Plasma Cells Neoplasms - 2° paragraph

2. PATHOLOGY and BIOLOGY

2.1 Pathology

2.1.1 Morphological description
In most instances of plasma cell neoplasms, the morphological appearance of malignant cells is quite comparable to the normal plasma cells. They are two to three times the size of lymphocytes, round or egg shaped, with one or more eccentrically placed nuclei containing either diffuse or clumped chromatin. The cytoplasm is rich in endoplasmic reticulum specialized for Ig synthesis and is usually blue or bluish-purple.
Occasional other cytoplasmic features include numerous vacuoles (Mott cells) and Russell bodies. In some cases, the cytologic aspect of malignant cells appears more immature with less differentiated nucleus, diffuse chromatin, one or several nucleoli (plasmablasts). Cytoplasmic immunofluorescence studies with anti heavy- and anti light- chain antibodies confirm that these plasma cells are monotypic.
In Waldenström's macroglobulinemia, cells may have a "lymphoplasmacytic" appearance, with morphologic variation in size and characteristics, from those of small lymphocytes to large plasma cells. Most of these cells contain large amounts of cytoplasmic monotypic IgM revealed by immunofluorescence.

2.2 Biology

2.2.1 Immunochemistry
M-component can be detected and discriminated from normal immunoglobulins by serum electrophoresis when its concentration is .5 g/dl or higher. The usual aspect of serum M-component is a sharp peak or "spike" in the beta or gamma globulin regions on electrophoresis. Urinary M-component can be detected by electrophoresis on concentrates of 24 hour urine collections.
The definition of an M-component as monoclonal requires heavy and light chain typing by immunoelectrophoresis or immunofixation.
The different immunological subtypes of multiple myeloma are the following:

IgG (approximately 55% of cases)
IgA (approximately 26% of cases)
Bence-Jones or light chain multiple myeloma (approximately 14% of cases)
non secreting (or non excreting) multiple myeloma (less than 2% of cases)
IgD (1 to 2% of cases)
IgM (see below), IgE or biclonal multiple myelomas are extremely rare.

Kappa light chains are more frequently produced than lambda light chains (2:1).
The presence of a serum monoclonal IgM-component is a constant finding in Waldenström's macroglobulinemia. Patients with a monoclonal IgM, osteolytic bone lesions and bone marrow plasmacytosis with > 30% plasma cells are rare and are generally classified as having multiple myeloma.

2.2.2 Phenotypic characterization of the malignant cell
Plasma cells are characterized by the expression of cytoplasmic Ig and by a very high level of CD38. Recently, it has been shown that monoclonal antibody B-B4 specifically recognizes plasma cells. The use of two-color immunofluorescence with B-B4 and anti CD38 antibodies is a new approach to identify plasma cells in the bone marrow. Immunophenotype may help distinguish myeloma from normal plasma cells. For instance, normal plasma cells are CD19+ CD56-, whereas myeloma cells are often CD19- and CD56+ but never CD19+ CD56-. However, the myeloma cell phenotype appears to be heterogeneous and to vary in relation to the clinical presentation and to the stage of the disease.

2.2.3 Genotypic studies in multiple myeloma
Analysis of nuclear DNA content by flow cytometry has demonstrated aneuploidy in 80% of patients. DNA hyperdiploidy is the most common observation (70% of cases).
Cytogenetic studies in multiple myeloma have been hampered by the low proliferative rate of myeloma cells. The number of abnormal karyotypes is about 40% in most published series. However, the stimulation of cultures by cytokines like GM-CSF, IL3 or IL6 could yield better results with 55% cytogenetic abnormalities. The most frequent gains involved chromosomes 3, 5, 7, 9, 11, 15 and 19. The most frequent losses involved chromosomes 13 and 8. The most frequent structural changes involved chromosome 1 and 14. The single most frequent chromosome breakpoint involves band 14q32. It has recently been shown that partial or complete deletions of chromosome 13 or abnormalities involving 11q are associated with a poor prognosis.
Fluorescence in situ hybridization enables the study of interphase nuclei and improves the detection of aneuploidy (>90% of patients at diagnosis). This technique also detects aneuploid cells in some patients with MGUS. Prospective follow-up is needed to determine the clinical impact of these abnormalities considered as characteristic of plasma cell malignancy. Oncogenes (c-myc, ras, bcl2, bcl1) and tumor suppressor genes (p53, Rb) have also been studied in multiple myeloma. Although a variety of abnormalities of oncogene expression have been found, none has yet been described consistently. The most significant finding comes from longitudinal studies showing that disease progression is associated with overexpression of both an oncoprotein and a tumor suppressor gene product.

References

2.I
Barlogie B, Alexanian R, Smith L, Dixon D, Smallwood L, Delasalle K. Prognostic implications of tumor cell DNA and RNA content in multiple myeloma. Blood 1985;66:338-42.

2.II
Blade J, Lust JA, Kyle RA. Immunoglobulin D multiple myeloma: presenting features, response to therapy and survival in a series of 53 cases. J Clin Oncol 1994;12:2398-404.

2.III
van Camp B, Durie BGM, Spier C et al. Plasma cells in multiple myeloma express a natural killer cell-associated antigen: CD56 (NKH H1;lun 19). Blood 1990;76:377-82.

2.IV
Drach J, Angerler J, Schuster J et al. Interphase fluorescence in situ hybridization identifies chromosomal abnormalities in plasma cells from patients with monoclonal gammopathy of unknown significance. Blood 1995;86:3915-21.

2.V
Drach J, Schuster J, Nowotny M et al. Multiple myeloma: high incidence of chromosomal aneuploidy as detected by interphase fluorescence in situ hybridization. Cancer Research 1995;55:3854-9.

2.VI
Durie BGM, Grogan TM. Calla positive myeloma: an aggressive subtype with poor survival. Blood 1985;66:229-32.

2.VII
Epstein J, Barlogie B, Katzmann J, Alexanian R. Phenotypic heterogeneity in aneuploid multiple myeloma indicates pre-B cell involvement. Blood 1988;71:861-5.

2.VIII
Greipp R, Raymond NM, Kyle RA, O'Fallon WM. Multiple myeloma: significance of plasmablastic subtype in morphological classification. Blood 1985;65:305-10.

2.IX
Grogan T, Tangen C, Dalton W, Frutiger Y, Salmon S. The Ki67 proliferative index as an indicator of early death among SWOG myeloma patients. Proc Vth international workshop on multiple myeloma - La Baule, 1995 p 123.

2.X
Harada H, Kawano MM, Huang N et al. Phenotypic difference of normal plasma cells from mature myeloma cells. Blood 1993;81:2658-63.

2.XI
Joshua DE, Brown RD, Gibson J. Multiple myeloma: why does the disease escape from plateau phase?. Br J Haematol 1994;88:667-71.

2.XII
Kawano M, Huang N, Harada H et al. Identification of immature and mature myeloma cells in the bone marrow of human myeloma. Blood 1993;82:564-70.

2.XIII
Lai JL, Zandecki M, Mary JY et al. Improved cytogenetics in multiple myeloma: a study of 151 patients including 117 patients at diagnosis. Blood 1995;85:2490-7.

2.XIV
Leo R, Boeker M, Peest et al. Multiparameter analysis of normal and malignant human plasma cells: CD38++, CD56+, CD54+, CIg+ is the common phenotype of myeloma cells. Ann Hematol 1992;64:132-9.

2.XV
Mac Intyre OR. Correlation of abnormal immunoglobulin with clinical features of myeloma. Arch Intern Med 1975;135:46-52.

2.XVI
Pellat-Deceunynck C, Bataille R, Robillard N et al. Expression of CD28 and CD40 in human myeloma cells: a comparative study with normal plasma cells. Blood 1994;84:2597-603.

2.XVII
Riedel DA, Pottern LM. The epidemiology of multiple myeloma. Hematol Oncol Clin North Am 1992; 6: 225-248.

2.XVIII
Sawyer JR, Waldron JA, Jagannath S, Barlogie B. Cytogenetic findings in 200 patients with multiple myeloma. Cancer Genet Cytogenet 1995;82:41-9.

2.XIX
Shustik C, Bergsagel DE, Pruzanski W. k and i chain disease: survival rates and clinical manifestations. Blood 1976;48:41-51.

2.XX
Tricot G, Barlogie B, Jagannath S et al. Poor prognosis in multiple myeloma is associated only with partial or complete deletions of chromosome 13 or abnormalities involving 11q and not with other karyotype abnormalities. Blood 1995;86:4250-6.

2.XXI
Witzig TE, Dhodapkar MV, Kyle RA, Greipp PR. Quantification of circulating peripheral blood plasma cells and their relationship to disease activity in patients with multiple myeloma. Cancer 1993;72:108-13.

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