—  SHORT COURSE  —

OPHTHALMIC PATHOLOGY FOR THE NON-SPECIALIST


CASE 2 – SQUAMOUS CELL CARCINOMA OF CONJUNCTIVA AND CORNEA

J. Godfrey Heathcote, M.B.,Ph.D.  —  Janice R. Safneck, M.D.




History
A recurrent conjunctival tumor in a 62-year-old man treated by orbital exenteration.

Diagnosis
1. Conjunctival squamous cell carcinoma-in-situ
 - upper and lower eyelids
2. Corneal squamous cell carcinoma
(a) intra-ocular extension:
(1) retrocorneal epithelial cyst
(2) retinal detachment (tractional)
(b) status post:
(i) cataract extraction
(ii) iridectomy
(iii)penetrating keratoplasty

Histopathology
In both eyelids the conjunctival squamous epithelium is dysplastic, focally of sufficient severity to constitute carcinoma-in-situ. The lower fornix is unremarkable. In the upper fornix, on the bulbar surface, there is abrupt thickening with severe dysplasia of the surface epithelium. There is some flattening of the surface and a small amount of parakeratosis as the dysplastic process extends on to the cornea.


Case 2, Slide 4 - Squamous Cell Carcinoma of Conjunctiva and Cornea: Upper fornix with carcinoma-in-situ of bulbar and palpebral conjunctival epithelium
Case 2, Slide 5 - Squamous Cell Carcinoma of Conjunctiva and Cornea: Squamous cell carcinoma-in-situ of bulbar conjunctiva

In the peripheral cornea Bowman's membrane is disrupted and replaced by scar tissue that is continuous with the full-thickness scar of a previous penetrating keratoplasty. The stroma is of irregular thickness and exhibits neovascularization and a mixed inflammatory infiltrate. Inferiorly the corneal epithelium is only moderately dysplastic but nests of squamous cell carcinoma are seen in the keratoplasty scar and in a retrocorneal fibrous membrane. Malignant squamous cells are seen on both the anterior and posterior faces of Descemet's membrane. The posterior layer of squamous cells has grown over the vitreous base and has formed a retrocorneal epithelial cyst.

The trabecular meshwork is sclerotic but has not been infiltrated by tumor. The iris is absent and the ciliary processes have been drawn forward by the retrocorneal fibrous membrane in which a small remnant of cataractous lens material is embedded. A coronal adenoma is seen on the ciliary processes superiorly. There is partial organization of the vitreous base as it is covered by squamous cells and there is a tractional detachment of the peripheral retina. Photoreceptor elements are absent from the peripheral retina, particularly inferiorly, and there is subretinal gliosis. The remainder of the retina is a little disorganized with a slight reduction in the number of ganglion cells. The eye is otherwise unremarkable. There is no evidence of secondary orbital invasion by the squamous cell carcinoma.

Discussion
Squamous cell carcinoma (SCC) of the conjunctiva is an uncommon disease. Its annual incidence has been estimated at 1 - 2.8 per 100,0001  and it is found principally in men over the age of 60 years.2  A variety of factors have been implicated in its causation, including infection by Human Papilloma Virus (type 163  and type 18)4  and Human Immunodeficiency Virus (HIV).5-8  In some African countries the incidence has increased dramatically in recent years with the tumors developing at an earlier age.9  Serological testing for HIV infection may be indicated in patients under the age of 50 with conjunctival intraepithelial neoplasia.8  Probably the most important cause is exposure to sunlight, since ocular surface dysplasia usually occurs in the interpalpebral zone and is a feature of xeroderma pigmentosum.10  Squamous epithelial dysplasia, carcinoma-in-situ (CIN: conjunctival intraepithelial neoplasia) and SCC are parts of the spectrum of ocular surface dysplasia.

CIN is generally found at the limbus, less commonly the fornices or palpebral conjunctiva.10  Isolated corneal CIN or SCC is rare and the cornea is usually involved secondarily by radial spread of a conjunctival lesion.11  The limbal tumor may appear as a leukoplakia or in papillary, verrucous, gelatinous or vascularised forms. Very occasionally the conjunctival epithelium may be diffusely involved.12  In approximately two-thirds of cases the presenting symptoms may be a red eye and ocular irritation rather than a tumor13  and occasionally the carcinoma may mimic a necrotizing scleritis.14  The lesion is of low malignant potential and limited conjunctival resection, possibly combined with cryotherapy, may be adequate. More aggressive behavior has been described in African cases.15  The recurrence rate overall is approx. 24% but may be as high as 53% if the surgical margin is involved by CIN.2  Dysplastic corneal epithelium appears as a grey plaque and can be removed by scraping, with care not to damage the underlying Bowman's membrane since this structure provides a barrier to stromal invasion. Disruption of Bowman's membrane by lamellar or penetrating keratoplasty may, as in the case presented, have serious consequences.16  Topical application of the alkylating agent mitomycin C has been used successfully as an alternative to surgical removal of dysplastic corneal epithelium17  and there are indications that topical interferon alpha-2b may be effective.18  Although superficial infiltration of the corneal stroma may occur, intra-ocular extension occurs through the aqueous drainage channels at the limbus.

In Erie's series there were 19 invasive lesions and 98 cases of CIN.2  Of the invasive lesions 15 showed microinvasion, i.e., confined to the subepithelial substantia propria, and the others had extended into the orbit (2) or the eye (2). Iliff et al.10  found approx. similar proportions of orbital (3/27) and intra-ocular (2/27) extension in their study of invasive carcinoma. Although recurrences are relatively common, metastatic disease is unusual and tends to occur in those cases with extension into orbit or eye.2,10,19  Regional metastases are found in the parotid gland, the pre-auricular lymph nodes and the cervical (including submandibular) nodes; distant metastases involve bone and lung.19  Orbital involvement may have a greater impact on prognosis than regional metastasis because of the risk of intracranial extension.

A spindle cell variant of SCC has been described in the conjunctiva,20  as in other mucous membranes. The literature also contains several reports of mucoepidermoid carcinoma arising from the conjunctival epithelium.21 

Actinic keratosis of the conjunctiva is an intra-epithelial lesion that may be confused by the pathologist with dysplasia or carcinoma-in-situ. A study of 45 intra-epithelial lesions with a minimum of 2 years of follow-up provided criteria for distinction between dysplasia and actinic keratosis:22 

Actinic Keratosis Dysplasia
(n=24) (n=21)
Sun-exposed areas Anywhere, esp. limbus
Associated with pterygium  
Focal; leukoplakic Diffuse; gelatinous
Irregular acanthosis  
Squamoid (eosinophilic) Basaloid (basophilic)
Parakeratosis (PK) PK minimal or absent
Variable architectural disarray Gradation of architectural disarray (mild-severe)
Variable cellular atypia non-uniform Cellular atypia more uniform
No CIS (always maturation) Progression to CIS
Recurrence infrequent (8%) Recurrence frequent (62%)
Elastotic degeneration of substantia propria Elastotic degeneration less frequent

Recurrence is probably more likely in dysplasia because the epithelial change is more diffuse and its margins are clinically ill-defined. If features of both actinic keratosis and dysplasia are present in a lesion then, according to Mauriello et al.,22  the pathological diagnosis should be based primarily on (a) the presence or absence of parakeratosis and (b) the extent of the lesion.

Pinguecula
This is the name given to a yellowish-grey mass at the limbus caused by focal elastotic degeneration of the conjunctival substantia propria.23  Although related to sun exposure, there is no epithelial abnormality and the lesion is of no clinical significance. It is occasionally excised at the time of cataract extraction but is more often seen by the pathologist as an incidental finding in an enucleated eye.

Pterygium
An excised pterygium is the most common conjunctival specimen received in surgical pathology.24  It consists of a fleshy, triangular vascular membrane that extends, usually on the nasal side, across the limbus on to the cornea where it may grow to obscure the visual axis. Like a pinguecula, pterygium is caused by exposure to ultraviolet radiation25,26  and the principal histopathological feature of a pterygium is hyalinization of the substantia propria with a variable amount of elastotic degeneration. This is accompanied by a fibroblastic proliferation in the limbus that advances into the cornea on both sides of Bowman's membrane. Topical application of mitomycin C to bare sclera at the time of excision has been shown to reduce the rate of recurrence, presumably by preventing fibroblastic proliferation.27  The epithelium is usually of variable thickness and may show secondary changes, such as dysplasia, goblet cell hyperplasia and ulceration. Secondary changes in the stroma include deposits of calcium phosphate and spheroidal droplet degeneration.

References

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  3. McDonnell JM, Mayr AJ, Martin WJ. DNA of human papillomavirus type 16 in dysplastic and malignant lesions of the conjunctiva and cornea. N Engl J Med 1989;320:1442-1446.
  4. Lauer SA, Malter JS, Meier JR. Human papillomavirus type 18 in conjunctival intraepithelial neoplasia. Amer J Ophthalmol 1990;110:23-27.
  5. Winward KF, Curtin VT. Conjunctival squamous cell carcinoma in a patient with human immunodeficiency virus infection. Amer J Ophthalmol 1989;107:554-555.
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