Woman referred for choroidal mass in right eye

Dec 12, 2023

A 58-year-old white woman was referred to the retina service at the New England Eye Center for a new right eye choroidal mass.

She endorsed right eye progressive vision decline with nasal field defect and flashes for 6 months, as well as redness and pain for 2 days.

Ocular history was significant for a stable choroidal nevus of the left eye, lost to follow-up for 4 years. Medical history included meningioma complicated by refractory seizures leading to spine fractures status post (s/p) surgery with no residual visual field deficits, breast cancer s/p lumpectomy, multiple skin lesions of the eyelids and face including squamous cell carcinomas and basal cell carcinomas s/p Mohs of the right upper and lower lids with reconstruction, colonic adenomas, migraines, and sick sinus syndrome s/p pacemaker placement. She had a family history of cutaneous melanoma, and two brothers passed away from malignant mesothelioma.

Visual acuity with glasses was 20/100 and improved to 20/70 with pinhole in the right eye and 20/30 with no improvement with pinhole in the left eye. Pupils were normal without any afferent pupillary defect. IOP was 10 mm Hg and 11 mm Hg in the right and left eyes by applanation, respectively. Extraocular movements were full. Evaluation of the lids revealed papillomatous lesions of the right upper and lower lids. Anterior segment exam was remarkable only for 1+ diffuse conjunctival injection of the right eye without anterior chamber reaction. Fundus exam showed an inferotemporal elevated amelanotic mass measuring 9 mm × 9 mm × 5 mm with areas of pigmentation, hemorrhage at the base and subretinal fluid with no obvious drusen or orange pigment (Figures 1a and 1b). The left eye had a stable superotemporal nevus measuring roughly 1.5 mm × 3 mm in size (Figure 1c).

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The features of this new choroidal mass, including its size, presence of subretinal fluid and hemorrhage, absence of surrounding clear halo, areas of pigmentation, absence of drusen, and presence of symptoms such as decreased vision and flashes, were most consistent with choroidal melanoma. The pain and injection raised concern for the possibility of extrascleral extension, necrotic choroidal melanoma or scleritis. Given the significant personal and family history of malignancy, it is also important to consider a metastatic lesion. Other less likely diagnoses included melanocytoma, benign choroidal nevus, congenital hypertrophy of the retinal pigment epithelium, hamartoma, osteoma, hemangioma or massive retinal gliosis.

B-scan ultrasound of the right eye revealed a dome-shaped choroidal mass with a thickness of 7.05 mm without evidence of extrascleral extension (Figures 2a to 2c).

Fluorescein angiography and indocyanine green angiography of the right eye showed hypofluorescent blockage of the mass in all phases likely due to pigmentation or hemorrhage (Figure 3), with demonstration of the intrinsic vasculature (Figure 4).

Treatment options for choroidal melanoma were discussed, including observation, plaque radiotherapy, Gamma Knife stereotactic radiosurgery, proton beam irradiation or enucleation, with the possibility of fine needle aspiration biopsy. The patient preferred to consider the options for a few weeks before reaching a decision and in the meantime was referred to radiation oncology and started on topical prednisolone acetate and oral NSAID with resolution of pain and injection. Consultation with radiation oncology resulted in no evidence of metastases, including negative CT of the chest, abdomen and pelvis with normal liver function tests; however, it was discovered that Gamma Knife would not be an option as the patient was unable to undergo MRI due to her pacemaker. The patient elected for plaque brachytherapy with simultaneous pars plana vitrectomy for fine needle aspiration biopsy. The pathology returned non-diagnostic due to scant cellularity of the sample received. Staging of the tumor by Castle Biosciences revealed Castle class 2, the most aggressive phenotype of choroidal melanoma.

At this point, the patient’s personal and family history of malignancy was suspicious for a possible heritable systemic syndrome. The patient was referred for genetic counseling at the Dana-Farber Cancer Institute, where she and her family members elected to undergo the genetic screening blood test CancerNext-Expanded comprehensive sequencing analysis of 49 genes (APC, ATM, BAP1, BARD1, BRCA1, BRCA2, BRIP1, BMPR1A, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, FH, FLCN, GREM1, MAX, MEN1, MET, MITF, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, NF1, PALB2, PMS2, POLD1, POLE, PTEN, RAD50, RAD51C, RAD51D, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, SMAD4, SMARCA4, STK11, TMEM127, TP53, TSC1, TSC2 and VHL). Test results returned with systemic positivity for BAP1 (BRCA-associated protein 1) c.659+3A>C monoallelic gene mutation categorized as a variant of uncertain significance. This was consistent with BAP1 tumor predisposition syndrome given her multiple primary tumors associated with the BAP1 germline pathogenic variant, such as ocular melanoma, meningioma, basal cell carcinomas, papillomas and potentially her early-onset ductal carcinoma in situ. Further genetic testing of her family members revealed multiple BAP1-positive first-degree relatives, including her daughter, who was cancer-free (Figure 5).

In the interim, the patient developed multiple recurrences of eyelid and facial basal cell carcinomas with localized spread requiring initiation of vismodegib, which was switched to cemiplimab due to better tolerance. Nevertheless, the lesions continued to enlarge bilaterally, and after multidisciplinary discussions between oculoplastic surgery and oncology, the team decided to perform cryotherapy with topical 5-fluorouracil in the oculoplastic surgery clinic (Figure 6). This treatment was repeated several times for recurrences.

BAP1 tumor predisposition syndrome (BAP1-TPDS) is an autosomal dominant syndrome characterized by increased risk for atypical Spitz tumors of the skin, uveal melanoma, malignant mesothelioma, cutaneous melanoma, basal cell carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma and meningioma, among other suspected associations such as breast cancer and urinary bladder cancer. Choroidal melanoma overall represents the most frequent primary intraocular malignancy in adults, totaling an incidence of six cases per million. Of patients with uveal melanomas, 1% to 2% have BAP1-TPDS, which accounts for up to 20% to 25% of familial cases of uveal melanoma. Risk factors for uveal melanoma, in addition to family history, include white race, light skin, light iris and welding history.

Compared with the general population, choroidal melanoma in BAP1-TPDS tends to present younger at a median age of 50 years, with a more aggressive Castle class 2 tumor conferring higher risk for metastases. The clinical presentation of choroidal melanoma is often asymptomatic; however, for sizeable lesions, as in our patient described above, symptoms can include decreased vision, visual field scotoma, metamorphopsia, flashes or floaters. However, simultaneous primary cancers of BAP1 origin may clue the suspicion for ocular involvement.

The diagnosis of choroidal melanoma involves clinical examination of lesion features including size, color, thickness, surrounding halo, proximity to the optic disc, presence of drusen, orange pigment or subretinal fluid. Diagnostic imaging includes fundus photography and B-scan ultrasonography, as well as consideration of additional modalities such as fundus autofluorescence, fluorescein and indocyanine green angiography, and OCT scan. If the tumor is large, close to the optic nerve or suspicious for extraocular involvement, MRI of the orbits with and without IV contrast is recommended. Systemic metastatic evaluation should be pursued with assistance of the oncology team, including possibly CT of the chest/abdomen/pelvis with contrast, PET CT, and liver function tests with liver ultrasound.

The diagnosis of BAP1-TPDS is made via molecular genetic testing identifying a germline pathogenic variant in BAP1 in the choroidal melanoma and the serum. Years ago, when our patient underwent Castle staging, the test did not provide gene sequencing of the tumor. Castle Biosciences now offers multigene expression profiling of the intraocular sample using the DecisionDx-UM uveal melanoma next-generation sequencing panel. It is important to note that testing of the tumor only is not sufficient to discriminate between BAP1 somatic mutations (23.8% of uveal melanomas) and BAP1 germline mutations (1% to 2% of uveal melanomas). The Castle gene sequencing also categorizes the 5-year metastatic risk for choroidal melanoma from lowest in Class 1A (2%), intermediate in Class 1B (21%) and highest in Class 2 (72%), with this more likely to be associated with BAP1 mutation. As such, the higher Castle classes require more frequent surveillance, according to the National Comprehensive Cancer Network guidelines. For systemic germline genetic workup, gene analysis for the BAP1-TPDS from serum sample can be pursued via CancerNext-Expanded comprehensive sequencing analysis. Once the germline BAP1 variant is identified in the patient, family member and prenatal genetic counseling is possible.

Management of BAP1-related choroidal melanoma typically follows the established guidelines of aggressive class 2 choroidal melanomas. Treatment goals include preservation of vision, destruction of tumor, and prevention of metastases and recurrence. Eye-preserving treatments include observation, plaque brachytherapy, stereotactic radiosurgery or particle beam radiotherapy, depending on the size, thickness and location of the tumor. Surgical options include local resection, enucleation or orbital exenteration.

Radiation retinopathy was first described in 1933 by Stallard and manifests as macular edema, microaneurysms, telangiectasias, hard exudates, vitreous hemorrhage, cotton wool spots and neovascularization. Therapy options are limited but typically include laser treatment and injections of anti-VEGF medications or triamcinolone. Various prophylactic options have been explored for the prevention of radiation therapy, with some promising findings for periocular triamcinolone at the time of plaque application or intravitreal anti-VEGF medications every 4 months starting from plaque removal.

The patient’s choroidal melanoma initially responded well to the plaque radiotherapy treatment, achieving 20/40 vision by 1 year after treatment. Just a few months later, though, the vision in the right eye dropped to count fingers, with new findings of dot-blot hemorrhages in the macula, sclerosis of vessels, and cystoid macular edema concerning for radiation retinopathy. After no response to four injections of intravitreal bevacizumab, the patient was switched to periodic aflibercept without improvement for years. At the time, brolucizumab-dbll was in use, so this was trialed once with good temporary response in reduction of macular edema, although the vision remained count fingers and the fluid recurred within a few months. Given the risk for retinal vasculitis and occlusion with brolucizumab-dbll, her limited functional response to treatment, poor vision potential, and stability of macular edema for years, the patient elected to observe. Her most recent visit 7 years after plaque radiotherapy revealed a stable 3.53-mm choroidal mass with overlying atrophy and stable large intraretinal fluid (Figures 7a to 7d).

The patient regularly visits the retina and oncology clinics for surveillance, and she and her family continue to be followed at Dana-Farber Cancer Institute for active screening for malignancy.