a) Definition and types
Systemic mastocytosis (SM) results from clonal proliferation of abnormal, aberrant mast cells in various organs and tissues, with or without skin involvement [36,46]. It is characterised by symptoms that originate from mast cell-associated organ dysfunction or overactivity and thus an excessive release of numerous cellular mediators.
The disease is notable for the large number and hyperactivation of mast cells. This may lead to a highly variable disease phenotype . An acute release of mast cell mediators causing anaphylaxis is a sudden and life-threatening manifestation of the disease, especially during anaesthesia. Furthermore, SM leads to organ infiltration and acute and chronic release of mast cell mediators, which is occasionally a related clinical manifestation .
Since 2016, SM is no longer considered a subgroup of myeloproliferative neoplasms but constitutes a separate category according to WHO classification, which distinguishes five subtypes of SM: indolent SM (ISM), smoldering SM (SSM), aggressive SM (ASM), SM with an associated haematological neoplasm (SM-AHN), and the mast cell leukaemia (MCL). ASM, SM-AHN and MCL are summarised as advanced SM. A disposition to allergic reactions is more frequently observed in patients with indolent subtypes compared to advanced SM, which underlines the significance of a correct initial diagnosis and classification. For detailed information referring to each subtype, we recommend checking the specific literature [1,33,39].
Beside the systemic form, the cutaneous form or cutaneous mastocytosis (CM) is limited to the skin and constitutes the most frequent type (90 %) of mastocytosis.
The origin of symptoms in SM result from overactivation of mast cells and consecutive ex-cessive release of histamine, heparin, tryptase, acid hydrolases, leukotrienes, prostaglandins, platelet activating factor, interleukins and tumour necrosis factor . In ISM, symptoms usually originate from the release of mast cell mediators, e.g. flush, allergic and anaphylactic reactions, while clinical features in advanced SM are more the consequence of mast cell infiltration with consecutive organ dysfunction, e.g. cytopenia, abnormal liver function, spleno-megaly, malabsorption, rather than mast cell mediator release itself.
In the aetiology of SM, most patients show activating, gain-of-function mutations in a trans-membrane tyrosine kinase receptor for stem-cell factor (KIT) in their neoplastic mast cells. More than 80 % show a KIT D816V mutation, which stimulates uncontrolled mast cell prolife-ration and migration as well as their immortality. Additional, somatic mutations especially in advanced SM may have prognostic relevance .
The following list shows some of peri-operative triggers, which may be relevant for the anaesthesia team:
Psychological factors: psychological or emotional stress, anxiety, sleep deprivation ,
Temperature changes: hypo- or hyperthermia ,
Mechanical factors: mechanical irritation, skin stimuli, tourniquet use, trauma, surgery itself (e.g. located in gastrointestinal tract due to a rich source of mast cells) [14,17],
Pharmacological factors: histamine-releasing benzylisoquinolines (e.g. atracurium, mivacurium) and nefopam are not recommended, furthermore rapid intravenous administration of histamine-releasing medication should be avoided whenever possible ,
Other: pain, infections .
Mast cell activation may also occur spontaneously without an obvious trigger. Patients should also be provided with an emergency kit for self-administration containing an epinephrine pen to be used in case of anaphylaxis and awareness of disease exacerbation at any time [14,39].
d) Epidemiology (prevalence, age and sex distribution, inheritance pattern)
There are no precise data on the incidence or prevalence of SM. Due to the difficulty in recognising this disorder and its rarity, the incidence and prevalence of SM are likely to be underestimated. The incidence of advanced SM is significantly lower than that of ISM.
Depending on regions and population, the prevalence is estimated between 13:100,000 and 1:364,000 whereas its worldwide incidence is estimated to be 1:150,000. The prevalence in Europe is estimated to range between 1:7,700 and 1:10,400 . Regarding Germany with 82 million inhabitants, a prevalence of at least 380 advanced SM cases is estimated [9,13,15,16,20, 34,40,45,46].
SM preferentially affects Caucasians . The gender distribution is approximately equal .
In children, 80 % of mastocytosis cases appear during the first year of life, and the majority is limited to the skin. Symptoms improve or resolve usually completely by adolescence. However, adults who develop mastocytosis more often have systemic forms of the disease, in which the individual disorders tend to persist. Less than 5 % of adult cases are limited to the skin only. But (mostly as urticaria pigmentosa) the skin of 80 % of the patients is chronically affected with ISM, the most frequent form in adulthood .
e) Clinical signs and symptoms
The clinical spectrum of SM is heterogeneous and ranges from a mild course with almost normal life expectancy in ISM to life-threatening organ involvement with a poor prognosis in advanced SM. Various organs may be involved and the degree and magnitude of affection of different organs may vary in each individual patient up to multiorgan dysfunction, shortened survival and death in advanced SM [36,48]. The table below gives an overview of the organs potentially affected and summarises the corresponding clinical symptoms [9,25,28,36,39,41,45]:
Skin: pruritus, flushing, hives, angioedema
Gastrointestinal: nausea, bloating, hyperacidity, vomiting, diarrhea, abdominal cramps, epigastric discomfort, gastroduodenal ulcer disease, ascites, hypersplenism, hepatomegaly, malabsorption or protein- losing enteropathy, weight loss
Cardiovascular: collapse, syncope, dizziness, palpitations, heartburn
Respiratory: dyspnea, wheezing, bronchospasm, infants: apneic spells and cyanosis
Central nervous system: memory or cognitive difficulties, depression, headache, sleep disturbance, anxiety, mood changes; children: aggressive behavior
Musculoskeletal: general constitution, generalised weakness, fatigue, arthralgias, myalgias, osteopenia, osteoporosis, back pain, bone pain
Immune system: lymphadenopathy, splenomegaly, episodic anaphylactoid attacks)
Further symptoms: sweats, chills, rhinorrhea
Diagnosis of SM needs at least fulfilment of one major and one minor criterion or more than three minor criteria. Major criterion means microscopic detection of multifocal, dense infiltrates of mast cells (≥15 mast cells in aggregates) in the bone marrow and/or other extracutaneous tissues. There are four supplementary minor criteria: a) >25 % of the mast cells (in biopsy of bone marrow or other extracutaneous organs) in the infiltrate are spindle-shaped or have atypical morphology, or (of all mast cells in bone marrow aspirate smears) >25 % are immature or atypical, b) detection of an activating point mutation at codon 816 of KIT in the bone marrow, blood or other extracutaneous organ, c) mast cells in bone marrow, blood or other extracutaneous organ express CD25 with/without CD2 in addition to normal mast cell markers, d) serum total tryptase persistently exceeds 20 ng/mL (unless there is an associated myeloid neoplasm, in which case this parameter is not valid) .
Up to now, SM is not curable. Treatment of SM is highly individualised and varies (especially in indolent subtypes) between observation and continued monitoring alone (for abnormal blood counts, end organ damage and disease progression) to symptom management (e.g. pruritus, diarrhea, vomiting), supportive measures (e.g. transfusion or osteoporosis treatment) to cytoreductive therapy (e.g. cladribine, hydroxyurea) for mast cell debulking in cases of advanced or treatment-refractory disease [36,39]. Advanced SM might be treated with tyrosine-kinase inhibitors (e.g. midostaurine, avapritinib). Allogenic stem-cell transplantation should be considered in eligible patients with aggressive disease or MCL [36,39].
All SM patients and their medical staff should be aware of potential triggers of an SM exacerbation at any time and find strategies to avoid excessive mast cell activation in situations that may have caused release syndrome in the past . Acute treatment of degranulation is recommended according to current guidelines for the treatment of anaphylaxis .
The prognosis of SM varies in each individual patient depending on the degree of systemic affection and organ failure. Usually, the median survival ranges between a few months and several years from the date of diagnosis in aggressive forms. The MCL carries the highest mortality of all subtypes. Moreover, life expectation may be even normal in indolent forms of SM [31,35,39]. Scoring systems are used for a better assessment of the patient’s prognosis [24,35].