A recurrent conjunctival tumor in a 62-year-old man treated by orbital exenteration.
|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 |
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
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.
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
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
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.
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.
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
- Lee GA, Hurst LW. Incidence of ocular surface epithelial dysplasia in metropolitan Brisbane. Arch
- Erie JC, Campbell RJ, Liesegang TJ. Conjunctival and corneal intraepithelial and invasive neoplasia.
- 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.
- Lauer SA, Malter JS, Meier JR. Human papillomavirus type 18 in conjunctival intraepithelial neoplasia.
Amer J Ophthalmol 1990;110:23-27.
- Winward KF, Curtin VT. Conjunctival squamous cell carcinoma in a patient with human immunodeficiency
virus infection. Amer J Ophthalmol 1989;107:554-555.
- Muccioli C, Belfort Jr R, Burnier M, Rao N. Squamous cell carcinoma of the conjunctiva in a patient with
the acquired immunodeficiency syndroma. Amer J Ophthalmol 1996;121:94-96.
- Margo CE, Mack W, Guffey, JM. Squamous cell carcinoma of the conjunctiva and human immunodeficiency
virus infection. Arch Ophthalmol 1996;114:349.
- Karp CL, Scott IU, Chang TS, Pflugfelder SC. Conjunctival intraepithelial neoplasia. A possible marker
for human immunodeficiency virus infection? Arch Ophthalmol 1996;114:257-261.
- Poole TRG. Conjunctival squamous cell carcinoma in Tanzania. Br J Ophthalmol 1999;83:177-179.
- Iliff WJ, Marback R, Green WR. Invasive squamous cell carcinoma of the conjunctiva. Arch Ophthalmol
- Cameron JA, Hidayat AA. Squamous cell carcinoma of the cornea. Amer J Ophthalmol 1991;111:571-574.
- Khalil MK, Pierson RB, Mihalovits H, Bell RA, Lorenzetti DWC. Intraepithelial neoplasia of the bulbar
conjunctiva clinically presenting as diffuse papillomatosis. Can J Ophthalmol 1993;28:287-290.
- Tunc M, Char DH, Crawford B, Miller T. Intraepithelial and invasive squamous cell carcinoma of the
conjunctiva: analysis of 60 cases. Br J Ophthalmol 1999;83:98-103.
- Mahmood MA, Al-Rajhi A, Riley F, Karcioglu ZA. Sclerokeratitis: an unusual presentation of squamous
cell carcinoma of the conjunctiva. Ophthalmology 2001;108:553-558.
- Lewallen S, Shroyer KR, Keyser RB, Liomba G. Aggressive conjunctival squamous cell carcinoma in three
young Africans. Arch Ophthalmol 1996;114:215-218.
- Khalil MK, Rosen J, Heathcote JG, Nianiaris N, Lorenzetti DWC. Intraepithelial neoplasia of the cornea.
Can J Ophthalmol 1993;28:283-286.
- Frucht-Pery J, Rozenman Y. Mitomycin C therapy for corneal intraepithelial neoplasia. Amer J Ophthalmol
- Karp CL, Moore JK, Rosa RH Jr. Treatment of conjunctival and corneal intraepithelial neoplasia with
topical interferon alpha-2b. Ophthalmology 2001;108:1093-1098.
- Tabbara KF, Kersten R, Daouk N, Blodi FC. Metastatic squamous cell carcinoma of the conjunctiva.
- Huntington AC, Langloss JM, Hidayat AA. Spindle cell carcinoma of the conjunctiva. An
immunohistochemical and ultrastructural study of six cases. Ophthalmology 1990;97:711-717.
- Margo CE, Weitzenkorn DE. Mucoepidermoid carcinoma of the conjunctiva: report of a case in a
36-year-old with paranasal sinus invasion. Ophthalmic Surgery 1986;17:151-154.
- Mauriello JA, Napolitano J, McLean I. Actinic keratosis and dysplasia of the conjunctiva: a
clinicopathological study of 45 cases. Can J Ophthalmol 1995;30:312-316.
- Jaros PA, DeLuise VP. Pingueculae and pterygia. Surv Ophthalmol 1988;32:41-49.
- Grossniklaus HE, Green WR, Luckenbach M, Chan CC. Conjunctival lesions in adults. A clinical and
histopathologic review. Cornea 1987;6:78-116.
- Moran DJ, Hollows FC. Pterygium and ultraviolet radiation: a positive correlation. Brit J Ophthalmol
- Karai I, Horiguchi S. Pterygium in welders. Brit J Ophthalmol 1984;68:347-349.
- Frucht-Pery J, Siganos CS, Ilsar M. Intraoperative application of topical mitomycin C for pterygium
surgery. Ophthalmology 1996;103:674-677.