Dr. Benjamin Kelley covers the risk that dysplastic nevi play in melanoma including assessing and treating atypical nevi as the sole diagnosis.
dr Ben Kelly who's part of scripts clinic here. He grew up in SAn Diego and currently resides in Encinitas with his wife and three kids. Ben kelly is in a unique group and that after doing is Durham residency at the Mayo clinic. He remained for a year and did a tomato pathology fellowship and then came and joined us here at scripts doing Ammo's fellowship. So he's one of the unique group of dermatologists who has completed both the D'amato pathology fellowship and Imo's micro graphic surgery and cutaneous oncology Fellowship depends on the faculty of our fellowship program here and has been a great addition to our clinic. Ben's going to talk to us on this plastic. Never welcome dr kelly. Thanks dr Gramm. We appreciate it. I'm honored to be here. Um So again today I'm not talking about this plastic nev. I I have no relevant disclosures. I cut out a little bit. I apologize guys. Okay. Mhm. Okay, this is a quick overview of my talk first. I'm going to talk about why this capacity are important in other words. Why are we talking about this to begin with next, I'm going to go over some of the clinical and histological criteria for this plastic navy. Uh We're going to go for some of the historical overview. So how did we arrive at this terminology and we're going to conclude the talk with the management of this plastic nearby. Mhm. Seem to be uh I'm having a hard time advancing here. Give me a second here. Okay, so a brief definition of what is the display asic nervous. So it is an acquired pigmented lesion of the skin with clinical and histological features which are different from common levi and which shares some clinical and histological features with malignant melanoma. Yeah, So the natural history of this plastic nearby are somewhat different from just regular acquired divine um common acquired, never usually appear in childhood. The increase in number until about the age of 30. After that, they gradually decrease in number. They stabilized at about 3-5 mm and they rarely develop over the age of 40. To contrast this plastic Nev I usually begin around puberty. They remain dynamic throughout adulthood. They're usually greater than five in diameter and then they continue to develop. So why is this topic debated? I think it's nicely summarized in this article. Way back from 1990 by George Murphy in it. He states that the display ASic nevis is perhaps the most controversial. Nia Plasm and the practice of dermatology and pathology Critics question whether it exists and if it exists by what criteria, it should be defined. And if it can be defined whether it's occurrences of any biological significance. And I think again, this was about 30 years ago, we're still asking some of these questions even today. So why is this important? Well, first their common we see these almost on a daily basis in our dermatology clinic. Now, just how common they are. It's kind of hard to find reliable numbers if you look at the site of numbers in the literature, it's anywhere between two and 12% of the general population. To give me a better Estimate. I looked at some of the larger studies that have been published and I average their um their numbers and I came up with around 5% of the general population. If they walk into your clinic is going to have a dis plastic nervous. And I think that correlates with what I see at least anecdotally in my clinic. Now, what if you take people who have already been diagnosed with the melanoma in the past and you screen them As this article did in 1984. They found that around 16% of those patients um that had a previous melanoma also have DNS. So to summarize this Around 5% or so of the general population have clinically dis plastic navy. And in anyone who's had a melanoma, around 16% of them will have DNS. So next patients with DNS are at risk of developing melanoma. This is a very important point here. So just are if we look at these pictures, I think most of us would agree that the patient on the right probably has a higher risk of melanoma than the patient on the left. And that is supported by the literature. But once again, these numbers are kind of hard to find. Uh reports vary widely between 1.5 to 47 fold risk of developing melanoma in patients with DNS, Thankfully, there have been a few larger meta analysis that have been written on this. For example, this one from 2005, they looked at 47 articles and found a relative risk of 6.36. And they also found that that risk seems to increase based on the number of DNS that one might have. Another meta analysis in 2010. Where they looked at case controlled studies, they found an odds ratio of 3.6. Now in this article, they took patients that had already had a biopsy proven moderately dis plastic nevis and they tracked them over time and they found that up to 23% of them actually one of developing a melanoma that seems high. But that is what this article demonstrated. And then this one, they actually looked at the degree of his pathological tippy and try to correlate that with the risk of developing melanoma. So they compared severely atypical nev i uh to mild and they found the odds ratio to before Then they went on and compared severe to moderate and found 2.8 and moderate to mild and found 1.1.4. So to summarize this, if you see a patient with clinically dis plastic Navy, they have somewhere between a three and a six fold risk of developing melanoma and having only one of them might increase your risk. Nearly two fold. Now, there's not a whole lot of evidence for again these histone pathologic DNS. But some articles have shown like I just showed you that there's up to a 20-23% risk of developing melanoma and the degree of histological tapia may correlate with that risk. So next there is quite a bit of controversy over whether not DNS actually progress to melanoma. Uh some of that controversy is summarized in this article by Dr. Bernie Ackerman back in 1988. Um uh he asked the question what Nevis is this plastic a riddle and an answer. And in his opinion and he feels strongly about this no nevis is this plastic, they don't exist. Uh some people do believe they exist. So let's go over some of that. Here's some of the evidence that they are in fact intermediate lesions. We already discussed that epidemiologically they are markers for melanoma histological. We we know that they share some of the features with melanoma and are frequently found in association with melanoma. And then genetically these are clonal lesions and there appeared to be stepwise acquisition of mutations from comedy all the way to melanoma In this article, the authors looked at 234 primary melanomas and they found that about 20% of them actually had an associated d. n. In this article in 2015. The authors looked at 37 melanomas, all of which had a nevis component to it. And they took samples out of each one of the areas and analyze them genetically and they found that there appeared to be again successive genetic alterations. And they also identified an intermediate category of monosodium pleasure. Now let's go over some evidence that they are not intermediate lesions. Again the majority of people with the ends don't get melanoma. The majority of melanomas arise de Novo about 80% of them. And just because there's a higher mutation a burden, it doesn't necessarily mean there's a higher rate of malignant transformation in this case. And so far there's really no conclusive evidence. So in this large men analysis the authors looked at 38 studies 20,000 melanomas and found that about 29% of them were associated with me by now. The interesting thing though is that there is really no difference between common, even associated melanoma and this plastic nevis associated melanoma. In this article the authors looked at all the evidence in the literature and tried to calculate mathematically the rate of transformation of A. D. N. To melanoma. And they found that rate to be in males around 1 30,000 and in females one in 39,000 hardly impressive numbers. So the main points here do they actually progress to melanoma? Well again they share histological features with melanoma. They can be found in association with melanoma. They have intermediate mutations. But so far there is really insufficient evidence to show that this is of clinical significance. So let's go over some of the clinical and histological criteria that define these lesions. Well clinically it's just the A B c D E. S. So I'll skip over this because we are all pretty familiar with that. But histological, in other words, when we look under the microscope, we look for two things. One is the architecture and the other is the cytology. Now, architectural disorder is something that we examine at low power under the microscope. So we're looking for basilar milan acidic hyperplasia. We're looking for confluence bridging and strum alterations and I'll show you a couple examples here. Here's an example of hyperplasia and confluence. As you can see there are a lot of melanocytes. They're going up and down the reedy ridges. Here's an example of a shoulder, there's a dermal component on the right side of this lesion and a junction, all component that extends multiple reedy ridges beyond that dermal component that is called a shoulder. And just because we're here in san Diego. I just, whenever I look at this, I think of waves, this is cardiff, one of my favorite surf spots and a shoulder on a wave is a good thing. A shoulder on a nevis is not a good thing. Here's an example of conflicts and bridging. As you can see, these really ridges appear to be fusing together because of these melanocytes and here's some fibrosis. This kind of thicker pink stuff. That's fibrosis. And here's an example of capillary act asia. These small little vessels down here as well as inflammation, these small lymphocytes down in the dermis. And all those things are summarized by this diagram. Here we have that confluence and hyperplasia of the melanocytes. We have the bridging of the really ridges, inflammation fibrosis and that capillary act asia. So psychological logic, utopia is more of a week criteria. And the main reason is because there's not a real great consensus as to what uh what psychological tibia is. But basically what we look for is variations in the size and the shape of the nucleus. For example, here's an example of a display asic nervous architecturally. But as you can tell, these nuclear pretty small bland about the same size as one of the characters. Besides above, Contrast that to this one this one has more severe psychological tibia. You can see there's some, there's some pretty large nuclei um probably twice the size as a correction inside and there's prominent nuclear lie. Okay, let's move on and talk about the historical overview again. Where did this terminology? Where did this concept actually originate? How has it evolved over time? And where exactly do we stand today? So this originated back in 1978 to 1980 with three articles by Lynch Clark and Elder. So all three commented on the number of the navy, the size, the shape and the color and the fact that the families that had these nev I had a very high incidence of melanoma that's been alluded to previously by several of the speakers. Elder was the first to comment on some of the hyssop pathologic features. Now, what they were talking about was this familiarly typical multiple most melanoma syndrome. Um again that's that C. D. K. Into a mutation. But what we're talking about here is what about those individual lesions? What about the patient that comes in with five or six of these? So after those original articles were written, multiple people came out with their articles On the subject. As a matter of fact, if you do a pub med search right after that 1980, the publications exploded all the way up to um a peak of 1992. And at about that time, 1991-1993, a lot of different larger groups started to come up with their own criteria. Trying to specifically define what a this plastic Nevis is. And this really culminated with an NIH consensus statement. So they argued that the word, this plastic nevis, they stayed here should be discouraged. And instead when you see a clinically atypical mole, we should just call those atypical moles. And when you're looking under the microscope, they should be termed nephi with architectural disorder. And accompanied by a statement describing the degree of milan acidic a tibia. So this was again a consensus statement and they were hoping that everybody would adopt it. So, didn't it work? This is 1992 Fast forward about 12 years. And this is a survey of a sdp members and 80 members. What is your preferred terminology? And as you can see, it's still this plastic nevis up top followed by nevis with architectural disorder, Clark's nearby and multiple other ones. So what do we call them today? Now, if you do a quick literature search, we're still calling them by all kinds of different names. We have this plastic nearby Clark steve I and many others. And that's in terms of literature. If you look just clinically what we see on a daily basis, people are still in the community colonies by different names as well. These are some more recent pathology reports here. We have a severely typical nervous. This plastic nevis clark's nervous and at the bottom my favorite one, a display stick tight nevis. And they actually comment on that in a conference. So there is confusion in terminology what people have termed Path of Babel. So, again, the idea of a displacing nevis was originally used to describe the syndrome of melanoma. Now it's used for individual lesions. Not only that it was originally used for clinical lesions and now it's used for histological lesions. Uh we have a whole lot of different names for the same exact thing. And to make matters worse, some dermatologists refer to DNS as pre melanoma. Again, that negative framing, we also refer to comedy by as benign and that kind of implies that DNS or not. The good news is that regardless of what they're called, the histological criteria are generally agreed upon. The names can be used interchangeably. The bad news is as Dr Patterson mentioned earlier is that while there's agreement about the histological features, there's less than perfect intra observer variability for grading and significant variability in the treatment recommendations. So this is a paper showing that the the rate at which dramatic pathologists agree is pretty good if there's no a tipi at all. But as you start to get into the intermediate lesions like moderately typical Niva, they only agree about 75% of the time. This one is even more alarming. So a group of experts amount of pathologists were given a single melon aesthetic lesion. And in the left column they were asked to write in what their diagnosis is. And in the middle column they were asked to give their treatment recommendations and for the same lesion, The diagnosis range from solar linda. Go haul away to melanoma insight you and treatment recommendations from no treatment to treatment as though this were melanoma. And this article just shows that in addition to having disagreements about the actual diagnosis to the degree of a typical uh pathologist also give varying degrees for recommendations, recommendations of treatment. This is one of my favorite titles for an article, clinicians are from Mars and pathologists are from Venus. And the authors concluded that surgeons misunderstood. The pathologist reports nearly 30% of the time. Which bridges us bridges us into the final part of my talk which is the management of this plastic nearby. Now dr patterson already went over some of the biopsy techniques. Why I'm going to skip over a couple of slides also for the sake of time. But suffice to say it's really important to get a good sample. So I'm going to skip over to the excision of this plastic nearby and what is the evidence for this? So over the past several years there's been quite a few articles written about whether or not we should be re excising this plastic nearby. Um there's a consensus statement in 2015 where they specifically looked at mildly and moderately atypical nearby and their conclusion was that for mildly and moderately typical nev I as long as you don't have a ton of residual pigment, it's probably safe and reasonable to just observe these. And so what I did here is I gathered all the studies that I could find and I put them into two different categories observation only. In other words a biopsy was taken and the clinicians just watched the lesion over time and then the re excision group where they took a biopsy. Then they subsequently re excised it Now for the observation group. There are a total of almost 1500 cases and only seven of these overtime wind up developing melanoma at the side of the original biopsy. That's a 0.5%. Um and there were no deaths in this group. For the re excision group. There were and again 1515 of them are 1% of them were actually upgraded after the re excision was complete. About Again about 1%. But one thing about the observation group that interests me is that again the total here were seven cases. Six of those Actually came from one article. So I thought we would dive into that article just briefly. Um again this is by Fleming from 2016 and again, six out of the 304 that were observed eventually developed a melanoma at that site. But here's the kicker. Five out of the six of those were only partial biopsies with grossly positive margins. And not only that the type of melanoma that these patients developed, we're all lead to go malignancies which we know typically are fairly broad lesions. Yeah. Okay, just a quick interjection here uh This uh note to dramatic pathologist when it comes to moderately typical Niva. It's important to leave the treatment plan to the clinicians. Okay so what do most people do If you look at this 2014 New England um survey. If you have positive histological margins, most people will simply observe for mild atypical nearby for moderate, about 40% of them will go on and re excise and for severe just about everybody will go and re excise. Now if you have negative margins even if it's severe, about half of the clinicians will re excise and most of them will just simply watch moderate or mildly typical. Yeah. And this is another survey of academic dermatologists. If you have a moderately dis plastic nervous with clear margins, no visible pigment, just about everybody will simply monitor if you have lateral positive margins with no pigment, about half of them will watch. About a quarter of them will actually go and do a re biopsy. And if you have grossly positive margins and residual pigment most will do something else about it. All right. So just to summarize there's growing evidence to suggest that re exercising these mild and moderately typical Navy is not necessary. Some have suggested that even re exercising severely DNS are may not be necessary, but this is controversial. Currently most practitioners still re excise modern severe which involve the margins especially if there's residual pigment. Um And again beware if your biopsy is a partial sample of a larger lesion. Like that article demonstrated. So just a couple of important limitations to this data, that is diagnostic uncertainty. So if we're saying that a. D. N. Is greater than five millimeters and we're cutting sections at four microns and the pathologist maybe looks at two slides. We're looking at far less than 1% of the total lesion. So diagnostic uncertainty and I'll just go to this art here. It doesn't necessarily mean that the pathologist got the diagnosis wrong. What it means is that what is the risk that the portion not visualize actually might contain something worse? So to summarize um we talked about why DNS are important. Um We talked about the clinical and histological criteria, the historical overview and then the management of DNS. So thank you very much. Great, thank you. Ben. Um Then there was one question Doctor Hostel is going to talk on sunday pointed out that the W. H. O. Put out some guidelines that we should not diagnose this plastic Niva if they're under four millimeters that kind of fit with one of your later slides. Do you have any thoughts on that? Yeah I mean most of those are going to be larger lesions. Uh you know and that's going to be you know what you're looking at clinically. Um So that is one of the criteria that a lot of people use for them definitely. Good. Thank you. And you'll be involved with some of our case presentations later. So thank you. Thank you