CEBP FOCUS Precursors to Lymphoproliferative Malignancies Lynn R. Goldin, Mary L. McMaster, and Neil E. Caporaso Abstract We review monoclonal B-cell lymphocytosis (MBL) as a precursor to chronic lymphocytic leukemia and monoclonal gammopathy of undetermined significance (MGUS) as a precursor to plasma cell disorders. These conditions are present in the general population and increase with age. These precursors aggregate with lymphoproliferative malignancies in families suggesting shared inheritance. MBL and MGUS may share some of the same risk factors as their related malignancies but data are limited. Although these conditions are characterized by enhanced risk for the associated malignancy, the majority of individuals with these conditions do not progress to malignancy. A key focus for current work is to identify markers that predict progression to malignancy. Cancer Epidemiol Biomarkers Prev; 22(4); 533–9. Ó2013 AACR. Introduction, Definition, and History with cell surface markers consistent with CLL in an Hematologic neoplasms are classified according to individual that does not meet the criteria for CLL. These cell lineage. The use of the term "precursors" with monoclonal populations were first noted in studies of respect to these malignancies includes a broad range unaffected relatives in families segregating for CLL of conditions. We will focus on the precursors that are (10). A large cross-sectional study was started in 1995 to premalignant lymphoproliferative conditions. We will evaluate by flow cytometry individuals living near haz- discuss monoclonal B-cell lymphocytosis (MBL) as a ardous waste sites in the United States compared to precursor to chronic lymphocytic leukemia (CLL) and controls. This study found evidence of an MBL phenotype monoclonal gammopathy of undetermined significance in several individuals, the prevalence being significantly (MGUS) as a precursor to multiple myeloma and higher in those living near the hazardous waste sites (11). Waldenstrom€ macroglobulinemia. Lymphoid malig- Other researchers described monoclonal B-cell findings in nancies show significant familial aggregation (1–5). different clinical settings and for a number of years there Many studies of MBL and MGUS have been conducted was no standard nomenclature or definition. In 2005, the in the setting of high-risk families; these have shown the International Familial CLL Consortium published diag- coaggregation of the precursors with their related nostic criteria for MBL (12). Briefly, diagnosis requires € detection of a monoclonal B-cell population with overall malignancies (6, 7). In addition, CLL, Waldenstrom k l > < > macroglobulinemia, and other lymphomas often aggre- : ratio of 3:1 or 0.3:1, or 25% of B cells lacking or gate together in families suggesting that they may expressing low-level surface immunoglobulin, and with a share common etiologic pathways. Moreover, expres- disease-specific immunophenotype. The monoclonal sion studies have shown that Waldenstrom€ macro- population must be stable. Other lymphoproliferative globulinemia is more closely related to CLL then either disorders or symptoms indicative of CLL must be exclud- Â 9 of them are related to multiple myeloma (8), although ed. The B-lymphocyte count must be less than 5 10 /L. one study showed that each subtype could be distin- MBL clones are classified similarly to CLL clones (i.e., by guished (9). To date, such studies that directly compare immunophenotype) into the following 3 subtypes: (1) CLL-like: CD5þ23þ (vast majority), (2) atypical CLL: these B-cell lineage diseases are limited. Genetic, epi- þ À À demiologic, and molecular studies of MBL and MGUS CD5 23 , and (3) non-CLL–like: CD5 (12). provide opportunities to elucidate disease mechanisms and define common etiologic pathways. Monoclonal gammopathy of undetermined significance Monoclonal B-cell lymphocytosis Essential monoclonal gammopathy was first described MBL is detected by multicolor flow cytometry of lym- by Waldenstrom€ in 1960 following his observation of phocytes and is defined as a monoclonal B-cell population abnormal narrow bands in the serum of apparently healthy individuals tested by serum protein electropho- Authors' Affiliation: Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, NCI, Bethesda, Maryland resis (13). Although this observation was also termed "benign," Kyle introduced the term "monoclonal gammo- Corresponding Author: Lynn R. Goldin, Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, NCI, 6120 Executive Blvd., pathy of undetermined significance (MGUS)" in 1978 after Bethesda, MD 20892. Phone: 301-402-9656; Fax: 301-402-4489; E-mail: documenting that asymptomatic patients with monoclo- [email protected] nal protein are at higher risk of developing a variety of doi: 10.1158/1055-9965.EPI-12-1348 malignant and nonmalignant conditions, including mul- Ó2013 American Association for Cancer Research. tiple myeloma, Waldenstrom€ macroglobulinemia, and www.aacrjournals.org 533 Downloaded from cebp.aacrjournals.org on September 29, 2021. © 2013 American Association for Cancer Research. CEBP FOCUS amyloidosis, among others (14). Following 3 decades of previously have met criteria for CLL are now diagnosed research, 3 distinct clinical subtypes of MGUS have been as MBL. We and others have reported that MBL is signif- defined: non-IgM MGUS, IgM MGUS, and light-chain icantly morefrequentamong individuals who aremembers MGUS. In 2003, consensus definitions were developed of high-risk CLL families compared to those in the general for non-IgM MGUS and IgM MGUS by the International population (6, 28, 29). We recently reported a study of 505 Myeloma Working Group (IMWG) and the International first-degree relatives ofCLL patients representing 140 high- Workshop for Waldenstrom€ Macroglobulinemia risk families (28). Overall, 17% of relatives were diagnosed (IWWM), respectively. The definitions of these 2 entities to have MBL consistent with earlier data based on smaller overlap substantially. MGUS is defined as the presence of samples and substantially larger than the 3% to 7% rate in a serum monoclonal protein with concentration <3 g/dL, the population using similar methodology. The probability less than 10% infiltration of the bone marrow by plasma of developing MBL by age 90 was 61%. Consistent with (non-IgM MGUS) or lymphoplasmacytic (IgM MGUS) CLL patterns, males had a significantly higher prevalence cells, and the absence of constitutional symptoms, anemia, than did females. These family studies imply a shared lymphadenopathy, hepatosplenomegaly, or other symp- inherited risk for CLL and MBL. Molecular studies have toms related to the clonal process (refs. 15 and 16). In 2010, shown that MBL cells have similar chromosome abnormal- the IMWG revised its diagnostic criteria such that non- ities and other genetic markers as do CLL cells suggesting IgM MGUS is defined as the presence of serum M protein that these chromosome aberrations occur early in the <3 g/dL, fewer than 10% clonal plasma cells in the bone development of MBL/CLL. One study reported that MBL marrow, and absence of end-organ damage characterized clones found in individuals from high-risk CLL families by hypercalcemia, renal insufficiency, anemia, or lytic had similar molecular characteristics as indolent CLL (30). bone lesions (the "CRAB" criteria; ref. 17). Recently, Ongoingstudies arebeingconductedto determinewhether researchers have proposed criteria to identify the precur- MBL is present in families at risk for other types of non- sor entity for light-chain multiple myeloma, termed light- Hodgkin lymphoma at a higher rate than in the population. chain MGUS, which is defined by an abnormal k–l free From an epidemiologic perspective, MBL has strong light-chain ratio, elevation of free light-chain level, and parallels with CLL being associated with age, gender, and absence of an identifiable monoclonal heavy chain band family history of CLL. However, as with CLL, the etiologic on serum immunofixation (18). origin is unknown. It may derive from a dysregulated Not all nonmalignant monoclonal gammopathy, how- antigen response or inducted by some currently unknown ever, is of undetermined significance. Patients may have environmental or infectious factor. Although no extrinsic symptoms because of their specific monoclonal protein in risk factors for CLL are established, there is some evidence the absence of morphological evidence of a bone marrow for herbicides and emerging evidence for radiation expo- infiltrate or symptoms related to tumor burden. Thus, sure (31, 32). Whether these factors are associated with patients who have an IgM monoclonal protein together MBL is unknown. Several SNPs that were identified from with specific symptoms attributable to the IgM (i.e., cryo- GWAS studies as being associated with CLL have also globulinemia or autoimmune phenomena such as periph- been shown to be associated with MBL (33, 34). Additional eral neuropathy or cold agglutinin disease) have been genetic and environmental studies will help clarify these proposed to represent a clinically distinct subset, termed relationships. "IgM-related disorders" (16). Similarly, renal deposition of any immunoglobulin type represents another recently Monoclonal gammopathy of undetermined proposed clinical subgroup (19). Patients in these subsets significance often require treatment to manage the immunoglobulin- Similar to MBL, MGUS is a common premalignant related symptoms, and care should be taken to disting- conditions, with overall