Acanthosis Nigricans: Pathophysiology

00:01 Welcome. With this talk we're going to explore another interesting benign epithelial proliferation.

00:08 This one's called acanthosis nigricans.

00:11 Acanthosis nigricans is a hyperpigmented lesion.

00:15 The plaques they tend to form plaques so big areas of the skin.

00:19 And they have kind of a velvet like quality.

00:22 This is due to proliferation with hyperpigmentation of the epithelium. The epidemiology of this is that it's equally common in men and women. All age groups can potentially get it more commonly in this day and age.

00:37 We see it associated with diabetes and obesity, and with the kind of the current tendency to get bigger and bigger, people were seeing this potentially more and more. It's important for you to recognize what is driving it and it's not something malignant.

00:56 Having said that, in a moment we'll see on the slide that occult malignancy can also be a cause. So take it with a grain of salt.

01:05 Risk factors. So obesity and we'll see in a minute.

01:08 We'll talk about the pathophysiology having to do with the production of either insulin or insulin like growth factors.

01:13 And that's what's driving the proliferation of the epithelial cells.

01:17 So clearly, a variety of endocrine and metabolic disorders, particularly insulin resistant states, can drive this.

01:24 You can have genetic syndromes where the receptors are have kind of gain of function mutations.

01:32 Or you may have a increased number of the genes associated with the receptors. And in down syndrome you may say see acanthosis nigricans in that setting. There are familial forms again associated with some of the receptor overexpression.

01:49 Malignancy is something to consider if you've ruled out everything else.

01:53 Be aware that you should look for an occult cancer and then various drug reactions. A variety of drugs can drive that same epithelial proliferation. So the pathophysiology of this, although it's said here not well understood, we have an improving appreciation for what may be driving this.

02:14 And in particular because of the association with obesity, insulin resistance, A diabetes and things like that.

02:21 What's really going on, at least in those cases, is that insulin is in overproduction and insulin resistant state, obesity, diabetes, etc., is stimulating keratinocytes and dermal fibroblasts through their insulin like growth factor one receptors. And those exogenous signals, the insulin, are driving proliferation of those cells.

02:47 So that's how we get the majority of the lesions, at least those associated with insulin resistant states.

02:55 Without insulin resistance and this is the patients like down syndrome etc., we may have mutations in fibroblast growth factor receptors, FGFR3 in particular. And those may promote keratinocyte proliferation and survival.

03:12 And we may also see activating mutations.

03:15 So acquired mutations or inherited mutations such as in the Crouzon syndrome, which is a craniofacial dysostosis syndrome that also drive the same proliferation of the Keratinocytes.

03:30 In the case of occult malignancy, it's probably because tumors are secreting or can secrete transforming growth factor alpha, and that cytokine may contribute to the acanthosis nigricans by activating the epidermal growth factor receptors.

03:48 The clinical presentation.

03:51 It's one of recognizing this and then recognizing it for what it is.

03:55 There are thickened areas of the skin.

03:57 Again this is a hyper proliferation of the epithelial layer.

04:00 They typically are velvety sometimes verrucous meaning kind of wart like. They're gray-gray brown with hyperpigmentation.

04:09 And this is due to increased melanin production by the melanocytes that are normally present in the skin.

04:15 Classic sites at the back of the neck, sides of the neck and the axilla.

04:21 Making the diagnosis is one of clinical diagnosis.

04:25 Knowing what you're looking at, you can also do a biopsy, although this is not typically performed, but in that you would expect to see hyperkeratosis a thickening of the layer of the stratum spinosum, and you will expect to see accentuation of the epidermal papillae. So papillomatosis.

04:46 The dermis may or may not have a little bit of a lymphocytic infiltrate.

04:48 That's not part of what's driving this.

04:50 This is due to the stimulation of cells within the epithelium to just grow more. How do we manage this? Well, in fact, now that you understand what's driving this, in a majority of cases obesity, insulin resistance, etc., you treat the underlying cause, you normalize glycemia.

05:08 You don't want to encourage a lot of scrubbing.

05:11 You're not going to scrub these guys away. They're going to stay there. But by having kind of mechanical forces, you can actually exacerbate the proliferation. Topical retinoids will have a variety of effects, including improving maturation of the epithelial cells.

05:29 And you will have less of a keratin layer over the surface.

05:33 And it turns out the topical vitamin D analogs reduce the keratinocyte proliferation. So that can also be a mechanism by which you can treat these.

05:42 And with that an interesting topic.

05:45 Acanthosis nigricans.