Uveal melanoma: From diagnosis to treatment and the science in between

Abstract

Melanomas of the choroid, ciliary body, and iris of the eye are collectively known as uveal melanomas. These cancers represent 5% of all melanoma diagnoses in the United States, and their age-adjusted risk is 5 per 1 million population. These less frequent melanomas are dissimilar to their more common cutaneous melanoma relative, with differing risk factors, primary treatment, anatomic spread, molecular changes, and responses to systemic therapy. Once uveal melanoma becomes metastatic, therapy options are limited and are often extrapolated from cutaneous melanoma therapies despite the routine exclusion of patients with uveal melanoma from clinical trials. Clinical trials directed at uveal melanoma have been completed or are in progress, and data from these well designed investigations will help guide future directions in this orphan disease. Cancer 2016;122:2299-312. V C 2016 American Cancer Society.KEYWORDS: breast cancer 1-associated protein 1 (BAP1), choroidal melanoma, diagnosis, guanine nucleotide binding protein a11 (GNA11), guanine nucleotide-binding protein Q polypeptide (GNAQ), ocular melanoma, review, science, treatment, uveal melanoma. BACKGROUND AND EPIDEMIOLOGYUveal melanoma is the most common primary intraocular malignancy. The uveal tract is the pigmented layer of the globe encompassing the iris, ciliary body, and choroid (Fig. 1). The terms choroidal melanoma and ocular melanoma are alternative terms for this cancer, because most of the uveal tract is choroidal. However, the term ocular melanoma should be avoided, because it implies the inclusion of conjunctival and adnexal melanomas, which behave and are managed like cutaneous rather than uveal primaries. Approximately 1500 new cases of uveal melanoma are diagnosed in the United States each year, most commonly arising in the choroid followed by the ciliary body. Iris melanomas are the least common location for uveal melanoma (Fig. 2).1 Although the disease has no sex preference, it is more common in middle-aged Caucasians (median age at presentation, 58 years). Risk factors include the presence of a choroidal nevus, which can be observed in 7% to 8% of the Caucasian population. Certain skin conditions, such as dysplastic nevus syndrome and nevus of Ota, are also associated with uveal melanoma.2 It has been theorized by some investigators that exposure to ultraviolet radiation increases the risk of this neoplasia, but this has not been definitively proven. Whereas certain somatic mutations are associated with neoplastic growth and distant metastasis, the malignancy is not inherited in a traditional genetic fashion, although it is believed that individuals who have germline breast cancer 1 (BRCA1)-associated protein 1 (BAP1) mutations are at higher risk for uveal and cutaneous melanoma as well as mesothelioma and renal cancers.

Identification of novel chemotherapeutic strategies for metastatic uveal melanoma

“…Adjuvant treatment with bacillus Calmette-Guerin and interferon-α, as well as, intra-arterial hepatic infusion of fotemustine, have been previously studied in an effort to reduce the occurrence of liver metastasis, but none of these studies has demonstrated significant improvement in metastasis free survival or OS4.…”

Gene of the month:BAP1

“…Therefore, BAP1 functions in uveal melanocytes primarily as a regulator of differentiation. The connection of BAP1 loss to UM metastasis has been reinforced by multiple independent studies, forming the basis of developing targeted therapies based on the BAP1 pathway 20. For example, histone deacetylase inhibitors have been shown to reverse the effects of increased ubiquitinated histone 2A levels in BAP1 -deficient tumour cells, changing their attributes to a more differentiated, class 1-like profile 21…”

Pancreatic metastases from ocular malignant melanoma: the use of endoscopic ultrasound-guided fine-needle aspiration to establish a definitive cytologic diagnosis: a case report

“…Uveal malignant melanoma is the most common primary intraocular malignancy. The majority of patients present with visual complaints, but as part of their primary workup, abdominal cross-sectional imaging should be performed since the primary metastatic location is the liver, in over 90 % of cases [8]. We found only one case report of a patient with metastatic uveal melanoma where the lesion spread to the gallbladder and head of the pancreas [9].…”