Marginal Zone B-cell lymphoma

Clinics and Pathology

Disease	Marginal zone B-cell lymphoma (MZBCL), including three distinct clinicopathological forms (Harris et al, 1999), namely: 1- extra-nodal MZBCL of mucosa-associated lymphoid tissue ( MALT) type, 2- splenic MZBCL, corresponding to splenic lymphoma with villous lymphocytes (SLVL) 3- nodal MZBCL
Phenotype / cell stem origin	The morphologic and phenotypic characteristics of malignant cells correspond to those of lymphocytes belonging to the marginal zone, harbouring hypermutated IgV genes with the following immunophenotype: pan-B+; CD5-/+; CD10-; CD23-; CD11c+/-; cyIg +(40% of the cells), sIgM+ bright; sIgD-
Epidemiology	The global incidence of MZBCL in western countries is approximately 10% of all non Hodgkin lymphomas (NHL) diagnosed by histologic examination
Clinics	Extra-nodal MZBCL of MALT type (7% of all NHL) is an indolent disease involving most often the stomach, where it usually follows chronic gastritis due to Helicobacter pylori (HP) infection. The disease may also localize in the lung, the thyroid the salivary gland and in the orbit, where an association was documented with Chlamydia Psittaci infection. Splenic MZBCL (1% of all NHL on histologic samples) usually, though not invariably, presents splenomegaly associated circulating villous lymphocytes and BM involvement. It runs an indolent course. Nodal MZBCL (2% of al NHL) is a low-grade lymphoma, frequently presenting with advanced-stage disease, but not with large masses. Early relapse after chemotherapy may be observed in some patients and survival is shorter that in MZBCL of MALT type. All subsets may transform into a high grade lymphoma
Pathology	The tumour consists of a cytologically heterogeneous infiltrate including centrocyte-like cells, monocytoid B-cells small lymphocytes and plasma cells. Large cells and/or blast-like cells may be present. In epithelial tissues (i.e. stomach) typical lymphoepithelial lesions are characteristically seen. In the spleen, involvement of the mantle zone and marginal zone of the white pulp occur, usually centered around a residual germinal centre. The red pulp is usually involved.
Treatment	Low grade MALT with limited disease involving the stomach is usually HP+ and respond to eradication of the HP infection. Cases presenting at a more advanced stage or with transformation into high grade lymphoma require single-agent or multi-agent chemotherapy. Rituximab (anti-CD20 monoclonal antibody) is an effective treatment. Gastrectomy is indicated in non-responding patients. Splenic MZBCL and nodal MZBCL are treated using various forms of chemotherapy depending on the disease stage and patient's conditions. Splenectomy is an option for splenic MZBCL
Prognosis	The patients usually have prolonged survival, as in other indolent lymphomas, but some cases may feature an aggressive disease.

Cytogenetics

Cytogenetics Morphological

The most common anomalies in extra-nodal MZBCL of MALT type include: the t(11;18)(q21;q21) / API2 - MLT fusion, having a 20-50% incidence. The translocation is associated with low-grade MALT lymphoma of the stomach and of the lung. Importantly, this translocation was associated with resistance to HP eradication therapy. the translocation t(14;18)(q32;q21)/IgH-MLT1 fusion, leading to enhanced MLT1 expression may occur in 10-20% of all MALT lymphomas. It is associated with MALT lymphoma of the liver, skin, ocular adnexa, lung and salivary gland. It was not found in MALT lymphomas of the stomach, intestine, thyroid, or breast The translocation t(1;14)(p22;q32)and/or the corresponding deregulation or rearrangement of BCL10 at 1p22 is another recurrent chromosome aberration in a minority of cases (6% by molecular genetics, including cases with BCL10 mutations and small deletions not detectable by cytogenetics) and it appears to be more frequent in high grade-MALT than in low grade MALT lymphoma. the t(3;14)/IgH-FOXP1 fusion may occur in 10% of all MALT lymphomas. It is associated with MALT lymphoma of the orbit, of the thyroid and skin, whereas it was not found in MALT lymphoma of the stomach, of the salivary gland and in other forms of MZBCL Trisomy 3 and trisomy 18 were reported in low-grade as well as high-grade MALT lymphoma. FISH studies found a 20-60% incidence for + 3, the difference being possibly accounted for by the variable sensitivity of methods adopted in different studies and by heterogeneity of patient populations. At the present time, there is no evidence that +3 plays an important role in disease progression. Trisomy 18 was observed more frequently in high grade MALT than in low grade MALT lymphomas. The most common anomalies in splenic MZBCL include: 7q deletions or unbalanced 7q translocations, usually involving a relatively large segment, centred around the 7q22-q32 region. The incidence is 10-30%, but as many as 40% of the cases may harbour a sub-microscopic deletion of this region. The commonly deleted segment spans a region between 7q32.1 to 7q32-3. total or partial trisomy 3, involving the 3q21-23 and 3q25-29 chromosome regions. The incidence of +3q falls in the 30-50% range total or partial trisomy 12, found in 20-30% of the cases 17p- involving the p53 gene, found in 10-30% of the cases. This aberration is associated with a more aggressive clinical course. A recurrent translocation t(11;14)(p11;q32) was found in a minority of cases featuring a relatively aggressive disease with PB involvement by a blast-like cell component. The classical t(11;14)(q13;q32) was found in some cases of splenic lymphoma with villous lymphocytes (Oscier et al, 1993), but more recent studies did not detect this translocation in histologically documented splenic MZBCL. Nodal MZBCL At the present time there is insufficient data to establish whether nodal MZBCL has a distinct cytogenetic profile. Trisomy 12 may be more frequent in nodal MZBCL, but there is evidence that this disease subset may share clinicopathologic and cytogenetic features with other forms of MZBCL. In the 3 principal clinicopathological subsets of MZBCL, BCL6 rearrangements were documented to occur in a minority of cases, especially in the presence of a high-grade component.

Probes

The most frequently occurring DNA gains or losses which can be studied by interphase/metaphase fluorescence in situ hybridisation (FISH) are the following: Deletions: a 5cM segment at 7q31, defined by the D7S685 and D7S514 markers; 17p/p53 Total/partial trisomies: 3q21-23; 3q25-29; 5q13-15; 12q15-21 BCL6 rearrangements and the API2-MLT fusion, encoded on the derivative chromosome 11 resulting form the t(11;18)(q21;q21), can be studied by FISH as well as by molecular genetic methods IgH-FOXP1 and IgH-MLT1 fusions can be studied by FISH BCL10 rearrangements associated with the t(1;14) can be detected by Southern blotting, whereas mutations or small deletion not associated with the t(1;14) can be studied by PCR-SSCP analysis and gene sequencing

Genes involved and Proteins

Note

Oncogenesis: MALT1 overexpression and API2-MALT fusion confer constitutional NFkB activity. This, in turn, leads to enhanced proliferation and resistance to apoptosis by B lymphocytes. BCL10 has a pro-apoptotic action on cell lines. However, it functions in conjunction with intracellular proteins (Carma1 and MALT1), producing the ubiquitination of NFkB inhibitor, leading to NFkB activation. These findings, along with the documented role of BCL10 in promoting survival of antigen-stimulated lymphocytes, suggest that IgH/BCL10 translocation may contribute to lymphomagenesis by enhancing BCL10 function. P53 is a key tumour suppressor gene having an established role in disease progression in a number of hematologic and extra-hematologic neoplasias, including MZBCL.

Bibliography

Cytogenetic studies in splenic lymphoma with villous lymphocytes.

Oscier DG, Matutes E, Gardiner A, Glide S, Mould S, Brito-Babapulle V, Ellis J, Catovsky D

British journal of haematology. 1993 ; 85 (3) : 487-491.

PMID 8136270

p53 in hematologic malignancies.

Imamura J, Miyoshi I, Koeffler HP

Blood. 1994 ; 84 (8) : 2412-2421.

PMID 7919360

A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group.

Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, Delsol G, De Wolf-Peeters C, Falini B, Gatter KC

Blood. 1994 ; 84 (5) : 1361-1392.

PMID 8068936

Characteristic pattern of chromosomal gains and losses in marginal zone B cell lymphoma detected by comparative genomic hybridization.

Dierlamm J, Rosenberg C, Stul M, Pittaluga S, Wlodarska I, Michaux L, Dehaen M, Verhoef G, Thomas J, de Kelver W, Bakker-Schut T, Cassiman JJ, Raap AK, De Wolf-Peeters C, Van den Berghe H, Hagemeijer A

Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1997 ; 11 (5) : 747-758.

PMID 9180302

BCL6 gene rearrangements also occur in marginal zone B-cell lymphoma.

Dierlamm J, Pittaluga S, Stul M, Wlodarska I, Michaux L, Thomas J, Verhoef G, Verhest A, Depardieu C, Cassiman JJ, Hagemeijer A, De Wolf-Peeters C, Van den Berghe H

British journal of haematology. 1997 ; 98 (3) : 719-725.

PMID 9332330

The t(11;18)(q21;q21) chromosome translocation is a frequent and specific aberration in low-grade but not high-grade malignant non-Hodgkin's lymphomas of the mucosa-associated lymphoid tissue (MALT-) type.

Ott G, Katzenberger T, Greiner A, Kalla J, Rosenwald A, Heinrich U, Ott MM, Mˆşller-Hermelink HK

Cancer research. 1997 ; 57 (18) : 3944-3948.

PMID 9307277

A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project.

Blood. 1997 ; 89 (11) : 3909-3918.

PMID 9166827

B-cell lymphoma of MALT type: a review with special emphasis on diagnostic and management problems of low-grade gastric tumours.

Zucca E, Roggero E, Pileri S

British journal of haematology. 1998 ; 100 (1) : 3-14.

PMID 9450784

The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with mucosa-associated lymphoid tissue lymphomas.

Dierlamm J, Baens M, Wlodarska I, Stefanova-Ouzounova M, Hernandez JM, Hossfeld DK, De Wolf-Peeters C, Hagemeijer A, Van den Berghe H, Marynen P

Blood. 1999 ; 93 (11) : 3601-3609.

PMID 10339464

Frequent mutation of bcl-6 proto-oncogene in high grade, but not low grade, MALT lymphomas of the gastrointestinal tract.

Gaidano G, Capello D, Gloghini A, Fassone L, Vivenza D, Ariatti C, Migliazza A, Saglio G, Carbone A

Haematologica. 1999 ; 84 (7) : 582-588.

PMID 10406897

World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997.

Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD

Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1999 ; 17 (12) : 3835-3849.

PMID 10577857

Gastric low-grade MALT lymphoma, high-grade MALT lymphoma and diffuse large B cell lymphoma show different frequencies of trisomy.

Hoeve MA, Gisbertz IA, Schouten HC, Schuuring E, Bot FJ, Hermans J, Hopman A, Kluin PM, Arends JW, van Krieken JH

Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1999 ; 13 (5) : 799-807.

PMID 10374886

7q31-32 allelic loss is a frequent finding in splenic marginal zone lymphoma.

Mateo M, Mollejo M, Villuendas R, Algara P, Sanchez-Beato M, Martˆ‚nez P, Piris MA

The American journal of pathology. 1999 ; 154 (5) : 1583-1589.

PMID 10329610

Marginal zone B-cell lymphoma: A clinical comparison of nodal and mucosa-associated lymphoid tissue types. Non-Hodgkin's Lymphoma Classification Project.

Nathwani BN, Anderson JR, Armitage JO, Cavalli F, Diebold J, Drachenberg MR, Harris NL, MacLennan KA, Mˆşller-Hermelink HK, Ullrich FA, Weisenburger DD

Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1999 ; 17 (8) : 2486-2492.

PMID 10561313

Translocation t(11;18) absent in early gastric marginal zone B-cell lymphoma of MALT type responding to eradication of Helicobacter pylori infection.

Alpen B, Neubauer A, Dierlamm J, Marynen P, Thiede C, Bayerdˆrfer E, Stolte M

Blood. 2000 ; 95 (12) : 4014-4015.

PMID 10939796

Detection of t(11;18)(q21;q21) by interphase fluorescence in situ hybridization using API2 and MLT specific probes.

Dierlamm J, Baens M, Stefanova-Ouzounova M, Hinz K, Wlodarska I, Maes B, Steyls A, Driessen A, Verhoef G, Gaulard P, Hagemeijer A, Hossfeld DK, De Wolf-Peeters C, Marynen P

Blood. 2000 ; 96 (6) : 2215-2218.

PMID 10979968

BCL10 gene mutation in lymphoma.

Du MQ, Peng H, Liu H, Hamoudi RA, Diss TC, Willis TG, Ye H, Dogan A, Wotherspoon AC, Dyer MJ, Isaacson PG

Blood. 2000 ; 95 (12) : 3885-3890.

PMID 10845924

The product of the t(11;18), an API2-MLT fusion, is an almost exclusive finding in marginal zone cell lymphoma of extranodal MALT-type.

Maes B, Baens M, Marynen P, De Wolf-Peeters C

Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2000 ; 11 (5) : 521-526.

PMID 10907943

Non Hodgkin's lymphoma: Molecular features of non Hodgkin's lymphoma.

Macintyre E, Willerford D, Morris AW

Congress of the American Society of Hematology..

Molecular cytogenetic characterization of marginal zone B-cell lymphoma: correlation with clinicopathologic findings in 14 cases.

Cuneo A, Bigoni R, Roberti MG, Milani R, Agostini P, Cavazzini F, Minotto C, De Angeli C, Bardi A, Tammiso E, Negrini M, Cavazzini P, Castoldi G

Haematologica. 2001 ; 86 (1) : 64-70.

PMID 11146573

Molecular cytogenetic characterization of marginal zone B-cell lymphoma: correlation with clinicopathologic findings in 14 cases.

Cuneo A, Bigoni R, Roberti MG, Milani R, Agostini P, Cavazzini F, Minotto C, De Angeli C, Bardi A, Tammiso E, Negrini M, Cavazzini P, Castoldi G

Haematologica. 2001 ; 86 (1) : 64-70.

PMID 11146573

p53 abnormalities in splenic lymphoma with villous lymphocytes.

Gruszka-Westwood AM, Hamoudi RA, Matutes E, Tuset E, Catovsky D

Blood. 2001 ; 97 (11) : 3552-3558.

PMID 11369650

Novel genomic imbalances in B-cell splenic marginal zone lymphomas revealed by comparative genomic hybridization and cytogenetics.

Hernˆ°ndez JM, Garcˆ‚a JL, Gutiˆİrrez NC, Mollejo M, Martˆ‚nez-Climent JA, Flores T, Gonzˆ°lez MB, Piris MA, San Miguel JF

The American journal of pathology. 2001 ; 158 (5) : 1843-1850.

PMID 11337382

Resistance of t(11;18) positive gastric mucosa-associated lymphoid tissue lymphoma to Helicobacter pylori eradication therapy.

Liu H, Ruskon-Fourmestraux A, Lavergne-Slove A, Ye H, Molina T, Bouhnik Y, Hamoudi RA, Diss TC, Dogan A, Megraud F, Rambaud JC, Du MQ, Isaacson PG

Lancet. 2001 ; 357 (9249) : 39-40.

PMID 11197361

Splenic marginal zone B-cell lymphomas: two cytogenetic subtypes, one with gain of 3q and the other with loss of 7q.

Solˆİ F, Salido M, Espinet B, Garcia JL, Martinez Climent JA, Granada I, Hernˆ°ndez JM, Benet I, Piris MA, Mollejo M, Martinez P, Vallespˆ‚ T, Domingo A, Serrano S, Woessner S, Florensa L

Haematologica. 2001 ; 86 (1) : 71-77.

PMID 11146574

T(14;18)(q32;q21) involving IGH and MALT1 is a frequent chromosomal aberration in MALT lymphoma.

Streubel B, Lamprecht A, Dierlamm J, Cerroni L, Stolte M, Ott G, Raderer M, Chott A

Blood. 2003 ; 101 (6) : 2335-2339.

PMID 12406890

Primary pulmonary MALT lymphomas show frequent and heterogeneous cytogenetic abnormalities, including aneuploidy and translocations involving API2 and MALT1 and IGH and MALT1.

Remstein ED, Kurtin PJ, Einerson RR, Paternoster SF, Dewald GW

Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2004 ; 18 (1) : 156-160.

PMID 14574335

MALT1 and the API2-MALT1 fusion act between CD40 and IKK and confer NF-kappa B-dependent proliferative advantage and resistance against FAS-induced cell death in B cells.

Ho L, Davis RE, Conne B, Chappuis R, Berczy M, Mhawech P, Staudt LM, Schwaller J

Blood. 2005 ; 105 (7) : 2891-2899.

PMID 15598810

Clinical activity of rituximab in gastric marginal zone non-Hodgkin's lymphoma resistant to or not eligible for anti-Helicobacter pylori therapy.

Martinelli G, Laszlo D, Ferreri AJ, Pruneri G, Ponzoni M, Conconi A, Crosta C, Pedrinis E, Bertoni F, Calabrese L, Zucca E

Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2005 ; 23 (9) : 1979-1983.

PMID 15668468

T(3;14)(p14.1;q32) involving IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT lymphoma.

Streubel B, Vinatzer U, Lamprecht A, Raderer M, Chott A

Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2005 ; 19 (4) : 652-658.

PMID 15703784

Bcl10 can promote survival of antigen-stimulated B lymphocytes.

Tian MT, Gonzalez G, Scheer B, DeFranco AL

Blood. 2005 ; 106 (6) : 2105-2112.

PMID 15878976

Contributor(s)

Written	07-2001	Antonio Cuneo and Gianluigi Castoldi
Updated	12-2005	Antonio Cuneo and Gianluigi Castoldi

Citation

This paper should be referenced as such :

Cuneo A, Castoldi GL . Marginal Zone B-cell lymphoma. Atlas Genet Cytogenet Oncol Haematol. July 2001 . URL : http://AtlasGeneticsOncology.org/Genes/MarginalZoneBID2078.html

Cuneo A, Castoldi GL . Marginal Zone B-cell lymphoma. Atlas Genet Cytogenet Oncol Haematol. December 2005 . URL : http://AtlasGeneticsOncology.org/Genes/MarginalZoneBID2078.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Mon Aug 11 21:19:05 2008

For comments and suggestions or contributions, please contact us