Haematologica, Vol 93, Issue 1, 145-146 doi:10.3324/haematol.11927
Copyright © 2008 by Ferrata Storti Foundation
Hongtao Ye1 ,
Ellen D. Remstein2 ,
Chris M. Bacon1 ,
Andrew G. Nicholson3 ,
Ahmet Dogan2 ,
Ming-Qing Du1,
Chromosomal translocations involving BCL6 were detected in 7 out of 392 cases of MALT lymphoma by interphase fluorescence in situ hybridisation with a BCL6 break-apart probe. With the exception of BCL6 protein expression in 2 of the 7 cases, these BCL6 translocation-positive MALT lymphomas were histologically and immunophenotypically identical to classic cases.
BCL6 immunohistochemistry was performed in all BCL6 translocation-positive cases and was successful in each case as shown by nuclear staining of lymphocytes in reactive germinal centres. However, only 2 of the 7 cases showed BCL6 staining in MALT lymphoma cells. One case (case #1) showed moderately intense nuclear BCL6 staining in a minority of MALT lymphoma cells but, interestingly, showed strong positivity in lymphoma cells in and around lymphoepithelial lesions (Figure 1). The other case (case #3) displayed weak BCL6 staining in approximately 50% of lymphoma cells. None of the remaining 5 cases showed any BCL6 immunostaining in MALT lymphoma cells. Irrespective of BCL6 expression, all 7 cases were negative for the germinal centre marker CD10.
Funding: the Du lab is supported by research grants from Leukaemia Research Fund, UK. CB is supported by a Senior Clinician Scientist Fellowship from The Health Foundation, The Royal College of Pathologists and The Pathological Society of Great Britain and Ireland.
Copyright © 2008 by Ferrata Storti Foundation
Malignant Lymphomas |
Chromosomal translocations involving BCL6 in MALT lymphoma
1 Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, United Kingdom
2 Divisions of Anatomic Pathology and Hematopathology, Mayo Clinic, Rochester, USA
3 Department of Histopathology, Royal Brompton Hospital, London, United Kingdom
Correspondence: Ming-Qing Du, Professor of Oncological Pathology, Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Box 231, Level 3, Lab block, Addenbrooke’s Hospital Hills Road, Cambridge CB2 0QQ, United Kingdom. Tel: +44.1223.767092. Fax: +44.1223. 586670. Email: mqd20{at}cam.ac.uk
ABSTRACT
 TOP ABSTRACT References |
|---|
Chromosomal translocations involving BCL6 were detected in 7 out of 392 cases of MALT lymphoma by interphase fluorescence in situ hybridisation with a BCL6 break-apart probe. With the exception of BCL6 protein expression in 2 of the 7 cases, these BCL6 translocation-positive MALT lymphomas were histologically and immunophenotypically identical to classic cases.
Deregulation of BCL6 expression by chromosome translocation and somatic mutation of its 5’ non-coding region is one of the most common molecular events in B-cell lymphomagenesis. BCL6 translocations involve not only immunoglobulin genes but also a number of non-immunoglobulin gene loci, and can occur either as a primary or secondary genetic event, largely depending on the lymphoma subtypes. These translocations bring the coding region of BCL6 under the transcriptional control of the heterologous promoters and enhancer elements of its translocation partner genes. BCL6 translocations are frequently seen in nodal diffuse large B-cell lymphomas (DLBCL) and in grade 3 follicular lymphomas.1,2 At extranodal sites, BCL6 translocations have been reported in 50% of gastric DLBCL with a residual MALT lymphoma.3 Such translocations have also been reported in a few cases of MALT lymphoma/marginal B cell lymphoma of the stomach,4 small intestine,5 Waldeyer’s ring, and liver.6 However, the true incidence of BCL6 translocation in MALT lymphoma of various sites is unknown. We investigated the presence of BCL6 translocations in 392 cases of MALT lymphoma of the stomach (n=135), lung (n=80), salivary gland (n=63), ocular adnexa (n=57), skin (n=27), thyroid (n=15), liver (n=6) and intestine (n=9), using interphase fluorescence in situ hybridization (FISH) on formalin-fixed paraffin-embedded whole tissue sections (306 cases) or tissue microarray slides (86 cases). All cases were screened using a BCL6 dual-colour break-apart probe (Abbott Laboratories Ltd, Maidenhead, United Kingdom). The positive cases were further examined for chromosome translocations involving some or all of the IGH, MALT1, BCL10 and BCL2 loci using the respective dual-colour break-apart probes, and for IGH-BCL6 translocations using an in-house dual-color fusion probe. The cases positive for BCL6 translocation were subjected to thorough review of histology and immunophenotype.
Seven cases (1.8%) with typical histologic and immunophenotypic features of MALT lymphoma were found to harbour a BCL6-involved chromosome translocation (Supplement table 1, Figure 1). These cases arose at various extranodal sites and none showed evidence of transformation. Of these BCL6 translocation-positive cases, 4 (cases 2, 5–7) showed evidence of a breakage at the IGH locus and further FISH with a dual-colour fusion probe confirmed IGH-BCL6 fusion, suggesting the presence of a t(3;14)(q27;q32). Long distance PCR for the IGH-BCL6 genomic fusion was performed in case 5 where high molecular weight DNA was available,7 and the results showed that BCL6 was fused to the IGH switch region. None of the 6 cases examined showed evidence of chromosome translocations involving the MALT1 locus. Bcl10 immunohistochemistry was carried out in 6 cases and none of them showed the strong nuclear positivity seen in cases harbouring a BCL10 translocation. The remaining case showed no evidence of a BCL10 translocation by FISH (Supplement table 1).
 View larger version (78K): [in a new window] [Download PPT slide] |
Figure 1. All cases showed the typical morphologic features of MALT lymphoma. Low and high power views of case 6 (A, thyroid) and case 7 (B, lung) are shown. All cases showed a BCL6 translocation by interphase FISH using a BCL6 break-apart probe (C). Case 1 (stomach) contained BCL6-positive, CD10-negative MALT lymphoma cells, particularly around lymphoepithelial lesions (D, H&E; E, BCL6 immunostaining; F, CD10).
|
The present study provides further evidence for the existence, although rare, of BCL6 translocations in MALT lymphomas. Based on the cases studied here, the BCL6 translocation-positive MALT lymphomas are indistinguishable from classic MALT lymphomas on both histologic and immunophenotypic grounds with the exception of BCL6 expression, which may be positive in cases with BCL6 translocation. The finding of a lack of BCL6 expression by immunohistochemistry in 5/7 cases of BCL6 translocation-positive MALT lymphoma is intriguing. However, negative BCL6 immunostaining has been well described in DLBCL and grade 3 follicular lymphomas carrying a BCL6 translocation.2,8,9 The reason for this is unclear. It is possible that in such cases the level of BCL6 protein expression is below the threshold detectable by immunohistochemistry, but studies have also shown a lack of correlation between BCL6 mRNA levels and BCL6 translocation status in such cases.10
Given that BCL6 is a protein of germinal centre B cells and is commonly expressed in germinal centre-derived lymphomas, it is interesting to find BCL6 translocations in MALT lymphomas, which originate from the post-germinal centre marginal zone B cells of acquired MALT. However, neither BCL6 translocation nor BCL6 protein expression is associated exclusively with lymphomas with a germinal centre B cell phenotype. For example, both are found frequently in activated B cell-like DLBCL, which show features of post-germinal centre B-cells, often undergoing plasmacytic differentiation.11 The finding of BCL6 translocations in different lymphoma subtypes deriving from B-cells at various stages of maturation is in keeping with the diverse functions of BCL6 during B cell development and differentiation. BCL6, a nuclear transcriptional repressor, plays important roles in regulating the differentiation, survival, proliferation and genetic stability of B-cells. Through these properties, in combination with the effects of other genetic changes, BCL6 is believed to contribute to lymphoma development.
Footnotes
Funding: the Du lab is supported by research grants from Leukaemia Research Fund, UK. CB is supported by a Senior Clinician Scientist Fellowship from The Health Foundation, The Royal College of Pathologists and The Pathological Society of Great Britain and Ireland.
References
|
TOPABSTRACTReferences |
|---|
- Katzenberger T, Ott G, Klein T, Kalla J, Muller-Hermelink HK, Ott MM. Cytogenetic alterations affecting BCL6 are predominantly found in follicular lymphomas grade 3B with a diffuse large B-cell component. Am J Pathol 2004;165:481-90.
[Abstract/Free Full Text] - Guo Y, Karube K, Kawano R, Yamaguchi T, Suzumiya J, Huang GS, et al. Low-grade follicular lymphoma with t(14;18) presents a homogeneous disease entity otherwise the rest comprises minor groups of heterogeneous disease entities with BCL2 amplification, BCL6 translocation or other gene aberrances. Leukemia 2005;19:1058-63.[CrossRef][Web of Science][Medline]
- Chen YW, Hu XT, Liang AC, Au WY, So CC, Wong ML, et al. High BCL6 expression predicts better prognosis, independent of BCL6 translocation status, translocation partner, or BCL6-deregulating mutations, in gastric lymphoma. Blood 2006;108:2373-83.
[Abstract/Free Full Text] - Chen YW, Liang AC, Au WY, Chu KM, Wong KY, Hu X, et al. Multiple BCL6 translocation partners in individual cases of gastric lymphoma. Blood 2003;102:1931-2.
[Free Full Text] - Yoshida N, Nomura K, Wakabayashi N, Konishi H, Nishida K, Taki T, et al. Cytogenetic and clinicopathological characterization by fluorescence in situ hybridization on paraffin-embedded tissue sections of twenty-six cases with malignant lymphoma of small intestine. Scand J Gastroenterol 2006;41:212-22.[CrossRef][Web of Science][Medline]
- Dierlamm J, Pittaluga S, Stul M, Wlodarska I, Michaux L, Thomas J, et al. BCL6 gene rearrangements also occur in marginal zone B-cell lymphoma. Br J Haematol 1997;98:719-25.[CrossRef][Web of Science][Medline]
- Akasaka T, Muramatsu M, Ohno H, Miura I, Tatsumi E, Fukuhara S, et al. Application of long-distance polymerase chain reaction to detection of junctional sequences created by chromosomal translocation in mature B-cell neoplasms. Blood 1996;88:985-94.
[Abstract/Free Full Text] - Skinnider BF, Horsman DE, Dupuis B, Gascoyne RD. Bcl-6 and Bcl-2 protein expression in diffuse large B-cell lymphoma and follicular lymphoma: correlation with 3q27 and 18q21 chromosomal abnormalities. Hum Pathol 1999;30:803-8.[CrossRef][Web of Science][Medline]
- Jardin F, Gaulard P, Buchonnet G, Contentin N, Lepretre S, Lenain P, et al. Follicular lymphoma without t(14;18) and with BCL6 rearrangement: a lymphoma subtype with distinct pathological, molecular and clinical characteristics. Leukemia 2002;16:2309-17.[CrossRef][Web of Science][Medline]
- Jardin F, Buchonnet G, Parmentier F, Contentin N, Lepretre S, Lenain P, et al. Follicle center lymphoma is associated with significantly elevated levels of BCL-6 expression among lymphoma subtypes, independent of chromosome 3q27 rearrangements. Leukemia 2002;16:2318-25.[CrossRef][Web of Science][Medline]
- Lenz G, Nagel I, Siebert R, Roschke AV, Sanger W, Wright GW, et al. Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma. J Exp Med 2007;204:633-43.
[Abstract/Free Full Text]
This article has been cited by other articles:
 |
|
 |
|
  L. D. Sjo, S. Heegaard, J. U. Prause, B. L. Petersen, S. Pedersen, and E. Ralfkiaer Extranodal Marginal Zone Lymphoma in the Ocular Region: Clinical, Immunophenotypical, and Cytogenetical Characteristics Invest. Ophthalmol. Vis. Sci., February 1, 2009; 50(2): 516 - 522. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||