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  Table of Contents    
LETTER TO EDITOR  
Year : 2022  |  Volume : 65  |  Issue : 3  |  Page : 739-741
EBV positive diffuse large B-cell lymphoma, NOS in a patient of Crohn's disease treated with immunomodulator


1 Department of Pathology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, New Delhi, India
2 Department of molecular Pathology, Scientist, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
3 Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, New Delhi, India
4 Department of Radiodiagnosis, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, New Delhi, India

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Date of Submission20-Sep-2020
Date of Decision14-Feb-2021
Date of Acceptance17-Jun-2021
Date of Web Publication26-May-2022
 

How to cite this article:
Patnaik N, Pasricha S, Gupta G, Durga G, Sharma SK, Sharma A, Kamboj M, Goel V, Jajodia A, Mehta A. EBV positive diffuse large B-cell lymphoma, NOS in a patient of Crohn's disease treated with immunomodulator. Indian J Pathol Microbiol 2022;65:739-41

How to cite this URL:
Patnaik N, Pasricha S, Gupta G, Durga G, Sharma SK, Sharma A, Kamboj M, Goel V, Jajodia A, Mehta A. EBV positive diffuse large B-cell lymphoma, NOS in a patient of Crohn's disease treated with immunomodulator. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 Aug 15];65:739-41. Available from: https://www.ijpmonline.org/text.asp?2022/65/3/739/345852




Dear Editor,

Epstein-Barr virus (EBV) positive diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS), is a rare subtype of lymphoma which is associated with poor prognosis. Besides nodal involvement, this subtype is also associated with higher rates of extra-nodal involvement of the gastrointestinal tract, skin, and bone marrow, being the most commonly affected site.[1] The increased risk of lymphoma after solid organ transplant and in patients of rheumatoid arthritis with or without treatment with immunosuppressive therapy is well known; however, there is growing evidence from the prevailing literature that patients of inflammatory bowel disease (IBD) treated with immunomodulatory drugs are also associated with moderate risk of development of lymphoma.[2] Here we report one such case of EBV positive DLBCL-NOS in an elderly male on immunomodulatory drug for the last 3 years in a known case of Crohn's disease.

A 69-year-old man and a known case of Crohn's disease was being treated with sulfasalazine since the last 3 years. Patient had past history of renal cell carcinoma (RCC) operated 4.5 years back and no evidence of recurrence or metastasis till 4 months back when the patient underwent a PET scan (yearly follow-up) which showed multiple metabolically active lymph nodes in mesenteric region (4.3 × 3 cm, SUV 40.2) and aortocaval region (largest 1.6 × 1.2 cm) and subsequently underwent open retroperitoneal lymph node dissection.

On gross examination; mesenteric lymph node matted mass measured 5.5 × 5 × 1 cm and Aortocaval lymph node measured 5 × 4 × 1 cm. On microscopic examination, sections revealed partial effacement of nodal architecture comprising of large confluent areas showing diffuse sheets of large neoplastic lymphoid cells having vesicular chromatin, prominent nucleoli exhibiting brisk mitosis [Figure 1]. These cells were intricately admixed with tingible body macrophages along with few preserved germinal centers. Few ill-formed epithelioid cell granulomas along with significant areas of necrosis were also identified. ZN stain for AFB was negative. No evidence of metastatic RCC was seen.{Figure 1}

On Immunohistochemistry, neoplastic cells were strongly and diffusely positive for CD 20, CD10, BCL6, MUM-1 while were negative for CK, CD3, CD5, cmyc, Bcl2. MIB-1 index was 90% [Figure 2]. EBV encoded small RNA (EBER) by in situ hybridization (ISH) was strongly and diffusely positive in the large neoplastic cells [Figure 3]. CD21/CD23 highlighted the residual surrounding follicular centers and no expression was seen in confluent tumor areas. The overall features were suggestive of Non-Hodgkin Lymphoma––B-cell type, EBV positive DLBCL––NOS. EBV DNA copy number has been estimated and the result was 840 copies/mL.{Figure 2}{Figure 3}

As per the latest edition of the World Health Organization classification (revised 4th edition), EBV positive DLBCL, NOS is a separate clinicopathological entity.[3] This entity was previously called DLBCL of the elderly, but now with increasing incidence in young immunocompetent individuals, this has been renamed as EBV positive DLBCL- NOS.

EBV is a common herpesvirus that has a unique ability to evade the host immune response and exist in a latent form within B lymphocytes. Impairments in cellular immunity, occurring in the setting of concurrent infections, older age, solid organ, and hematopoietic stem cell transplantation, and immunosuppressive therapies, results in a particularly high risk of EBV reactivation and B-cell transformation leading to lymphoma of various types.[4] There are various complex mechanisms through which EBV induces B-cell transformation and proliferation. Viral gene products cause an increase in the expression of a variety of cellular antigens and genes in B cells and henceforth activate key molecular pathways of cell cycle, for example, NF-kB and virus-induced cytokines pathways, leading to proliferation in a paracrine manner.[5]

As per the prevailing literature, the patients of IBD have been associated with increased risk of lymphoproliferative disorders, attributed to long-term inflammation and use of immunomodulator drugs; however, data on actual incidence is lacking. Furthermore, the role of IBD itself as a cause of lymphoproliferative disorders is contentious.[6],[7],[8]

The presented case was a proven case of Crohn's disease on sulfasalazine for last 3 years. Sulfasalazine is an immunomodulatory drug. There are no case reports or literature review that shows long-term use of this drug has been associated with risk of lymphoproliferative disorders to the best of our knowledge. The drug acts via causing suppression of both B- and T-lymphocyte proliferation leading to a decrease in activated lymphocytes in the peripheral blood. TNF-α, which is a major pro-inflammatory cytokine, is inhibited by suppression of production as well as inhibition of receptor binding. Similarly, other transcription inhibitors like nuclear factor κB (NF-κB) also got inhibited.[9] So via this mechanism, proliferation of EBV infected lymphocytes is facilitated by impairment of cell-mediated immunity promoting malignant transformation.

IBD patients treated with thiopurines appear to have three to five times increased risk for lymphoma, than IBD patients not exposed to these drugs.[8] There are also some data regarding the risk of lymphoma development in IBD patients treated with methotrexate and from anti-TNF therapy; however, none such association is found for immunomodulatory drug sulfasalazine.

Bernardes et al.[10] showed in their case series of 900 patients of IBD, that primary intestinal lymphoma was more common lymphoproliferative disorders, while we had a case of abdominal and aortocaval lymph nodal involvement.

The current standard of treatment of DLBCL is anti CD20 monoclonal antibody (rituximab) with anthracycline-based chemotherapy, most commonly R-CHOP. It has been seen that overall response (ORR) rates and complete response (CR) rates are lower in EBV positive versus EBV negative DLBCL patients. 1 CD30 expression is also a poor prognostic factor in these patients, which was negative in our case.

In recent studies, it has been reported that most of the EBV positive DLBCL patients may show pdl1 positivity by IHC and this marker is associated with poorer prognosis when these patients were treated with standard treatment with R-CHOP.[1] So, some studies are going on to look for the efficacy of monoclonal antibodies targeting PDL1 in these patients. However, in one phase 2 trial nivolumab, that is, anti PDL1 antibody has been tried in Relapsed/Refractory Diffuse Large B-Cell Lymphoma in Patients Ineligible for or Having Failed Autologous Transplantation, but this drug has failed to show any significant efficacy.[11] Our case was negative for PDL1.

EBV-associated lymphoproliferative disorders have heterogeneous presentations with variable responses to therapy. Clinicians should be vigilant about this potential complication while treating IBD patients with immunomodulatory drugs like sulfasalazine and pathologists should also be on the guard while reporting lymphomas in patients of IBD and consider the possibility of EBV positive DLBCL-NOS so that timely screening and appropriate investigations can be done for early diagnosis and treatment of this complication.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Castillo JJ, Beltran BE, Miranda RN, Young KH, Chavez JC, Sotomayor EM. EBV-positive diffuse large B-cell lymphoma, not otherwise specified: 2018 update on diagnosis, risk-stratification and management. Am J Hematol 2018;93:953-62.  Back to cited text no. 1
    
2.
Chang MD, Markham MJ, Liu X. Epstein-Barr virus-positive diffuse large B-Cell lymphoma involving the colon in a patient with ulcerative pancolitis and polymyositis on long-term methotrexate therapy. Gastroenterology Res 2016;9:83-6.  Back to cited text no. 2
    
3.
Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016;127:2375-90.  Back to cited text no. 3
    
4.
Crombie JL, LaCasce AS. Epstein Barr virus associated B-cell lymphomas and iatrogenic lymphoproliferative disorders. Front Oncol 2019;7;9:109.  Back to cited text no. 4
    
5.
Lakatos PL, Lovasz BD, David G, Pandur T, Erdelyi Z, Mester G, et al. The risk of lymphoma and immunomodulators in patients with inflammatory bowel diseases: Results from a population-based cohort in Eastern Europe. J Crohns Colitis 2013;7:385-91.  Back to cited text no. 5
    
6.
Hamanaka S, Nakagawa T, Ota S, Iida M, Ohta Y, Isshiki Y, et al. Immunomodulator-associated Epstein-Barr virus-positive mucocutaneous ulcer in a patient with refractory Crohn's disease. Clin J Gastroenterol 2019;12:330-5.  Back to cited text no. 6
    
7.
Ferraro S, Leonardi L, Convertino I, Blandizzi C, Tuccori M. Is there a risk of lymphoma associated with anti-tumor necrosis factor drugs in patients with inflammatory bowel disease? A systematic review of observational studies. Front Pharmacol 2019;10:247.  Back to cited text no. 7
    
8.
Bewtra M, Lewis JD. Update on the risk of lymphoma following immunosuppressive therapy for inflammatory bowel disease. Expert Rev Clin Immunol 2010;6:621-31.  Back to cited text no. 8
    
9.
Chan Edwin SL, Oliver Stephen N, Cronstein Bruce N. Immunomodulating pharmaceuticals, In: Robert RR, Editor. Clinical Immunology: Principles and Practice. 3rd ed. Philadelphia, USA. elsevier limited; 2008. p. 1331-9.  Back to cited text no. 9
    
10.
Bernardes C, Russo P, Carvalho D, Saiote J, Ramos J. Lymphoproliferative disorders in inflammatory bowel disease patients: Is it the drugs or the disease. GE Port J Gastroenterol 2018;25:175-8.  Back to cited text no. 10
    
11.
Ansell SM, Minnema MC, Johnson P, Timmerman JM, Armand P, Shipp MA, et al. Nivolumab for relapsed/refractory diffuse large B-cell lymphoma in patients ineligible for or having failed autologous transplantation: A single-arm, phase II study. J Clin Oncol 2019;37:481-9.  Back to cited text no. 11
    

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Correspondence Address:
Sunil Pasricha
Department of Pathology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, New Delhi - 110 085
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJPM.IJPM_1099_20

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