophthalmol. 1977 Jan;95(1):63-9.
  15. ↑ Schmittel A, Bechrakis NE, Martus P, Mutlu D, Scheibenbogen C, Bornfeld N et al. Independent prognostic factors for distant metastases and survival in patients with primary uveal melanoma. Eur J Cancer 2004; 40: 2389–2395.
  16. ↑ 16.0 16.1 Shields C, Materin M, Shields J, Gershenbaum E, Singh A, Smith A. Factors associated with elevated intraocular pressure in eyes with iris melanoma. Br J Ophthalmol 2001;85:666-669
  17. ↑ 17.0 17.1 Kanski, Jack. Clinical Diagnosis in Ophthalmolog. Mosby Elsevier, Philadelphia 2006.
  18. ↑ Knut Eichhorn-Mulligan, Ivana K. Kim. Nevus or Melanoma? How to Differentiate. 4/17/2008. Review of Ophthalmology. Accessed 7-2-13. http://www.revophth.com/content/d/retinal_insider/i/1229/c/23122/
  19. ↑ Say EA, Shah SU, Ferenczy S, Shields CL. Optical coherence tomography of retinal and choroidal tumors. J Ophthalmol. 2012;2012:385058.
  20. ↑ Ho A, Brown G, McNamara J, Recchia F, Regillo C, Vander J. Retina: Color Atlas of Synpopsis of Clinical Ophthalmology; second edition.
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  22. ↑ Char D, Miller T. Accuracy of presumed uveal melanoma diagnosis before alternative therapy. British Journal of Ophthalmology 1995;79:692-696.
  23. ↑ McCannel TA. Fine-needle aspiration biopsy in the management of choroidal melanoma. Curr Opin Ophthalmol. 2013 May;24(3):262-6
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  25. ↑ Packer S, Rotman M, Salanitro P.Iodine-125 irradiation of choroidal melanoma. Clinical experience. Ophthalmology. 1984; 91(12):1700-8.
  26. ↑ Gass JD. Comparison of prognosis after enucleation vs cobalt 60 irradiation of melanomas. Arch Ophthalmol. 1985 Jul;103(7):916-23.
  27. ↑ 27.0 27.1 Nag S, Quivey JM, Earle JD, et al. The American Brachytherapy Society recommendations for brachytherapy of uveal melanomas. Int J Radiat Oncol Biol Phys 2003; 56:544.
  28. ↑ J.M Quivey, J Augsburger, L Snelling et al. 125I plaque therapy for uveal melanoma. Analysis of the impact of time and dose factors on local control. Cancer, 77 (1996), pp. 2356–2362
  29. ↑ 29.0 29.1 Wang Z, Nabhan M, Schild SE, et al. Charged particle radiation therapy for uveal melanoma: a systematic review and meta-analysis. Int J Radiat Oncol Biol Phys 2013; 86:18.
  30. ↑ Oosterhuis JA, Journee-de Korver HG, Kakebeeke-Kemme HM, Bleeker JC. Transpupillary thermotherapy in choroidal melanomas. Arch Ophthalmol 1995;113:315-321.
  31. ↑ Shields JA, Glazer LC, Mieler WF, Shields CL: Comparison of xenon arc and argon laser photocoagulation in the treatment of choroidal melanomas. Am J Ophthalmol 109: 647-655,1990.
  32. ↑ Donaldson MJ, Lim L, Harper CA, Mackenzie J, G Campbell W. Primary treatment of choroidal amelanotic melanoma with photodynamic therapy. Clin Experiment Ophthalmol. 2005;33:548-9.
  33. ↑ Shields JA, Shields CL, Shah P, Sivalingam V: Partial lamellar sclerouvectomy for ciliary body and choroidal tumors. Ophthalmology, 98:971-983, 1991.
  34. ↑ C Migdal. Effect of the method of enucleation on the prognosis of choroidal melanoma. Br J Ophthalmol. 1983 June; 67(6): 385–388.
  35. ↑ Dunn J, Langer P. Basic Techniques of Ophthalmic Surger. American Academy of Ophthalmology. San Francisco; 2009.
  36. ↑ P.T Finger. Tumour location affects the incidence of cataract and retinopathy after ophthalmic plaque radiation therapy. Br J Ophthalmol, 84 (2000), pp. 1068 -1070
  37. ↑ Murray TG, Markoe AM, Gold AS, Ehlies F, Bermudez E, Wildner A, Latiff A. Long-term follow-up comparing two treatment dosing strategies of (125) I plaque radiotherapy in the management of small/medium posterior uveal melanoma. J Ophthalmol. 2013;2013:517032.
  38. ↑ Archer DB, Amoaku WM, Gardiner TA. Radiation retinopathy--clinical, histopathological, ultrastructural and experimental correlations. Eye. 1991;5 ( Pt 2):239-251.
  39. ↑ Rundle P, Singh AD, Rennie I. Proton beam therapy for iris melanoma: a review of 15 cases. Eye (Lond). 2007 Jan;21(1):79-82.
  40. ↑ Tsuji H, Ishikawa H, Yanagi T, et al.: Carbon-ion radiotherapy for locally advanced or unfavorably located choroidal melanoma: a Phase I/II dose-escalation study. Int J Radiat Oncol Biol Phys 67 (3): 857-62, 2007.
  41. ↑ Sato T, Babazono A, Shields JA, et al. Time to systemic metastases in patients with posterior uveal melanoma. Cancer Invest 1997; 15:98.
  42. ↑ F. Tschentscher, J. Husing, T. Holter et al. Tumor classification based on gene expression profiling shows that uveal melanomas with and without monosomy 3 represent two distinct entities. Cancer Res, 63 (2003), 2578–2584.
  43. ↑ S E Coupland, S L Lake, M Zeschnigk and B E Damato. Molecular pathology of uveal melanoma. Eye. 2013; 27, 230-242.
  44. ↑ 44.0 44.1 Onken MD, Worley LA, Ehlers JP, Harbour JW. Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death. Cancer Res. 2004;64(20):7205–7209.
  45. ↑ 45.0 45.1 Onken MD, Worley LA, Tuscan MD, Harbour JW. An Accurate, Clinically Feasible Multi-Gene Expression Assay for Predicting Metastasis in Uveal Melanoma. J Mol Diagn. 2010 July; 12(4): 461–468
  46. ↑ Van Raamsdonk CD, Griewank KG, Crosby MB, et al. Mutations in GNA11 in uveal melanoma. N Engl J Med 2010; 363:2191.
  47. ↑ Van Raamsdonk CD, Bezrookove V, Green G, et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 2009; 457:599.
  48. ↑ Coupland SE, Lake SL, Zeschnigk M. Damato BE. Molecular pathology of uveal melanoma. Eye (2013) 27, 230–242.
  49. ↑ Harbour JW, Onken MD, Roberson ED, et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 2010; 330:1410.
  50. ↑ Jensen DE, Proctor M, Marquis ST, Gardner HP, Ha SI, Chodosh LA et al. BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene 1998; 16(9): 1097–1112.
  51. ↑ Gill HS, Char DH. Uveal melanoma prognostication: from lesion size and cell type to molecular class. Can J Ophthalmol. 2012 Jun;47(3):246-53.
  52. ↑ Onken MD, Worley LA, Dávila RM, Char DH, Harbour JW. Prognostic Testing in Uveal Melanoma by Transcriptomic Profiling of Fine Needle Biopsy Specimens. J Mol Diagn. 2006 Nov; 8(5): 567–573.
  53. ↑ Petrausch U, Martus P, Tönnies H, Bechrakis NE, Lenze D, Wansel S, Hummel M, Bornfeld N, Thiel E, Foerster MH, Keilholz U. Significance of gene expression analysis in uveal melanoma in comparison to standard risk factors for risk assessment of subsequent metastases. Eye (Lond). 2008 Aug;22(8):997-1007.
  54. ↑ Callejo SA, Antecka AE, Blanco PL, Edelstein C, Burnier MN. Identification of circulating malignant cells and its correlation with prognostic factors and treatment in uveal melanoma: A prospective longitudinal study. Eye (2007) 21, 752–759.
  55. ↑ Chang MY, McCannel TA. Local treatment failure after globe-conserving therapy for choroidal melanoma. Br J Ophthalmol. 2013 Jul;97(7):804-11.
  56. ↑ Marucci L, Lane AM, Li W, Egan KM, Gragoudas ES, Adams JA, Collier JM, Munzenrider JE.Conservation treatment of the eye: Conformal proton reirradiation for recurrent uveal melanoma. Int J Radiat Oncol Biol Phys. 2006;15;64(4):1018-22.
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  59. ↑ Aoyama T, Mastrangelo MJ, Berd D, Nathan FE, Shields CL, Shields JA, Rosato EL, Rosato FE, Sato T. Protracted survival after resection of metastatic uveal melanoma. Cancer. 2000;89:1561–1568
  60. ↑ Marucci L, Lane AM, Li W, Egan KM, Gragoudas ES, Adams JA, Collier JM, Munzenrider JE. Uveal melanoma: natural history and treatment options for metastatic disease. Wöll E, Bedikian A, Legha SS. Melanoma Res. 1999 Dec;9(6):575-581.
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