Diagnosis and treatment of systemic mastocytosis: state of the art

Mast cells are tissue-fixed cells originating from uncommitted and mast cell-committed haematopoietic progenitors (Kitamura et al, 1981; Kirshenbaum et al, 1992; Agis et al, 1993; Rottem et al, 1994; Kempuraj et al, 1999). Mast cellcommitted progenitors co-express CD13 and KIT with CD34 (Kirshenbaum et al, 1999) and are detectable in the bone marrow as well as in the peripheral blood (Valent et al, 1992; Rottem et al, 1994; Valent, 1994). Homing, differentiation and maturation of mast cell progenitor cells are regulated by a complex network of growth factors, receptors and other antigens (Galli, 1990; Valent, 1994). The most important growth factor for human mast cells appears to be stem cell factor (SCF) (Irani et al, 1992; Kirshenbaum et al, 1992; Valent et al, 1992; Mitsui et al, 1993). This cytokine is a natural ligand for the c-kit proto-oncogene product, KIT, a tyrosine kinase receptor expressed on the surface of precommitted myelopoietic progenitor cells, mast cell-committed progenitor cells as well as mature mast cells (Galli et al, 1993; Simmons et al, 1994; Valent, 1994). Based on their unique phenotype and distinct functional properties, mast cells represent a distinct myeloid cell lineage within lympho-haematopoietic tissues. Likewise, mast cells express a unique composition of CD antigens and granular mediators when compared with other myeloid cells (Schwartz, 1985; Valent et al, 1989; Valent & Bettelheim, 1992; Agis et al, 1996) (Table I). Moreover, in contrast to blood basophils and other myeloid cells, mast cells exhibit an extremely long life span in vivo ranging from several months to years (Galli, 1990; Födinger et al, 1994). In contrast to other haematopoietic cells, mast cells produce substantial amounts of histamine and heparin and express the high-affinity IgE receptor on their surface (Ishizaka & Ishizaka, 1984; Schwartz, 1985; Galli, 1990). The concept that mast cells represent a unique myeloid lineage is in line with the notion that systemic mastocytosis (SM) is a distinct haematopoietic (myeloid) neoplasm with unique pathogenetic and clinical features (Lennert & Parwaresch, 1979; Parwaresch et al, 1985; Metcalfe, 1991a; Valent, 1996). The clonal nature of the disease has been reinforced by the association with the somatic c-kit mutation Asp-816-Val (Nagata et al, 1995; Longley et al, 1996, 1999; Buttner et al, 1998). This transforming mutation is detectable in the bone marrow (mast cells) in a majority of patients with SM but usually is not found in other myeloid neoplasms (Fritsche-Polanz et al, 2001). Remarkably, in a group of patients with (advanced) SM, the c-kit mutation Asp-816-Val is detectable not only in mast cells but also in other haematopoietic lineages, including blood monocytes (Akin et al, 2000a; Sotlar et al, 2000; Yavuz et al, 2002). Based on this notion and several clinical observations, SM can be regarded as a myeloproliferative disorder. In line with this concept, patients with SM are at a certain risk of acquiring a secondary myeloid leukaemia (Travis et al, 1988a,b; Horny et al, 1990a; Lawrence et al, 1991; Sperr et al, 2000). In the management of patients with SM, two major problems have to be faced. The first is mediator release from mast cells with respective clinical symptoms that can be observed frequently in these patients (Horan & Austen, 1991; Metcalfe, 1991a; Austen, 1992; Valent, 1996). In fact, mast cells store (in their granules) or generate a number of vasoactive mediators [histamine, tumour necrosis factor-a (TNFa), vascular endothelial growth factor (VEGF), leukotrienes, prostaglandin D2 (PGD2)] and other biologically active molecules (interleukins, proteases, heparin) (Roberts et al, 1980; Lewis & Austen, 1981; Serafin & Austen, 1987; Burd et al, 1989; Plaut et al, 1989; WodnarFilipowicz et al, 1989; Gordon et al, 1990; Gordon & Galli, 1990) (Table II). In response to activating stimuli, mast cells can generate and ⁄ or release their mediator substances (Lewis & Austen, 1981; Ishizaka & Ishizaka, 1984; Schwartz, 1985; Burd et al, 1989; Plaut et al, 1989; Wodnar-Filipowicz et al, 1989; Gordon et al, 1990). Resulting clinical symptoms include headache, flushing, pruritus, diarrhoea, vascular instability, hypotension and shock (Austen, 1992) (Table II). Such symptoms may be grave and life threatening, especially in patients with SM who also have a co-existing disease predisposing for mediator secretion (allergies). The second management problem in SM results from the uncontrolled (aggressive) growth and infiltration of mast cells in diverse organs with consecutive organopathy (Lennert & Parwaresch, 1979; Parwaresch et al, 1985; Metcalfe, 1991a; Valent, 1996). Such organopathies are seen in patients with aggressive systemic mastocytosis (ASM), mast cell leukaemia (MCL) and in a group of patients with an associated clonal haematological nonmast cell lineage disease (SM-AHNMD), but not in those with indolent systemic mastocytosis (ISM). The organ systems most frequently affected in patients with aggressive Correspondence: Peter Valent, Department of Internal Medicine I, Division of Haematology & Haemostaseology, University of Vienna, Währinger Gürtel 18–20, A-1090 Vienna, Austria. E-mail: peter.valent@akh-wien.ac. at British Journal of Haematology, 2003, 122, 695–717