Context.—Plasma cell myeloma and chronic lymphocytic leukemia are both common hematologic malignancies, sharing many epidemiologic features. Concomitant detection of the 2 conditions poses special diagnostic challenges for the pathologist.

Objective.—To describe the pathologic findings in cases of concomitant bone marrow involvement by myeloma and CD5+ monoclonal B cells and to outline the differential diagnostic possibilities, suggest a workup for correct diagnosis, and examine clinical outcome.

Design.—Fifteen cases that met the diagnostic criteria were identified from pathology databases at 4 participating institutions. Morphologic findings were reviewed, additional immunohistochemical stains performed, and flow cytometric, cytogenetic, and relevant laboratory and clinical information was summarized. Previously published cases were searched from electronic databases and cross-references.

Results.—Most patients (13 of 15) were older males. Often (11 of 15) they presented clinically with myeloma, yet had both monotypic plasma cells and B cells in the diagnostic marrow. In 4 patients, myeloma developed 24 months or later after chronic lymphocytic leukemia. In 7 patients, myeloma and CD5+ B cells showed identical immunoglobulin light-chain restriction. Primary differential diagnoses include lymphoplasmacytic lymphoma, marginal zone lymphoma, and chronic lymphocytic leukemia with plasmacytoid differentiation. CD56 and/or cyclin D1 expression by plasma cells was helpful for correct diagnosis. Most patients in our cohort and published reports were treated for plasma cell myeloma.

Conclusions.—Concomitant detection of myeloma and chronic lymphocytic leukemia in the bone marrow is a rare event, which must be carefully differentiated from lymphomas with lymphoplasmacytic differentiation for correct treatment.

Plasma cell myeloma (PCM) (or multiple myeloma) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) are both common hematologic neoplasms, each constituting about 10% to 11% of all hematologic malignancies.1,2  Chronic lymphocytic leukemia/small lymphocytic lymphoma is the most common type of chronic leukemia in the United States and the Western world (annual incidence of 6.75 and 3.65 per 100 000 males and females, respectively)3  in which the abnormal cells characteristically express CD5 and CD23 and involve the blood, bone marrow, and lymph nodes.4  Monoclonal B-cell lymphocytosis (MBL) is a recently recognized condition in which low levels of monoclonal B cells are detected in blood of otherwise normal older adults, and the incidence of this phenomenon may be at least 100 times higher than that of CLL.57  Small numbers of clonal B cells may be seen in fewer than 1% of bone marrow specimens from patients without overt lymphoma.8  Plasma cell myeloma constitutes about 0.8% of all new cancers worldwide and also commonly involves the bone marrow.2  Plasma cell myeloma, CLL, and MBL all occur predominantly in older adults with a male preponderance and have a significantly higher incidence in the developed countries.9,10 

Despite their origin from mature B cells and similar epidemiology, CLL and PCM have widely different clinical presentations, pathologic features, treatment, and outcomes. Chronic lymphocytic leukemia/small lymphocytic lymphoma has a variable, but typically indolent course with life expectancy ranging from 10 years to more than 25 years.11,12  Plasma cell myeloma follows a variable, but generally more aggressive course, with a median survival of only 3 to 4 years.2,10  Importantly, these 2 hematologic neoplasms are treated by entirely different chemotherapy regimens.13,14 

Even though these 2 hematologic neoplasms are individually quite common, it is rare to find them together in the same patient, according to large clinical series.15,16  A little more than 50 patients showing evidence of both CLL and PCM have been described in the English literature, most as case reports1744  and only 2 case series.45,46  Many prior reports do not address the pathologic differential diagnosis, and the clinical implications of this dual involvement are not clear from individual case reports. We present 15 new cases of concomitant bone marrow involvement by PCM and CLL or MBL. We have also comprehensively reviewed clinicopathologic findings in previously reported cases. From findings from both sources, we present practical guidelines for differential diagnosis and the likely clinical outcome in such cases.

Case Selection

After obtaining respective institutional review board approval, the electronic databases of surgical pathology reports at 4 institutions were searched, covering a 10-year period between 2000 and 2009, to identify reports of bone marrow biopsies seen in which monotypic B cells and monotypic plasma cells were both identified. From the cases flagged by the automated searches, a manual review of pathology reports was conducted to identify cases of concurrent occurrence of CD5+ monotypic B cells and monotypic plasma cells. All available cytologic and histologic preparations were reviewed along with flow cytometric, cytogenetic, and molecular diagnostic data. The available hematology laboratory data and radiographic and clinical information were reviewed from the electronic hospital information systems at the respective institutions.

Immunohistochemical Staining

Additional immunohistochemical stains were performed as required. Five-micron-thick sections of the bone marrow core biopsies were stained for CD56 (clone TB01, Leica Microsystems, Bannockburn. Illinois) and cyclin D1 (clone SP4, Thermo Fisher Scientific, Fremont, California) by using established labeled polymer immunohistochemical staining technique. The sections were cut and mounted on adherent glass slides, dewaxed in xylene, and rehydrated in graded ethanols. Endogenous peroxidase activity was blocked by immersion in 0.3% aqueous peroxide for 15 minutes, followed by 2 washes in 1× Tris-buffered saline (TBS) for 5 minutes each. Slides were treated with a cocktail of 10 mmol/L Tris and 1 mmol/L EDTA pH 9.0 and heated in a pressure cooker for 2.5 minutes at 125°C, followed by a 20 minute cooling period. The sections were then incubated for 1 hour at room temperature with the primary antibody diluted in TBS. The negative control consisted of substitution of the primary antibody in selected cases with mouse immunoglobulin (Ig) G. This was followed by 2 washes in TBS and then incubation with anti-mouse horseradish peroxidase–labeled secondary antibody (Envision Plus, Dako Corp, Carpinteria, California) for 30 minutes. The bound complexes were visualized by the application of diaminobenzadine (Dako) containing 0.3% hydrogen peroxide as a substrate. After incubation, the sections were washed, lightly counterstained with hematoxylin or light green solution, washed again, dehydrated, cleared, and cover slipped.

Literature Review

The online database PubMed, maintained by National Center for Biotechnology Information, was searched for English language articles describing case reports or case series of patients with concurrent or sequential diagnosis of PCM and CLL. Complete versions of all selected articles were obtained and the clinical and pathologic information was abstracted from each and tabulated.

Statistical Analysis

All clinical and pathologic information from the selected cases, as well as from the published articles, was tabulated with Excel (Microsoft Corporation, Redmond, Washington). The same software was used to apply the t test. The Web-based software provided at http://www.quantitativeskills.com/sisa/index.htm (accessed December 25, 2011) was used to perform the χ2  and Fisher exact tests, and the GraphPad Prism (GraphPad Software, Inc, La Jolla, California) was used to perform a Kaplan-Meier survival analysis.

Clinical Features and Chronology of Disease Processes

Fifteen cases were identified in which the bone marrow showed simultaneous presence of monotypic and/or atypical plasma cells and a CD5+/CD23+ monotypic B-cell population. The clinical features in these patients are summarized in Table 1. There were 13 male (86.6%) and 2 female patients. The median age was 74 years (range, 56–91 years). In eleven of 15 cases (73.3%), the initial presentation was related to the plasma cell dyscrasia; but in all 11 of these, the first bone marrow specimen obtained showed the presence of both abnormal plasma cells and CD5+ monotypic B cells. The plasma cell dyscrasia was further characterized as symptomatic plasma cell myeloma (PCM) in 8 patients and as smoldering (asymptomatic) myeloma in 3 patients. Among the patients with symptomatic PCM, the primary clinical findings were related to pathologic fractures/lytic bone lesions in 6, while amyloid nephropathy and polyneuropathy with weight loss and anemia were the presenting features in 1 patient each. In 2 patients with smoldering myeloma, an incidentally detected monoclonal gammopathy prompted the bone marrow examination, while the third patient had a 14-year history of stable monoclonal gammopathy with more recent leukocytosis and an increasing level of the monoclonal paraprotein. Only 1 patient with symptomatic PCM had a documented 5-year history of monoclonal gammopathy preceding the diagnosis of PCM. In 4 of 15 patients (26.7%), the initial clinical and pathologic diagnosis was CLL, preceding the diagnosis of plasma cell dyscrasia by 2 years or longer (average, 34 months), and the bone marrow examination was performed to rule out disease progression or to investigate a new finding of monoclonal paraprotein in serum or urine. In 1 of these 4 patients (case 14), the CLL was in an advanced stage and required treatment, while the other 3 patients with CLL had not received specific treatment for this condition. Except for case 14, clinically detectable lymphadenopathy was not noted in any patient.

Table 1.

Clinical Findings for Patients Showing Presence of CD5+/CD23+ Monotypic B Cells Together With Monotypic Plasma Cells in the Bone Marrow

Clinical Findings for Patients Showing Presence of CD5+/CD23+ Monotypic B Cells Together With Monotypic Plasma Cells in the Bone Marrow
Clinical Findings for Patients Showing Presence of CD5+/CD23+ Monotypic B Cells Together With Monotypic Plasma Cells in the Bone Marrow

Peripheral Blood Findings

The peripheral blood findings at the time when the bone marrow biopsy showed the 2 monotypic processes concomitantly are summarized in Table 2. Peripheral blood counts are not available for 4 cases (cases 1, 2, 11, and 14) because the bone marrow biopsy was obtained at an outside institution. For the remaining 11 cases, 6 patients (54.5%) were anemic at the time of diagnosis. The mean hemoglobin level for the 11 cases was 12.1 g/dL (range, 10.1–15.5 g/dL). The platelet count was largely unaffected with only 1 case having a platelet count of less than 150 000/μL. Two of 11 patients (18.2%) had a circulating leukocytosis (cases 8 and 13) with an absolute lymphocyte count greater than 5000/μL. One of these patients had a diagnosis of CLL for 3.5 years, while the other had a stable IgG monoclonal paraprotein for 14 years and recent lymphocytosis. Three more patients (cases 5, 6, and 7) had lymphocytosis of greater than 1500/μL. Peripheral blood flow cytometry was performed in 3 cases, including the 2 cases with greater than 5000/μL lymphocytosis (cases 8 and 13), which showed 52% and 59% circulating abnormal lymphocytes with the CLL phenotype. The third case (case 3) showed only 2% abnormal circulating lymphocytes but the marrow showed 10% abnormal B cells (see below).

Table 2.

Peripheral Blood Findings at the Time of Bone Marrow Examination Showing Concomitant Plasma Cell Myeloma and Chronic Lymphocytic Leukemia (CLL)/Monoclonal B-Cell Lymphocytosis

Peripheral Blood Findings at the Time of Bone Marrow Examination Showing Concomitant Plasma Cell Myeloma and Chronic Lymphocytic Leukemia (CLL)/Monoclonal B-Cell Lymphocytosis
Peripheral Blood Findings at the Time of Bone Marrow Examination Showing Concomitant Plasma Cell Myeloma and Chronic Lymphocytic Leukemia (CLL)/Monoclonal B-Cell Lymphocytosis

Bone Marrow Findings

The salient bone marrow findings are summarized in Table 3. The bone marrow cellularity varied from 30% to 90% (average, 53%) in the whole group. The average bone marrow cellularity was similar in those diagnosed first with PCM (54%) or with CLL (50%). The marrow was moderately to markedly hypercellular for age in 7 of 15 patients, most (6) of whom were initially diagnosed with PCM. The proportion of abnormal plasma cells varied from 2% to 50% of total marrow cells (average, 23%), while the CD5+/CD23+ monotypic B cells accounted for 0% to 50% of total cells (average, 17%). Neither type of cells occurred at significantly different proportions when comparing cases initially diagnosed as plasma cell dyscrasia or CLL. The proportion of either type of abnormal cells or overall proportion of abnormal cells did not correlate with marrow cellularity (linear regression, r2 < 0.01). Reticulin fibrosis was present around the lymphoid cells in 5 of 10 cases initially presenting as plasma cell dyscrasia (reticulin stain was not performed in 1 case), but only in 1 of 4 cases with the initial diagnosis of CLL. Cytogenetics and/or fluorescence in situ hybridization abnormalities were detected in 7 of 10 patients for whom data were available. Abnormalities including deletions of 13q or 17p, and numeric abnormalities of chromosomes 11 or 12, were observed in 5 patients, generally in a small proportion of total cells (3% to 15%). One case showed fusion of cyclin D1 and IGH gene and 1 patient had deletion of the Y chromosome.

Table 3.

Bone Marrow Findings

Bone Marrow Findings
Bone Marrow Findings

Immunophenotypic Identification of the 2 Abnormal Populations

In every case, the abnormal B cells coexpressed CD5 and CD23, either by flow cytometry (14 cases) or immunohistochemistry (1 case). In 10 of 15 cases, the abnormal plasma cells were restricted for immunoglobulin κ light chain and in the remaining 5 for λ. For the CD5+/CD23+ abnormal lymphocytes, flow cytometric characterization of light-chain expression was available for 13 patients, while 1 case had essentially no surface immunoglobulin light-chain expression and flow cytometry was not performed in 1 case. The CD5+/CD23+ B cells were κ restricted in 8 of 13 cases and λ restricted in 5 of 13. The distribution of light-chain restriction between the plasma cells and lymphocytes is not significantly different (P = .29, Fisher exact). In these 13 cases for which light-chain restriction for both abnormal cell types was known, the expressed light chains were different for the 2 populations in 6 cases and the same in 7 (both were κ in 6 and λ in 1). Both immunohistochemistry and flow cytometry results are required for correct diagnosis when the light-chain restriction by the 2 abnormal populations is different but CD56 or cyclin D1 are not aberrantly expressed by the plasma cells, as illustrated in Figure 1, A through H, and Figure 2, A through D. Cyclin D1 overexpression occurred in the plasma cells in 8 of 14 cases (tissue was exhausted in 1 case and could not be tested). CD56 was aberrantly expressed in the plasma cells in 6 of 12 cases, along with cyclin D1 expression in all but 1 case. In 4 of 6 cases for which both abnormal B cells and plasma cells were κ light-chain restricted, the plasma cells were cyclin D1 positive and a fifth case had CCND1-IGH fusion by fluorescence in situ hybridization in all plasma cells. In the sixth case, the plasma cells aberrantly expressed CD56. This immunoreactivity pattern identified the plasma cells as constituting a plasma cell dyscrasia separate from the CD5+ monotypic B cells. In the case illustrated in Figure 3, A through F, the abnormal plasma cells and B cells both showed κ light-chain restriction (not shown), but the 2 hematologic malignancies can be clearly identified by the distinct nodular infiltrates of CD5+ B cells and CD138+/cyclin D1+ plasma cells. Overall, in 12 cases the B cells and plasma cells were shown to be distinct monotypic populations (6 by virtue of different light-chain restriction and 6 by virtue of cyclin D1 and/or CD56 expression in plasma cells). In 3 cases, the additional immunostaining was negative and the light-chain restriction did not clearly differentiate the plasma cells and B cells as separate clonal processes. In 1 case, the restriction was concordant (λ) and in 2 cases the B-cell light-chain restriction was unknown. In these 3 cases, flow cytometric or immunohistochemical demonstration of the CD5+/CD23+ phenotype of the abnormal B cells was important to rule out other differential diagnostic considerations (see discussion).

Figure 1

A through H, Bone marrow biopsy with immunohistochemistry showing intermixed populations. A, Bone marrow core biopsy from a representative case (case 13) shows several small clusters of plasma cells and scattered mature lymphocytes. B, The mature lymphocytes demonstrate membranous staining with CD79a. C, The mature lymphocytes also demonstrate nuclear staining for PAX-5. D, The B cells aberrantly express CD5. E, Scattered CD3+ T cells are seen in the background. F, CD138 highlights numerous plasma cells present singly and in small clusters. G, The plasma cells (arrowheads) demonstrate cytoplasmic staining for λ light chain. H, Only occasional plasma cells demonstrate staining for κ light chain (hematoxylin-eosin, original magnification ×200 [A]; original magnifications ×200 [B through F]; original magnifications ×400 [G and H]).

Figure 1

A through H, Bone marrow biopsy with immunohistochemistry showing intermixed populations. A, Bone marrow core biopsy from a representative case (case 13) shows several small clusters of plasma cells and scattered mature lymphocytes. B, The mature lymphocytes demonstrate membranous staining with CD79a. C, The mature lymphocytes also demonstrate nuclear staining for PAX-5. D, The B cells aberrantly express CD5. E, Scattered CD3+ T cells are seen in the background. F, CD138 highlights numerous plasma cells present singly and in small clusters. G, The plasma cells (arrowheads) demonstrate cytoplasmic staining for λ light chain. H, Only occasional plasma cells demonstrate staining for κ light chain (hematoxylin-eosin, original magnification ×200 [A]; original magnifications ×200 [B through F]; original magnifications ×400 [G and H]).

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Figure 2

A through D, Flow cytometry histograms from case 13 (the same bone marrow as depicted in Figure 1). A, Gating on lymphocytes reveals a distinct CD19+ B-cell population (green), which also aberrantly expresses CD5. Putative T cells (CD19, CD5+) are yellow and NK cells (CD19, CD5) are black. B, The atypical B cells express CD23. C, Gating on the B cells, the abnormal population (green) is κ light-chain restricted with dim expression. A few B cells express higher levels of κ (kappa) and λ (lambda; magenta), constituting the background normal B cells. D, Gating on the plasma cells, a discrete CD38+/CD138+++ plasma cell population is seen (cyan). Note that flow cytometry often underestimates the proportion of plasma cells. The percentage shown in each quadrant indicates the proportion of gated cells present in that quadrant. Abbreviations: Axes labels indicate antibody and conjugated fluorochromes as follows: FITC, Fluorescein isothiocyanate; PE, Phycoerythrin; PerCP-Cy5.5, Peridinin-chlorophyll-protein -Cyanine 5.5; APC, Allophycocyanin. Antibodies to kappa and lambda were purchased from Dako, Carpinteria, California, and all others from Beckton Dickinson, San Jose, California. Lymphs, lymphocytes.

Figure 2

A through D, Flow cytometry histograms from case 13 (the same bone marrow as depicted in Figure 1). A, Gating on lymphocytes reveals a distinct CD19+ B-cell population (green), which also aberrantly expresses CD5. Putative T cells (CD19, CD5+) are yellow and NK cells (CD19, CD5) are black. B, The atypical B cells express CD23. C, Gating on the B cells, the abnormal population (green) is κ light-chain restricted with dim expression. A few B cells express higher levels of κ (kappa) and λ (lambda; magenta), constituting the background normal B cells. D, Gating on the plasma cells, a discrete CD38+/CD138+++ plasma cell population is seen (cyan). Note that flow cytometry often underestimates the proportion of plasma cells. The percentage shown in each quadrant indicates the proportion of gated cells present in that quadrant. Abbreviations: Axes labels indicate antibody and conjugated fluorochromes as follows: FITC, Fluorescein isothiocyanate; PE, Phycoerythrin; PerCP-Cy5.5, Peridinin-chlorophyll-protein -Cyanine 5.5; APC, Allophycocyanin. Antibodies to kappa and lambda were purchased from Dako, Carpinteria, California, and all others from Beckton Dickinson, San Jose, California. Lymphs, lymphocytes.

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Figure 3

A through F, Bone marrow biopsy with immunohistochemistry showing 2 distinct cell populations. A, Bone marrow biopsy from another case (case 8) shows aggregates of small lymphoid cells. B, CD20 immunostain identifies mature B cells in most areas except the right upper side. C, CD3 immunostain shows few scattered T cells among the B cells. D, CD5 immunostain is strongly positive in the B-cell aggregate located in lower left portion. E, CD138 stains the aggregates of plasma cells in the right and upper area of the section and surrounds the lymphoid aggregate. F, Cyclin D1 immunostain is positive in the nuclei of the plasma cells. (Note that all panels represent the same area of the bone marrow biopsy, but A through C are consecutive sections and D through F are another set of consecutive sections separated from the other 3 sections by several levels (hematoxylin-eosin, original magnification ×200 [A]; original magnifications ×200 [B through F]).

Figure 3

A through F, Bone marrow biopsy with immunohistochemistry showing 2 distinct cell populations. A, Bone marrow biopsy from another case (case 8) shows aggregates of small lymphoid cells. B, CD20 immunostain identifies mature B cells in most areas except the right upper side. C, CD3 immunostain shows few scattered T cells among the B cells. D, CD5 immunostain is strongly positive in the B-cell aggregate located in lower left portion. E, CD138 stains the aggregates of plasma cells in the right and upper area of the section and surrounds the lymphoid aggregate. F, Cyclin D1 immunostain is positive in the nuclei of the plasma cells. (Note that all panels represent the same area of the bone marrow biopsy, but A through C are consecutive sections and D through F are another set of consecutive sections separated from the other 3 sections by several levels (hematoxylin-eosin, original magnification ×200 [A]; original magnifications ×200 [B through F]).

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Clinical Course

Five of 15 patients did not receive any specific treatment, 4 of whom were diagnosed first with plasma cell dyscrasia. For these 4 patients, treatment was withheld per patient request either owing to advanced age and/or because the disease was clinically stable. Seven of 11 patients who first presented with symptoms related to plasma cell dyscrasia were treated with myeloma-specific therapy (melphelan, bortezomib, thalidomide, lenalidomide, steroids, or localized radiation in different combinations), even though CD5+ monoclonal B cells were documented in the marrow. Only 1 patient received additional therapy directed at the monoclonal B cells (anti-CD20 antibody rituximab). Two of 11 patients underwent stem cell transplant, 1 with allogeneic and one with autologous cells. Only 1 of 4 patients initially presenting with CLL received disease-specific treatment (cyclophosphamide and fludarabine). In another patient from this group, anti-PCM treatment was given when abnormal plasma cells were later detected. Follow-up information was available for 14 patients and duration of follow-up varied from 1 month to 122 months (median, 6.5 months; average, 27.3 months). Three patients died; for 2, death was disease related and for the third it was due to a third malignancy (pancreatic adenocarcinoma). Eight of 11 patients initially presenting with PCM and 3 of 4 presenting with CLL had a reduced amount of marrow disease and/or clinically stable disease at last follow-up.

Plasma cell myeloma and CLL are the 2 most common B-cell malignancies occurring in the older adult population.1  Despite largely overlapping epidemiologic features and origin from mature B cells, simultaneous occurrence of both diseases in a patient is rare. A study from the Mayo Clinic,15  spanning 10 years, found 31 cases of CLL with a second malignancy, but none of these was PCM. The authors also conducted a literature review and noted that none of the 107 cases of a second malignancy found in patients with CLL was PCM. In a large epidemiologic study spanning 38 years and including 54 159 patients with hematolymphoid malignancies from Sweden, only 3 cases of plasma cell myeloma and lymphoid leukemia were found together.16  This low incidence is remarkable because greater than 8000 patients each with myeloma and lymphoid leukemia were included in this series and the total number of second malignancies noted was 475 and 659 in myeloma and lymphoid leukemia, respectively. In a recent German study47  involving 589 consecutive patients with myeloma seen at a single institution in 11 years, 59 (10%) had a second neoplasm before, during, or after the diagnosis of myeloma. Of these cases, 5 (0.84%) were CLL, while 6 cases of MDS and 46 cases of solid tumors were seen in the same cohort. All CLL cases occurred in males and the condition was diagnosed nearly 2 years before the diagnosis of myeloma. With the recognition of MBL, the proportion of older adults having detectable monoclonal B cells with CLL-like phenotype in the blood has dramatically increased48  but, to our knowledge, data on actual incidence of concurrent occurrence of PCM and MBL are not available.

We have identified 30 case reports or case series published in the English language literature describing CLL and PCM together in the same patient.1746  During the span of 50 years covered by these reports, 51 total cases showing the presence of CLL and PCM in the same patient are described. The salient findings from these studies are summarized in Table 4. In comparing the published data to our findings, the demographic profile of patients is similar (most are males in their sixth or seventh decade of life), but in our series only 4 of 15 (26.7%) were first diagnosed with CLL and then developed PCM, compared to 31 of 51 such cases (60.8%) in the published literature (P = .02, Fisher exact). This difference is probably due to the case selection bias: we selected cases from surgical pathology reports of bone marrow, while many published reports have selected cases by clinical criteria. The published literature reports a significantly higher proportion of abnormal cells in the bone marrow than was observed in our series (46.6% versus 16.5% CLL cells and 34.1 versus 23.1% plasma cells, P < .001 and P = .08, respectively, t test). Relevant data are missing in 12 published reports for CLL cells and in 7 reports for plasma cells. The differences in the level of marrow involvement by PCM are difficult to explain because they are unlikely to be the result of previous treatment, which was given in a similar proportion of cases in our series (73.3%) and published reports (66%).

Table 4.

Summary of Clinical and Pathologic Findings in Published Cases

Summary of Clinical and Pathologic Findings in Published Cases
Summary of Clinical and Pathologic Findings in Published Cases

On the other hand, the lower level of marrow involvement by CD5+ B cells seen in our series appears to be a consequence of the method of case selection and the inclusion of patients with MBL in our series. In the absence of extramedullary tissue involvement, the diagnosis of CLL, according to the World Health Organization (WHO) classification,4  requires the presence of greater than 5000 monotypic B cells per μL in the blood, with a CD5+ and CD23+ phenotype for at least 3 months. Notably, this definition differs from earlier definitions that required the presence of 5000 lymphocytes per μL (rather than monotypic B cells).49  According to the current definition, the presence of fewer than 5000 monotypic B cells per μL is now categorized as MBL, provided there are no clinical or laboratory features of lymphoma/leukemia.

It is now widely accepted that MBL is an extremely common occurrence in older adults.5,6,50  In about 75% of these cases, the monoclonal B cells have the same phenotype as CLL cells. Only a minority of MBL cases have absolute lymphocytosis of 1500/μL or greater but less than 5000/μL and these are designated as “clinical MBL” (cMBL). The incidence of cMBL is estimated at 0.6% to 0.9% in persons older than 50 years (which is about 100 times higher than the incidence of CLL, estimated at 5 to 6 cases per 100 000). Presence of very low levels of monoclonal B cells (median, 1 monoclonal B cell per μL) without significant lymphocytosis is much higher, estimated to affect 20% of otherwise healthy older adults in some European countries such as Spain. These cases are detected by population screening with high-sensitivity flow cytometry methods and are designated “screening MBL.” 7,51 Perhaps all cases of CLL are preceded by cMBL, but fewer than 1% of cMBL cases progress to CLL.6  In 1 study,52  the median level of bone marrow lymphocytes in cMBL was found to be 20%.

In the 11 patients from our cohort for whom peripheral blood findings were available, only 2 patients had abnormal B-cell lymphocytosis at a level sufficient to fulfill the WHO definition of CLL (cases 8 and 13). In addition to case 13, three other cases involved patients who were earlier diagnosed with CLL (cases 12, 14, and 15). In 2 patients (cases 1 and 7), the level of CD5+ monoclonal B cells in the marrow was 30% or greater, which is significantly higher than the median value of 20% monotypic B cells noted in cMBL, and these cases also likely represent CLL rather than MBL. Thus, 7 patients in our cohort appear to have CLL (cases 1, 7, 8, 12, 13, 14, and 15). The remaining 8 cases are best considered as MBL. However, the actual distinction between MBL and early-stage CLL may not be clinically relevant as these 2 conditions are a continuum rather than discrete entities.48  Admittedly, the incidence of very-low-level MBL in patients with PCM cannot be inferred from our study because high-sensitivity flow cytometric detection of monoclonal B cells in the blood is not performed routinely in every patient with PCM. Small numbers of clonal B cells are detected incidentally in the bone marrow at a low frequency. In a single center retrospective study,8  fewer than 1% of flow cytometry analyses of bone marrow specimens from patients without a diagnosis of overt lymphoma contained 0.05% to 4.5% (median, 1.28%) clonal B cells. Of these, fewer than a third had the CLL phenotype and about a third of the total cohort subsequently developed non-Hodgkin lymphoma. This rate of progression to overt lymphoma is much higher than the approximately 1% rate of progression from cMBL to CLL.48  This may suggest that subclinical/undetectable lymphoma in extramedullary locations may exist in a higher proportion of patients showing low-level clonal B cells in the bone marrow than in those showing low-level clonal B cells in the blood. Notably, none of the patients in this study, in whom clonal B cells were incidentally detected in the marrow, showed plasma cell myeloma in that or subsequent marrow.8 

While it is probably clinically not very significant to differentiate cMBL from CLL in patients with concomitant PCM, it is critical that this rare co-occurrence is correctly differentiated from other causes of a lymphoplasmacytic infiltration in the bone marrow. Most patients in published studies, as well as our cohort, required treatment for PCM, while CLL/MBL was often managed without specific treatment (Tables 1 and 4). On the other hand, hematologic malignancies with a lymphoplasmacytic infiltrate may need lymphoma-specific treatments. The differential diagnoses of a lymphoplasmacytic or lymphoplasmacytoid infiltration in the bone marrow include at least 3 neoplastic conditions: lymphoplasmacytic lymphoma (LPL) (also called immunocytoma or Waldenstrom macroglobulinemia), marginal zone lymphoma (MZL) with plasmacytic differentiation, and CLL with plasmacytic differentiation. The characteristic clinical, morphologic, and immunophenotypic features useful in this differential diagnosis are summarized in Table 5.

Table 5.

Characteristic Findings Differentiating Concomitant Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL) and Plasma Cell Myeloma (PCM) From Other Monotypic Lymphoplasmacytic Infiltrates in Bone Marrow

Characteristic Findings Differentiating Concomitant Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL) and Plasma Cell Myeloma (PCM) From Other Monotypic Lymphoplasmacytic Infiltrates in Bone Marrow
Characteristic Findings Differentiating Concomitant Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL) and Plasma Cell Myeloma (PCM) From Other Monotypic Lymphoplasmacytic Infiltrates in Bone Marrow

Deviation from the classic immunophenotype of the lymphoid neoplasms included in this differential diagnosis may confound the correct interpretation. While characteristically the small lymphocytes in LPL are CD5,53,54  from 5% to 43% of LPL cases may express CD5, at least partially.5557  Asplund et al58  reported 1 case of LPL among 26 CD5+ B-cell neoplasms with ambiguous immunophenotype. Some of these CD5+ LPL cases may have partial expression of CD23 but other immunophenotypic features of CLL, such as dim CD20 and dim surface immunoglobulin,56,57  are absent and cyclin D1 is not expressed.58  The morphologic finding of plasma cell collections completely separated from the lymphoid collections can occasionally occur in LPL,57  which mimics the pattern seen in concurrent marrow involvement by CLL and PCM (Figure 3, A), but the plasma cells in LPL do not express cyclin D1 or CD56,55  in contrast to PCM cells, which expressed these markers in 53.3% and 42.8% of our cases, respectively. The presence of an intimate mixture of lymphocytes and plasma cells, reported in a prior case report of concurrent CLL and PCM,59  more closely resembles LPL and needs more careful workup (Figure 1). The paraprotein is typically (but not invariably) IgM in lymphoplasmacytic lymphoma.56  The paraproteins produced by plasma cells in our patients were either IgG or IgA, but among the published reports, several cases include IgM-producing PCM,26,36,44,45  and patients with CLL can produce IgM paraprotein at levels overlapping those of LPL.60  Thus, the isotype of the paraprotein is not a reliable discriminator between LPL and concomitant PCM and CLL.

Of the 3 major types of MZLs (splenic, nodal, and mucosa-associated lymphoid tissue type), only splenic marginal zone lymphoma involves the bone marrow with any regularity,61,62  but a significant proportion (21%–74%) may show plasmacytic differentiation.63,64 Up to 20% of splenic MZLs can express CD5,65  leading to difficulty in distinguishing these cases from CLL; however, splenic MZL typically shows strong expression of CD20 and surface immunoglobulin, which aids in the distinction between these 2 entities. Splenomegaly can occur in CLL, as well as splenic MZL, and cannot be used to distinguish the two. Splenic MZLs lack expression of cyclin D1,63  which is helpful to separate them from cyclin D1+ plasma cell neoplasms occurring concurrently with CLL. Rarely, a monotypic plasma cell proliferation can occur in marrow involved by splenic MZL, and molecular study may be necessary to identify the 2 monotypic populations if the light-chain restriction is the same for both monotypic processes.64  Chronic lymphocytic leukemia/small lymphocytic lymphoma itself can show lymphoplasmacytoid differentiation, but these cases lack true plasma cells and may appear as “atypical” CLL. True plasmacytic differentiation in CLL appears to be very rare and may only be seen in the lymph node.66  Clinical and radiographic findings, such as lytic bone lesions, hypercalcemia, non-IgM paraprotein, support a diagnosis of PCM because these features are very rare in the lymphoid malignancies discussed above (LPL, splenic MZL, and CLL). An erroneous diagnosis of mantle cell lymphoma is a critical diagnostic pitfall if it is not realized that the CD5+ monoclonal B cells are separate from the cyclin D1+ plasma cells (Figure 3, D and F). Indeed, 1 of our patients (case 2) was referred for treatment after an outside diagnosis of mantle cell lymphoma. Conversely, the plasma cells may express CD20 in about 10% of cases67  and may have a lymphocyte-like “small cell” morphology in about 3% to 4% of cases.68  When small plasma cells express CD20 and CD45, along with cyclin D1 (which is seen in 75% of “small cell” myelomas), distinction from mantle cell lymphoma is facilitated by demonstrating the CD138+ and CD5 phenotype of the plasma cells.68 

Are the CD5+ abnormal B cells and monotypic plasma cells occurring concomitantly in the marrow biologically related and what are the clinical implications of this rare event? It is generally accepted that normal plasma cells are terminally differentiated, specialized cells arising from B cells,69  and it is theoretically possible that the monotypic plasma cells are further differentiated or transformed CLL cells. But the 2 processes may arise independently from the same stem cell or arise from different B cells purely coincidentally. Interestingly, only 3 of 51 published reports,17,44,45  and none of our cases, show PCM preceding CLL (Table 4). Putative transformation of CLL cells to plasma cells may be inferred only by showing clonal identity between the 2 processes. Such clonal identity can be established definitively by sequencing the rearranged immunoglobulin heavy-chain genes from pure populations of each of the 2 abnormal cell types, but these data are not available in most cases. Lacking molecular data, we can use the well-known property of allelic exclusion in B cells70  to estimate clonal relatedness. Caution must be exercised when interpreting such data, because nonidentical light chains may occasionally occur in clonal evolution.24  In our cohort, information for light-chain restriction of CLL and PCM cells was available for 13 cases: restriction was the same in 7 and different in 6 cases. In the published reports, excluding the 3 cases first presenting with PCM,17,44,45  information for light-chain restriction of CLL and PCM cells was available for 28 cases and the light-chain restriction was the same in 15 cases and different in 13. A Kaplan-Meier survival analysis (data not shown) in which the published cases and our cases were divided on the basis of same or different light-chain restriction showed statistically similar disease-specific median survival rates of 22 months and 28 months, respectively. Notably, these survival rates are shorter than the 36- to 48-month survival seen in de novo plasma cell myeloma.2,10  Whether this apparent shortening of survival reflects a true change in the biology of PCM occurring on a background of CLL/MBL needs further study.

In summary, we have presented the clinicopathologic findings in 15 cases in which the bone marrow showed simultaneous presence of CD5+ monoclonal B cells and monotypic plasma cells. We have compared our results with the 51 cases of concurrent CLL and PCM previously reported in 30 articles. The distinction between CLL and the newly described precursor entity “monoclonal B-cell lymphocytosis” is discussed. Differentiating cases with concomitant presence of PCM and CLL/MBL from other causes of lymphoplasmacytic or lymphoplasmacytoid marrow infiltration is crucial for correct treatment. A careful review of immunophenotype of the B cells and immunohistochemical staining for CD56 and/or cyclin D1 to identify abnormal plasma cells will allow separation from conditions such as LPL, splenic MZL, and CLL with plasmacytic differentiation. Notably, despite the presence of the 2 abnormal populations, almost all of our patients, and many patients from published reports, required treatment for myeloma rather than for CLL.

Table 4.

Extended

Extended
Extended
Table 5.

Extended

Extended
Extended

We thank Steven Conlon, AAS, Photopath Division, Department of Pathology, Duke University Medical Center, for expert help with the Figures.

1
Jemal
A
,
Siegel
R
,
Ward
E
,
et al
.
Cancer statistics, 2008
.
CA Cancer J Clin
.
2008;
58
(
2
):
71
96
.
2
McKenna
RW
,
Kyle
RA
,
Kuehl
WM
,
Grogan
TM
,
Harris
NL
,
Coupland
RW
.
Plasma cell neoplasms
.
In
:
Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed
.
Lyon, France
:
IARC Press;
2008
:
200
213
.
World Health Organization Classification of Tumours; vol 2
.
3
Yamamoto
JF
,
Goodman
MT
.
Patterns of leukemia incidence in the United States by subtype and demographic characteristics, 1997–2002
.
Cancer Causes Control
.
2008;
19
(
4
):
379
390
.
4
Muller-Hermelink
HK
,
Monteserrat
E
,
Catovsky
D
,
Campo
E
,
Harris
NL
,
Stein
H
.
Chronic lymphocytic leukemia/small lymphocytic lymphoma
.
In
:
Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed
.
Lyon, France
:
IARC Press;
2008
:
180
182
.
World Health Organization Classification of Tumours; vol 2
.
5
Marti
GE
,
Rawstron
AC
,
Ghia
P
,
et al
.
Diagnostic criteria for monoclonal B-cell lymphocytosis
.
Br J Haematol
.
2005;
130
(
3
):
325
332
.
6
Shanafelt
TD
,
Ghia
P
,
Lanasa
MC
,
Landgren
O
,
Rawstron
AC
.
Monoclonal B-cell lymphocytosis (MBL): biology, natural history and clinical management
.
Leukemia
.
2010;
24
(
3
):
512
520
.
7
Fazi
C
,
Scarfo
L
,
Pecciarini
L
,
et al
.
General population low-count CLL-like MBL persists over time without clinical progression, although carrying the same cytogenetic abnormalities of CLL
.
Blood
.
2011;
118
(
25
):
6618
6625
.
8
Chen
W
,
Asplund
SL
,
McKenna
RW
,
Kroft
SH
.
Characterization of incidentally identified minute clonal B-lymphocyte populations in peripheral blood and bone marrow
.
Am J Clin Pathol
.
2004;
122
(
4
):
588
595
.
9
Becker
N
.
Epidemiology of multiple myeloma
.
Recent Results Cancer Res
.
2011;
18325
18335
.
10
Rajkumar
SV
.
Multiple myeloma: 2011 update on diagnosis, risk-stratification, and management
.
Am J Hematol
.
2011;
86
(
1
):
57
65
.
11
Shanafelt
TD
,
Geyer
SM
,
Kay
NE
.
Prognosis at diagnosis: integrating molecular biologic insights into clinical practice for patients with CLL
.
Blood
.
2004;
103
(
4
):
1202
1210
.
12
Van Bockstaele
F
,
Verhasselt
B
,
Philippe
J
.
Prognostic markers in chronic lymphocytic leukemia: a comprehensive review
.
Blood Rev
.
2009;
23
(
1
):
25
47
.
13
Kumar
A
,
Galeb
S
,
Djulbegovic
B
.
Treatment of patients with multiple myeloma: an overview of systematic reviews
.
Acta Haematol
.
2011;
125
(
1–2
):
8
22
.
14
Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials
;
CLL Trialists' Collaborative Group
.
J Natll Cancer Inst
.
1999;
91
(
10
):
861
868
.
15
Moertel
CG
,
Hagedorn
AB
.
Leukemia or lymphoma and coexistent primary malignant lesions: a review of the literature and a study of 120 cases
.
Blood
.
1957;
12
(
9
):
788
803
.
16
Dong
C
,
Hemminki
K
.
Second primary neoplasms among 53159 haematolymphoproliferative malignancy patients in Sweden, 1958–1996: a search for common mechanisms
.
Br J Cancer
.
2001;
85
(
7
):
997
1005
.
17
Srinivasan
S
,
Schiffer
CA
.
Concurrent B-cell chronic lymphocytic leukemia and multiple myeloma treated successfully with lenalidomide
.
Leuk Res
.
2009;
33
(
4
):
561
564
.
18
Chang
H
,
Wechalekar
A
,
Li
L
,
Reece
D
.
Molecular cytogenetic abnormalities in patients with concurrent chronic lymphocytic leukemia and multiple myeloma shown by interphase fluorescence in situ hybridization: evidence of distinct clonal origin
.
Cancer Genet Cytogenet
.
2004;
148
(
1
):
44
48
.
19
Aktan
M
,
Akkaya
A
,
Dogan
O
,
Dincol
G
.
Chronic lymphocytic leukemia and multiple myeloma in the same patient: case report
.
Leuk Lymphoma
.
2003;
44
(
8
):
1421
1424
.
20
Kaufmann
H
,
Ackermann
J
,
Nosslinger
T
,
et al
.
Absence of clonal chromosomal relationship between concomitant B-CLL and multiple myeloma: a report on two cases
.
Ann Hematol
.
2001;
80
(
8
):
474
478
.
21
Patriarca
F
,
Gaidano
G
,
Capello
D
,
Zaja
F
,
Fanin
R
,
Baccarani
M
.
Occurrence of multiple myeloma after fludarabine treatment of a chronic lymphocytic leukemia: evidence of a biclonal derivation and clinical response to autologous stem cell transplantation
.
Haematologica
.
2000;
85
(
9
):
982
985
.
22
Makower
D
,
Venkatraj
U
,
Dutcher
JP
,
Wiernik
PH
.
Occurrence of myeloma in a chronic lymphocytic leukemia patients after response to differentiation therapy with interleukin-4
.
Leuk Lymphoma
.
1996;
23
(
5–6
):
617
619
.
23
Novak
PM
,
Mattson
JC
,
Crisan
D
,
Chen
J
,
Poulik
MD
,
Decker
D
.
Separate clones in concomitant multiple myeloma and a second B-cell neoplasm demonstrated by molecular and immunophenotypic analysis
.
Eur J Haematol
.
1995;
54
(
4
):
254
261
.
24
Saltman
DL
,
Ross
JA
,
Banks
RE
,
Ross
FM
,
Ford
AM
,
Mackie
MJ
.
Molecular evidence for a single clonal origin in biphenotypic concomitant chronic lymphocytic leukemia and multiple myeloma
.
Blood
.
1989;
74
(
6
):
2062
2065
.
25
Fermand
JP
,
James
JM
,
Herait
P
,
Brouet
JC
.
Associated chronic lymphocytic leukemia and multiple myeloma: origin from a single clone
.
Blood
.
1985;
66
(
2
):
291
293
.
26
Pines
A
,
Ben-Bassat
I
,
Selzer
G
,
Ramot
B
.
Transformation of chronic lymphocytic leukemia to plasmacytoma
.
Cancer
.
1984;
54
(
9
):
1904
1907
.
27
Bassan
R
,
Comotti
B
,
Minetti
B
,
Viero
P
,
Barbui
T
.
Concurrent multiple myeloma and chronic lymphocytic leukemia
.
Am J Clin Pathol
.
1984;
82
(
5
):
624
627
.
28
Kontozoglou
T
,
Skinnider
LF
.
Concurrent appearance of multiple myeloma with other B-cell lymphoid neoplasms: a report of two cases
.
Arch Pathol Lab Med
.
1983;
107
(
5
):
232
234
.
29
Jeha
MT
,
Hamblin
TJ
,
Smith
JL
.
Coincident chronic lymphocytic leukemia and osteosclerotic multiple myeloma
.
Blood
.
1981;
57
(
3
):
617
619
.
30
Pedersen-Bjergaard
J
,
Petersen
HD
,
Thomsen
M
,
Wiik
A
,
Wolff-Jensen
J
.
Chronic lymphocytic leukaemia with subsequent development of multiple myeloma: evidence of two B-lymphocyte clones and of myeloma-induced suppression of secretion of an M-component and of normal immunoglobulins
.
Scand J Haematol
.
1978;
21
(
3
):
256
264
.
31
Kough
RH
,
Makary
AZ
.
Chronic lymphocytic leukemia (CLL) terminating in multiple myeloma: report of two cases
.
Blood
.
1978;
52
(
3
):
532
536
.
32
Hoffman
KD
,
Rudders
RA
.
Multiple myeloma and chronic lymphocytic leukemia in a single individual
.
Arch Intern Med
.
1977;
137
(
2
):
232
235
.
33
Narasimhan
P
,
Jagathambal
K
,
Elizalde
AM
,
Rosner
F
.
Chronic lymphocytic leukemia and lymphosarcoma associated with multiple myeloma: report of three cases
.
Arch Intern Med
.
1975;
135
(
5
):
729
732
.
34
Vander
JB
,
Johnson
HA
.
Chronic lymphatic leukemia and multiple myeloma in the same patient
.
Ann Intern Med
.
1960;
53
(
11
):
1052
1059
.
35
Naidu
RT
,
Rosner
F
.
Combined multiple myeloma and chronic lymphatic leukemia
.
New Engl J Med
.
1971;
284
(
2
):
108
.
36
Fitzgerald
PH
,
Rastrick
JM
,
Hamer
JW
.
Acute plasma cell leukaemia following chronic lymphatic leukaemia: transformation or two separate diseases?
Br J Haematol
.
1973;
25
(
2
):
171
177
.
37
Crowley
JP
,
Churchill
WH
,
Simon
J
,
Albala
MM
.
Absence of lymphocyte immunoglobulin production in chronic lymphocytic leukemia and multiple myeloma
.
Ann Intern Med
.
1977;
86
(
6
):
750
752
.
38
Zawadzki
ZA
,
Kapadia
S
,
Barnes
AE
.
Leukemic myelomatosis (plasma cell leukemia)
.
Am J Clin Pathol
.
1978;
70
(
4
):
605
611
.
39
Shuster
M
,
Causing
WC
.
Chronic lymphatic leukemia and lymphosarcoma terminating in multiple myeloma
.
J Med Soc N J
.
1971;
68
(
5
):
365
368
.
40
Clinicopathologic conference: multiple malignancies: chronic lymphocytic leukemia, malignant melanoma, multiple myeloma and acute myelomonocytic leukemia
.
Am J Med
.
1975;
58
(
3
):
408
416
.
41
Browett
PJ
,
Leber
BF
,
Coustan-Smith
E
,
Norton
JD
.
Independent clonal origin of coexisting chronic lymphocytic leukaemia and multiple myeloma
.
Br J Haematol
.
1988;
70
(
1
):
126
127
.
42
Shpilberg
O
,
Mark
Z
,
Biniaminov
M
,
et al
.
Transformation of chronic lymphocytic leukemia to multiple myeloma: clonal evolution of second malignancy?
Leukemia
.
1995;
9
(
11
):
1974
1978
.
43
McLaughlin
H
,
Melinn
M
,
Farrelly
PA
.
Multiple myeloma and chronic lymphatic leukemia in the same patient
.
Oncology
.
1978;
35
(
6
):
267
270
.
44
Zalcberg
JR
,
Cornell
FN
,
Ireton
HJ
,
et al
.
Chronic lymphatic leukemia developing in a patient with multiple myeloma: immunologic demonstration of a clonally distinct second malignancy
.
Cancer
.
1982;
50
(
3
):
594
597
.
45
Brouet
JC
,
Fermand
JP
,
Laurent
G
,
et al
.
The association of chronic lymphocytic leukaemia and multiple myeloma: a study of eleven patients
.
Br J Haematol
.
1985;
59
(
1
):
55
66
.
46
Pantic
M
,
Schroettner
P
,
Pfeifer
D
,
et al
.
Biclonal origin prevails in concomitant chronic lymphocytic leukemia and multiple myeloma
.
Leukemia
.
2010;
24
(
4
):
885
890
.
47
Hasskarl
J
,
Ihorst
G
,
De Pasquale
D
,
et al
.
Association of multiple myeloma with different neoplasms: systematic analysis in consecutive patients with myeloma
.
Leuk Lymphoma
.
2011;
52
(
2
):
247
259
.
48
Molica
S
,
Mauro
FR
,
Molica
M
,
Giudice
ID
,
Foa
R
.
Monoclonal B-cell lymphocytosis
:
a reappraisal of its clinical implications [published online ahead of print March 16
,
2012]
.
Leuk Lymphoma
. doi:.
49
Cheson
BD
,
Bennett
JM
,
Grever
M
,
et al
.
National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment
.
Blood
.
1996;
87
(
12
):
4990
4997
.
50
Rawstron
AC
.
Monoclonal B-cell lymphocytosis
.
Hematol Am Soc Hematol Educ Program
.
2009;
430
439
.
51
Rawstron
AC
,
Shanafelt
T
,
Lanasa
MC
,
et al
.
Different biology and clinical outcome according to the absolute numbers of clonal B-cells in monoclonal B-cell lymphocytosis (MBL)
.
Cytometry B Clin Cytom
.
2010;
78
(
suppl 1
):
S19
S23
.
52
Rossi
D
,
Sozzi
E
,
Puma
A
,
et al
.
The prognosis of clinical monoclonal B cell lymphocytosis differs from prognosis of Rai 0 chronic lymphocytic leukaemia and is recapitulated by biological risk factors
.
Br J Haematol
.
2009;
146
(
1
):
64
75
.
53
Andriko
JA
,
Swerdlow
SH
,
Aguilera
NI
,
Abbondanzo
SL
.
Is lymphoplasmacytic lymphoma/immunocytoma a distinct entity: a clinicopathologic study of 20 cases
.
Am J Surg Pathol
.
2001;
25
(
6
):
742
751
.
54
Swerdlow
SH
,
Berger
F
,
Pilleri
SA
,
Harris
NL
,
Jaffe
ES
,
Stein
H
.
Lymphoplasmacytic lymphoma
.
In
:
Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed
.
Lyon, France
:
IARC Press;
2008
:
194
195
.
World Health Organization Classification of Tumours; vol 2
.
55
San Miguel
JF
,
Vidriales
MB
,
Ocio
E
,
et al.
Immunophenotypic analysis of Waldenstrom's macroglobulinemia
.
Semin Oncol
.
2003;
30
(
2
):
187
195
.
56
Konoplev
S
,
Medeiros
LJ
,
Bueso-Ramos
CE
,
Jorgensen
JL
,
Lin
P
.
Immunophenotypic profile of lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia
.
Am J Clin Pathol
.
2005;
124
(
3
):
414
420
.
57
Morice
WG
,
Chen
D
,
Kurtin
PJ
,
Hanson
CA
,
McPhail
ED
.
Novel immunophenotypic features of marrow lymphoplasmacytic lymphoma and correlation with Waldenstrom's macroglobulinemia
.
Mod Pathol
.
2009;
22
(
6
):
807
816
.
58
Asplund
SL
,
McKenna
RW
,
Doolittle
JE
,
Kroft
SH
.
CD5-positive B-cell neoplasms of indeterminate immunophenotype: a clinicopathologic analysis of 26 cases
.
Appl Immunohistochem Mol Morphol
.
2005;
13
(
4
):
311
317
.
59
Peters
JH
,
Heller
P
,
Valaitis
J
.
Malignant lymphoma, plasmacytosis, dysproteinemia
.
Arch Intern Med
.
1961;
107
(
6
):
903
907
.
60
Lin
P
,
Hao
S
,
Handy
BC
,
Bueso-Ramos
CE
,
Medeiros
LJ
.
Lymphoid neoplasms associated with IgM paraprotein: a study of 382 patients
.
Am J Clin Pathol
.
2005;
123
(
2
):
200
205
.
61
Isaacson
PG
,
Piris
MA
,
Berger
F
,
et al
.
Splenic B-cell marginal zone lymphoma
.
In
:
Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed
.
Lyon, France
:
IARC Press;
2008
:
185
187
.
World Health Organization Classification of Tumours; vol 2
.
62
Berger
F
,
Felman
P
,
Thieblemont
C
,
et al
.
Non-MALT marginal zone B-cell lymphomas: a description of clinical presentation and outcome in 124 patients
.
Blood
.
2000;
95
(
6
):
1950
1956
.
63
Duong Van Huyen
JP
,
Molina
T
,
Delmer
A
,
et al.
Splenic marginal zone lymphoma with or without plasmacytic differentiation
.
Am J Surg Pathol
.
2000;
24
(
12
):
1581
1592
.
64
Molina
TJ
,
Lin
P
,
Swerdlow
SH
,
Cook
JR
.
Marginal zone lymphomas with plasmacytic differentiation and related disorders
.
Am J Clin Pathol
.
2011;
136
(
2
):
211
225
.
65
Gimeno
E
,
Salido
M
,
Sole
F
,
et al
.
CD5 negative and CD5 positive splenic marginal B-cell lymphomas have differential cytogenetic patterns
.
Leuk Res
.
2005;
29
(
8
):
981
982
.
66
Evans
HL
,
Polski
JM
,
Deshpande
V
,
Dunphy
CH
.
CD5+ true SLL/CLL with plasmacytic differentiation and an unusual 1p36 translocation: case report and review of the literature
.
Leuk Lymphoma
.
2000;
39
(
5–6
):
625
632
.
67
Lin
P
,
Owens
R
,
Tricot
G
,
Wilson
CS
.
Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma
.
Am J Clin Pathol
.
2004;
121
(
4
):
482
488
.
68
Heerema-McKenney
A
,
Waldron
J
,
Hughes
S
,
et al
.
Clinical, immunophenotypic, and genetic characterization of small lymphocyte-like plasma cell myeloma: a potential mimic of mature B-cell lymphoma
.
Am J Clin Pathol
.
2010;
133
(
2
):
265
270
.
69
Shapiro-Shelef
M
,
Calame
K
.
Regulation of plasma-cell development
.
Nat Rev Immunol
.
2005;
5
(
3
):
230
242
.
70
Vettermann
C
,
Schlissel
MS
.
Allelic exclusion of immunoglobulin genes: models and mechanisms
.
Immunol Rev
2010;
237
(
1
):
22
42
.

Author notes

The authors have no relevant financial interest in the products or companies described in this article.