|Year : 2017 | Volume
| Issue : 1 | Page : 1-8
Association between immunophenotypic markers and cytogenetic aberrations in Egyptian patients with plasma cell myeloma
Noha H Boshnak MD , Azza E Hashem
Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
|Date of Submission||04-Oct-2016|
|Date of Acceptance||17-Nov-2017|
|Date of Web Publication||18-May-2017|
Noha H Boshnak
66 Ebn EL Nafees Street, 6th area, Naser City, Cairo, 002
Source of Support: None, Conflict of Interest: None
Background Plasma cell myeloma is a devastating disease of clonal plasma cells that show considerable diversity both in their immunophenotypic and in their cytogenetic features. Immunophenotyping has been used widely for diagnostic and prognostic evaluation of malignant plasma cells.
Aim The aim of this study was to evaluate the relationship between the immunophenotypic profile and standard prognostic factors, and also to determine the correlation between different antigenic expression and the cytogenetic aberrations as well as clinical stage in patients with plasma cell myeloma.
Patients and methods A total of 31 newly diagnosed Egyptian patients with plasma cell myeloma were evaluated by multiparameter flow cytometry. Interphase fluorescence in situ hybridization was performed for detection of the expression of the 14q32 immunoglobulin H rearrangement, t(11;14), t(4;14), 13q del, and 17p del on bone marrow samples collected from the patients at diagnosis.
Results Positive expression of CD19, CD20, CD13, and CD33 was detected in 38.7, 51.6, 19.4, and 12.9% of patients, whereas CD56, CD45, CD65, and CD117 were expressed in 41.9, 77.4, 9.7, and 25.8% of patients, respectively. A statistically significant correlation was found between CD13 positivity, CD56 positivity, or CD45 negativity and advanced International Staging System (P=0.011, 0.036, and 0.004, respectively). CD33-negative cases were significantly associated with absence of the 14q32 immunoglobulin H rearrangement (P=0.050) and absence of t(4;14) (P=0.018). CD45 positivity and CD13 negativity were correlated with absence of 13q del (P=0.031 and 0.011, respectively).
Conclusion Immunophenotypic antigenic expression profile is associated with advanced clinical stage and absence of some cytogenetic aberrations in plasma cell myeloma.
Keywords: cytogenetic, fluorescence in situ hybridization, flow cytometry, plasma cell myeloma
|How to cite this article:|
Boshnak NH, Hashem AE. Association between immunophenotypic markers and cytogenetic aberrations in Egyptian patients with plasma cell myeloma. Egypt J Haematol 2017;42:1-8
|How to cite this URL:|
Boshnak NH, Hashem AE. Association between immunophenotypic markers and cytogenetic aberrations in Egyptian patients with plasma cell myeloma. Egypt J Haematol [serial online] 2017 [cited 2018 Feb 22];42:1-8. Available from: http://www.ehj.eg.net/text.asp?2017/42/1/1/206433
| Introduction|| |
Plasma cell myeloma is a clonal proliferative disorder of terminally differentiated B-cell resulting in the accumulation of neoplastic plasma cells in the bone marrow . Considerable variability has been observed in the patients’ prognoses, leading to diverse survival times ranging from several days up to 10 years ,,. Therefore, it is essential to evaluate the biological and clinical prognostic factors at the time of diagnosis to interpret the patient’s outcome and to identify patients who need more aggressive therapy . The most important prognostic factors of plasma cell myeloma the cytogenetic abnormalities and the International Staging System (ISS), which categorizes the patients on the basis of their serum albumin and β2-microglobulin (β2MG) levels . Besides its diagnostic value, many studies have shown the prognostic impact of flow cytometry in plasma cell myeloma ,,,. The association between the immunophenotypic antigenic expression and cytogenetic abnormalities has been assessed by several studies ,,,,,. The aims of this study were to determine the frequencies of different antigen expressions and evaluate the association between them and each of the standard prognostic factors, the cytogenetic aberrations as well as the clinical stage according to the ISS for multiple myeloma.
| Patients and methods|| |
The current prospective study was carried out on 31 newly diagnosed Egyptian patients with plasma cell myeloma referred to Ain Shams University Hospitals. Informed consent was obtained from the patients. The study was carried out according to the stipulations of the Local Ethical Committee. All the patients were subjected to the following: complete assessment of history, clinical examination, and laboratory investigations including complete blood count using the Beckman Coulter LH750 cell counter (Coulter, Electronics, Hialeah, Florida, USA), along with examination of Leishman-stained peripheral blood smears, erythrocyte sedimentation rate (ESR), serum chemistry [creatinine, blood urea nitrogen, calcium, albumin, total protein, lactate dehydrogenase (LDH), and β2MG], together with 24-h urine collection for light-chain (Bence Jones protein) excretion, serum protein electrophoresis, and immunofixation studies of serum and/or urine to confirm the presence of the M-band and detect the type of the immunoglobulin (Ig) heavy chain and its light-chain type. Bone marrow aspirate samples were obtained from all the patients for morphological assessment, immunophenotyping, and interphase fluorescence in situ hybridization (iFISH) analysis. The diagnostic criteria for plasma cell myeloma were based on those obtained by the WHO . The ISS for multiple myeloma  was used to stratify the patients.
| Methods|| |
Bone marrow samples were collected on EDTA (1.5 mg/ml) for immunophenotypic analyses and on a sterile preservative-free heparin-coated vacutainer tube for iFISH analysis. A few microliters of bone marrow aspirate samples were used for morphological evaluation of Leishman-stained films.
Immunophenotypic analysis by flow cytometry
About 100 µl of count-adjusted anticoagulated bone marrow sample was incubated with monoclonal antibodies in the dark at room temperature for 15 min. After incubation, red blood cells were lysed and washed twice with PBS, the supernatant was discarded, and the cell pellet was resuspended in PBS. Stained cells were quickly detected and analyzed using an EPICS XL Coulter flow cytometer using the following panel of cluster of differentiation (CD) antigens: CD138, CD38, CD45, CD56, CD19, CD20, CD13, CD33, CD117, CD65, κ and λ light-chain Ig to confirm clonality. Side scatter together with a high expression of CD138 were used to gate plasma cells. Neoplastic plasma cells were defined as the CD38-positive and CD138-positive populations with light-chain restriction (κ/λ>4 : 1 or <0.5) . Cells were considered positive for a marker when more than 20% of cells expressed that marker. The percentage of positive cells was provided by the percentage of the events above the cursor defined on the negative control .
Fluorescence in situ hybridization analysis
Patients’ samples were assessed using the following probes (Vysis, Downers Grove, IL): locus-specific identifier (LSI) IGH dual color, breakapart rearrangement probe (14q32) for the 14q32 gene rearrangement, LSI IGH/CCND1 Dual Color Dual Fusion Probes for the detection of t(11;14)(q13;q32), the LSI IGH/FGFR3 Dual Fusion Probe for the detection of t(4;14)(p16;q32), and the LSI D13S319 (13q14.3) probe for 13q14 deletion and LSI TP53 Probe maps to the 17p13.1 region on chromosome 17 containing the p53 gene for the detection of P53 gene deletion.
Statistical analyses were carried out using the SPSS statistical software (SPSS 15.O.1 for Windows; SPSS Inc, Chicago, Illinois, USA). Descriptive quantitative data were shown as mean or median, range values, and SD, whereas descriptive qualitative data were presented as number and percentage. Independent-samples t-test was used to evaluate the statistical significance of the difference between the means of two study group. χ2-test and Fisher exact test were used to examine the relationship between two qualitative variables. Statistical difference was considered significant if the P-value was less than 0.05 and highly significant if the P-value was less than 0.001.
| Results|| |
This study was carried out on 31 newly diagnosed multiple myeloma patients. Seventeen (54.8%) were men and 14 (45.2%) were women, with a male to female ratio of 1.2 : 1. Their ages ranged from 21 to 76 years, with a mean of 56.23±11.90, and the median age was 59 years. Descriptive analysis of the demographic and laboratory characteristics of the studied patients is shown in [Table 1]. The results of the iFISH analysis are shown in [Table 2].
|Table 2 Genetic abnormalities detected by interphase fluorescence in situ hybridization|
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Description of antigen expression in the patients studied
In terms of the immunophenotypic analysis of the studied patients, it was found that all the 31 patients expressed CD38 and CD138; the pan-B-cell marker CD19 was positive in 12 (38.7%) patients. The CD20, which is an antigen associated with the early stages of the B-cell maturation, was present in 16 (51.6%) patients; CD13 was expressed in six (19.4%) patients. CD33 was detected in four (12.9%) patients and CD56 was positive in 13 (41.9%) patients. CD45, CD65, CD117, κ and λ were expressed in 24 (77.4%), three (9.7%), eight (25.8%), 21 (67.7%), and 10 (32.3%) patients, respectively ([Figure 1]).
Association between antigen expression and the standard prognostic factors
We studied the association between antigen expression and patients’ characteristics (age, sex, total leukocytic count, hemoglobin, platelet count, β2MG, albumin, total protein, calcium, LDH, creatinine, blood urea nitrogen, ESR, and Bence Jones protein). Expression of CD56 was associated with a significantly higher level of β2MG (>5.5 mg/dl) (P=0.019), lower albumin level (<3.5 g/dl) (P=0.023), and higher creatinine level (>1.2 mg/dl) (P=0.02). CD45 negativity was strongly associated with a higher level of β2MG (>5.5 mg/dl) (P=0.008), a higher calcium level (>10 mg/dl) (P=0.038), and a higher ESR level (P=0.024) ([Table 3]). Lack of CD117 expression showed a strong association with higher creatinine concentrations (P=0.011) as 21 out of 23 (91.3%) patients who did not express CD117 had creatinine level greater than 1.2 mg/dl. There was no significant difference in patients’ characteristic on the basis of CD65 expression. CD13 expression did not show an association with clinical characteristics, except for a higher level of β2MG (>5.5 mg/dl) (P=0.019). CD33 negativity was detected in 21 out of 27 (77.8%) patients and was correlated with a higher platelet count (>150 ×109/l) (P=0.03) and negative Bence Jones protein in urine (P=0.048). On analyzing the correlation between CD19 expression and the standard prognostic factors, there was no significant difference, except for the absence of Bence Jones protein in urine (P=0.05); also, there was a strong correlation between CD20 negativity and negative Bence Jones protein in urine (P=0.018).
|Table 3 Association between CD56, CD45 expression, and the standard prognostic factors|
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Association between antigen expression and clinical stage according to the International Staging System for myeloma
CD13 positivity was significantly associated with the advanced ISS (P=0.011). The percentages of stages I, II, and III in CD56-positive cases were 0.0% (0/13), 35.8% (5/13), and 61.5% (8/13), respectively. A statistically significant correlation was found between CD56-positive cases and advanced stage (P=0.036). Lack of CD45 expression showed a strong association with advanced stage (P=0.004). However, there was no significant correlation between CD19/CD20/CD33/CD65/CD117 expression and myeloma stage ([Table 4]).
|Table 4 Association between antigen expression and the International Staging System for myeloma (N=31)|
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Comparison between antigen expression and each of the fluorescence in situ hybridization abnormalities studied
A significant correlation was found between the presence of any of the studied iFISH abnormalities and the absence of the λ immunophenotypic marker (P=0.023). CD33 negativity was significantly associated with the absence of the 14q32 IgH rearrangement (P=0.050) and absence of t(4;14) (P=0.018). Patients who did not show 13q del were associated with a positive expression of CD45 (P=0.031) and absence of CD13 (P=0.011). However, we failed to find any significant association between t(11;14) or 17p del and any of the immunophenotypic markers studied ([Table 5]).
|Table 5 Comparison between the pattern of antigen expression and cytogenetic aberrations|
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| Discussion|| |
The pattern of antigen expression of clonal plasma cells shows considerable heterogeneity and is actually different from that of normal plasma cells. Antigenic diversity observed in plasma cell myeloma patients might not only be related to a variable clinical picture but also associated with heterogeneous genetic abnormalities in plasma cells. The potential relationship between antigenic profile of tumor cells and cytogenetic abnormality is an area of expanding interest . Therefore, this study aimed to assess the frequencies of different antigen expression and evaluate the association between them and the cytogenetic aberrations as well as the clinical stage in Egyptian patients with plasma cells.
The B-lineage-associated antigen CD19 is a marker acquired early during B-cell differentiation, expressed during B-cell maturation, and still present in most normal plasma cells; however, it is retained in a small proportion of plasma cell myeloma patients . In our study, CD19 was positive in 38.7% of the patients, which was markedly higher than that reported by Shin et al.  (8.8%), Mateo et al.  (4%), and Lin et al.  (1%). There was no association between CD19 and cytogenetic or myeloma stage in our study. Similar results were reported by Shin et al. . This might be explained by what was found by some studies that CD19 was of diagnostic value rather than a prognostic indicator ,,.
CD20, a B-cell-specific transmembrane protein, is expressed in committed B-cells throughout their development, but is lost upon differentiation to plasma cells; however, CD20 is present in 30% of abnormal plasma cells . In our study, CD20 was expressed in 51.6% of the patients, which was markedly higher than that observed by Robillard et al.  (25%), Mateo et al.  (17%), Lin et al.  (9.3%), Shim et al.  (6%), and Pan et al.  (6%).
Robillard et al.  found a strong association between t(11;14) and CD20 expression in plasma cell myeloma patients: 10 of 12 (83%) patients with CD20 expression had t(11;14). However, in a larger study, carried out be Mateo et al. , lower incidence of CD20 positivity was found in patients with t(11;14) (21 of 66 patients, 32%). Grigoriadis et al.  and Yokoi et al.  observed a nearly similar much lower incidence of CD20 expression in patients with t(11;14) [(2/19 patients (11%) and 2/21 patients (11%), respectively]. However, we did not find an association between CD20 expression and any of the cytogenetic abnormalities or ISS myeloma stages studied.
CD33 expression is restricted to malignant plasma cells (not or slightly expressed on normal bone marrow plasma cells) . There was no suggested pathway of the mechanism of CD13 and CD33, the myeloid lineage markers, in myeloma cells; however, the expression of these markers in neoplastic plasma cells was correlated with a poor prognosis in plasma cell myeloma patients independent of other prognostic factors . CD13 and CD33 were detected in 19.4 and 12.9% of our cases, respectively. Pan et al.  found results that were almost similar to those of our study as CD33 was expressed in 12% of their patients. In contrast, Shim et al.  reported a higher incidence of CD13 and CD33 (53% and 18%, respectively). Mateo et al. , Robillard et al. , and Sahara et al.  found that 20, 35, and 22% of their patients, respectively, were CD33 positive.
Shim et al.  did not found an association between CD13 expression and clinical characteristics, high-risk cytogenetics, or ISS stage; however, they found that CD13 positivity was significantly associated with shorter overall survival (P=0.025). In our study, higher β2MG (>5.5 mg/dl) (P=0.019) and advanced ISS stage (P=0.011) were significantly associated with CD13 expression. Moreover, CD13 negativity was observed in patients who lacked 13q del (P=0.011). Therefore, these results indicate that cases that express CD13 might belong to the potential poor prognosis group.
In the current study, it was found that the absence of CD33 was correlated with elevated platelet count and was significantly associated with absence of the 14q32 IgH rearrangement (P=0.05) and absence of t(4;14) (P=0.018). Robillard et al.  found a higher incidence of t(4;14) in CD33-positive patients. Expression of CD33 was associated with an increased incidence of anemia or thrombocytopenia and elevated serum β2MG and LDH concentrations in a study carried out by Sahara et al. , whereas Shim et al.  found a significant association between CD33 positivity and higher serum LDH concentration; also, they found a correlation between CD33 expression and poor prognosis.
CD56 is an adhesion molecule that is involved in anchoring plasma cells to the stromal structure of the bone marrow. The absence of CD56 has been related to malignancy in plasma cells and its downregulation showed high proliferation and spreading of malignant plasma cells ,. A study carried out by Sahara et al.  reported higher β2MG, lower platelets, higher incidence of anemia, renal failure, and poor prognosis in CD56-negative cases, whereas Pan et al.  did not find any significant differences between CD56-positive and CD56-negative cases in terms of serum albumin, β2MG, stage of disease, and renal failure; however, they found that the absence of CD56 and CD117 expression on malignant plasma cells was associated with a poor prognosis. Kraj et al.  did not find a correlation between CD56 expression and adverse prognosis; also, Chang et al.  reported that CD56 was not associated with adverse prognosis or genetic abnormality in the high-dose chemotherapy group or the autologous stem cell transplant group.
The current study showed that CD56 was positive in 13 (41.9%) patients, which was lower than that observed by Kraj et al.  (66%), Shin et al. (75%), Mateo et al.  (70%), Lin et al.  (71.7%), and Pan et al.  (74.0%). Such discrepancies may be attributed to differences in the sample size and treatment heterogeneity. We found that CD56 positivity was associated with higher serum β2MG (>5.5 mg/dl), lower albumin level (<3.5 g/dl), higher creatinine level (>1.2 mg/dl), and advanced stage; however, we did not find an association between CD56 expression and cytogenetic abnormality or myeloma stage, which coincided with what was observed by Shin et al. . In contrast, Mateo et al.  and Hundemer et al.  found an association between downregulation of CD56 and the presence of t(11;14), the favorable cytogenetic abnormality in multiple myeloma.
The c-kit receptor (CD117) is a progenitor cell-associated marker that is not expressed by normal plasma cells; however, it can be present on some malignant plasma cells. CD117 expression could serve as an anchor molecule leading to less spread of plasma cells. Therefore, several studies found an association between CD117 expression and good prognosis ,, and the European Myeloma Network recommended the use of CD117 as a prognostic marker .
CD117 was expressed in eight (25.8%) of our patients, which was lower than that observed by Pan et al. (32%), Mateo et al. (36%), and Shin et al. (39.7%) and higher than that reported by Lin et al. (17.8%). In terms of the association with biological risk factors, we found that CD117 negativity was strongly correlated with a higher serum creatinine level (P=0.011). Similar results were found by Shim et al.  and Pan et al. , but the possible mechanism was unclear.
Mateo et al.  found an association between negativity of CD117 and the presence of t(11;14), nonhyperdiploid DNA content, and 13q del. Shim et al.  reported an association between CD117-negative cases and 13q del, t(4;14), t(11;14), whereas Shin et al.  found that CD117-negative cases were associated with hypodiploidy and advanced stage. We did not find any association between CD117 and any iFISH abnormality or stage. This might be because of the small number of patients in this study.
CD45 is a common leukocyte antigen. It is mainly expressed early during plasma cell development and its expression is reduced with maturation. Studies have shown that CD45 expression is heterogeneous among the plasma cells in the bone marrow of patients with multiple myeloma ,. The existence of two populations of myeloma cells in the marrow, early plasma cells with CD45 expression and late plasma cells with low or no expression, has been suggested ,. Low expression or absence of CD45 was found in about 30% of plasma cell myeloma patients. CD45 was negative in 22.6% of patients in our study, whereas Shin et al.  found that CD45 was negative in 50% of their cases. The biological role of CD45 in myeloma patients remains unclear. Asosingh et al.  reported that expression of CD45 was associated with delayed disease progression. Moreau et al.  and Kumar et al.  found that CD45 negativity was associated with disease progression and adverse prognostic factors. In one previous study, CD45-negative cases were associated with advanced stage, del(13q) or aneuploidy, and del(17p) . Similar results were found in the current study as CD45 negativity was associated with elevated β2MG, higher calcium levels, and advanced stage. Moreover, absence of 13q del was associated with CD45 expression. Therefore, these findings suggest that absence of CD45 is associated with a potentially poor prognosis. The mechanism may be correlated to the control role that CD45 plays in the receptors of interleukin-6 and insulin-like growth factor-1, which are two major growth factors for myeloma cells . In contrast, Robillard et al.  showed that the plasma cells that express CD45 brightly are the proliferating plasma cell compartment that is involved in disease progression. Menke et al.  found that the CD45RO expression is associated with poor survival in patients with multiple myeloma. However, in a large study, carried out by Mateo et al. , there was no prognostic impact for CD45 in patients with multiple myeloma.
In conclusion, we evaluated the association between different antigen expressions and each of the standard prognostic factors, the cytogenetic aberrations as well as the clinical stage in newly diagnosed plasma cell myeloma patients, and we found that CD45-positive cases and CD13-negative cases were correlated with the absence of 13q del; also, lack of CD33 expression was associated significantly with absence of the 14q32 IgH rearrangement and absence of t(4;14). Advanced clinical stage was associated with expression of CD13, CD56, and absence of CD45. Therefore, there is a correlation between antigen expression on clonal plasma cell clinical stage as well as cytogenetic aberrations. Further studies are recommended on larger numbers of plasma cell myeloma patients to evaluate the impact of different antigen expressions of clonal plasma cells on the survival of the patients.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]