Dr. Ashley Wysong offers a review of the effect of ultraviolet rays on the skin and how it contributes to the development of melanoma.
actually is my classic example of the underachiever. After graduating victorian uh in her medical school class at Duke, she went to stanford did a dermatology residency, picked up a Masters in epidemiology in her spare time and then did a fellowship at scripts with Dr Greenway and she is now chairman of the dermatology at the University of Nebraska. So Ashleigh tell us about UV radiation exposure melanoma. Thank you so much. Doctor Barrett for the introduction and to both you and Dr Greenway for having me back again this year. Doctors Blaylock and hum Burson both alluded to the important role of ultraviolet radiation in the development of melanoma. So we're going to do a little deeper dive into that today. So uh excited to have you guys join me for this discussion. I have one disclosure. I am a I do have a research grant that's pending with Castle Biosciences for a squamous cell study. So when we look at melanoma over the last several decades we see that there has been an increasing rate overall of new cases. Um but as dr Blaylock alluded to, we are starting to see a decline in death rates really for the first time in over 100 years. So this is a really, really exciting time for melanoma and I think there are lots of different ways we can look into these trends. And I'm going to specifically be looking at that through the lens of ultraviolet radiation today. You know when I think about ultraviolet radiation as a dermatologist and dermatologic surgeon. I really get excited because ultraviolet radiation and understanding its role in the pathogenesis of melanoma. Uh, this is a risk factor in an aspect that we really can empower our patients to help prevent melanoma, our deadliest skin cancer of course. So looking at sear incidents rates or the number of individuals that develop melanoma per 100,000. Um, we're looking specifically here from 2013 to 2017. We see that the vast majority of individuals are Caucasian or white, but we are seeing an increase in, I'm sorry, American Indians, alaskans as well as Hispanics within our country. And we do of course see melanomas as well in both black and Asian patients. So we really do want to be thinking about prevention and the role of ultraviolet radiation across all of our different races and ethnicities. Now, what about distribution across the country itself in terms of incidents of melanoma? So we can see here in the dark blue that the upper midwest as well as the Northeast are really having the highest incidents currently of melanoma. Now, overall prevalence or number of melanomas are higher in the states that have the largest populations such as California. Oh, I think the old ultraviolet story does tell a a little bit here when we look at where we are seeing the highest incidence of melanoma and why that may be the case. We're going to talk about that a little bit more. So overall again, the trends and the epidemiologic data suggests that melanoma increased incidences primarily happening among white populations and this is believed to be multifactorial. Of course one. We are seeing of course an increase in overall sun exposure over the last several decades and a change in recreational behaviors as well as the clothing and protective gear that people are wearing. Uh and tanning bed exposure also has played a role in this increase we believe. Uh And finally as dr Henderson remarked upon an increased surveillance from a dermal pathologic as well as dermatology perspective may play a role in this increased incidence as well. The lifetime risk for melanoma across all Americans is actually one and 28 and the annual increases in melanoma of incidences varying between 3-7% per year depending on the year but effectively is associated with a doubling rate every 10-20 years which of course is concerning And currently annually melanoma costs approximately $3.3 billion dollars in the United States alone. So what are known risk factors for melanoma. So genetics of course play a very large role and we can typically connect that with having a light Fitzpatrick skin type, light hair, light eyes, freckle ng family history plays a large role. Specifically a two fold increased risk if there is a first degree family member that is affected. Um And as dr Henderson alluded to, there are several inherited mutations that can be associated with a 30 to 40% increased risk of melanoma including C. D. K. N. To a as well as back one and M. C. R. One which is associated with of course fair skin, red hair and freckles. And the remainder of this talk is really going to focus on the environmental risks for ultraviolet radiation for that. I'm sorry, environmental risks for melanoma, specifically ultraviolet radiation. And we're going to look at that exposure in terms of lifetime ultraviolet radiation, intermittent exposure such as going on vacation or using tanning beds and then specifically looking at the risk of sunburns during childhood and its association for developing melanoma long term. And this can be associated with the latitudes in which people live as well as underlying immuno suppression. And we know a higher SCS rate is associated with an increased risk of melanoma. So overall kind of taking all of these these different risk factors together, we estimate that 70% of melanomas are believed to be you be related. And so I'm going to talk with you a little bit more about the mechanisms of actual damage to the melanocytes caused by UV. That we believe goes on to predispose the patient to melanoma. So, looking across the ultraviolet spectrum, we know there are three major U. V. S. That we are that we see here on the planet Earth UV A UV B and UBC, less than 1% of UBC actually gets through the ozone. And so that really is not a factor when it comes to skin cancer and the development of melanoma. So what we're primarily looking at is UV B, Which makes up 5% of the total UV at the surface. And as a reminder, you bebe is blocked by glass and then you? Ve a which makes up 95% of the total UV at the earth's surface can penetrate glass. And we'll talk a little bit more about the specific effects on the melanocytes themselves. Now, just as a little sidebar, there are so many wonderful new devices that really can measure U. V. Over the last decade or so. Uh and so we can see here there are multiple devices that are on smartphones. There are color changing bracelets when you're out in U. V. And more recently there are real time a UV dosimeters that can track and give feedback via smartphones to individuals who might be wanting to monitor their ultraviolet exposure more closely. So photo muted genesis and specifically how do ultraviolet rays play a role in making melanocytes turn into melanoma cells. So you? Ve b we know is associated clinically with sunburns and delayed tanning. But what's happening under the surface if you will is that you bebe is causing direct DNA damage through the formation of perimeter and die MERS and that can actually be seen now through mutation analysis. And we've gotten a very good idea over the last several decades of what is actually happening here. And so the response downstream to this DNA damage includes an inhibition of cell replication and transcription. True uncle jean transformation, which leads to downstream you to genesis and Carson a genesis as well as it does have a direct role with immuno suppression in the local tumor micro environment. Now. What about U. V. A. So you've a clinically causes immediate tanning and long term photo aging that we see in the clinics and in terms of its impact on the melanocytes themselves, it causes an indirect damage to the DNA through generating reactive oxygen species and ultimately have creating a large, substantial amount of immuno suppression there locally, which predisposes the melanocytes to Carson a genesis. So it's really a combination of both UV A. And UV B. In terms of U. V. S. Role on developing melanoma. So I want to get a little bit more into detail on the immuno suppressive effects of UV light. So clinically as dermatologists in my field and we utilise UV light and we take advantage of the fact that you ve causes immunosuppression locally in the skin when we're treating inflammatory conditions such as psoriasis eczema, where we actually want to get that excess in inflammation out of the skin. However, we need to be aware of the role of immuno suppression caused by UV light in developing cancer within the skin. And so UV light has been associated with the depletion of longer hans cells within the epidermis and really we think it leads to a decreased ability for antigen presentation. Uh essentially those immune cells that are typically running around the epidermis and dermis and helping to clean out DNA damage are being are getting immuno suppression from ultraviolet light and leading to unopposed tumor growth in a decrease in tumor surveillance. We see this clinically and epidemiologically in the setting of organ transplant patients that of course have exogenous immuno suppression through taking their immunosuppressant medications That allows their organ to stay alive. What we actually see an increase of melanoma of 1.6-2.5 fold among organ transplant recipients. Mhm. So I'd like to get a little bit into the genetics of melanoma. And just as a little bit of a reminder there are two main types of mutations that we look at when we are talking about genetics in oncology. So there are germline mutations that are present in every cell of the body and are passed down through generations and are carried within the gametes. Um both sperm and egg. Whereas somatic mutations are actually affected only in specific cells and are not passed down throughout families and are considered to be a sporadic mutation. So specifically talking about inherited or somatic mutations and their role in melanoma. Um And that we typically will talk about familial melanomas. What we know is about 3 to 15% of melanomas arise due to a familial genetic predisposition in which often UV independent mutations play a specific role. And so these are going to be those germline mutations or polymorphisms most commonly in C d. K. And to a that are found in approximately 20 to 40% of melanoma families. But if you can see the graphic here down below, about about 60% of familial melanoma is due to an unknown gene. So still some more work to be done here and just as a little sidebar conversation with some clinical relevance, I did want to just review when we should consider sending our melanoma patients for familial genetic testing. So really we want to think about two different incidences in terms of risk for melanoma within the population. So where there is a low melanoma incidents, the patient should have two primary melanomas, two cases of melanoma within a first or second degree relative or one case of melanoma or pancreatic cancer in a first or second degree relative. However, if it is a moderate to high melanoma incidence population, then we really want to see either three primary melanomas within the patient themselves, three cases of melanoma within a first or second degree relative to cases of melanoma and one pancreatic cancer or to pancreatic cancer and one melanoma in those moderate to high melanoma incidences. And that's just going to really be taking into account the positive predictive value of sending them for genetic testing or the risk that they may have an underlying familial melanoma syndrome. Now there's been a lot of interesting data coming out more recently utilizing G WA. Studies which is essentially in terms of how we do that swapping the cheek and then testing patients germline mutations to see if there are specific mutations that put patients at risk for developing melanoma. And here's one study that came out recently looking at 281 patients with multiple primary melanomas, higher risk group of course and looking at what variants are most predictive of developing melanoma. And we can see that the variants of C D. K. And two a.m. C one R and M tap were more frequent in patients who develop melanomas at a younger age. But we're also in those whose melanomas run visibly UV damage sites. So some more that we need to understand but we are getting better at developing apologetic risk scores to ultimately increase that would ultimately identify patients at increased risk for single or multiple melanoma. So lots of advancements happening in this area. However, we really were reviewing somatic mutations and we know that the majority of melanomas, I'm sorry germline mutations but we know that the majority of melanomas are actually sporadic and not passed down through families. And so dr Henderson had a wonderful slide reviewing this but I just want to break it down a little bit further into non UV signature mutations and you ve signature mutations. So on the left. We see that be wrapped and unwrapped are typically not associated with UV but are more common in sun exposed areas. Whereas our UV signature mutations tend to be listed there on the right and so trying to understand this a little bit further. This was a wonderful paper that came out and sell looking at the role of ultraviolet radiation and what are called driver mutations are those mutations that are most important in the development of melanoma. And so this study looked at whole exam sequencing of 121 melanomas and looked at the signatures or the number of primitive diners essentially that we were talking about earlier and found that 46% of driver mutations in melanoma were associated with that unique UV signature. And this was really the first paper to provide unequivocal genomic evidence of the direct mutagenic role of UV light in the development of melanoma. And this came out and sell in 2012. So really exciting news at that time however, we know that there is a lot of heterogeneity to melanoma by ultraviolet exposure And so intermittent sun exposure and superficial spreading melanoma or novelas. Subtypes tend to be seen in younger patients. And we tend to see a higher percentage of the raft mutations. Now when we look at some chronic sun induced damage and the subtype lent to go malignant melanoma. And we tend to see that in older patients and end brass mutations are more common in that population and then finally sun protected sites or like a cruel indigenous mucosal ocular, we see different types of mutations and they can be less likely to be you be dependent. So that's important to remember. And the most commonly mutated. The most common mutations that we see in these. These subtype melanomas tend to be a kit A C D. K. As well as turkey mutations which are common angina attack is common in your dealer and ocular melanoma. So just again, the whole concept that the type of sun exposure, the location of the tumor and the subtype of the tumor, that the role of ultraviolet radiation may be different based on those different breakdowns and factors. And a little bit more data suggesting the role of ultraviolet radiation in terms of inducing DNA damage in melanoma. And actually this is work that my group does looking at the signature seven for ultraviolet radiation mutation signatures. We do that in squamous cell carcinoma, but it's commonly used across lots of UV related cancers. And so essentially when we talk about signature seven, what it really is is a group of mutations that are known to be associated with ultraviolet radiation. And that has been called the UV signature. And in this paper that came out in Nature medicine last year, we did find here in this paper that signature seven patients are those with UV mutations had a longer disease free and better overall survival than patients that did not have you the signature, which is really interesting and that actually correlated clinically with if you had a signature seven mutation and UV mutations, patients actually had a more favorable outcome undergoing immunotherapy. And that clinically makes sense because typically when we have a high number of UV mutations, those also tend to have a higher number of overall mutations which is also associated with an increased improvement on immunotherapy. Okay, I just wanted to briefly talk about april indigenous melanoma as this is a unique subtype. And this paper actually just came out in the Jad and was beautiful. So I highly recommend reading it but did suggest that there are different cancer pathways that are activated in april melanoma and that UV radiation signatures are identified in only a very small proportion of of april indigenous melanomas and LMS are more common in skin of color in terms of percentage of overall subtypes within the melanoma. And so this makes sense overall as there's less of a UV radiation signature involved. And just also of note, there is data that the nail plate itself does a good job of blocking the majority of ultraviolet radiation. And then finally, I just wanted to hit on the subtype of ugo melanoma as there's recent data that genetic mutations um that are associated with ultraviolet exposure may be more common than initially or previously thought. So we used to think you vo melanoma was just kind of genomic or non UV related. However, there are recent papers coming out as recently as this last year suggesting that there may be a more more roll, a larger role of UV than previously expected. So even more reason as we're counseling patients to include the importance of utilizing photo protective photo protective eyewear. And then briefly I want to go through the ultra, go through the epidemiologic data for ultraviolet exposure and dr blaylock highlighted this study, so I won't go into it into too much detail. But this is a large systematic review and meta analysis looking at the role of ultraviolet exposure in the development of melanoma. And here we see that intermittent sun exposure, Meaning I don't typically get Sun Sun Sun, but then I go on vacation and get a sunburn. This type of exposure is the most high risk. And so we really want to be counseling our patients about that intermittent sun exposure or the vacations or the sun tanning beds because this is really the type of exposure that is associated with a relative risk of 2.35. Um in terms of the risk for developing melanoma compared to more chronic sun exposure, a relative risk of just under one and really no statistically significant difference. And compared to cumulative or total sun exposure over a lifetime which has a relative risk of 1.34 or 34% increased risk of developing melanoma over time. So overall that intermittent sun exposure, meaning patients that don't get a lot of sun much throughout the year and then all of a sudden get a ton of sun in the summer or maybe over spring break. That's really that pattern that we're most concerned about. And then finally a history of Sunburns is extremely important as well and associated with the relative risk of over two. And here's a paper out of pediatrics where we see that blistering sunburns in particular are associated with an increased risk of melanoma and something we want to be counseling our pediatrics colleagues on. However, um what's really concerning if you look at this paper out of the C. D. C. Is that 62% of all high school students have reported a sunburn within the last year. So that's definitely concerning and shows that we have some work to do in terms of prevention and counseling Transitioning into tanning beds. Overall the tanning bed thing I think we've gotten we've started to learn more and more about over the years. I think the real important thing is ever using a tanning bed even one time is associated with the 16% increased risk of developing melanoma. And over 10 tanning bed sessions in the lifetime is associated with an odds ratio of 1.34 Age matters. So the earlier the patient the higher the earlier the patient is in a tanning bed in terms of age, the higher the risk cumulatively over time for developing melanoma. So if first tanning bed use was less than 35 years of age, That's a 75% increased risk of melanoma compared to patients whose first tanning bed use was over the age of 35. So it just really brings home that idea that we need to be counseling against tanning bed use. And really the ban ban the bed campaign across the country has done a phenomenal job. The legislative efforts started in 2009 and now we have 42 states that limit the use of tanning beds for minors, but we still have work to go. The surgeon general had a call to action to prevent skin cancer that came back a few came out a few years ago. And um Borislav Lesniak is a dermatologist of practicing board certified dermatologist and put together a phenomenal report that really puts skin cancer on the map if you will in terms of its importance within our health care system. But tanning bed use, we are seeing again with these kinds of ban the town and all these data coming out that we are seeing a decrease in high school students reporting the use of tanning beds. And so it used to be hovering between 15 and 24% and now over the last 10 years or so we're seeing that we have decreased to really below 10% across the board for teenagers, which is fantastic. And it was kind of skipped through this one. Now, what can we do about prevention. And so I briefly just would like to review the the data that we have on sunscreen use and other photo protective behaviours in terms of preventing melanoma. Um so I think we've known for a while that sunscreens can prevent the risk for actinic keratosis, squamous cell carcinomas, the development of new nev I However, historically the data we're really lacking in terms of its role, the role of sunscreen and the development of melanoma. Um the sentinel paper that came out was here in the Journal of Clinical Oncology, that was the first randomized controlled trial, looking at sunscreen use for melanoma prevention in a prospective way. And this looked at 1600 adults in Australia that were followed over 10 years and found a 50% reduction in melanomas in patients that had daily sunscreen use compared to those who did not. And so this was really the definitive paper that came out and conclusively has shown the role of sunscreen for preventing melanoma. And there are several of their studies that have come out from there and I'll let you guys kind of review those. But here's the real issue compliance is really awful with sunscreen use. And anyone that has a teenager knows this is very challenging. Um so the percent of high school students were really hovering around 10% in terms of always wearing any type of sunscreen. So we do have work to do. And when you look at the differences. Um and this is looking at adults. Um really, and even in the highest percentages, we're looking at the forties, in terms of patients that actually you 40% of patients actually using sunscreen. We also can see when we're looking at the primary care literature that sunscreen recommendations are just not a part of what we're doing in medicine on a regular, regular basis. And so this paper, which really looked at primary care visits across the country, found that internists and pediatricians mentioned sunscreen use at less than .1% of visits, even those that were also coded for having a skin disease or a history of skin cancer. And so what more can we do? I think there's just it's a really challenging a world that we're living in. There are so many things that patients are needing to do on a regular basis to help prevent all types of disease. Um and so especially for our high risk patients, those patients that have had a melanoma before, that maybe have genetic risk factors or those chronic disease patients that we know developed lots of different types of skin tumors over time. I think as a field we're starting to get more and more unique about ways to implement these messages. And so this is a paper actually that came out from june robinson's group just in november of 2020 it's online right now, it hasn't even hit press yet, But this is the first paper looking at wearable technology with the UV sensor that's associated with text reminders once the patient has reached a peak of UV exposure for the day and then allows that it's almost a Gamification of ultraviolet exposure and allows patients to goal set and to try to improve on a daily basis. So I think we're going to start to see more of these technologies integrated into what we do on a regular basis. Okay, okay. So that was a whirlwind of discussion of the role of ultraviolet radiation in melanoma. I think what we've learned today is really the development of melanoma is multi factorial. It's heterogeneous, probably a combination of ultraviolet exposure. Both jeans you're born with and genes that are actually developed over time, inflammation, immune status of patients and so multifactorial. But there's no doubt that ultraviolet plays a role and of all of those things, it's the one risk factor that we really can control and we can counsel our patients on in reducing their overall ultraviolet exposure. And I always say to my patients, look, we can't go back and change what's happened in the past, but I really try to empower them to take control of the ultraviolet radiation that they get going forward. Finally, there is evidence for a large role of ultraviolet exposure in the development of cutaneous melanoma. I think the data is clear on that, both in terms of basic science genetic genomic as well as epidemiologic data and so photo protection and council of our patients is really going to be an integral part of skin. And I would argue overall health for our patients, uh and thank you very, very much again for the opportunity. And I just love being a part of this course every year. And um at that I'll take any questions or we can move forward to the break.
