| Abstract|| |
Background: The Epstein-Barr virus (EBV), also called human herpesvirus 4, is a virus of the herpes family. The EBV-associated lymphomas include Burkitt lymphoma, classic Hodgkin lymphoma (HL), lymphomas arising in immunocompromised individuals, peripheral T-cell lymphomas, angioimmunoblastic T-cell lymphoma, extranodal nasal-type natural killer/T-cell lymphoma, and other rare histotypes. Objective: The present study evaluated the role of EBV as an etiologic agent in various lymphomas and determined an Indian perspective in a tertiary care cancer center compared to that of Western literature. Materials and Methods: Clinicopathological spectrum was studied in 184 cases of lymphomas using a standard immunohistochemistry panel and in situ hybridization for Epstein-Barr virus-encoded RNA (EBER) expression. Results and Conclusions: The prevalence of EBV was described in various HL and non-HL's and was found similar to that of Western literature. EBER expression was also observed in the nonneoplastic bystander cells in the studied cases which need further evaluation on larger scale studies.
Keywords: Epstein-Barr virus-encoded RNA, Epstein-Barr virus, in situ hybridization, lymphoma
|How to cite this article:|
Gala R, Gandhi JS, Gupta G, Grover SK, Sharma A, Pasricha S, Mehta A. Study of association of Epstein-Barr virus in lymphomas by Epstein-Barr virus-encoded RNA in situ hybridization: An Indian perspective from a tertiary care cancer institute. Indian J Pathol Microbiol 2017;60:341-9
|How to cite this URL:|
Gala R, Gandhi JS, Gupta G, Grover SK, Sharma A, Pasricha S, Mehta A. Study of association of Epstein-Barr virus in lymphomas by Epstein-Barr virus-encoded RNA in situ hybridization: An Indian perspective from a tertiary care cancer institute. Indian J Pathol Microbiol [serial online] 2017 [cited 2020 Feb 26];60:341-9. Available from: http://www.ijpmonline.org/text.asp?2017/60/3/341/215387
| Introduction|| |
The Epstein-Barr virus (EBV), also called human herpesvirus 4, is a virus of the herpes family. Discovered more than 40 years ago from a Burkitt lymphoma biopsy, it was the first virus to be directly associated with human cancer.
EBV has evolved a life cycle that mimics the natural differentiation pathway of antigen-activated B cells, giving the virus access to its site of latent infection, the resting memory B cell. By steering the infected cells through various stages of lymphocyte differentiation, EBV can enter a cell type suitable for long-term latent persistence and periodic reactivation. However, its presence in various stages of B-cell development, and its ability to infect certain epithelial cells, can have pathogenic consequences and can contribute to the development of a diverse group of lymphomas and carcinomas. The EBV-associated lymphomas include B-cell lymphomas such as Burkitt lymphoma, classic Hodgkin lymphoma (HL), and lymphomas arising in immunocompromised individuals (posttransplant and HIV-associated lymphoproliferative disorders). T-cell lymphomas include a subset of peripheral T-cell lymphomas (PTCLs), angioimmunoblastic T-cell lymphoma, extranodal nasal-type natural killer (NK)/T-cell lymphoma, and other rare histotypes.
During an acute phase of infection, the virus replicates in the stratified squamous epithelium of oropharyngeal mucosa, followed by a latent infection of B lymphocytes. EBV encodes a series of products interacting with or exhibiting homology to a wide variety of antiapoptotic molecules, cytokines, and signal transducers, hence, promoting EBV infection, immortalization, and transformation. Based on these patterns of expression of the EBV genome, three types of latent gene expression patterns have been described latency I, II, and III. In latency I pattern, Epstein-Barr nuclear antigen-1 (EBNA-1) and the two small noncoding Epstein-Barr virus-encoded RNAs (EBERs) are expressed. EBV gene expression in latency II is usually limited to EBNA-1, the EBERs, latent membrane protein-1 (LMP-1), and LMP-2A and LMP-2B. Latency III usually involves the unrestricted expression of all EBNAs, EBERs, and LMPs.
EBER in situ hybridization (ISH) is the methodology of choice for the detection of the EBV in tissue sections. The presence of EBV in the tumor cells of EBV-associated cancers might provide a basis for specific therapy.
The aim of the present study was to evaluate the role of EBV as an etiologic agent in various lymphomas, determine an Indian perspective in a tertiary care cancer center and compare it to that in the Western literature.
| Materials and Methods|| |
This was an observational study, carried out at the Department of Pathology; Rajiv Gandhi Cancer Institute and Research Centre, New Delhi. All cases diagnosed as lymphoma of either Hodgkin or non-Hodgkin type from January 2013 to November 2014, were included in the study. Those cases whose paraffin-embedded blocks of tissues were not available or those having insufficient material left in blocks were excluded from the study.
Tissue blocks and hematoxylin and eosin stained slides of lymphomas from January 1, 2013, to November 7, 2014, were retrieved. All cases were examined and studied in detail for data acquisition. All cases were categorized using the WHO Classification of Hematopoietic and Lymphoid Tissues, 2008 edition based on morphological and immunohistochemistry (IHC) features.
The IHC slides of the cases, in which the complete panel of antibodies necessary for rendering a diagnosis of lymphoma had already been applied were retrieved and evaluated. In the remaining cases, few additional IHC markers were applied and assessed. The comprehensive panel of IHC markers included CD20, CD45RB, CD30, CD15, CD10, CD57, CD3, CD4, CD8, CD23, BCL2, BCL6, MUM1, CD79a, PAX-5, OCT-2, BOB-1, Mib1, p53, and c-myc. The stains examined in each case, the antibodies, the type of antigen represented, manufacturers, and dilutions are listed in [Table 1]. All the stains were performed using an automated instrument (Ventana Benchmark XT) following the manufacturers' instructions. Appropriate positive and negative controls were run in each case.
|Table 1: List and details of antibodies used for the diagnosis of lymphoma|
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IHC was performed on formalin-fixed, paraffin-embedded freshly cut 4 μ thick sections. From a tissue floatation bath of deionized H2O, the cut paraffin section of the patient case was retrieved on the poly-L-lysine (50 ml poly-L-lysine + 500 ml distilled water) coated microslide which had the known positive tissue or multitissue controls on the top of the slide for the requested antibody. Then, the section was air dried at 600°C for 15 min.
The reagent carousel tray(s) containing the dispensers required for protocols being performed was removed from the IHC refrigerator. Preparation for operation was done by uncapping, priming, and visually validating the satisfactory reagent volume of all dispensers.
All primary antibody dispensers that corresponded with the prepared slides were installed onto reagent carousel tray(s), and the satisfactory reagent volume of all dispensers was validated. The reagent carousel tray(s) was installed onto the Benchmark instrument. Antibodies/reagents/stains were allowed to reach room temperature before staining.
Slide barcode labels were prepared. Ventana Benchmark XT instrument was turned on. A predetermined protocol was chosen for the respective slides. The operation was started. On completion of staining, an audible alarm was heard, at the time of which the slides were removed and counterstained. The slides were washed in running water twice, dehydrated with acetone, cleared with xylene, and mounted with DPX.
Procedure of in situ hybridization for Epstein-Barr virus-encoded RNA
Representative sections containing a maximum number of neoplastic cells were chosen. Automated chromogenic ISH was performed using Ventana INFORM EBER Probe, ISH NIEWblue detection kit and accessory reagents on Ventana Benchmark XT autostainer. Known prediagnosed cases of EBER-positive HL were taken as positive controls. Nonneoplastic cells in these known cases of HL were taken as negative controls.
Those cases which demonstrate blue-colored reaction in nucleus of neoplastic cells were taken as EBER positive. Percentage of neoplastic cells was derived semi-quantitatively. In EBER-positive cases, areas of strongest positivity (hot spots) were chosen. 500–2000 neoplastic cells in these hotspots were counted, and percentage of neoplastic EBER-positive cells was derived from those. Whenever the number of EBER-positive cells was low, the 10 most positive fields were chosen, and using a 10× ocular lens and a 20× objective, average number of positive cells per field was counted. In addition to neoplastic cells, any nonneoplastic bystander cells if showing nuclear staining for EBER-ISH were noted, and their percentage was counted in similar manner as above. Two-independent pathologists reviewed the results (GG, JSG). Statistical analysis of results was done using standard SSPE software using Student's t-test, Fisher's exact test, and Chi-square test. Analyzed results were compared with similar studies from both Indian and Western population.
| Observations and Results|| |
The study population included 184 cases of lymphomas, of which majority were non-HL (NHL) (n = 145 [79%]) while HL constituted 21% (n = 39) of the total number as depicted in [Table 2]. In the HL study group, classical HL (cHL; n = 35) was more common compared to nodular lymphocyte predominant HL (NLPHL) (n = 4). cHL was categorized into subtypes in 9 cases. A similar assessment could not be done for rest of the cases as in majority of these the submitted diagnostic materials were trucut biopsies. Diffuse large B-cell lymphoma (DLBCL) was the most common subtype of NHL which constituted 66% (n = 86) of the total NHL cases.
|Table 2: Comparison of various parameters between various other studies and the current study|
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Considering the age distribution, it was observed that HL was prevalent in a younger population with a median age of 33 years compared to NHL's where median age of patients was 53 years.
In both HL and NHL, disease was more prevalent in males compared to females. Male:female ratio was 3.3:1 and 2.4:1 in cases of HL and NHL, respectively.
There was a significant difference between the two study groups in terms of extranodal involvement at the time of evaluation. All patients of HL (100%) had lymph nodal involvement with no extranodal disease, whereas a significant number of cases of NHL (28%) showed extranodal involvement at the time of evaluation. This result was significant on Fisher's Exact Test as depicted by the (P = 0.01). All the above findings are listed in [Table 2].
Epstein-Barr virus-encoded RNA status in Hodgkin lymphoma and non-Hodgkin lymphoma
Considering the expression of EBER in our cases, positivity in NHLs was seen mostly in patients from 41 to 50 years of age while in cases of HL's, EBER positivity was more common in a younger age group (21–30 years). These findings are illustrated in [Table 2].
This study demonstrated a significant difference in EBER expression in HL and NHL subgroups (P = 0.000 by Pearson's Chi-square test). Of the total cases of HL, 51% (20 out of 39) showed nuclear expression of EBER in neoplastic Reed-Sternberg (RS) cells compared to NHL where only 5% cases (7 of 145) showed nuclear expression of EBER. Among the cHL, majority of cases were EBER positive (54%) [Figure 1], while only one of three cases of NLPHL demonstrated EBER expression [Figure 2] and [Figure 3].
|Figure 1: A case of classical Hodgkin lymphoma-nodular sclerosis type showing Epstein-Barr virus-encoded RNA-positive neoplastic Reed-Sternberg cells More Details (arrows) Epstein-Barr virus-encoded RNA-in situ hybridization (×200)|
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|Figure 2: Case of nodular lymphocyte predominant Hodgkin lymphoma showing nuclear expression of Epstein-Barr virus-encoded RNA in neoplastic (~5%) as well as bystander cells (~15%). Arrow: Neoplastic cells; arrowheads: Bystander cells. (a) Epstein-Barr virus-encoded RNA-in situ hybridization (×400). (b) Epstein-Barr virus-encoded RNA-in situ hybridization (×200)|
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|Figure 3: Corresponding hematoxylin and eosin section of nodular lymphocyte predominant Hodgkin lymphoma (H and E, ×200)|
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The nuclear positivity for EBER ranged from 2% to 100% in neoplastic RS cells in cases of hl. Few showed nuclear positivity in bystander cells (n = 7) in addition to neoplastic cells. The percentage of such bystander cells ranged from 1% to 10%. Interestingly, two cases also showed EBER positivity in ~1% bystander cells in the absence of EBER expression in the neoplastic rs cells.
EBER expression in NHL was seen in only 3% (n = 4) cases of B-cell NHL, of which two were DLBCL [Figure 4], one was plasmablastic lymphoma in an HIV positive patient [Figure 5], and one was unclassifiable with features intermediate between DLBCL and Burkitt's lymphoma [Figure 6]. The two cases of DLBCL showing EBER expression were 50 and 55 years old, respectively. Of the T-cell NHL, 13% (3 of 23 cases) showed EBER expression in neoplastic cells. Two of these positive cases were NK/T-cell lymphoma – nasal type and one was PTCL-not otherwise specified (NOS).
|Figure 4: Case of Diffuse large B-cell lymphoma showing nodular and serpiginous pattern of Epstein-Barr virus-encoded RNA expression. Epstein-Barr virus-encoded RNA-in situ hybridization ×40 inset shows corresponding (H and E, ×200)|
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|Figure 5: Case of plasmablastic lymphoma showing Epstein-Barr virus-encoded RNA positivity in ~50% neoplastic cells Epstein-Barr virus-encoded RNA-in situ hybridization (×200)|
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|Figure 6: Case of B-cell lymphoma unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma showing Epstein-Barr virus, encoded RNA positivity in ~90% neoplastic cells within the hotspots. Epstein-Barr virus-encoded RNA-in situ hybridization (×40)|
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Percentage of neoplastic cells positive for EBER ranged from 20% to 90% in cases of NHL. Highest was seen in a case of NK/T-cell Lymphoma – nasal type [Figure 7] and one case showing intermediate features between DLBCL and Burkitt's. Both these cases showed positive expression in 90% of the neoplastic cells.
|Figure 7: Case of extranodal natural killer/T-cell lymphoma showing Epstein-Barr virus-encoded RNA positivity in ~90% of neoplastic cells. Epstein-Barr virus-encoded RNA-in situ hybridization (×100)|
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Our study also unveiled that apart from neoplastic cells, few bystander nonneoplastic cells also showed EBER expression. Amidst NHL cases, bystander cell expression was observed in the range of 1%–7%. Among these, one was EBER-positive and four were EBER-negative cases. The positive case was of DLBCL while negative cases including DLBCL, follicular lymphoma, and PTCL-NOS.
Morphological patterns of Epstein-Barr virus-encoded RNA expression
Various morphologic patterns of EBER expression were observed in the current study which included nodular and serpiginous pattern in DLBCL and diffuse pattern in extranodal NK/T-cell lymphoma.
A median follow-up was available for 8 months for the cases included in the study, and a substantial number of patients had a disease-free survival.
| Discussion|| |
Distribution of lymphomas
HL was seen in relatively younger patients with a median age of 33 years compared to NHL where the median age was 52 years. The present study showed a male predominance in both HL (male:female ratio = 3.3:1) and NHL (male:female ratio = 2.8:1) as shown by various studies in literature. Hence, sex distribution was found to be similar in both the study groups.
The current study showed that NHL (79%) was more common than HL (21%). This finding has been validated by various other authors such as Arora et al., who documented similar proportions of HL and NHL in a study population from South India. In our study, B-cell, NHL constituted the majority of the cases (84%) while T-cell NHLs accounted for only 16% of the total cases. This observation is also in concordance with Arora et al. and Naresh et al. as B cell neoplasms accounted for 78.6% and 79.1% of the total NHLs in their studies.,
The most common subtype of NHL in various Indian studies in literature was DLBCL. However, the percentage of cases of DLBCL of all the NHLs in the current study was much higher (66%) compared to study by Arora et al. (46.9%), Naresh et al. (34%), and Mondal et al. (35.2%).,,
Extranodal disease at the time of presentation was more common in NHL compared to HL. A significant number of NHL cases (28%) had extranodal involvement at the time of evaluation compared to HL where all patients (100%) presented with nodal disease in the absence of extranodal involvement. This observation is supported by the result of a South Indian study where primary extranodal lymphoma (ENL) accounted for 32.8% (n = 1321) of all NHLs, most frequently involving the gastrointestinal tract.
Epstein-Barr virus-encoded RNA positive lymphomas
The present study showed nuclear EBER positivity in various subtypes of lymphomas as depicted in [Table 2] and [Table 3]. [Table 4] compares the expresseion of EBER in our study with other studies.
|Table 4: Comparison of Epstein-Barr virus-encoded RNA expression in various lymphomas with other studies|
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WHO divides HL into two subtypes: cHL and NLPHL. The incidence of EBV is markedly different depending on the histologic variant.
In classic HL, the prevalence of EBER expression can have a broad range depending on the geographic area. EBV positivity has been observed from 30% to 50% of patients in North America, Brazil, Taiwan, United Arab Emirates, and Western Europe, whereas it is seen in nearly 100% in children of developing countries.,,, Glaser et al. have shown that in all age groups, mixed cellularity, and lymphocyte depleted were associated with high levels of EBV-positive cases, whereas nodular sclerosis and particularly lymphocyte predominant had relatively low percentages. In the present study, 51% of cHL cases were EBER positive while 49% cases were EBER negative. In this study, subgrouping of cHL was available only in nine cases as diagnostic material in majority was a small tissue biopsy, making subgrouping less accurate.
The incidence of EBV reported in literature is very less in the lymphocyte-predominant subtype. There have been few case reports on EBV-positive NLPHL by Khalidi et al. and Wang et al., The present study result corroborates with the previous studies of EBER positivity being rare in cases of NLPHL. There were four cases of NLPHL, of which one was EBER positive. In this case, neoplastic as well as bystander cells showed nuclear expression of EBER.
In patients with DLBCL, the incidence of EBV among patients of Asian or Latin American origin ranges from 9% to 15%.,, However, the incidence is only <5% in Western populations., In the present study, incidence was found to be 2% similar to Western population. EBV-positive DLBCL of the elderly is among the newer inclusions as a provisional entity in the 2008 WHO classification of tumors of hematopoietic and lymphoid tissues. Patients in this category usually tend to over 50 years of age, present with extranodal disease and have worse prognosis. In the present study, the two cases of DLBCL, which were EBER positive, had presented at the age of 50 and 55 years; however, they had nodal disease. Published studies by Oyama et al. and Park et al. support a possible prognostic relationship between EBV tumoral status and DLBCL. EBER-ISH positive DLBCL patients in these studies had lower survival rates.,
Plasmablastic lymphoma is an uncommon, aggressive entity originally described in the oral cavity in HIV-positive patients, predominantly in males, but it has recently been described in many other extranodal sites and has been associated with other immunodeficiency states. EBV has been detected in these patients in about 60% of the cases regardless of the HIV status.,, This study included only two cases of plasmablastic lymphoma, as it is a rare entity, of which one was EBER positive with extranodal disease with HIV positivity. The other case was EBER negative, also had extranodal disease, however, immune status of this patient was not known.
B-cell lymphoma, unclassifiable with features intermediate between DLBCL and Burkitt lymphoma is a gray zone aggressive lymphoma that has morphological and genetic features of both DLBCL and Burkitt lymphoma. EBV has been detected in virtually all cases of the endemic variant, 15%–20% of the sporadic variant, and 30%–40% of the immunodeficiency-related variant of Burkitt lymphoma. While EBV is positive in 5%–15% cases of DLBCL as discussed above, we stumbled on one case of B-cell lymphoma, unclassifiable with features intermediate between DLBCL and Burkitt lymphoma in the present study which was EBER-ISH positive. As previous studies have demonstrated that Burkitt lymphomas are much more commonly associated with EBV than DLBCL, a diagnosis of Burkitt lymphoma was favored in this case so that it could be treated aggressively similar to Burkitt lymphoma.
Considering NK/T cell lymphoma-nasal type, a predominantly ENL characterized by vascular damage and destruction, prominent necrosis, cytotoxic phenotype, and association with EBV. In the present study, we came across two cases of NK/T-cell lymphoma-nasal type, both of which presented with nasal mass, and were EBER positive. Percentage of EBER-positive neoplastic cells was high in both these cases (90% and 50%, respectively). This result is supported by various other authors like Li et al. who reported 100% positivity in their study (n = 73), and others who reported a positivity rate of 97.6% and 87%.,,
As far as PTCL-NOS is concerned there are no strict cutoffs for defining EBER positive expression in such cases. EBER expression has been associated with worse prognosis in these cases. Went and colleagues proposed a cutoff of 25% positivity in the neoplastic cells, while an International Peripheral T-cell Lymphoma Project considered a cutoff as 20%. In the present study, there were 6 cases of PTCL-NOS; 1 out of these 6 cases was EBER positive and showed 20% neoplastic positive cells. In addition, one of the cases showed EBER expression in 7% nonneoplastic cells while none in the neoplastic cells and was interpreted as EBER negative.
The WHO (2008) states that anaplastic large cell lymphoma (ALCL) is “consistently negative for EBV, “ i.e., EBER and LMP-1. In the present study, four cases of ALCL were included. In concordance with the WHO, all four cases were EBER negative.
Epstein-Barr virus-encoded RNA positivity in nonneoplastic bystander cells
In Bosnian study, the presence of EBER RNA was found in nonneoplastic lymphocytes of the studied group in 31 (38.3%) cases of HL. Considerable majority of these cases (90.3%) showed the presence of EBER RNA in neoplastic cells as well, while in 9.7% cases neoplastic cells were negative for EBV. In the present study, seven cases of HL which were EBER positive showed nuclear staining in additional nonneoplastic bystander cells. Percentage of these cells ranged from 1% to 10% in these cases. Two additional cases of cHL showed bystander cell positivity in ~1% cells. The presence of EBV in neoplastic and nonneoplastic cells of HL could indicate coexistence of a clonal proliferation of EBV-infected RS and Hodgkin's cells and nonspecific infection of nonneoplastic lymphocytes. The finding that speaks in favor of this hypothesis is that EBV-positive neoplastic cells and nonneoplastic lymphocytes of HL are infected with different strains of EBV, contributing to different oncogene abilities of this virus. Viral infection of nonneoplastic lymphocytes could affect their function, thus impairing their defense mechanism against neoplastic tissue.
Many authors have reported bystander cell positivity in various NHL cases. Quintanilla-Martinez et al. have reported such a phenomenon in few rare cases among primary intestinal NHLs. In our study, among cases of NHL, a single EBER positive DLBCL case showed nonneoplastic bystander cell positivity in ~2% of the cells. In addition to these, four cases of EBER-negative NHL showed bystander cell nuclear staining of <1%–7% cells.
Limitations of the current study
Subclassification of cHL was not possible in all cases due to unavailability of the exact morphological spectrum where core biopsy was submitted as tissue material for diagnosis.
| Conclusions|| |
EBER-ISH is a useful test to detect EBV infection in various types of lymphomas, including HL and NHLs. In comparison with NHLs, EBV infection is more common in HLs with prevalence similar to that seen in Western countries. DLBCL is the most common type of NHL and prevalence of EBV infection in this subtype was similar to that in the Western population. A small percentage of nonneoplastic bystander cells also expressed EBER in a variety of cases. Large-scale studies are required to evaluate the significance of EBER expression in bystander nonneoplastic cells and further address this issue in terms of their role in the etiopathogenesis of lymphomas, if any.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Shrruti K Grover
Department of Pathology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2], [Table 3], [Table 4]