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EBV positive DLBCL, NOS

Written2018-07Ding-Bao Chen
Department of Pathology, Peking University People's Hospital, Beijing 100044, People's Republic of China;

Abstract Epstein-Barr virus positive DLBCL, NOS (EBV + DLBCL, NOS) occurs in apparently immunocompetent patients usually older than 50 years, which can also occur in younger patients and has a worse prognosis than EBV negative tumors. EBV + DLBCL, NOS has a broader morphological spectrum. Here the clinicopathological of EBV positive DLBCL will be discussed.

Keywords EBV positive DLBCL; immunophenotype; Cytogenetics

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ICD-Topo C420,C421,C424
ICD-Morpho 9680/3 Diffuse large B-cell lymphoma (DLBCL), NOS; Primary DLBCL of the CNS; Primary cutaneous DLBCL, leg type; EBV positive DLBCL of the elderly; DLBCL associated with chronic inflammation; B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma
Atlas_Id 1834
Other namesSenile EBV-associated B-cell lymphoproliferative disorder; age-related EBV+ lymphoproliferative disorder; EBV-associated B-cell lymphoproliferative disorder of the elderly.

Clinics and Pathology

Disease EBV+ diffuse large B-cell lymphoma (DLBCL), NOS was initially described by Oyama et al in 2003 (Oyama et al,2003). The 2008 monograph included "EBV-positive DLBCL of the elderly" as a provisional entity. These tumors occur in apparently immunocompetent patients usually older than 50 years and have a worse prognosis than EBV negative tumors. But EBV+ DLBCL have been increasingly recognized in younger patients, with a broader morphological spectrum and better survival than initially thought. This new information has led to substitution of the modifier "elderly" with "not otherwise specified" (EBV+ DLBCL, NOS) in the updated classification (Swerdlow, et al ,2008. Swerdlow, et al, 2016. Nicolae A, et al, 2015. Uccini S, et al, 2015. Ok CY, et al. 2013).
Phenotype / cell stem origin The neoplastic cells are of B-cell lineage, expressing the pan B-cell antigens CD19, CD20, CD22, CD79a, and PAX5 and are negative for pan T-cell antigents. Immunoglobulin light chain restriction may be difficult to demonstrate, except in cases with immunoblastic or plasmablastic features in which cytoplasmic Ig can be assessed. Plasmacytoid cases can be weakly positive or negative CD20. EBV+ DLBCL of the elderly usually has an ABC immunophenotype being MUM1/IRF41 and CD102 and usually BCL6. BCL-2 and CD30 are usually positive, and CD15 is negative. It is speculated that either there is a change in B-cell population during aging or there is putative pathological specificity of EBV in elderly patients with DLBCL. Most cases displayed a striking shift to an ABC immunophenotype with prominent activation of NF-kB pathway (Swerdlow, et al ,2008. Swerdlow, et al ,2016).
Epidemiology The median age of patients with EBV+ DLBCL is 71 years (range, 50-91 years), however, younger patients can be affected. There is a slight male predominance, with a male to female ratio of 1.4 :1. There is a higher prevalence of EBV+ DLBCL among East Asians (8.7%-11.4%) compared with 5% in Western countries. The definitive criterion for EBV positivity in EBV+ DLBCL remains under discussion (Swerdlow, et al ,2008).
Clinics EBV+ DLBCL is characterized by higher age distribution and an aggressive clinical course with a median survival of 2 years in Asian patients. Initial reports emphasized that EBV+ DLBCL of the elderly commonly involved extranodal sites. Site of primary extranodal involvement include the skin, soft tissue, bones, nasal cavity, pharynx/hypopharynx, tonsils, tongue, lung, pleura, stomach, liver, spleen, peritoneum, cecum, and bone marrow. Patients with EBV+ DLBCL of the elderly have a poorer overall survival and progression-free survival than patients with Activated B-cell-like (ABC) -type EBV-negative DLBCL in older European patients (Swerdlow, et al ,2008).
Pathology Two morphologic subtypes of EBV+ DLBCL have been recognized: polymorphic and monomorphic. Both subtypes may include large transformed cells or immunoblasts, as well as HRS-like giant cells and may demonstrate increased mitotic activity and areas of geographic necrosis.
The polymorphic subtype displays a broad range of B-cell maturation, and lesions are composed of centroblasts, immunoblasts, and plasmablasts with a variable component of admixed reactive cells, including small lymphocytes, plasma cells, histiocytes, and epithelioid histiocytes.
The monomorphic subtype of EBV+ DLBCL of the elderly is composed of monotonous sheets of large transformed B cells. Cases of EBV+ DLBCL of the elderly also can have a mixed pattern with intermingled polymorphic/and monomorphic areas, suggesting that the subtypes represent 2 ends of a morphologic spectrum.
Figure1. EBV+ DLBCL, polymorphic subtype. A broad range of B-cell maturation, composed of centroblasts, immunoblasts, and plasmablasts with a variable component of admixed reactive cells (HE staining).
Figure 2. EBV+ DLBCL, monomorphic subtype. Sheets of large transformed B cells HE staining).
Figure 3. The lymphoid cells are positive for CD20.
Figure 4. The lymphoid cells are positive for EBER (In situ hybridization).
Treatment EBV+ DLBCLs, including EBV+DLBCL of the elderly, respond more poorly to treatment with a poorer outcome compared with patients who have EBV-negative DLBCL. Novel therapeutic approaches need to be considered for patients with EBV+ DLBCL. Possible therapeutic approaches include (1) EBV-specific adoptive immunotherapy; (2) miRNA-targeted therapy; (3) combination therapy based on EBV lytic phase induction followed by exposure of the tumor cells to antiherpsvirus drugs (Swerdlow, et al ,2008. Swerdlow, et al ,2016). Less toxic treatment strategy such as a cell therapy for EBV-specific viral antigens will be needed and should be evaluated in clinical trials (Oyama T, et al, 2007).
Prognosis Young patients present with nodal disease and have a good prognosis (Nicolae A, et al 2015). The International prognostic index (IPI) and the Oyama score can be used for risk-stratification. The Oyama score includes age >70 years and presence of B symptoms. The expression of CD30 is emerging as a potential adverse, and targetable, prognostic factor (Castillo JJ, et al. 2018).  In contrast to non-Western populations, the North American population had a low prevalence of EBV+ DLBCL that did not convey an adverse prognosis. A history of immunosuppression, while known to be a risk factor for the development of diffuse large B-cell lymphoma, did not affect subsequent prognosis (Tracy SI, et al, 2018).


Note Only a few genetic studies on cases of EBV+DLBCL have been performed. The immunoglobulin genes are monoclonally rearranged in most cases, with clonality of EBV also usually detectable using EBV terminal repeat regions probes and molecular techniques. IGH-mediated translocations are uncommon (15%). However, these analyses were restricted to single loci (IGH, IGK, IGL, PAX5, MYC, BCL2, and BCL6). Given the presence of a low number of genomic aberrations in EBV+ DLBCL, it has been suggested that immunosenescence coupled with the EBV oncogenic properties is sufficient, and additional chromosomal alterations are therefore usually not needed for lymphomagenesis.
Although viral miRNA constitutes only 2% of all miRNA in EBV-positive DLBCL, the viral miRNAs share seed sequence homology with cellular miRNA. It also becomes evident that EBV miRNAs have evolved to target multiple cellular pathways rather than a single pathway. Interestingly, cellular miRNAs are modulated by viral proteins. MIR155 has been shown in DLBCL, especially in the ABC subtype, and can be induced by PDLIM7 (LMP1) via the NF-kB pathway (Swerdlow, et al ,2008. Ok CY, et al. 2013).
A study showed that the gene expression profiling and microRNA profiles of younger patients with EBV+ DLBCL is similar to older patients (Ok CY, et al. 2015).


EBV-positive diffuse large B-cell lymphoma, not otherwise specified: 2018 update on diagnosis, risk-stratification and management
Castillo JJ, Beltran BE, Miranda RN, Young KH, Chavez JC, Sotomayor EM
Am J Hematol 2018 Jul;93(7):953-962
PMID 29984868
EBV-positive large B-cell lymphomas in young patients: a nodal lymphoma with evidence for a tolerogenic immune environment
Nicolae A, Pittaluga S, Abdullah S, Steinberg SM, Pham TA, Davies-Hill T, Xi L, Raffeld M, Jaffe ES
Blood 2015 Aug 13;126(7):863-72
PMID 25999451
EBV-positive diffuse large B-cell lymphoma of the elderly
Ok CY, Papathomas TG, Medeiros LJ, Young KH
Blood 2013 Jul 18;122(3):328-40
PMID 23649469
Age cutoff for Epstein-Barr virus-positive diffuse large B-cell lymphoma--is it necessary? Oncotarget
Ok CY, Ye Q, Li L, Manyam GC, Deng L, Goswami RR, Wang X, Montes-Moreno S, Visco C, Tzankov A, Dybkaer K, Zhang L, Abramson J, Sohani AR, Chiu A, Orazi A, Zu Y, Bhagat G, Richards KL, Hsi ED, Choi WW, van Krieken JH, Huh J, Ponzoni M, Ferreri AJ, Zhang S, Parsons BM, Xu M, Møller MB, Winter JN, Piris MA, Xu-Monette ZY, Medeiros LJ, Young KH
2015 Jun 10;6(16):13933-45 PubMed Central PMCID: PMC4546442
PMID 26101854
Senile EBV+ B-cell lymphoproliferative disorders: a clinicopathologic study of 22 patients
Oyama T, Ichimura K, Suzuki R, Suzumiya J, Ohshima K, Yatabe Y, Yokoi T, Kojima M, Kamiya Y, Taji H, Kagami Y, Ogura M, Saito H, Morishima Y, Nakamura S
Am J Surg Pathol 2003 Jan;27(1):16-26
PMID 12502924
Age-related EBV-associated B-cell lymphoproliferative disorders constitute a distinct clinicopathologic group: a study of 96 patients
Oyama T, Yamamoto K, Asano N, Oshiro A, Suzuki R, Kagami Y, Morishima Y, Takeuchi K, Izumo T, Mori S, Ohshima K, Suzumiya J, Nakamura N, Abe M, Ichimura K, Sato Y, Yoshino T, Naoe T, Shimoyama Y, Kamiya Y, Kinoshita T, Nakamura S
Clin Cancer Res 2007 Sep 1;13(17):5124-32
PMID 17785567
The 2016 revision of the World Health Organization classification of lymphoid neoplasms
Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz AD, Jaffe ES
Blood 2016 May 19;127(20):2375-90
PMID 26980727
Outcomes among North American patients with diffuse large B-cell lymphoma are independent of tumor Epstein-Barr virus positivity or immunosuppression
Tracy SI, Habermann TM, Feldman AL, Maurer MJ, Dogan A, Perepu US, Syrbu S, Ansell SM, Thompson CA, Weiner GJ, Nowakowski GS, Allmer C, Slager SL, Witzig TE, Cerhan JR, Link BK
Haematologica 2018 Feb;103(2):297-303
PMID 29170255
Epstein-Barr virus-positive diffuse large B-cell lymphoma in children: a disease reminiscent of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly
Uccini S, Al-Jadiry MF, Scarpino S, Ferraro D, Alsaadawi AR, Al-Darraji AF, Moleti ML, Testi AM, Al-Hadad SA, Ruco L
Hum Pathol 2015 May;46(5):716-24
PMID 25704629


This paper should be referenced as such :
Ding-Bao Chen
EBV positive DLBCL, NOS
Atlas Genet Cytogenet Oncol Haematol. 2019;23(5):120-123.
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