The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 81

94. How are mast cells involved in cancer?

  • Mast cells are very involved in cancer biology. They are frequently found in tumors. Tumors can trick mast cells into doing things they need to stay alive, like make blood vessels to supply the tumor with blood, and tissue remodeling, to push aside the healthy tissue and make room for the tumor.
  • Cancer is mast cell activating. All cancers. This is because cancers often trick the body into doing things that help the cancer and not the body, like I just described above. Having cancer frequently causes allergy symptoms because of mast cell activation.
  • Cancer can also cause the body to make more mast cells than normal, a condition called mast cell hyperplasia. This can happen because the body is trying to fight off the cancer with more immune cells or because it has been tricked by the cancer to make more mast cells to help the cancer.
  • Please note that mast cell hyperplasia is NOT the same as mastocytosis. Mast cell hyperplasia is too many healthy mast cells that function normally. Mastocytosis is too many aberrant mast cells that do not function normally. Cancer does not cause mastocytosis.
  • Long term inflammation increases future risk of cancer at the site of inflammation. This applies almost universally. Mast cells participate significantly in inflammation so they can contribute to the risk of cancer. For example, patients with long term colon inflammation, which may be caused by mast cells, are at increased risk of colon cancer.
  • Patients with mastocytosis have increased risk of developing cancer, especially those with systemic mastocytosis. As many as 40% of patients with systemic mastocytosis develop another blood disorder with too many broken cells. Frequently, the other blood disorder is a blood cancer like chronic myelogenous leukemia.
  • It is not yet known if mast cell activation carries an increased risk of developing cancer.
  • Two forms of systemic mastocytosis are cancerous, mast cell leukemia and mast cell sarcoma. These are both extremely rare and it is extremely rare for a person with a history of mast cell disease to develop either of these conditions.

For further reading, please visit the following post:

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 48

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

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

The 2014 Doyle paper provides mast cell counts in colon biopsies for healthy controls, MCAS, and IBS. Mast cells were identified using antibodies for tryptase, CD117, CD25 and CD30 (IHC). Mast cells were counted in both one HPF in the densest portion of the slide and in five HPF and averaged.  In the densest portion of the slide, mast cell counts were higher in 1 HPF than in the average of 5 HPF.  Differences in methodology such as this can contribute to lack of consensus on what constitutes too many mast cells. See Table 21 for details.

Table 21: Comparison of mast cell count in 1 HPF and in the average of 5 HPF
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.
Microscopy method: 400x magnification, mast cells counted in 1 hpf
Visualization: IHC for tryptase, CD117, CD25 and CD30
HPF Control group A:

Healthy controls

Control group B:

MCAS

Control group C:

IBS

Average Range Average Range Average Range
Average of 5 hpf 19 mast cells/hpf 7-39 mast cells/hpf 20 mast cells/hpf 12-31 mast cells/hpf 23 mast cells/hpf 9-45 mast cells/hpf
1 hpf 26 mast cells/hpf 11-55 mast cells/hpf 28 mast cells/hpf 14-48 mast cells/hpf 30 mast cells/hpf 13-59 mast cells/hpf

 

Other papers also investigated factors that could contribute to differences in mast cell counts. The 2015 Sethi paper evaluated differences in GI mast cell counts between men and women.  Women had  marginally higher counts in both IBS and control groups. See Table 22 for details.

Table 22: Difference in mast cell count between men and women with chronic diarrhea and asymptomatic controls
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.
Microscopy method: 400x magnification, mast cells counted in 5 hpf and averaged
Visualization: CD117 (IHC)
Sample type Study group: Women Study group: Men Control group: Women Control group: Men
Colon Average Range Average Range Average Range Average Range
30 mast cells/hpf 27-34 mast cells/hpf 27 mast cells/hpf 24-31 mast cells/hpf 24 mast cells/hpf 22-37 mast cells/hpf 21 mast cells/hpf 19-24 mast cells/hpf
Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters.

 

One paper looked at the difference in mast cell count in the rectum of healthy patients over the age of 55 and under.  Please note that these counts were made using a much lower magnification than other papers in this series, so mast cell counts are not directly comparable. Mast cells were identified using antibodies to tryptase (IHC). See Table 23 for details.

Table 23: Differences in GI mast cell count in healthy patients over and under 55 years of age.
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.
SPECIAL NOTE: THESE COUNTS WERE MADE AT HALF THE MAGNIFICATION OF OTHER PAPERS IN THIS SERIES.  THESE MAST CELL COUNTS ARE NOT DIRECTLY COMPARABLE TO OTHER STUDIES.
200x magnification, number of hpf not explicitly stated, assumed mast cells counted in 1 hpf
Visualization: Tryptase (IHC)
Sample type Study group: Healthy, over 55 years old Study group: Healthy, under 55 years old Control group B:

No control group

Rectum Average Range Average Range Average Range
40.5 ± 2.4 mast cells/hpf 51.7 ± 4.1 mast cells/hpf N/A N/A

 

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 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 Five)

One of the most interesting papers on mast cell burden in the GI tract evaluates patients with chronic urticaria.  The patients in this study did not have GI symptoms, but they did have skin symptoms related to consumption of trigger foods.  Mast cells were identified using antibodies to CD117 and tryptase, and were counted in five hpf and averaged.  The healthy controls for this study were from two countries in order to evaluate the effect of diet on mast cell count in healthy patients.  There was no difference between the control groups from different countries.

The control group as a whole averaged 20.2 mast cells/hpf in the stomach.  The chronic urticaria group as a whole averaged 32.4/hpf in the stomach.  This paper also assessed the mast cell count in chronic urticaria patients whose biopsies did not display any tissue damage.  In this group, mast cell count averaged 30.4/hpf. In all instances, cells were scattered and not clustered.  Mast cell count in CU patients were 61% increased compared to controls. See Table 15 for details.

In the duodenum (small intestine), the healthy control group averaged 32.5 mast cells/hpf.  The chronic urticaria group had 44.8/hpf and chronic urticaria patients with normal biopsies (not tissue damage) averaged 45.2/hpf.  Again, cells were scattered and not clustered. Mast cell count in CU patients were 37.8% increased compared to controls. See Table 16 for details.

The implication here is that even in the absence of GI symptoms, activation of mast cells in the GI tract might release enough histamine to cause urticaria.  An important feature of this paper is that it discusses “pseudoallergens”, which it describes as “non-specific histamine-release” substances. Fourteen of the patients in this study had a history of “pseudoallergen” food triggers that irritated their urticaria. In these patients, mast cell count was actually lower in the stomach than those who didn’t have food “pseudoallergen.” See quote below.

“The skin lesions of CU are caused by vasoactive mediators released through specific or non-specific mast cell degranulation in the skin or elsewhere. CU patients are particularly susceptible to the non-specific histamine-releasing effect of pseudoallergenic substances in various foods and drugs, and the success rate of pseudoallergen-free diets varies between 30 and 50%.  It is conceivable that food pseudoallergens induce non-specific mast cell degranulation, rather in the gastrointestinal tract than elsewhere. Activation of many intestinal mast cells may then result in enough histamine release to cause urticaria either directly or indirectly.” (Minnei 2006)

 

Table 15: Mast cell count in stomach of patients with chronic urticaria
Minnei F, et al. Chronic urticaria is associated with mast cell infiltration in the gastroduodenal mucosa. Virchows Arch 2006; 448(3): 262-8.
Microscopy method: 400x magnification, counted in 5 hpf and averaged
Visualization: CD117 and tryptase
Sample type Study group: Chronic urticaria Study group: Chronic urticaria, biopsies normal Control group A:

Healthy controls

Stomach Average Range Average Stomach Average Range
32.4 mast cells/hpf 29.5-35.4 mast cells/hpf 30.4 mast cells/hpf 26.2-34.6 mast cells/hpf 20.2 mast cells/hpf 17.4-22.9 mast cells/hpf
Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters.

 

Table 16: Mast cell count in small intestine (duodenum) of patients with chronic urticaria
Minnei F, et al. Chronic urticaria is associated with mast cell infiltration in the gastroduodenal mucosa. Virchows Arch 2006; 448(3): 262-8.
Microscopy method: 400x magnification, counted in 5 hpf and averaged
Visualization: CD117 and tryptase
Sample type Study group: Chronic urticaria Study group: Chronic urticaria, biopsies normal Control group A:

Healthy controls

Duodenum Average Range Average Stomach Average Range
44.8 mast cells/hpf 39.2-50.3 mast cells/hpf 45.2 mast cells/hpf 38.4-52.1 mast cells/hpf 32.5 mast cells/hpf 29.4-35.6 mast cells/hpf
Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters.

 

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 Four)

The 2009 Walker paper evaluates the mast cell count in patients with irritable bowel syndrome (both diarrhea and constipation predominant forms) and functional dyspepsia (indigestion, upper abdominal pain). This study recorded the total count of mast cells in five fields.  Additionally, two biopsies from different sections of the duodenum were taken for each patient.  I performed some calculations to convert it to mast cells/hpf to be comparable to other data presented in this series.

Mast cells were identified using an antibody to CD117, the CKIT receptor found on the surface of all mast cells. This paper found that the average mast cell count for each patient (averaged between two biopsy sites) was 33/hpf for functional dyspepsia; 45/hpf average for both types of irritable bowel syndrome; 42.7/hpf for irritable bowel syndrome with predominant diarrhea; 47.7/hpf for irritable bowel syndrome with predominant constipation.  The control group of healthy patients demonstrated an average cell count of 29.4/hpf, with a maximum cell count of 46.5 mast cells/hpf. See Table 9 for details.

Table 9: Mast cell count in stomach of patients with irritable bowel syndrome and functional dyspepsia
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.
Microscopy method: 400x magnification, mast cells counted in 5 hpf and totaled

*Note: I made some calculations to yield information that would be comparable to other research (mast cells/hpf).

 

This paper provided total cell counts in 5 hpf for two biopsies for each patient.  For example, patient A had two biopsies with one having 50 mast cells/hpf and the other having 30 mast cells/hpf. I divided each cell count by 5 to give mast cells/hpf. (50/5 = 10 for biopsy 1; 30/5 = 6 for biopsy 2).  I added these together (10+6 = 16) and divided by 2 to get the average (16/2 = 8 mast cells/hpf).

Visualization: CD117 (IHC)
Sample type Study group: Functional dyspepsia Study group: Irritable bowel syndrome (both diarrhea and constipation groups) Study group: Irritable bowel syndrome, diarrhea Study group: Irritable bowel syndrome, constipation Control group: Healthy controls
Duodenum Average Range Average Range Average Range Average Range Average Range
33 mast cells/hpf 39.2-65.4 mast cells/hpf 45 mast cells/hpf 22.2-74.8 mast cells/hpf 42.7 mast cells/hpf 22.2-65.5 mast cells/hpf 47.7 mast cells/hpf 29.7-74.8 mast cells/hpf 29.4 mast cells/hpf 15.2-46.5 mast cells/hpf
Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters.

 

A 2012 paper by Zare-Mirzaie evaluated colonic tissue of patients with chronic diarrhea.  Cells were detected by two methods: an antibody to tryptase, and through the use of a simple stain, toluidine blue.  The counts presented in table 10 were found using the antibody to tryptase.  Cells were counted in 10 hpf and averaged.

Table 10: Mast cell count in colon of patients with chronic diarrhea
Zare-Mirzaie A, et al. Analysis of colonic mucosa mast cell count in patients with chronic diarrhea. Saudi J Gastroenterol 2012; 18 (5): 322-326.
Microscopy method: 400x magnification, mast cells counted in 10 hpf and averaged
Visualization: Tryptase, toluidine blue
Sample type Study group: Chronic diarrhea Control group A:

Healthy controls

Control group B:

No control group

Colon Average Range Average Range Average Range
21.3 ± 4.8 mast cells/hpf 17-24 mast cells/hpf 14.2 ± 3.4  mast cells/hpf 11-17 mast cells/hpf N/A N/A
Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters.

 

A 2007 paper by Guilarte mentioned mast cell counts in the jejunum (small intestine) of patients with chronic diarrhea.   Cells were detected with an antibody to CD117. The cells were counted in 10 hpf and averaged.  Please note the correct use of the term “mast cell hyperplasia” rather than “mastocytosis.” See Table 11 for details.

Table 11: Mast cell count in colon of patients with diarrhea predominant irritable bowel syndrome
Guilarte M, et al. Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum. Gut 2007; 56: 203-209.

 

Microscopy method: 400x magnification, mast cells counted in 8 hpf and averaged
Visualization: CD117
Sample type Study group: Irritable bowel syndrome, diarrhea Control group A: Healthy controls
Jejunum Average Range Average Range
34 mast cells/hpf 15.3 mast cells/hpf

 

A 2014 paper by Vivinus-Nebot assessed mast cell counts in the colon of patients with persistent GI symptoms in quiescent (inactive) inflammatory bowel diseases.   Cells were detected with an antibody to CD117. The cells were counted in 3 hpf and averaged.  The mast cell counts in this paper were uniformly low.  This implies that mast cells are involved more directly in the inflammatory GI processes, rather than specifically in diarrhea or constipation. See Table 12 for details.

Table 12: Mast cell count in colon of patients with inactive inflammatory bowel conditions
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.
Microscopy method: 400x magnification, mast cells counted in 3 hpf and averaged
Visualization: CD117
Sample type Study group: Irritable bowel syndrome, constipation Study group: Irritable bowel syndrome, diarrhea Study group: Irritable bowel syndrome, mixed Study group: Quiescent Crohn’s disease with irritable bowel syndrome type symptoms
Colon Average Range Average Range Average Range Average Range
12 mast cells/hpf 9-16 mast cells/hpf 12 mast cells/hpf 10-15 mast cells/hpf 12 mast cells/hpf 10-17 mast cells/hpf 12 mast cells/hpf

 

6-16 mast cells/hpf
Distribution not stated. Distribution not stated. Distribution not stated. Distribution not stated.
Sample type Study group: Quiescent Crohn’s disease Study group: Quiescent ulcerative colitis with irritable bowel syndrome type symptoms Study group: Quiescent ulcerative colitis Study group: Healthy controls
Colon Average Range Average Range Average Range Average Range
12 mast cells/hpf 4-16 mast cells/hpf 12 mast cells/hpf 9-15 mast cells/hpf 10 mast cells/hpf 5-15 mast cells/hpf 6 mast cells/hpf 2-9 mast cells/hpf
Distribution not stated. Distribution not stated. Distribution not stated. Distribution not stated.

 

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.