The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 15

I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.
23. Is mast cell disease progressive?
No, mast cell disease is not inherently progressive. Many patients live their entire lives with the same diagnosis.
“Progressive” is not the same thing as “changing.” The way mast cell disease can change over time and often does.
• “Progressive” has a very specific meaning in this context. It means movement from one diagnostic category to another, essentially changing your diagnosis to a more serious form of mast cell disease.
We do not have studies yet on whether or not MCAS “becomes” SM. However, we know that many people live with MCAS for decades without evidence of SM.
• There are several subtypes of systemic mastocytosis. In order of increasing severity, they are: indolent systemic mastocytosis; smoldering systemic mastocytosis; systemic mastocytosis with associated hematologic disease; aggressive systemic mastocytosis; and mast cell leukemia.
• The relative danger of systemic mastocytosis with associated hematologic disease (SM-AHD) when compared with other forms of systemic mastocytosis varies wildly. SM-AHD is when you have SM and another blood disorder where your body makes way too many cells. The other blood disorder is an important factor in life expectancy and risk of organ damage so it is difficult to compare it to other forms of mastocytosis.
• For patients with indolent systemic mastocytosis, in the 5-10 years following diagnosis, about 1.7% of patients progressed to smoldering mastocytosis, aggressive systemic mastocytosis, or mast cell leukemia.
• For patients with indolent systemic mastocytosis, in the 20-25 years following diagnosis, about 8.4% of patients progressed to smoldering mastocytosis, aggressive systemic mastocytosis, or mast cell leukemia.
• For patients with indolent systemic mastocytosis, one study found that roughly 8% of patients progressed to smoldering systemic mastocytosis.
• For patients with indolent systemic mastocytosis, two studies found that roughly 3% and 4% of patients progressed to aggressive systemic mastocytosis.
• For patients with indolent systemic mastocytosis, about 0.6% of patients progressed to acute leukemia (mast cell leukemia or acute myelogenous leukemia)..
• For patients with smoldering systemic mastocytosis, about 18% of them progressed to aggressive systemic mastocytosis or mast cell leukemia.
• For patients with aggressive systemic mastocytosis, about 6.5% of them progressed to acute leukemia (mast cell leukemia or acute myelogenous leukemia).
• For patients with systemic mastocytosis with associated hematologic disease, about 13% of them progressed to acute leukemia (mast cell leukemia or acute myelogenous leukemia).

For more detailed reading, please visit these posts:

Progression of mast cell diseases: Part 2

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 14

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

22. Is MCAS an early form of SM?

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

For more detailed reading, please visit these posts:

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

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

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

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

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

 

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

For more detailed reading, please visit these posts:

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

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

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

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

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

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 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: Mast cell activation syndrome (MCAS)

Mast cell activation syndrome (MCAS), also called mast cell activation disorder (MCAD), is an immunologic condition in which mast cells are aberrantly activated, resulting in inappropriate mediator release.

Presentation

  • MCAS can be responsible for chronic symptoms in multiple organs that cannot be attributed to another cause[vi].
  • Patients frequently receive diagnosis for a number of idiopathic conditions prior to correct diagnosis with MCAS[vi].
  • Mast cell activation syndrome is overwhelmingly a secondary condition. MCAS can be secondary to a number of conditions, including autoimmune diseases, connective tissue diseases, and atopic conditions[i].
  • The term “primary MCAS” refers to mediator release symptoms associated with mastocytosis[xvii] . However, the term “mastocytosis” generally conveys the understanding that both proliferation and mediator release symptoms are possible.
  • In idiopathic MCAS, no cause for symptoms can be identified[xvii] .
  • The presence of multiple mast cell patients in one family is not uncommon. A heritable gene has not yet been identified. Epigenetic mechanisms are suspected for transmission of mast cell disease to another generation[iv].
  • Approximately 75% of mast cell patients have at least one first degree relative with mast cell disease and not always the same subtype[ii]. For example, a mother may have MCAS, while one of her children has SM and the other has CM.

Diagnostic criteria

  • MCAS is a recently described diagnosis. In the absence of large studies, several groups have developed their own, sometimes conflicting, diagnostic criteria.
  • Differential diagnoses with potential to cause similar symptoms should be considered and excluded[iii].
  • The criteria most frequently used include those by a 2010 paper by Akin, Valent and Metcalfe[iii]; a 2011 paper by Molderings, Afrin and colleagues[iv]; and a 2013 paper by Castells and colleagues[v].
  • The criteria described in the 2011 paper by Molderings, Afrin and colleagues have been updated to include response to medication[vi].
  • Of note, a 2012 consensus proposal[x] was authored by a number of mast cell experts including Valent, Escribano, Castells, Akin and Metcalfe. It sees little practical use and is not generally accepted in the community.
  • The major sets of criteria listed above all include the following features:
    • Recurrent or chronic symptoms of mast cell activation
    • Objective evidence of excessive mast cell mediator release
    • Positive response to medications that inhibit action of mast cell mediators
  • Valent warns that in some cases, patients may not fulfill all criteria but still warrant treatment: “In many cases, only two or even one of these three criteria can be documented. In the case of typical symptoms, the provisional diagnosis of ‘possibly MCA/MCAS’ can be established, and in acute cases, immediate treatment should be introduced.”[vii]

Evidence of mediator release

  • Mast cells produce a multitude of mediators including tryptase, histamine, prostaglandin D2, leukotrienes C4, D4 and E4, heparin and chromogranin A[viii].
  • Serum tryptase and 24 hour urine testing for n-methylhistamine, prostaglandin D2, prostaglandin 9a,11b-F2 are frequently included in testing guidelines in literature (Castells 2013)[ix], (Akin 2010)[x], (Valent 2012)[xi].
  • It can be helpful to test for other mast cell mediators including 24 hour urine testing for leukotriene E4[xii]; plasma heparin[xiii]; and serum chromogranin A[xiv].
  • In most instances, elevation of a mediator must be present on two occasions[ix]. This helps to exclude situations of appropriate mast cell activation, such as infection or wound healing.
  • For patients with baseline tryptase level >15 ng/mL, elevation of tryptase above this baseline is only required on one occasion[viii].

Symptoms associated with mast cell activation

  • Mediator release causes a wide array of symptoms, including hypertension[xv], hypotension, hypertension, wheezing, itching, flushing, tachycardia, nausea, vomiting, diarrhea, constipation, headache, angioedema, fatigue, and neurologic symptoms[iv].
  • In a small MCAS cohort (18 patients), 17% had a history of anaphylaxis[xvii] . A larger data set is desirable.
  • Patients with history of anaphylaxis should be prescribed epinephrine autoinjectors[v]. If patient must be on a beta blocker, they should be prescribed a glucagon injector for use in the event of anaphylaxis[v].

Response to medications that inhibit action of mast cell mediators

  • Treatment of MCAS is complex and may require a number of medications. Second generation H1 antihistamines; H2 antihistamines; and mast cell stabilizers are mainstays of treatment[xvi].
  • Additional options include aspirin; anti-IgE; leukotriene blocker; and corticosteroids[xiii] .
  • First generation H1 antihistamines may be used for breakthrough symptoms[xiii] .
  • “An important point is that many different mediators may be involved in MCA-related symptoms so that the final conclusion the patient is not responding to antimediator therapy should only be drawn after having applied several different antimediator-type drugs[xiii] .
  • Inactive ingredients are often to blame for reaction to mast cell mediator focused medications. Many mast cell patients see benefit from having medications compounded[xvii].

Natural history

  • In one MCAS cohort of 18 patients, 33% had a complete (no unmanaged symptoms) response and 33% had a major (only one serious symptom) response after one year of mast cell treatment[xviii].
  • In another MCAS cohort of 135 patients, 51% demonstrated significant improvement, 11% had no obvious change in symptom severity and 38% experienced worsening symptoms[v]. (Author’s note: While described in an Afrin 2016[v] paper, the data from this cohort has not yet been published. Molderings is the principle investigator.

 

References

[i] Frieri M, et al. (2013). Mast cell activation syndrome: a review. Current Allergy and Asthma Reports, 13(1), 27-32.

[ii] Molderings GJ, et al. (2013). Familial occurrence of systemic mast cell activation disease. PLoS One, 8, e76241-24098785

[iii] Akin C, et al. (2010). Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol, 126(6), 1099-1104.e4

[iv] Molderings GJ, et al. (2011). Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. Journal of Hematology & Oncology, 4(10), 10.1186/1756-8722-4-10

[v] Castells M, et al. (2013). Expanding spectrum of mast cell activation disorders: monoclonal and idiopathic mast cell activation syndromes. Clin Ther, 35(5), 548-562.

[vi] Afrin LB, et al. (2016). Often seen, rarely recognized: mast cell activation disease – a guide to diagnosis and therapeutic options. Annals of Medicine, 48(3).

[vii] Valent P. (2013). Mast cell activation syndromes: definition and classification. European Journal of Allergy and Clinical Immunology, 68(4), 417-424.

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

[ix] Picard M, et al. (2013). Expanding spectrum of mast cell activation disorders: monoclonal and idiopathic mast cell activation syndromes. Clinical Therapeutics, 35(5), 548-562.

[x] Akin C, et al. (2010). Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol, 126(6), 1099-1104.e4

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

[xii] Lueke AJ, et al. (2016). Analytical and clinical validation of an LC-MS/MS method for urine leukotriene E4: a marker of systemic mastocytosis. Clin Biochem, 49(13-14), 979-982.

[xiii] Vysniauskaite M, et al. (2015). Determination of plasma heparin level improves identification of systemic mast cell activation disease. PLoS One, 10(4), e0124912

[xiv] Zenker N, Afrin LB. (2015). Utilities of various mast cell mediators in diagnosing mast cell activation syndrome. Blood, 126(5174).

[xv] Shibao C, et al. (2005). Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension, 45(3), 385-390.

[xvi] Cardet JC, et al. (2013). Immunology and clinical manifestations of non-clonal mast cell activation syndrome. Curr Allergy Asthma Rep, 13(1), 10-18.

[xvii] Afrin LB. “Presentation, diagnosis and management of mast cell activation syndrome.” In: Mast Cells. Edited by David B. Murray, Nova cience Publishers, Inc., 2013, 155-232.

[xviii] Hamilton MJ, et al. (2011). Mast cell activation syndrome: a newly recognized disorder with systemic clinical manifestations. Journal of Allergy and Clinical Immunology, 128(1), 147-152.e2

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

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

First, let’s review a few things.

The WHO diagnostic criteria for systemic mastocytosis are as follows:

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

 

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

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

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

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

 

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

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

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

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

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

 

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

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

 

References:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

 

 

 

Off the reservation

I am not sure how this is possible, but I have actually never interacted with Brynn Duncan. For those who don’t know, she is one of our young adult mast cell patients. She is very photogenic and seems lovely. She writes a blog about her life and her health struggles. Recently, she has been the subject of some articles on various sites (Buzzfeed, among them) and so I have read about her a lot in the last few weeks.

Today, the American Academy of Allergy, Asthma & Immunology (AAAAI) posted a link to an article in Cosmo about Brynn. (Link here: http://bit.ly/1FvAlUN) In the way that often happens when you have a relatively new, complex medical condition, people began speculating in the comments. Some had questions about her diagnosis (specifically, the criteria used, and whether she met them).

One of the better aspects of rare disease communities is that when the internet feels like doubting the disabling and life altering nature of your condition, there are plenty of people to have your back. The mast cell community showed up in the comments and made their reality known. Mast cell patients know what it is to be doubted, and to suffer for years because of that doubt. They felt that people were doubting Brynn and they reacted in the way they felt best supported her.

Also, please keep in mind that sick people who share their stories for awareness are people. They are people with boundaries and rights to privacy. It is very possible that all of the salient details are not captured in public media.

But there is another layer here that needs to be addressed. And that is this: what exactly is MCAS, and how do you know if you have it? And if you test negative, do you still have it? And that is a conversation that we need to have both inside the community, for patients, and outside the community, for providers to be able to treat mast cell patients effectively.

If you go through the peer reviewed literature, there are multiple sets of diagnostic criteria for MCAS. This is not helpful, but is pretty common for newer diagnoses. Specifically, it is not unusual for clinical entities that don’t have WHO or ICD diagnostic criteria. Clinicians group people together based upon sets of clinical findings, and sometimes lab findings, and uses those as markers for this previously undescribed entity. Doctors and scientists disagree with each other a lot, and so you develop multiple schools of thought on what constitutes X diagnosis. So you potentially multiple distinct groups of patients with the same name attached to their diagnosis. It is very confusing, and can really complicate things when you try to identify exactly what commonalities unify these people.

One of the commentors mentioned that he felt a well-known doctor in the mast cell community used very lax criteria to diagnose MCAS, and in particular, did not meet the criteria published in JACI (J Allergy Clin Immunol). For clarity when referencing my post on differing MCAS criteria, the 2010 Akin and the 2012 Akin, Valent, et al, Consensus proposal, were published in JACI. The Afrin and Molderings 2011 was published in J Hematol Oncol. Here is a comparison of published diagnostic criteria for MCAS:

Gerhard J Molderings, Stefan Brettner, Jürgen Homann, and Lawrence B Afrin. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J Hematol Oncol. 2011; 4: 10.

Cem Akin, MD, PhD, Peter Valent, MD, Dean D. Metcalfe, MD. Mast cell activation syndrome: Proposed diagnostic criteria. Volume 126, Issue 6, December 2010, Pages 1099–1104.e4 Peter Valent, Cem Akin, Michel Arock, Knut Brockow, Joseph H. Butterfield,

Melody C. Carter, Mariana Castells, Luis Escribano, Karin Hartmann, Philip Lieberman, Boguslaw Nedoszytko, Alberto Orfao, Lawrence B. Schwartz, Karl Sotlar,

Wolfgang R. Sperr, Massimo Triggiani, Rudolf Valenta, Hans-Peter Horny,

Dean D. Metcalfe. Definitions, Criteria and Global Classification of Mast Cell Disorders with Special Reference to Mast Cell Activation Syndromes: A Consensus Proposal. Int Arch Allergy Immunol 2012;157:215–225.

MCAD (umbrella term including both MCAS and SM) diagnosed if both major criteria, or one major criterion and one minor criterion, are present; following bone marrow biopsy, diagnosis is narrowed down to either SM or MCAS MCAS diagnosed if all criteria are met MCAS diagnosed if all criteria are met

Major Criteria

Multifocal of disseminated dense infiltrates of mast cells in bone marrow biopsies and/or in sections of other extracutaneous organ(s) (GI tract biopsies; CD117-, tryptase- and CD25- stained)
Episodic symptoms consistent with mast cell mediator release affecting ≥2 organ systems evidenced as follows:
  1. Skin: urticaria, angioedema, flushing
  2. Gastrointestinal: nausea, vomiting, diarrhea, abdominal cramping
  3. Cardiovascular: hypotensive syncope or near syncope, tachycardia
  4. Respiratory: wheezing
  5. Naso-ocular: conjunctival injection, pruritus, nasal stuffiness
Typical clinical symptoms
Unique constellation of clinical complaints as a result of a pathologically increased mast cell activity (mast cell mediator release symptom) A decrease in the frequency or severity or resolution of symptoms with antimediator therapy: H1– and H2-histamine receptor inverse agonists, antileukotriene medications (cysteinyl leukotriene receptor blockers or 5-lipoxygenase inhibitor), or mast cell stabilizers (cromolyn sodium) Increase in serum total tryptase by at least 20% above baseline plus 2 ng/ml during or within 4 h after a symptomatic period
Evidence of an increase in a validated urinary or serum marker of mast cell activation: documentation of an increase of the marker to greater than the patient’s baseline value during a symptomatic period on ≥2 occasions or, if baseline tryptase levels are persistently >15 ng, documentation of an increase of the tryptase level above baseline value on 1 occasion. Total serum tryptase level is recommended as the marker of choice; less specific (also from basophils) are 24-hour urine histamine metabolites or PGD2 or its metabolite 11-β-prostaglandin F2. Response of clinical symptoms to histamine receptor blockers or MC-targeting agents e.g. cromolyn
Rule out primary and secondary causes of mast cell activation and well-defined clinical idiopathic entities

Minor Criteria

Mast cells in bone marrow or other extracutaneous organ(s) show an abnormal morphology (>25%) in bone marrow smears or in histologies
Mast cells in bone marrow express CD2 and/or CD25
Detection of genetic changes in mast cells from blood, bone marrow or extracutaneous organs for which an impact on the state of activity of affected mast cells in terms of an increased activity has been proved
Evidence of a pathologically increased release of mast cell mediators by determination of the content of:

  1. Tryptase in blood
  2. N-methylhistamine in urine
  3. Heparin in blood
  4. Chromogranin A in blood
  5. Other mast cell specific mediators (leukotrienes, PGD2)

 

Additionally, there are differences of opinion on whether or not having a primary mast cell disease (mastocytosis, etc) disqualifies you from having MCAS. Most agree that MCAS can be secondary to another condition, including a number of autoimmune conditions. However, whether allergic type symptoms accompanying systemic mastocytosis, for example, qualifies as MCAS is still not agreed upon. Some feel that these symptoms are inherently part of the SM diagnosis, and that MCAS is a diagnosis of exclusion. Others feel SM refers to a proliferative condition, whereas MCAS refers to the inappropriate allergic response. It is a mess for patients, caregivers, researchers, doctors familiar with the condition and doctors who aren’t.

Compounding this issue is the fact that the test most doctors are likely to be familiar with (tryptase) often yields results in normal range. Sometimes, patients experiencing flagrant anaphylaxis under the banner of MCAS will not even demonstrate the 2ng/ml + 2% above baseline that some experts consider indicative of degranulation. Tryptase, like all other mediator tests used to diagnose MCAS, is time sensitive. But sometimes one normal tryptase is enough for doctors to dismiss MCAS as a possible diagnosis (for the record, about 15% of SM patients also have normal tryptase levels).

But then how do you know it’s MCAS and not something else? Therein lies the crux. I think for patients who are experiencing unmistakable anaphylaxis resolved by epinephrine, it is a smaller jump of logic to land on MCAS. But what about so many mast cell patients with non-specific symptoms and negative test results? Do they all have MCAS?

The answer is that we don’t know, and furthermore, that it depends heavily on how you define it. Many doctors use response to typical mast cell medications (antihistamines, stabilizers) as proof of MCAS. But mast cells are involved in so many types of inflammation that treating mast cell degranulation is likely to help with a number of other conditions as well. If the patient is improving, I think most doctors are inclined to continue treatment while still looking for other possible causes. But what if the patient doesn’t improve? What if they get worse?

Diagnoses of exclusion can be dangerous in that many times it is eventually proven wrong. Treating for the wrong disease can be disastrous – both in the potential adverse effects and in the potential to mask the true diagnosis indefinitely. I understand the reluctance to operate under an unusual diagnosis with no empirical proof that it is the right one.

However, there is also a long precedent in medicine in treating “like” diseases with treatments defined for its look alike condition. For example, treating someone who “looks” like they have lupus, as regards symptoms or borderline laboratory findings, with lupus medications is not unusual. And I think that this needs to be considered. Because at the end of the day, MCAS patients are sick. These are people who often have severe, life threatening anaphylactic episodes and daily symptoms that affect their ability to function in the world. Making an educated guess and proceeding cautiously is a well established practice in medicine.

All biomarkers were once unknown. Medicine, and science, are living entities that evolve over time. Eventually causes for diseases are identified and tests developed, and then better tests. This is just another example of not being able to detect well something we haven’t known for very long we needed to look for.

In spite of these difficulties, I think it’s important for clinicians not to lose sight of this fact: MCAS is real. And it’s quite possible that it’s not as rare as we think. One researcher has estimated that MCAS associated mutations may occur in over 5% of the population (Molderings 2014). If this bears fruit, then these people in your office needing help are only the first wave of a growing population that is allergic to the world. We are off the reservation right now, but these people still need help.

 

References:

G.J. Molderings. The genetic basis of mast cell activation disease – looking through a glass darkly. Critical Reviews in Oncology/Hematology 2014.

G.J. Molderings, B. Haenisch, M. Bogdanow, R. Fimmers, M.M. Nöthen. Familial occurrence of systemic mast cell activation disease. PLoS One, 8 (2013), p. e76241

Gerhard J Molderings, Stefan Brettner, Jürgen Homann, and Lawrence B Afrin. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J Hematol Oncol. 2011; 4: 10.

Cem Akin, MD, PhD, Peter Valent, MD, Dean D. Metcalfe, MD. Mast cell activation syndrome: Proposed diagnostic criteria. Volume 126, Issue 6, December 2010, Pages 1099–1104.e4

Peter Valent, Cem Akin, Michel Arock, Knut Brockow, Joseph H. Butterfield, Melody C. Carter, Mariana Castells, Luis Escribano, Karin Hartmann, Philip Lieberman, Boguslaw Nedoszytko, Alberto Orfao, Lawrence B. Schwartz, Karl Sotlar, Wolfgang R. Sperr, Massimo Triggiani, Rudolf Valenta, Hans-Peter Horny, Dean D. Metcalfe. Definitions, Criteria and Global Classification of Mast Cell Disorders with Special Reference to Mast Cell Activation Syndromes: A Consensus Proposal. Int Arch Allergy Immunol 2012;157:215–225.

Juan-Carlos Cardet, Maria C. Castells, and Matthew J. Hamilton. Immunology and Clinical Manifestations of Non-Clonal Mast Cell Activation Syndrome. Curr Allergy Asthma Rep. Feb 2013; 13(1): 10–18.

Britta Haenisch, Markus M. Nothen and Gerhard J. Molderings. Systemic mast cell activation disease: the role of molecular genetic alterations in pathogenesis, heritability and diagnostics. Immunology 2012, 137, 197–205.

Matthieu Picard, Pedro Giavina-Bianchi, Veronica Mezzano, Mariana Castells. Expanding Spectrum of Mast Cell Activation Disorders: Monoclonal and Idiopathic Mast Cell Activation Syndromes. Clinical Therapeutics, Volume 35, Issue 5, May 2013, Pages 548–562.

 

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Progression of mast cell diseases (Part 4)

If ISM is life threatening, why is not considered as dangerous as ASM or MCL?

ISM is not life threatening. Anaphylaxis is life threatening. They are not the same. Many people with ISM never experience anaphylaxis. ISM can make anaphylaxis more dangerous, but ISM is not the same as anaphylaxis. Outside of anaphylaxis, ISM is not life threatening.

“Indolent systemic mastocytosis (SM) patients have a varied clinical presentation, ranging from predominantly cutaneous symptoms to recurrent systemic symptoms (eg, flushing, palpitations, dyspepsia, diarrhea, bone pain) that can be severe and potentially life threatening (anaphylaxis.)” (Pardanini 2013)

 

Is MCAS more or less dangerous than ISM?

“From a clinical standpoint, MMAS and MCAS share many similarities with systemic mastocytosis (SM), a primary disorder of mast cells in which patients experience symptoms ranging from pruritus and flushing to anaphylaxis.” (Picard 2013)

Again, the real danger here is anaphylaxis rather than these entities themselves. Statistically, the numbers don’t have a lot of uniformity regarding frequency of anaphylaxis in SM, what constitutes a severe reaction, and so on. Additionally, there are multiple definitions of MCAS and how that is distinguished from IA, which is really important to understanding the true frequency of anaphylaxis in MCAS. However, the data currently shows a trend of anaphylaxis being less common in MCAS than in SM. Still, it is important to realize that this may be due to less research being available on MCAS than mastocytosis.

“In our cohort 3 [MCAS] patients (17%) had a history of anaphylaxis. These patients were included in our cohort because they had primary symptoms characteristic of MCAS that responded to medications and had other laboratory evidence of MC mediator release…There likely exists a spectrum of disease for MCAS in which the more severe form includes anaphylaxis and a spectrum of IA in which a form includes MCAS symptoms.” (Hamilton 2011)

It is well known that people with mastocytosis are more likely to experience anaphylaxis than the general public. In adults with any type of mastocytosis, 49% experience anaphylaxis. Patients with systemic mastocytosis were more likely to anaphylax than those with cutaneous mastocytosis. In adults, 48% of the anaphylactic reactions were severe, with 38% causing unconsciousness. 60% of those reactions were Grade III anaphylaxis. (Brockow 2008)

“In 4 of the 137 [SM] patients (3%), severe life-threatening anaphylaxis resulting in a severe handicap with or without transient or permanent disability occurred.” (Wimazal 2012)

“Prolonged hypotension following anaphylaxis and cerebral hypoxia were identified as major factors leading to a substantial handicap, clinical deterioration or even death in these patients.” (Wimazal 2012)

“However, in both patients in whom recurrent life-threatening anaphylaxis was recorded, the smoldering subtype of SM with a huge burden of MCs was diagnosed, whereas most patients in whom only one documented severe life-threatening event had occurred were found to have low-grade SM with a low burden of MCs.” (Wimazal 2012)

“Thirty-six [SM] patients (43%) had had at least one episode of an anaphylactic reaction. The clinical courses of the reactions were usually severe and patients often presented with syncope attacks (72%). Most patients reacted after hymenoptera venom stings (19/36; 53%). In 39% (14/36), a clear etiology could not be determined. While males and females were equally frequent among the patients with SM, anaphylaxis patients showed a male predominance (61%). Anaphylactic reactions occurred more frequently in patients without cutaneous engagement. The rate of allergy sensitization was significantly higher in SM patients with anaphylaxis as compared with non-anaphylaxis SM patients, 70% vs. 23%, respectively.” (Gulen 2014)

 

Does an elevated GI mast cell count tract (in the absence of aberrant receptors, clustering or spindled mast cells) indicate MCAS or SM?

“Our immunohistochemical analysis led us to the conclusion that there was no significant difference between the numbers of intestinal mucosal MCs in our patients with MCAS and our reference standard. We recognize that there is currently no consensus for what constitutes a normal number of MCs in the various intestinal tissues. We therefore chose data from a recently published study by one of the authors to be the reference standard. In this study normal numbers of MCs were tabulated for each tissue site. Although we did not find appreciably increased numbers of MCs or abnormal morphology, it is possible that patients with MCAS have a different threshold for MC activation and differentially release MC mediators on activation or that peripheral tissues have an abnormal response to these mediators. We also recognize that a population of patients with chronic diarrhea has been described and labeled as having mastocytic enterocolitis. These patients had a greater number of MCs per hpf in duodenal and colon biopsy specimens compared with the control population (>20 vs 13 MCs/hpf). We were not able to verify this observation in our cohort because many of our control population biopsy specimens had more than 20 MCs/hpf.” (Hamilton 2011)

 

What is the relationship between CM and MCAD (including SM and MCAS)?

“[M]ost patients with adult-onset MIS [mastocytosis in the skin (commonly called cutaneous mastocytosis,CM)] have demonstrable bone marrow (BM) involvement with clonal mast cells when modern-era diagnostic tools are used, in most instances, satisfying WHO diagnostic criteria for SM. While historical series of patients with MIS revealed an 18% to 50% prevalence of systemic involvement based on conventional histologic criteria, more modern series suggest that only a minority of adult patients have skin-limited disease. Further, approximately 50% of adults with apparent skin-limited mastocytosis may have a clonal BM mast cell infiltrate that falls short of the diagnostic threshold for SM (satisfies major criterion only or only 1 or 2 minor criteria), suggesting prediagnostic or early stage of ISM.” (Pardanini 2013)

“The relationship between systemic MCAD and cutaneous mastocytosis (CM, synonyms: paediatric or childhood onset mastocytosis) remains unclear. Early studies suggested that CM and systemic MCAD were separate disease entities, because the majority of CM patients were found to lack mutations of the tyrosine kinase KITgene. However, subsequent studies have demonstrated that the frequency of clonal KIT mutations is similar in patients with CM, SM and MCAS, and that they are present in up to 86% of patients from each diagnostic group.” (Haenisch 2012)

“Interestingly, in contrast to adult-onset systemic MCAD, more than 50% of paediatric cases of cutaneous mastocytosis appear to enter long-term remission spontaneously, though whether such remissions are permanent or relapse in adulthood as systemic MCAD is unknown.” (Haenisch 2012)

“In contrast, most adults with CM have an underlying SM and should undergo a bone marrow biopsy regardless of the presence of associated systemic symptoms of mediator release. Conversely, 80% of SM patients have cutaneous disease that manifests as urticaria pigmentosa. In contrast, patients with MMAS and MCAS never have CM, and patients with ASM or MCL frequently lack CM.” (Picard 2013)

 

References:

Juan-Carlos Cardet, Maria C. Castells, and Matthew J. Hamilton. Immunology and Clinical Manifestations of Non-Clonal Mast Cell Activation Syndrome. Curr Allergy Asthma Rep. Feb 2013; 13(1): 10–18.

Britta Haenisch, Markus M. Nothen and Gerhard J. Molderings. Systemic mast cell activation disease: the role of molecular genetic alterations in pathogenesis, heritability and diagnostics. Immunology 2012, 137, 197–205.

Animesh Pardanani. How I treat patients with indolent and smoldering mastocytosis (rare conditions but difficult to manage.) April 18, 2013; Blood: 121 (16).

Matthieu Picard, Pedro Giavina-Bianchi, Veronica Mezzano, Mariana Castells. Expanding Spectrum of Mast Cell Activation Disorders: Monoclonal and Idiopathic Mast Cell Activation Syndromes. Clinical Therapeutics, Volume 35, Issue 5, May 2013, Pages 548–562.

Gerhard J Molderings, Stefan Brettner, Jürgen Homann, Lawrence B Afrin. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. Journal of Hematology & Oncology 2011, 4:10.

Brockow, C. Jofer, H. Behrendt and J. Ring. Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients. Allergy, Volume 63, Issue 2, pages 226–232, February 2008.

Wimazal F., Geissler P., Shnawa P., Sperr W.R., Valent P. Severe Life-Threatening or Disabling Anaphylaxis in Patients with Systemic Mastocytosis: A Single-Center Experience. Int Arch Allergy Immunol 2012; 157: 399–405.

Gülen, H. Hägglund, B. Dahlén and G. Nilsson. High prevalence of anaphylaxis in patients with systemic mastocytosis – a single-centre experience. Clinical & Experimental Allergy, Volume 44, Issue 1, pages 121–129, January 2014.

 

 

 

Progression of mast cell diseases (Part 3)

What causes aberrant mediator release in mast cell activation diseases (including MCAS and SM)?

“Selective release of mediators during mast cell activation may be accomplished in three important and possibly interrelated ways. One is by activation via one of the mast cell’s non-IgE receptors, for instance, through the activation of the IL-1 receptor… Another way in which mast cells may selectively activate is through ‘piecemeal’ release of mediators stored in the secretory granules (such as histamine and serotonin)… Lastly, downstream signaling pathways may affect mast cell activation… Differential activation of mast cells in any of these ways may clinically manifest as nc-MCAS.” (Cardet 2013)

“It is also conceivable that mast cells in this group of patients may aberrantly possess a lower threshold to release mediators… It is also conceivable that patients with nc-MCAS are symptomatic because of an abnormal tissue response to physiologically appropriate release of MC mediators.” (Cardet 2013)

“The mutations underlying systemic MCAD drive aberrant mediator production/release with or without readily histologically detectable mast cell accumulation. Mast cell accumulation is due predominantly to a decrease in mast cell apoptosis (refs 30,31 and further references therein). On a limited scale, it is also due to an increase in proliferation.” (Haenisch 2012)

 

Do all SM patients have elevated n-methylhistamine and prostaglandin F2a?

71% had elevated urinary histamine in 24 hr test; 81% had elevated urinary n-methylhistamine in 24 hr test; 75% had elevated urinary PGF2a in 24 hr test. (Lim 2009)

 

If my tryptase is normal, does that mean I don’t have SM?

In patients tested, 96% had elevated tryptase over 11.5 ng/ml. (Lim 2009)

“20% to 30% of SM patients have serum tryptase levels below the WHO-defined threshold of 20 ng/mL (sensitivity 80%, specificity 98%).” (Pardanini 2013)

 

If my blood test for the D816V mutation is negative, I definitely don’t have it, right?

“The sensitivity of KITD816V detection in peripheral blood is suboptimal, and tests for non-KITD816V mutation screening may not be readily available.” (Pardanini 2013)

“I prefer using DNA from BM aspirate for KITD816V screening given the low sensitivity of peripheral blood in this regard… Using this approach, we found 78% of ISM patients to harbor KITD816V.” (Pardanini 2013)

“Although, the sensitivity of KITD816V detection may be higher when using sorted or purified mast cells, this option is not routinely available. Consequently, the inability to detect KITD816V in peripheral blood does not exclude SM [].” (Pardanini 2013)

 

How often do SM patients not meet the major diagnostic criteria (mast cell aggregates)?

“Attempts at validating the WHO diagnostic criteria reveal that approximately 20% of ISM patients lack mast cell clusters in the BM and approximately 30% exhibit a serum tryptase level < 20 ng/mL.” (Sanchez 2011)

 

Is MCAS the same as HIT (histamine intolerance)?

“[S]ome have proposed that a deficiency in the enzymes responsible for histamine metabolism, diamine oxidase (DAO) and histamine N-methyltransferase, leads to excess levels of histamine and therefore histamine intolerance, with clinical manifestations not unlike those described for nc-MCAS… There is no scientific literature to support their relevance to nc-MCAS.” (Cardet 2013)

 

Are MCAS patients usually positive for the three most commonly tested mediators (tryptase, n-methylhistamine, PGD2?)

“Although all of our patients with MCAS had a positive test result for at least 1 MC mediator, only 33%, 56%, and 44% of the patients had positive test results for tryptase, histamine, and PGD2, respectively.” (Hamilton 2011)

 

Will my MCAS symptoms ever get better?

“Most patients with MCAS in our cohort who were treated with anti-MC mediator medications responded dramatically. After an average of 4.6 years of MC-related symptoms, 66% of the patients with MCAS achieved a complete or major regression in symptoms to MCAS treatment.” (Hamilton 2011)

“It is important to mention that no defining characteristics (eg, presence of allergies or history of anaphylaxis) could be identified that distinguished those who had a complete regression in symptoms versus those who did not.” (Hamilton 2011)

“The most impressive treatment responses were for abdominal pain (14/17 of the patients who initially had the symptom responded), headache (12/15), poor concentration and memory (7/12), and diarrhea (9/12); there was a more modest response to flushing (6/16). We also found that all but 1 of our patients with MCAS had a sustained response to anti-MC mediator medications. Patients in our cohort were followed for an average of 2.8 years (range, 1-4 years).” (Hamilton 2011)

“In patients with MCAS the rate of response to antimediator therapy is rather good, with 33% showing complete response, 33% a major response, and 33% a minor response after 1 year of treatment.” (Picard 2013)

 

How prevalent is MCAS?

“MCAS seems to be a more common disorder. Evidence has been presented that MCAS may be an underlying cause of various clinical presentations, e.g. in subsets of patients with fibromyalgia and irritable bowel syndrome. Hence, the prevalence of MCAS is likely to lie within the single-digit percentage range.” (Haenisch 2012)

“Mast cell activation disease in general has long been thought to be rare. However, although SM and MCL as defined by the WHO criteria are truly rare, recent findings suggest MCAS is a fairly common disorder. Evidence has been presented for a causal involvement of pathologically active mast cells not only in the pathogenesis of SM and MCAS but also in the etiology of idiopathic anaphylaxis, interstitial cystitis, some subsets of fibromyalgia and some subsets of irritable bowel syndrome.” (Molderings 2011)

 

References:

Juan-Carlos Cardet, Maria C. Castells, and Matthew J. Hamilton. Immunology and Clinical Manifestations of Non-Clonal Mast Cell Activation Syndrome. Curr Allergy Asthma Rep. Feb 2013; 13(1): 10–18.

LimKH, TefferiA, LashoTL, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood 2009; 113(23): 5727-5736.

Britta Haenisch, Markus M. Nothen and Gerhard J. Molderings. Systemic mast cell activation disease: the role of molecular genetic alterations in pathogenesis, heritability and diagnostics. Immunology 2012, 137, 197–205.

Animesh Pardanani. How I treat patients with indolent and smoldering mastocytosis (rare conditions but difficult to manage.) April 18, 2013; Blood: 121 (16).

Matthieu Picard, Pedro Giavina-Bianchi, Veronica Mezzano, Mariana Castells. Expanding Spectrum of Mast Cell Activation Disorders: Monoclonal and Idiopathic Mast Cell Activation Syndromes. Clinical Therapeutics, Volume 35, Issue 5, May 2013, Pages 548–562.

Gerhard J Molderings, Stefan Brettner, Jürgen Homann, Lawrence B Afrin. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. Journal of Hematology & Oncology 2011, 4:10.