How to Recognise Mastocytosis?

Mast cells develop from pluripotential cells in the bone marrow and populate tissues, including skin, by migration via the blood. Mastocytosis is characterised by clonal mast cell expansion. Accumulation of clonal mast cells leads to increased tissue burden and may result in clinical symptoms. Mastocytosis is usually suspected on the basis of persistent, pruritic skin lesions that urticate and confirmed by specialists. Patients presenting to allergists with anaphylaxis may have undiagnosed systemic mastocytosis, especially those without skin lesions who have bone marrow mastocytosis (BMM). An unwell adult may present directly with advanced haematological disease. Adults with low trauma fractures or vertebral collapse secondary to unexplained osteoporosis may have mastocytosis. Over 90% of adults have the common D816V mutation in exon 17 of KIT. Bone marrow is the richest source of mast cells, but PCR-assays with high sensitivity for detecting KIT mutations in blood, are now available in specialist clinical practice [1]. Other KIT mutations have been detected in skin of children [2] and blood in research studies although the implication of this on prognosis is unknown. Skin lesions are present in childhood mastocytosis and the majority of adults, but may be hard to recognise. Head to toe examination may be required to find localised maculopapular lesions. Adult patients presenting with anaphylaxis should undergo full skin examination, though the absence of skin lesions does not exclude mastocytosis, and have blood checked for tryptase as a biomarker of systemic mastocytosis (SM). The D816V KIT mutation should be looked for in blood, even with a normal tryptase, where the technology is available in hymenoptera venom-induced and idiopathic anaphylaxis. The WHO classification distinguishes subsets of cutaneous mastocytosis (CM) on clinical features and SM by bone marrow biopsy (or other extracutaneous tissue) (Table 1) [3]. Children presenting with skin lesions are assumed to have CM, even though some will have raised tryptase and many will have mutations in known hotspots of KIT (exons 8, 9, 17) on skin biopsy or in blood. Few adults have extensive maculopapular skin lesions with normal tryptase and no evidence of D816V KIT mutation. Others with confirmed SM may have no skin lesions (BMM). This blurring of boundaries is consistent with a concept of mastocytosis being a clinical spectrum due to mast cell clonality presenting in different patient populations with different clinical behaviours and possible co-morbidities. The term “mastocytosis in the skin” (MIS) is a useful terminology for patients with skin lesions, but no proof of systemic disease (without bone marrow biopsy). The term CM is usually understood to describe skin lesions with different subtypes defined by WHO without systemic disease, but MPCM and DCM may also present with systemic disease so the term CM should not be considered to exclude systemic involvement in children. In fact, an adult with MPCM will almost always have systemic involvement when fully investigated. Maculopapular cutaneous mastocytosis (MPCM) is the commonest presentation of mastocytosis in the skin. It is still widely known as urticaria pigmentosa (UP) since the lesions are usually, but not always, pigmented. They urticate rapidly after gentle rubbing and occasionally blister. Whealing of a lesion after minimal friction (Darier's sign) is almost 100% specific but not completely sensitive in children and less so in adults. Testing with a calibrated dermographometer (HTZ, East Grinstead, UK) at 20 and 36 g/mm2 is recommended when available, although in daily clinical practice, a wooden tongue spatula can be used. The response is reduced but not usually prevented by taking H1 antihistamines. It may be minimal in adult patients with long standing skin lesions. Polymorphic MPCM presenting with different sized macules, papules and plaques is primarily seen in children and may have a better prognosis for resolution than monomorphic MPCM [4]. The term ‘telangiectasia macularis eruptiva perstans’ (TMEP) has been used historically to describe persistent telangiectatic patches of CM in adults but is now merged with MPCM to reflect overlap with typical UP. Adult MPCM may be generalised but is often predominantly on the lower torso, buttocks and thighs with sparing of the face. It is associated with flushing, itching and localised swelling of visible lesions (and occasionally invisible marks that only show as hives after local mast cell activation, for instance with towelling after a shower). Mastocytomas are present at or shortly after birth. They are skin-coloured superficial nodules that are solitary or multiple (Table 1). Gentle friction will result in redness and swelling within the lesion that may progress to blistering and weeping. The urticarial reaction subsides over an hour or two. Loss of the blister roof results in superficial erosions that take a week or two to heal without scarring. The infant may become transiently flushed and distressed. Blistering recedes over two to three years as lesions regress. There is no adult counterpart. Diffuse cutaneous mastocytosis (DCM) starts early in life with generalised erythodermic or yellow-red (xanthelasmoid) thickened skin, which may be subtle or pronounced. The difference between DCM and extensive xanthelasmoid plaque-type UP may be subtle. Blistering with widespread erosions is common and may resemble staphylococcal impetigo or epidermolysis bullosa. The skin quality may remain subtly thickened in adult life but DCM is not primarily seen as an adult pattern of mastocytosis. Mastocytosis presenting with systemic features is more likely in adults with confirmed SM than children. The tryptase level or KIT D816V allele burden as an indicator of mast cell burden does not correlate well with clinical mediator related symptoms. Depression, fatigue and loss of concentration (‘brain fog’) may be reported by adults with and without skin lesions. Gastrointestinal tract symptoms include hyperacidity, bloating, pain and diarrhoea. Bone pain in adults may be due to fractures from osteoporosis, bone cysts or osteosclerosis of the spine and pelvis. Respiratory complaints are uncommon. Anaphylaxis is a serious complication of mastocytosis. Up to 50% of adults had grade I to IV anaphylaxis over the period of follow up [5]. Increased risk in children is only seen in those with extensive skin lesions or indolent systemic mastocytosis. Identifiable causes are primarily Hymenoptera stings and less commonly include, general anaesthesia, contrast media, drugs and foods, but anaphylaxis may remain unexplained after full evaluation. The REMA score using clinical criteria is useful to screen for underlying clonal mast cell disease in patients presenting with anaphylaxis but no skin lesions [6]. More severe reactions may occur when hereditary alpha tryptasaemia (HαT) is a co-morbidity. Diagnosis of mastocytosis in children is primarily clinical in combination with a positive Darier's sign. Lesional skin biopsy for mast cell enumeration is confirmatory. Criteria for making a pathological diagnosis of cutaneous lesions of mastocytosis have been published [7]. Finding KIT mutations in lesional skin biopsies is 100% specific and sensitive. Paired biopsies from adjacent normal appearing skin for comparative mast cell counts may be helpful when skin lesions are indistinct. All adults should be offered skin biopsy to confirm mastocytosis since the differential diagnosis includes inflammatory dyspigmentation and benign skin lesions [8]. Diagnostic criteria for skin and bone marrow biopsy are summarised in Table 2. Although baseline serum tryptase of 20 mcg/l is a minor criterion for diagnosing systemic mastocytosis, other reasons for persistent tryptasaemia include HαT. A correction factor for this is now applied when HαT is a co-morbidity of mastocytosis based on the copy number of TPSAB1 [9]. Tryptase is a useful measure of mast cell burden that can be followed longitudinally. Blood KIT D816V variant allele frequency (VAF) may also be useful to monitor disease progression. The morphology of skin lesions of mastocytosis varies and may overlap. Some patients present with very few lesions while others are widespread. Lesions in children often flatten with minimal discolouration as a prelude to clearing around puberty. MPCM often becomes more extensive after diagnosis in adults but also uncommonly can fade or resolve completely over decades. Clinicopathological correlation of skin biopsies is essential when mast cell numbers appear slightly increased in chronic inflammatory states, such as chronic spontaneous urticaria, and mast cell density varies by body region in normal skin. Increased baseline serum tryptase (BST) is often regarded as diagnostic for mastocytosis but is not specific because it may be a feature of HαT, renal failure or myeloproliferative neoplasms. A rise and fall within 6 h of an allergic event supports anaphylaxis. Mast cell activation syndrome (MCAS) is a term used for recurrent systemic mast cell activation, almost exclusively presenting with anaphylaxis. This may be allergic, idiopathic or associated with mastocytosis [10]. We firmly reject interpretations of chronic illness symptoms and unrelated co-morbidities. A different concept altogether is histamine intolerance secondary to reduced diamine oxidase with higher levels of dietary histamine leading to possible flushing, gastrointestinal symptoms and migraine. Recognition of mastocytosis is an important step for appropriate investigations on blood and tissue, including molecular genetics to confirm the diagnosis. Allergists have an important role in identifying patients presenting with anaphylaxis who were not aware of underlying mastocytosis and advising on how to manage risk in venom allergic patients, and those requiring medical interventions, including general anaesthesia. Adults with proven systemic disease require multidisciplinary follow up for recognised complications including loss of bone density and progression to advanced systemic disease (development of an associated haematological neoplasm or aggressive disease characterised by organ failure) and opportunities for clinical studies. C.G. wrote the first version and S.B.-O. and K.B. contributed to the writing of the final manuscript. The authors declare no conflicts of interest.