The Provider Primer Series: Relevance of mast cells in common health scenarios

 

Symptom Cough
Role of mast cells Several mast cell mediators contribute to airway inflammation and subsequent symptoms including cough:

•             Histamine promotes bronchoconstriction, excessive production of mucus, and airway edema.[i]

•             Prostaglandin D2 promotes bronchoconstriction, mucus production, and airway edema.[i]

•             Leukotrienes C4 and D4 and chymase also contribute to mucus production and airway edema.[i]

•             Tryptase promotes overall increased reactivity of the airway.[i]

Chronic airway inflammation, as in asthma, is sometimes associated with increased mast cell population in pulmonary tissues.[i]

Mast cells remain activated in inflamed airways.[i]

Impact of condition on mast cells Mast cell activation can occur as a result of the physical stimuli such as coughing[ii].

Pain can trigger mast cell activation[iii].

Notes regarding condition treatment Dextromethorphan can trigger mast cell degranulation[iv].

Codeine and derivatives can trigger mast cell degranulation[v].

Beta-2 adrenergic agonists, inhaled and oral steroids, and inhaled cromolyn are frequently used in mast cell patients[vi].

Notes regarding mast cell treatment Antihistamines, leukotriene receptor antagonists, and COX inhibitors are routinely taken by mast cell patients and can provide relief.[vii]

Racemic epinephrine can provide relief of pulmonary symptoms.[viii]

Special considerations for mast cell patients Chronic dry, unproductive cough sometimes occurs in mast cell patients.[ix]

Mast cell patients frequently have reactive airways.[ix]

Mast cells can produce and release prostaglandin E2, a mediator that participates in asthmatic inflammation and cough[x].

Prostaglandin E2 can also downregulate or promote mast cell degranulation via binding at prostaglandin E2 receptors on mast cell surface[x].

 

Symptom Sore throat
Role of mast cells Pain can trigger mast cell activation.[iii]
Impact of condition on mast cells Mast cell driven nasal congestion can result in postnasal drip can irritate the throat.[ix]

Mast cell irritation of the throat can present similarly to infection by Streptococcus spp. or other pathogen. Cultures should be taken to properly evaluate for infection.[ix]

Viral, bacterial and fungal infection will activate mast cells through toll like receptors and through perpetuated inflammatory signaling.[xiii]

Notes regarding condition treatment Acetaminophen is recommended for pain relief in mast cell patients.[iv]
Notes regarding mast cell treatment Antihistamines and COX inhibitors are routinely taken by mast cell patients and can provide relief.[vi]
Special considerations for mast cell patients Angioedema of the throat driven by mast cell disease is always a consideration in mast cell patients. If angioedema secondary to mast cell disease impinges upon airway, epinephrine and subsequent anaphylaxis treatments should be undertaken.[vii]

Oral allergy syndrome should be considered.[ix]

 

Symptom Rash
Role of mast cells Acute urticaria is usually driven by mast cell and basophil activation through IgE or non-IgE pathways.[xi]

Mast cell mediators histamine, leukotrienes and platelet activating factor contribute to itching.[xii]

Impact of condition on mast cells Viral, bacterial and fungal infection will activate mast cells via toll like receptors and perpetuated inflammatory signaling.[xiii]

Non-mast cell driven conditions causing skin rashes can irritate mast cells in the skin.[xii]

Pain can trigger mast cell activation.[iii]

Notes regarding condition treatment Some -azole antifungals can induce mast cell degranulation.[xiv]
Notes regarding mast cell treatment Antihistamines and steroids, topical or systemic, and topical cromolyn can provide relief.[xii]
Special considerations for mast cell patients Mediator release by activated mast cells can produce systemic symptoms.[x]

In patients with a history of mast cell disease, mastocytosis in the skin should be considered.

o             Cutaneous mastocytosis accounts for approximately 90% of mastocytosis cases.[xii]

o             Cutaneous mastocytosis lesions demonstrate Darier’s sign, a wheal and flare reaction to touch.[xii]

o             A skin biopsy is necessary to confirm a diagnosis of cutaneous mastocytosis.[xii]

o             Patients with adult onset cutaneous mast cell lesions are usually later found to have systemic mastocytosis.[xii]

 

Symptom Fever
Role of mast cells Mast cells can produce prostaglandin E2.[x]

Mast cells can produce and release several pyrogens, including IL-1α, IL-1β, IL-6, IL-8, TNF, interferon-α, interferon-β, and interferon-γ.[x]

Impact of condition on mast cells Prostaglandin E2 can also downregulate or promote mast cell degranulation via binding at prostaglandin E2 receptors on mast cell surface.[x]

Pain can trigger mast cell activation.[iii]

Viral, bacterial and fungal infection will activate mast cells via toll like receptors and perpetuated inflammatory signaling.[xiii]

Notes regarding condition treatment NSAIDS can trigger mast cell degranulation. Some mast cell patients are unable to take them.[xv]

Acetaminophen is generally recommended for use in mast cell patients.[iv]

Notes regarding mast cell treatment COX inhibitors are routinely taken by mast cell patients and may provide relief.[vi]
Special considerations for mast cell patients

 

Symptom Earache
Role of mast cells Mast cells are involved in the transmission of pain stimuli, including nerve pain.[iii]

Mast cells are involved in sensorineural hearing loss and tinnitus.[ix]

Impact of condition on mast cells Pain can trigger mast cell activation.[iii]

Viral, bacterial and fungal infection will activate mast cells via toll like receptors and perpetuated inflammatory signaling.[xiii]

Notes regarding condition treatment NSAIDS can trigger mast cell degranulation. Some mast cell patients are unable to take them.[xv]

Acetaminophen is generally recommended for use in mast cell patients.[iv]

Steroids (local and systemic) can stabilize mast cells.[vi]

Notes regarding mast cell treatment COX inhibitors are routinely taken by mast cell patients and may provide relief.[vi]

Antihistamines can provide relief for vestibular symptoms.[vi]

Special considerations for mast cell patients Hearing loss, tinnitus and hyperacusis sometimes occur in mast cell patients.[ix]

Sensorineural hearing loss of unknown origin has been documented in mast cell patients.[ix]

Some mast cell patients also have Ehlers Danlos Syndrome which can cause conductive hearing loss.[ix]

Mast cell disease can also cause auditory processing disorder.[ix]

Red ears are a common sign of mast cell activation. Sometimes, only one ear is affected.[ix]

 

Symptom Stomachache
Role of mast cells Mast cells are commonly found in the GI tract.[xvi]

Mast cell activation is involved in a number of GI conditions, including inflammatory bowel disease, ulcerative colitis and food allergies.[xvi]

Mast cell activation can cause chronic diarrhea, pseudoobstruction, obstruction, dysmotility, constipation, nausea, vomiting, and visceral GI pain.[xvi]

Impact of condition on mast cells GI inflammation can recruit mast cells to inflamed tissues.[xvi]

GI inflammation can trigger mast cell mediator release.[xvi]

Pain can trigger mast cell activation.[iii]

Viral, bacterial and fungal infection will activate mast cells via toll like receptors and perpetuated inflammatory signaling.[xiii]

Notes regarding condition treatment
Notes regarding mast cell treatment Histamine H2 blockers and PPIs are commonly taken by mast cell patients and can provide relief.[vi]
Special considerations for mast cell patients Mast cell patients can experience a wide array of severe GI symptoms with or without dense infiltration of GI tract by mast cells.[ix]

 

[i] Cruse G, Bradding P. (2016). Mast cells in airway diseases and interstitial lung disease. European Journal of Pharmacology 778, 125-138.

[ii] Zhang D, et al. (2012). Mast-cell degranulation induced by physical stimuli involves the activation of transient receptor-potential channel TRPV2. Physiol Res, 61(1):113-124.

[iii] Chatterjea D, Martinov T. (2015). Mast cells: versatile gatekeepers of pain. Mol Immunol, 63(1),38-44.

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

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

[vi] Molderings GJ, et al. (2016). Pharmacological treatment options for mast cell activation disease. Naunyn-Schmiedeberg’s Arch Pharmol, 389:671.

[vii] Molderings GJ, et al. Mast cell activation disease: a concise, practical guide to diagnostic workup and therapeutic options. J Hematol Oncol 2011; 4 (10).

[viii] Walsh P, et al. (2008). Comparison of nebulized epinephrine to albuterol in bronchiolitis. Acad Emerg Med, 15(4):305-313.

[ix] Afrin LB. (2013). Diagnosis, presentation and management of mast cell activation syndrome. Mast cells.

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

[xi] Bernstein JA, et al. (2014). The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol, 133(5):1270-1277.

[xii] 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.

[xiii] Sandig H, Bulfone-Paul S. (2012). TLR signaling in mast cells: common and unique features. Front Immunol, 3;185.

[xiv] 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.

[xv] 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.

[xvi] Ramsay DB, et al. (2010). Mast cells in gastrointestinal disease. Gastroenterology & Hepatology, 6(12): 772-777.

 

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.

 

Take home points: October 2015

Childhood mastocytosis: Update

  • Cutaneous mastocytosis in children is the most common form of mastocytosis
  • True systemic mastocytosis is very rare in children
  • An NIH study of 105 children found 30-65% improved over time
  • Elevated baseline tryptase level and organ swelling were good indicators of SM
  • Serum tryptase should be measured every 6-12 months
  • Children with swelling of both liver and spleen were positive for CKIT D816V mutation
  • Swelling of liver and spleen together was linked to disease persisting into adulthood
  • Most children with UP with skin and minor GI issues had normal tryptase
  • Diffuse cutaneous mastocytosis patients had a much higher average tryptase but no organ swelling
  • Serum tryptase and IgE were inversely related (high tryptase with low IgE, low tryptase with high IgE)

Chronic mast cell leukemia: a new variant of systemic mastocytosis

  • Mast cell leukemia (MCL) has a significantly shortened lifespan
  • Usually over 20% of nucleated cells in bone marrow are atypical mast cells
  • Mast cells are present in large quantities on the blood
  • Cases where less than 10% of white blood cells in blood are mast cells are called aleukemic variant MCL
  • Cases where over 20% of nucleated cells in bone marrow are mature mast cells are called chronic MCL
  • Chronic MCL patients do not have any C findings (the clinical markers for SM patients associated with very aggressive disease)
  • Chronic MCL patients have stable disease state but can progress to acute MCL at any time
  • Mediator release symptoms are more common in chronic MCL than acute MCL
  • Acute MCL is marked by immature CD25+ mast cells
  • Acute MCL patients do have C findings (the clinical markers for SM patients associated with very aggressive disease)
  • Acute MCL has a very short survival time, usually less than a year

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.

Progression of mast cell diseases (Part 5)

What is the typical age of onset for children with mastocytosis?

“Mastocytosis [cutaneous, in children]… 55% of cases presenting from birth to 2 years of age, 10% in children younger than 15 years old, and 35% in those over the age of 15. There has, however, been no gender bias noted in the cases of pediatric mastocytosis.” (Frieri 2013)

 

Do symptoms outside of the skin mean my child has systemic, not cutaneous, mastocytosis?

“Systemic symptoms are typically a result of mast-cell mediator release but do not prove systemic mast-cell hyperplasia [overproliferation].” (Frieri 2013)

“Clinical presentation was evaluated in an earlier study conducted by the National Institutes of Health (NIH) in which 83% of the children presented with pruritis, 65% with flushing, 53% with vesicles, 41% with abdominal pain, 18% with bone pain, and least commonly 12% with headache.” (Frieri 2013)

“Systemic mastocytosis in children is extremely rare.” (Frieri 2013)

 

What do studies say about kids growing out of mastocytosis?

“Pediatric mastocytosis is generally a benign disease that is transient in nature, as there is generally a spontaneous regression of the condition by puberty.” (Frieri 2013)

“There was complete regression of disease as defined by cutaneous findings and symptoms (clinical disease severity) in 10 of 15 patients (67%). Three patients had major (20%) and two had partial regression of disease (13%). Repeat marrow examinations on three patients with persistent disease documented systemic mastocytosis based on marrow findings in one patient who had partial regression of disease and was the only patient with initial [] evidence of systemic disease. Of the remaining two patients, one demonstrated partial regression and the other major regression of disease; and neither had evidence of systemic mastocytosis.” (Frieri 2013)

“10 of 15 of patients had complete resolution of cutaneous disease and symptoms at follow-up approximately 20 years later. This resolution of disease, based on cutaneous findings and symptom scores, occurred in the absence of use of topical or systemic steroids, PUVA or cytoreductive agents including imatinib… the natural history of disease is improvement.” (Uzzaman 2009)

“In one [] pediatric report where records and follow-up examinations were available for 25 children with UP, and an average follow-up was approximately 5 years, 76 % improved, 16 % remained unchanged, one had complete disease resolution, and one was worse.” (Uzzaman 2009)

“In a second [] study, 55 children with UP were followed for at least two years after initial examination, during which time 9% had involution of all lesions. In this study, where the average follow-up was 4.1 years, 36% had shown improvement over 6.1 years, and in 55% disease remained unchanged.” (Uzzaman 2009)

“In a third [] study, records of mastocytosis patients [] were available to assess disease outcome over a 1–15 year period. Thirty-five of 62 patients with UP (56%) showed complete disease resolution.” (Uzzaman 2009)

“In a fourth [] study, of 72 cases of UP, 20% cleared disease over an average of 13 years, while 50% improved, 18% were no different, and 10% were worse.” (Uzzaman 2009)

“The age of inception of pediatric-onset cutaneous mastocytosis has been reported to have prognostic implications. In previous studies, skin lesions characterized as hyperpigmented red brown macules or papules typically were reported to appear prior to two years of age. In five such studies with 180, 112, 71, 55 and 17 patients, disease-onset prior to age 2 years was seen in 78, 92, 98, 92, and 82%, respectively. In the majority of patients, these lesions were reported to fade or resolve by late adolescence or early adulthood. Fading or resolution of UP is also reported in some adults (around 20%), although bone marrow disease persisted.” (Uzzaman 2009)

 

How do biopsies of children with mastocytosis differ from adults with mastocytosis?

“In order to analyze the extent of mast-cell hyperplasia, [] bone-marrow biopsies were performed and analyzed. In one study, it was found that in 10 of 17 children with mastocytosis, there were focal areas of mast-cell hyperplasia, which had [] aggregates of mast cells, eosinophils, and early myeloid cells.(Frieri 2013)

“Another study found that the bone-marrow lesions of children had small, [] clusters of mast cells with round and oval nuclei rather than spindle-shaped mast cells, as found in adult bone-marrow lesions.” (Frieri 2013)

“Overall when quantifying mast-cell hyperplasia, there was a higher load of mast cells in children with mastocytosis than in adults with mastocytosis.” (Frieri 2013)

“[T]he difference in presentation between adult and pediatric cases of mastocytosis may result from the difference not only in the mast-cell load but also the distribution of where the mast cells are most likely to be found.” (Frieri 2013)

 

Do increased mast cells in the bone marrow mean my child will not grow out of their disease?

“Five patients had increased mast cells and three patients had spindle shaped mast cells on the initial bone marrow biopsy. One of these patients had complete resolution of clinical and constitutional symptoms at follow-up. Three of the remaining four patients were re-evaluated. One of these was the patient with continued systemic disease, one had persistent DCM and one had continued UP. However, two other patients with continued UP had neither an increase in mast cells nor spindle shaped mast cells noted on original bone marrow examination. Thus, while the presence of increased mast cells and of spindle-shaped mast cells was more often observed in those with persistent disease, the association was not sufficient to predict outcome.” (Uzzaman 2009)

 

Are children with mastocytosis CKIT+?

“Earlier studies by Verzijl found that 25% of pediatric patients with UP had an activating D816V mutation present. Another Longley study found that 36% of pediatric patients had another mutation at codon 816. (This is where the D816V mutation is found.)…One study found that 25% of pediatric patients with the UP form of mastocytosis had a D816V mutation. It was also found that 10 out of 12 patients had another [non-D816V] mutation at the location.” (Frieri 2013)

“A later study by Bodemer in 50 pediatric patients with ages ranging from birth to 16 years found 86% of them had a c-KIT mutation, with 36% being a D816V point mutation, 2 out of 50 cases being a D816Y mutation, and one case being a D816I mutation. There were also 29 of 50 patients with [no mutation] at the 816 codon.” (Frieri 2013)

“44% of the patients were found to have a mutation outside of c-KIT with the mutations lying in exons 8, 9, and 11. There was also a subset of 28% of the patients with a M541L mutation at exon 10. [T]he patients with a M541L mutation had [no mutation] at codon 816. When the blood sample of 13 patients was analyzed, it was found that there was no c-KIT mutation, which suggests that the mutation is somatic rather than germline, meaning that this mutation is not inherited from a patient’s parents.” (Frieri 2013)

 

Do mastocytosis children generally have problems with anesthesia?

Note: always follow appropriate premedication protocols for mast cell patients and work with managing physician.

“Twenty-two patients with pediatric mastocytosis, with a median age of 3.2 years (range 6 months to 20 years) at the time of the procedure, were anesthetized for 29 diagnostic and surgical procedures. All variants of the disease are represented in this series. Most patients had a history of flushing, pruritus, gastroesophageal refux disease (GERD), and abdominal pain; one patient had history of spontaneous anaphylaxis. Routine anesthetic techniques were used, and despite the complexity of the disease, the perioperative courses were uncomplicated and without serious adverse events.” (Frieri 2013)

 

Note: These quotes are all drawn from two papers which extensively referenced previous publications. I ran down the articles referenced, but felt that these two reviews gave excellent summaries, and so I quoted them exclusively.

 

References:

Frieri, Marianne, et al. Pediatric mastocytosis: A review of the literature. Pediatr Allergy Immunol Pulmonol. Dec 1, 2013; 26(4): 175-180.

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.

Kettelhut BV., Metcalfe DD. Mastocytosis. J Invest Dermatol 1991; 96:115S–118S.

Lange M., Bogusław 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.

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.

 

Progression of mast cell diseases (Part 4)

If ISM is life threatening, why is not considered as dangerous as ASM or MCL?

ISM is not life threatening. Anaphylaxis is life threatening. They are not the same. Many people with ISM never experience anaphylaxis. ISM can make anaphylaxis more dangerous, but ISM is not the same as anaphylaxis. Outside of anaphylaxis, ISM is not life threatening.

“Indolent systemic mastocytosis (SM) patients have a varied clinical presentation, ranging from predominantly cutaneous symptoms to recurrent systemic symptoms (eg, flushing, palpitations, dyspepsia, diarrhea, bone pain) that can be severe and potentially life threatening (anaphylaxis.)” (Pardanini 2013)

 

Is MCAS more or less dangerous than ISM?

“From a clinical standpoint, MMAS and MCAS share many similarities with systemic mastocytosis (SM), a primary disorder of mast cells in which patients experience symptoms ranging from pruritus and flushing to anaphylaxis.” (Picard 2013)

Again, the real danger here is anaphylaxis rather than these entities themselves. Statistically, the numbers don’t have a lot of uniformity regarding frequency of anaphylaxis in SM, what constitutes a severe reaction, and so on. Additionally, there are multiple definitions of MCAS and how that is distinguished from IA, which is really important to understanding the true frequency of anaphylaxis in MCAS. However, the data currently shows a trend of anaphylaxis being less common in MCAS than in SM. Still, it is important to realize that this may be due to less research being available on MCAS than mastocytosis.

“In our cohort 3 [MCAS] patients (17%) had a history of anaphylaxis. These patients were included in our cohort because they had primary symptoms characteristic of MCAS that responded to medications and had other laboratory evidence of MC mediator release…There likely exists a spectrum of disease for MCAS in which the more severe form includes anaphylaxis and a spectrum of IA in which a form includes MCAS symptoms.” (Hamilton 2011)

It is well known that people with mastocytosis are more likely to experience anaphylaxis than the general public. In adults with any type of mastocytosis, 49% experience anaphylaxis. Patients with systemic mastocytosis were more likely to anaphylax than those with cutaneous mastocytosis. In adults, 48% of the anaphylactic reactions were severe, with 38% causing unconsciousness. 60% of those reactions were Grade III anaphylaxis. (Brockow 2008)

“In 4 of the 137 [SM] patients (3%), severe life-threatening anaphylaxis resulting in a severe handicap with or without transient or permanent disability occurred.” (Wimazal 2012)

“Prolonged hypotension following anaphylaxis and cerebral hypoxia were identified as major factors leading to a substantial handicap, clinical deterioration or even death in these patients.” (Wimazal 2012)

“However, in both patients in whom recurrent life-threatening anaphylaxis was recorded, the smoldering subtype of SM with a huge burden of MCs was diagnosed, whereas most patients in whom only one documented severe life-threatening event had occurred were found to have low-grade SM with a low burden of MCs.” (Wimazal 2012)

“Thirty-six [SM] patients (43%) had had at least one episode of an anaphylactic reaction. The clinical courses of the reactions were usually severe and patients often presented with syncope attacks (72%). Most patients reacted after hymenoptera venom stings (19/36; 53%). In 39% (14/36), a clear etiology could not be determined. While males and females were equally frequent among the patients with SM, anaphylaxis patients showed a male predominance (61%). Anaphylactic reactions occurred more frequently in patients without cutaneous engagement. The rate of allergy sensitization was significantly higher in SM patients with anaphylaxis as compared with non-anaphylaxis SM patients, 70% vs. 23%, respectively.” (Gulen 2014)

 

Does an elevated GI mast cell count tract (in the absence of aberrant receptors, clustering or spindled mast cells) indicate MCAS or SM?

“Our immunohistochemical analysis led us to the conclusion that there was no significant difference between the numbers of intestinal mucosal MCs in our patients with MCAS and our reference standard. We recognize that there is currently no consensus for what constitutes a normal number of MCs in the various intestinal tissues. We therefore chose data from a recently published study by one of the authors to be the reference standard. In this study normal numbers of MCs were tabulated for each tissue site. Although we did not find appreciably increased numbers of MCs or abnormal morphology, it is possible that patients with MCAS have a different threshold for MC activation and differentially release MC mediators on activation or that peripheral tissues have an abnormal response to these mediators. We also recognize that a population of patients with chronic diarrhea has been described and labeled as having mastocytic enterocolitis. These patients had a greater number of MCs per hpf in duodenal and colon biopsy specimens compared with the control population (>20 vs 13 MCs/hpf). We were not able to verify this observation in our cohort because many of our control population biopsy specimens had more than 20 MCs/hpf.” (Hamilton 2011)

 

What is the relationship between CM and MCAD (including SM and MCAS)?

“[M]ost patients with adult-onset MIS [mastocytosis in the skin (commonly called cutaneous mastocytosis,CM)] have demonstrable bone marrow (BM) involvement with clonal mast cells when modern-era diagnostic tools are used, in most instances, satisfying WHO diagnostic criteria for SM. While historical series of patients with MIS revealed an 18% to 50% prevalence of systemic involvement based on conventional histologic criteria, more modern series suggest that only a minority of adult patients have skin-limited disease. Further, approximately 50% of adults with apparent skin-limited mastocytosis may have a clonal BM mast cell infiltrate that falls short of the diagnostic threshold for SM (satisfies major criterion only or only 1 or 2 minor criteria), suggesting prediagnostic or early stage of ISM.” (Pardanini 2013)

“The relationship between systemic MCAD and cutaneous mastocytosis (CM, synonyms: paediatric or childhood onset mastocytosis) remains unclear. Early studies suggested that CM and systemic MCAD were separate disease entities, because the majority of CM patients were found to lack mutations of the tyrosine kinase KITgene. However, subsequent studies have demonstrated that the frequency of clonal KIT mutations is similar in patients with CM, SM and MCAS, and that they are present in up to 86% of patients from each diagnostic group.” (Haenisch 2012)

“Interestingly, in contrast to adult-onset systemic MCAD, more than 50% of paediatric cases of cutaneous mastocytosis appear to enter long-term remission spontaneously, though whether such remissions are permanent or relapse in adulthood as systemic MCAD is unknown.” (Haenisch 2012)

“In contrast, most adults with CM have an underlying SM and should undergo a bone marrow biopsy regardless of the presence of associated systemic symptoms of mediator release. Conversely, 80% of SM patients have cutaneous disease that manifests as urticaria pigmentosa. In contrast, patients with MMAS and MCAS never have CM, and patients with ASM or MCL frequently lack CM.” (Picard 2013)

 

References:

Juan-Carlos Cardet, Maria C. Castells, and Matthew J. Hamilton. Immunology and Clinical Manifestations of Non-Clonal Mast Cell Activation Syndrome. Curr Allergy Asthma Rep. Feb 2013; 13(1): 10–18.

Britta Haenisch, Markus M. Nothen and Gerhard J. Molderings. Systemic mast cell activation disease: the role of molecular genetic alterations in pathogenesis, heritability and diagnostics. Immunology 2012, 137, 197–205.

Animesh Pardanani. How I treat patients with indolent and smoldering mastocytosis (rare conditions but difficult to manage.) April 18, 2013; Blood: 121 (16).

Matthieu Picard, Pedro Giavina-Bianchi, Veronica Mezzano, Mariana Castells. Expanding Spectrum of Mast Cell Activation Disorders: Monoclonal and Idiopathic Mast Cell Activation Syndromes. Clinical Therapeutics, Volume 35, Issue 5, May 2013, Pages 548–562.

Gerhard J Molderings, Stefan Brettner, Jürgen Homann, Lawrence B Afrin. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. Journal of Hematology & Oncology 2011, 4:10.

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, Volume 63, Issue 2, pages 226–232, February 2008.

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.

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.

 

 

 

Just a horse

This past spring, I started developing a rash on my back.  It was macular and itchy and swelled and turned red when I touched it. 
“It looks like urticaria pigmentosa except it’s not dark,” one doctor told me.  It’s important to note here that my rash pigmentation has been unusual for my entire life.  I have, on several occasions, had rashes misdiagnosed because they were “too pink” or “too faint.”  I don’t know the reason for this, but it happens.  “I’m sure it’s some kind of mast cell issue, your skin is very reactive,” he followed up.
“That is definitely urticaria pigmentosa,” another doctor told me.  He touched the spots and they puffed up and got itchy.  “See, it has a positive Darier’s sign.”  My skin will urticate will very little provocation so I was not convinced.  But I figured I was probably bound to have UP eventually, so I wasn’t very concerned.
“It is probably a mast cell rash, but you should get it biopsied just in case,” a third doctor told me.  By this point, the rash was all over my back and shoulders.  It was itchy, but not all the time.  I scheduled an appointment with a dermatologist. 
I saw the dermatologist on Thursday.  She took one look at it and said, “Oh, that’s not cutaneous mastocytosis.  That’s a harmless fungal rash.  It’s more common in people who are immunosuppressed.  I’ll give you a cream.”
We had a good laugh over the fact that when you have a rare disease, everyone assumes it is the cause of all your symptoms.  She told me a funny story about a patient with several rare diseases who had a “mysterious rash” that the residents couldn’t identify.  It was tinea versicolor, a very common fungal rash.  The residents had assumed it was something exotic and had not considered more mundane options.
Then there was a small fire in the building while I was dressed only in a gown, educating the visiting PCP about systemic mast cell symptoms from skin reactions.  I threw my clothes on and ran outside as the fire department arrived.  Always lively. 
Mast cell disease is hard to manage in part because it can cause so many problems.  But just because it can cause all of them doesn’t mean it does. 
Mast cell patients are zebras, often many times over.  But even zebras mingle with horses once in a while.

Neurologic symptoms of mast cell disease

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

Diagnosis of mast cell diseases

There seems to be a lot of confusion regarding diagnosis of mast cell diseases, so I figured I’d do a review.

Cutaneous mastocytosis (CM) is diagnosed by skin biopsy.  Urticaria pigmentosa (UP), also called maculopapullar cutaneous mastocytosis (MPCM), diffuse cutaneous mastocytosis (DCM) and telangiectasia macularis eruptive perstans (TMEP) are types of cutaneous mastocytosis.  They each present with a rash and may have accompanying systemic symptoms. 
Mastocytoma of the skin is also diagnosed by skin biopsy.
Systemic mastocytosis (SM) has the following diagnostic criteria:
Major:
1.       Multifocal, dense infiltrates of mast cells (15 or more in an aggregate) detected in sections of bone marrow and/or extracutaneous organ. 
Minor:
1.       In biopsy sections, more than 25% of mast cells in infiltrated area are spindle-shaped or have atypical morphology; or, of all mast cells in bone marrow aspirate smears, more than 25% are immature of atypical. 
2.       Detection of Kit mutation at codon 816 in bone marrow, blood or other extracutaneous organ.
3.       Mast cells in bone marrow, blood or other extracutaneous organ that co-express CD117 with CD2 and/or CD25.
4.       Serum total tryptase persistently >20 ng/mL (if there is not a clonal myeloid disorder.)
SM is diagnosed if a patient has either one major and one minor criteria, or three minor criteria.  So let’s look at how this plays out.
A patient with mast cell symptoms gets a bone marrow biopsy.  It shows more than 25% abnormal mast cells in the section.  They are CKIT negative, have a serum tryptase of 2, and do not express CD2/CD25.  They are diagnosed with SM.
A patient has a biopsy that does not show dense infiltrates.  All their mast cells are shaped normally.  In blood tests, their mast cells are found to express CD2.  They are CKIT+, also from blood.  Their serum tryptase is 28.  They are diagnosed with SM.
A patient has a biopsy that shows dense infiltrates, but they have less than 25% abnormal mast cells and their mast cells do not express CD2/CD25.  They are CKIT- and have a serum tryptase of 18.  They are not diagnosed with SM.
A few things to keep in mind:
Most people with SM are diagnosed by bone marrow biopsy, but a biopsy from any non-skin organ showing mast cell infiltration as described above can be used.  This means if you have a positive lung biopsy, liver biopsy, whatever, you may not necessarily need a bone marrow biopsy. 
It can take up to six bone marrow biopsies to diagnose SM in a patient who has had it the entire time.  This is because there is no way to know where the mast cells will cluster.  A negative bone marrow biopsy does not necessarily mean that you do not have SM.  Hence the minor criteria.
The CKIT test looks for a specific mutation, the D816V mutation.  There are other mutations found in codon 816.  You may have a mutation but test CKIT- because you do not have the D816V mutation.  Also, the blood test for CKIT is not always reliable.  The test way to test this is from a bone marrow sample.  You could test CKIT- in blood and then test CKIT+ in bone marrow.
The serum tryptase criterion refers to persistent baseline level tryptase, not reaction level tryptase. 
So let’s say you have a negative bone marrow biopsy and a blood test that shows you are CKIT+ and have mast cells expressing CD2/CD25.  What do you have?  You have monoclonal mast cell activation syndrome (MMAS.)  MMAS is diagnosed in patients who have one or two of the minor criteria for systemic mastocytosis.
Let’s say you have a negative bone marrow biopsy and blood work that shows normal mast cells and tryptase below 20, but you have systemic symptoms.  What do you have?  You probably have MCAS (mast cell activation syndrome.)  There are some other tests for that.  24 hour urine tests are usually done to measure the levels of histamine metabolites and prostaglandin D2 metabolites.
The following are the diagnostic criteria for MCAS:
1.       Episodic symptoms consistent with mast cell mediator release affecting two or more organ systems: skin (urticarial, angioedema, flushing); GI (nausea, vomiting, diarrhea, cramping); cardiovascular (fainting or near fainting due to low blood pressure, rapid heartbeat); respiratory (wheezing); naso-ocular (itching, nasal stuffiness, red eyes.)
2.       A decrease in frequency or severity; or resolution of symptoms with antihistamines, leukotriene inhibitors or mast cell stabilizers.
3.       Evidence of elevation of urinary or serum marker of mast cell activation: Documentation of elevation of marker during a symptomatic period on at least two occasions, or if baseline tryptase is persistently above 15 ng.  This includes urinary histamine and prostaglandin D2.
4.       Clonal and secondary disorders of mast cell activation ruled out.
MCAS is a diagnosis of exclusion.  It is the diagnosis you receive if you have mast cell symptoms that are ameliorated with mast cell medications if you do not meet the criteria for any other mast cell disease.
Back to SM.  Let’s say you’re positive for SM.  Now what?
They will determine if you have other important markers of disease severity.  These are called B and C findings.  They are as follows:
B findings:
1.       Increased mast cell burden (>30% mast cell aggregates on bone marrow biopsy and/or serum tryptase >200 ng/ml).
2.       Hypercellular marrow, signs of overproduction or abnormal development of blood cells, normal or slightly abnormal blood counts that are not abnormal enough to be considered an associated hematologic disorder.
3.       Swelling of the liver that can be felt manually, no free fluid or signs of dysfunction, persistently swollen glands, swelling of the spleen that can be felt manually without signs of dysfunction.
If you have two or more B findings, you have SSM (smoldering systemic mastocytosis.) 
C findings:
1.       Unusual blood counts (low ANC, low Hb, low platelets)
2.       Swelling of the liver that can be felt manually, with impaired liver function, free fluid and/or portal hypertension.
3.       Large osteolytic lesions and/or pathological fractures.
4.       Swelling of the spleen with impaired function.
5.       Malabsorption with weight loss and/or low albumin.
If you have one or more C finding, you have ASM (aggressive systemic mastocytosis.)
How are these B and C findings identified?  Bone marrow biopsy, blood tests and imaging (ultrasounds, MRI, etc.) 
If you have SM and one B finding, or no B findings, you have indolent systemic mastocytosis (ISM.) 
If your bone marrow biopsy shows significant overproduction or abnormal development of a cell type that is not a mast cell, you may be diagnosed with SM-AHNMD (systemic mastocytosis with associated hematologic non-mast cell lineage disease.)  People with this type of SM also have another blood disorder, such as chronic myelogenous leukemia, myelodysplasia, etc.  In these patients, serum tryptase is not reliable to assess mast cell burden.  
Mast cell leukemia (MCL) is extremely rare.  It is diagnosed by >20% mast cells on the bone marrow aspirate smear.   
Mast cell sarcoma is a very aggressive form of sarcoma.  It is diagnosed by biopsy of the tumor.  People with these tumors quickly developed mast cell leukemia.  There have only been three cases reported in literature.  To be clear, this is NOT the same as mastocytoma.  Mastocytomas are benign.
I think I got everything.  Any questions?  Ask in the comments.