Topical interferon alpha-2b for a giant ocular surface squamous neoplasia: 7 years of follow-up after complete remission

Abstract

A man with a history of blind eye due to trauma 22 years earlier consulted at 53 years of age with a large conjunctival neoplastic lesion, compromising almost the entire temporal limbus, and reaching a size of approximately 16 mm on its larger diameter, in the conjunctiva. Management was started with topical and subconjunctival chemotherapy (interferon alpha-2b) in order to perform immunoreduction, but a dramatic response with total disappearance of the lesion was observed. In the follow-up time period of more than 7 years, there were no signs of recurrence.

Background

Ocular surface squamous neoplasia (OSSN) is a rather uncommon condition in Europe and in most of North America but is much more common in the intertropical zone, as well as in Australia and Africa.^1–4 All ophthalmologists may have a case, at least occasionally, in their practice and must be prepared for its diagnostic and therapeutic approach. This condition usually begins in the limbus in the interpalpebral area and can spread to the cornea and/or the conjunctiva, but cases with isolated involvement of the cornea, without clear limbal or conjunctival lesions, have also been reported.^1–8

Although the surgical treatment was traditionally considered the gold standard, in the last two decades, multiple reports have shown positive results with the use of perilesional and topical interferon alpha-2b, including some cases with large tumours.^8–14 We show an excellent result in a patient with a giant conjunctival tumour, with a follow-up of more than 7 years (according to our knowledge, the longest period of time ever reported), without recurrence. In these cases of extensive tumours, in which surgery has a higher risk of leaving sequelae, this approach of topical and perilesional immunotherapy seems to be an excellent alternative.

Case presentation

A 53-year-old man consulted in October 2013 for presenting a lesion that had grown progressively in the last 3 or 4 months, in his left eye. That eye was blind after a blunt trauma, and retinal detachment that could not be corrected with surgery, 22 years earlier. The right eye had a corrected distance visual acuity of 20/25 with a manifest refraction of +0.50 D.

The anterior segment of the right eye was normal. Nasal pterygium, aphakia and discoria were found in the left eye. The central cornea was of good transparency, but approximately the peripheral 2 mm of the cornea, from the 2 o’clock to 6:30 o’clock meridians, was invaded by a neoplastic lesion, the epithelium was greyish in appearance and had multiple irregular vessels. There was a large conjunctival mass approximately 16 mm at its largest diameter (obliquely), by approximately 7 mm at its smallest diameter. The conjunctival lesion was elevated, with prominent intrinsic vascularity, many of those vessels with a loop or hairpin shape, and in addition exhibited several feeder vessels thicker than the rest of the conjunctival vasculature. The tumour had a fine papilliform appearance. The clinical diagnosis of giant OSSN was made (figure 1).

Figure 1.

Slit-lamp photographs of the tumour in the left eye in October 2013, before initiating the treatment.

Differential diagnosis

One of the main differential diagnoses of a squamous neoplasm of the ocular surface, especially in its papilliform form, is benign squamous papilloma of the conjunctiva. Differentiation of large sessile squamous papillomas, which may appear in adults, and a papilliform OSSN can be difficult. A useful sign is that benign papillomas are not usually found in direct relation to the limbus. Additionally, they do not present a tendency to invade the cornea, which is the case with malignant squamous neoplasms. In addition, the pattern of the internal vasculature of the tumour in benign papillomas has been described as a clinical sign that helps in diagnosis. Benign papillomas in their initial stages may present the intrinsic vessels in the form of a hairpin and horizontally directed in a symmetrically radial pattern. However, several cases of papillomatous conjunctiva tumours that were very similar clinically to benign papillomas exhibiting this radial vascular pattern have been found to be conjunctival intraepitheliaI neoplasia.⁵ Later, as the tumour thickens in the benign papillomas, the intrinsic vessels are vertically redirected and therefore tend to be observed at the slit lamp as a set of regularly arranged red dots, also described as ‘strawberry’ or ‘cauliflower’ pattern, while in papilliform OSSN, many vessels take the shape of a loop, hairpin or corkscrew (figure 2).^15–18

Figure 2.

Hairpin configuration of several vessels in the intrinsic vascularity of the tumour (black arrows).

Another tumour that should be included in the differential diagnosis is conjunctival keratoacanthoma, which is very rare in this location and unlike when it occurs in the eyelids, in which case it exhibits a typical central crater filled with keratin surrounded by raised edges, when it is located in the conjunctiva manifests as a nodular tumour, without central umbilication.^{19 20} Although this tumour is benign, it can take on a clinical appearance very similar to a gelatinous OSSN, and in addition, some cases of malignant transformation with intraocular involvement have been described.²¹ Conjunctival keratoacanthoma growth usually occurs in a matter of days or weeks, and not months as is the case with OSSN.²⁰

Other lesions that must be differentiated from an OSSN are the pigmented tumours, which include benign such as conjunctival nevi, which are typically characterised by intralesional cysts, and malignant such as conjunctival melanoma.^{2 22} These tumours can in some rare cases be amelanotic and therefore represent a diagnostic challenge, which is often only clarified after the pathological study of the surgical specimen.^22–24

Finally, OSSN is a broad spectrum term coined by Lee and Hirst in 1995, which includes from neoplastic proliferation of a non-invasive dysplastic conjunctival (or corneal) epithelium (ie, conjunctival intraepithelial neoplasia, called CIN, encompassing both partial thickness of epithelial tissue dysplasia and carcinoma in situ, when changes involve full thickness of epithelium), where the basement membrane is intact, to invasive squamous cell carcinoma, where the malignant cells penetrate the basement membrane of the epithelium and invade the stroma of the conjunctiva.¹ Invasive conjunctival squamous tumours usually involve a greater proportion of the limbal area and are larger than CIN.^{1 5}

The clinical diagnosis of squamous neoplasia of the ocular surface in this case was then based on the appearance of the pink conjunctival lesion, raised, with a papilliform appearance, located in the interpalpebral space, which is more exposed to ultraviolet B (UVB) radiation from the sunlight, compromising the limbus and extending to both the cornea and the conjunctiva, and with the presence of dilated and tortuous feeding vessels and many intrinsic vessels with hairpin configuration (figure 2). The evolution time was also suggestive of this type of tumour. Most likely, due to the involvement of almost two quadrants of the limbus, and a large raised conjunctival lesion, it could be an invasive squamous cell carcinoma.

Treatment

Due to the large size of the tumour, it was proposed to apply subconjunctival (3.0 million IU every week) and topical (1.0 million IU/mL 4 times a day) interferon alpha-2b (Intron A, Merck & CO, Whitehouse Station, New Jersey, USA), to generate immunoreduction and later perform a surgical resection.

Outcome and follow-up

After receiving four injections and the topical interferon for 1 month, a notable reduction in the thickness and size of the tumour was found, although the peripheral corneal epithelium still showed an abnormal appearance (figure 3). In the first 3 months of treatment, the patient received topical interferon and seven subconjunctival injections. At that moment, the resolution of the lesion was almost complete (figure 3). The injections were stopped and the topical interferon was continued. The tumour completely disappeared after around 5 months of using the topical immunomodulator. To be sure that a recurrence did not occur, taking into account that the original tumour was very large, topical immunotherapy was maintained until 11 months of treatment were completed.

Figure 3.

Slit-lamp photographs showing the progressive regression of the tumour in the left eye, after (A) 1 month and (B) 3 months of treatment with interferon alpha-2b. The tumour completely disappeared 5 months after the diagnosis. No signs of recurrence were found 5 years (C) and more than 7 years (D) after the initial evaluation.

The patient returned to a follow-up visit only until 4 years later, and there was not any sign of recurrence.

In his last examination, a little more than 7 years after diagnosis, the conjunctiva, limbus and cornea were completely free of any finding suggestive of tumour recurrence (figure 3).

Discussion

Although it is uncommon in certain areas of the world, particularly in the temperate climates that include Europe and most of North America, OSSN is still globally the most common ocular malignant tumour.^1–4 Africa has the highest incidence and a rather different presentation, since the condition tends to affect younger individuals and the conjunctival lesions to be more frequently pigmented.³ HIV infection, also frequent in populations in Africa, seems to have an important role in the high incidence of OSSN along with the UVB radiation exposure.³ OSSN most of the time grows from the UVB exposed limbus in the interpalpebral area.

Although it is completely true that the definitive diagnosis of an OSSN requires a biopsy, currently with the availability of topical immunotherapies or chemotherapies, there is no universal consensus that histological confirmation of the diagnosis is always necessary, particularly if the clinical features are very clear. Some experts indicate that, given the very high clinical suspicion, in cases like these, where the slit-lamp examination is clearly consistent with OSSN, topical immunotherapy or chemotherapy can be started, without the need for a prior biopsy (CL Karp, personal communication, 3 June 2019). The use of anterior segment optical coherence tomography (AS OCT) has recently been described as a non-invasive tool that is also useful in these cases.¹⁴ If there is any doubt about the diagnosis clinically or by AS OCT, then an incisional biopsy would be indicated. In this case, given the typical clinical characteristics, we decided to start immunotherapy considering the tumour as malignant and probably invasive, to reduce the volume of the tumour, and a few weeks later make a surgical excision with which we would have histological confirmation. However, surprisingly for us, despite the large size of the tumour, it responded very early and very noticeably to therapy, until it totally disappeared and did not present recurrence in the long term. This could indicate that early response to immunotherapy could be an indication of excellent prognosis without surgery. Interferon alpha-2b (Intron A, Merck & CO) is a protein from the group of cytokines, which is a modifier of the biological response, that is produced naturally by humans, but has been manufactured by recombinant DNA techniques. It is obtained from the bacterial fermentation of a strain of Escherichia coli carrying a genetically modified plasmid that contains a gene for interferon alpha-2b from human leucocytes. It is used for immunotherapy. It is approved in the treatment of hairy cell leukaemia, malignant melanoma, AIDS-related Kaposi’s sarcoma and follicular non-Hodgkin’s lymphoma. Interferons can enhance phagocytic and cytotoxic mechanisms, inhibit biosynthetic enzymes, decrease blood vessel proliferation, induce apoptosis and inactivate viral RNA. Interferon alpha-2b contains 165 amino acid residues. Intralesional injections of interferon alpha-2b improve the production of interleukin 2 (IL-2) and IFN-mRNA by the immune system and reduce the production of IL-10, mechanisms that aid in the recognition of neoplastic cells.

From 1999, interferon alpha-2b has been used to treat OSSN as topical eye drops, subconjunctival injections or a combination of both alternatives. The usual concentration for injections are 3.0 million IU and 1 million IU/mL for topical eye drops. Higher concentrations have been found to yield similar results.^{8–10 13}

Topical interferon alone or in combination with subconjunctival injections has been found to be effective as primary treatment for OSSN with between 82% and 92% of the cases showing complete resolution. With regard to recurrence rates, it has been found to be similar to surgical treatment: 3% vs 5% after 1 year of follow-up.^{9 13 14} Due to these good published results, and to positive experiences with some previous cases, we decided to use interferon alpha-2b and not other therapies such as mitomycin or 5-fluorouracil.

Topical and/or subconjunctival immunotherapy have been used in cases of massive OSSN. Usually an OSSN is considered giant if its diameter is larger than 15 mm or more than six clock hours of the limbus are involved.

Kim et al reported the efficacy of interferon alpha-2b for giant OSSN in 18 eyes that received it through topical administration (1 million IU/mL), or subconjunctival injections (10.0 million IU) or both ways. Complete tumour regression was reached in 13 eyes (72.2%) and reduction in size in the remaining 5 (27.7%). There were no tumour recurrences in the follow-up time (mean 11 months, range: 2–43 months), but two new malignant lesions appeared at a different site from the original OSSN mass, requiring operative intervention (including exenteration in one case due to orbital involvement). The researchers suggested that if the lesion was thin, topical interferon alpha-2b could lead to complete resolution, even for a giant OSSN.¹⁰ In our case, despite being a massive and thick tumour, it completely disappeared with topical and subconjunctival interferon. Ghanavati et al reported five cases with four-quadrant involvement of the limbus by OSSN, both primary or recurrent, treated with topical interferon alpha-2b (3 million IU/mL) with good response and resolution of the tumour after 2 months of treatment. No recurrences were observed after 8–12 months of follow-up.¹⁰ Hernandez-Bogantes et al published a case series including five eyes with giant OSSN, treated with topical (three cases) or subconjunctival (two cases) interferon alpha-2b with a median follow–up of 22 months (range: 6–28 months). They reached resolution of the tumour in the three cases with topical interferon, and in the two where subconjunctival interferon was used, which were those with the largest tumours, after 1 month the size of the lesion decreased and surgery was performed as a second step of treatment. According to the clinical pictures shown, the reduction in one of these two cases was subtotal, and it could have been possible that with a longer immunotherapy treatment, that tumour might have completely disappeared without the need for surgery.¹²

Kaliki et al in a retrospective series included 11 cases with maximum tumour base larger than 10 mm, with a mean size of 20 mm (range: 12–30 mm). Eighty-two per cent of such giant tumours showed complete regression following topical and subconjunctival interferon alpha-2b therapy, with no signs of recurrence after a mean follow–up period of 9 months (range: 3–28 months).⁸

According to our knowledge, the case reported here is the one with a giant OSSN treated with topical and subconjunctival interferon alpha-2b with the longest follow-up period (more than 7 years, exactly 85 months). In sum, complete resolution without any sign of recurrence in the long term was achieved in a case with a giant OSSN involving cornea, limbus and conjunctiva. This finding, as well as the published literature, supports that topical/subconjunctival interferon alpha-2b could be a first therapeutic option in such cases.

Patient’s perspective.

I presented, according to what was indicated to me in 2013, a malignant-looking tumour in my left eye. It was big. My doctors explained to me at that time, that they would first try to reduce the size of this tumour with a special treatment with interferon drops and injections in the eye. Fortunately, there was a progressive positive response and finally I did not need surgery. The end result was the cure of my disease, as evidenced by the complete disappearance of the tumour, which has not yet reappeared after more than 7 years. For this reason, I consider it important that my case, which was very successful, be known by specialists from other places through this publication, so that they can also apply it to their patients with this type of disease.

Learning points.

• Ocular surface squamous neoplasia (OSSN) can present as giant tumours, posing a therapeutic challenge.

• Immunotherapy using interferon alpha-2b has shown effective results in causing regression of OSSN, even in giant tumours.

• The case of the complete resolution of a giant OSSN, with no signs of recurrence in the long term (more than 7 years of follow-up, the longest ever reported) is here presented.