The conjunctival epithelium consists of both stratified squamous and columnar epithelium. Squamous epithelium is found near the limbus changing to the columnar type near the fornix.
Actinic induced dysplasia is considered the predominant etiology with the conjunctiva being the only mucous membrane in relatively constant exposure to sunlight.
In temperate climates, the highest prevalence is in Caucasian males over the age of 60, range 20–88 years (Lee GA, Arch Ophthalmol 1992) (Shields et al., Ophthalmology Sept 2004).
There is generally a male over female preponderance, however prevalence affects genders equally in Africa (Gichuhi et al. Exp Eye R, 2014).
Overall incidence of OSSN ranges from 0.02 to 3.5 per 100,000 per year worldwide.
In the US (NIH study), Australia, and Uganda, the incidence of OSSN is 0.03, 1.9, and 0.13 cases per 100,000 per year, respectively (Alves LF, Arq Bras Oftalmol 2011).
The average of incidence of carcinoma in situ lesions is 5–9 years lower than invasive OSSN, this difference representing the time taken for progression from CIN to invasive carcinoma.
Intraocular extension may occur in 2% to 13% of cases (McKelvie P, BJO 2002).
Recurrence and mortality rates are not clearly established due to a paucity of prospective studies and differing follow-up periods.
Significant predictors for recurrence are size of lesion, positive surgical margins, elevated proliferation index measured by Ki‑67 score, and increased age (McKelvie P, BJO 2002).
Recurrence rates can reach up to one-third of patients; this varies due to treatment and follow-up differences across centers (McKelvie P, BJO 2002).
Mortality ranges from 0% to 8% across various studies. Metastasis is not necessarily a predictor of death in OSSN (McKelvie P, BJO 2002).
The patient may complain of pain, irritation, and hyperemia, occasionally of a pre-existing pterygium site. Lee GA et al., Aust NZ J Ophthalmol 1997 determined ocular irritation to predict a 2.4-fold increase in recurrence (after treatment) in patients with OSSN.
Inquire regarding a history of increased sun exposure, hereditary, and acquired immunodeficient conditions (including HIV infection) and HPV infection.
Most commonly occur on the bulbar conjunctiva in the limbal region on the nasal side (Wadell et al. 2006)
Typically arises over a pr-eexisting area of solar elastosis such as a pterygium
OSSN is characterized by epithelial thickening with possible extension onto the cornea. Corneal involvement may only appear as a subtle, gray surface opacity sometimes only discernible on slit-lamp biomicroscopy (hence the need for vigilant examination before surgery).
Clinically, symptoms may range from asymptomatic to a chronically irritated, red eye. Masses are initially mobile; the conjunctiva in later stages becoming fixed to the globe with deeper scleral infiltration.
OSSN and MEC are difficult to distinguish clinically; key findings of these placoid, gelatinous or fern-like lesions are the coexistence of a skein of corkscrew or hairpin vessels indicating an underlying sessile papillary architecture. A feeder vessel may be seen.
The involved epithelium may also be subtly opalescent and show punctate staining with supravital dyes (Rankin et al., Surv Ophth July-Aug 2012).
Surface keratinization is not pathognomonic for OSSN and may be seen over any elevated lesion not covered by an adequate tear film; however it should arouse suspicion particularly when correlated to a leukoplakic lesion.
MEC is a rare variant of OSSN occurring in older patients with a yellow-globular cystic component due to the presence of multiple mucus secreting cells within cysts. This lesion (as with the spindle cell variant of SCC) is more aggressive and requires detailed clearance as well as closer follow-up (Shields CL, Shields JA, Oculoplastics and Orbit, Springer 2006).
Figure 1. Ocular surface squamous neoplasia.
Figure 2. Advanced ocular surface squamous neoplasia of the conjunctiva.
A incisional or excisional biopsy is usually recommended to confirm the diagnosis; the latter technique is preferably for relatively smaller lesions (involving 4 clock hours or less of the limbus or 15mm or less in basal dimension).
Occasionally exfoliative cytology and fine-needle aspiration biopsy can provide useful information on the basis of a few cells (Spinak et al. Surv Ophthalmol 1977).
Clinical photography, high-resolution OCT, and in-vivo confocal laser scanning microscopy (CLSM) have been reported as recent methods to aid diagnosis, determine treatment effects and monitor for recurrence (Xu Y et al., Eye (Lond) 2012, Shousha MA Ophthalmology 2011 and Parrozzani R Eye (Lond) 2011).
High-resolution OCT may show thickened hyper-reflective epithelium with abrupt transition from normal to hyper-reflective epithelium (Shousha MA, Ophthalmology 2011).
CLSM may reveal features such as
- Large areas of superficial cell/keratin debris accompanied by syncytial-like groupings
- Loss of the normal structure of the conjunctival epithelium and/or of the corneal basal epithelial layer
- Papillomatous organization
- Large fibrovascular structures
- Fine vessels perpendicular to the tumor surface
- Cellular anisocytosis, pleocytosis and anisonucleosis (Parrozani R et al., Eye (Lond) 2011)
- Enlarged nuclei with a high nuclear to cytoplasmic ratio, high reflective cytoplasm and indistinct cytoplasmic borders (100% of 10 cases described by Parrozani et al)
Interruptions of the layered epithelial structure along with cellular changes such as enlargement and polymorphic nuclei may be more predictive of transition to CIN or frank SCC (Falke K, Klin Monbl Augen Jul 2012).
Histopathological diagnosis remains the key tool in diagnosis:
- The epithelium exhibits hyperplasia, loss of goblet cells, loss of normal cell polarity, nuclear hyperchromasia and pleomorphism as well as mitotic figures.
- Dyskeratosis may be seen.
- A chronic inflammatory process may be present within the substantia propria.
- Degree of epithelial layer change and integrity of the basement membrane determines classification as intraepithelial (CIN), carcinoma in situ, or frank invasive carcinoma (SCC).
- Cellular atypia determines CIN grading into mild (basal one-third), moderate (inner two-thirds) or severe (full thickness)- this has not been correlated with prognosis.
- Severe atypia results in full-thickness epithelium involvement often with squamous eddies or keratin pearls (carcinoma in situ).
- Invasion of the stroma by neoplastic cells is required for a diagnosis of invasive carcinoma/SCC.
- Immunostaining with antibody to Ki-67, which is a nuclear antigen expressed in proliferating cells, allows evaluation of the growth fraction of normal and neoplastic cells allowing prognostic information (McKelvie P, BJO 2002).
Testing for staging, fundamental impairment
Grading based on description of OSSN by Lee and Hirst (Lee GA, Hirst LW Surv Ophthalmol 1995):
- I. Benign dysplasia
- Pseudotheliomatous hyperplasia
- Benign hereditary intraepithelial dyskeratosis
- II. Preinvasive OSSN
- Conjunctival/corneal carcinoma in situ
- III. Invasive OSSN
- Squamous carcinoma
- Mucoepidermoid carcinoma
Staging based on the AJCC (American Joint Committee on Cancer) (Edge SB et al., AJCC Cancer Staging Manual 2009)
- TX Primary tumor cannot be assessed
- T0 No evidence of primary tumour
- Tis Carcinoma in situ (would include lesser degrees of dysplasia collectively referred to as conjunctival intraepithelial squamous neoplasia)
- T1 Squamous cell carcinoma (SCC) 5 mm or less in greatest dimensions (T1 stage and beyond represent invasive cancer)
- T2 SCC > 5 mm in greatest dimension, without invasion of adjacent structures (excludes carcinomas that invade cornea, eye, forniceal, conjunctiva, tarsus, lacrimal punctum, canaliculi, plica, caruncle, anterior or posterior eyelid lamella or eyelid margin)
- T3 SCC invades adjacent structures but not orbit (includes involvement of adjacent structures excluded in T2)
- T4 SCC invades orbit with or without further extension
- T4a SCC invades bone
- T4b SCC invades paranasal sinuses
- SCC invades brain