Chapters Transcript Video Metastatic Evaluation of the Melanoma Patient Back to Symposium Dr. Douglas Winstanley discusses the pertinent lab and imaging needed to appropriately evaluate early and advanced stage melanoma patients. Good morning. Welcome to day two of our 31st annual Melanoma conference. We had a wonderful day yesterday and look forward to our speakers today. Again, let me just do a couple of housekeeping things. The conference agenda and materials are in the scripts, health cmI conference app and on the livestream page event. The apps available for all participants. And again, just as a reminder of the program is being recorded, it will be available for you to access approximately one month after the event. This is all live streaming, so all participants will be muted during the lecture series and that will help avoid background noise. So please on your computer close all the other web pages and apps that might just slow down your internet connection. 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The survey will be available for approximately the next 3 to 4 weeks after the conference. So again as we start. Thank you for attending on day two, I hope you have a great day on day one. The course next year. The dates for our 32nd will be january 22nd and 23rd 2000 and 22. So we want to start this morning with a very important talk. Um We want to look at basically the metastatic evaluation of the melanoma patient which is extremely important and we heard quite a bit yesterday from the various speakers about that. There are some things we do and don't do and you need to do and not do. So we're very blessed to have dr Doug winstanley who is assistant clinical professor at Michigan State University and as a mother surgeon at west michigan dermatology, Dr winstanley finished with his internship ship here at Naval Hospital san Diego. He was deployed to Afghanistan for operation enduring freedom. So, Dr winstanley, we thank you for that after his residency and fellowship with us here at Scripps Clinic in La joya California. So Doug we appreciate you taking time out in michigan today to be part of the course. So we look forward to your presentation. Thank you. Well thanks Dr Greenway, I certainly appreciate that kind introduction. I also wanted to thank doctors. Barrett and dr kelly for having me this year. Uh In addition there's been so much going on behind the scenes with getting this together and I've really been impressed with the team um including Kerry and Megan and scott and Justin they've really just done a great job putting this together. So I hope you're all enjoying the conference is dr Greenway mentioned I'm going to be discussing in metastatic evaluation this morning and I included this. Um Let me see if I can get this slide deck to go. There we go. Hopefully you're all saying that this is a picture that I took from my front door a day before I left to come to this conference last year and I had been lamenting at the conference about how cold it was here and how grateful I was to be in SAn Diego. Never thinking of course that I might be giving this talk from my living room on a day that looks very much like this one today but in finding that silver lining at least I didn't have to iron my pants. So we're going to dig into this. I don't have any conflicts of interest here but I do have to put some glasses on so that I can see. So all of our all of our guidelines have been updated within the past few years and we've got the A. J. C. C. Eighth edition the N. C. C. And guidelines as well as guidelines for management that were published in the Journal of the American Academy of Dermatology pretty pretty recently rather so these are all easily referenced and um instead of going through an algorithm I wanted to focus on some of the supporting data that governs these recommendations for evaluation of metastases or melanoma patients. So giving a diagnosis of melanoma is certainly a life altering event carries with it a heavy burden for our patients, physically and economically to be sure. But as physicians, we also need to make sure that we're acknowledging the emotional and psychological distress that comes along with this diagnosis. Certainly patients here, that word melanoma and immediately their their mind jumps to um you know, how long do I have? So a lot of questions come up. What kind of treatment do I need? How do we know if this disease has spread or not? Am I going to need radiation and chemotherapy and I'm gonna lose my hair? I'm going to get sick. Does my family need to be checked for melanoma? How long do I have to live? And what's the likelihood of something like this coming back? So with all that concern, why don't we just stream everybody from metastasis well beyond the cost, it would likely cause more harm than it would help to detect occult disease. And I'm hoping to convince you this morning that careful consideration should be given when we're ordering these evaluations. The rate of false positive tests can be quite high depending on the modality that we're talking about and that in turn can subject our patients to more potentially invasive procedures that can become not only costly but can be associated with some morbidity. So if not everyone should be screened for metastatic disease, then we need to narrow our scope to decide what portion of our melanoma population warrants a more extensive investigation. And there are several questions that we can ask regarding this population. To establish our threshold for ordering these tests, Who is most likely to develop metastases. What are the signs and symptoms that we should be aware of? That may be an indication of metastatic disease? Where mets most likely to show up in an individual patient and when your treatment is done, how often should that patients have follow up and do they need imaging as part of that follow up evaluation. So the evidence is quite clear on who should not get a workout. Those patients who are stage zero to stage two and are asymptomatic. Don't need imaging and lab work up. Keep in mind though that further work should be done in a directed way for any patient of any stage who has symptoms concerning for metastases. So Consideration also needs to be given to each individual circumstances with regard to age, overall health and performance status as well as the location of the tumor. So, for example, a 95 year old patient with melanoma on the scalp and a Karnowski score of 50 may not benefit from a node biopsy your imaging. If there are a good candidate for a gene therapy. So where do we begin? And what tools do we have at our disposal while our periodic and regular office visit with history and physical examination are certainly the first step and it's important to direct our assessment and anywhere lab tests based on how our patient is doing? So we can check blood work. But how useful are those tests Then we have an array of imaging modalities that we can use as well. But does everyone who gets a diagnosis of melanoma need a chest X ray for example. Or how good is ultrasound of detecting nodal metastases? Is C. T. Sufficient to evaluate for distant disease? Or should it be a pet ct? And that's is emery better than CT And if so under what circumstances and then if we do discover something, what are we going to do with that information? So all questions that we need to keep in mind. So obviously history and physical are the first step. And a detailed review of systems should touch on acute and sub acute changes in the patient's overall health status. So during that doing that thorough review. Systems is important. Asking about weight loss, nuance that headaches or constitutional symptoms. The skin examination with evaluation of all available no basins needs to be done as well. Dr Blaylock spoke on DeMoss copy which has proven very useful in the evaluation of pigmented lesions and has mentioned several as mentioned several times in the course. It's very important to spend the time to educate our patients. Uh certainly about the importance of regular self skin exams. Also sun avoidance and protection and the need for regular follow up evaluations, especially in the near term after a new diagnosis of melanoma. So what about me? Back that up? Sorry. What about labs? Does somebody who walks in the door with a lesion like this automatically have to have blood work. How useful are these tests and determine the patient status with regard to the melanoma and potential for metastatic disease? So as it turns out, lab tests really don't offer very much. Blood counts can be altered in the context of widespread disease. But those findings are pretty variable and they're non specific. Certainly if the patient has signs or symptoms that warrant getting a cBc then you order cBc. But similarly chemistry and LFTs don't offer much assistants either. Even in the context of a patient with metastatic liver disease, only 8% of those will manifest with abnormal LFTs. So the sensitivity there is quite low lactaid di hydrogen in its core. LDH is currently the only blood test that has enough evidence to support its utility in assessing disease status. So you can see LDH elevations in a variety of different malignancies. Of course it was incorporated into the A. J. C. C. Six edition guidelines back in 2000 and two and it's the only blood test that is still included in the eighth edition guidelines and it remains. So because it's the strongest prognostic serum biomarker in the setting of advanced melanoma. So elevated LDH levels are associated with war survival and can be helpful in predicting response to therapy and stage four patients, which is a low cost test to reform. Um and it really doesn't offer much risk for the patient. So there's not too much of a downside with checking. It's just that outside the setting of advanced disease, it may not be very useful in the information that it provides. Yeah. So based on the characteristics, the next question that we need to answer is whether or not the patient needs a sentinel lymph node biopsy, sentinel node positivity or negativity will determine what we need to do next in our evaluation. So sentinel node remains the strongest predictor of survival in patients with clinical stage one or stage two disease. And it also informs decisions about the need for adjuvant therapy as well as the need for follow up surveillance of the regional node basins. So who should get a biopsy? We've seen this a number of times at this point. Dr ross went through this in some detail yesterday. So we know what the indications at this point. Our first sentinel node again, you may have some patients whose health status dictates that several. No, doesn't make sense even though they meet some of these criteria. Yeah. So let's look at some of the data here for ultrasound. Uh huh. Yeah. Yeah. Um This is a Cochrane review that was published just two years ago, looking at the utility of imaging modalities for the assessment of melanoma. So, In reviewing the data here, the Cochran group reviewed 11 studies which included about 2600 patients with about 542 cases of proven noble metastases. Um going back to this though, it was determined through this meta analysis that ultrasound alone had a sensitivity of 35% and the specificity of about 94%. So they then want to see how ultrasound did in conjunction with fine needle aspiration cytology. And in this part of the review, they had 1164 patients, participants in 259 cases of Nodal Mats. So this review demonstrated sensitivity of 18% and the specificity of almost 100%. So looking at that a different way. So, ultrasound with finding an aspiration correctly identifies about 1/5 of people with nodal mets uh and has very few false positives as you might imagine. So, if you have 1000 people with melanoma who are good candidates for a node biopsy statistically out of that group 237 patients are going to have disease in the lymph node. If you were doing an ultrasound with fine needle aspiration on this group, 43 of those patients would be able to avoid sentinel lymph node biopsy based on this review. Two of those would be false positive results for which the patient may go on to have the wrong treatment, but those who did not have a positive ultrasound result would go on to have a sentinel lymph node biopsy. What the others came up with in this review is a conclusion was that they suggested that ultrasound with finding an aspiration may allow a patient with a positive result to avoid sentinel lymph node biopsy, it gets a little bit more complicated than that. Certainly based on what Dr Ross had said yesterday about the potential therapeutic value of having a sentinel node. So this was another study that was actually done by um Merrick Ross and some of his colleagues dr jean dr Bronstein Back in 2011. And this was a meta analysis that looked at 74 studies and included over 10,500 patients. So it evaluated four imaging modalities. Ultrasound ct, pet and pet ct. In an effort to determine which work best when evaluating for nodal disease and which work best for evaluating for distant metastases. So, looking at ultrasound for evaluation of lymph nodes and primary staging, The medium specificity was 97%, which is pretty comparable to other modalities. But if you look at the medium sensitivity for ultrasound it's quite a bit higher than other modalities, even though it's at 60%. So if you then look at the diagnostic odds ratios, it's easy to see how these imaging modalities. Breakout and these different circumstances. So the conclusion offered from this study was the ultrasound is the preferred test for surveillance and patients at a low risk for metastases and is more suitable for the detection of medicine, patients with intermediate or high risk of metastatic disease. So current guidelines recommend that ultrasound be done for patients for whom there's an equivocal physical exam. And it's highly encouraged for patients who meet criteria for central node but don't undergo the procedure for whatever reason. So there are also instances when a central node procedures unsuccessful in this case, ultrasound can be done to help identify potentially affected nodes. Additionally, it should be used for surveillance and patients for whom a sentinel node is positive. But a completion dissection is not performed. Take into account this test is highly operator dependent. So it's nice if you have some familiarity with the radiologist uh and the stenographer team that are doing this and ideally they have a lot of experience in doing this test on a regular basis. But again, if you're looking for nodal nets, ultrasound seems to be the way to go. Yeah, all right. So X ray, relatively easy. It's the lowest task. It's a low cost study and is still ordered frequently as part of a baseline work up for many, many physicians for evaluation of our melanoma patients. But how useful is it? So as it turns out it's not very useful and in most circumstances probably doesn't need to be done. So this is a study by Terhune model that was done just over 20 years ago at the University of michigan. And it looked at 1032 consecutive patients with localized melanoma, including patients with Stage one and Stage two disease. So 876 of that group had a chest X ray done. Of those patients, 130 had a finding that warranted follow up investigations including repeat imaging your biopsy. And of those patients, just one had a true positive finding which demonstrated the pulmonary metastases. So an overall rate there of 0.1%. And the authors of the study calculated false positive rate of 15%. Mhm. So this was a study that was done at N. Y. U. And it looked at a broader range of 100 and 58 stage melanoma patients. Uh in this this group the tumors were T one B two, T three B. Primary lesions without clinical lymph node involvement and without other symptoms. A total of 344 imaging studies were done including chest X ray and CT. They did pet cT. All prior to wide local excision with sentinel lymph node biopsy. So 142 of 158 patients had a central node of which 22 are positive. Of 144 chest x rays that were done, seven had suspicious findings. Five of the seven findings were false positive and the other two patients were lost to follow up. Um We're gonna take another look at this slide and just a little bit. Yeah. All right. So this is a more recent retrospective study with a larger group of patients that wake for us, Which looked at patients who had undergone that sentinel lymph node biopsy for clinical stage one or stage two disease. So they gathered information. A total of 463 patients, 315 of whom had a preoperative chest X. Ray. 20 of those patients had positive results in 10 of these patients underwent further imaging. They didn't do any biopsies for confirmation. What they found is a tool of 15 patients experienced a recurrence of disease within a year following their surgery. Only two of these patients had positive chest X ray findings, neither of which were actual melanoma. And of the remaining 13 in that group seven had thoracic thoracic metastases that weren't identified on chest X. Ray. So none of the chest X rays identified any metastatic disease and any suspicious findings of chest X ray did not lead to the identification of metastasis within a year following the imaging. So, there's a there's a number of other studies that support similar findings as it relates to chest X rays and utility of getting a chest X ray in the setting of melanoma at this point is more or less agreed on. It's a test with very few positive true positive findings, but a high rate of false positives that may lead to additional imaging or procedures that aren't necessary. Its cost and efficient given it's significant limitations it can be useful in some context. After the diagnosis, diagnosis, staging and definitive treatment has been completed for this violence specifically of lung mets. Beyond that it's really it's really quite quite limited. Mhm. All right. Well if x rays are no good, how much better if at all is C. T. Mhm. Okay. Well Seti offers a higher degree of sensitivity certainly than chest X ray does. It provides some nice imaging of lymph nodes and bony structures for you are, imaging contrast should be ordered for better visualization. It's not evasive but it is attended by a fairly high amount of ionizing radiation which is certainly a drawback. So you see T.A. test to order for a baseline examination or staging of disease. This is a study um it was a cross sectional study that was done in Spain and published in 2016. So this looked at 310 Patients with insight to disease all the way up to T. four melanomas. In about 82% of these patients had a negative CT. There are incidental findings in 18 additional primary tumors were found in two patients and metastases was found in one patient. So for all those CTS 310 patients metastases was founded in one. So I'm going back to this N. Y. U. Study that we looked at a few minutes ago for chest X ray In evaluating the data for C. T. for a total of 37 findings that were either suspicious or highly suspicious across chest head and then abdominal and pelvic CT. None were to positive exams. All right. So how does C. T. Compared to ultrasound for evaluation of lymph nodes? This was a meta analysis published in a european radiology journal that showed a median Sensitivity and specificity of 61 and 97% respectively. Which made it inferior to ultrasound and the detection of local regional lymph node metastasis. According to this study. While it can identify the majority of Metz with the sensitivity as high as 63% and a specificity as high as 78%. It wasn't fear to MRI and inferior to pet ct as well. So looking at next some of the data for pet ct. Yeah There's certainly some um advantages that pet CT offers. It's become the standard for evaluating metastatic disease. The whole body can be imaged produces not just structural data but functional data as well. The resolution on pet CT is pretty good. It's down to about 3-5 mm. Which is just about as good as it gets but oftentimes it's not good enough as we will review in the next few slides here and uh something to keep in mind as well. In addition because the brain uses so much glucose. It's not a test that has the ability to assess the brain for METs. So if you're concerned about that, you need to do an M. R. I. Rather than Pet ct. Let's look at a few of these data points for pet pet ct. Mhm. So I had mentioned in the previous slide that pet ct lacks the resolution to detect very small tumors. Um certainly nothing less than three is just not gonna picked up, not going to get picked up on imaging. So it has very limited utility and early stage disease. For that reason, the main utility of pet ct and cutaneous melanoma is to detect recurrence or to restage disease. Following the detection of recurrence, especially in patients who could be candidates for surgical removal of a metastatic focus with the intent to cure. So it's also the mainstay to assess the response to chemotherapy or immunotherapy. So, this slide uh again refers to the same Cochran study that I referenced earlier in discussion regarding ultrasound. These reviewers. When they looked at whole body imaging with Pet ct, they really didn't have much good dad. I was fairly limited, but what they did determine was that the sensitivities and specificities for the detection of Metz appeared to be higher for those having restaging and less so for those in primary staging did pet ct did seem to be more sensitive than cT alone. But the study was limited by various small number of patients um just based on what they did have the group. uh this cochran group uh concluded that pet cT is better for identifying those with spread of recurrence rather than those with a new diagnosis of melanoma. Oh, okay. So what about MRI? Mhm. Well, I'm really, really has an advantage when you're looking at soft tissue, there's no ionizing radiation. But certainly patients that have any implants that have various metals are obviously not candidates for M. R. And keep in mind too, that if you're looking for R. M. R. Is best used with contrast as well. So how does it compare to pet ct? Well, this was a study that was published again, a european radiology journal. Pet C team was more accurate and staging and detection of long and soft tissue mets. But M. R. Was superior in detecting liver, bone and brain mets. So we don't have much information yet regarding the use of pet M. R. I suspected this becomes more available. We'll start seeing some prospective studies on this but it's probably at least as useful as pet cT for the assessment of therapy response and characterization of their behavior. Okay, so what about imaging replacing sentinel lymph node biopsy? Are we even close to that? Well, I hope we got a good impression up to this point in the talk that there's there's quite a few limitations regarding current imaging that we have available. But this was a study that there was a retrospective review looking at how well pet mar performs against pet ct uh and paid um are with diffusion weighted imaging to detect disease specifically in lymph nodes. So it included 52 patients with thicker melanomas who underwent staging imaging with pet CT and pet um are prior to getting a sentinel node. So of 87 notes that were sampled in the group 17 nodes were found to contain tumor histological e. Looking at how those results correlated to imaging, it was found that the sensitivity of pet ct was about 18% while that of pet M. R. Was 23 a half. So the addition of the diffusion weighted imaging led to two additional false positive findings, but it didn't increase the number of two positive findings. So it's not great. And it's certainly not um sophisticated to the point where imaging can can replace doing a node biopsy. All right. So let's touch briefly on follow up surveillance here too. All right. So, once the primary melanomas treated and surgery is done and adjuvant therapy is completed uh If it's indicated, how often does the patient need to follow up what's the best way to screen for the disease coming back or for its spreading? Uh And what should we do about labs and imaging tests? So it's worth knowing that most uh metastasis are going to occur within 1-3 years following the treatment of the primary tumor. So on average, about 4-8% of patients with a history of cutaneous melanoma will develop a new primary lesion. The risk is certainly higher in those patients who have an increased mould count have multiple clinically atypical moles, have a family history of melanoma who are blessed with a fair complexion and those who are male. So I did include a study that was published just this last year and the General american Academy of Dermatology. And this looked at the risk of a second primary, not only in the skin, but in non cutaneous systems, including the eye and mucosal sites. So this was a retrospective cohort study that was using the seer database and reviewed data from 1975 through 2016. So in all, they had almost 170,000 patients with 1.7 million person years of follow up. And what they did is they compared the observed number of melanomas to the expected number of primary melanomas and I'm not going to dig into this study too much. But this table does summarize the results and overall we see that a second primary melanoma was eight times more likely to develop it. These sites and patients with a history of primary cutaneous melanoma than in their match counterparts in the general population. That was interesting to, they did break um this data down uh as well based on patient race and the risk of a second primary continuous melanoma is significantly elevated. Um in our black patients, but not so for the non cutaneous melanoma. But I think, you know, on occasion we may have the impression that those with darker skin types are at lower risk. And in fact those that those patients who do have darker skin types that do have a primary melanoma have the same rates of developing a second primary as those patients with lighter skin. So those guidelines for follow up really need to apply to to all of us. Yeah, this was a table that was published in the A. D. Working group recommendations for the management of melanoma. And this was based on the synthesis of data course. So the recommendations on this charter for those patients with Stage Zero disease, um We usually see them back every six months for two years. Uh Those visits of course need to include a thorough uh skin examine a review of systems. Similarly, patients with Stage one A and two A disease should be seen at least once a year, but for a longer duration up to five years. And for those with stage two B. Or higher, um They should be every scene every 3 to 6 months for the first two years and then twice a year, twice a year. Um Mhm. For years 3-5 and then annually really for the rest of their lives. I do tend to see these patients on the more aggressive end of the spectrum. I find that most people appreciate coming in more frequently rather than less when they're dealing with melanoma. But I do have those who are are a little bit more reluctant to come in and if they have a heavy risk factors, I really really make the point that they need to follow up closely. So getting follow up imaging has been somebody a matter of routine. Remember though that overall imaging gives us a pretty low yield of true positive findings in patients who are asymptomatic. It certainly follow up imaging to monitor for response to therapy should be done. But it seems that beyond five years of disease free follow up routine imaging is not recommended for patients at any stage of cutaneous melanoma who remain asymptomatic. So looking at the future, there's several new tools that will may not have proven themselves up to date have may offer us improved ability to identify a cult metastatic disease and our patients and better engage their response to therapy. Gene expression profiling has become more common. I suspect most of you, if not all of you have ordered a castle test um to stratify risk for patients with thinner melanomas um and well it's promising there isn't enough data yet to include this in current guidelines, although it is mentioned in the most recent and CCN guidelines, I think it'll probably pay a much larger role in the near future. Looking at refining current imaging modalities and introducing new technologies that may allow finer resolution to pick up microscopic nodal involvement. Um, that is beyond the resolution of current technologies is certainly in the works. And then you are derived and tumor associated proteins look promising to service urologic markers to identify disease and monitor response to therapy. Micro RNA S are also a new development that are being investigated as predictive biomarkers. So there's uh certainly lots of work going on and lots to work forward. Lots to look forward to rather in the future. Yeah. And with that I will I'll conclude, I thank you for your attention and I'm certainly happy to address any questions that you might have. Thanks Doug. We'll hold the questions and we'll forward those to you so you can answer them over the next few days. And the answers for all the questions will go to all the attendees. Published August 16, 2021 Created by Related Presenters Douglas Winstanley, DO Clinical Assistant Professor, Michigan State University Mohs Surgeon, West Michigan Dermatology Spectrum Health Dr. Douglas Winstanley attended the University of Michigan and Midwestern University-CCOM. View full profile
