Monoclonal B-cell lymphocytosis

MBL falls into three phenotypes that are distinguished based on the cell surface marker proteins which they express viz., the CLL/SLL, atypical CLL/SLL, and non-CLL/SLL phenotypes. These markers are: CD5, CD19, CD20, CD23, and immunoglobulins (Ig) (either Ig light chains or complete Ig, i.e. light chains bound to Ig heavy chains. Monoclonal B-cell lymphocytosis of the marginal zone Cases of non-CLL/SLL MBL in which the monoclonal B cells do not express CD5, CD23, CD10, or CD103 but strongly express CD79B and light chain Ig have been tentatively designated as having monoclonal B-cell lymphocytosis of the marginal zone (i.e. CBL-MZ). This term is used because normal marginal zone B-cell lymphocytes express these markers. Individuals with CBL-MZ commonly present with: B-cell blood counts that are extremely high (>4.0 billion; range 3.0 billion/L to 37.1 billion/L);, represent a large percentage of cases that would otherwise be designated as non-CLL/SLL MLB; often have an IgM monoclonal gammopathy, i.e. high blood levels of a monoclonal IgM antibody; and in addition to the IgM gammopathy, other features that are seen in Waldenström's macroglobulinemia and IgM monoclonal gammopathy of undetermined significance. These individuals are more likely than those with other types of MBL to have their disorder progress to a malignancy. These malignancies appear to have been primarily marginal zone B-cell lymphomas of the splenic marginal zone B-cell, splenic lymphoma/leukemia unclassifiable, hairy cell leukemia, and possibly Waldenström's macroglobulinemia. MBL-MZ requires further studies to evaluate its frequencies, rate of progression to malignancy, and treatment. == Pathophysiology ==

Genome abnormalities Most studies on the genomic abnormalities in MBL did not distinguish between the disorder's phenotypes. However, familial studies have found that hereditary factors can contributor to the development of specifically CLL/SLL MLB. Of all the hematologic malignancies, CLL/SLL is the most likely to afflict multiple family members with estimates of familial CLL/SLL ranging from 6 to 10% of all CLL/SLL cases. About 18% of first-degree relatives of individuals with familial CLL/SLL and ~16% of the close relatives of patients with non-hereditary CLL/SLL have CLL/SLL MBL. Chromosome abnormalities, single nucleotide polymorphisms (SNPs, i.e. substitutions of a single nucleotide in a DNA sequence at a specific position in the genome) and gene mutations, while each occurs in <15% of cases, are present in CLL/SLL MBL and to some extent are similar to those found in CLL/SLL. For example, position 21.33 to 22.2 on the long (i.e. "q" ) arm of chromosome 13 is a potential susceptibility locus for familial CLL/SLL. This locus has been identified not only in individuals with familial CLL/SLL but also in their blood relatives who have CLL/SLL MBL. are commonly associated with unfavorable prognoses in CLL/SLL. Infectious diseases Studies have identified MBL in ~30% of patients infected with the hepatitis C virus, found increased risks of CLL/SLL-MLB in patients with pneumonia, and decreased risk of CLL/CSS MBL in patients who have been vaccinated for influenza or pneumonia. Herpes Zoster and various upper respiratory tract infections are also considered to be risk factors for developing CLL/SLL MBL. It seems possible that the pathogens involved in these diseases provide antigens that stimulate the development of MBL although further studies are required to explore this hypothesis further. This concern as well as the concern of transmitting CLL/SLL in transfusions of blood from patients with CLL/SLL has been voiced elsewhere. However, a study conducted in Sweden and Denmark on 7,413 recipients of blood from 796 donors diagnosed with CLL/SLL found no evidence of CLL/SLL clustering among recipients of blood from these donors. It therefore appears that CLL/SLL and, by implication, CLL/SLL MBL have little or no ability to be transmitted by blood transfusions, at least when the donors and recipients are unrelated. Bone marrow transplantation Rare cases of MBL have been reported to develop in individuals who receive a, autologous stem cell bone marrow transplant from donors who have MBL. Currently, the risk of this development is unclear and requires further study. In those special cases where related donors are used for transplantation, it may be useful to screen these donors for MBL. == Diagnosis ==

Blood B-cell counts Individuals with MBL usually present with unexplained increases in blood lymphocyte counts (i.e. lymphocytosis). The most common causes for lymphocytosis are viral infections, autoimmune diseases (particularly connective tissue diseases), hypersensitivity reactions, acute stress reactions, and prior splenectomy. These cells, similar to the monoclonal cells in Hairy cell leukemia, may have the V600E mutation in the BRAF gene. Patients with this lymphoma commonly have enlarged spleens. == Treatment ==

Low-count MBL is an indolent disorder that in virtually all individuals does not progress to a malignant phase. Overall survival in low count MBL does not differ from that found in age-matched healthy individuals. whereas MBL-MZ progresses to a marginal zone B-cell lymphoma, Waldenström's macroglobulinemia, or Hairy cell leukemia at a ~3% per year. Factors predisposing to this progression in CLL/SLL MBL include the expression of CD38 cell-surface glycoprotein on the monoclonal B-cells, deletion of the short arm of chromosome 17 in these cells, high serum levels of beta-2 macroglobulin, and circulating B cell levels >10 billion/L. There is relatively little information on the features promoting the progression of atypical CLL/SLL MBL, non-CLL/SLL MBL, and MBL-MZ to their respective lymphomas. Individuals with high-count MBL (studies based primarily on the CLL/SLL phenotype) are at an increased risk for developing: 1) cancers of the breast, lung, and gastrointestinal tract in up to 13% of all cases; 2) autoimmune hemolytic anemia and immune thrombocytopenic purpura; 3) unexplained kidney disease as manifested by chronic kidney disease and/or the nephrotic syndrome; and 4) serious infections. While earlier studies suggested that only very high-count MBL (i.e. >10 billion B-cells/L) was associated with a decrease in survival, more recent studies indicate that high-count MBL (i.e. (i.e. >0.5 billion B-cells/L) do show a shorter overall survival. In addition to having very high numbers of B-cells, high-count CLL/SLL MLB patients whose monoclonal B cell clone lacks mutations in IGVH genes (see above section on genome abnormalities) or whose |β2 macroglobulin is elevated have a shorter survival. However, the shortened survival times in high-count CLL/SLL MBL does not appear due to its progression to CLL/SLL. Rather, this shortened survival appears due to the disorders' susceptibility to serious infections, other types of cancers, immune cytopenias, and renal disease. Recommended treatments for patients with high-count MBL and MBL-MZ include yearly follow-up evaluations to test for the malignant progression of their disorder and for the development of other forms of cancer, infections, immune cytopenias, and renal disease. It may also be beneficial to ensure that high-count MBL patients are up to date on vaccinations including those for influenza, pneumococcal pneumonia, and tetanus before they become more severely immunocompromised by the progression of their disorder. In all cases live vaccines should be avoided in these individuals. ==See also==