As immunophenotyping by flow cytometry came into common use, it was evident that monoclonal B-cells with the CLL-phenotype could be detected in the peripheral blood of some individuals who did not have CLL or any other B-cell malignancy. A unified nomenclature for this condition was lacking (21
) until the term MBL was introduced in 2005 by the International Familial-CLL Consortium (1
). The 10 articles included in this systematic review collectively reveal several important considerations in assessing the prevalence of MBL. Both the laboratory methods used and the populations studied have a major impact on the reported prevalence rates. Although it is difficult to quantify their respective contributions, some general tendencies are apparent.
Regarding laboratory methodology, the major factor that influences MBL detection is the number of B-cells acquired for analysis (22
). This impact is most clearly demonstrated by Nieto et al. (13
), who acquired 5 × 106
leukocytes and reported the highest prevalence of MBL among all general population studies. Their reported prevalence approached that in familial-CLL kindreds reported by Marti et al. (18
). In the Nieto study, 50 monoclonal B-cell events were required to define MBL, and the clonal B-cells in many of the MBL cases represented a very low proportion (median: 0.38%, interquartile range: 0.14–4.2%) of the total B-cell population (13
). It is not clear whether the study of familial-CLL kindreds was also capable of detecting such low levels of monoclonal B-cells. It would be interesting to know what the MBL prevalence would have been in the kindred study if the laboratory methods employed by Nieto et al. had been used. In any case, the most clinically relevant issue is the likelihood that MBL progresses to CLL or some other significant endpoint. The size of the clone in absolute and relative terms, as well as the total B-cell count and the total lymphocyte count, should be explored to identify the most predictive combination of prognostic factors.
Another laboratory source of variability that could influence MBL prevalence estimates is the ability to identify unique clonotypes by combinatorial patterns of staining. The studies that employed two different fluorescent labels could identify only four phenotype combinations. Five-color methods can distinguish 32 combinations, and eight-color methods can distinguish 256. Although it is not possible to visualize so many combinations at once, distinct populations can be identified by sequential gating or graphical representation of multivariate analysis (e.g. principal component analysis of flow cytometry data) (23
). In addition, the intensity of staining for each receptor reflects differential expression, providing further capability to identify unique clonotypes (24
Despite the variability in prevalence estimates resulting from the differences in laboratory methodologies, it is clear from this systematic review that MBL is more common among older adults and is most common among first-degree relatives of familial-CLL patients. The age-related trend was consistent across the studies regardless of the sources of the study population. These features parallel those of CLL, which is one of the most age-related of all malignancies and has a strong familial risk.
Other demographic risk factors are less certain or remain unexplored. Although male excess has been well documented in CLL, our systematic review shows that the gender difference appears to be less pronounced in MBL. This difference may be real or may be an artifact.
The male: female ratio ranged from 1.2–1.8 in general population-based studies and from 1.3–2.1 in outpatient-based studies. However, none of the studies reported the age-sex specific prevalence, and it is possible that women included in the studies were older than men. In fact, we speculate that future refinements in defining subtypes of MBL may delineate a condition with a higher probability of progression, and in this group the male: female ratio may coincide with that of CLL more closely.
No prevalence study of MBL from Asia or Africa was available for the review, and the studies included in this review did not report MBL prevalence by ethnic group. Given the fact that CLL is reportedly less common among Asians (5
), one might speculate that this could be due to a lower prevalence of MBL, or a lower risk of progression from MBL to CLL, or a combination. To our knowledge, at this time, no study has been conducted to address these questions.
The reported subgroupings of MBL contain intriguing but inconsistent characterizations that do not allow a formal classification scheme. This inconsistency is due partly to differences in laboratory immunophenotyping methods and partly to a lack of consensus case definitions for MBL subgroups. Of particular importance is the distinction between “low-count” and “high-count” MBL. The total lymphocyte count, total B-cell count, and the proportion of monoclonal B-cells are all important parameters to explore in optimizing the definition of low-count and high-count subtypes. An optimized classification system is essential in assessing etiology, pathogenesis, and the likelihood of progression (25
Studies of MBL will provide a greater understanding of the interaction between genetic and environmental factors in the natural history of CLL and other BLPD. Although CLL has strong familial associations, the overall genetic basis for the disease remains unclear (26
). Both biological agents (27
) and chemical exposures have been linked to CLL (28
), including the herbicide Agent Orange (29
). However, studies to date have not been able to establish a statistically significant association between any environmental agent and CLL, and an extrinsic environmental cause for CLL remains elusive. As MBL occurs earlier and has a much higher prevalence than CLL, it provides a more sensitive marker of biological effect for epidemiologic studies (30
In summary, large population-based studies of MBL that employ standardized laboratory methods with consensus case definition are needed to assess prevalence and establish risk factors. These studies should include follow-up of MBL cases to determine the relationship between MBL and B-cell malignancies (particularly CLL), including risk factors associated with progression. They also should explore correlations with molecular markers and potential gene-environment interactions. Finally, our review underscores the importance of reporting data from original studies in sufficient detail to allow future synthesis of information from multiple studies, including meta-analysis.