Ocular melanoma

Introduction

Melanoma in the eye region can arise from the uvea, conjunctiva or eyelid. Melanomas of the eyelid are treated cutaneous melanomas, with similar pathology, molecular lesions, natural history and therapeutic liability. They are typically managed wholly within the SMD Alliance but require multiprofessional surgical assessment by maxillofacial surgeons and ophthalmologists.
Uveal melanoma and conjunctival melanoma are initially managed by the specialist ocular oncology service at Moorfields Eye Hospital NHS Foundation Trust, East London. Baseline and surveillance imaging for metastatic disease for uveal melanoma, and oncological treatment for advanced and/ or metastatic disease are carried out within the SMD Alliance.
Alliance protocols for treatment are based on regional expertise and literature review. Surveillance protocols have been developed with Moorfields Ocular Oncology specialists, Royal Surrey radiologists and local experience and expertise.

Uveal melanomas are located in the iris (4%), ciliary body (6%) and choroid (90%).
Germline BAP1 mutations predispose patients to uveal melanoma, mesothelioma, cutaneous melanoma, basal cell carcinoma and renal cell carcinoma.
Chromosome 3 monosomy is associated with worse prognosis; this is also associated with partial loss of chromosome 3 and is related to the BAP1 locus. Gain of chromosome 8q is also associated with worse prognosis.
GNAQ11 and GNAQ are the most commonly mutated oncogenes but these do not impact prognosis, nor are they currently directly targetable.
Uveal melanomas do not have an ultraviolet radiation damage signature and have a much lower mutation burden than cutaneous melanomas.
15% are associated with SF3B1 mutations which are associated with a better prognosis.
These molecular characteristics can inform discussions with patients about the desirability of tissue diagnosis versus empiric treatment, which is a Moorfields decision that can remain open at the time of the patient's initial contact with Oncology for baseline imaging investigations. Some patients wish to have this extra prognostic information, whilst others may consider that prior knowledge of a worse potential prognosis will render excessive long term anxiety. It may also guide the duration of surveillance imaging.

Staging of posterior uveal and ciliary body melanoma is provisioned by AJCC 8.
The T number is derived from a combination of tumour thickness and diameter as summarised in the table below (credited to Martin Hyrcza), with suffixes as below:

a - without ciliary body involvement or extraocular extension

b - with ciliary body involvement

c - without ciliary body involvement but with extraocular extension ≤ 5 mm in largest diameter

d - with ciliary body involvement and extraocular extension ≤ 5 mm in largest diameter

In addition pT4e denotes any size tumour with extraocular extension > 5 mm in largest diameter
pN1a denotes metastasis in one or more regional lymph nodes (preauricular, submandibular and cervical). pN1b denotes discrete orbital tumour deposits discontinuous with the globe without regional lymph node deposits.
pM1 denotes distant metastasis with suffixes as below:

a - largest diameter of the largest metastasis is ≤ 3 cm

b - largest diameter of the largest metastasis is 3.1 - 8.0 cm

c - largest diameter of the largest metastasis is > 8 cm

6. AJCC 8 stage grouping is given in the table below.

Two out of five patients with uveal melanoma will succumb to their disease, although only 1% will have metastatic disease at baseline.
The first site of metastasis is almost always the liver, although Alliance experience is that early non-hepatic metastasis is sufficiently frequent to justify both systemic and hepatic imaging at least at baseline. In correspondence with the Oncology service at Barts, which is closely allied with Moorfields, the value of a baseline PETCT was promoted, including its ability to discover other potentially significant synchronous malignancies; this perspective has been published. The Alliance will continue to evaluate the cost/benefit and adverse false positive/ morbidity risks of baseline PETCT imaging in this group of patients.
Current SMD Alliance policy is to offer:
1. At baseline
  1. A first clinical consultation, including assessments of comorbidities, drug history and allergies, MRI contraindications, and guidance on ocular melanoma treatment and surveillance strategies
  2. 18FDG-PETCT whole body
  3. MRI liver with hepatobiliary contrast
2. Every six months
  1. MRI liver without contrast initially, escalated to contrast-enhanced scan if required.
If the patient is not able to have MR imaging due to implanted metalwork, a PETCT and ultrasound liver should be offered at baseline, with ultrasound surveillance every six months thereafter.

Isolated hepatic perfusion involves surgical isolation of the liver using a veno-venous bypass and clamps, and then perfusion of the liver with high dose melphalan for 1 hour. Delcath offer a percutaneous hepatic chemosaturation system. This has recently been subject to a clinical trial and may be available for occasional cases from the Alliance at Southampton University Hospital NHS Trust (via MA). A metaanalysis has suggested these treatments can be worthwhile with progression-free survival of 7-9 months and overall survival of around 17 months.
With the availability of a regional specialist hepatopancreaticobiliary surgical service at RSH, Alliance experience is that surgery and repeat surgery for solitary or oligometastatic liver metastases from uveal melanoma can provide significant disease-free intervals, at least delaying time to institution of immune checkpoint blockade and its associated risks.
Radiofrequency ablation is also an effective option. Certain patients may be referred to Imperial Healthcare NHS Trust for consideration of cryoablation.
Selective internal radiotherapy, or SIRT, is offered locally but not NHS funded. Alliance experience of one private patient is of disease stabilisation lasting several months.

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