Uveal and Conjunctival Melanoma: Close Together-but Only Distantly Related

January 15, 2016

There has been rapid progress in the treatment of metastasis associated with cutaneous melanoma, including impressive results achieved with targeted molecular therapies and immunotherapies, and it is possible (but still unproven) that patients with metastasis from conjunctival and eyelid melanomas may benefit from these new therapies.

Primary melanomas can arise from melanocytes residing within the eye (uveal melanoma), on the surface of the eye (conjunctival melanoma), within the epidermis of the eyelids (a form of cutaneous melanoma), and rarely in the eye socket (orbital melanoma). Despite their close anatomic proximity, these melanomas have very little in common aside from their shared ancestry from neural crest–derived melanocytes. Because their clinical behavior, management, prognosis, tumor node metastasis (TNM) classification schemes, and molecular characteristics differ markedly, these neoplasms are better thought of as distinct forms of melanoma, rather than being grouped together as “ocular melanoma.”

Uveal melanoma arises from the iris, ciliary body, or choroid of the eye, and it is very aggressive and resistant to therapy once metastasis has occurred. In contrast to cutaneous melanoma, a link between uveal melanoma and ultraviolet light exposure is tenuous at best.[1] Primary uveal melanoma is usually treated by high-dose localized radiotherapy (delivered by brachytherapy or charged-particle therapy) or enucleation (eye removal). Primary uveal melanoma demonstrates a strong propensity for liver metastasis in up to half of patients, and it almost never metastasizes to regional lymphatics in the head and neck.

Uveal melanoma is associated with several characteristic chromosomal gains and losses, and it frequently harbors driver mutations in several genes: GNAQ, GNA11, BAP1, SF3B1, and EIF1AX. These genes are rarely mutated in other forms of melanoma. Likewise, genes that are frequently mutated in other forms of melanoma, such as BRAF, NRAS, and KIT, are rarely mutated in uveal melanoma. Indeed, the finding of GNAQ/GNA11 mutations has been used clinically as a means of determining the likely primary site in patients with melanoma of unknown origin. Uveal melanoma is notable for a distinctive and prognostically significant gene expression profile that has been prospectively validated for clinical use in a multicenter study.[2] Uveal melanomas with the Class 1 signature have a low metastatic risk, whereas those with the Class 2 signature have a high metastatic risk. This classification scheme is widely used to stratify patients for clinical trial entry and metastatic surveillance. Although Blum et al focus on targeted therapies based on mutations in GNAQ/GNA11 in their review,[3] these mutations are early and possibly initiating events in uveal melanoma. Thus, it is unlikely that pharmacologic modulation of these mutations alone will be sufficient to achieve durable efficacy, as has been the case with BRAF inhibitors in cutaneous melanoma. Inactivating mutations in BAP1 occur later in tumorigenesis, are strongly associated with metastasis, and cause uveal melanoma cells to undergo a stem cell–like phenotypic reversion that may render them more resistant to therapy.[4] Thus, it is possible that the biochemical and physiologic effects of BAP1 mutations must also be addressed to achieve optimal therapeutic efficacy. Histone deacetylase inhibitors and EZH2 inhibitors have shown promise in reversing the epigenetic alterations that occur with loss of BAP1, and these compounds require further investigation in clinical trials.[5,6]

In contrast to uveal melanoma, conjunctival melanoma is a form of mucosal melanoma, and primary conjunctival melanoma is most commonly treated by local surgical excision. Conjunctival melanoma can metastasize hematogenously, but it can also undergo regional lymphatic dissemination, which is another characteristic that distinguishes it from uveal melanoma. Although controversial, sentinel lymph node biopsy has been proposed as part of the management of conjunctival melanoma, whereas this procedure has no role in uveal melanoma. Little is known about the molecular genetics of conjunctival melanoma, except that BRAF and NRAS mutations are fairly common, whereas GNAQ/GNA11 mutations are not.

Eyelid melanoma is a form of cutaneous melanoma. Consequently, eyelid melanoma is strongly linked to UV light exposure, and can display regional lymphatic spread as well as hematogenous metastasis. Eyelid melanoma is usually treated by local surgical excision, sometimes requiring extensive oculoplastic reconstructive surgery. Very little is known about the molecular genetics of eyelid melanoma aside from what is known about cutaneous melanoma in general.

Most orbital melanoma is secondary to invasion of the orbit by uveal or conjunctival melanoma, or metastasis to the orbit from a primary melanoma arising elsewhere in the body. True primary orbital melanoma is extraordinarily rare and poorly characterized.

While melanomas arising in and around the eye are relatively rare compared with cutaneous melanoma, they represent a microcosm of the various forms of melanomas that occur in humans. Eyelid melanoma and conjunctival melanoma are typical of the epithelium-associated cutaneous and mucosal subtypes, respectively, whereas uveal melanoma is representative of the non–epithelium-associated subtype.[7] There has been rapid progress in the treatment of metastasis associated with cutaneous melanoma, including impressive results achieved with targeted molecular therapies and immunotherapies, and it is possible (but still unproven) that patients with metastasis from conjunctival and eyelid melanomas may benefit from these new therapies. Although there are still no effective therapies for metastatic uveal melanoma, there has been significant recent progress in our understanding of the genetics and pathobiology of this entity. Promising new therapeutic strategies are slowly making their way into clinical trials.

Financial Disclosure: Dr. Harbour is the inventor of intellectual property mentioned in the commentary and receives royalties from its commercialization. He is a paid consultant for Castle Biosciences, licensee of intellectual property presented in the commentary.

References:

1. Singh AD, Rennie IG, Seregard S, et al. Sunlight exposure and pathogenesis of uveal melanoma. Surv Ophthalmol. 2004;49:419-28.

2. Onken MD, Worley LA, Char DH, et al. Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma. Ophthalmology. 2012;119:1596-603.

3. Blum ES, Yang J, Komatsubara KM, Carvajal RD. Clinical management of uveal and conjunctival melanoma. Oncology (Williston Park). 2016;30:29-32, 34-43, 48.

4. Matatall KA, Agapova OA, Onken MD, et al. BAP1 deficiency causes loss of melanocytic cell identity in uveal melanoma. BMC Cancer. 2013;13:371.

5. Landreville S, Agapova OA, Matatall KA, et al. Histone deacetylase inhibitors induce growth arrest and differentiation in uveal melanoma. Clin Cancer Res. 2012;18:408-16.

6. LaFave LM, Beguelin W, Koche R, et al. Loss of BAP1 function leads to EZH2-dependent transformation. Nat Med. 2015;21:1344-9.

7. Bastian BC. The molecular pathology of melanoma: an integrated taxonomy of melanocytic neoplasia. Annu Rev Pathol. 2014;9:239-71.