INTRODUCTION
Myelodysplastic syndromes (MDS) are clonal disorders characterized by bone marrow
(BM) failure and an increased risk of transformation into acute myeloid leukemia (AML).
Typically, MDS patients are elderly and are already anemic, leucopenic and/or thrombocytopenic
upon presentation. Despite their myeloid origin, many MDS cases show abnormalities
in B-cells, usually related to a decrease in the B-cell production and/or an increase
in apoptosis (1,2). Such alterations may be due to an increased production demand
for essential hematopoietic cells, such as red cells and neutrophils. Alternatively,
a blockade on B-cell maturation might occur (2).
A low level of monoclonal B-cells (<5×109/L) in otherwise healthy individuals characterizes
a condition called monoclonal B-cell lymphocytosis (MBL). The overall reported frequency
of MBL is between 0.5% and 12% of adults, depending on the age of the population and
the sensitivity of the flow cytometry approach used to detect the B-cell clones (3,4).
MBL is more frequently observed among the relatives of patients with familial chronic
lymphocytic leukemia (CLL) and in individuals exposed to toxic environments. Although
coexistence of CLL and AML or CML has been sporadically reported, the actual frequency
of MBL in association with other hematological neoplasias remains to be established.
CASE DESCRIPTION
Here, we report a 61-year-old female patient diagnosed with both MDS and MBL. She
complained of a three-month history of fatigue associated with sustained anemia and
thrombocytopenia detected on a routine blood test. Splenomegaly or lymphadenomegaly
were not observed. Her hemoglobin level was 3.8 g/dL, her absolute white blood cell
(WBC) count was 7.6×109/L (neutrophils 68%; eosinophils 1%; lymphocytes 23%; monocytes
9%) and her platelet count was 34×109/L. Hyposegmented neutrophils were observed on
blood film examination. The BM aspirate was hypercellular and showed increased blast
cells (9%), marked dysplastic abnormalities in the erythroid, granulocytic and megakaryocytic
lineages and no ring sideroblasts. The BM biopsy showed mild reticulin fibrosis without
the presence of lymphoid aggregates or infiltrates. Cytogenetic analysis was inconclusive.
A diagnosis of refractory anemia with excess blasts-1 was established according to
the WHO classification and the patient received supportive therapy consisting of red
blood cell transfusions.
Five months later, the patient's myeloblasts had increased to 15% (BM) and an abnormal
karyotype (46,XX,del(9)(q22) [20]) was detected. Immunophenotyping of BM cells was
performed using a large panel of monoclonal antibodies in a four-color combination
to analyze precursor cells, granulocytic, monocytic and erythroid BM compartments
(5) (Table 1). Multiparameter flow cytometry confirmed the increased number of myeloblasts
(Figure 1) with an aberrant (CD7+, CD56+), immature (CD34+, CD117+, HLA-DR+) myeloid
(CD13+, CD33+) phenotype. No CD34+ B-cell precursors were detected and phenotypic
abnormalities were identified in the maturing neutrophils (e.g., aberrant CD13/CD11b
expression) and in the monocytic (e.g., CD2+, CD56+) and erythrocytic (e.g., CD71lo)
compartments (Figure 1). In addition, 8% of the marrow cells were mature T-lymphocytes
and 9% were mature B-lymphocytes that presented aberrant CD25 and CD22dim expression.
A detailed study was performed due to this B-cell phenotype, which demonstrated that
88% of B-cells were monoclonal, surface kappa light chain restricted and a CD5+, CD19+,
CD23+ and CD25+ phenotype (Figure 2).
Further analysis of the peripheral blood (PB) demonstrated the presence of monoclonal
B-lymphocytes with a CD19+, CD20dim, CD22dim, CD5+, CD23+, CD79bdim, CD25+, CD43+
and CD38+ phenotype, lacking in reactivity to FMC-7, sIgM, CD10, CD103, and CD11c.
The absolute PB B-lymphocyte count was 3.0×109/L and a diagnosis of CD5+CD23+ MBL
was made.
The patient was treated for MDS with daunorubicin and cytarabine, with no response
and died six months later with AML and the persistence of the PB monoclonal B-cell
population (2×109/L).
The reported case followed the guidelines of the local ethics committees and the Helsinki
Declaration. This patient was included in a large study on MDS (6) and informed consent
was obtained after the study was approved by the Institutional Review Board of UNIFESP
(Brazil).
DISCUSSION
Association of MDS and B-chronic lymphoproliferative disorders (B-CLPD) is an uncommon
finding that has been sporadically described (Table 2). We found that 31 cases had
been reported since 1974. The median age at presentation was 72 years (range: 49-95)
and the male-to-female ratio was 1.2:1. Most cases corresponded to patients with MDS
and CLL (19/31) and no significant association with specific subtypes of MDS was observed.
Florensa et al. showed a frequency of 1% of B-CLPD in a series of 1198 MDS patients
(CLL 0.5%, lymphoplasmacytic lymphoma 0.4% and multiple myeloma 0.1%) (7). At present,
the general consensus is that these associations may occur randomly (8-10). In line
with this idea, we found only one case report supporting the existence of an ontogenic
association between both disorders: trisomy 8 was detected in 55% of CD13+ neutrophils
and in 13% of CD19+/CD5+ B lymphocytes in a case with MDS and systemic vasculitis,
suggesting a common stem cell precursor had generated the two neoplastic cell populations
(11).
Low numbers of circulating monoclonal B-cells in otherwise healthy individuals has
been investigated in the last ten years. A MBL diagnosis is confirmed by the presence
of <5×109/L monoclonal B-cells associated with a normal physical examination and negative
history for lymphoproliferative disease, as observed in our case (12). The progression
rate to CLL has been described as approximately 1-2% of MBL cases per year (12). MBL
has been observed in a significant number of healthy individuals and in, particular,
in elderly people. Despite its frequency, the association of MBL in patients with
other hematological neoplastic diseases (e.g., MDS) remains to be established.
To the best of our knowledge, this is the first report describing the association
of MDS and CD5+with CD23+MBL. Interestingly, despite the presence of a monoclonal
B-cell population, no CD34+B-cell precursors were identified in the patient's BM,
as usually occurs in MDS cases.
Caballero et al. reported a patient with AML associated with CLL in which the progression
of CLL disease was observed after treatment for AML and remission was achieved (13).
In contrast, the lymphoid clone remained stable in our case, without change after
therapy during the follow-up.
MDS develops in a multistep way. An increasing number of accumulated genetic abnormalities
lead to ineffective hematopoiesis. In addition, it has been noted that immune dysfunction
in MDS could also contribute to the development of cytopenia in some groups of patients.
Accumulating evidence has demonstrated the association of MDS and autoimmune manifestations,
T-cell mediated myelosuppression and cytokine-induced cytopenia (14,15). Immunosuppressive
therapy in selected MDS patients results in high rates of hematological recovery with
improved survival, especially in young patients and in the presence of HLA-DR15 (16).
In addition, autoimmune complications are well recognized in CLL, occurring in 10%
to 25% of patients at some time during the course of the disease. Autoimmunity in
CLL predominantly targets blood constituents, most commonly red cells. The association
of MBL and immune dysfunction is uncertain, although Mittal et al. (17) reported a
high prevalence (20%) of CLL phenotype lymphocytes in 31 patients with autoimmune
disorders (AIHA, idiopathic thrombocytopenic purpura and Evans' Syndrome), suggesting
the importance of these clones in the pathogenesis of autoimmune blood disorders.
For the reasons stated above, the coexistence of a monoclonal B-cell disorder with
MDS deserves special interest. This is particularly true because multiparameter flow
cytometry immunophenotyping is the method of choice to detect MBL. Although numerous
reports had described the immunophenotypic abnormalities in MDS, it has only recently
begun to be applied during the routine work-up for the diagnosis and prognosis of
potential MDS cases (18). Moreover, our case illustrates the importance of well-designed
flow cytometry panels, capable of analyzing all hematopoietic cell populations because
more than one neoplastic disorder may be present in the same case. We suggest the
addition of one screening tube in the MDS investigational panel, containing CD19,
CD5, anti-κ and λ light chains, which could be expanded when necessary. Widespread
use of flow cytometry in the routine evaluation of MDS patients will potentially contribute
to defining the actual frequency of the association between MBL and MDS and it may
provide new insights into the association of these disorders.
ACKNOWLEDGMENTS
This report was supported by grants from FAPESP (proc no. 05/57792-0) and FADA (Unifesp).
AFS was supported by CNPq (proc n.142968/2006-4) and CAPES (proc.n. PDEE BEX 1025/05-8).