Mastocytosis

• Dense infiltrates of >15 mast cells in the bone marrow or an extracutaneous organ

• Aberrant phenotype on the mast cells (pos. for CD2 and/or CD25)
• Aberrant mast cell morphology (spindle-shaped)
• Finding of mutation in KIT(D816V)
• S-tryptase >20 ng/ml

Other types of mast cell disease include:

• Monoclonal mast cell activation, defined by the World Health Organization definitions 2010, also has increased mast cells but insufficient to be systemic mastocytosis (in World Health Organization Definitions)
• Mast cell activation syndrome – has normal number of mast cells, but all the symptoms and in some cases the genetic markers of systemic mastocytosis[10]
• Another known but rare mast cell proliferation disease is mast cell sarcoma.[11]

Mastocytosis can occur in a variety of forms:

• The most common cutaneous mastocytosis is maculopapular cutaneous mastocytosis, previously named papular urticaria pigmentosa (UP), more common in children, although also seen in adults. Telangiectasia macularis eruptiva perstans (TMEP) is a much rarer form of cutaneous mastocytosis that affects adults.^[2] MPCM and TMEP can be a part of indolent systemic mastocytosis. This should be considered if patients develop any systemic symptoms[12]
• Generalized eruption of cutaneous mastocytosis (adult type) is the most common pattern of mastocytosis presenting to the dermatologist, with the most common lesions being macules, papules, or nodules that are disseminated over most of the body but especially on the upper arms, legs, and trunk[13]
• Diffuse cutaneous mastocytosis has diffuse involvement in which the entire integument may be thickened and infiltrated with mast cells to produce a peculiar orange color, giving rise to the term homme orange.[14]

Cutaneous mastocytosis in children usually presents in the first year after birth and in most cases vanishes during adolescence.

Immunohistochemistry for c-KIT highlights mast cells (darkly stained) in the mucosa of the small intestine.

Systemic mastocytosis involves the bone marrow in the majority of cases and in some cases other internal organs, usually in addition to involving the skin. Mast cells collect in various tissues and can affect organs where mast cells do not normally inhabit such as the liver, spleen and lymph nodes, and organs which have normal populations but where numbers are increased. In the bowel, it may manifest as mastocytic enterocolitis.[15] However, normal ranges for mast cell counts in the gastrointestinal tract mucosa are not well established in the literature, and depend upon the exact location (e.g. right versus left colon), gender, and patient populations (such as asymptomatic patients versus patients with chronic diarrhea of unknown etiology). Quantitative mast cell stains may yield little diagnostic information, and further research studies are warranted to determine whether "mastocytic enterocolitis" truly represents a distinct entity.[16]

There are five types of systemic mastocytosis:[9]

• Indolent systemic mastocytosis (ISM). The most common SM (>90%)
• Smouldering systemic mastocytosis (SSM)
• Systemic mastocytosis with associated hematological neoplasm (SM-AHN)
• Aggressive systemic mastocytosis (ASM)
• Mast cell leukemia (MCL)

• Antihistamines block receptors targeted by histamine released from mast cells. Both H₁ and H₂ blockers may be helpful, often in combination.[18]
• Leukotriene antagonists block receptors targeted by leukotrienes released from mast cells.
• Mast cell stabilizers help prevent mast cells from releasing their chemical contents. Cromoglicic acid is the only medicine specifically approved by the FDA for the treatment of mastocytosis. Ketotifen is available in Canada and Europe and more recently in the U.S. It is also available as eyedrops (Zaditor).
• Proton-pump inhibitors help reduce production of gastric acid, which is often increased in patients with mastocytosis. Excess gastric acid can harm the stomach, esophagus, and small intestine.
• Epinephrine constricts blood vessels and opens airways to maintain adequate circulation and ventilation when excessive mast cell degranulation has caused anaphylaxis.
• Salbutamol and other beta-2 agonists open airways that can constrict in the presence of histamine.
• Corticosteroids can be used topically, inhaled, or systemically to reduce inflammation associated with mastocytosis.
• Drugs to prevent/treat osteoporosis include Calcium-Vitamine D, bisphosphonates and in rare cases inhibitors of RANK-L

Antidepressants are an important and often overlooked tool in the treatment of mastocytosis. Depression and other neurological symptoms have been noted in mastocytosis.[4][19] Some antidepressants, such as doxepin and mirtazapine, are themselves potent antihistamines and can help relieve physical as well as cognitive symptoms.

In cases of advanced systemic mastocytosis or rare cases with indolent systemic mastocytosis with very troublesome symptoms, cytoreductive therapy can be indicated.[20]

• ɑ-interferon. Given as subcutaneous injections. Side effects include fatigue and influenza-like symptoms
• Cladribine (CdA). Chemotherapy which is given as subcutaneous injections. Side effects include immunodeficiency and infections.
• Tyrosine kinase inhibitors (TKI)
  • Midostaurin. TKI acting on many different tyrosine kinases, approved by FDA and EMA for advanced mastocytosis
  • Imatinib. Can have effect in rare cases without mutation in KIT(D816V)
  • Masitinib. Is being tested in trials. Not approved.
  • Midostaurin - 60% respond.[21]
  • Avapritinib in trials; currently being tested but showing promise in reduction of tryptase levels.[21]

Allogeneic stem cell transplantation has been used in rare cases with aggressive systemic mastocytosis in patients deemed to be fit for the procedure.

Treatment with ultraviolet light can relieve skin symptoms, but may increase the risk of skin cancer.[22]