Melanoma: Diagnosis and Management

00:00 Diagnosis.

00:02 So the history. Um, yeah.

00:05 History is important. It's really it's going to come down to tissue is the issue.

00:09 In terms of a family history, remember there is a very high kind of genetic component. So if someone in your family had melanoma, you probably have genes that are going to maybe make more melanoma in you than others.

00:20 And if you previously yourself had previous melanomas, yeah, then you're at risk for another one.

00:26 You need to do a physical exam.

00:28 You need to look at this.

00:29 This is this one. I think that even now, after this brief talk, you would have said, yeah I think that's melanoma.

00:35 It's, it's it's variegated in color.

00:37 It's got an irregular border.

00:39 It's big, all of that stuff.

00:41 But you can also use a variety of dermoscopy.

00:45 You can look at confocal microscopy.

00:47 So you can see cells of the epidermis and papillary dermis etc..

00:51 Um and and increasingly we're relying on computers to tell us what do you think. But I think that to the most casual observer this is like, yeah, I think you ought to get that one removed biopsy or in fact, preferably if possible, at the very beginning.

01:10 An excisional full thickness biopsy.

01:12 Let's let's get it out and let's see how deeply it invaded.

01:17 And we want to take very large margins.

01:19 It turns out I'll show you in a couple slides.

01:21 Depth of invasion is going to be the best predictor for whether a tumor is going to behave poorly. And that is to say it's going to metastasize or not.

01:30 In cases where it is a large lesion or it's in an area that's, you know, you don't want to take out a big hunk of skin, say it's on the face, then you may do an incisional biopsy with the intent that you're going to go back and radiate it, or do other things to treat it, and eventually get rid of it because it will behave poorly.

01:49 You want to do a variety of labs, so these are mainly once you make the diagnosis of melanoma, you'd like to see whether you think it's metastatic or not, because that's going to be important in terms of the longer term therapy. So you do a complete blood count and see whether there might be, say, involvement of the bone marrow that is affecting your complete blood count.

02:11 Liver function tests again looking for evidence of hepatic metastases and LDH. In general, you're looking at that because that gives us a sense of whether or not you have biliary tract obstruction.

02:23 If the if the LDH lactate dehydrogenase is markedly elevated.

02:27 And that would again suggest metastatic disease in the liver.

02:31 Chest x ray, ultrasound CT or Pet or other things looking for distant metastases. If you have a relatively smaller lesion with good margins all the way around it, you may not necessarily do the additional stuff at this point and just kind of follow the patient expectantly.

02:53 But in terms of the management, so you want to get the original excision.

02:57 If it's a relatively large lesion, you're worried about metastatic disease because of physical exam or other reasons.

03:04 Then you may do a sentinel lymph node biopsy.

03:06 That is to say, you inject radioactive material with a little bit of dye in the primary tumor, and then you use a Geiger counter to figure out where that dye is going, say, into the axillary region or into the inguinal region.

03:20 The first lymph node is is the sentinel lymph node.

03:25 So that's where this everything would be draining to.

03:28 And you can't excise that and evaluate that.

03:31 In general, if that is negative you're good to go.

03:34 There will be no other nodes involved other places.

03:37 And you're probably okay in terms of metastatic disease probably.

03:42 On the other hand, if that sentinel node is involved, it's likely to be other places.

03:46 So you're going to need to be a little bit more aggressive.

03:50 I mentioned this before.

03:52 This is a a way of thinking about risk for melanoma spread. And the black dots on here represent melanocytes. And the deeper and deeper the invasion that we see on histology, the worse and worse and worse the prognosis is in terms of metastatic disease. There are two different pathologists or dermatopathologist that have signed their names to them, Wally Clark and Craig Breslow.

04:20 They have slightly different ways of doing this.

04:24 But basically, how deep does it go? How where do the melanocytes go.

04:29 And that allows us to assign increasing risk.

04:34 And in fact the tumor classification don't normally show this for lesions of the skin. But the tumor classification in this patient is dependent on the depth of invasion.

04:45 That's the T classification.

04:47 Nodal disease also affects it.

04:49 And whether there's metastatic disease. That's our TNM tumor node metastasis. And depending on how deep it was and whether nodes are involved or how many nodes are involved and presence or absence of The metastases, you can put patients into various stages.

05:05 Those stages are actually pretty good in terms of giving us longevity. What is going to be their survival and stage one disease? Not too bad. Um, stage four disease.

05:17 Really bad, in fact. With stage four disease, that is to say with metastatic spread, 50% of patients are going to be dead within a year. So targeted therapy, what do we do about this.

05:29 So we now have a whole bunch of pharmacologic tricks in our therapeutic bag that we can kind of throw at melanoma.

05:39 The diagram indicates a whole variety of things that are mutated or can be mutated in melanocytes that have gone rogue, have gone bad, and we can target each one of those.

05:50 A very common early change is BRAF.

05:55 So BRAF is a tyrosine kinase and you get a gain of function mutation. Mutations, so a valine at the 600 amino acid gets mutated either to glutamic acid or lysine.

06:07 And that makes it more active, which makes which drives proliferation of the cell. So we can give tyrosine kinase inhibitors if we know that our tumor has a BRAF mutation.

06:18 And it goes the same for other kind of mutations.

06:21 So what we want to do is sample the tumor, send it off to your friendly neighborhood pathologist for diagnosis and depth of invasion.

06:29 But also what's the molecular signature? What things that are driving the proliferation and or survival are or have been mutated? And then we have drugs.

06:40 We have a whole variety of drugs that we can kind of throw at this.

06:43 The problem is, is that melanomas are really genetically unstable. They you know, you may have a dominant clone that's 90% of the tumor that is making it has a BRAF mutation.

06:57 Cool. I can treat those 90% with BRAF inhibitors, but there's 10% that I didn't really pick up on because of my original molecular analysis that have a different mutation, and I will miss those.

07:10 And melanoma will tend to have a lot of mutations.

07:14 The mutational burden is probably the highest of any tumor in the body anywhere. So how how how do we address that.

07:23 Well fortunately we have an immune system.

07:25 Right. So the idea is that with all the genetic instability and all the mutant proteins that these cells are cranking out, we got a lot of immune responses, T lymphocytes that can potentially respond to the mutated antigens and kill tumor cells. Great. Except sometimes tumor cells are clever little devils, and they will make inhibitors of the immune response, so they will make proteins programmed death ligand-1 and that will if a T cell comes up and says, I want to kill you and they say, ha ha ha, I have Pd-L1.

08:05 The Pd-L1 turns off the T cell.

08:07 Clever tumor. Bad for the immune system.

08:10 However, if we use antibodies against Pd-L1.

08:15 Okay, that that now frustrates the ability of the tumor cell to turn off the T cell.

08:22 That's what checkpoint inhibitors are all about.

08:25 And in the last 5 to 10 years, that's been like a godsend.

08:29 Now, it doesn't work all the time, but when it does work, it tends to provide a complete cure, a durable cure upwards of 25, maybe 30% of patients with widely metastatic melanoma.

08:42 And a good example of how effective this is is the ex US president Jimmy Carter, who had metastatic melanoma in fact had melanoma in his brain and got checkpoint inhibitors and completely eliminated his tumor.

09:00 It was remarkable. So he's kind of a poster child for checkpoint inhibitors. Cytotoxic therapy.

09:07 Unfortunately, not all that helpful.

09:10 We can give all the cytotoxic drugs in the world.

09:13 We will kill off more normal cells than we will kill off melanocytes, unfortunately. So when we have nothing else to offer patients, we'll give them that. It's usually palliative at best.

09:24 Similarly, radiation is palliative at best, and in fact we can only radiate so much. You may be able to radiate a brain met.

09:32 But if you have widespread metastases there's very precious little that you can do. So with that hopefully I haven't scared you to death.

09:40 I am living proof that you can survive, even though you think you're going to die of melanoma. And hopefully you've gotten some interesting tidbits to take home and talk with people about.