Mast Cell Disorders

Synonyms: Mastocytoma, urticaria pigmentosa (UP), telangiectasia macularis eruptiva perstans (TMEP)=paucicellular mastocytosis, diffuse erythrodermic mastocytosis, systemic mastocytosis, systemic mast cell disease (SMCD).

This condition is due to an excessive proliferation and retention of reactive mast cells, most commonly in the skin, but also in other tissues and organs. The mast cells are stimulated to release chemical mediators such as histamine, interleukins and prostaglandins in response to mechanical stimulation, changes in ambient temperature or in response to medication. Most patients have some dermatological evidence of the disease, particularly urticaria pigmentosa, but systemic symptoms and signs can predominate or exist in isolation.¹ The various disease classifications are outlined below:

It may reflect a hyperplastic response to an unidentified antigenic stimulus, or be a paraneoplastic condition due to proliferation of a clone of mast cells outwith normal cell regulation. Failure of genetic mechanisms involved in mast cell apoptosis (programmed cell death), or up-regulation of mast cell oncogenes such as c-kit² are putative mechanisms for mast cell proliferation and accumulation. Interleukin-6 levels are elevated in sufferers and correlate to disease activity, possibly indicating that dysregulation of IL-6 activity is important in susceptibility to the condition.³

This is a rare and heterogeneous group of disorders, of which urticaria pigmentosa is the commonest manifestation. It affects <1% of attendees at dermatology clinics but there are no good population-based figures.³ Systemic mastocytosis appears to be incredibly rare with surveys finding approximately 2 cases per 300,000 population.⁴

Cutaneous mastocytosis

• About 80% of sufferers first have symptoms during childhood.⁵
• 80% have classical urticaria pigmentosa or a maculopapular rash of cutaneous mastocytosis⁵ – widely distributed pruritic, light-brown, slightly raised lesions that vary in number from a few to >100.
• Lesion may become swollen and inflamed on stroking/rubbing due to mast-cell degranulation (Darier's sign).
• Dermatographism is found in a significant proportion of patients after stroking 'unaffected' skin.³
• Urticaria in response to physical stimuli such as heat cold or pressure strongly suggests the diagnosis.
• Pigmentation is due to effect of mast cell products on neighbouring melanocytes causing melanin deposition.
• Around 20% of cases present as solitary mastocytoma⁵ – usually single, large, yellow-light brown lesion demonstrating Darier's sign; may become blistered.
• TMEP – numerous freckle-like lesions seen mainly on the trunk with fine telangiectasia in older lesions; Darier's sign often negative due to low number of mast cells in lesions.
• Diffuse cutaneous mastocytosis – can present in erythrodermic form with intense skin reddening or with 'doughiness'/leathery character of widespread areas of skin, possibly with blistering; tends to affect groin and axillae.

Systemic mastocytosis

Can cause a wide range of symptoms, depending on affected organs/tissues and varying pathophysiological effect of mast cell mediators on the individual. The symptoms may be precipitated by exposure to certain drugs such as penicillin, recreational narcotics such as cocaine, aspirin, NSAIDs and dipyridamole. The condition may be unmasked by an anaphylactoid response to a stinging insect.⁶ Such agents are reported to cause anaphylactoid reactions and shock in some patients with systemic mastocytosis.⁴ The following can be presenting features:

• Symptoms of anaemia such as tiredness and pallor due to bone marrow infiltration
• Sudden flushing following exposure to heat or cold
• Headache
• Nausea and vomiting
• Diarrhoea
• Shortness of breath or wheeziness
• Fainting
• Rhinorrhea
• Syncope
• Angina
• Bone pain
• Neuropsychiatric disturbance

Signs that can be detected in the systemic form of the disease include:

• Anaemic pallor and pale mucous membranes
• Hepatomegaly
• Splenomegaly
• Signs of portal hypertension
• Lymphadenopathy
• Hypotension and tachycardia due to cardiovascular effects of mast cell products

Skin lesions may have a similar history/appearance to:

• Prurigo nodularis
• Other causes of urticaria
• Macular or nodular localised amyloidosis
• Epidermolysis bullosa
• Herpes simplex infection
• Generalised eruptive histiocytoma
• Histiocytosis X
• Xanthogranluomata
• Secondary syphilis

Systemic mastocytosis may present similarly to:

• Carcinoid syndrome
• Zollinger-Ellison syndrome
• VIP-secreting tumour (VIPoma)
• Inflammatory bowel disease
• Irritable bowel syndrome
• Myeloproliferative disorder
• Malabsorption syndromes

• Skin biopsy may be needed to confirm the nature of any skin lesions and demonstrate the presence of mast cells.
• FBC – possible evidence of marrow involvement causing anaemia, thrombocytopenia, thrombocythaemia, leukocytosis or eosinophilia.
• 24-hour urinary histamine excretion may be elevated at 2–3 times baseline levels – can also be elevated in hypereosinophilic syndromes (N-methylhistamine and N-methylimidazoleacetic acid levels are more specific to mast cell proliferation and correlate with disease severity).
• Serum tryptase levels (a mast cell product) are usually elevated.
• Specialist labs may measure urinary prostaglandin D2 metabolites which are elevated in the vast majority of cases.
• Bone scan and skeletal survey are carried out in those with evidence of haematological involvement.
• Gastrointestinal investigations such as endoscopy and abdominal ultrasound may form part of initial investigation of systemic complaints.
• Serum gastrin levels, urinary catecholamine studies and VIP levels may be needed to exclude the major differential diagnoses of systemic mastocytosis.
• Bone marrow aspiration and biopsy are necessary in cases of systemic mastocytosis

Systemic mastocytosis has reportedly been associated with:

• Hypereosinophilia
• Hairy cell leukaemia
• Non-Hodgkin's lymphoma
• Polycythaemia rubra vera
• Monoclonal gammopathy

Systemic mastocytosis may progress to become mast cell leukaemia/sarcoma.

This is concerned mainly with symptom control as no curative therapies currently exist. Most patients with the condition have a benign outlook and respond well to treatments. Patients should avoid precipitants that promote mast cell degranulation such as aspirin, NSAIDs, opioids, alcohol, thiamine, quinine, gallamine, procaine, some radiographic dyes, dextran, polymyxin B, scopolamine and tubocurarine.³ Care should be taken to reduce the risk of insect stings or other envenomations.

Drugs

• Patients who suffer acute anaphylaxis should be treated with subcutaneous adrenaline and H1/H2 receptor antagonists; those who suffer recurrent anaphylactoid reactions should carry injectable adrenalin in pen format for emergency use.
• H1- and H2- receptor antagonists such as chlorpheniramine and cimetidine are effective at treating flushing, pruritus and wheal formation.
• Similarly, sodium cromoglycate may ameliorate cutaneous symptoms and some systemic manifestations (particularly those affecting the GI tract) by reducing the likelihood of mast cell degranulation.
• Aspirin may be used cautiously in some patients who do not respond to H1 and H2 receptor blockade, as it is an inhibitor of prostaglandin synthesis. However, because it can trigger mast cell mediator release, it should be given in a supervised setting initially and the dose titrated slowly upwards under specialist supervision with plasma level monitoring.³
• Local corticosteroids under occlusion or intralesional steroids may be used to treat troublesome skin lesions, but must be carefully supervised due to the risk of skin atrophy.
• Systemic corticosteroids have been used successfully to control malabsorption, ascites, bone pain and to prevent anaphylaxis in case of systemic mastocytosis.⁴
• H2-receptor antagonists and proton pump inhibitors are used to treat peptic ulcer disease associated with systemic mastocytosis.
• Psoralen-ultraviolet A (PUVA) therapy may be used to treat skin lesions to provide relief from pruritus and provide cosmetic benefit, particularly in the TMEP form of the disease.
• Aggressive systemic forms of mastocytosis may be treated with interferon-A, imatinab mesylate⁷ and cladribine (2-Chlorodeoxyadenosine) in resistant cases.⁸
• Allogeneic bone marrow transplantation may be considered in some extreme case but is currently an experimental therapy.⁴

• Anaphylaxis in response to drug ingestion, changes in ambient temperature or insect stings
• Hypotension and cardiovascular collapse in response to mast cell mediator release
• Mast cell leukaemia/sarcoma

• Childhood cases of UP and mastocytoma often resolve spontaneously whilst adults are more likely to develop the systemic form of the disease.
• Less than 10% of juvenile-onset cases will undergo malignant transformation, compared to about 30% of adult-onset systemic forms of the disease.
• Most cases of systemic disease are indolent but an aggressive, severe form does exist.
• Systemic mastocytosis has no known cure and tends to be progressive.