Chapter 24 : Plasma Cell Disorders

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Clonal plasma cell disorders (PCDs) encompass a heterogeneous group of distinct entities characterized in common by a clonal expansion and accumulation of plasma cells (PCs) in the bone marrow (BM) and/or other tissues, which is associated in the vast majority of cases with the presence of their product(s) (monoclonal immunoglobulin [Ig], M component) at detectable amounts in serum or urine (1). Although the so-called diseases of immunoglobulin deposits (e.g., primary light chain [AL] amyloidosis) and lymphoplasmacytic lymphoma (e.g., Waldenström macroglobulinemia) also belong to this heterogeneous group of disorders, its most representative diagnostic subtypes include monoclonal gammopathy of undetermined significance (MGUS), solitary plasmacytoma, multiple myeloma (MM), plasma cell leukemia (PCL), and several subvariants of these entities (1, 2) (Table 1). The last four diagnostic categories of PCD are the main focus of this chapter.

Citation: Flores-Montero J, Sanoja L, Pérez J, Pojero F, Puig N, Vidriales M, Orfao A. 2016. Plasma Cell Disorders, p 235-250. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch24
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Image of FIGURE 1

Normal bone marrow (BM) plasma cells (PCs) in an illustrating example of a consensus PC-gating strategy. Classic bivariate dot plots showing the minimal set of parameters recommended for accurate identification and gating of total BM PCs (dark blue dots). A combination of sequential gating, which must include CD138, CD38, and preferably CD45, together with light scatter properties, is recommended for accurate identification of PCs in BM samples. Once identified, PCs can be quantitated (0.12% of total nucleated cells in the illustrated example [gray dots]) and further characterized on phenotypic grounds. Abnormal PC populations may display lower levels of CD38 expression than normal BM PCs.

Citation: Flores-Montero J, Sanoja L, Pérez J, Pojero F, Puig N, Vidriales M, Orfao A. 2016. Plasma Cell Disorders, p 235-250. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch24
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Image of FIGURE 2

Illustrating example of a bone marrow (BM) sample from a multiple myeloma (MM) patient whose clonal plasma cells (PCs) aberrantly expressed several typical phenotypic markers, as may be seen through comparison against the immunophenotypic profile of normal PCs coexisting in the same BM sample. Classical bivariate dot plot representations illustrate the normal phenotypic characteristics of polyclonal PCs (dark blue dots) for surface membrane markers. The same dot plots also illustrate the aberrant phenotypic profiles expressed by the patient clonal PCs (red dots), i.e., CD38, CD45, CD19, CD56, CD117, and CD81. In addition, the normal and myeloma PC populations were further discriminated by their cytoplasmic (Cy) expression of immunoglobulin (Ig) light chains, highlighting the polyclonal nature of normal PCs (CyIgκ and CyIgλ [ratio of 1:3], dark and light green events, respectively) versus the monotypic expression of CyIgk of clonal PCs (red dots). The middle bottom panel displays the automated population separator (APS) view of principal component 1 versus principal component 2 ( and axes, respectively) specifically obtained for the two populations of BM PCs (normal versus myeloma PCs, red and blue dots, respectively) when compared to a set of normal/reactive PCs from 31 reference BM samples; circles represent the median fluorescence intensity of all fluorescence parameters stained, while dotted and continuous borders represent 1 and 2 standard deviations of the distribution obtained for the reference normal PC population; please note how normal PCs from the sample (blue dots) cluster within the reference population cloud, while phenotypically aberrant PCs (red dots) are clearly separated. The right panel in the row in the bottom shows the rank of individual markers and their contribution for the discrimination shown in the APS 1 plot for principal component 1. The overall PC populations correspond to 0.6% of all nucleated BM cells in the sample (gray dots). Normal PCs were 59.9%, while clonal PCs represented 40.1% of all BM PCs.

Citation: Flores-Montero J, Sanoja L, Pérez J, Pojero F, Puig N, Vidriales M, Orfao A. 2016. Plasma Cell Disorders, p 235-250. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch24
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Image of FIGURE 3

Highly sensitive minimal residual disease (MRD) detection in a bone marrow sample from a multiple myeloma (MM) patient. Bivariate dot plot representations of merged files from two different sample aliquots/tubes stained with the EuroFlow-International Myeloma Foundation MM MRD panel to illustrate the highly sensitive detection of aberrant/clonal myeloma plasma cells (PC; red events) coexisting with normal/polyclonal BM PCs (8 × 10 total BM events measured). Normal PCs display a characteristically normal phenotypic profile for surface membrane markers (dark blue dots). In turn, clonal PCs (red dots) from the same individual displayed a distinct pattern characterized by several myeloma-associated phenotypes (MAP; i.e., CD45, CD19, CD56, CD117, and CD81) in addition to higher forward and sideward scatter properties. Normal and abnormal PC populations could be further discriminated by their cytoplasmic (Cy) expression of immunoglobulin (Ig) light chains, highlighting the polyclonal nature of normal PCs (CyIgκ and CyIgλ [ratio of 0.8], dark and light green, respectively) versus monotypic expression of CyIgκ of clonal PCs. The overall BM PC population in this patient corresponded to 0.01% of all nucleated cells in the sample (gray dots); normal PCs were 0.008%, while clonal PCs represented 0.002% (227 dots) of all BM cells.

Citation: Flores-Montero J, Sanoja L, Pérez J, Pojero F, Puig N, Vidriales M, Orfao A. 2016. Plasma Cell Disorders, p 235-250. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch24
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Current classification of clonal plasma cell disorders according to the WHO 2008 criteria refined by the IMWG in 2014

Citation: Flores-Montero J, Sanoja L, Pérez J, Pojero F, Puig N, Vidriales M, Orfao A. 2016. Plasma Cell Disorders, p 235-250. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch24
Generic image for table

IMWG diagnostic criteria for the major categories of PCDs

Citation: Flores-Montero J, Sanoja L, Pérez J, Pojero F, Puig N, Vidriales M, Orfao A. 2016. Plasma Cell Disorders, p 235-250. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch24
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List of the most relevant plasma cell (immunophenotypic) markers and their respective clinical values

Citation: Flores-Montero J, Sanoja L, Pérez J, Pojero F, Puig N, Vidriales M, Orfao A. 2016. Plasma Cell Disorders, p 235-250. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch24
Generic image for table

IMWG criteria for treatment response categories including those proposed for defining immunophenotypic and molecular CR

Citation: Flores-Montero J, Sanoja L, Pérez J, Pojero F, Puig N, Vidriales M, Orfao A. 2016. Plasma Cell Disorders, p 235-250. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch24

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