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The Hematology Journal (2002) 3, 90 ± 94 2002 The European Hematology Association All rights reserved 1466 ± 4680/02 $25.00 www.nature.com/thj
MINI REVIEW
Myelomastocytic leukemia: myeloid neoplasm characterized by partial dierentiation of mast cell-lineage cells Peter Valent*,1, Puchit Samorapoompichit2, Wolfgang R Sperr1, Hans-Peter Horny3 and Klaus Lechner1 1
Department of Internal Medicine I, Division of Hematology and Hemostaseology, University of Vienna, Austria; 2Institute of Histology and Embryology, University of Vienna, Austria; 3Institute of Pathology, University of LuÈbeck, Germany
A novel subtype of myeloid leukemia exhibiting a partial dierentiation of mast cell-lineage cells is described. The disease is characterized by an increase in myeloblasts as well as an increase in immature (blast-like) metachromatic cells (410% in bone marrow or blood smears). Metachromatic cells express KIT (CD117) and tryptase, but lack basophil-related antigens. In contrast to mast cell leukemia/systemic mastocytosis, metachromatic cells do not express CD2 or CD25, do not form multifocal dense aggregates in the bone marrow, and do not exhibit transforming mutations at codon 816 of c-kit. In the few patients recorded so far, a complex karyotype without recurring anomaly was found. The prognosis appears to be grave, although complete remission in response to chemotherapy has been described. The Hematology Journal (2002) 3, 90 ± 94. DOI: 10.1038/sj/thj/6200164 Keywords:
myeloid leukemia; mastocytosis; mast cells; c-kit; tryptase
Introduction Mast cells (MC) are hemopoietic cells that produce diverse mediators including cytokines, proteases, or histamine.1 In common with other hemopoietic cells, MC derive from uncommitted progenitors that can be detected in the bone marrow (bm) as well as in the peripheral blood. In contrast to other myelopoietic cells, however, MC complete their dierentiation in extramedullary organs and usually are not detectable in the blood stream.1 In addition, MC dier from blood basophils in terms of granular mediators, expression of surface antigens (Table 1), and response to cytokines.1,2 The stroma cell-derived cytokine stem cell factor (SCF) is a major regulator of growth and function of MC.3,4 This cytokine acts on MC and their progenitor cells by binding to the c-kit proto-oncogene product (=SCF receptor, KIT=CD117).3,4 SCF receptors are expressed on uncommitted and MC-committed progenitor cells as well as on mature MC. Functional defects in the SCF gene or c-kit gene in mice are associated with a MC-de®cient phenotype.5 Signi®cant dierentiation of MC in myeloid neoplasms has been described. Thus, in patients with myelodysplastic syndromes (MDS) or myeloprolifera6±9
*Correspondence: Dr P Valent, Department of Internal Medicine I, Division of Hematology and Hemostaseology, University of Vienna, Austria; Tel: +43 1 40400 6085; Fax: +43 1 402 6930; E-mail:
[email protected] Received 13 February 2002; accepted 25 February 2002
tive diseases (MPD), an increase in the number of bm MC is often recorded.6 However, in most cases, the increase is slight and not accompanied by clinical symptoms or ®ndings (criteria) of systemic mastocytosis.6 In some patients, however, the increase in MC is remarkable. In such cases, the disease can even mimic mast cell leukemia (MCL) although the criteria for a primary MC disease (mastocytosis) are not met.7 ± 10 These cases have been referred to as myelodysplastic mast cell syndrome or myelomastocytic leukemia.8 ± 11 The current article gives a short overview on our knowledge about this novel type of myeloid neoplasm.
Hematologic ®ndings and diagnostic criteria Patients with myelomastocytic leukemia have an increase in blast cells (45% in bone marrow smears) as well as 410% metachromatic cells in their bm or/ and peripheral blood smears.9 Blast cells are myeloblasts by morphologic or/and immunophenotypic criteria. Thus, patients are diagnosed to have MDS, MPD, or AML (blast cells 520%) according to FAB and WHO criteria.12 ± 16 Based on recently established WHO criteria, two of the patients described so far had AML, one had RAEB, one chronic myeloid leukemia (CML), and one patient chronic myelomonocytic leukemia (CMML). Myelomastocytic leukemia is a rare disease. Less than 5% of all patients with MDS and AML fall into this category.
Myelomastocytic leukemia P Valent et al
91 Table 1 Comparison of the phenotype of normal human mast cells, basophils, and blood monocytes Expression on CD antigen Structure CD2 CD11b CD14 CD15 CD17 CD25 CD35 CD88 CD117 CD203c n.c. n.c. n.c.
LFA-2 C3biR LPSR 3FAL lactosylceramid IL-2Ra CR1 C5aR KIT E-NPP3 FceRI MC-tryptase MC-chymase
Mast cells
Basophils
Monocytes
7 7 7 7 7 7 7 + + + + + +
7 + 7 7 + + + + 7 + + + 7
7 + + + + + + + 7 7 7 7 7
+, weakly expressed or expressed on a subset of cells only. n.c., not yet clustered.
Figure 1 Morphology of metachromatic cells in a bone marrow smear (Giemsa-staining) in a patient with myelomastocytic leukemia. Some of the metachromatically granulated cells exhibit an immature morphology. Other cells have lobulated nuclei. In case of blast-like cells it is impossible to determine from morphologic aspects whether a given cell would belong to either the mast cell or the basophil lineage.
Metachromatic cells in myelomastocytic leukemia are immature, often exhibit a blast-like morphology (Figure 1) and are MC-lineage cells by electron microscopic (Figure 2) and immunophenotypic criteria (CD117++, tryptase++, CD11b7, CD1237) (Table 2).7 ± 9 Mature MC may be seen occasionally. As in other patients with MDS (or AML) major signs of dysplasia can be found in the erythroid and granulomonocytic lineages. A sub-population of (circulating) metachromatic cells may represent basophils.7,8 In bm histologies, metachromatic cells show a diuse in®ltration pattern.8,9 Focal aggregates of tryptase+ cells, typically seen in systemic mastocytosis,17 ± 19 are not found. Other criteria of systemic mastocytosis (SM-criteria11) are also not met. In fact,
Figure 2 Immunoelectron microscopy of a mast cell lineage cell in a patient with myelomastocytic leukemia. The cell is characterized by multiple surface projections, a lobulated nucleus, and numerous granule-like structures. Immunogold labeling revealed the presence of tryptase- immuno-reactive material in the granule chambers. In light of its ultrastructure and expression of tryptase, the cell was classi®ed as an immature mast cell.
MC are CD2-negative and CD25-negative, and do not exhibit the c-kit mutation Asp-816-Val typically found in systemic mastocytosis.20,21 In patients with systemic mastocytosis (SM), MC usually are more mature and easily recognized by conventional morphology.22 However, in `true' mast cell leukemia (MCL), MC may also be quite immature.23,24 Thus, it may be dicult to dierentiate between myelomastocytic leukemia and MCL (Table 3). Other dierential diagnoses to be considered for myelomastocytic leukemia are basophilic leukemia, the basophilic variant of acute promyelocytic leukemia (APL=AML FAB M3), and chronic myelomonocytic leukemia (CMML) especially when leukemic cells are very immature. The application of cell-speci®c markers and electron microscopy is helpful in these cases (Tables 1 and 2, Figure 2). In addition, the karyotype may point to distinct hematologic disorders de®ned by WHO criteria.
Biology of aicted cells and pathophysiologic considerations The abnormal dierentiation of MC-lineage cells in a myeloid neoplasm is of interest and raises several questions concerning the biology of the aicted cells and the pathophysiology of the disease. The ®rst important question is whether MC in such patients belong to the leukemic (myeloid) clone. In fact, in myelomastocytic leukemia, the morphology is highly suggestive of clonal (leukemic) MC since these cells often exhibit a blast-like morphology without signi®cant maturation.7 ± 9 Moreover, we have recently been able to show that these immature MC express the same chromosomal abnormalities that can be found in the AML blasts in the same patients (manuscript in preparation). The Hematology Journal
Myelomastocytic leukemia P Valent et al
92 Table 2 Expression of leukocyte antigens on neoplastic bone marrow mast cells in various neoplasms Expression of CD antigens on mast cells Diagnosis Normal marrow Systematic Mastocytosis Mast cell leukemia Myelomastocytic leukemia MDS
CD2
CD9
CD11b
CD25
CD35
CD117
CD123
7
+
7
7
7
+
7
+
+
+
+
+
+
7
+*
+
7
+
+
+
n.k.
7 7
+ +
7 7
7 7
n.k. +
+ +
7 7
*In most cases of mast cell leukemia, MC are CD2-positive, n.k., not known.
Table 3 Myelomastocytic leukemia and dierential diagnosis: typical features Neoplasm Typical ®ndings
Mast cell leukemia
Myelomastocytic leukemia
CMML
Clinical: Flush Splenomegaly Survival time
frequency frequency short
frequent frequent short*
rare frequent variable
dense, focal+diuse MC 520% blast cells
