Systemic Masto Review

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Review

DIAGNOSIS AND TREATMENT OF SYSTEMIC MASTOCYTOSIS: STATE OF THE ART

BIOLOGY OF DISEASE CURRENT STATUS

Mast cells are tissue-fixed cells originating from uncommit-

ted 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, differ-

entiation and maturation of mast cell progenitor cells are

regulated by a complex network of growth factors, receptorsand 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-com-

mitted 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 myeloidcells (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; Fodinger 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 myeloprolif-

erative disorder. In line with this concept, patients with SM

are at a certain risk of acquiring a secondary myeloidleukaemia (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 necro-

sis factor-a (TNFa), vascular endothelial growth factor

(VEGF), leukotrienes, prostaglandin D2 (PGD2)] and other

biologically active molecules (interleukins, proteases, hep-

arin) (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 andor 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). Result-

ing 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 secre-

tion (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 sys-

tems most frequently affected in patients with aggressive

Correspondence: Peter Valent, Department of Internal Medicine I,

Division of Haematology & Haemostaseology, University of Vienna,

Wahringer Gurtel 1820, A-1090 Vienna, Austria. E-mail:

[email protected]

British Journal of Haematology, 2003, 122, 695717

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disease variants are the liver, bone marrow, skeletal

system, spleen and the gastrointestinal (GI) tract (Parwa-

resch 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, hypersplen-

ism 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-Find-

ings, organomegalies (palpable splenomegaly, hepatomeg-

aly or lymphadenopathy) are recorded as B-Finding and

may be indicative of smouldering mastocytosis, a novel

subtype of ISM defined by an excessive burden of

neoplastic cells, organomegaly and slow progression (Akin

et al, 2001; Jordan et al, 2001a; Valent et al, 2002a)

(Table III).

Considering clinical symptoms in aggressive systemic

mastocytosis, it is also of importance to distinguish carefully

between mediator-related symptoms and organopathy

caused by mast cell infiltrates. Thus, mediator-related

symptoms, even if life threatening, are not considered to

represent C-Findings (Valent et al, 2001a). Sometimes,

however, it may be quite difficult to distinguish between

mediator effects and organopathy caused by a local aggres-

sive infiltrate of mast cells (GI symptoms, hypersplenism,

pathologic fracture). In these cases, a tissue biopsy may lead

to the correct diagnosis.One paradox is that patients with aggressive mast cell

disease often lack urticaria pigmentosa-like skin lesions,

whereas those with ISM exhibit skin lesions in a high

proportion of cases (Lennert & Parwaresch, 1979; Parwa-

resch et al, 1985; Metcalfe, 1991a). This paradox may

explain why patients with aggressive systemic mastocytosis

or mast cell leukaemia are often misdiagnosed by confusion

with endocrinological, rheumatological, hepatic or infec-

tious disorders (Table IV), and why it may take some time

until the correct diagnosis is established. Moreover, SM

shows considerable disease heterogeneity (Metcalfe & Akin,

2001). Thus, under various circumstances and clinical

conditions, SM should also be considered as a potential

diagnosis in the absence of skin lesions.

In addition, even in patients in whom an increase in mast

cells in the bone marrow or mast cell-related markers can be

demonstrated, the question often remains whether a

primary mast cell disease (mastocytosis) is present. This

holds especially true for cases with an apparently unrelated

myeloid neoplasm and a major increase in immature highly

atypical mast cells (myelomastocytic disorders) (Prokocimer

& Polliack, 1981; Wimazal et al, 1999; Valent et al 2001b,

2002b) (Table V).

Table I. CD antigen phenotype of normal mast cells and neoplastic mast cells in patients with systemic masto-

cytosis (SM): comparison with other cells.

CD Antigen

Neoplastic

MCs (SM)

Normal

MCs*

Cultured

MC progenitors

Blood

basophils

Blood

monocytes

CD2 LFA-2 +

CD3 TcR

CD4 T4 +/)

+/)

+/)

CD9 MRP-1 + + + + +

CD13 AP-N +/) + + +

CD14 LPSR +

CD15 3-FAL +

CD25 IL-2Ra + + +/)

CD33 Siglec-3 + + + + +

CD34 HPCA-1 +/)

CD35 CR1 +/) +/) + +

CD45 CLA + + + + +

CD63 LIMP + + + + +

CD88 C5aR + +/) + +

CD116 G-CSFRa +/) +/) +

CD117 KIT + + +

CD123 IL-3Ra +/) + +

MC, mast cell.

*Phenotype of normal mature tissue MCs.

CD2 and CD25 are expressed on bone marrow mast cells in the vast majority of patients with SM (minor SM

criterion).

These antigens are also expressed on precommitted CD34+ MC progenitors.

Data refer to published results obtained with normal and neoplastic cells (Valent & Bettelheim, 1992; Saito

et al, 1995; Agis et al, 1996; Kempuraj et al, 1999; Ochi et al, 1999; Escribano et al, 2001; Schernthaner et al,

2001).

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Table II. Mast cell-derived mediators and mediator-related findings in patients with SM.

Mediator(s)

Proposed mechanisms

and site of action

Clinical and pathological findings

considered to be mediator related

Histamine H1-receptors

on vascular and

perivascular cells as

well as epithelial cellsin various organs

H2-receptors on

epithelial and other

cells in the GI tract

H3-receptors in

brain and GI tract

Vascular instability, headache,

oedema, flushing, (acute) urticaria,

bronchoconstriction, mucus

secretion, leucocyte marginationbefore transmigration (selectins)

Gastric acid hypersecretion, peptic

ulcer disease, diarrhoea, abdominal

pain, cramping

Neurological abnormalities,

abdominal pain, diarrhoea

PGD2, LTC4and other

leukotrienes

PG and LT receptors on

vascular and perivascular

cells and other cell types

Oedema, (acute) urticaria,

flushing, bronchoconstriction,

abdominal discomfort, cramping

VEGF VEGF receptors

on endothelial cells in

diverse organs

Oedema, increased angiogenesis

in the bone marrow and other

organs (in SM infiltrates)

bFGF bFGF receptors on

fibroblasts, endothelial

cells and other cell typesin various organs

Bone marrow fibrosis, tissue

fibrosis, increased angiogenesis,

osteosclerosis

Tryptases Diverse effects on fibroblasts, endothelial

cells, leucocytes and other

mesenchymal cells, and

their products

Fibrosis, angiogenesis, tissue

remodelling, degradation of

matrix molecules, abnormal

coagulation, bone resorption,

osteopenia, osteolysis

tPA

Heparin

TNF-a

Plasmin activation

ATIII-cofactor, anti-

coagulant, cofactor

for tPA, FGF and

other growth factors

TNF receptors on

Hyperfibrinolysis

Coagulation abnormalities,

bleeding diathesis,

fibrosis, angiogenesis,

osteoporosis, osteopenia

Endothelial cell activation and

endothelial cells and

other cell types

CAM expression with

transmigration of leucocytes,

cachexia, vascular instability

TGF-b

Interleukins

(IL-1-2-3-5

-6-9-10-13,

GM-CSF)

TGF-b receptors on

various cells in tissues

IL receptors on leucocytes

and other cell types

Tissue fibrosis, abnormal bone

remodelling, osteopenia

Leucocyte differentiation and

activation, eosinophilia,

accumulation of eosinophils,

growth and accumulation of

lymphocytes in bone marrow,

tissue fibrosis and activation

of various stromal cells,

myeloid hyperplasia

Chemokines

(IL-8, MCP-1,

MIP-1a, others)

Chemokine receptors on

leucocytes and stromal

cells

Activation and chemotaxis of

leucocytes, accumulation of

lymphocytes, monocytes

and eosinophils

GI tract, gastrointestinal tract; PG, prostaglandin; LT, leukotriene; VEGF, vascular endothelial growth

factor; bFGF, basic fibroblast growth factor; tPA, tissue type plasminogen activator, TNF, tumour necrosis

factor; TGF, transforming growth factor; IL, interleukin, GM-CSF, granulocytemacrophage colony-

stimulating factor; MCP-1, monocyte chemoattractant protein-1; MIP-1a, macrophage inflammatory

protein-1a.

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DIAGNOSTIC PARAMETERS, PROGNOSTIC

VARIABLES AND CLASSIFICATION

A number of cell-specific and disease-related parameters

appear to be helpful in the diagnostic work up of patients

with SM (Valent et al, 1999). When SM is suspected, a first

important step is the evaluation of the serum tryptase level.

This parameter is normal (< 20 ngml) in most patients

with cutaneous mastocytosis (CM) but is almost invariably

> 20 ngml in those with SM (a minor SM criterion)

(Schwartz et al, 1987, 1995; Schwartz & Irani, 2000;

Sperr et al, 2002a; Akin & Metcalfe, 2002). Moreover,

tryptase levels reflect the total burden of mast cells in SM

and correlate with mast cell infiltration in the bone

marrow (Akin et al, 2000b; Schwartz & Irani, 2000;

Schwartz, 2001; Sperr et al, 2002a). However, a persist-

ently elevated serum tryptase level is not specific for SM.

Rather, such elevated tryptase levels are also found in

other myeloid neoplasms in the absence of SM (Sperr et al,

2001a, 2002b) (Table VI). This is of particular importance

for patients with SM who show additional haematological

abnormalities. In fact, an elevated serum tryptase level

should not count as an indication (criterion) of SM in

patients who have an unrelated (non-mast cell lineage)

myeloid neoplasm (Valent et al, 2001a,c). Another import-

ant aspect is that tryptase levels increase (transiently)

during significant mast cell activation that may, forexample, occur during a systemic allergic reaction

(Schwartz et al, 1987; Schwartz, 2001). In such cases, it

is recommended to repeat the test a few weeks later. If the

tryptase level is persistently elevated, SM (or another

myeloid neoplasm) should be considered as an underlying

disease (Schwartz & Irani, 2000; Schwartz, 2001).

In paediatric patients, a baseline serum tryptase level

30 ngml), the likelihood of SM is > 90%.

Diagnostic review of the bone marrow in an adult patient

with suspected SM includes a histological and cytochemical

assessment of a bone marrow section, morphological

investigation of neoplastic cells on a bone marrow smear,

an immunophenotypic examination of mast cells by immu-

nohistochemistry or by flow cytometry and a molecular

analysis for the presence of the c-kit point mutation Asp-

816-Val. In suspected SM-AHNMD, a chromosome analysis

Table III. Clinical and laboratory findings in patients with SM.

Finding

Typically found in patients with

ISM BMM SSM SM-AHNMD ASM MCL

B-Findings

Hepatomegaly +/) +/) +/) +/)

Splenomegaly + +/)

+ +/)

Lymphadenopathy +/) )/+ +/) )/+

Hypercellular marrow + + + +

Mild dysplasia + +/) +/) +

Myeloproliferation + + +/) +

Mast cell infiltration in bone marrow > 30% + +/) + +

Tryptase > 200 ngml + +/) +/) +

C-Findings

Anaemia (Hb < 10 gdl) +/) + +

Thrombocytopenia (< 100 109l) +/) + +

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(karyotyping) and determination of numbers of colony-

forming progenitor cells is also recommended.

A thorough histological investigation of the bone marrow

remains the most important investigation in suspected SM

(Lennert & Parwaresch, 1979; Horny et al, 1985; Parwa-

resch et al, 1985; Horny & Valent, 2001; Li, 2001). In fact,

the demonstration of multifocal dense infiltrates of mast

cells in a representative bone marrow biopsy section is a

diagnostic finding (major criterion of SM) (Horny & Valent,

2001; Valent et al, 2001a) (Fig 1). In a majority of cases,

the mast cells in these infiltrates are spindle-shaped (minor

SM criterion), thereby confirming the diagnosis of SM.

Sometimes, however, the focal mast cell infiltrates are small

and composed of round (but not spindle-shaped) cells or are

accompanied by a diffuse component (Horny et al, 1998;

Horny & Valent, 2001). In other patients, the mast cells

may be extremely immature and hypogranulated, and

therefore escape conventional staining techniques (Horny

et al, 1998; Horny & Valent, 2001). Therefore, the use of an

antitryptase antibody is recommended (Fukuda et al, 1995;

Li et al, 1996; Horny et al, 1998). In fact, antitryptase

antibodies appear to be sufficient to detect even small

infiltrates or those composed of immature non-granulated

mast cells (Horny et al, 1998; Horny & Valent, 2001). Other

immunohistochemical markers to be considered in SM

include CD25 (IL2Ra), CD68 (macrosialin), CD117 (KIT)

and CD2 (LFA-2) (Horny et al, 1990b, 1993, 1998; Fukuda

et al, 1995; Li et al, 1996; Jordan et al, 2001b; Horny &

Valent, 2002). CD2 and CD25 appear to be particularly

helpful as these antigens are almost exclusively detectable in

mast cells in SM, but not in mast cells in normal or reactive

bone marrow (minor SM criteria) (Jordan et al, 2001b;

Table IV. Clinical findings in patients with suspected systemic mastocytosis and important

differential diagnoses to be considered at first presentation.

Findings Differential diagnoses

Skin

Unexplained flushing

Unexplained urticaria or oedema

Benign cutaneous flushing, allergies,

hereditary or acquired angioedema, carcinoid

syndrome, autonomic neuropathyOccurrence of cutaneous mast

cell lesions after puberty*

Cutaneous mastocytosis*

Cardiovascular system

Unexplained anaphylactoid reaction Allergies, idiopathic anaphylaxis

Unexplained syncope and tachycardia

with or without hypotension

Aortic stenosis, vascular disorders, cardiac

diseases, neurological disorders

Severe recurrent allergic shock Severe allergic disorder

Hypotension of unknown aetiology Cardiac, infectious, or neurological disease

Hypertension of unknown aetiology Essential hypertension, adrenal tumour

Liver, spleen and lymph nodes

Unexplained hepatosplenomegaly

with or without ascites or

elevated enzyme levels

Hepatitis, liver cirrhosis, hepatic tumour,

lymphoma, carcinosis (metastasis),

cholecystitis, cholecystolithiasis

Lymphadenopathy Malignant lymphoma, infectious disease

Gastrointestinal tract

Unexplained diarrhoea Inflammatory bowel disease, gluten-sensitive

enteropathy, lactase deficiency, parasitic

diseases, eosinophilic gastroenteritis

Recurrent peptic ulcer Helicobacter pylori infection, gastrinoma

Skeletal system

Diffuse osteoporosis Hormone deficiency, drug effects, idiopathic

Osteolysis of unknown aetiology Multiple myeloma, histiocytosis, metastases

Recurrent severe bone or

musculoskeletal pain

Bone tumour, myeloma, tumour metastases,

fibromyalgia, autoimmune disorders

Constitutional and others

Headache, neurological abnormalities Neurological or psychiatric disorders

Weight loss Neoplastic diseases including lymphomasFever Infectious diseases, lymphomas

Nausea Intoxication, neurological disorder,

peptic ulcer disease, drug effects

*In most paediatric cases, the diagnosis will be cutaneous mastocytosis, whereas in the

majority of adults, the diagnosis will be systemic mastocytosis.

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Horny & Valent, 2002) (Tables I and VII). The KIT antigen

may be helpful in the discrimination between mast cells and

basophils (Fukuda et al, 1995) (Table I). Depending on the

characteristics of the infiltrate and cytomorphological

aspects of mast cells, a number of different infiltration

patterns can be distinguished in SM (Horny & Valent, 2001,

2002) (Table VII). Figure 1 shows representative examples

for such patterns. Another important histopathological

aspect is the accompanying (non-specific) reaction of the

surrounding microenvironment. Such reactive changes

include osteosclerosis with thickening of adjacent bony

trabeculae, bone marrow fibrosis, increased bone marrow

angiogenesis, eosinophilia and focal accumulation of

lymphocytes (Horny et al, 1985; Horny & Valent, 2001;

Baek et al, 2002; Wimazal et al, 2002) (Table VII). These

changes are sometimes excessive, thereby masking the

underlying mast cell disease. From a pathophysiological

point of view, these changes are most likely to result from

effects of cytokines [VEGF, basic fibroblast growth factor

(bFGF), others] derived from local neoplastic mast cells

(Table II).

The morphological assessment of a representative bone

marrow smear is a crucial diagnostic procedure in SM. First,

the recorded percentage of mast cells in a bone marrow

smear (for counting mast cells, areas examined should be

located away from any bone marrow particles) is an

important diagnostic and prognostic parameter (Sperr et al,

2001b). Notably, in most cases of ISM, the percentage of

mast cells is below 5%, whereas in aggressive mast cell

disease, the percentage of mast cells will often exceed 5%

(Table VIII). Moreover, an inverse correlation between the

percentage of mast cells and survival in SM has been

described (Sperr et al, 2001b). In those patients with SM

who have 20% mast cells in their bone marrow smear,

circulating mast cells are usually detected, and the final

diagnosis is mast cell leukaemia (Valent et al, 2001a,c;

Sperr et al, 2001b) (Table VIII). The morphology of mast

cells may yield additional information. In most patients with

Table V. Systemic mastocytosis: differential diagnoses to be considered during the haem-

atological and haematopathological work up.

Diagnosis Major considerations

Systemic mastocytosis a. At least one major and one minor or

three minor SM criteria are fulfilled

(for SM criteria see Table X)

Reactive mast cell hyperplasia a. Underlying disease; typical examples:

lymphomas, helminth infection, basal cell

carcinoma, melanoma, tissue inflammation

b. SM criteria to diagnose SM not fulfilled

Myelomastocytic leukaemia a. Diagnosis of non-mast cell lineage myeloid

neoplasm established (FABWHO criteria):

MDS, AML or MPD

b. Increase in immature metachromatic cells

in bone marrow smears or blood (> 10%)

c. These metachromatic cells are mast cells

defined by their phenotype or ultrastructure

d. SM criteria to diagnose SM not fulfilled

Tryptase+ myeloid neoplasm a. Diagnosis of non-mast cell lineage myeloid

neoplasm established (FAB

WHO criteria):MDS, AML or MPD

b. No increase in metachromatic cells

c. Serum tryptase level > 20 ngml

d. SM criteria to diagnose SM not fulfilled

AML with aberrant expression

of c-kit point mutation Asp-816-Val

a. Diagnosis AML established (WHO criteria)

b. No increase in metachromatic cells

c. SM criteria to diagnose SM not fulfilled

d. Asp-816-Val mutation detectable

Acutechronic basophilic leukaemia a. Criteria to diagnose basophilic leukaemia

b. SM criteria to diagnose SM not fulfilled

c. Metachromatic cells are basophils defined

by their phenotype andor ultrastructure

Non-Hodgkins lymphoma with

reactive focal increase in bone

marrow mast cells

a. Minor SM criteria missing even in cases

with focal dense mast cell accumulation at

lymphoma infiltrates (major criterion)

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ISM, the majority of mast cells appear to be spindle-shaped

with oval nuclei and a hypogranulated cytoplasm (atypical

mast cells type I; minor SM criterion) (Sperr et al, 2001b)

(Table VIII). In some patients with ISM, mast cells are round

and indistinguishable from normal tissue mast cells. In

contrast, in most patients with aggressive systemic masto-

cytosis and mast cell leukaemia, mast cells appear to be

immature with bi- or multilobed nuclei (atypical mast cells

type II; promastocytes) or even have a blast-like morphology

(metachromatic blasts) (Sperr et al, 2001b). Table IX pro-vides cytomorphological criteria for the classification of

various types of mast cells that can be detected on bone

marrow smears in patients with SM. All in all, the

cytomorphological and histological assessment of bone

marrow (mast) cells remains the most important diagnostic

approach in suspected SM. Lastly, the investigation of the

bone marrow may reveal a co-existing myeloid neoplasm

[FrenchAmericanBritish (FAB) or World Health Organ-

ization (WHO) criteria] thereby leading to the final diagnosis

of SM-AHNMD.

Apart from histological and morphological studies, it is

helpful to define the cell surface phenotype of aspirated bone

marrow mast cells by flow cytometry in patients with

suspected SM (Escribano et al, 1998, 2001). This may be

crucial when sufficient biopsy material cannot be obtained or

when the histological analysis is indeterminate. As described

above, mast cells in most patients with SM express an

aberrant phenotype including CD2 and CD25 (Escribano

et al, 1998, 2001) (Table I). Thus, using a multicolour flow

cytometry staining technique and antibodies against KIT for

mast cell detection, and CD2 and CD25, expression of these

antigens on mast cells can easily be demonstrated, consistent

with the diagnosis of SM (Escribano et al, 2001). However,

these antigens are not expressed on mast cells in all patients

with SM. Thus, a negative staining result for CD2 andor

CD25 on mast cells does not exclude the diagnosis of SM.

Another disease-related parameter (minor criterion) is the

transforming c-kit mutation Asp-816-Val. This c-kit muta-

tion is detectable in the bone marrow in a majority of

patients with SM, but is not detectable in most patients with

CM or those with a non-mast cell lineage haematopoietic

neoplasm in the absence of SM (Nagata et al, 1995; Longley

et al, 1996, 1999; Buttner et al, 1998; Fritsche-Polanz et al,2001). Therefore, this mutation is helpful in the diagnostic

work up in patients with suspected SM. In most cases of SM,

the c-kit mutation Asp-816-Val is detectable in aspirated

bone marrow cells, but is not detectable in the peripheral

blood. In some cases, however, the clonal disease process

disseminates into multiple haematopoietic cell lineages

[smouldering SM, SM-chronic myelomonocytic leukaemia

(SM-CMML), some cases with aggressive mastocytosis or

MCL] so that the mutation is also found in peripheral blood

cells (Nagata et al, 1995; Akin et al, 2000a; Jordan et al,

2001a; Hauswirth et al, 2002; Yavuz et al, 2002). Never-

theless, it is recommended that bone marrow cells (not only

blood-derived cells) should always be analysed for the c-kit

mutation Asp-816-Val in the work up of suspected SM (SM

criteria). Apart from the recurrent c-kit mutation Asp-816-

Val, several other c-kit mutations have been described in

patients with SM (Longley et al, 2001; Feger et al, 2002).

However, these mutations occur with much lower fre-

quency and therefore are not included in routine screening

tests in patients with suspected SM.

Based on the disease-related histopathological, molecular

and biochemical markers described above, criteria for the

diagnosis of SM (SM criteria) have been established by the

Table VI. Serum tryptase levels in myeloid neoplasms*.

Neoplasm Abbreviation

% of patients with

tryptase > 20 ngml

Systemic mastocytosis SM > 90

Acute myeloid leukaemia AML 3040

AML-M0 5060

AML-M1 2030AML-M2 6070

AML-M3 5060

AML-M4 1020

AML-M4eo > 80

AML-M5 < 20

AML-M6 < 20

AML-M7 < 50

Acute lymphoblastic leukaemia ALL < 10

Chronic myeloid leukaemia CML 3040

Chronic myelomonocytic leukaemia CMML 3040

Refractory anaemia RA 2030

RA with ringed sideroblasts RARS 2030

RA with excess of blasts RAEB < 10

*Data refer to the available literature (Schwartz et al, 1995; Schwartz, 2001; Sperr

et al, 2001a, 2002a,b).

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WHO (Table X). The major criterion is positive histology as

defined by multifocal dense infiltrates of mast cells in one or

more extracutaneous organ biopsies (in most cases, the

bone marrow is the primary site of detection of SM) (Valent

et al, 2001a,c). Minor criteria of SM include (i) the presence

of atypical spindle-shaped or promastocytic mast cells in the

Fig 1. Infiltration patterns of mast cells in the bone marrow of patients with indolent systemic mastocytosis (A and C), mast cell leukaemia (B)

and myelomastocytic leukaemia (D). Bone marrow sections were stained with an antibody against mast cell tryptase. The multifocal dense

mast cell infiltrate is typically found in patients with indolent disease. Note the prominent spindling of mast cells in (A). In some cases, the

infiltrate shows an additional diffuse component (C). However, this diffuse component does not alter the underlying normal bone marrow

architecture in indolent mastocytosis (C). In contrast, in patients with mast cell leukaemia (B) or myelomastocytic leukaemia (D), the diffuse

infiltrate of mast cells is typically associated with a significant alteration in the architecture of the surrounding bone marrow. In mast cell

leukaemia, mast cells form a dense and diffuse pattern of infiltration (B). Original magnification 100.

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bone marrow (> 25%); (ii) an elevated serum tryptase level

(>20 ngml) (not valid in the presence of an AHNMD); (iii)

presence of the c-kit mutation Asp-816-Val in one or more

extracutaneous organs (in most cases, the bone marrow is

examined); and (iv) expression of CD2 orand CD25 by bone

marrow mast cells. If at least one major and one minor or

three minor criteria are fulfilled, the diagnosis of SM is

established (Valent et al, 2001a,c) (Table X).

Once the diagnosis SM has been established, the subtype

needs to be determined. In fact, SM variants appear to vary

greatly in their clinical behaviour and in prognosis. Thus, a

number of prognostic factors concerning survival have been

identified in patients with SM (Lawrence et al, 1991; Sperr

et al, 2001b). These parameters include an elevated lactate

dehydrogenase (LDH) or alkaline phosphatase level, occur-

rence of significant haematological abnormalities or an

AHNMD, a high percentage of mast cells in bone marrow

smears and absence of urticaria pigmentosa (UP)-like skin

lesions. Some of these disease-related markers have (among

others) been used as the basis to define criteria and

subvariants for patients with SM (Valent et al, 2001a).

Based on these criteria and the WHO consensus classifica-

tion of mastocytosis, four major groups of patients with SM

and several subvariants have been defined: indolent sys-

temic mastocytosis (ISM), SM-AHNMD, aggressive systemic

mastocytosis (ASM) and mast cell leukaemia (MCL) (Valent

et al, 2001a,c).

Typical ISM is defined by SM criteria, presence of skin

lesions and absence of clinical or laboratory signs of (i)

smouldering disease (B-Findings); (ii) aggressive disease

(C-Findings); (iii) MCL; and (iv) an AHNMD. In some patients

with ISM, mastocytosis is confined to the bone marrow and

is then termed isolated bone marrow mastocytosis (BMM).

These patients fulfil the criteria for ISM, lack skin lesions,

have low tryptase levels and exhibit small mast cell infiltrates

in bone marrow biopsies. In smouldering systemic mastocy-

tosis (SSM), another subentity of ISM, SM criteria are fulfilled

and B-Findings (Table II) are detectable, whereas (i) no

C-Findings, (ii) no signs of MCL and (iii) no signs of an

AHNMD are found. B-Findings are indicative of a large

burden of neoplastic cells and include: (i) a high serum

tryptase level together with a high infiltration grade of mast

cells in the bone marrow; (ii) a hypercellular marrow with a

loss of fat cells and with signs of myeloproliferation; and (iii)

organomegaly (hepatosplenomegaly, lymphadenopathy)

that is attributable to mast cell infiltration (Valent et al,

Table VII. Histopathological and immunohistochemical findings in patients with systemic mastocytosis (SM).

Finding



Multifocal mast cell infiltrates*

Dense focal + + )/+ )/+ )/+

Dense plus diffuse +/)

+/)

+ +Dense plus focal with diffuse component (mixed pattern) )/+ + +/) + +

Loosely diffuse

Paratrabecular mast cells + + + + + +

Infiltration grade > 30% + +/) + +

Increased angiogenesis + + + + +

Focal accumulations of polyclonal lymphocytes

follicle-like aggregates

+ +/) )/+ +/)

Bone marrow eosinophilia +/) + +/) + +

Bone marrow fibrosis + + + +/) )/+

Osteosclerosis, thickening of bony trabeculae + +/) + + +

Myeloproliferation with loss of fat cells in

non-affected bone marrow

+ + +/) +/)

Dysplastic changes in the erythropoietic or

megakaryopoietic compartment

+ +/) +/) +/)

Expression of CD25 in mast cell infiltrates + + + + + +Expression of CD2 in neoplastic mast cells +/) +/) +/) +/) )/+ )/+

Expression of CD68 in neoplastic mast cells + + + + + +

*A diagnostic infiltrate (major criterion) is defined as a cluster composed of at least 1520 mast cells.

A diffuse pattern with loosely scattered mast cells is rarely found in patients with SM, i.e. in those with primary extramedullary (e.g.

splenic) involvement or those who have additional three minor criteria to fulfil the diagnosis SM.

In the immunohistochemical examination of mast cells in SM, the sensitivity of CD25 exceeds that of CD2 (contrasting flow cytometry).

ISM, indolent systemic mastocytosis; BMM, isolated bone marrow mastocytosis; SSM, smouldering systemic mastocytosis; SM-AHNMD,

systemic mastocytosis with an associated haematological clonal non-mast cell lineage disease; ASM, aggressive systemic mastocytosis;

MCL, mast cell leukaemia.

The following literature constitutes the basis of the material presented in this table: Lennert & Parwaresch (1979); Horny et al (1990b,

1993); Fukuda et al (1995); Li et al (1996); Jordan et al (2001b); Horny & Valent (2001, 2002); Li (2001); Wimazal et al (2002).

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2001a,c). If two out of these three B-Findings are detectable,

the diagnosis of SSM is established. Aggressive systemic

mastocytosis (ASM) is defined by organopathy with C-

Findings, a percentage of bone marrow mast cells of < 20%in bone marrow smears (excluding MCL) and no signs of an

AHNMD. As mentioned, C-Findings are indicative of

organopathy caused by aggressive mast cell infiltration.

The organ systems most frequently involved are the bone

marrow, skeletal system, liver, spleen and the GI tract

(Parwaresch et al, 1985; Travis & Li, 1988; Horny et al,

1989, 1992a,b; Metcalfe, 1991b; Valent, 1996). A special

subvariant of aggressive systemic mastocytosis is lympha-

denopathic mastocytosis with eosinophilia (Metcalfe,

1991a). In patients with SM-AHNMD, WHO criteria to

diagnose the AHNMD are fulfilled together with SM criteria.

MCL is defined by circulating mast cells and 20% mast cells

in bone marrow smears (Valent et al, 2001a). Table XI

shows a summary of SM variants.

The WHO criteria to diagnose SM and SM variants are

helpful in discriminating patients with SM from those with a

mast cell activation syndrome or a reactive mast cell

hyperplasia (Jordan et al, 2002) as well as in discriminating

SM from myelomastocytic disorders (Prokocimer & Polliack,

1981; Valent et al, 2001a,b,c, 2002b) or myeloid neoplasms

that express tryptase or the c-kit mutation Asp-816-Val

without convincing morphological evidence of mast cell

lineage involvement (Valent et al, 2001b) (Table V).

An exact knowledge about the disease and the particular

SM variant is an important basis for the management of

these patients. However, only a few recommendations for

the treatment of SM are based on solid evidence. Especiallyin the rare aggressive disease variants, no significant

database exists, and all drugs and therapies applied to these

rare variants must be judged experimental in nature. In

the following sections, we discuss briefly aspects of the

management and treatment of SM with an attempt to

provide and discuss available treatment options.

MANAGEMENT OF MEDIATOR-RELATED

SYMPTOMS

Mediator-related symptoms occur in patients with all

subtypes of SM (Austen, 1992; Marone et al, 2001; Castells

& Austen, 2002). Symptoms that are recurrent, severe and

require continuous medical treatment should be recognized

as a distinct disease-related problem by the physician. One

approach has been to define these patients by adding the

subscript SY in the final diagnosis (ISMSY, SM-AHNMDSY,

ASMSY, MCLSY) (Valent et al, 2001a). Mediator-related

symptoms in patients with SM are treated with agents that

interfere with mediator function, mediator production or

mediator release (Metcalfe, 1991c; Austen, 1992; Worobec,

2000; Marone et al, 2001; Castells & Austen, 2002;

Escribano et al, 2002a; Worobec & Metcalfe, 2002).

Table VIII. Typical cytomorphological findings on bone marrow and peripheral blood smears in patients with systemic

mastocytosis (SM).

Finding



Bone marrow

Percentage of mast cells< 1% +/) + )/+

< 5% + + +/) + +/)

> 5% +/) +/) +/) +

> 10% )/+ +

> 20% +

Spindle-shaped mast cells predominant + +/) + + +/) )/+

A substantial portion of mast cells have

bi- or multilobed nuclei promastocytes

)/+ +/) +/) +

Metachromatic blasts )/+ +/) +

Blast cells > 5% +/)

Eosinophilia +/) + +/) + +

Monocytosis* +/) +/) +/) +/) +/)

Myelodysplasia )/+ +/) )/+ )/+

Peripheral blood

Circulating mast cells +

Eosinophilia +/) + +/) + +

Monocytosis* )/+ +/) +/) +/) +/)

Circulating blasts +/) +/)

*Immature (agranular) mast cells may be counted as atypical monocytes in routine bone marrow and blood counts.

ISM, indolent systemic mastocytosis; BMM (isolated) bone marrow mastocytosis; SSM, smouldering systemic mast-

ocytosis; SM-AHNMD, systemic mastocytosis with an associated haematological clonal non-mast cell lineage disease;

ASM, aggressive systemic mastocytosis; MCL, mast cell leukaemia.

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Histamine-related symptoms generally respond to H1- and

H2-histamine receptor antagonists (Metcalfe, 1991c; Aus-

ten, 1992; Worobec, 2000; Marone et al, 2001). Other

antimediator drugs include glucocorticoids, cromolyn

sodium, acetylsalicylic acid (aspirin) and leukotriene antag-

onists (Metcalfe, 1991c; Austen, 1992; Worobec, 2000;

Escribano et al, 2002a; Worobec & Metcalfe, 2002). In

general, these drugs are prescribed based on the organ(s)and mediator(s) involved (Metcalfe, 1991c; Austen, 1992;

Marone et al, 2001; Castells & Austen, 2002; Escribano

et al, 2002a) (Table XII). Likewise, peptic ulcer disease

requires the use of a proton pump inhibitor andor

H2-antihistamines (Frieri et al, 1985; Gasior-Chrzan & Falk,

1992; Worobec, 2000; Escribano et al, 2002a). H1-blockers

are used to control pruritus in patients with SM (Worobec,

2000; Escribano et al, 2002a). Oral cromolyn sodium has

been reported to be effective in patients with SM suffering

from abdominal pain, diarrhoea, nausea or vomiting

(Dolovich et al, 1974; Soter et al, 1979; Horan et al,

1990) (Table XII). In addition, this drug may be effective

in some patients with SM suffering from pruritus or bone

pain (Alexander, 1985; Miner, 1991; Escribano et al,

2002a). In patients with recurrent and severe mediator-

associated symptoms (SMSY), short-term glucocorticoids

(2550 mg prednisone p.o. daily for several weeks) may

be considered (Worobec, 2000). In those who have devel-

oped or are at apparent risk of developing anaphylactoid

shock, the administration of epinephrine on demand

through a self-injector (Epi-Pen) seems an appropriate

recommendation (Metcalfe, 1991c; Austen, 1992; Woro-

bec, 2000; Worobec & Metcalfe, 2002). Aspirin, a

Table X. Criteria to diagnose systemic mastocytosis (SM criteria)*.

Major criterion Multifocal dense infiltrates of mast cells

(> 15 mast cells in aggregates) in bone

marrow biopsies andor in sections of other

extracutaneous organ(s)

Minor criteria a. > 25% of all mast cells are atypical cells

(type I or type II) on bone marrow smears

or are spindle-shaped in mast cell infiltrates

detected on sections of visceral organs

b. c-kit point mutation at codon 816 in the

bone marrow or another extracutaneous

organc. mast cells in bone marrow or blood or

another extracutaneous organ express

CD2 orand CD25

d. Baseline serum tryptase concentration

>20 ngml (in the case of an unrelated

myeloid neoplasm, (d) is not valid as an

SM criterion)

If at least one major and one minor or three minor criteria are

fulfilled, then the diagnosis is systemic mastocytosis SM.

*SM criteria have recently been published and have been adop-

ted by the WHO: Valent et al (2001a, c).

Table IX. Cytomorphological criteria of subsets of mast cells (MCs) detectable in the bone marrow of patients

with systemic mastocytosis (SM).

Cell type Criteria Proposed normal counterpart

Typical mast cell Round cells,

well granulated,

central round

nucleus

Mature tissue mast cell

Atypical mast cell type I a. Elongated surface

projections, often

spindle-shaped cells,

b. Hypogranulated

with focal granule

accumulations

c. Oval decentralized

nucleus.

Out of a, b and c,

at least two must be

fulfilled to call a cell

atypical MC type I

Unknown; spindle-shaped

normal mast cells are often

found in histological analyses

(MCs lining tissue elements)

but usually not on bone

marrow smears in the absence of SM

Atypical mast cell type II

promastocyte

Mostly immature, with

bi- or multi-lobed nuclei

Immature mast cell

Metachromatic blast Myeloblast with a

few metachromatic

granules

Immature mast cell-

committed progenitor

The nomenclature and criteria refer to the published literature and recently defined WHO criteria:

Sperr et al (2001b); Valent et al (2001a, c).

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compound that interferes with prostaglandin production,

has been proposed for patients with severe flushing,

tachycardia and syncope (Austen, 1992). However, aspirin

must be used with great caution. First, the starting dose

may itself cause vascular collapse in an idiosyncraticresponse. Moreover, the risk of gastrointestinal bleeding

has to be taken into account, especially in patients with a

known peptic ulcer, thrombocytopenia or hyperheparinae-

mia. Therefore, aspirin cannot be routinely recommended

to all patients with SM. Together, a number of antime-

diator drugs are available for the treatment of SM. In

contrast, mediator-related symptoms should usually not be

treated with cytoreductive drugs, i.e. cytostatic agents or

chemotherapy, although such an approach has been

considered for some patients with severe and recurrent

life-threatening episodes of mediator-related events resist-

ant against antimediator drugs. In such cases, the

hazards and risks of side-effects of the cytostatic drug

have to be calculated carefully and balanced against thebenefit that may result from a reduction in the mast cell

burden. In addition, some of these drugs may again cause

the release of mediators from mast cells in these patients.

Similarly, in patients with aggressive mast cell disease,

cytoreductive drugs or polychemotherapy may quite often

lead to (an increased) release of mast cell mediators. In

these patients, mediator-targeting drugs should be used as

important prophylactic adjuncts to cytoreductive drugs

(chemotherapy).

Apart from cytostatic drugs, a number of other triggering

factors and compounds may variably induce or promote

mediator release from mast cells in patients with SM. These

factors include environmental or emotional stress, some

drugs (aspirin, morphine and its derivatives, tubocurarin-type muscle relaxants, some antibiotics, amphotericin B and

others), alcohol or radiographic contrast media (Benyon

et al, 1987; Lawrence et al, 1987; Stellato et al, 1991, 1992,

1996; Marone & Stellato, 1992; Stellato & Marone, 1995;

Peachell & Morcos, 1998; Marone et al, 2001; Escribano

et al, 2002a). In patients with a co-existing allergy, mediator

release may be a significant and life-threatening problem

(Fricker et al, 1997; Oude-Elberink et al, 1997; Biedermann

et al, 1999; Metcalfe, 2000). Therefore, it is of particular

importance to be aware of these reactions, and to avoid

possible triggering factors in patients with SM (Escribano

et al, 2002a). In addition, it is important to be aware of such

reactions in patients who undergo surgery (anaesthesia).

Respective perioperative recommendations have been pro-posed (Scott et al, 1983; James et al, 1987; Greenblatt &

Chen, 1990; Lerno et al, 1990; Goins, 1991; Yaniv et al,

1992; Borgeat & Ruetsch, 1998).

THERAPY OF CUTANEOUS INVOLVEMENT

Typical cutaneous lesions in SM are maculopapular and

indistinguishable from that detectable in patients with CM.

The extent of involvement of the skin is variable, ranging

Table XI. WHO classification of systemic mastocytosis.

Variants and subvariants Proposed abbreviation

Indolent systemic mastocytosis ISM

Provisional subvariants:

Isolated bone marrow mastocytosis BMM

Smouldering systemic mastocytosis SSM

SM with an associated haematopoietic clonal non-mast

cell lineage disease

SM-AHNMD

Proposed subvariants:

SM acute myeloid leukaemia* SM-AML

SM myelodysplastic syndrome (RA, RARS, )* SM-MDS

SM myeloproliferative disease (IMF, ET, PV, )* SM-MPD

SM chronic myeloid leukaemia* SM-CML

SM chronic myelomonocytic leukaemia* SM-CMML

SM non-Hodgkins lymphoma* (diverse subentities)* SM-NHL

Aggressive systemic mastocytosis ASM

Proposed subvariant:

Lymphadenopathic mastocytosis with eosinophilia

Mast cell leukaemia MCL

The classification of SM is part of the recently established WHO consensus classifi-

cation of mastocytosis (Valent et al, 2001a, b).

*Criteria and the classification of AML, MDS and other haematopoietic malignancies

have to be applied according to guidelines provided by the FrenchAmericanBritish

co-operative study group (FAB) and the WHO.

IMF, idiopathic myelofibrosis; ET, essential thrombocythaemia, PV, polycythaemia

vera.

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from a few lesions to extensive generalized exanthema

(Hartmann et al, 2001; Wolff et al, 2001; Hartmann &

Henz, 2002). Unlike in the paediatric age groups, skin

lesions in SM in adults are persistent in most cases. In fact,

only a few adult patients (roughly 10%) appear to have

spontaneous regression (Metcalfe, 1991a; Brockow et al,

2002). In some of these individuals, disappearance of

cutaneous lesions is accompanied by a progression of

visceral mastocytosis (Brockow et al, 2002). This observa-

tion is consistent with the paradox that patients with

aggressive mast cell disease typically lack urticaria pigmen-

tosa-like skin lesions (Parwaresch et al, 1985; Metcalfe,

1991a; Valent, 1996).

In most patients with SM, the skin lesions primarily

represent a cosmetic problem. In other patients, however,

the lesions do cause severe discomfort or are accompanied

by severe mediator-related symptoms including flushing

and itching (Hartmann et al, 2001; Wolff et al, 2001). A

number of strategies have been proposed for the treatment

of urticaria pigmentosa-like skin lesions. Mild symptoms

may respond to antihistamines. A more intensive and

effective treatment is oral psoralen + UV-A PUVA

(Hartmann et al, 2001; Wolff et al, 2001) (Table XII).

Thus, in response to PUVA, a substantial regression of skin

lesions is seen in many patients (Christophers et al, 1978;

Kolde et al, 1984; Czarnetzki et al, 1985; Godt et al, 1997;

Wolff, 2002). However, responses are variable in duration,

and most patients require long-term treatment, with

repeated cycles of PUVA. An alternative to PUVA is the

application of topical glucocorticoids (Hartmann et al,

2001; Wolff, 2002) (Table XII). In patients with severe

systemic symptoms, mediator-targeting drugs including

H1- plus H2-antihistamines and short-term oral glucocor-

ticoids may be required.

Table XII. Mediator-targeting drugs prescribed in patients with systemic mastocytosis (after diagnosis is confirmed).

Clinical symptoms and

mediator effects Step Drugs to be considered

Skin

Pruritus, flushing 1 H1 + H2-histamine receptor antagonists

2 Ketotifen, topical glucocorticoids

3 PUVACardiovascular system

Recurrent hypotension 1 H1 + H2-histamine receptor antagonists

and tachycardia 2 Glucocorticoids

3 Aspirin in selected cases (if tolerable)

Recurrent shock 1 H1 + H2-histamine receptor antagonists +

epinephrine on demand (self injector)

2 Oral glucocorticoids + epinephrine on demand

(self injector)

3 Aspirin in select cases (if tolerable) + epinephrine

on demand (self injector)

Co-existing allergy 1 H1 + H2-histamine receptor antagonists

2 Short-term oral glucocorticoids

Consider also:

Hyposensitizationimmunotherapy

Avoidance of triggering factorsGastrointestinal tract

Peptic ulcer disease 1 H2-histamine receptor antagonists

2 Proton pump inhibitors + H2-blockers

Diarrhoea, abdominal pain,

abdominal cramping, nausea, vomiting

1 H1 + H2-histamine receptor antagonists

2 Oral cromolyn sodium

3 Consider trial with leukotriene antagonists

4 Short-term glucocorticoids

Skeletal system

Bone pain 1 Analgesias, aspirin-like drugs (if tolerable)

Also consider radiation for severe localized bone pain

Osteopenia, diffuse osteoporosis 1 Vitamin D + calcium or oestrogentestosterone

on demand

2 Biphosphonates

3 Consider IFN-a (suspected aggressive disease)

Neurological symptoms

1 H1 + H2-histamine receptor antagonists

2 Oral cromolyn sodium

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WHO SHOULD RECEIVE SYSTEMIC

GLUCOCORTICOIDS?

Glucocorticoids counteract the growth of mast cells through

multiple mechanisms, including a direct inhibitory effect on

mast cells, as well as a suppressive effect on SCF-producing

cells in tissues (Daeron et al, 1982; Robin et al, 1985;

Finotto et al, 1987; Wershil et al, 1995; Eklund et al, 1997).

However, as long-term treatment is often associated withsevere side-effects, the administration of systemic glucocor-

ticoids in SM should be restricted to distinct clinical

situations, and the dose kept as low and brief as possible in

all cases (Escribano et al, 2002a; Valent et al, 2003). Apart

from significant mediator-related symptoms, glucocorticoids

should be considered for patients with aggressive systemic

mastocytosis and MCL (Valent et al, 2003) (Table XIII). In

fact, the initiation of prednisolone (5060 mg p.o. daily)

without other drugs may improve SM-related organopathy,

especially in patients with GI tract involvement and malab-

sorption or hepatomegaly with ascites (Metcalfe, 1991a;

Worobec, 2000). However, glucocorticoids are usually not

prescribed as a single agent in aggressive SM, but are usually

combined with cytoreductive drugs. In most cases of

aggressive systemic mastocytosis, prednisone (or predniso-

lone) is combined with interferon-alpha-2b (IFN-a2b) (see

below). We recommend starting glucocorticoids a few days

before initiating IFN-a2b (Valent et al, 2003). In addition,

glucocorticoids have been considered as an adjunct to

polychemotherapy in patients with MCL. In respondingpatients, the glucocorticoid dose can (sometimes) be tapered

down to a low maintenance dose (e.g. 510 mg of predni-

sone p.o. daily) after some weeks (or months), and then

possibly be discontinued. In those with diffuse osteoporosis,

the use of glucocorticoids should be avoided if possible.

SELECTION OF PATIENTS FOR CYTOREDUCTIVE

THERAPY

Cytoreductive drugs have multiple side-effects, and most of

them are considered to be mutagenic, thereby potentially

Table XIII. Options for cytoreductive treatment in patients with systemic masto-

cytosis (SM).

Disease variant Treatment options

Typical indolent systemic

mastocytosis (ISM)

No cytoreductive treatment required*

Exception: consider IFN-a2b for severe osteoporosis

even if no histology documenting ASM is available,

these cases are considered as probably ASM

Smouldering systemic

mastocytosis (SSM)

Watch and wait in most cases. However,

in selected cases (rapidly progressive B-Findings),

IFN-a2b glucocorticoids can be considered

SM-AHNMD Treat AHNMD as if no SM is present

and also treat SM as if no AHNMD is found

If splenomegaly and hypersplenism prohibit

therapy consider splenectomy

Aggressive systemic

mastocytosis (ASM)

with slow progression

IFN-a2b glucocorticoids or

cladribine 2CdA.



ASM rapid progression

and patients who do not

respond to IFN-a2b

Polychemotherapy ( IFN-a2b); consider

bone marrow transplantation in select cases.



Consider cladribine (2CdA)

Consider hydroxyurea as palliative drug

Mast cell leukaemia

(MCL)

Polychemotherapy or 2CdA ( IFN-a2b)

Consider bone marrow transplantationIf splenomegaly and hypersplenism prohibit


Consider hydroxyurea as palliative drug

IFN, interferon; SM-AHNMD, systemic mastocytosis with an associated haemato-

logical clonal-non-mast cell lineage disease.

*In some studies, IFN-a was also found to improve mediator-related symptoms, and

therefore was recommended for patients with ISM (Casassus et al, 2002). However, in

these cases, the side-effects of the drug have to be taken into account and balanced

against beneficial effects.

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increasing the risk of disease progression and the develop-

ment of secondary leukaemias. Many have to be used in

various countries on a humanitarian basis as they may not

be recognized therapy, there being insufficient numbers of

patients to permit clinical trials. These drugs should thus be

administered only to those patients with SM who have clear

signs of an aggressive disease (C-Findings) and only after the

full information regarding the potential risks and side-effects

is understood by the patient and medical care team. In thisregard, it is important to document the presence of C-

Findings that are reflective of significant organopathy

(impaired organ function) caused by mast cell infiltration

and thus are a reliable indication for an aggressive SM

variant. Sometimes it may be necessary to perform organ

biopsies to confirm the diagnosis of aggressive systemic

mastocytosis (C-Findings).

In contrast to aggressive mastocytosis, patients with ISM

should usually not be considered for cytoreductive therapy.

An exception may be smouldering SM. In these patients,

clinical and laboratory signs of a significant proliferation of

neoplastic cells (hepatomegaly, splenomegaly, lymphaden-

opathy, hypercellular marrow, leucocytosis, mild cytope-nias) without frank organopathy (no C-Findings) are found

(Akin et al, 2001; Jordan et al, 2001a; Valent et al, 2002a).

In these patients, it is difficult to predict the clinical course

and thus to decide on cytoreductive therapy at first

presentation. These cases should be followed carefully over

time in order to determine whether the disease process

shows rapid progression. In some patients, it may then be

justified to recommend cytoreductive therapy, even if no

overt impairment of organ function is found (Table XIII).

For most patients with smouldering SM, the approach is to

watch and wait until clear signs of organopathy (shift to

aggressive category of SM) develop.

Once the diagnosis of aggressive mast cell disease (ASM,

MCL or ASM-AHNMD) has been established, patients shouldbe considered for treatment with cytoreductive drugs. It must

be noted, however, that all available drugs are experimental

in nature. Experimental cytoreductive drugs that have been

proposed include interferon-alpha, cytosine arabinoside

(ARA-C), cladribine (2CdA), doxorubicin, daunorubicin,

hydroxyurea and vincristine (Travis et al, 1986; Kluin-

Nelemans et al, 1992; Worobec, 2000; Tefferi et al, 2001;

Valent et al, 2003). These drugs have been used alone or in

combination (Travis et al, 1986; Worobec, 2000; Valent

et al, 2003). The treatment outcome in SM using such drugs

appears to be variable andto dependon thesubtype of disease.

Thus, it is of importance to determinethe subtype of SM before

initiating treatment. When considering these drugs, it should

also be kept in mind that SM cannot be cured using currently

available compounds, and that no evidence-based approach

or standard therapy exists.

WHO SHOULD RECEIVE INTERFERON-ALPHA?

Over the past several years, interferon alpha (IFN-a) has

been introduced successfully as a stem cell targeting and

probably non-mutagenic cytoreductive drug for patients

with myeloproliferative disorders. The view that SM is

related to this group of myeloid neoplasms encouraged

clinicians to use this drug also in patients with aggressive

systemic mastocytosis or mast cell leukaemia. Indeed, in

some patients with aggressive mastocytosis, IFN-a2b,

administered in combination with or without glucocortic-

oids, produced long-lasting depression in mast cells (Kluin-

Nelemans et al, 1992; Pulik et al, 1994; Delaporte et al,

1995; Fiehn et al, 1995; Lehmann et al, 1996; Weide et al,

1996; Worobec et al, 1996; Butterfield, 1998; Chosidowet al, 1998). Moreover, IFN-a may improve mediator-related

symptoms in patients with SM (Casassus et al, 2002). As no

other effective treatment has become available for patients

with aggressive mastocytosis to date, it seems appropriate to

start with a combination of IFN-a2b and glucocorticoids in

these patients (Table XIII). One approach is to start with

prednisolone(5075 mg p.o. daily)a fewdaysbefore IFN-a2b

is introduced and to keep the patient hospitalized initially.

During the first weeks, IFN-a2b is usually administered at 3

million units three times a week. Depending on the response

and occurrence of side-effects, the dose of IFN-a2b is then

increased, whereas prednisolone should be tapered to a low

maintenance dose, or discontinued if possible. In patientswith MCL, IFN-a2b may also be administered together with

glucocorticoids, although the response may not be long-

lasting. In fact, more aggressive therapy appears to be

required to treat patients with MCL (Table XIII). In patients

with severe diffuse osteopenia (osteoporosis) and multiple

bone fractures considered to be a result of mast cell

infiltration (C-Finding), it may be appropriate to prescribe

IFN-a2b without glucocorticoids (Lehmann et al, 1996;

Escribano et al, 2002a).

ALTERNATIVES TO INTERFERON-ALPHA FOR

TREATMENT OF AGGRESSIVE MASTOCYTOSIS

Based on the current literature, only a subgroup ofpatients with aggressive systemic mastocytosis have exhib-

ited long-lasting clinical responses to IFN-a2b (Worobec

et al, 1996; Butterfield, 1998; Tefferi et al, 2001; Valent

et al, 2003). For non-responding patients, a number of

treatment options have been proposed (Table XIII). For

those patients who show a rapid progression despite IFN-

a2b, more aggressive treatment such as polychemotherapy

or even bone marrow transplantation should be considered

(similar to patients with MCL) (Table XIII). In patients with

slowly progressing disease, a number of experimental

drugs such as 2-chlorodeoxy-adenosine (cladri-

bine 2CdA) or cyclosporin A may be used (Tefferi et al,

2001; Escribano et al, 2002b; Valent et al, 2003). Espe-

cially, 2CdA appears to be an effective agent and may

significantly reduce the mast cell burden, albeit temporar-

ily, in a subgroup of patients with SM. Palliative cytor-

eductive treatment with hydroxyurea (on demand) is an

alternative for those patients who do not respond to IFN-a

or 2CdA (or other drugs) (Worobec, 2000; Valent et al,

2003). The use of the tyrosine kinase inhibitor STI571

(Imatinib) has also been proposed. However, although

STI571 can effectively kill mast cells bearing the wild-type

c-kit (Akin et al, 2003), the presence of the Asp-816-Val

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mutation causes resistance to STI571 (Ma et al, 2002).

Thus, such therapy may only be considered for those

(minor group) SM patients in whom no transforming

mutation at codon 816 was found. In line with this

notion, patients with aggressive systemic mastocytosis or

mast cell leukaemia in whom the c-kit mutation Asp-816-

Val is found fail to show clinical responses to Imatinib

(unpublished observation). However, a number of other

tyrosine kinase inhibitors are currently being developed,and some of them appear to counteract not only wild-type

KIT, but also the tyrosine kinase activity of the Asp-816-

Val-mutated form of KIT (Liao et al, 2002).

Apart from drug therapies, a number of other palliative

treatment options have been proposed for patients with

aggressive mastocytosis or mast cell leukaemia. In case of

severe bone pain and local osteodestruction, radiation

therapy is a treatment option. In patients with massive

splenomegaly and resulting severe thrombocytopenia,

splenectomy may be considered in an attempt to increase

platelet counts and to maintain cytoreductive therapy at the

required dose (Friedman et al, 1990).

TREATMENT OPTIONS FOR PATIENTS WITH MAST

CELL LEUKAEMIA

MCL is a rare disease characterized by the rapid growth of

neoplastic cells in the bone marrow as well as in visceral

organs, with resultant organopathy (Lennert & Parwaresch,

1979; Parwaresch et al, 1985; Dalton et al, 1986; Travis

et al, 1986; Metcalfe, 1991b; Valent, 1996). As in other

aggressive variants of SM, skin lesions are usually absent

(Parwaresch et al, 1985). In contrast to other SM variants,

circulating mast cells are detectable in MCL, and the bone

marrow smear contains 20% mast cells (Travis et al,

1986; Sperr et al, 2001b; Valent et al, 2001a). The prog-

nosis in MCL is grave, and no effective treatment is yetavailable for these patients (Travis et al, 1986). Thus, in

contrast to aggressive mastocytosis, patients with MCL may

not have long-lasting remissions when treated with IFN-a2b

and glucocorticoids. Monotherapy with other conventional

cytoreductive drugs may also be without a long-lasting

effect (Travis et al, 1986). However, in some patients with

MCL, short-term remission has been achieved using poly-

chemotherapy regimens or using IFN-a2b in combination

with other drugs (Travis et al, 1986; Worobec, 2000).

Therefore, administration of aggressive polychemotherapy

should be considered in patients with MCL in an attempt to

induce remission or at least lead to a significant reduction in

the tumour burden (Table XIII). Chemotherapy regimens

similar to those used to treat high-risk acute myeloid

leukaemia (AML) patients may be an option (Travis et al,

1986; Sperr et al, 2000; Worobec, 2000). The application of

2CdA together with other drugs may also be considered. In

each case, the patient must be able to tolerate chemother-

apy. If a bone marrow donor is available, responding

patients may be considered for bone marrow transplanta-

tion (Table XIII), although no reported experience with this

experimental therapeutic manoeuvre in MCL is available.

Another strategy would be to apply consolidation chemo-

therapy as for AML in the responding patients or to

introduce maintenance treatment with IFN-a and gluco-

corticoids or other experimental drugs.

MAST CELL SARCOMA

Mast cell sarcoma (MCS) is an extremely rare mast cell

disease. In contrast to SM, MCS is a local tumour that

consists of immature atypical mast cells and shows adestructive growth pattern (Parwaresch et al, 1985). There-

fore, MCS is considered as a separate disease entity (Parwa-

resch et al, 1985; Horny et al, 1986; Valent et al, 2001a).

However, the biology and pathology of the afflicted cells and

the clinical course suggest that mast cell sarcoma is related

to the group of aggressive mast cell disorders (ASM, MCL).

Moreover, in all cases recorded, secondary dissemination

with involvement of visceral organs has been reported, and

the terminal phase may closely resemble aggressive systemic

mastocytosis or mast cell leukaemia (Horny et al, 1986;

Kojima et al, 1999; Gunther et al, 2001). Treatment options

for patients with MCS appear to be limited. In the few cases

reported, survival time was short despite surgery, radiationand polychemotherapy (Horny et al, 1986; Kojima et al,

1999; Gunther et al, 2001). Once secondary generalization

has occurred (transition to aggressive mastocytosis or MCL),

the management and treatment should follow the guidelines

described above for the management of aggressive masto-

cytosis and mast cell leukaemia.

TREATMENT OF ASSOCIATED HAEMATOPOIETIC

MALIGNANCIES (AHNMD)

The frequent occurrence of an AHNMD in patients with SM is

consistent with the notion that SM behaves as a myelopro-

liferative disease. In most patients, a myeloid neoplasm such

as a myelodysplastic syndrome (MDS), a myeloproliferativedisease (MPD) or an AML is diagnosed (Travis et al, 1988b;

Horny et al, 1990a; Lawrence et al, 1991; Sperr et al, 2000).

Lymphoid neoplasms may also develop, but less frequently

compared with myeloid malignancies. Such lymphoid neo-

plasms aremostly of B-cellorigin. In allcases, WHOcriteriato

diagnose myeloid or lymphoid neoplasms should be applied.

In most patients, it willbe easy todiagnose an AHNMD in SM.

However, sometimes it may be difficult to distinguish between

SM-AHNMD and smouldering mastocytosis, or between

aggressive systemic mastocytosis and SM-AHNMD. In such

cases, additional disease characteristics (karyotype, colony-

forming progenitors) and the clinical course may ultimately

lead to the correct diagnosis. Once the diagnosis of

SM-AHNMD has been established, separate treatment plans

for SM andthe AHNMD have to be established (Parker, 1991;

Sperr et al, 2000; Worobec, 2000; Valent et al, 2001a). In

this process, it is of importance to be aware that the mast cell

componentof thedisease(SM)in patients with SM-AHNMD

can be indolent (ISM-AHMD) or aggressive (ASM-AHNMD)

and, similarly, the AHNMD can be an aggressive or indolent

disorder (Valent et al, 2003). The general approach for

patients with SM-AHNMD is to treat SM as if no AHNM is

present, and the AHNMD as if no SM has been diagnosed

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(Sperr et al, 2000; Valent et al, 2001a,c; Escribano et al,

2002a) (Table XIII). For example, it has been reported that

standard polychemotherapy is quite effective in producing

complete remission of AML in patients with SM-AML

(although SM may not respond to this therapy) (Sperr et al,

1998, 2000). Sometimes, both SM and AHNMD may be

responsive to a single drug such as IFN-a2b. Thus, the

treatment of patients with SM-AHNMD depends on the

nature and course of the SM and the AHNMD, as well as onthe overall status of the patient (Parker, 1991; Valent et al,

2001a).

DISEASE MONITORING AND FOLLOW-UP

Patients with SM should be evaluated at routine intervals,

depending on the type of SM, presence of mediator-related

symptoms, co-existing disorders and therapy. In ISM with-

out significant medical complications, annual determina-

tions of the serum tryptase level and monitoring of blood

counts and liver function is appropriate. For patients with

ISM suffering from severe mediator-related symptoms

(ISMSY

), it may sometimes be helpful to monitor serumtryptase levels. In patients who have the smouldering

subtype of ISM, more frequent evaluations may be required

to monitor the course (progression) of disease (B-Findings).

Important parameters include the serum tryptase levels,

blood counts and degree of organomegaly (spleen, liver,

lymph nodes). In patients with suspected progression to MCL

or SM-AHNMD, a repeat bone marrow aspirate and biopsy

should be performed. Patients with aggressive systemic

mastocytosis and mast cell leukaemia must be monitored

closely before and during treatment with cytoreductive

drugs. In these patients, a number of parameters should be

followed, namely those reflecting C-Findings (such as liverenzymes, serum calcium, haemoglobin, abnormal X-rays,

others) and those reflecting the burden of neoplastic mast

cells (bone marrow histology, serum tryptase levels). During

treatment with cytoreductive drugs, C-Finding-related

parameters may show significant improvement (clinical

response). In responding patients, the mast cell-related

parameters may also improve or even return to normal

(complete remission). However, such complete remissions

are only seen in exceptional cases using currently available

forms of treatment. Notably, even when using polychemo-

therapy, mast cell infiltrates often remain unchanged.

RESPONSE CRITERIA

The response to mediator-targeting drugs is judged on clin-

ical criteria including the patients subjective assessment

Table XIV. Proposed response criteria for patients with systemic mastocytosis

treated with cytoreductive drugs.

Response Criteria

I. Major response Complete resolution of one or more

C-Findings and no progression

of other organopathiesa. Complete remission Disappearance of mast cell infiltrates

and decrease in tryptase to < 20 ngml;

Disappearance of organomegaly

b. Incomplete remission Decrease in mast cell infiltrates

in affected organs andor substantial

decrease in serum tryptase andor

visible regression of organomegaly

c. Pure clinical response No decrease in mast cell infiltrates,

no decrease in tryptase levels and

no regression of organomegaly

II. Partial response Incomplete regression of one or more

C-Finding(s)* without complete regression

and no progress in other C-Findings

a. Good (significant) partial

response

> 50% regression

b. Minor response 50% regression

III. No response C-Finding(s) persistent or progressive

a. Stable disease C-Findings show constant range

b. Progressive disease C-Finding(s) show(s) progression

*With or without decrease in mast cell infiltrates, serum tryptase levels and

organomegaly.

In case of progressive C-Findings and documented response in other

C-Finding(s), the final diagnosis is still progressive disease. For details con-

cerning response criteria, see Valent et al (2003).

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of improvement, and thus is difficult to quantify. Con-

cerning organopathy and the effect of cytoreductive

drugs, however, objective treatment response criteria have

been proposed (Valent et al, 2003). Thus, a major

response, a partial response and the failure of treatment

have been defined. Respective criteria can be applied to

patients with aggressive systemic mastocytosis (ASM),

mast cell leukaemia (MCL) and ASM-AHNMD. Table XIV

shows a summary of proposed response criteria. A majorresponse (MR) is defined by complete regression of

organopathy (defined by resolution of C-Findings).

Patients exhibiting such a major clinical response can

be divided further into those achieving complete remission

(pathologically confirmed response disappearance of

mast cell infiltrates and surrogate markers), incomplete

remission (incomplete regression of mast cell infiltrates)

and an isolated clinical response (disappearance of

organopathy without changes in mast cell infiltrates). A

partial response (PR) is defined by a measurable improve-

ment in organopathies. This group of patients can be

divided further into those with a good partial response

(regression of C-Findings to > 50%) and those with aminor response (regression of C-Findings to < 50%).

Patients without a response can either exhibit stable dis-

ease (no change in organopathy) or progressive disease.

Table XIV provides a summary of response types and

respective criteria. Applying these criteria, patients treated

with IFN-a glucocorticoids show an actual rate of

major response of approximately 20% (Valent et al,

2003).

FINAL REMARKS AND FUTURE PERSPECTIVES

Systemic mastocytosis is a heterogeneous disease of myel-

omastocytic progenitors with clonal expansion and a

relationship to myeloproliferative disorders. The course ofthe disease and prognosis vary among patients. The

treatment of patients with SM has to be selected based on

the subtype of disease, presence of mediator-related symp-

toms and occurrence of an associated haematopoietic non-

mast cell lineage disease. Mediator-related symptoms are

managed using mediator-targeting drugs. Uncontrolled

growth of mast cells in aggressive disease variants is treated

with (experimental) cytoreductive drugs such as IFN-a,

2CdA or polychemotherapy. Based on available informa-

tion, the tyrosine kinase inhibitor STI571 (Imatinib) does

not appear to inhibit the autophosphorylation of KIT

bearing the Asp-816-Val mutation, and is thus not predic-

ted to be useful in the majority of patients with aggressive

mastocytosis. However, there may be occasional patients

who are found to lack a mutation in KIT at codon 816 after

careful molecular analysis of lesional mast cells. Such

patients may be potential candidates for experimental

therapy with Imatinib, although this possibility has yet to

be explored. In addition, new treatment options may

become available with the generation of more specific

targeted therapy, including those drugs that inhibit the

tyrosine kinase activity of KIT exhibiting transforming

mutations at codon 816.

Peter Valent1

Cem Akin2

Wolfgang R. Sperr1

Hans-P. Horny3

Michel Arock4

Klaus Lechner1

John M. Bennett5

and Dean D. Metcalfe2

1Department of Internal

Medicine I, Division of

Haematology, University of

Vienna, Austria, 2Laboratory

of Allergic Diseases, National

Institute of Allergy andInfectious DiseasesNational

Institutes of Health,

Bethesda, MD, USA,3

Institute of Pathology,

University of Lubeck,

Germany,4

Laboratoire

dHematologie Cellulaire

et Moleculaire, Faculte

de Pharmacie, Paris,

France, and 5Haematology,

Medical Oncology Division,

James P. Wilmot

Cancer Center, University

of Rochester,

Medical Center,

Rochester, NY, USA

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