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Arch Ophthalmol. 2003;121:280-282.

Squamous cell carcinoma of the conjunctiva is usually a slowly progressive neoplasm that rarely invades the eye or orbit.^1-2 Immunosuppressed patients are at increased risk to develop conjunctival squamous cell carcinoma.³ Tumors in immunosuppressed patients can behave aggressively.³ We describe a patient receiving immunosuppression treatment after liver transplantation, who developed an aggressive conjunctival squamous cell carcinoma that caused his death within 1 year of diagnosis.

Report of a Case
A 56-year-old man was referred for additional therapy after a biopsy of a conjunctival lesion revealed a poorly differentiated invasive squamous cell carcinoma that had been incompletely excised. His medical history included a liver transplantation for chronic sclerosing cholangitis 3 years previously and treatment with immunosuppressive drugs (azathioprine and tacrolimus).

On examination, his visual acuity was 20/20 OU. The left eye was unremarkable. The right eye showed a temporal conjunctival wound without clinical evidence of tumor. Based on a review of the previous histopathologic findings, wide surgical excision of the wound, double freeze-thaw cryotherapy, and superficial alcohol keratectomy were performed to remove residual microscopic disease and prevent recurrence. Histopathologic examination showed a completely resected tumor with uninvolved surgical margins.

Six months later, the patient developed sudden redness and swelling of the right upper eyelid. An external examination showed hemorrhagic axial proptosis and a palpable firm mass near the superolateral margin of the orbit (Figure 1). Ocular motility was restricted in all gazes and corneal sensation was intact. Magnetic resonance imaging of the brain and orbits disclosed a diffuse, enhancing mass that extended along the lateral wall of the right orbit from the rim to the apex (Figure 2), without radiologic evidence of cavernous sinus thrombosis.

View larger version (87K): [in this window] [in a new window] Figure 1. External photograph demonstrates proptosis, eyelid ecchymosis, and diffuse subconjunctival hemorrhage of the right eye.

View larger version (56K): [in this window] [in a new window] Figure 2. Axial magnetic resonance imaging of the orbits (T1-weighted, gadolinium enhancement) demonstrates a diffuse enhancing orbital mass that extends along the lateral orbital wall to the orbital apex.

An orbital exenteration was performed using an eyelid-splitting technique after an incisional biopsy revealed poorly differentiated squamous cell carcinoma. The small, poorly cohesive tumor cells had relatively scanty cytoplasm and vesicular nuclei with prominent nucleoli. The tumor filled the temporal third of the orbit and contained foci of hemorrhage and necrosis (Figure 3A). One to 2 mitotic figures were present per high power field. Several nerves near the orbital apex were entrapped in the tumor but others were tumor-free.

View larger version (171K): [in this window] [in a new window] Figure 3. A, Deeply invasive squamous cell carcinoma fills temporal half of horizontally sectioned orbit. Focally hemorrhagic tumor extends to orbital apex (hematoxylin-eosin; original magnification x2.5). B, Tumor cells show positive immunoreactivity for cytokeratin AE3 (peroxidase antiperoxidase; original magnification x100).

The tumor cells showed intense positive immunoreactivity for basic cytokeratin marker AE3 (Figure 3B), strongly coexpressed vimentin, and were focally positive for acid cytokeratin marker AE1. The cells were nonreactive for low–molecular weight cytokeratin marker CAM5.2, involucrin, leukocyte common antigen, melanoma marker HMB45, and S100 protein. In situ hybridization for panhuman papilloma virus DNA was negative, with appropriate positive and negative controls.

Two months later, the patient had a massive orbital recurrence with direct extension of the tumor to the brain and preauricular and cervical lymph node metastases. External beam radiotherapy was delivered but the patient died of brain invasion 2 months later.

Comment
Squamous cell carcinoma of the conjunctiva is a low-grade malignancy with little potential for local invasion and metastasis.¹ It most often occurs in the interpalpebral area near the corneoscleral limbus in older patients and appears as a fleshy, gelatinous, or leukoplakic mass.² Metastasis of conjunctival squamous cell carcinoma occurs in less than 1% of patients, usually to the regional lymph nodes.⁴ Rarely, intraocular invasion² or distant metastases to the lung and bone have occurred.⁴

Immunosuppressed patients are at risk for developing opportunistic malignancies.⁵ Patients with human immunodeficiency virus infection are at a risk for developing lymphoid tumors and Kaposi sarcoma, while patients with organ transplantation are at a risk for developing lymphoid tumors and skin cancer.⁶ Aggressive conjunctival squamous cell carcinoma has been reported in patients with human immunodeficiency virus infection³ and conjunctival epithelial neoplasia in patients with organ transplantation receiving cyclosporine therapy.⁷ The patient described here received azathioprine and tacrolimus therapy. It is not clear whether one or both drugs had a role in the development of the aggressive conjunctival squamous cell carcinoma in this patient.

Conjunctival squamous cell carcinoma has been associated with human papillomavirus, especially type 16.⁵ Human papillomavirus was not found in the orbital specimen in this patient; however, it is not clear whether the development of conjunctival squamous cell carcinoma in this patient was related to the carcinogenic effect of immunosuppressive drugs or to the diminished immune surveillance of transformed cells.^6-7

Recurrence of conjunctival squamous cell carcinoma is generally greater in patients with higher grade undifferentiated tumors and in those with incomplete initial excision.⁶ Our patient was referred to us after incomplete initial excision, and despite a seemingly adequate reexcision of his tumor, he developed aggressive recurrence of the tumor, with rapid extension to the brain and regional lymph nodes. Generally, involvement of the surgical margin by tumor cells on histopathologic examination is an indication to repeated surgical resection with wider margins, especially in immunosuppressed patients.

In summary, we described a 56-year-old patient with liver transplantation who developed aggressive conjunctival squamous cell carcinoma that invaded the brain and led to death despite orbital exenteration. Physicians should be aware that conjunctival squamous cell carcinoma may be more aggressive in immunosuppressed patients.

Support was provided by the Eye Tumor Research Foundation, Philadelphia, Pa (Drs C. Shields and J. Shields), the Paul Kayser International Award of Merit in Retina Research, Houston Tex (Dr J. Shields), the Macula Foundation, New York, NY (Dr C. Shields), and the Noel T. and Sara Simmonds Endowment for Ophthalmic Pathology, Wills Eye Hospital (Dr Eagle).

Abdallah E. Shelil, MD; Carol L. Shields, MD; Jerry A. Shields, MD; Ralph C. Eagle, Jr, MD
Philadelphia, Pa

Corresponding author and reprints: Carol L. Shields, MD, Ocular Oncology Service, Wills Eye Hospital, 900 Walnut St, Philadelphia, PA 19107.

REFERENCES
1. Shields JA, Shields CL. Premalignant and malignant tumors of the conjunctiva epithelium. In: Shields JA, Shields CL, eds. Atlas of Eyelid and Conjunctiva Tumors. Philadelphia, Pa: Lippincott Williams & Wilkins; 1999;226-241. 2. Shields JA, Shields CL, Gunduz K, Eagle RC. Intraocular invasion of conjunctiva squamous cell carcinoma in five patients: the 1998 Pan American Lecture. Ophthalmic Plast Reconstr Surg. 1999;15:153-160. PUBMED 3. Lewallen S, Shroyer KR, Keyser RIB, Liomba G. Aggressive conjunctiva squamous cell carcinoma in three young Africans. Arch Ophthalmol. 1996;114:215-218. ABSTRACT 4. Tabbara KF, Kersten R, Daouk N, Blodi FC. Metastatic squamous cell carcinoma of the conjunctiva. Ophthalmology. 1988;95:318-321. ISI | PUBMED 5. McKelvie PA, Daniell M, McNab A, et al. Squamous cell carcinoma of the conjunctiva: a series of 26 cases. Br J Ophthalmol. 2002;86:168-173. FREE FULL TEXT 6. Rao NA, Dunn SA, Romero JL, Stout W. Bilateral carcinoma of the eyelid. Am J Ophthalmol. 1986;101:480-482. PUBMED 7. Macarez R, Bossis S, Robinet A, et al. Conjunctival epithelial neoplasias in organ transplant patients receiving cyclosporine therapy. Cornea. 1999;18:495-497. PUBMED

SECTION EDITOR: W. RICHARD GREEN, MD

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