General overview of mature B-cell neoplasms

The term mature B-cell neoplasms is used to describe biologically and clinically heterogeneous diseases of the B-lymphatic system. This includes the following entities, for which the MLL offers further information:

Definition and characteristics

Diseases of the lymphatic system of B-cells are characterized by a high heterogeneity. Depending on the entity, the clinical courses are indolent to aggressive. The different entities also differ in terms of genetics. For example, mature B-cell neoplasms exhibit a wide range of possible genetic abnormalities. Individual entities show typical patterns of balanced and/or unbalanced aberrations, but these are not specific enough for a final diagnosis. In the following overview, the characteristic immunophenotypic (see Table 1) and genetic features (see Table 2) of mature B-cell neoplasms are presented, which in combination with the methods of histology, immunohistochemistry and cytomorphology allow an exact diagnostic classification.

Classification

In the category of mature B-cell neoplasms, the WHO classification describes 34 different entities (Swerdlow et al. 2017), based on histology and immunophenotype. Cytogenetic and molecular genetic diagnostics significantly support differential diagnosis by detecting typical genetic patterns where appropriate. However, histology and immunophenotyping must always be consulted for an exact assignment of the disease to a specific entity.

Diagnostics

Diagnostics is based on the interaction of different methods:

  • Cytomorphology: Assessment of the degree of maturity and infiltration in the bone marrow or peripheral blood.
  • Immunophenotyping: assignment to the B or T cell lines. Many lymphomas show characteristic immunophenotypes (e.g. follicular lymphoma or mantle cell lymphoma), these are summarized in Table 1 (see Diagnostics, Immunophenotyping).
  • Chromosome analysis, FISH, molecular genetics: Detection of characteristic genetic abnormalities, an overview is given in Table 2 (see Diagnostics, Chromosome analysis / FISH / Molecular genetics).
  • Immunohistochemistry: central role in histopathology, especially of the lymph nodes.
Cytomorphology

Cytomorphology and histology are leading in the diagnosis of the different lymphoma entities for the control of the subsequent diagnostics. The assessment of the blood or bone marrow smear allows a first groundbreaking statement to be made as to whether lymphoma infiltration exists or is possible. Cytomorphology and histology are also necessary to assess the degree of lymphoma maturity.

Immunophenotyping

Besides CLL, other subtypes show characteristic immunophenotypes: Follicular lymphomas show a strong surface expression of immunoglobulins and mostly express the antigen CD10, whereas CD5 is not expressed. Mantle cell lymphomas express CD5 and are mostly negative for CD23 in contrast to B-CLL. Hairy cell leukemia expresses CD103, CD11c and CD25, whereas CD25 is not expressed in the variant form of hairy cell leukemia. Other lymphomas show less specific immunophenotypes, e.g. diffuse large B-cell lymphoma (DLBCL) or marginal zone lymphoma.

Table 1: Characteristic immunophenotypic findings in B-cell lymphomas

Antigene

B-CLL

B-PLL

MZL

SMZL

HZL

FL

MCL

DLBCL

CD19

+

+

+

+

+

+

+

+

CD20

(+)

+

+

+

+

+

+

+

CD22

(+)

+

+

+

+

+

+

+

CD23

+

-

-

-/+

-/+

+/-

-/+

+/-

CD25

-

-

-

-/+

+

-

-

 

FMC7

-

+

+

+

+

+

+

+/-

CD79a

+

+

+

+

+

+

+

+

CD5

+

-

-

-

-/+

-

+

-

slg

(+)

+

(+)

(+)/+

(+)

+

+

+/-

CD10

-

-

-

-/+

-/+

+/-

-/+

-/+

CD11c

-

-

+/-

-/+

+

-

-

 

MZL: marginal zone lymphoma, SMZL: splenic marginal zone lymphoma, HZL: hairy cell leukemia, FL: follicular lymphoma, MCL: mantle cell lymphoma, DLBCL: diffuse large cell B-cell lymphoma

Chromosome analysis / FISH / Molecular genetics

Overview of cytogenetic abnormalities and molecular markers

In different entities of mature B-cell neoplasms, characteristic translocations occur which contribute to the pathogenesis. Often 14q32 is involved, whereby an oncogene gets close to the enhancer of the heavy chain of the immunoglobulin complex (IGH) and is overexpressed. More rarely, so-called variant translocations occur, in which instead of the IGH locus, one of the loci coding for one of the immunoglobulin light chains IGK (2p11) or IGL (22q11) is involved. Chromosomal analysis and interphase FISH analysis can be used to detect such characteristic rearrangements in B-cell lymphomas. Some of these (balanced) rearrangements, such as t(11;14)(q13;q32) or t(14;18)(q32;q21), can also be detected at the molecular level by PCR. However, since the break points at the genomic level can be very different, the hit rate of PCR is only 40-80%.

Table 2 provides a detailed overview of the genetics of the various mature B-cell neoplasms.

Table 2: Overview of cytogenetic and molecular changes in B cell neoplasms

Disease

Cytogenetic abnormalities

Molecular markers

BL
Burkitt-lymphoma

Balanced translocations: t(8;14)(q24;q32)/IGH-MYC, t(2;8)(p11;q24)/IGK-MYC,
 t(8;22)(q24;q11)/IGL-MYC
Gains: 1q, +7, +12
Losses: 6q, 13q32-34, 17p

see also BL

TCF3, CCDN3, TP53, RHOA, SMARCCA4, ARID1A

CLL
Chronic Lymphocytic leukemia

Balanced translocations: t(14;18)(q32;q21)/IGH/BCL2
Gains: 12, 2p, 8q24
Losses: 13q, 11q, 6q, 17p, 14q
see also CLL

TP53, SF3B1, NOTCH1, ATM, BIRC3, POT1, MYD88

DLBCL
Diffuse large B-cell lymphoma

Balanced translocations: 3q27/BCL6, 8q24/MYC und 18q21/BCL2 rearrangements: e.g.: t(14;18)(q32;q21)
Gains: 3q, 9q

see also DLBCL

TP53, EZH2Y64, FOXO1

FL
Follicular lymphoma

Balanced translocations: t(14;18)(q32;q21)/IGH-BCL2 rarely t(8;14)(q24;q32)/IGH-MYC or other 8q24/MYC-rearrangements, 3q27/BCL6-rearrangements
Gains: 1(q), 6p, 7, 8, 12(q), 17, 18/18q, 21, X
Losses: 1p, 6q, 7q, 9p, 10q, 13q, 17p
see also FL

BCL2, KMT2D,
TNFRSF14, EZH2Y641, EPHa7, CREBBP, BCL6, MEF2B, EP300, TNFAIP3(A20), FAS, TP53

HZL und HZL-v
Hairy cell leukemia and variant hairy cell leukemia

HZL: no specific abnormalities
HZL-v:
-Gain: 5
- Losses: 7q, 17p
see also HZL

BRAF V600E
(only for HZL)
TP53
(for HZL-v)

LPL
Lymphoplasmacytic lymphoma

Balanced translocation: t(9;14)(p13;q32)/IGH-PAX5
Gains: Trisomien 3, 4, 18
Losses: 6q (not specific for LPL)
see also Morbus Waldenström

MYD88 L265P,
CXCR4 S338X, ARID1A, TP53, CD79B, KMT2D

MCL
Mantle cell lymphoma

Balanced translocations: t(11;14)(q13;q32)/IGH-CCND1, rarely: t(8;14)(q24;q32)/IGH-MYC, 3q27/BCL6-rearrangements
Gains: 3q, 7p, 8q, 11q, 12, 13q, 15q, 18q, often tetraploid clones
Losses: 1p, 6q, 8p, 9p, 11q, 13q, 17p, Y
see also MCL

IGH-CCND1,
SOX11,
UBR5, TP53, ATM, NOTCH1, NOTCH2,
CCND1-overexpression

PCM/MGUS
Plasma cell myeloma/
monoklonal gammopathy of undetermined significance

Balanced translocations: t(4;14)(p16;q32), t(6;14)(p21;q32), t(11;14)(q13;q32), t(14;16)(q32;q23), t(14;20)(q32;q12), t(12;14)(p13;q32), 8q24/MYC-rearrangements
Gains: 1q, 3, 5, 7, 9, 11, 15, 19, 21
Losses: 1p, 13
see also MM

NRAS, KRAS, BRAF

MALT
Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue

Balanced translocations: t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21), t(3;14)(p14.1;q32)
Gains: 3, 18
Losses: 6q
Frequencies of abnormalities vary depending on the location of the disease

-

nod. MZL
Nodal marginal zone lymphoma

Gains: 3, 18
Losses: 6q

-

SMZL
splenic mrginal zone lymphoma

Balanced translocations: complex cytogenetic abnormalities including t(9;14)(p13;q32) with PAX5 and IGH-Gens
Gains: 3(q), 12, 18
Losses: 6q, 8p, 7q, 13q, 17p

NOTCH2

B-PLL
Prolymphocytic leukemia

17p13/TP53-Deletion, frequently complex karyotype, similar cytogenetic abnormalities as in CLL

TP53, JAK1, JAK3

HGBL
High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements

8q24/MYC-rearrangements together with 18q21/BCL2- and/or 3q27/BCL6-rearrangements.
Gains: 1q, 3q, 7q, 8q, 12q, 18q
Losses: 17p and 6q

Exceptions are cases in which the criteria for follicular lymphoma or lymphoblastic lymphoma are met. In the past, these lymphomas were called "double hit lymphoma" or "triple hit lymphoma". These cases show a variable morphology of DLBCL, Burkitt lymphoma and rarely follicular lymphomas.

see also HGBL

TP53, MYC

Prognosis

Due to the heterogeneity and complexity of the abnormalities, the prognostic significance in individual cases is highly variable within the different entities. Therefore, in addition to clinical parameters, many individual diagnostic findings are crucial for the correct timing between watch and wait and initiation of therapy. Increasingly, these findings also directly influence the choice of therapeutic agents (precision medicine) and are taken into account in the approval of drugs (e.g. TP53 alterations in CLL).

Recommendation

The diagnosis of mature B-cell neoplasms is currently much more comprehensive than 5 - 10 years ago and their results from blood, bone marrow and/or lymph nodes often have a direct impact on the choice of a potential therapy in addition to diagnostic and prognostic relevance. Various therapeutic approaches are so effective that today the determination of measurable residual disease (MRD) is partly introduced into remission controls. The method of choice here is usually immunophenotyping.

Important note on the test material

If lymphoma cells are detected in the peripheral blood, the diagnosis can initially be made with a high degree of certainty without a bone marrow biopsy or lymph node removal. Based on these findings, an extended material withdrawal is then advisable in individual cases and if clinically relevant.

References

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Swerdlow SH et al. The 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms. Blood 2016;127:2375-2390.