Mastocytosis and mast cell disorders

¹Synonym: systemic mast cell disease

What is mastocytosis?

Mastocytosis is a rare disease characterised by a substantial increase and accumulation of clonal mast cells (MCs) in the skin only (cutaneous mastocytosis) or in various extracutaneous organs (systemic mastocytosis [SM]) with or without skin involvement.²

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 tract, bone marrow, liver, spleen, and lymph nodes.

The clinical features of systemic mastocytosis are caused by accumulation of clonally derived mast cells in different tissues, including bone marrow, skin, gastrointestinal tract, liver and spleen. Systemic mastocytosis is now classified as a myeloproliferative neoplasm.

Mastocytosis

Mastocytosis is divided into 2 main types:¹

• Cutaneous mastocytosis - usually affects children:

  • Urticaria pigmentosa (now known as maculopapular cutaneous mastocytosis) - the most common type.

  • Diffuse cutaneous mastocytosis (very rare).

  • Isolated mastocytoma of skin.

• Systemic mastocytosis - usually affects adults:

  • Indolent systemic mastocytosis.

  • Systemic mastocytosis with associated haematological non-mast cell lineage disease (SM-AHNMD).

  • Aggressive systemic mastocytosis.

  • Mast cell leukaemia (very rare).

Systemic mastocytosis (SM) can be categorised into 2 main clinical groups - nonadvanced SM (nonAdvSM) and advanced SM (AdvSM):

• NonAdvSM includes indolent SM (ISM), bone marrow mastocytosis (BMM), and smoldering SM (SSM).

• AdvSM includes SM with an associated haematological neoplasm (SM-AHN), aggressive SM (ASM), and MC leukaemia (MCL).

Mast cell activation syndrome (MCAS)³

• MCAS - synonym: mast cell activation disorder (MCAD) - is characterised by the accumulation of genetically altered mast cells and/or abnormal release of mast cell mediators, affecting functions in potentially every organ system, particularly the skin, the gastrointestinal tract and the cardiovascular and nervous systems.

• Patients experience many of the same symptoms as with mastocytosis. Chronic MCAS can be difficult to diagnose, especially when symptoms are mild or atypical.

• The use of antihistamines and mast cell membrane-stabilising drugs with symptomatic treatment is often effective.

The classification of MCAS is a gradually evolving process, with additions and amendments occurring on a regular basis as more becomes known about the condition. Current classification systems rely on the following criteria:

• Recurrent or chronic symptoms of mast cell activation.

• Laboratory results showing evidence of mast cell activation (eg, a transient rise in serum tryptase or urinary N-methyl histamine, or the histamine metabolites prostaglandin D2 and prostaglandin F2-alpha).

• Response of clinical symptoms to anti-mediator therapy.

• Histopathological changes.

The debate continues concerning various aspects of diagnosis, notably the cut-off levels of laboratory results. Every classification amendment has had its critics with regard to over- or under-diagnosis.⁴⁵

Mastocytosis is a rare disorder with an estimated prevalence of 1-3 in 10,000 persons.⁶ 95% of the systemic form occurs in adults and it affects men and women equally.⁷

90% of the cutaneous form occurs in children.⁸

Mast cell production is under the regulation of a gene named KIT, which encodes CD117 transmembrane tyrosine kinase. CD117 helps in the growth, survival as well as the migration of mast cells. Once the progenitors get produced, they migrate to various tissue and acquire different phenotypes specific to the tissues. Activating and inactivating mutations of KIT are implicated in the pathogenesis of systemic mastocytosis.

Cutaneous mastocytosis symptoms⁹

Urticaria pigmentosa

• 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.

• It 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; 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

• This usually occurs in the first year of life.

• The rash is very itchy, with generalised yellowish, thickened skin.

• Blisters are large and sometimes haemorrhagic; they 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 symptoms ¹⁰

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 and a variety of triggers (see box, above). The condition may be unmasked by an anaphylactoid response to a stinging insect.

Possible symptoms and signs of systemic mastocytosis are:

• Skin:

  • Facial flushing (may be pruritic or burning).

  • Urticaria pigmentosa (as above).

• Gastrointestinal:

  • Abdominal pain.

  • Diarrhoea or steatorrhoea (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.

  • Lymphadenopathy.

  • Fractures (if bone marrow involved).

  • Rarely, a bleeding disorder due to heparin-like anticoagulant (case report).

• Respiratory:

  • Bronchospasm.

  • Nasal congestion and upper pharyngeal symptoms are also reported.

• Neurological:

  • Headaches.

  • Peripheral neuropathy.

• Skin biopsy (with analysis of KIT mutations).

• Blood tests:

  • FBC (anaemia, thrombocytopenia and leukocytosis), clotting studies, renal function tests and LFTs.

  • Serum tryptase - almost all patients with systemic mastocytosis have serum tryptase >20 ng/mL.

• Urinary histamine metabolite levels (eg, 11β-prostaglandinF2α or N-methyl histamine) may be elevated.

• If there is suspected systemic involvement (including most adults with suspected mast cell disorders) then complete staging is needed. This includes:

  • CXR (or chest CT scan) for lymphadenopathy.

  • Gastrointestinal investigations - eg, endoscopy and ultrasound of abdomen.

  • Bone density scan and skeletal X-rays.

  • Bone marrow biopsy/aspirate.

• Other tests include:

  • Chromosomal analysis: 20% of patients with systemic mastocytosis have an abnormal karyotype.

  • Molecular testing for KIT D816V mutation is always positive but JAK2 V617F is rarely positive.

  • The mast cell clone is CD-117 positive and CD-25 and/or CD-2 positive. Expression of CD-25 on mast cells is seen in systemic mastocytosis but not in reactive states of mast cell hyperplasia.

There is a suggested diagnostic protocol. The diagnostic criteria are:⁷

• Major criteria:

  • Biopsy finding of multiple dense accumulations of mast cells (greater than 15% of mast cells in clusters) in bone marrow or in other non-skin tissue.

• Minor criteria:

  • 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.

  • Abnormal mast cell CD25 expression.

  • Serum total tryptase level persistently greater than 20 ng/mL.

  • Presence of KITD 816V mutation.

  • Presence of greater than 25% atypical mast cells.

• 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 - eg, other forms of urticaria.

• Other causes of flushing:

  • Carcinoid syndrome.

  • Phaeochromocytoma.

  • Other causes of anaphylaxis.

  • Rarely, medullary carcinoma of the thyroid, pancreatic cell tumour, renal cancer.

• Other causes of abdominal pain, peptic ulceration or liver disease, including:

  • Inflammatory bowel disease.

  • Irritable bowel syndrome.

  • Malabsorption syndromes.

  • Zollinger-Ellison syndrome.

  • Other types of hepatitis or cirrhosis.

• Other haematological or myeloproliferative disorders.

The treatment of non-advanced SM focuses primarily on the prevention and treatment of anaphylactic reactions and symptom relief using histamine receptor blockers and MC-stabilising agents. Systemic mastocytosis is usually managed by haematologists.

The treatment of advanced SM involves various factors, such as managing symptoms and minimising organ damage. Addressing MC release-related symptoms in advanced SM follows a similar approach to that of patients with other types, however, advanced subtypes are characterised by MC infiltration in organs, requiring the use of TKIs and/or cytoreductive agents to control/decrease MC burden.

Acute anaphylaxis treatment

• Those prone to acute severe symptoms should avoid trigger factors where possible, wear a medical emergency identification bracelet or similar and carry written treatment protocols from their specialist.

• Acute anaphylaxis is treated with intramuscular adrenaline (epinephrine), antihistamines (H₁ and H₂ receptor blockers), fluids and pressor agents.

• Patients with recurrent anaphylactoid reactions should carry injectable adrenaline (epinephrine) in pen format for emergency use.

• Consider immunotherapy against insect venom.

Skin and vascular treatment

• For pruritus, weals and flushing - H₁ and H₂ receptor antagonists such as chlorphenamine, ketotifen and cimetidine.

• There is some evidence that long-term use of antihistamines can affect cognition, so these drugs should be titrated to the lowest effective dose and used for the shortest possible time.

• Mast cell stabilisers - sodium cromoglicate, nedocromil and ketotifen.

• Local corticosteroids for skin lesions. Intralesional steroid injection is sometimes used.

• Psoralen in combination with ultraviolet A (PUVA) treatment - gives temporary benefit for skin lesions.

Bronchospasm treatment

Inhaled bronchodilators - eg, salbutamol.

Gastrointestinal treatment

• H₂ receptor antagonists or proton pump inhibitors for peptic ulceration.

• Oral sodium cromoglicate for diarrhoea and abdominal pain. .

• Anticholinergics for diarrhoea.

Other possible systemic treatments

• Leukotriene inhibitors have been used in the treatment of systemic mastocytosis.

• Systemic corticosteroids may be helpful for malabsorption, ascites and bone pain, to prevent anaphylaxis and for severe skin disease.

• Low-dose aspirin may be helpful for symptoms resistant to H₁ and H₂ antagonists alone but must be started cautiously under supervision.

Bone pain treatment

• Oral sodium cromoglicate may help.

• Osteoporosis prevention/treatment - calcium, vitamin D, and bisphosphonates.

Drugs to avoid¹²

• Beta-blockers are contra-indicated in patients with systemic mastocytosis undergoing surgery - these drugs may counteract endogenous adrenaline (epinephrine) and may precipitate anaphylaxis.

• Avoid alpha-blockers and cholinergic antagonists.

Aggressive disease

• 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 alfa, pegylated interferon alpha, corticosteroids, or cladribine. In some cases, more intensive treatments such as imatinib, or drug combinations, may be considered.

• The National Institute for Health and Care Excellence (NICE) recommends midostaurin monotherapy as an option for treating aggressive systemic mastocytosis, systemic mastocytosis with associated haematological neoplasm, or mast cell leukaemia in adults.¹³

• Bone marrow transplantation may be considered in some extreme cases. Haematopoietic stem cell transplant is being explored.

Guidelines for management in children are available.¹⁴

Osteopathy is a major complication in SM, with patients variably suffering from osteopaenia, osteoporosis, and/or osteolysis.¹ Whereas osteopaenia and osteoporosis develop quite frequently in the context of SM, osteolyses are rarely found. In addition, osteosclerosis may be diagnosed in SM. The most relevant and frequent bone pathology is osteoporosis, which may be severe and may lead to local bone fractures.

Additionally many other haematological conditions are associated with SM such as monoclonal gammopathy, hairy cell leukaemia , non-Hodgkin lymphoma, polycythaemia vera, primary thrombocythaemia, anaemia and hypereosinophilic syndrome.⁷

Cutaneous mastocytosis

About half to two thirds of children with CM have spontaneous resolution before adulthood and most others show a regression of skin lesions or a stable disease.¹⁵ This is paralleled by a decrease of increased baseline serum tryptase (BST) levels. Adults are more likely to develop the systemic form of the disease.

Systemic mastocytosis

• This 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 displaying significantly longer survival at a median of 24.3 years, although life-threatening problems can occur.¹⁶

  • Survival in Aggressive SM (median 5.8-6 years) is longer than that of SM‐AHN (associated haematological neoplasm) (median 2.3 years) and SM‐AMN (associated myeloid neoplasm) (median 2 years) (p < 0.01 in all instances). Overall survival is the shortest with ICC‐defined MCL (median 0.08 years) followed by WHO‐defined MCL (median 1.8 years), SM‐AHN (median 2.3 years), SM‐AMN (median 2 years), and ASM (median 5.8–6 years).¹⁶