CH Fu, JJT Chan, HL Yuen, CW Luk

Abstract

Differential diagnosis of paediatric malignant ocular tumour is limited, with retinoblastoma being the most common among all ethnicities in the world. The incidence of paediatric malignant cutaneous melanoma among Asians is low and paediatric ocular melanoma is even scarce. We reported the first case of paediatric malignant ocular melanoma in Hong Kong, a 10-year-old boy with a large localised choroidal melanoma managed by enucleation uneventfully. Genetic tests for high-risk features were negative. He remained under close surveillance with no evidence of metastasis 1 year post enucleation.

Introduction

Melanomas are malignant tumours that develop from melanocytes. They most commonly occur on skin but can also arise from mucous membranes and the eye including uvea, conjunctiva, eyelid and orbit. Uveal melanoma constitutes over 80% of cases of ocular melanoma. They are primarily reported in White Caucasians, followed by Hispanics, Asians and rarely in Africans. According to the most updated Hong Kong Paediatric Haematology & Oncology Study Group's childhood cancer registry and Hong Kong Cancer Registry, this is the first reported case of malignant choroidal melanoma in a Chinese boy in Hong Kong.

Case Report

A 10-year-old Chinese boy first presented in February 2017 with right eye localised retinal detachment found incidentally during routine eye examination. He enjoyed good past health. He had non-consanguineous parents and no family history of cancer. Magnetic resonance imaging (MRI) of the orbit and brain showed a biconvex lesion in the supero-temporal region of the right vitreous chamber. It measured 10.7 mm x 9.5 mm (transaxial plane) and 9.3 mm (height). The anterior limit of the lesion lied in the region of the ora serrata while it was separated from optic nerve posteriorly. It showed T1-weighted hyperintensity and marked T2-weighted hypointensity with subtle contrast enhancement.

He was referred to Hong Kong Eye Hospital (HKEH) by the private ophthalmologist for management immediately. However, he did not attend until one year later in April 2018. By that time, he had developed right divergent squint for 6 months. His right eye visual acuity deteriorated to light perception only with a right relative afferent pupillary defect. Examination under anesthesia showed a large retrolental choroidal pigmented mass arising from the superotemporal quadrant near the ora serrata. It measured 15.53 mm x 16.04 mm and was associated with total exudative retinal detachment. Anterior segment was normal with clear cornea and lens without iris neovascularisation. Ultrasound biomicroscopy showed that the tumour was in close proximity to the ciliary body. No calcification was seen on B-scan ultrasound. The left eye was normal without intraocular mass. MRI repeated in April 2018 showed a mass with 'mushroom' configuration (Figure 1) measuring up to 17.8 mm x 12.3 mm (transaxial plane) and 18.6 mm (height) with interval increase in size. It showed heterogenous internal T1 hyperintensity and marked T2 hypointensity with subtle contrast enhancement along the medial border of the lesion. Positron emission tomography and computed tomography (PET-CT) showed a mildly hypermetabolic nodule (Standardised Uptake Values max 3.8) in lateral aspect of right globe. There was no evidence of distant metastasis. He was thus referred to our paediatric oncology centre for multi-disciplinary evaluation. Systemic review was negative for metastatic disease.

The clinical and radiological findings were compatible with malignant choroidal melanoma with scleral involvement as per our radiologists review. Differential diagnoses included other intraocular tumours such as retinoblastoma, choroidal haemangioma or inflammatory, infective lesions and haemorrhage. In view of the large tumour size and very guarded visual prognosis, right eye enucleation and orbital implant was advised and performed immediately. Macroscopic examination of the globe showed a 'Black' endophytic circumscribed tumour measuring 20 mm x 17 mm (largest dimension) associated with retinal detachment (Figure 2A). The vitreous cavity was filled with a dark brownish jelly-like material. Both the ciliary body and iris were intact. Microscopic examination confirmed the diagnosis of choroidal melanoma consisting of diffuse sheets of epithelioid cells with vesicular chromatin, prominent nucleoli and abundant eosinophilic cytoplasm filled with melanin (Figure 2B). The mitotic count was not high at 1 per 10 high power fields. The tumour showed invasion of the inner layer of the sclera but no ciliary body involvement. There was no extra-ocular extension or vascular invasion. The pathological staging was pT4a (American Joint Committee on Cancer 7th edition).

Genetic test on tumour tissue and peripheral blood were performed in Hong Kong (Queen Elizabeth Hospital) and Canada (ImpactGenetics ^®). Tests on tumour tissue showed chromosome 3 disomy and were negative for chromosome 8q gain. Tests on the peripheral blood showed no germline mutation of the BAP1 Tumour Predisposition Syndrome gene. These were good prognostic factors indicating a 'lower risk' of systemic metastasis. Nevertheless, we were very cautious with regular imaging surveillance arranged for him since metastatic melanoma was associated with high mortality. Both MRI abdomen and CT thorax in September 2018 were normal with no metastasis. This patient was undergoing jointed follow-up by ophthalmologists and paediatric oncologists. He remained clinically well with no evidence of metastasis 1 year post-enucleation.

Discussion

Uveal melanoma is the most common primary malignant ocular tumour in adults, with a mean age-adjusted incidence of 1 to 9 cases per 1,000,000 per year. However, it is rare in the paediatric population. In a study published by Dr. C.L. Shields with 8033 uveal melanoma patients from August 1970 to August 2008, only 1% of them were under 20 years of age.1 In children, uveal melanomas tend to be smaller in size, less pigmented, more often located on the iris, further from the optic disc and fovea, and less extrascleral extension.

Figure 1 MRI orbit showing the 'Mushroom' configuration of the right intraocular mass (T1 post-contrast).

Uveal melanoma most commonly occurs in White Caucasians. Weis et al performed a meta-analysis to study the relationship between host susceptibility factors and incidence of uveal melanoma.² Light eye colour (Relative Risk, 1.75), fair skin colour (RR, 1.80) and inability to tan (RR, 1.64) were statistically significant factors while blond hair was not. It is postulated that lighter-skinned and light (blue or grey) coloured eyes may have less melanin in the choroid and retinal pigment epithelium, leading to less protection from ultraviolet light with increased risk. Other susceptible factors include presence of oculodermal melanocytosis, cutaneous, iris or choroid naevi.

BAP1 (BRCA 1-associated protein 1) is a nuclear protein encoded by a tumour suppressor gene located on chromosome 3p21.1. The BAP1 tumour predisposition syndrome is a hereditary cancer syndrome such that patients with somatic or germline BAP1 mutation are predisposed to developing uveal melanoma, malignant mesothelioma, cutaneous melanoma, basal cell carcinoma and renal cell carcinoma.³ Mrinali et al reported that germline BAP1 mutation occurred infrequently in uveal melanoma patients but its presence exhibited larger tumour diameters, higher rates of ciliary body involvement and higher metastatic rate compared with controls in univariate analysis.⁴

Iris melanoma usually presents as a circumscribed mass (90%) or less commonly, a diffuse infiltrative growth pattern (10%). It is less common compared to ciliochoroidal melanoma and is usually diagnosed 10 to 20 years earlier. Ciliary body and choroidal melanoma may present with blurred vision, floaters, visual field loss, visible tumour or pain but can also be asymptomatic (30%). Ciliary body melanoma is often diagnosed late since it is obscured by the iris. The patient may remain asymptomatic until the lesion become quite large. Choroidal melanoma usually presents as a dome-shaped (75%) or a mushroom-shaped mass because of rupture of Bruch's membrane (19%). It can be pigmented (55%), non-pigmented (15%) or mixed (30%). Complications include retinal detachment (71%), intraocular haemorrhage (10%) or extraocular extension (3%). ⁵

Mainstay of diagnosis relies on detailed ophthalmological assessment and investigations depending on tumour location. These include slip-lamp examination for iris melanoma and detailed fundus evaluation by direct and indirect ophthalmoscopy for ciliochoroidal melanoma. B-scan ultrasound and ultrasound biomicroscopy delineate the extent, shape and dimensions of the tumour. Fluorescein angiography and indocyanine green angiography may help differentiate melanomas from simulating lesions such as choroidal haemangioma and neovascularisation. Imaging studies such as CT and MRI provide important diagnostic information. On CT orbit, uveal melanoma appears as a hyperdense lesion with slight to moderate contrast enhancement. On MRI, melanoma is typically hyperintense on T1 but hypointense on T2-weighted images. The presence of contrast enhancement in melanoma distinguishes it from haemorrhage. PET shows a mildly hypermetabolic lesion.

Figure 2 (A) Macroscopic appearance of the black circumscribed choroidal melanoma; (B) Microscopic appearance of predominantly epithelioid, heavily-pigmented melanoma cells.

Occasionally, fine needle aspiration biopsy may be necessary to confirm the diagnosis, such as in small iris lesions. Microscopically, tumour cells can be spindle, epithelioid or mixed shape.

Treatment of uveal melanoma depends on the tumour location, extent and size, visual acuity on presentation, and systemic health status of the patient. Small asymptomatic tumours may be monitored conservatively unless there is documented growth. The risks and benefits of treatment versus observation need to be carefully balanced. Treatment options can be broadly categorised into thermotherapy, radiotherapy (plaque or external beam), surgery and a combination of the above (for example, plaque radiotherapy and transpupillary thermotherapy). Transpupillary thermotherapy has a maximum depth penetration of 4 mm and is only suitable for small choroidal melanomas.⁵ Plaque brachytherapy is most commonly used for posterior uveal melanomas and can be considered in tumours ≤18 mm in diameter & ≤12 mm in thickness.⁵ The Collaborative Ocular Melanoma Study (COMS), a multi-center randomised controlled trial, found no difference in the long-term survival between plaque brachytherapy and enucleation in medium-sized tumours.⁶ Local resection may be considered in melanomas located in the ciliary body or periphery of choroid. Enucleation is indicated when tumour is large, presence of extraocular extension or poor visual potential. Orbital exenteration is reserved for tumours with extensive extraocular and orbital extension.

Prognosis of iris melanoma is more favorable than posterior uveal (ciliochoroidal) melanoma and it is associated with a five to ten times lower mortality rate. Posterior uveal melanoma has a high tendency to metastasise, especially to liver (89%), lung (29%), bone (17%), skin and subcutaneous tissue (12%) and lymph nodes (11%). Unfortunately, patients with metastasis have high mortality rates. Clinical trials on chemotherapy, target therapy or immunotherapy have not shown effective adjuvant therapy to reduce the risk of metastasis or improve survival.⁷ Older age is associated with a higher risk of metastasis. To the contrary, lower metastatic rates in younger patients may be related to smaller tumours, a more robust immune response and fewer genetic mutational events within the melanoma. Cytogenetics and tumour size (largest basal diameter and thickness) are the two most important clinical predictors of metastasis and hence prognosis in posterior uveal melanoma. Large tumours (>8 mm thickness & >15 mm basal diameter) have an estimated 5-year mortality rate of around 50%, when compared to small tumours (<2 or 3 mm tumour thickness & <10 or 11 mm basal diameter) at 16%.⁸ Each millimeter increase in tumour thickness is estimated to result in a 5% increase in metastatic risk at 10 years.⁹ Aberrations in chromosomes 1, 3, 6, and 8 have been shown to prognosticate the risk of tumour metastasis and survival. Monosomy 3 signifies a high-risk melanoma with a higher incidence of clinical and histopathologic risk factors, such as larger tumour, ciliary body tumour location, extraocular extension. The 3-year mortality rate is 50% compared with 0% without monosomy 3.¹⁰ BAP1 mutation is also associated with an increased risk of metastasis. In addition, uveal melanoma can be broadly divided into 2 distinct molecular classes (Class 1 and 2) by gene expression profiling.¹¹ Most Class 1 tumours have disomy 3, chromosome 6p gain and are considered low-risk tumours. In contrast, most, if not all Class 2 tumours have monosomy 3 and are high-risk aggressive tumours with increased rates of metastasis and melanoma-related mortality.

Conclusion

Our patient illustrates a rare but challenging case of paediatric tumour which is especially uncommon in our locality and among Asians. Retrospectively, early intervention might have allowed globe salvage therapy when he first presented. Unfortunately, he required enucleation as the tumour had grown too large by the time he sought treatment after becoming symptomatic. Fortunately, his tumour's genetic profile was favorable and associated with a lower-risk of metastasis. Nonetheless, regular surveillance by ophthalmologists and paediatric oncologists will remain a crucial part of his management in the future. There is no clinical telltale sign to suggest this rare tumour. Therefore, I would recommend an early detailed ophthalmological assessment when patient first aware of symptom.

Acknowledgement

The authors sincerely thank pathologist, Dr. Cheuk Wah for providing the precious slide images.

Declaration of Interest

The authors declare that there is no conflict of interest.

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