Mastocytosis: Pathophysiology

00:01 Welcome. With this talk we're going to discuss an entity called Mastocytosis.

00:06 It is increased numbers of mast cells.

00:10 So although in kids, as we'll see, the major manifestations are in skin or cutaneous mastocytosis.

00:19 And that's why we're talking about it here in Dermatopathology.

00:22 In adults it's going to be mainly a systemic disorder with a lot of manifestations related to mast cell degranulation.

00:30 So we'll do a little bit of the biology of mast cells too, because it's important to understand why, what are the manifestations of the disease. So overall mastocytosis is rare.

00:42 It's a pathologic accumulation of mast cells and tissues.

00:46 And it's not really a malignancy of mast cells, although such an entity does exist, but rather this is an increased number of mast cells doing their normal mast cell things.

00:58 Cutaneous mastocytosis is pretty much limited to the skin, and it's going to be mainly a pediatric issue.

01:03 Systemic mastocytosis involves extracutaneous tissues and can even include the bone marrow.

01:10 Epidemiology. Already said it's rare one per 10,000 people, though, is not all that rare.

01:16 And in your community where you live, there are probably at least a handful of people who are afflicted.

01:24 Both sexes are affected.

01:25 There is said to be a slight predominance of women in the adulthood.

01:30 Less than 5% of the adult cases are just cutaneous.

01:33 Like I said, most adults have the systemic form.

01:37 Conversely, over 90% of children with Mastocytosis will have disease limited to the skin. And interestingly enough, with puberty, with the onset of a variety of the hormones associated with puberty, the disease spontaneously remits.

01:54 So with regard to the pathophysiology, we actually know quite a bit.

01:58 The major cause of Mastocytosis involves a mutation in KIT or c-KIT . And if you know the nomenclature, it's also called CD1 171 17.

02:12 c-KIT is a transmembrane tyrosine kinase that sits on the surface of mast cells and will tell the mast cell whether to be activated or not. It is a the target receptor for ligands such as stem cell factor.

02:29 It can also drive not only activation of mast cells, but the proliferation of mast cells.

02:35 In Mastocytosis we get a gain of function point mutation. So amino acid 816 goes from an aspartate or aspartic acid to a valine.

02:48 And that gives us constitutive activation.

02:52 You should not remember that.

02:54 You should just know that that c-KIT is a major driver.

02:58 It's present that mutation gain of function in greater than 90% of adults with systemic mastocytosis.

03:05 It's also present in about 35% of cases of pediatric disease.

03:09 There are other c-KIT mutations, but again, c-KIT is going to be driving mast cell activation and particularly be the driver for mast cell proliferation.

03:19 There are other molecular changes all listed there.

03:22 It's alphabet soup. Do not remember them.

03:25 Know that it's that c-KIT is the major driver.

03:29 And there may also be abnormal expression of a variety of other surface molecules, including the interleukin five receptor.

03:37 How much Cd25 which is going to bind to IL two, etc.. Il two receptor and then the soluble, how much soluble c-KIT is present in mast cells.

03:47 So all of those can potentially impact the overall disease.

03:52 Just remember c-KIT activating mutation.

03:56 Okay. So mutation in the c-KIT gene is present on the surface of those mast cells.

04:05 And it leads to ligand independent activation of this tyrosine kinase Autophosphorylation so they get phosphorylated. That drives increased proliferation and reduced apoptosis of mast cells.

04:20 So now we've got too many mast cells running around.

04:23 Excessive mast cells accumulate in various tissues in kids, mostly in the skin and adults everywhere else.

04:30 And then that excessive mast cell activity.

04:34 Mast cells do what mast cells do.

04:36 They release vasoactive mediators.

04:38 So histamine heparin leukotrienes which is our arachidonic acid metabolites prostaglandins which are also arachidonic acid metabolites. They also release a variety of cytokines. So mast cells truly are the initial tripwire in a variety of inflammatory diseases.

05:00 It's our way of knowing that someone has invaded into a particular tissue. And so when there's infection or trauma or a variety of things happening, mast cells, degranulate release all those mediators.

05:12 And then that starts the process of inflammatory cell recruitment.

05:18 To many mast cells even if they're not super duper releasing their activities, are still releasing it at some level, and you get an inflammatory response.

05:28 So you get the itching and flushing.

05:30 And then if you have a lot of mast cells in your in your GI tract, you get abdominal cramping, which will cause pain.

05:38 And you can even get anaphylaxis, systemic mast cell degranulation all at once will drive laryngeal edema, bronchospasm and hypotension, anaphylaxis.

05:53 So the macules themselves where you have the accumulation of the mast cells, if they hang out in a large enough area and induce enough vasoactive changes, you can see them as reddish brown macules.

06:06 As regards the clinical presentation, we're looking for those kind of reddish brown macules. Again, it is a collection of mast cells, but it's also the mast cells driving local vascular reactive responses, causing vasocongestion and increased vascular permeability with vasodilation.

06:29 The lesions in systemic mastocytosis may start appearing in young to middle adulthood, and then they will increase in number over the years. And remember, adult mastocytosis is skin and it's systemic. It's everywhere else as well.

06:46 An interesting thing to do, if you suspect that this is going on, is for you, or the patient may notice it as well.

06:53 Rub or scratch a lesion.

06:56 Trauma will cause mast cells to release.

06:58 And you'll you will get erythema or hives.

07:01 You'll get urticaria within minutes.

07:03 And that's Darier's sign.

07:06 Depending on how many granules are being released and how many mast cells you have, you can have a variety of systemic manifestations, including flushing, tachycardia, diarrhea, et cetera, et cetera. Physical factors, medications, dietary factors, and stress can all impact whether a mast cell is going to degranulate or not, and anaphylactic episodes where you get systemic release of all of the mast cells all at once.

07:33 So you get anaphylaxis that can be triggered by bee stings, Hymenoptera, exercise and some medications.

07:40 The diagnosis it's a physical exam.

07:43 You can do a skin biopsy.

07:45 A darier's sign is actually pretty good .

07:47 For laboratory studies, one of the contents of the granules in mast cells is tryptase. And so you can measure serum tryptase levels.

07:56 You can do a complete blood count with a differential just to get a sense of whether you have circulating precursors.

08:03 And you can do liver function tests to get a sense of whether or not there is hepatic damage as well. And then if it becomes important, you can do the genetic analysis and look at whether you have a true c-KIT mutation that we typically recognize on the peripheral blood.

08:22 So now that you've made the diagnosis of mastocytosis.

08:25 What do you do about it? Well, okay. There are obvious things you avoid triggers.

08:29 So trauma, hot or cold? Um, alcohol. Things that can trigger mast cell degranulation.

08:37 You avoid that. Given that one of the products and one of the major vasoactive products of mast cells are histamines, you give antihistamines, and that works pretty well for relatively moderate disease.

08:50 You can also give anti-inflammatory agents like we do for all inflammatory diseases.

08:55 So topical corticosteroids could be in the mix.

08:58 You can add oral sodium cromolyn.

09:01 So cromolyn actually stabilizes the granules.

09:04 So you get less degranulation of the mast cells.

09:08 That can be particularly helpful for severe gastrointestinal symptoms.

09:12 It won't work acutely.

09:13 You have to take it chronically. But if you do, that significantly reduces the release of all the the various vasoactive and smooth muscle active mediators being generated by mast cells. Remember that mast cells are also making leukotrienes and prostaglandins, and those will have definite systemic effects. So to control that we can add anti leukotriene drugs.

09:39 Or you can add aspirin to inhibit the cyclooxygenase.

09:43 That's going to drive the production of the prostaglandins.

09:46 Do so cautiously with aspirin because in fact in some individuals they have an aspirin sensitivity.

09:53 And aspirin can be a driver for mast cell degranulation.

09:56 Finally you can try to destroy all those mast cells.

10:00 You can do phototherapy so that you administer a drug that is potentially toxic and then hit it with ultraviolet light.

10:08 And sometimes you can achieve relatively good control of at least the cutaneous. Phototherapy will not work for systemic mastocytosis. With that, we've concluded our discussion of a disease that includes both cutaneous and systemic manifestations.

10:27 Mastocytosis.