Lecture: A to Z of Ocular Surface Squamous Neoplasia

>> DR. ANASUA KAPOOR: Hello, everyone. I am Dr. Anasua Kapoor. I am an ocular oncologist at the Center for Eye Cancer and head of LV Prasad Eye Institute in India. Today I will be taking you through, in this webinar, on all aspects of diagnosis, management of cases of ocular surface squamous neoplasia. All the consents have been taken for all the photographs. So I will begin the webinar with this first poll question. You can see on the left hand side of your screen this clinical photograph of the ocular surface of a patient. I want you to diagnose the condition. Is it necrotizing scleritis? Is it OSSN? Is it a ciliary staphyloma? Or is it a scleral abscess? You can see the question on your screen. Please pick up the right answer. Great. So 41% of you feel it is necrotizing scleritis. 34% feel it is OSSN. 21% feel it is ciliary staphyloma and 5% feel it is scleral abscess. Let us now dive deep into it and try and understand how OSSN can present. So the correct answer is, it is a case of a variant of OSSN, I will go into how we differentiate it from necrotizing scleritis. Conjunctival tumors constitute 35% of all periocular tumors and 30% of these are malignant. Out of these, 94% are ocular surface form of neoplasia, the global since being.02 to 3.5 cases per 100,000 individuals per year. The highest incidence being in the tropical countries and in Africa. OSSN causes a lot of risk on the vision, eye, and life of the patient if not treated appropriately. So with this I’ll move on to the second poll question. Which of the following is not a risk factor for OSSN? The options are UV exposure, human papillomavirus infection, chronic use of corticosteroids, age under 20 years, xeroderma pigmentosum. Choose which you feel is not a risk factor for OSSN. Okay. So we have the poll results. And yes, 66% have correctly chosen age under 20 years is not a risk factor, because it predominantly happens in middle age and elderly. UV exposure is a risk factor, human papilloma infection is a risk factor. The correct answer was age under 20 years. So the risk factors are multifactorial, ultraviolet B exposure, human papillomavirus, vitamin A deficiency, chronic inflammation, ocular surface injury, exposure to petroleum chemicals, immunodeficiency, increasing age, all of these are risk factors. Whenever you see a young patient with OSSN-like features, rule out xeroderma pigmentosum, a common is scenario where we see OSSN in young. What is OSSN? OSSN is an umbrella term which includes all of these. Mild dysplasia, moderate dysplasia, severe dysplasia, carcinoma in situ, invasive cell carcinoma. Mild to moderate dysplasia, all of them together are known as conjunctival intraepithelial neoplasia. Everything together, we call it OSSN. So in the next 40 minutes, I will be taking you through the different aspects of OSSN under these headings. The diagnosis of OSSN is majorly based on clinical features, so what clinical features we look for. Then I will be touching upon the imaging features of OSSN, then the management protocol, surgical management, medical management. And at the end I will be giving ways to differentiate OSSN from similar-looking mimics. To begin with, let us see how clinically OSSN looks like. This is the most common location of an OSSN. It is limbal location, I mean the epicenter. If you draw two perpendicular lines they will meet at the limbus. They have a limbal epicenter. Their intrinsic vascularity, like you can see here, there are loops which are basically indicative of the vascular core of the tumor. Interesting vascularity. Keratin is a very important sign of OSSN. Whenever you see ocular surface keratin, you will have to rule out OSSN. Feeder vessels are dilated, torturous conjunctival vessels which are helping the lesion to grow. Presence of feeder vessels are a very important sign of OSSN. Many times it is pigmented like in this particular case, confused with conjunctival melanoma. But here you need to focus on the grayish white areas of keratin on the surface of the lesion, giving away the diagnosis of OSSN. Morphology, it is very important for us to understand the different morphological presentations of OSSN so that we can diagnose early. So nodular is the most common presentation, where it appears as a circumscribed, raised lesion. Leukoplakic is where there is a plug sitting on the surface. Papilliform, there are projections, as you can see, on the lesion. But we need to remember that the types may overlap. The other two are diffuse and nodulo-ulcerative. Diffuse appears as a flat sheet of cells with not well-demarcated on the entire conjunctival surface. Maybe times it is misdiagnosed as conjunctivitis. Unilateral chronic conjunctivitis will rule out OSSN. We need to know the typical clinical features in nodulo-ulcerative OSSN like you see on your screen. There is an area of dehiscence from where you see the uvea showing up. You can see a dilated, torturous vessel dipping into the lesion. And also there is an adjoining area of corneal haze. This is how a typical nodulo-ulcerative looks like. If you are in doubt go ahead and do an incision biopsy by this surrounding conjunctiva, that will give away the diagnosis. This is the first poll question where I showed a similar one, in that patient there was also blocks of keratin present giving away the diagnosis of OSSN. It may mimic necrotizing scleritis. We need to be aware of the morphological appearance and diagnose appropriately. Corneal are different in morphology. But corneal OSSN, like you can see on the screen, are different. They appear like a sheet of cells, as you can see, a sheet of cells on the cornea. And if you are not aware of the different morphology, if you don’t look at them under the high magnification of the slitlamp, many a times you might miss the diagnosis. Here what comes handy is noting the edges of these lesions. Whenever you have a suspicion of a corneal OSSN, go ahead and note the edges. Here you can see on the left hand side it is an fimbriated edge, either it is fimbriated like this or the edge is heaped up. These are the corneal which are different in morphology from conjunctival OSSN. A good way to demonstrate if you’re in confusion, a good way to demonstrate this, dilating the pupil, and you can see how nicely the fimbriated edges are getting accentuated with the slit lamp. There may be scleral extension, once you are in doubt, you feel there is a scleral fixity, go ahead and perform a UBM if available. Whenever you see an OSSN lesion and the posterior extent is not visible, most likely there is an orbital extension. You can see in this patient the posterior extent is not visible, so we went ahead and did a CT orbit. And you can see the lesion extending into the orbit. Having understood the clinical appearance of OSSN, the third poll question for you, which imaging technique is most helpful in evaluating the depth of invasion of ocular surface squamous neoplasia? Is it OCT, MRI orbit, rose bengal staining, ultrasound biomicroscopy or impression cytology? Okay. So majority of you have got it right, it is indeed ultrasound biomicroscopy. Why I am stressing on this is because for treatment of OSSN, it is important, as we move on to the treatment section, the depth of involvement is about most importance to plan the treatment. So whenever clinically you are suspicious, go ahead and perform ultrasound biomicroscopy if available. With this we have now understood how our typical OSSN looks like clinically. And the diagnosis of OSSN is predominantly clinical. So the modalities help us but the cornerstone is knowing the clinical presentation. Having understood the diagnosis, clinical pointers, let us now look into what are the amazing features of OSSN. So this is a typical OSSN, how it looks on an anterior segment OCT. What do you see here? You see if you compare it with the surrounding epithelium, it is a thickened epithelium. It is hyperreflective, which means it is more white than the surrounding normal epithelium. It is thickened hyperreflective epithelium lesion. There is abrupt transition from normal to abnormal epithelium. You can also sometimes make out the tissue plane of separation from the underlying stroma. But whenever the lesion has a lot of keratin or pigment, there is a lot of shadowing and the tissue plane may not be very clear. So this is how a typical OSSN looks on ASOCT. Posterior shadowing is a possibility whenever there is a lot of keratin and pigment. This particular patient has OSSN clinically. The UBM shows the fibers. The management whenever there is scleral involvement or the intraocular extension. These are the two major imaging modalities we use for OSSN management. But again, I would like to reemphasize that a diagnosis of OSSN is essentially clinical. These are adjunctive modalities which help us diagnose whenever there is a confusion. So, impression cytology in OSSN. In our practice, we are not using impression cytology. So impression cytology is a very easy, rapid investigation which can be done where we apply a cellulose acetate or biocompatible filter membrane to the ocular surface to collect superficial epithelial cells for cytological analysis. But it cannot differentiate between the different grades of dysplasia. It is extremely operator-dependent and requires a lot of expertise to perform. So it doesn’t give any additional information. And as I said, clinically OSSN can well be picked up, so impression cytology is not required in all cases. So with this we move on to the management protocol of OSSN. I would like all of you to pay attention on this particular slide. So until now we have understood that OSSN can have different morphological presentations, papillary, gelatinous, pigmented, et cetera. But what is important while planning the management is the extent of the lesion and the depth of the lesion. So for a localized lesion like a nodular OSSN, the gold standard of care has always been a wide excision with the cryotherapy. However there is evidence in the literature and the tables have turned towards a topical immuno/chemotherapy, so the localized lesions which are essentially epithelial, topical immuno/chemotherapy is the first line of treatment at present. So for diffuse OSSN, corneal OSSN, and where there is a margin of positivity, topical immuno/chemotherapy should be the first line of treatment. So until now we have understood that localized lesion, topical immuno/chemotherapy, wherever there is a scleral involvement, superficial scleral involvement, with excision we can do lamellar sclerectomy or plaque brachytherapy is also a great option for these cases. Whenever there is intraocular invasion we need to perform an extended enucleation. This is the management protocol for OSSN. And with this we move on to the surgical management. So we all use the no touch surgical excision technique which has been proposed by the Shields Group where they excise the tumor. Surface reconstruction, lamellar keratectomy where required. Surgery is definitely an option. Also in cases where topical therapy is not available. We take a margin on the corneal side and perform a double-double freeze thaw cryotherapy. I will be demonstrating it with a video. Surface reconstruction we do with amniotic membrane. This video will explain the steps in a better way. You see OSSN, the nodular OSSN there. The two millimeter margin on the corneal surface being marked. This is the area we need to excise. I am cauterizing the margin so there is less intraoperative bleed. You can see I dissected without touching the tumor. At no point in time am I touching the tumor. I am rolling the epithelium with the help of a crescent blade. So we are not using the line wash so the tumor cells don’t go all on the ocular surface. Here we are dissecting the tumor at the limbus. So I’m putting pressure on the blade so that the cut is absolutely flush with the ocular surface. So this is how we send to the pathologist. And with the proper orientation of the tumor so that the pathologist then understands. The margins have been taken on all sides. To be sent separately for a margin assessment. These are the margins being sent, again, to the pathologist. Now this is cryotherapy, on the inner surface we’re doing cryo. We are letting the cryo ball refreeze on its own. So that is the double freeze cryo. Now we are reconstructing the surface with the help of amniotic membrane which we are fixing with the help of fibrin tissue glue. So one more important aspect I want to stress at this point is that the adjuvant therapy that we give post surgery should be based on histology. It shouldn’t be a routine pain, we still see patients coming to us after surgery elsewhere where topical chemo is given routinely. That is absolutely not required. For margin, whenever there is a mild dysplasia, we just observe, in the margins, histopathology, we just observe it because we have already done a double freeze cryotherapy there. For moderate or severe dysplasia or a CIN lesion in the margin, we give three sites, the subtopical chemo or immunotherapy. For CIS, we re-excise one or more millimeter of margin. If the base is positive, we should ideally do plaque brachytherapy for all such patients. So this is one such patient before and after surgery. You can see the pseudo being formed because of localized limbic cell deficiency. There lies the importance of giving topical chemo or immunotherapy as a first line treatment. And as I said, these days with the advent of chemotherapy, we treat majority of the patients with topical chemotherapy. So this is the fourth poll question for you guys, which of the following is not true about 5-fluorouracil topical chemotherapy for OSSN? One, requires refrigeration. Needs to be freshly prepared. Reduces the risk of LSCD. Treats microscopic disease. Requires multiple patient followups. So out of these, which one is not true about 5-fluorouracil? So, majority have not answered it right. So it doesn’t require refrigeration, 5-fluorouracil is a good option for farmers, people who are — a majority of the day are outdoors, and they don’t have refrigeration because interferon requires us to maintain the cold chain. But that is not the case for 5-fluorouracil. Yes, it needs to be freshly prepared. It reduces the stem cell deficiency, otherwise for surgery you will end up in the limbus stem cells, that is not there in this case. It treats microscopic disease on the ocular surface but it requires multiple patient followups so it’s very important for us to discuss the need for multiple follow up with the patient at the very onset of treatment. So, requires refrigeration is wrong about 5-fluorouracil. With this we move on to the medical management of OSSN. Just a quick recap, by now we understand how typical OSSN looks like. We also understand how it looks on ASOCT. Having understood this, I would like to stress upon the ten important points about topical chemo or immunotherapy. When you start a patient on topical chemo or immunotherapy, you need to document the extent of the lesion meticulously so for each followup, you can assess the response and how the treatment — how with treatment the size of the lesion is coming down. Here you can see the size of the lesion, the size of the corneal component, presence of vascularity, feeder vessels, keratin. The documentation is important. Then what are the options available in hand? The options available are mitomycin C, .02 to 0.04%. 5-fluorouracil, 1%. Interferon a2b, 1 million units. Cidofovir has also been prescribed but very rarely used. So for topical interferon a2b, what we use in our institute is 1 million international units for times a day for three to 12 months based on the response. For extensive lesion, we top it off with injection, interferon a2b, and we also continue one month post resolution. What are the indications for using topical chemo or immunotherapy? When you want to reduce the size, you use it as a neo-adjuvant to reduce the size. You can use it as adjuvant therapy. The patient of the patients, this is what we see, that the lesion resolves completely with the help of topical chemotherapy. You can use it as adjuvant therapy, whenever there is a margin positivity, as we already discussed, after excision, you can use for treatments. Even though modulation is for a specific indication where you can use while enhancing the immune system, majorly for patients with xeroderma pigmentosum, modulation is helpful. Reduction to reduce human size, extensive OSSN, these are ideal candidates for topical immunotherapy. So this is a patient, pre. You can see a diffuse OSSN, with the help of rose bengal staining. This is after three months of staining, you can see the entire lesion has gone away. For corneal immunotherapy, for complete tumor control, this is a predominantly corneal OSSN, a sheet of cells. You can see post two months of treatment with 5-fluorouracil, for small tumors, immunotherapy should be given, it is the sole treatment for tumor regression. Post PK patients, recurrent tumors, these are great options. Immunoprevention, as I already said, as adjuvant therapy, histopathology evidence. The histopathology guided by adjuvant therapy should be given, it should never be routine, it should be based on the histopathology. Immunomodulation, as I already said, for young patients with aggressive tumors, bilateral moment focal recurrent tumors, xeroderma pigmentosum, HIV, post organ transplant, to reduce chances of recurrence, interferon-a2b. In which of the following OSSN scenarios should topical chemotherapy not be considered? So it’s very important to understand, as we said, these days all patients, we are giving topical immunotherapy but it’s very, very important to understand, we tell the contraindications, we tell the cases where you can’t use topical immunotherapy. So diagnosis is doubtful, intraocular extension is there, patient is noncompliant, routinely post-op, all of the above. So all of the above is the answer. So whenever the diagnosis is in doubt, go ahead, perform an incision biopsy. Don’t start topical immuno or chemotherapy. You only start when you are very clear of the diagnosis with the typical features of OSSN. Whenever there is an invasion, intraocular extension, we can’t start the patient on topical immunotherapy. Noncompliant patient, again, we can’t start because this requires a monthly followup for the patients. Whenever we give topical chemotherapy. As I already said, routinely shouldn’t be given post operatively, it should always be histology guided. The correct answer is all of the above. So this to reemphasize, whenever the diagnosis is in doubt, like in this particular patient, the patient was on months of 5-fluorouracil. But this is not a case of OSSN to begin with. You can see the condition there. This was diagnosed as diffuse OSSN but that’s not the case. This is a pagetoid spread. The loss of lashes, the thickening in duration of the eyelid which is also bad. Whenever diagnosis is in doubt, it is prudent to go ahead and do an incision biopsy, establish your diagnosis, and then go ahead with treatment. Similarly, nodular ulcerative OSSN, establish the diagnosis if you are in a dilemma. Depth in doubt. Whenever the depth is in doubt, the immuno And chemotherapy, when depth is in doubt, go ahead and do UBM. If you see scleral involvement, this is not a patient where topical therapy should be given, go ahead and perform surgery based on the depth. Now this is a very important slide. How do you understand whether there is scleral invasion or not, whether there is intro ocular extension or not, clinically? For scleral fixity, you need to instill, look at the video. Move the adjoining normal conjunctiva. OSSN being ocular surface lesion, whenever we move the adjoining conjunctiva, the OSSN lesion will also move along with it. Whatever you see that the OSSN lesion is not moving along with the conjunctiva, we call it scleral fixity positive. Similarly, intraocular extension. What are the markers for intraocular extension? So clinically, you can see deep corneal invasion like in the patient I showed you, there is a corneal haze. You can see in the stroma the lesion is going inside. That means there is a deep corneal invasion. You will have to treat this patient surgically. Whenever there are AC cells, there is an synechiae, these are indications the lesion has gone into the anterior chamber. If there is a corneal perforation, these are all cases the tumor has gone inside, go ahead and perform UBM. So when OSSN involves the adjacent structures like intraocular extension, corneal extension, tarsus extension, like here the eyelid is involved, punctum is involved. Whenever it is involving adjacent structures, again, not a candidate for topical therapy. When the patient compliance is doubtful, again, talk to the patient. If they do not follow up, they will only come back with a larger lesion. Good discussion with the patient in terms of compliance is very important at the onset of treatment. And fifth, routinely post surgery we can’t give. So the topical therapy needs to be histopathology guided. The response rate is very good, 80 to 100% resolved, mean resolution time is two to four months. Recurrence rate is 8 to 12%, all comparable to other treatments. As you can see, this is pre and this is post with the lesion gone. What are the side effects? Majority of the patients tolerate the topical chemotherapy well. The minor side effect which can happen, stinging sensation, conjunctival hyperemia, lid toxicity, punctal stenosis. So interferon has the least side effect, topical interferon. That is followed by 5-fluorouracil, we give 1% four times a day for a week, followed by three weeks of drug holiday. So in that drug holiday, the lubricant we continue. So the lubricant is continued for the entire month. So with that, the application rate is very low. So it is pretty safe. Systemic, flu-like symptoms can happen with interferon injections. The advantage of topical therapy over surgical excision is that it is noninvasive. It has reduced risk of limb balance stem cell deficiency, the chance is less. Treatment of microscopic disease, so reduced chance of recurrence, whereas the disadvantage is there is no histopathology evidence. We don’t do an incision biopsy in all cases before starting therapy, it is based on clinical diagnosis, so there’s no histopathology evidence. Interferon needs to be freshly prepared, which is not the case with mitomycin C. When the patient is a lot of times outdoor, it is preferable to give mitomycin C. A long treatment duration and importance of patient compliance is always there with topical therapy. So, systemic screening is also important. All patients, OSSN patients, we need to palpate the original lymph nodes, the submandibular, anterior and posterior, this needs to be routine in all cases, whenever you see lymph node, go ahead, perform a fine needle cytology to see whether it is a reactive lymph node or a malignant lymph node. That also requires simultaneous treatment if it is there, excision. So lymph node evaluation is a must. The best investing modality being whole body. With this, having understood the pros, cons, and the important aspects of medical management, we move on to the last part of my presentation, where I will help you understand the different features to differentiate OSSN from similar lesions. So in a busy practice, many times all these lesions appear similar. It is extremely important to diagnose appropriately. 30% of OSSNs are misdiagnosed, which is quite a high percentage. So let us understand how do we differentiate it from the common mimickers. Pingueculitis, you don’t see a keratin there, and it is subepithelial. You can see clinically the nicely glistening conjunctiva above, which is not the case for OSSN. Here it is a subepithelial lesion. Go ahead and do an OCT and see that the lesion is subepithelial. This ten-year-old girl, limb balance lesions, referred to our clinic as a case of bilateral OSSN. All such patients, it’s not something where a common age for OSSN. So you need to dilate in all such cases. This is what we see, itching, papillae, epithelial downgrowth, and subepithelial lesion with epithelial downgrowth. This is on the inner eye with ocular inflammation. They nicely come down on treating with topical steroids. So it’s important we differentiate it from OSSN. Again, granuloma, red, fleshy, richly vascular lesion often pedunculated, bleeds on touch. They usually have a history of surgery or trauma. Conjunctival lymphoma is again a subepithelial, small, diffuse, slightly elevated, typical salmon patch appearance, looks like the salmon fish. Hyporeflective subepithelial lesion helps differentiate it from OSSN. Conjunctival melanoma, darkly pigmented lesion, thickened lesion, highly vascular, corneal involvement may be there. We need to focus the majority of the times the existing lesions. You can see the surrounding areas of melanosis, it’s important to differentiate it from an OSSN where keratin. Keratin is not there in a case of conjunctival melanoma. This looks very different from what a typical OSSN looks like. Conjunctival nevus are usually unilateral, variable pigmentation, limited to limbus. Well-defined margins. They have cysts, around 65% of them. History of change in size at puberty. There can also be a fetal vessel, that doesn’t necessarily mean transformation in these cases. Subepithelial lesion with cysts. This is nothing but complexion associated melanosis. The patient was about to be taken up for cataract surgery. These patients are very typical. Bilateral, symmetrical, dark-skinned individuals, flat, cobblestone pigmentation with microfolds, fine pigments on peripheral cornea, there can be extension. Conjunctival and scleral dehiscence, feeder vessels, surrounding induration, corneal haze, we need to differentiate from necrotizing scleritis. Corneal OSSN can often be confused with corneal scars or corneal dystrophies. But we need to focus at the edges, which are often fimbriated, heaped up. And the lesion appears translucent, ground-glass-like sheet of cells. So again, whenever in doubt, go ahead and perform an OCT. Look at the thickened hyperreflective epithelial. The last point, the last mimicker which I wanted to stress upon, OSSN can coexist with microbial keratitis. We have OSSN lesions missed because they were co-existent with the microbial keratitis, missing the OSSN which led to devastating outcomes. So we have shared treatment management for these cases, which is primarily dependent on the intraocular extension and orbital extension in these cases. This brings me to the end of my presentation. I would like to summarize whatever we learned in the past 45 minutes. OSSN diagnosis is predominantly based on clinical features. They are limbal masses with intrinsic vascularity, feeder vessels, keratin, pigmentation located in the interpalpebral area. OSSN can have different morphology. It is important to identify the diffuse and nodulo-ulcerative types. The aggressive nodulo-ulcerative type appears as a localized ulceration of conjunctiva and sclera surrounded by indurated thickened conjunctiva. Ocular surface keratin always rule out OSSN. Document the extent of tumor meticulously, assess the margin and the base in all cases. Topical therapy in OSSN has specific indications. They’re used for immunoreduction and immunotherapy. Topical therapy can’t be considered when the diagnosis is in doubt. OSSN involving adjacent structures of the patient is not compliant. Surgical excision needs to be done by the no-touch technique with wide excision and margin cryo. Following, histopathology guided adjuvant therapy is most important. Examine regional lymph nodes in all cases and if present, needs to be managed appropriately. Advantages of medical therapy include ability to treat the entire ocular surface and the potential to avoid stem cell deficiency. The common mimickers are pingueculitis which is subepithelial lesion with no keratin. PEH has a history of itching, inflamed ocular surface, papillae, a subepithelial lesion with epithelial downgrowth. Pyogenic granuloma bleeds on touch. Conjunctival lymphoma, smooth, diffuse, slightly elevated lesion. Conjunctival nevus, limited to limbus, variable pigmentation. Complexion associated melanosis, they have the microfolds. Conjunctival melanoma, there is no keratin. Nodulo ulcerative OSSN, feeder vessels, surrounding indurated country junk type of have a. Corneal OSSN, translucent ground glass like sheet of cells. Thank you, everyone, for patiently listening. That brings me to the end of the presentation. So now we will take up questions. Please type your questions in the chat box. Okay. Now I am able to see the questions. So what is the technique used for in. >>> Biopsies? Incision biopsy, as I said, we don’t do routinely, we only do when the diagnosis is in doubt and we need to find out whether there is OSSN or not. Like for nodulo ulcerative OSSN, we use the lesion. We try to take from the region where we see the vascularity. Where the diagnosis is in doubt, you can take from any of the area, any place on the surface of the lesion. There are a few articles on 5-fluorouracil. In my opinion, I have tried for a few patients, but topical 5-fluorouracil, they work magically. The onset of action is even earlier than what we see with interferon alpha 2b. I don’t think there is a need, because topical or just like for us, one week on, three weeks off, that takes care within one to two months, 90% of the patients, the lesion is completely gone. Any role of scleral cryo if basal extension is noted intraoperatively? Yes, we do perform base cryo, but however, in the postoperative, as I mentioned, it is important to look into the histopathology for a very small area the cryo might have, but the standard of care is brachytherapy. Can topical chemotherapy be given as combined therapy in aggressive cases rather than mono therapy? Yes. We can give like — so it’s not a good idea to combine, but in aggressive cases, what we usually do is we start with the monotherapy, but many a times we see that the lesion is nonresponsive. Usually we wait for three months, for three months after the particular topical chemotherapy, the lesion is not decreasing in size, we shift to a different topical chemotherapy. But giving more than one topical chemotherapy may not be a good idea because they have the individual ocular surface toxicity, so best to use, once you see suboptimal response. Are there known genetic predispositions to OSSN? Yes, there are known genetic predispositions to OSSN, like genetic mutations are noted, like all those conditions can cause OSSN, like xeroderma pigmentosum. So yes, it can happen. Topical 5-fluorouracil or interferon can increase IOP? The reaction has been documented in literature causing increased intraocular pressure. Difference between incision and excision biopsy. As I said, incision biopsy, we only do when the diagnosis is in doubt, and we are not able to plan treatment because if it is a malignant lesion, we need to do a wide excision biopsy whereas if it is a benign lesion, we just need to do in total excision, remove the tumor and nothing else. Whenever we have that dilemma, we do excision biopsy, the typical no-touch technique, we take four millimeter margin and two millimeter margin on the corneal side. Any experience of combined — yes, we do combined with tumor excision. We used to do this for all tumors with more than six clock hours of involvement. Earlier, we used to do a primary simple limbal epithelial transplant along with the tumor excision. And it used to work well. But it was an option for us when the tumor topical therapy was not involved. But immunoreduction, these days we almost don’t do the tumor excision. But in areas where the topical chemo or immunotherapy is not available, yes, combining of primary with tumor excision is a good option. What is the management secondary to surgery of steroids? Go ahead and give tapering course of topical steroids, the majority of them will go away with that. If steroids is not taking care of the granuloma then we do go ahead and excise the lesion. How quickly? As soon as possible. We are dealing with oncology, eye cancer, so as soon as possible we need to refer the patient to an ocular oncologist to treat these patients appropriately. What are the indications for incision and excision biopsy? Yes, diagnosis in doubt, excision biopsy, yes, excision biopsy in total we do for benign tumors, wide margins as we discussed. In case of in HIV-positive patient, what would be your next management? Tarsal conjunctiva. So we need to make out that whether there is palpable conjunctiva that you are talking about, topical chemotherapy is the ideal treatment, but if there is a toxin involvement, it won’t come down, the invasion won’t come down with topical chemotherapy, as I said, if a carcinoma doesn’t respond to topical chemo or immunotherapy, if there is an invasion, it won’t respond, then we will have to go ahead and, based on how much of the tarsus is involved, if it’s localized, we need to excise that part. When do you decide to stop topical therapy? Very good question, Rosa. We will stop the subtopical therapy, as I said, one month after clinical resolution. So, suppose we see complete clinical resolution, today I will continue the patient for one more cycle, in order to take care of the microscopic residues. That’s the protocol we follow. After, you would stop the topical therapy. What is your promote for mitomycin therapy? The two most common topical chemotherapeutic agents we’re using, mitomycin C, the OSSN goes off very quickly, it is very effective, but the problem there with mitomycin C is the surface and lid toxicity that it causes. If you want to use mitomycin C, use it 0.4% and four days a week, three days of holiday. That’s how we use. And for how long, the answer so this, for all topical chemo and immunotherapies, the same. The day you see complete clinical resolution from there we give one more cycle of topical chemo or immunotherapy to take care of the microscopic residue. What is the primary mode of OSSN? As we discussed, it spreads to the regional lymph nodes, so it is very important that we do regional lymph node palpation for all patients with OSSN. And if there is any palpable lymph node we have to find out if it is reactive or metastatic. If it is metastatic, completed note dissection needs to be done otherwise the management is incomplete. Conjunctival nevus transformation to malignancy. Conjunctival nevus transforms to a conjunctival melanoma, not OSSN. If we see conjunctival nevus, a majority of the cases, we observe periodically and we document the size of the lesion with photographs. If you see that the size of the lesion has suddenly started increasing, or it’s crossing the limbus, which usually it doesn’t cross, we need to look for malignant transformation in that case. All cases of keratosis have dysplasia. This is a controversial area. Basically because of UV radiation, it used to be the lesion is away from the limbus, but now we know that all patients of acanthoma keratosis, it’s best we treat them in the same manner as the patient of OSSN. If cornea is fully involved, how to do excision. If it is fully involved, the cornea is fully involved, you can’t do an excision biopsy. These are patients where you will have to go in for an enucleation. The topical chemotherapy and wide excision biopsy are only options for localized lesions. Whenever there is a corneal invasion or intraocular extension, we need to plan an extended enucleation. And whenever there is orbital extension, we need to plan orbital. So scleral cornea, fully involved, no excision. It is an enucleation which you will have to do in all such cases. How to confirm corneal, again, as I said, diagnosis of OSSN is based on clinical findings. So that’s the reason, I am again stressing on the clinical features of OSSN. So corneal OSSN, it’s a clinical diagnosis. You can go ahead and try doing an impression cytology where you just use the filter paper and the analysis is done, to see whether dysplasia is there or not. But it is extremely operative dependent. It is not much help. So it is basically the clinical finding of a translucent sheet of cell on the corneal with a fimbriated or heaped up margin is when you need to start on topical therapy. Can you kindly take us to the preparation of 1% of 5-fluorouracil. So, yeah, I can take you through the preparation of 1% 5-fluorouracil, maybe at the end I will take this up. Between topical 5-fluorouracil and — as I said, it is preferred over mitomycin C because of less toxicity. Mitomycin C has more toxicity on the ocular surface and the eyelids. So it is better to use 5-fluorouracil. What we use in our practice is one week on, three weeks off, and in that period we also give topical lubricants to take care of the surface toxicity. So again, the same question is coming up, how long should mitomycin C topical be administered. How long depends on the response. The response is the complete clinical resolution. You need to note complete clinical resolution. From that point, one more month of topical chemotherapy to take care of the microscopic disease. When you talk of intraocular involvement, which intraocular surface is involved in the worst case of OSSN? When I talk of intraocular involvement, as I showed you in one patient, it can then go into the angle where you see secondary glaucoma, it can go into the deeper layers of the cornea, the stroma, it can go into the lens. And we have also seen patients where the patient has denied treatment and the entire high cavity is filled with the lesion. So they can also go into the orbit. That is the most common. Topical chemotherapy, the response is so nice that I don’t feel there is a need for subconjunctival SSC. How long do you follow up patients with OSSN? So we have a protocol at our institute of following up OSSN patients first like once resolution, every month we need to follow up the patient. Once the resolution is there, first we collect two months, then we collect three months, four months, six months, then yearly. That’s the protocol we follow. What would be the best therapy? As I said, we need to understand the treatment protocol, localize the lesion, topical chemotherapy, patient not ready to come, noncompliant, consider wide excision biopsy. If there is intraocular, corneal extension, extended enucleation, so that’s how we plan the treatment based on the extent and depth of involvement in a case of OSSN. If there is scleral fixation but without visible lesion on fundus, how should I approach it? Scleral fixation means the surface, ocular surface tumor has gone inside. There won’t be access to the fundus, best to go ahead, look at the depth of involvement. So if there is — if it is a superficial sclera involved, then you can consider lamellar sclerectomy or postoperative brachytherapy in these patients. Concentration of 5-fluorouracil. Concentration is 1%, so I will also address the question, I think the same question is coming up time and again. How do I prepare 5-fluorouracil. What is available in India, 250 milligram, rejection of 5-fluorouracil. We take 1 ml of 5-fluorouracil, and 4 millimeter of sterile water, that makes it 1%. What is the treatment, is there room for systemic immunotherapy? Treatment, yes, there are some protocols of systemic neo-adjuvant chemotherapy where we can see whether the lesions are coming down in size or not. But we have tried in few patients, but the squamous cell carcinoma, the response is not as great as we see. So topical systemic chemotherapy is an option. We can give it a try. But in case there is no resolution, we need to perform our vital. Is there any danger for nevus? Yes, as we discussed, nevus can undergo a malignant transformation. We need to look for the increase in size or more pigmentation, development of multiple fetal vessels, the lesion going beyond the limbus into the cornea, all these are signs of malignant transformation of the nevus. If there is lymph node invasion what should be the management? Go ahead and do a fine needle aspiration cytology on the lymph node. If it is reactive, nothing to be done. If it is malignant invasion, then we need to go and do a radical dissection and also radio therapy. How many years we should follow up the patient? It is a good idea to follow up the patient lifelong, at least yearly, once. Also tell the patient if there is recurrence to come back. Interferon a2b, you can choose which you want but the interferon-a2b, the toxicity is less, the patients are comfortable, it is almost, apart from some follicular conjunctiva. The patient is working outdoors, I think that after having had discussion with the patient it is best to give 5-fluorouracil. The problem with interferon-a2b, it was not available worldwide. Now in India it is again available. 5-fluorouracil, it is abundantly available, and price is much less. So which one you choose is based on a discussion with the patient, the pros and cons needs to be weighed, but any of them can be used. Is there increased recurrence in excision done without cryotherapy? Yes, there is the chance of recurrence, it goes multiple fold higher if we do only excision without cryotherapy, it is documented in literature, cryotherapy is a must in all such cases. Can it interfere with ART drugs? No, they usually don’t increase with the drugs and can be given safely. How do you assess deficiency? Development of corneal scar or, it overrides the limbus and goes on to the cornea. For a very small CIN, a followup? Treat with topical chemotherapy, will you see one within to two months complete resolution. The entire umbrella of OSSN, I would not recommend to just observe. It is best treated, because the treatment profile is very safe. Clinically suspected corneal OSSN, how to perform tissue diagnosis? So as I said, incision biopsy can be taken from any part of the lesion. So where you see the lesion prominently, it can be taken and diagnosis can be confirmed. We can go ahead and do a lamellar sclerectomy along with taking the other steps of efficient biopsy. Clerical involvement means excision is required. These are not patients who can be treated with topical chemotherapy. Go ahead and plan a lamellar sclerectomy. Biopsy is not required of OSSN. In these cases, if you are in doubt, just having the diagnosis helps because the treatment is topical chemotherapy and topical chemotherapy will take care of the entire ocular surface. In case of vital extension, do you first — you can, if it’s a young patient, you can go ahead and give new adjuvant chemotherapy and assess response. If there is response, and the size comes down, then you can plan surgery. But if there is no response after chemotherapy, it’s best to go ahead and perform a [indiscernible]. Conjunctival lymphoma, if it is just a lymphoma, bone marrow biopsy to rule out a systemic mass, and after ruling out, brachytherapy is a great option. Have you seen OSSN simulating BUK? Yes, many a time I have seen it simulate peripheral keratitis and microbial keratitis. You need to focus on the typical features that we discussed, it will have the intrinsic vascularity, that is the giveaway that there is a lesion there which you need to pick up. In patients on topical chemo, can the [indiscernible] be done to ensure the lesion has a result? If so, will the [indiscernible] have specific pointers? Yes, it can help us understand the resolution of the lesion. Many a times you can see there is some remaining hyperreflectivity which goes off with treatment. The thickening goes down. But there can be that residual hyperreflectivity which we see in these patients. If you work in a center [indiscernible] to decrease livelihood of recurrence. Yes, this is a difficult situation. Without cryo, the chances of recurrence are pretty high. Maybe you can consider, for these — like in resources are limited in this setting, you can consider postoperative chemotherapy to reduce the chances of recurrence. Can we [indiscernible]? I don’t think to the best of my knowledge there is any such literature existing. How long can we try interferon to see if it is working before we stop it? You need to start it for at least three months before calling it off or switching to a different topical therapeutic agent. Three months is what we usually give and then we assess. So I think with that, we are done with all the 54 questions which were there. Thank you, everyone, for patiently listening and for such an interact session with all sorts of very pertinent questions coming up. I’m sure with this, you all will be able to treat your patients appropriately. Please feel free to reach out to me on my email with questions or if you want an opinion on any particular patient. I will be available to help you guys. Thank you. Have a great day.