Systemic mastocytosis was first described in France in the 1930s (6). Its prevalence is uncertain (7), although a retrospective cohort study of adults diagnosed with systemic mastocytosis in Denmark showed an annual incidence of 0.89 per 100 000 (8). Patient registries are now being established to obtain accurate data on incidence and prevalence (9).
An interdisciplinary approach is often necessary to achieve a correct diagnosis in patients with complex clinical pictures, such as the current patient. The signs and symptoms of mastocytosis result from a combination of mast cell activation with release of mast cell mediators, and mast cell infiltration of organs. The diagnosis is confirmed by biopsy and genetic analysis of the KIT mutation. Tryptase, an enzyme found in mast cell granules, can also provide diagnostic information and can be used in follow-up, as increasing tryptase levels are associated with a greater mast cell burden and disease progression (10).
There are three variants of mastocytosis: mast cell sarcoma, cutaneous mastocytosis and systemic mastocytosis (9). Mast cell sarcoma is a very rare and malignant form of solid tumour with the capacity for destructive infiltration and metastasis. In cutaneous mastocytosis, the pathological mast cells are restricted to the skin and give rise to various types of rash, the most common being the maculopapular rash urticaria pigmentosa (9). When the disease is identified in another organ besides the skin, it is defined as systemic if the criteria in figure 3 are fulfilled (11). Our patient fulfilled the major criterion and three minor criteria. Bone marrow is the most commonly affected site (6), but mast cell infiltration can also occur in the liver, spleen, gastrointestinal tract, skeleton and other organ systems. The prevalence in these different organs is unknown (9). Our patient had no signs of skeletal involvement on CT. His initial back pain was probably unrelated to the mastocytosis.
Mastocytosis is thought to originate from mutated haematopoietic stem cells (12). Studies have shown that >90 % of patients have an activating mutation in the KIT gene, of whom >80 % have a specific point mutation in exon 17, KITD816 V (13, 14). KIT is a transmembrane receptor tyrosine kinase for stem cell factor CD117 (6, 13). Mutation of KIT results in ligand-independent constitutive activation and autophosphorylation of tyrosine kinase (15) and stimulates proliferation and survival of mast cells (16).
Systemic mastocytosis was formerly classified as a myeloproliferative neoplasm (17). In accordance with the WHO classification from 2016, the condition is now considered a separate disease entity owing to unique clinical and pathological features and a highly variable disease course (18). Indolent systemic mastocytosis has a good prognosis with almost normal life expectancy (9). Clinical findings that are indicative of organ damage caused by mast cell infiltration are referred to as 'C findings' (9, 19). Systemic mastocytosis is defined as 'aggressive' in the presence of at least one C finding; aggressive systemic mastocytosis has a poorer prognosis (10).
For indolent systemic mastocytosis, treatment is mainly focused on symptom management and monitoring (6). This is based primarily on the use of antihistamines, antihistaminergic gastric acid secretion inhibitors, proton pump inhibitors, leukotriene receptor antagonists, cromoglycate and possibly steroids (6, 9, 20, 21). Patients with systemic mastocytosis are also at risk of episodes of pronounced mast cell activation with the release of large amounts of histamine and other inflammatory markers. Triggers can be emotional stress, trauma, infections, allergic reactions and medications such as acetylsalicylic acid, non-steroidal anti-inflammatory drugs (NSAIDs), opiates, anticholinergics and some contrast agents (6, 21).
Our patient was assessed as having aggressive mastocytosis, although it was difficult to determine the extent to which his associated haematological neoplasm – in the form of unclassifiable myeloproliferative disease – contributed to the clinical picture. There is a general consensus that systemic mastocytosis and any associated haematological disease should be treated independently of one another (9). Treatment of aggressive systemic mastocytosis with disease-modifying therapy remains a challenge. Some patients respond to cladribine or interferon, but most relapse or prove to have resistant disease (20). A response rate of 50–55 % to cladribine was seen in 22 patients with advanced mastocytosis. A very good (major) response, defined as the complete absence of at least one previous form of mastocytosis-related organ damage, was achieved in 37 % (22).
The tyrosine kinase inhibitor midostaurin is effective in inhibiting activated KIT (23). However, even if initial disease control is achieved, this does not always result in lasting remission. A study with midostaurin in 116 patients with advanced systemic mastocytosis showed an overall response rate of 60 %, with a very good response in 45 % of patients (23). The drug was not tested against any other form of treatment, and its effect was temporary in the majority of patients, with median progression-free survival of 14.1 months (23). Other drugs, including alternative KIT inhibitors, are undergoing testing in various phases of clinical trials, with a view to achieving disease control (6). Stem cell transplantation should be considered for young patients with aggressive disease, as it is the only treatment that offers the possibility of a lasting response and cure (6, 9). Genetic analyses with next-generation sequencing may contribute to better prognostic evaluation and more personalised treatment for patients with systemic mastocytosis (6, 24, 25).
Systemic mastocytosis can affect many organ systems. It should be considered a differential diagnosis in particular in cases of diffuse symptoms in combination with skin rash. The disease should be suspected in cases of unusual, repeated or episodic anaphylactoid reactions, flushing and syncope. The skin of such patients should be inspected for the characteristic rash urticaria pigmentosa (cutaneous mast cell infiltration). Elevated tryptase levels and possible eosinophilia strengthen suspicion of systemic mastocytosis (26). Due to the risk of anaphylactoid reactions, it is recommended that all patients with systemic mastocytosis carry adrenaline pens, and healthcare personnel must be aware of the risk associated with this patient group.