Mastocytosis and Mast Cell Disorders

Mast cells are found in the perivascular spaces of most tissues, and contain pro-inflammatory and vasoactive mediators. These mediators are released after IgE receptor cross-linking induced by allergens or other stimuli.¹

Mast cell disorders may involve:

• Either - excessive proliferation of mast cells, known as mastocytosis
• Or possibly - normal numbers of cells but abnormal reactivity²

The excess release of mediators can cause clinical features such as pruritus, flushing, nausea, vomiting, diarrhoea, abdominal pain, vascular instability and anaphylaxis. Also, complications may arise when mast cells accumulate in the skin, gastrointestinal (GI) tract, bone marrow, liver, spleen, and lymph nodes.³

Mastocytosis¹

The WHO classification (simplified here) is:

1. Cutaneous mastocytosis - usually children
   • Urticaria pigmentosa (maculopapular cutaneous mastocytosis) - the most common type
   • Diffuse cutaneous mastocytosis (very rare)
   • Mastocytoma of skin
2. Systemic mastocytosis
   • Indolent systemic mastocytosis
   • SM-AHNMD (systemic mastocytosis with associated haematological non-mast cell lineage disease)
   • Aggressive systemic mastocytosis
   • Mast cell leukaemia (very rare)
3. Localised mast cell proliferations (very rare)
   • Extracutaneous mastocytoma
   • Extracutaneous mast cell sarcoma

Mast cell activation syndrome²

Synonym: Mast Cell Activation Disorder (MCAD).
Some patients with mast cell disorders may not fit the above categories of mastocytosis. Some researchers have defined a new category, Mast Cell Activation Syndrome (MCAS). This is described as a condition in which there is evidence of the systemic, inappropriate release of mast cell mediators, but a near-normal tryptase level and a normal number of mast cells on bone marrow biopsy. Patients experience many of the same symptoms as with mastocytosis.

The cause is unknown, but is probably multifactorial. An mutation of the oncogene c-kit D816V is found in many (but not all) cases.⁵

This is a rare and heterogeneous group of disorders, of which urticaria pigmentosa is the commonest manifestation. It affects under 1 in 1000 patients attending dermatology clinics. Estimated incidence is 1 in 150,000.

Cutaneous mastocytosis

Urticaria pigmentosa:⁴

• The rash comprises light brown, itchy, raised patches - on any part of the body.
• The lesions blister when rubbed (Darier's sign) and become red, swollen and itchy. This confirms the presence of mastocytosis.
• Rarely, anaphylactic reactions can occur after mechanical/thermal stimulation of skin lesions.
• Dermatographism may be found on unaffected skin.⁶
• Usually affects infants from a few months of age. The lesions can persist and gradually increase in number for several months or years.
• Symptoms gradually improve as the child gets older, and the condition usually disappears by puberty.
  The younger the patient and the smaller the number of the lesions the higher the probability of spontaneous remission. An adult onset increases the risk of systemic involvement and persistence.

Diffuse cutaneous mastocytosis:

• Usually occurs in the first year of life.
• The rash is very itchy, with generalised yellowish, thickened skin.
• Blisters are large, sometimes haemorrhagic, and occur spontaneously or following mild trauma.
• With more extensive skin involvement, systemic symptoms are more likely. These include flushing, headache, palpitations, abdominal pain, diarrhoea, dyspnoea, wheezing, syncope, hypotensive shock and death.
• Early onset of blisters worsens the prognosis.

Mastocytoma of skin:

• This is a macular, papular or nodular lesion of yellow, brown or reddish colour.

Systemic mastocytosis^5,7,8

Patients may present with "inexplicable" symptoms related to mast cell mediator release, such as vascular instability, anaphylactic shock, flushing, diarrhoea and headache (sometimes without skin lesions).

There is a wide range of symptoms (below), and also variety of triggers (see box). The condition may be unmasked by an anaphylactoid response to a stinging insect.⁹

Possible symptoms and signs of systemic mastocytosis are:

• Skin:
  • Facial flushing (may be pruritic or burning)⁷
  • Urticaria pigmentosa (as above)
• Gastro-intestinal:⁷
  • Abdominal pain
  • Diarrhoea or steatorrhea (due to malabsorption or altered motility)
  • Nausea and vomiting
  • Hyperacidity, dyspepsia and peptic ulcers
  • Hepatomegaly and splenomegaly
• Cardiovascular:
  • Syncope, hypotension or anaphylactic shock
• Haematological and bones:
  • Anaemia or other cytopenias (if bone marrow involvement)
  • Hypersplenism
  • Fractures (if bone marrow involved)
  • Rarely, a bleeding disorder due to heparin-like anticoagulant (case report)⁸
• Respiratory:
  • Bronchospasm
  • Nasal congestion and upper pharyngeal symptoms are also reported^7,10
• Neurological:²
  • Headaches
  • Peripheral neuropathy

Localised mastocytosis⁵

• Mastocytoma is a benign tumour with uniform growth.
• Mast cell sarcoma is a locally destructive tumour.

• Skin biopsy (with analysis of c-kit D816V)
• Blood tests:
  • Full blood count, clotting, renal and liver function
  • Serum tryptase - almost all patients with systemic mastocytosis have serum tryptase >20ng/mL⁸
• Urinary histamine levels or 1,4-methylimidazole acetic acid may be elevated⁴
• If suspected systemic involvement (including most adults with suspected mast cell disorders), then complete staging is needed. This includes:²
  • Chest x-ray (or chest CT scan) for lymphadenopathy
  • Gastrointestinal investigations, e.g. endoscopy and ultrasound of abdomen
  • Bone density scan and skeletal x-rays
  • Bone marrow biopsy/aspirate

There is a suggested diagnostic protocol.¹

The diagnostic criteria are:²

• Major criteria:
  • Biopsy finding of multiple dense accumulations of mast cells in bone marrow or in other non-skin tissue.
• Minor criteria:
  • In bone marrow biopsy, more than 25% of the mast cells are spindle-shaped; or in bone marrow smears, more than 25% of the mast cells are atypical mast cells.
  • Detection of a point mutation at codon 816 in the kit receptor gene. This may be found in bone marrow or blood or other internal organs.
  • Mast cells in bone marrow, blood, or other internal organs are found to have on their surface the kit receptor plus CD2 and/or CD25.
  • Serum total tryptase level persistently greater than 20 ng/ml. This criterion cannot be used if the patient has a clonal non-mast cell associated haematological disorder.
• The diagnosis of systemic mastocytosis may be made if one major and one minor criterion are present, or if three minor criteria are fulfilled.

• Other pruritic rashes, e.g. other forms of urticaria
• Other causes of flushing:¹¹
  • Carcinoid syndrome
  • Pheochromocytoma
  • Other causes of anaphylaxis
  • Rarely, medullary carcinoma of the thyroid, pancreatic cell tumour, renal carcinoma
• Other causes of abdominal pain, peptic ulceration or liver disease, e.g.
  • Inflammatory bowel disease
  • Irritable bowel syndrome
  • Malabsorption syndromes
  • Zollinger-Ellison syndrome
  • Other types of hepatitis or cirrhosis
• Other haematological or myeloproliferative disorders

This is concerned mainly with symptom control, as there is currently no cure. Systemic mastocytosis is usually managed by haematologists.

For acute anaphylaxis:

• Those prone to acute severe symptoms should avoid trigger factors where possible, wear a medical alert bracelet and carry written treatment protocols from their specialist.
• Acute anaphylaxis is treated with epinephrine (adrenaline), antihistamines (H1 and H2 receptor blockers)¹², fluids and pressor agents.¹⁰
• Patients with recurrent anaphylactoid reactions should carry injectable epinephrine in pen format for emergency use.²
• Consider immunotherapy against insect venom.

For skin and vascular symptoms:

• For pruritus, weals and flushing - H1 and H2 receptor antagonists such as chlorphenamine, ketotifen and cimetidine.⁶
• Mast cell stabilizers - these are sodium cromoglicate, nedocromil and ketotifen.²
• Local corticosteroids for skin lesions. Intralesional steroid injection is sometimes used.⁶
• Psoralen-ultraviolet A (PUVA) - gives temporary benefit for skin lesions.

For bronchospasm:

• Inhaled bronchodilators e.g. salbutamol.

For gastro-intestinal symptoms:

• H2-receptor antagonists or proton pump inhibitors for peptic ulceration.
• Oral sodium cromoglicate for diarrhoea and abdominal pain.⁶
• Anticholinergics for diarrhoea.

Other possible systemic treatments:

• Leukotriene inhibitors have been used in the treatment of systemic mastocytosis.¹²
• Systemic corticosteroids they may be helpful for malabsorption, ascites, bone pain, to prevent anaphylaxis¹² and for severe skin disease.¹⁰
• Low-dose aspirin may be helpful for symptoms resistant to H1 and H2 antagonists alone, but must be started cautiously under supervision:^4,6
  • The patient, premedicated with H1 and H2 antihistamines, may take small doses of aspirin, titrated slowly to reach a plasma level of 20-30 mg/100 mL.
  • Treatment should be started in a controlled environment, because aspirin can induce mast cell mediator release and subsequent cardiovascular collapse.

Bone pain:

• Oral sodium cromoglicate may help.⁶
• Osteoporosis prevention/treatment - calcium, vitamin D, and bisphosphonates.³

Drugs to avoid:¹²

• Beta-blockers are contraindicated in patients with systemic mastocytosis undergoing surgery - these drugs may counteract endogenous epinephrine and may precipitate anaphylaxis.
• Avoid alpha-blockers and cholinergic antagonists.

For aggressive disease:³

• Splenectomy may be helpful for patients with significant hypersplenism or portal hypertension (it may reduce the mast cell burden and improve cytopenias).
• Aggressive systemic forms of mastocytosis may be treated with interferon-α, with or without corticosteroids, or cladribine. In some cases, more intensive treatments such as imatinib, or drug combinations, may be considered.¹
• Bone marrow transplantation may be considered in some extreme cases but is currently experimental treatment.³
• For patients with MC sarcoma, surgical excision with consecutive radiation and/or high-dose chemotherapy.

Children:
A protocol for management in children is available.¹³

Cutaneous mastocytosis:

• Childhood cases of urticaria pigmentosa and mastocytoma often resolve spontaneously. Adults are more likely to develop the systemic form of the disease.

Systemic mastocytosis:

• Has no known cure and tends to be progressive.
• Prognosis depends on the degree of haematological and organ involvement, as the classification(above) suggests.
  • Indolent systemic mastocytosis has a relatively good prognosis - decades of life, using mainly symptomatic treatment, although life-threatening problems can occur.
  • In SM-AHNMD, the prognosis depends on the course of the associated haematological disorder.
  • Agressive systemic mastocytosis and mast cell leukaemia have a poorer prognosis.

Localised mastocytosis:⁵

• Mastocytoma is a benign tumour with a good prognosis.
• Mast cell sarcoma is locally destructive and usually has poor prognosis.