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Prevention and Management of Skin Problems - (full conference transcript)

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Tony Chu

Head of the Section of Dermatology at the Imperial College of Science, Technology and Medicine, Senior Lecturer and Honorary Consultant Dermatologist at the Hammersmith Hospital and Ealing Hospital.

Just to put things in context. How many of you here have had skin problems with your transplant? So a relatively small number. How many of you were warned about sun exposure when you had your transplant? So the message is getting out. When I asked that question ten years ago there was hardly a hand came up. And one of my patients that I see regularly, every six weeks, and weve taken a skin cancer off him probably ten times this year so far, was told when he had his transplant to go and sit in the sun and have a good time. And thats exactly what he did for the next five years. He went to Thailand, he went to Spain, and he sat and basked in the sun. And that of course was the worst possible thing he could do.

So Im going to run through some of the factors that influence skin problems in the transplant patient, and end up with things that you can do about it. And theyre very important.

Transplantation demands immunosuppression to prevent graft rejection. Immunosuppression has changed over the years. Were now using more and more different drugs. Every time a new drug comes up, everybody thinks this will be better, it wont have the same side effects. Unfortunately that hasnt been the case. Immunosuppression does have a major impact on the skin increasing incidence of infection, pre-cancerous and cancerous changes, and the reason for that is obvious. If your immune system isnt 100 per cent then youre going to get more infections. And many of the skin problems related to immunosuppression can be reduced with adequate advice and management. I feel very strongly that all transplant units should have a package that they give to the patient telling them exactly what they should and should not do.

Non-Viral Infections

Infections I wont dwell on. They are much more common in the immunosuppressed patient. Acute bacterial infections, boils, cellulitis, abscesses all more common, all treated in a conventional way. Chronic infections such as tuberculosis tend to be more common. They are often missed, because people dont think about them. Once again, once they are identified, they will respond to conventional therapy.

Viral Infections

Viral infections, very important, herpes simplex and particularly warts, and Ill dwell on warts in a moment. These once again can be treated conventionally. And ringworm, fungal infections, all very common, all conventionally treated. As long as they are identified theres no problem with them.

Warts

Now the real problem is with warts. Now warts are caused by a virus called human papilloma virus. Theyre very common in childhood. Most kids will have developed warts, usually on the hands or the feet. Theyre a damn nuisance and we do see them throughout life, because immunity to the wart virus is short-lived. Therefore as you get older you acquire more warts. If youve got a verruca, its painful. If youve get warts on your fingers, they dont look nice. But in general theyre not life threatening in any way. But the human papilloma virus is now implicated in cervical cancer and the human papilloma virus types 15, 18, 45 and 31 we now have about 100 HPV types, and each year we are finding more. The way this works is that parts of the viral DNA E6 and E7 link to specific genes in the human cell. That causes the cell to divide more rapidly and eventually to transform into a cancer cell. And thats why, in cervical cancer, HPV is of enormous importance.

How does that affect you? If we look at a genetic model, and dermatologists are very fond of big long fancy names. This is a disease called epidermodysplaxia verriciforma (EDV). Its an autosomodominant, so its passed one in two to children, and in this disease theres an inherent immunosuppression, which is genetically based. And these children develop warts at a very early age, and these are very widespread warts, and theyre due to a very specific type of virus, HPV 5 and 8. These are the EDV type of viruses. In the second decade or even late first decade, so youre talking about ten, 15, 20 year old people, following sun exposure the virus transforms the cell and you develop skin cancers. These children tend not to do very well and they often die of widespread skin cancer at an early age. And they develop into these specific squamous cell carcinomas.

So we have a genetic model and that shows us to an extent what is happening in the renal transplant patients. Instead of having a genetic immunosuppression, youve got a drug induced immunosuppression, but it has the same sort of effect.

If we look at transplant patients, they tend to develop warts, usually after four or five years post transplant, and thats why at the Hammersmith these days I routinely review all patients five years after their transplant and thereafter. The warts are increased in sun-exposed areas and the sun does seem to have an effect on the susceptibility of developing warts on the skin. And many of these warts contain both the EV viruses as well as other oncogenic human papilloma viruses. So once again with sun exposure these viruses can transform the cells into a skin cancer. Therefore there is a real risk that these warts developing into squamous cell carcinomas after sun exposure. That is the primary reason that you have to be so careful in the sun.

How do we manage them? Well certainly at the Hammersmith I regularly check all the transplant patients. We treat the warts, usually with cryotherapy. How many of you have had cryotherapy? A few. Did you find it pleasant or unpleasant? Its really very painful. Its not pleasant at all. What we do with cryotherapy is use a very cold solution, to induce a thermal burn in the skin. The solution is liquid nitrogen, its down to minus 180 degrees C, its great for freezing strawberries, its a great party trick. But when you put it on the skin, you induce a burn and that literally does burn. The patients dont like it. But it does kill the virus, it kills the warts themselves and it does clear them. And obviously avoid sun exposure. Now one major problem is the number of warts some of you develop. In some of my patients it can number in the thousands. Now can you imagine having a thousand warts on your body? And thats not uncommon. Ive got at least ten patients we are seeing regularly at the moment, I see them every six weeks, and I have to freeze a hundred warts every time. Now that takes me a long time, its incredibly painful for the patient and once again very time consuming on clinic time. And its very important to target all the warts, because you cannot predict when you see a wart whether the wart will develop into a skin cancer or not. Many of them wont, many of them will be of the common HPV types, but if youve got one of these rogue viruses present you could develop a skin cancer.

Now one thing that has come out recently and its probably something none of you have heard of, is a new cream called 'Imiquinod'. This is developed by an American company called 3Ms and its licensed in Britain, but its licensed for genital warts. The way it works is to enhance the immune system locally to cope with a viral infection. And its very successful. Now obviously you notice it enhances the immune system could that have an effect on your transplant, because youre taking the drugs to suppress your immune system? In a few patients with renal transplants that have been treated, they have monitored renal function very carefully and theyve monitored immunosuppression, and no, it does not seem to have an effect on immunosuppression and graft survival. So at the Hammersmith were just about to embark on a trial looking at 'Imiquinod'. Applying the cream three times a day does clear viral warts very effectively, and if we can ensure that it is safe in the renal transplant patient, this could well be a way forward in treating patients. They can treat themselves at home, it will save us time at the clinic and its not painful in any way.

What do warts look like? This is one of my patients. He comes up literally every six weeks. He was the patient who was told to go and bask in the sun for five years. You can see lots of change in his skin (see 2 Diagrams, left and right), all these warts, and how do you tell a wart from a callus or just another sort of skin bump? If you look at a wart, you can usually see little black dots in it, and these are little blood vessels that have grown up into the wart, then theyve thrombosed. And if you pare them down with a pumice stone or a scalpel blade youll often get little bleeding points there. But here we have multiple warts. This patient literally comes with a little diagram, and says where do we start? We usually start on his hands, go up his arms, on to his body, his face, and then legs, and eventually his feet. And a hundred warts are painful.

They are increased in sun-exposed areas. And so if you protect yourself from the sun from an early stage, you can often prevent these from developing.

Skin Cancer

Now what about skin cancer? I dont know what the practice is in your local units, but in our unit at the Hammersmith, if you have had a skin cancer they will take that as a reason to refuse a second transplant. So its very important to protect against them.

In the normal population, the commonest type of skin cancer is what we call a basal cell carcinoma. These arent too bad, they grow locally, they dont spread round the body, and you can usually treat them very easily. The ratio of basal to squamous cell carcinomas is 10: 1. In the transplant patients, squamous cell carcinomas are ten times as common as basal cell carcinomas. Its the squamous cell carcinomas that are induced when it is of those particular types and causes the cell to transform in relation to sun. Therefore the majority of squamous cell carcinomas were seeing in transplant patients seem to be related to HPV infections. The thing with squamous cell carcinomas are that they are metastatic that means they dont just grow locally, they spread to the lymph glands, theyll eventually go through to other parts of the body, and once theyve actually spread beyond the skin then theres very little you can do about it. And of course because of immunosuppression the body cant control that spread as well and therefore these sorts of tumours are much more serious than they would be in a normal person.

Melanoma is probably the worst cancer we see in the skin. Its increased in transplant patients, its a very aggressive skin cancer, it may arise from a pre-existing mole, or it may come up in normal skin. And in the immunosuppressed patient it is often very aggressive, and often therefore we first see a patient who has already got deep invasion in the skin and once again early recognition isnt possible.

Now generally the major factor in the development of skin cancer is the sun. Now we all like the sun. I always tell my patients dont go in the sun, dont get a sun tan, and I come back from my summer holidays four or five shades darker. They all tell me off. And quite rightly so. But its very difficult because you feel good in the sun, and you like being in the sun and you like going to sunny climates. And with travel nowadays we can all go to different parts of the world and get too much sun exposure. The skin type is also very important in dictating how the skin will react to the sun. So if youve got a very pale Celtic skin with freckles, blue eyes, blond or red hair, youre going to do very badly in the sun. And even if youre not immunosuppressed, youre at high risk of developing skin cancer. If youve got nice Afro-Caribbean skin, youve got an innate protection against the sun, and therefore the risk of skin cancer is very low.

Now if you look at what the sun does to man, the effects really are divided into acute and chronic effects. And the acute effects you have to regard as being protective. Now how many of you think that sunburn is protective? How many of you have sunburn? A few little hands tentatively going up. You shouldnt have, its dangerous. But sunburn is still protective. If youre burnt, you dont go in the sun the next day. The skin also tans and the tan that you develop protects you against the sun, because the pigment in the skin takes up some of the suns energy and quenches it, so its not as active. And the skin actually thickens in the sun. If you measure it histologically, it almost doubles in its thickness and that protects the more sensitive cells at the bottom of the skin from the ultra-violet rays. Chronic effects are skin cancer, but also ageing. Did you know that 90 per cent of skin ageing is due to the sun? If you lived in a black box all your life, you would have skin like a babys bottom when youre 90. And thats partly why people with darker skins tend to have much nicer skin later on, and people with pale skin who like to sunbathe have really tough old boot leather skin when theyre very young. So, particularly ladies here, if you want my skin you slap on your sunblock regularly.

If we look at ultra-violet light, its divided into divided into three different bands (see Diagram, left)- UVC, UVB and UVA. UVB is probably the most important as far as developing skin cancer goes. These are the wavelengths - UVC 100-289; UVB 280-310, UVA 315-400. The shorter the wavelengths, the more carcinogenic, so UVC is the most carcinogenic. Thankfully it doesnt get down to the earths surface. Beyond that you get X-rays and this side you get visible light. Weve all heard about the ozone layer and the holes in the ozone layer, and the importance of those is that the ozone filters out the dangerous wavelengths. So no UVC gets through to the earth because of the ozone layer. A lot of UVB is filtered out, some still penetrates down to sea level. UVA still gets through and it goes down even to the Dead Sea level. So those of you who want a nice sunny holiday and dont like slapping on the sunblock, if you go to the Dead Sea you get no UVBs so you dont sunburn, you get UVA, and even UVA can cause skin cancer if you have too much of it, but its a much safer bet than going to the Mediterranean. And if you like climbing mountains, at the top of a mountain you are much closer to the stratosphere and therefore much more energy gets through and so you have to take even greater precautions. So if you want a nice holiday and youre walking in the Alps you still have to wear your Factor 60 sunblock.

Now basal cell carcinomas are the commonest cancers we see in the Caucasian populations. Sun exposure is the major cause. Common sites are face and the trunk, but these are the good guys. Theyre not metastatic, they dont spread round the body. Transplant patients still get them, and theyre very easily recognised. Theyre lumps in the skin (see Diagram, left). You often get these little blood vessels coursing over the surface. And theyll often ulcerate and then break down in the middle. Theyre called rodent ulcers because they look as if a rat has been chewing at you. Now squamous cell carcinomas are the second most common cancer we see in the normal Caucasian population. If you look at transplant patients, they take over as the most common. Theyre caused by sun exposure and its usually chronic sun exposure, and so those of you who work outdoors, who work on your allotments, who like to play tennis and golf once again, beware. Most at risk are those with pale skins who burn in the sun, theyre commonest on sun exposed areas like the face and the hands, the ears, the scalp. And a pre-cancerous lesion is the solar keratosis. These are little hard knobbly bits that occur on the skin. When you feel them it feels as if you are touching a nut grater, and if you try and pick the scale off you get a bleeding point. They need to be treated. They are pre-cancerous and could develop into a skin cancer later on. These do have metastatic potential. They can spread to the lymph nodes, then to the liver, the lungs, and once they have got out of the skin, unfortunately theres not a lot we can do about them.

This is one of my transplant patients (see Diagram, right), a lovely lady whom Ive been seeing for the past ten years, shes got multiple red scaly patches scattered over her face. Shes an Irish lady, Celtic skin, does very badly in the sun, and thats all been compounded by her immunosuppression. Each time we see her we freeze the keratoses with cryotherapy, and thats one of the only ways of getting rid of them effectively.

Another patient you can see these scaly patches on the backs of the hands (see Diagram, left), and here where the scales have accumulated to develop a cutaneous horn. It looks like a nail sticking out of the skin. Thats because the skin is growing abnormally and youre getting the accumulation of dead skin that pushes up. All of these areas are pre-cancerous. If you left them, after a period of time they could develop into skin cancers. Therefore they have to be treated. Really the only effective treatment we have at the moment is cryotherapy.

This shows what happens if one of these turns and becomes malignant. This is a squamous cell carcinoma (see Diagram, right). Once again they can grow rapidly and even more so in the transplant patients. I have some patients I see every six weeks and Ill see them on day one and theyll be clear, Ill see them six weeks later and theyve got a lesion this size. They can grow rapidly, they need to be treated as a matter of some urgency, and if you remove these surgically that can be cured. If you leave them too long, then they will spread through the rest of the body.

This is another large squamous cell carcinoma which has developed from solar keratosis (not shown). So there is a need for you to regularly attend a doctor and have the keratoses treated and examined. If you pick up a skin cancer early, its not a problem. Surgery is curative. If you leave it then it can spread, and once it spreads youre into problems.

Melanoma is the third most common skin cancer, but if you look at young women, its the second most common skin cancer to affect young women, so its increasing in its rate enormously in its incidence over the last ten years in Britain. The major cause is severe intermittent sun exposure, so its going to the Costa Brava and sitting out and burning on the beach every year it also appears in non-exposed sites. You often see them on the trunk, on the bottom, on the legs. And it does have a very high metastatic potential. It spreads rapidly, it goes to local areas of the skin, it can go to lymph nodes, the lungs, the liver and the brain. As with squamous cell carcinoma, once it spreads beyond the skin, theres very little we can do about it.

Thirty per cent arise from a pre-existing mole, so you need to keep your eye on your moles. The things to look out for are the mole becoming asymmetric. If you look at a mole, most moles are nice and round or oval, and theyre an even colour. They can vary in colour from skin colour to black, but when a mole changes it becomes asymmetric, it becomes irregular in its shape, and irregular in its colour. At this stage, if you remove it, thats totally curative. If you leave it too long, it can spread. In the transplant patient it often arises on normal skin without a pre-existing mole, so any dark mark that comes up should be looked at and given attention to.

And this is a very early melanoma (see Diagram, left). Here you can see the mole becomes asymmetric, its become irregular and theres some colour variation there. Thats at a very early stage removal of that is 100 per cent curative, theres no problem.

Another melanoma does other things. When moles first start, they often spread through the skin rather than going deep into the skin. Therefore at this stage it is totally curable by removal. Here you can see the irregular border and the colour change (see Diagram, right). So theyre the sort of features youve got look for.By the time its reached that level, then youre into a bit of a hiding, Im afraid.

Here youve got a large lump (see Diagram, left) which has developed, its ulcerated, its already penetrated right through the skin, and at that stage you would expect it have spread into the lymph nodes, even if its microscopic. At this stage it still needs to be removed, there are still things we can do about it, but its been left too long. It needs to be dealt with immediately. As in a case in point, one of the transplant nurses at Hammersmith asked me to see a patient urgently. She said that the patient had seen one of the surgeons, and had said this mole is looking a bit funny and the transplant surgeon put him on the waiting list to have it removed three months later. I saw him the next day it was a melanoma, we removed it immediately, and theres been no problem since then. If hed left it for three weeks, that could have been a problematic mole.

Avoiding Skin Cancer

So how can we actually prevent these long-term problems? Well, its very easy. If you avoid the sun, then thats fine, certainly avoid the midday sun. Use photo-protective clothing and hats, and use high factor (60) sun block.

Now about avoiding the sun, I tell patients all the time Avoid the sun. and the answer I get back is Oh, I dont sit in the sun. I dont have any sun exposure. Well, why are you getting solar kerotosis then? And when you ask them do they wear a hat when they go into the garden to get the washing in, do they wear protective clothing when they go down to the shops, and no, they dont.

Well, I walk in the shade, and well look at that in a moment, because walking in the shade doesnt help you. If youre out in daylight, you need to have protection, and the protection can either be a sun block or it can be some protective clothing. But dont rely on avoidance, because you cant avoid the sun and live a normal life, unless youre a completely nocturnal animal. Now lots of teenagers are, they dont get up until three or four in the afternoon, and they seem to be partying all night. Thats OK. The real problem is that society does worship the brown body beautiful. If youve got a nice tan, people say Oh, you look well, dont you? and if youre nice and pale and pasty, they say, Ooh, dont you look unwell? If you want a bronze body beautiful there are very good artificial suntans. My wife uses one all the time and everybody comments on her legs, saying they look really good, where have you been, the Caribbean? And its all out of a bottle. So if you want a tan, go and get a bottle. And these days you dont just go orange with them and you dont necessarily go streaky, you actually look quite good.

Youve got to remember that, even on a cloudy day, ultra violet light gets through the cloud cover. So, dont say, its cloudy today, its raining today, I wont bother to put sun block on. Thats hopeless. Even on a cloudy day, you get enough ultra-violet light through to damage your skin. So certainly for the whole of the summer, from the end of March till the end of September, you need your high factor sunblock. Now I see a lot of people thinking, Well, I dont put mine on when its raining. Youve got to from now on. And youve got to remember, sunlight is tricky, its there to trip you up the whole time. It will reflect off water, it will reflect off sand, it will reflect off other structures, so even if youre sitting in the shade youre not protected. And this shows it rather nicely (see Diagram, left); here we have little Luby Loo sitting under the shade of a tree. The sun is still getting through cloud cover, its bouncing off water, its bouncing off sand, and still hitting your body. If youre sitting in the shade, that is not enough. You still wear your sunblock. And for you lot, its even more important than for me.

Why avoid the midday sun? Its purely a simple physics problem. At midday the sun is directly above you and therefore there is less of a stratosphere to get through. And therefore less stratosphere to absorb the energy, and therefore you get much more sun. And so if you avoid the sun, at least an hour or two either side of midday, then youre doing yourself a lot of good. At three oclock its got to get through a lot more stratosphere and therefore only about 60 per cent is getting through to you, so if youre on a nice sunny holiday on Lanzarote and its very beautiful, Ive got no objection to your going to Lanzarote, wear your high factor sunblock and dont go out of doors between 11 and two oclock.

What about UB protective clothing? I see it all the time, I go to the beach with my kids, and having three-year-old triplets its a bit of a nightmare. But even then I have the chance to look around, and Im gobsmacked at what parents will put their kids in. If you have a bit of clothing that you think is going to protect you, hold it up against the light. If you can see light through it, then its not going to give you much protection. Essentially the finer the weave the greater the protection, because that blocks the sun from getting through. So silk is the best and silk is rather nice to use Ive got some silk boxer shorts I was given and theyre lovely. I dont get to use them very often, certainly not with triplets.

Women have for years thought Ive got stockings on, that protects me against the sun. Stockings have an SPF (Sun Protective Factor) of about two, and so were seeing lots of problems with older women now who have lots of skin cancer changes on their legs. Even if youre wearing stockings, youve got to wear your sunblock underneath. How many of you wear a Panama? Well, stop it. Panamas look nice, they look terribly trendy, but its not going to do you much good, because the sun gets through the holes and straight on to your skin. If youre going to wear a hat, use a cricket hat, a nice cotton one with a nice broad brim. And these days hats are elegant. Ladies can get away with wearing these beautiful hats with large brims and thats the sort you need. It protects your whole face and it protects your neck as well. So when you are thinking about some protective clothing, you can actually buy it now and for kids they have these quite trendy coloured suits that you can put them in. When you are looking at clothing, look at it in the sun, if the lights getting through, then bin it. Silks best and beware of your legs, particularly if youre wearing stockings.

Now, what about sun screens? Now you can buy them in the chemist, there are a whole range and they are very confusing. There are two types there are the reflectants, and these just reflect ultra-violet light away from the skin. The trouble with them is because of their nature they tend to be white. So you tend to go round with a white face and a white body and you look hideous and people dont like them and rightly so. You can get tinted ones that make you look a bit better, but even so it looks as if you have a bit of pancake make-up on. The absorbent ones tend to be much better, they dry on to the skin and you cant really see them, unless you are in the water. Have you ever noticed, your skin looks a bit blue when youve got these on? These principally absorb ultra-violet B and the chemicals render the energy into minor quantities of heat, so they do protect.

And what is an SPF? You see that on the bottle, and the sun protection factor is an indication of the time it is safe to spend in the sun without burning. So if you normally spend ten minutes out in the sun and burn, with an SPF 10 you could be out there for 100 minutes without burning. Theres no such thing as a total sunblock. Youre kidding yourself if you think there is. And these days we have very good sunblocks up to Factor 60. One type is very nice to put on, you dont get the white sheen afterwards, its also water and sand resistant for the children. And thats the sort of sunblock you should be using on a regular basis.

So how can the renal transplant recipient avoid skin cancer? Now I think this should be part of your education when you first are considered for a renal transplant. You should be warned about the dangers, and you should be given proper counselling. High factor sunblocks, SPF 60, regardless of the weather, and if you want to be dogmatic you should use them throughout the year. If you want to be less dogmatic, you could go down to Factor 25 from the end of September to the end of March, but if youre using Factor 60 you might as well carry on with that.

Wear protective clothing, avoid intense sun exposure, and avoid the midday sun. But certainly the risk to you after transplantation is greatest after five years, and certainly the protocol in my hospital is that all patients are reviewed annually after five years. And we look at the whole body and we make sure youre not developing anything serious. If you start developing warts, we see you more frequently, and we treat them. If you start developing skin cancers, we see you even more frequently and we remove them.

So seek advice and treatment for any warts that come up, and once again many of you around the country may not have access to quite the dermatological care that we have at the Hammersmith, but you should still force the issue. Your warts can be dangerous, so they need to be treated. Regular screening after five years post-transplant, and if you develop a lump or a bump, dont just sit there and think perhaps it will go away. Playing ostrich doesnt help you at all. Go and get it seen to. Get an urgent referral. These days the Government guidelines are if you are referred to a hospital with a suspected skin cancer you have to be seen within two weeks, and thats certainly the rule in my hospital. Its usually within one week youre seen. But do go and have it seen to, dont be complacent with it.

Immunosuppressants

Now what about the immunosuppressant you use. The first one that was used was azathioprine and when ciclosporin came along we thought Perhaps thatll be better, perhaps that wont have the same nasty side-effects and perhaps people wont develop the same risk of skin cancer. That has not been the case. Ciclosporin seems to be just as bad if not worse as azathioprine. Tacrolimus, which is now being used, is going to be exactly the same, so these three are all going to have the same sort of effect on the skin. So being on one of those doesnt help. Now one of my patients and this was a particularly problematic patient, in that we were removing a squamous carcinoma roughly every six weeks from his body he was changed to mycophenolate mofetil, and since then weve seen him over the last six months and hes developed no further tumours. He still has the warts, and we still freeze those, but hes developed no further tumours. So I think that the search for newer immunosuppressants that could be as effective in the transplant but with fewer long-term side effects is still there and we need to push that further.

So a quick run through skin problems. I havent tried to scare you but I think you need to be nudged into action because you are responsible for your own skin. If you dont ask people about them, they cant really treat them and they cant really give you the advice you need. So if any of you have any problems, see your doctor about them.

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