Case of the Month | November 2021

Case of the Month
November 24, 2021

The Case

The patient was a 65-year-old woman referred for a macular lesion. She complained of decreased vision in the right eye for at least six months, which she had thought was due to needing new glasses. Her visual acuity without correction OD was finger counting and OS was 20/200, pinhole 20/100, J2. She was found to have a brownish lesion with a small amount of associated subretinal fluid in the posterior pole of the right eye. What was the most likely diagnosis? What treatment, if any, would you recommend?

The patient has a large, elevated (and thus out of focus) melanocytic lesion with an internal vasculature consistent with uveal melanoma. The ultrasound showed a large mushroom-shaped lesion with low internal reflectivity, consistent with a uveal melanoma. Due to the lesion’s size and location, the patient had the eye enucleated. Pathology revealed an 11.3 diameter, 6 mm height melanoma with mixed epithelioid and spindle cells.

Comment

Uveal melanoma is the most common primary ocular malignancy, with about 2000 new cases per year in the United States. There is a heavy predominance in the Caucasian population, and most cases are diagnosed in the sixth or seventh decade of life. Despite recent advances in the management of many tumors, the prognosis of uveal melanoma patients has not changed significant. By five years after diagnosis, survival has remained at about 80%, and 50-60% develop metastatic disease for which there are currently no effective treatments and the prognosis is poor. Live, lung, and bone are the most frequent metastatic sites.

There have been remarkable advances in the understanding of uveal melanoma pathogenesis and prognosis through genomic analyses. The BRAF mutation, which is common in cutaneous melanomas, is not a major factor in uveal melanomas. Instead, there are several other mutations and genomic alterations involved in the pathogenesis and course of uveal melanomas. When it comes to prognosis, one of the most important mutations involves BRCA-associated protein 1 (BAP1) inactivation. BAP1 is tumor-suppressor gene located on chromosome 3. Malignant transformation can result from either monosomy 3 or somatic knock-out of the second BAP1 allele.

Recently, gene expression profiling, which quantifies mRNA expression of certain genes, has led to classification of uveal melanoma into classes 1A, 1b, and 2. Class 2 has a substantially worse prognosis and, among other features, often includes BAP1 inactivation. Class 2 tumors have a 72% risk of metastases at 5 years. Class 1B tumors have a 21% risk of metastases at 5 years, but many have the SF3B1 mutation that puts patients at high risk of late metastases. Class 1A tumors have only a 2% risk of metastases at 5 years. Interestingly, recent research has indicated that metastatic lesions can undergo further transformations such that the primary and metastatic lesions can have different genomic compositions.

Chemotherapies have had little, if any, effect on survival of patients with metastatic uveal melanoma. While immunotherapy has shown remarkable benefit for many patients with metastatic cutaneous melanoma, there are currently no effective immunotherapies for metastatic uveal melanoma. There is an ongoing phase III clinical trial of the immunotherapy drug tebentafusp, which has shown some promise in vitro and in early clinical trials. Another therapeutic option currently in a phase Ib clinical trial involves use of photosensitive nanoparticles that preferentially bind to tumor cells. Light-activated nanoparticles kill tumor cells while largely sparing adjacent normal tissues.

Schefler AC, Kim RS. Recent advancements in the management of retinoblastoma and uveal melanoma. Faculty Reviews 2021; 10:51.

Toro MD, Gozzo L, Tracia L, et al. New therapeutic perspectives in the treatment of uveal melanoma: A systemic review. Biomedicines 2021; 9:1311.

Case Photos

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The patient has a large, elevated (and thus out of focus) melanocytic lesion with an internal vasculature consistent with uveal melanoma. The ultrasound showed a large mushroom-shaped lesion with low internal reflectivity, consistent with a uveal melanoma. Due to the lesion’s size and location, the patient had the eye enucleated. Pathology revealed an 11.3 diameter, 6 mm height melanoma with mixed epithelioid and spindle cells.

Comment

Uveal melanoma is the most common primary ocular malignancy, with about 2000 new cases per year in the United States. There is a heavy predominance in the Caucasian population, and most cases are diagnosed in the sixth or seventh decade of life. Despite recent advances in the management of many tumors, the prognosis of uveal melanoma patients has not changed significant. By five years after diagnosis, survival has remained at about 80%, and 50-60% develop metastatic disease for which there are currently no effective treatments and the prognosis is poor. Live, lung, and bone are the most frequent metastatic sites.

There have been remarkable advances in the understanding of uveal melanoma pathogenesis and prognosis through genomic analyses. The BRAF mutation, which is common in cutaneous melanomas, is not a major factor in uveal melanomas. Instead, there are several other mutations and genomic alterations involved in the pathogenesis and course of uveal melanomas. When it comes to prognosis, one of the most important mutations involves BRCA-associated protein 1 (BAP1) inactivation. BAP1 is tumor-suppressor gene located on chromosome 3. Malignant transformation can result from either monosomy 3 or somatic knock-out of the second BAP1 allele.

Recently, gene expression profiling, which quantifies mRNA expression of certain genes, has led to classification of uveal melanoma into classes 1A, 1b, and 2. Class 2 has a substantially worse prognosis and, among other features, often includes BAP1 inactivation. Class 2 tumors have a 72% risk of metastases at 5 years. Class 1B tumors have a 21% risk of metastases at 5 years, but many have the SF3B1 mutation that puts patients at high risk of late metastases. Class 1A tumors have only a 2% risk of metastases at 5 years. Interestingly, recent research has indicated that metastatic lesions can undergo further transformations such that the primary and metastatic lesions can have different genomic compositions.

Chemotherapies have had little, if any, effect on survival of patients with metastatic uveal melanoma. While immunotherapy has shown remarkable benefit for many patients with metastatic cutaneous melanoma, there are currently no effective immunotherapies for metastatic uveal melanoma. There is an ongoing phase III clinical trial of the immunotherapy drug tebentafusp, which has shown some promise in vitro and in early clinical trials. Another therapeutic option currently in a phase Ib clinical trial involves use of photosensitive nanoparticles that preferentially bind to tumor cells. Light-activated nanoparticles kill tumor cells while largely sparing adjacent normal tissues.

Schefler AC, Kim RS. Recent advancements in the management of retinoblastoma and uveal melanoma. Faculty Reviews 2021; 10:51.

Toro MD, Gozzo L, Tracia L, et al. New therapeutic perspectives in the treatment of uveal melanoma: A systemic review. Biomedicines 2021; 9:1311.

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