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Reading list: Papers to better understand mast cells and mast cell disease

I get asked semi-regularly for literature recommendations.  This post (and the other posts marked “Reading list”) lists papers I have found helpful in understanding mast cell disease and the roles of mast cells in other diseases.

As a general rule of thumb, read the guidance documents first.  They give comprehensive overviews that include symptoms, diagnosis, treatment, statistics and so on.  Please keep in mind that at this time, there are multiple sets of diagnostic criteria for MCAS.  I have included papers here that represent the competing schools of thought on MCAS.

Enjoy!

 

Guidance documents: Overviews of mast cell diseases

  • Afrin, Lawrence B. Presentation, Diagnosis and Management of Mast Cell Activation Syndrome. 2013. Mast Cells.
  • Akin C, Valent P, Metcalfe D. Mast cell activation syndrome: Proposed diagnostic criteria. Journal of Allergy and Clinical Immunology 2010: 126 (6): 1099–1104.e4
  • Bodemer C., Hermine O., Palmérini F., Yang Y., Grandpeix-Guyodo C., Leventhal PS., Hadj-Rabia S., Nasca L., Georgin-Lavialle S., Cohen-Akenine A., Launay JM., Barete S., Feger F., Arock M., Catteau B., Sans B., Stalder JF., Skowron F., Thomas L., Lorette G.Plantin P, Bordigoni P, Lortholary O, de Prost Y, Moussy A, Sobol H, Dubreuil P. Pediatric mastocytosis is a colonal disease associated with D816V and other activating C-KIT mutations. J Invest Dermatol 2010; 130:804–815.
  • Brockow, C. Jofer, H. Behrendt and J. Ring. Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients. Allergy 2008, 63 ( 2):, 226–232.
  • Cardet JC, Castells M, Hamilton MJ. Immunology and Clinical Manifestations of Non-Clonal Mast Cell Activation Syndrome. Curr Allergy Asthma Rep. Feb 2013; 13(1): 10–18.
  • Carter et al. Assessment of clinical findings, tryptase levels, and bone marrow histopathology in the management of pediatric mastocytosis. J Allergy Clin Immunol 2015.
  • Carter MC, Escribano L, Hartmann K, Lieberman P, Nedoszytko B, Orfao A, Schwartz LB, Sotlar K, Valent P, Akin C, Arock M, Brockow K, Butterfield JH, Sperr WR, Triggiani M, Valenta R, Horny HP, Metcalfe DD. Definitions, Criteria and Global Classification of Mast Cell Disorders with Special Reference to Mast Cell Activation Syndromes: A Consensus Proposal. Int Arch Allergy Immunol 2012;157:215–225.
  • Frieri, Marianne, et al. Pediatric mastocytosis: A review of the literature. Pediatr Allergy Immunol Pulmonol. Dec 1, 2013; 26(4): 175-180.
  • Georgin-Lavialle, Sophie, et al.  Mast cell leukemia.  Blood 2013;10 (11).
  • Gülen, H. Hägglund, B. Dahlén and G. Nilsson. High prevalence of anaphylaxis in patients with systemic mastocytosis – a single-centre experience. Clinical & Experimental Allergy, Volume 44, Issue 1, pages 121–129, January 2014.
  • Haenisch B, Nothen M, Molderings GJ. Systemic mast cell activation disease: the role of molecular genetic alterations in pathogenesis, heritability and diagnostics. Immunology 2012, 137, 197–205.
  • Hamilton, Matthew J, et al.  Mast cell activation syndrome : A newly recognized disorder with systemic clinical manifestations.  2011, Vol 128, Issue 1, pp. 147-152.
  • 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.
  • Kettelhut BV., Metcalfe DD. Mastocytosis. J Invest Dermatol 1991; 96:115S–118S.
  • Lange M., Nedoszytko B., Górska A., Żawrocki A., Sobjanek M., Kozłowski D. Mastocytosis in children and adults: clinical disease heterogeneity. Arch Med Sci 2012; 8:533–541.
  • Lim KH, Tefferi A, Lasho TL, et al.Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood 2009; 113(23): 5727-5736.
  • Matito, Almudena, et al. Serum tryptase monitoring in indolent systemic mastocytosis: association with disease features and patient outcome. 2013; PLOS One.
  • Mital A, Piskorz A, Lewandowski K, Wasag B, Limon J, Hellmann A. A case of mast cell leukaemia with exon 9 KIT mutation and good response to imatinib.Eur J Haematol 2011; 86(6):531-535.
  • Molderings GJ, Brettner S, Homann J, and Afrin LB. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J Hematol Oncol. 2011; 4: 10.
  • Molderings GJ, Haenisch B, Bogdanow M, Fimmers R, Nöthen MM. Familial occurrence of systemic mast cell activation disease. PLoS One, 8 (2013), p. e76241
  • Molderings GJ. The genetic basis of mast cell activation disease – looking through a glass darkly. Critical Reviews in Oncology/Hematology 2014.
  • Noack F, Sotlar K, Notter M, Thiel E, Valent P, Horny HP. Aleukemic mast cell leukemia with abnormal immunophenotype and c-kit mutation D816V.Leuk Lymphoma 2004; 45(11): 2295-2302.
  • Pardanani A. How I treat patients with indolent and smoldering mastocytosis (rare conditions but difficult to manage.) Blood 2013: 121 (16).
  • Pardanini A. Prognostically relevant breakdown of 123 patients with systemic mastocytosis associated with other myeloid malignancies. Blood 2009, 114 (18).
  • Pardanini, Animesh. Systemic mastocytosis in adults: 2013 update on diagnosis, risk stratification, and management. 2013; American Journal of Hematology: 88 (7).
  • Picard M, Giavina-Bianchi P, Mezzano V, Castells M. Expanding Spectrum of Mast Cell Activation Disorders: Monoclonal and Idiopathic Mast Cell Activation Syndromes. Clinical Therapeutics 2013: 35 (5), 548–562.
  • Sperr, Wolfgang. Diagnosis, progression patterns and prognostication in mastocytosis. Expert Review of Hematology 2012: 5 (3): 261-274.
  • Uzzaman, Ashraf, et al. Pediatric-onset Mastocytosis: A long term clinical follow-up and correlation with bone marrow histopathology. Pediatr Blood Cancer. Oct 2009; 53 (4): 629-634.
  • 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.
  •  Valent et al. Chronic mast cell leukemia: A novel leukemia-variant with distinct morphological and clinical features. Leukemia Research 39 (2015) 1-5.
  • Valent, Peter, et al. How I treat patients with advanced systemic mastocytosis. 2010; Blood: 116 (26).
  • Wimazal F., Geissler P., Shnawa P., Sperr W.R., Valent P. Severe Life-Threatening or Disabling Anaphylaxis in Patients with Systemic Mastocytosis: A Single-Center Experience. Int Arch Allergy Immunol 2012; 157: 399–405.

Testing and diagnosis of mast cell disease

  • Freeman JG, Ryan JJ, Shelburne CP, Bailey DP, Bouton LA, Narasimhachari N, Domen J, Siméon N, Couderc F, Stewart JK. Catecholamines in murine bone marrowderived mast cells. J. Neuroimmunol. 2001 Oct;119(2):231-238.
  • Gordon JR, Galli SJ. Mast cells as a source of both preformed and immunologically inducible TNF-α/cachectin. Nature 1990 Jul 19; 346:274-276.
  • Laroche D, Vergnaud MC, Sillard B, Soufarapis H, Bricard H. Biochemical markers of anaphylactoid reactions to drugs: comparison of plasma histamine and tryptase. Anesthesiol. 1991 Dec; 75(6):945-949.
  • Maclouf J, Corvazier E, Wang ZY. Development of a radioimmunoassay for prostaglandin D2 using an antiserum against 11-methoxime prostaglandin D2. Prostaglandins 1986 Jan; 31(1):123-132.
  • Pregun I, Herszényi L, Juhász M, Miheller P, Hritz I, Patócs A, Rácz K, Tulassay Z. Effect of proton-pump inhibitor therapy on serum chromogranin A level. Digestion 2011; 84:22-28.
  • Seidel H, Molderings GJ, Oldenburg J, Meis K, Kolck UW, Homann J, Hertfelder HJ. Bleeding diathesis in patients with mast cell activation disease. Thromb. Haemost. 2011 Nov; 106(5):987-989.
  • Sur R, Cavender D, Malaviya R. Different approaches to study mast cell functions.  Int. Immunopharmacol. 2007 May;7(5):555-567.
  • Takeda J, Ueda E, Takahashi J, Fukushima K. Plasma N-methylhistamine concentration as an indicator of histamine release by intravenous d-tubocurarine in humans: preliminary study in five patients by radioimmunoassay kits. Anesth. Analg. 1995; 80:1015-1017.

Neurologic aspects of mast cell activation

  • Ikuko Mohri, Masako Taniike, Hidetoshi Taniguchi, Takahisa Kanekiyo, Kosuke Aritake, Takashi Inui, Noriko Fukumoto, Naomi Eguchi, Atsuko Kushi, Hitoshi. Prostaglandin D2-Mediated Microglia/Astrocyte Interaction Enhances Astrogliosis and Demyelination in The Journal of Neuroscience 2006; 26(16):4383– 4393.
  • Rogers MP, et al. Mixed organic brain syndrome as a manifestation of systemic mastocytosis. Psychosom Med. 1986 Jul-Aug; 48(6):437-47.
  • 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.

Gastrointestinal aspects of mast cell disease

  • 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.
  • Hahn, Hejin P., Hornick, Jason L.  Immunoreactivity for CD25 in Gastrointestinal Mucosal Mast Cells is Specific for Systemic Mastocytosis.  American Journal of Surgical Pathology. Volume 31 (11). 2007.
  • Jensen RT. Gastrointestinal abnormalities and involvement in systemic mastocytosis. Hematol Oncol Clin North Am. 2000;14:579–623.
  • Kirsten Alfter, Ivar von Ku gelgen, Britta Haenisch, Thomas Frieling, Alexandra Hu lsdonk, Ulrike Haars, Arndt Rolfs, Gerhard Noe, Ulrich W. Kolck, Jurgen Homann and Gerhard J. Molderings. New aspects of liver abnormalities as part of the systemic mast cell activation syndrome. 2009 Liver International 29(2): 181-186.
  • Lee, Jason K, et al.  Gastrointestinal manifestations of systemic mastocytosis.  World J Gastroenterol. 14(45): 7005-7008.

Mastocytic enterocolitis

  • Akhavein, A, et al.  Allergic mastocytic gastroenteritis and colitis: An unexplained etiology in chronic abdominal pain and gastrointestinal dysmotility.  2012, Gastroenterology Research and Practice.
  • Hahn, Hejin P., Hornick, Jason L.  Immunoreactivity for CD25 in Gastrointestinal Mucosal Mast Cells is Specific for Systemic Mastocytosis.  American Journal of Surgical Pathology. Volume 31 (11). 2007.
  • Hamilton, Matthew J, et al.  Mast cell activation syndrome : A newly recognized disorder with systemic clinical manifestations.  2011, Vol 128, Issue 1, pp. 147-152.
  • Shriram Jakate, Mark Demeo, Rohan John, Mary Tobin, and Ali Keshavarzian (2006) Mastocytic Enterocolitis: Increased Mucosal Mast Cells in Chronic Intractable Diarrhea. Archives of Pathology & Laboratory Medicine: March 2006, Vol. 130, No. 3, pp. 362-367.

Raw

Summer packed up quickly. Humidity and too hot days were gone in an instant.  The days are short now, the last waves of golden autumn sun just barely shadows when I get home from work.  It was below freezing as I walked to work yesterday morning. Two nights ago, when I stepped outside, it smelled like snow.

I blinked and suddenly the ground was covered in dry leaves, the chorus of fall sung in deep musical gusts.  It really seems like just a moment ago I was eager for summer to end and now it has been gone for weeks.

This year’s autumn has been fraught with emotions.  I am having some big feelings these days and they are leeching from my other reservoirs: patience, kindness, love.   But mostly patience.  Loss of patience is where it shows the most.

We were so scared that Seth would die, and he didn’t but we still don’t really know how to feed him.  I read papers by the hundreds, make notes, send emails.  He is better but not good.  We still don’t have a good plan.  What happened with Seth felt immediate, traumatic. Like the pain of landing hard after falling, hands and knees stinging, blood seeping through the wounds.  Startling, alarming but survivable.

Then I picked up my phone and read a text telling me that my friend was having a bad reaction in an emergency room.  I relive that night constantly.  The back and forth, my let’s not panic attitude when we should have been panicking.  I am too used to this, I have seen us all be fine after so many panic-worthy episodes.  I am too used to us all being fine.  But we should have been panicking.  And by the time we understood what was happening, she had already had a stroke in her brainstem.

It feels so slow in my memory, like a parchment map being slowly unrolled.  By the time we knew where we were, it was too late.  There is this heavy sorrow inside of my heart that makes it hard to breathe.  We didn’t even know where we were and now she is locked inside of her body. It is suddenly the end of October and the sorrow doesn’t feel lighter. I am just learning to carry the weight.

Everything is a fight sometimes.  Every. Thing.  Insurance companies, doctors’ offices, hospitals and pharmacies all call to inform me about the ways in which bureaucracy and the broken American health care system is messing up my care again.  Not in a way that will kill me, just in a way that requires a patience I no longer have.  My eye has started twitching again when I have to explain something about my healthcare again to someone who has already heard it and was previously unmoved.

Someone called me today to say that they could waive part of my bill. I had a panic attack in a grocery store, because even receiving good news about my healthcare is too stressful right now.

I was medically cleared to fly to China by all relevant medical professionals but had to undergo a medical clearance by the airline since I needed to use an infusion pump during flight.  I filled out forms, provided notarized letters.  In their infinite wisdom, the airline decided it wasn’t safe for me to fly alone.

I paid a visit to my PCP’s office after having a mid-level nervous breakdown on the phone with a nurse about the fact that the airline may not let me go to China. I apologized for getting so upset.  While she wrote another letter for me, I told her that mast cell patients get labelled as psych patients a lot because we look fine until we are in liver failure or having a stroke. I told her about my friend.

She called the pharmacist working downstairs and he came up to notarize her letter.  After some back and forth, the airline relented and agreed I can fly with my pump.

My skin is burning this week. I am flushed a deep pink all over.  I realized today that I am reacting to my ketotifen after eighteen months of taking it every day without an issue.  More phone calls with my fingers pressing on my eyelid in a vain attempt to stop the twitching, heat creeping up the back of my neck.

Last week, some guy kept obstructing my path down the sidewalk in an attempt to make me donate to some charity.  When I finally maneuvered around him successfully, he made a snide comment.  I turned around and yelled at him.  Because get the fuck out of my way.

I am grieving and angry and impatient and raw and exposed.  In two weeks I will be in Hong Kong and it feels wrong that I am stable enough to travel to Asia, a sort of betrayal and survival’s guilt.

 

 

 

 

Great wall

I have always wanted to travel. From a young age, I was fascinated by language and traveling seemed an extension of that, places to hear foreign words and see strange alphabets. When I was 19, while sitting at my desk one night, it occurred to me that there was no reason I couldn’t just save up and go wherever I wanted to. I planned my first trip abroad and spent 26 days in Europe the following summer.

Traveling made me happy in a way that I have never been able to replicate in any other way. Over the next several years, I spent all my money on travel. I didn’t care if I ate the same thing every day or drove a junkbox. Nothing mattered to me like the joy of being in strange, faraway places. I started planning my magnum opus: a nine month trip around the world that took me through six continents. It was slated for January 2011.

In 2009, I lost a lot of my hearing. I spent all of the money I had saved for the trip on medical expenses, much in an effort to stop my rapid march towards deafness. I lost my hearing anyway. I haven’t travelled out of the US since 2010.

For a while, I went through the motions, even when I was clearly in no shape, financially or physically, to go anywhere. I bought guidebooks, priced flights and drew maps of places I hoped to visit. I printed out pictures of every country in the world and glued them to cardstock. I hung them in my apartment, passive encouragement that I would once again be strong enough to see some of them.

Then my health declined rapidly and I was in massive pain and puking constantly and unable to go to the bathroom. I stopped everything. I couldn’t fly anywhere anyway, so there was really no point. I couldn’t even think about it. I was so tired and the pain was so bad and I was scared. My illness was this huge wall around my life and I couldn’t even try to climb out. I could only hope not to be buried by it.

Last year, I decided that it was time to try again. I flew to Seattle with my best friend, emboldened by my ready IV access and growing restlessness. I took a few other domestic trips, Colorado, Florida, California. My health was mostly fine and when it wasn’t, I knew how to manage it with medication to stay safe. Every new trip gave me confidence that I could be independent in travel, provided I had a predetermined, safe place to stay and eat, and someone to help me if I got sick. The majority of my luggage was medication and medical supplies and I didn’t care.

In less than a month, I will be flying to Asia and fulfilling a lifelong dream of seeing the Great Wall of China. It has been logistically complicated, with medical notes and forms and notaries and translations and all the doctors. I will be taking a sixteen hour direct flight from Boston to Hong Kong, where I will spend some time with a dear friend before we travel to Beijing and then the Great Wall.

I feel it again. And even though I’m scared, I am happy.

Happiness is a kind of fighting. It is a way of saying that maybe today was miserable and so were a lot of yesterdays but maybe tomorrow will be different. It is the refusal to be subjugated by pain and fear and uncertainty. It is the memory of joy and the knowledge that even if you don’t believe it, you could again. It is the way memories catch light in your mind, a technicolor feeling that goes on forever. It is the only fight that matters.

Some things are best viewed not as they are, but in the light of a prior incarnation and the hope that it could reascend to this splendor once again. It took years, but I climbed out of the high walled prison of this disease and next month, on the other side of the world, I will put my hands on another Great Wall.

The violence done unto us

It was a Saturday when I found out about Seth. One of my masto friends called to give me a breathless update at almost 11pm.

“He’s in liver failure,” she said with a rising lilt in her voice, the kind that barely masks panic.

I laid down on my living room floor while we talked. Seth is my friend who has MCAS and he is three years old.

Less than 48 hours before, he had begun presenting with severe neurologic deficits. By Sunday morning, he could no longer speak, see or clot properly. He was air lifted to a different hospital with tanking vital signs.

The next several days were a blur, more one long impossible experience than individual actions. Things were grim. For a time, it looked very much like he would not survive.

Seth’s parents are good friends of mine. Our friends and I communicated every piece of information to each other and anyone we thought could help. I woke up to messages every morning asking if there was any news. I was 3000 miles away and out of helpful ideas and utterly powerless.

By some miracle, Seth did not die. He is still in the PICU and will need involved care for some time. There is still not a great treatment plan for the future. But he is alive. And he is still Seth.

On Friday, I found out that my friend, the friend who called me about Seth, was having her own medical event. Things were fairly progressed by the time I was in the loop. It was literally sickening. A couple of days passed until I got a phone call telling me she had a catastrophic injury. I ran to the bathroom and threw up.

There are moments when you lose pieces of yourself. Sometimes it is organic, a skin shed as you move forward. Sometimes it is violent, a piece carved out with deep gouges, more than you could afford to lose. A piece you never get back. A piece that leaves a hollow so deep that no matter what you use to shore up the edges, it never feels strong again.

I want to go back to the time before this violence but I can’t remember what it feels like. It’s already gone.

These are my people and they are every bit as connected to me as the family I was born into.

How could this happen?

Childhood mastocytosis: Update

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

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

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

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

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

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

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

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

Reference:

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

Chronic mast cell leukemia: A new variant of systemic mastocytosis

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

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

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

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

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

Reference:

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

Glossary of mast cell related terms: P-Z

Parasympathetic nervous system: Part of the autonomic nervous system.  Regulates digestion and other functions.

Prostaglandin D2 (PGD2): The dominant prostaglandin produced by mast cells.

9a,11b-PGF2: a breakdown product of prostaglandin D2; can be measured to assess level of mast cell activation

Platelet activating factor (PAF): a mast cell mediator that correlates with severity of anaphylaxis; induces degranulation and release of leukotrienes and prostaglandins

Postural orthostatic tachycardia (POTS): increase of 30 bpm or more when standing in the absence of orthostatic hypotension.

Premedication: taking medication in advance of an event in order to suppress an undesirable reaction during the event, such as premedicating before surgery

Pre-stored: as relates to mast cell biology, mediators that are made inside the cell and stored in granules to be released at a later time

Progenitor cell: a cell that develops into another type of cell

Proliferation: growth and expansion of a cell population

Prostaglandin: a type of eicosanoid with wide ranging biological effects; PGD2 is the prostaglandin most abundantly produced by mast cells

Protracted anaphylaxis: a long episode of anaphylaxis symptoms despite treatment

Rare disease: a disease that affects only a small amount of people in a population; in the US, defined as affecting 200,000 people or less in the US

Rebound: a resurgence of symptoms after quelling symptoms earlier

Receptor: a protein on the outside of cells that bind specific molecules, causing a specific action to occur

Secretion: the release of molecules from inside the cell to the outside environment without degranulation

Sensitization: production of IgE specific to an allergen without obvious allergic reaction to the allergen

Serotonin: a neurotransmitter released by a number of cell types, including mast cells

Smouldering systemic mastocytosis (SSM): a form of SM in which organ damage and failure could eventually occur; diagnosed when someone with SM has two or more B findings

Splenomegaly: swelling of the spleen

Stem cell factor (SCF): a mast cell growth factor; SCF binds to CKIT and tells mast cells to stay alive and make more mast cells

Sympathetic nervous system: Part of the autonomic nervous system.  Controls the fight or flight response

Systemic mastocytosis (SM): a proliferative mast cell disease in which too many mast cells are produced

Systemic mastocytosis with associated clonal hematologic non-mast cell lineage disease (SM-AHNMD): co-occurrence of SM with another proliferative blood cell disorder, such as essential thrombocythemia or chronic myelogenous leukemia

Tachycardia: rapid heartbeat

Third spacing: when fluid is forced out of a place the body can use it and becomes trapped, such as ascites or angioedema

TLR: toll like receptor; receptors on the outside of many cells (including mast cells) that activate immune response to infections

Telangiectasia macularis eruptive perstans (TMEP): a less common form of cutaneous mastocytosis.  Found almost exclusively in adults.

Tryptase: a mast cell mediator; when tested outside of a symptomatic episode, it is used to measure the baseline amount of mast cells present ; when tested during a symptomatic episode, it can be used to identify mast cell activation

Urticaria pigmentosa (UP): also called maculopapular cutaneous mastocytosis (MPCM).  The most common form of cutaneous mastocytosis.

Urticaria: hives

Wheal and flare response: a reaction marked by redness and raised, taut skin due to histamine release

Glossary of mast cell related terms: M-O

Mast cell: white blood cells with important roles in allergy, anaphylaxis and immune defense that live in tissues and only briefly circulate in the blood; also called mastocytes

Mast cell activation: a change in mast cell behavior that occurs following exposure to a trigger that may indicate allergy or infection; a state in which mast cells release mediators, both through degranulation and through secretion; in some instances, culminating in anaphylaxis

Mast cell disease: a disease that occurs due to fundamental error in mast cell proliferation or activation physiology

Mast cell disorder: used synonymously with mast cell disease

Mast cell leukemia: a very aggressive mast cell disease marked by massively excessive proliferation of mast cells, culminating in progressive organ failure

Mast cell sarcoma: a very aggressive mast cell disease that presents as a connective tissue tumor and progresses to mast cell leukemia

Mast cell stabilizer: a medication that decreases the likelihood of mast cell degranulation and mediator release

Mastocytic enterocolitis: the phenomenon of having too many mast cells in the GI tract; originally described as more than 20 mast cells/ high power field, but there is no consensus on how many mast cells in a field is too many

Mastocytoma: a benign mast cell tumor. Most frequently occurs on skin, but can occur elsewhere in the body.

Mast cell activation disease (MCAD): usually a catchall term for mast cell diseases, although some people exclude cutaneous mastocytosis from this category

Mast cell activation disorder (MCAD): an alternate term for mast cell activation syndrome (MCAS); a non-proliferative mast cell disease that is usually diagnosed by detecting an elevation in mast cell mediators

Mast cell activation syndrome (MCAS): a non-proliferative mast cell disease that is usually diagnosed by detecting an elevation in mast cell mediators; occurs secondary to a known condition or idiopathically, in which no primary condition is identified; “primary” mast cell activation syndrome has its own name, MMAS

Mediator: a molecule released from a cell that has effects on the environment outside the cell; mast cells release dozens of mediators

Monoclonal mast cell activation syndrome (MMAS) : a mast cell disease diagnosed when a patient meets some criteria for SM but not enough for an SM diagnosed

Monophasic anaphylaxis: an anaphylactic event in which symptoms resolve following administration of medication and do not recur at a later time

Mutation: a change in the genetic sequence that can affect the way a gene is expressed, or in the way its gene product is made or functions

Myeloid: concerning cells that develop into granulocytes, monocytes, platelets or erythrocytes

Myeloproliferative neoplasm: a disorder caused by aberrant proliferation of a myeloid cell line, such as SM, myelofibrosis, essential thrombocythemia or polycythemia vera, among others

Neoplasm: an abnormal cell

N-methylhistamine: a breakdown product of histamine; can be tested for to assess mast cell activation

Oral allergy syndrome: An IgE reaction to raw fruits and vegetables that causes itching and swelling in the mouth and throat.

Orthostatic hypotension (OH): reduction of systolic blood pressure of more than 20 mm Hg or diastolic blood pressure of more than 10 mm Hg within three minutes of standing.

Orthostatic intolerance (OI): symptoms that occur when transitioning to a standing position

Glossary of mast cell related terms: F-L

FceRI: the high affinity IgE receptor; where IgE molecules bind to the outside of cells, like mast cells; binding the FceRI receptor triggers mast cell activation

Food associated, exercise induced anaphylaxis: An IgE mediated reaction that is triggered by ingesting certain foods in close time proximity to exercise

Food protein induced enterocolitis syndrome (FPIES): An allergic reaction to food proteins that is not mediated by IgE, usually found in infants; the most severe non-IgE mediated food hypersensitivity

Gastroparesis: a condition in which stomach contents are not emptied into the small intestine within an appropriate time period without an obvious anatomical explanation

Granule: a pocket inside a cell that holds molecules to be released outside of the cell

Granulocyte: white blood cells that have granules inside the cells that hold molecules to be released outside of the cell; mast cells, eosinophils, basophils and neutrophils are granulocytes

H1: histamine 1 receptor

H1 inverse agonist: a class of drugs that interferes with the effect of histamine at the H1 receptor

H2: histamine 2 receptor

H2 blocker: a class of drugs that interferes with the effect of histamine at the H2 receptor

Heparin: a mast cell mediator; a blood thinner

Hepatomegaly: swelling of the liver

Hepatosplenomegaly: swelling of the liver and spleen

Hereditary angioedema (HAE): a heritable blood disorder that causes episodes of protracted swelling that can be life threatening.

Histamine: a neurotransmitter; responsible for a large portion of symptoms seen in mast cell disease and anaphylaxis

HPA axis: the signals and feedback loops that regulate the activities of the hypothalamus, pituitary gland and adrenal glands to coordinate the body’s stress response; also helps regulate digestion, immune activation, sexuality and energy metabolism

Hypersensitivity: allergic reaction

Hypersplenism: overactivity of the spleen

IgE: an antibody that triggers allergic responses

Kounis Syndrome: an event in which a patient experiences severe chest pain or heart attack as the result of an allergic reaction; also called allergic angina or allergic myocardial infarction

Late onset anaphylaxis: Anaphylaxis that begins several hours after exposure to trigger

Leukotrienes: Structural class related to prostaglandins produced by the enzyme 5-lipoxygenase (5-LO); mediators released by mast cells.

Leukotriene receptor antagonist: A class of drugs that interferes with the function of leukotrienes; examples include montelukast and zafirlukast.

Ligand: a molecule that binds to another molecule, triggering a specific effect; with regards to mast cell disease, ligands bind to receptors, such as IgE (ligand) binding to FceRI (receptor)

LO: lipoxygenase; the enzyme that produces leukotrienes

Low histamine diet: a diet which minimizes dietary sources of histamine, which can help reduce symptoms for some mast cell patients; there is no authoritative list of low histamine foods and some trial and error is required

 

Glossary of mast cell related terms: A-E

Allergic march: the progressive accumulation of atopic conditions beginning in the first year of life; usually atopic dermatitis, allergic rhinitis, asthma, food allergy

Anaphylaxis: a rapidly progressing allergic reaction that involves multiple organ systems; can be fatal

Angioedema: Swelling caused when fluid leaves the bloodstream and becomes trapped between the deep dermis and subcutaneous tissue.

Anticholinergic: blocking the molecule acetylcholine from sending signals in the nervous system.  Many medications are anticholinergic, which can cause many side effects.

Ascites: free fluid in the abdomen; a form of third spacing

Aggressive systemic mastocytosis (ASM): a form of systemic mastocytosis in which mast cells invade organs, causing damage and dysfunction; diagnosed when a person meeting the criteria for SM has one or more C finding, criteria that indicate organ damage caused by mast cells

Asthma: inflammation of the airways causing swelling, narrowing and extra mucus production; can be allergic in nature

Atopy: tendency of a person to develop allergic diseases like asthma

Autoimmune disease: a disease caused when the immune system attacks healthy cells; mast cell diseases are not autoimmune diseases

Autonomic nervous system: a part of the nervous system that controls many involuntary functions of the body, including digestion.  It is composed of both the parasympathetic nervous system and the sympathetic nervous system.

B finding: criteria that indicate SM is progressing towards mast cells invading organs and damaging them; if 2 or more are present, smouldering systemic mastocytosis (SSM) is diagnosed

Biphasic anaphylaxis: Second episode of anaphylaxis symptoms after resolution

Bradykinin: a mediator released by mast cells that causes inflammation, pain and swelling

CD117: another name for CKIT receptor, found normally on the outside of mast cells

CD2: a marker not usually found on the outside of mast cells; an indicator of systemic mastocytosis; a cell adhesion molecule

CD25: a marker not usually found on the outside of mast cells; an indicator of systemic mastocytosis; part of a receptor for IL-2

CD34: a marker normally found on the outside of cells that become mast cells, and on new mast cells

Chronic urticaria: hives lasting longer than six weeks; can include angioedema

Circadian rhythm: the body’s internal clock

CKIT: a receptor on the outside of mast cells that binds stem cell factor, telling mast cells to stay alive and make more cells; is often mutated in systemic mastocytosis

Complement : a system of many small proteins circulating in the blood that can attack infectious agent ; can also cause angioedema

Cortisol : a steroid hormone produced by the adrenal glands ; critical in regulating stress response

COX : cyclooxygenase; enzymes that produce prostaglandins

Cutaneous mastocytosis (CM): infiltration of the skin by excessive mast cells.  The most common type of mastocytosis.

D816V/CKIT+: a specific mutation at codon 816 of the CKIT gene that causes the CKIT receptor to be misshapen so that mast cells get inappropriate signals to stay alive and keep making more cells

Darier’s sign: a wheal and flare response elicited by touching mast cell lesions; caused by histamine release

Desensitization: the elimination of the body’s allergic response to something

Diffuse cutaneous mastocytosis (DCM): The most severe presentation of cutaneous mastocytosis.  Lesions cover much of the body and may blister or bleed.

Deconditioning: when the body becomes acclimated to less physical stress and becomes less able to function properly under normal conditions.

Degranulation: the release of mediators stored in granules inside a cell; mast cell degranulation contributes to immune response as well as symptom profile in mast cell disease and anaphylaxis

Delayed food-induced anaphylaxis to meat: An IgE mediated reaction to beef, pork or lamb that occurs several hours after eating; caused by a tick bite inducing production of antibodies to carbohydrate a-gal.

Dysautonomia: fundamental dysfunction of the autonomic nervous system; there are many types, including POTS

Ehlers-Danlos Syndrome (EDS): a group of conditions caused by hypermobility and/or known genetic mutation affecting production of connective tissue components; Hypermobility EDS is seen disproportionately in the mast cell community

Edema: swelling; excess fluid trapped in tissues

Eicosanoid: the molecular class that includes prostaglandins and leukotrienes

Eosinophilia: elevation of eosinophils in the blood

Eosinophilic esophagitis: infiltration of the esophagus by eosinophils

Eosinophilic GI disease: IgE and delayed cell mediated reactions to foods caused by overactive eosinophils, affecting the GI tract.

Eosinophils: a granulocyte functioning similar to mast cells; mast cells and eosinophils can activate each other

Epinephrine: a hormone used to treat anaphylaxis

Exercise intolerance: diminished ability or inability to perform physical exercise; can be caused by a number of medical conditions