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Management of Ocular Surface Squamous Neoplasia
Mark Daniell Head of Cornea RVEEH
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Clinical features
• Leukoplakia
• Papilliform
• Gelatinous with tufted vessels
• Velvety
• Nodular or diffuse
• Nasal or temporal limbus
• Present as a mass, redness or irritation
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Differential diagnosis
• Papilloma (A)– Younger patient, anywhere on
conj.,vascular pattern
• Solar elastosis (B)
• Corneal conjunctival dysplasia (C)
• SCC (D)
• Pyogenic granuloma
• Limbal vernal– Suspect in younger patient
• Malignant melanoma (E)– Smooth surface, not gelatinous or
leukoplakia
Rudkin et al BJO 95;350-354
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Impression cytology
Useful to confirm diagnosis prior to topical chemotherapy
• Use of Biopore membrane
• High reliability >90% correlation rate with histology
• High degree of suspicion in heavily keratinized lesion
• Cannot identify SCC reliably
• Post MMC effect noticed
Tole et al BJO 2001;85:154-8
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Pathology
• Dysplasia– Cellular atypia
• mild <1/3 atypical cells
• Moderate ¾ atypical cells
• Severe nearly full thickness
• Carcinoma in situ– Full thickness atypia with
loss of normal surface layer
• SCC invasion of BM
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How do you distinguish SCC from dysplasia?SCC of the Conjunctiva Clinico-pathological review
• Identify clinical diagnostic features
• Establish reliability of impression cytology as an aid to diagnosis
• Outcome/ prognosis markers
McKelvie et al BJO 2002;86:168-173
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Clinical diagnosis
• Correct pre-operative diagnosis in 35%
• Pre-operative diagnosis of OSSN 85%
• If lesion> 10mm correct 67%
• Sex: 77% male
• Age: 69% >60 years
• Presentation:
– mass 80%
– redness/ irritation 36%
– Vision impaired 10%
• Size: 50% >10 mm
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Follow-up
• Median follow-up 26 months
• 7/26 recurrence (27%)
• 4/6 positive margins recurred
• 4 deaths
• 2 died of metastatic disease (8%)
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Risk factors for recurrence
• Positive margins p=0.028
• Size(>10mm) p=0.049
• Ki 67 score p=0.047
• Increased age p=0.0028
Non significant factors: sex, shape, differentiation, invasion of orbit/cornea/sclera or intraocular extension
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SCC Pathology
• All lesions keratinised
• Solar damage in all cases
• Invasive tumour arose from field of CIS in 7/26, dysplasia in 16/26
• Scleral/corneal invasion 30%
• Orbital invasion 15%
• Intraocular invasion 11%
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Keratotic variant
• Most common 16/26
• Invasion varied from minimal to deep
• minimal invasion 11/26
• Leukoplakia present
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Endophytic variant
• 8/26 endophytic type
• lobules of invasive keratinising SCC in stroma
• Nodular or diffuse
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Papillomatous SCC
• 2/26 papillomatous or exophytic
• velvety, papilloform
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SCC invading angle
• Invasion AC/ trabecular mesh/ iris 2/26
• ciliary body invasion 3/26
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Impression cytology
• Using Biopore membrane 80+% accuracy in OSSN diagnosis
• No tumour diathesis seen in SCC
• 60% had CIN or partial thickness epithelial atypia that would not yield atypical cells
• endophytic and orbital lesions not identified
NOT A RELIABLE METHOD TO EXCLUDE SCC
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Summary
• Large lesions with hyperkeratotic plaques most correctly diagnosed
• CIC not reliable aid to diagnosis
• Proliferation index Ki-67 offers useful prognostic information
• Adequate margin at time of first surgery critical
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Management of OSSN
• Excisional biopsy
• Cryotherapy
• Topical chemotherapy
– MMC
– 5 FU
– Interferon
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Surgical technique
• Wide resection of conjunctival tumour
– Partial lamellar scleroconjunctivectomy
– Conjunctival margin 2mm
– 0.2mm thin scleral flap
– Emerging into cornea, @ Bowmans
• Double freeze thaw cryotherapy
• Closure of conjunctival wound
Shields et al Arch Ophthalmol 1999
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Long term results with surgery
• 15 year follow-up
• 79 cases, 52 dysplasia, 27 CIS
• Complete excision 33% recurrence
• Incomplete excision 56% recurrence
• 15% recurred more than 5 years after surgery
• 9% progressed to SCC
Tabin et al Ophthalmol 1997
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Chemotherapy options
• Mitomycin
Dose 0.02-0.04% QID for one-three weeks
• Interferon alpha 2B
Topical QID until resolved
Intra lesional injection
Plus Retinoic acid
• 5-Fluorouracil 1%
Topical QID daily for one week followed by drug holiday of 3 weeks
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Mitomycin results
MMC 0.04% week on and week off
• Clinical resolution of disease 19/20
• Time to resolution 2-8 weeks (median 4)
• Number of cycles 1-5 (median 2)
MMC 0.04% 3 weeks
• 24/26 resolved
Daniell et al Clin Exp Ophth 2002;30:94-98
Hirst Ophthalmol 2007 976-982
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Complications
Epithelial toxicity 34%
Epiphora 14%
Lid/skin toxicity
Limbal stem cell deficiency rare
Khong et al BJO 2006;90:819-22
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Interferon results
IFN alpha2B (1x 106 iu/ml) QID until resolved
• 27/28 resolved, median 3 months treatment
IFN alpha 2B QID topically plus retinoic acid 0.01% alternate days
• 87/89 resolved
• 98% resolution in 1-7 months
• Side effects papillary conjunctivitis
IFN alpha 2B 0.5ml intralesional 2 weekly (10 x 106iu/ml)
• 13/15 resolved, median 6 injections
Schecter et al Ophthalmol 2008
Karp et al Ophthalmol 2010
Krilis et al Ophthalmol 2012
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Current protocol
• Primary disease treated with surgical excision + cryotherapy (excisional biopsy)
• Recurrent/ residual disease considered for interferon
• Interferon alpha 2a 1x106IU/ml QID until resolves
• Work-up including impression cytology
• MMC 0.04% qid for one week for recalcitrant disease– One week off treatment and review
– 2nd cycle of treatment and review
– If not resolved by 8 weeks consider 3rd cycle
– Punctal plug not required
• Long term follow up recommended
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Comparison of costs of topical meds
The retail price at Slade Pharmacy (Richmond) :
• MMC 0.04% - $247.90 (2 x 5 mL) or $192.95 (1 x 5 mL) – 28 days expiry from date of manufacture but 7 days expiry once opened.
• Interferon alpha 2b 1x106IU - $269 (note 14 day expiry and interferon alpha 2b (IntronA) deleted from market 1 June 2018 – may not be able to be prepared in future)
• 5 FU 1% - $121 (4 x 3 mL)
Eye and Ear Pharmacy
• Interferon alpha 2a (Roferon A) $200 (14 day supply)
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Management options
• Amniotic membrane transplant
– Large conjunctival defect
• Pre operative chemoreduction
– Extensive disease involving limbus
– Consider subconj high dose monthly injections 10x106iu/ml
• Post operative adjunctive therapy
– Incomplete margins
– High grade disease
– Immunoprevention in HIV
– ? All cases (IFN QID for 2 months)
• Long-term outcomes after adjunctive topical 5-flurouracil or mitomycin C
153 eyes followed 3+ years. There was one recurrence in the 5-fluorouracil group and no recurrences in the mitomycin C group (but more side effects in MMC group)
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Conclusion• Difficult to make a clinical diagnosis, need to check pathology
• Primary disease treated with surgical excision + cryotherapy
• Exception is widespread disease, consider chemoreduction
• Recurrent/ residual disease considered for medical treatment