Monoclonal B-cell lymphocytosis: right track or red herring?

Abstract

Monoclonal B-cell lymphocytosis (MBL), a newly recognized entity found in approximately 3% of normal persons, precedes chronic lymphocytic leukemia. However, MBLs progress into overt malignancy only in a very minor portion of cases, thus raising the clinical concern of whether and how we can discriminate at diagnosis which rare cases will evolve into a fully fledged tumor. Understanding the molecular/ biologic features underlying the risk of progression may significantly modify our strategies for correctly managing B-cell premalignant states. MBL cells bear the same chromosomal abnormalities of chronic lymphocytic leukemia. Genomewide sequencing and animal models indicate that genetic abnormalities disrupting the control of cell growth and survival cooperate with microenvironment- IntroductionMature B-cell tumors represent approximately 4% of new cancers arising each year in the world. 1 B-cell premalignant states are vastly more common, but only rare cases progress into overt malignancy, raising the clinical concern of whether and how we can discriminate at diagnosis which cases will evolve into a fully fledged tumor. At diagnosis, we are presently unable to unequivocally state to the individual subject to which category (progressive or nonprogressive) he/she belongs. This causes frustration in the doctor and anxiety in the subject, both leading to controls and tests that are economically and socially costly. Understanding the molecular/biologic features associated with a risk of progression would significantly impact on the strategies of clinical management of B-cell premalignancies. This would allow physicians to focus onto the rare risky subjects and to refrain from unnecessary monitoring of the majority of otherwise healthy persons.The presence of tiny numbers of apparently indolent monoclonal B cells with a malignancy-specific phenotype is common to the very early phases of most mature B-cell tumors. The time-honored example is monoclonal gammopathy of uncertain significance (MGUS), which has an incidence of 1% in the population older than 50 years (and up to 10% older than 75 years). 2 At least 2 independent studies 3,4 have demonstrated that most cases of multiple myeloma are preceded by MGUS whose transformation rate is 1% to 2% per year. 5 A more recent example of B-cell premalignant state is the detection of in situ lymph node aggregations of cells that reproduce the immunophenotypic and molecular features of follicular lymphoma 6,7 and/or of mantle cell lymphoma. These aggregations that appear to represent "in situ lymphomas" are found incidentally, show a localization restricted to the areas usually involved by follicular lymphoma or mantle cell lymphoma, 8 and have an uncertain clinical behavior.The entity defined monoclonal B-cell lymphocytosis (MBL) 9 has given great impulse to investigate how B-cell premalignant states relate to overt malignancies. MBL: terra incognitaMBLs are found in approximately 3% of normal persons and even attain higher frequency (Ͼ 10%) when more sophisticated analytical...

Follicular lymphoma-like B cells of uncertain significance (in situ follicular lymphoma) may infrequently progress, but precedes follicular lymphoma, is associated with other overt lymphomas and mimics follicular lymphoma in flow cytometric studies

“…Chronic lymphocytic leukemia-type MBL has a rate of progression to CLL of only 1-2%/year. [35][36][37][38] However, almost all CLL are preceded by MBL. 7 The situation may be similar with MCLBUS, although the proportion of MCL with preceding in situ MCL or small foci of cyclin D1 + lymphoid cells is controversial.…”

Morphology and immunophenotyping issues in the integrated diagnosis of hematologic disorders of elderly patients

“…7 A correlation between platelet count and age was also found by a larger study that evaluated 12,142 adult inhabitants of the United States and found statistically significant differences between young and old individuals. 8 However, these differences were small: less than 30x10 9 /L between people of 17-19 years and those over 70. Thus, until a few years ago, both the existence and the possible extent of age-related changes in platelet count were uncertain, but a series of cross-sectional studies performed recently in different Italian populations has definitively clarified this matter.…”

“…6 In contrast, a progressive decline in platelet count with aging was shown a few years later in 477 ambulatory patients, with a difference of over 100x10 9 /L between children aged 1-5 years old and seniors over the age of 71 years. 7 A correlation between platelet count and age was also found by a larger study that evaluated 12,142 adult inhabitants of the United States and found statistically significant differences between young and old individuals.…”

“…However, methods to enumerate platelets remained inaccurate until the middle of the last century, and the proposed reference intervals for platelet count ranged from 130-350 to 500-900x10 9 /L of whole blood. 2 The development of the Coulter Principle in 1953 3 revolutionized blood counting and resulted in the development of the electronic instruments currently used in our laboratories.…”

“…8 Chronic proliferations of the lymphoid lineage are also likely to cause greater concern. There remains uncertainty as to how to manage monoclonal B-cell lymphocytosis, diagnosed by cell count and immunophenotyping, 9 or lowgrade chronic B-cell disorders such as marginal zone lymphoma 10 or hairy cell leukemia, even if the recent discovery of BRAF mutations targetable by vemurafemib provides a new opportunity for refractory patients, who are likely to be older. 11 Conversely, large trials and efficient therapeutic © F e r r a t a S t o r t i F o u n d a t i o n approaches are now available for chronic lymphoid leukemia 10 and mantle cell lymphoma.…”