CASE 1

A 33-year-old Hispanic man was referred to the ocular oncology service with concern for UM after presenting with a one-year history of worsening vision. Ophthalmic examination of the right eye was notable for 20/400 visual acuity, 2 to 3+ pigmented cells in the anterior vitreous, and a large, heavily pigmented choroidal tumor involving the inferonasal macula with disc obscuration and an overlying exudative retinal detachment. B-scan ultrasonography revealed a dome shaped choroidal mass with a base thickness of 11.6 mm and mixed echogenic reflectivity ( Figure 1 ). Whole-body PET scan did not show any evidence of metastatic disease. The patient was offered treatment with proton beam irradiation (PBI) or an enucleation; he opted for enucleation. Histopathologic examination of the enucleated eye revealed a high-grade, epithelioid cell melanoma centered in the peripapillary choroid and extending over the optic nerve head, with emissary canal extension of the tumor along the ciliary nerves and vessels ( Figure 1 ). The melanoma cells were variably pigmented with an epithelioid to rhabdoid cytomorphology and cherry red nucleoli. A second population of magnocellular tumor cells distinct from the melanoma was identified, with abundant obscuring heavily pigmented cytoplasm ; both tumor cell populations were highlighted with SOX-10 and Melan-A immunostains, confirming melanoma arising in the background of an optic nerve head ocular melanocytoma. No staining of the heavily pigmented cells for PU-1 (which highlights histiocytes) was seen (heavily pigmented histiocytes may closely mimic the appearance of melanocytoma cells; see Discussion). The melanoma cells also had moderate staining for PRAME, which the melanocytoma cells did not show. Castle Biosciences™ assay was performed on a sample taken at the time of enucleation for gene expression profiling and next-generation sequencing. This resulted as a class 2, PRAME + tumor with altertaions in GNA11 and BAP1 . Six months after enucleation, MRI of the liver showed multiple newsubcentimeterhepatic lesions favored to be melanoma metastases.

Clinical and histopathologic features of case 1. A. Wide-field fundus photography shows a large choroidal tumor obscuring the optic disc and involving the macula with an overlying exudative retinal detachment. B. B-scan ultrasonography shows a large, broad-based, irregular, dome shaped lesion inferior and anterior to the optic nerve head with mixed echogenic reflectivity, prominent intrinsic vascularity and choroidal excavation. C. Low power photomicrograph shows a heavily, but variably, pigmented mass straddling the optic nerve head (ON) (H&E, x20). D. Adjacent populations of amelanotic melanoma (M) and melanocytoma (MC) cells were seen(H&E, x100). E. On the left portion of the image, the melanoma cells (M) are epithelioid to rhabdoid with abundant eosinophilic cytoplasm and cherry red nucleoli; the melanocytoma cells (MC) have abundant heavily pigmented cytoplasm (H&E, x400). F. SOX-10 nuclear immunostain highlights (in red) both the melanoma (M) and melanocytoma (MC) cells, confirming the melanocytic, rather than histiocytic, lineage of the latter (SOX-10 immunostain, x400). G. Melanin bleach stain allows for cytomorphologic examination of the melanocytoma (MC) showing characteristically plump cells with uniformly round nuclei, tiny nucleoli and very low nuclear to cytoplasmic ratios, in contrast to the melanoma cells (M) with higher nuclear to cytoplasmic ratios (melanin bleach, x400). H. PU-1 nuclear immunostain does not stain either the melanoma (M) or the melanocytoma (MC) cells (PU-1 immunostain, x600).

CASE 2

A 44-year-old Caucasian woman presented to the Massachusetts Eye and Ear emergency department from an outside optometrist; she endorsed a three-week history of progressive vision loss and occipital headaches. Notable examination findings included visual acuity of 20/200 in the right eye with a relative afferent pupillary defect, one out of eight Ishihara color plates correctly identified, inferior conjunctival sentinel vessels, 2+ pigmented anterior vitreous cells, and a uveal mass in the inferior fundus with an overlying exudative retinal detachment. The patient was referred to the ocular oncology service where fundus examination confirmed a large, inferior, ciliochoroidal tumor with associated exudative retinal detachment ( Figure 2 ). B-scan ultrasonography showed a base thickness of 11.4 mm with low internal reflectivity of the mass and potential extension into the inferior orbit (i.e., concern for extra-scleral extension). MRI brain did not show definite extra-scleral extension. Management options included PBI or enucleation; the patient opted for the latter. Baseline CT chest and abdomen did not reveal metastatic disease.

Clinical and histopathologic features of case 2. A. Wide-field fundus photography shows a large ciliochoroidal tumor inferotemporal to the macula with associated exudative retinal detachment. B. B-scan ultrasonography shows a broad-based, irregular, dome shaped lesion inferiorly with moderate reflectivity, intrinsic vascularity, and choroidal excavation. C. The mass shows a multinodular architecture and variable pigmentation (H&E, x20). D. The spindled and epithelioid atypical melanoma (M) cells are intimately admixed with the melanocytoma cells (MC) in this case (H&E, x200). E. On the right, Melanin bleach stain allows for cytomorphologic examination of the melanocytoma (MC) with abundant cytoplasm, in contrast to the pleomorphic melanoma cells (M) (melanin bleach, x600). On the left, melanoma (M) admixed with many pigment-laden macrophages (MP) closely mimics the admixed melanocytoma, although with more variation in cell shape (H&E, x200). F. Melanocytoma (MC) and pigmented macrophages (MP) are easily distinguished from one another using a SOX-10 immunostain, the former with red nuclear staining (red arrow), and the latter without (black arrow) (SOX-10 immunostain, red chromogen, x400). G. PU-1 nuclear immunostain highlights melanophages confirming their histiocytic lineage but does not highlight the melanoma (M) or the melanocytoma (MC) cells (PU-1 immunostain, brown chromogen, x600). H. Ki-67 immunostain does not stain any of the melanocytoma cells (left) but shows multifocal proliferative activity in the melanoma on the right (Ki-67 immunostain, red chromogen, x400).

An enucleation was performed. Histopathology ( Figure 2 ) was notable for a mixed cell type spindled and epithelioid ciliochoroidal melanoma with inner scleral invasion and focal tumor necrosis. Admixed within the malignant tumor cells were pigmented macrophages and a similar but distinct population of plump, polyhedral epithelioid cells with abundant, heavily pigmented cytoplasm and a low nuclear to cytoplasmic ratio. The latter population showed nuclear immunopositivity for SOX-10, consistent with a precursor melanocytoma; the pigmented histocytes did not stain for SOX-10. The patient was diagnosed with a ciliochoroidal melanoma arising from an unknown precursor OM. Castle Biosciences assay showed a class 2, PRAME + tumor with detected abnormalities in GNA11 and BAP1.

CASE 3

A 62-year-old Caucasian woman presented to an ophthalmologist with a one-week history of right eye cloudiness. Visual acuity, intraocular pressures, pupillary exam, and anterior segment examination were all normal. Fundus examination revealed a superotemporal, pigmented mass with overlying hemorrhage and tortuous vessels, and surrounding guttering from subretinal fluid. The patient was referred to an outside ocular oncology service where B-scan ultrasonography revealed a suspected choroidal melanoma with low-to-medium internal reflectivity and a base thickness of 4.4 mm. A transscleral biopsy was performed and sent to Castle biosciences for gene expression profiling which resulted in a class 1A, PRAME + tumor with no genetic abnormalities detected on the interrogation of seven genes included in the assay (GNAQ, GNA11, CYSLTR2, BAP1, EIF1AX, PLCB4, and SF3B1). Initial staging work-up revealed no evidence of metastases.

The patient subsequently underwent two gamma knife (GK) radiosurgeries approximately five months apart due to evidence of recurrence at the inferior border of the tumor. Two months after the second GK procedure, the patient was found to have a new pigmented mass near the superior pars plana, in addition to progression along the inferior border of the previously treated lesion. Interval surveillance imaging revealed a colonic mass. The patient underwent a hemicolectomy and was found to have a well differentiated carcinoid tumor of the ileum. The patient was referred to the ocular oncology service at Massachusetts Eye and Ear for further management.

On examination, vision was reduced to 20/50 in the right eye. The fundus showed a diffuse, flat, pigmented lesion superotemporally involving the macula. The mid-peripheral aspect was elevated with overlying orange pigmentation. In the superotemporal periphery, contiguous with the previously treated tumor, there was a pigmented, choroidal mass ( Figure 3 ). B-scan ultrasonography demonstrated a dome-shaped, superior ciliochoroidal lesion 3.7 mm in thickness. Re-evaluation after 6 weeks demonstrated growth of the new ciliochoroidal tumor with increase in thickness to 8 mm. Given the rapid growth and history of recurrence after GK, enucleation was recommended. Repeat gene expression profiling and sequencing from an aspirate taken from the new ciliochoroidal tumor revealed class 1A, PRAME + with a GNA11 mutation (c.626A> T ).

Clinical and histopathologic features of case 3. A. Wide-field fundus photography shows a diffuse superotemporal pigmented choroidal lesion with adjacent dome-shaped tumor involving the ciliary body. B. B-scan ultrasonography revealed an elevated ciliochoroidal mass with low to medium internal reflectivity. C. The broad tumor shows a darkly pigmented component on the left, and a more amelanotic, expansile component on the right (H&E x20). D. The expansile melanoma (M) shows high-grade cytologic atypia; the inset displays a multinucleated tumor giant cell (H&E, x200; inset x400). E. Ki-67 immunostain shows a very high proliferative index with visible mitoses in the frankly malignant appearing portion of the mass; the inset displays no proliferative activity in the melanocytoma cells (Ki-67 immunostain, red chromogen, x200). F. The heavily pigmented melanocytoma cells with an area of adjacent necrosis superiorly mimics tumoral melanosis on low power photomicroscopy (H&E, x100). G. SOX-10 immunostain diffusely stains the high-grade melanoma cells (M) on the right and the melanocytoma cells (MC, yellow arrow) on the left; the very similar-appearing admixed pigmented macrophages (MP, red arrow) do not stain (SOX-10 immunostain, red chromogen, x400). H. Melanin bleach stain allows for cytomorphologic examination of the melanocytoma showing characteristically plump cells with uniformly round nuclei, tiny nucleoli and very low nuclear to cytoplasmic ratios (melanin bleach, x400).

Histopathology ( Figure 3 ) was notable for a largeciliochoroidal melanoma extending from the ciliary body into the posterior choroid, with focal involvement of the iris and angle. The ciliary component of the tumor was expansile and composed of strikingly pleomorphic, epithelioid to plasmacytoid melanocytes, including multinucleated tumor giant cells, with cherry red nucleoli. This more anterior component had a very high Ki-67 proliferative index. The more posterior component of the tumor was comprised of spindled cells, tumoral melanosis (i.e., abundant melanophages), and a distinct population of large, polyhedral cells with low nuclear to cytoplasmic ratio, round nuclei, and heavily pigmented cytoplasm suspicious for a precursor melanocytoma. Immunostaining with SOX-10 highlighted the melanoma cells, as well as this latter population of cells near the optic nerve head and macula; melanophages did not stain.

REVIEW OF THE LITERATURE

Review of the literature identified 15 previously reported cases of UM arising from OM in PubMed between 1973 and 2024 which had histopathological confirmation. These cases, and the current 3 novel cases, are summarized in Table .

TABLE

Summary of all histopathologically confirmed cases of uveal melanoma arising from ocular melanocytoma.

Author	Year Published	Reason for Presentation at Initial Visit or Re-Visit at Time of Melanoma Diagnosis	Examination	Demographics	Histopathology	Presence of Pigmentation clinically	Previously Known History of Melanocytoma	Location of Melanocytoma	Location of Melanoma	Immunostains	Molecular genetics
Barker-Griffith et al	1976	Distorted and reduced vision OD	Enlargement of a known macular melanocytoma; 3-4-disc diameter in size, pigmented lesion in and above the macula with a crescent-shaped yellow-orange area in the upper portion of the lesion. Fluorescein angiography showed early and progressive mottled transmission of choroidal fluorescence persisting for an hour.	55-year-old Caucasian male	Mixed tumor cells (spindle A and spindle B cells), and large, densely pigmented polyhedral cells	Yes, deeply pigmented tumor with a pigmented orange crescent over the tumor	Yes	Macula	Macula with choroidal involvement	None reported	None reported
Apple et al	1984	Painless, progressive vision loss OD	Ophthalmic exam showed a large retinal detachment in the superior quadrant with a pigmented mass encompassing most of the superior half of the right eye and extending anteriorly past the nerve.	30-year-old female; no race reported	Mixed tumor cells (spindle and epithelioid cells) with noncohesive, medium sized polygonal cells with large hyperchromatic nuclei, prominent nucleoli, numerous mitotic figures and high nuclear to cytoplasmic ratio. Contiguous to this section were sheets of large, plump, polygonal and polyhedral cells with distinct borders with small-to-medium sized, normochromic nuclei surrounded by abundant, densely pigmented cytoplasm.	Yes, densely pigmented	Yes	Optic nerve head	Superior retina, extending anteriorly past the optic nerve head	None reported	None reported
Heitman et al	1988	Referral for significant enlargement of a pigmented, elevated subretinal mass OS over 6-months;u nknown clinical presentation	Ophthalmic examination of the eye showed tumor extending into the visual axis. B-scan U/S revealed large, highly elevated inferonasal mass OS.	69-year-old mixed race (African American and Caucasian) male	Mixed tumor cells (predominantly epithelioid with admixed spindle cells), and a separate population of uniformly large, polygonal shaped cells with densely pigmented cytoplasm, with a low nuclear to cytoplasmic ratio.	Yes, deeply pigmented	No; history of unknown inferonasal lesion OS	N/A	Inferonasal; involving the ciliary body and choroid with extension to 7 mm from the optic nerve	None reported	None reported
Cialdini et al	1989	Pain, photophobia, and reduced VA OS, with a growing melanocytoma	Slit lamp showed an iris tumor at 1:30 meridian. Ultrasound Biomicroscopy (UBM) showed a solid iris mass. Fluorescein angiography showed a hyperfluorescent lesion.	34-year-old Caucasian female	Spindle B cells and a population of large, pigmented polyhedral cells	Yes, heavily pigmented	Yes	Peripheral iris	Peripheral iris lesion extending into the cornea and trabecular meshwork	None reported	None reported
Shields et al	1990	Painless, progressive vision loss OD, with a growing melanocytoma	Slit lamp examination showed scattered golden-brown pigment in the anterior vitreous cavity. Indirect ophthalmoscopy showed a dome-shaped 5 × 5 × 4 mm brown, choroidal mass obscuring the optic nerve. B-scan U/S revealed acoustic solidity without choroidal excavation; A-scan U/S showed mass with high internal reflectivity. CT and MRI showed a rounded mass overlying the optic nerve head. Fluorescein angiography showed hypofluorescence of the mass in early and late phases.	53-year-old Caucasian male	Mixed tumor cells (predominantly spindle-B with few admixed epithelioid cells), and a population of large, round, deeply pigmented cells with small, round, bland nuclei	Yes, pigmented throughout with increased density near the apex of the tumor	Yes	Optic disc with involvement of the choroid	Anterior to optic disc and retina in the posterior segment of the globe	None reported	None reported
Leidenix et al	1994	Progressive vision loss OD (light perception) with rapidly developing cataract and elevated intraocular pressure (IOP)	B-scan U/S revealed 5.8 × 5.5 mm pale, mushroom-shaped, trilobed mass protruding out of the posterior pole with two separate mass densities. A-scan U/S revealed echodense areas suggestive of a malignant melanoma and echolucent areas suggestive of a melanocytoma.	26-year-old Caucasian male	Epithelioid tumor cells and large, pigmented, polyhedral cells	Yes, deeply pigmented with a nonpigmented protrusion from the center of the pigmented area	No	N/A	Choroid	HMB-45 positive, S-100 positive	None reported
Meyer et al	1999	Progressive vision loss OD over 2 years	Fundus examination showed a noticeable increase in tumor size and change of color from black to gray mixed with light orange. B-scan U/S revealed a tumor height of 8.7 mm. Fluorescein angiography showed abundant tumor vessels and leakage.	69-year-old Caucasian female	Spindle-B melanoma cells, and an adjacent interwoven component of large, polyhedral and round cells with abundant cytoplasm and small, bland nuclei.	Yes	Yes	Optic disc	Optic disc	None reported	None reported
Sagoo et al	2007	Reduced vision OD for 2 days, elevated IOP, and a left hemicranial headache for 18 months	Two new pigmented regions in the inferotemporal iris in addition to the iris melanocytoma diagnosed 5 years earlier. UBM revealed two, separate, elevated areas on iris and ciliary body Gonioscopy showed a pigmented mass in the peripheral iris involving the angle	33-year-old Caucasian female	Mixed tumor cells (epithelioid and spindle cell) with a separate population of large, heavily pigmented cells	Yes	Yes	Iris	Peripheral iris lesion with invasion into the trabecular meshwork and angle	None reported	None reported
Inoue et al	2008	Reduced VA OD, ocular pain OD and elevated IOP	MRI showed dramatic spreading and growth of originally suspected melanocytoma. towards the anterior chamber. 123I-IMP SPECT showed high accumulation of 123I-IMP in affected eye. FNAB showed malignant transformation and two different components in the tumor suggesting malignant transformation of previous melanocytoma.	54-year-old Asian male	Spindle cells with large, polygonal pigmented cells with round nuclei	Yes, areas of deep pigment	Yes	Superonasal iris	Superonasal iris	None reported	None reported
Li et al	2010	Painless vision loss OS over a 5-year period	Ophthalmic examination showed corectopia due to iris involvement, and a superonasal pigmented ciliary body mass. B-scan U/S showed a mushroom-shaped echolucent mass.	15-year-old African American female	Mixed tumor cells (predominantly spindle B cells with few epithelioid cells), and a separate component of intensely pigmented cells displaying indistinct, bland nuclei	Yes, areas of intense pigmentation and less pigmentation	No	N/A	Superonasal equatorial mass with invasion into the superonasal angle and iris	None reported	None reported
Shukla et al	2012	Gradual vision loss over 33 years (from 20/20 to HM)	Fundus imaging showed progressive growth of pigmented optic nerve lesion with disc obscuration and surrounding retinal edema. Fluorescein angiography showed early hypofluorescence and late mid hyperfluorescence of the mass with late leakage OCT showed retinal invasion by previously suspected melanocytoma.	56-year-old female, no race reported	Spindle B cells, and a large population of polygonal cells with abundant pigmented cytoplasm	Yes, intensely pigmented	Yes	Optic nerve	Optic disc with invasion into choroid	None reported	None reported
Francis et al *	2016	Unknown	Unknown	Unknown	Histopathologically confirmed by ophthalmic pathologist, however, no description available.	Unknown	Unknown	N/A	Optic nerve	None reported	BAP1
Francis et al *	2016	Decreased vision OD (Light perception)	Growth of previously known optic nerve melanocytoma to 5.5 mm in height on B-scan U/S. Color fundus photography showed a dense vitreous hemorrhage with disc obscuration.	Unknown	Histopathologically confirmed by ophthalmic pathologist, however, no description available.	Yes, intensely pigmented	Yes	Optic nerve	Optic nerve	None reported	GNAQ BAP1
Salinas-La Rosa et al	2017	Acute, severe, ocular pain OS with injection, mild proptosis, lid retraction, angle closure with elevated IOP, and a sluggish pupil	Growth of previously diagnosed optic nerve melanocytoma (25 years prior). CT showed large intraocular mass intruding into vitreous and no extension beyond globe. Gross findings showed 21 × 21 × 22 mm friable, granular pigmented, nodular mass with anterior displacement of the lens.	60-year-old Caucasian female	Mixed tumor cells (spindle B and epithelioid cells) with large, heavily pigmented, polyhedral cells	Yes, heavily pigmented	Yes	Optic nerve	Optic Nerve	Melan A and HMB45 positive. S100 positive.	None reported
Lee et al	2023	Slightly reduced vision OS, with pain, injection of the conjunctiva, and elevated IOP	Conjunctival, corneal, and iris pigmentation in the same distribution as the previously excised iridociliary melanocytoma. B-scan U/S showed increase in ciliary thickness from 1.9 mm to 5.1 mm over 6.5 years	40-year-old African American female	Spindle B with few intermixed large, pigmented polygonal cells	Yes, areas of pigment and no pigment	Yes, excised 5 years prior to presentation with ciliary body melanoma.	Superonasal iris and ciliary body	Superonasal	Ciliary body melanoma was PRAME + Previously excised iridociliary melanocytoma was PRAME –	None reported
Case 1	Diagnosed 04/2023	Decreasing VA OD and increased floaters	Fundus exam showed large choroidal tumor extending from 4 to 7:30 o’clock with an overlying exudative RD. B-scan U/S showed 11.6 mm broad based, irregular, dome shaped inferior lesion with mixed echogenic reflectivity.	32-year-old Hispanic Male	Mixed tumor cells (high grade, epithelioid to rhabdoid cells) with emissary canal extension, variable pigmentation, and cherry red nucleoli. A separate population of magnocellular, heavily pigmented tumor cells were near the optic nerve head.	Yes, heavily pigmented	No	N/A	Central choroidal mass obscuring optic disc and macula	SOX-10 and Melan-A immunostains confirmed presence of melanoma cells, and large magnocellular cells with heavy pigment, small nuclei and abundant cytoplasm.	GNA11 BAP1 PRAME +
Case 2	Diagnosed 06/2023	Decreasing VA OD with new onset occipital headaches	RAPD and superior VF defect OD. Inferior ciliochoroidal mass from 4:30 to 9 o’clock with large overlying RD and small vitreous hemorrhage noted on fundus exam. B-scan U/S showed 11.4 mm irregular dome shaped lesion with area of low reflectivity inferiorly concerning for extrascleral extension. Moderate reflectivity, intrinsic vascularity and choroidal excavation. MRI brain showed no definite extrascleral extension.	44-year-old Hispanic Female	Mixed tumor cells (spindle and epithelioid) with inner scleral invasion and focal tumor necrosis. A separate population of heavily, but variably pigmented large, magnocellular cells, with low nuclear to cytoplasmic ratio, and round nuclei were seen.	Yes, moderately pigmented	No	Unknown location	Inferior ciliochoroidal tumor at 4:30 to 9 o’clock	SOX-10 positive staining in large, polyhedral, heavily pigmented cells with low Nuclear: Cytoplasmic ratio, and melanoma cells, but negative in the melanophages.	GNA11 BAP1 PRAME +
Case 3	Diagnosed 11/2023	Decreased VA OD	Fundus examination showed a superotemporal elevated, pigmented mass with overlying vessel tortuosity, surrounding vitreous hemorrhage, and subretinal fluid with guttering. Original B-scan U/S showed 4.40 mm diffuse broad based dome-shaped lesion with low-medium internal reflectivity. Subsequent B-scans showed stable thickness and a new 4.29 mm superior lesion at edge. OCT showed elevated choroidal mass with overlying SRF/IRF.	62-year-old Caucasian Female	Mixed tumor cells (high grade, pleomorphic, epithelioid to plasmacytoid cells, multinucleated tumor giant cells and cherry red nucleoli) A separate population of polyhedral cells with low nuclear to cytoplasmic ratio, round nuclei, and heavily pigmented cytoplasm were seen.	Yes, pigmented	No	N/A	Superotemporal choroidal mass with temporal macular involvement	PRAME positive SOX-10 positive staining in large, polyhedral, heavily pigmented cells with low Nuclear: Cytoplasmic ratio, and melanoma cells, but negative in the melanophages.	PRAME +; No genetic mutations found on Castle biosciences™ assay

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