Squamous Cell Carcinoma: Pathophysiology

00:01 Welcome. With this talk, we're going to look at another important malignant lesion of the skin squamous cell carcinoma.

00:10 Uh squamous cell carcinoma is a tumor arising from epidermal keratinocytes as opposed to basal cell carcinoma.

00:18 These are going to be the cells more superficial than the basal layer. So the epidemiology.

00:25 Overall it is the second most common skin cancer.

00:29 And actually that makes it the second most common cancer overall in the world, following basal cell carcinoma, which has the dubious distinction of being number one. Probably because of lifetime sun exposure and or lack of wearing makeup or something, men tend to get this more commonly than women.

00:49 The incidence increases with age again, speaking to a lifetime exposure of ultraviolet light, and the incidence is certainly higher in people with fair skin who have less protective melanin pigmentation.

01:02 The risk factors clearly align with everything I've already said it's exposure to ultraviolet light. UVB is the primary factor, but UVA exposure from other sources certainly can drive this.

01:16 Other exposures to ionizing radiations may also be causal.

01:20 So if you have radiation because of a deep-seated malignancy, the skin in that path may also be prone to developing squamous cell carcinoma. So anything that's going to drive double-stranded DNA breaks.

01:34 Other risk factors include certain other exposures.

01:38 It turns out that arsenic interacts and synergizes with UV light to cause increased mutagenesis.

01:45 Radon is another source of radiation that will drive a double-stranded DNA breaks, and if you don't have a good way of surveilling and then removing tumors . If you're immunosuppressed, in other words, if you have HIV or immunosuppressive medications, say for a transplant, then you are also at increased risk of developing squamous cell carcinoma.

02:07 Interestingly, chronic inflammation from burn scars or chronic ulcers, inflammatory dermatoses draining sinus tracts with a lot of inflammation all also drive the formation of squamous cell carcinoma.

02:23 That's probably due to the effect of that chronic inflammation releasing into the environment a number of inflammatory mediators, and in particular reactive oxygen species, which can drive malignant change. It can drive DNA damage.

02:40 Squamous cell carcinoma that arises in a chronic wound gets a name a marjolin's ulcer. I'll show you an example of that later on.

02:49 These tumors arising in chronic inflammation tend to be much more aggressive than spontaneous UV driven alone squamous cell carcinomas.

03:00 And that HPV infections.

03:02 Remember that HPV and in other talks in this series in Dermatopathology, we've talked about what human papillomavirus does to enable its own personal proliferation is that it drives ongoing proliferation of the keratinocytes .

03:20 If you do that and you happen to acquire a mutation, it tends to get fixed because the cell goes through a proliferative cycle.

03:28 So HPV infections, by driving ongoing proliferation can also be a substrate by which we develop squamous cell carcinomas.

03:37 Okay. There are genetic factors as well.

03:40 Of course there are. So if you have someone in your family with increased risk, it's not just because you've been out in the sun together. There may actually be a genetic basis. And there are a number of genetic syndromes that are associated with squamous cell carcinomas.

03:55 Obviously, if you don't have good mismatch repair, you have a disease called xeroderma pigmentosum.

04:02 You are at increased risk for getting squamous cell carcinomas, epidermolysis bullosa leading to defective intercellular adhesions with increased keratinocyte turnover can also put you at risk of oculocutaneous albinism, where you don't have any melanin pigment.

04:20 Yeah, obviously you don't have a way to protect yourself against UV damage and epidermodysplasia verruciformis.

04:28 Just like saying that where you have a defective immune response specifically against HPV, you kind of get unopposed.

04:35 Human papillomavirus driven proliferation of keratinocytes, interesting disease. Pathophysiology.

04:44 So the molecular pathogenesis is really a multi-step process like a lot of cancers involving the accumulation of increasing genetic and epigenetic alterations.

04:55 Generally first up, one of the earlier changes that occur in cutaneous squamous cell carcinoma are going to be Tp53 mutations.

05:05 Recall that p53, the guardian of the genome, is going to be responsible for recognizing DNA damage and initiating the process by which cells correct that damage or undergo apoptosis in the event that they can't fix the damage, if you get a mutation in p53, that's a very important domino that starts falling early.

05:28 So it typically is a very early event.

05:31 We see it in about 90% of cutaneous squamous cell carcinomas and it's usually UV-related . It's also found in actinic keratosis.

05:41 So other talks in this series in Dermatopathology we talked about the precursor lesions pre-malignant lesions of actinic keratosis, and those also typically involve early mutations in p53. So just by way of a quick reminder here, actinic keratoses are proliferations of atypical or dysplastic epidermal keratinocytes.

06:07 It's not yet malignant.

06:09 It doesn't have all of the necessary genetic changes to make this invasive or metastatic.

06:16 But basically the risk factors are exceptionally similar to squamous cell carcinoma. And left to their own devices, actinic keratosis will eventually those cells will eventually undoubtedly acquire additional mutations that will make them malignant.

06:32 So there is a rate of progression to cutaneous squamous cell carcinoma that has been described as high as 20% per year.

06:40 So that's also why we want to be aggressive in in treating and removing actinic keratosis before they go bad.

06:47 Actinics may spontaneously regress.

06:50 That's if the immune system catches up with them or they may persist.

06:55 Bowen's disease. Interestingly so this is a cutaneous squamous cell carcinoma in situ not yet invasive.

07:04 It's driven by human papillomavirus and various types of the human papillomavirus will induce this.

07:13 And we'll see it in different distributions depending on which human papillomavirus has been has infected. It grows very slowly.

07:20 So Bowen's disease is not a particularly aggressive.

07:24 But it will continue and it can eventually become progressive.

07:29 It presents as an erythematous or skin colored area of patch or plaque on the skin, typically on lower extremities.

07:37 But we get involved with the genital area with HPV that are particular to that location. And when we see it on the penis, we call it erythroplasia of Queyrat.

07:48 Again, something I just like saying.