Persistent polyclonal B-cell lymphocytosis (PPBL)

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Diagnostics

Method:
Anticoagulant:
Recommendation:

Method:

Cytomorphology
Anticoagulant:

EDTA
Recommendation:

obligatory

Method:

Immunophenotyping
Anticoagulant:

EDTA or Heparin
Recommendation:

obligatory

Method:

Chromosome analysis
Anticoagulant:

Heparin
Recommendation:

facultative

Method:

FISH
Anticoagulant:

EDTA or Heparin
Recommendation:

facultative

Method:

Molecular genetics
Anticoagulant:
Recommendation:

no

Characteristics
Diagnostics
Prognosis

Based on the current guidelines and the current state of research, there are different diagnostic recommendations for patients with persistent polyclonal B-cell lymphocytosis (PPBL). We have summarized the most important information on classification and diagnostic methods at MLL. In addition, we provide further literature on persistent polyclonal B-cell lymphocytosis so that you can inform yourself in more detail.

Persistent polyclonal B-cell lymphocytosis: Characteristics

Persistent polyclonal B-cell lymphocytosis (PPBL) is a rare benign disease with chronic lymphocytosis of polyclonal origin, which occurs more frequently in middle-aged female smokers. These women are mostly asymptomatic with mild leukocytosis/lymphocytosis or show non-specific symptoms such as fatigue. Therefore, PPBL is often an incidental finding and no other underlying diseases are found, but an association with EBV infections has been discussed (Delage et al. 2001). Bilobulated, usually even binucleated B lymphocytes in the peripheral blood and a polyclonal increase of IgM in the serum are characteristics. Splenomegaly has been described in some cases (Cornet et al. 2009, Del Giudice et al. 2009). Lymphomas and secondary solid tumors appear to be more frequent in the year-long course, but this is controversial (Cornet et al. 2009, Cornet et al. 2016).

The actual cause of the disease persistent polyclonal B-cell lymphocytosis and the associated mechanism are unknown and probably represent a gradual process. In addition to the external factor "smoking", a genetic predisposition for persistent polyclonal B-cell lymphocytosis is very likely due to its gender-dependent and familial clustered occurrence (Carr et al. 1997, Delage et al. 2001).

Persistent polyclonal B-cell lymphocytosis: Diagnostic methods

The number of lymphocytes in the peripheral blood can vary considerably. Morphologically characteristic are binucleated, cytoplasm-rich B lymphocytes in the blood smear, which have a polyclonal origin as demonstrated by immunophenotyping (Mossafa et al. 1999).

The immunophenotype of B lymphocytes in persistent polyclonal B cell lymphocytosis resembles that of lymphocytes in the splenic marginal zone (CD27⁺, CD21^high, IgM^high, CD5^low, CD23^low) or memory B cells, suggesting an origin of the disease in the marginal zone (Salcedo et al. 2002). Consistent with the polyclonality of the disease, a normal kappa/lambda light chain quotient is seen (Cornet et al. 2009). An association with a particular HLA haplotype is often found. HLA::DR7 expression has been described most frequently (Troussard & Flandrin 1996, Cornet et al. 2016).

Despite the polyclonality of the disease, recurrent genetic aberrations are found. For example, patients with persistent polyclonal B-cell lymphocytosis have an above-average number of polyclonal IGH::BCL2 rearrangements (t(14;18)) with different breakpoints, whereby the type and occurrence of the rearrangements often correlate with the HLA type (Delage et al. 2001). The gain of an isochromosome 3q (BCL6/3q27) is also typical (Cornet et al. 2009). In addition, trisomy 3 or duplications of the long arm of chromosome 3 (Callet-Bauchu et al. 1999), 8q gains (MYC/8q24), and aberrations of other chromosomes and independent clones have been described (Mossafa et al. 1999, Mossafa et al. 2004, Cornet et al. 2016). Another distinctive feature in PPBL is the so-called "premature chromosome condensation (PCC)" (Mossafa et al. 1999). This is a premature condensation of DNA in interphase, probably due to the binuclearity of the cells.

If chromosomal analysis cannot be performed, the chromosomal aberrations that occur in persistent polyclonal B-cell lymphocytosis (see above) can also be detected by FISH.

While molecular genetics does not play a role in the routine diagnosis of persistent polyclonal B-cell lymphocytosis, molecular genetic characterization of the disease is the subject of current research. In two studies, whole-genome and whole-exome sequencing, respectively, detected mutations associated with tumors and especially lymphomas, such as MYD88, ATM, NOTCH2, and TRAF1, among others (Tesson et al. 2017, Stengel et al. 2018). However, characteristic driver mutations are lacking (Tesson et al. 2017). Due to the rarity of the disease, previous data regarding the incidence of mutations in persistent polyclonal B-cell lymphocytosis are difficult to compare. Gene expression analysis also suggests that lymphoma-associated genes, such as BCL11B and MYC, among others, are overexpressed (Stengel et al. 2018).

Persistent polyclonal B-cell lymphocytosis: Prognosis

Persistent polyclonal B-cell lymphocytosis has several characteristics associated with malignant tumors. These include the occurrence of cytogenetic abnormalities and the frequently observed chromosomal instability (Mossafa et al. 2004, Cornet et al. 2016) as well as the detectability of various tumor-associated mutations (Stengel et al. 2018). Nevertheless, persistent polyclonal B-cell lymphocytosis often shows an indolent, stable course over many years or slight progress with continued cigarette consumption. Only in isolated cases of persistent polyclonal B-cell lymphocytosis has the occurrence of a malignant disease, e.g. lymphoma, been described and an association discussed (Del Giudice et al. 2009, Cornet et al. 2009, Cornet et al. 2016). The achievement of cytomorphological remission by stopping cigarette consumption is controversially discussed but observed (Mossafa et al. 1999, Cornet et al. 2009), the cytogenetic abnormalities seem to persist. A clear separation of malignant lymphomas is important, because due to the indolent course and the lack of malignancy, a therapy is generally not indicated. Regular follow-ups are recommended.

Callet-Bauchu E et al. Distinct chromosome 3 abnormalities in persistent polyclonal B-cell lymphocytosis. Genes Chromosomes. Cancer 1999;26(3):221-228.

Carr R et al. Persistent polyclonal B-cell lymphocytosis in identical twins. Br J Haematol 1997;96(2):272-274.

Cornet E et al. Long-term follow-up of 111 patients with persistent polyclonal B-cell lymphocytosis with binucleated lymphocytes. Leukemia 2009;23(2):419-422.

Cornet E et al. Persistent polyclonal binucleated B-cell lymphocytosis and MECOM gene amplification. BMC Res Notes 2016;9(138.

Del Giudice I et al. Histopathological and molecular features of persistent polyclonal B-cell lymphocytosis (PPBL) with progressive splenomegaly. Br. J. Haematol 2009;144(5):726-731.

Delage R et al. Persistent polyclonal B-cell lymphocytosis: further evidence for a genetic disorder associated with B-cell abnormalities. Br. J. Haematol 2001;114(3):666-670.

Mossafa H et al. Persistent polyclonal B lymphocytosis with binucleated lymphocytes: a study of 25 cases. Groupe Francais d'Hematologie Cellulaire. Br J Haematol 1999;104(3):486-493.

Mossafa H et al. Chromosomal instability and ATR amplification gene in patients with persistent and polyclonal B-cell lymphocytosis (PPBL). Leuk Lymphoma 2004;45(7):1401-1406.

Salcedo I et al. Persistent polyclonal B lymphocytosis: an expansion of cells showing IgVH gene mutations and phenotypic features of normal lymphocytes from the CD27+ marginal zone B-cell compartment. Br J Haematol 2002;116(3):662-666.

Stengel A et al. Whole Genome Sequencing and RNA Sequencing of 27 Patients with Persistent Polyclonal B-Cell Lymphocytosis Reveals a High Mutation Frequency/Overexpression of Lymphoma Associated Genes: Really a Benign Disorder? Blood 2018;132(Supplement 1):924.

Tesson B et al. Absence of driver mutations in persistent polyclonal B-cell lymphocytosis with binucleated lymphocytes. Blood 2017;130(10):1267-1269.

Troussard X, Flandrin G. Chronic B-cell lymphocytosis with binucleated lymphocytes (LWBL): a review of 38 cases. Leuk Lymphoma 1996;20(3-4):275-279.

Status: June 2022

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