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Advances in Anatomic Pathology:
doi: 10.1097/PAP.0000000000000010
Review Articles

Uveal Melanoma: A Pathologist’s Perspective and Review of Translational Developments

Schoenfield, Lynn MD

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Author Information

Department of Pathology, Wexner Medical Center, Ohio State University, Columbus, OH

The authors have no funding or conflicts of interest to disclose.

Reprints: Lynn Schoenfield, MD, Department of Pathology, Wexner Medical Center, Ohio State University, Rm. 337B, Doan Hall, 410 West 10th Avenue, Columbus, OH 43210 (e-mail: lynn.schoenfield@osumc.edu).

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Abstract

The eye and periorbital soft tissue are derived from the neuroectodermal neural crest, leading to a wide range of tumor types that arise at this site. The uveal tract (iris, ciliary body, and choroid) normally contains melanocytes, and thus both benign nevi and malignant melanoma can arise there, the choroid being the most frequent site. Uveal melanoma (UM) in adults and retinoblastoma (in young children) are the 2 most common primary intraocular malignancies. Retinoblastoma is the most common eye cancer worldwide, but the most common ocular cancer in the United States and Europe is UM. This review will focus on UM and will include the epidemiology, pathologic findings, prognosis and treatment, and review of ongoing molecular discoveries aimed at elucidating the pathways that could lead to adjuvant therapy. These tumors are not uncommon to dedicated ocular pathologists and may occasionally be encountered by general pathologists as well. First, a short word about metastases to the uveal tract is in order, because of its importance in the differential diagnosis. Although the most common primary malignancy in the adult eye is UM, the most frequent adult intraocular malignancy identified in autopsy studies is metastatic carcinoma to the uveal tract. Metastases usually occur late, and the eye is thus rarely enucleated in this setting. However it is important to be aware of this as sometimes, the ophthalmologist cannot determine clinically if an amelanotic tumor represents melanoma or metastasis, possibly from an unknown primary. Shields and colleagues reported on their experience and found that the most common primary sites for uveal metastasis are breast, followed by lung, and then the gastrointestinal tract. Immunohistochemical stains for cytokeratin or more specific markers such as CK7, CK20, TTF-1, BRST-2, CDX2, and PSA may be helpful if there is no known primary. Metastases to the eye also occur in the orbit, eyelid, and rarely to the retina.
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UVEAL MELANOMA

Uveal melanoma (UM)1–4 is an uncommon cancer, accounting for only 3% of all melanomas (Fig. 1). Singh et al5 reviewed the SEER (Surveillance, Epidemiology, and End Results) program database in the United States from 1973 to 2008, which showed that the age-adjusted incidence of UM is 5.1 per million and that it has remained unchanged during this time period. By far the majority of patients (97.8%) are white, with a male to female ratio of 5.8:4.4. Although the etiology is unknown, risk factors include light skin color,6 red or blonde hair and blue or light irides,7 uveal nevi,8 dysplastic nevi,9,10 and oculodermal melanocytosis.11 Although sun exposure has been suggested as a risk factor, its role is unclear with conflicting data reported in UV exposure studies12 compounded by the fact that rates of UM have not increased over recent decades, unlike that of cutaneous melanoma, where sun exposures is known to have a role.3 The RARECARE project in Europe13 looked at 89 cancer registries covering approximately 32% of the European population to study the epidemiology of rare and poorly understood cancers, including UM. Those data showed geographical variation in rates, ranging from <2 cases per million in Southern Europe to >8 cases in Scandinavian countries. Thus there may be a sun-susceptibility factor in play. Familial UM is recognized but is rare (<1%).14

FIGURE 1
FIGURE 1
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TREATMENT AND PROGNOSIS

Treatment has traditionally been enucleation following a funduscopic clinical diagnosis without histopathologic confirmation, a fairly unique scenario in cancer treatment. A decreasing trend has been observed in patients being treated with surgery at the time of diagnosis. From 1973 to 1975, the rate was 93.8% compared with 28.3% during the years 2006 to 2008. There was a corresponding increase in cases treated with radiation (currently plaque radiotherapy) during that time frame (1.8% for 1973 to 1975 vs. 62.5% for 2006 to 2008).3 Therefore, ocular pathologists see approximately one third the number of enucleated eyes as in the previous years. Some ocular oncologists do fine needle aspiration biopsy of the tumor at the time of plaque placement to confirm their diagnosis of melanoma and/or to acquire tumor cells for genetic prognostic testing.15,16 Prognostic applications exceed diagnostic, however, and the cells acquired are typically submitted for fluorescence in situ hybridization (FISH), single-nucleotide polymorphism arrays, or gene expression profiling (GEP).15 Despite a shift toward more conservative treatments at the time of diagnosis as well as advances in treating metastases, survival has not improved in the last 50 years. Death occurs due to metastasis, particularly to the liver (93%), but also to the lung (24%) and bone (16%).17 The mortality rate at 15 years postdiagnosis is about 50%,18 with many of the deaths occurring in the first 5 years. It is important to note that while UM shows histopathologic similarities to cutaneous and other melanomas, including expression of melanocytic lineage markers (HMB-45, melanA, S-100), as well as similarities with high metastatic potential and resistance to known therapies, it differs in many ways. There is no in situ melanoma or basement membrane invasion as in cutaneous melanoma, lymphatics in the eye are mostly absent (so it typically spreads hematogenously), and it demonstrates different changes in genetic pathways. For example, cutaneous melanoma has been found to frequently harbor BRAF or NRAS mutations in a mutually exclusive manner, but these are rare in UM.19 Thus the search for molecular targets for therapy as well as for prognosis has over the years focused on different pathways than that of cutaneous melanoma. This divergence creates a disadvantage for UM research as the case numbers are so much less.

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PROGNOSTICATION FOR UVEAL MELANOMA

UM occurs most commonly in the choroid, followed by the ciliary body and finally the iris. Location is prognostically significant, with ciliary body melanomas having the worse prognosis20 and iris melanomas the best.21 Other clinical factors are advanced age at diagnosis and tumor size,22 which is measured as largest basal diameter and height by B-scan ultrasonography as well as pathologic measurements. Interestingly, tumor site and size have recently been reported to be related to sex,23 which will be discussed in further detail below. Macroscopically, these tumors can form a focal tumor, which in the choroid sometimes takes on a mushroom-like appearance, when Bruch’s membrane is breached; or they can grow in a diffuse pattern within the choroid, in which a mass effect does not occur. In a similar fashion, ciliary body melanomas can form a localized tumor that invades anterior chamber structures or grow in a circumferential pattern along the trabecular meshwork, known as a ring melanoma.24 Extraocular extension of melanoma, which occurs via the vortex veins, is associated with increased mortality.25

Histopathologic prognostic factors include cell type (spindle cell vs. epithelioid), mitotic count per 40 high-power fields (HPFs), pigmentation, presence of tumor-infiltrating lymphocytes, and vasculogenic mimicry patterns. Callendar26 is credited with the classification of UMs in 1931 as being of spindle cell (A or B) or epithelioid type. This was modified in 1983 at the Armed Forces Institute of Pathology27 which deleted the spindle A type, which are considered to represent nevi, and reclassified these tumors as being spindle, epithelioid, or mixed-cell type. Increasing proportions of epithelioid cells typically worsens prognosis. However, it is often difficult to assign an exact classification leading to both intraobserver and interobserver variability in assignment of cell type. Significant tumor-infiltrating lymphocytes are present when there are 100 or more intratumoral lymphocytes per 20 HPFs, and unlike in cutaneous melanoma, their presence is a poor prognostic indicator.28 Also the presence of intratumoral macrophages has been found to contribute to a poorer prognosis.29–31 Vasculogenic mimicry refers to the formation of a fluid-conducting system, which is actually produced by the tumor cells and thus not considered to represent angiogenesis. It is called mimicry because these channels are not lined by endothelial cells. It is demonstrated by staining with PAS and is enhanced if the hematoxylin counterstain is omitted and viewed with a green filter.32–36

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CYTOGENETIC AND MOLECULAR PATHOLOGY

The cytogenetic and molecular aberrations of UM have been the focus of much research. Loss of 1 copy of chromosome 3 (monosomy 3) is the most frequent and prognostically significant cytogenetic marker,37–42 occurring in approximately 50% of cases and strongly associated with metastatic death. The evaluation of this chromosome has been considered by many the gold standard for both prognostication as well as for triaging patients for closer follow-up and possible entry into clinical trials. Other changes include loss on 1p,43,44 6q, and 8p, as well as gain on 1q, 6p, and 8q, which are variously identified by traditional karyotyping, FISH, comparative genomic hybridization, single-nucleotide polymorphism, or multiplex ligation-dependent probe amplification, as well as other means. GEP will be discussed below.

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MONOSOMY 3

Because of the implication that a tumor suppressor gene resides on this chromosome, attention has been drawn to partial deletions or other partial 3 alterations, with published frequencies ranging from 0% to 48%.45 Abdel-Rahman et al45 studied partial deletions using cytogenetics and comparative genomic hybridization and found partial chromosome 3 alterations in 38% of cases, but many were gains and not just losses. These changes did not predict poor outcome. One issue in making conclusions from the literature on this aspect is the differences in specimen types (fresh, frozen, formalin-fixed paraffin-embedded) used and the molecular techniques employed. More recently, inactivating somatic mutations of the BAP1 (BRCA1-associated protein 1) gene, located on chromosome 3p21.1, were identified using exome capture coupled with massively parallel sequencing.46 This gene may represent a tumor suppressor gene involved in UM pathogenesis. This finding is exciting because the BAP1 protein is a deubiquitinating enzyme,47 and the BAP1 pathway has some potential for therapeutic targeting. Hereditary UM is rare, but a germline truncating BAP1 mutation has been reported in a family in which there is UM as well as meningioma, abdominal adenocarcinoma, and cutaneous melanoma.48 Several studies have found UMs to be heterogeneous in regard to monosomy 3 by FISH,49 as well as abnormalities with chromosomes 1p, 3, 6, and 8 by multiplex ligation-dependent probe amplification.50 This has implications both in regard to the type of sample obtained for analysis, as well as cutoff points. Typically for the diagnosis of monosomy 3 a cutoff point of 20% is used, but some think that even 5%51 or 8%52 may be best for sensitivity and specificity.

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LOSS OF 1p

Loss of all or part of 1p occurs in approximately 25% of UMs, often with monosomy 3, and the literature suggests on the one hand that this aberration is an independent predictor of decreased disease-free survival44 and that it loses its predictive value after adjusting for certain demographic and tumor variables.53

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GAIN OF 6p

Gain of 6p is usually associated with loss of 6q and thought to represent formation of isochromosome 6p.41 In general, 6p gain confers a better prognosis40,54; however, relative mutual exclusivity of 6p gain and monosomy 3 has been noted.55,56 These findings have led support to the idea that these 2 abnormalities represent alternative evolutionary pathways for tumor progression, the former leading to a good prognosis and the latter to a poor prognosis.

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GAIN OF 8q

Gain of 8q has been found in approximately 40% of UMs and 8p loss in approximately 25%.57–59 8q gain has been shown to have a statistical association with metastasis,54,60 especially in association with monosomy 3.40 However, Onken et al61 found that 8p loss rather than 8q gain was more significant, and in a recent study using whole-genome copy number variation and comparing results with clinical data such as sex and tumor size, 8p loss was found to impart increased risk for metastasis even after monosomy 3 and 8q gain were acquired by the tumor.53

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GENE EXPRESSION PROFILING

In 2004, Onken et al46 used GEP to classify UMs into 2 prognostically significant groups: class 1 (low metastatic risk) and class 2 (high metastatic risk). Several subsequent studies have demonstrated the prognostic power of this assay.62–65 A large collaborative study of 459 patients from 12 medical centers,66 found a strong association between GEP class 2 and other adverse prognostic factors, including increased age, ciliary body involvement, larger tumor diameter and thickness, epithelioid cell type, and monosomy 3. However, in multivariate analysis, no combination of other variables, including chromosome 3 status, was more closely associated with metastasis than GEP alone. This test has recently become available to patients with a patented assay (DecisionDx-UM) and has received much publicity in the lay media.

An alternative predictive model is that of artificial neural networks in which multivariate assessment of age, sex, clinical tumor stage, cytogenetic type, and histologic grade is incorporated.67 This type of algorithm has been used and found to be an effective tool in the United Kingdom for determining the frequency of clinical follow-up to rule out metastases.

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METASTASES AND TREATMENT TRENDS

Most deaths due to UM are due to metastases, usually hepatic; and this occurs in approximately 50% of patients despite successful local treatment of the eye. Metastases usually occur within the first 5 years following diagnosis, but may occur as much as 25 years later.18 As previously mentioned, enucleation rates have decreased and brachytherapy (or external beam radiation) rates have increased. These alternate therapies have been proven effective only for tumors that do not involve the optic disc and are small to medium in size. The Collaborative Ocular Melanoma Study group reported that after 10 years of follow-up, brachytherapy with Iodine-125 (I-125) is as good as enucleation in terms of survival.68 Ruthenium-106 is now often preferred for better sight preservation and less damage to other parts of the eye.69 However, approximately half of tumors still prove to be lethal, and this is probably because clinically undetectable micrometastases are probably already present in the liver at the time of local therapy with the tumors having high metastasizing potential (class 2 or those with monosomy 3 with or without 8q gain). There is currently no adjuvant chemotherapy available to prevent or eliminate micrometastases. Thus, survival has improved little in the last 50 years. Still, there is some reason for optimism, as studies showing that with aggressive treatment of the liver metastases, especially if found early, survival can be prolonged. Frenkel et al70 looked at surgically treated patients (ranging from wedge resections of liver metastases to lobectomies) and found that these patients had a 3-fold increase in metastatic survival than those patients who did not have surgery. Other options for treatment include systemic therapy and isolated hepatic perfusion. Long-term survival with metastatic UM was seen in a series of 9 patients who underwent treatment (surgical, systemic therapy, or isolated hepatic perfusion) with survivals averaging 51 months (range, 27 to 123 mo),71 far better than the median of 5 to 7 months previously reported.72 A more pessimistic view was reported by Augsburger et al73 in which a literature search was performed to evaluate the effectiveness of surveillance and aggressive treatment when metastases were detected. While acknowledging the increased survival times reported in various reports, the concern of selection bias, surveillance bias, and publication bias was raised. The lack of randomized phase III clinical trials was noted. This is a known problem with a tumor with such a low prevalence. Obviously, the need for early intervention requires cost-effective and directed surveillance to triage patients for more intensive follow-up, which has generally consisted of abdominal ultrasound examinations directed towards the liver and serum liver function testing (ALK-P, AST, ALT, GGT, LDH, and total bilirubin). Tumor markers that have been studied include osteopontin, melanoma inhibitory activity, S-100β, and tissue polypeptide-specific antigen.74 More recently, it was reported that significantly lower serum levels of insulin-like growth factor-1 (IGF-1) at 10 years in disease-free UM patients were present compared with levels in healthy subjects, and they were even lower levels in patients with metastases.75 They also found a trend in decreasing values in the 6 months before diagnosis of metastasis. Since high expression levels of IGF-1R (IGF-1 receptor) are known to correlate with lower survival rates,76 and blockage of IGF-1R activity with picropodophyllin causes tumor regression in xenografted mice,77 this suggests a possible therapeutic target.

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SEX AND UVEAL MELANOMA

This author has been intrigued by the role sex and hormonal influences may play in UM The RARECARE project in which 4097 cases of UM were evaluated13 found that 5-year survival rates were better for women than for men. In another study of 723 patients, men were noted to have earlier and more frequent metastases in the first decade after diagnosis.78 Tumors have been found to be larger and more posterior, including location within 3 mm of the optic disc, in men in a study of 3380 patients.23 Finally, this author has found a trend for the immunohistochemical presence of estrogen receptor to correlate with monosomy 3, metastasis, and death due to disease, especially in males (unpublished data of small patient set).79 Hopefully, further study will elucidate the role of sex and hormones, potentially leading to a therapeutic target.

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PSYCHOLOGICAL CONSIDERATIONS

Recently, various groups have begun to look at emotional issues in patients diagnosed with UM. In a current and ongoing prospective study, Schuermeyer and colleagues (current study) have been using the Hospital Anxiety and Depression Scale to look at not only anxiety and depression but also decision regret. The latter is relevant to all involved in the diagnosis and treatment of UM because, at the present time, the prognostic tests now available are helpful for research, surveillance protocols, and life planning; but they cannot guide adjuvant therapy. Preliminary findings indicate a decline in depression and anxiety over the first 3 months, but plans are to continue to monitor this for 12 months (I. Schuermeyer, current study).

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CONCLUSIONS

In summary, UM is a lethal disease usually due to liver metastasis in approximately half of patients; and to date, the prognosis for these patients is dismal. One of the largest challenges is the relative rarity of the disease, making data difficult to interpret and funding for research difficult to obtain. However, with the increasing understanding of the molecular pathways and novel approaches to surveillance and treatment that are occurring, there is hope for better outcomes in the future.

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Keywords:

melanoma; uveal; pathology; molecular; monosomy 3

Copyright © 2014 by Lippincott Williams & Wilkins

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