Mediastinal Large B-Cell Lymphoma

Background

This is a large B-cell lymphoma which occurs in the anterior mediastinum, often localized to the thymus. It is thought to arise form the B cells within the thymic medulla. Overall, it accounts for 2.4% of non-Hodgkin's lymphomas. Although when it was first described, it was thought to be another variant of a large cell lymphoma, new research has discovered unique characteristics which justify classifying it by itself.

These are tumors of young females with a median age of 37 yrs. It usually presents with the superior vena cava obstruction leading to cough and shortness of breath. Most of these tumors are bulky (>10 cm) and usually present at Stage I or II disease (66%). Only rarely (3%) does the tumor involve the bone marrow. Serum studies reveal a raised lactate dehydrogenase in 75% of cases and rare elevations of beta-2-microglobulin.

These tumors usually do not respond as well to conventional chemotherapy such as CHOP and are better treated with intensive multiagent chemotherapy or conventional chemotherapy with consolidation radiation treatment. The complete remission rate is 80% and the 5 year survival rate is 50-60%, similar to conventional large B-cell lymphomas. These tumors have a tendency to spread to sites which are not commonly involved by lymphoma, including the ovaries, kidneys, adrenals, and intestines.

Genetic analysis have revealed distinct chromosomal translocations, providing the most compelling evidence that this is a distinct entity.

Under the microscope, this tumor exhibits the usual features of a large cell lymphoma. Some identifying characteristics can be found, however. Immunohistochemical analysis reveals additional unique features.

PATHOGENESIS CHARACTERIZATION

bcl-6 gene rearrangement Rearrangement found in only 4-6% of cases
Conventional lymphomas have 35%

bcl-6 gene mutations
Uncommon
10% vs. 50% for conventional cases

bcl-2 gene No rearrangements
20-30% for conventional cases

MAL gene Overexpression

MAL Expression in Lymphoid Cells: Further Evidence for MAL as a Distinct Molecular Marker of Primary Mediastinal Large B-Cell Lymphomas.

Copie-Bergman C, Plonquet A, Alonso MA, Boulland ML, Marquet J, Divine M, Moller P, Leroy K, Gaulard P.

Departement de Pathologie, Service d'Immunologie Biologique, Service d'Hematologie Clinique, Hopital Henri Mondor, Creteil, France.

Mod Pathol 2002 Nov;15(11):1172-80 Abstract quote
The MAL mRNA was initially identified during T-cell development and was later found in myelin-forming cells and certain polarized epithelial cell lines. It encodes a proteolipid believed to participate in membrane microdomains stabilization, transport machinery and signal transduction. Using a differential display reverse-transcription approach, we identified MAL as a distinct molecular marker of primary mediastinal large B-cell lymphoma compared with nonmediastinal diffuse large B-cell lymphomas.

In the present study, we used immunohistochemistry to extend MAL expression analysis to normal lymphoid tissues; to 185 lymphomas representing most B, T, and Hodgkin lymphoma entities; and to the primary mediastinal large B-cell lymphoma derived B-cell line MedB-1. In addition, B and T cells from peripheral blood, tonsil, and spleen were analyzed by flow cytometry.

Our results show that MAL is highly expressed in thymocytes, in a large percentage of peripheral CD4 T cells, and in a lower proportion of CD8 peripheral T cells. In the normal B-cell compartment, MAL expression appears to be restricted to a minor subpopulation of thymic medullary B cells and to occasional mature plasma cells located in the interfollicular areas of tonsil and lymph nodes.

Among B-cell lymphomas (n = 110), MAL expression in tumor cells was observed in 21/33 primary mediastinal large B-cell lymphomas (70%) and in 3/5 plasmacytoma/myeloma, but not in all other B-cell lymphomas with the exception of 1/33 nonmediastinal diffuse large B-cell lymphomas. The MedB-1 B-cell line was also MAL positive. Among T-cell neoplasms, MAL was highly expressed in lymphoblastic tumors (5/6), whereas mature T-cell lymphomas were essentially MAL negative (27/28). Among 41 Hodgkin lymphomas, 3 nodular-sclerosing cases with mediastinal involvement showed MAL-positive Reed Sternberg cells.

In conclusion, this study further supports thymic B cells as the putative normal counterpart of primary mediastinal large B-cell lymphomas and supports MAL as a distinct molecular marker of this lymphoma subtype among diffuse large B-cell lymphomas.

HISTOPATHOLOGY CHARACTERIZATION

Clear cells 40% of cases
Rare in conventional large B-cell lymphomas

Sclerosis Frequent resulting in compartmentalization

Residual islands of thymus May show reactive proliferation or undergo cystic change

IMMUNOHISTOCHEMISTRY AND SPECIAL STAINS CHARACTERIZATION

Surface Immunoglobulin (sIg) Usually lacks expression although there is expression of Ig associated CD79 molecule

Bcl-6 protein Usually positive
>50% positive in conventional large B-cell lymphomas

HLA expression Abnormal

Expression of bcl-6 and CD10 in Primary Mediastinal Large B-Cell Lymphoma Evidence for Derivation From Germinal Center B Cells?

Laurence de Leval, M.D., Ph.D.; Judith A. Ferry, M.D.; Brunangelo Falini, M.D.; Margaret Shipp, M.D.; Nancy Lee Harris, M.D.

From the Departments of Pathology (L.d.L., J.F., N.L.H.), Massachusetts General Hospital, Boston, Massachusetts; the University of Perugia, Italy (B.F.); and the Department of Adult Oncology (M.S.), Dana Farber Cancer Institute, Boston, Massachusetts, U.S.A. L.d.L. is currently affiliated with the Department of Pathology, University of Li�ge, Belgium.

Am J Surg Pathol 2001;25:1277-1282 Abstract quote

Primary mediastinal large B-cell lymphomas (LBCLs) constitute a unique subtype of diffuse LBCLs, with distinct clinical, immunophenotypic, and morphologic features. These lymphomas are thought to originate from the thymus, and it has been hypothesized that they derive from a population of B lymphocytes normally present in the thymic medulla. Most diffuse LBCLs harbor somatic mutations in their immunoglobulin genes, suggesting that they have been exposed to the germinal center.

To investigate the possible relationship of mediastinal LBCLs to germinal center B cells, we analyzed the expression of bcl-6 and CD10 in 19 mediastinal LBCLs, using an immunoperoxidase technique on formalin-fixed tissue.

We found that 19 of 19 (100%) mediastinal LBCLs were bcl-6+ and 6 of 19 (32%) mediastinal LBCLs were CD10+. Because mediastinal LBCLs usually lack BCL-6 gene rearrangement or mutations, expression of bcl-6 and CD10 in these tumors tends to support a germinal center derivation.

Blood 1999;94:3567-3575

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Last Updated 12/12/2002

PATHOGENESIS	CHARACTERIZATION
bcl-6 gene rearrangement	Rearrangement found in only 4-6% of cases Conventional lymphomas have 35%
bcl-6 gene mutations	Uncommon 10% vs. 50% for conventional cases
bcl-2 gene	No rearrangements 20-30% for conventional cases
MAL gene	Overexpression
MAL Expression in Lymphoid Cells: Further Evidence for MAL as a Distinct Molecular Marker of Primary Mediastinal Large B-Cell Lymphomas. Copie-Bergman C, Plonquet A, Alonso MA, Boulland ML, Marquet J, Divine M, Moller P, Leroy K, Gaulard P. Departement de Pathologie, Service d'Immunologie Biologique, Service d'Hematologie Clinique, Hopital Henri Mondor, Creteil, France.	Mod Pathol 2002 Nov;15(11):1172-80 Abstract quote The MAL mRNA was initially identified during T-cell development and was later found in myelin-forming cells and certain polarized epithelial cell lines. It encodes a proteolipid believed to participate in membrane microdomains stabilization, transport machinery and signal transduction. Using a differential display reverse-transcription approach, we identified MAL as a distinct molecular marker of primary mediastinal large B-cell lymphoma compared with nonmediastinal diffuse large B-cell lymphomas. In the present study, we used immunohistochemistry to extend MAL expression analysis to normal lymphoid tissues; to 185 lymphomas representing most B, T, and Hodgkin lymphoma entities; and to the primary mediastinal large B-cell lymphoma derived B-cell line MedB-1. In addition, B and T cells from peripheral blood, tonsil, and spleen were analyzed by flow cytometry. Our results show that MAL is highly expressed in thymocytes, in a large percentage of peripheral CD4 T cells, and in a lower proportion of CD8 peripheral T cells. In the normal B-cell compartment, MAL expression appears to be restricted to a minor subpopulation of thymic medullary B cells and to occasional mature plasma cells located in the interfollicular areas of tonsil and lymph nodes. Among B-cell lymphomas (n = 110), MAL expression in tumor cells was observed in 21/33 primary mediastinal large B-cell lymphomas (70%) and in 3/5 plasmacytoma/myeloma, but not in all other B-cell lymphomas with the exception of 1/33 nonmediastinal diffuse large B-cell lymphomas. The MedB-1 B-cell line was also MAL positive. Among T-cell neoplasms, MAL was highly expressed in lymphoblastic tumors (5/6), whereas mature T-cell lymphomas were essentially MAL negative (27/28). Among 41 Hodgkin lymphomas, 3 nodular-sclerosing cases with mediastinal involvement showed MAL-positive Reed Sternberg cells. In conclusion, this study further supports thymic B cells as the putative normal counterpart of primary mediastinal large B-cell lymphomas and supports MAL as a distinct molecular marker of this lymphoma subtype among diffuse large B-cell lymphomas.

HISTOPATHOLOGY	CHARACTERIZATION
Clear cells	40% of cases Rare in conventional large B-cell lymphomas
Sclerosis	Frequent resulting in compartmentalization
Residual islands of thymus	May show reactive proliferation or undergo cystic change

IMMUNOHISTOCHEMISTRY AND SPECIAL STAINS	CHARACTERIZATION
Surface Immunoglobulin (sIg)	Usually lacks expression although there is expression of Ig associated CD79 molecule
Bcl-6 protein	Usually positive >50% positive in conventional large B-cell lymphomas
HLA expression	Abnormal
Expression of bcl-6 and CD10 in Primary Mediastinal Large B-Cell Lymphoma Evidence for Derivation From Germinal Center B Cells? Laurence de Leval, M.D., Ph.D.; Judith A. Ferry, M.D.; Brunangelo Falini, M.D.; Margaret Shipp, M.D.; Nancy Lee Harris, M.D. From the Departments of Pathology (L.d.L., J.F., N.L.H.), Massachusetts General Hospital, Boston, Massachusetts; the University of Perugia, Italy (B.F.); and the Department of Adult Oncology (M.S.), Dana Farber Cancer Institute, Boston, Massachusetts, U.S.A. L.d.L. is currently affiliated with the Department of Pathology, University of Li�ge, Belgium.	Am J Surg Pathol 2001;25:1277-1282 Abstract quote Primary mediastinal large B-cell lymphomas (LBCLs) constitute a unique subtype of diffuse LBCLs, with distinct clinical, immunophenotypic, and morphologic features. These lymphomas are thought to originate from the thymus, and it has been hypothesized that they derive from a population of B lymphocytes normally present in the thymic medulla. Most diffuse LBCLs harbor somatic mutations in their immunoglobulin genes, suggesting that they have been exposed to the germinal center. To investigate the possible relationship of mediastinal LBCLs to germinal center B cells, we analyzed the expression of bcl-6 and CD10 in 19 mediastinal LBCLs, using an immunoperoxidase technique on formalin-fixed tissue. We found that 19 of 19 (100%) mediastinal LBCLs were bcl-6+ and 6 of 19 (32%) mediastinal LBCLs were CD10+. Because mediastinal LBCLs usually lack BCL-6 gene rearrangement or mutations, expression of bcl-6 and CD10 in these tumors tends to support a germinal center derivation.