Mature B-cell neoplasm
(Overview)

Request forms

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:

obligatory

Method:

Molecular genetics
Anticoagulant:

EDTA or Heparin
Recommendation:

entity specific

Overview
Classification
Diagnostics
Prognosis
Recommendation

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.

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:

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 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.

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	-	+	+	+	+	+	+	+/-
CD79b	+	+	+	+	+	+	+	+
CD5	+	-	-	-	-/+	-	+	-
sIg	(+)	+	(+)	(+)/+	(+)	+	+	+/-
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.

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	Zytogenetische Aberrationen	Molekulare Marker
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	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	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	TP53, EZH2 Y641, 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	BCL2, KMT2D, TNFRSF14, EZH2 Y641, EPHa7, CREBBP, BCL6, MEF2B, EP300, TNFAIP3(A20), FAS, TP53
HZL and HZL-v Hairy cell leukemia and variant hairy cell leukemia	HZL: no specific abnormalities HZL-v: -Gain: 5 - Losses: 7q, 17p	BRAF V600E (nur bei HZL) TP53 (bei 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)	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	IGH-CCND1, SOX11, UBR5, TP53, ATM, NOTCH1, NOTCH2, CCND1-Überexpression
MM/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	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.	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.

Bea S et al. Increased number of chromosomal imbalances and high-level DNA amplifications in mantle cell lymphoma are associated with blastoid variants. Blood 1999;93:4365-4374.

Campo E et al. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood 2011;117:5019-5032.

Johnson NA et al. Lymphomas with concurrent BCL2 and MYC translocations: the critical factors associated with survival. Blood 2009;114:2273-2279.

Lestou VS et al. Multicolour fluorescence in situ hybridization analysis of t(14;18)-positive follicular lymphoma and correlation with gene expression data and clinical outcome. Br J Haematol 2003;122:745-759.

Ott G, Rosenwald A. Molecular pathogenesis of follicular lymphoma. Haematologica 2008;93:1773-1776.

Rinaldi A et al. Genome-wide DNA profiling of marginal zone lymphomas identifies subtype-specific lesions with an impact on the clinical outcome. Blood 2011;117:1595-1604.

Salaverria I et al. Multiple recurrent chromosomal breakpoints in mantle cell lymphoma revealed by a combination of molecular cytogenetic techniques. Genes Chromosomes. Cancer 2008;47:1086-1097.

Salido M et al. Cytogenetic aberrations and their prognostic value in a series of 330 splenic marginal zone B-cell lymphomas: a multicenter study of the Splenic B-Cell Lymphoma Group. Blood 2010;116:1479-1488.

Schwaenen C et al. Microarray-based genomic profiling reveals novel genomic aberrations in follicular lymphoma which associate with patient survival and gene expression status. Genes Chromosomes Cancer 2009;48:39-54.

Swerdlow SH et al. WHO classification of tumours of haematopoetic and lymphoid tissue. International Agency of Research on Cancer 2017; 4. überarbeitete Version.

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

You may also be interested in

Career

As a rapidly growing, innovative medical laboratory, we are always looking for bright minds to help us bring new and more effective therapies to patients around the world.

Learn more

Services

Do you have questions about sample submission, analyses performed or findings? Here you will find contact details, contact persons and our most frequently asked questions (FAQs).

Learn more

Quality management

We have been certified according to national and international standards since 2009 and have successfully maintained these accreditations.

Learn more

Mature B-cell neoplasm (Overview)

General overview of mature B-cell neoplasms

Classification

Diagnostics

Prognosis

Recommendation

Important note on the test material

You may also be interested in

Mature B-cell neoplasm
(Overview)