I just got a piece of paper from the Mastocytosis Society enclosed in plastic. (Sorry my brain can't remember the right name for this tonight.) Anyway, on the paper under the heading MCAS is says that MCAS can also be found in 3 other circumstances.  The fist of which is "In patients who meet only one or two criteria of SM. These patients are believed to have an abnormal clone of mast cells and the disorder is termed "monoclonal" mast cell activation syndrome".

I have a Tryptase of 23 but a negative BMB.  I am diagnosed with MCAD.  Does the above mean that my diagnosis should be MMCAS?  Please help, I am SO confused now.  

vicmjones wrote on 02/14/13 at 15:45:06:




Okay, let me dig out one of the very best articles which deals with this of differentiating amongst the forms of masto.   But first of all, before I do so, allow me to say that when you are talking about MCAS you must know that there are two divided groups of authorities out there - one is definitively in favor of MCAS and the other fights it tooth and nail.   Depending upon the authority who is speaking upon MCAS you are going to get a slightly different report, of which there are now about 10 which have been published since 2010.  So, of these two groups you have Dr. Castells, Dr. Escribano and Dr. Molderings who are the foremost authorities on MCAS.   On the other side you have Dr. Metcalfe, Dr. Horny, and Dr. Valent are the foremost authorities on SM.  So, this is what makes these articles a bit tricky in trying to gain understanding.   This is such a tricky thing that the official WHO consensus article on MCAS took a full 18 months to get published!  There are more politics involved but I'm not going to go any further into that.  

Another thing we MUST keep in mind is this:   THIS IS WHAT IS KNOW AS OF WHERE MC RESEARCH IS NOW!!!!!   All of this could possibly change in 2 years with new findings.  New findings bring new understanding and this disease is "IN DISCOVERY"  meaning that there is a great deal that they are still learning from their research and every new finding, brings more understanding.  What looked like an "elephant" a few years ago is beginning to look like a gazelle, or perhaps a giraffe, but who knows, they may find that the elephant actually was 3 or 4 other creatures instead.   So, this is what we know AS OF NOW, so don't hold it as law, these are guidelines for now.  


Now, one of the best articles written recently is by Dr. Escribano.  He chose to try to help doctors figure out how to differentiate between SM patients, MMAS patients and nc-MCAS patients.    This article is called:

Clinical, biological, and molecular characteristics of clonal
mast cell disorders presenting with
systemic mast cell activation symptoms

http://www.ncbi.nlm.nih.gov/pubmed/20434205

Abstract
BACKGROUND:
Systemic mast cell activation disorders (MCADs) are characterized by severe and systemic mast cell (MC) mediators-related symptoms frequently associated with increased serum baseline tryptase (sBt).
OBJECTIVE:
To analyze the clinical, biological, and molecular characteristics of adult patients presenting with systemic MC activation symptoms/anaphylaxis in the absence of skin mastocytosis who showed clonal (c) versus nonclonal (nc) MCs and to provide indication criteria for bone marrow (BM) studies.
METHODS:
Eighty-three patients were studied. Patients showing clonal BM MCs were grouped into indolent systemic mastocytosis without skin lesions (ISMs(-); n = 48) and other c-MCADs (n = 3)-both with CD25(++) BM MCs and either positive mast/stem cell growth factor receptor gene (KIT) mutation or clonal human androgen receptor assay (HUMARA) tests-and nc-MCAD (CD25-negative BM MCs in the absence of KIT mutation; n = 32) and compared for their clinical, biological, and molecular characteristics.
RESULTS:
Most clonal patients (48/51; 94%) met the World Health Organization criteria for systemic mastocytosis and were classified as ISMs(-), whereas the other 3 c-MCAD and all nc-MCAD patients did not. In addition, although both patients with ISMs(-) and patients with nc-MCAD presented with idiopathic and allergen-induced anaphylaxis, the former showed a higher frequency of men, cardiovascular symptoms, and insect bite as a trigger, together with greater sBt. Based on a multivariate analysis, a highly efficient model to predict clonality before BM sampling was built that includes male sex (P = .01), presyncopal and/or syncopal episodes (P = .009) in the absence of urticaria and angioedema (P = .003), and sBt >25 microg/L (P = .006) as independent predictive factors.
CONCLUSIONS:
Patients with c-MCAD and ISMs(-) display unique clinical and laboratory features different from nc-MCAD patients. A significant percentage of c-MCAD patients can be considered as true ISMs(-) diagnosed at early phases of the disease.
Copyright (c) 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.


Now let's take a look here and try to understand what they are saying.  


Prior to accepting the MCAS diagnosis, the authorities insisted in strictly defining the patients as to the WHO criteria for SM, which at the time of it's latest publication in 2007, were as such:

A. Major criteria
Multifocal, dense mast cell infiltrates (‡15 mast cells in clusters) in bone marrow biopsy sections and/or in other extracutaneous
organ(s)
B. Minor criteria
1. Greater than 25% mast cells in bone marrow or other extracutaneous organ(s) showing an atypical (spindle-shaped) morphology
2. KIT mutation at codon 816 is present in extracutaneous tissues, bone marrow, or blood
3. Mast cells in bone marrow coexpressing CD117 and either CD2, CD25, or both, as assessed by flow cytometry
4. Serum tryptase persistently ‡20 ng/mL (not applicable to patients with an associated clonal hematologic nonmast cell disorder)



Until 2010 with the MCAS diagnosis, if you did not fit into this criteria you were left out in the cold.  PERIOD!   Some doctors recognized that the patients smelled like, looked, like and behaved like and even responded to the very same treatment like SM patients, but without fulfilling this criteria the doctors either said,  "I don't know what you have"  or they gave you a diagnosis of Idiopathic Anaphylaxis if you were one who was going through anaphylaxis.

Yet, what was going on was that there were PLENTY of patients who had something elevated - histamines, or prostaglandins or tryptase, or showed morphologically changed MCs, or had a few aggregates but not enough  to show SM or they had a combination but nevertheless, fell short of the criteria.     Well, for some doctors this was unacceptable and they kept pushing for MCAS.   But the group who only accepted SM as the REAL mastocytosis insisted, "YOU CAN'T PROVE THE ACTIVATION"  so it must not exist!   Yet this is where mast cell research was back in the 80s prior to finding the clonal genetic defect.   This is why such emphasis has been placed upon the genetic defect, as though it was the ONLY way you could explain the proliferation and the activation.  

You see, at one time they believed that the only form was that of the proliferative form and with having way too many MCs, obviously when they got triggered, they explained all the activation!!   Because they didn't have exams sophisticated enough and could not find the defect on the MCs to explain activation, there was no way to PROVE it!!   So they stuck to their guns and resisted MCAS until there was no way to disprove it any more.  

Why?   Because of Dr. Akin, Dr. Molderings and Dr. Escribano.   Dr. Akin blew the masto world away by testing IA patients who had no apparent alterations in their markers.   He found the genetic defect on the apparentely normal MCs of these patients.   Yet, in retrospect, if we put them up against the MMAS patients today, some of them have tryptase which is at 5ng and although this is not considered "elevated"  is it above "normal which normal is 1.0ng established by Dr. Schwartz.   So, this article by Dr. Escribano, the one I've cited above, shows that in his studying of this group of patients, some of them had tryptase which was 3.5 and the such!  So in 2007 what was then considered as not having any markers, is now being seen as having a tryptase which is showing some elevation, but is not considered out of the "normal" range and diagnostic for mastocytosis.   Understand?   That document is way outdated and there are newer, more updated articles dealing with Systemic Mastocytosis and the various forms which have since been discovered.  There are several more forms of SM which have been since discovered which show that this is still a new area of research.  

Dr. Molderings, who is a researcher in MCAS has published an incredible paper  in which he has found a NUMBER of genetic mutations on Kit.

Comparative analysis of mutation of tyrosine kinase kit
in mast cells from patients with systemic mast cell activation
syndrome and healthy subjects
http://www.ncbi.nlm.nih.gov/pubmed/20838788


In this paper Dr. Molderings reveals that there are many more genetic alterations on Kit than just the one which was known when the 2007 WHO SM consensus document was published.   In 2007 they knew of only one.  When Dr. Akin published his study they still only knew of the one.  Now, they know that there are a great many more and that dependent upon these mutations, this is what may make the difference between the SM patient, the MMAS patient and the MCAS patient.  

Dr. Escribano's paper, published in 2010, shortly after Dr. Molderings paper, reinforces these findings and helps to show that there are differences between the patients.   This may explain why some of us have angioedema and others don't.  Why some have anaphylaxis and others don't and why some don't even have many symptoms while others of us take a beating daily.  


So, in having explained this, let me go specifically to your question:  

"In patients who meet only one or two criteria of SM. These patients are believed to have an abnormal clone of mast cells and the disorder is termed "monoclonal" mast cell activation syndrome".

I have a Tryptase of 23 but a negative BMB.  I am diagnosed with MCAD.  Does the above mean that my diagnosis should be MMCAS?  Please help, I am SO confused now.  


The fact you have a tryptase of 23 is already diagnostic for SM.  This could be that you are a pre-SM patient, or that you are a MMAS patient.  This is because the MCAS patients usually have a tryptase level which is lower "usually".   This is because the trytpase reflects the mast cell burden in the bone marrow.  But let me say this - the researchers know that the higher the tryptase the more MCs in the bone marrow of patients, however, they have seen that there are patients who have low levels and yet have found MC aggregates in their tissues like the skin or the intestines and they don't know what to make of these patients.   There are also others who have high levels and can't find the MC aggregates in their bone marrow, so they don't quite know what to make of these exceptions.    They suspect that these patients may be in a pre-SM form, that the disease is still immature and that time will tell what this patient is.  

Dr. Escribano came up with an EXCELLENT table for being able to know where you fit in.  

The score is based upon your gender, symptoms and tryptase level.

Add it up:

If you are:
male,  +1
female -1

If you have:
Absence of urticaria and angioedema +1
Urticaria and/or angioedema  -2
Presyncope and/or syncope +3

If you have a Tryptase level of:
<15ng/mL     -1
>25 ng/mL    +2


Score <2:   low probability of clonal MCAS
Score > 2:  high probability of clonal MCAD

Sensitivity: 092 Positive predictive value: 0.89

Specificity:  0.81
Negative Predictive Value 0.87



Now, according to Dr. Escribano's article, there is a non-clonal MCAD (this MCAS/MCAD is very confusing in my opinion but I had Dr. Molderings give me some insight to this.    MCAD is the umbrella name for the ENTIRE disorder, in that you can have patients who have the disorder but have not had their disease become active and therefore are not showing the syndrome which would be called MCAS, or the syndrome form of MCAD.   Understand?!   I hope so, but I don 't blame you if it's confusing.


Anyway, according to Dr. Molderings' findings, ALL forms of masto are clonal, but not all are neoplastic.  So, to help doctors understanding this, they have chosen to call those forms of MCAS which are NOT showing any kind of proliferative evidence, these are the forms of MCAS which they consider "non-clonal".  They are mainly an activation form and they show no serious pathological damage in any form, only inflammatory and reactive issues.   They call them "non-clonal MCAS or non-clonal MCAS more to help keep down the panic and hysteria which so many of us go through thinking we have a "CANCER"!   Masto at it's very worst is considered a cancer, but this is only when the patient shows an agressive form of masto.   For the vast majority of us, as one of my doctors said to me - "you will die WITH your masto at the ripe old age of 100 and not die FROM it!!"  

It's so easy to get freaked out but let me give you some PEACE.   MMAS although it is considered clonal is at this point being considered a very, very mild and non-threatening form of masto.   Although the authorities are not yet certain, they have two theories about this form.   Either it is a pre-SM  - being an immature form of ISM and thus not yet showing all of the SM markers,   OR it is a new form all of it's own and even more benign than the ISM form.    

The researchers, AT THIS POINT IN TIME, think that it may be it's own form and the reason is because of this grading table if Dr. Escribano's.    His study showed that most of these patients are men - do not show urticaria or angioedema and go through a lot of presyncope and/or syncope (and severe cardiovascular reactions)  and have a tryptase which is slightly elevated.

Now, obviously this report raises more questions than it answers and shows that there is a great deal more research which must be made to answer the whys that are seen in this report.  But what is shows to us is that the jury is not only still out, but they are going to be on a long extended stay out of the courthouse on this one!!  They've only begun to open up the diagnostic possibilities and we need to not lose our heads over this.  

I understand you fears and your confusions and when I did this test I came up with a +2.  My doctors along with Dr. Castells and Dr. Escribano want for me to redo my bone marrow biopsy, but to do so, I'd need to have access to the more sophisticated, thus expensive testing which it requires to reach this diagnosis.   But my tryptase was 4.6ng/mL 2 years ago and Dr. Escribano said it's way too low to be worth testing.   This is not your case and you should be in the hands of an expert who can have this testing performed.  

But here's the bottom line question -  How much of a difference will this make for you in pinning down this diagnosis?   Probably very little!   I agree with both Dr. Castells and Escribano and my doctors that I need to have a new BMB performed.  It's a matter of being WISE and KEEPING AN EYE on the disease.   I could be a pre-SM and only by keeping an eye on me will we know for sure.   Is it important to know?  Well, yes and  no.   Yes, because it's good to know what the truth is, however, as long as my CBCs and liver counts are stable and good then those are the overall indicators as to how my health is and how I am doing and how my masto is behaving.  By knowing exactly my form, they can perhaps help me to keep down my triggers and avoid my masto getting out of hand by going through too much stress.   It also provides understanding as to what may need to be avoided, etc.    But, overall, my treatment will remain the same and my need to avoid triggers as well and I can very honestly tell you that I'm NOT going to die from this, and instead, celebrate my 100th still living WITH masto!!!


I hope this helps and I hope it can bring you PEACE!!


Hugs!


Lisa

Wow, thanks Lisa. That was a lot of information. I'll have to go back and read again more thoroughly to understand it all. But for now tell me if this makes sense to you.

Here's my computation as I see it--

Add it up:

If you are:
male,  +1
female -1      (easy -1 I'm female)

If you have:
Absence of urticaria and angioedema +1  (Not sure, I have seen dermagraphism but no hives, don't think I've had angioedema)  I'll give this a +1
Urticaria and/or angioedema  -2
Presyncope and/or syncope +3  ---Again not sure.  I get VERY tired when I stand, I have felt like I was going to pass out but it is rare. Mostly I just feel tired when standing and sit most of the time.  I'll give myself a 0

If you have a Tryptase level of:
<15ng/mL     -1
>25 ng/mL    +2

(This is easy I get a zero)


Score <2:   low probability of clonal MCAS
Score > 2:  high probability of clonal MCAD

Total score is a zero or a 3 depending on my answer to pre syncope. If I have "pre-syncope"  then I probably should get a BMB now. But I have never been diagnosed with pre-syncope to my knowledge.

I think I will wait until my Tryptase raises more (over 25) until I get another BMB. It started at 20 and now it's 23, I really don't expect it to stop going up because my symptoms seem to be progressing as well.

After all of your explanation, I think I will stick with my zero. If my Tryptase rises then I will still only be a 2. I don't think I have pre syncope as when I get that dizzy feeling I am very aware of it. The only two times I have fainted before, there really wasn't any warning and one was when I was pregnant and another I held my breath too long, so those two don't count.

Lisa could you please clarify whether the urticaria and angioedema in this case are specifically in connection with the fainting episodes, or at any time?

Cameron has urticaria, and he has near fainting epodes, but they don't go together. So when he is near fainting he is not necessarily itchy or puffy (I don't think so anyway) but he has these symptoms at other times (although never throat swelling, mostly lips and face, maybe hands). Do you know how that scores with this table?

Ruth, I´m really not sure.   I could make a stab at it and say that this is when the pct is in an acute reacting process, but it may be all the time.   Dr. Escribano is who could clarify this and perhaps I´ll throw this question at him sometime for it´s a great question, but usually when you read the studies cited on this form they are usually talking about patients who were stung by bees or wasps and the reactions they presented at the hospital.   So, I would say that this is citing acute reacting and not the leaking reacting.  


But when I look at this article, and consider my own case, I never show any urticaria ever.  I did have a few cases of this prior to when my masto became activated and I would have cases of hives as a child, but ever since my masto activated, I almost NEVER have any kind of hives and not once has it shown when I´ve been in an acute situation.  

As to the swelling of the lips and face, this is angioedema.  

As to fainting, this is a pretty common complaint amongst masto patients.   This is not what this article is talking about.   There is a difference when syncope is a marked reaction in the patient and that patient knows it.   For me it´s CONSTANT!  It was a symptom which showed itself from the time my masto became activated!   It was never anything I encountered prior to its activation except those two situations which when pregnant is considered pretty common and related to pregnancy and the prior situation I had when I was a teen it was emotional-stress related and understandable then too.   These are different things we are talking about.

Also, has Cameron had his prostaglandin D2 measured?  There is a subset of patients who have been found to have elevated prostaglandins and they go through syncope.  I don' t think that this is the group which the MMAS patient is referring to for there's more than just symptomatology involved here, there are other things that are involved like having pathological damage which is in line with the SM patient thus showing that the MC aggregates are present.   For instance the evidence of lymphoid aggregates in the bone marrow.   This is found in SM patients and when it's found in the MMAS patient it casts the shadow that the MC aggregates are somewhere in the bone marrow as well.   There also is usually the presence of CD2 and CD25 on the MCs of these patients as well.   So, there's more to it than just the symptoms which show what this patient has.  

So, before anybody goes jumping to conclusions based upon the score, be careful not to make the typical patient mistake by lining up your symptoms and convincing yourself that this is or is not what you have.   This is why we MUST have our doctors working with us to do.  They understand the overall picture and they are who help us to keep moving in the right directions.   When my doctors read this article, both my dermatologist (masto specialist) and my hematologist (who never saw a masto patient before) said, "Lisa, for the first time we can see your case!"    They'd not been able to see my case show itself in the literature before this one.   They saw similarities but always gaps.  With this article they saw everything line up finally and when I spoke with both Dr. Castells and Dr. Escribano they too agreed for they know about my case.  

So, it's not just because I felt that I lined up, but because I had my own doctors confirming this and then two authorities agreeing with my doctors.   Remember, however, neither Dr. Castells nor Dr. Escribano are my doctors.   They can't make a call on my case because they've never seen me.  However, my case has driven my doctors to total distraction and we haven't any authorities here in Brazil at this time!  I first contacted both of these authorities back in 2008 and Dr. Castells agreed to help me, but it's never been to the point of being my doctor.  I sent to her my biopsies, she saw them and confirmed what my pathologist's work was and so she's very familiar with my case.  With Dr. Escribano I wrote to him asking for a copy of the REMA protocols.  He even asked me to translate them into Portuguese.   And when I began having all kinds of reactions in spite of using those protocols I had to speak with him about why and what was happening and so since I kept going through the prolonged syncope regardless of using those protocols he needed to know about it so that we could figure out what was wrong.  This is why he has become a reference for me.    But again, neither of these two doctors could help me directly since they are not my doctors but once my doctors gave me their opinions both of them had a means of confirming their own opinions from what they've seen and learned about my case over time.  

So, this is why I say, we can't just take this article and this scoring system on our own, we have to have our doctor's give their input for they can see the overall situation as to how it lines up against this.


Lisa

Okay, I´ve spoken with Dr. Escribano and he´s given me an answer!!!!


"MMAS is an exception if the bone marrow is well done; anyway both urticaria and angioedema can appear in such pathology but at very low frequency when compare with non-clonal cases"

In other words, what Dr. Escribano is saying here is that the diagnosis of MMAS is being found to be an exception for a diagnosis.  If the Bone Marrow biopsy is well done, with the right techniques, the right processes, with the right pathologists who are very familiar with the testing, they usually can identify that patient properly.  So those who really fall into MMAS are few.     And with these patients angioangema and urticaria can be present but only at very low frequencies when you compare them with the non-clonal MCAS patients.


So, does that make sense?


This is why I prefer asking the researchers because so very often we can dicker and compare and wonder and come up with many presumptions but they are the ones who know what the real situation is.   It keeps us from making presumptions which can end up being dangerous!


I hope this helps!

Lisa