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Blood, Vol. 91 No. 8 (April 15), 1998:
pp. 2731-2736
Indolent Systemic Mast Cell Disease in Adults: Immunophenotypic
Characterization of Bone Marrow Mast Cells and Its Diagnostic
Implications
By
Luis Escribano,
Alberto Orfao,
Beatriz Díaz-Agustin,
Jesús Villarrubia,
Carlos Cerveró,
Antonio López,
María A. García Marcos,
Carmen Bellas,
Serafín Fernández-Cañadas,
Manuela Cuevas,
Alberto Sánchez,
José L. Velasco,
José Luis Navarro, and
Jesús F. San Miguel
From the Servicio de Hematología, Anatomía
Patológica, Dermatología, and Inmunología,
Hospital Ramón y Cajal, Universidad de Alcalá de Henares,
Madrid, Spain; and the Servicio Central de Citometría and
Departamento de Medicina, Servicio de Hematología, Universidad
de Salamanca, Salamanca, Spain.
 |
ABSTRACT |
The aim of the present study was to explore the diagnostic value of
the immunophenotypic analysis of bone marrow mast cells (BMMC) in
indolent systemic mast cell disease (SMCD) patients. For that purpose,
a total of 10 SMCD patients and 19 healthy controls were analyzed. Our
results show that BMMC from SMCD are different from normal BMMC with
regard to both their light scatter and immunophenotypic characteristics. Accordingly, forward light scatter (FSC), side (90°) light scatter (SSC), and baseline autofluorescence levels were higher in BMMC from indolent SMCD patients than they were in
control subjects. From the immunophenotypic point of view, the most
striking findings were the constant expression of CD2 (P = .0001), CD25 (P = .0001), and CD35 (P = .06)
molecules by BMMC from SMCD patients, markers that were absent from all
normal controls. In contrast, CD71, absent in BMMC from indolent SMCD, was positive in BMMC from normal subjects. Although, slight differences between BMMC from SMCD patients and normal controls were found in
several other markers, they did not reach statistical significance. In
conclusion, our results show that simultaneous assessment of FSC/SSC
and reactivity for the CD117, CD2, CD25, CD33, and CD35 forms the basis
for the immunophenotypic characterization of BMMC from SMCD in adults
and should be integrated with clinical and morphologic studies for the
diagnosis of the disease.
| |
INTRODUCTION |
MASTOCYTOSIS IS A rare disorder
characterized by an increased number of tissue mast cells (MCs) that
may involve either the skin alone or several organs such as bone marrow
(BM), bone, spleen, liver, and lymph nodes. Among the systemic types, a
recent consensus classification,1 which is based on the
work of Travis et al,2 recognizes four different forms: (1)
indolent systemic mast cell disease (SMCD), (2) aggressive mastocytosis
(also known as lymphadenopathic mastocytosis with eosinophilia), (3)
systemic mastocytosis associated with different hematologic disorders,
and (4) mast cell leukemia.
The immunophenotype of normal human MCs has been extensively studied in
different tissues.3-7 In addition, we have recently shown
that bone marrow mast cells (BMMC) can be easily identified and
enumerated using multiparametric flow cytometry on the basis of their
strong reactivity for the CD117 and Fc RI antigens.8 In
our experience,9 normal BMMC virtually always express CD9, CD11c, CD29, CD33, CD43, CD44, CD45, CD49d, CD49e, CD51, CD54, CD71,
CD117, and FcRI, while other markers such as CD11b, CD13, CD18,
CD22, CD35, CD40, and CD61 displayed a variable expression. Apart from
this report, the immunophenotype of BMMC has only been analyzed in
samples from chronic myeloid leukemia,3,5 mast cell
leukemia,10-12 and a case of malignant mastocytosis with
circulating mast cells.13 Moreover, to the best of our
knowledge, no extensive studies about the immunophenotype of BMMC have
been performed in SMCD.
The aim of the present report is to define the immunophenotype of human
BMMC from patients suffering from SMCD using a large panel of
monoclonal antibodies (MoAbs) and to establish the possible role of
immunophenotyping in the differential diagnosis between SMCD and
normal/reactive mast cell. In addition, results on the reactivity
obtained for each of the markers analyzed are expressed as molecules
equivalent of soluble fluorochrome (MESF), which would allow the
comparison with previous results obtained in BMMC from normal controls,
as well as with future studies in which the same MoAb conjugates are
used.
| |
MATERIALS AND METHODS |
A total of 12 BM samples were obtained from 10 patients suffering from
indolent SMCD (six men and four women), with a mean age of 45 ± 14 years, ranging from 26 to 67 years. Cases of mastocytosis associated
with hematologic disorders, aggressive mastocytosis, or mast cell
leukemia were excluded from this study. The diagnosis of indolent SMCD
was made according to the criteria proposed in previous
reports.1,2,14-16 Table 1 shows
the clinical and biological characteristics of each patient enrolled in
the present study. Immunophenotypical studies were performed at
diagnosis in eight cases (patients 1 to 7, and 9) and 1 and 8 years
after the diagnosis in the other two cases (patients 10 and 8, respectively). At the moment of entering this study, five patients (2, 7, 8, 9, and 10) were under anti-H1 (chlorpheniramine maleate or
hydroxyzine) and anti-H2 (ranitidine) therapy. Of these, three cases
were receiving treatment with sodium cromoglycate (patients 7, 8, and
9) and one (patient 8) also received aspirin; no case was treated with interferon before entering this study. A total of 19 healthy volunteers undergoing either orthopedic surgery or BM harvest were sudied as
normal controls.
In all cases, samples were collected in K3-EDTA
anticoagulant and immediately diluted 1/1 (vol/vol) in
phosphate-buffered saline (PBS). After collection, the sample was
passed several times through a 25-mm gauge needle to disaggregate the
BM particles and cell concentration was adjusted to 7.5 × 109 nucleated cells/L.
Immunologic marker analysis.
BM samples were analyzed by direct immunofluorescence using either
triple or double-staining combinations of MoAb directly conjugated with
fluorescein isothiocyanate (FITC), phycoerythrin (PE), and either the
PE-cyanin 5 (PE-Cy5) fluorochrome tandem or PerCP. The following MoAb
conjugates were used: (1) FITC-conjugated: CD2, CD10, CD13, CD14, CD15,
CD16, CD19, CD20, CD22, CD25, CD33, CD34, CD44, CD71, (purchased from
Becton Dickinson, San Jose, CA), CD38, CD65, (Caltag Laboratories, San
Francisco, CA), CD11a, CD11b, CD11c, CD35, CD54, CD66 (CLB, Amsterdam,
The Netherlands), CD29 (Coulter Corp, Miami, FL) CD21, CD30, CD42b,
CD61 (Dakopatts, Copenhagen, Denmark), CD41a (Immunotech, Marseille,
France), CD18, CD51 (Menarini Diagnostics, Barcelona, Spain), CD117
(Nichirei Corporation, Tokyo, Japan), CD9, CD43, CD49d, CD49e (Serotec, Oxford, UK) anti-IgE (The Binding Site, Birmingham, England), and BB4
(CD138) (Immunoquality Products, Gröningen, The Netherlands); (2)
PE-conjugated: CD23 (purchased from Becton Dickinson), and CD117
(Nichirei Corporation); (3) PE/Cy5-conjugated: CD38, and HLA-DR (Caltag
Laboratories); (4) Per-CP conjugated CD45 (Becton-Dickinson).
Briefly, 200 µL of the sample containing aproximately 1.5 × 106 nucleated cells were incubated for 10 minutes at room
temperature with the above mentioned MoAbs. After this, erythrocytes
were lysed by incubating cells for 10 minutes (room temperature) with 2 mL/tube of FACS lysing solution (Becton Dickinson) diluted 1/10 vol/vol
in distilled water. Isotype-matched mouse nonspecific immunoglobulins
and a tube stained for CD117-PE were used as negative and positive
controls to assess nonspecific binding and BMMC autofluorescence, respectively.
Data acquisition was performed on a FACScan flow cytometer (Becton
Dickinson) using the LYSYS II software program (Becton Dickinson).
Initially, a minimum of 10,000 events/tube from the total
BM cells was acquired. In addition, a second acquisition step, through
a SSC/CD117 live gate, was performed to increase the sensitivity of the
method for the analysis of MC present at a low frequency.8
For data analysis, the Paint-A-Gate PRO software (Becton Dickinson) was
used. The quantitation of positivity for each of the markers tested was
performed using QuickCal beads (Flow Cytometry Standards Corporation,
San Juan, Puerto Rico) and results were expressed as the mean number of
molecules equivalent of soluble fluorochrome (MESF) obtained
specifically for the MC. The threshold for positivity was
5,000 MESF for both FITC and PE after subtracting the
autofluorescence levels obtained for BMMC.
Statistical methods.
Mean values and their standard deviations were calculated for all
variables in each group of samples. The Mann-Whitney U and the
 2 tests were used to assess the statistical significance
of the immunophenotypic differences observed between BMMC from SMCD
patients and those of normal controls for continuous and dichotomic
variables, respectively.
| |
RESULTS |
Despite their low frequency, MCs were clearly identified in all BM
samples analyzed based on their strong CD117 expression (Fig 1). The mean number of BMMC in
indolent SMCD patients was significantly higher (P > .001)
than in normal controls (0.27% ± 0.19% and 0.021 ± 0.0025 of
the nucleated BM cells analyzed, respectively). BMMC from indolent SMCD
displayed a relatively homogenous FSC and SSC distribution, the values
of both light scatter parameters being higher than those found for
normal BMMC (Fig 2A and B). Moreover, the
autofluorescence level was also higher in BMMC from indolent SMCD than
it was in normal individuals (Fig 2C and D).
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| Fig 1.
Representative dot plots of ungated (dot plots A to F)
and CD117 gated events from a healthy control (left panel) and a
patient suffering from indolent SMCD (right panel). Black dots
correspond to BMMC. Total number of events in plots A to F is 10,000 (note that no mast cells are present among 10,000 ungated events in dot
plots A, C, and E). The events shown in plots G to J correspond to the
BMMC present in a total of 600,000 events analyzed. N, neutrophils; M,
monocytes; L, lymphocyte; Er, erythroid nucleated cells.
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View larger version (26K):
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| Fig 2.
Representative example of the light scatter and
immunophenotypic differences between BMMC (black dots) from healthy
controls (left panel) and patients suffering from indolent SMCD. As can be seen, CD2 (E and F), CD25 (G and H), and CD35 molecules were positive in SMCD patients, but negative in normal controls. The events
represented in each dot plot correspond to the CD117+
gated cells present in a total of 600,000 events analyzed.
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|
The immunophenotypical characteristics of BMMC from indolent SMCD are
shown in Fig 2 and Table 2. As may be seen,
three patterns of antigen expression were detected in BMMC from
indolent SMCD patients: (1) markers that were constantly positive (CD2,
CD9, CD11c, CD13, CD25, CD29, CD33, CD35, CD44, CD45, CD54, CD117, and
FcRI); (2) antigens that were always negative (CD10, CD11a, CD14,
CD15, CD16, CD19, CD20, CD21, CD23, CD30, CD34, CD38, CD65, CD66, CD71,
HLA-DR, and CD138); and (3) markers that were positive in a variable
proportion of cases: CD11b (25%), CD18 (40%), CD22 (78%), CD41a
(71%), CD42b (25%), CD43 (60%), CD49d (50%), CD49e (25%), and CD61
(28%). In addition, among those antigens that were positive, three
groups could be identified according to the intensity of antigen
expression detected: (1) strong positive markers (> 12,000 and > 50,000 MESF for FITC and PE,
respectively): CD9, CD11c, CD25, CD33, CD44, CD49d, CD54, CD117 and
FcRI; (2) uniform dim positive antigens (from 5,000 to 12,000 MESF
of FITC): CD2, CD11b, CD18, CD41a, CD49e, and CD51; and (3) antigens
showing a variable intensity of expression (from 5,000 to 51,000 MESF of FITC): CD13, CD22, CD29, CD42b, CD43, and CD61.
After comparing the immunophenotype of BMMC from indolent SMCD patients
and healthy subjects, significant differences were observed regarding
both the incidence of positivity and the fluorescence intensity (Table
2). Accordingly, in all indolent SMCD patients, BMMC expressed the CD2,
CD25, and CD35 antigens, which were never found in BMMC from normal
controls (P = .0001, .0001, and .006, respectively). In
contrast, the CD71 molecule was constantly present in normal controls,
but never detected in indolent SMCD cases (P = .004). Other
molecules such as CD41a and CD42b were present in a variable proportion
of SMCD cases, but constantly absent in normal controls (P = .6 and .06, respectively). Additional differences between BMMC from
indolent SMCD cases and healthy individuals were observed upon
analyzing the levels of mean fluorescence intensity estimated for
several antigens: CD33 expression was significantly higher in SMCD
patients (P = .02), while CD29 and CD117 expression
was greater in healthy subjects (P = .03 and .008, respectively).
| |
DISCUSSION |
The present report represents a first attempt at the extensive
characterization of the immunophenotype of BMMC from indolent SMCD
adult patients using a large panel of MoAb. Our major goal was to
explore the use of immunophenotyping for the differential diagnosis
between SMCD and normal/reactive MC. Although, as expected, the mean
number of BMMC in indolent SMCD was significantly higher than in normal
controls,8 the overall number of BMMC in indolent SMCD was
low. This is concordant with histologic studies that show a low number
of MC17,18 with focal distribution.2,17,19-23
Interestingly, BMMC from SMCD displayed light scatter characteristics
that were higher than those found for their normal counterpart, as well
as a greater level of autofluorescence. Light scatter properties of
cells analyzed at flow cytometry to a large extent reflect
morphologically-related features such as cell size and internal
complexity.24 As a matter of fact, a slightly larger size
has been reported for BMMC in SMCD25 and this could explain the higher FSC values found in the present study. Interestingly, both
piecemeal and anaphylactic degranulation have been described in vivo at
the ultrastructural level in MC from different
tissues,26-30 including BMMC31 from SMCD
patients. Accordingly, MC undergoing degranulation display several
changes regarding granule size, shape, and
contents,29,30,32 and these morphologic changes, together
with an increased content in endoplasmic membranes, Golgi apparatus and
endoplasmic reticulum, may explain the increased SSC (internal
complexity) of BMMC from SMCD found in the present study. Additionally,
this would also help to increase the autofluorescence levels of SMCD
BMMC. Isolation of mast cells from a SMCD using a fluorescence
activated cell sorter according to previously described methods8 confirmed that these MC displayed an abnormal
morphology (data not shown).
Increased autofluorescence of SMCD BMMC may limit the measurement of
the fluorescence levels obtained for specific antigens detected through
the use of immunofluorescence techniques. Therefore, the assessment of
the immunophenotype of BMMC from SMCD patients should take into account
the autofluorescence levels of these cells, and the fluorescence
intensity for a specific marker should be calculated after subtracting
the baseline autofluorescence of the cells under study. To allow the
comparison of the results of the present report with those of other
studies in which the same MoAb conjugates are used, results on the
reactivity obtained for each of the markers analyzed were expressed as
MESF after subtracting the MESF values corresponding to the mean
autofluorescence level obtained for those specific mast cells.
From the immunophenotypic point of view, the most striking findings
were the expression of CD2, CD25, and CD35 molecules by BMMC from all
SMCD patients, markers that were constantly absent in normal
BMMC.3,5,9,33,34 Coexpression of both CD2 and CD25 by BMMC
could be considered as characteristic of indolent SMCD, but not normal
and reactive BMMC,9 and it could be of great help for the
differential diagnosis between SMCD and reactive mastocytosis.
Nevertheless, reactivity for CD35 cannot be pathognomonic of SMCD,
because although negative in MC from several
tissues5,7,34-36 including normal BM,9 it has
been observed to be weakly positive in BMMC from some patients (27%)
with B-cell malignancies.9 On the other hand, the
reactivity for CD71 (transferrin receptor) was shown to be constantly
negative in indolent SMCD cases, while positive in BMMC from normal
subjects,9 as well as in the MC from a case of mast cell
leukemia.12 However, because CD71 expression in normal BMMC
was always weak (from 5 to 6.5 × 103 MESF), this
would limit its use in the differential diagnosis of SMCD. It should be
noted that this antigen is absent in human MC from different
tissues.3,5,35
The CD29 and the myeloid-associated markers CD33 and CD117, although
present in BMMC from all indolent SMCD patients and normal controls
studied, displayed a significantly different intensity of expression in
both groups of individuals. In this sense, while reactivity for CD33
was higher in SMCD patients, CD29 and CD117 were expressed at a greater
intensity in BMMC from control subjects.
In summary, our results show that multiparametric flow cytometry using
direct immunofluorescence on erythrocyte-lysed whole BM is of great
help for the diagnosis of adult indolent SMCD and its differential
diagnosis with reactive mastocytosis. Simultaneous assessment of
FSC/SSC and reactivity for the CD117, CD2, CD25, CD29, and CD33, in the
presence of BM involvement, forms the basis for the immunophenotypic
diagnosis of SMCD in adults.
| |
FOOTNOTES |
Submitted June 3, 1997;
accepted November 20, 1997.
Supported by Grant No. FIS 95/0768 from the Fondo de Investigaciones
Sanitarias de la Seguridad Social (to B.D.-A.).
Address reprint requests to Alberto Orfao, MD, Servicio
Central de Citometría, Hospital Clínico Universitario,
Paseo de San Vicente s/n, 37007 Salamanca, Spain.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
We thank Professor Frank K. Austen for reading the manuscript.
| |
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C. Akin, L. M. Scott, C. N. Kocabas, N. Kushnir-Sukhov, E. Brittain, P. Noel, and D. D. Metcalfe
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A. C. Garcia-Montero, M. Jara-Acevedo, C. Teodosio, M. L. Sanchez, R. Nunez, A. Prados, I. Aldanondo, L. Sanchez, M. Dominguez, L. M. Botana, et al.
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H-P Horny, K Sotlar, F Stellmacher, M Krokowski, H Agis, L B Schwartz, and P Valent
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S. M. Wiesner, J. M. Jones, D. E. Hasz, and D. A. Largaespada
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C. Akin, G. Fumo, A. S. Yavuz, P. E. Lipsky, L. Neckers, and D. D. Metcalfe
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A. D. Klion, J. Robyn, C. Akin, P. Noel, M. Brown, M. Law, D. D. Metcalfe, C. Dunbar, and T. B. Nutman
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A. D. Klion, P. Noel, C. Akin, M. A. Law, D. G. Gilliland, J. Cools, D. D. Metcalfe, and T. B. Nutman
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C. Akin, L. B. Schwartz, T. Kitoh, H. Obayashi, A. S. Worobec, L. M. Scott, and D. D. Metcalfe
Soluble stem cell factor receptor (CD117) and IL-2 receptor alpha chain (CD25) levels in the plasma of patients with mastocytosis: relationships to disease severity and bone marrow pathology
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Abstract
Introduction
Abstract