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Review
. 2025 Aug 14;26(16):7843.
doi: 10.3390/ijms26167843.

CD20-Negative Large B-Cell Lymphomas: The Diagnostic Challenge of Tumors with Downregulation of Mature B-Cell Marker Expression

Magda Zanelli  1 , Maurizio Zizzo  2 , Francesca Sanguedolce  3 , Stefano Ricci  1 , Andrea Palicelli  1 , Alessandra Bisagni  1 , Valentina Fragliasso  4 , Giuseppe Broggi  5 , Serena Salzano  5 , Ioannis Boutas  6 , Nektarios Koufopoulos  6 , Ione Tamagnini  1 , Claudia Camposeo  1 , Andrea Morini  2 , Rosario Caltabiano  5 , Luca Cimino  7   8 , Massimiliano Fabozzi  2 , Paola Parente  9 , Lucia Mangone  10 , Alberto Cavazza  1 , Antonino Neri  11 , Stefano Ascani  12
Affiliations
Review

CD20-Negative Large B-Cell Lymphomas: The Diagnostic Challenge of Tumors with Downregulation of Mature B-Cell Marker Expression

Magda Zanelli et al. Int J Mol Sci. .

Abstract

CD20-negative aggressive B-cell lymphomas are a rare and heterogeneous group of lymphomas representing a diagnostic challenge for pathologists and a therapeutic issue for clinicians, because the outcome of these patients is poor with the current therapeutic approaches. CD20-negative aggressive lymphomas include plasmablastic lymphoma, primary effusion lymphoma, ALK-positive large B-cell lymphoma and HHV8-positive diffuse large B-cell lymphoma. Conditions of immunosuppression and viral infections, such as Epstein-Barr virus and Human Herpes virus 8, are associated with all of these lymphomas with the exclusion of ALK-positive large B-cell lymphoma, which occurs in immunocompetent hosts and is not associated with viral infections. Common features of these aggressive tumors are high-grade histology with immunoblastic or plasmablastic differentiation, the absence or weak expression of mature B-cell markers such as CD20 and the frequent expression of plasma cell-associated markers. The aim of this review is to highlight the diagnostic challenges associated with the group of CD20-negative aggressive B-cell lymphomas, emphasizing key morphologic and molecular features, which are critical in the diagnosis of the different entities belonging to this rare group of diseases.

Keywords: ALK-positive large B-cell lymphoma; Epstein Barr virus; HHV8-positive diffuse large B-cell lymphoma; Human Herpes virus 8; plasmablastic lymphoma; primary effusion lymphoma.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
PBL: diffuse proliferation of large cells with prominent nucleoli (hematoxylin and eosin staining, magnification 400×; original image from Prof. S. Ascani).
Figure 2
Figure 2
PBL: case showing expression of B-cell markers only in a minority of cells (CD20 immunostaining, magnification 400×; original image from Prof. S. Ascani).
Figure 3
Figure 3
PBL: expression of plasma cell-associated markers (CD138 immunostaining, magnification 200×; original image from Prof. S. Ascani).
Figure 4
Figure 4
PBL: diffuse EBV expression of neoplastic cells (EBER-ISH, magnification 200×; original image from Prof. S. Ascani).
Figure 5
Figure 5
EC-PEL: high-power view showing the cytological features of large neoplastic cells with evident nucleoli (Giemsa staining, magnification 400×; original image from Prof. S. Ascani).
Figure 6
Figure 6
EC-PEL: diffuse expression of HHV8 in the neoplastic cells (HHV8 immunostaining, magnification 200×; original image from Prof. S. Ascani).
See this image and copyright information in PMC

References

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