OCULAR SURFACE SQUAMOUS NEOPLASIA(OSSN)

INTRODUCTION

• The term Ocular Surface Squamous Neoplasia [OSSN] presently refers to the entire spectrum of dysplastic, pre-invasive and malignant squamous lesions of the conjunctiva and cornea

• We have suggested the use of the "umbrella“ term ocular surface epithelial dysplasia (OSED) but now feel that ocular surface squamous neoplasia (OSSN) is a better terminology.

• OCULAR SURFACE denotes involvement of the conjunctiva or cornea;

• SQUAMOUS excludes other epithelial cells such as basal cells and melanocytes

• and NEOPLASIA includes both dysplastic and carcinomatous lesions.

Ocular Surface Squamous Neoplasia Graham a. lee, MBBS, and Lawrence w. hirst, MDSurvey of ophthalmology volume 39, number 6. may-june 1995

The term Ocular Surface Squamous Neoplasia (OSSN) was coined by Lee and Hirst which has three grades :-

I. BENIGN DYSPLASIA • Papilloma • Pseudoepitheliomatous hyperplasia • Benign hereditary intraepithelial dyskeratosis

II. PREINVASIVE OSSN • Conjunctival/corneal carcinoma in situ

III. INVASIVE OSSN • Squamous carcinoma • Mucoepidermoid carcinoma

EPIDEMIOLOGY• Third most common ocular tumour after melanoma

and lymphoma• Common in Caucasians• Common in older age group(6-7 decade) Males are affected more commonly than females • Earlier onset in areas in latitude 30 degree from

equator, declines considerably with increase in latitude • Pts with HIV and Xeroderma pigmentosum present

earlier All young patients with OSSN should be screened for

HIV.

ETIOLOGY

• LIMBAL TRANSITION ZONE/STEM CELL THEORY

• Stem cells in the limbal epithelial crypts are the likely originators of this disease, and may

take on cancer stem cell properties.

Effects of solar ultraviolet radiation

• UVB radiation causes direct DNA damage by crosslinking adjacent bases to form cyclobutane pyrimidine dimers (CPDs) and 6-4

photoproducts (6-4 PPs)• Specific CC/TT dimer transitions of the p53

tumour-suppressor gene have been observed in OSSN lesions

• 29% increase in incidence of SCC per unit increase in exposure to ambient solar ultraviolet radiation

• Other eye diseases thought to be related to UV-B exposure also have a high association with OSSN.

• pterygium• pingueculum • climatic droplet keratopathy • cataract • corneal degeneration

Reactivation of latent HPV infection.

• UV radiation also reactivates latent viruses such as HPV 16

• HPV's E7 protein keeps infected cells in a proliferative state

• while E6 inhibits cell cycle arrest of DNA-damaged cells.

Failure of DNA repair mechanisms

• An increased incidence of OSSN has been reported in conditions like Xeroderma Pigmentosa, where the DNA repair mechanism is defective

Immunosuppression

• UV radiation• HIV and • vitamin A deficiency weakens the tumour

surveillance system and allows DNA damaged cells to proliferate into tumours.

• Vitamin A deficiency interferes with ocular surface integrity creating micro-abrasions through which HPV may invade the conjunctival basement membrane and epithelial cells.

Miscellaneous• Chronic exposure keratopathy secondary to long• standing facial nerve palsy may be associated with

OSSN• exposure to petroleum products• heavy cigarette smoking• chemicals such as trifluridine and arsenicals• ocular surface injury• Chronic inflammatory conditions-pemphigoid,

atopic eczema, chronic blepharoconjunctivitis

Clinical Features

• Patients with OSSN may be asymptomatic or present with chronic redness and irritation of the eye.

• Visual acuity is not affected unless there is extensive corneal involvement

• OSSN may grow within weeks to years; in most cases, the history is of several months

• The lesions are described as being slightly elevated, variably shaped, relatively sharply demarcated from the surrounding normal tissues, accompanied by feeder blood vessels and colored from pearly gray to reddish gray depending on the vascularity of the tumor

• They most commonly straddle the nasal or temporal limbus between the palpebral fissures

• The following appearances may be seen. • a Gelatinous mass with superficial vessels

b White leukoplakic plaque that covers the lesion c Papillomatous lesion with corkscrew-like surface blood vessels

• In clinical practice, gelatinous type is the commonest.

• The gelatinous lesion can again be• circumscribed, which are most common • nodular variety , which has a propensity for

rapid growth • diffuse variety, the least common, which can

masquerade as chronic conjunctivitis

• The corneal side of the lesion may be seen as an opalesence of the epithelium, slightly raised in comparison to adjacent normal epithelium the edges of which are usually sharply defined.

• It is best appreciated by retroillumination.• The lesion is usually nonpigmented though

pigmented OSSN may also occur. • OSSN may sometimes mimic a pterygium or a

pinguecula. It has also been known to occur in a pre-existing pinguecula or pterygium.

• It is nearly impossible to categorise OSSN as benign or malignant based on clinical appearance alone.

• Larger lesions that are fixated to the underlying tissue are usually malignant.

• Staining with fluorescein sodium or Rose Bengal helps in the diagnosis by showing up the papillary or granular nature of the lesion and by delineating its extent

• Anterior segment OCT may be done to find out the extent of deep involvement as well as intraocular and angle invasion

• Intraocular invasion is rare ,heralded by onset of iritis, glaucoma, scleral thinning or retinal detachment.

• Regional and systemic metastases are also uncommon.

• Common sites of metastasis include preauricular,submandibular and cervical lymph nodes, parotid gland, lungs, and bone.

DIFFERENTIAL DIAGNOSIS• Pterygium• papilloma• pingueculum,• nevus. • Malignant melanoma• pyogenic granuloma • pseudo-epitheliomatous hyperplasia• Corneal pannus from any cause• Mooren's ulcer,• fatty degeneration of the cornea and epithelial dystrophy

of the cornea

• Papilloma may occur anywhere on the conjunctiva, may be sessile or pedunculated, has a punctate vascular pattern, occurs in younger patients,but ultimately may only be difterentiated by histologic examination

• Malignant melanoma has a regular smooth surface, lacks gelatinous or leukoplakic surface disturbances and may become ulcerated

• Benign nevi tend to occur in the interpalpebral zone, from the limbus to the caruncle, to

occur in younger patients, and to have distinctive cysts on slit-lamp examination

HISTOPATHOLOGY• DYSPLASIA:• Mild - less than a third thickness occupied by atypical cells• Moderate - three quarters thickness occupied by atypical

cells • Severe -- nearly full thickness occupied by atypical cells • CARCINOMA IN SITU: as above with loss of the normal

surface layer • INVASIVE SQUAMOUS CELL CARCINOMA: as above when

the basement membrane of the basal epithelial layer has been breached and invasion of the substantia propria has occurred.

• Spindle cell, Mucoepidermoid and Adenoid-Squamous are three aggressive variants

TREATMENT

• SURGICAL EXCISION

• video

TOPICAL CHEMOTHERAPY

• Topical chemotherapy may be used preoperatively, intraoperatively or postoperatively.

Its preoperative use is seen in cases with extensive lesions where it helps to reduce the tumor size and makes the tumor more amenable to surgical excision.

Intraoperatively, chemotherapy may have a role in place of adjuvant cryotherapy

postoperatively can be beneficial for managing cases with residual disease or positive surgical margins.

MITOMYCIN C

• Mitomycin C is the most commonly used topical chemotherapy agent

• It is a non cell cycle specific ALKYLATING AGENT that acts by alkylating the cross-linked DNA and inhibits DNA, RNA, and protein synthesis.

• MMC is used in concentrations of 0.04% qid, 4 days a week for 4 weeks.

• Overall, success rates ranging from 87 to 100% have been reported.

5-FU

• Is a pyrimidine analogue that acts by integrating with the DNA during S phase. It also interferes with RNA synthesis.

• It is used as 1% topical solution.• Side effects are similar to MMC

INTERFERONS

• Interferons are protein molecules that bind to cell receptors and trigger synthesis of effector proteins that can inhibit viruses, activate immunocompetent cells, and regulate oncogenes.

• Reports are emerging on the use of topical IFN- 2b for OSSN.

• It is more expensive than MMC and 5 FU, requires prolonged treatment but has a better safety profile

RADIOTHERAPY

• Plaque brachytherapy using radiation sources like Strontium 90 or Rhuthenium 106 is useful as an adjuvant to support surgical excision. Complications include conjunctival scarring, symblepharon, dry eye, cataract, scleral and corneal ulceration.

SUMMARY

• [1] Suspected OSSN < 3 clock hours –Excision biopsy + base/ edge cryotherapy + alchoholepitheliectomy is done.

• [2] Suspected OSSN 3 – 6 clock hours – As there is a risk of producing limbal stem cell deficiency, excision biopsy + cryotherapy is better avoided.

• A diagnostic biopsy is required • In pre-invasive lesions topical chemotherapy

is likely to achieve tumour resolution.• If invasive, surgery + cryotherapy is done after

chemoreduction with 4 to 6 cycles of topical chemotherapy.

• [3] OSSN > 6 clock hours – A diagnostic biopsy is required.

• In pre-invasive lesions topical chemotherapy is quite likely to achieve tumour resolution.

• If invasive, surgery + cryotherapy is done after chemoreduction with 4 to 6 cycles of topical chemotherapy.

• If there is no response to chemotherapy palliative radiotherapy or extensive surgery like enucleation / exenteration may be required.