The most common ocular surface neoplasms are those of the squamous family. Of these, the most common benign variant is squamous papilloma. Clinically, squamous papilloma may be divided into pedunculated and sessile subtypes.
Pedunculated papilloma is an exophytic, pink-red, strawberry-like frond frequently localized to the caruncle (Fig 5-15A), plica semilunaris, or forniceal conjunctiva. It occurs most commonly in children and young adults, with multiple lesions sometimes present in affected patients. Pedunculated papilloma is associated with human papillomavirus (HPV) infection, subtypes 6 and 11. Histologic examination of a pedunculated papilloma demonstrates fingerlike projections of hyperplastic squamous epithelium with a central fibrovascular core (Fig 5-15B). Goblet cells may be present as in normal conjunctival epithelium. When overlying tear film disruption results in exposure, the number of goblet cells may become reduced and the surface keratinized. Neutrophils may be seen within the epithelium, and a chronic inflammatory infiltrate is frequently present in the stroma. Pedunculated papillomas typically exhibit benign behavior and rarely undergo malignant transformation.
A sessile papilloma generally arises on the bulbar conjunctiva, especially at the limbus, and occurs more commonly in adults. This type of papilloma is also associated with HPV infection, subtypes 16 and 18—the same subtypes associated with squamous malignancies. Clinical features worrisome for malignant transformation include leukoplakia (ie, white patches indicative of keratinization), inflammation, atypical vascularity, and corneal involvement. Histologically, a sessile papilloma exhibits a broad base and lacks the prominent fingerlike projections seen in a pedunculated papilloma. The epithelium is hyperplastic with intervening fibrovascular cores but is otherwise normal. The presence of nuclear hyperchromatism and pleomorphism, altered maturation (dysplasia), dyskeratosis, and frequent mitotic figures suggests a diagnosis of ocular surface squamous neoplasia.
Figure 5-15 Squamous papilloma. A, Clinical photograph shows squamous papilloma located at the caruncle (arrows).B, The epithelium is hyperplastic with fingerlike projections surrounding fibrovascular cores.
(Part A courtesy of George J. Harocopos, MD.)
Ocular surface squamous neoplasia
Ocular surface squamous neoplasia (OSSN) comprises a wide spectrum of dysplastic changes of the ocular surface epithelium, including conjunctival and corneal intraepithelial neoplasia (CIN), squamous cell carcinoma in situ, and squamous cell carcinoma (SCC), which, by definition, invades through the epithelial basement membrane (Fig 5-16).
The prevalence of OSSN is increased in equatorial regions of the world. Ultraviolet (UV) light exposure is a known risk factor for the condition, especially in individuals with light skin pigmentation. Some reports have shown mutations in tumor suppressor genes such as p53 secondary to UV light exposure. A hereditary impairment of DNA repair (as in xeroderma pigmentosum) also increases the risk of OSSN. In addition, OSSN occurs more frequently in patients who are immunosuppressed, such as those with HIV infection/AIDS, and in those with ocular surface HPV infection (subtypes 16 and 18). OSSN is commonly the first presenting sign of HIV/AIDS in regions where HIV infection is endemic. HIV-associated OSSN may demonstrate rapid growth and aggressive behavior, and HIV infection should be suspected in any patient with OSSN who is younger than 50 years.
OSSN typically arises in the interpalpebral limbal zone. It usually presents as a unilateral vascularized, gray, gelatinous limbal mass located medially or laterally in the sun-exposed interpalpebral fissure; the lesion may extend onto the peripheral cornea. Other features such as overlying leukoplakia (white plaque) and tortuous dilated “corkscrew” feeder vessels may be present (Figs 5-17, 5-18A, B). Clinical features overlap with those of other ocular surface lesions, making diagnosis of OSSN based solely on clinical assessment difficult. Other entities in the clinical differential diagnosis of OSSN include pannus, benign papilloma, pinguecula, pterygium, vitamin A deficiency, benign intraepithelial dyskeratosis, and nevus.
Figure 5-16 Schematic representation of the degrees of ocular surface squamous neoplasia (OSSN). The first panel represents normal epithelium with a basement membrane (pink line). In conjunctival intraepithelial neoplasia (CIN), the deeper layers of the epithelium are replaced with disorganized, often atypical cells that are not maturing normally (dysplasia). Carcinoma in situ is full-thickness replacement of epithelium by dysplastic cells, with the basement membrane still intact. In invasive squamous cell carcinoma, note the invasion through the basement membrane into the stroma.
(Courtesy of Patricia Chévez-Barrios, MD.)
Anterior segment optical coherence tomography (AS-OCT), ultrasound biomicros-copy (UBM), and impression cytology (IC) are less invasive options for possible diagnosis of CIN and OSSN. AS-OCT imaging has been reported to correlate with histologic findings in distinguishing noninvasive and invasive OSSN (Fig 5-18C, D). However, these diagnostic techniques are not routinely used for this purpose, and biopsy remains the standard for accurate diagnosis of these entities.
Conjunctival biopsy and handling of these specimens require special care and attention for accurate diagnosis of OSSN and evaluation of the margins of excision (see Chapter 3 for more information on specimen preparation). Histologically, the epithelium often demonstrates an abrupt transition to an area of hyperplasia, loss of goblet cells, loss of polarity (loss of normal maturation from basal to superficial layers), nuclear hyperchromatism and pleomorphism, and mitotic figures that may be atypical. Dyskeratosis, including surface keratinization (resulting in the clinical appearance of leukoplakia) and formation of keratin pearls within the epithelium, may be present. Often, there is chronic inflammation and increased vascularity in the underlying superficial stroma. Elastotic degeneration is also often present in the stroma (Fig 5-18E, F; see also Fig 5-17B).
The most important histologic assessment in OSSN is determining whether the neoplasia is contained by the epithelial basement membrane (ie, intraepithelial or in situ) or whether neoplastic cells have breached the basement membrane and invaded the stroma (see Figs 5-17, 5-18). The term conjunctival intraepithelial neoplasia (CIN) is often used for lesions contained by the basement membrane. The neoplasia is graded as mild, moderate, or severe according to the degree of cellular atypia. In cases of the most severe dysplasia, there is full-thickness involvement of the epithelium, often with squamous eddies or keratin whorls or pearls (see Figs 5-17C, D and 5-18E). For full-thickness dyplastic lesions, the term squamous carcinoma in situ is used.
Figure 5-17 Ocular surface squamous neoplasia (OSSN). A, Clinical photograph. Note the vascular tortuosity of the conjunctival portion and the gelatinous appearance with focal leukoplakia of the corneal portion. Also note the prominent feeder vessels. B, Histologic examination shows the sharp demarcation (arrow) between normal and abnormal epithelia in OSSN. The epithelium is hyperplastic, with surface keratinization (K). Because the basement membrane is intact and there is partial-thickness dysplasia of the epithelium, a diagnosis of CIN is made. There is a chronic inflammatory response in the stroma (CI). Also note areas of elastotic degeneration in the stroma (arrowheads), indicating that the lesion arose over a pinguecula. C, High magnification (image from a different patient) shows the transition zone where neoplasia begins (arrow). To the right of the arrow, the epithelium exhibits mild surface keratinization, hyperplasia, nuclear hyperchromatism and pleomorphism, goblet cell loss, altered cell polarity, full-thickness involvement, and mitotic figures (M). The basement membrane is intact (arrowheads), making this a squamous cell carcinoma (SCC) in situ. D, In SCC, tongues of epithelium violate the basement membrane and invade the stroma (arrows), with whorls of epithelial cells known as squamous eddies (arrowheads).E, Gross photograph of a large ocular surface squamous carcinoma that invaded the limbus and anterior chamber angle through a previous surgical incision (arrow).
(Part A courtesy of Vahid Feiz, MD; parts B–E courtesy of George J. Harocopos, MD.)
Figure 5-18 Noninvasive and invasive ocular surface squamous neoplasia (OSSN). A, Slit-lamp photograph of a superior limbal gelatinous, grayish lesion with vascularity and extension onto the cornea. B, Slit-lamp photograph of a temporal limbal gelatinous lesion with large feeder vessels and extension onto the cornea. C, Anterior segment optical coherence tomography (AS-OCT) image of the lesion depicted in part A, demonstrating epithelial thickening and hyperreflectivity consistent with OSSN; in addition, there is hyperreflectivity at the epithelial base (arrow), possibly suggestive of more superficial epithelial disease. D, AS-OCT image of the lesion depicted in part B, demonstrating epithelial thickening and hyperreflectivity as well as prominent subepithelial hyperreflectivity (arrow), possibly suggestive of deeper invasion. E, Histology of the lesion depicted in parts A and C, demonstrating moderate to severe epithelial dysplasia consistent with noninvasive OSSN. F, Histology of the lesion depicted in parts B and D, demonstrating superficially invasive squamous cell carcinoma consistent with invasive OSSN.
(Reproduced with permission from Polski A, Sibug Saber M, Kim JW, Berry JL. Extending far and wide: the role of biopsy and staging in the management of ocular surface squamous neoplasia. Clin Exp Ophthalmol. 2019;47(2):193–200.)
Invasion of the stroma by neoplastic cells is diagnostic of invasive SCC (see Figs 5-17D, E, and 5-18F). Invasion of the sclera or cornea with intraocular spread is an uncommon complication of invasive SCC that typically occurs at the site of a previous surgical procedure or in patients whose immune response is suppressed. In addition, mucoepidermoid carcinoma and spindle cell carcinoma, rare variants of conjunctival carcinoma, may demonstrate aggressive behavior, with higher rates of recurrence, intraocular spread, and orbital invasion. Although regional lymph node metastasis and distant metastasis are less common with conjunctival SCC than with squamous carcinomas of the skin or other sites, dissemination and death occur in a small percentage of cases.
Conway RM, Graue GF, Pelayes DE, et al. Conjunctival carcinoma. In: American Joint Committee on Cancer (AJCC). AJCC Cancer Staging Manual. 8th ed. Springer; 2017: 787–793.
Moyer AB, Roberts J, Olsen RJ, Chévez-Barrios P. Human papillomavirus-driven squamous lesions: high-risk genotype found in conjunctival papillomas, dysplasia, and carcinoma. Am J Dermatopathol. 2018;40(7):486–490.
Polski A, Sibug Saber M, Kim JW, Berry JL. Extending far and wide: the role of biopsy and staging in the management of ocular surface squamous neoplasia. Clin Exp Ophthalmol. 2019;47(2):193–200.
Excerpted from BCSC 2020-2021 series: Section 4 - Ophthalmic Pathology and Intraocular Tumors. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.