Research

RANZCO NSW and ISOO combine conference resources

This year RANZCO NSW combined its Annual Scientific Meeting with the 18th Biennial Conference of the International Society of Ocular Oncology (ISOO). Several streams were run concurrently and while the overarching the for both meetings was ocular oncology, an ocular pathology course was also conducted as a series of workshops on the first day of the programme.The first sessionSession chairman, ophthalmologist Dr Simon Taylor, spoke briefly about periorbital malignancies. He divided the skin cancers into melanomas and the non-melanomas, ie, basal cell carcinomas (BCCs), squamous cell carcinomas (SCCs), and the rarer non-melanoma skin cancers (NMSCs).Taylor said two out of three Australians will have had a brush with a skin cancer by the time they reach 70 and, according to a 2013 Australian Institute of Health and Welfare report, care of those probls consumed 8.1% of all medical spending. NMSCs rain the most costly cancers to treat and their incidence is increasing. Fortunately, despite the high incidence, their mortality rate rains low.Aside from sun exposure, skin cancer prevalence is also affected by age and gender. NMSCs have a high recurrence rate of about 8% that can be the result of; an incomplete excision, a large number of primary tumours, a recurrent tumour, a perineural invasion, or concurrent immunosuppression.Treatments include surgery, radiotherapy, photodynamic therapy, topical agents, and newer agents such as EGFRi (epidermal growth factor receptor inhibitor). Topical agents include Imiquimod and 5-fluorouracil (5-FU) for conjunctival lesions, Ipilimumab for scleritis, uveitis, and myositis, and MEKi (inhibitors of the mitogen-activated enzymes MEKI and/or MEK2) for hypophysitis (pituitary gland inflammation).Next, oculaplastic surgeon, Dr Manon Morris from Sydney Eye Hospital (SEH), spoke about the SEH’s experience of periorbital malignancies. She noted that one-third of all cancers treated at SEH are skin cancers (367 of 1,419), with Caucasian males born in Australia the most likely to be affected.Most cases involve the lower lid while some involved the medial canthus. Most were BCCs (77% between 2011–2015 at SEH). In the same time period, 46 cases of SCC were diagnosed and just one case of sebaceous gland carcinoma.Professor of Dermatology at USyd, Diona Damian, spoke about periorbital malignancy prevention and provided an overview of the role DNA and UV-mediated DNA damage plays in oncology, especially its role in cell replication/repair and cell energy levels. Because DNA damage can trigger a cancer, prevention of the former means cancers are less likely.Apart from sunscreen, chical preventative agents are also a possibility. Retinoids (acitretin, an oral retinoid) and the vitamin nicotinamide, which reduces flushing and headaches, increase the rate of DNA repair, and reduce UV-mediated damage. Oral nicotinamide has been shown to decrease skin cancers by 23%, but the benefit is lost soon after cessation of medication.Almost paradoxically, the best responders were those with the most cancers, and reductions of 15% in actinic keratosis were reported when one gram per day was taken. However, only cases at serious risk of cancer are suitable.Professor Angela Hong from USyd and the Melanoma Institute of Australia (MIA) revealed that DNA damage attributable to UV was due to the release of free radicals. She stated that most skin cancers do not need radiotherapy and such therapy around the eyes was unwise due to the area’s radio sensitivity. Radiotherapy was usually reserved only for those that are unsuited to a surgical intervention.Oncologist Professor Michael Boyer from USyd and Chris O’Brien Lifehouse said the 120,000 new cancer cases recorded each year was the probl that confronts Australian society. Males represent 55% of those cases and 70% are aged 60 or older. The 46,000 fatal cases also represent around 30% of Australia’s annual death total.Metastatic disease implies a need for systic rather than local treatment. Chotherapy was followed by targeted therapies, but during the last 5–10 years, immuno-oncology has become the treatment of choice.Boyer likened chotherapy as an attack on all cellular reproduction and nominated therapeutic targeting as being the hallmark of cancer treatment. He stated that the driver of most cancers was mutations of cell division and gave an example from his specialty, lung cancer, as being the result of one of 12 or more mutations. The Hedgehog signalling pathway has also been implicated, especially in the case of BCCs.Boyer expected that targeted therapy would become more effective as more about the diseases is understood, however, he predicted that immunotherapy is likely to become the backbone of future treatment.

KEYNOTE SPEAKERS

Carol Shields Manon Morris Peter McCluskey Georgina Long John Thompson AO Bita Esmaeli

The anophthalmic socketThis session had a gory elent when eyes were either, enucleated (roved completely), eviscerated (sclera rains, cornea and contents roved), or exenterated (basically, the orbital contents are roved). Dr Manon Morris limits orbital exenteration to those cases of massive infection or life-threatening malignancies.Ocularist Mr James Morphett advised that ocular prostheses be replaced 18–24 months after the initial fitting and every 5–6 years thereafter. He recommended the use of an RGP contact lens cleaner on the prostheses and a complete re-polish every 2–3 years, patient-dependent. For children, he recommended replacing the prosthesis annually until such time as the growth rate slows and less frequent replacent becomes practicable.Professor Peter McCluskey, CEO of the Save Sight Institute, discussed the controversial issue of sympathetic ophthalmia (SO). SO is believed to be a T-cell-mediated autoimmune reaction and current data suggests a rate of 1 in 100,000.McCluskey posed the question, “Does eye roval prevent SO?” – short answer: No! Furthermore, he does not believe there is a protective time window. Rather, he thinks it is the ocular surgery itself that triggers SO, and that targeted immunosuppressive therapy for SO usually has a good outcome.He believes that the innate autoimmune response starts almost immediately and, because of the complex pathophysiology involved, eye roval will not prevent SO. Regardless, the pathogenesis is still unclear and enucleation or evisceration might still be needed. His parting advice was to not allow SO factors/considerations interfere with surgical decisions.Finally, ophthalmologist Dr Jenny Danks stressed the importance of taking all possible steps to protect the ‘good’ eye when dealing with a monocular patient. Consideration should also be given to the use of a polycarbonate or similar heavy-duty, protective spectacle lens to protect it maximally.

KEYNOTE SPEAKERS

Gina Kourt Arun Singh Sam Lerts Jerry Shields Angela Hong Mandeep Sagoo

Retinoblastoma and other ocular tumoursDr Jerry Shields from the Wills Eye Hospital and founder of the Wills Ocular Oncology Service advised practitioners to be wary of cases in which astigmatism is manifest but proves difficult to correct. Full pupil dilation was advised, as were efforts to assess the ciliary body. Causes of the problatic astigmatism include melanoma, strabismus, leucocoria, and retinoblastoma.A chalazion needs to be viewed with suspicion, as a sebaceous carcinoma is a possibility. The latter accounts for 5% of all malignant lid tumours with an attendant 5–14% mortality rate. Furthermore, eyelid metastases of breast cancer can assume the appearance of a chalazion.In older patients, a rare type of skin cancer, a Merkel cell carcinoma – appearing as a flesh-coloured or bluish-red nodule – can metastasise but worse, has a mortality rate of 25%. Eyelids can host diffuse BCCs, often of the so-called rodent ulcer type. Conjunctival intraepithelial neoplasias need to be differentiated from ‘simple’ pterygia.Dr Carol Shields listed the topical therapies of OSSNs as MMC (mitomycin C), 5-FU (5-Fluorouracil), IFN (topical interferon alfa-2b – IFNa2n), cidofovir, and aloe vera. Most such therapies are relatively recent arrivals, with MMC introduced in 1994 to treat CINs (corneal intraepithelial neoplasias). IFNa2n is used to modulate the immune syst and was stated to be therapeutic, immuno-reductive, or even immuno-preventative.According to Shields, immunotherapy was said to be more than 80% effective. Immuno-reduction gave a more than 75% reduction of mass in more than 70% of cases, and immuno-prevention, especially in the immuno-suppressed, was effective but necessitated a lifelong usage of the treatment.MMC and 5-FU therapies are deployed when MMC therapy fails to solve a probl. IFN tends to be used more in the elderly and cidofovir was stated to be too costly, while 5-FU is the cheapest and quickest option.Addressing the topic of conjunctival tumours in children, Shields noted that 97% were benign, 2% were melanomas, and 1% were lymphomas.Dr Mandeep Sagoo returned to the subject of retinoblastomas and secondary cancers, giving an incidence of 1 in 18,000 live births with symptoms of leucocoria and strabismus.He defined the two key subtypes as exophytic retinoblastoma (subretinal) and endophytic retinoblastoma (protruding/invading into the vitreous). Ultrasound (B-scan) of the affected eye will show the tumour and any calcification.Biopsies are not performed because of the real danger of fragmenting the tumour and seeding more tumours. Likewise, to minimise the patient’s exposure to unnecessary radiation, CT scans are not done.There is now an international classification of retinoblastoma (ICRB since 2006) using the indices A to E as follows:A: Small, <3 mm
B: Large, >3 mm
C: Focal seeding, within 3 mm of primary tumour
D: Diffuse seeding, >3 mm from primary tumour
E: Extensive, with damageDiffuse, infiltrative retinoblastoma is usually secondary to uveitis and 40% of cases have a family history (an autosomal dominant disease).Shields returned to provide an overview of retinoblastoma treatment in the US.Most treatment was chotherapy-based but she phasised that a correct diagnosis was critical because analysis at the Wills Eye Hospital found only 78% of cases were actually arriving with a correct diagnosis. Coat’s disease was the most common misdiagnosis among the raining 22%. Sub-Tenon’s capsule therapy is no longer used because of its complication rates.Shields referred the audience to oorca.org, an image-reading centre for the online risk evaluation of melanoma patients with known choroidal naevi.In her presentation on ocular lymphomas, Shields described their care ‘as much an art as a science’.Lymphomas generally are the fourth most common malignancy in the US, one that is increasing by as much as 4% per annum currently. She described conjunctival lymphomas as being typically salmon-pink, fleshy patches for which intravenous chotherapy was the usual treatment.

KEYNOTE SPEAKERS

Diona Damian Alison Skalet James Morphett David J Wilson Simon Taylor Andrew Chang

Uveal melanomaDr Alison Skalet, an ocular oncologist at Oregon Health & Science University (OHSU) Healthcare gave a presentation on the evolving field of OCT angiography (OCTA) in iris melanocytic tumours. Noteworthy among her co-authors are the inventors of ophthalmic OCT technology – Professors James Fujimoto and David Huang. Important signs include any increase in vascularity, as that can be a sign of malignant transformation, and tumour aggression.Traditionally, fluorescein angiography has been used to differentiate between iris naevi and melanoma. OCTA at either 1,050 nm (offering greater tissue penetration) or 840 nm (offering higher resolution) can now be used on iris lesions and, using blood vessel density data from OCTA, naevi, melanomas, and high-risk melanomas can be differentiated.Skalet asserted that the spread from naevus to high-risk melanoma and the vascularity that increased over that same range forms a continuum. She believes that OCTA can image iris vascularity, melanotic lesions, and blood vessel density.Dr David J Wilson, director of the OHSU’s Casey Eye Institute also spoke on OCTA as a tool to monitor peripapillary blood vessel density following brachytherapy in 15 uveal melanoma patients treated with iodine (I125) plaques. The optic disc and surrounds were monitored for peripapillary capillary density. He showed that OCTA was a powerful tool for investigating the local effects of radiation-induced changes for which small vessel density was a suitable proxy.Despite the narrow focus of the topics aired at the combined societies’ meeting, it was well supported by exhibitors and the venue was well accepted by the delegates.Relevance of cutaneous melanoma to ocular oncologyAccording to Professor Georgina Long from the MIA, the most common targeted cutaneous melanoma treatments are BRAFi, MEKi, anti-CTLA-4, and Anti-PD1. Some are in effect immunotherapy, ie, assistance given to the body’s defence mechanisms to combat melanomas.{{image20-a:l-w:400}}The therapy evolved from the observation that in some patients, tumour size was reduced over time, apparently as a result of the patient’s own immune syst attpting to deal with the disease. The two approaches are so-called checkpoint inhibitors (Nivolumab and Ipilimumab) and a vaccine approach, whereby an antigen is created from the melanoma and a relevant vaccine developed. However, currently, this approach is inconsistent in its efficacy.Long also provided a timeline of treatments and survival. Up to 1990, treatment was mostly surgical and the survival rate was 25–35% only. However, since then it has steadily increased and reached 73% by 2016 by using a combination of Nivolumab and Ipilimumab. The survival rate at two years also improved as the targeted therapies evolved.The news is not as encouraging in the ophthalmic field and to date there is still no effective drug for uveal melanoma, however, the FDA recently decided to fast-track a novel targeted therapy candidate drug, AU-011 from Aura Biosciences.Professor Bita Esmaeli from the University of Texas’ Department of Plastic Surgery addressed the often cosmetic issue of dealing with eyelid and conjunctival melanomas. She described eyelid melanomas as rare (<1% of ocular cancers) but revealed that they account for more than two-thirds of the deaths attributable to ocular tumours and have a high local recurrence rate of up to 30%.Esmaeli said because of the st cell deficiency issues that follow any limbal tissue destruction/functional alteration, conjunctival melanomas were challenging when their location included the limbus. The mortality rate was given as 20%.Cutaneous and eyelid melanomas shared a lot in common including the recommendation for wide margin surgery. A conservative approach necessitates 5–10 mm margins and Esmaeli recommended delayed reconstruction. Prognostic signs are tumour thickness, ulceration, and mitotic figures.Later, executive director of the MIA, Dr John Thompson AO described the tracing technique. This is where a dye (eg. Patent Blue) is injected into a melanoma and the so-called sentinel (lymph) node is disclosed at biopsy (SNB) by sampling all possible local lymph nodes for the presence of the disclosing blue dye. It’s important to note the sentinel node is not necessarily the closest physically to the tumour.The alternative technique is lymphoscintigraphy, in which a small quantity of radioactive material is injected into the tumour and a gamma-radiation detector is used to trace where the material is dissinated to, thereby locating the sentinel node without surgery. SNB determination is now a reliable process and Thompson believes that in 2017 we are on the threshold of being able to offer low toxicity, highly effective melanoma treatments.Ocular surface neoplasias{{image21-a:r-w:400}}London consultant ophthalmic surgeon, Dr Mandeep Sagoo, defined ocular surface squamous neoplasia (OSSN) as those in which the basent mbrane had not been breached. Risk factors include sun/UV, HPV, HIV, allergic eye diseases, and an immunodeficiency.In one Australian study by Hirst et al. (Arch Ophthalmol., 2009), OSSN was found in 9.8% of pterygium cases, leading to the suggestion that all pterygium excisions be submitted to pathology for assessment to rule out the possibility that the patient’s condition was not more complicated. Using ultrahigh-resolution OCT (not yet available commercially) it has been shown that the epithelium is thickened in OSSN cases, whereas pterygium shows a thickening of the subepithelial mucosal layer.

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