Supplementary Material for: Uveal Melanocytoma Without GNAQ/GNA11 Mutations

Introduction: Uveal melanocytomas are benign melanocytic proliferations characterized histologically by large polyhedral cells, abundant intracytoplasmic melanin, small centrally located nuclei, and low nuclear-to-cytoplasmic ratios (N:C). Activating missense changes of the G-protein subunits, GNAQ/GNA11, drive uveal melanocytic proliferation and are characteristic molecular mutations found in intraocular nevi including melanocytomas, as well as malignant uveal melanomas. Sequencing of uveal melanocytic proliferations from biopsies or enucleations identifies these mutations and complements traditional histochemical approaches to classify and diagnose the uveal melanocytic neoplasm as well as offering valuable clinical prognoses about patient outcomes.

Case Presentation: A 56-year-old female presented with gradual, painless vision loss in the left eye. On exam, a large (11.1 x 12.8 x 10.6 mm by ocular ultrasound), hyperpigmented ciliochoroidal mass was found in the superior nasal quadrant abutting the lens. The patient elected for enucleation given the tumor’s large size and vision loss in the affected eye. An FNA biopsy of the fresh mass, collected immediately after enucleation, revealed no mutations in the 7-gene DecisionDX-UMSeq panel. Histologic and immunohistochemical evaluation of pupil-optic nerve cross-sections from the formalin fixed paraffin embedded (FFPE) enucleation revealed a ciliary body melanocytoma. DNA extracted from the melanocytoma enucleation cross-sections was sequenced for 197 clinically actionable tumor genes through the Stanford’s Actionable Mutation Panel for Solid Tumors (STAMP). The sequencing results confirmed no mutations in GNAQ, GNA11, and the other uveal melanoma genes tested via the DecisionDX-UMSeq panel but identified missense variants of unknown significance in three genes previously not reported in uveal melanocytic neoplasms.

Conclusion: To our knowledge, this is the first reported uveal melanocytoma lacking GNAQ/GNA11 oncogenic variants or other known uveal melanocytic neoplasm driver mutations. This case supports that there are additional to-be-identified molecular pathways and genes that drive uveal melanocyte proliferations.