Residency Program - Case of the Month
January 2012 - Presented by Sarah Barnhard, M.D.
At autopsy, the findings were consistent with metastatic disease. The decedent was cachexic and jaundiced with icteric sclerae. Bilateral pleural effusions and bloody ascites (3 liters) were apparent. A hyperpigmented mass was found located in the right eye (Image 1). Apparent metastases were found in the pleura and lung parenchyma bilaterally. The liver was nearly entirely replaced by tumor (weight 8 kilograms; Image 2).
On microscopic examination, the primary tumor was composed of invasive, darkly pigmented, highly pleomorphic cells, predominantly spindle in shape, and containing prominent nucleoli (image 3). Areas of necrosis were identified. The lungs (image 4), pleura, right endocardium (image 5), and liver (image 6) had metastatic disease. Other findings included mild chronic cystitis and mild systemic atherosclerosis.
Intraocular melanomas constitute the most common primary ocular malignancy in the Caucasian population. The annual age-adjusted incidence of non-skin melanomas is 0.7 per 100,000 population in the United States, about one eighth that of melanoma of the skin in the United States. Ocular tumors constitute 80% of all the non-cutaneous melanomas reported. There is a slight male predominance, and the risk of ocular melanoma in whites is eightfold higher than in blacks. Blue eyes carry an increased risk as well as environmental retinal exposure to UV light (welders, etc).
Two populations of pigmented cells exist within the eye. The pigment epithelium of the iris, ciliary body, and retina is embryologically part of the central nervous system derived from the neural tube and can undergo non-neoplastic proliferation (reactive hyperplasia) in response to a variety of stimuli, but only rarely does it undergo malignant transformation. In contrast, uveal melanocytes originate from the neural crest and possess long dendrite-like processes emanating from the center of the cell body, similar to dermal melanocytes. They do not undergo reactive hyperplasia, but are the origin of malignant melanomas of the eye.
Most choroidal melanomas arise in the posterior choroid. The histogenesis is believed to be nevoid in nature. Up to 30% of the US population has choroidal nevi. The vast majority (>90%) are smaller than 2 millimeters in maximum dimension. There are five risk factors associated with malignant transformation in these small melanocytic proliferations: thickness >2mm, posterior margin touching the optic disc, visual symptoms, orange pigment, and subretinal fluid.
They may spread laterally between the sclera and retina or may produce bulbous masses projecting into the vitreous cavity and pushing the retina ahead of them. By the Callendar Classification system, uveal melanomas are often classified into two primary categories: the spindle cell variety (combining spindle A and spindle B types) and the non-spindle cell type (combining epithelioid, mixed, and necrotic types).
Slightly less than 50% of ciliary body and choroidal malignant melanomas are of the spindle cell variety, and a little more than 50% are of the non-spindle cell variety. A number of parameters have been correlated with survival. Features considered the most significant are cell type, largest dimension, scleral extension, and mitotic activity. Morphometry is also useful, with a high degree of pleomorphism of nucleoli indicating a poor prognosis. The molecular pathogenesis of uveal melanomas is incompletely understood but appears to differ from that of cutaneous and mucosal melanomas. Monosomy of chromosome 3 and amplification of chromosome 8q are common in patients with uveal melanoma and have been associated with the development of metastatic disease, but are rare in patients with cutaneous melanoma.
Somatic mutations that lead to activation of the mitogen activated protein (MAP) kinase pathway have been implicated in the development of neoplasms from melanocytes. In combined results from three series, somatic mutations in the GNAQ gene codon 209 (downstream from BRAF), were found in 95 in 190 patients (50%) with uveal melanoma. On the initial core biopsy of the hepatic metastases, the decedent was shown to have this somatic mutation. However, the presence of the mutation has not been shown to correlate with prognostic significance.
The pattern of metastatic disease in ocular melanoma differs from that of cutaneous melanoma in that hepatic metastases predominate. Approximately 95% of patients with metastatic uveal melanoma have liver metastases, and in almost all of these, the liver is the first site affected with metastases. The reason for the metastatic pattern is yet unknown, but the resulting massive disease burden, as in the case of this decedent, typically results in liver failure with subsequent fatality.
Robertson, Dennis. Changing Concepts in the Management of Choroidal Melanoma. Am J of Ophthalmol 2004;136(1):161-170.
Singh, Arun, et. al. The Collaborative Ocular Melanoma Study. Ophthalmol Clin N Am 2005;18:129-142.
Grossniklaus et. al. Protocol for the Examination of Patients with Uveal Melanoma: From AJCC/UICC 7th Ed. College of American Pathologists, 2009.
Kujalla, E. et. al. Tumor, Node, Metastasis Classification of Malignant Ciliary Body and Choroidal Melanoma. Ophthalmology 2005; 112(6):1135-1144.
Onken, Michael et. al. Oncogenic Mutations in GNAQ Occur Early in Uveal Melanoma . Investigative Ophthalmol & Vis Science 2008; 49 (12):5230-5234.
Yanoff, Myron et. al. Ocular Pathology, 5th Ed. Mosby 2002.