Rachell: I think the perceived delay in diagnosis from a patient perspective, there is many things that it can cause for myself and for others within some community. For me, it started with a hive on my left ankle. I did not really pay much attention to it and then the symptoms progressed over time and it went from that 2 full immunologic response. I was covered from my head to my toes.

Then it progressed to where I had chronic urticaria that presented with it. Then came weird edema and swelling. Half my face would swell, 1 of my eyes would swell. Then came the anaphylaxis.

During that delay in diagnosis, my symptoms went from something very minor to something very severe because nobody that I came in contact with during that period knew what was going on with me. I think that for myself and for others within the SM community that I have spoken with, that it is not a matter that we feel like that the providers do not care. I just feel like maybe there is a lack of education around this disease because it is so rare.

During that period when nobody can tell you what is going on, you tend to look for answers and you tend to end up in ERs. ERs are for trauma and to treat you in that moment. They are not the answer giver in the situation, but that is where the majority of us end up at during this process when nobody can tell you what is going on and what is wrong with you.

There is also a mental component to that that plays into it with us that you lose trust within the medical community. You start questioning yourself. A lot of people are told that what is going on with them when they first present tends to be anxiety or you are coming into contact with something that you are allergic to.

SM is not even thought of from the front or even mast cell activation disorder in a lot of cases. Again, I do not think it is a lack of not caring what the patient is presenting. I think it is just a lack of having information and education around what this disease presents like and knowing that it does not always present the same in each person.

[00:10:05]

What Is Mastocytosis?

Kristine Kucera (University of North Texas Health Sciences Center): Hello, everyone. Let us dive in. What is mastocytosis? Its definition. It is a neoplastic disorder with substantial increase and accumulation of mast cells. It can present a few ways. It can be cutaneous mastocytosis, which is a skin-only component. We have systemic mastocytosis, which is extracutaneous organs with or without skin involvement. Then we have mast cell sarcoma.

Today, we are going to dive deep into systemic mastocytosis. It is important to remember though that systemic mastocytosis is not the same as mast cell activation syndrome. This is a hyperactivation disorder of mast cells and symptoms due to mast cell activation can be similar. Sometimes it is a little bit difficult to distinguish them apart. Hopefully, we can paint a clear picture for you today.

[00:11:08]

Systemic Mastocytosis: Epidemiology and Pathway to Diagnosis

Systemic mastocytosis, or SM is an easier way for us to call it going forward. Looking at just epidemiology, pathway to diagnosis, the prevalence is 1 in 10,000. About 32,000 people in the US have been diagnosed. It is considered an orphan disease. A definition of an orphan disease in the US is less than 200,000 people are affected.

Diagnosis within SM, there is multiple different types. The most common type, which 90% or more of patients have is called indolent. There is also a few types that are very rare. One is SM with a hematologic component or disorder that goes along with it. That is only about 6%. Then we have mast cell leukemia, which is very rare. It is about 0.5%.

The interesting thing, this is a difficult condition to actually diagnose and you can see that on the right here, time from symptom onset to diagnosis. These patients, some of them have to wait anywhere between 7 to 12 years to get a diagnosis, depending on the type. Across the bottom, you can see, I guess, the more aggressive the type, the harder it is to diagnose.

[00:12:39]

Skin Lesions of Mastocytosis

The mean years is about 6.5. These 4 patients have to suffer for a long time sometimes before they actually get a diagnosis. Hopefully we can change that today.

Let us look at the skin. On the left, you have an adult and on the right you have pediatric. Now typically in an adult patient, they have the type which is called indolent systemic mastocytosis, and they get monomorphic small lesions. Then you see on the right is the pediatric, which usually appears as cutaneous mastocytosis, so skin-only, and they get polymorphic lesions. That is typical of cutaneous mastocytosis.

[00:13:27]

Adult vs Pediatric Onset Mastocytosis

Now let us just compare them a little bit. You will see the feature and the characteristics and then we are going to look at adult and pediatric.

Let us go with adult first. The most frequent category we just said is indolent systemic mastocytosis, and it is a chronic disease. Anaphylaxis frequency is about 50%. Tryptase levels are usually over 20. There is a KIT mutation and it is usually a high percent of the patients that have it, 85% to 90%. The morphology is monomorphic if they do have cutaneous lesions. The lesions are small and they usually start on the thigh and then move to the trunk.

Now in the pediatric population, most frequent is the cutaneous type. Course is it usually resolves, which is great for our patients. Anaphylaxis frequency, 10% or less. Tryptase levels are also less than 20%. The KIT mutation could be a small percentage or it actually could be absent.

Then the morphology, we just saw the photo where it is polymorphic. Size of the lesions are variable, and the distribution can be on the trunk, head or extremities.

[00:14:46]

More on Small Monomorphic Maculopapular Lesions

Now let us look a little bit closer at the adult lesions. This is associated again with indolent SM, rarely cutaneous mastocytosis. When you see the small lesions, think rarely cutaneous, usually systemic. It is present in more than 80% of patients and it often starts on the thighs, gradually spreads to the trunk, distal extremities and neck.

Now 1 sign that is usually present, which can help you in your diagnosis is something called the Darier’s sign. What this is, it is reddening or wheeling of the skin with stroking or rubbing. Keep that in mind, the Darier’s sign.

[00:15:32]

Systemic Mastocytosis Clinical Presentation

Now systemic mastocytosis clinical presentation. On the left here, you can see all the different presentations and all the different systems in the body. Cutaneous, GI, CV and bone symptoms and signs are among the most common. As you look down the list, you can see on the right, what are the key drivers of these clinical presentations?

Cutaneous, it is highly involved. Histamine, tryptase, IL-6, PAF among others. Cutaneous, you can get skin signs, heart signs, GI, musculoskeletal, neurologic, respiratory and systemic. This is a great little chart and I know the slides you will be able to get. This sums it all up what are the key mediators that are driving these symptoms.

[00:16:30]

Common Triggers in Systemic Mastocytosis

Now common triggers in SM. This can actually trigger the patient to get these symptoms. Temperature extremes or changes, stress, fatigue, food and beverage, medications, infection, and venom, which is interesting. Then surgery and procedures.

[00:16:53]

Why Is Systemic Mastocytosis Presentation So Heterogeneous?

Why is systemic mastocytosis presentation so heterogeneous? Why is it so varied? Well, the variability in the mast cells and the mast cell activation are based on the locale, the surface receptors and the mediator profiles. There is an impact of high mast cell counts in a range of tissues and organs. Then, of course, we have the genetic mutation component. 90% of patients with SM do carry the mutation of KIT and there can be mutations in other genes as well. They have been associated with advanced SM and you can see those there.

[00:17:38]

KIT Mutations as Drivers of Systemic Mastocytosis

Now let us talk a little bit about KIT mutations. This is the driver of systemic mastocytosis. We just said to reiterate. More than 90% people with mastocytosis have some sort of KIT somatic point mutation. It is a ligand-independent activation. Mast cell survival and accumulation occurs.

The D816V is the most common mutation with 85% to 90% of adult cases having that mutation.

[00:18:13]

Differential Diagnosis

Let us dive into differential diagnosis. When you see this, what do you think of? You need to consider other mast cell disorders. There is the monoclonal mast cell activation syndrome, the idiopathic mast cell activation syndrome, and then of course anaphylaxis. But other conditions to consider, and this is broken down by different systems.

We have dermatologic. You want to think about urticaria, atopic dermatitis and rosacea. Endocrine, things should start running through your head like thyroid disease, adrenal insufficiency, carcinoid syndrome. Gastrointestinal: IBD, IBS. Is it Zollinger-Ellison syndrome? Neurologic: seizure, stroke, multiple sclerosis. Psychologic: anxiety, panic. Lots and lots of things can be running through your head when you are actually evaluating these patients.

[00:19:09]

Diagnostic Algorithm for Mastocytosis

Now let us talk about when you do evaluate then, and this is a diagnostic algorithm. If you are suspicious, meaning there are symptoms, anaphylaxis and/or elevated serum tryptase or you have adult-onset mastocytosis in the skin, which is actually biopsy proven, this is what you want to do moving to evaluation.

Now the emphasis is placed on identifying the KIT gene mutation. There is an increase or elevated serum tryptase level, and bone marrow findings also can be there. However, keep in mind if eosinophilia is present, you want to screen for what we call FIP1L1::PDGFRA. This is a genetic abnormality when these 2 genes fuse together. Just keep those in mind.

[00:22:18]

Diagnostic Criteria for Systemic Mastocytosis

Kristine Kucera: Okay. Let us talk a little bit about the diagnostic criteria for SM. We have major and minor. The major: multifocal dense aggregates of mast cells in the bone marrow and or other extra cutaneous organs. Minor: greater than or equal to 25% of mast cells with a typical morphology.

There is aberrant CD2 25 and/or 30 expressions on mast cells. Of course, we talked about the KIT mutation. Baseline serum tryptase of greater than 20 nanograms per mL in the absence of associated myeloid neoplasm.

Two different criteria here. We have the WHO, World Health Organization Fifth Edition. They require 1 major plus 1 minor criteria, or 3 or more minor criteria. Then the International Consensus Classification requires one major criteria or more than 3 minor criteria.

[00:23:27]

Minor Criteria 1: Atypical Mast Cell Morphology

Let us just look a little bit closer at these minor criteria. We have atypical mast cell morphology. On the left is a bone marrow aspirate. The very middle top picture is actually normal, well differentiated mast cells. Then of course the other 3 are a typical morphology that you might see when you are diagnosing mastocytosis.

[00:23:58]

Minor Criteria 2: High-Sensitivity PCR Testing to Avoid False Negatives for KIT D816V Mutation

Then look at criteria 2, a high sensitivity PCR testing to avoid false negatives. Very important for the KIT mutation. If it is positive, you want it to be positive and you certainly do not want a false negative. This is individual patient samples. This actually shows that if you are using a test such as a droplet digital PCR or a next-generation sequencing detection, you should get a fairly accurate sample.

On the left side here, you can see it says allele frequency, and allele is just a word for specific version of a gene. This is just looking at the different patient samples, the 2 different tests that were used, and the accuracy of the testing. Just make sure you are using the proper testing when you are looking at that mutation.

[00:25:04]

Minor Criteria 3: CD2, CD25, and/or CD30 Expression on Mast Cells

This is minor criteria 3. This is just showing the different CD cells. CD 2, 25 and/or 30 can be expressed on the mast cells. There is some photographs here. Then also tryptase.

[00:25:17]

Minor Criteria 4: Elevated Basal Serum Tryptase >20 ng/mL*

Then looking at criteria 4, the elevated basal serum tryptase of greater than 20 nanograms per mL. Remember that an average serum tryptase in a healthy individual is usually less than 5. Roughly 6% of the general population does have an elevated tryptase. An elevated serum tryptase can be seen in hereditary things. The WHO recommends adjusting that serum tryptase level if this is present. Again, important to do a really good medical history on these patients, especially family history.      

[00:27:53]

Identifying Systemic Mastocytosis Subtypes

Identifying systemic mastocytosis subtypes. There is a lot. Let us look at these. Again, love that you guys get to have this little chart because it can help a lot in a clinical setting. Looking to the left, the different variants here. You have:

• Indolent;
• Bone marrow mastocytosis;
• Smoldering SM called short SSM;
• SM with associated hematologic neoplasms;
• Aggressive SM; and then,
• The final one is mast cell leukemia.

Each one of these variants, the second column tells you whether they are advanced or non-advanced and if skin lesions are typical. Then what I think is interesting is the middle column which says B or C findings. If you look at the bottom of the slide here, it will show you that the B-findings are things like hepatomegaly, splenomegaly and lymph nodes. The C-findings is organ damage due to MC infiltration.

Some have B-findings and some have C-findings and some have both or none. This is a great little chart here.

Then, of course, other just kind of gives you a few little hints here. If you do not have skin lesions or if your basal tryptase is less than 125 nanogram per mL, of course, the WHO criteria comes into play here and peripheral blood smears in the mast cell leukemia.

Great little chart here for you just to go through and see if this actually will help you out in a clinical setting.

[00:29:46]

Symptoms in the Spectrum of Mast Cell Disorders

Symptoms in the spectrum of mast cell disorders. I thought this was really interesting because there are so many symptoms that these patients can have. What we are looking at here as well as the bottom of the slide all the way to the left, you see prediagnostic indolent smoldering.

As you go to the right, the disease is getting more aggressive. As the disease gets more aggressive, so does the burden of this disease on patients and we have to keep that in mind. Quality of life needs to be addressed.

Now looking through just all the symptoms, we talked about skin, you can have pruritus, flushing or hives, that can go with tons of dermatologic diagnoses.

Gastrointestinal: patients can get nausea, vomiting, diarrhea, abdominal cramps, heartburn, and does not that spark a lot of differentials there.

Cardiovascular: syncope, dizziness, palpitations, neurologic things can be involved even as little as just difficulties remembering things, headache, not being able to sleep. Then of course anaphylaxis, certainly hope that patients don't have that. You can get anaphylaxis though, remember, from stings. We talked about the hornet sting. Any stings, drugs, food, things like that can bring on anaphylaxis.

Then bone. Patients may just have back pain or bone pain. Then constitutional, generalized weakness, fatigue, achy, myalgias, sweats, chills. I mean that can go along with so many things. One thing do keep in mind, confirm effects on organs are caused by the mast cell infiltration. You want to make sure with organ involvement what the patient has going on.

[00:31:59]

Expected Survival by WHO Classification

Okay, expected survival. This made me a little bit sad because first of all, we know that early diagnosis, of course, you get a better outcome. But then we saw that these patients sometimes are waiting 7 to 12 years or more to get a diagnosis. If you look at this chart, the indolent systemic mastocytosis, of course, survival is much better.

But if they have the advanced, it actually survival tanks pretty quickly as early as it looks like 4 or 5 years there. Then the blue line, that is when you have a hematologic disorder that goes along with it, and there, survival is actually even lower. Then if you look at the MCL, the mast cell leukemia, I mean, these patients do not even have a chance hardly. Very, very, very important early diagnosis and treatment because we have to get these survival rates up.

[00:33:16]

Adult-Onset Mastocytosis: Recap

Just to recap, adult onset mastocytosis, adults with cutaneous mastocytosis lesions, you could think about urticaria pigmentosus. Look for the monomorphic maculopapular cutaneous mastocytosis, so the rash that we talked about and saw the photographs of. You want to think about is it systemic mastocytosis or is it cutaneous only? And could there be a sampling error?

Workup: remember serum tryptase, high sensitivity testing for KIT, skin biopsy, bone marrow biopsy with the appropriate studies, all of that is very important to get a diagnosis in these patients.

[00:34:20]

Skill Building and Feedback I: Recognizing SM

Speaker: Absolutely. I think it speaks volumes, Kristine, when you look at those survival rates, right? Like the indolent SM patients, they look very similar to normal patients within the United States, but stratifying them based on what type of mastocytosis they have is of utmost important. You are right, by the time you are already 6 to 12 years in, that is a long time to wait for a diagnosis.

[00:34:31]

Case I: Introduction to 40-Yr-Old Man With Itchy Skin Lesions

Let us talk a little bit more about recognizing systemic mastocytosis with our first case. Here is our 40-year-old man with itchy skin lesions and they have been present for about 6 years on his trunk and extremities. They are much itchier after a hot shower or touching the lesion. Epinephrine was prescribed to him after severe reaction to a hornet sting. But he has no other notable history, no reaction to food or drugs, no palpable lymph nodes or hepatosplenomegaly.

The patient has seen multiple doctors and topical skin creams were prescribed, but no skin biopsy is available.

Yeah, so bone marrow biopsy, biopsy of the involved organ, which could be skin, the high sensitivity molecular testing, mast cell phenotyping, and screening for the specific gene mutation if eosinophilia is present as well as the KIT and the KIT is negative.

Kristine, do you have anything to add for this? I mean this is a tough condition, right, in trying to decide what the workup should be.

Kristine Kucera: Very tough. All the above. I think the more tests you can run, the better idea and picture you will have of what is going on with the patient.

Speaker: Yes. Again, remember this is an orphan disease, right? It is not something you are going to see very often, but when you do, you do not want to miss it. I do not know about you Kristine, but the old adage always runs through my head with these orphan diseases. If you are not looking for it, you are not going to find it kind of thing.

Kristine Kucera: Yes, and I am really glad that we are actually diving into this because I have been practicing as a dermatology PA for 29 years and I think I have seen cutaneous mastocytosis maybe 5 times and systemic may be 2 to 3. It is very, very rare. I practiced in a university setting where we got all the crazy things referred to us.

Speaker: Yeah. No, I am saying I have been a derm PA for about 23 years and community dermatology and I think I have seen maybe 1, right? But again, if you are not looking for it, you do not find it. I think it is really important for all of us to be aware of what needs to be done for sure.