|Year : 2013 | Volume
| Issue : 4 | Page : 359-364
|Association of Epstein Barr virus deoxyribonucleic acid with lung carcinoma
Amir Hossein Jafarian1, Abbsali Omidi-Ashrafi1, Nema Mohamadian-Roshan1, Mahdi Karimi-Shahri1, Kiarash Ghazvini2, Samaneh Boroumand-Noughabi1
1 Department of Pathology, Quaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
2 Department of Microbiology, Quaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
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|Date of Web Publication||18-Jan-2014|
| Abstract|| |
Context: Lung cancer is the leading cause of cancer death worldwide. In addition to smoking, a variety of other contributing factors, including viral infection, have been suggested in tumorigenesis. Epstein Barr virus (EBV), which is linked to various malignancies, seems to be a good candidate. Aims: The aim of this study was to investigate the association of EBV with lung carcinomas. Settings and Design: A total number of 90 formalin fixed paraffin embedded lung tissue samples including 48 cases of lung cancers (18 squamous cell carcinomas [SCCs], 18 adenocarcinomas and 12 small cell carcinomas) and 42 non-tumoral samples (control group), were retrieved from the pathology archive. Materials and Methods: Following deoxyribonucleic acid extraction, polymerase chain reaction (PCR) was performed using an EBV-Eph PCR kit. The positive cases were studied immunohistochemically for the expression of EBV-late membrane protein-1 (EBV-LMP-1) in tumoral tissues. Statistical Analysis Used: The t-test and Fisher exact test were used and P < 0.05 was considered statistically significant. Results: Five of our cases, including four SCCs and one adenocarcinoma and two control samples showed a positive reaction in PCR. All positive tumoral cases showed diffuse staining with LMP-1 in immunohistochemistry. Conclusions: We found a significant difference in the presence of the EBV genome in cases of lung SCC compared to other lung lesions (P = 0.02). According to our data, EBV is not at major play in the non-lymphoepithelioma-like cancers of the lung in general, but may have a role in the tumorigenesis of some lung SCCs.
Keywords: Epstein Barr virus, lung cancer, polymerase chain reaction
|How to cite this article:|
Jafarian AH, Omidi-Ashrafi A, Mohamadian-Roshan N, Karimi-Shahri M, Ghazvini K, Boroumand-Noughabi S. Association of Epstein Barr virus deoxyribonucleic acid with lung carcinoma. Indian J Pathol Microbiol 2013;56:359-64
|How to cite this URL:|
Jafarian AH, Omidi-Ashrafi A, Mohamadian-Roshan N, Karimi-Shahri M, Ghazvini K, Boroumand-Noughabi S. Association of Epstein Barr virus deoxyribonucleic acid with lung carcinoma. Indian J Pathol Microbiol [serial online] 2013 [cited 2019 Dec 6];56:359-64. Available from: http://www.ijpmonline.org/text.asp?2013/56/4/359/125290
| Introduction|| |
Lung cancer is the most common cancer and the leading cause of cancer-related mortality world-wide. Despite the occurrence of lung carcinoma is decreasing in men and approaching a plateau in women in the US, it has an increased incidence in the developing countries. ,,, The causal role of tobacco smoking is well-known in carcinogenesis of the lungs; however, there are various other risk factors with different degrees of importance. , Viral infections have been suggested as a possible risk factor for lung cancer. Among viral agents, Epstein Barr virus (EBV) seems to be a good candidate because this virus has been the major carcinogenic virus in humans since its discovery. 
About 80% of the population over the age of 30 have had a history of EBV infection.  The EBV-associated tumors include some types of lymphomas and epithelial tumors such as undifferentiated nasopharyngeal carcinoma and some other types of carcinomas. ,, Regarding the association of EBV with lung cancer, few investigations have been carried out around the world. Although the presence of any such relation is under question in the occidental patients, a number of authors have found a significant correlation between EBV infection and lung carcinomas in the orient. Until date, the association of EBV with lung carcinomas, not classified as lymphoepithelioma-like, is restricted to 60 cases. ,,,,
Based on the mentioned information, we decided to perform a retrospective case-control study to investigate the association of EBV deoxyribonucleic acid (DNA) with lung carcinomas.
| Materials and Methods|| |
Patients and tissue samples
A total number of 60 cases of primary lung cancers including 23 squamous cell carcinomas (SCCs), 20 adenocarcinomas and 17 small cell carcinomas were retrieved from the surgical pathology archive. Patients had undergone lobectomy or pneumonectomy between 2004 and 2010 at this center. The criteria to include a sample in our study were the presence of information on age and gender of the patient as well as unequivocal histological diagnosis in the related files and having enough tissue leftover for further morphological examination and DNA extraction. The tissues had been routinely fixed in 10% formalin and embedded in paraffin. The related hematoxylin and eosin stained slides were reviewed by two pathologists. The histopathologic features of the surgical specimens were classified according to the World Health Organization (2004) criteria. One of the tissue paraffin blocks, which contained tumoral tissue and the least inflammatory cells was selected for each case.
Control tissue samples
A total of 50 formalin fixed paraffin embedded tissue samples of patients with non-tumoral diseases of the lung, including hydatid cyst, bronchiectasis, tuberculosis, pulmonary fibrosis and non-specific inflammation, registered in the surgical pathology archive during 2004-2010 were selected to form the control group. The inclusion criteria were documentation of the histological diagnosis, patient age and gender in the recorded files and having enough remaining tissue for further investigations.
The protocols of this study were approved by the ethics committee of our university.
10 μm thick sections from the samples were obtained using a microtome. In order to prevent DNA contamination and carry over, a separate disposable blade was used for each sample. The sections were placed into sterile microtubes and deparaffinized by xylene. Then the isolation of DNA was carried out, according to the AmpliSense instruction manual of the nucleic acid extraction kit (DNA-sorb-C, Ref: K1-6-50-CE, K1-6-100-CE/Ver: 27/08/09). Accordingly the deparaffinized tissue samples first underwent lysis procedure and after being incubated at 60°C for 1 h, purified DNA was extracted through successive steps of adding enzymatic and washing solutions and centrifugation after each step.
Polymerase chain reaction (PCR)
In the current study, all stages were performed based on the instruction manual of AmpliSens; EBV-EPh PCR kit (Ref: V9-100-R0, 2-CE; V9-200-CE; V9-200-CE/Ver: 29.06.09-03.03.10 from Federal State Institution of Science Central Research Institute of Epidemiology, Russia) as the following:
- Tubes with PCR-mix-1-R EBV with wax, provided by the ApmliSens Company, were used for amplification of DNA from clinical and control samples.
- 10 pl of PCR-mix-2 blue was added to the surface of wax layer and mixed with reagents in the tube.
- One drop of mineral oil for PCR (about 25 pl) was added.
Then, 10 pl of DNA samples, obtained from clinical or control samples at the stage of DNA extraction, was added to the PCR tubes. The control amplification reactions were carried out:
Negative control of amplification: 10 pl of DNA-buffer was added to the tube for NCA.
C + : 10 pl of positive control DNA EBV and human DNA was added to the tube for positive control of amplification.
The following program on the thermo cycler (Astec thermal cycler, PC818, Japan) was run that lasted 2/5 h [Table 1]. After the reaction was finished PCR tubes were collected and sent to the room for PCR products analysis. Analysis of amplification products was performed by separation of DNA fragments in agarose gel.
Analysis of results was based on the presence or absence of specific bands of amplified DNA in agarose gel (1.7%). The length of specific amplified DNA fragments was:
The sample was considered to be positive for EBV DNA if the band of 500 bp is present in agarose gel regardless of the presence of IC band.
The sample was considered to be negative for EBV DNA if the band of 500 bp was absent and the band of 723 bp is present in agarose gel [Table 2].
Performing the mentioned procedures of PCR, the samples with inappropriate amplifications and band formation on agarose gel were omitted from our study. Finally, the size of our cases and control samples was reduced to 48 (including 18 SCCs, 18 adenocarcinomas and 12 small cell carcinomas) and 42 respectively.
We performed an IHC study for the positive cases to check the presence of EBV in the tumoral cell as follows: After deparaffinization and hydration of slides, antigenic retrieval was done by incubation with molar citrate buffer 1% (pH = 6) in a microwave oven for 12 min. For IHC, the immunoperoxidase streptavidin biotin procedure was performed by incubation at room temperature for:
- 10 min with 3% hydrogen peroxide;
- 60 min with antibody against EBV-late membrane protein (LMP)-1 prepared by Serotec (Kidlington, UK) (IgG1 mouse anti-EBV LMP cocktail of four antibodies recognizing different epitopes of EBV LMP-1 (MCA1874), clone (CS1, CS2, CS3, and CS4));
- 10 min each with biotinylated link antimouse and antirabbit immunoglobulin, then streptavidin peroxides (DAKOLSAB 25 system, peroxidase kit; Dako, Glostrup, Denmark) and finally with chromogen (diaminobenzidene hydrochloride).
Counterstaining was done with Mayer's hematoxylin and mounted in Canada balsam. The cytoplasmic immunoreactivity of tumoral cells to LMP-1 antibody was evaluated microscopically.
| Results|| |
We studied a total number of 90 formalin fixed paraffin embedded samples of lung tissue from 48 cases of pulmonary carcinomas (including 18 SCCs, 18 adenocarcinomas and 12 small cell carcinomas), and 42 control samples. The latter obtained from the lung tissues of patients with pulmonary lesions such as bronchiectasis, hydatid cysts and interstitial lung diseases. The case group consisted of 28 males and 20 females with an average age of 59.4 years. The control group included 22 males and 20 females with a mean age of 51.8 years. Patients' age and gender showed normal distribution between our cases and controls and the mean age of the patients was not significantly different in these two groups. EBV genome found to be present in five cases of lung cancers, including four SCCs and one adenocarcinoma, using PCR, while no single case of small cell carcinoma showed positive reaction. On the other hand, two of the control samples were EBV related as well. As mentioned in the previous chapter, a reaction considered to be positive when it showed a 500 bp band on agar gel electrophoresis and negative when it showed the internal control of a 723 bp fragment [Figure 1]. The specifications of these EBV related lesions are summarized in [Table 3].
|Table 3: Age, gender and histologic diagnosis of samples with positi ve PCR for EBV genome|
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|Figure 1: Banding patt ern of Epstein Barr virus genome in selected cases of lung cancers showing positi ve and negati ve controls (C+ and C−), the 50 bp ladder (L), two positi ve cases (samples 4 and 6) and fi ve negati ve cases (1, 2, 3, 8, 9). Note the presence of the internal control (723 bp) in negative cases|
Click here to view
In an immunohistochemistric study of LMP-1 on the positive cases, 40-65% of the neoplastic cells showed moderate to severe cytoplasmic staining [Figure 2] and [Figure 3]. There was no LMP-1 staining in the background stromal, endothelial and inflammatory cells and also non-tumoral peritumoral lung parenchyma. IHC study in both control samples, which had positive PCR results for EBV genome, represented LMP-1 expression mainly in background lymphocytes.
|Figure 2: A case of well diff erenti ated squamous cell carcinoma of lung related to Epstein Barr virus genome (a) H and E, ×100 and (b) H and E, ×400|
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|Figure 3: The immunoperoxidase reaction for late membrane protein-1 in the same case of fi gures 3-5 showing diff use reacti on in tumoral cells, not in the background stromal cells at (a) ×100 and (b) ×400|
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We failed to find a significant relation in terms of EBV genome status between the cases of lung cancers and the controls by PCR (Fisher exact test, P = 0.44). The difference in the mean age and gender distribution between those with and without EBV DNA amplification were not significant either (independent samples test with a P value of 0.44 and Fisher exact test with a P value of 0.45 respectively). However, the frequency of EBV genome in the sample tissues of patients with SCC was significantly higher than all other pulmonary lesions (Fisher exact test, P = 0.02).
| Discussion|| |
Regarding the association of EBV with lung cancer, few investigations have been carried out to date. In 1979, Desgranges  found out that 21 out of 46 cases of broncopulmunary carcinoma had IgA anti EBV viral capsid antigen. In 1990, Zyriano  measured titers of antibodies against EBV antigens in 450 subjects aged 40 years and older. They studied patients with lung cancer, cases of non-specific chronic lung pathology and healthy individuals. He demonstrated a significant increase in the level of antibodies to EBV capsid antigen in patients with lung cancer and chronic non-specific lung pathology compared with healthy controls.  Although the relation of EBV with lymphoepithelial carcinoma of the lower respiratory system in Asians had been proposed before, in 1994 Kasai  indicated that EBV associated lung cancers are not limited to the typical lymphoepithelioma-like carcinoma; he examined 81 cases of lung cancers in Japanese patients using a highly sensitive in situ hybridization (ISH) method, with utilizing an antisense oligonucleotide probe for EBV encoded small nuclear ribonucleic acid-1 (RNA-1) Epstein-Barr Early Ribonucleoprotein 1 (EBER1). ,,, EBER1 expression was detected in one poorly differentiated SCC associated with marked lymphoid stroma, two well differentiated adenocarcinomas and two moderately differentiated SCCs. Most of the cancer cells in the poorly differentiated SCC showed strong EBER1 signals. 
To present the association of EBV with lung carcinomas, not classified as lymphoepithelioma-like, is restricted to six cases of SCCs in Chinese patients, three SCCs and two adenocarcinomas in Japanese patients and the largest series in a Chinese population with 36 EBER-positive cases. ,, Furthermore, an EBV associated pulmonary adenocarcinoma with signet ring cells in Caucasian patients as well as 12 lung carcinomas (four SCCs and eight adenocarcinomas) in an occidental population, have been recently reported. , Otherwise, several cases of lymphocyte rich adenocarcinomas, but without EBV association have been documented. ,
In the current study, the types of cancers examined for EBV genome were restricted to the three major types; SCC, adenocarcinoma and small cell carcinoma. The reasons for doing so are more reproducibility in their morphological evaluation and more frequent occurrence comparing to other subtypes. From a total number of 48 cases of lung cancers, we found five cases related with the EBV genome (10.4%), which shows a frequency somewhat between the oriental and the occidental studies. ,, Although this value may be due to differences in regional distributions of EBV, the controversy between studies is too high to let us reach such a conclusion. Moreover, the selection of our cases may not be a true representation of the population with lung cancer because several cases were excluded from the study because of the small amount of tissue that would remain for DNA extraction or excluded due to inappropriate DNA concentration. To suggest a carcinogenic role for an oncogenic virus, it should be especially detected in the tumor cells. This also means that the virus should be present in all tumor cells as a consequence of monoclonality.  In addition, viruses such as EBV, CMV and sometimes HPV are ubiquitous and infect a high percentage of people, which can lead to false positivity in PCR investigation as a result of bystander non-tumoral infected cells. This is commonly the problem with EBV and also HPV. , As we showed that the virus is present in neoplastic cells with IHC study of LMP-1, our PCR results are not related to bystander non-tumoral infected cells. In addition, two non-neoplastic lung tissue samples out of 42 controls showed EBV genome by PCR (4.7%). Consequently, the difference between the two groups is not significant in terms of EBV genome status by PCR (Fisher exact test, P = 0.44). However, the IHC study of the positive control cases demonstrated that EBV genome was mainly present in the inflammatory cells and the related PCR results in control samples could be regarded as false positives, a fact that may help to make the difference of EBV expression more significant between the two groups. In a comparable study conducted by Zhang,  he collected surgically resected and paraffin embedded pulmonary carcinoma specimens from 87 cases while each specimen contained separable carcinoma tissue and normal lung tissue, to detect EBV infection and infective copy number by PCR and dot blot hybridization. Of the 87 cases (174 samples), EBV genomic DNA sequences were positive in 52 carcinoma tissue samples and 39 normal tissue samples by PCR. There were no significant differences in positive rates between the two tissues. By dot blot hybridization however, a significant difference was found between carcinoma (43.7%) and normal lung (8.0%) tissues.  Our control samples were not from healthy individuals and the positive ones belonged to two patients, one with tuberculosis and the other with pulmonary hydatid cyst, both of them with marked chronic lymphomononuclear infiltrates. This may be one reason that in our study, the prevalence of EBV DNA in lung cancers did not differ significantly from non-neoplastic pulmonary lesions in PCR.
Apart from the sampling limitations, researchers were unsuccessful in finding a role for EBV in pulmonary carcinogenesis in some other studies as well; In Brouchet  study, a series of 122 cases of small cell lung carcinomas and non-small cell lung carcinomas were studied to detect the presence of several oncogenic viruses in humans, including EBV. None of the cases displayed a single positive tumor cell for all the viruses tested no matter what the technique applied. Of note, in five cases of tumors with lymphoid infiltrates, they detected scattered EBV (EBER)-positive bystander lymphocytes.  Similarly, Conway  did not find any evidence for an etiologic role of EBV in the development of pulmonary or pleural adenocarcinoma by performing EBV encoded RNA-1 ISH on 80 pulmonary adenocarcinoma and 50 mesothelioma specimens.
Until date SCC has been the most frequent type of non-lymphoepithelioma like pulmonary cancers to show the EBV genome. ,, This finding is along with our results while lung cancers, in general, did not correlate with EBV infection, the presence of its DNA in SCCs were significantly higher than any other pulmonary lesions (Fisher exact test, P = 0.02). However, in the Li  study the histopathological type of the cancer was not correlated with EBER-1 expression. He studied 108 cases of primary pulmonary cancers to find evidence of EBV correlation by ISH of formalin fixed and paraffin embedded lung tissues. EBER-1 was detected in 36 cases of lung cancers and only one of the 22 normal lung controls.  EBV DNA PCR was negative in all cases of our small cell carcinomas. Although it may reflect a small sample size, it seems that the presence of the viral fragments is less frequent in this type of cancer in other studies as well; In the Kasai  study, three cases of SCC and two cases of adenocarcinoma showed hybridization of EBER-1 and none of the other types of lung cancers, including small cell carcinoma showed a reaction. Moreover, Chu  studied 23 cases of small cell carcinoma of the lung searching for evidence of EBV infection by ISH, IHC, and PCR methods in America in 2004. None of the 23 cases were positive for EBER-1 by ISH. Using IHC, eight cases demonstrated non-specific staining. 
The most reliable method reported in the literature for detecting latent EBV in this kind of carcinomas has been ISH for EBER. EBER, a short non-polyadenylated chain of RNA, does not translate to protein and consists of two fragments including EBER1 and EBER2. They express nuclearly and their function is unknown, but it is strongly believed that they have an oncogenic effect. 
In the current study, detection of EBV genomic DNA did not correlated with age or gender of patients. Similarly in the Li  series, EBER detection did not show a correlation with patients' age and gender.
| Conclusion|| |
Only a few cases of EBV-associated lung tumors have been reported in the literature. We do not exactly know the role of EBV in these kinds of carcinomas. It can be deduced from our data that EBV is generally not at play in the non-lymphoepithelioma-like cancers of the lung. However, it seems that EBV infection may play a role in the tumorigenesis of some sporadic lung cancers, in particular, SCCs.
| Acknowledgment|| |
We are grateful to Mrs. Behnaz Barazandeh and Mr. Mahmoud Bagheri for their technical assist.
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Department of Pathology, Quaem Hospital, Mashhad University of Medical Sciences, Mashhad
Source of Support: This study was supported by a Grant (No.: 88828)
from Mashhad University of Medical Sciences,, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]
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