Ocular Surface Squamous Neoplasia: Risk factors, diagnosis, management and outcomes at a Tertiary Eye Hospital in South Africa

Abstract

Introduction: Ocular surface squamous neoplasia (OSSN) is the most common ocular surface tumour with a high burden of disease in sub-Saharan Africa. In high-income countries it typically affects older males and in low-income countries younger females. The commonly described risk factors for OSSN include ultraviolet-B radiation exposure, HIV and human papillomavirus (HPV) infection. Diagnosis is suspected clinically and confirmed with histology or other less invasive tests. Management of OSSN can be divided into two main groups, surgical and medical. Surgical management has been the primary management approach traditionally. It is indicated when four or less limbal clock hours are involved and when the basal tumour diameter is less than 15mm. This ensures that the main complication from surgery, limbal stem cell failure, is avoided. Medical therapy is used for larger tumours and includes interferon α2b, mitomycin-C and 5- fluorouracil (5FU). Methods: We conducted an interventional prospective study. Patients that presented between December 2019 and February 2022 with conjunctival masses suspicious of OSSN, or symptomatic conjunctival growths despite medical therapy were considered for inclusion in the study. An electronic questionnaire was completed at enrolment to document demographic data, presenting history, and associated risk factors. A clinical examination and anterior segment photography were performed with slit lamp to document clinical features. Optical coherence tomography (OCT) and methylene blue stain were performed at the initial visit, with liquid-based cytology (LBC) and biopsy for histology at the time of surgery. Masses suspicious of OSSN that occupied less than or equal to four clock hours of the limbus had an excision biopsy with 4mm margins using ix the Shields no-touch technique and double freeze-thaw cryotherapy to the limbus and free conjunctival edge. Larger lesions had an incision biopsy performed to confirm diagnosis and received topical chemotherapy in the form of 5FU. Positive surgical margins and recurrence were managed with 5FU. The participants were followed up for 24 months. Results: One hundred and seventy-five patients were enrolled in the study. Based on biopsy results, 130 were defined as OSSN cases and 45 as benign controls. Median age was 44 years (IQR: [35-51]) with an equal gender distribution in cases. The prevalence of HIV in cases was 74% and was strongly associated with OSSN (p<0.001). Conjunctival intra-epithelial neoplasia made up 82% of cases. There were 182 conjunctival masses among the 175 patients for which three non- invasive diagnostic tests were evaluated (OCT, cytology and methylene blue). There were 135 lesions identified as OSSN on biopsy and 47 lesions were benign. OCT had a sensitivity and specificity of 87.2% (95% CI: 80.0 – 92.5) and 75.6% (95% CI: 60.5 – 87.1) respectively, when an epithelial thickness cut-off of 140μm was used. LBC had a sensitivity of 72.4% (95% CI: 62.5 – 81.0) and specificity of 74.3% (95% CI: 56.7 – 87.5). Methylene blue had a high sensitivity of 91.9% (95% CI: 85.9 – 95.9), but low specificity of 55.3% (95% CI: 40.1 – 69.8). One hundred and nine patients with 114 conjunctival masses completed at least three months of follow-up and were assessed for outcomes. Ninety-four percent (n=107) of patients had surgery as their primary management, with a recurrence rate of 0.9%. Seven patients had 5FU as primary therapy with a resolution rate of 71% and a recurrence rate x of 14%. All patients with partial resolution to 5FU resolved with surgery and additional cycles of 5FU. Side effects from 5FU were mild and did not result in cessation of therapy. Discussion: Our study describes a middle-aged demographic with no gender predisposition and has HIV as the primary assessed risk factor. The age of presentation is slightly younger than other middle-income countries, presumably due to the high prevalence of HIV in South Africa. The histology profile of the tumours was mostly premalignant, which is different from other African countries that show a predominance of SCC. Our study also showed a high percentage of pigmented tumours (55%). Three minimally invasive diagnostic tests were evaluated. OCT performed the best and is a reliable alternative to histology. LBC performed well, but was found to be inferior to OCT. Our main rationale for investigating the use of LBC was to have a biologic specimen with which to conduct ancillary tests, such as HPV polymerase reaction. Methylene blue performed well as a screening test and could be used at a primary care level to assess urgency of referral. We used a standardised management approach which had high resolution, low recurrence rates and had low morbidity for the patient. Conclusion: Our study provides essential data on the urban South African patient with OSSN. We have a middle-aged demographic with no gender predisposition, most of our patients have HIV as a risk factor, and present with premalignant disease. OCT performed well as a non-invasive diagnostic test, with LBC a promising new modality. A combined surgical and medical management strategy yielded high resolution and low recurrence rates.