The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 14

I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

22. Is MCAS an early form of SM?

MCAS is not viewed as an early form of SM but the diagnosis of MCAS may precede a later diagnosis of SM.
• In the last few years, we have learned a lot about the genetics associated with mast cell diseases and how it occurs in families. As a result, we are beginning to understand that mast cell diseases occur more along a spectrum than as distinct categories. This means that there is a lot of overlap between conditions.
• While it is certainly not a new disorder, MCAS is a pretty recent diagnostic entity. The last decade has seen a large increase in diagnosis as it has been more frequently described. Because of how new it is, and also the fact that there aren’t uniform criteria for what MCAS is, there will be a level of uncertainty about how this disease tends to progress for some time.
• That uncertainty aside, we know that at least some patients with a long history of MCAS have continued to have symptoms without developing markers of systemic mastocytosis.
• However, some patients with history of MCAS do develop markers of systemic mastocytosis.
• Many patients do not receive bone marrow biopsies when they are diagnosed with MCAS because there is not always a reason to have one. It often doesn’t affect treatment. If there is no sign of organ damage, the patient has a negative blood test for the CKIT D816V mutation, and their baseline tryptase is below 20 ng/mL, most doctors do not order a bone marrow biopsy. This means that some patients who are diagnosed with MCAS may have had SM all along but it wasn’t found until a biopsy was performed later.
• In 2007, monoclonal mast cell activation syndrome was described in scientific literature. This condition is diagnosed when a patient meets some criteria of systemic mastocytosis but not enough for a diagnosis of SM.
Monoclonal mast cell activation syndrome is more often viewed as a “pre-SM”. I personally view it this way. Before it had a name, researchers called it “pre-diagnostic SM.” Literally, SM before they could diagnose it as SM.

For more detailed reading, please visit these posts:

The Provider Primer Series: Mast cell activation syndrome (MCAS)

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (SM-AHD, MCL, MCS)

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, part 7

I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

 

13. What do these biopsy tests look for?
• They look for the shape, quantity, and distribution of mast cells.
• They also look for specific proteins on the outside of mast cells and tissue damage around mast cells.
• Systemic mastocytosis and cutaneous mastocytosis are generally diagnosed by biopsy. With very, very few exceptions, you cannot meet the criteria for systemic mastocytosis without having a positive biopsy. Sometimes people with monoclonal mast cell activation syndrome are diagnosed by having a biopsy that looks like a very early phase of systemic mastocytosis.
• The diagnostic criteria for mast cell activation syndrome are hotly contested. Most doctors do not use biopsies to diagnose MCAS because there are not uniform criteria. Some doctors feel that more than 20 mast cells in a field when you look through the microscope is a sign of MCAS.
• Cutaneous mastocytosis is having too many broken mast cells in your skin. For this condition, they are looking for either 20 mast cells to be present in the microscope field (hpf) when looking at the skin, or for there to be at least one cluster of at least fifteen mast cells.
• Clustering is a very important feature of mastocytosis. When mast cells bunch together in a cluster, it is easier to damage the tissue. They are essentially punching holes in the tissue by clustering.
• Systemic mastocytosis is having too many broken mast cells made by the bone marrow. Systemic mastocytosis is usually diagnosed by a positive bone marrow biopsy. However, sometimes people are diagnosed by biopsies of other organs. Skin biopsy is NOT enough to diagnose systemic mastocytosis.
• For systemic mastocytosis, there are three key things they are looking for in the biopsy.
• They are looking for at least one cluster of at least fifteen mast cells.
• They are looking for some of the mast cells to be shaped like spindles, sort of smushed at the ends and round in the middle. You see this shape a lot when cells are trying to stick together in a cluster.
• They are looking for special proteins that are only found when a patient has systemic mastocytosis or monoclonal mast cell activation syndrome. They are called CD25 and CD2. These are like flags that the mast cells fly to tell us they are broken. One of them, CD25, actually helps mast cells cluster together.
• In biopsies, they usually also look for the protein CD117. This is a normal flag for mast cells to fly and just allows us to know that we are looking at mast cells.

For more detailed reading, please visit these posts:

The Provider Primer Series: Management of mast cell mediator symptoms and release

The Provider Primer Series: Mast cell activation syndrome (MCAS)

The Provider Primer Series: Cutaneous Mastocytosis/ Mastocytosis in the Skin

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (SM-AHD, MCL, MCS)

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 5

I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

10. How is mast cell disease diagnosed?
• There are several tests you need to definitively determine if you have mast cell disease and what kind you have.
The most well known test for mast cell disease is serum tryptase. This is a blood test. This is the test doctors are most likely to have heard of. Doctors may think that you can’t have mast cell disease if tryptase is normal. This is not true.
• If a patient has a tryptase over 20 ng/mL, the next step is usually a bone marrow biopsy. A tryptase over 20 ng/mL increases the likelihood that a patient has systemic mastocytosis. SM is most commonly confirmed by a bone marrow biopsy.
• You need a special stain in order to see mast cells in any biopsy. Stains that show mast cells include Giemsa Wright stain and toluidine blue. Your doctor should specify these stains.
• Several tests must be run on the bone marrow biopsy to look for clonal mast cell disease. Remember that in clonal diseases, the body makes too many broken cells.
• The shape of the mast cells in the biopsy is very important. If the mast cells are not shaped right, this can be a sign of mast cell disease.
• The number of mast cells grouped together in the body is also important. If 15 or more mast cells are all stuck together, this is called a cluster. When mast cells are clustered together like this, they can punch holes in the tissue and damage it a lot. This prevents the tissue from working right.
• Immunohistochemistry (IHC) is a way to find specific proteins that allow us to know what cells we are looking at in the biopsy. Often, these proteins are on the outside of the cells. Think of these are flags that a cell can wave. IHC can look for the specific flags a cell is waving so that we know for sure which cell is which. For mast cell disease, they want to look for CD117, CD25, and CD2. The CD117 flag is flown normally by all mast cells. CD25 and CD2 are special flags flown by mast cells if you have clonal mast cell disease.
• PCR is a way to look for genetic mutations. They need to look for a mutation in the mast cells in the bone marrow. The mutation is found at a specific place in the CKIT gene. This mutation is found in 80-90% of patients with systemic mastocytosis. It may also be found if patients have monoclonal mast cell activation syndrome.
• If a patient does not have a tryptase over 20 ng/mL, a bone marrow biopsy is often not ordered. There are other tests that can indicate mast cell disease.
• Urine collected over 24 hours can be tested for specific chemicals. In the case of mast cell disease, they are looking for chemicals that can be high if you have mast cell disease. These chemicals have very long, complicated names. I will explain in a later post exactly what they are and what they do. The most common ones are called n-methylhistamine, prostaglandin D2, 9a,11b-prostaglandin F2, and leukotriene E4. Anti-heparin Xa and chromogranin A are sometimes tested. They are much less reliable as indicators of mast cell disease than the others mentioned here.
• If a patient is suspected to have cutaneous mastocytosis, a skin biopsy is needed to confirm. As with bone marrow biopsies, your doctor should specify that they need to use toluidine blue or Giemsa Wright stain to be sure they see the mast cells.
• The skin biopsy should also receive the other tests I described above for bone marrow biopsy: the counting of mast cells and looking at the shape; looking for CD117, CD2, and CD25; and looking for the same mutation with PCR.
11. What kind of doctor diagnoses mast cell disease? Can any doctor order these tests?
Doctors from all different specialties may diagnose and manage mast cell disease. It depends upon the individual provider and where you are located. It could be a dermatologist, allergist, hematologist, pulmonologist, gastroenterologist, or another specialist.
• The serum tryptase is the easier to order and the most well known test. Many labs can run this test.
• The 24 hour urine tests are specialized. Some of them are run in only a few places and samples are usually shipped there. Most often, these samples are run at the Mayo Clinic. Many outpatient labs have no way to run those tests. You will need to speak with your doctor about how to get these tests. It is often easiest if they are run by a hospital lab but again, this depends upon the hospital.
• The PCR genetic test for this specific gene is run in more places than the urine tests but is still not very common. Again, it is often easiest if they are run by a hospital lab.
• A bone marrow biopsy is usually ordered by a hematologist or by another specialist that works commonly with hematologists. They are usually performed by hematology providers. Some testing can usually be performed in house (the counting of the cells and looking at the shape) while others may need to be sent out (the IHC testing).
• A skin biopsy is usually ordered by a dermatologist. Some testing can usually be performed in house (the counting of the cells and looking at the shape) while others may need to be sent out (the IHC testing).
For more detailed reading, please visit these posts:

The Provider Primer Series: Management of mast cell mediator symptoms and release

The Provider Primer Series: Mast cell activation syndrome (MCAS)

The Provider Primer Series: Cutaneous Mastocytosis/ Mastocytosis in the Skin

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (SM-AHD, MCL, MCS)

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 2

I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

3. What causes mast cell disease?

  • The cause of mast cell disease is not yet definitively known.
  • As mentioned yesterday, when the body makes too many copies of a broken cell, those cells are called ‘clonal’ cells. In clonal forms of mast cell disease, the bone marrow makes too many mast cells. Those mast cells also don’t work correctly. Examples of clonal mast cell diseases are systemic mastocytosis and cutaneous mastocytosis.
  • Patients with systemic mastocytosis often have a specific genetic mutation called the CKIT D816V mutation. About 80-90% of systemic mastocytosis patients have this mutation. This mutation is in mast cells and it tells the mast cells to stay alive WAY longer than they should. And mast cells already live for months or years, a very long time for cells to live in the body. So patients with this mutation can end up with way too many broken mast cells.
  • Despite the fact that we know that many patients have this mutation, we do not say that this mutation CAUSES the disease. The reason for this is that sometimes, mast cell patients don’t have the mutation when they get sick but they develop it later. Sometimes, mast cell patients have the mutation and then lose it later. So we are still looking for something that causes the disease.
  • Patients with non-clonal mast cell disease do not have a single major mutation like the CKIT D816V mutation. This makes it harder to diagnose. Researchers have found that many times, patients with MCAS DO have mutations similar to the ones systemic mastocytosis patients do. But the MCAS patients often have different mutations from each other. That’s why it’s not helpful yet for diagnosis.
  • Despite the fact that the mutations described here are not considered to be heritable, there is more and more evidence that mast cell disease can happen to many people in the same family. See the next question for more details.

4. Is mast cell disease heritable?

  • Mast cell disease often affects multiple members of the same family. Importantly, patients often have a different type of mast cell disease than their relatives. This implies that mast cell disease is more of a spectrum rather than several different diseases.
  • A survey found that 74% of mast cell patients interviewed reported at least one first degree relative that had mast cell disease. This same study found that 46% of those patients had mast cell disease that affected more than just their skin. This is called systemic disease.
  • The CKIT D816V mutation is the mutation most strongly associated with clonal mast cell disease. The CKIT D816V mutation is NOT heritable.
  • There are very rare instances of other heritable mutations in families that have mast cell disease. The significance of this is not clear.

5. Can mast cell disease be cured?

  • Generally speaking, there is no cure for mast cell disease.
  • Children who present with cutaneous mastocytosis sometimes grow out of their disease. Their lesions disappear. Their mast cell symptoms affecting the rest of the body may disappear. We do not know why this happens. It has been heavily researched with long term follow up of children with childhood mastocytosis (at least one paper followed them for 20 years).
  • Children with true systemic mastocytosis do not grow out of their disease.
  • There is not yet data on children with MCAS. Anecdotally, they do not seem to grow out of their disease like kids with cutaneous mastocytosis can. Importantly, this is just what it looks like to me. Again, there is no data.
  • People with adult onset mast cell disease have lifelong disease.
  • There is one notable exception to this scenario. There are reports of curing mast cell disease following hematopoietic stem cell transplant/bone marrow transplant.
  • Transplantation is EXTREMELY dangerous. The transplant is MUCH, MUCH more dangerous than mast cell disease. Many people do not survive the protocol necessary to prepare for transplant. Many die from complications, or from a disease they acquired after their transplant.
  • Rarely, people may have malignant forms of mast cell disease, aggressive systemic mastocytosis (ASM) or mast cell leukemia (MCL). A few patients with these diseases have tried transplants after everything else failed. While some did see improvement after transplant, no one has survived more than a few years.
  • Conversely, sometimes people with mast cell disease have these transplants for other reasons, like having another blood cancer or bone marrow disease that requires transplant. In this group of people, some see drastic improvement of their mast cell disease. Some see a full remission of mast cell disease. Some do not get any improvement. These findings are pretty recent so it’s hard to be more specific.

For more detailed reading, please visit these posts:

The Provider Primer Series: Introduction to Mast Cells

The Provider Primer Series: Mast cell activation syndrome (MCAS)

The Provider Primer Series: Cutaneous Mastocytosis/ Mastocytosis in the Skin

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (SM-AHD, MCL, MCS)

Mast cell disease in families

Heritable mutations in mastocytosis

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 1

I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

  1. What are mast cells?
    • Mast cells are white blood cells that live in tissues. It is a little misleading that mast cells are white blood cells because they don’t live in the blood. Mast cells are born in the bone marrow, the squishy tissue inside bones where blood cells are made. From the bone marrow, they are sent to the blood stream. Mast cells use the bloodstream to carry them to their final destination so they do not stay in the blood for very long. Mast cells move out of the blood stream and into tissues throughout the body. Mast cells live for months or years, a long time for cells to live in the human body.
    • Mast cells do many things in the body. They are largely responsible for allergic reactions and anaphylaxis. They have many other jobs, like healing wounds, regulating reproductive activities (menstruation, pregnancy), and fighting infections from viruses, bacteria, fungi, and even intestinal parasites like worms. The original function of mast cells thousands of years ago was probably to fight off intestinal parasites. Mast cells are found in many tissues and are essential for correct functioning of the body.
    • Mast cells have many pouches inside of them called granules. These granules hold chemicals made by the mast cells. These chemicals help the mast cells to do their various jobs. They also help mast cells to communicate with other cells nearby or in other parts of the body. These chemicals can be released into the bloodstream to signal for other immune cells to come to the mast cell that released them.
  2. What is mast cell disease?
    • Mast cell diseases are rare diseases in which your body makes too many mast cells and/or mast cells do not function correctly. In the US, diseases that affect fewer than 200,000 people are called rare diseases.
    • Mast cell diseases are broadly classified into two groups: clonal and non-clonal (also called proliferative and non-proliferative).
    • When the body makes too many copies of a broken cell, those cells are called ‘clonal’ cells. In clonal forms of mast cell disease, the bone marrow makes too many mast cells. Those mast cells also don’t work correctly. They use too much energy on the wrong things. Because these mast cells are often busy making truble, they don’t have as much energy to do their normal necessary functions.
    • Clonal mast cell diseases include all forms of systemic mastocytosis (indolent, smoldering, aggressive, and mast cell leukemia); all forms of cutaneous mastocytosis (urticaria pigmentosa, of which telangiectasia macularis eruptiva perstans is a subtype, diffuse cutaneous mastocytosis); mastocytoma (usually found on the skin but also found elsewhere); mast cell sarcoma; and monoclonal mast cell activation syndrome. Importantly, in clonal mast cell diseases, the problem is not just that too many mast cells are made – those mast cells must also be dysfunctional for the disease to be clonal.
    • In non-clonal mast cell disease, the number of mast cells may be normal, but the cells are broken. Importantly, people with non-clonal mast cell disease may make more mast cells than normal, but not enough to be considered a clonal disease. In these diseases, even if the bone marrow makes the normal amount of mast cells, they still do not work correctly. They use too much energy on the wrong things. Because these mast cells are often working to inflame the body when it is not needed, they don’t have as much energy to do their normal necessary functions.
    • Non-clonal mast cell diseases include all other forms of mast cell disease: mast cell activation syndrome (secondary and idiopathic); familial hypertryptasemia; and mastocytic enterocolitis, which is recognized by some groups as its own disease, and by other groups as part of different mast cell diseases.
    • In these diseases, mast cells do not function properly. In all mast cell diseases, mast cells can get irritated easily. They respond to things in the environment and inside the body that they think are dangerous, even when those things are normal and safe for most people. This response is called mast cell activation.
    • Mast cell activation causes many symptoms. Many of these symptoms are “allergic” in nature. Some are not directly recognizable as “allergic”. Symptoms can affect every bodily system or may be localized to only one or two. It differs from person to person and can change over time within a person. You cannot know which mast cell disease a person has based upon their symptoms.

For more detailed reading, please visit these posts:

The Provider Primer Series: Introduction to Mast Cells

The Provider Primer Series: Mast cell activation syndrome (MCAS)

The Provider Primer Series: Cutaneous Mastocytosis/ Mastocytosis in the Skin

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (SM-AHD, MCL, MCS)

Mast cells in the GI tract: How many is too many? (Part Three)

In 2009, Walker and colleagues published a paper called “Duodenal mastocytosis, eosinophilia and intraepithelial lymphocytosis as possible disease markers in the irritable bowel syndrome and functional dyspepsia.”  The term “mastocytosis” as used here is not equivalent the term “mastocytosis” as in cutaneous mastocytosis or systemic mastocytosis. It is one of several papers to do so and has generated a lot of confusion as a result.

The suffix –osis is commonly used in medical terminology.  It means increase or production of something, but it also connotes that this increase results from a disease process.  Here, the author means not that these patients meet the criteria for systemic mastocytosis, which we know to be a neoplastic disease originating in the bone marrow, but that there are more mast cells than expected in these biopsies.

Excessive production of mast cells in an organ that is not the skin is the defining feature of systemic mastocytosis.  SM patients show some combination of the following characteristics: infiltration of tissue with mast cells clustered together; expression of receptors CD25 and/or CD2 on the mast cells; spindle shaped mast cells; presence of the CKIT D816V mutation; and  baseline tryptase over 20 ng/ml.  When a patient shows too many mast cells without having any of these markers, it is not called mastocytosis.  It is called mast cell hyperplasia.

Consider the following two scenarios:

Let’s imagine that you are a house builder.  For many years, you only build houses when people call your boss and say they need a house.  After your boss gets the call, she calls you to tell you to build a house for these people in the location they have requested.  Sometimes more people need houses than others, so at times you make more, and other times, you make less.  You never build houses unless your boss tells you to and you are able to build them correctly due to having the correct time and resources.  You may think that your boss is telling you to build too many houses sometimes but it is always because she is getting lots of requests from customers to build houses.

In this scenario, mast cells are house builders. They only make new mast cells when they receive appropriate signals from the body.  Sometimes your body makes more mast cells, like to fight an infection or when you have an allergic response.  But the mast cells ALWAYS wait for the correct signal from the body to make more cells.  They do not decide to make too many cells on their own.

Now let’s imagine that after years of being a house builder, you wake up one day with a compulsion to see how fast you can build a house.  Your boss calls you and says she needs one house, so you build that house and then you build four more at the same time.  Instead of building carefully one at a time, you are building five houses at the same time.  This means the houses are not built correctly.  You call your boss to say you are done with the five houses and your boss gets mad.  Where are we going to put these extra four houses?  She decides to move those four houses to another town that doesn’t have too many houses yet.  She tells you not to make too many houses again.

But you just cannot stop making houses.  Making houses is the best!  Who cares if there are little mistakes?  People can still live in them safely.  You wake up every day with a fervent need to build houses.  Your friends and family are concerned about you and stage an intervention.  You will not be moved.  You are building tons of houses at once now.  Your boss is calling you screaming at you to stop making houses because they are defective and she doesn’t have anywhere to put them.  She has been sending them to places that already have too many houses so it is getting really crowded and people are complaining.  You stop answering your boss’s calls.  These people don’t understand the importance of building houses.  No matter what anyone says to you, you will not stop making houses and they cannot make you stop.

In this scenario, the problem isn’t that the boss is telling the builder to make too many houses.  The problem here is that the builder is ignoring all the signals to stop.  This scenario represents systemic mastocytosis.  The mast cells here are making too many mast cells for the wrong reasons and they don’t work right.

I want to be very clear about something – the fact that a person has a lot of mast cells per hpf but doesn’t have markers for SM does NOT mean that these people are not suffering.  Regardless of how the mast cells ended up there in excessive populations, they will cause large scale inflammation and GI symptoms.  Nor am I saying that phenomena like mastocytosis enterocolitis or allergic mastocytic enterocolitis are definitely not mast cell diseases – it is possible that the mast cells in those cases demonstrate markers we have not yet found or that there is an error in the cells that become mast cells.  I am just describing the way these two categories are distinguished from one another at this time.  It is not my intention to disenfranchise anyone.  We are all united in the suckage that is GI symptoms as a result of mast cells.

How do you tell the difference between systemic mastocytosis and mast cell hyperplasia?  That is the purpose of the SM diagnostic criteria.  As I said before, you need to meet one major and one minor criterion, or three minor criteria, from the WHO Systemic mastocytosis criteria.  If you meet some of the criteria, but not enough for SM, that is still evidence of a clonal, proliferative mast cell disease.  This means that it is still evident that too many mast cells are being made despite signals to stop.  The state of meeting some criteria for SM but not enough for an SM diagnosis is called monoclonal mast cell activation syndrome (MMAS). This topic will be covered in detail in a later post in this series.

Many diseases involve mast cells, including various cancers and autoimmune diseases, among others. So why aren’t they considered mast cell diseases like systemic mastocytosis and mast cell activation syndrome? These are not mast cell diseases because in these situations, mast cells are getting signals to make too many mast cells and to cause inflammation.  They are the house builder when the boss is telling them to make more houses than usual, but the boss is doing that because customers need those houses.  Mast cell diseases are the house builder that has a compulsion to build houses even when they aren’t needed and everyone is telling them to stop.

Remember this distinction when you are reviewing papers and pathology reports.  The word mastocytosis is often used when they really mean mast cell hyperplasia.  Mastocytosis in proper usage means too many mast cells because the mast cells are defective.  Mast cell hyperplasia means too many mast cells because the mast cells are receiving inflammatory signals from elsewhere.

Mast cells in the GI tract: How many is too many? (Part One)

Let’s have a chat about the idea that 20 mast cells/hpf (high powered field) in gastrointestinal biopsy is higher than normal.

First, let’s review a few things.

The WHO diagnostic criteria for systemic mastocytosis are as follows:

Table 1: World Health Organization Criteria for Systemic Mastocytosis (2008)
  • Systemic mastocytosis is diagnosed in the presence of: 1 major and 1 minor criterion; or 3 minor criteria.
  • Biopsy specimens can be from any non-cutaneous organ (any organ that is not the skin).
Major criterion:
Multifocal, dense aggregates of mast cells (15 or more) detected in sections of bone marrow and confirmed by tryptase immunohistochemistry or other special stains:
Minor criterion:
1.       In biopsy section, more than 25% of mast cells in the infiltrate have atypical morphology, or, of all the mast cells in the smear, more than 25% are immature or atypical. (25% of the mast cells are shaped wrong.)
2.       Mast cells co-express CD117 with CD25 and/or CD2. (Mast cells show markers CD25 or CD2 on their outsides.)
3.       Detection of KIT point mutation at codon 816 in bone marrow, blood or other extracutaneous organs. (Positive for the CKIT D816V mutation.)
4.       Serum total tryptase persistently >20 ng/ml (not a valid criteria in cases of systemic mastocytosis with associated clonal non-hematologic mast-cell lineage disease). (Baseline serum tryptase over 20 ng/ml – baseline, not reaction.)

 

There are several different diagnostic algorithms floating around for mast cell activation syndrome (MCAS).  They are summarized here:

Table 2: Diagnostic algorithms for  mast cell activation syndrome (MCAS, also called mast cell activation disorder, MCAD)
  • Biopsy specimens can be from any non-cutaneous organ (any organ that is not the skin).
Molderings, Afrin 2011 Akin, Valent, Metcalfe 2010 Valent, Akin, Castells, Escribano, Metcalfe et al 2012
MCAD (mast cell activation disease, an  umbrella term including both MCAS and SM) is diagnosed if both major criteria, or one major criterion and one minor criterion, are present; following bone marrow biopsy, diagnosis is narrowed down to either SM or MCAS MCAS diagnosed if all criteria are met MCAS diagnosed if all criteria are met
Major Criteria
Multifocal of disseminated dense infiltrates of mast cells in bone marrow biopsies and/or in sections of other extracutaneous organ(s) (GI tract biopsies; CD117-, tryptase- and CD25- stained) Episodic symptoms consistent with mast cell mediator release affecting ≥2 organ systems evidenced as follows:

  • Skin: urticaria, angioedema, flushing
  • Gastrointestinal: nausea, vomiting, diarrhea, abdominal cramping
  • Cardiovascular: hypotensive syncope or near syncope, tachycardia
  • Respiratory: wheezing
  • Naso-ocular: conjunctival injection, pruritus, nasal stuffiness
Typical clinical symptoms
Unique constellation of clinical complaints as a result of a pathologically increased mast cell activity (mast cell mediator release symptom) A decrease in the frequency or severity or resolution of symptoms with antimediator therapy: H1– and H2-histamine receptor inverse agonists, antileukotriene medications (cysteinyl leukotriene receptor blockers or 5-lipoxygenase inhibitor), or mast cell stabilizers (cromolyn sodium) Increase in serum total tryptase by at least 20% above baseline plus 2 ng/ml during or within 4 h after a symptomatic period
  Evidence of an increase in a validated urinary or serum marker of mast cell activation: documentation of an increase of the marker to greater than the patient’s baseline value during a symptomatic period on ≥2 occasions or, if baseline tryptase levels are persistently >15 ng, documentation of an increase of the tryptase level above baseline value on 1 occasion. Total serum tryptase level is recommended as the marker of choice; less specific (also from basophils) are 24-hour urine histamine metabolites or PGD2 or its metabolite 11-β-prostaglandin F2. Response of clinical symptoms to histamine receptor blockers or MC-targeting agents e.g. cromolyn
  Rule out primary and secondary causes of mast cell activation and well-defined clinical idiopathic entities
Minor Criteria
Mast cells in bone marrow or other extracutaneous organ(s) show an abnormal morphology (>25%) in bone marrow smears or in histologies
Mast cells in bone marrow express CD2 and/or CD25
Detection of genetic changes in mast cells from blood, bone marrow or extracutaneous organs for which an impact on the state of activity of affected mast cells in terms of an increased activity has been proved
Evidence of a pathologically increased release of mast cell mediators by determination of the content of:

  • Tryptase in blood
  • N-methylhistamine in urine
  • Heparin in blood
  • Chromogranin A in blood
  • Other mast cell specific mediators (leukotrienes, PGD2)

 

Additionally, a questionnaire (found here: http://www.wjgnet.com/2218-6204/abstract/v3/i1/1.htm) designed to assess the likelihood of mast cell activation disease (MCAS or SM) in a patient was published in 2014 by Lawrence Afrin.  It assigns numerical values to various findings, such as mediator elevation, symptoms, clinical findings, and biopsy features.

The criteria for systemic mastocytosis can be met with a gastrointestinal biopsy showing the features listed above in Table 1.  So if you have gastrointestinal scopes and your biopsy shows mast cells with the features listed in Table 1, then that contributes to receiving a diagnosis of SM.  If you meet some of the criteria but not all of them, with a GI biopsy or otherwise, then you receive a diagnosis of monoclonal mast cell activation syndrome (MMAS), which is like a pre-SM.

A common adage in the mast cell community is that having 20 or more mast cells in a high powered field (hpf, what you see when you look through a microscope with high magnification) is diagnostic for mast cell activation syndrome.

In 2006, a paper was published called “Mastocytic enterocolitis: Increased mucosal mast cells in chronic intractable diarrhea.” This paper detailed a study that quantified the mast cells in biopsies of duodenum (small intestine) and colon in patients with chronic diarrhea that resisted treatment. These counts were then compared to patients who had other conditions that caused chronic diarrhea, and to some control subjects that had no GI symptoms.

Table 3: Average mast cell count per hpf in colon and duodenum (Jakate 2006)
Group Average mast cell count in colon and duodenum
Healthy control group 13.3 ± 3.5
Inflammatory GI disease control group 12.4 ± 2.3
Intractible chronic diarrhea group 25.7 ± 4.5

 

The average mast cell count in the healthy control group was 13.3/hpf.  (See Table 3 for details.) Two standard deviations from this value is approximately 20/hpf.  Two standard deviations (SD) is a statistical mechanism that allows for variation in the patient, sample or test procedure.  It is common to round to an even number.

The patients in this group were not evaluated for typical mast cell symptoms.  No information is provided regarding history of allergic or atopic disease. This paper is the origin of the idea that more than 20 mast cells/hpf in the gastrointestinal tract is considered higher than normal.

 

References:

Jakate S, et al. Mastocytic enterocolitis: Increased mucosal mast cells in chronic intractable diarrhea.  Arch Pathol Lab Med 2006; 130 (3): 362-367.

Akhavein AM, et al. Allergic mastocytic gastroenteritis and colitis: An unexplained etiology in chronic abdominal pain and gastrointestinal dysmotility. Gastroenterology Research and Practice (2012): Article ID 950582.

Martinez C, et al. Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier. Gut 2013; 62: 1160-1168,

Sethi A, et al. Performing colonic mast cell counts in patients with chronic diarrhea of unknown etiology has limited diagnostic use. Arch Pathol Lab Med 2015; 139 (2): 225-232.

Doyle LA, et al. A clinicopathologic study of 24 cases of systemic mastocytosis involving the gastrointestinal tract and assessment of mucosal mast cell density in irritable bowel syndrome and asymptomatic patients. Am J Surg Pathol 2014; 38 (6): 832-843.

Ramsay DB, et al. Mast cells in gastrointestinal disease. Gastroenterology & Hepatology 2010; 6 (12): 772-777.

Zare-Mirzaie A, et al. Analysis of colonic mucosa mast cell count in patients with chronic diarrhea. Saudi J Gatroenterol 2012; 18 (5): 322-326.

Walker MM, et al. Duodenal mastocytosis, eosinophilia and intraepithelial lymphocytosis as possible disease markers in the irritable bowel syndrome and functional dyspepsia. Aliment Pharmacol Ther 2009; 29 (7): 765-773.

Hahn HP, Hornick JL. Immunoreactivity for CD25 in Gastrointestinal Mucosal Mast Cells is Specific for Systemic Mastocytosis. American Journal of Surgical Pathology 2007; 31(11): 1669-1676.

Vivinus-Nebot M, et al. Functional bowel symptoms in quiescent inflammatory bowel diseases : role of epithelial barrier disruption and low-grade inflammation. Gut 2014; 63: 744-752.

Minnei F, et al. Chronic urticaria is associated with mast cell infiltration in the gastroduodenal mucosa. Virchows Arch 2006; 448(3): 262-8.

Hamilton MJ, et al. Mast cell activation syndrome: A newly recognized disorder with systemic clinical manifestations. J Allergy Clin Immunol 2011; 128: 147-152.

Barbara G, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 2004; 126(3): 693-702.

Guilarte M, et al. Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum. Gut 2007; 56: 203-209.

Dunlop SP, et al.  Age related decline in rectal mucosal lymphocytes and mast cells. European Journal of Gastroenterology and Hepatology 2004; 16(10): 1011-1015.

Afrin LB, Molderings GJ. A concise, practical guide to diagnostic assessment for mast cell activation disease. World J Hematol 2014; 3 (1): 1-17.

Molderings GJ, et al. Mast cell activation disease: a concise, practical guide to diagnostic workup and therapeutic options. J Hematol Oncol 2011; 4 (10).

Akin C, et al. Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol 2010; 126 (6): 1099-1104.

Valent P, et al. Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol 2012: 157 (3): 215-225.

 

 

 

Housekeeping: Revising posts and MCAS month

In February of this year, I decided to post a fact about mast cell disease every day for Rare Diseases Month.  I honestly had no idea how much attention that would generate.  People asked if I had a blog, so I decided to start one.  I started posting on April 26 of this year.  Since then, this blog has had over 21,000 page views, about 1,000 a week, and has been read in over 50 countries.  I am really humbled that so many people find this helpful. 

When I started the blog, I transferred over all the posts I had done for Rare Diseases Month. These posts are very short, and comprise the posts on this blog dated before April 26.  I have noticed recently that some of those are being read frequently now, so I am going to go back and revise them to reflect the style of my later posts.  Once I do, these posts will be republished.  These include the Mixed Organic Brain post, symptoms posts, and a bunch of others.

Most of the posts I have done have been on mastocytosis, which is more well studied and documented.  But I don’t want the MCAS and MMAS kids to feel left out, which is why for the month of October, I will be doing daily posts about mast cell activation syndrome, with additional posts on monoclonal mast cell activation syndrome.  

As always, please feel free to email me at Lisa.Klimas@gmail.com if you have questions you would prefer to ask privately. Thanks so much for reading.  

In which I answer your questions (part 1)

One of the things I like about this blog is that it shows me what search terms people use that lead them to finding this blog.  So since I’m going to answer some email questions this week, I figured I’d address some of the topics people search for as well.

“Bone marrow biopsy and mcas”

This is a big one.  Mast cell patients generally get bone marrow biopsies when SM is suspected.  Most of the time, for MCAS patients, the biopsy comes back normal, which rules out SM.  However, occasionally, it comes back with some findings but not enough for an SM diagnosis.  So what do you have then?
Generally speaking, you have MMAS (monoclonal mast cell activation syndrome.)  These patients have bone marrow biopsies that are negative for dense infiltrates, but positive for CD25 receptor expression and/or the D816V CKIT mutation. 
I know of two instances in which patients had bone marrow biopsies that were positive for dense infiltrates but they had normal tryptases, normal receptor expression, no D816V mutation, and no spindled mast cells.  So what do you have then?  Beats me.  Of these two patients, one has a diagnosis of MCAS and the other has a diagnosis of MMAS. (And if we’re being picky, neither of them have known systemic reactions to bee stings.)  My guess is that if they had repeat biopsies, they would eventually find spindled cells and CD2/CD25 expression.  I think they are both probably very early in their diseases and we just caught it while it was developing.  

“Bone pain aggressive mastocytosis”
Aggressive systemic mastocytosis is defined as systemic mastocytosis with at least one C finding: low blood cell count; impaired liver function; free fluid in the abdomen; high pressure in the vessels connecting the liver and digestive organs; large osteolytic lesions and/or pathological fractures; impaired splenic function; malabsorption with weight loss; low serum albumin. 
Mast cells are involved in bone loss and osteolysis and/or fractures causes by osteolysis are not uncommon in ASM.  Mast cells release factors associated with bone resorption, bone formation and bone remodeling.  Having more mast cells speeds up these processes. 
Conventional wisdom has long held that bone pain in mastocytosis patients came from inside the bone, where too many mast cells inhabited the marrow.  However, consistent reports of bone pain from patients with non-proliferative disease (MCAS) indicate that this may not be true.  In particular, histamine is known to be irritating to osteocytes (bone cells) and may be causing pain from outside the bones. 

“Effects of systemic mast cell disease”
This is more loaded than the other topics because it is so wide reaching.  Regarding symptoms, it can cause low blood pressure, rapid heart beat, flushing, rashes, hives, itching, abdominal pain, nausea, vomiting, diarrhea (or constipation), numbness, tingling, headaches, sinus pain, swelling, coughing, difficulty breathing and more.  Regarding long term damage, mast cell disease can cause organ damage due both to mast cell infiltration and the effects of anaphylaxis and mast cell mediators.  Regarding lifestyle and such, mast cell disease can restrict your activities, your ability to work and affect your relationships with others.  I have dozens of entries in this blog regarding these topics; if you have specific questions, please let me know.

“How to activate mast cells”
If you have mast cell disease, unfortunately, activating mast cells is not hard.  Common triggers include sunlight, heat, pressure, exercise.  stress.  Common food triggers include soy, alcohol, vinegar, tomatoes, and like a million other things.  I use the low histamine diet described by the Canadian Mastocytosis Society and have found it to be pretty accurate for me.  That said, everyone is different and triggers are super individual.  I just blew my nose too hard and started degranulating.  Activating mast cells is not so hard.

“Mast cell activation disorder prognosis”
Every reliable source reports that patients with mast cell activation disorder have normal life expectancies.  The data looks good to me.  If you think I’m a reliable source, that’s also what I’m reporting. 

“Mast cell and high heart rate”
Tachycardia (heartbeat over 110 bpm) is a common symptom for mast cell patients.  When mast cells degranulate, the histamine released causes blood vessels to leak fluid into the tissues and out of the blood stream.  This lowers the blood pressure.   The body responds with “reflex tachycardia.”  This means that your heart starts beating faster in response to the drop in blood pressure.
Many mast cell patients also have POTS, which causes tachycardia when moving to a standing position.  My POTS is managed effectively with fluid infusions and a conscious effort to not stand up quickly.
I have a PICC line and about a month after I had it placed, I started having really bad tachycardia at night.  I mentioned it to my infusion nurse who told me that this can be a sign that the end of the PICC line is too close to a heart valve, which can increase heart rate in response.  She pulled my line out about a centimeter and the problem went away.  Not exactly mast cell disease related but I know a lot of us have central lines so I figured it was worth mentioning.