Actinic Keratosis: Pathophysiology

00:01 Welcome. With this talk, we're going to get into the world of pre-malignant lesions of the skin.

00:07 And actinic keratosis is a very important player on that particular stage. Actinic literally is the Greek word for caused by the sun. If we were going to use the Latin word, it would be solar. So actinic keratosis already tells you what's going on.

00:24 It's something involved the the hair the keratinocytes epithelium. And it's caused by the sun.

00:32 So actinic keratosis really is, as I said, pre-malignant. We're starting to see atypia in these lesions of the keratinocytes. They don't look entirely normal.

00:44 The fact that they don't look entirely normal means that their genetic makeup is also not entirely normal. And these really are precursors to squamous cell carcinoma. Left untreated, left to their own devices, they will acquire additional mutations and frankly, become malignant. So with regards to the epidemiology this is really common because so many people are out walking in the sun.

01:08 The prevalence is upwards of 15% in the population, and you will definitely see this in your sun-loving patients.

01:15 The incidence is two or so per 1000 person years.

01:19 So again, speaking to the the very commonality of this much more common in fair-skinned adults.

01:26 And that speaks to the protective effects of melanin.

01:29 And the more melanin you make, the more you're going to be protected against ultraviolet-associated damage.

01:34 It is definitely associated with sun exposures.

01:37 Individuals in Australia, northern Europe, and especially in the middle of heat waves and they're out in the sun.

01:43 The United States, those are all going to be individuals who are going to see more sun. The pathophysiology.

01:52 As I've already intimated, this is due to ultraviolet radiation.

01:56 It's that exposure to ultraviolet light is a high energy frequency light that will drive double-stranded DNA breaks.

02:04 That means that we are making all the time mutations in keratinocytes.

02:08 And most of the time we fix those appropriately.

02:12 But if we have mutations in things like p53, that's going to be a very important gene or gene product that's going to help us recognize when there's DNA damage and initiate the process to fix it, or to kill off cells if they can't appropriately fix it.

02:29 And individuals with Li-Fraumeni syndrome, those are the ones who have germline mutations, loss of function in p53 that increases your risk of developing actinic keratosis.

02:39 So that all kind of makes sense.

02:42 There are additional genetic and epigenetic alterations that affect a variety of oncogenic pathways. And again, there are multiple ways to get to cancer. But a lot of genes have to change fundamentally.

02:55 At the end of the day, what really ends up driving it from actinic or premalignant into malignant is really defective repair mechanisms.

03:04 And a good example of how this particular pathway intersects with UV damage is our patients with Xeroderma Pigmentosum.

03:13 That's one of nine different genes that are associated with proteins that are involved in DNA mismatch repair.

03:20 And patients who have xeroderma pigmentosum, germline mutations and mismatch repair have a lot more actinic keratosis because they're not fixing the UV damage. And in fact, they're much more prone to developing frank squamous cell carcinoma malignancy.

03:36 So in thinking about actinic keratosis kind of the premalignant lesions let's look at this schematic. UV damage and UV radiation is going to be the major driver. And it is going to cause double-stranded DNA breaks that may be in more superficial cells.

03:53 And in most cases at least early on you will have efficient and adequate correct repair.

04:02 So no harm no foul. Okay.

04:04 And in fact happens all the time if you're walking around in ultraviolet light, which we all are. You can, however, acquire mutations that don't perfectly get repaired and particularly if it involves genes like p53.

04:19 P53 is going to be a very important protein for recognizing DNA damage and then initiating the repair process.

04:28 So it's an important guardian of the genome.

04:31 And if we mutate that and we don't effectively repair that, we're starting down a pathway to genetic instability.

04:38 Our repair mechanisms are off, not just another pathway that is going to be involved in kind of early DNA repair.

04:45 So we may get more and more cells that are getting a little bit atypical, because our repair mechanisms are not as good as they are in cells that don't have permanent mutations. Now we can acquire additional mutations.

05:03 It's a multi-step process and it doesn't follow A to B to C to D.

05:08 You can go A to E and then have a mutation in C or F, etc. As we acquire more and more and more mutations, particularly those involving cells deeper within the epidermis.

05:21 Then we will progress from actinic keratosis to squamous cell carcinoma in situ.

05:28 So in situ just means it's above the basement membrane.

05:32 But it is malignant. Now it is curable by excision.

05:37 It hasn't invaded beyond the basement membrane.

05:40 So it has not been able to access lymphatics or capillaries etc..

05:44 But we now have full thickness involvement of the epidermis. Remember that it's not if it's just a single cell or just a small collection of cells in the superficial epithelium, such as in actinic keratosis.

05:59 Then with normal maturation of the skin, we're going to eventually kick those guys out. And no harm no foul.

06:07 But it's a marker of more extensive DNA damage when we see the actinic keratosis. Okay. So when we have full thickness without invasion beyond the basement membrane that squamous cell carcinoma in situ and then additional mutations on top of that again, because of genetic instability and not good repair mechanisms.

06:30 Then we're going to get into invasive squamous cell carcinoma where cells are crossing that Rubicon.

06:36 They are getting into the dermis where they can access blood vessels and lymphatics. So the general mechanisms to reiterate this UV damage. UV radiation causes DNA damage.

06:52 UV radiation can will also elicit inflammation and reactive oxygen species. Those can also lead to DNA damage.

07:01 So it's all about making DNA breaks and not completely repairing them. And the accumulated injury associated with all of those DNA mistakes are due to imperfect repair means that we begin to fix mutations in proliferating cells. And now more and more and more cells are expressing those.

07:25 And eventually a combination of Everything gets us to the point where we have frank malignancy. So actinic keratosis is everything up to that becoming frank frankly malignant.

07:36 But it's on its way and it is premalignant.

07:40 The clinical presentation.

07:41 So recognizing it in sun-damaged skin we see erythematous scaly macules or papules. It's typically in sun-exposed areas.

07:49 You won't see it in areas say around the genitals unless your person your patient is a sun worshiper who goes to nudist colonies.

07:59 There are other variants.

08:01 So the classic are these kind of erythematous, scaly macules or plaques that are recognizable once you've been introduced to them as actinic keratosis, you can have hypertrophic variants where the skin becomes much thicker, or you may have atrophic where the skin is not proliferating as effectively.

08:23 So you can have all kinds of variants.

08:25 And being able to recognize those is what you'll get good at when you go into dermatology. The diagnosis Well, in fact, it's a clinical examination and dermoscopy.

08:35 But just by physical examination, you can't tell whether it's pre-malignant or malignant.

08:42 And therefore you need to get a biopsy.

08:45 And there are certain kind of clinical indications for when you get a biopsy if it's big, greater than a centimeter, if it's really thickened, if there is necrosis. So there's ulceration if it doesn't respond to your treatments. All of those are good reasons to do a biopsy.

09:01 And you may either do a punch or more likely you're going to do a shave biopsy.

09:05 You may even for lesions that you're very concerned about do excisional biopsies.

09:10 In terms of the management, you want to get rid of the weird cells.

09:13 So there are a variety of ways that you can do that.

09:16 If it's quite localized you can do cryosurgery or cryoablation.

09:20 Just put liquid nitrogen on it.

09:22 You can do a surgical excision.

09:24 And those are all just fine.

09:26 But for things that are more widespread, there's a field effect, you may want to give topical antineoplastic agents such as five fluorouracil.

09:34 You want to maybe modulate the immune response.

09:38 So give immune inhibitors to reduce the amount of reactive oxygen species and other things that may be driving the process.

09:47 Nonsteroidals can work, but are not super duper effective overall. For more broad involvement of the skin, you can do photodynamic therapy where you administer an agent, and then you hit it with UV light with the goal of killing off a whole a whole area of keratinocytes.

10:09 You can do chemical peels.

10:11 So again, if it hasn't invaded, getting rid of the epidermis is curative. And then you kind of resurface it.

10:19 And lasers laser zapping is also a possibility.

10:23 So with this we're concluding our discussion of pre-malignant lesions.

10:28 Hopefully you have a good understanding of how this is happening at a genetic level.

10:32 But also you can tell your patients to put on that sunscreen.

10:36 Thanks.