Diagnosis of mast cell diseases

There seems to be a lot of confusion regarding diagnosis of mast cell diseases, so I figured I’d do a review.

Cutaneous mastocytosis (CM) is diagnosed by skin biopsy.  Urticaria pigmentosa (UP), also called maculopapullar cutaneous mastocytosis (MPCM), diffuse cutaneous mastocytosis (DCM) and telangiectasia macularis eruptive perstans (TMEP) are types of cutaneous mastocytosis.  They each present with a rash and may have accompanying systemic symptoms. 
Mastocytoma of the skin is also diagnosed by skin biopsy.
Systemic mastocytosis (SM) has the following diagnostic criteria:
Major:
1.       Multifocal, dense infiltrates of mast cells (15 or more in an aggregate) detected in sections of bone marrow and/or extracutaneous organ. 
Minor:
1.       In biopsy sections, more than 25% of mast cells in infiltrated area are spindle-shaped or have atypical morphology; or, of all mast cells in bone marrow aspirate smears, more than 25% are immature of atypical. 
2.       Detection of Kit mutation at codon 816 in bone marrow, blood or other extracutaneous organ.
3.       Mast cells in bone marrow, blood or other extracutaneous organ that co-express CD117 with CD2 and/or CD25.
4.       Serum total tryptase persistently >20 ng/mL (if there is not a clonal myeloid disorder.)
SM is diagnosed if a patient has either one major and one minor criteria, or three minor criteria.  So let’s look at how this plays out.
A patient with mast cell symptoms gets a bone marrow biopsy.  It shows more than 25% abnormal mast cells in the section.  They are CKIT negative, have a serum tryptase of 2, and do not express CD2/CD25.  They are diagnosed with SM.
A patient has a biopsy that does not show dense infiltrates.  All their mast cells are shaped normally.  In blood tests, their mast cells are found to express CD2.  They are CKIT+, also from blood.  Their serum tryptase is 28.  They are diagnosed with SM.
A patient has a biopsy that shows dense infiltrates, but they have less than 25% abnormal mast cells and their mast cells do not express CD2/CD25.  They are CKIT- and have a serum tryptase of 18.  They are not diagnosed with SM.
A few things to keep in mind:
Most people with SM are diagnosed by bone marrow biopsy, but a biopsy from any non-skin organ showing mast cell infiltration as described above can be used.  This means if you have a positive lung biopsy, liver biopsy, whatever, you may not necessarily need a bone marrow biopsy. 
It can take up to six bone marrow biopsies to diagnose SM in a patient who has had it the entire time.  This is because there is no way to know where the mast cells will cluster.  A negative bone marrow biopsy does not necessarily mean that you do not have SM.  Hence the minor criteria.
The CKIT test looks for a specific mutation, the D816V mutation.  There are other mutations found in codon 816.  You may have a mutation but test CKIT- because you do not have the D816V mutation.  Also, the blood test for CKIT is not always reliable.  The test way to test this is from a bone marrow sample.  You could test CKIT- in blood and then test CKIT+ in bone marrow.
The serum tryptase criterion refers to persistent baseline level tryptase, not reaction level tryptase. 
So let’s say you have a negative bone marrow biopsy and a blood test that shows you are CKIT+ and have mast cells expressing CD2/CD25.  What do you have?  You have monoclonal mast cell activation syndrome (MMAS.)  MMAS is diagnosed in patients who have one or two of the minor criteria for systemic mastocytosis.
Let’s say you have a negative bone marrow biopsy and blood work that shows normal mast cells and tryptase below 20, but you have systemic symptoms.  What do you have?  You probably have MCAS (mast cell activation syndrome.)  There are some other tests for that.  24 hour urine tests are usually done to measure the levels of histamine metabolites and prostaglandin D2 metabolites.
The following are the diagnostic criteria for MCAS:
1.       Episodic symptoms consistent with mast cell mediator release affecting two or more organ systems: skin (urticarial, angioedema, flushing); GI (nausea, vomiting, diarrhea, cramping); cardiovascular (fainting or near fainting due to low blood pressure, rapid heartbeat); respiratory (wheezing); naso-ocular (itching, nasal stuffiness, red eyes.)
2.       A decrease in frequency or severity; or resolution of symptoms with antihistamines, leukotriene inhibitors or mast cell stabilizers.
3.       Evidence of elevation of urinary or serum marker of mast cell activation: Documentation of elevation of marker during a symptomatic period on at least two occasions, or if baseline tryptase is persistently above 15 ng.  This includes urinary histamine and prostaglandin D2.
4.       Clonal and secondary disorders of mast cell activation ruled out.
MCAS is a diagnosis of exclusion.  It is the diagnosis you receive if you have mast cell symptoms that are ameliorated with mast cell medications if you do not meet the criteria for any other mast cell disease.
Back to SM.  Let’s say you’re positive for SM.  Now what?
They will determine if you have other important markers of disease severity.  These are called B and C findings.  They are as follows:
B findings:
1.       Increased mast cell burden (>30% mast cell aggregates on bone marrow biopsy and/or serum tryptase >200 ng/ml).
2.       Hypercellular marrow, signs of overproduction or abnormal development of blood cells, normal or slightly abnormal blood counts that are not abnormal enough to be considered an associated hematologic disorder.
3.       Swelling of the liver that can be felt manually, no free fluid or signs of dysfunction, persistently swollen glands, swelling of the spleen that can be felt manually without signs of dysfunction.
If you have two or more B findings, you have SSM (smoldering systemic mastocytosis.) 
C findings:
1.       Unusual blood counts (low ANC, low Hb, low platelets)
2.       Swelling of the liver that can be felt manually, with impaired liver function, free fluid and/or portal hypertension.
3.       Large osteolytic lesions and/or pathological fractures.
4.       Swelling of the spleen with impaired function.
5.       Malabsorption with weight loss and/or low albumin.
If you have one or more C finding, you have ASM (aggressive systemic mastocytosis.)
How are these B and C findings identified?  Bone marrow biopsy, blood tests and imaging (ultrasounds, MRI, etc.) 
If you have SM and one B finding, or no B findings, you have indolent systemic mastocytosis (ISM.) 
If your bone marrow biopsy shows significant overproduction or abnormal development of a cell type that is not a mast cell, you may be diagnosed with SM-AHNMD (systemic mastocytosis with associated hematologic non-mast cell lineage disease.)  People with this type of SM also have another blood disorder, such as chronic myelogenous leukemia, myelodysplasia, etc.  In these patients, serum tryptase is not reliable to assess mast cell burden.  
Mast cell leukemia (MCL) is extremely rare.  It is diagnosed by >20% mast cells on the bone marrow aspirate smear.   
Mast cell sarcoma is a very aggressive form of sarcoma.  It is diagnosed by biopsy of the tumor.  People with these tumors quickly developed mast cell leukemia.  There have only been three cases reported in literature.  To be clear, this is NOT the same as mastocytoma.  Mastocytomas are benign.
I think I got everything.  Any questions?  Ask in the comments.

18 Responses

  1. Sandy July 3, 2014 / 12:40 pm

    You have once again cleared it all up! Thank you!

  2. Anonymous July 3, 2014 / 3:31 pm

    Thank you for your blog… your information… your wisdom! One question here, what does a positive Darier’s sign mean, or not mean? Thank you!

  3. Lisa July 4, 2014 / 12:37 am

    This is a good question. I’ll do a post on Darier’s sign tomorrow.

  4. Anonymous August 6, 2014 / 2:38 pm

    Just signed up for the email subscription! 🙂

  5. Anonymous October 13, 2014 / 2:55 pm

    I started having allergic symptoms about 6 months ago. (Itching everywhere,Hives,Acid Reflux,and increased asthma attacks) the only relief I’ve had is taking 360mg. Of Alegra, proton pump inhibitors,Inhalors and prednisone) Though I still itch a bit and still have dermitagraphia. Not sure how much to read into this but my Alergist had my Dermatologist Re-Run one of my skin biopsies that previously had come back as “inconclusive” to look for mast cells and as it turns out there was a “Slight Increase” in Mast cells and added possible (T.E.M.P.) to the diagnosis which is a form of Mastocytosis apparently. Found a new Hemotologist to see me out of University of Chicago Cancer Centsr and they are saying they don’t rem ever seeing this and are as curious as I am about this now! Just took C-Kit test along with 24 Hr. Urine as well as other blood work. Does any of this sound familiar and do you think the Skin Biopsy says anything? Just looking for any opinions…Hope everyone else is well!

    • Anonymous October 13, 2014 / 3:07 pm

      I forgot to add I’ve had “IBS” issues for years as well along with blood tests a year ago indicating “High Liver function”

  6. Anonymous October 13, 2014 / 4:12 pm

    Sorry, another correction. That diagnosis on the Biopsy was “T.M.E.P.” I must be getting Dyslexia too…. Too much medical language for me.

  7. L Wright January 27, 2015 / 1:46 pm

    I recently had biopsies via colonoscopy. There were a significantly high number of mast cells per HPF (60). You mentioned it may not be necessary to have a BMB to get a diagnosis. Is there something I could ask the pathologist to do retrospectively that would give me a diagnosis without having a BMB? Thank you for your information. I always learn from your comments.

    • Lisa Klimas January 27, 2015 / 9:28 pm

      The biopsies should be tested for CD2 and CD25 receptors. The report should say if the mast cells are clustered and if they are spindled. If they are clustered and you have either 25% spindled cells, CD2 or CD25 receptors, have a baseline tryptase over 20, or have the CKIT D816V mutation, that is diagnostic for SM. If they are not clustered, but you meet three of the last four conditions I just mentioned, that is also diagnostic for SM. In that case, it may not be necessary to have a BMB.

    • L Wright March 5, 2015 / 7:22 pm

      Thank you for your response. Your answers always clarify things for me. I have another question. I just got blood results back and have very low white blood cells, especially leukocytes and monocytes. Have been diagnosed with MSAD, possibly indolent mastycytosis based on history, symptoms, colon biopsies. How do the low white blood cells fit into this picture, or do they? Thanks for so graciously sharing your knowledge.

  8. Cheri May 28, 2015 / 7:12 pm

    I have been ill since June 2014 with a mystery illness. Bright red facial/neck flushing, shortness of breath, feeling like I’m going to pass out, abdominal bloating, and so on. Many wierd symptoms. Ruled out carcinoid syndrome and pheochromocytoma. Recently sent to a Dermatologist to do a punch biopsy of the flushing area on neck. Positive for increased perivascular mast cells. Referred to hem/onc who has never seen a case of Mastocytosis. He did bone marrow biopsy and I get results tomorrow. Tryptase and serum histamine were normal. I’m so ill every day with these horrible symptoms. Have learned to stay away from alcohol and chocolate. I can’t believe I’m actually hoping my bone marrow is positive so at least I’ll know what I have! I can’t believe I’m thinking that way but being in the dark is worse. Can I have all these symptoms if it’s just Cutaneous Mastocytosis? It’s been 2 weeks sine bone marrow and haven’t heard from my home hem/onc so assuming it’s normal.

    • Lisa Klimas May 28, 2015 / 9:56 pm

      It’s easier to have an answer so you can move forward, even if the answer is that you have an incurable disease. Yes, you can have all these symptoms with just cutaneous mastocytosis. You can also have them from MCAS, which is a normal number of mast cells behaving badly. That is diagnosed by 24 urine testing from n-methylhistamine and F2a prostaglandin. I hope you get some answers soon and I’m sorry you’re feeling so crummy.

  9. Laura July 3, 2015 / 4:06 am

    Hi there, I’ve got a Primary Immune Deficiency called CVID. I have alot of symptom you’re describing in these illnesses. I had last year a massive change in my body I gained double my body weight. I am carrying alot of general oedema abs pedal oedema. I have tachycardia, i had hypertension, I’m now hypothyroid and diabetic type two. I had high liver function tests, always have IBS but wowser cramps and diarrhoea more often. I have low blood haemaglobin and low platelets. But my GP doctor is concerned with bowel cancer. I keep telling them my lymph glands are always up and tender to touch sometimes but they’re always elevated and swollen. My stomach is bloated and hard not soft. What tests would you recommend for me to have please Lisa? Abs do i have possible SM?? Many thanks, Laura.

    • Lisa Klimas July 3, 2015 / 4:20 pm

      I am familiar with CVID, I was actually misdiagnosed with it many years ago. Primary immune deficiencies are not unusual in mast cell patients. Let me see what tests are available in the UK. If available, 24 hour urine testing for n-methylhistamine and D2 or F2 prostaglandin is generally the best way to tell if you have mast cell disease and then you can narrow down the type.

      Of course it is possible that you may have SM but there is no way to know for sure without a bone marrow biopsy. However, SM is much rarer than MCAS.

      Have you been tested for hereditary angioedema? Is the edema constant?

  10. Brittany April 14, 2016 / 11:59 pm

    I have a question, I have been having issues for the last few years- started with stomach pains and random anaphylaxis from different/random things and got worse. I have been to see a few different specialists, GI and allergy. My most recent doctor thinks I may have a mast cell activation disorder and referred me to Brigham and womens after he did a few tests; tryptase was normal, but my 2,3-Dinor-11beta-prostaglandin F2 alpha level was 3680. He had them check biopsies from a colonoscopy and endoscopy done a few months ago and I had 20-25 mast cells per hpf. Which isn’t abnormal, they said. So could I have a mcad, or is there something else that would cause the prostaglandin level to be high?

  11. Cris April 28, 2016 / 12:33 pm

    Can those markers on the 24hr urine test can be tested by blood serum also? We suspect my son has MCAS, tryptase is normal and we are having a hard time testing the urine because he still on diapers. Doctor is puzzled in how to test him

    • Lisa Klimas April 29, 2016 / 11:15 am

      It’s hard with kids. I actually had this conversation with a pediatric GI specialist not long ago. I think for children, or in persons where 24 hour urine collection is impossible, you can use a blood level to inform treatment. Your blood levels of histamine and prostaglandin D2 fluctuate throughout the day, so, if possible, two collections might be best to give firmer guidance. That said, the treatment for mast cell disease in children is pretty straightforward to start and uses medications that are pretty safe. If your doctor feels better getting a high blood n-methylhistamine before prescribing cromolyn or something, I think that’s okay. You can always retest when they get older. Just keep in mind that these tests are not widely considered to be reliable so it is important that the doctor document the clinical presentation thoroughly so other providers understand that the diagnosis is not based just on these tests.

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