Carol L. Shields

BASICS

DESCRIPTION

• The term “ocular surface squamous neoplasia (OSSN)” describes a spectrum of conjunctival and corneal epithelial dysplasia ranging from conjunctival/corneal intraepithelial dysplasia (CIN) to squamous cell carcinoma (SCC) (1).

– CIN is analogous to actinic keratosis and does not invade conjunctival substantia propria or corneal Bowman’s layer.

– Mild CIN: partial dysplasia of epithelium.

– Severe CIN (carcinoma in situ): full-thickness intraepithelial neoplasia.

– Invasive SCC (when neoplasia breaches the basement membrane) is locally invasive and may metastasize in 1–2%.

EPIDEMIOLOGY

Incidence

• Most common tumor of the ocular surface

– 0.03/100,000 persons in the U.S. (only of SCC; 18-year period)

– 0.13/100,000 persons in Uganda (6-year period)

– 1.9/100,000 persons in Australia (10-year period)

Prevalence

• Ranks among the top three most common ocular surface malignancies with melanoma and lymphoma

• In one pathology series, it was the most prevalent malignancy of the ocular surface at 4% of 2,455 conjunctival lesions in adults.

RISK FACTORS

• Advanced age (>60 years)

• Male

• Smokers

• Light complexion

• Exposure to UV light or petroleum products.

• Human papillomavirus (HPV) 16 and 18 (conflicting data)

• Atopic eczema

Genetics

Expression of aberrant p53 tumor suppressor gene observed in 73% of ocular surface SCC.

GENERAL PREVENTION

• Smoking cessation

• Protection from the sun

PATHOPHYSIOLOGY

UV-induced mutation or HPV-encoded destruction of p53 gene

ETIOLOGY

UV light, HPV infection

COMMONLY ASSOCIATED CONDITIONS

• HIV/AIDS

• Immunosuppressed state

• Xeroderma pigmentosum

• Atopic eczema

• Organ transplantation

DIAGNOSIS

HISTORY

• Presenting symptoms: ocular irritation

• Ask about history of smoking, sun burns, and chemical exposure.

• Ask about prior eye medications and surgery.

• Ask about systemic conditions.

PHYSICAL EXAM

• Commonly occur in the exposed interpalpebral area at or near the limbus

– Conjunctival component can be gelatinous, papilliform, or leukoplakic (white due to hyperkeratosis).

– Corneal component appears as a translucent, gray epithelial sheet with pseudopodia-like margins.

– Rose bengal staining helps to delineate tumor margins.

• Invasive SCC can be fixed to the underlying tissue and have large feeder vessels, with varying amounts of leukoplakia.

• CIN and SCC cannot be differentiated based on clinical features alone.

• Gonioscopy to evaluate iris and trabecular meshwork

• May be pigmented in patients with dark complexion (2)

DIAGNOSTIC TESTS & INTERPRETATION

Lab

Initial lab tests

HIV test if OSSN present in a young adult.

Follow-up & special considerations

• Gonioscopy to evaluate for invasion of iris and trabecular meshwork through which SCC can access the systemic circulation.

• Uveitis and high intraocular pressure in the setting of known SCC should be considered to have intraocular invasion until proven otherwise.

Imaging

Initial approach

Ultrasound biomicroscopy to estimate the depth of limbal invasion of the SCC.

Follow-up & special considerations

• Two less common but more aggressive variations of SCC are the following:

– Mucoepidermoid carcinoma: affect the elderly, has yellow mucinous cysts, tendency for intraocular and orbital invasion

– Spindle cell carcinoma: greater tendency to metastasize

Diagnostic Procedures/Other

• Primary complete excisional biopsy is most appropriate if possible.

• Map biopsy for large and diffuse OSSN in which a plan for topical chemotherapy is considered.

• Some advocate impression cytology to establish the diagnosis.

• Rose bengal staining helps delineate tumor margins.

Pathological Findings

• Mild CIN: partial-thickness replacement of the epithelium by anaplastic cells that lack normal maturation

• Severe CIN: full-thickness replacement of the epithelium by anaplastic cells

• Invasive SCC: anaplastic squamous cells displaying hyperkeratosis and dyskeratosis invading the underlying stroma and adjacent tissues.

– Mucoepidermoid carcinoma: a malignant epithelial lesion containing both mucinous and epidermoid differentiation, which immunostain for acid mucopolysaccharide and cytokeratin markers, respectively.

– Spindle cell carcinoma: also known as sarcomatous carcinoma with both epithelial and mesenchymal differentiation, which immunostain for cytokeratin markers and vimentin, respectively.

DIFFERENTIAL DIAGNOSIS

• Benign

– Conjunctivitis (for diffuse, flat OSSN)

– Pinguecula, pterygium

– Papilloma

– Pyogenic granuloma

– Nevus

• Malignant

– Amelanotic melanoma

– Sebaceous carcinoma

– Metastasis

TREATMENT

MEDICATION

Not relevant (complete excision preferred)

ADDITIONAL TREATMENT

General Measures

Complete surgical removal with negative margins is most desirable for tumor removal and diagnostic confirmation.

Issues for Referral

Because of high recurrence after an incomplete removal, early referral to an Ocular Oncology Service may be considered.

COMPLEMENTARY & ALTERNATIVE THERAPIES

• For extensive (>8 mm in basal diameter) or recurrent OSSN, use topical chemotherapeutic as an adjunct to reduce the size and thickness:

– Mitomycin C (MMC; toxic to ocular surface): 0.4 mg/mL (0.04%) 1 gtt q.i.d.; resolution in 4 months (3)[A], (4,5)

– 5-Fluorouracil (5-FU; toxic to ocular surface): 10 mg/mL (1%) 1 gtt q.i.d. (6)

– Interferon α-2b (IFN; follicular conjunctivitis): 1–3 million IU/mL 1 gtt q.i.d.; resolution in 6 months (7)[B]

• Subconjunctival injection of IFN (transient flu-like symptoms)

• Plaque brachytherapy for local recurrence or anterior orbital invasion

SURGERY/OTHER PROCEDURES

• Excisional biopsy for localized OSSN

– “No touch” technique with alcohol corneal epitheliectomy, partial sclerokeratoconjunc-tivectomy, and double freeze-thaw cryotherapy (8)[A]

– Margins: 2–4 mm (greater if suspecting invasive SCC) beyond the clinical margins of the tumor and a thin lamella of the underlying sclera should be removed.

• Excision of larger OSSN requires tissue graft.

• Plaque radiotherapy for local intraocular invasion

• Enucleation for diffuse intraocular invasion

• Eyelid-sparing exenteration for extensive orbital invasion

IN-PATIENT CONSIDERATIONS

Not relevant

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

• Long-term follow-up (>10 years) necessary because of high recurrence, but most occur within the first 2 years.

– Up to 30% with negative surgical margins

– More than 50% with positive surgical margins

– Recurrence is now much less with the use of adjunctive topical chemotherapy and IFN.

PATIENT MONITORING

Follow-up every 2–4 months until clinical resolution if using topical agents

DIET

Not relevant

PROGNOSIS

• Overall prognosis is good with extremely rare OSSN-related mortality.

– Associated with local invasion

• Intraocular invasion via limbal perforating vessels gaining access to Schlemm’s canal, trabecular meshwork, anterior chamber, suprachoroidal space, and choroid.

– Associated with large (>2 cm) OSSN

– Manifest as uveitis and glaucoma

• Can metastasize to preauricular, submandibular, and cervical lymph nodes; parotid gland; lungs; and bone in advanced disease

• Immunosuppressed patients are at highest risk for lymph node metastasis.

COMPLICATIONS

• Surgical treatment: potential limbal deficiency because of preferential location of OSSN at the limbus, conjunctival scarring, recurrence if multifocal disease unrecognized

• Medical treatment: local toxicity, recurrence due to poor penetration beyond the epithelium

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