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PubMed2002

[Correlation between Fas/Fas-ligand expression and apoptosis in undifferentiated nasopharyngeal carcinoma].

We determined whether resistance to Fas-mediated apoptosis is involved in the development of undifferentiated nasopharyngeal carcinomas (UNPCs). In UNPC tissue sections from 20 cases, we conducted immunohistochemistry to detect Fas and FasL, in situ hybridization to detect Epstein-Barr virus-encoded small RNA (EBER), and immunohistochemistry for single-stranded DNA (ssDNA) to detect apoptotic cells. Fas was detected in 17/20 (85%), FasL in 15/20 (75%), and EBER in 16/20 (80%). Fas was detected in all 16 EBER-positive UNPCs, but not in 3 (75%) of 4 EBER-negative UNPCs. FasL was detected in 12 (75%) of 16 EBER-positive UNPCs and 3 (75%) of 4 EBER-negative UNPCs. Interestingly, despite Fas and FasL co-expression in UNPC cells (Fas+/FasL+ cases = 13/20 or 65%), apoptotic UNPC cells were significantly lower in Fas+/FasL+ than in other cases. These results suggest that Fas+/FasL+ UNPC cells are resistant to Fas-mediated apoptosis in vivo by mechanisms excluding lack of Fas expression.

Apoptosis↗
PubMed1998

[Expression of cytotoxic-granule-associated protein TIA-1 in nasal NK/T cell lymphomas and lymphoid hyperplasia].

OBJECTIVE: 27 cases of nasal NK/T cell lymphomas were studied for the expression of the cytotoxic-granule-associated protein TIA-1, its immunophenotype, genotype and Epstein-Barr virus infection status. METHODS: Immunohistochemical staining for TIA-1, CD3, CD56, CD45RO, CD8, CD20; polymerase chain reaction (PCR) for TCR gamma chain gene and immunoglobulin JH chain gene rearrangement analysis; in situ hybridization for EBER 1/2 and double staining for TIA-1, CD8 with EBER 1/2. 10 cases of lymphoid hyperplasia were used for comparison. RESULTS: (1) In the 27 cases of nasal NK/T cell lymphomas, most tumor cells expressed TIA-1, CD3, CD45RO and EBER 1/2; expression of CD56 was found in 26 cases; no CD8 or CD20 were detected in tumors cells of this series of cases. Double labelled staining showed that the TIA-1 positive tumor cells coexpress EBER 1/2. TCR gamma chain gene rearrangement was detected in only 1 of the 27 cases. (2) In the 10 cases of lymphoid hyperplasia of nasal pharynx, a small amount of TIA-1 positive cells were present in 8 cases and their distribution similar to that of CD8+ cells, in 4 of these cases a few EBER 1/2+ cells were detected, the number of CD45RO+ cells and CD20+ cells were similar in all 10 cases. Double labelled staining showed that the EBER 1/2+ cells did not coexpress TIA-1. CONCLUSION: A high percentage of these tumor cells express TIA-1 and correlate with that of CD56, CD3 epsilon, CD45RO and EBER1/2 in nasal NK/T cell lymphomas. It is suggested that expression of TIA-1 in this tumor may be related to the tumor origin and may also be responsible for its special biologic behavior.

Adolescent↗
PubMed2003

[Primary adenoid cystic carcinoma of the nasopharynx and its relation to Epstein-Barr virus infection].

OBJECTIVE: To investigate the clinicopathologic characteristics of primary nasopharyngeal adenoid cystic carcinoma (NPACC) and its relation to Epstein-Barr virus (EBV) infection in Guangzhou where is a high-incidence area of EBV-associated nasopharyngeal carcinoma (NPC). METHODS: 17 cases of NPACC with clinical record and biopsy samples were collected in Guangzhou and their clinical manifestations were reviewed. Besides HE, Alcian blue and PAS, LSAB immunohistochemistry was performed for detecting the expression of a variety of epithelial markers, CD21 and EBV encoded LMP1. EBV encoded early RNAs (EBER) was detected by using in-situ hybridization. Nested PCR was applied for studying the presence of EBV W-fragment in tissues. RESULTS: The ratio of male to female was 7:10. The patients' age ranged from 30 to 63 years, and the median age was 46 years. 14 out of 17 tumors showed markedly local aggressive growth, presenting as T3 or T4. However, only 1 patient had metastasis of an ipsilateral cervical lymph node. The majority of neoplastic cells were basal-cell like in shape and with scanty cytoplasm and a deeply stained nucleus. Intercellular hyaline or mucinous substance was always present in between the carcinoma cells. Cribriform structure formed by the neoplastic cells could be found in 16 out of these 17 biopsies. The NPACC always express the wide-spectrum cytokeratin and the epithelium membrane antigen. Only a few or a small number of carcinoma cells showed nuclear EBER-signals in 9 cases (9/17). Concurrently, these 9 NPACCs showed a 192 bp W-fragment positive band on electrophoresis gel by nested PCR. LMP1 expression had been found in 5 out of the 9 NPACCs (55.6%) accompanying with EBER-positive carcinoma cells. The EBER-positive infiltrating lymphocytes could also be found in the stroma of 3 out of the 9 EBER-stained NPACC slides. All the tumor cells, including the EBER-positive cell of the 17 NPACCs showed no CD21 expression. CONCLUSIONS: The female is predominant over the male in development of NPACC, which often accompanied with a markedly invasive capacity at the nasopharynx and its neighboring sites. Only a small number of tumor cells, nearly a half of the studied cases were infected with EBV. Therefore, it's postulated that there seems no close relation present between NPACC and EBV infection.

Adult↗
PubMed1995

Localization of Epstein-Barr virus in Castleman's disease by in situ hybridization and immunohistochemistry.

Paraffin wax sections of lymph node biopsies from a total of thirteen patients with the morphologic and clinical features of Castleman's disease were analyzed for the presence of the Epstein-Barr virus (EBV) by in situ hybridization for the noncoding EBV early RNAs (EBERs) and by immunohistochemistry for the EBV-encoded latent membrane protein-1 (LMP-1). Of twelve cases of localized Castleman's disease EBER-positive cells were identified in five, and in these cases were only rarely found and were always confined to the interfollicular regions. LMP-1 was not detected in any of these cases, either alone or after dual staining for EBERs and LMP-1. (A similar pattern of EBER expression is seen in nonneoplastic lymphoid tissue from EBV-positive individuals.) No EBER-positive or LMP-1 positive cells were identified in a single case of multicentric Castleman's disease. In two additional patients initially diagnosed with Castleman's disease of localized plasma cell type, repeat biopsy showed Hodgkin's disease. In both cases Reed-Sternberg cells and their variants were identified in the original biopsy on which the diagnosis of Castleman's disease was made. In one of these cases these cells showed expression of EBERs and LMP-1, indicating latent infection with EBV. The results suggest that EBV is not generally associated with Castleman's disease. Further analysis of a series of cases of multicentric Castleman's disease is indicated.

Adult↗
PubMed1993

Assessment of the methods for the detection of Epstein-Barr virus nucleic acids and related gene products in Hodgkin's disease.

BACKGROUND: Epstein-Barr virus (EBV) is present in the pathogenic cells of a significant number of cases of Hodgkin's disease, particularly of the mixed cellularity subtype. EBV remains latent and the incidence of detection rate of the genomes and gene products varies greatly with the methods employed. EXPERIMENTAL DESIGN: From a pool of 137 cases of Hodgkin's disease previously studied by cold in situ hybridization (ISH) for the presence or absence of EBV DNA and the immunohistochemical reactivity with anti-latent membrane protein 1 antibody, we selected 24 cases (12 EBV DNA-positive, 12 EBV DNA-negative) for Southern blotting, as well as for study with nonisotopic EBER and BHLF1 oligonucleotide probes and amplification of DNA by polymerase chain reaction. EBV positive cases were further tested with anti-ZEBRA (BZLF1) antibody. RESULTS: The EBV DNA detection rate was found to be lower with Southern blotting compared to ISH and IHC methods because 8 of the 12 EBV positive cases were positive with BamHI W probe and only 7 (of the 8) with XhoI 1.9 kb probe. These 7 cases contained monoclonal episomal circular EBV genomes. All EBV DNA-positive cases showed EBER gene transcription by ISH. EBER probes also reacted with small lymphocytes in all EBV DNA+ and 9 EBV DNA- cases. These EBER-positive small lymphocytes were detected neither by BamHI W DNA probe nor by immunohistochemical methods with anti-latent membrane protein 1 and anti-EBNA2 antibodies. Polymerase chain reaction produced a positive result in all EBV DNA+ cases and 2 (of the 9) EBV DNA- cases containing EBER+ small lymphocytes. This discrepancy was attributed to amplification of EBV in reactive lymphocytes. Anti-ZEBRA antibody was positive in 2 cases (one BHLF1+) suggesting infrequent viral replication and probable abortive lytic cycle. CONCLUSIONS: ISH and immunohistochemical methods are more sensitive than Southern blot for detecting EBV in Hodgkin and Reed-Sternberg cells of Hodgkin's disease. Polymerase chain reaction appears to be very sensitive but is less sensitive and specific (amplification of EBV DNA of non-neoplastic lymphocytes) than ISH with non-isotopic EBER oligoprobes, which often detects and localizes EBV in pathogenic cells even when they are in small numbers and also in a few small lymphocytes. In addition, this method offers the advantage of being applied to routinely processed tissue sections.

Antigens, Viral↗
PubMed1999

Detection of Epstein-Barr virus in Korean peripheral T-cell lymphoma.

One hundred thirty-seven patients with peripheral T-cell lymphomas (PTL) were examined for the presence of Epstein-Barr virus (EBV) using in situ hybridization for EBV-encoded RNA (EBER) and Bam H-fragment, lower strand frame (BHLF) and immunohistochemical stain for latent membrane protein (LMP). EBER was detected in tumor cells in 79 cases (58%); 26/66 PTL, unspecified (39%), 3/4 AILD (75%), 47/51 angiocentric lymphomas (AL) (92%), and 3/13 anaplastic large cell lymphoma (ALCL) (23%) by Revised European-American Lymphoma (REAL) classification. EBER was detected in 17/36 nodal (47%) vs. 62/101 extranodal PTLs (61%); 21/24 nasal, 12/32 Waldeyer's ring, 9/13 gastrointestinal, and 20/32 skin and soft tissue PTL. AL was consistently associated with the highest frequency of EBER among the extranodal PTL: nose (19/20), GI tracts (3/3), skin (14/15), and Waldeyer's ring (11/14). In extranodal lymphomas, coagulative-type zonal necrosis was seen almost exclusively in AL and showed correlation with EBER-positivity (P < 0.01). LMP was detected in 24 among 107 cases tested (22%). No signal for BHLF was detected in 76 cases tested, implying absent or negligible incidence of lytic infection. In conclusion, high incidence of EBV was observed in PTL among Koreans, with predilection for angiocentric lymphomas and extranodal presentation, especially involving nose, skin, and gastrointestinal tract.

Adolescent↗
PubMed2004

Molecular characterization of Epstein-Barr virus and oncoprotein expression in nasopharyngeal carcinoma in Korea.

BACKGROUND: We evaluated the characteristics of nasopharyngeal carcinoma in Korea, including its clinical, pathologic, and molecular features, especially emphasizing on the EBV strains involved, latent membrane protein 1 (LMP1) expression, and the alterations of matrix metalloproteinase 9 (MMP9) and E-cadherin expression. METHODS.: The presence of EBV was evaluated by EBER in situ hybridization, and the expression of LMP1, MMP9, and E-cadherin by immunohistochemistry. The characterization of EBV type and LMP1 variant was performed by PCR. RESULTS: EBER was detected in 55 of 57 cases (96%) of nonkeratinizing carcinoma (NKC) and undifferentiated carcinoma, but in only four of nine cases (44%) of squamous cell carcinoma (SCC). EBER positivity was much higher in the group with nodal metastases (p =.003). The predominant strain of EBV infection was type A (81%) and a 30-bp deletion LMP1 variant (77%). All EBER-positive SCCs were infected with EBV type A. LMP1 expression was detected in 36 of 59 (61%) patients with latent EBV infection and MMP9 in 41 of these 59 (69%). LMP1 positivity was much higher among the patients aged 50 years and younger. MMP9 expression was associated with LMP1 expression (p =.008), and nodal and distant metastasis (p =.019, p =.045). Loss of E-cadherin expression was correlated with MMP9 and nodal metastasis. The survival rate was much lower in patients with a higher TNM classification, stage, and a histology of SCC. EBER positivity was associated with a better prognosis in the Kaplan-Meier test, but had no prognostic value by Cox regression analysis. Loss of E-cadherin expression and nodal metastasis were also correlated with local recurrence and distant metastasis. CONCLUSION: EBV type and LMP1 variant had no significant influence on the clinicopathologic properties of tumor. However, there was a tendency toward a better survival in the EBV type B group. Histology and clinical staging were the two most important prognostic factors.

Adolescent↗
PubMed1993

The association between Epstein-Barr virus and Chinese Hodgkin's disease.

Epstein-Barr virus (EBV) can be detected in Hodgkin and Reed-Sternberg (HRS) cells in about one-half of cases of Hodgkin's disease (HD) in Western countries. To determine whether EBV is also associated with HD in a developing country such as China, we studied paraffin sections from 28 Chinese cases of HD for expression of latent membrane protein-I (LMP-I) and EBV-encoded small RNA (EBER-I), using immuno-histology and RNA/RNA in situ hybridization respectively. The cases were selected from a large series of Chinese lymphomas following histological and immunophenotypical revision. EBV gene expression was found in HRS cells in 17/28 cases, and was related to histological sub-type, being present in 10/11 of mixed cellularity, 6/14 nodular sclerosis, 0/1 lymphocytic predominance, 0/1 lymphocytic depletion, and 1/1 unclassified HD. The 2 methods for detecting EBV gene expression gave similar results, except in one case of nodular sclerosis, in which HRS cells were negative for EBER-I, but weakly positive for LMP-I. In 5/12 cases with EBER-negative HRS cells, rare small or medium-sized lymphocytes expressed EBER-I but not LMP-I. These results suggest that (i) Chinese HD is frequently associated with EBV; (ii) the proportional frequency and sub-type distribution of EBV-positive HD are similar in China and in the West; (iii) both LMP-I immunohistology and EBER in situ hybridization reliably detect EBV in HRS cells in routine biopsies, but the former is simpler and less resource-consuming to perform.

Adult↗
PubMed2001

Epstein-Barr virus involvement is mainly restricted to lymphoepithelial type of gastric carcinoma among various epithelial neoplasms.

To demonstrate the association of Epstein-Barr virus (EBV) with primary epithelial neoplasms in the south part of Kyushu, Japan, 761 carcinomas consisting of 75 lung, 61 breast, 107 esophagus, 102 colon, 58 pancreas, 45 thyroid, and 313 gastric cancers were examined by EBER-1 in situ hybridization. EBER-1 was detected in 23 cases (7.3%) out of 313 gastric carcinomas, while none of the other carcinomas was positive for EBER-1. Twenty-eight (9.4%) out of 313 gastric carcinomas were differentiated poorly to moderately carcinomas with prominent lymphoid cell infiltration, similar to so-called lymphoepithelioma-like carcinoma, and 19 cases (67.9%) were positive for EBER-1. Although two (2.6%) and 11(10.3%) out of 75 lung and 107 esophagus carcinomas were so-called lymphoepithelioma-like carcinomas, respectively, but EBER-1 was not detected in other epithelial neoplasms that originated from the lung, esophagus, breast, colon, pancreas, and thyroid in the south of Kyushu, Japan. As a result, EBV was associated with only some gastric carcinomas but not with other epithelial neoplasms originating from the lung, esophagus, breast, colon, pancreas, and thyroid in southern Japan.

Adenocarcinoma↗
PubMed1995

Evidence for lytic infection by Epstein-Barr virus in mucosal lymphocytes instead of nasopharyngeal epithelial cells in normal individuals.

Normal nasopharyngeal tissues from 23 individuals who died of causes unrelated to the upper respiratory system and had no evidence of Epstein-Barr virus (EBV)-related diseases were studied using in situ hybridisation (ISH) and immunohistochemistry for the detection of EBV RNA and expression of EBV proteins, respectively. ISH using 35S-labelled riboprobe for EBV EBER RNA showed occasional to a few EBER+ lymphocytes in the stroma of nasopharyngeal mucosa in 14/16 cases with available paraffin-embedded tissues. In addition, very rare intraepithelial EBER+ lymphocytes were also detected in 3/16 cases. However, in none of these cases was EBER detected in the epithelial cells. Similar results were obtained using a nonradioactive ISH method for EBER (Dako). In 3/23 cases, immunostaining using monoclonal antibodies for EBV proteins on cryostat sections showed occasional cells in the stroma expressing EBV nuclear antigen 2 (EBNA2), latent membrane protein-1 (LMP), and switch protein encoded by BZLF1 gene (ZEBRA) in two cases and only very rare LMP+ and ZEBRA+ cells in one other case. Double immunostaining combining alkaline phosphatase anti-alkaline phosphatase (APAAP) for CD markers and indirect immunofluorescence for LMP showed that the LMP+ cells were either CD19+ or less frequently CD3+, but none were CD68+. These results show that both B and T lymphocytes harbouring EBV can be found in the normal nasopharyngeal tissues. Interestingly, EBV proteins associated with lytic viral replication--diffuse early antigen (EA-D), viral capsid antigen (VCA), or membrane antigen (MA)--were also detected in rare cells in the stroma in one case, and in another case only one MA+ cell was detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Presence of Epstein-Barr virus harbouring small and intermediate-sized cells in Hodgkin's disease. Is there a relationship with Reed-Sternberg cells?

Forty-four cases of Hodgkin's disease (HD), mostly of the nodular sclerosing type, were investigated for the presence of Epstein-Barr virus (EBV) by polymerase chain reaction (PCR) and DNA and RNA in situ hybridization (DISH, RISH), as well as by immunohistochemistry for the detection of latent membrane protein-1 (LMP-1) of EBV. In situ hybridization (ISH) was combined with immunohistochemistry to correlate the presence and activity of the virus at the cellular level. In 18/34 (53 per cent) cases, EBV-DNA sequences could be detected with the PCR method. In 12/18 positive cases, DISH and RISH were also positive. In the remaining six EBV-PCR positive cases, two were also positive with RISH and LMP-1, whereas no positive signal with DISH could be obtained. All DISH and/or RISH positive cases were also positive for LMP-1. With RISH, not only the Reed-Sternberg cells and their mononuclear variants (RS cells) stained positive, but also small and intermediate cells frequently reacted with the EBV-specific probes (EBER-1 and -2). Double staining with cellular markers (CD3, CD20, CD45, CD45RO, CD68, and the lectin PNA) revealed that most of the smaller EBER-positive cells frequently did not express T, B, or histiocytic markers, but that they, as well as the RS cells, showed cytoplasmic and membranous staining with PNA. These smaller EBER-positive cells were not found in EBV-PCR negative HD. EBER-positive RS cells were almost always LMP-1 positive, as well as a substantial proportion of the intermediate-sized cells, whereas the majority of the small EBER-positive cells remained LMP-1 negative.(ABSTRACT TRUNCATED AT 250 WORDS)

DNA, Viral↗
PubMed2000

Malignant transformation of B lymphoma cell line BJAB by Epstein-Barr virus-encoded small RNAs.

EBV-encoded small RNAs (EBERs) are non-polyadenylated and abundantly transcribed RNAs, whose functions have not yet been fully elucidated. Here, we report that the EBV-negative B lymphoma cell line, BJAB, was rendered more malignant and resistant to apoptosis by EBERs. EBER-transfected cells exhibited enhanced growth potential in SCID mice as well as in soft agar, and showed resistance to apoptotic stimuli in comparison with the vector control. EBERs inhibited the activity of the double-stranded RNA-dependent protein kinase, PKR, which is reputed to act as a tumor-suppressor. These results suggest that EBERs play an important role in the pathogenesis of EBV-associated malignancies through the inhibition of PKR.

Apoptosis↗
PubMed1996

A study of the possible etiologic association of Epstein-Barr virus with reactive hemophagocytic syndrome in Hong Kong Chinese.

The herpes group of viruses, particularly Epstein-Barr virus (EBV), has frequently been implicated in the causation of reactive hemophagocytic syndrome (RHS) in the Western populations. EBV has also been implicated in the rare fulminant form of RHS occurring in Oriental children. However, our previous adult-predominant study indicated little clinical and serological evidence of EBV infection in patients with RHS in Hong Kong. In the present study, we further examined this issue using a more sensitive and specific technique for the demonstration of EBV, ie, in situ hybridization for EBV encoded RNA (EBER). The 43 Chinese patients studied were mostly adults with a mean age of 44 years, and a male to female ratio of 1.5:1. About two-thirds (28) of patients had associated malignant lymphoma at the time of diagnosis. Five patients had documented infection (typhoid fever 2; systemic candidiasis 1; adenovirus pneumonia 1; viral encephalitis 1), and two had systemic lupus erythematosus. EBER signals were detected in only 11 cases (25.6%). All positive cases were associated with malignant lymphoma, and the positive signals were exclusively localized to the lymphoma cells but not in the histiocytes. On comparing the results (11 of 28 cases positive; 39.3%) with our previous data on EBER-expression in malignant lymphomas in Hong Kong, no significant difference is observed in the frequency of EBV-positivity between the two groups of lymphomas. Thus, a definite pathogenetic link between EBV and lymphoma-associated RHS cannot be established. However, the overrepresentation of T and T/NK lineage lymphoma in this sample of lymphoma-associated with RHS (61%) versus nonselected cases of lymphomas (31%) suggests that it is the T and T/NK cell origin of the lymphoma rather than the EBV positivity that predisposes to RHS. Notwithstanding the previous findings, EBER in situ hybridization may still serve as a useful adjunct in the investigation of patients with RHS, because the presence of EBER-positive cells should raise a strong suspicion of an underlying malignant lymphoma.

Adolescent↗
PubMed1999

Histological and immunophenotypic profile of nasal NK/T cell lymphomas from Peru: high prevalence of p53 overexpression.

Nasal NK/T-cell lymphoma is a unique form of lymphoma highly associated with Epstein-Barr virus (EBV). These lymphomas are rare in Western populations and much more prevalent in some Asian and Latin American countries. Although there are several sizable studies from Asian countries, the same is not true from South America. The aim of this study was to analyze a series of 32 cases of nasal T-cell lymphoma from Peru and to further extend the characterization of this disease. Immunohistochemistry was performed on paraffin sections using the following antibodies: CD20 (L26), CD45RO, CD3, Ki67, CD57, CD56, TIA-1, bcl-2, and p53. The presence of EBV was investigated with immunohistochemical analysis for latent membrane protein (LMP)-1 and in situ hybridization using an antisense riboprobe to EBER 1. The 32 patients included 18 men and 14 women (M:F ratio, 1.2:1), with a median age of 43 years (11 to 72). Three categories were identified: (1) Nasal NK/T cell lymphomas (28 cases): The morphology ranged from small or medium-sized cells to large transformed cells. Necrosis was present in 86% of the cases, and angioinvasion was seen in 36% of the cases. All cases were positive for CD45RO, CD3, and for TIA-1. CD56 was positive in 21 of 27 cases (78%), and CD57 was negative in all cases. EBER 1 positivity was identified in most of the tumor cells in 27 of 28 cases (96%), including the six cases in which CD56 was negative. Overexpression of p53 was detected in 24 cases (86%). (2) Blastic NK cell lymphoma (1 case): The neoplastic cells resembled those of lymphoblastic lymphoma. CD56 and CD45RO were positive; TIA-1, TdT, and EBER-1 were negative. (3) Peripheral T-cell lymphoma (PTCL) unspecified (3 cases): CD56, TIA-1, and EBER-1 were negative. Nasal lymphomas from Peru with a T cell phenotype are predominantly EBV-associated NK/T cell lymphomas, similar to those described in Asian countries. The expression of CD56, TIA-1, and EBER-1, in combination, are very useful markers for the diagnosis of nasal NK/T cell lymphoma in paraffin-embedded tissue. The differential diagnosis of T-cell lymphomas in the nasal region should include rare cases of PTCL unspecified and the blastic variant of NK cell lymphoma. P53 is overexpressed in 86% of the cases. The significance of this finding with regard to clinical behavior and prognosis remains to be determined.

Adolescent↗
PubMedDate not supplied

Epstein-Barr virus early ribonucleic acids as a diagnostic adjunct for relapsed metastatic tumors in patients with cured primary undifferentiated nasopharyngeal carcinoma.

PURPOSE: Epstein-Barr virus (EBV) has been consistently shown to be associated with undifferentiated nasopharyngeal carcinoma (NPC). In this article, the authors attempt to detect Epstein-Barr virus in distant relapsed metastatic sites in undifferentiated NPC patients with cured primary cancer. MATERIALS AND METHODS: In situ hybridization (ISH) technique is a reliable method to detect EBV early RNAs (EBERs) within NPC cells. We used a nonisotopical ISH technique to examine the presence of EBERs in paraffin-embedded tissues obtained from 1 paired specimen of primary NPC and its metastatic counterpart at liver and 2 metastatic specimens of retroperitoneal lymph nodes and bone. RESULTS: All the primary lesions and the metastatic tumors of NPC with undifferentiated histology contained EBERs that could be clearly detected in the nuclei of cancer cells. CONCLUSIONS: This article shows that EBERs can be successfully detected in cells of the distant relapsed metastatic sites. These results suggest that this nonisotopical ISH method of EBERs can be potentially used to diagnose NPC patients developing distant relapsed metastatic lesions with cured primary cancer early. It can offer quick information as to institute suitable salvage chemotherapy for these patients.

Adult↗
PubMed2005

Distribution and phenotype of Epstein-Barr virus-infected cells in human pharyngeal tonsils.

Although Epstein-Barr virus (EBV) is often found in human tonsils, it remains to be precisely determined in what cells and microenvironment the virus is present. Although generally regarded as a B lymphotropic virus, EBV is associated with non-B-cell tumors, for example, NK/T-cell lymphoma, carcinoma, and leiomyosarcoma. To provide a basis for understanding the origin and biology of EBV-infected non-B cells, the immunophenotype of all EBV-infected cells in reactive human tonsils was determined by subjecting tonsil sections to dual/triple EBER in situ hybridization and immunohistochemistry with monoclonal antibodies to T cells (CD3, CD4, CD8, CCR3), B cells (CD20), plasma cells (CD138), natural killer (NK) cells (PEN5), and epithelial cells (cytokeratin), as well as frozen section immunostaining with antibodies to EBV latent proteins EBNA1, EBNA2, LMP1, and EBV early protein BZLF1. Most tonsils contained nearly equal numbers of EBNA1- and LMP1-positive cells (latency program) while only a few contained EBNA2-positive cells (growth program). More than 1000 EBER-positive cells from six tonsils were detected in the interfollicular zone (59%), tonsillar crypts (26%), and follicles (15%). Most (82%) EBER-positive cells are CD20-positive B cells, 7% are CD3-positive T cells, and 11% are cells of indeterminate lineage, often with plasmacytoid morphology. However, no EBER-positive plasma cells were identified. Rare EBER-positive NK cells and EBER/BZLF1-positive epithelial cells were identified. The direct demonstration of EBV within rare T cells, NK cells, and epithelial cells in reactive human tonsils provide a basis for further understanding of the origin of EBV-associated tumors of non-B-cell type.

Adolescent↗
PubMed1999

Association of Epstein-Barr virus infection with p53 protein accumulation but not bcl-2 protein in nasopharyngeal carcinoma.

AIMS: The aim of this study was to investigate the association of Epstein-Barr virus (EBV) infection with status of p53 protein expression in nasopharyngeal carcinoma (NPC). The expression of EBV gene and gene product, p53 protein and bcl-2 protein in NPC was histopathologically studied. METHODS AND RESULTS: In-situ hybridization using oligonucleotide probe to EBV-encoded small RNAs (EBERs) and immunohistochemistry using monoclonal antibodies against EBV latent membrane protein 1 (LMP1), p53 protein and bcl-2 proteins were performed in 56 primary NPCs. EBERs were detected in 46 (82%) cases and LMP1 in 17 (30%) cases. While 30 of 32 (94%) cases in differentiated nonkeratinizing carcinoma (NKC, WHO type 2) and 16 of 17 (94%) cases in undifferentiated carcinoma (UC, WHO type 3) showed EBERs expression, neither five cases of keratinizing squamous cell carcinoma (KSCC, WHO type 1) nor two cases of adenocarcinoma showed EBERs. bcl-2 protein was detected in 50 (89%) cases, but its expression did not depend on expression of LMP1. p53 protein was detected in 31 (55%) cases, and there was a correlation between expression of EBERs and p53 protein (P < 0.05) but not between LMP1 and p53 protein. CONCLUSION: In this study, close association of NKC and UC but not KSCC with the latent infection with EBV was demonstrated. The induction of bcl-2 protein by LMP1, as shown in vitro, was not demonstrated. The association between overexpression of p53 protein and the presence of EBV suggests that some EBV-encoded protein, which may be different from LMP1, may play a role for nuclear accumulation of p53 protein.

Epstein-Barr Virus Infections↗
PubMed2002

Epstein-Barr virus association and ALK gene expression in anaplastic large-cell lymphoma.

Anaplastic large cell lymphoma of T/null-cell type (ALCL) is associated with a characteristic genetic abnormality t(2;5) that results in the NPM-ALK chimeric gene and the protein product derived thereof. In 10% to 20% of ALCLs, the translocation partners of the ALK gene are genes other than NPM (variant translocations). ALK gene expression limited to the cytoplasm implies a variant translocation. In this study, we have investigated 46 cases of ALCL for expression and localization of ALK protein and its association with Epstein-Barr virus (EBV) (by hybridization to EBV-encoded nuclear RNA-1 [EBER-1] and immunostaining for LMP-1). ALCL patients with a null cell phenotype were significantly younger as compared with those of T-cell phenotype (mean age: 28 years v 42 years; P =.018). Sixteen of 46 ALCL cases (34%) were ALK positive. ALK-positive patients were significantly younger (mean age: 25 years for those with both cytoplasmic and nuclear staining; 22 years for those with exclusive cytoplasmic staining; and 41 years for those negative for the ALK gene; P =.023). EBER-1 was detected in 9 of 46 cases (20%), and LMP-1 expression was noted in 5 of them. By polymerase chain reaction analysis, all EBV-associated cases that were investigated showed type I EBV. Whereas 2 of 23 T-cell ALCLs (9%) were EBER-1+, and 7 of 23 null-cell ALCLs (30%) showed EBV association (P =.057). EBV association was seen in 20% of ALK-negative cases, in 0% of cases with ALK gene expression in both nucleus and cytoplasm, and in 60% of cases with ALK gene expression exclusively in the cytoplasm (P =.02). Further, although ALK-positive-EBER-1+ cases were LMP-1 negative, ALK-negative-EBER-1+ cases were LMP-1 positive. Our study raises the question whether EBV might have an etiological role in the evolution of ALCLs that lack classical t(2;5).

Adult↗