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systemic mastocytosis

Progression of mast cell diseases: Part 1

Among mast cell patients, we generally assume that a designation of SM means indolent systemic mastocytosis (ISM.) However, in research papers, this term can mean ISM, SSM, ASM or MCL. Advanced SM usually means ASM or MCL. These terms generate a lot of confusion in the patient population. When reading a paper, abbreviations are usually defined on the first page or within the introduction. It is important to check on what the researchers are using the term SM for.

As an example, let’s look at this really alarming quote to someone who thinks SM means ISM:

“The life expectancy of SM patients was shorter relative to age- and sex-matched controls. As initially observed by Travis et al, survival decreased rapidly after diagnosis: to 60% at 3 years, with a subsequent slower decline to 50% at 5 years. Beyond 5 years, the slope of the survival curve was similar to that of the control population. This observation confirms that the deaths in SM patients within the first 3 (and up to 5) years after diagnosis.” (Lim 2009)

In this paper, SM meant ISM, SM-AHNMD, SSM, ASM and MCL. When you average those survival rates together, you get a sharp decline in survival for the first five years. After that, it returns to normal, because most of the ASM and MCL patients in that study died by that time.


I get asked A LOT about whether or not ISM is progressive. I see a lot of people describe it as progressive. In medicine, progression usually means moving from one diagnostic category to a more serious one (like ISM to SSM.) However, a lot of patients use this term to mean a worsening of symptoms or disability while staying in the same diagnostic category (like ISM with mild daily symptoms to ISM with severe daily symptoms). Those are two different things. I’m going to answer both.


What is the life expectancy with ISM?

It’s normal.

“Patients with ISM have a favorable prognosis. These patients may suffer from mediator-release symptoms, but do not suffer from significant organopathy caused by MC infiltration.” (Valent, 2003)

In a study of 159 patients, 2.2% ± 1.3% died within five years of diagnosis, and 11% ± 5.9% died within twenty five years of diagnosis. “The majority of deaths in this ISM cohort were unrelated to mastocytosis.” (Pardanini 2013)

In a study of 342 patients, ISM was the largest subgroup with 159 patients.  They were significantly younger at presentation (median age 49 years.) “Overall median survival was not significantly different than that of the age and gender matched control population. Advanced age was the primary determinant of inferior survival.” (Pardanini 2013)


Will my ISM symptoms get worse with time?

There is really no way to know. In some people, they are stable, while in others, they fluctuate. However, mediator release symptoms (degranulation symptoms) are known to be more common in ISM than ASM and MCL.

“ISM patients can be highly symptomatic; in one study, 70% reported at least some degree of functional limitation, of which 17% reported severe limitation.” (Pardanini 2013)

“The type and severity of symptoms were independent of disease classification (CM vs SM), KITD816V status, and serum tryptase level.” (Pardanini 2013)


If my ISM symptoms get worse, does that mean I am progressing to a more severe category, like SSM, ASM or MCL?


“One important aspect in this regard is that mediator-related symptoms per se are not indicative of aggressive mastocytosis unless accompanied by C-findings.” (Valent 2003)

“Moreover, organomegaly per se is not necessarily indicative of aggressive SM.” (Valent 2003)

“In fact, in a group of patients with SM, organomegaly is recorded over many years without impairment of organ function or development of C-findings.” (Valent 2003)

“The type and severity of symptoms were independent of disease classification (CM vs SM), KITD816V status, and serum tryptase level.” (Pardanini 2013)



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

Pardanini, Animesh. Systemic mastocytosis in adults: 2013 update on diagnosis, risk stratification, and management. 2013; American Journal of Hematology: 88 (7).

Pardanini, Animesh. Prognostically relevant breakdown of 123 patients with systemic mastocytosis associated with other myeloid malignancies. 2009; Blood: 114 (18).

Lim, Ken-Hong, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. 2009; Blood: 113 (23).

Valent, Peter, et al. How I treat patients with advanced systemic mastocytosis. 2010; Blood: 116 (26).

Matito, Almudena, et al. Serum tryptase monitoring in indolent systemic mastocytosis: association with disease features and patient outcome. 2013; PLOS One.

Sperr, Wolfgang. Diagnosis, progression patterns and prognostication in mastocytosis. 2012; Expert Review of Hematology: 5 (3): 261-274.

Valent, Peter, et al. Aggressive systemic mastocytosis and related mast cell disorders: current treatment options and proposed response criteria. 2003; Leuk Res 27 (7): 635-41.

Hauswirth, Alexander, et al. Response to therapy with interferon alpha-2b and prednisolone in aggressive systemic mastocytosis: report of five cases and review of the literature. 2004; Leuk Res 28 (3): 249-257.

Mast cell mutations: JAK2 and myeloproliferative neoplasms

Janus kinase 2 is also a tyrosine kinase like CKIT, but it is not a receptor on the outside of the cell. JAK2 is a helper protein that helps other molecules to send signals. It also affects the signaling of many clinically important molecules, like interleukin 3, interleukin 5, interleukin 5, interferon gamma, erythropoietin, thrombopoietin, growth hormone and prolactin. These molecules are involved in cell proliferation and the inflammatory response.

JAK2 mutation V617F seems to make hematopoietic cells more responsive to growth factors, causing excessive proliferation. JAK2 V617F is used as a marker for some Philadelphia negaitve myeloproliferative neoplasms (Ph- MPN), which include essential thrombocythemia (ET), an indolent disease in which too many platelets are produced; polycythemia vera (PV), in which too many red cells are produced; and myelofibrosis (MF), in which bone marrow is replaced with connective tissue that cannot make blood cells. JAK2 V617F is present in 40-50% of ET cases, 95% of PV cases, and 60% of MF cases.

In multiple studies, the frequency of JAK2 mutations in SM has ranged from 0-20% depending on the patient group. However, multiple studies have found a frequency of 4.2-5%, which is the generally accepted figure. JAK2 mutation is a strong predictor of myeloproliferative neoplasm but not necessarily of mastocytosis. However, where present in SM patients, it indicates a higher probability of developing another MPN.

In the control group of one study, 10 ISM patients without another myeloprofilerative neoplasm were negative for JAK2 mutation, and 15 MF patients without SM were negative for CKIT mutation. In the patient group, five people had both CKIT+ SM and MF. In four patients, the JAK2 V617F mutation was present. In the four patients with the JAK2 V617F mutation, it was found not only in the myelofibrosis cells (CD15+ myeloid cells), but also in the mast cells. In two of the patients, the CKIT mutation was found in the CD15+ myeloid cells of two patients. The data suggests that the JAK2 mutation may occur before the CKIT mutation in patients who have both SM and an associated hematologic disorder.

One study looked extensively at other mutations present in various types of CKIT+ systemic mastocytosis. The patient group was composed of 39 people, with 10 having ISM, 2 SSM, 5 SM-AHNMD, 15 ASM and 7 MCL. Only 2 patients out of the group were positive for JAK2 mutation. One patient had MCL, the other had SM-AHNMD. Both also had another myeloproliferative neoplasm (in the case of the SM-AHNMD patient, it was MDS.) This study found that presence of at least one other mutation in addition to CKIT D816V was associated with poorer prognosis, although presence of JAK2 V617F was not specifically identified as causing shorter lifespans.



Schwaab, Juliana, et al. Comprehensive mutational profiling in advanced systemic mastocytosis. Blood 2013, 122 (14): 2460-2466.

Soucie, Erinn, et al. Molecular basis of mast cell disease. Molecular immunology 2015, 63 (1): 55-60.

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

Sotlar, Karl, et al. Systemic mastocytosis associated with chronic idiopathic myelofibrosis. J Mol Diagn Jan 2008; 10(1): 58-66.

Heritable mutations in mastocytosis

While the most well-known mutation associated with SM is the CKIT D816V, there are numerous other mutations that can contribute to mast cell disease and presentation. The CKIT gene produces a tyrosine kinase receptor on the outside of the mast cell. Tyrosine kinases function as switches that turn certain cell functions on and off. When stem cell factor binds to the CKIT receptor, it turns on the signal for the mast cell to live longer than usual and to make more mast cells.

The D816V mutation is located in a specific part of the CKIT gene called exon 17. As many as 44% of SM patients have CKIT mutations outside of exon 17, either alone or in addition to the D816V mutation. (Please note that for the purposes of this post, SM is used to refer to SM, ASM and SM-AHNMD in keeping with the source literature.) Still, most doctors and researchers believe the D816V mutation is not heritable. This has important implications because it means many doctors also believe mast cell disease is sporadic and not heritable.

Almost 75% of MCAD (SM, MCAS, MCL) patients had at least one first degree relative with MCAD. This study, published in 2013, demonstrated that despite the non-heritable nature of the D816V mutation, mast cell disease is indeed heritable. Currently, four heritable mutations present in mast cell patients have been identified.

CKIT is often called KIT. In one family in which the mother, daughter and granddaughter have all have indolent SM, they were all found to have a deletion at position 409 in KIT (called KITdel409.) The KIT F522C mutation has been associated with ISM.   Another heritable mutation, KIT K509I, has been identified multiple times by different researchers. The first publication to identify this mutation was published in 2006. It has been found in a mother/daughter set who have ISM, and in another mother/daughter set in which the mother has ASM and the daughter has CM. This mutation was noted in a 2014 paper to be associated with well differentiated SM.

There have been reports of families in which multiple members with ISM or SM-AHNMD had the D816V mutation. Importantly, in these patients, the mutation was readily found in numerous cell types, including mast cells, CD34+ hematopoietic precursor cells, blood leukocytes, oral epithelial cells, blast cells and erythroid precursors. Despite this finding, the majority of literature continues to report the D816V mutation as not heritable.



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

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

Hartmann, E. Wardelmann, Y. Ma, S. Merkelbach-Bruse, L.M. Preussenr, C. Woolery, et al. Novel germline mutation of KIT associated with familial gastrointestinal stromal tumors and mastocytosis. Gastroenterology, 129 (2005), pp. 1042–1046

R.A. Speight, A. Nicolle, S.J. Needham, M.W. Verrill, J. Bryon, S. Panter. Rare germline mutation of KIT with imatinib-resistant multiple GI stromal tumors and mastocytosis. J Clin Oncol, 31 (2013), pp. e245–e247

de Melo Campos, J.A. Machado-Neto, A.S.S. Duarte, R. Scopim-Ribeiro, F.F. de Carvalho Barra, J.Vassallo, et al.Familial mastocytosis: identification of KIT K509I mutation and its in vitro sensitivity to imatinib, dasatinib and PK412. Blood, 122 (2013), p. 5267

L.Y. Zhang, M.L. Smith, B. Schultheis, J. Fitzgibbon, T.A. Lister, J.V. Melo, et al. A novel K5091 mutation of KIT identified in familial mastocytosis – in vitro and in vivo responsiveness to imatinib therapy. Leukemia Res, 30 (2006), pp. 373–378

E.C. Chan, Y. Bai, A.S. Kirshenbaum, E.R. Fischer, O. Simakova, G. Bandara, et al. Mastocytosis associated with a rare germline KIT K509I mutation displays a well-differentiated mast cell phenotype. J Allergy Clin Immunol, 134 (2014), pp. 178–187

Akin, G. Fumo, A.S. Yavuz, P.E. Lipsky, L. Neckers, D.D. Metcalfe. A novel form of mastocytosis associated with a transmembrane c- Kit mutation and response to imatinib. Blood, 103 (2004), pp. 3222–3225

Escribano, R. Nunez-Lopez, M. Jara, A. Garcia-Montero, A. Prados, C. Teodosio, et al. Indolent systemic mastocytosis with germline D816 V somatic c-kit mutation evolving to an acute myeloid leukemia. J Allery Clin Immunol, 117 (Suppl.) (2006), p. S125

Language matters: Mast cell terminology

This is by no means a comprehensive list – just a review on definitions of some commonly confused terms.

Acute: This word gets used a lot when people mean “severe.” Acute does not mean severe. It means sudden onset or having a short, limited course. For example, stage III anaphylaxis is an acute complication of mast cell disease. Its symptoms come on suddenly, require immediate treatment, and once treated, resolves. (I am not referring to the after effects of anaphylaxis – just the emergency and treatment.) In a medical sense, acute is the opposite of chronic.

Chronic: Long term, occurs all the time, is expected to occur forever. I have mast cell disease and am chronically ill. I have acute anaphylactic emergencies.

Progressive: Getting worse or will get worse. This term gets used loosely by patients to mean that their symptoms get worse. Medically speaking, this generally refers to progression of disease from one stage to the next, like SM to ASM. SM and MCAS are not inherently progressive diseases. People who have progressed from SM to SSM or ASM have progressive disease.


Systemic symptoms: Any symptoms that do not involve the skin. Can be present in cutaneous mastocytosis or MCAS. So diarrhea is a systemic symptom. Tachycardia is a systemic symptom. Systemic symptoms do not mean you have SM.

Systemic mastocytosis: the diagnosis you receive if you meet either the major criterion listed subsequently and at least 1 of the 4 minor criteria, or at least 3 minor criteria if the major criterion is not met:

Major criterion

Multifocal, dense infiltrates of mast cells (≥15 mast cells in aggregates) detected in sections of bone marrow and/or other extracutaneous organ(s)

Minor criteria

In biopsy sections of bone marrow or other extracutaneous organs, >25% of the mast cells in the infiltrate are spindle-shaped or have atypical morphology, or, of all mast cells in bone marrow aspirate smears, >25% are immature or atypical

Detection of an activating point mutation at codon 816 of KIT in bone marrow, blood, or other extracutaneous organ

Mast cells in bone marrow, blood, or other extracutaneous organ express CD2 and/or CD25 in addition to normal mast cell markers

Serum total tryptase persistently exceeds 20 ng/mL (unless there is an associated clonal myeloid disorder, in which case this parameter is not valid)

The diagnosis of SM is unrelated to the symptoms the patient experiences. Some SM patients have no symptoms. Some have severe symptoms.

Systemic symptoms ≠ systemic disease (SM)


Aggressive symptoms: Frequent or severe symptoms, which may be life threatening.

Aggressive disease: Doctors sometimes use this term to mean a quick progression of symptoms or rapid change in quality of life.

Aggressive systemic mastocytosis: A diagnosis that indicates multiple organ infiltration and damage by mast cells. Lifespan is significantly shortened in many patients. It is diagnosed by already meeting the criteria for SM and then also having at least one C finding, listed here:

Bone marrow dysfunction manifested by one or more cytopenia (ANC < 1.0 × 109/l, Hb < 10 g/dl, or platelets < 100 × 109/l), but no frank non-mast cell haematopoietic malignancy

Palpable hepatomegaly with impairment of liver function, ascites and/or portal hypertension

Skeletal involvement with large-sized osteolysis and/or pathological fract

Palpable splenomegaly with hypersplenism

Malabsorption with weight loss due to GI mast cell infiltrates

Aggressive symptoms and aggressive disease ≠ aggressive systemic mastocytosis (ASM)


Smoldering systemic mastocytosis (SSM): A progression from SM with markers that indicate likelihood of developing ASM. Diagnosed if two or more of the following B findings are present with previous diagnosis of SM:

Bone marrow biopsy showing > 30% infiltration by mast cells (focal, dense aggregates) and/or

serum total tryptase level > 200 ng/ml


Signs of dysplasia or myeloproliferaion in non-mast cell lineage, but insufficient criteria

for definitive diagnosis of a haematopoietic neoplasm by WHO, with normal or only slightly

abnormal blood counts


Hepatomegaly without impairment of liver function, and/or palpable splenomegaly without

hypersplenism, and/or palpable or visceral lymphadenopathy


Effects of estrogen and progesterone and the role of mast cells in pregnancy

The term estrogen generally refers to estrogen estradiol (E2.)  This steroid hormone is induced when gonadotropin releasing hormone (GnRH) is released in the hypothalamus and acts on the pituitary gland.  This in term releases follicle stimulating hormone (FSH) which acts on the follicle, resulting in the release of estrogen.  Secretion of GnRH is stimulated by a protein called kisspeptin. High levels of estrogen or progesterone inhibit the secretion of kisspeptin.  Hormone levels are regulated in this way. 

Estrogen is mostly produced by the ovaries and placenta, but is made in smaller amounts by the liver, adrenal glands, breasts and fat cells.  E2 promotes secondary female sex characteristics, increases metabolism, increases fat stores, stimulates endometrial and uterine growth, promotes vaginal lubrication, thickens the vaginal wall, maintains integrity of blood vessels and skin, reduces bone resorption and increases bone formation.  It also promotes effective coagulation by increasing platelet adhesion.  E2 increases HDL cholesterol and triglycerides while decreasing LDL and fat deposition.  It balances salt and water retention, increases cortisol levels, reduces bowel motility, and increases the amount of cholesterol found in bile.  It also promotes wound healing and has anti-inflammatory properties.

With progesterone, E2 promotes and maintains the uterine lining, as well as increasing the amount of oxytocin released during pregnancy.  Estrogen surge induces the secretion of luteinizing hormone, triggering ovulation. 
Progesterone (P4) also regulates salt and water balance, prepares the uterus for implantation, affects vaginal tissue and cervical mucus to prevent sperm from entering the uterus during pregnancy, suppresses menstruation, decreases maternal immune response to pregnancy, decreases contractility of uterine smooth muscle and inhibits lactation during pregnancy.  With prolactin, progesterone prepares breast tissue for milk production after childbirth.  Drop in progesterone levels during pregnancy is thought to be a key step in induction of labor.  Progesterone also has a variety of other regulatory effects, though the exact nature of these functions is not entirely clear.
Progesterone receptors on cells can be increased by the action of estrogen.  Furthermore, the activity of progesterone is amplified by the presence of estrogen.
The importance of mast cells in reproductive biology has been known for over sixty years.  Mast cells express receptors for both estrogen and progesterone.  These hormones together attract mast cells from the peripheral tissues to the uterus.  Furthermore, they induce the maturation of mast cells and directly cause degranulation in a dose dependent manner.  Together, they induce more degranulation than individually.
During pregnancy, embryo-derived histamine releasing factor induces secretion of histamine by uterine mast cells.  Histamine is also secreted by endothelial and decidual cells.  Mast cells have a protective role in ensuring successful embryo implantation.  Mast cells also positively influence the growth of blood vessels and participate in tissue remodeling so that the pregnancy can be sustained through placental growth and adequate blood supply. Degranulation increases uterine contractility through histamine and serotonin action.  Allergic activation causes significant contractions. 
In placentas from intrauterine growth retardation, mast cell concentrations are significantly decreased.  When mast cell numbers are diminished, the cells formed following implantation are at different stages, and are smaller and delayed.  Pregnancies with this feature generally do not survive.
In some cases, severe allergic reactions are thought to be responsible for preterm labor.  Additionally, degranulation in pre-eclampsic patients caused increased vascular resistance, likely from vasoconstriction by histamine.  Asthmatic pregnant women are known to be at a higher risk of pre-eclampsia.  People with other mast cell diseases should likewise by monitored for this condition.
Estrogen and progesterone levels can be correlated to symptoms in asthma.  Postmenopausal women taking hormone replacement therapy have a higher risk of new onset asthma.  30-40% women have asthma with more symptoms during the premenstrual period when estrogen and progesterone concentrations are dynamic.  Many women with mast cell disease likewise report more degranulation when menstruating.  Mast cell density in non-uterine tissues is much higher in pregnant woman, likely due to the higher hormone concentrations. 
A paper released in 2013 referenced a 2001 study by Metcalfe and Akin that found that women with SM were more likely to have preterm labor and delivery.  However, a 2011 study in Spain found that only 3/45 (6.7%) women delivered prematurely.  The rate of preterm birth in the general Spanish population is 7.4%.  It is unclear whether this change was due to increasing understanding of SM and more effective treatment, or due to the changes in diagnostic criteria between these studies.
The presence of mast cells is crucial for healthy pregnancy.  However, excessive activation can cause contractions and increased symptoms for pre-eclampsia patients.  The most recent study demonstrates that overwhelmingly, women with SM deliver healthy babies at the appropriate time.


Woidacki, K., Jensen, F., Metz, Zenclussen, A. (2013). Mast cells as novel mediators of reproductive processes. Front. Immunol. 10.
Woidacki, K., Popovic, M., Metz, M., Schumacher, A., Linzke, N., Teles, A., et al. (2013). Mast cells rescue implantation defects caused by c-kit deficiency. Cell Death Dis.4, e462.
Metcalfe, D. D., and Akin, C. (2001). Mastocytosis: molecular mechanisms and clinical disease heterogeneity. Leuk. Res. 25, 577–582.
Jensen F, Woudwyk M, Teles A, Woidacki K, Taran F, Costa S et al. (2010). Estradiol and progesterone regulate the migration of mast cells from the periphery to the uterus and induce their maturation and degranulation. PLoS One 2010; 5: e14409.
Matito, A., et al.  (2011.) Clinical impact of pregnancy in mastocytosis: A study of the Spanish network on mastocytosis (REMA) in 45 cases.  Int Arch Allergy Immunol; 156: 104-111.

Gastrointestinal manifestations of SM: Part 2

In SM, the small intestine is sometimes normal when biopsied.  When comparing data across many studies, it is believed that at least 30% SM patients have small bowel structural abnormalities.
In one study, small nodules in the mucosa could be observed in the small intestine in 73% of patients.  It is thought that the small nodules (1 mm) represent focal edema (localized swelling) in superficial mucosa and intestinal villi, while the larger nodules are focal edema in the lamina propria. These nodules do not represent mast cell aggregates.  On endoscopy, biopsy of these lesions showed no aggregates.   
In 23% of patients, lesions show an indistinct jejunal mucosa pattern, probably from excessive secretions.  13% show a malabsorption pattern with flocculation and segmentation; irritability of the muscularis and circular muscle layer is likely responsible for jejunization of ileum in 18% of patients. 
In one study, 57% of patients had small intestinal mucosal thickening, nodularity and/or polypoid lesions.  In a second study, 29% had small bowel abnormalities, including 14% with jejunal or ileal nodules and 14% malabsorption pattern. 
However, a whole host of abnormalities are sometimes seen: thickened jejunal folds with edema; dilated small bowel; blunted villi; partial villous atrophy or edema; complete villous atrophy; infiltration by eosinophils and/or mast cells; spru like mucousal changes responding to gluten free diet; malabsorption with tetany; osteomalacia; vitamin A deficiency; mesenteric thickening or infiltration; bulls eye lesions.
A key aspect of small intestine disease in SM patients is malabsorption.  Previously thought to be rare, multiple studies have now shown that malabsorption is more common in SM and is due to small intestine defects.  Approximately 5-25% of SM have malabsorption, which is generally mild.  One study of SM patients found that 31% had impaired absorptive function.  This was determined by 72-hour fecal fat studies, D-xylose tolerance testing and Schilling test.  Pancreatic function is normal in all SM patients evaluated in these studies. 
An older study found that 23/34 patients studied had elevated fecal fat excretion.  In most, steatorrhea (excess fat in stool) was mild, but it can be severe.  In one study, four patients with steatorrhea all had abnormal findings on biopsy, including villi changes, increased inflammation in the mucosa, increased plasma cells and eosinophils, and sometimes increased mast cells.
Due to the excess excretion of fat in SM patients, they may have malabsorption of fat soluble vitamins such as D or calcium, causing tetany (involuntary muscle contraction) or osteomalacia (softening of the bones.)  Malabsorption of vitamin A can cause night blindness due to rod cone deficiency in retina.
Rarely, celiac disease is reported with SM.  In order to determine which is present, intestinal mucosa must be examined carefully by microscope.  In SM, patients may have patchy lesions with partial villous atrophy.  Enterocytes are normal, which is not seen in celiac.  Sparseness and destruction of crypts in seen in lamina propria, as well as lesions from mast cell infiltration along with neutrophils and eosinophils.  Villous atrophy secondary to crypt atrophy is sometimes seen.  But in SM, there is no crypt hyperplasia.
There have been a few reports of SM patients with selective deficiency of IgA in duodenal fluid only.
For many years, colon involvement was not considered to be an inherent part of SM. More recently, it has been found that up to 20% of SM patients have colon abnormalities.  Diverticulitis occurs in as many as 19% of patients.  Less distension of rectum is necessary to induce pain or urgency in SM patients.  They are also more likely to have overactive rectal contractility and decreased rectal compliance, making complete defecation more difficult.

13% of patients were found to have nodules in the colon mucosa.  Lesions seen by barium examination are thought to be due to edema and not mast cell infiltration, though mast cell infiltration of the colon has been reported.  Mastocytic enterocolitis has been described.  (I’m doing a separate post on this.)

Abnormalities seen include edema with or without granularity, edema with urticarial lesions, purple pigmented lesions.  Diffuse intestinal telangiectasia is sometimes present.  Biopsies of polypoid lesions show extensive infiltration by histiocyte like cells.  In some patients, colon or rectal mucosa showed mixed infiltrates of mast cells and eosinophils, increased mast cells in perivascular spaces, lamina propria, submucosa or muscularis mucosa. 
Diarrhea is a common complaint of SM patients.  There are several possible causes.  Fat absorption can cause diarrhea, but this is unlikely in SM.  It has been shown in these patients that diarrhea can occur with or without fat malabsorption, indicating that the two processes do not stem from a single origin.  Mast cell patients with diarrhea generally do not have malabsorption.  GI transit time in SM diarrhea patients may be normal or even slow, contributing further to the lack of the clarity.
Specific GI regulatory molecules directly causing diarrhea in SM have not been identified, although mediator release can certainly cause this symptom by various pathways.  PGD2 has been suggested repeatedly as a cause.  PGD2 can be 100X normal in SM patients.  In patients with very high prostaglandin levels, use of aspirin decreased diarrhea. 
The treatment for mast cell diarrhea includes the usual suspects, like H1 and H2 antagonists and cromolyn.  Tixocortol was also found to be helpful in decreasing abdominal pain and stool frequency.  Patients who improved with tixocortol also showed improvement on biopsy, decreased fecal fat excretion and increased absorption.

Jensen RT. Gastrointestinal abnormalities and involvement in systemic mastocytosis. Hematol Oncol Clin North Am. 2000;14:579–623.
Bedeir A, et al.  Systemic mastocytosis mimicking inflammatory bowel disease: A case report and discussion of gastrointestinal pathology in systemic mastocytosis.  Am J Surg Pathol.  2006 Nov;30(11): 1478-82.
Lee, Jason K, et al.  Gastrointestinal manifestations of systemic mastocytosis.  World J Gastroenterol. 14(45): 7005-7008.

Gastrointestinal manifestations of SM: Part 1

Gastrointestinal symptoms are among the most common in SM, with up to 80% of patients experiencing them regularly.  When averaging figures from many studies, about 51% of SM patients have abdominal pain, 43% have diarrhea, and 28% have nausea and vomiting.  11% of SM patients have GI bleeding, usually in the upper tract.  Other GI problems common in SM include steatorrhea (excess fat in the stool), malabsorption, swollen liver, swollen spleen, free fluid in the abdomen and portal hypertension.  GI distress in SM can be severe and often mimics Irritable Bowel Disease or Zollinger-Ellison Syndrome.
Abdominal pain in SM generally has two types.  The first is epigastric dyspeptic pain, found in the upper abdomen, and is associated with ulcer disease and oversecretion of stomach acid.  Despite early reports that peptic ulcer disease is rare in SM patients, more recent studies have repeatedly disproven this idea.  On average, about 23% of SM patients have peptic ulcer disease.  Ulcers in SM patients with dyspeptic pain are often found on endoscopy.  In one study, 19% had a duodenal ulcer, while 25% had severe duodenitis.
The other type of GI pain is characterized by lower abdominal cramping.  Generally, one type is more prominent in a patient than the other, and they rarely co-occur with equal intensity.
85-100% of SM patients demonstrate increased histamine production.  Histamine is known to stimulate acid secretion, so SM patients are generally expectly to produce too much acid in the stomach.  However, studies have shown a variety of conflicting results.  Some patients produce too much acid, some too little, and some in the normal range.  For those who overproduce acid, the levels can be extremely high, comparable to levels seen in Zollinger-Ellison Syndrome. 
Occasionally, achlorhydria, the absence of gastric acid, has been found in SM patients.  This is thought to be due to atrophic gastritis (chronic inflammation of the stomach mucosa) that leads to impaired signaling from the local cells; however, this is unproven. 
Multiple studies have attempted to link serum histamine levels with normal basal acid secretion.  In one study, all patients had high serum histamine, but 56% had normal basal acid secretion.  This finding can be attributed to several things, including measured histamine not being fully biologically active; circulating histamine level being less important to acid secretion rate than the level of histamine in the local mucosa.  High histamine has been found in the gastric mucosa of several SM patients with dyspeptic pain. 
Furthermore, the authors elaborated that the histamine levels might not have been high enough to stimulate acid production; that the H2 receptors on acid producing (parietal) cells may have become desensitized to such high histamine levels; or that parietal cells were unable to respond to the histamine signaling, for some other reason.  Of these possible explanations, desensitization is supported by previous research, though not in SM patients.
In a study of 21 patients, 30% of them showed abnormalities on upper GI barium studies.  19% had gastric nodules and 11% had gastritis or peptic disease.  Biopsies of gastric mucosa show increased histamine and increased inflammatory cell infiltration with increased mast cells.  GI symptoms did not correlate with mast cell counts.
Common endoscopic findings in SM patients with dyspeptic pain include: acid hypersecretion; peptic ulcer disease; thickened gastric or duodenal folds; nodular mucosal lesions; occasional altered motility; occasional urticarial lesions; and increased infiltration by inflammatory cells with or without increased mast cells.
Studies have shown that approximately 28% of SM patients have esophageal abnormalities.  These include esophagitis, reflux, varices (abnormally enlarged veins that may bleed) or motor uncoordination.  Difficulty swallowing was common in these patients.  When assessed, these patients showed that the lower esophageal sphincter did not close with enough pressure. 
Esophageal motor function was assessed in 16 patients by manometry.  In 15/16 patients, the esophageal body contractions were normal.  In 62% of these patients, the lower esophageal sphincter function was abnormal.  75% of patients had reflux symptoms.  2/16 did not relax the esophageal sphinter during swallowing.
Esophageal varices have been reported in several SM patients.  The current rate of occurrence is listed as 2.5%, but this is likely an underestimation.
Jensen RT. Gastrointestinal abnormalities and involvement in systemic mastocytosis. Hematol Oncol Clin North Am. 2000;14:579–623.
Bedeir A, et al.  Systemic mastocytosis mimicking inflammatory bowel disease: A case report and discussion of gastrointestinal pathology in systemic mastocytosis.  Am J Surg Pathol.  2006 Nov;30(11): 1478-82.
Lee, Jason K, et al.  Gastrointestinal manifestations of systemic mastocytosis.  World J Gastroenterol. 14(45): 7005-7008.

MCAD, MCAS and the hierarchy of mast cell disease classifications

I have seen several posts recently expressing confusion about various mast cell diagnoses so I figured I would put up a post to clear things up.
Mast cell activation disorder (MCAD) is a catch-all term for mast cell disease (MCD.)  MCAD and MCD can be used interchangeably.  So if you have any mast cell disease, you have MCAD.  If you have SM, you have MCAD, because SM is a type of MCAD.  If you have UP, you have MCAD, and so on.  MCAD is an umbrella term.  It is non-specific.  It is similar to being told that you have heart disease when you have mitral valve prolapse.  It is true, but it is not precise enough to give all information needed to treat effectively.
Mast cell activation syndrome (MCAS) is the diagnosis you get if you do not meet the criteria for any of the defined mast cell diseases, but have mast cell mediator related symptoms.  You cannot have MCAS and another mast cell disease because, by its definition, MCAS is ONLY diagnosed if you do NOT meet the criteria for any other mast cell disease.  You cannot have UP and MCAS.  You cannot have SM and MCAS.  I think some people think that MCAS means you have mediator related symptoms.  This is not the case.  You can have mediator related symptoms with pretty much any mast cell disease. 
A paper was published a few years ago by a doctor who considers mast cell activation symptoms to be due exclusively to proliferation (like in SM.)  He wrote a paper that says that MCAS is found in people with SM.  This paper sort of confused the issue for a lot of people.  However, the mast cell community (including researchers and prominent doctors) do not consider this to be the case.  They agree that you cannot have SM and MCAS.
Also confusing is the fact that mast cell activation (MCA) is NOT the same as MCAS.  MCA just means that your mast cells are activated, which occurs in any mast cell disease.  MCA is not a diagnosis, it is a symptom.  So you can have MCA in SM.  But you still can’t have MCAS in SM.
So if you have SM and have lots of mediator related symptoms, you have SM.  If you want to speak broadly, you have SM.
If you test negative for SM and have no CM, but have mast cell symptoms and elevated mast cell markers, you have MCAS. 
If you have UP and then later develop SM, you have SM with skin involvement, or SM with UP. 
If you have UP or TMEP and have lots of mediator related systemic symptoms, you do NOT have UP and MCAS.  You have UP.  UP and TMEP (forms of CM) can cause systemic symptoms.  But you cannot have MCAS because you can only have MCAS if you do not meet the criteria for another mast cell disease.
Let’s review.
If you have UP: you have UP, you have CM, you have MCAD.
If you have TMEP: you have TMEP, you have CM, you have MCAD.
If you have SM: you have SM, you have MCAD.
If you have SM with UP: you have SM with skin involvement, you have UP, you have MCAD.
If you have SM with TMEP: you have SM with skin involvement, you have TMEP, you have MCAD.
If you have SM-AHNMD: you have SM-AHNMD, you have MCAD.
If you have ASM: you have ASM, you have MCAD.
If you have MCL: you have MCL, you have MCAD.

If you have MCAS: you have MCAD.

Molderings GJ, Brettner S, Homann J, Afrin LB. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J. Hematol. Oncol.2011; 4:10-17.

Neurologic symptoms of mast cell disease

Mast cells are known to closely associate with nerve endings and to be important in neurotransmission.  This can translate into a variety of neurologic symptoms.
In 2011, a retrospective study on the neurologic symptoms of mast cell patients (171 SM patients, 52 CM patients, all adult) was published.  The following is a summary of the results.
Syncope (fainting) is a well-defined complication of mastocytosis, reported here in 14.3% of patients .  In these patients, evaluation revealed that the likelihood of epileptic involvement was likely low.  About 2/3 of patients who had fainting episodes also had loose stool, cramping, nausea, sweating and flushing accompanying the episode.  Prostaglandin D2 and histamine are known to cause low blood pressure and fainting in addition to GI symptoms.  Aspirin is thought to protect against acute vascular collapse and fainting, and sees use in tolerant patients for these purposes.   
16.6% of mastocytosis patients complained of back pain.  In all but one patient, the cause was determined to be multifocal compression fractures throughout the spine, including thoracic region.  Vertebroplasty, a procedure in which special bone cement is applied to the fractured vertebrae, has been suggested for symptom relief of these patients.  One patient was found to have back pain due to dense mast cell infiltration of the vertebrae.  In this patient, radiation therapy provided symptom relief.
35% of patients reported headaches.  Several of these patients met the criteria for migraines.  Mast cells have been implicated repeatedly in migraine pathology, and mastocytosis patients are more likely to suffer from them than the general population.  In response to mast cell degranulation, reactive changes have been noted in trigeminal nerve, the structure responsible for sensation in the face and activities like chewing.  Trigeminal neuralgia has been noted in some patients with mast cell disease.
This paper was also the first to find a link between mastocytosis and multiple sclerosis.  Two adults with ISM developed relapsing remitting MS, and a patient with isolated UP developed primary progressive MS.  Mast cells are known to associate with MS lesions, and mast cell activation can be detected in cerebrospinal fluid of MS patients.  This study found an MS frequency of 1.3% among mastocytosis patients, compared to 0.1% in the general population.
Lastly, an association has been found between overall mast cell burden and susceptibility to experimental autoimmune encephalitis (EAE.)
Smith, Jonathan H, Butterfield, Joseph H, Pardanini, Animesh, DeLuca, Gabriele, Cutrer, F Michael.  Neurologic symptoms and diagnosis in adults with mast cell disease.  Clinical Neurology and Neurosurgery 113 (2011) 570-574.

The question I get asked the most

Whether or not SM is cancer is, by far, the question I get asked the most.  Because I get asked so often, I have done a lot of digging on this topic in the last few months.  Here’s what I found.

On the surface, from a biological point of view, SM looks like cancer.  It is characterized by excessive, improper cell growth.  It can cause organ infiltration and damage.  Over 90% of patients have a mutation in the CKIT gene, which is a proto-oncogene.  A proto-oncogene is a gene that becomes an oncogene when mutated.  An oncogene is a gene that contributes to cancer.  CKIT mutations can lead to gastrointestinal stromal tumors (GIST), melanoma, acute myeloid leukemia and, of course, mast cell disease.  So if SM has unregulated cell growth and a mutation in a proto-oncogene, that makes it cancer, right?
The World Health Organization (WHO), an organization I generally consider to know what they are doing, says it doesn’t.  To find out exactly why, I talked to a pathologist familiar with mast cell disease.  This is what she said:
“All cancers are neoplasms, but not all neoplastic cells are cancerous.  It is cancerous when the cells grow out of control.  In mastocytosis, even if you do nothing (meaning take no medications designed to kill off the mast cells), most of the time, the prognosis is very good because the cells are not growing that much.  Not like a cancer.  The other thing is when the cells invade other organs and the bloodstream and damage the organs.  When it is widespread and damaging, it is malignant.”
The majority of people with systemic mastocytosis have indolent disease, for which the life expectancy is normal, usually without any kind of therapy to kill off mast cells.  So if we follow the guidelines laid out above, SM is not cancer.   It is a myeloproliferative neoplasm (MPN.)
I know some people with ASM identify as having cancer.  ASM has a lot more features we typically associate with cancer, so I think that’s fine.  And MCL, obviously, is leukemia.
There is some terminology that gets thrown around incorrectly and I think it scares people who don’t understand that the wrong terms are being used.  One of them is chemo.  People with more aggressive types of mast cell disease may need chemo drugs.  People sometimes use the term incorrectly to reference more common treatments.  If you’re a rookie, I can see how you might get scared thinking that lots of people with indolent disease are on chemo.
Another term is compassionate use.  Compassionate use is the use of an experimental drug outside of a clinical trial.  It is generally allowed only when the person has no other treatment options and is gravely ill.  I have seen some people use it when discussing patient assistance programs, in which a pharmaceutical company will distribute a drug to a patient at a significant discount or at no cost.  They are not the same thing.
In the last few months, I have noticed that some people with SM will tell people that they have a “rare kind of leukemia.”  This is not accurate.  With the obvious exception of MCL, mast cell disease is not leukemia.  SM is a blood disorder. 
I think that part of why some people with mast cell disease say they have leukemia is because they want the sort of empathy given to cancer patients.  I understand that.  I wrote a whole post about how I hate when people say, “At least it’s not cancer.”  But it’s important to remember that cancer has two entities: the medical, biological aspect of the disease, and the social construct.  When you have ISM and you tell someone you have leukemia, their first thought is that you could die from it.  Mast cell disease is scary enough with scaring everyone around you extra with misinformation. 
I know that it’s frustrating that people know what cancer is and they probably don’t know what mast cell disease is.  And to be clear, I’m not talking about an offhand comment you make to some stranger asking you why you have a port at the grocery store to get them to go away.  I’m talking about the people who are actually in your life.  (I’m also obviously not referring to the SM-AHNMD people, who may very well have leukemia in addition to SM.)  If our mission is to educate people, stuff like this matters.  The words we use  matter.  A lot.  
I’m aware that this post is probably going to make some people angry, and that’s fine.  You can feel however you want to feel.  But I’m getting enough questions about this from people who are really worried, so I feel it’s important to set the record straight.