The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 55

69. What routine monitoring should mast cell patients receive?

There are not yet routine testing recommendations for MCAS patients, but there are some for mastocytosis patients. Many doctors use the mastocytosis recommendations to monitor their MCAS patients in the absence of specific MCAS guidelines.

Mastocytosis patients should monitor tryptase level annually. In mastocytosis patients, tryptase level is often a good marker for how many mast cells are in the body (although this is not always true.) If a patient’s tryptase is increasing over time, the provider will need to check other things to see if their disease is moving to a more serious disease category.

DEXA scans measure bone density. Osteoporosis is a common complication of systemic mastocytosis. Patients should receive regular osteoporosis screening, even if they are young.

Mastocytosis patients usually receive routine bloodwork annually that includes a complete blood count (CBC), which counts the amount of blood cells a person has; and a metabolic panel, which looks at how well the liver and kidneys are working.

Repeat biopsies are usually only done if the result will change treatment in some way. Most patients with systemic mastocytosis are diagnosed based upon bone marrow biopsies. These don’t usually need to be repeated unless tryptase level increases sharply or there are unusual results in routine blood count testing. Increasing tryptase can indicate that the body is making more mast cells much faster, which is sometimes linked to a more serious disease category. Unusual blood cell counts can indicate not just too many abnormal mast cells, but also other bone marrow conditions sometimes seen in mast cell patients, like myelofibrosis and essential thrombocythemia.

Patients with cutaneous mastocytosis are diagnosed by skin biopsy. There is not usually a need to repeat a skin biopsy for patients with CM.

Patients with systemic mastocytosis are usually diagnosed by bone marrow biopsy but can also be diagnosed as a result of a positive biopsy in any organ that is not the skin. A person can be diagnosed with SM via a GI biopsy.

GI biopsies are a little different than bone marrow biopsies in that there are sometimes reasons to repeat them. GI biopsies may be repeated to see if the general inflammation in the GI tract is improved or worsened. The provider may also be interested in whether or not the amount of mast cells in the GI tract has decreased. The result of GI biopsies often change treatment options so it is not unusual to repeat them. However, unlike bone marrow biopsies, repeated GI biopsies do not tell the provider if the mastocytosis is moving toward a more serious disease category or not.

MCAS patients are diagnosed based upon positive tests for molecules that indicate mast cells are overly active, like n-methylhistamine, and D2- or 9a,11b-F2 prostaglandins. Once the patient is diagnosed, there’s not a clear rationale for repeating these tests, although some providers do for their own information. Some providers like to check prostaglandin levels to see if treatment to stop mast cells from making prostaglandins (like use of aspirin or other NSAIDs) is helping.

However, it is important to understand that the level of mast cell mediators is not associated with symptoms. A person who has a normal level of 9a,11b-F2 prostaglandin may have the same symptoms as a person above the normal level, who may have the same symptoms as a person who has three times the normal level. For this reason, many providers consider these mediator tests to be less about the numerical value of the test and more about whether it’s normal or high, period.

For more detailed reading, please visit the following post:
The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 5
The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 6
The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 7
The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 8
The Provider Primer Series: Diagnostic criteria of systemic mastocytosis and all sub variants
The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)
The Provider Primer Series: Mediator testing
The Provider Primer Series: Mast cell activation syndrome (MCAS)

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 37

44. What is a myeloproliferative neoplasm? Is that what mast cell disease is?

First, let’s pull this term apart.

“Myelo” means marrow, like bone marrow. In this context, it refers to a specific group of blood cells that are made in the bone marrow. These cells are called myeloid or myelogenous cells. These cells all start as one kind of cell called a myeloid progenitor cell. Mast cells and eosinophils are myeloid cells. There are other myeloid cells, too.

“Proliferative” means making lots of cells quickly. In this case, it means making many cells too quickly. When too many cells are made too quickly, the cells are often not made correctly so they don’t work right.

“Myeloproliferative” means making too many myeloid cells very quickly, producing cells that often don’t work right.

“Neo” means new.

“Plasm” means the substance that makes up something living, like what makes up a cell or a tissue. “Plasm” is part of many words used in biology.

“Neoplasm” means the body growing new things, things that don’t belong there. For example, cancers are neoplasms. (Although not all neoplasms are cancers).

Myeloproliferative neoplasm means your body making too many myeloid cells that don’t work correctly.

Speaking generally, any condition where the body makes too many of these myeloid cells when they shouldn’t is a myeloproliferative neoplasm. This means all form of mastocytosis and mast cell tumors (mast cell sarcoma and mastocytoma) are myeloproliferative neoplasms.

However, when people ask if mast cell diseases are myeloproliferative neoplasms, they are usually asking about the WHO (World Health Organization) classification of mast cell disease, which is a little different.

The WHO puts out an exhaustive list of diseases for reference. They group similar diseases together under one category. This list is also revised periodically as new data becomes available or experts request it.

Under the 2008 WHO guidelines, mast cell diseases were classified as myeloproliferative neoplasms along with several other diseases. The other diseases also included in this category make too many myeloid cells too quickly, like essential thrombocythemia, in which the body makes too many platelets.

The mast cell diseases classified as myeloproliferative neoplasms were cutaneous mastocytosis: maculopapular cutaneous mastocytosis (MPCM), diffuse cutaneous mastocytosis (DCM), and solitary mastocytoma of the skin; systemic mastocytosis: indolent systemic mastocytosis (ISM), systemic mastocytosis with associated hematologic disease (SM-AHD), aggressive systemic mastocytosis (ASM), and mast cell leukemia (MCL); and mast cell sarcoma. Smoldering systemic mastocytosis (SSM) was mentioned as a provisional category rather than a formal category, meaning that the WHO did not agree that this diagnosis was different enough from ISM to warrant its own category. Neither monoclonal mast cell activation syndrome (MMAS) or mast cell activation syndrome (MCAS) were classified anywhere in the 2008 WHO Guidelines as they were not yet recognized by the WHO as diseases.

Last year, the WHO revised the classification of myeloproliferative neoplasms. It removed all forms of mast cell disease from the myeloproliferative neoplasm category and made a different category for mast cell diseases. This was done because the WHO recognized that mast cell diseases differed from the other myeloproliferative neoplasms in specific ways. They also recognized that mast cell activation syndrome has a ton in common with other mast cell diseases even though it’s not a neoplastic disease. (Mast cell activation syndrome is not from the body making too many mast cells).

So all mast cell diseases were put together. In the new category, the following mast cell diseases were included: cutaneous mastocytosis: maculopapular cutaneous mastocytosis (MPCM), diffuse cutaneous mastocytosis (DCM), and solitary mastocytoma of the skin; systemic mastocytosis: indolent systemic mastocytosis (ISM), systemic mastocytosis with associated clonal hematologic non-mast cell lineage disease (SM-AHNMD), aggressive systemic mastocytosis (ASM), and mast cell leukemia (MCL); mast cell sarcoma; monoclonal mast cell activation syndrome (MMAS); and mast cell activation syndrome (MCAS).

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 34

41. Can my mast cell disease go away? Will it ever not be a problem?

There are several common questions that basically all distill down to these sentiments. I’m going to answer them all here.

I have previously answered the question “Can mast cell disease be cured?” in this series but I think this question is a little different. When people ask if mast cell disease can go away, they mean can it become no longer a problem even if it’s not cured. That’s what I’m answering here.

This answer is very complicated so I’m just going to give my thoughts let’s about all sides of this situation.

Yes, it is possible for mast cell disease to be controlled enough to no longer be a problem in your life. But there are a lot of caveats.

The most common presentation of mast cell disease in cutaneous mastocytosis (mastocytosis in the skin) in children. In about 2/3 of cases, children “grow out of” their mast cell disease. Specifically, this means that they lose their skin lesions and have no obvious mast cell symptoms by their late teenage/early adult years. We don’t know why this happens.

However, there are instances where a person who grew out of their childhood CM have mast cell issues later in life. We have a greater understanding of mast cell diseases now and we know that you can have a whole host of mast cell issues without having skin lesions. So it’s not as clean cut as was previously thought.

For more serious forms of systemic mastocytosis, it is possible that with treatment, the disease can be “knocked down” to a less serious category. For example, a patient with aggressive systemic mastocytosis who does chemo may find that it helped enough that their diagnosis is now smoldering systemic mastocytosis. Or a patient with SSM has a big drop in the number of mast cells zooming around after taking interferon and now they have indolent systemic mastocytosis. While symptom severity doesn’t necessarily change when a patient has a less serious diagnosis, that does sometimes happen.

With the exception of childhood cutaneous mastocytosis, all other forms of mastocytosis are considered lifelong ventures. This includes all forms of adult onset cutaneous mastocytosis and all forms of systemic mastocytosis for children or adults. However, there are instances of patients with SM where bone marrow transplant seems to cure their disease. We need to continue to follow mast cell patients who have had bone marrow transplants to see how many of them have recurrence of mast cell disease.

Mast cell activation syndrome is often secondary to some other condition. Basically, one disease irritates your body so much that your mast cells flip out in response to the disease. The disease that caused the mast cell problem is called the primary condition. In these instances, mast cell activation syndrome is sometimes considered to be dependent upon the primary condition. This means that some doctors and researchers feel that if you control the primary condition, the mast cell activation syndrome will go away.

This sentiment seems straightforward but is actually pretty complex. Let’s pull it apart. Let’s say your primary condition is lupus. You are a patient with lupus. The lupus irritates your body so much that your mast cells just go bananas. Now you are a patient with lupus who has secondary MCAS. The lupus in this instance caused the MCAS. But what does that mean? Does that mean that without the lupus, you would never have had MCAS? Or does it mean that you would eventually have had MCAS secondary to something else? This is the topic of a lot of debate. (I personally am of the belief that MCAS is genetic and therefore you were always going to develop it at some point.) So it’s not clear yet whether a primary condition really “causes” MCAS or just wakes it up.

However, what is not disputed at all is that any type of inflammation can trigger mast cell activation and symptoms. So if you are a lupus patient, and your lupus is going crazy, that’s going to really bug your mast cells. If you are able to control your lupus, it will decrease the inflammation, which will calm your mast cells. But calming your mast cells isn’t really the same thing as your mast cell disease going away. Not having symptoms is not the same thing as being cured.

Another thing to consider is that even if the lupus is what triggered your MCAS, once your MCAS is triggered, it’s going to be triggered by everything. You can very easy get locked into a cycle where the lupus irritates your MCAS, which irritates your lupus, and around you go. So in a situation like this, where the mast cell activation is really out of control, it sometimes doesn’t matter what the primary condition is, and controlling the primary condition might not help.

Many patients with mast cell disease have their symptoms controlled enough to live pretty normal lives. Some mast cell patients don’t have really symptoms at all, even without medications. In a small group of MCAS patients, after a year of treatment with antihistamines and mast cell stabilizers, about 1/3 had complete resolution of symptoms and another 1/3 had one only symptom that was a problem. 

However, it’s important to remember that this is not having debilitating symptoms is not the same as not having mast cell disease. These patients are still predisposed towards mast cell activation and should take mast cell precautions for things like surgery or dental work. Many patients stay on antihistamines and/or a mast cell stabilizer even with good symptom control because it affords some protection from bad reactions and anaphylaxis. Patients should only stop regular medication with the supervision and direction of a provider who knows them. Additionally, trialing things like foods you reacted to, or starting an exercise program, require provider input.

You should also keep in mind that mast cell disease can be very erratic. It doesn’t always follow a trend so symptoms steadily improving does not guarantee that symptoms will stay well controlled. So while mast cell disease can be managed enough to not be a problem, there is always the possibility that it will show up again. Once you have a mast cell diagnosis, you are always going to be looking over your shoulder.

 

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 33

40. What is mastocytosis of childhood? Is mast cell disease different for children than adults?

Cutaneous mastocytosis in children is the most common form of mastocytosis. True systemic mastocytosis, in which the WHO criteria are met, is very rare in children.

In many ways, mastocytosis in children has huge differences from mastocytosis in adults. The exact reason for this is unclear. Because of how different the disease path can be for children, doctors and researchers sometimes refer it as mastocytosis of childhood. However, there is not officially a distinct diagnostic category.

Unlike in adults, mastocytosis in children is sometimes both benign and transient. Many kids have symptoms that either stay the same or improve as they get older. Many kids grow out of their mastocytosis. About 2/3 of children with cutaneous mastocytosis have no evidence of disease (no skin lesions or symptoms) by their late teen years or early adulthood. Many other children have improvement of symptoms and signs without completing growing out of their condition.

Children with mastocytosis often have some unusual things in their bone marrow biopsies. They often have clusters of mast cells and eosinophils with other cells in their bone marrow. However, the mast cells in those clusters are often normal mast cells and do not have the same markers we see in adults. Many of these children have more mast cells in their bone marrow biopsies than adults with mastocytosis. However, unless the biopsy shows true SM, it does not affect prognosis for the children. Children may have unusual things in their bone marrow biopsies but still go on to grow out of it.

The exception is if the child has true SM. Children with true SM do not grow out of their disease.

Children with mastocytosis often have symptoms that affect multiple organ systems, not just their skin. Abdominal pain and bone pain are often reported. Systemic symptoms do not tell us whether or not the child has SM or whether or not they will grow out of their disease.

An NIH study that included 105 children with mastocytosis found that children with normal baseline tryptase tests had negative bone marrow biopsies. It also found that a tryptase level elevated after anaphylaxis or a bad reaction did not signify that the child had SM. However, they did find that all children with SM had internal organ swelling. Most children with SM were positive for the CKIT D816V mutation.

There are no studies yet on the differences between adults and children with MCAS. There are enough anecdotal findings to suggest that children with MCAS do not grow out of their disease the way children with CM sometimes do.

For more detailed reading, please visit these posts:

Childhood mastocytosis: Update

Progression of mast cell diseases (Part 5)

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 30

38. What is the difference between the forms of cutaneous mastocytosis?

Cutaneous mastocytosis is a form of mast cell disease in which way too many mast cells are found only in the skin and not in other organs. Over 80% of patients with mastocytosis have mastocytosis in their skin.

Patients who have systemic mastocytosis have too many mast cells in organs that are not in the skin. However, many of them also have too many mast cells in their skin. These patients are said to have “systemic mastocytosis with mastocytosis in the skin (MIS).” This terminology distinguishes these patients from those who only have too many mast cells in the skin.

There are three categories of cutaneous mastocytosis:

Maculopapular cutaneous mastocytosis (MPCM):
Previously called urticaria pigmentosa (UP). Many patients and providers still use the term UP and the term MPCM is more commonly found in research work.
This is the most common form of cutaneous mastocytosis.
UP causes lesions on the skin, often called “spots” or “masto spots”. In adults, these spots are usually little red/brown lesions. Sometimes a small amount of skin is affected. Other times, a lot of the skin becomes covered in spots.
In adults, UP spots are usually permanent. Some people who need chemo find that the chemo makes some of their UP spots disappear.
In children, UP spots are often larger. The shape and number of spots may change as they get older.
In children, UP spots sometimes resolve over time and disappear.
There is a type of UP called telangiectasia macularis eruptiva perstans (TMEP). This used to be a separate diagnosis from UP but we now know that it is just a kind of UP that looks different from the common red/brown spots.
In TMEP, little blood vessels growth very close to the skin and look like little red or brown spots.

Diffuse cutaneous mastocytosis (DCM):
DCM almost exclusively starts in childhood.
DCM does not cause spots. Instead, it causes overall redness and thickening of skin. It can also cause blistering. The blisters and wounds sometimes bleed.

Solitary cutaneous mastocytoma:
The third form of cutaneous mastocytosis is a little misleading in classification. This form is called solitary cutaneous mastocytoma.                                                                      This is a benign mast cell tumor that grows on the skin.                                         Mastocytomas can grow elsewhere in the body. When they do, they are not considered a form of cutaneous mastocytosis.
While the term is “solitary cutaneous mastocytoma”, some people do have multiple mastocytomas on their skin.

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)

The Provider Primer Series: Relevance of mast cells in common health scenarios

 

Symptom Cough
Role of mast cells Several mast cell mediators contribute to airway inflammation and subsequent symptoms including cough:

•             Histamine promotes bronchoconstriction, excessive production of mucus, and airway edema.[i]

•             Prostaglandin D2 promotes bronchoconstriction, mucus production, and airway edema.[i]

•             Leukotrienes C4 and D4 and chymase also contribute to mucus production and airway edema.[i]

•             Tryptase promotes overall increased reactivity of the airway.[i]

Chronic airway inflammation, as in asthma, is sometimes associated with increased mast cell population in pulmonary tissues.[i]

Mast cells remain activated in inflamed airways.[i]

Impact of condition on mast cells Mast cell activation can occur as a result of the physical stimuli such as coughing[ii].

Pain can trigger mast cell activation[iii].

Notes regarding condition treatment Dextromethorphan can trigger mast cell degranulation[iv].

Codeine and derivatives can trigger mast cell degranulation[v].

Beta-2 adrenergic agonists, inhaled and oral steroids, and inhaled cromolyn are frequently used in mast cell patients[vi].

Notes regarding mast cell treatment Antihistamines, leukotriene receptor antagonists, and COX inhibitors are routinely taken by mast cell patients and can provide relief.[vii]

Racemic epinephrine can provide relief of pulmonary symptoms.[viii]

Special considerations for mast cell patients Chronic dry, unproductive cough sometimes occurs in mast cell patients.[ix]

Mast cell patients frequently have reactive airways.[ix]

Mast cells can produce and release prostaglandin E2, a mediator that participates in asthmatic inflammation and cough[x].

Prostaglandin E2 can also downregulate or promote mast cell degranulation via binding at prostaglandin E2 receptors on mast cell surface[x].

 

Symptom Sore throat
Role of mast cells Pain can trigger mast cell activation.[iii]
Impact of condition on mast cells Mast cell driven nasal congestion can result in postnasal drip can irritate the throat.[ix]

Mast cell irritation of the throat can present similarly to infection by Streptococcus spp. or other pathogen. Cultures should be taken to properly evaluate for infection.[ix]

Viral, bacterial and fungal infection will activate mast cells through toll like receptors and through perpetuated inflammatory signaling.[xiii]

Notes regarding condition treatment Acetaminophen is recommended for pain relief in mast cell patients.[iv]
Notes regarding mast cell treatment Antihistamines and COX inhibitors are routinely taken by mast cell patients and can provide relief.[vi]
Special considerations for mast cell patients Angioedema of the throat driven by mast cell disease is always a consideration in mast cell patients. If angioedema secondary to mast cell disease impinges upon airway, epinephrine and subsequent anaphylaxis treatments should be undertaken.[vii]

Oral allergy syndrome should be considered.[ix]

 

Symptom Rash
Role of mast cells Acute urticaria is usually driven by mast cell and basophil activation through IgE or non-IgE pathways.[xi]

Mast cell mediators histamine, leukotrienes and platelet activating factor contribute to itching.[xii]

Impact of condition on mast cells Viral, bacterial and fungal infection will activate mast cells via toll like receptors and perpetuated inflammatory signaling.[xiii]

Non-mast cell driven conditions causing skin rashes can irritate mast cells in the skin.[xii]

Pain can trigger mast cell activation.[iii]

Notes regarding condition treatment Some -azole antifungals can induce mast cell degranulation.[xiv]
Notes regarding mast cell treatment Antihistamines and steroids, topical or systemic, and topical cromolyn can provide relief.[xii]
Special considerations for mast cell patients Mediator release by activated mast cells can produce systemic symptoms.[x]

In patients with a history of mast cell disease, mastocytosis in the skin should be considered.

o             Cutaneous mastocytosis accounts for approximately 90% of mastocytosis cases.[xii]

o             Cutaneous mastocytosis lesions demonstrate Darier’s sign, a wheal and flare reaction to touch.[xii]

o             A skin biopsy is necessary to confirm a diagnosis of cutaneous mastocytosis.[xii]

o             Patients with adult onset cutaneous mast cell lesions are usually later found to have systemic mastocytosis.[xii]

 

Symptom Fever
Role of mast cells Mast cells can produce prostaglandin E2.[x]

Mast cells can produce and release several pyrogens, including IL-1α, IL-1β, IL-6, IL-8, TNF, interferon-α, interferon-β, and interferon-γ.[x]

Impact of condition on mast cells Prostaglandin E2 can also downregulate or promote mast cell degranulation via binding at prostaglandin E2 receptors on mast cell surface.[x]

Pain can trigger mast cell activation.[iii]

Viral, bacterial and fungal infection will activate mast cells via toll like receptors and perpetuated inflammatory signaling.[xiii]

Notes regarding condition treatment NSAIDS can trigger mast cell degranulation. Some mast cell patients are unable to take them.[xv]

Acetaminophen is generally recommended for use in mast cell patients.[iv]

Notes regarding mast cell treatment COX inhibitors are routinely taken by mast cell patients and may provide relief.[vi]
Special considerations for mast cell patients

 

Symptom Earache
Role of mast cells Mast cells are involved in the transmission of pain stimuli, including nerve pain.[iii]

Mast cells are involved in sensorineural hearing loss and tinnitus.[ix]

Impact of condition on mast cells Pain can trigger mast cell activation.[iii]

Viral, bacterial and fungal infection will activate mast cells via toll like receptors and perpetuated inflammatory signaling.[xiii]

Notes regarding condition treatment NSAIDS can trigger mast cell degranulation. Some mast cell patients are unable to take them.[xv]

Acetaminophen is generally recommended for use in mast cell patients.[iv]

Steroids (local and systemic) can stabilize mast cells.[vi]

Notes regarding mast cell treatment COX inhibitors are routinely taken by mast cell patients and may provide relief.[vi]

Antihistamines can provide relief for vestibular symptoms.[vi]

Special considerations for mast cell patients Hearing loss, tinnitus and hyperacusis sometimes occur in mast cell patients.[ix]

Sensorineural hearing loss of unknown origin has been documented in mast cell patients.[ix]

Some mast cell patients also have Ehlers Danlos Syndrome which can cause conductive hearing loss.[ix]

Mast cell disease can also cause auditory processing disorder.[ix]

Red ears are a common sign of mast cell activation. Sometimes, only one ear is affected.[ix]

 

Symptom Stomachache
Role of mast cells Mast cells are commonly found in the GI tract.[xvi]

Mast cell activation is involved in a number of GI conditions, including inflammatory bowel disease, ulcerative colitis and food allergies.[xvi]

Mast cell activation can cause chronic diarrhea, pseudoobstruction, obstruction, dysmotility, constipation, nausea, vomiting, and visceral GI pain.[xvi]

Impact of condition on mast cells GI inflammation can recruit mast cells to inflamed tissues.[xvi]

GI inflammation can trigger mast cell mediator release.[xvi]

Pain can trigger mast cell activation.[iii]

Viral, bacterial and fungal infection will activate mast cells via toll like receptors and perpetuated inflammatory signaling.[xiii]

Notes regarding condition treatment
Notes regarding mast cell treatment Histamine H2 blockers and PPIs are commonly taken by mast cell patients and can provide relief.[vi]
Special considerations for mast cell patients Mast cell patients can experience a wide array of severe GI symptoms with or without dense infiltration of GI tract by mast cells.[ix]

 

[i] Cruse G, Bradding P. (2016). Mast cells in airway diseases and interstitial lung disease. European Journal of Pharmacology 778, 125-138.

[ii] Zhang D, et al. (2012). Mast-cell degranulation induced by physical stimuli involves the activation of transient receptor-potential channel TRPV2. Physiol Res, 61(1):113-124.

[iii] Chatterjea D, Martinov T. (2015). Mast cells: versatile gatekeepers of pain. Mol Immunol, 63(1),38-44.

[iv] Dewachter P, et al. (2014). Perioperative management of patients with mastocytosis. Anesthesiology, 120, 753-759.

[v] Brockow K, Bonadonna P. (2012). Drug allergy in mast cell disease. Curr Opin Allergy Clin Immunol, 12, 354-360.

[vi] Molderings GJ, et al. (2016). Pharmacological treatment options for mast cell activation disease. Naunyn-Schmiedeberg’s Arch Pharmol, 389:671.

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

[viii] Walsh P, et al. (2008). Comparison of nebulized epinephrine to albuterol in bronchiolitis. Acad Emerg Med, 15(4):305-313.

[ix] Afrin LB. (2013). Diagnosis, presentation and management of mast cell activation syndrome. Mast cells.

[x] Theoharides TC, et al. (2012). Mast cells and inflammation. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, 1822(1), 21-33.

[xi] Bernstein JA, et al. (2014). The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol, 133(5):1270-1277.

[xii] Hartmann K, et al. (2016). Cutaneous manifestations in patients with mastocytosis: consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma and Immunology; and the European Academy of Allergology and Clinical Immunology. Journal of Allergy and Clinical Immunology, 137(1):35-45.

[xiii] Sandig H, Bulfone-Paul S. (2012). TLR signaling in mast cells: common and unique features. Front Immunol, 3;185.

[xiv] Toyoguchi T, et al. (2000). Histamine release induced by antimicrobial agents and effects of antimicrobial agents on vancomycin-induced histamine release from rat peritoneal mast cells.  Pharm Pharmacol, 52(3), 327-331.

[xv] Grosman N. (2007). Comparison of the influence of NSAIDs with different COX-selectivity on histamine release from mast cells isolated from naïve and sensitized rats. International Immunopharmacology, 7(4), 532-540.

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

 

The Provider Primer Series: Cutaneous mastocytosis/ Mastocytosis in the skin

Mast cell disease: Categories

  • Mast cell disease is the collective term given to several distinct conditions mediated by mast cell dysfunction.  Speaking broadly, mast cell disease has two forms: mastocytosis, a clonal disease marked by excessive proliferation and infiltration of mast cells; and mast cell activation syndrome (MCAS), a disease that presents similarly to mastocytosis but demonstrates no clear indication of excessive proliferation. In addition, monoclonal mast cell activation syndrome (MMAS) can be viewed as straddling the two groupings with markers of clonality but minimum evidence to suggest overproduction of mast cells[i].
  • Mastocytosis has two forms: cutaneous, in which excessive mast cell infiltration is confined to the skin; and systemic, in which an organ that is not skin that is affected by excessive mast cell infiltration. Patients with systemic mastocytosis (SM) often have cutaneous mastocytosis; in this instance, this is called systemic mastocytosis with mastocytosis in the skin[ii].

Mastocytosis in the skin

  • Cutaneous mastocytosis (CM) is a proliferative condition marked by increased mast cell infiltration of the skin.  There are three subvariants of cutaneous mastocytosis: maculopapular cutaneous mastocytosis (MPCM), formerly known as urticarial pigmentosa (UP); diffuse cutaneous mastocytosis (DCM); and solitary mastocytoma of skin[ii].
  • Mast cell density in lesions is usually increased 4-8x above the density in healthy controls. However, some patients have mast cell density comparable to that in healthy controls[ii].
  • All forms of cutaneous mastocytosis can be found in children. Over 78% present by 13 months and some at birth[v]. Childhood onset CM often resolves by adolescence but not always[ii].
  • Most patients with mast cell lesions in childhood have CM rather than SM. Conversely, most patients who develop these macules in adulthood have systemic mastocytosis with mastocytosis in the skin[ii].
  • MPCM (UP) is overwhelmingly the dominant presentation of mastocytosis in the skin. Over 80% of all mastocytosis patients demonstrate the type of cutaneous involvement[ii].
  • In children, MPCM lesions are usually large and have variable morphology which may change over time. In adults, MPCM often occurs as small red/brown macules and may result in few lesions or cover the majority of the body[iii].
  • Telangiectasia macularis eruptive perstans (TMEP) is described as telangiectatic red macules generally found above the midtrunk. While previously thought to be a discrete entity, TMEP is now recognized as a form of MPCM[ii].
  • DCM is almost exclusively found in children with few adult onset cases. It does not present as discrete lesions but rather generalized erythema. Pachydermia may also be present, as well as darkening of the skin[ii].
  • DCM can be associated with formation of severe bullae from a variety of triggers, including rubbing the skin, infections and teething. Due to mast cell release of heparin, it is not unusual for skin wounds to bleed excessively[ii].
  • A mastocytoma is a low grade mast cell tumor most often found on the skin. It is frequently raised and yellow or brown in color. Touching the lesion usually evokes a strong wheal and flare reaction. Sweating may also occur. Blistering may be present[ii].

Diagnosis of mastocytosis in the skin

  • While a biopsy is the definitive diagnostic method, positive Darier’s sign is present in most children and many adults with mastocytosis in the skin. Use of antihistamines can suppress a positive Darier’s sign[ii].
  • Biopsies from lesional skin should be stained for mast cells using toluidine blue or Giemsa-Wright stain; evaluated for CD117, CD25 and CD2 using IHC; and evaluated for activating mutations in the CKIT gene using PCR or sequencing methods[i] .
Diagnostic criteria for cutaneous mastocytosis  (requires one major and one minor criterion)[iii]
Major Minor
Typical mast cell rash, usually maculopapular, or atypical rash with positive Darier’s sign Dense infiltration by tryptase positive mast cells, >15 mast cells/cluster or >20 mast cells/x40 magnification hpf if not clustered
Activating CKIT mutation detected in biopsy from skin lesion

 

Symptoms and treatment of mastocytosis in the skin

  • Common symptoms localized to the skin include flushing, itching, burning, hives and blistering[iv].
  • Mediator release symptoms can affect other organs regardless of whether or not they have systemic mastocytosis. Flushing, nausea, vomiting, diarrhea and low blood pressure have been reported among other symptoms. Wheezing, shortness of breath and rarely cyanosis may be present. Anaphylaxis can also occur[iii].
  • Treatment for cutaneous mastocytosis/mastocytosis in the skin relies upon histamine blockade with H1 inverse agonists and H2 antagonists; cromolyn sodium; leukotriene antagonists; and PUVA treatment in severe cases[v].
  • In treatment resistant cases, systemic glucocorticoids and topical cromolyn may be used.  In some instances, mastocytomas may be excisedi. Anaphylaxis should be treated with epinephrine per current guidelines[v].

[i] Molderings GJ, et al. (2011). Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J Hematol Oncol, 4(10), 10.1186/1756-8722-4-10

[ii] Hartmann K, et al. (2016). Cutaneous manifestations in patients with mastocytosis: consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma and Immunology; and the European Academy of Allergology and Clinical Immunology. Journal of Allergy and Clinical Immunology, 137(1), 35-45.

[iii] Valent P, et al. (2007). Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. European Journal of Clinical Investigation, 37, 435-453.

[iv] Carter MC, et al. (2014). Mastocytosis. Immunol Allergy Clin North Am, 34(1), 10.1016/j.iac.2013.09.001

[v] Castells M, et al. (2011). Guidelines for the diagnosis and treatment of cutaneous mastocytosis in children. Am J Clin Dermatol, 12(4), 259-270.