Take home points: October 2015

Childhood mastocytosis: Update

  • Cutaneous mastocytosis in children is the most common form of mastocytosis
  • True systemic mastocytosis is very rare in children
  • An NIH study of 105 children found 30-65% improved over time
  • Elevated baseline tryptase level and organ swelling were good indicators of SM
  • Serum tryptase should be measured every 6-12 months
  • Children with swelling of both liver and spleen were positive for CKIT D816V mutation
  • Swelling of liver and spleen together was linked to disease persisting into adulthood
  • Most children with UP with skin and minor GI issues had normal tryptase
  • Diffuse cutaneous mastocytosis patients had a much higher average tryptase but no organ swelling
  • Serum tryptase and IgE were inversely related (high tryptase with low IgE, low tryptase with high IgE)

Chronic mast cell leukemia: a new variant of systemic mastocytosis

  • Mast cell leukemia (MCL) has a significantly shortened lifespan
  • Usually over 20% of nucleated cells in bone marrow are atypical mast cells
  • Mast cells are present in large quantities on the blood
  • Cases where less than 10% of white blood cells in blood are mast cells are called aleukemic variant MCL
  • Cases where over 20% of nucleated cells in bone marrow are mature mast cells are called chronic MCL
  • Chronic MCL patients do not have any C findings (the clinical markers for SM patients associated with very aggressive disease)
  • Chronic MCL patients have stable disease state but can progress to acute MCL at any time
  • Mediator release symptoms are more common in chronic MCL than acute MCL
  • Acute MCL is marked by immature CD25+ mast cells
  • Acute MCL patients do have C findings (the clinical markers for SM patients associated with very aggressive disease)
  • Acute MCL has a very short survival time, usually less than a year

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

A 2007 paper assessed the reliability of CD25 on GI mast cells as a marker of systemic mastocytosis. This study determined mast cell burden in stomach, small intestine and colon of patients with SM and compared it to patients with urticaria pigmentosa, various inflammatory GI conditions and healthy controls. Mast cells were detected using antibodies for tryptase and CD25 (IHC) and counted in 10 hpf and averaged.

In the stomach, SM patients averaged 57 mast cells/hpf, compared to 14/hpf for urticaria pigmentosa patients; 23.7/hpf for other inflammatory GI conditions; and 12/hpf for healthy controls.  Conditions other than SM that caused over 20 mast cells/hpf in the stomach were H. pylori positive gastritis and bile reflux esophagus.  Some healthy controls also had a count of 20/hpf or higher. See Table 17 for details.

In the small intestine, SM patients averaged 175 mast cells/hpf; urticaria pigmentosa, 22 mast cells/hpf; other inflammatory GI conditions, 20.3 mast cells/hpf; and healthy controls, 27 mast cells/hpf in the duodenum and 32 mast cells/hpf in the terminal ileum. Conditions other than SM that caused over 20 mast cells/hpf in the small intestine were peptic duodenitis, celiac disease, irritable bowel syndrome and eosinophilic enteritis.  See Table 18 for details.

In the colon, SM patients averaged 209 mast cells/hpf; urticaria pigmentosa, 13/hpf; other inflammatory GI conditions, 20.4/hpf; and healthy controls, 21/hpf. Conditions other than SM that caused over 20 mast cells/hpf in the colon were ulcerative colitis, Crohn’s colitis, lymphocytic colitis, irritable bowel syndrome and parasitic infection.  See Table 19 for details.

Table 17: Mast cell count in stomach of patients with systemic mastocytosis
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.
Microscopy method: 400x magnification, mast cells counted in 10 hpf and averaged
Visualization: Tryptase and CD25 (IHC)
Sample type Study group: Systemic mastocytosis Study group: Urticaria pigmentosa Study group: Inflammatory GI conditions Control group A:Healthy control
Stomach Average Range Average Range Average Range Average Range
57 mast cells/hpf 24-90 mast cells/hpf 14 mast cells/hpf 10-17 mast cells/hpf 23.7 mast cells/hpf 6-23.3 mast cells/hpf 12 mast cells/hpf 5-21 mast cells/hpf
Clusters/dense infiltrates or confluent sheets. Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters.

 

Table 18: Mast cell count in small intestine of patients with systemic mastocytosis
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.
Microscopy method: 400x magnification, mast cells counted in 10 hpf and averaged
Visualization: Tryptase and CD25 (IHC)
Sample type Study group: Systemic mastocytosis Study group: Urticaria pigmentosa Study group: Inflammatory GI conditions Control group A:Healthy control
Small intestine Average Range Average Range Average Range Average Range
175 mast cells/hpf 74-339 mast cells/hpf 22 mast cells/hpf 12-32 mast cells/hpf 20.3 mast cells/hpf 17.5-33 mast cells/hpf 27 mast cells/hpf(duodenum)32 mast cells/hpf (terminal ileum) 4-51 mast cells/hpf (duodenum)21-40 mast cells/hpf (terminal ileum) 

 

Clusters/dense infiltrates or confluent sheets. Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters.

 

Table 19: Mast cell count in colon of patients with systemic mastocytosis
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.
Microscopy method: 400x magnification, mast cells counted in 10 hpf and averaged
Visualization: Tryptase and CD25 (IHC)
Sample type Study group: Systemic mastocytosis Study group: Urticaria pigmentosa Study group: Inflammatory GI conditions Control group A:Healthy control
Colon Average Range Average Range Average Range Average Range
209 mast cells/hpf 110-301 mast cells/hpf 13 mast cells/hpf 8-19 mast cells/hpf 20.4 mast cells/hpf 12.1-33.4 mast cells/hpf 21 mast cells/hpf 10-31 mast cells/hpf
Clusters/dense infiltrates or confluent sheets. Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters.

 

Table 20: Inflammatory GI conditions associated with mast cell over 20/hpf in at least one biopsy
Stomach Small intestine Colon
Gastritis from H. pylori infection Peptic duodenitis Ulcerative colitis
Bile reflux gastropathy Celiac disease Crohn’s disease colitis
Healthy stomach tissue Irritable bowel syndrome Collagenous colitis
Eosinophilic enteritis Lymphocytic colitis
Healthy duodenum and ileum Irritable bowel syndrome
Parasitic worm infection
Eosinophilic colitis
Healthy colon tissue

 

A 2014 paper (Doyle 2014) summarized results of GI biopsies from various locations for patients with systemic mastocytosis.  Mast cell count in SM patients ranged from 20-278/hpf, with an average of 116/hpf. Most biopsies in SM patients contained clusters of mast cells or confluent sheets. 25% of positive biopsies had only one cluster of mast cells. 21% showed multiple clusters within a biopsy while other biopsies from the same region showed no mast cells.  Three biopsies from SM patients showed dispersed cells that were CD25+.

In actual practice, many doctors do not take a variety of biopsies, especially if there is no gross abnormality visualized during scoping.  This highlights the need to test for CD25. It also provides evidence that while clustering is a defining characteristic of SM, in some tissue spaces, clustering may be absent despite being present elsewhere in the same organ.

Positivity for some markers associated with systemic mastocytosis, but not enough to receive a diagnosis of SM per WHO criteria, yields a diagnosis of monoclonal mast cell activation syndrome (MMAS).  Patients with MMAS display clonality of mast cells despite not meeting criteria for SM.  In research circles, MMAS is sometimes referred to as preclinical SM.  It is possible that MMAS represents a very early stage of SM.  MMAS is managed the same way as SM and markers of clonality (25% or more mast cells in a hpf spindle shaped, positivity for CD25 and/or CD2 receptor(s), clustering of mast cells in groups of 15 or more, positivity for CKIT D816V mutation, serum tryptase baseline of 20 ng/ml or higher) should be taken seriously as an indication of proliferative mast cell disease.

 

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.

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

In 2009, Walker and colleagues published a paper called “Duodenal mastocytosis, eosinophilia and intraepithelial lymphocytosis as possible disease markers in the irritable bowel syndrome and functional dyspepsia.”  The term “mastocytosis” as used here is not equivalent the term “mastocytosis” as in cutaneous mastocytosis or systemic mastocytosis. It is one of several papers to do so and has generated a lot of confusion as a result.

The suffix –osis is commonly used in medical terminology.  It means increase or production of something, but it also connotes that this increase results from a disease process.  Here, the author means not that these patients meet the criteria for systemic mastocytosis, which we know to be a neoplastic disease originating in the bone marrow, but that there are more mast cells than expected in these biopsies.

Excessive production of mast cells in an organ that is not the skin is the defining feature of systemic mastocytosis.  SM patients show some combination of the following characteristics: infiltration of tissue with mast cells clustered together; expression of receptors CD25 and/or CD2 on the mast cells; spindle shaped mast cells; presence of the CKIT D816V mutation; and  baseline tryptase over 20 ng/ml.  When a patient shows too many mast cells without having any of these markers, it is not called mastocytosis.  It is called mast cell hyperplasia.

Consider the following two scenarios:

Let’s imagine that you are a house builder.  For many years, you only build houses when people call your boss and say they need a house.  After your boss gets the call, she calls you to tell you to build a house for these people in the location they have requested.  Sometimes more people need houses than others, so at times you make more, and other times, you make less.  You never build houses unless your boss tells you to and you are able to build them correctly due to having the correct time and resources.  You may think that your boss is telling you to build too many houses sometimes but it is always because she is getting lots of requests from customers to build houses.

In this scenario, mast cells are house builders. They only make new mast cells when they receive appropriate signals from the body.  Sometimes your body makes more mast cells, like to fight an infection or when you have an allergic response.  But the mast cells ALWAYS wait for the correct signal from the body to make more cells.  They do not decide to make too many cells on their own.

Now let’s imagine that after years of being a house builder, you wake up one day with a compulsion to see how fast you can build a house.  Your boss calls you and says she needs one house, so you build that house and then you build four more at the same time.  Instead of building carefully one at a time, you are building five houses at the same time.  This means the houses are not built correctly.  You call your boss to say you are done with the five houses and your boss gets mad.  Where are we going to put these extra four houses?  She decides to move those four houses to another town that doesn’t have too many houses yet.  She tells you not to make too many houses again.

But you just cannot stop making houses.  Making houses is the best!  Who cares if there are little mistakes?  People can still live in them safely.  You wake up every day with a fervent need to build houses.  Your friends and family are concerned about you and stage an intervention.  You will not be moved.  You are building tons of houses at once now.  Your boss is calling you screaming at you to stop making houses because they are defective and she doesn’t have anywhere to put them.  She has been sending them to places that already have too many houses so it is getting really crowded and people are complaining.  You stop answering your boss’s calls.  These people don’t understand the importance of building houses.  No matter what anyone says to you, you will not stop making houses and they cannot make you stop.

In this scenario, the problem isn’t that the boss is telling the builder to make too many houses.  The problem here is that the builder is ignoring all the signals to stop.  This scenario represents systemic mastocytosis.  The mast cells here are making too many mast cells for the wrong reasons and they don’t work right.

I want to be very clear about something – the fact that a person has a lot of mast cells per hpf but doesn’t have markers for SM does NOT mean that these people are not suffering.  Regardless of how the mast cells ended up there in excessive populations, they will cause large scale inflammation and GI symptoms.  Nor am I saying that phenomena like mastocytosis enterocolitis or allergic mastocytic enterocolitis are definitely not mast cell diseases – it is possible that the mast cells in those cases demonstrate markers we have not yet found or that there is an error in the cells that become mast cells.  I am just describing the way these two categories are distinguished from one another at this time.  It is not my intention to disenfranchise anyone.  We are all united in the suckage that is GI symptoms as a result of mast cells.

How do you tell the difference between systemic mastocytosis and mast cell hyperplasia?  That is the purpose of the SM diagnostic criteria.  As I said before, you need to meet one major and one minor criterion, or three minor criteria, from the WHO Systemic mastocytosis criteria.  If you meet some of the criteria, but not enough for SM, that is still evidence of a clonal, proliferative mast cell disease.  This means that it is still evident that too many mast cells are being made despite signals to stop.  The state of meeting some criteria for SM but not enough for an SM diagnosis is called monoclonal mast cell activation syndrome (MMAS). This topic will be covered in detail in a later post in this series.

Many diseases involve mast cells, including various cancers and autoimmune diseases, among others. So why aren’t they considered mast cell diseases like systemic mastocytosis and mast cell activation syndrome? These are not mast cell diseases because in these situations, mast cells are getting signals to make too many mast cells and to cause inflammation.  They are the house builder when the boss is telling them to make more houses than usual, but the boss is doing that because customers need those houses.  Mast cell diseases are the house builder that has a compulsion to build houses even when they aren’t needed and everyone is telling them to stop.

Remember this distinction when you are reviewing papers and pathology reports.  The word mastocytosis is often used when they really mean mast cell hyperplasia.  Mastocytosis in proper usage means too many mast cells because the mast cells are defective.  Mast cell hyperplasia means too many mast cells because the mast cells are receiving inflammatory signals from elsewhere.

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.

 

 

 

Childhood mastocytosis: Update

One of the more confusing aspects of mastocytosis is that childhood mastocytosis often bears little resemblance to adult-onset mastocytosis and has a very different natural history.  Cutaneous mastocytosis in children is the most common presentation of mastocytosis. True systemic mastocytosis (meeting WHO SM criteria) is quite rare in pediatric cases.

A recent paper describes the features of 105 children assessed at the NIH.  They found that the children in this group either had a stable disease state or improved, with 30-65% getting better over time.  None of the children received cytoreductive therapy.

They found that in this group, children with normal baseline tryptase levels had negative bone marrow biopsies.  A single elevated tryptase level was not determined to correlate well with to a positive bone marrow, rather an elevated baseline tryptase was a good indicator of SM. No children without systemic mastocytosis had organ swelling.

Likewise, all children with systemic mastocytosis had both elevated baseline tryptase and swelling of internal organs.  Bone marrow mast cell burden correlated well with tryptase value. The average tryptase for children with SM in this study was 111.5 ng/ml. Tryptase decreased over time in some SM children.  The researchers recommended evaluation of serum tryptase every 6-12 months.

All children with organ swelling were found to have SM. Children with swelling of both liver and spleen were found to be positive for the D816V CKIT mutation.  Swelling of both of these organs indicates that disease is more likely to persist into adulthood.  Of total 19 children with SM, 16 were positive for the CKIT D816V mutation.

In children with UP, the average tryptase value was 5.9 ng/ml. Twelve children with UP had tryptase values of 11-20, and six had values over 20. Children with UP most often saw significant decreases in tryptase levels over time.   Most UP children with skin and minor GI issues had normal tryptase values.

Children with DCM had much higher average tryptase values, with an average of 67. 85% of DCM children had tryptase over 20 ng/ml when diagnosed.  None of them had swelling of organs.

Of 105 children assessed in this study, 3 had elevated monocytes; 22 had elevated white blood cells; and 12 had elevated platelets.  All of these values returned to normal by the end of the study.  Seven had increased clotting time (PTT). Of those with longer clotting times, four had lupus antibodies and one had Factor VII deficiency. All seven PTT values returned to normal.  Two children with DCM and one with UP had iron deficiency anemia.  One patient had significant elevation of alkaline phosphatase, which resolved.  Researchers noted an inverse correlation between serum tryptase and IgE levels in this group.

Reference:

Carter et al. Assessment of clinical findings, tryptase levels, and bone marrow histopathology in the management of pediatric mastocytosis. J Allergy Clin Immunol 2015.

Chronic mast cell leukemia: A new variant of systemic mastocytosis

Mast cell leukemia (MCL) is a variant of systemic mastocytosis (SM) marked by a significantly shortened lifespan.  In MCL, patients experience massive and devastating proliferation of immature mast cells.  The bone marrow is always affected and the huge amount of mast cells means there is no room for other types of blood cells. Usually, the bone marrow smear reveals over 20% of nucleated cells in bone marrow are atypical mast cells, as well as large quantities present in the blood.  In the aleukemic variant, less than 10% of all white cells in the blood are mast cells.

In most patients with MCL, C-findings (markers of organ infiltration and damage progressing to organ failure) are present.  These include such features as hypersplenism, liver damage, very low blood cell counts, and others.  However, in the last several years, a number of MCL patients described who do not have C findings.  These patients have over 20% mast cells in the nucleated cells of the bone marrow, but the mast cells are mostly mature, and most do not circulate in the blood stream.  This population often demonstrates stability rather than rapid progression toward death, as was previously seen in most MCL patients.  The term “chronic MCL” has been suggested to describe this group.

The more classic MCL presentation (now called acute MCL) has a number of differences from chronic MCL.  In acute MCL, most of the mast cells are not mature, with metachromatic blast cells.  In acute MCL, CD25 receptor is always present on the cells, while this only sometimes occurs in the chronic course.  Chronic MCL never expresses Ki-67 on the outside of the cells, while this is sometimes seen in acute MCL.  Both acute and chronic sometimes have CD2 and D816V mutation, but not always.  Spindle shaped mast cells are almost never present in acute MCL.  Swelling of the spleen is always seen in acute MCL, but only sometimes in the chronic form.  Chronic MCL patients have no C findings.  If they develop a C finding, they are reclassified as acute MCL.

Acute MCL has long been associated with very short survival times following diagnosis, most often less than a year.  This can be extended in some patients with the use of newer medications.  Remarkably, patients with chronic MCL demonstrate a largely stable clinical course comparable to smouldering SM.  In both of these conditions, tryptase levels are high but stable; the spleen is most often swollen; and mast cell burden is high.  Patients with chronic MCL usually have no mast cell skin lesions.

Chronic MCL patients can be stable for years, but can progress to acute MCL or MCL-AHNMD at any time.  Mediator release symptoms more often seen in indolent mast cell diseases are also common in chronic MCL, while less so in acute MCL.

Reference:

P. Valent et al. Chronic mast cell leukemia: A novel leukemia-variant with distinct morphological and clinical features. 23eukemia Research 39 (2015) 1-5.

Questions on bone involvement

I wrote these posts in direct response to an email I received from a person in the MastAttack Facebook group (feel free to join) who follows the blog. This person had the following questions:

1) Are osteosclerotic lesions the same as/affiliated with the terms sclerotic, blastic and osteoblast?

Lisa’s response: Sclerotic is associated with the term osteosclerotic. Osteosclerotic means “bone hardening”. Sclerotic can also be used to describe other pathologies, like dermatosclerotic.

Blastic is associated with the term osteoblast, but it can also mean several other cell types. One example of the word “blast” is to mean an immature blood cell. In this context, high levels of blasts can mean severe infection or blood cancers. Osteoblast is the cell type that makes new bone. So osteosclerosis is thought to occur because osteoblasts work faster at laying down new bone than osteoclasts work at eating up old bone.

2) Are osteolytic lesions the same as/affiliated with the terms lytic and osteoclast?

Lisa’s response: Lytic is associated with the term osteolytic. Lytic is the adjective form of lysis, which means to rupture. Osteolysis is caused by two distinct processes occurring together: the first is that rapid growth of abnormal cells (like neoplastic mast cells) inhibits the action of osteoblasts, which normally lay down new bone; and the second is that osteoclast activity is increased, so bone is being absorbed very quickly.

3) If above correlations are correct, A&C below seem contradictory to me, as do B&D.??? Perhaps I’m confused when I isolate it out of context (it was conversation where you were clarifying for someone that osteoporosis wasn’t criteria for SM). (Lisa’s note: Statements A, B, C and D are below these questions for reference.)

Lisa’s response: In multiple studies, patients with ISM, SSM, ASM and SM-AHNMD have been identified as having osteosclerosis. In the largest study (Barete 2010), they found osteosclerosis was more closely associated with aggressive forms of SM (SM-AHNMD and ASM). However, they are still only talking about four people in the aggressive group as opposed to two people in the other (ISM/SSM) group. So in that study, more people with aggressive disease had osteosclerosis than those who had less aggressive disease. In another study, there was no correlation found between osteosclerosis and disease severity.

In particular, what we do not know is whether or not osteosclerosis makes progression more likely by itself. The most robust study found that osteosclerosis in conjunction with swelling of the liver and spleen, presence of multilineage KIT mutation and high increase of baseline serum tryptase warranted careful monitoring for progression. So I’m not convinced that osteosclerosis as a standalone marker is immediately concerning regarding progression, but taken along with these other factors, it may be an indication for cytoreductive therapy.

4) Ultimately, I’m trying to get straight in my mind which is the “worse” lesion (or maybe it’s apples/oranges?) as it pertains to potential progression to an advanced SM category.

Lisa’s response: As pertains to mast cell pathology, large osteolytic lesions are considered the “worst” in that they immediately put you in the ASM category. Again, the only other way this happens is if you have multiple bone breaks as a result of severe osteoporosis (in which osteoporosis is not the qualifier, but the breaks).

So I would consider osteosclerosis as being less severe than osteolytic lesions for the specific purpose of staging SM. However, osteosclerosis is associated with some additional clinical considerations, like blood count abnormalities and higher tryptase, so that should be monitored carefully. Ultimately, this is an issue of research focusing – we need enough time to identify ISM, SSM, ASM and SM-AHNMD patients with osteosclerosis, osteoporosis and osteolysis and determine whether or not osteosclerosis by itself is a determinant of disease progression.

 

Statements:

Note: Both A and B are comments I made as part of a larger FB thread regarding what constitutes “bone involvement” as a diagnostic criterion in staging of SM.

A) Lisa Klimas Osteosclerotic lesions are not immediately a red flag in SM, and about half of SM patients have bone involvement. I wrote a couple of in depth posts about bone manifestations of SM that you may find helpful. I can’t cut and paste in comments on FB for some reason, but google “mastattack bone manifestations of sm” and it comes right up. It’s a two part series.

Lisa’s Response: This was part of a conversation about what constitutes “bone involvement” as a diagnostic marker in staging of SM. It is possible to have ISM or SSM and have osteosclerotic lesions. It does not immediately move you into ASM territory. My phrasing here was poor in that I used bone involvement very broadly (meaning anything involving your bones rather than just the types that affect staging), so that is my fault in that it was confusing.

B) Lisa Klimas Skeletal involvement as applies to mast cell disease means osteolytic lesions, which is a marker for ASM ONLY when you meet the criteria for SM already.

Lisa’s Response: This was part of that same conversation, in which we were discussing bone lesions. One of the markers that qualifies a person as having ASM as opposed to ISM is “bone involvement,” which is defined as large osteolytic lesions or successive fractures due to severe osteoporosis. Here, I was discussing lesions, which is why I omitted the successive fractures. As explained in the earlier part of this post, the osteoporosis does not qualify as “bone involvement” as criteria for ASM – it is the successive fractures.

C) Osteosclerosis is more closely associated with aggressive forms of SM.

http://www.mastattack.org/2014/10/bone-manifestations-sm-part-two/

Lisa’s Response: This was in reference to the Barete 2010 paper.

D) (I know these are older articles): “The severity of bone lesions on x-ray correlate with urinary histamine levels. Lytic lesions, which are the predominant finding, have been associated with moderate increases in bone marrow mast cells. Significantly more mast cell infiltration has been correlated with sclerotic ”

Reference: Jianguo Tao, Keith Flaherty and Adam Bagg. Unusual Hematologic Malignancies. Case 1. Hematologic Malignancy Presenting With Diarrhea and Bony Lesions: Systemic Mastocytosis. Journal of Clinical Oncology, Vol 20, No 17 (September 1), 2002: pp 3737-3744

Lisa’s Response: The paper quoted is from 2002 and the reference for this above statement is from 1992. It involved a patient group of nine people. Criteria for SM/ASM/etc were different then. I am waiting on a hard copy of the 1992 paper referenced and will do a follow up post when I have been able to review the primary source. This is the reference for the 1992 paper:

Reference: de Gennes C, Kuntz D, de Vernejoul MC. Bone mastocytosis. A report of nine cases with a bone histomorphometric study. Clin Orthop Relat Res. 1992 Jun; (279):281-91.

Bone involvement in SM (ISM, SSM, SM-AHNMD, ASM): Clarifications (part 1)

One of the more nuanced aspects of mastocytosis is how it affects bone structure. Previously, it was thought that only patients with systemic mastocytosis experienced bone pain, and that bone pain was always a function of increased proliferation in the marrow. This no longer appears to be the case. Some patients with non-proliferative mast cell disease have been found to experience bone pain, likely as a result of mediator activity on the outside of the bone. In particular, histamine can be very irritating to the cells on the outside of the bone.

Generally speaking, bone cells work like this:

Osteoblasts make new bone. Osteoclasts eat away (resorb) at bone so that new bone can be put in that place. When these processes aren’t balanced, you develop bone conditions.

In osteosclerosis, your body is making new bone faster than it can resorbed. In osteoporosis, your body is resorbing bone faster than new bone is made.   In osteolysis, your body is also resorbing bone faster than new bone is made, but to a much larger extent than usually seen in osteoporosis. Both osteoporosis and osteolysis can cause pathologic fractures, meaning that because your bone is weak from osteoporosis or osteolysis, the bone breaks.

Bone involvement in systemic mastocytosis is important because the type of bone involvement present can be used to stage the disease. Specifically, certain types of bone involvement can cause a person with indolent or smouldering systemic mastocytosis to be reclassified as aggressive systemic mastocytosis (ASM). Osteolysis (in which bone is eaten away) is a marker for ASM. If you have ISM or SSM and are found to have a large osteolytic lesion, you now have ASM.

More confusing is the relationship of osteoporosis to ASM. If you have ISM or SSM AND you have osteoporosis AND you have multiple fractures due to the severity of the osteoporosis (known as pathologic fractures), you are classified as having ASM. There is some debate in the community as to whether or not osteoporosis with successive pathologic fractures is a true indication of ASM. However, it is currently included in the diagnostic guidelines, and so if you meet this criteria while also having ISM or SSM, then you are classified as having ASM.

But I want to be very clear about something: the osteoporosis is NOT the factor that classifies someone as having ASM. It is the MULTIPLE FRACTURES as a result of bone disease that classifies someone as having ASM. So if you have SSM and are diagnosed with osteoporosis and have a single vertebral fracture as a result of osteoporosis, you are NOT classified as having ASM. It is easier I think to consider this “bone involvement” criterion of ASM as osteolysis or multiple fractures due to bone deterioration.

SM is well known as a possible risk factor for osteoporosis. This has been attributed by different groups to either infiltration of bone by mast cells or release of mediators, including histamine, heparin and tryptase. IL-6 levels were also shown to be proportional to disease severity and osteoporosis in mastocytosis patients (Theoharides 2002). Histamine regulates bone resorption by osteoclasts via H1 and H2 receptors (Dobigny 1997). In bone biopsies of osteoporotic patients, the number of osteoclasts is sometimes elevated and sometimes normal.

Up next: literature review of studies on bone involvement in ISM, SSM, SM-AHNMD, and ASM.

 

References:

Maurizio Rossini, et al. Bone mineral density, bone turnover markers and fractures in patients with indolent systemic mastocytosis. Bone 49 (2011) 880–885.

Theoharides TC, Boucher W, Spear K. Serum interleukin-6 reflects disease severity and osteoporosis in mastocytosis patients. Int Arch Allergy Immunol 2002;128: 344–50.

Dobigny C, Saffar JL. H1 and H2 histamine receptors modulate osteoclastic resorption by different pathways: evidence obtained by using receptor antagonists in a rat synchronized resorption model. J Cell Physiol. 1997 Oct;173(1):10-8.

Barete S, Assous N, de Gennes C, Granpeix C, Feger F, Palmerini F, et al. Systemic mastocytosis and bone involvement in a cohort of 75 patients. Ann Rheum Dis 2010;69:1838–41.

Nicolas Guillaume, et al. Bone Complications of Mastocytosis: A Link between Clinical and Biological Characteristics. The American Journal of Medicine (2013) 126, 75.e1-75.e7

van der Veer, W. van der Goot, J. G. R. de Monchy, H. C. Kluin-Nelemans & J. J. van Doormaal. High prevalence of fractures and osteoporosis in patients with indolent systemic mastocytosis. Allergy 67 (2012) 431–438.

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.