ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Monoclonal B cell lymphocytosis

Monoclonal B cell lymphocytosis
Author:
Matthew S Davids, MD, MMSc
Section Editor:
Peter Newburger, MD
Deputy Editor:
Alan G Rosmarin, MD
Literature review current through: Dec 2022. | This topic last updated: Apr 30, 2021.

INTRODUCTION — Monoclonal B cell lymphocytosis (MBL) refers to a monoclonal population of B lymphocytes <5000 cells/microL (<5 x 109/L) in peripheral blood for ≥3 months, without other features of a B cell lymphoproliferative disorder (eg, lymphadenopathy, organomegaly, cytopenias, or extramedullary involvement) [1,2].

This topic will discuss the epidemiology, evaluation, diagnosis, prognosis, and management of MBL.

Evaluation of lymphocytosis in the adult and in the child, and clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma are discussed separately:

(See "Approach to the adult with lymphocytosis or lymphocytopenia".)

(See "Approach to the child with lymphocytosis or lymphocytopenia".)

(See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma".)

EPIDEMIOLOGY — The incidence of MBL increases with age, and one study reported that the prevalence of MBL is 1.5-fold (95% CI 1.1-2.1) greater in men than women, on an age-adjusted basis [3]. The prevalence of MBL is >100-fold greater than chronic lymphocytic leukemia (CLL), the most common leukemia in adults [4,5]. The age-dependent increase in MBL incidence is observed in all categories of MBL [3,6]. (See 'Classification and prognosis' below.)

Population-based screening studies (using four- or five-color flow cytometry) have reported the following prevalence rates [7,8]:

<40 years old: 0.2 to 0.3 percent

≥40 to ≤60 years old: 3.5 to 6.7 percent

>60 years old: 5 to 9 percent

Reports of the prevalence of MBL are influenced by the sensitivity of the assay used to detect B cell clonality. Using highly sensitive techniques (eight-color flow cytometry), one study reported MBL in at least one-fifth of 608 healthy adults over age 60 years, and in more than three-quarters of individuals over age 90 [9]. Another study that used eight-color flow cytometry reported MBL in 12 percent of 984 asymptomatic adults ≥40 years old [10]. The effect of assay sensitivity on detection of MBL is discussed below. (See 'Sensitivity' below.)

Family studies and genetic markers suggest an inherited contribution to MBL development. In first-degree relatives of patients with CLL, MBL was detected in 14 to 22 percent of individuals with normal blood counts; the relative risk of MBL was increased fourfold overall, and 17-fold in younger adults (16 to 40 years old) [11-13]. Both familial and sporadic forms of CLL are associated with a higher incidence of MBL in relatives [14]. Genetic predisposition to MBL is also indicated by an association between MBL and single nucleotide polymorphisms [15,16]. Familial forms of CLL are discussed separately. (See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'Family studies'.)

Population-based studies have reported an association of MBL with chronic hepatitis C virus infection and with pneumonia; conversely, a lower incidence of MBL was reported among patients vaccinated for influenza or pneumonia [17-19].

EVALUATION — MBL may be encountered as an incidental finding in the setting of lymphocytosis, or in the assessment of another clinical disorder. Evaluation of a patient with lymphocytosis is described separately. (See "Approach to the adult with lymphocytosis or lymphocytopenia".)

Evaluation of MBL should seek evidence of associated conditions (eg, lymphoma or other lymphoproliferative disorder, autoimmune condition, infection), and should include:

History:

Active or prior infections (eg, hepatitis, pneumonia) or inflammatory processes (autoimmune conditions)

History of hematologic malignancy (eg, lymphoma, leukemia) or related clinical findings (eg, unexplained lymphadenopathy, fevers, sweats, weight loss)

Medications

Family history of chronic lymphocytic leukemia (CLL) or other lymphoproliferative disorders

Physical examination – The physical examination should seek evidence of infection, inflammation, or malignancy, such as fever, lymphadenopathy, hepatosplenomegaly, joint redness, abdominal pain, and lung findings.

Complete blood count (CBC) with differential – MBL may be detected in the setting of lymphocytosis (ie, ≥4000 lymphocytes/microL), or in a patient with a normal lymphocyte count.

Findings from the CBC may suggest an associated condition:

Neutrophilia or monocytosis, which may be associated with infections, or inflammatory processes. (See "Approach to the patient with neutrophilia".)

Eosinophilia and/or basophilia, which may be associated with allergic, infectious, or inflammatory conditions. (See "Approach to the patient with unexplained eosinophilia".)

Anemia (eg, hemolytic anemia, anemia of chronic disease from underlying inflammation or infections). (See "Diagnostic approach to anemia in adults".)

Blood smear – The blood smear should be reviewed to assess lymphocyte morphology and other lineages. Lymphocytes in MBL have no distinguishing appearance and typically appear as small, mature mononuclear cells. (See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'Peripheral smear'.)

The diagnosis of MBL does not require bone marrow examination or imaging [1].

Documentation of B cell clonality is described below. (See 'Flow cytometry' below.)

DIAGNOSIS — Diagnostic criteria for MBL are [2]:

Monoclonal population of B cells <5000 cells/microL (<5 x 109/L) that persists for ≥3 months, as defined below. (See 'B cell clonality' below.)

No systemic features of a lymphoproliferative disorder (eg, no lymphadenopathy, hepatosplenomegaly, cytopenias, fever, weight loss, or sweats), autoimmune disorder, or infectious disease, as discussed above. (See 'Evaluation' above.)

MBL should be categorized on the basis of immunophenotype and the size of the population of the B cell clone, as described below. (See 'Classification and prognosis' below.)

B cell clonality — Documentation of B cell clonality is required to diagnose MBL. For most patients, flow cytometry is the preferred method.

Flow cytometry — Multiparameter flow cytometry is used to document clonality, quantitate the size of the clonal population, and categorize the immunophenotype of MBL.

Flow cytometry analysis should at a minimum evaluate all of the following antigens:

B cell: CD19, CD20, and CD23

T cell: CD3, CD5

Surface immunoglobulin (sIg) kappa and lambda light chains

Immunophenotype — MBL should be categorized as one of the following on the basis of the immunophenotype (table 1) (see 'Classification and prognosis' below):

Chronic lymphocytic leukemia (CLL)-like MBL – CD5+, CD19+, CD23+, CD20 dim or negative, light chain restriction (ie, either kappa or lambda), sIg dim or negative (see 'CLL-like MBL' below)

Atypical CLL type MBL – CD5+, CD19+, CD20 bright, sIg moderate or bright, CD23 positive or negative (see 'Atypical MBL' below)

Non-CLL type MBL – CD5 negative or dim, CD19+, CD20+, sIg moderate to bright (see 'Non-CLL type MBL' below)

Detection of either atypical CLL-type or non-CLL type MBL phenotype requires further evaluation for lymphoma or other lymphoproliferative disorder, as described separately. (See 'B cell NHL' below.)

Clone size — Flow cytometry is used to measure the size of the B cell clonal population. There is a bimodal distribution of patients with MBL, and patients with CLL-like MBL can be characterized as either high-count MBL (>2000/microL) or low-count MBL (<50/microL); it is somewhat unusual to detect a clonal B cell count between 50 and 2000/microL. High-count and low-count MBL differ in regard to clinical setting, natural history, and prognosis, as described below. (See 'High-count MBL' below and 'Low-count MBL' below.)

Sensitivity — Sensitivity of flow cytometry to detect clonal B cells increases with the use of more antibodies (ie, colors) and greater numbers of cells analyzed. This is illustrated by reports of MBL prevalence in individuals ≥40 years old using increasingly sensitive flow cytometry techniques:

3.5 percent with four-color flow cytometry evaluating 200,000 cells [7,20]

6.7 percent with five-color flow cytometry evaluating 500,000 cells [8]

12 percent with eight-color flow cytometry evaluating 5 million cells [9]

Molecular characterization — PCR (polymerase chain reaction) for immunoglobulin heavy chain (IGHV) rearrangement or other DNA-based assays can demonstrate B cell clonality. Occasionally, molecular analysis of blood or bone marrow (eg, for lymphoma or leukemia) will lead to detection of a B cell clone and the diagnosis of MBL. However, DNA-based assays do not identify the immunophenotypic category of MBL nor the size of the clonal population, which require flow cytometry, as described above. (See 'Flow cytometry' above.)

DNA-based assays are not required to make the diagnosis of MBL, but can be useful for special circumstances:

Confirmation of a small clone of B cells by IGHV PCR on separated B cells in cases of low-count MBL

Detection of IGHV gene somatic hypermutation may have prognostic value in high-count MBL, as it does with CLL (see "Staging and prognosis of chronic lymphocytic leukemia", section on 'IGHV mutation status, ZAP-70, and CD38')

DIFFERENTIAL DIAGNOSIS — The differential diagnosis is influenced by whether or not there is lymphocytosis (ie, >4000 lymphocytes/microL) or other clinical findings (eg, adenopathy, organomegaly, cytopenias, constitutional symptoms), the immunophenotype, and the size of the B cell clonal population.

In the presence of lymphocytosis, the differential diagnosis includes reactive causes (eg, infections, inflammatory states) and various lymphoproliferative disorders, as described separately. (See "Approach to the adult with lymphocytosis or lymphocytopenia".)

Infections — Infections can cause lymphocytosis that generally resolves within weeks and may be associated with lymphadenopathy or organomegaly. Atypical lymphocytes (picture 1) may be seen on the blood smear, and the lymphocytosis is polyclonal. In contrast, MBL is a clonal disorder that persists for ≥3 months and has no associated lymphadenopathy or organomegaly. Diagnosis of infectious causes of lymphocytosis is discussed in greater detail separately. (See "Approach to the adult with lymphocytosis or lymphocytopenia", section on 'Infectious causes'.)

CLL/SLL — The diagnosis of chronic lymphocytic leukemia (CLL) requires peripheral blood lymphocytosis ≥5000/microL, a characteristic immunophenotype (ie, CD5+, CD19+, CD23+, dim or absent surface immunoglobulin [sIg], dim CD20), and may be associated with lymphadenopathy, organomegaly, and/or cytopenias [21].

Malignant cells of the related disorder, small lymphocytic lymphoma (SLL), are immunophenotypically similar, but the clinical presentation is dominated by lymphadenopathy or organomegaly, and the peripheral blood has <5000 lymphocytes/microL. Clinical features of CLL/SLL are discussed separately. (See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma".)

Although the immunophenotype of CLL/SLL lymphocytes is indistinguishable from that of MBL, the latter is distinguished by the size of the population of the malignant clone (ie, <5000/microL) and the absence of lymphadenopathy, organomegaly, and cytopenias. Detection of marrow infiltration by clonal B cells alone does not change the diagnosis from MBL to CLL/SLL. (See 'Incidental marrow/tissue involvement' below.)

B cell NHL — B cell non-Hodgkin lymphomas (NHL) are associated with clonal B cells and lymphadenopathy, organomegaly, cytopenias, and/or other tissue infiltration. B cell NHL may or may not be associated with circulating CD19+ B lymphocytes; in some cases, circulating cells may also be CD5+. However, MBL is excluded by a clone >5000/microL and/or the presence of lymphadenopathy or organomegaly.

The B cell immunophenotype (table 1) and other characteristics determine the specific categories of NHL in the differential diagnosis, which may include:

Mantle cell lymphoma (MCL) – Circulating lymphocytes in MCL are generally small and often have irregular or cleaved nuclei. MCL cells may be CD5+, CD19+, and CD20+, but are generally negative for CD23. MCL cells typically stain strongly for cyclin D1, CD20, and sIg, and usually have the characteristic t(11;14) chromosomal abnormality and/or CCD1 rearrangement. (See "Clinical manifestations, pathologic features, and diagnosis of mantle cell lymphoma".)

Marginal zone lymphoma (MZL) – MZL can present with lymphocytosis and is associated with lymphadenopathy, splenomegaly, cytopenias, and/or infiltration of other organs. Circulating B cells of MZL may have small surface "villous" projections (picture 2), and they express CD19, CD20, sIg, and CD23; some cases of MZL also express CD5. Although some cases of MBL have the same immunophenotype (eg, atypical MBL, non-CLL type MBL), a B cell clone >5000/microL, lymphadenopathy, cytopenias, or organomegaly excludes the diagnosis of MBL. (See "Splenic marginal zone lymphoma".)

Waldenström macroglobulinemia (WM) – WM and its lymphomatous counterpart, lymphoplasmacytic lymphoma (LPL), produce a prominent monoclonal immunoglobulin M (IgM) protein and may be associated with circulating B lymphoid cells (often with lymphoplasmacytic morphology); in a minority of cases WM/LPL cells are CD5+. WM/LPL can be distinguished from MBL by the presence of a monoclonal protein on serum protein electrophoresis, strong staining for surface IgM and CD20, and cytoplasmic immunoglobulin. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia".)

Acute lymphoblastic leukemia (ALL) — Patients with ALL typically present with variable levels of circulating lymphoblasts, cytopenias, constitutional symptoms, and may have a mediastinal mass or lymphadenopathy. Lymphoblasts may be small with scant cytoplasm or larger with moderate amounts of cytoplasm. Cells are positive for terminal deoxytransferase (TdT), and depending on the lineage, express either B cell antigens (eg, CD19, CD20, and CD10) or T cell antigens (eg, CD3, CD7).

MBL is distinguished by immunophenotype; the absence of lymphoblasts, adenopathy, organomegaly, cytopenias, and constitutional symptoms; and TdT negativity. (See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma".)

Large granular lymphocyte (LGL) leukemia — Lymphocytosis in LGL leukemia is typically modest, but LGLs (picture 3) are large, with abundant cytoplasm containing fine or coarse azurophilic granules and a reniform or round nucleus. Patients often present with cytopenias, splenomegaly, and constitutional symptoms. T cell LGL leukemias are CD3+, CD57+, and express the alpha/beta T cell receptor (TCR). NK cell LGL leukemias are CD56+ but CD3 negative. MBL is distinguished by immunophenotype and absence of constitutional symptoms and splenomegaly. (See "Clinical manifestations, pathologic features, and diagnosis of T cell large granular lymphocyte leukemia" and "Natural killer (NK) cell large granular lymphocyte leukemia".)

Sézary syndrome (SS) — The peripheral blood of patients with SS is characterized by a large number of atypical mononuclear cells with moderately to highly grooved (ie, cerebriform) nuclei (picture 4), and patients commonly present with erythroderma and generalized lymphadenopathy. The circulating lymphocytes are CD4+, and skin biopsy usually reveals atypical lymphocytes in a sparse dermal infiltrate. MBL is distinguished by the absence of the characteristic SS morphology, immunophenotype, and skin involvement and organomegaly. (See "Clinical manifestations, pathologic features, and diagnosis of peripheral T cell lymphoma, not otherwise specified".)

CLASSIFICATION AND PROGNOSIS — All cases of MBL should be categorized on the basis of immunophenotype. The various categories of MBL are associated with distinct natural history, prognosis, and management, as described in the sections below.

CLL-like MBL — Chronic lymphocytic leukemia (CLL)-like MBL is the most common category and accounts for about three-quarters of all cases of MBL [7,12,20,22].

CLL-like MBL is so-named because of its close immunophenotypic resemblance to CLL (table 1). The clonal cells of CLL-like MBL are CD5+, CD19+, CD23+, and have dim or no expression of CD20. They demonstrate light chain restriction (ie, either kappa or lambda) and express dim surface immunoglobulin (sIg) or no sIg (in one-quarter of cases) [7,22].

More than one clone of B cells may detected [8,9,23,24].

High- versus low-count CLL-like MBL — Based on the size of the malignant clone, there is a bimodal distribution of patients with CLL-like MBL, and cases can be classified as either high-count MBL (>2000/microL) or low-count MBL (<50/microL), which differ in regard to clinical setting, natural history, and prognosis [22].

It is somewhat unusual to detect a clonal B cell count between 50 and 2000/microL, but we manage such patients as high-count MBL.

High-count MBL — High-count CLL-like MBL (>2000 clonal B lymphocytes/microL) is the most common category of MBL that is identified in the course of evaluation for lymphocytosis or other clinical findings [25]. In many respects, it resembles an indolent form of early stage CLL. Compared with low-count MBL, patients with high-count MBL have a higher risk of infection, progression to CLL, and development of a nonhematologic cancer.

Clonal B cells constitute the predominant lymphocyte population in high-count MBL; the median clonal B cell count is 2939/microL [22]. By definition, there is no associated lymphadenopathy, organomegaly, cytopenias, or other findings of a lymphoma or other underlying disease. (See 'Diagnosis' above.)

High-count MBL has biologic features that are similar to early stage CLL, and its natural history appears to dovetail into the CLL clinical disease spectrum [8,23,26,27]. Indeed, the cutoff of 5000 clonal B lymphocytes/microL for distinguishing clinical MBL from CLL is somewhat arbitrary, lacking a definitive clinical and/or biological justification [1,4]. High-count MBL and CLL have similar chromosomal abnormalities (eg, loss of 13q) and frequency of mutated immunoglobulin heavy chain (IGHV), but in MBL there is a higher proportion of patients with favorable prognostic markers (eg, about 75 to 90 percent of MBL patients have mutated IGHV, whereas only about 50 percent of CLL patients do). MBL patients also tend to have fewer somatic mutations (eg, NOTCH1, SF3B1, ATM, TP53) than CLL patients [23,28-31]. Some patients have clonal lymphocyte counts that oscillate between MBL and CLL (ie, above or below 5000/microL) for years. (See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma".)

Although the overall survival of patients with high-count MBL does not differ from that of the general population [32-34], there is an association with the following:

Infections – Infections are the greatest risk to health. In a case control study, MBL was associated with a threefold increased risk of hospitalization due to infection [35]. The risk of serious infection for a patient with high-count MBL is four times higher than the rate of progression to CLL.

Progression – The estimated rate of progression from high-count MBL to CLL is 1 to 2 percent per year, and there is no apparent plateau in incidence [25,26]. In a single-institution study that included 415 individuals with MBL, median overall survival (OS) was 17.9 years (longer than that of age- and sex-matched general population) and the time to first therapy (TTFT) for CLL was 2.9 percent/year [36]. Approximately 60 percent of these patients had a low-risk CLL-IPI score, 28 percent had an intermediate-risk score, and 10 percent had a high/very high risk score; both TTFT and OS were inversely correlated with the CLL-IPI score.

Nonhematologic cancers – There is an increased risk of developing a nonhematologic cancer. Compared with controls, with nearly five years of follow-up, patients with high-count MBL had twice the rate of developing breast, lung, or gastrointestinal cancers [37].

Follow-up and monitoring of patients with high-count MBL is described below. (See 'Monitoring' below.)

Low-count MBL — Low-count CLL-like MBL (<50/microL) is rarely associated with lymphocytosis or other findings, but affected individuals may have an increased risk for serious infections and progression to CLL. At present, it is uncertain if low-count MBL is part of a spectrum that extends to high-count MBL and CLL or if it is simply an epiphenomenon associated with aging.

Because individuals with low-count MBL generally have normal blood counts, no lymphocytosis, and no other clinical findings, it is usually detected in population-based surveys. The median size of the malignant clone is 1 clonal B lymphocyte/microL, and 95 percent of affected individuals have <56/microL [22].

Compared with the general population, low-count MBL may be associated with increased risk for serious infections and progression to CLL, but these findings should be validated with independent reports.

Infections – One study identified 106 individuals with low-count MBL from a biobank of asymptomatic adults ≥40 years old and compared their outcomes with 865 controls from the same biobank who did not have MBL; the groups were well-matched with regard to demographics, medical history, baseline blood counts, and comorbid illnesses [10]. Compared with the controls, patients with MBL had an increased eight-year cumulative incidence of infections (23 versus 11 percent, respectively), pneumonia (9 versus 2 percent), and sepsis (9 versus 2 percent), but there was no difference in overall survival.

Progression – In a study of 310 families that had ≥2 family members with CLL, highly-sensitive flow cytometry identified low-count MBL in 13 percent (139 individuals among 1045 relatives); individuals with low-count MBL were estimated to have a 1.1 percent/year rate of progression from low-count MBL to CLL [13]. In addition, among 264 relatives who had no MBL at baseline, 60 subsequently developed MBL (58 with low-count MBL and 2 with high-count MBL) after a median of six years of follow-up. In a prospective study of 76 individuals with low-count CLL-like MBL, with median follow-up of nearly three years, the B cell clone persisted in 90 percent, but no patient progressed to CLL or other lymphoid malignancy [26].

It is presently uncertain whether low-count MBL is part of a spectrum that extends to high-count MBL and CLL. Low-count MBL differs from CLL and high-count MBL in regard to immunoglobulin repertoire, cytogenetic abnormalities, and molecular mutations [8,23,26,30,38]. Some investigators have hypothesized that low-count MBL may reflect an epiphenomenon of immunosenescence associated with aging, because highly sensitive assays can detect small B cell clones in the majority of older patients [26,27,39]. (See 'Flow cytometry' above.)

Follow-up and monitoring of patients with low-count MBL is described below. (See 'Monitoring low-count MBL' below.)

Atypical MBL — In atypical CLL-like MBL, a monoclonal B cell clone <5000/microL expresses CD5 and CD19, but it differs from typical CLL because of bright expression of CD20 and moderate or bright sIg expression; CD23 may be positive or negative (table 1). Although this immunophenotype is compatible with certain B cell non-Hodgkin lymphomas (especially mantle cell lymphoma), by definition, it is not accompanied by lymphadenopathy, organomegaly, cytopenias, or other findings of a lymphoma. (See 'Diagnosis' above.)

Atypical CLL-like MBL must be distinguished from B cell lymphomas by imaging, cytogenetics, molecular studies, and/or other tests. Lymphadenopathy, splenomegaly, and other organ involvement should be excluded by computerized tomography (CT) of chest, abdomen, and pelvis. Differential diagnosis and tests to exclude B cell non-Hodgkin lymphomas are discussed above. (See 'B cell NHL' above.)

Compared with CLL-like MBL, atypical MBL is much less common and its biology and natural history are less well described [6,7,9,20].

Monitoring of atypical MBL is described below. (See 'Monitoring high-count, atypical, and non-CLL type MBL' below.)

Non-CLL type MBL — Non-CLL type MBL is characterized by <5000/microL monoclonal B cells that are CD5 negative or dim, but express CD19, CD20, and moderate to bright sIg; by definition, there is no lymphadenopathy, organomegaly, cytopenias, or other findings of a lymphoma. The immunophenotype is consistent with certain B cell non-Hodgkin lymphomas and the distinction of non-CLL type MBL from mantle cell lymphoma, marginal zone lymphoma, and Waldenström macroglobulinemia by cytogenetics, molecular studies, and/or other tests is discussed above. (See 'B cell NHL' above.)

Non-CLL type MBL represents less than one-fifth of cases of MBL. The prevalence of non-CLL type MBL is estimated at 1 to 2 percent in the general population, and the incidence rises with increasing age [6,20,25]. Some cases of non-CLL type MBL may be transient and self-limited [26]. In one report, 4 of 13 cases of atypical MBL were biclonal [6].

A study of 23 patients with non-CLL type MBL reported lymphocytosis in 16 patients, and bone marrow involvement in all patients [5]. In another study, four of seven patients had cytogenetic abnormalities (eg, 7q abnormalities, isochromosome 17 with loss of TP53) [40].

The natural history of non-CLL type MBL is not well characterized. This disorder may be related to splenic marginal zone lymphoma, but reports of outcomes are not consistent across various studies. In a study that followed seven patients for 4 to 16 years, there was no evidence of progression to overt lymphoma despite the persistence of lymphocytosis [40]. However, in another study, as many as 17 percent eventually developed splenomegaly, suggesting that this disorder may be related to splenic marginal zone lymphoma [41].

Monitoring of non-CLL type MBL is described below. (See 'Monitoring high-count, atypical, and non-CLL type MBL' below.)

CLINICAL DILEMMAS — Management dilemmas may arise in some settings of MBL.

Incidental marrow/tissue involvement — The serendipitous finding of clonal B cell infiltration of bone marrow, lymph nodes, or other tissues may lead to the diagnosis of MBL. Such patients should be evaluated by computerized tomography (CT) scans to exclude lymphoma. Detection of such B cell infiltration in the setting of MBL (ie, <5000 clonal B cells/microL in peripheral blood with no lymphadenopathy, organomegaly, or cytopenias) does not alter the diagnosis or prognosis of MBL.

As examples, bone marrow examination for staging of a hematologic malignancy (eg, leukemia, lymphoma) or for other reasons (eg, immune thrombocytopenic purpura) may unexpectedly reveal infiltration by chronic lymphocytic leukemia (CLL)-like cells. The degree of infiltration is variable, but one study reported a median of 20 percent bone marrow involvement by MBL cells [42]. The degree of bone marrow involvement by MBL cells does not predict the likelihood of clinical progression of MBL [43,44].

Similarly, liver biopsy or staging of a cancer (eg, lymph node biopsy for prostate cancer or breast cancer) may unexpectedly reveal infiltration by CLL-like cells. Clonal MBL cells have been detected in 2 percent of liver biopsy specimens and up to 0.4 percent of prostate tissues at the time of prostatectomy, but progression to CLL/SLL is only rarely seen [45-49]. Lymph node infiltration by CLL-type cells without proliferation centers and no evidence of organomegaly or lymphadenopathy (ie, none >1.5 cm on CT scans) may constitute a nodal equivalent of MBL (rather than small lymphocytic lymphoma [SLL]) [50].

We manage the unexpected/serendipitous finding of MBL cells in bone marrow or other tissue based on the immunophenotype, clone size, and classification. (See 'Classification and prognosis' above.)

Monitoring of MBL is described below. (See 'Monitoring' below.)

Stem cell/blood donation — The presence of high-count CLL-like MBL may affect the patient's candidacy as a stem cell donor for allogeneic hematopoietic cell transplantation (HCT), but it does not affect the ability to donate blood for transfusion.

MBL is more frequent in first-degree relatives of patients with both familial and sporadic CLL, and transfer of MBL from donor to recipient following allogeneic HCT has been described [51-53]. Consideration of patients with MBL as potential stem cell donors is discussed separately. (See "Donor selection for hematopoietic cell transplantation", section on 'Effect of donor characteristics' and "Evaluation of the hematopoietic cell transplantation donor", section on 'Candidacy for donation'.)

There are no reports of transmission of MBL via blood transfusion. We suggest not screening blood donors for MBL, even though the prevalence of MBL in voluntary blood donors has been reported as high as 7 percent [3,54]. Some epidemiologic studies have suggested that blood transfusions may be associated with an increased risk of developing CLL [55,56], but this has been disputed because some cases may have been related to transfusion-associated hepatitis C virus infection [57].

MONITORING — Monitoring of individuals with MBL is guided by the immunophenotypic category and the size of the B cell clonal population. (See 'Classification and prognosis' above.)

Monitoring high-count, atypical, and non-CLL type MBL — Individuals with high-count CLL-like MBL, atypical MBL, and non-CLL type MBL should be monitored clinically for progression to chronic lymphocytic leukemia (CLL) or other lymphoproliferative disorder (eg, progression of non-CLL type MBL to marginal zone lymphoma). In the absence of clinical progression, there is no need for routine imaging studies, bone marrow examination, or repeat flow cytometry.

We obtain interval history, physical examination, and complete blood count (CBC) with differential count twice a year for the first two years. If the patient is clinically stable and the lymphocyte count is relatively unchanged, we extend the interval to annual visits. We inform the patient of the diagnosis and discuss the small but cumulative risk of progression to CLL. (See 'High-count MBL' above.)

Patients should report lymphadenopathy or B symptoms (eg, fever, sweats, weight loss) to their clinician. If such findings develop, or the lymphocyte count rises to >5000/microL on two consecutive visits, we typically repeat flow cytometry to evaluate immunophenotypic shift in association with progression to CLL. Management of early stage CLL is described separately. (See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma".)

Routine imaging is not performed because detection of subclinical findings does not alter prognosis in MBL. In one study, 29 of 62 patients (42 percent) had adenopathy detected on CT scanning, but after a median of 35 months, only 2 of 29 progressed on CT (7 percent), which is not different from cases of MBL without lymphadenopathy (9 percent; 3 of 33 patients) [58].

Monitoring low-count MBL — Low-count CLL-like MBL has a low risk of progression to CLL, but there may be an increased risk for serious infections, as discussed above. (See 'Low-count MBL' above.)

There is no consensus regarding optimal management of low-count MBL. Follow-up should be individualized and may be influenced by concerns on the part the clinician and/or affected individual. We favor informing the patient of the diagnosis and advising about a possible increased risk for serious infections, recognizing that this potential risk is based on a single, unconfirmed report [10]. Other experts suggest that because the prognosis is excellent and there is no increased risk for transformation to CLL, it is not necessary to inform the patient of the diagnosis.

SUMMARY

Monoclonal B cell lymphocytosis (MBL) refers to a monoclonal population of B lymphocytes <5000 cells/microL without associated lymphadenopathy, organomegaly, cytopenias, or any other feature of a B cell lymphoproliferative disorder. (See 'Diagnosis' above.)

Evaluation of a patient with MBL includes history and physical examination, complete blood count (CBC) with differential, review of the blood smear, and documentation of a B cell clone. (See 'Evaluation' above.)

For most patients, multiparameter flow cytometry is used to define clonality. Flow cytometry is also required to define the immunophenotype of MBL and to measure the size of the B cell clonal population. (See 'Flow cytometry' above.)

The differential diagnosis is influenced by whether there is lymphocytosis (>4000/microL) or other clinical findings (eg, adenopathy, organomegaly, cytopenias, constitutional symptoms), the immunophenotype, and the size of the B cell clonal population. The differential diagnosis of MBL includes reactive causes of lymphocytosis (eg, infections, inflammatory conditions) and malignant B cell disorders, as described above. (See 'Differential diagnosis' above.)

MBL should be classified as one of the following categories, which have distinct natural history, prognosis, and management:

CLL-like MBL shares the immunophenotypic characteristics of chronic lymphocytic leukemia (CLL) (ie, CD5+, CD19+, CD23+, dim or absent CD20, low level or absent surface immunoglobulin [sIg]) and accounts for three-quarters of MBL cases. (See 'CLL-like MBL' above.)

CLL-like MBL should be subcategorized based on the size of the B cell clone:

-High-count MBL (>2000 clonal B lymphocytes/microL) (see 'High-count MBL' above)

-Low-count MBL (<50/microL) (see 'Low-count MBL' above)

Atypical MBL is characterized by CD5+, CD19+, moderate/bright CD20, and sIg expression. All cases of atypical MBL should be evaluated for an underlying lymphoma, such as mantle cell lymphoma. (See 'Atypical MBL' above.)

Non-CLL type MBL has an immunophenotype that is distinct from CLL (ie, CD5 negative/dim, CD19+, CD20+, moderate to bright sIg expression) but resembles that of marginal zone lymphoma and other B cell non-Hodgkin lymphomas, from which it should be distinguished, as discussed above. (See 'Non-CLL type MBL' above.)

MBL may be encountered incidentally when clonal B cell infiltration of bone marrow, lymph node, or other tissue is found in the course of evaluating other disorders; such a finding may require further evaluation to rule out lymphoma, but on its own does not alter the prognosis. (See 'Incidental marrow/tissue involvement' above.)

The presence of high-count CLL-like MBL may affect the patient's candidacy as a stem cell donor for allogeneic hematopoietic cell transplantation, but it does not affect the ability to donate blood for transfusion. (See 'Stem cell/blood donation' above.)

Monitoring of MBL is guided by the immunophenotype and size of the clonal population:

Patients with high-count CLL type MBL, atypical MBL, and non-CLL type MBL are followed periodically with history, physical examination, and complete blood count with differential count.

Flow cytometry or imaging is performed only in patients who develop a sustained rise in lymphocyte count and/or symptoms suggestive of progression to CLL or another non-Hodgkin lymphoma. (See 'Monitoring high-count, atypical, and non-CLL type MBL' above.)

Approaches to management of patients with low-count MBL are discussed above. (See 'Monitoring low-count MBL' above.)

ACKNOWLEDGMENT — The editors of UpToDate acknowledge the contributions of Stanley L Schrier, MD as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.

  1. Marti GE, Rawstron AC, Ghia P, et al. Diagnostic criteria for monoclonal B-cell lymphocytosis. Br J Haematol 2005; 130:325.
  2. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised 4th edition, Swerdlow SH, Campo E, Harris NL, et al. (Eds), International Agency for Research on Cancer (IARC), Lyon 2017.
  3. Shim YK, Rachel JM, Ghia P, et al. Monoclonal B-cell lymphocytosis in healthy blood donors: an unexpectedly common finding. Blood 2014; 123:1319.
  4. Shanafelt TD, Ghia P, Lanasa MC, et al. Monoclonal B-cell lymphocytosis (MBL): biology, natural history and clinical management. Leukemia 2010; 24:512.
  5. Kalpadakis C, Pangalis GA, Sachanas S, et al. New insights into monoclonal B-cell lymphocytosis. Biomed Res Int 2014; 2014:258917.
  6. Nieto WG, Teodosio C, López A, et al. Non-CLL-like monoclonal B-cell lymphocytosis in the general population: prevalence and phenotypic/genetic characteristics. Cytometry B Clin Cytom 2010; 78 Suppl 1:S24.
  7. Rawstron AC, Green MJ, Kuzmicki A, et al. Monoclonal B lymphocytes with the characteristics of "indolent" chronic lymphocytic leukemia are present in 3.5% of adults with normal blood counts. Blood 2002; 100:635.
  8. Dagklis A, Fazi C, Sala C, et al. The immunoglobulin gene repertoire of low-count chronic lymphocytic leukemia (CLL)-like monoclonal B lymphocytosis is different from CLL: diagnostic implications for clinical monitoring. Blood 2009; 114:26.
  9. Nieto WG, Almeida J, Romero A, et al. Increased frequency (12%) of circulating chronic lymphocytic leukemia-like B-cell clones in healthy subjects using a highly sensitive multicolor flow cytometry approach. Blood 2009; 114:33.
  10. Shanafelt TD, Kay NE, Parikh SA, et al. Risk of serious infection among individuals with and without low count monoclonal B-cell lymphocytosis (MBL). Leukemia 2021; 35:239.
  11. Marti GE, Carter P, Abbasi F, et al. B-cell monoclonal lymphocytosis and B-cell abnormalities in the setting of familial B-cell chronic lymphocytic leukemia. Cytometry B Clin Cytom 2003; 52:1.
  12. Rawstron AC, Yuille MR, Fuller J, et al. Inherited predisposition to CLL is detectable as subclinical monoclonal B-lymphocyte expansion. Blood 2002; 100:2289.
  13. Slager SL, Lanasa MC, Marti GE, et al. Natural history of monoclonal B-cell lymphocytosis among relatives in CLL families. Blood 2021; 137:2046.
  14. Matos DM, Ismael SJ, Scrideli CA, et al. Monoclonal B-cell lymphocytosis in first-degree relatives of patients with sporadic (non-familial) chronic lymphocytic leukaemia. Br J Haematol 2009; 147:339.
  15. Crowther-Swanepoel D, Corre T, Lloyd A, et al. Inherited genetic susceptibility to monoclonal B-cell lymphocytosis. Blood 2010; 116:5957.
  16. Kleinstern G, Camp NJ, Goldin LR, et al. Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis. Blood 2018; 131:2541.
  17. Anderson LA, Landgren O, Engels EA. Common community acquired infections and subsequent risk of chronic lymphocytic leukaemia. Br J Haematol 2009; 147:444.
  18. Casabonne D, Almeida J, Nieto WG, et al. Common infectious agents and monoclonal B-cell lymphocytosis: a cross-sectional epidemiological study among healthy adults. PLoS One 2012; 7:e52808.
  19. Anderson LA, Pfeiffer R, Warren JL, et al. Hematopoietic malignancies associated with viral and alcoholic hepatitis. Cancer Epidemiol Biomarkers Prev 2008; 17:3069.
  20. Ghia P, Prato G, Scielzo C, et al. Monoclonal CD5+ and CD5- B-lymphocyte expansions are frequent in the peripheral blood of the elderly. Blood 2004; 103:2337.
  21. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood 2018; 131:2745.
  22. Rawstron AC, Shanafelt T, Lanasa MC, et al. Different biology and clinical outcome according to the absolute numbers of clonal B-cells in monoclonal B-cell lymphocytosis (MBL). Cytometry B Clin Cytom 2010; 78 Suppl 1:S19.
  23. Henriques A, Rodríguez-Caballero A, Nieto WG, et al. Combined patterns of IGHV repertoire and cytogenetic/molecular alterations in monoclonal B lymphocytosis versus chronic lymphocytic leukemia. PLoS One 2013; 8:e67751.
  24. Lanasa MC, Allgood SD, Volkheimer AD, et al. Single-cell analysis reveals oligoclonality among 'low-count' monoclonal B-cell lymphocytosis. Leukemia 2010; 24:133.
  25. Rawstron AC, Bennett FL, O'Connor SJ, et al. Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. N Engl J Med 2008; 359:575.
  26. Fazi C, Scarfò L, Pecciarini L, et al. General population low-count CLL-like MBL persists over time without clinical progression, although carrying the same cytogenetic abnormalities of CLL. Blood 2011; 118:6618.
  27. Vardi A, Dagklis A, Scarfò L, et al. Immunogenetics shows that not all MBL are equal: the larger the clone, the more similar to CLL. Blood 2013; 121:4521.
  28. Kern W, Bacher U, Haferlach C, et al. Monoclonal B-cell lymphocytosis is closely related to chronic lymphocytic leukaemia and may be better classified as early-stage CLL. Br J Haematol 2012; 157:86.
  29. Puente XS, Beà S, Valdés-Mas R, et al. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature 2015; 526:519.
  30. Greco M, Capello D, Bruscaggin A, et al. Analysis of SF3B1 mutations in monoclonal B-cell lymphocytosis. Hematol Oncol 2013; 31:54.
  31. Foà R, Del Giudice I, Guarini A, et al. Clinical implications of the molecular genetics of chronic lymphocytic leukemia. Haematologica 2013; 98:675.
  32. Molica S, Mauro FR, Giannarelli D, et al. Differentiating chronic lymphocytic leukemia from monoclonal B-lymphocytosis according to clinical outcome: on behalf of the GIMEMA chronic lymphoproliferative diseases working group. Haematologica 2011; 96:277.
  33. Molica S, Levato D, Dattilo A. Natural history of early chronic lymphocytic leukemia. A single institution study with emphasis on the impact of disease-progression on overall survival. Haematologica 1999; 84:1094.
  34. Shanafelt TD, Kay NE, Rabe KG, et al. Survival of patients with clinically identified monoclonal B-cell lymphocytosis (MBL) relative to the age- and sex-matched general population. Leukemia 2012; 26:373.
  35. Moreira J, Rabe KG, Cerhan JR, et al. Infectious complications among individuals with clinical monoclonal B-cell lymphocytosis (MBL): a cohort study of newly diagnosed cases compared to controls. Leukemia 2013; 27:136.
  36. Parikh SA, Rabe KG, Kay NE, et al. The CLL International Prognostic Index predicts outcomes in monoclonal B-cell lymphocytosis and Rai 0 CLL. Blood 2021; 138:149.
  37. Solomon BM, Chaffee KG, Moreira J, et al. Risk of non-hematologic cancer in individuals with high-count monoclonal B-cell lymphocytosis. Leukemia 2016; 30:331.
  38. Rasi S, Monti S, Spina V, et al. Analysis of NOTCH1 mutations in monoclonal B-cell lymphocytosis. Haematologica 2012; 97:153.
  39. Almeida J, Nieto WG, Teodosio C, et al. CLL-like B-lymphocytes are systematically present at very low numbers in peripheral blood of healthy adults. Leukemia 2011; 25:718.
  40. Amato D, Oscier DG, Davis Z, et al. Cytogenetic aberrations and immunoglobulin VH gene mutations in clinically benign CD5- monoclonal B-cell lymphocytosis. Am J Clin Pathol 2007; 128:333.
  41. Xochelli A, Kalpadakis C, Gardiner A, et al. Clonal B-cell lymphocytosis exhibiting immunophenotypic features consistent with a marginal-zone origin: is this a distinct entity? Blood 2014; 123:1199.
  42. Rossi D, Sozzi E, Puma A, et al. The prognosis of clinical monoclonal B cell lymphocytosis differs from prognosis of Rai 0 chronic lymphocytic leukaemia and is recapitulated by biological risk factors. Br J Haematol 2009; 146:64.
  43. Oliveira AC, Fernández de Sevilla A, Domingo A, et al. Prospective study of prognostic factors in asymptomatic patients with B-cell chronic lymphocytic leukemia-like lymphocytosis: the cut-off of 11 × 10(9)/L monoclonal lymphocytes better identifies subgroups with different outcomes. Ann Hematol 2015; 94:627.
  44. Randen U, Tierens AM, Tjønnfjord GE, Delabie J. Bone marrow histology in monoclonal B-cell lymphocytosis shows various B-cell infiltration patterns. Am J Clin Pathol 2013; 139:390.
  45. Rawstron AC. Occult B-cell lymphoproliferative disorders. Histopathology 2011; 58:81.
  46. Winstanley AM, Sandison A, Bott SR, et al. Incidental findings in pelvic lymph nodes at radical prostatectomy. J Clin Pathol 2002; 55:623.
  47. Chu PG, Huang Q, Weiss LM. Incidental and concurrent malignant lymphomas discovered at the time of prostatectomy and prostate biopsy: a study of 29 cases. Am J Surg Pathol 2005; 29:693.
  48. Liu CL, Fan ST, Lo CM, et al. Hepatic resection for incidentaloma. J Gastrointest Surg 2004; 8:785.
  49. He H, Cheng L, Weiss LM, Chu PG. Clinical outcome of incidental pelvic node malignant B-cell lymphomas discovered at the time of radical prostatectomy. Leuk Lymphoma 2007; 48:1976.
  50. Gibson SE, Swerdlow SH, Ferry JA, et al. Reassessment of small lymphocytic lymphoma in the era of monoclonal B-cell lymphocytosis. Haematologica 2011; 96:1144.
  51. Perz JB, Ritgen M, Moos M, et al. Occurrence of donor-derived CLL 8 years after sibling donor SCT for CML. Bone Marrow Transplant 2008; 42:687.
  52. Hardy NM, Grady C, Pentz R, et al. Bioethical considerations of monoclonal B-cell lymphocytosis: donor transfer after haematopoietic stem cell transplantation. Br J Haematol 2007; 139:824.
  53. Ferrand C, Garnache-Ottou F, Collonge-Rame MA, et al. Systematic donor blood qualification by flow cytometry would have been able to avoid CLL-type MBL transmission after unrelated hematopoietic stem cell transplantation. Eur J Haematol 2012; 88:269.
  54. Rachel JM, Zucker ML, Fox CM, et al. Monoclonal B-cell lymphocytosis in blood donors. Br J Haematol 2007; 139:832.
  55. Brandt L, Brandt J, Olsson H, et al. Blood transfusion as a risk factor for non-Hodgkin lymphoma. Br J Cancer 1996; 73:1148.
  56. Cerhan JR, Wallace RB, Dick F, et al. Blood transfusions and risk of non-Hodgkin's lymphoma subtypes and chronic lymphocytic leukemia. Cancer Epidemiol Biomarkers Prev 2001; 10:361.
  57. Slager SL, Benavente Y, Blair A, et al. Medical history, lifestyle, family history, and occupational risk factors for chronic lymphocytic leukemia/small lymphocytic lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr 2014; 2014:41.
  58. Gentile M, Cutrona G, Fabris S, et al. Total body computed tomography scan in the initial work-up of Binet stage A chronic lymphocytic leukemia patients: Results of the prospective, multicenter O-CLL1-GISL study. Am J Hematol 2013; 88:539.
Topic 118011 Version 8.0

References