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Evolution

The first scientific theory that really intrigued me was the endosymbiotic theory. I don’t know if I think it’s true or not but I think it’s a fascinating idea. It goes like this: many years ago, all life is single celled organisms, like bacteria. At some point in history, a bacterium brought another kind of bacterium into its cell. You now have one bacterium living inside another bacterium.

So what’s the benefit? One of them provides safety for the other by keeping it away from the outside environment. And the other provides energy. Over time, the bacterium brought inside becomes a mitochondrion, the place where many cells make energy. Mitochondria are noteworthy in that they have their own genes that are completely separate from the rest of an organism’s genes. Cells that were able to make energy like this evolved into complex organisms, like humans.

Evolution is an amazing thing but it comes at a cost. Both bacteria eventually lost their ability to survive on their own. One cell needed the extra energy and the other needed protection from the environment. Both of these cells lost their individual traits in the progression toward something larger. They became trapped.

I have been actively involved in the mast cell community for several years. I have been very involved for about three years. I will never forget the feeling I got when I realized that these people understood what it was like to live in a body ravaged by this disease. I will never forget the first people who made me feel welcome and valued in this community.

In the last few years, I have laid bare my secret pains and fears to a bunch of people I had never met and might never meet. These people carried me through some of the hardest days of my life. They listened to me scream and cry and forgave me when I was an asshole and tried to soothe me when I was desperate to not feel like this and not live in this broken body anymore.

Whether or not we want to be, the people in this community are all connected. We share a common fate. These relationships are laced with primal and fierce emotion because they could be over in an instant. When you are very sick, and you have friends who are very sick, you live in a world where death is an ever present threat. You learn to not be surprised but you can’t learn to not hurt. The pain is the same, every time.

Caring about people and their struggles is not optional. We are too much the same. When the worst happens and one of us dies, it is impossible not to feel your own mortality on top of the sadness of losing someone who is too much like us. You remember the kinship and the shared suffering and a mutual understanding that all of this sucks but we can still have good days and good lives.

The people in this community have become a larger, living thing, bigger than our individual selves. We are bound together by the smoke and dark magic of these diseases and the lives we make despite them. We have evolved to become more powerful and dependent upon each other at once.

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

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

Presentation

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

Diagnostic criteria

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

Evidence of mediator release

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

Symptoms associated with mast cell activation

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

Response to medications that inhibit action of mast cell mediators

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

Natural history

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

 

References

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The Provider Primer Series: Mediator testing

Evidence of mediator release

  • Mast cells produce a multitude of mediators including tryptase, histamine, prostaglandin D2, leukotrienes C4, D4 and E4, heparin and chromogranin A[i].
  • Objective evidence of mast cell mediator release is required for diagnosis of MCAS (Castells 2013)[ii], (Akin 2010)[iii], (Valent 2012)[iv].
  • Serum tryptase and 24 hour urine testing for n-methylhistamine, prostaglandin D2, prostaglandin 9a,11b-F2 are frequently included in MCAS testing recommendations (Castells 2013)[ii], (Akin 2010)[iii], (Valent 2012)[iv].
  • It can be helpful to test for other mast cell mediators including 24 hour urine testing for leukotriene E4[v]; plasma heparin[ix]; serum chromogranin A[ix]; and leukotriene E4[ix].

Tryptase

  • Tryptase is extremely specific for mast cell activation in the absence of hematologic malignancy or advanced kidney disease. Of note, rheumatoid factor can cause false elevation of tryptase[ix].
  • Serum tryptase levels peak 15-120 minutes after release with an estimated half-life of two hours[vi].
  • Per key opinion leaders, tryptase levels should be drawn 15 minutes to 4 hours after onset of anaphylaxis or activation event (Castells 2013[ii]), (Akin 2010[iii]), (Valent 2012)[iv]). Phadia, the manufacturer of the ImmunoCap® test to quantify tryptase, recommends that blood be drawn 15 minutes to 3 hours after event onset[vii].
  • Serum tryptase >11.4 ng/mL is elevated[i]. In addition to measuring tryptase level during the event, another sample should be drawn 24-48 hours after the event, and a third sample drawn two weeks later. This allows comparison of event tryptase level to baseline[vi].
  • An increase in serum tryptase level during an event by 20% + 2 ng/mL above patient baseline is often accepted as evidence of mast cell activation[v],[i].
  • Absent elevation of tryptase level from baseline during an event does not exclude mast cell activation[viii].
  • Sensitivity for serum tryptase assay in MCAS patients was assessed as 10% in a 2014 paper[ix].
  • A recent retrospective study of almost 200 patients found serum was elevated in 8.8% of MCAS patients[x].
  • Baseline tryptase >20.0 ng/mL is a minor criterion for diagnosis of systemic mastocytosis. 77-85% of SM patients have baseline tryptase >20.0 ng/mL[ix].

Histamine and degradation product n-methylhistamine

  • N-methylhistamine is the breakdown product of histamine.
  • Histamine is degraded quickly. Samples should be drawn within 15 minutes of episode onset[vii].
  • Serum histamine levels peak 5 minutes after release and return to baseline in 15-30 minutes[vii].
  • Sample (urine or serum) must be kept chilled[xi].
  • In addition to mast cells, histamine is also released by basophils. Consumption of foods or liquids that contain histamine can also inflate the level when tested[ix].
  • A recent retrospective study of almost 200 patients found that n-methylhistamine was elevated in 7.4% of MCAS patients in random spot urine and 5.4% in 24-hour urine[xi].
  • Sensitivity of 24-hour n-methylhistamine for MCAS was assessed as 22% in 24-hour urine[ix].
  • Plasma histamine was elevated in 29.3% of MCAS patients[xi].
  • 50-81% of systemic mastocytosis patients demonstrate elevated n-methylhistamine in 24-hour urine[ix].

Prostaglandin D2 and degradation product prostaglandin 9a,11b-F2

  • 9a,11b-prostaglandin F2 is the breakdown product of prostaglandin D2.
  • Prostaglandin D2 is only produced in large quantities by mast cells. Basophils, eosinophils and other cells produce minute amounts[ix].
  • A recent retrospective study of almost 200 patients found that PGD2 was elevated in 9.8% of MCAS patients in random spot urines and 38.3% in 24-hour urine[xi].
  • PGD2 was elevated in 13.2% of MCAS patients in plasma[xi].
  • 9a,11b-PGF2 was elevated in 36.8% in 24-hour urine[xi].
  • 62-100% of systemic mastocytosis patients demonstrate elevated prostaglandin D2 or 9a,11b-PGF2 in urine[ix].
  • Prostaglandins are thermolabile and begin to break down in a minutes. This can contribute to false negative results[xi].
  • Medications that inhibit COX-1 and COX-2, such as NSAIDs, decrease prostaglandin production[xi].

Leukotriene E4

  • Leukotriene E4 is produced by mast cells and several other cell types[ix] including eosinophils, basophils and macrophages.
  • A recent retrospective study of almost 200 patients found that LTE4 was elevated in 4.4 % of MCAS patients in random spot urines and 8.3% in 24-hour urine[xi].
  • 44-50% of systemic mastocytosis patients demonstrate elevated leukotriene E4 in urine[ix].
  • Medications that inhibit 5-LO, such as lipoxygenase inhibitors, decrease leukotriene production[xii].

Chromogranin A

  • Chromogranin A is produced by mast cells and several other cell types including chromaffin cells and beta cells.
  • Proton pump inhibitors can cause increased values during testing[xi].
  • A 2014 paper reported chromogranin A was elevated in 12% of MCAS patients and 63% of systemic mastocytosis patients tested[ix].

Heparin

  • Heparin is a very specific mediator for mast cell activation[ix].
  • Heparin is extremely heat sensitive. The sample must be kept on ice or refrigerated at all times[ix].
  • Venous occlusion of upper arm for ten minutes has been successful in provoking mast cell activation leading to heparin release[ix].
  • A 2014 paper reported plasma heparin was elevated in 59% of MCAS patients and 47% of systemic mastocytosis patients tested[ix].
  • A recent retrospective study of almost 200 patients found that plasma heparin was elevated in 28.9% tested[ix].

 

References

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

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

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

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

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

[vi] Payne V, Kam PCA. (2004). Mast cell tryptase: a review of its physiology and clinical significance. Anaesthesia, 59(7), 695-703.

[vii] Phadia AB. ImmunoCAP® Tryptase in anaphylaxis. Retrieved from: http://www.phadia.com/Global/Market%20Companies/Sweden/Best%C3%A4ll%20information/Filer%20(pdf)/ImmunoCAP_Tryptase_anafylaxi.pdf

[viii] Sprung J, et al. (2015). Presence or absence of elevated acute total serum tryptase by itself is not a definitive marker for an allergic reaction. Anesthesiology, 122(3), 713-717.

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

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

[xi] Afrin LB. “Presentation, diagnosis and management of mast cell activation syndrome.”  Mast Cells, edited by David B. Murray, Nova Science Publishers, Inc., 2013, 155-231.

[xii] Hui KP, et al. (1991). Effect of a 5-lipoxygenase inhibitor on leukotriene generation and airway responses after allergen challenge in asthmatic patients. Thorax, 46, 184-189.

The Provider Primer Series: Natural history of SM-AHD, MCL and MCS

Natural history of systemic mastocytosis with associated hematologic disease (SM-AHD):

  • SM-AHD is defined by systemic mastocytosis in the presence of another clonal hematologic disease. SM-AHD is thought to comprise 30-40% of all mastocytosis cases[i].
  • In about 90% of cases, the associated blood disorder is a myeloid neoplasm such as myelodysplastic syndrome, myeloid leukemias, or myeloproliferative diseases such as polycythemia vera or essential thrombocythemia[i] . Janus kinase 2 (JAK2) V617F mutation, which has a known association with myeloproliferative neoplastic conditions such as essential thrombocythemia and polycythemia vera, is sometimes present in SM-AHD patients[vii].
  • In this condition, SM and the other blood disorder are treated as separate entities as if they did not co-occur[i]. The conditions are synchronous and the associated hematologic disease does not occur secondarily to SM or treatment thereof. Prognosis in SM-AHD depends almost exclusively upon the associated hematologic concern. In multiple studies, fatalities are reported as result of associated malignancies[ii].
  • Myeloid neoplasms are the most common AHD, including chronic myelomonocytic leukemia or other leukemias, myelodysplastic syndrome, or myeloproliferative diseases[i].
  • In a 138 patient cohort: about 1/3 demonstrated Hgb <100 g/L and platelets<100×109/L; 51% had elevated white cell count; 31% demonstrated frank eosinophilia <1.5×109/L[vii].
  • SM-AHD patients are at increased risk of leukemic transformation relative to other forms of systemic mastocytosis (excluding mast cell leukemia) with a frequency of 14% in a 138 patient cohort[vii].
  • The SM aspect of SM-AHD is diagnosed and staged according to the SM diagnostic algorithm. It is therefore possible for a patient with SM-AHD to have mast cell leukemia or any other subtype of SM[vii].

Natural history of mast cell leukemia (MCL):

Table 1: Diagnostic criteria for mast cell leukemia[iii] 
Meets criteria for systemic mastocytosis Mast cells compromise 20% of all nucleated cells in blood smears

 

Table 2: C findings present in acute MCL[iii] 

 
C findings One or more cytopenias (absolute neutrophil count <1000/µl; Hemoglobin <10g/dl; platelets <100000/µl) Hepatomegaly with ascites, elevated liver enzymes with or without portal hypertension Splenomegaly with hypersplenism Malabsorption evidenced by low albumin and weight loss Large osteolysis and/or severe osteoporosis and pathologic fractures (2 or more fractures as direct result of mast cell activity)

 

  • Mast cell leukemia is defined by SM where ≥20% nucleated cells in marrow are mast cells. In leukemic variant, >10% of nucleated cells in blood are mast cells; in aleukemic variant, there are <10% mast cells[iii].
  • MCL can occur de novo or from a previous mast cell neoplastic condition such as aggressive systemic mastocytosis or mast cell sarcoma[iii].
  • CKIT D816V mutation is less common in MCL than in other forms of systemic mastocytosis (50-80%). Some patients have mutations elsewhere in the coding regions of CKIT or a non-D816V mutation at CKIT codon 816. An unusual feature of MCL is that when the disease progresses quickly, the patient may lose positivity for the D816V mutation[iv].
  • MCL patients do not typically demonstrate mastocytosis in the skin[iii].
  • In the absence of C findings, some MCL patients have stable disease without markers of progression. This is referred to as chronic MCL[iii] .
  • >90% mature mast cells is a positive prognostic indicator. Presence of mostly immature mast cells is associated with more aggressive disease[iii] .
  • Acute MCL rapidly causes catastrophic organ damage. Median survival in acute cases is six months, though some MCL patients live for years through the use of newer targeted therapies[iv].
  • Hematopoietic stem cell transplant (HSCT) is an experimental option for MCL patients. In one study, overall survival at the three year mark was 17% (2 of 12 patients)[viii].

Natural history of mast cell sarcoma:

  • Mast cell sarcoma is an exceedingly rare tumor with high grade cytology that can present in a variety of tissues[v].
  • Mast cells that comprise the tumor resemble neither morphologically normal mast cells or spindled cells often seen in SM. In mast cell sarcoma, mast cells are often bilobed and multinucleated tumor cells have been reported. Of note, mast cells compromising the sarcoma often express CD30[iv].
  • Mast cell sarcomas often have neither CKIT D816V mutation nor mutations elsewhere in CKIT coding regions[vi].
  • Mast cell sarcomas often induce only local symptoms at the time of diagnosis but systemic involvement rapidly follows. Mast cell sarcoma may progress to mast cell leukemia. Median survival is 12 months[vi].

References:

[i] Gotlib J. (2013). Approach to the diagnosis and management of mastocytosis. The Hematologist, 10(1). Retrieved from: http://www.hematology.org/Thehematologist/Ask/5960.aspx

[ii] Wang SA. (2013). Systemic mastocytosis with associated clonal hematologic non-mast cell lineage disease (SM-AHNMD): clinical significance and comparison of chromosomal abnormalities in SM and AHNMD components. Am J Hematol, 88(3), 219-224.

[iii] Valent P, et al. (2014). Refined diagnostic criteria and classification of mast cell leukemia (MCL) and myelomastocytic leukemia (MML): a consensus proposal. Ann Oncol, 25(9), 1691-1700.

[iv] Youk J. (2016). A scientific treatment approach for acute mast cell leukemia: using a strategy based on next-generation sequencing data. Blood Res, 51(1), 17-22.

[v] Ryan RJH, et al. (2013). Mast cell sarcoma: a rare and potentially underreecognized diagnostic eneity with specific therapeutic implications. Modern Pathology, 26, 533-543.

[vi] Georgin-Lavialle S, et al. (2013). Mast cell sarcoma: a rare and aggressive entity – report of two cases and review of the literature. JCO, 31(6), e50-e57.

[vii] Lim KH, et al. (2009). Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood, 113(23), 5727-5736.

[viii] Ustun C, et al. (2014). Hematopoietic stem-cell transplantation for advanced systemic mastocytosis. J Clin Oncol, 32(29), 3264-3274.

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

Systemic mastocytosis (SM) is a primary hematologic disorder marked by the excessive proliferation of mast cells.

Neoplastic nature of mastocytosis:

  • Mast cells produced in this disease are neoplastic and may have some or all of the following markers: presence of somatic gain-of-function mutation at codon 816 of CKIT (KIT), usually, but not always, the D816V mutation; expression of CD2 or CD25 on mast cell surface; atypical spindled morphology of mast cells[i].
  • Mastocytosis is a neoplastic condition that is not described exclusively by excessive population of mast cells. Mast cell hyperplasia can occur in response to a number of conditions including chronic urticaria[ii], irritable bowel syndrome[iii], and other hematologic neoplasia, including chronic lymphocytic leukemia, non-Hodgkin lymphoma, and myeloproliferative conditions[iv].
  • To meet criteria for SM, mast cell infiltration must be dense with at least 15 mast cells per cluster. In many instances, there is not a validated range of mast cells/hpf in healthy controls[iv].
Table 1: Diagnostic criteria for systemic mastocytosis[v]

1 major and 1 minor criterion; or 3 minor criteria
Major Multifocal dense infiltrates of mast cells (15 or more in aggregate) detected in sections of bone marrow and/or extracutaneous organ
Minor In biopsy sections, more than 25% of mast cells in infiltrated space are spindle-shaped or otherwise morphologically abnormal; or, of all mast cells in bone marrow aspirate smears, more than 25% mast cells are immature or abnormal. Detection of CKIT mutation at codon 816 in bone marrow, blood or extracutaneous organ Mast cells in bone marrow, blood or other extracutaneous organ that co-expresses CD-117 with CD2 and/or CD25 Baseline serum tryptase of 20 ng/ml or higher.

 

Presence of dense infiltrates:

  • The hallmark sign of systemic mastocytosis is multifocal dense infiltration of an organ that is not the skin. Despite this fact, it is possible to biopsy negative while still having SM. A 2004 study reported the pathological findings of bilateral bone marrow biopsies for 23 patients. 83% of patients demonstrated positive biopsy for SM bilaterally while 17% of patients had only one positive biopsy[vi].
  • One study found that 20% of ISM patients did not have dense infiltration of mast cells in bone marrow[vii].

Tryptase level in systemic mastocytosis:

  • Tryptase ≥20 ng/mL is a minor criterion for SM. In order to meet this criterion, tryptase must be ≥20 ng/mL at baseline, not during or following a reactive or anaphylactic event. Per Phadia, producer of ImmunoCAP® Tryptase test, it can take up to fourteen days for tryptase to return to baseline[viii]. However, other sources recommend shorter time to baseline, as low as “24 hours after clinical signs and symptoms have completely subsided”[ix].
  • 20-30% of SM patients do not meet the minor criterion of tryptase level ≥20 ng/mL[xiii].

Detection of CKIT D816V mutation:

  • The CKIT D816V mutation may not be detected in peripheral blood in a positive patient. Bone marrow aspirate is the preferred sample type for reliable testing for this mutation[xii].
  • One study reported as few as 78% of ISM patients were positive for the CKIT D816V mutation in bone marrow[xiii].

Natural history of indolent systemic mastocytosis:

  • Indolent systemic mastocytosis (ISM) is SM that does not meet criteria for smoldering systemic mastocytosis, aggressive systemic mastocytosis or mast cell leukemia.
  • ISM is largely described by mediator release symptoms and increased risk of anaphylaxis. Mast cell infiltration does not cause appreciable organ dysfunction in this variant[x].
  • Progression from ISM to SSM occurred in about 8% of patients in a cohort of 74. In this same cohort, 4% ISM patients progressed to ASM[xi]. The risk of leukemic transformation from ISM was 0.6% in a cohort of 159[xii].
  • Organomegaly can present without loss of function at any level of hematologic disease in SM. Organ swelling may be stable over long periods of time without progression to aggressive systemic mastocytosis (ASM)[x].
  • Lifespan for indolent systemic mastocytosis is normal[x].
Table 2: Diagnostic criteria for smoldering systemic mastocytosis

 (2 or 3 B findings in addition to meeting criteria for systemic mastocytosis)[i]
B findings Increased mast cell burden (>30% mast cell aggregates on bone marrow biopsy and/or serum tryptase >200 ng/mL) Hypercellular marrow, signs of myelodysplasia or myeloproliferation in absence of MDS or MPN Organ swelling without deficit of organ function (hepatomegaly without ascites, palpable splenomegaly, lymphadenopathy >2 cm)

 

Natural history of smoldering systemic mastocytosis:

  • Smoldering systemic mastocytosis (SSM) is defined by increased systemic mast cell burden, presence of markers associated with progression toward ASM (B findings), and potential need for cytoreduction[xiii].
  • SSM can remain stable for many years, even decadesix. In a cohort of 22 patients with SSM, 1 transformed to acute leukemia and 3 progressed to ASM[xiv].
  • Lifespan may be shortened in SSM. A widely reported study found an average lifespan of 10 years but reported that death was often unrelated to mastocytosis and in some cases was of natural old age[xiii].
Table 3: Diagnostic criteria for aggressive systemic mastocytosis

(1 or more C finding in addition to meeting criteria for systemic mastocytosis)[i]
C findings One or more cytopenias (absolute neutrophil count <1000/µl; Hemoglobin <10g/dl; platelets <100000/µl) Hepatomegaly with ascites, elevated liver enzymes with or without portal hypertension Splenomegaly with hypersplenism Malabsorption evidenced by low albumin and weight loss Large osteolysis and/or severe osteoporosis and pathologic fractures (2 or more fractures as direct result of mast cell activity)

 

Natural history of aggressive systemic mastocytosis:

  • Aggressive systemic mastocytosis (ASM) is defined by significant organ damage and failure as a direct result of mast cell infiltrationxv. Lifespan is often significantly shortened and can be as short as three years[ix] .
  • ASM generally follows one of two paths: a slow progressing form that resembles SSM but has C findings; or a rapidly progressing form that resembles mast cell leukemia. In rapidly progressing ASM, the patient may lose the CKIT D816V mutation[ix] .
  • ASM is managed with cytoreduction but patient response is often short lived. Tyrosine kinase inhibitors and other kinase inhibitors are also used in this population[ix] .
  • In treatment resistant cases, hematopoietic stem cell transplant offers an experimental option. One study on HSCT in advanced systemic mastocytosis included seven ASM patients. 3 (43%) achieved complete remission; 3 (43%) demonstrated progression free survival at the three year mark[xv].

References:

[i] Arber DA, et al. (2016). The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood, 127(20), 2391-2405.

[ii] Minnei F, et al. (2006). Chronic urticaria is associated with mast cell infiltration in the gastroduodenal mucosa. Virchows Arch, 448(3), 262-268.

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

[iv] Hamilton MJ, et al. (2011). Mast cell activation syndrome a newly recognized disorder with systemic clinical manifestations. J Allergy Clin Immunol, 128, 147-152.

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

[vi] Butterfield JH, Li, CY. (2004). Bone marrow biopsies for the diagnosis of systemic mastocytosis: is one biopsy sufficient? Hematopathology, Am J Clin Pathol, 121: 264-267.

[vii] Sanchez-Munoz L, et al. (2011). Evaluation of the WHO criteria for the classification of patients with mastocytosis. Mod Pathol, 24(9), 1157-1168.

[viii] Phadia AB. ImmunoCAP® Tryptase: Clinical utility of Total Tryptase. Retrieved from: http://www.phadia.com/Global/Market%20Companies/Sweden/Best%C3%A4ll%20information/Filer%20(pdf)/ImmunoCAP_Tryptase_Clin_Util.pdf

[ix] Schwartz LB. (2006). Diagnostic value of tryptase in anaphylaxis and mastocytosis. Immunology and Allergy Clinics of North America, 26(3), 451-463.

[x] Valent P, et al. (2010). How I treat patients with advanced systemic mastocytosis. Blood, 116(26), 5812-5817.

[xi] Matito A, et al. (2013). Serum tryptase monitoring in indolent systemic mastocytosis: association with disease features and patient outcome. PLoS One, 8(10), e76116.

[xii] Lim KH, et al. (2009). Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood, 113(23), 5727-5736.

[xiii] Pardanini A. (2013). How I treat patients with indolent and smoldering mastocytosis (rare conditions but difficult to manage). Blood, 121, 3085-3094.

[xiv] Pardanini A. (2010). WHO subvariants of indolent mastocytosis: clinical details and prognostic evaluation in 159 consecutive adults. Blood, 115, 150-151.

[xv] Ustun C, et al. (2014). Hematopoietic stem-cell transplantation for advanced systemic mastocytosis. J Clin Oncol, 32(29), 3264-3274.

[xvi] Pardanini A. (2013). Systemic mastocytosis in adults: 2013 update on diagnosis, risk stratification, and management. American Journal of Hematology, 88(7, 612-624).

[xvii] Valent P, et al. (2003). Aggressive systemic mastocytosis and related mast cell disorders: current treatment options and proposed response criteria. Leuk Res, 27(7), 635-641.

The Provider Primer Series: Diagnostic criteria of systemic mastocytosis and all subvariants

World Health Organization Classification

  • Mastocytosis was classified by the WHO as a myeloproliferative neoplasm for a number of years. In 2016, the WHO placed mastocytosis into its own category, separate from myeloproliferative neoplasms.
  • In a paper summarizing changes to WHO classification of myeloid neoplasms and acute leukemias, the author stated that “mastocytosis…is no longer considered a subgroup of the MPNs due to its unique clinical and pathologic features, ranging from indolent cutaneous disease to aggressive systemic disease, and is now a separate disease category in the classification[i].”
Table 1: WHO Classification of Mastocytosisi
Category Subtype
Cutaneous mastocytosis (CM) Cutaneous mastocytosis (CM), including maculopapular cutaneous mastocytosis (MPCM, previously called urticaria pigmentosa); solitary mastocytoma of the skin; diffuse cutaneous mastocytosis*Author’s note: Telangiectasia macularis eruptiva perstans (TMEP) is considered a variant of maculopapular cutaneous mastocytosis (MPCM, previously called urticaria pigmentosa)
Systemic mastocytosis (SM) Indolent systemic mastocytosis (ISM)
Smoldering systemic mastocytosis (SSM)
Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN)
Aggressive systemic mastocytosis (ASM)
Mast cell leukemia (MCL)
Mast cell sarcoma (MCS) Mast cell sarcoma (MCS)

 

Diagnostic criteria for subvariants of systemic mastocytosis

Table 2: Diagnostic criteria for indolent systemic mastocytosis[ii] 1 major and 1 minor criterion; or 3 minor criteria
Major Multifocal dense infiltrates of mast cells (15 or more in aggregate) detected in sections of bone marrow and/or extracutaneous organ
Minor In biopsy sections, more than 25% of mast cells in infiltrated space are spindle-shaped or otherwise morphologically abnormal; or, of all mast cells in bone marrow aspirate smears, more than 25% mast cells are immature or abnormal. Detection of CKIT mutation at codon 816 in bone marrow, blood or extracutaneous organ Mast cells in bone marrow, blood or other extracutaneous organ that co-expresses CD-117 with CD2 and/or CD25 Baseline serum tryptase of 20 ng/ml or higher.

 

Table 3: Examples that meet minimum criteria for indolent systemic mastocytosis
Scenario 1:

1 major criterion, 1 minor criterion

 Major criterion: Multifocal dense infiltrates of mast cells (15 or more in aggregate) detected in sections of bone marrow and/or extracutaneous organ Minor criterion: Baseline serum tryptase of 20 ng/ml or higher.
Scenario 2:

1 major criterion, 1 minor criterion

 Major criterion: Multifocal dense infiltrates of mast cells (15 or more in aggregate) detected in sections of bone marrow and/or extracutaneous. Minor criterion: In biopsy sections, more than 25% of mast cells in infiltrated space are spindle-shaped or otherwise morphologically abnormal; or, of all mast cells in bone marrow aspirate smears, more than 25% mast cells are immature or abnormal
Scenario 3:

1 major criterion, 1 minor criterion

 Major criterion: Multifocal dense infiltrates of mast cells (15 or more in aggregate) detected in sections of bone marrow and/or extracutaneous Minor criterion: Detection of CKIT mutation at codon 816 in bone marrow, blood or extracutaneous organ
Scenario 4:

1 major criterion, 1 minor criterion

 Major criterion: Multifocal dense infiltrates of mast cells (15 or more in aggregate) detected in sections of bone marrow and/or extracutaneous Minor criterion: Mast cells in bone marrow, blood or other extracutaneous organ that co-expresses CD-117 with CD2 and/or CD25
Scenario 5:

3 minor criteria

 Minor criterion: Mast cells in bone marrow, blood or other extracutaneous organ that co-expresses CD-117 with CD2 and/or CD25 Minor criterion: Detection of CKIT mutation at codon 816 in bone marrow, blood or extracutaneous organ Minor criterion: Baseline serum tryptase of 20 ng/ml or higher.
Scenario 6:

3 minor criteria

 Minor criterion: Mast cells in bone marrow, blood or other extracutaneous organ that co-expresses CD-117 with CD2 and/or CD25 Minor criterion: Detection of CKIT mutation at codon 816 in bone marrow, blood or extracutaneous organ Minor criterion: In biopsy sections, more than 25% of mast cells in infiltrated space are spindle-shaped or otherwise morphologically abnormal; or, of all mast cells in bone marrow aspirate smears, more than 25% mast cells are immature or abnormal
Scenario 7:

3 minor criteria

 Minor criterion: Mast cells in bone marrow, blood or other extracutaneous organ that co-expresses CD-117 with CD2 and/or CD25 Minor criterion:Baseline serum tryptase of 20 ng/ml or higher. Minor criterion: In biopsy sections, more than 25% of mast cells in infiltrated space are spindle-shaped or otherwise morphologically abnormal; or, of all mast cells in bone marrow aspirate smears, more than 25% mast cells are immature or abnormal
Scenario 8:

3 minor criteria

 Minor criterion: In biopsy sections, more than 25% of mast cells in infiltrated space are spindle-shaped or otherwise morphologically abnormal; or, of all mast cells in bone marrow aspirate smears, more than 25% mast cells are immature or abnormal Minor criterion:Baseline serum tryptase of 20 ng/ml or higher. Minor criterion: Detection of CKIT mutation at codon 816 in bone marrow, blood or extracutaneous organ

Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) is essentially treated as two separate condition: systemic mastocytosis and an associated hematologic neoplastic condition. Accordingly, the diagnostic criteria for the systemic mastocytosis aspect of this diagnosis is the same as described here.

Table 4: Diagnostic criteria for smoldering systemic mastocytosis (2 or 3 B findings)[ii]
B findings Increased mast cell burden (>30% mast cell aggregates on bone marrow biopsy and/or serum tryptase >200 ng/mL) Hypercellular marrow, signs of myelodysplasia or myeloproliferation in absence of MDS or MPN Organ swelling without deficit of organ function (hepatomegaly without ascites, palpable splenomegaly, lymphadenopathy >2 cm)

 

Table 5: Examples that meet the criteria for smoldering systemic mastocytosis (2 or 3 B findings)
Scenario 1:

2 B findings

 Meets criteria for systemic mastocytosis Increased mast cell burden (>30% mast cell aggregates on bone marrow biopsy and/or serum tryptase >200 ng/mL) Hypercellular marrow, signs of myelodysplasia or myeloproliferation in absence of MDS or MPN
Scenario 2:

2 B findings

 Meets criteria for systemic mastocytosis Increased mast cell burden (>30% mast cell aggregates on bone marrow biopsy and/or serum tryptase >200 ng/mL) Organ swelling without deficit of organ function (hepatomegaly without ascites, palpable splenomegaly, lymphadenopathy >2 cm)
Scenario 3:

2 B findings

 Meets criteria for systemic mastocytosis Hypercellular marrow, signs of myelodysplasia or myeloproliferation in absence of MDS or MPN Organ swelling without deficit of organ function (hepatomegaly without ascites, palpable splenomegaly, lymphadenopathy >2 cm)
Scenario 4:

3 B findings

 Meets criteria for systemic mastocytosis Increased mast cell burden (>30% mast cell aggregates on bone marrow biopsy and/or serum tryptase >200 ng/mL) Hypercellular marrow, signs of myelodysplasia or myeloproliferation in absence of MDS or MPN Organ swelling without deficit of organ function (hepatomegaly without ascites, palpable splenomegaly, lymphadenopathy >2 cm)

 

Table 6: Diagnostic criteria for aggressive systemic mastocytosis (1 or more C finding)[ii]
C findings One or more cytopenias (absolute neutrophil count <1000/µl; Hemoglobin <10g/dl; platelets <100000/µl) Hepatomegaly with ascites, elevated liver enzymes with or without portal hypertension Splenomegaly with hypersplenism Malabsorption evidenced by low albumin and weight loss Large osteolysis and/or severe osteoporosis and pathologic fractures (2 or more fractures as direct result of mast cell activity)

 

Table 7: Examples that meet the minimum criteria for aggressive systemic mastocytosis (1 or more C finding) 
Scenario 1:

1 C finding

 Meets criteria for systemic mastocytosis 1 or more B findings may be present, not a requirement One or more cytopenias (absolute neutrophil count <1000/µl; Hemoglobin <10g/dl; platelets <100000/µl)
Scenario 2:

1 C finding

 Meets criteria for systemic mastocytosis 1 or more B findings may be present, not a requirement Malabsorption evidenced by low albumin and weight loss
Scenario 3:

1 C finding

 Meets criteria for systemic mastocytosis 1 or more B findings may be present, not a requirement Large osteolysis and/or severe osteoporosis and pathologic fractures (2 or more fractures as direct result of mast cell activity)
Scenario 4:

1 C finding

 Meets criteria for systemic mastocytosis 1 or more B findings may be present, not a requirement Hepatomegaly with ascites, elevated liver enzymes with or without portal hypertension
Scenario 5:

1 C finding

 Meets criteria for systemic mastocytosis 1 or more B findings may be present, not a requirement Splenomegaly with hypersplenism

 

Table 8: Diagnostic criteria for mast cell leukemia[iii]
Meets criteria for systemic mastocytosis Mast cells compromise 20% of all nucleated cells in blood smears

 

Table 9: Examples that meet the minimum criteria for mast cell leukemia
Scenario 1 Meets criteria for systemic mastocytosis B findings may be present but are not required C findings may be present but are not required Mast cells compromise 20% of all nucleated cells in blood smears

 

[i] Arber DA, et al. (2016). The 2016 revisioin to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood, 127(20), 2391-2405.

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

[iii] Valent P, et al. (2014). Refined diagnostic criteria and classification of mast cell leukemia (MCL) and myelomastocytic leukemia (MML): a consensus proposal. Ann Oncol, 25(9), 1691-1700.

The silver thread

I am a big believer in the emotional memory of the physical body. Our mind is the province of feelings but not of the visceral responses they evoke. Once we have received information and churned forth a limbic reaction, it is stored forever in our skin and muscles and bones. When I see something that reminds me of a deep loss, the percussion of my pulse swells and tears cling to my lower lashes before I even feel sadness. The body first, the mind second.

Earlier this week, I developed hives on my hands and arms. I occasionally get hives at this point but not like this. Within a few hours, they blistered. At the same time, I realized that I had bruising all over my arms and a few hives and bruises were developing on my chest and abdomen. It was well and truly bizarre but I wasn’t surprised at the onset of peculiar symptoms this week. This week, it has been a year. My body remembers.

It remembers laying on my yoga mat talking to Kristina about Seth. It remembers the hum of panic overlaying the dull bass of exhaustion. It remembers the headache from reading papers well into the night. It remembers the twisting pain and breathlessness of awful news. It remembers the way my skin burned like fire when anxiety woke me after two hours of sleep.

It remembers the soft click of the keyboard as I talked to friends thousands of miles away about this shared horror unfurling before us. The quiet pain of waiting for them to respond, both of us typing and deleting, sharing these things we cannot say. Conversations in short, informal sentences. For me, experiencing these awful moments in Facebook groups and group chats with a worldwide community has becoming an indelible part of having this rare disease. It is hard to pull masto away from social media. They are so intertwined for me.

It seems impossible that it has been a year. Last fall changed me fundamentally as a person. It is hard to realize that in some ways, things have not changed a lot. But there has been progress. There have been soul rending struggles. There have been moments where you dredge up tiny flecks of courage when you were so, so sure that there nothing left. There has been acceptance and perseverance and devotion. And in some ways, there has been healing.

We are alive. We are still here. Sometimes that is the only triumph.

I have to believe that there is a point to all of this. I have to believe that I am more than this vessel and its physical limitations. I have to believe that one day, I will be free of it.

But for now, I am still here. We didn’t lose anyone.  My body stores these emotions, a silver thread woven into every part of me that catches sometimes when I don’t expect it.

The Provider Primer Series: Cutaneous mastocytosis/ Mastocytosis in the skin

Mast cell disease: Categories

  • Mast cell disease is the collective term given to several distinct conditions mediated by mast cell dysfunction.  Speaking broadly, mast cell disease has two forms: mastocytosis, a clonal disease marked by excessive proliferation and infiltration of mast cells; and mast cell activation syndrome (MCAS), a disease that presents similarly to mastocytosis but demonstrates no clear indication of excessive proliferation. In addition, monoclonal mast cell activation syndrome (MMAS) can be viewed as straddling the two groupings with markers of clonality but minimum evidence to suggest overproduction of mast cells[i].
  • Mastocytosis has two forms: cutaneous, in which excessive mast cell infiltration is confined to the skin; and systemic, in which an organ that is not skin that is affected by excessive mast cell infiltration. Patients with systemic mastocytosis (SM) often have cutaneous mastocytosis; in this instance, this is called systemic mastocytosis with mastocytosis in the skin[ii].

Mastocytosis in the skin

  • Cutaneous mastocytosis (CM) is a proliferative condition marked by increased mast cell infiltration of the skin.  There are three subvariants of cutaneous mastocytosis: maculopapular cutaneous mastocytosis (MPCM), formerly known as urticarial pigmentosa (UP); diffuse cutaneous mastocytosis (DCM); and solitary mastocytoma of skin[ii].
  • Mast cell density in lesions is usually increased 4-8x above the density in healthy controls. However, some patients have mast cell density comparable to that in healthy controls[ii].
  • All forms of cutaneous mastocytosis can be found in children. Over 78% present by 13 months and some at birth[v]. Childhood onset CM often resolves by adolescence but not always[ii].
  • Most patients with mast cell lesions in childhood have CM rather than SM. Conversely, most patients who develop these macules in adulthood have systemic mastocytosis with mastocytosis in the skin[ii].
  • MPCM (UP) is overwhelmingly the dominant presentation of mastocytosis in the skin. Over 80% of all mastocytosis patients demonstrate the type of cutaneous involvement[ii].
  • In children, MPCM lesions are usually large and have variable morphology which may change over time. In adults, MPCM often occurs as small red/brown macules and may result in few lesions or cover the majority of the body[iii].
  • Telangiectasia macularis eruptive perstans (TMEP) is described as telangiectatic red macules generally found above the midtrunk. While previously thought to be a discrete entity, TMEP is now recognized as a form of MPCM[ii].
  • DCM is almost exclusively found in children with few adult onset cases. It does not present as discrete lesions but rather generalized erythema. Pachydermia may also be present, as well as darkening of the skin[ii].
  • DCM can be associated with formation of severe bullae from a variety of triggers, including rubbing the skin, infections and teething. Due to mast cell release of heparin, it is not unusual for skin wounds to bleed excessively[ii].
  • A mastocytoma is a low grade mast cell tumor most often found on the skin. It is frequently raised and yellow or brown in color. Touching the lesion usually evokes a strong wheal and flare reaction. Sweating may also occur. Blistering may be present[ii].

Diagnosis of mastocytosis in the skin

  • While a biopsy is the definitive diagnostic method, positive Darier’s sign is present in most children and many adults with mastocytosis in the skin. Use of antihistamines can suppress a positive Darier’s sign[ii].
  • Biopsies from lesional skin should be stained for mast cells using toluidine blue or Giemsa-Wright stain; evaluated for CD117, CD25 and CD2 using IHC; and evaluated for activating mutations in the CKIT gene using PCR or sequencing methods[i] .
Diagnostic criteria for cutaneous mastocytosis  (requires one major and one minor criterion)[iii]
Major Minor
Typical mast cell rash, usually maculopapular, or atypical rash with positive Darier’s sign Dense infiltration by tryptase positive mast cells, >15 mast cells/cluster or >20 mast cells/x40 magnification hpf if not clustered
Activating CKIT mutation detected in biopsy from skin lesion

 

Symptoms and treatment of mastocytosis in the skin

  • Common symptoms localized to the skin include flushing, itching, burning, hives and blistering[iv].
  • Mediator release symptoms can affect other organs regardless of whether or not they have systemic mastocytosis. Flushing, nausea, vomiting, diarrhea and low blood pressure have been reported among other symptoms. Wheezing, shortness of breath and rarely cyanosis may be present. Anaphylaxis can also occur[iii].
  • Treatment for cutaneous mastocytosis/mastocytosis in the skin relies upon histamine blockade with H1 inverse agonists and H2 antagonists; cromolyn sodium; leukotriene antagonists; and PUVA treatment in severe cases[v].
  • In treatment resistant cases, systemic glucocorticoids and topical cromolyn may be used.  In some instances, mastocytomas may be excisedi. Anaphylaxis should be treated with epinephrine per current guidelines[v].

[i] Molderings GJ, et al. (2011). Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J Hematol Oncol, 4(10), 10.1186/1756-8722-4-10

[ii] Hartmann K, et al. (2016). Cutaneous manifestations in patients with mastocytosis: consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma and Immunology; and the European Academy of Allergology and Clinical Immunology. Journal of Allergy and Clinical Immunology, 137(1), 35-45.

[iii] Valent P, et al. (2007). Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. European Journal of Clinical Investigation, 37, 435-453.

[iv] Carter MC, et al. (2014). Mastocytosis. Immunol Allergy Clin North Am, 34(1), 10.1016/j.iac.2013.09.001

[v] Castells M, et al. (2011). Guidelines for the diagnosis and treatment of cutaneous mastocytosis in children. Am J Clin Dermatol, 12(4), 259-270.

 

Until the light reaches me

Every year for several years, before I had any idea why, I would get sick the third week of September. It was bafflingly consistent. The fact that it was so reliable led a number of doctors to insist that this was clearly psychologically induced, a re-experiencing of some nameless trauma.

It took me longer to figure this out than it should have, if I’m being honest. I was diagnosed with mast cell disease in 2012 but it wasn’t until the fall of 2013 that I figured it out why I always got sick that week. As a student and instructor, my life had been built around the school year. Every year, I would recommit myself to exercising, which I often stopped over the summer due to feeling sick in the heat. The first week of exercise at the start of the school went fine. The second week of exercise was progressively more difficult but I was still intoxicated with the impossible optimism of the new school year and pushed through. Then I would crash in the third week of September, often in spectacular fashion. It would take me weeks to recover.

Turns out I’m not the only mast cell patient who has trouble this time of year. As a community, we just cannot hang. For the last several years, I have affectionately referred to September and early October as the “Death Zone”. I’m kidding but only just. You may remember the Death Zone for such features as Seth’s miraculous survival despite significant evidence that he would not, and Kristina’s brainstem stroke. The rest of us take turns shocking and puking and sleeping for days while Mother Nature sorts out her issues. Despite my cliché love of fall, pumpkin flavored things, Halloween, boots and thick tights, it is always an uneasy time for me.

Last week was the third week in September and good grief was it a week. As if his body has a preternatural need to reset itself during this week, Seth once again crashed. He is hanging in there. The similarities between last year and this week are uncanny and not a little spooky.

I met Yssabelle and her parents a few years ago when she was airlifted to Boston after shocking on a weekly basis. She is 7 now and one of my little people. Yzzy has dense colon infiltration like me and a host of complicated SM issues. True SM in children is extremely rare and she has true SM. She has had a difficult few years and has spent a lot of time in the hospital.

This past year has seen the advent of a truly terrifying series of episodes: without any obvious provocation, and irrespective of her mast cell reactivity that day, she would spike fevers of 104F and 105F, have severe abdominal pain, and her metabolic function tests would tank. After a few days, it would just stop. She has had over a dozen of these episodes this year and every time, no one knew what it was and was not particularly concerned with diagnosing it.

Yzzy spiked a screaming high fever and started vomiting blood about two weeks ago. This time, someone knew what she had. She was diagnosed with another rare blood disorder, hemophagocytic lymphohistiocytosis (HLH). In pretty short order, she was on a hemonc floor being prepped for chemo by a team that didn’t know her.

There are a lot of things I don’t like about having my life all over the internet but it can be really helpful sometimes. The blog serves as a credential; if a provider wants to know if I actually understand these diseases, they can google me, find my work, and verify that I do in fact have a deep understanding of these conditions. I talked to Yzzy’s hemonc on Monday night and we talked about rescue protocols, anaphylaxis, and her generally complicated health. I poured over literature all week and spent the next few days putting together directly cited primers for Yzzy’s team. (The primers I have been posting are the ones I prepped for them).

It never ceases to surprise me that after so long, I can still be terrified by the danger of these lives we lead. It’s different with mast cell disease. I know mast cell disease. I know anaphylaxis. I can rattle off facts seconds after being woken out of a deep sleep. There is almost no thought involved anymore when I answer questions. I just know. And because I understand, I am not as scared.

But while the danger of mast cell disease feels smaller to me than it really is, the danger of everything that’s not mast cell disease feels much larger. I’m experiencing this right now with Yzzy but I have experienced it many times before.

It never gets less scary and is lonely somehow, something you have to experience on your own to contribute to this common desperation. There is so often nothing to be done. The fact that it will end at some point is little consolation.

I didn’t realize when I got sick that I would never get used to it and that it would never stop being scary. I didn’t realize how much worse it would be to watch people I care about suffer than to suffer myself.

But it is. I’m caught here in the void between two distant stars, trying to hold on until the light reaches me.

The Provider Primers Series: Medications that impact mast cell degranulation and anaphylaxis

A number of medications can induce mast cell degranulation and histamine release. Other medications increase the risk of anaphylaxis and can increase the severity of anaphylaxis.

Medication reaction profile is very individual and not all mast cell patients react to the medications listed below. Additionally, there may be a need for some mast cell patients to take  medications listed below if the benefit outweighs the risk.

Medications that are reported to induce mast cell degranulation and histamine release
Alcohol[i] Amphoterecin B[ii] Aspirin[i] Atracurium[iii]
Caine anesthetics (esters)[iv] Codeine[v] Colistin (polymyxin E)[vi] Dextran[iii]
Dextromethorphan[iii] Gelatine[iii] Iodine based radiographic dye[vii] Meperidine[viii]
Miconazole[ix] Mivacurium[iii] Morphine[iv] Nefopam[iii]
NSAIDs[x] Phentolamine[xi] Polymyxin B[v] Reserpine[xii]
Rocuronium[iv] Succinylcholine[iv], [xiii] Thiopental[iv] Tolazoline[v]
Vancomycin[xiv] (especially when given intravenously)

 

Patients on beta blockers are more likely to experience anaphylaxis and more likely for that anaphylaxis to be severe and treatment resistant. Beta blockers also impede treatment of anaphylaxis by interfering with the action of epinephrine[xvi]. Patients at risk for anaphylaxis who are on beta blockers should get a glucagon pen to use prior to epinephrine[xv].

Beta adrenergic blockers[xvi] (Note: List is not exhaustive)
Acebutolol Atenolol Betaxolol Bisoprolol
Bucindolol Butaxamine Cartelol Carvedilol
Celiprolol Esmolol Metoprolol Nadolol
Nebivolol Oxprenolol Penbutolol Pindolol
Propranolol Sotalol Timolol

 

Alpha blockers impede treatment of anaphylaxis by interfering with the action of epinephrine[xvii].

Alpha-1 adrenergic blockers[xvii] (Note: List is not exhaustive)
Alfuzosin Amitryptiline Amoxapine Atiprosin
Carvedilol Chlorpromazine Clomipramine Clozapine
Dapiprazole Dihydroergotamine Doxazosin Doxepin
Ergotamine Etoperidone Fluphenazine Hydroxyzine
Imipramine Labetalol Loxapine Mianserin
Nefazodone Olanzapine Phentolamine Prazosin
Quetiapine Risperidone Silodosin Tamsulosin
Thimipramine Thioridazine Trazodone

 

Alpha-2 adrenergic blockers[xvii] (Note: List is not exhaustive)
Buspirone Chlorpromazine Clozapine Esmirtazapine
Fluophenazine Idazoxan Loxapine Lurasidone
Mianserin Mirtazapine Olanzapine Phentolamine
Risperidone Thioridazine Yohimbe

Patients on angiotensin-converting enzyme (ACE) inhibitors are also more likely to experience anaphylaxis and more likely for that anaphylaxis to be severe and treatment resistant. The exact reason for this is unclear but ACE inhibitors impede appropriate bradykinin metabolism which may contribute to anaphylaxis[xvi].

Angiotensin converting enzyme (ACE) inhibitors[xvi] (Note: List is not exhaustive)
Benazopril Captopril Enalapril Fosinopril
Lisinopril Moexipril Perindopril Quinapril
Ramipril Trandolopril

Special notes:

Aspirin use in mast cell patients to suppress prostaglandin production is becoming increasingly common[xviii]. In some situations, other NSAIDs are also used.

Fentanyl, sufentanil, remifentanil and alfentanil are the preferred opioids for mast cell patientsiv. Hydromorphone releases minimal histamine and is also used in mast cell patients.[xix]

References:

[i] Valent P. (2014). Risk factors and management of severe life-threatening anaphylaxis in patients with clonal mast cell disorders. Clinical & Experimental Allergy, 44, 914-920.

[ii] Lange M, et al. (2012). Mastocytosis in children and adults: clinical disease heterogeneity. Arch Med Sci, 8(3), 533-541.

[iii] Dewachter P, et al. (2014). Perioperative management of patients with mastocytosis. Anesthesiology, 120, 753-759.

[iv] Eggleston ST, Lush LW. (1996). Understanding allergic reactions to local anesthetics. Ann Pharmacother, 30(7-8), 851-857.

[v] Brockow K, Bonadonna P. (2012). Drug allergy in mast cell disease. Curr Opin Allergy Clin Immunol, 12, 354-360.

[vi] Kwa A, et al. (2014). Polymyxin B: similarities to and differences from colistin (polymyxin E). Expert Review of Anti-infective Therapy, 5(5), 811-821.

[vii] Kun T, Jakubowski L. (2012). Pol J Radiol, 77(3), 19-24.

[viii] Blunk JA, et al. (2004). Opioid-induced mast cell activation and vascular responses is not mediated by mu-opioid receptors: an in vivo microdialysis study in human skin. Anesth Analq, 98(2), 364-370.

[ix] Toyoguchi T, et al. (2000). Histamine release induced by antimicrobial agents and effects of antimicrobial agents on vancomycin-induced histamine release from rat peritoneal mast cells.  Pharm Pharmacol, 52(3), 327-331.

[x] Grosman N. (2007). Comparison of the influence of NSAIDs with different COX-selectivity on histamine release from mast cells isolated from naïve and sensitized rats. International Immunopharmacology, 7(4), 532-540.

[xi] Powell JR, Shamel LB. (1979). Interaction of imidazoline alpha-adrenergic receptor antagonists with histamine receptors. J Cardiovasc Pharmacol, 1(6), 633-640.

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