In this issue of Blood, Xochelli et al have identified, in otherwise healthy individuals with no clinical signs of lymphoproliferative disorders, a circulating clonal B-cell population with an immunophenotype consistent with a marginal zone B-cell population (CBL-MZ).1 This scenario is reminiscent of monoclonal B-cell lymphocytosis (MBL)2 of the “CD5-negative type,” although the report includes cases with rather prominent B lymphocytosis (up to 34 × 109/L, K. Stamatopoulos, Institute of Applied Biosciences, Thessaloniki, Greece, written communication, December 16, 2013), being above the MBL threshold of 5 × 109 B lymphocytes/L2.
It is interesting to note that at the time of the original report, the authors found it difficult to identify cases lacking CD5 expression, while CD5+ cases were more easily classified as chronic lymphocytic leukemia (CLL)-like or non–CLL-like (atypical CLL) MBL.3 The definition of marginal-type MBL was not widely accepted due to the lack of distinct phenotype for marginal zone (MZ) cells, with the diagnosis being made by exclusion of other more disease-specific phenotypes.
Xochelli et al have demonstrated the occurrence of a circulating monoclonal B-cell population with a distinct MZ-like phenotype using a flow-cytometric profile consistent with a MZ origin. The authors conclusively demonstrate that at least a fraction of the so-called CD5-negative (or expressing very weakly) monoclonal B-cell populations can indeed be defined based on the coexistence of immunophenotypical and morphologic features typically associated with MZ lymphomas involving the spleen (SMZL), including expression of CD49d and FMC7, in the absence of GC markers such as CD10 and/or CD38.
Despite the resemblance to SMZL, some features of CBL-MZ are different. Of particular interest and unexpectedly, none of the reported cases were associated with hepatitis C virus infection, a condition that in the past was considered to underlie most CD5− MBL cases.4 Thus, the relationship between the CBL-MZL cases described by Xochelli and collaborators and those arising in the context of viral infections remains to be elucidated.
These entities share with MBL the indolent course and the low propensity to progress to overt malignancy. Among the patients followed for 5 years, only 17% of them progressed to clinically overt, splenic B-cell lymphoma of MZ origin, and only 3 needed treatment over the follow-up time. It is likely that CBL-MZ represents a more heterogeneous group than expected and could include more subgroups, similar to what happens for physiological MZ subsets.
Despite the similarities with MBL, one could still ask whether these monoclonal expansions could be indeed actual neoplasms, and it remains questionable if these conditions could be easily differentiated from bona fide lymphoproliferative disorders, because splenomegaly is not an absolute requirement for the diagnosis of SMZL. On one hand, even the subgroup of “nonprogressing” CBL-MZL seems to fulfill the criteria of neoplastic disease, because 27% of cases carried chromosome 7 abnormalities. On the other hand, it is remarkable that, at the histopathological level, some cases have been reported to display a bone marrow infiltration up to 70% of overall cellularity.
The description of a tissue counterpart of CBL-MZL still needs to be defined. In fact, available data are exclusively based on peripheral blood smear and bone marrow biopsy, while other data on the histopathological examination of extra nodal sites associated with the presence of MZ are not yet available, in contrast to previously published tissue observations in the case of in situ mantle cell lymphoma5 and follicular lymphoma6 and proposed also for CLL.7 Further follow-up as well as the experience of additional groups may help clarify these questions, which involve both diagnostic and clinical aspects. In any case, the features reported by Xochelli et al provide a useful tool to track the characteristics of MZ B-cell lymphoproliferations in their very early stages and can be exploited as an experimental model for the study of the natural history of these diseases.
Finally, this paper brings attention to the contentious issue of overdiagnosis of indolent lymphoproliferative disorders. Performance of blood tests for no specific clinical indications will lead more frequently to the diagnosis of MBL or CBL, generating ethical and medical issues regarding patient management, including what type of diagnosis to communicate. A lot needs still to be done in this “gray zone” between health and disease, but awareness of multiple and, usually, nonprogressive conditions like CBL-MZL is helpful in preventing unnecessary clinical interventions and avoiding risky diagnostic or therapeutic procedures. In this respect, we fully agree with the authors’ message of caution, suggesting not to include in the routine workup procedures such as endoscopy or bone marrow examination in the absence of suggestive clinical signs or symptoms.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
