Nasal T-cell lymphoma: a clinicopathologic entity associated with peculiar phenotype and with Epstein-Barr virus

Abstract Recent evidence has shown that most nasal lymphomas (NL) are associated with a T-cell phenotype and are thus called nasal T-cell lymphomas (NTCL), but little information is available about the T-cell receptor (TCR) expression. The presence of Epstein-Barr virus (EBV) genome has been recently reported in NTCL in Oriental populations in which NL and EBV-associated tumors are more common and in occasional Occidental cases. This prompted us to investigate lymphoma biopsies from 7 non- Oriental patients with NTCL for the expression of natural killer (NK) and T-cell antigens, including TCR proteins, for the presence of EBV- encoded latent membrane protein (LMP) using immunohistochemistry and for the presence of EBV DNA and Epstein-Barr early region (EBER) RNA using in situ hybridization (ISH). Six cases displayed a CD3-, TCR alpha beta-, TCR gamma delta-, CD2+, CD7+, CD5-, CD4-, CD8-, CD56+ phenotype, suggesting that these tumors may be peripheral T-cell lymphomas (PTCL) with extensive loss of T-cell antigens and expression of the NK-cell (CD56) antigen or, alternatively, NK-cell neoplasias. The remaining case was a gamma delta PTCL, as shown by the CD3+, TCR gamma delta+ phenotype and the biallelic gamma and delta TCR gene rearrangements. Using ISH, EBER RNA transcripts were detected in tumor cells in all cases and EBV DNA was shown in the 6 tested cases. In all cases, tumor cells expressed LMP. These findings support the concept that NTCL constitute a distinct group of lymphomas that, in addition to their peculiar clinical features, exhibit an unusual TCR “silent” CD56+ or TCR gamma delta+ phenotype and harbor the EBV. In view of the LMP transforming potential, these data suggest that EBV may play a role in the pathogenesis of NTCL.

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Nasal T-cell lymphoma: a clinicopathologic entity associated with peculiar phenotype and with Epstein-Barr virus

Blood ◽

10.1182/blood.v81.10.2688.bloodjournal81102688 ◽

1993 ◽

Vol 81 (10) ◽

pp. 2688-2695 ◽

Cited By ~ 4

Author(s):

P Kanavaros ◽

MC Lescs ◽

J Briere ◽

M Divine ◽

F Galateau ◽

...

Keyword(s):

T Cell ◽

Tumor Cells ◽

Epstein Barr Virus ◽

Nk Cell ◽

Gamma Delta ◽

Barr Virus ◽

T Cell Lymphomas ◽

T Cell Antigens ◽

Ebv Dna ◽

Epstein Barr

Recent evidence has shown that most nasal lymphomas (NL) are associated with a T-cell phenotype and are thus called nasal T-cell lymphomas (NTCL), but little information is available about the T-cell receptor (TCR) expression. The presence of Epstein-Barr virus (EBV) genome has been recently reported in NTCL in Oriental populations in which NL and EBV-associated tumors are more common and in occasional Occidental cases. This prompted us to investigate lymphoma biopsies from 7 non- Oriental patients with NTCL for the expression of natural killer (NK) and T-cell antigens, including TCR proteins, for the presence of EBV- encoded latent membrane protein (LMP) using immunohistochemistry and for the presence of EBV DNA and Epstein-Barr early region (EBER) RNA using in situ hybridization (ISH). Six cases displayed a CD3-, TCR alpha beta-, TCR gamma delta-, CD2+, CD7+, CD5-, CD4-, CD8-, CD56+ phenotype, suggesting that these tumors may be peripheral T-cell lymphomas (PTCL) with extensive loss of T-cell antigens and expression of the NK-cell (CD56) antigen or, alternatively, NK-cell neoplasias. The remaining case was a gamma delta PTCL, as shown by the CD3+, TCR gamma delta+ phenotype and the biallelic gamma and delta TCR gene rearrangements. Using ISH, EBER RNA transcripts were detected in tumor cells in all cases and EBV DNA was shown in the 6 tested cases. In all cases, tumor cells expressed LMP. These findings support the concept that NTCL constitute a distinct group of lymphomas that, in addition to their peculiar clinical features, exhibit an unusual TCR “silent” CD56+ or TCR gamma delta+ phenotype and harbor the EBV. In view of the LMP transforming potential, these data suggest that EBV may play a role in the pathogenesis of NTCL.

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Presence of Epstein-Barr virus in extranodal T-cell lymphomas: differences in relation to site

Blood ◽

10.1182/blood.v83.6.1612.bloodjournal8361612 ◽

1994 ◽

Vol 83 (6) ◽

pp. 1612-1618 ◽

Cited By ~ 1

Author(s):

PC de Bruin ◽

M Jiwa ◽

JJ Oudejans ◽

P van der Valk ◽

P van Heerde ◽

...

Keyword(s):

T Cell ◽

Tumor Cells ◽

Epstein Barr Virus ◽

Large Cell ◽

Differentiation Markers ◽

Similar Morphology ◽

Barr Virus ◽

T Cell Lymphomas ◽

Epstein Barr ◽

Hodgkin's Lymphomas

T-cell lymphomas with similar morphology but with different sites of origin have a different clinical behavior. The theoretical explanation for this finding originates from the hypothesis that non-Hodgkin's lymphomas (NHLs) are neoplastic equivalents of immunological reactions involving tissue-restricted lymphocytes. This hypothesis also implies that T-NHLs originating from different sites differ in their genesis, and thus may differ in oncogen expression, expression of adhesion molecules, or presence of certain DNA/RNA viral sequences. Therefore, we have investigated in T-cell lymphomas with similar morphology originating from different sites, ie, nose (n = 5; all pleomorphic small- or medium- and large-cell T-cell lymphomas [PTL]), skin (PTL, n = 6; anaplastic large-cell [ALCL], n = 11), gut (PTL, n = 8; ALCL, n = 4), and lung (PTL, n = 6), the presence of Epstein-Barr virus (EBV) at the DNA, RNA (EBER 1 and EBER 2), and protein level (LMP-1). A double- staining technique was used to detect EBER 1/2, LMP-1, and differentiation markers at the single-cell level. High numbers of EBER 1/2-positive tumor cells (> 100 per medium power field [mpf]) were found in five of five nasal T-cell lymphomas, none of 17 primary cutaneous T-cell lymphomas, one of 12 gastrointestinal T-cell lymphomas (ALCL), and two of six pulmonary T-cell lymphomas. These lymphomas are therefore called EBV-associated lymphomas. In contrast to our earlier findings in lymph nodes, no extranodal lymphomas were found, with only a few EBV-positive tumor cells. Five gastrointestinal cases positive for EBV by polymerase chain reaction (PCR) showed that EBER 1/2 was only found in sporadic nonneoplastic, ie, reactive lymphocytes. Angiocentricity was present in 18 PTL and one ALCL, but not associated with the presence of EBV. These results indicate that the presence of EBV in extranodal T-cell lymphomas is site-restricted and argues for a different pathogenesis of T-cell lymphomas with similar morphology but originating from different sites. The presence of EBV in most tumor cells in these EBV-associated lymphomas suggests that when present, EBV might be important in the pathogenesis of these lymphomas.

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Presence of Epstein-Barr virus in extranodal T-cell lymphomas: differences in relation to site

Blood ◽

10.1182/blood.v83.6.1612.1612 ◽

1994 ◽

Vol 83 (6) ◽

pp. 1612-1618 ◽

Cited By ~ 65

Author(s):

PC de Bruin ◽

M Jiwa ◽

JJ Oudejans ◽

P van der Valk ◽

P van Heerde ◽

...

Keyword(s):

T Cell ◽

Tumor Cells ◽

Epstein Barr Virus ◽

Large Cell ◽

Differentiation Markers ◽

Similar Morphology ◽

Barr Virus ◽

T Cell Lymphomas ◽

Epstein Barr ◽

Hodgkin's Lymphomas

Abstract T-cell lymphomas with similar morphology but with different sites of origin have a different clinical behavior. The theoretical explanation for this finding originates from the hypothesis that non-Hodgkin's lymphomas (NHLs) are neoplastic equivalents of immunological reactions involving tissue-restricted lymphocytes. This hypothesis also implies that T-NHLs originating from different sites differ in their genesis, and thus may differ in oncogen expression, expression of adhesion molecules, or presence of certain DNA/RNA viral sequences. Therefore, we have investigated in T-cell lymphomas with similar morphology originating from different sites, ie, nose (n = 5; all pleomorphic small- or medium- and large-cell T-cell lymphomas [PTL]), skin (PTL, n = 6; anaplastic large-cell [ALCL], n = 11), gut (PTL, n = 8; ALCL, n = 4), and lung (PTL, n = 6), the presence of Epstein-Barr virus (EBV) at the DNA, RNA (EBER 1 and EBER 2), and protein level (LMP-1). A double- staining technique was used to detect EBER 1/2, LMP-1, and differentiation markers at the single-cell level. High numbers of EBER 1/2-positive tumor cells (> 100 per medium power field [mpf]) were found in five of five nasal T-cell lymphomas, none of 17 primary cutaneous T-cell lymphomas, one of 12 gastrointestinal T-cell lymphomas (ALCL), and two of six pulmonary T-cell lymphomas. These lymphomas are therefore called EBV-associated lymphomas. In contrast to our earlier findings in lymph nodes, no extranodal lymphomas were found, with only a few EBV-positive tumor cells. Five gastrointestinal cases positive for EBV by polymerase chain reaction (PCR) showed that EBER 1/2 was only found in sporadic nonneoplastic, ie, reactive lymphocytes. Angiocentricity was present in 18 PTL and one ALCL, but not associated with the presence of EBV. These results indicate that the presence of EBV in extranodal T-cell lymphomas is site-restricted and argues for a different pathogenesis of T-cell lymphomas with similar morphology but originating from different sites. The presence of EBV in most tumor cells in these EBV-associated lymphomas suggests that when present, EBV might be important in the pathogenesis of these lymphomas.

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Epstein–Barr Virus (EBV) Viral Load in Tumor Cells Did Not Predict Tumor Extensiveness in Nasopharyngeal Cancer

Microbiology Research ◽

10.3390/microbiolres12010011 ◽

2021 ◽

Vol 12 (1) ◽

pp. 150-156

Author(s):

Soehartati A. Gondhowiardjo ◽

Handoko ◽

Marlinda Adham ◽

Lisnawati Rachmadi ◽

Henry Kodrat ◽

...

Keyword(s):

Viral Load ◽

Tumor Cells ◽

Epstein Barr Virus ◽

Tumor Volume ◽

Nasopharyngeal Cancer ◽

Dna Quantification ◽

Barr Virus ◽

Nasopharyngeal Biopsy ◽

Ebv Dna ◽

Epstein Barr

Background: Nasopharyngeal cancer is commonly associated with Epstein–Barr virus (EBV) infection, especially undifferentiated non-keratinized histology. EBV DNA quantification through nasopharyngeal brushing was previously reported to be not related to disease stage. This study aimed to reinvestigate the relationship of EBV viral load in tumor tissue with tumor extensiveness by more accurate EBV DNA quantification through microscopically confirmed tumor cells from nasopharyngeal biopsy. Method: The specimens for EBV DNA quantification were derived from histopathology slides which were pre-treated following the QIAsymphony® SP protocol for tissue DNA extraction. Then, the extracted DNA underwent real-time polymerase chain reaction (RT-PCR) using the artus® EBV RG PCR Kit for EBV DNA quantification. The tumor volume was determined by delineating the gross tumor based on 3D imaging of the patient’s nasopharynx. Result: Twenty-four subjects were included in this study. All subjects were stage III and above, with more males (75%) than females. EBV viral load in tumor cells was found to have no correlation to tumor volume both in local and nodal regions. The median local tumor volume was 81.3 cm3 ± 80 cm3. The median EBV viral load in tumor cells was 95,644.8 ± 224,758.4 copies/100 ng of DNA. The median nodal or regional tumor volume was 35.7 ± 73.63 cm3. Conclusion: EBV viral load from tumor cells from nasopharyngeal biopsy has no relationship with tumor extensiveness in nasopharyngeal cancer. The presence and amount of EBV in tumor cells did not translate into larger or smaller tumors. The EBV viral proteins and RNAs were perhaps more likely to confer some prognostic information due to the fact that those molecules were related to carcinogenesis.

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Quantification of circulating Epstein-Barr virus (EBV) DNA in the diagnosis and monitoring of natural killer cell and EBV-positive lymphomas in immunocompetent patients

Blood ◽

10.1182/blood-2003-12-4197 ◽

2004 ◽

Vol 104 (1) ◽

pp. 243-249 ◽

Cited By ~ 208

Author(s):

Wing-Yan Au ◽

Annie Pang ◽

Carolyn Choy ◽

Chor-Sang Chim ◽

Yok-Lam Kwong

Keyword(s):

Multivariate Analysis ◽

Natural Killer ◽

Epstein Barr Virus ◽

Nk Cell ◽

Disease Stage ◽

Tumor Biomarker ◽

Barr Virus ◽

Ebv Dna ◽

Epstein Barr ◽

Immunocompetent Patients

Abstract In Epstein-Barr-virus (EBV)–positive lymphomas in immunocompetent patients, release of EBV DNA from tumor cells into the plasma might be useful for disease monitoring and prognostication. To test this hypothesis, we quantified serially plasma EBV DNA by quantitative polymerase chain reaction in 39 cases of EBV-positive (natural killer [NK] cell, n = 23; T cell, n = 8; B cell, n = 4; Hodgkin, n = 4) lymphomas. As control, EBV DNA was undetectable in 34 cases of EBV-negative lymphomas at diagnosis and during chemotherapy. In all cases of EBV-positive lymphomas, EBV DNA was detectable (105-1010 copies/mL) at diagnosis. It paralleled the clinical course, with EBV DNA becoming undetectable at remission and remaining elevated in refractory disease. On multivariate analysis, high-presentation EBV DNA (> 7.3 × 107 copies/mL) was significantly associated with an inferior overall survival (OS). Subgroup analysis of NK cell lymphomas, the largest cohort in this study, showed that presentation EBV DNA was correlated with disease stage and lactate dehydrogenase. On multivariate analysis, high-presentation EBV DNA (> 6.1 × 107 copies/mL) was significantly associated with an inferior disease-free survival. During treatment, patients with EBV DNA that showed further increases or failed to become undetectable had significantly inferior OS. In EBV-positive lymphomas, plasma EBV DNA is valuable as a tumor biomarker and for prognostication.

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The latency pattern of Epstein–Barr virus infection and viral IL-10 expression in cutaneous natural killer/T-cell lymphomas

British Journal of Cancer ◽

10.1054/bjoc.2000.1687 ◽

2001 ◽

Vol 84 (7) ◽

pp. 920-925 ◽

Cited By ~ 32

Author(s):

Z-G Xu ◽

K Iwatsuki ◽

N Oyama ◽

M Ohtsuka ◽

M Satoh ◽

...

Keyword(s):

T Cell ◽

Virus Infection ◽

Epstein Barr Virus ◽

Epstein Barr Virus Infection ◽

Natural Killer T Cell ◽

Barr Virus ◽

T Cell Lymphomas ◽

Epstein Barr ◽

Barr Virus Infection ◽

Killer T Cell

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Identification of potential hot spots in the carboxy-terminal part of the Epstein-Barr virus (EBV) BNLF-1 gene in both malignant and benign EBV-associated diseases: high frequency of a 30-bp deletion in Malaysian and Danish peripheral T-cell lymphomas

Blood ◽

10.1182/blood.v84.12.4053.bloodjournal84124053 ◽

1994 ◽

Vol 84 (12) ◽

pp. 4053-4060 ◽

Cited By ~ 85

Author(s):

K Sandvej ◽

SC Peh ◽

BS Andresen ◽

G Pallesen

Keyword(s):

T Cell ◽

Hot Spots ◽

Epstein Barr Virus ◽

Terminal Part ◽

Gene Encoding ◽

Single Base ◽

Barr Virus ◽

T Cell Lymphomas ◽

Epstein Barr ◽

Peripheral T Cell Lymphomas

In this study, we have sequenced the C-terminal part of the Epstein- Barr virus (EBV)-BNLF-1 gene encoding for the latent membrane protein-1 from tissues of EBV-positive Danish Hodgkin's disease (HD) and of Danish and Malaysian peripheral T-cell lymphomas (PTLs) and from tonsils of Danish infectious mononucleosis (IM). Our study showed that some of the 7 single-base mutations and the 30-bp deletion previously detected between codons of amino acid 322 and 366 in the BNLF-1 gene of the nasopharyngeal carcinoma cell line CAO were present in all Malaysian PTLs and in 60% of the Danish PTLs. In HD and the IM cases, the mutations were present in about 30%. The 30-bp deletion and the single base mutations occurred independently, and mutations were detectable in the majority of EBV type B-positive cases. These findings suggest that the 30-bp deletion and the 7 single-base mutations in the C-terminal part of the CAO-BNLF-1 gene do not characterize a new EBV type A substrain. Rather, some of the positions of single base mutations and the 30-bp deletion are hot spots that may have mutated independently through the evolution of EBV strains.

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Hydroa Vacciniforme and Hydroa Vacciniforme-Like Lymphoproliferative Disorder: A Spectrum of Disease Phenotypes Associated with Ultraviolet Irradiation and Chronic Epstein–Barr Virus Infection

International Journal of Molecular Sciences ◽

10.3390/ijms21239314 ◽

2020 ◽

Vol 21 (23) ◽

pp. 9314

Author(s):

Chien-Chin Chen ◽

Kung-Chao Chang ◽

L Jeffrey Medeiros ◽

Julia Yu-Yun Lee

Keyword(s):

T Cell ◽

Natural Killer ◽

Ultraviolet Irradiation ◽

Epstein Barr Virus ◽

Nk Cell ◽

Current Evidence ◽

Barr Virus ◽

Ebv Infection ◽

Hydroa Vacciniforme ◽

Epstein Barr

Hydroa vacciniforme (HV) is a rare form of photosensitivity disorder in children and is frequently associated with Epstein–Barr virus (EBV) infection, whereas HV-like lymphoproliferative disorders (HVLPD) describe a spectrum of EBV-associated T-cell or natural killer (NK)-cell lymphoproliferations with HV-like cutaneous manifestations, including EBV-positive HV, atypical HV, and HV-like lymphoma. Classic HV occurs in childhood with papulovesicules on sun-exposed areas, which is usually induced by sunlight and ultraviolet irradiation, and mostly resolves by early adult life. Unlike classic HV, atypical or severe HV manifests itself as recurrent papulovesicular eruptions in sun-exposed and sun-protected areas associated occasionally with facial edema, fever, lymphadenopathy, oculomucosal lesions, gastrointestinal involvement, and hepatosplenomegaly. Notably, atypical or severe HV may progress to EBV-associated systemic T-cell or natural killer (NK)-cell lymphoma after a chronic course. Although rare in the United States and Europe, atypical or severe HV and HV-like lymphoma are predominantly reported in children from Asia and Latin America with high EBV DNA levels, low numbers of NK cells, and T cell clones in the blood. In comparison with the conservative treatment used for patients with classic HV, systemic therapy such as immunomodulatory agents is recommended as the first-line therapy for patients with atypical or severe HV. This review aims to provide an integrated overview of current evidence and knowledge of HV and HVLPD to elucidate the pathophysiology, practical issues, environmental factors, and the impact of EBV infection.

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How I treat NK/T-cell lymphomas

Blood ◽

10.1182/blood-2013-01-453233 ◽

2013 ◽

Vol 121 (25) ◽

pp. 4997-5005 ◽

Cited By ~ 144

Author(s):

Eric Tse ◽

Yok-Lam Kwong

Keyword(s):

T Cell ◽

Nk Cell ◽

Early Stage ◽

Receptor Gene ◽

Cell Receptor ◽

Hematopoietic Stem ◽

Barr Virus ◽

T Cell Lymphomas ◽

Ebv Dna ◽

Nk T Cell

Abstract Natural killer (NK)/T-cell lymphomas and NK-cell leukemias are aggressive malignancies. Occurring worldwide, they show a predilection for Asian and South American populations. Neoplastic cells are surface CD3−, cytoplasmic CD3ε+, CD56+, cytotoxic-molecule positive, Epstein-Barr virus (EBV) positive, with germline T-cell receptor gene. Lymphomas occur commonly in the nasal and upper aerodigestive region. Occasional cases present in the skin, salivary gland, testis, and gastrointestinal tract. Rare cases are disseminated with lymphadenopathy, hepatosplenomegaly, and a leukemic phase. Positron emission tomography computed tomography is useful in staging, as lymphomas are 18-fluorodeoxyglucose avid. Quantification of circulating EBV DNA is an accurate biomarker of tumor load. Nasal NK/T-cell lymphomas present mostly with stage I/II disease. Concomitant/sequential chemotherapy and radiotherapy is standard treatment. Radiotherapy alone is inadequate because of high systemic failure rate. For stage III/IV nasal, nonnasal, and disseminated lymphomas, systemic chemotherapy is indicated. Regimens containing l-asparaginase and drugs unaffected by P-glycoprotein are most effective. Hematopoietic stem cell transplantation (HSCT) is not indicated for early-stage nasal lymphomas. HSCT for lymphomas not in remission has poor results. In advanced-stage nasal, nonnasal, disseminated, or relapsed lymphomas, HSCT may be considered when remission is achieved. Prognostic modeling and EBV DNA monitoring may be useful in risk stratification for HSCT.

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