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Skin biopsy

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 8

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

14. Are there any special instructions for the tests to diagnose mast cell disease?
• There are a lot of tests used to diagnose mast cell disease. There are certainly people who slip through the cracks with the current diagnostic criteria.
• Remember this as you read the following: DO NOT, UNDER ANY CIRCUMSTANCES, EVER, DISCONTINUE MEDICATION FOR TESTING WITHOUT EXPLICIT INSTRUCTIONS TO DO FROM A DOCTOR THAT UNDERSTANDS MAST CELL DISEASE. Stopping medications for mast cell disease can be very dangerous.
• The biopsy forms the centerpiece of diagnosis of both cutaneous and systemic forms of mastocytosis.
You can increase your chance of positive skin biopsy by choosing either a permanent lesion or an area of skin that is frequently reactive.
• For internal organs, including bone marrow, you can’t always tell where to biopsy just by looking. The area may look normal but show inflammation when viewed with a microscope.
• If patients do not need to take daily corticosteroids because they do not make their own (adrenal insufficiency or Addison’s disease), they are often recommended to not use corticosteroids (prednisone or similar) for five days before a bone marrow biopsy. Taking corticosteroids can tell your body to make a lot of extra white blood cells which can make it harder to give a correct diagnosis.
• The CKIT D816V mutation test is often done on a blood sample. It is much more accurate when a bone marrow biopsy is tested because there are many more mast cells. Mast cells do not live in the blood so the blood test is less accurate. If the test is positive in blood, we assume that the patient is truly positive. If the test is negative in blood, we are not sure if the patient is truly negative.
• Serum tryptase is a test with a lot of caveats. It is influenced heavily by timing and patient factors like weight. Many people with mast cell disease have normal serum tryptase. It is good for tracking progression of disease in patients with systemic mastocytosis.
• About 85% of patients with systemic mastocytosis have a baseline tryptase value over 20 ng/mL. Patients with monoclonal mast cell activation syndrome may also have baseline tryptase value over 20 ng/mL. For these patients, they should have two different tests from days when they are not especially reactive, or have had anaphylaxis.
• For patients with mast cell activation syndrome, we are often looking for an increase in tryptase during a reaction or anaphylactic event. In these patients, experts recommend having blood drawn 15 minutes to 4 hours after onset of the event.
• Another sample should be drawn 1-2 days later so that you have a sample to compare with the tryptase level during the event. Many experts accept a level increased by 20% plus 2 ng/mL above the baseline to be indicative of mast cell activation. (I made a typo on this that said 20% to 2 – sorry!)
• As we have previously discussed, many mast cell mediators should be kept cold because they break down quickly. 24 hour urines for n-methylhistamine, prostaglandin D2, 9a,11b prostaglandin F2, and leukotriene E4 should be kept cold.
Performing a 24 hour urine when you are having a reaction event can increase the likelihood of mediator release.
COX inhibitors will interfere with prostaglandin production. Some patients stop these meds before giving 24 hour urines for prostaglandin testing. DO NOT STOP MEDS WITHOUT BEING ADVISED BY AN EXPERIENCED MAST CELL PROVIDER.
Lipoxygenase inhibitors will interfere with leukotriene production. Some patients stop these meds before giving 24 hour urines for leukotriene testing. DO NOT STOP MEDS WITHOUT BEING ADVISED BY AN EXPERIENCED MAST CELL PROVIDER.
• Heparin is very heat sensitive. Plasma heparin must be kept cold. One study reported that a tourniquet on the upper arm for ten minutes before drawing the sample increased the change of detecting mast cell activation with this test.
• Chromogranin A is influenced by many other conditions and medications. It is important that those other conditions be ruled out. This may require lengthy body scans and other tests. Chromogranin A is influenced by proton pump inhibitors, meds that are commonly taken by mast cell patients. DO NOT STOP MEDS WITHOUT BEING ADVISED BY AN EXPERIENCED MAST CELL PROVIDER.

For more detailed reading, please visit these posts:

The Provider Primer Series: Mediator testing

Patient questions: Everything you wanted to know about tryptase

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 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)