Plasma cell neoplasm

Plasma cell dyscrasias (also termed plasma cell disorders and plasma cell proliferative diseases) are a spectrum of progressively more severe monoclonal gammopathies in which a clone or multiple clones of pre-malignant or malignant plasma cells (sometimes in association with lymphoplasmacytoid cells or B lymphocytes) over-produce and secrete into the blood stream a myeloma protein, i.e. an abnormal monoclonal antibody or portion thereof. The exception to this rule is the disorder termed non-secretory multiple myeloma; this disorder is a form of plasma cell dyscrasia in which no myeloma protein is detected in serum or urine (at least as determined by conventional laboratory methods) of individuals who have clear evidence of an increase in clonal bone marrow plasma cells and/or evidence of clonal plasma cell-mediated tissue injury (e.g. plasmacytoma tumors). Here, a clone of plasma cells refers to group of plasma cells that are abnormal in that they have an identical genetic identity and therefore are descendants of a single genetically distinct ancestor cell.aggressive: Sézary disease Plasma cell dyscrasias (also termed plasma cell disorders and plasma cell proliferative diseases) are a spectrum of progressively more severe monoclonal gammopathies in which a clone or multiple clones of pre-malignant or malignant plasma cells (sometimes in association with lymphoplasmacytoid cells or B lymphocytes) over-produce and secrete into the blood stream a myeloma protein, i.e. an abnormal monoclonal antibody or portion thereof. The exception to this rule is the disorder termed non-secretory multiple myeloma; this disorder is a form of plasma cell dyscrasia in which no myeloma protein is detected in serum or urine (at least as determined by conventional laboratory methods) of individuals who have clear evidence of an increase in clonal bone marrow plasma cells and/or evidence of clonal plasma cell-mediated tissue injury (e.g. plasmacytoma tumors). Here, a clone of plasma cells refers to group of plasma cells that are abnormal in that they have an identical genetic identity and therefore are descendants of a single genetically distinct ancestor cell. At one end of this spectrum of hematological disorders, detection of one of these myeloma proteins in an individual's blood or urine is due to a common and clinically silent disorder termed MGUS, i.e. monoclonal gammopathy of undetermined significance. At the other end of this spectrum, detection of the myeloid protein is due to a hematological malignancy, i.e. multiple myeloma, Waldenström's macroglobulinemia, or other B cell-associated neoplasm, that has developed, often in a stepwise manner, from their MGUS precursors. The clinical importance of understanding this spectrum of diseases is that it can be used to: a) advise individuals on the likelihood of their condition progressing to a malignant phase; b) monitor individuals for the many complications that may occur at any stage of the dyscrasias so that they can be treated to avoid or reduce their clinical impacts; and c) monitor patients for transitions to malignancy so that the malignancy can be treated at an early stage when treatment results are best. Unless otherwise noted, the advice and monitoring given here are those recommended by the International Myeloma Working Group in 2014 and updated in 2016. Plasma cells are key effector elements of the adaptive immune system. They contribute to immunity by making antibodies that bind with and thereby initiate the process of neutralizing specific antigens that usually are found on the surface of invading pathogens and foreign substances. Plasma cells develop from B lymphocytes (i.e. B cells) which are stimulated to undergo this maturational development by T lymphocytes during the latter cells' processing of these antigens. As they are stimulated to become plasma cells, B cells refashion parts of their genome in efforts to create a new gene that encodes a functional antibody. Antibodies are composed of two identical heavy chains which are of the gamma (γ), alpha (α), epsilon (ε), delta (δ), or mu (μ) subtypes and two identical light chains which are of the kappa (κ) or lambda (λ) subtypes. Antibodies are classified as IgG, IgA, IgE, IgD, and IgM based on their being made up of γ, α, ε, δ, or μ heavy chains, respectively. Formation of the genes that make these antibodies requires B cells and/or their descendent plasma cells to mutate, break, and recombine various genes at the immunoglobulin heavy chain antigen-binding locus on the long (i.e. 'q') arm of human chromosome 14 at position 32.33 (notated as 14q32.33) and the immunoglobulin light chain antigen binding locus on the q arm of chromosome 22 at position 11.2 (i.e. 22 q11.2) by processes termed V(D)J recombination, somatic hypermutation, and immunoglobulin class switching. These genomic changes can go awry by placing a gene that controls cell growth an/or survival adjacent to a normally highly active antibody gene promoter and/or by causing the formation of extra chromosomes (see trisomy) or chromosomes with large deletions that result in the overexpression or under-expression, respectively, of genes that control cell growth and/or survival. In consequence of these 'primary genomic changes', an expanding clone of cells develops; overproduces and secretes a monoclonal IgM, IgG, IgA, IgE, or IgD antibody, a κ or λ light chain, an α, γ, or μ heavy chain, or, very rarely, fragments of these proteins; and may accumulate 'secondary genomic changes' that cause them to become malignant. The overproduced monoclonal proteins, termed myeloma proteins, commonly circulate in blood, may accumulate in urine, and are the hallmarks of plasma cell dyscrasias including their most malignant forms viz., multiple myeloma, light chain multiple myeloma, and plasma cell leukemia. IgG-secretory, IgA-secretory, and light-chain secretory multiple myeloma represent 52%, 21%, and 16%, respectively, of all multiple myeloma cases; these myelomas are associated with various types of chromosomal aberrancies and mutations. IgD-secretory multiple myeloma occurs in only 1% to 2% of multiple myeloma cases and is commonly associated with somatic mutations in the gene encoding the gV (i.e. variable) region of the monoclonal antibody. IgE-secretory multiple myeloma has been reported in <50 cases as of 2013 and is characteristically associated with translocations between the q arms of chromosome 11 and 14, i.e. t(11;14)(q13;q32) translocations. In other cases, plasma cells and/or lymphoplasmacytoid cells (a type of B cell resembling, and possible precursor to, plasma cells) suffer other kinds of mutations that lead to the production of an IgM myeloma protein. Overproduction of this myeloma protein may progress to a different form of plasma cell/lymphoplasmacytoid cell malignancy, Waldenström macroglobulinaemia. Genetic mutations thought to be involved in the development and/or progression of the latter disease include the L265P mutation in the MYD88 gene found in >90% of Waldenström macroglobulinaemia patients as well as various mutations in the CXCR gene found in 27% to 40% of Waldenström macroglobulinaemia patiens. The clonal plasma cells involved in plasma cell dyscrasias exhibit a high degree of genetic instability. For example, the clonal plasma cell population formed by initial genetic alterations that lead to multiple myeloma contains cells that develop further genetic changes that enhance their survival, proliferation, tissue-injuring, and metastatic capacities. This allows the new cell clones to crowd out older cell clones and thereby establish a more malignant disease. Repetition of such genetic changes underlie the evolution of a clinically silent plasma cell dyscrasia to an overt malignancy. The progressive genetic changes in clonal plasma cells include accumulating numerous single nucleotide polymorphisms, increases and decreases in gene and chromosome copy numbers, and chromosomal translocations. Genes affecting include those regulating genome stability itself (e.g. KIF2B) as well as cellular activation, proliferation, and apoptosis (e.g. CIDEC, TP52, ATM, KRAS, NRAS, Wnt, and NF-κB). In the most malignant form of plasma cell dyscrasias, primary plasma cell leukemia, the plasma cell population contains >1900 distinct DNA alterations in >600 genes. In general, the plasma cell dyscrasias are defined by 1) the presence of these genetically unstable clonal plasma cells, lymphoplasmacytoid cells, or B cells infiltrating the bone marrow or forming distinct masses in bone, and/or other tissues as defined by biopsy of involved tissues and 2) the presence of these cells' myeloma proteins (i.e. intact monoclonal antibody, free light chain, free heavy chain, shortened version of these proteins, or any combination of these proteins) in blood and/or urine as defined by various types of gel electrophoresis. Obviously, the latter criterion does not apply to the rare cases of true non-secretory myeloma. Myeloma proteins form as a result of gene mutations rather than physiological gene remodeling responses to an instigating foreign antigen: typically these proteins are non-functional. However, they sometimes cause serious tissue damage with the kidney being a particularly vulnerable target. The toxic effects of monoclonal proteins may occur at early stages in the plasma cell dyscrasia spectrum and require treatment independently of the mass or tissue-destructive effects of the myeloma protein-producing cells. Myeloma protein toxicities include: Monoclonal gammopathy of undetermined significance (MGUS), is defined as the presence in the blood or urine of a monoclonal antibody, antibody heavy chain, or antibody light chain in a person lacking symptoms or signs of a more serious plasma cell dyscrasia. The condition is typically discovered as an incidental finding when serum protein electrophoresis is done for various reasons unrelated to plasma cell dyscrasias. Protein electrophoresis generally detects one of the following patterns of monoclonal myeloma protein spikes representing: a) intact IgG, IgA, IgE, IgE, or IgM; b) intact IgG, IgA, IgE, IgD, or IgM plus high concentrations of a free (i.e. not bound to a heavy chain) κ or λ light chain; c) a free κ chain in great excess of a λ chain or a free λ chain in great excess of a κ chain; and d) free γ, δ, or μ heavy chains unbound to a light chain (free α and ε heavy chain myeloma protein spikes have not been reported). Among MGUS cases expressing an intact antibody, 70%, 15%, 12%, and 3% express either IgG, IgM, IgA, or two of these M proteins, respectively, with or without excessive levels of a light chain; these cases represent ~80% of all MGUS. About 20% of MGUS cases express either κ or λ light chains. As a group, these MGUS findings occur more commonly in men and are ~2-fold more common in individuals of African descent than Caucasians. MGUS cases expressing free γ, δ, or μ heavy chains are extremely rare. MGUS is categorized into the following sub-types based upon the identity and levels of the myeloma proteins detected as well as the prognoses for progressive disease indicated by these myeloma protein findings.