Diagnosis and treatment of systemic mastocytosis: state of the art (2003)

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 cell-committed 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-α (TNFα), 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; Wodnar-Filipowicz 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 non-mast cell lineage disease (SM-AHNMD), but not in those with indolent systemic mastocytosis (ISM). The organ systems most frequently affected in patients with aggressive disease variants are the liver, bone marrow, skeletal system, spleen and the gastrointestinal (GI) tract (Parwaresch et al, 1985; Travis et al, 1988a; Travis & Li, 1988; Horny et al, 1989; Metcalfe, 1991b; Horny et al, 1992a; Valent, 1996). Respective clinical findings include ascites, cytopenias, osteolysis, pathological fractures, hypersplenism and malabsorption (Rafii et al, 1983; Roth et al, 1985; Reisberg & Oyakawa, 1987; Floman & Amir, 1991; Mican et al, 1995; Kyriakou et al, 1998; Valent et al, 2001a). These organopathy-related clinical consequences have been termed C-Findings (Table III). It is of importance to be aware that organomegaly per se is not considered as ‘C-Finding-organopathy’. Rather, in the absence of C-Findings, organomegalies (palpable splenomegaly, hepatomegaly or lymphadenopathy) are recorded as B-Finding and may be indicative of smouldering a of by an of cells, organomegaly and (Akin et al, et al, Valent et al, (Table III). clinical symptoms in aggressive systemic is also of importance to symptoms and organopathy by mast cell life threatening, are not considered to represent C-Findings (Valent et al, 2001a). may be to mediator and organopathy by a aggressive of mast cells In these a may to the is that patients with aggressive mast cell disease those with exhibit in a of (Lennert & Parwaresch, 1979; Parwaresch et al, 1985; Metcalfe, This may patients with aggressive systemic mastocytosis or mast cell leukaemia are by with or (Table and may the is Moreover, SM disease & 2001). and clinical SM also be considered as a in the absence of In in patients in an in mast cells in the bone marrow or mast can be the a mast cell disease is This especially for with an myeloid neoplasm and a major in mast cells & 1981; et al, 1999; Valent et (Table number of and to be in the of patients with SM (Valent et al, 1999). SM is a first important is the of the This is in most patients with mastocytosis but is in those with SM SM et al, 1995; & 2000; Sperr et al, & Metcalfe, 2002). Moreover, the of mast cells in SM and with mast cell infiltration in the bone marrow (Akin et al, & 2000; Schwartz, Sperr et al, a is not for Rather, are also found in other myeloid neoplasms in the absence of SM et al, (Table This is of importance for patients with SM who haematological In fact, an not as an of SM in patients who have an cell myeloid neoplasm (Valent et al, important is that mast cell that for a systemic et al, 1987; Schwartz, 2001). In is to the a the is SM myeloid be considered as an disease & 2000; Schwartz, 2001). In a is a of systemic & 2000; Sperr et al, In these bone marrow is not In an of the bone marrow is to or the of SM, and to the of In those with a the of SM is of the bone marrow in an with SM a and of a bone marrow of cells on a bone marrow an of mast cells by or by and a for the of the c-kit mutation In a and of of progenitor cells is also of the bone marrow the most important in SM (Lennert & Parwaresch, 1979; Horny et al, 1985; Parwaresch et al, 1985; Horny & Valent, Li, 2001). In fact, the of of mast cells in a bone marrow is a of & Valent, Valent et al, In a majority of the mast cells in these are SM the of the mast cell are and of not cells or are by a et al, 1998; Horny & Valent, 2001). In other the mast cells may be extremely and and et al, 1998; Horny & Valent, 2001). the of an is et al, 1995; et al, Horny et al, 1998). In fact, to be to or those of mast cells et al, 1998; Horny & Valent, 2001). to be considered in SM include and et al, 1998; et al, 1995; et al, et al, Horny & Valent, 2002). and to be as these antigens are detectable in mast cells in SM, but not in mast cells in or bone marrow SM et al, Horny & Valent, and The KIT may be in the mast cells and basophils et al, (Table I). on the of the and of mast cells, a number of infiltration can be in SM & Valent, (Table for important is the of the Such include with of bone marrow bone marrow and of et al, 1985; Horny & Valent, et al, et al, (Table These are the mast cell a of these are most to from of growth factor from mast cells (Table II). of mast cells in the bone marrow of patients with indolent systemic mastocytosis and mast cell leukaemia and leukaemia marrow with an mast cell The mast cell is found in patients with indolent the of mast cells in In the an this not the bone marrow in indolent mastocytosis In in patients with mast cell leukaemia or leukaemia the of mast cells is associated with a in the of the bone In mast cell mast cells a and of infiltration The of a bone marrow is a in the recorded of mast cells in a bone marrow mast cells, be from bone marrow is an important and et al, in most of the of mast cells is in aggressive mast cell the of mast cells Moreover, an the of mast cells and in SM has been et al, In those patients with SM who have mast cells in their bone marrow mast cells are usually and the is mast cell leukaemia (Valent et al, Sperr et al, (Table The of mast cells may In most patients with the majority of mast cells to be with and a mast cells SM et al, (Table In patients with mast cells are and from mast In in most patients with aggressive systemic mastocytosis and mast cell mast cells to be with or mast cells or have a et al, for the of of mast cells that can be on bone marrow in patients with in the and of bone marrow cells the most important in the of the bone marrow may a co-existing myeloid neoplasm or to the of from and is to the cell surface phenotype of bone marrow mast cells by in patients with SM et al, 2001). This may be when be or when the is mast cells in most patients with SM express an phenotype including and et al, (Table I). a and KIT for mast cell and and of these antigens on mast cells can be with the of SM et al, 2001). these antigens are not expressed on mast cells in patients with a for and/or on mast cells not the of is the transforming c-kit mutation This c-kit mutation is detectable in the bone marrow in a majority of patients with SM, but is not detectable in most patients with or those with a cell haematopoietic neoplasm in the absence of SM (Nagata et al, 1995; Longley et al, 1996, 1999; Buttner et al, 1998; et al, 2001). this mutation is in the in patients with In most of SM, the c-kit mutation Asp-816-Val is detectable in bone marrow cells, but is not detectable in the peripheral In the clonal disease haematopoietic cell SM, leukaemia with aggressive mastocytosis or that the mutation is also found in peripheral blood cells (Nagata et al, 1995; et al, 2000a; et al, et al, Yavuz et al, 2002). is that bone marrow cells only cells) be for the c-kit mutation Asp-816-Val in the of SM from the c-kit mutation several other c-kit have been in patients with SM et al, et al, 2002). these with and are not in in patients with Based on the and for the of SM have been by the (Table The major is as by of mast cells in or organ (in most the bone marrow is the of of (Valent et al, of SM include the of or mast cells in the bone marrow an in the of an of the c-kit mutation Asp-816-Val in or organs (in most the bone marrow is and of by bone marrow mast at major and or are the of SM is (Valent et al, (Table the SM has been the to be In fact, SM variants to in their clinical and in a number of have been in patients with SM et al, 1991; Sperr et al, These include an or of haematological or an a of mast cells in bone marrow and absence of of these have been as the to and for patients with SM (Valent et al, 2001a). Based on these and the of major of patients with SM and several have been indolent systemic mastocytosis aggressive systemic mastocytosis and mast cell leukaemia (MCL) (Valent et al, is by SM of and absence of clinical or of smouldering disease aggressive disease and an In patients with mastocytosis is to the bone marrow and is termed bone marrow mastocytosis These patients the for have and exhibit mast cell in bone marrow In smouldering systemic mastocytosis of SM are and (Table are C-Findings, of and of an are are indicative of a of cells and a with a infiltration of mast cells in the bone a marrow with a of cells and with of and organomegaly lymphadenopathy) that is to mast cell infiltration (Valent et al, two of these are the of is systemic mastocytosis is by organopathy with C-Findings, a of bone marrow mast cells of in bone marrow and of an C-Findings are indicative of organopathy by mast cell The organ systems most frequently are the bone marrow, skeletal system, liver, spleen and the tract (Parwaresch et al, 1985; Travis & Li, 1988; Horny et al, Metcalfe, 1991b; Valent, 1996). of aggressive systemic mastocytosis is mastocytosis with In patients with to the are with SM is by mast cells and mast cells in bone marrow (Valent et al, 2001a). a of SM The to SM and SM variants are in patients with SM from those with a cell or a mast cell et al, as well as in SM from & 1981; Valent et al, or myeloid neoplasms that express or the c-kit mutation Asp-816-Val of mast cell lineage (Valent et al, (Table the disease and the SM is an important for the management of these only a for the of SM are on in the aggressive disease and and to these variants be in In the of the management and of SM with an to and symptoms in patients with of SM (Austen, 1992; et al, & Austen, 2002). that are and be as a distinct problem by the has been to these patients by the in the (Valent et al, 2001a). symptoms in patients with SM are with that with mediator mediator or mediator release Austen, 1992; 2000; et al, & Austen, et al, & Metcalfe, 2002). symptoms to and receptor Austen, 1992; 2000; et al, 2001). include and Austen, 1992; 2000; et al, & Metcalfe, 2002). In these are on the and Austen, 1992; et al, & Austen, et al, (Table Likewise, disease the of a and/or et al, 1985; & 1992; 2000; et al, are to in patients with SM 2000; et al, has been to be in patients with SM from diarrhoea, or et al, et al, 1979; et al, 1990) (Table In this may be in patients with SM from or bone 1985; 1991; et al, In patients with and symptoms for several may be considered 2000). In those who have or are at risk of the of on a an Austen, 1992; 2000; & Metcalfe, 2002). a that with prostaglandin has been for patients with flushing, and (Austen, be with the may vascular in an Moreover, the risk of gastrointestinal has to be especially in patients with a or be to patients with a number of are for the of In symptoms usually not be with or an has been considered for patients with and of In the and of of the have to be and the that may from a in the mast cell In of these may the release of mediators from mast cells in these in patients with aggressive mast cell or may to release of mast cell In these be as important to from a number of other and may or mediator release from mast cells in patients with These include or and and or contrast et al, 1987; Lawrence et al, 1987; et al, & 1992; & 1995; & 1998; et al, et al, In patients with a co-existing mediator release may be a and problem et al, et al, et al, 1999; Metcalfe, 2000). is of importance to be aware of these and to in patients with SM et al, In is important to be aware of in patients who Respective have been et al, 1983; et al, 1987; & 1990; et al, 1990; 1991; et al, 1992; & 1998). in SM are and from that detectable in patients with The of of the is ranging from a to et al, et al, & 2002). in the in SM in are in most In fact, only a patients to have 1991a; et al, 2002). In of these of is by a of mastocytosis et al, 2002). This is with the that patients with aggressive mast cell disease (Parwaresch et al, 1985; Metcalfe, 1991a; Valent, 1996). In most patients with SM, the represent a In other the or are by symptoms including and et al, et al, 2001). number of have been for the of symptoms may to and is et al, et al, (Table in response to a substantial of is seen in patients et al, et al, 1984; et al, 1985; et al, 2002). are in and most patients with of to is the of et al, (Table In patients with systemic including and may be the growth of mast cells including a on mast cells, as well as a on cells in et al, et al, 1985; et al, 1987; et al, 1995; et al, as is associated with the of systemic in SM be to distinct clinical and the as and as in et al, Valent et al, from be considered for patients with aggressive systemic mastocytosis and (Valent et al, (Table In fact, the of other may especially in patients with tract and malabsorption or hepatomegaly with 1991a; 2000). are usually not as a in aggressive SM, but are usually with In most of aggressive systemic is with a (Valent et al, In have been considered as an to in patients with In the can be to a of and be In those with the of be have and most of are considered to be the risk of disease and the of secondary have to be in on a as may not be of patients to clinical These be only to those patients with SM who have of an aggressive disease and only the the and is by the and In this is important to the of C-Findings that are of organopathy organ by mast cell infiltration and are a for an aggressive SM may be to organ to the of aggressive systemic mastocytosis In contrast to aggressive patients with usually not be considered for may be smouldering In these clinical and of a of cells splenomegaly, marrow, organopathy are found (Akin et al, et al, Valent et al, In these is to the clinical and to on at first These be in to the disease In may be to of organ is found (Table most patients with smouldering SM, the is to and of organopathy to aggressive of the of aggressive mast cell disease or has been patients be considered for with It be that are in that have been include and (Travis et al, et al, 1992; 2000; et al, Valent et al, These have been or in (Travis et al, 2000; Valent et al, The in SM appears to be and to on the of is of importance to the of SM these also be in that SM be and that or the several has been as a cell and for patients with myeloproliferative The that SM is to this group of myeloid neoplasms to this also in patients with aggressive systemic mastocytosis or mast cell in patients with aggressive in with or in mast cells et al, 1992; et al, 1994; et al, 1995; et al, 1995; et al, et al, et al, 1998; et al, 1998). Moreover, may symptoms in patients with SM et al, 2002). other has for patients with aggressive mastocytosis to to with a of and in these patients (Table is to with a is and to the the first is usually at a on the response and of the of is be to a or In patients with may also be with the response may not be In fact, aggressive appears to be to patients with (Table In patients with and bone considered to be a of mast cell infiltration may be to et al, et al, Based on the only a of patients with aggressive systemic mastocytosis have clinical to et al, 1998; et al, Valent et al, a number of have been (Table those patients who a aggressive as or bone marrow be considered to patients with (Table In patients with a number of as or may be et al, et al, Valent et al, appears to be an and may the mast cell in a of patients with with is an for those patients who not to or other 2000; Valent et al, The of the tyrosine kinase has also been can mast cells the c-kit (Akin et al, the of the Asp-816-Val mutation to et al, 2002). may only be considered for those SM patients in transforming mutation at In line with this patients with aggressive systemic mastocytosis or mast cell leukaemia in the c-kit mutation Asp-816-Val is found to clinical to a number of other tyrosine kinase are and of to not only KIT, but also the tyrosine kinase of the of KIT et al, 2002). from a number of other have been for patients with aggressive mastocytosis or mast cell In of bone and is a In patients with and may be considered in an to and to at the et al, 1990). is a disease by the growth of cells in the bone marrow as well as in with organopathy (Lennert & Parwaresch, 1979; Parwaresch et al, 1985; et al, Travis et al, Metcalfe, 1991b; Valent, 1996). in other aggressive variants of SM, are usually (Parwaresch et al, In contrast to other SM mast cells are detectable in and the bone marrow mast cells (Travis et al, Sperr et al, Valent et al, 2001a). The in is and is for these patients (Travis et al, in contrast to aggressive patients with may not have when with and with other may also be a (Travis et al, in patients with has been or in with other (Travis et al, 2000). of aggressive be considered in patients with in an to or at to a in the tumour (Table to those to myeloid leukaemia patients may be an (Travis et al, Sperr et al, 2000; 2000). The of with other may also be In the be to a bone marrow is patients may be considered for bone marrow (Table with this in is be to as for in the patients or to with and or other Mast cell is an extremely mast cell In contrast to SM, is a tumour that of mast cells and a growth (Parwaresch et al, is considered as a disease (Parwaresch et al, 1985; Horny et al, Valent et al, 2001a). the and of the cells and the clinical that mast cell is to the group of aggressive mast cell Moreover, in secondary with of organs has been and the may aggressive systemic mastocytosis or mast cell leukaemia et al, et al, 1999; et al, 2001). for patients with to be In the and et al, et al, 1999; et al, 2001). secondary has to aggressive mastocytosis or the management and the for the management of aggressive mastocytosis and mast cell The of an in patients with SM is with the notion that SM as a myeloproliferative In most a myeloid neoplasm as a a myeloproliferative disease or an is (Travis et al, Horny et al, 1990a; Lawrence et al, 1991; Sperr et al, 2000). neoplasms may also but frequently compared with myeloid Such neoplasms are of In to myeloid or neoplasms be In most be to an in may be to and smouldering or aggressive systemic mastocytosis and In disease and the clinical may to the the of has been for SM and the have to be 1991; Sperr et al, 2000; 2000; Valent et al, 2001a). In this is of importance to be aware that the mast cell of the disease in patients with can be indolent or aggressive the can be an aggressive or indolent (Valent et al, The for patients with is to SM as is and the as SM has been et al, 2000; Valent et al, et al, (Table has been that is in of in patients with SM may not to this et al, 2000). SM and may be to a as the of patients with on the nature and of the SM and the as well as on the of the 1991; Valent et al, 2001a). with SM be at on the of SM, of co-existing and In of the and of blood and is patients with from symptoms may be to In patients who have the smouldering of may be to the of disease include the blood and of organomegaly liver, In patients with to or a bone marrow and be with aggressive systemic mastocytosis and mast cell leukaemia be and with In these a number of be those C-Findings as and those the of mast cells marrow with may In the mast may also or to are only seen in of when mast cell The response to is on clinical including the of and is to organopathy and the of response have been (Valent et al, a major a response and the of have been Respective can be to patients with aggressive systemic mastocytosis (ASM), mast cell leukaemia (MCL) and a of response major response is by of organopathy by of a major clinical response can be those response of mast cell and of mast cell and an clinical response of organopathy in mast cell response is by a in This group of patients can be those with a response of C-Findings to and those with a response of C-Findings to a response can exhibit disease in or a of response and respective these patients with an of major response of (Valent et al, mastocytosis is a disease of progenitors with clonal and a to myeloproliferative The of the disease and The of patients with SM has to be on the of of symptoms and of an associated haematopoietic non-mast cell lineage symptoms are growth of mast cells in aggressive disease variants is with as or Based on the tyrosine kinase not to the of KIT the Asp-816-Val and is not to be in the majority of patients with aggressive may be patients who are found to a mutation in KIT at of mast Such patients may be for with this has to be In may with the of including those that the tyrosine kinase of KIT transforming at