I have beavering away at the chapter I promised to write and have completed this section on monoclonal B-cell lymphocytosis. The references are not yet complete but if anyone particularly needs them, they will be ready in a day or two, so ask.
Monoclonal B-cell lymphocytosis
Having defined CLL as a lymphocytosis with a characteristic immunophenotype it became clear to CLL specialists that early stage CLL was apparently getting commoner. In fact, apparent fluctuations in the incidence of CLL have been occurring for a long time. In the nineteen fifties and sixties several studies reported incidences in excess of 6 per 100,000 . This was in the days before immunophenotyping when any lymphocytosis over 10 x 10^9 per microlitre of relatively appropriate morphology was designated CLL. From our own experience we can be sure that we misdiagnosed many patients during this period and in our work as a reference center we have recognized that these types of mistakes were not rare. Immunophenotyping has excluded the majority of interlopers and as a result the perceived incidence of CLL fell between the nineteen seventies and nineteen nineties. Sgambati et al  reporting on statistics from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) Program described a fall in incidence rates for CLL for white males from 4.2 per 100,000 to 3.2 per 100,000 between 1973 and 1976 while the rate for white females fell from 3.8 to 2.6 over the same period. The rates for those of African-American, Hispanic or Asian origin were much lower.
Exactly how many cases of CLL are collected depends on how assiduous is the collection. Simply relying on death certificates or hospital admissions will miss all those early stage patients that never progress and never require treatment. Between 1984 and 1988 Cartwright et al  enlisted the help of hematologists performing blood tests for one third of the population of England and Wales to register every new diagnosis of CLL. The annual incidence was 5.54 per 100,000 with a male to female ratio of 1.95. There was no temporal variation, but a threefold difference between districts. Racial differences could not explain the discrepancies, though districts where the disease was commoner tended to have more old people. What was noticeable was that the disease was apparently commoner where the hematologists took a special interest in the disease, suggesting that such specialists would be more likely to make the diagnosis with relatively low lymphocyte counts that less obsessed doctors might pass as normal.
Guidelines for the diagnosis of CLL were published in 1988 by a National Cancer Institute Working Group (NCI-WG)  and in 1989 by the International Workshop on CLL (IWCLL) . The former required a lymphocytosis of >5 x 10^9/L but the latter a lymphocytosis of >10 x 10^9/L. This confusion was removed by the 1996 guidelines published by the NCI-WG  which settled on a lymphocytosis of >5 x 10^9/L but has been further complicated by the 2008 guidelines published by the IWCLL  which raise the threshold to a B-cell lymphocytosis (rather than a total lymphocytosis) of >5 x 10^9/L.
In 2002 Rawstron et al , using four-color flow cytometry of the dregs of blood samples taken for other reasons, discovered that 3.5% of the population over the age of 40 harbors a population of cells immunophenotypically similar to those of CLL and this has been confirmed by others, who emphasize that marginal zone lymphoma also exists in this pre-clinical form . The prevalence of such cells rises with age, to 7.7% of people in their seventies. Recently the group from Salamanca, Spain, using a more highly sensitive multicolor flow technique have suggested that as many as 12% of the population over the age of 40 have a small population of CLL-like cells in heir blood .
An International Working Group  has designated this condition as Monoclonal B-cell Lymphocytosis (MBL) and laid down diagnostic criteria (Table 1). Of course, this new entity did not suddenly appear in 2002, and the International Group also reported on previous sightings of the condition under such names as ‘smoldering CLL’ and ‘benign monoclonal B-lymphocytosis’.
Rawstron et al [16 NEJM 2008] have reported on the relationship between MBL and CLL. Among subjects with a normal blood count, the prevalence of MBL was 78 in 1520 or 5.1%. Because the samples were taken from anonymous subjects no follow-up was possible. In such patients the B-lymphocyte count could be as low as 0.015 x 10^9/L and none were higher than 1.2 x 10^9/L (normal range: 0.025-0.49 X 10^9/L). Another cohort, who did have a lymphocytosis (lymphocyte count >4.0 x 10^9/L) could be followed up. Of 2228 such individuals, 309 had MBL (13.9%) and 185 of these had sequential monitoring for between 0.2 and 11.8 years (median 6.7). While in most cases the lymphocytosis was stable or regressive, in 51 subjects (28%) there was progressive lymphocytosis; in 31 to a lymphocyte count of >30 x 10^9/L. Among the 51, other features of progressive CLL, predominantly lymphadenopathy, developed in 28 (55%) while 13 (25%) required chemotherapy a median of four years after the initial diagnosis. The estimated rate of progression to CLL requiring treatment of MBL with lymphocytosis was 1.1% per year; about the same rate at which monoclonal gammopathy of undetermined significance (MGUS) transforms to myeloma.
The only factor among those examined that predicted progression was the absolute B-lymphocyte count. Those with B-lymphocyte counts below 1.9 x 10^9/L seldom progressed, while of those with a B-lymphocyte count of greater than 4 x 10^9/L, more than half had progressed at 10 years follow-up. There were 62 deaths among the 185 who were followed up; the majority had died from an unrelated cause, but 13 had had progressive CLL, although CLL was mentioned on the death certificate of only four.
Although MBL only seldom transforms to CLL, almost all cases of CLL were once MBL. Taking advantage of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, Landgren et al  were able to identify among 77,469 healthy adults 129 subjects who eventually developed. Of these, 45 had available pre-diagnostic cryopreserved whole blood. Using flow cytometry and molecular techniques they were able to identify an MBL clone in 44 of the specimens.
The new definition of CLL and its relationship to MBL will change clinical practice. One of the consequences would be a demand to monitor cases of MBL with flow cytometry to check on B-cell numbers. Shanafelt et al  have addressed this problem by re-evaluating 459 Rai stage 0 patients in view of the new guidelines. They found that 190 patients would be reclassified as MBL. By studying the likelihood of progression they determined that a threshold B-cell count of 11 x 10^9/L was necessary for the condition to progress to clinically significant CLL. This equates to an absolute lymphocyte count of 20 x 10^9/L. The fascinating corollary is that CLL should not be diagnosed until the absolute lymphocyte count consistently exceeds 20 x 10^9/L. This would obviate the need for expensive flow cytometry measurements for follow-up patients. For those more conservatively minded, their study found that the current CLL definition threshold of a B-cell count of 5 x 10^9/L equates to an absolute lymphocyte count of 11 x 10^9/L. So much for progress over the past 35 years.