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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: 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.



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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.

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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.