Published in Ocular Surface

Diagnosis and Treatment of Ocular Surface Neoplasms

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Familiarize yourself with protocols for ophthalmologists to manage ocular surface neoplasms, such as pterygium, plannus, and ocular surface squamous neoplasia.

Diagnosis and Treatment of Ocular Surface Neoplasms
The term ocular surface neoplasm refers to a lesion located on the conjunctiva and/or cornea, and encompasses a wide spectrum of conditions, ranging from benign to malignant.1
Benign entities include pterygium and corneal pannus, which must be distinguished from malignant entities, such as ocular surface squamous neoplasia (OSSN).

Pterygium

Pterygium is a common and often benign ocular surface lesion with a “wing-shaped” appearance that begins most frequently at the nasal limbus and extends onto the cornea.2 The prevalence of pterygium ranges from about 1.2% to 40%, with a greater prevalence in regions located near the equator.3,4
The main risk factor for pterygium is exposure to ultraviolet (UV) light, and it is commonly seen in those who work outdoors or live in tropical climates.4 Other possible risk factors include living in a dry or dusty environment and various viral infections, such as herpes simplex virus (HSV) and human papillomavirus (HPV).3,4

Diagnosing patients with a pterygium

Diagnosis of pterygium is made based on clinical examination findings. Typical features of pterygium include a raised, triangular-shaped, white- to pink-colored conjunctival growth extending from within the palpebral fissure onto the corneal surface. The lesion is characteristically located at 3 o’clock or 9 o’clock, and can be present unilaterally or bilaterally.
Patients with pterygium may be asymptomatic, but in some cases, the lesion can cause ocular surface irritation when inflamed. In addition, it is possible for pterygia to cause visual disturbances, either by inducing corneal astigmatism or by directly covering the visual axis. Some patients may also dislike the appearance of pterygium and desire removal for cosmetic reasons.4,5

Using imaging to identify a pterygium

Optical coherence tomography (OCT) has been described as a useful tool for confirming the diagnosis of pterygium. Classic features of pterygium on OCT include a mildly hyperreflective, normal to slightly thinned epithelium with a highly hyperreflective subepithelial lesion in the space between the epithelium and Bowman’s layer.6
The slit lamp photo in Figure 1 shows a pterygium of the left eye that extended onto the cornea nasally at 8 to 10 o’clock.
Pterygium
Figure 1: Courtesy of Anat Galor, MD, MSPH.
In Figure 2, OCT demonstrates a hyperreflective, subepithelial lesion (white arrowheads) with mild epithelial hyperreflectivity and thinning.
OCT epithelial thinning
Figure 2: Courtesy of Anat Galor, MD, MSPH.

Discerning between benign and malignant lesions

It is possible for benign lesions, such as pterygium, to coexist with malignant lesions, such as OSSN. For example, one study conducted in South Florida of 2,005 surgically excised pterygia found that 1.7% harbored OSSN.3
Therefore, it is crucial for clinicians to differentiate pterygium from OSSN and be cognizant of the possibility of OSSN existing concomitantly with benign lesions, such as pterygium. It is for this reason that it is recommended to send all excised tissue for histopathologic analysis in order to prevent missing a malignant diagnosis.

Treating a pterygium

Treatment options for pterygia range from conservative management to surgery. Nonsurgical therapies include lubricating eye drops for irritation and short-term usage of topical vasoconstrictors (e.g., Naphazoline HCl 0.025%) or anti-inflammatory agents during periods of inflammation.
Surgical excision is indicated in cases of persistent ocular irritation, documented growth, visual disturbance, or concern for malignancy.4,5

Surgical treatment of pterygium

The two main surgical techniques currently used for pterygium removal are excision with conjunctival autograft (CAG) and excision with amniotic membrane transplantation (AMT), with our preferred approach being CAG.
Literature supports our approach as well. In one study of 86 eyes with pterygium randomized to CAG (n=42) or AMT (n=44), the AMT group had a significantly greater rate of pterygium recurrence compared to the CAG group (40.9% vs. 4.8%; p<0.007) up to 12 months post-operatively.7
The bare sclera technique is no longer favorable due to recurrence rates as high as 80%.4 Surgical excision may be combined with adjuvant therapies, such as application of mitomycin C (MMC).
We use MMC in individuals with a higher risk of aberrant wound healing after surgery (e.g., young age, inflamed pterygium), taking care to avoid direct contact of MMC with the sclera, which can result in complications such as scleral ulceration and calcification.

Pannus

A corneal pannus is a benign, subepithelial ingrowth of fibrovascular tissue that appears as a white, vascularized, variably elevated opacity. Pannus extends centrally from the limbus onto the cornea and, in severe cases, can involve the entirety of the cornea for 360°.8 Causes of pannus include contact lens wear, keratitis, inflammation, and trauma.9

Diagnosing patients with a pannus

The diagnosis of pannus is made clinically based on examination findings. However, it is important to distinguish pannus from malignant entities, such as OSSN, as they can present with overlapping clinical features.
In cases where pannus may be difficult to differentiate from OSSN, OCT has been previously described as a helpful diagnostic tool. Classic features of pannus on OCT include a normal to thin epithelium overlying a flat, hyperreflective subepithelial lesion along Bowman’s layer.10

Utilizing OCT to differentiate between pannus and OSSN

A retrospective study comparing clinical features and OCT findings between corneal pannus (n=6) and OSSN (n=4) found that clinically, blood vessels often reached the border in pannus (noted in 67% of eyes), whereas this was not the case in OSSN (0% had a vessel that reached the border).9
Additionally, on OCT, none of the pannus cases had epithelial thickening, whereas this feature was seen in 100% of OSSN cases. Finally, the angle of transition between normal and abnormal epithelium was noted to be an important distinction between the two entities.
Specifically, pannus appeared as an angled transition around 45° to Bowman’s layer, whereas OSSN appeared as an abrupt, 90° angle perpendicular to Bowman’s layer.9
Figure 3 illustrates a slit lamp photo of a right, inferotemporal opacity (dashed white line) at 6:30 to 8:30 o’clock with blood vessels that extended to the border (white arrows).
Inferotemporal opacity
Figure 3: Courtesy of Anat Galor, MD, MSPH.
The OCT image in Figure 4 shows a thin epithelium overlying a hyperreflective subepithelial lesion along Bowman’s layer and an angled (~45°) transition (white dotted line and arrowhead) between normal and abnormal tissue, consistent with pannus.
OCT pannus
Figure 4: Courtesy of Anat Galor, MD, MSPH.

Treating a pannus

Treatment of pannus is primarily dependent on addressing the underlying cause. For example, in cases of contact lens wear, the contact lenses may need to be refitted, such as with rigid gas permeable lenses, or discontinued.11
In severe cases, surgery may be considered.8 However, in cases where the pannus is stable and there is no visual disturbance, the lesion can be monitored over time.

Ocular surface squamous neoplasia

Ocular surface squamous neoplasia encompasses a spectrum of squamous epithelial malignancies involving the cornea or conjunctiva, ranging from mild dysplasia, to non-invasive intraepithelial neoplasia, to invasive squamous cell carcinoma.12
Occurring primarily in elderly white males, OSSN is the most common non-melanocytic tumor of the ocular surface.9,13 Various risk factors have been implicated in the development of OSSN, including UV light exposure, immunosuppression, and genetic predisposition (e.g., xeroderma pigmentosum).12

Diagnosing OSSN

OSSN presents as a variably elevated, white or grey opacity with irregular borders, vessel abnormalities (e.g., hairpin loop, feeder vessels), and a leukoplakic, gelatinous, or papilliform appearance.9,12
Along with clinical characteristics, OCT has been described as a useful tool for the diagnosis of OSSN. Classic features of OSSN on OCT include epithelial hyperreflectivity, epithelial thickening, and an abrupt (90°) transition from normal to abnormal epithelium.14

Discerning between OSSN and pterygium with ophthalmic imaging

Specifically, when differentiating between OSSN and pterygium, an epithelial thickness cut-off of 120 to 140μm has been previously found to have a sensitivity of 94% to 100% and a specificity of 100%.6,15
In addition, in vivo confocal microscopy has been investigated as a noninvasive imaging tool for the diagnosis of OSSN due to its ability to reveal abnormal squamous epithelial cell number and morphology, but it is less commonly used in clinical practice.16 However, excisional biopsy with histopathological examination remains the gold standard for the diagnosis of OSSN.17
The slit lamp photo in Figure 5 captures a right, inferotemporal, opalescent lesion at 7 to 9:30 o’clock with irregular borders (dashed white line) and vascularization that did not reach the edges (white arrows).
Slit lamp squamous neoplasia
Figure 5: Courtesy of Anat Galor, MD, MSPH.
The OCT image in Figure 6 shows a hyperreflective and thickened epithelium with an abrupt, vertical (90°) transition (white dotted line and arrowhead) between normal and abnormal epithelium, consistent with ocular surface squamous neoplasia.
Squamous neoplasia OCT
Figure 6: Courtesy of Anat Galor, MD, MSPH.

Medical treatment of OSSN

Treatment of OSSN includes medical therapy with topical chemotherapeutic agents and surgical excision. In particular, three common medical treatment options are 5-fluorouracil (5FU), interferon alfa-2b (IFN-2b), and MMC.18
Our first line agent is 5FU, as IFN-2b is no longer available in the United States, and MMC has the least favorable side effect profile of the three agents. Side effects that are seen more frequently with MMC include redness, pain, corneal erosion, punctal stenosis, and limbal stem cell deficiency.

Comparing the various medical treatment options for OSSN

In a study comparing the efficacy of topical 5FU (n=54) and IFN-2b (n=48) for the treatment of OSSN, the frequency of resolution was greater with 5FU versus IFN-2b (96.3% vs. 81.3%; p=0.01); however, this difference did not remain significant in a multivariable analysis.
Time to resolution (6.6±4.5 vs. 5.5±2.9 months; p=0.62) and recurrence frequency are generally similar between 5FU and IFN-2b. Of note, 5FU does have a less favorable side effect profile, with tearing (22.2% vs. 4.3%; p=0.02) and eyelid edema (9.3% vs. 0%; p=0.04) more frequently noted in comparison to IFN-2b.19
However, most patients tolerate 5FU therapy well. We use a topical corticosteroid in cases of 5FU-associated conjunctival inflammation and recommend petroleum jelly on the skin around the eye in individuals who develop contact dermatitis. Although rare, we advise patients to occlude their puncta after 5FU application to minimize the risk of punctal stenosis.

Surgical treatment of OSSN

If an excision biopsy is performed, the technique for surgical excision involves a “no-touch” technique with wide margins of 3 to 4mm.18 In a study of 389 OSSN lesions excised using the “no-touch” technique, the 1-year and 5-year recurrence rates were 10% and 21%, respectively.21
Factors associated with an increased risk of tumor recurrence after surgical excision included a previous history of OSSN (hazard ratio [HR]: 2.32; p=0.03), superior location (HR: 3.33; p=0.003), tarsal involvement (HR: 4.12; p=0.007), papillomatous appearance (HR: 1.95; p=0.04), and positive surgical margins (HR: 2.73; p=0.008).
The risk of tumor recurrence was found to be decreased with treatment with adjuvant cryotherapy (HR: 0.51; p=0.03). Additionally, in patients with positive margins, the usage of post-operative topical IFN-2b was found to reduce recurrence to a similar rate as in patients with negative margins.21

Differences between medical and surgical treatments for OSSN

When comparing medical therapy with topical IFN-2b (n=49) to surgical excision (n=49), the 1-year and 5-year recurrence rates were found to be similar between the groups (3% vs. 5% and 25% vs. 11%; p=0.80).22 Adverse effects, including pain, irritation, itching, and redness, were also not significantly different when comparing medical therapy and surgical excision.22
Overall, we prefer medical therapy for the treatment of OSSN, but consider surgical excision when the lesion is small enough (<4 clock hours of limbal involvement) that the risk of subsequent limbal stem cell deficiency is low.

Conclusion

Due to the possibility of malignant lesions, such as OSSN, masquerading as benign lesions, such as pterygium and pannus, clinicians must distinguish between the various ocular surface neoplasms.
Diagnostic tools, such as OCT, can be invaluable in identifying features that may raise suspicion for malignancy, lending to proper evaluation and management of ocular surface lesions.
When in doubt, it is never wrong to refer to a subspecialist (e.g., ocular oncologist or cornea specialist) for diagnosis, management, and possible excisional biopsy.
  1. Shields CL, Shields JA. Tumors of the conjunctiva and cornea. Surv Ophthalmol. 2004;49(1):3-24.
  2. Coroneo MT. Pterygium as an early indicator of ultraviolet insolation: a hypothesis. Br J Ophthalmol. 1993;77(11):734-739.
  3. Oellers P, Karp CL, Sheth A, et al. Prevalence, treatment, and outcomes of coexistent ocular surface squamous neoplasia and pterygium. Ophthalmology. 2013;120(3):445-450.
  4. Akbari M. Update on overview of pterygium and its surgical management. J Popul Ther Clin Pharmacol. 2022;29(4):e30-e45.
  5. Hirst L, Bunya VY Woodward MA, et al. Pterygium. American Academy of Ophthalmology. Published 2022. https://eyewiki.aao.org/Pterygium.
  6. Nanji AA, Sayyad FE, Galor A, et al. High-Resolution Optical Coherence Tomography as an Adjunctive Tool in the Diagnosis of Corneal and Conjunctival Pathology. Ocul Surf. 2015;13(3):226-235.
  7. Tananuvat N, Martin T. The results of amniotic membrane transplantation for primary pterygium compared with conjunctival autograft. Cornea. 2004;23(5):458-463.
  8. Jakobiec FA, Stacy RC, Mendoza PR, Chodosh J. Hyperplastic corneal pannus: an immunohistochemical analysis and review. Surv Ophthalmol. 2014;59(4):448-453.
  9. Huang JJ, Locatelli EVT, Huang JJ, et al. It Is All About the Angle: A Clinical and Optical Coherence Tomography Comparison of Corneal Ocular Surface Squamous Neoplasia and Corneal Pannus. Cornea. Published October 26, 2023.
  10. Theotoka D, Wall S, Galor A, et al. The use of high resolution optical coherence tomography (HR-OCT) in the diagnosis of ocular surface masqueraders. Ocul Surf. 2022;24:74-82.
  11. Chan WK, Weissman BA. Corneal pannus associated with contact lens wear. Am J Ophthalmol. 1996;121(5):540-546.
  12. Basti S, Macsai MS. Ocular surface squamous neoplasia: a review. Cornea. 2003;22(7):687-704.
  13. Monroy D, Serrano A, Galor A, Karp CL. Medical treatment for ocular surface squamous neoplasia. Eye (Lond). 2023;37(5):885-893.
  14. Shousha MA, Karp CL, Perez VL, et al. Diagnosis and management of conjunctival and corneal intraepithelial neoplasia using ultra high-resolution optical coherence tomography. Ophthalmology. 2011;118(8):1531-1537.
  15. Kieval JZ, Karp CL, Abou Shousha M, et al. Ultra-high resolution optical coherence tomography for differentiation of ocular surface squamous neoplasia and pterygia. Ophthalmology. 2012;119(3):481-486.
  16. Xu Y, Zhou Z, Xu Y, et al. The clinical value of in vivo confocal microscopy for diagnosis of ocular surface squamous neoplasia. Eye (Lond). 2012;26(6):781-787.
  17. Thomas BJ, Galor A, Nanji AA, et al. Ultra high-resolution anterior segment optical coherence tomography in the diagnosis and management of ocular surface squamous neoplasia. Ocul Surf. 2014;12(1):46-58.
  18. Alvarez OP, Zein M, Galor A, Karp CL. Management of ocular surface squamous neoplasia: Bowman Club Lecture 2021. BMJ Open Ophthalmol. 2021;6(1):e000842.
  19. Venkateswaran N, Mercado C, Galor A, Karp CL. Comparison of Topical 5-Fluorouracil and Interferon Alfa-2b as Primary Treatment Modalities for Ocular Surface Squamous Neoplasia. Am J Ophthalmol. 2019;199:216-222.
  20. Kusumesh R, Ambastha A, Kumar S, et al. Retrospective Comparative Study of Topical Interferon alpha2b Versus Mitomycin C for Primary Ocular Surface Squamous Neoplasia. Cornea. 2017;36(3):327-331.
  21. Galor A, Karp CL, Oellers P, et al. Predictors of ocular surface squamous neoplasia recurrence after excisional surgery. Ophthalmology. 2012;119(10):1974-1981.
  22. Nanji AA, Moon CS, Galor A, et al. Surgical versus medical treatment of ocular surface squamous neoplasia: a comparison of recurrences and complications. Ophthalmology. 2014;121(5):994-1000.
Jaxon Huang, BHSc
About Jaxon Huang, BHSc

Jaxon Huang is a fourth year medical student at the University of Hawaii John A. Burns School of Medicine. During medical school, he completed a year of research at the University of Miami Bascom Palmer Eye Institute conducting studies on dry eye disease and neuropathic ocular pain. He is pursuing ophthalmology and plans to incorporate clinical research into his future career.

Jaxon Huang, BHSc
Anat Galor, MD, MSPH
About Anat Galor, MD, MSPH

Dr. Galor is a cornea and uveitis trained specialist with a dual appointment at the Miami Veterans Affairs (VA) medical center and the Bascom Palmer Eye Institute, University of Miami Miller School of Medicine. Dr. Galor completed an ophthalmology residency at the Cole Eye Cleveland Clinic, a uveitis fellowship at the Wilmer Eye Institute, Johns Hopkins University, and a cornea and external diseases fellowship at Bascom Palmer Eye Institute. Dr. Galor currently runs the ocular surface program at the Miami VA and has focused her research on understanding mechanisms of pain in dry eye, with an emphasis on studying new diagnostic and treatment modalities. She has lectured and published extensively on how nerve status may underlie the often noted disconnect between dry eye symptoms and signs. This includes individuals with decreased sensation and chronic epithelial abnormalities (neurotrophic phenotype) and individuals with hypersensitive nerves and chronic ocular pain with minimal ocular surface abnormalities (neuropathic phenotype). Over the years, she has participated in several dry eye-related committees including the Tear Film and Ocular Surface Society (TFOS) Dry Eye Workshop (DEWS) II Pain and Sensation Committee and the Dry Eye Awareness Month Congressional Briefing. In addition, she served as President of the Ocular Microbiology and Immunology Group and sits on several educational committees within the Academy of Ophthalmology.

Anat Galor, MD, MSPH
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