The Young Farmworker Who Saw a Spot and Constant Shimmering

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One morning, Bart Jones,* a 23-year-old farmworker, awoke with a dark spot in the peripheral vision of his left eye as well as a constant shimmering effect, which fluctuated on and off.

When these visual phenomena did not resolve after two days, he called our office for an appointment and was seen emergently.

We Get a Look

Mr. Jones described a blurry peripheral spot on the lower left visual field and a shimmering effect, like a light reflect­ing off water. He noted that his central vision was clear, although he had small central floaters without discrete flashes of light.

History. Mr. Jones had not expe­rienced any recent injury or known chemical exposure. There was no signif­icant family ocular history.

He had a history of accommodative esotropia and had undergone bilateral medial rectus recession as a toddler; he later developed consecutive exotropia and was treated with unilateral lateral rectus recession at age 13. In addition, a choroidal nevus, superonasal to the optic disc in his left eye, had been noted when he was last seen five years before this visit.

Exam. On examination, his visual acuity was 20/20 in the right eye and 20/25+2 in the left, with normal pupil reactions and no afferent pupillary defect. His IOP was normal at 16 mm Hg in both eyes. The slit-lamp exam was unremarkable, with a quiet anterior chamber and normal-appearing anterior segment.

Fundus examination revealed an elevated, partially pigmented choroidal lesion superonasal to the optic disc, although the optic disc itself appeared normal. There were no drusen over the lesion, but there was surrounding subretinal fluid that extended inferiorly along the nasal retina to the inferonasal retina. No vitreous cells were seen.

Our Initial Differential

Clinically, choroidal melanoma was highest on our differential list, but it is unusual in a 23-year-old, especially in the absence of a significant family his­tory of cancer. However, as mentioned above, a choroidal nevus had been documented in the same area at the pri­or exam five years earlier. The differen­tial diagnosis also included choroidal hemangioma or a metastasis.

Diagnosis and Next Steps

We sent Mr. Jones to a nearby retina specialist, who considered choroidal melanoma to be the most likely diag­nosis; consequently, our patient was referred to an ocular oncologist at a university center. There he was diag­nosed with a choroidal melanoma, measuring 16 × 12 × 5.3 mm. It was accompanied by surrounding subreti­nal fluid, which extended inferonasally (Fig. 1A). On A-scan ultrasonography, the lesion showed low internal reflec­tivity; and on B-scan ultrasonography, it demonstrated acoustic hollowness and intralesional vascularity with no extrascleral extension (Fig. 1B).

The patient had a systemic workup, including computed tomography (CT) of the chest, abdomen, and pelvis. No metastases were found.

Mr. Jones was treated with plaque radiotherapy, which resulted in a decrease in the size and thickness of the tumor. He also underwent gene ex­pression profiling, which showed Class 2 PRAME-negative uveal melanoma, containing BAP1 and GNAQ variant mutations. PRAME (PReferentially expressed Antigen in MElanoma) is a melanoma-associated antigen that is a biomarker for metastatic risk, with Class 2 PRAME carrying higher risk than Class 1 PRAME. Mr. Jones is now under the care of a medical oncologist and ocular oncologist.

TWO VIEWS OF A LESION. Fundus photo (1A) and B-scan ultrasound (1B) of the same superonasal choroidal melanoma.

Overview of the Disease

Choroidal melanoma is a rare cancer, with an incidence of 5 per million population.¹ It is more common among White individuals,¹ and it is the most common primary intraocular cancer. The vast majority of uveal melanomas arise from the choroid.²

Choroidal melanoma is frequently asymptomatic and thus is often discov­ered on routine eye exam. However, approximately 50% of patients present with flashes, floaters, or visual field defects such as loss of peripheral vision secondary to subretinal fluid or macu­lar edema.³ The mean age at diagnosis is 58 years.

Risk factors for development of choroidal melanoma include fair skin, light eye color, and BAP1 tumor pre­disposition syndrome.^3,4 There is mixed evidence on the risk posed by UV light exposure. Choroidal nevi is a risk factor with an estimated conversion rate to melanoma of 1/5,000 to 1/8,800 cases.⁵

Diagnosis

The diagnosis of uveal melanoma is usually based on clinical findings. Diagnostic techniques such as A-scan and B-scan ultrasonography, OCT, and fluorescein angiography may aid in diagnosis.

Differential diagnosis. The differen­tial diagnosis of choroidal melanoma includes suspicious choroidal nevus, choroidal hemorrhage secondary to macular degeneration, peripheral exudative hemorrhagic chorioretinop­athy, congenital hypertrophy of the retinal pigment epithelium (CHRPE), choroidal metastasis, and choroidal hemangioma.

Fundus appearance. On fundus examination, choroidal melanoma appears as a gray-to-brown elevated choroidal lesion. The clinical features that help distinguish choroidal melano­ma from nevus include tumor thickness greater than 2 mm, subretinal fluid, orange pigment, hollowness on ultraso­nography, absence of halo, and absence of drusen. In addition, choroidal mel­anoma is more likely than a nevus to have symptoms.

Ultrasound and FA. On ultrasound examination, choroidal melanomas demonstrate acoustic hollowness and intrinsic vascularization on B-scan and medium to low internal reflectivity on A-scan.

Choroidal melanomas show clumps of hyperautofluorescence on fundus autofluorescence imaging.⁶ And fluo­rescein angiography may show multiple pinpoint leaks at the level of the retinal pigment epithelium, late staining, extensive leakage with progressive fluo­rescence, and double circulation.⁴

OCT findings. Newer imaging tech­nologies such as spectral domain, swept source, and enhanced depth imaging (EDI) OCT offer greater detail than other methods. EDI-OCT can help visualize “deep optical shadowing, thin­ning or compaction of the choriocapil­laris, disruption of the adjacent retinal photoreceptor layer, presence of sub­retinal fluid with or without lipofuscin deposition, and presence of intraretinal fluid” in choroidal melanoma.⁷

In addition, OCT angiography (OCTA) can demonstrate an enlarge­ment of the deep foveal avascular zone in eyes with choroidal melanoma com­pared with healthy eyes and eyes with choroidal nevi, as well as a decrease in superficial and deep parafoveal capillary vascular densities.⁶ OCTA can also help to differentiate choroidal melanoma from choroidal nevi by revealing border irregularity, chorio­capillaris hyporeflectivity, presence of avascular areas, and vascular anom­alies in cases of melanoma but not in nevi.⁶

Prognosis

Prognosis varies depending on indi­vidual tumor features; in general, local treatment for primary uveal melano­ma can provide effective local tumor control. However, up to 50% of patients remain at risk for metastatic disease at 15 years, most likely as a result of early micrometastasis.⁴ Common sites of metastasis include the liver, lung, and skin.⁴ Regular systemic evaluations are recommended, including twice-yearly physical evaluation and annual liver MRI/CT/ultrasound and chest radiog­raphy/CT.^3,8 Liver function tests are an important part of surveillance.

Clinical features associated with poor prognosis include older age at presentation, male sex, large tumor bas­al diameter, extraocular tumor exten­sion, and advanced tumor staging.^1-3 Histopathological features associated with poor prognosis include epitheli­oid cell type, high mitotic rate, closed loops, tumor-infiltrating lymphocytes and macrophages, higher expression of insulin-like growth factor 1 receptor, and higher expression of human leuko­cyte antigen classes I and II.^1,2

The loss of one copy of chromosome 3, termed monosomy 3, is a unique risk factor that is an important predictor of mortality in patients with ocular mela­noma. It is associated with an increased metastatic risk and correlates with decreased overall melanoma survival.

Gene expression profiling measures the level of multiple genes in a tumor and helps to stratify risk and predict a clinical outcome. The process involves fine needle aspiration sampling from the lesion. Possible applications include disease diagnosis, classification, predic­tion of drug response, and prognosis.

Pathology

Choroidal melanomas may have three different cell types: type A spindle cells, type B spindle cells, and epithelioid cells.⁹ Spindle A tumor has the best prognosis, followed by spindle B, mixed spindle B with epithelioid, and epitheli­oid alone, which has the worst progno­sis.¹ Tumors can also be of mixed cell type.

Uveal melanoma can be staged ac­cording to the American Joint Committee on Cancer (AJCC) or the Collabora­tive Ocular Melanoma Study (COMS) systems. The AJCC system is based on the size and extent of the main tumor, spread to nearby lymph nodes, and me­tastasis.¹ The COMS system is based on the size of the melanoma. Large basal diameter of the tumor, involvement of the ciliary body, extension of the tumor beyond the sclera, epithelioid cell type, and vasculogenic mimicry patterns are pathological features that predict poor prognosis.^1-3

Genetics

Most choroidal melanomas do not have a genetic predisposition; only about 1% are thought to be inherited.²

Genetic variants specific to posterior uveal melanoma, including choroidal melanoma, include mutations of GNAQ and GNA11 genes. These mutations are found in up to 90% of uveal melano­mas, but not in cutaneous melano­mas.^2,10

Over 80% of metastatic uveal melanomas have an inactivation of the BAP1 gene.¹⁰ The BAP1 protein, when functional, helps to maintain genome stability, epigenetic modification, tran­scription regulation, and the response to DNA damage. BAP1 mutations may predispose to certain hereditary uveal melanomas.¹⁰

Finally, inactivation of MBD4 and mutations in the SF3B1 and EIF1AX genes are also associated with posterior uveal melanoma.^2,10

Treatment

Treatment of choroidal melanoma varies according to many factors. In asymptomatic patients with a suspi­cious choroidal nevus, observation with regular follow-up imaging is indicated. However, once it is confirmed that a small nevus is a small melanoma, treatment is indicated with the possible exception of cases where the patient has significant underlying health issues.

Radiation therapy. Radiation therapy is most often used, typically by means of plaque brachythera­py, in which a radioisotope such as iodine-125 is inserted to irradiate the tumor.⁸ Somewhat less frequently, charged-particle radiation therapy is employed, using beams of protons, carbon ions, and helium ions.⁸ Both of these therapies have similar rates of control, with approximately 3% risk of recurrence at eight years.⁸

Complications associated with both of these modalities include dry eye and cataracts, which can be managed conventionally, as well as radiation reti­nopathy and optic neuropathy. Between 5% and 10% of patients treated with radiotherapy require eventual enu­cleation, because of either recurrence of the tumor or complications of the treatment.⁸

Noninvasive modalities. Less commonly used noninvasive treat­ment modalities include transpupillary thermotherapy (TTT), photodynamic therapy, and laser photocoagulation.^8,11 TTT is most often used to augment plaque brachytherapy, rather than as a standalone treatment.⁶ It is most effec­tive when delivered to small tumors—generally <3.0 mm. Photodynamic therapy, which uses an intravenously administered photosensitive dye, is used rarely for nonpigmented melano­mas. Laser photocoagulation has fallen out of favor due to significant hemor­rhagic complications and general lack of effectiveness.¹

Surgery. Surgical treatments include enucleation, local tumor resection, and rarely exenteration. The best candidates for treatment with local resection have small, more anteriorly located tumors such as iris or ciliary body melanomas.⁸ Although local resection has more short-term risks than radiotherapy—including vitreous hemorrhage, retinal detachment, and cataracts—it carries fewer long-term risks. Enucleation may be indicated if the melanoma has advanced to occupy most intraocular structures or if the tumor has produced a secondary glaucoma.⁸ Similarly, orbit­al exenteration is very rarely indicated, only in cases of massive extraorbital extension.⁸

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* Patient name is fictitious.

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1 Kaliki S et al. Indian J Ophthalmol. 2015;63(2):93-102.

2 Griewank KG, Murali R. Pathology. 2013;45(1):18-27.

3 Chattopadhyah C et al. Cancer. 2016;122(15):2299-2312.

4 Gallenga C et al. Front Oncol. 2022;12:828112.

5 Singh AD et al. Ophthalmology 2005:112(10):1784-1789.

6 Verbeek S, Dalvin L. Can J Ophthalmol. Pub­lished online July 18, 2023.

7 Davila JR, Mruthyunjaya P. F1000Res. 2019;8: F1000 Faculty Rev-1706. doi:10.12688/f1000re­search.19979.

8 Bai H et al. Clin Exp Ophthalmol. 2023;51(5):484-494.

9 Coroi M et al. Rom J Morphol Embryol. 2006;47(3):269-272.

10 Pašalić D et al. Int J Mol Sci. 2023;24(16):12807.

11 Shields CL et al. Ophthalmology. 2002;109(2):225-234.

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Dr. Armounfelder is a resident at Memorial Hospital Family Practice Residency, South Bend, Ind. Dr. Gerber is in practice at Advanced Oph­thalmology of Michiana in South Bend, Ind., and is Clinical Professor of Ophthalmology at Indiana University School of Medicine. Dr. Demirci is Director of the Ocular Oncology Service and the Richard N. and Marilyn K. Witham Professor of Ophthalmology and Visual Science at the University of Michigan School of Medicine, in Ann Arbor. Relevant financial disclosures: Dr. Demirci: Castle Biosciences: C. Drs. Armounfelder and Gerber: None.

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