Mastocytosis is one of the rare heterogenous diseases, caused by mast cells expansion and accumulation in one or many organs. Mast cells were discovered by Paul Ehrlich in 1877. He identified mast cells in breast tissue and called them “Mastzellen”. Mast cells belong to white blood cells family, and their precursors are CD34 cells. Mast cells are produced in bone marrow, however their final differentiation takes place in several tissues and is influenced by local growth factors. The majority of mast cells are located around vessels and nerves. They can be found, among others, in skin connective tissue, gastrointestinal tract mucosa, respiratory tract connective tissue and lymphoid organs . Mast cells are the source of numerous mediators, e.g. histamine, proteases (tryptase, chymase, carboxypeptidase, cathepsin G), serotonin, heparin, leukotrienes (LTB4, LTC4), prostaglandins (PGE2, PGD2), cytokines (IL-1, IL-5, IL-6, IL-13, IL-16, IL-18, TNFα, TNFβ, INFα, INFβ) chemokines (IL-8,MCP-1,MCP-3,MIP1α, MIP1β) and growth factors (SCF, M-CSF, GM-CSF, βFGF, VEGF, NGF, PDGF) . Mast cells degranulation can be influenced by several factors, e.g. drugs (chinine, morphine, aspirin, NSAID, anaesthetics, β-blockers, α-blockers, cholinergic drugs, polymers i.e. dextran), physical factors (warm, cold, sunlight, vibration, pressure, rubbing, physical exercise), chemical factors (alcohol, iodinated contrasts, peanuts, insect sting venom, snake venom, jellyfish venom, polypeptides present in some hormones, crabs, fish), and invasive procedures (biopsy, endoscopy) .
According to WHO classification, we distinguish 7 subtypes of mastocytosis: cutaneous mastocytosis, indolent systemic mastocytosis (ISM) which involves bone marrow mastocytosis (BMM) and smouldering systemic mastocytosis (SSM), systemic mastocytosis with an associated hematologic (non-MC lineage) neoplasm (SM-AHN), aggressive systemic mastocytosis (ASM), mast cell leukaemia (MCL), mast cell sarcoma (MCS) and extracutaneous mastocytosis . Cutaneous mastocytosis was first described in 1869. There is no clearly defined and perfect division of cutaneous mastocytosis, three subtypes can be distinguished: maculopapular cutaneous mastocytosis, diffuse cutaneous mastocytosis and mastocytoma of skin [3,4]. Some authors, due to clinical manifestation of skin lesions, use historical division of maculopapular cutaneous mastocytosis on: urticaria pigmentosa, plaque papular mastocytosis, nodular and teleangectasia mastocytosis. Pathognomonic symptom of cutaneous mastocytosis is Darier’s symptom, which consists of itching, redness and oedema of the skin, and sometimes blisters occurring after mechanical irritation of skin lesions. The most common type of cutaneous mastocytosis is urticaria pigmentosa. It is characterised by the presence of small, poorly defined skin macules or blisters, ovate or circular, pink or yellow-brown, of several millimetres in diameter. Skin lesions are usually located on the trunk and extremities, sparing hands, feet and scalp [4,5]. Presence of light brown or yellow-orange sessile skin lesions with tendency to fuse, which resemble plaques (plaque papular mastocytosis) is typical for paediatric mastocytosis. It is characterised by good prognosis and a small risk of changes to the organs. Another subtype of cutaneous mastocytosis in the paediatric population is nodular mastocytosis, where lesions in a form of diffused nodules are located mainly on extremities. This subtype is characterised by a strong tendency to form blisters within skin lesions [3,5]. The teleangiectasia type occurs in adults, predominantly in women. Clinically numerous, small, red-brown spots are present on the skin, always connected with teleangiectasiae. Skin lesions are symmetrical, located on the trunk and extremities. In the case of this subtype, Darier’s symptom is often negative [3,5]. Diffuse cutaneous mastocytosis is another subtype of cutaneous mastocytosis. Skin becomes yellow-orange or reddish, thickened and swallowed, itchy with strong Darier’s symptom. It occurs almost exclusively in children and is characterised by skin blisters and haemorrhagic blisters appearing after minor stimuli. It may be accompanied by strong symptoms dependent on released mediators [3,5]. The third mastocytosis group is mastocytoma, well separated, red, yellow or brown spot, papula or nodule, present usually in children, of good prognosis and tendency to regress in childhood [3,5]. No organ lesions were recorded for that type of mastocytosis.
For diagnosing of cutaneous mastcytosis it is necessary to meet 1 large criterion and 1 small criterion or 2 small criteria. The large criterion is the presence of typical skin lesions. Small criteria are the presence of the below listed symptoms in histologic and immunohistochemical skin examination: a) monomorphic infiltrations containing >15 tryptase-positive cells in one cluster, or b) fusiform mast cells (> 20 mast cells in the field of view, magnification 40x), or c) c-kit proto-oncogene mutation in codon 816 present in mast cells collected from skin lesion .
Two types of mastocytosis symptoms can be distinguished. First type is associated with the release of mediators, and the second type with infiltration of organs by mast cells. Symptoms induced by mast cells mediators can be chronic or paroxysmal, those are: cachexia, malaise, fever, paroxysmal face reddening, itching, urticaria, anaphylaxis, angioedema, arterial hypotension, automatic tachycardia, paroxysmal atrial fibrillation, arterial hypertension, syncope, bronchospasm, excessive gastric juice production, emphysema, abdominal pain, diarrhoea, malabsorption, osteopenia, osteoporosis, fibrosis, fibrinolysis and headaches . Symptoms connected with organ infiltration can be divided into group B symptoms (which indicate organ infiltration without function abnormalities) and group C symptoms (indicate severe function disorders). Group B involves: above 30% of mast cells in trepanobiopsy and serum tryptase level >20 ng/ml; signs of dysplasia or myeloproliferation in non-mast cell lines that don’t meet the criteria of blood neoplasms, or unobtrusive changes in a complete blood count, accompanied by palpable liver enlargement without liver function disorders, and/or lymph node enlargement in physical or imaging examination, and/or palpable spleen enlargement. Group C includes: bone marrow function abnormalities resulting in one, two or three cell lines cytopenia (Hb<10g%, granulocytes <1000/mm3, platelets <100000/mm3); palpable liver enlargement with function disorders, ascites and/or portal hypertension; malabsorption with weight loss due to infiltration of gastrointestinal tract mucosa by mast cells; severe osteolysis and/or osteoporosis with bone fractures [3,4,6,7]. Bone damage can be found in 70% of patients with systemic mastocytosis. Bone lesions involve mainly proximal parts of long bones, pelvis, sternum, ribs, spine and skull bones. Most common symptoms are osteoporosis, focal osteolysis, pathological fractures and bone pain. Osteoporosis and osteopenia are caused by increased bone turnover (resorption is stimulated by histamine, PGD2). The symptoms in patients with digestive tract involvement are: diarrhoea, abdominal pain, malnutrition, and weight loss. In case of CNS involvement every brain structure may be infiltrated, and that may result in dull headaches in the frontal area, vascular origin headaches of symptomatology similar to migraine and histamine headaches with rhinorrhea and lacrimation. In addition, cognitive disorders and mood disorders may occur. Dyspnoea is the most common respiratory tract involvement symptom. In patients with mastocytosis, circulatory system is often involved, and symptoms of such involvement are: loss of consciousness, severe hypotension, cardiac arrhythmia including paroxysmal atrial fibrillation and chest pain . Systemic mastocytosis was first described in 1949. For diagnosing systemic mastcytosis it is necessary to meet 1 large criterion and 1 small criterion, or 3 small criteria. The large criterion is: multifocal dense infiltration containing ≥15 mast cells in one infiltration focus in bone marrow and/or other organs. Small criteria: >25% fusiform or atypical mast cells in bone marrow biopsy or other organs biopsy, or >25% immature or atypical mast cells in myelogram, b) presence of mutation 816 of KIT gene in bone marrow cells, blood cells, or other extracutaneous organs, c) kit-positive mast cells present in bone marrow, blood or other extracutaneous organs with co-expression of CD25 and/or CD2, d) serum tryptase level >20 ug/l (not applicable to SM-AHNMD) .
There are significant differences between paediatric and adult mastocytosis. In children, 98% of mastocytosis cases is cutaneous mastocytosis, with a tendency for remission and good prognosis. On the contrary, in adults, the predominant type of mastocytosis is systemic mastocytosis (in most cases indolent systemic mastocytosis with skin involvement), and prognosis is uncertain. Additionally, in adults, bone marrow biopsy is obligatory, whereas in children it should be performed only in case of suspicion of systemic mastocytosis (abnormal complete blood count, liver enlargement, spleen enlargement, tryptase level > 100 ng/ml or > 20 ng/ml persisting in adulthood) .
In case of cutaneous mastocytosis and indolent systemic mastocytosis, treatment is symptomatic with the use of H1 and H2 blockers, corticosteroids, and mast cells stabilizers (for example, disodium cromoglycate). Additionally, in case of cutaneous mastocytosis PUVA therapy may be introduced. Cytostatics are used to inhibit mast cells growth in case of aggressive mastocytosis and mast cell leukaemia. What should be emphasised is the need for patient education on factors triggering mast cells degranulation and to supply every patient with an individual anti-shock kit [5,11,12,13].
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