Melanoma: Pathophysiology

00:01 Welcome. With this talk, we're going to delve into one of the more malignant tumors that you'll ever encounter, a melanoma.

00:10 This is a little bit of a longer talk.

00:13 So buckle in. I also want to start with a story.

00:16 So when I was a medical student and I had my first lecture on melanoma, I was convinced I was going to die of melanoma.

00:23 I have a lot of moles, and I remember going down to the lecture after the talk and and saying, I think I'm going to die.

00:31 And he took pity on me, arranged for me to meet with his dermatology colleague. And I was assured that after all, I was going to live.

00:39 And here I am, about 40 years later, still alive.

00:43 Okay, so don't think you're going to die of it.

00:46 Although it is a malignant tumor.

00:48 So melanoma, a highly malignant tumor, it arises from melanocytes. We'll talk a little bit later on in why melanocytes going bad is much worse than keratinocytes or basal cells going bad.

01:04 The epidemiology of this.

01:06 So overall, if we take away basal cell carcinomas and squamous cell carcinomas of the skin, this is the fifth most common malignancy that's diagnosed in the US.

01:19 About 6% of all skin or all cancer diagnoses are going to be melanoma. The average age of diagnosis is older kind of 50 to 60s. Overall, there is an increasing incidence and some of this is global warming. But people are also out more in the sun.

01:37 Hopefully this will be corrected as we do more and more kind of public health and and get people to use sunblock.

01:45 But with increasing UV exposure it is increasing overall incidence. The highest it is the highest mortality of skin cancers.

01:54 It's actually high mortality of all cancers.

01:57 That's in part because if you think about it, melanocytes originally are neural crest derived.

02:03 And so they have migrated from the original notochord, the neural tube, and have then gone out to the skin.

02:11 That means that at baseline they are a migratory cell type.

02:16 They're able to kind of move around much more easily because of just their, their makeup.

02:23 And so they've already learned one of the tricks necessary actually more than that, but one of several tricks necessary in order to be a metastatic tumor.

02:33 So that's why melanocytes are bad actors when they go bad.

02:37 The pathophysiology. So I've already intimated this.

02:41 Again, like all of the skin cancers, exposure to ultraviolet light causing double -stranded DNA breaks is one of the major driving forces.

02:50 So we're seeing more of melanoma in areas where there's more UV exposure. Interestingly, if you've had five or more sunburns. Actually five sunburns typically kind of around the time of puberty or pre-pubertal that doubles your risk.

03:09 Wow. Tanning beds with UVA are also increased risk and then radiation and things that can potentially induce DNA mutations like Psoralen.

03:21 Treatment for psoriasis can also drive melanoma.

03:25 So what about sunscreen? Yeah. Sunscreen is protective against most UVB exposure.

03:31 Less so, depending on the sunscreen for UVA.

03:35 Uh, but, uh, the people who slather on sunscreen are also more likely to spend more time in the sun and may not necessarily have the perfect coverage and apply reapply their sunscreen effectively.

03:48 So when you're counseling your patients, just be aware of that.

03:52 Other melanoma risk factors.

03:54 Immunosuppression. So in fact it's interesting.

03:58 Melanoma as we will also talk about later has one of the highest mutational burdens of any tumor. There's a lot of genetic instability.

04:07 So they make a lot of mutant proteins overall.

04:10 And so that makes a lot of immunologic targets.

04:13 And so in fact we may be developing low grade melanomas maybe frequently. But our immune system catches up with them and destroys them.

04:22 So if you're immunosuppressed you're a transplant patient.

04:24 You're getting chemotherapy, you have HIV.

04:27 You may be at risk. Greater risk for developing melanomas A genetic predisposition also clearly plays a role.

04:35 So there's a positive family history of melanoma in 5 to 10% of cases. And it's it's a variety of genes.

04:42 It's not just one clearly fair skin if there's not a lot of pigmentation puts you at risk because you're not making melanin, that's going to Uh, protect you against the DNA breaking potential of that ionizing radiation. Blue eyes, interestingly enough, by allowing UV through to the retina, can put you at increased risk for getting retinal melanomas.

05:08 Not huge, but it's real.

05:10 Red hair. So Jessica Chastain, lovely, is indicated there.

05:15 So red hair and fair skin are due to mutations in the Melanocortin -1 receptor.

05:22 And that changes your melanin synthesis from something that's protective eumelanin to something that's potentially, uh, increases or augments the effect of ultraviolet light. That's pheomelanin.

05:34 Um, interesting. And then if you have greater than 40 nevi. So this is why I thought I was going to die.

05:42 If you were greater than 40 nevi, then you are at increased risk.

05:47 It tends to indicate that there may be a genetic basis for melanocyte hyperplasia, giving you more moles.

05:57 So in these genetic syndromes there is something called familial atypical multiple mole melanoma or femme syndrome autosomal dominant.

06:06 It is a mutation in a in a CDK inhibitor, the CDK N2A .

06:14 Remember that CDK inhibitors in kind of in mute the proliferative response in cells.

06:23 So it's a tumor suppressor.

06:25 And if you have multiple atypical moles so histologically they look a little funky a little weird, then you may have that mutation.

06:34 Xeroderma pigmentosum clearly associated with melanoma.

06:39 Because what's happening is you've lost the DNA repair mismatch repair genes, one or more of them and you don't repair DNA damage as effectively. So those patients are much more susceptible to UV damage and melanoma. Other mutations you may have germline and or acquired mutations in tyrosine kinases such as BRAF.

07:03 Or you may have transcription factor changes MITF.

07:08 You could have mutations in NRAS.

07:11 All of those are activating mutations.

07:13 Or you may have loss of function mutations and things like neurofibromatosis -1. So you're not expected to memorize this truly.

07:22 But just be aware that there are genetic syndromes that may increase the risk for melanoma.