Epstein–Barr virus-associated lymphoproliferative disease in non-immunocompromised hosts: a status report and summary of an international meeting, 8–9 September 2008

BackgroundRecently novel Epstein–Barr virus (EBV) lymphoproliferative diseases (LPDs) have been identified in non-immunocompromised hosts, both in Asia and Western countries. These include aggressive T-cell and NK-cell LPDs often subsumed under the heading of chronic active Epstein–Barr virus (CAEBV) infection and EBV-driven B-cell LPDs mainly affecting the elderly.DesignTo better define the pathogenesis, classification, and treatment of these disorders, participants from Asia, The Americas, Europe, and Australia presented clinical and experimental data at an international meeting.ResultsThe term systemic EBV-positive T-cell LPD, as adopted by the WHO classification, is preferred as a pathological classification over CAEBV (the favored clinical term) for those cases that are clonal. The disease has an aggressive clinical course, but may arise in the background of CAEBV. Hydroa vacciniforme (HV) and HV-like lymphoma represent a spectrum of clonal EBV-positive T-cell LPDs, which have a more protracted clinical course; spontaneous regression may occur in adult life. Severe mosquito bite allergy is a related syndrome usually of NK cell origin. Immune senescence in the elderly is associated with both reactive and neoplastic EBV-driven LPDs, including EBV-positive diffuse large B-cell lymphomas.ConclusionThe participants proposed an international consortium to facilitate further clinical and biological studies of novel EBV-driven LPDs.     

Mono/oligoclonal pattern of Kaposi Sarcoma-associated herpesvirus (KSHV/HHV-8) episomes in primary effusion lymphoma cells

Primary effusion lymphoma (PEL) is a rare lymphoma of B-cell origin, developed in serous cavities. PEL tumor cells are latently infected with Kaposi sarcoma-associated herpesvirus (KSHV) and in most cases co-infected with Epstein-Barr virus (EBV). In 15 primary PEL tumors including 10 EBV-positive cases, we analyzed the fused terminal repeat (TR) regions of KSHV episomes using pulsed-field gel electrophoresis and Southern blot. On the same genomic DNA samples, the cellular clonality was assessed by Southern blot and PCR detection of monoclonal immunoglobulin heavy chain (IGH) VDJ gene rearrangements, associated in the EBV-infected cases, with Southern blot analysis of the fused termini of EBV episomes. Monoclonal IGH gene rearrangements were detected in 13 tumors using Southern blot, in 11 cases using PCR, and in all cases considering both methods. EBV infection was monoclonal in all EBV-positive cases. However, only 5 PEL tumors were found to be monoclonally infected with KSHV. In the 10 other cases, we found a biclonal (2 bands; n = 4) or an oligoclonal pattern (3-6 bands; n = 6) of KSHV episomes. We hypothesized that the apparent discrepancy between viral and cellular clonalities in PEL might be due to several phenomena including complex mechanisms of genomic recircularization, insertion of duplicated sequences into the TR region and simultaneous infection of tumor cells with defective KSHV variants. KSHV infection of contaminating nontumoral cells, superinfection from lytically infected cells or viral integration events might also explain the oligoclonal pattern of KSHV infection. Several of these mechanisms, not mutually exclusive, might coexist in a single tumor.     

Prevalence of mycosis fungoides and its association with EBV and HTLV-1 in Pakistanian patients

Mycosis fungoides (MF) is an indolent T cell lymphoma that is distinguished from other lymphomas by its initial appearance on the skin. The histologic diagnosis of MF may be difficult because there is significant overlap in the histologic features of neoplastic T-cell infiltrates and inflammatory dermatoses. This T-cell neoplasm commonly occurs in a mixed, reactive background and can show only a subtle degree of cytologic atypia, rendering histologic diagnosis difficult. In this study MF constituted 0.86% of all non-Hodgkin s lymphoma (NHL) both T and B, as compared to the Western studies which have reported 0.5% prevalence for MF of all NHL. Polymerase chain reaction (PCR) technique was used to assess T-cell clonality in paraffin-embedded skin biopsies clinically and pathologically suspicious for early MF. Out of the 14 cases diagnosed as MF, amplifiable DNA was isolated from 6 cases, which were further studied for T-cell receptor (TcR) beta, gamma, and delta chain gene rearrangements. Clonal product was seen in 4 out of 6 cases for beta, gamma, and delta TcR chain genes. Association for Epstein Barr virus (EBV) was observed in 3 out of 6 cases (50%) of MF. Although these 3 cases were positive for EBV by PCR, but were negative by in-situ hybridization (ISH). No heterogeneity was noted in these 3 cases of MF for BamHI E, K, N, and Z regions of EBV. All six cases were negative for HTLV-1 (tax region) by PCR. It was concluded that the prevalence of MF in Pakistani population is comparable to the Western data, and that EBV association to MF cases was higher than in Western studies.     

胃肠道B细胞淋巴瘤中bcl-2的表达及与EB病毒的相关性研究

 目的　研究胃肠道B细胞淋巴瘤与bcl 2蛋白的表达及与EB病毒感染的关系。方法　采用免疫组织化学、原位杂交方法分别检测 16例胃肠道B细胞淋巴瘤中bcl 2、LMP 1蛋白及EB病毒编码的E BER1/2表达水平。结果　bcl 2蛋白阳性表达 13例 (81.3% ) ,均为高表达 ,其中 7例低度恶性MALT型淋巴瘤均为阳性。EB病毒编码的EBER1/2及LMP 1均为阴性。结论　胃肠道B细胞淋巴瘤特别是低度恶性MALT型B细胞淋巴瘤 ,与bcl 2蛋白的高表达密切相关 ,而与EB病毒的感染似乎无相关性     

KHSV− EBV− post‐transplant effusion lymphoma with plasmablastic features: variant of primary effusion lymphoma?

Primary effusion lymphoma (PEL) is a rare type of B‐cell non‐Hodgkin lymphoma (NHL), which predominantly occurs in HIV‐infected individuals, and is pathogenetically linked with Kaposi sarcoma (KS)‐associated herpes virus/human herpes virus‐8 (KSHV/HHV‐8) infection with or without evidence of Epstein–Barr virus (EBV) co‐infection. Although uncommon, PELs have been reported in immunocompetent patients and recipients of solid organ allografts. Rare cases of KSHV^? EBV⁺ post‐transplant effusion lymphomas resembling PEL have also been described, as have KSHV^? EBV^? effusion lymphomas, the latter including those arising in individuals with chronic liver disease. We report a unique KSHV^? EBV^? post‐transplant effusion lymphoma associated with serum paraproteins, occurring in an HIV^? individual, which had cytologic features and phenotype similar to PEL, and displayed a complex karyotype including isochromosome 12p and translocation t(8;22), resulting in rearrangement of c‐MYC. Copyright © 2009 John Wiley & Sons, Ltd.     

中线T细胞淋巴瘤与EB病毒关系的研究

为了解ＥＢ病毒在中线Ｔ细胞淋巴瘤中的感染情况，作者对遵义地区４６例中线Ｔ细胞淋巴瘤进行ＥＢＶ检测，用聚合酶链反应检测ＥＢＶ特征性的ＤＮＡ序列（ＥＢＶＤＮＡ），用ＲＮＡ原位杂交法检测ＥＢＶ编码的ＲＮＡ（ＥＢＥＲ１／２）。结果：ＥＢＶＤＮＡ阳性率为７６．１％（３５／４６）；ＥＢＥＲ１／２阳性率为６７．４％（３１／４６）。鼻腔、鼻咽、口咽Ｔ淋巴瘤ＥＢＥＲ１／２阳性率分别为８８．９％（１６／１８）、７１．４％（５／７）、４７．６％（１０／２１）。在多形细胞性淋巴瘤中，中多形和大多形细胞性ＥＢＥＲ１／２阳性率为８０．０％（１６／２０），小多形细胞性为７３．３％（１１／１５）。结果表明ＥＢＶ感染与中线Ｔ淋巴瘤关系密切，它在该肿瘤的发病中可能起重要作用，中线Ｔ淋巴瘤的ＥＢＶ感染率与解剖学部位有关，多形细胞性淋巴瘤ＥＢＶ感染率较高，特别是中多形和大多形细胞性     

天津地区上呼吸道恶性淋巴瘤临床病理、免疫表型及其与EB病毒相关性的研究

目的 :研究天津地区上呼吸道恶性淋巴瘤的临床病理、免疫表型及与 EB病毒的关系。方法 :应用单克隆抗体 U CHL - 1、CD3、L2 6 、4KB5 、CD79a、L CA、EMA、溶菌酶等抗体及 CS1- 4(L MP- 1)进行免疫组化染色 ,以进行淋巴瘤确诊、淋巴瘤免疫表型研究和 EB病毒感染情况的分析 ;EB病毒寡核苷酸探针 (EBER1/ 2 )原位杂交检测 ,探讨瘤细胞 EB病毒感染情况及与 EB病毒潜在膜蛋白表达的相关性。结果 :12 5例上呼吸道原诊断为恶性淋巴瘤和高度怀疑恶性淋巴瘤的病例中 112例确诊为淋巴瘤 ,诊断符合率 89.6 %。其中 6 6例为 T细胞性淋巴瘤 (占5 8.93% ) ,46例为 B细胞性淋巴瘤 (占 41.0 7% )。男性明显多于女性 (85例 / 2 7例 )。平均年龄 48.2 7岁 (10岁～ 88岁 )。 EBV- EBER1/ 2原位杂交检测 T细胞性淋巴瘤 34例 ,17例阳性 ,占 5 0 % ,阳性细胞占肿瘤细胞的 2 0 %～80 % ,EBV潜在膜蛋白 L MP- 1检测 5 3例 ,11例阳性 ,占 2 0 .75 % ,阳性率低于 EBER探针。结论 :天津地区上呼吸道恶性淋巴瘤以 T细胞性淋巴瘤为多见 ,发病可能与 EB病毒感染有关。     

中线T细胞淋巴瘤与EB病毒关系的观察

为研究中线Ｔ细胞淋巴瘤（ＭＴＬ）与ＥＢ病毒的关系，运用原位杂交和免疫组化技术检测２０例中线Ｔ细胞淋巴瘤，观察其ＥＢ病毒的存在情况，结果２０例ＭＴＬ均显示Ｔ细胞标记阳性，Ｂ细胞标记阴性；原位杂交ＥＢ病毒（ＥＢＥＲ－１）阳性率７０％（１４／２０），ＬＭＰ－１检出率５０％（１０／２０），结果表明ＥＢ病毒感染与ＭＴＬ存在密切关系，可能在其发病中起着重要作用     

Monoclonality or oligoclonality of human herpesvirus 8 terminal repeat sequences in Kaposi's sarcoma and other diseases

BACKGROUND: Infection with human herpesvirus 8 (HHV8), also termed Kaposi's sarcoma (KS)-associated herpesvirus, is associated with all forms of KS, with primary effusion lymphoma (PEL), and with some forms of multicentric Castleman's disease (MCD), but the pathogenic role of HHV8 in these tumors and the clonal nature of KS are still unclear. The purpose of this study was to examine whether the number of terminal repeats (TRs) contained in the fused TR region of HHV8 could be used as a marker of clonality in HHV8-associated tumors. METHODS: Pulsed-field gel electrophoresis (PFGE) and multiple-probe Southern blot analysis of the HHV8 TR region were performed on high-molecular-weight DNA obtained from tumoral KS, PEL, and MCD lesions. RESULTS: These analysis showed that the fused TR region contains a large but variable number of TR units (ranging from 16 to 75) and that the viral genome is present as extrachromosomal circular DNA in these tumors in vivo, with occasional ladders of heterogeneous linear termini reflecting lytic replication. All PEL tumors and PEL-derived cell lines as well as some KS tumors contained monoclonal or oligoclonal fused TR fragments; however, the TR region appeared polyclonal in MCD tumors and in a few KS lesions. CONCLUSION: Several KS and PEL lesions are monoclonal expansions of a single infected cell, suggesting that HHV8 infection precedes tumor growth and thus supporting an etiologic role of latent HHV8 in these proliferations. Our finding that nodular KS lesions display all possible patterns of clonality supports the model according to which KS begins as a polyclonal disease with subsequent evolution to a monoclonal process.     

EBV primary infection in childhood and its relation to B‐cell lymphoma development: A mini‐review from a developing region

In most underdeveloped countries, the initial contact with Epstein Barr virus (EBV) usually happens in the first decade of life and results in an asymptomatic infection, whereas in developed areas, primary infection in adolescence or adulthood is accompanied by infectious mononucleosis in 50% cases. Although it is generally a harmless passenger, in some individuals, it is associated with B‐cell lymphoma. In Argentina, EBV primary infection shows the classical pattern observed in developing populations, given that nearly 70% of patients are seropositive by the age of 2 years. However, EBV association with pediatric Hodgkin and Burkitt lymphoma resembles that observed in developed regions. Concerning diffuse large B‐cell lymphoma, our series demonstrated higher EBV association than other adult ones from either developed or underdeveloped countries. Interestingly, the early EBV primary infection observed, characteristic of an underdeveloped population, together with the statistically significant EBV association with patients ≤10 years old demonstrated in all types of lymphoma studied, suggest a relationship between low age of EBV seroconversion and B‐cell lymphoma development risk.     

Epstein-Barr virus-associated peripheral T-cell lymphoma of activated CD8 phenotype

Two childhood cases are reported of peripheral T-cell lymphoma; the neoplastic cells expressed activated CD8 (T8) phenotype and contained Epstein-Barr viral (EBV) DNA. Both patients had an aggressive and rapid clinical course despite chemotherapy. Elevated titers of antibodies to EBV-viral capsid antigen (greater than 640) and early antigen (greater than 10) were found in both patients. Histology revealed pleomorphic immunoblastic lymphoma with extensive necrosis in one case and an angioimmunoblastic lymphadenopathy-like pattern containing Reed-Sternberg-like giant cells in the other. Southern blot hybridization studies showed clonal rearrangement of the T-cell-receptor beta gene in both cases, and a cytogenetic study on one case revealed clonal structure abnormality involving chromosomes 1, 6, 7, 10, and 19. Analysis of the tumor DNA showed a high copy number of EBV genome per cell compared with that of Raji and Marmoset B 95.8 lines; the study for human T-cell leukemia virus type I was negative. The EBV genome was found by in situ hybridization in the tumor nuclei in both cases. In addition to Burkitt's lymphoma, T-cell lymphoma of the helper phenotype, and Hodgkin's disease, EBV can contribute to the development of CD8-positive aggressive T-cell lymphoma.     

Incidence and pathology of primary brain lymphoma in Hong Kong Chinese patients

Primary brain lymphoma (PBL) is an uncommon extranodal lymphoma. Its incidence is rapidly increasing in both immunocompromised and immunocompetent patients in Western countries. Eighteen cases of PBL were identified during a 16-year period among HIV negative patients in Queen Mary Hospital, Hong Kong. One case of post-transplantation lymphoproliferative disease (PTLD) was positive for Epstein Barr virus (EBV) encoded RNA (EBER) by in situ hybridization. All the remaining 17 immunocompetent cases were classified as diffuse large B-cell lymphoma, except for one case of Burkitt's lymphoma. EBER expression was negative in all 13 cases tested. Immunostaining for bcl-2 and bcl-6 was positive in 8/11 and 6/11 cases tested, with heterogeneous combination of expression and intensity. The incidence rate of PBL in immunocompetent patients was stable at 1.03 per million per year. The incidence of PBL in post transplantation (0.16%) and HIV related setting (0.29%) is also low in Chinese. PBL in Chinese patients is almost uniformly represented by EBV negative, diffuse large B-cell lymphoma, confined to the brain. However, the molecular pathogenesis may be heterogeneous.     

Powerful strategy for polymerase chain reaction-based clonality assessment in T-cell malignancies Report of the BIOMED-2 Concerted Action BHM4 CT98-3936.

Polymerase chain reaction (PCR) assessment of clonal T-cell receptor (TCR) and immunoglobulin (Ig) gene rearrangements is an important diagnostic tool in mature T-cell neoplasms. However, lack of standardized primers and PCR protocols has hampered comparability of data in previous clonality studies. To obtain reference values for Ig/TCR rearrangement patterns, 19 European laboratories investigated 188 T-cell malignancies belonging to five World Health Organization-defined entities. The TCR/Ig spectrum of each sample was analyzed in duplicate in two different laboratories using the standardized BIOMED-2 PCR multiplex tubes accompanied by international pathology panel review. TCR clonality was detected in 99% (143/145) of all definite cases of T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, peripheral T-cell lymphoma (unspecified) and angioimmunoblastic T-cell lymphoma (AILT), whereas nine of 43 anaplastic large cell lymphomas did not show clonal TCR rearrangements. Combined use of TCRB and TCRG genes revealed two or more clonal signals in 95% of all TCR clonal cases. Ig clonality was mostly restricted to AILT. Our study indicates that the BIOMED-2 multiplex PCR tubes provide a powerful strategy for clonality assessment in T-cell malignancies assisting the firm diagnosis of T-cell neoplasms. The detected TCR gene rearrangements can also be used as PCR targets for monitoring of minimal residual disease.     

Oncogenic spiral by infectious pathogens: Cooperation of multiple factors in cancer development

Chronic infection is one of the major causes of cancer, and there are several mechanisms for infection‐mediated oncogenesis. Some pathogens encode gene products that behave like oncogenic factors, hijacking cellular pathways to promote the survival and proliferation of infected cells in vivo. Some of these viral oncoproteins trigger a cellular damage defense response leading to senescence; however, other viral factors hinder this suppressive effect, suggesting that cooperation of those viral factors is important for malignant transformation. Coinfection with multiple agents is known to accelerate cancer development in certain cases. For example, parasitic or bacterial infection is a risk factor for adult T‐cell leukemia‐lymphoma induced by human T‐cell leukemia virus type 1, and Epstein‐Barr virus and malaria are closely associated with endemic Burkitt lymphoma. Human immunodeficiency virus type 1 infection is accompanied by various types of infection‐related cancer. These findings indicate that these oncogenic pathogens can cooperate to overcome host barriers against cancer development. In this review, the authors focus on the collaborative strategies of pathogens for oncogenesis from two different points of view: (i) the cooperation of two or more different factors encoded by a single pathogen; and (ii) the acceleration of oncogenesis by coinfection with multiple agents.     

ANALYSIS OF T CELL CLONALITY BY CDR3 SIZE OF T-CELL ANTIGEN RECEPTOR Vβ REPERTOIRE IN HCL AND c-ALL

DuringTcelldevelopment,theVDandJregionofTCRcompletelyrearrangedt0comp0seafuncti0nalTCRgene.Inadditi0n,inthisprocessthenucleotides(Nregion)wererandomlyaddedbetweenV-DandD-Jandcomp0seahighvariableVNDNJregion,whichiscalledcomplementaritydeterminingregi0n3(CDR3).TheCDR3lengthandsequencewouldbedifferent,iftheTCRrearrangementoccursatdifferentclonalTcells.Thus,thedetectionofCDR3lengthandsequencecouldbeaspecificmethodforidentificationofTcellclonality.IthasbeenidentifiedthatTCR6geneconta…     

Serologic markers of viral infection and risk of non‐Hodgkin lymphoma: A pooled study of three prospective cohorts in China and Singapore

Incidence rates of non‐Hodgkin lymphoma (NHL) and distributions of certain viruses differ between East Asian and Western populations. There are limited data on associations between serologic markers of multiple viral infections in pre‐diagnostic blood and NHL risk in East Asians. We conducted a nested case‐control study of 214 NHL cases and 214 matched controls from three population‐based prospective cohorts in Shanghai and Singapore. Antibodies against antigens from herpesviruses, Hepatitis B (HBV) and C (HCV) virus and polyomaviruses were measured in plasma or serum using fluorescent bead‐based multiplex assays. Conditional logistic regression was used to evaluate associations between antibody levels and NHL risk. An increased risk of NHL was observed for higher compared to lower EA‐D (Odds Ratio (OR) = 2.04, 95% Confidence Interval (CI) = 1.10‐3.81; p_trend = 0.005) and ZEBRA (OR = 2.17, 95% CI = 0.96‐4.89; p_trend = 0.008) Epstein‐Barr Virus (EBV) antibodies, as well as for antibody seropositivity against the IE1A human herpesvirus‐6 (HHV‐6) antigen (OR = 1.85, 95% CI = 1.04‐3.29). An increased NHL risk was also observed for higher compared to lower antibodies against the HBV‐HBc and HBe antigens. An increased risk of NHL in relation to EBV and HBV infection in East Asians is consistent with findings in several studies of Western populations, suggesting similar viral risk factors for NHL in these diverse populations with distinct patterns of NHL. The association between HHV‐6 antibodies and NHL has not previously been reported in a prospective study in this population and will require replication.     

Expression of activating natural killer‐cell receptors is a hallmark of the innate‐like T‐cell neoplasm in peripheral T‐cell lymphomas

Peripheral T‐ or natural killer (NK)‐cell lymphomas are rare and difficult‐to‐recognize diseases. It remains arduous to distinguish between NK cell‐ and cytotoxic T‐lymphocyte‐derived lymphomas through routine histological evaluation. To clarify the cells of origin, we focused on NK‐cell receptors and examined the expression using immunohistochemistry in 22 cases with T‐ and NK‐cell neoplasms comprising angioimmunoblastic T‐cell lymphoma, anaplastic lymphoma kinase (ALK)‐positive and ‐negative anaplastic large‐cell lymphomas, extranodal NK/T‐cell lymphoma, nasal type, monomorphic epitheliotropic intestinal T‐cell lymphoma, aggressive NK‐cell leukemia, and other peripheral T‐cell lymphomas. Inhibitory receptor leukocyte immunoglobulin‐like receptor subfamily B member 1 (LILRB1) was detected in 14 (64%) cases, whereas activating receptors DNAM1, NKp46, and NKG2D were expressed in 7 (32%), 9 (41%), and 5 (23%) cases, respectively. Although LILRB1 was detected regardless of the disease entity, the activating NK‐cell receptors were expressed predominantly in TIA‐1‐positive neoplasms (DNAM1, 49%; NKp46, 69%; and NKG2D, 38%). In addition, NKp46 and NKG2D were detected only in NK‐cell neoplasms and cytotoxic T‐lymphocyte‐derived lymphomas including monomorphic epitheliotropic intestinal T‐cell lymphoma. One Epstein‐Barr virus‐harboring cytotoxic T‐lymphocyte‐derived lymphoma mimicking extranodal NK/T‐cell lymphoma, nasal type lacked these NK‐cell receptors, indicating different cell origin from NK and innate‐like T cells. Furthermore, NKG2D expression showed a negative impact on survival among the 22 examined cases, which mainly received the standard chemotherapy regimen (log‐rank test, P = .024). We propose that the presence of activating NK‐cell receptors may provide new insights into understanding peripheral T‐cell lymphomas and characterizing them as innate‐like T‐cell neoplasm.     

Epstein–Barr virus presence in pediatric diffuse large B‐cell lymphoma reveals a particular association and latency patterns: Analysis of viral role in tumor microenvironment

Non‐Hodgkin's lymphoma represents 6–10% of pediatric malignancies, and diffuse large B‐cell lymphoma (DLBCL) is one of the three major subtypes. The 2008 WHO classification included a new entity, Epstein–Barr virus (EBV)‐positive DLBCL of the elderly, affecting patients >50 years. It has been demonstrated that EBV may play a role in tumor microenvironment composition, disturbing antitumor immune response and disease progression. As most studies were performed in adults, our aim was to assess EBV presence and latency pattern, as well as T‐cell microenvironment in a pediatric DLBCL series of Argentina. The study was conducted on formalin‐fixed paraffin‐embedded biopsies from 25 DLBCL patients. EBV‐encoded small nuclear early regions (EBERs) expression was performed by in situ hybridization, whereas EBV gene expression was analyzed using real‐time PCR. Epstein–Barr virus latent membrane proteins (LMP)1, LMP2A, CD3, CD4, CD8 and Foxp3 expression were assessed by immunohistochemistry (IHC). Forty percent of cases showed EBV expression, with a significantly higher incidence among patients <10 years (p = 0.018), and with immunosuppressed (p = 0.023). T‐cell subsets were not altered by EBV presence. Full EBV latency antigen expression (latency type III) was the most frequently pattern observed, together with BZLF1 lytic gene expression. One patient showed II‐like pattern (LMP1 without LMP2A expression). Based exclusively on IHC, some patients showed latency II/III (EBERs and LMP1 expression) or I (EBERs only). These findings suggest that EBV association in our series was higher than the previously demonstrated for elderly DLBCL and that EBV latency pattern could be more complex from those previously observed. Therefore, EBV could be an important cofactor in pediatric DLBCL lymphomagenesis.     

Immunophenotypic and genotypic characterization of nasal lymphoma with polymorphic reticulosis morphology.

Nasal lymphoma with polymorphic reticulosis (PR) morphology is now categorized as T/natural killer (T/NK) cell lymphoma. In this study, immunophenotypes and genotypes of proliferating cells in 21 cases with PR were examined. The patients included 13 men and 8 women ranging in age from 20 to 74 (median 37) years. All patients presented with lesions in the upper respiratory tract, mostly in the nasal cavity. Histological specimens obtained from the primary lesions (19 cases) and metastatic cervical lymph nodes (2 cases) were used for analyses. Histologically, polymorphous proliferation was found in 20 cases, and these were thus diagnosed as PR. A monomorphous pattern was found in the remaining last case. Immunohistochemical analysis revealed that the proliferating cells were CD56 (123C3)+ and/or CD16 (2H7)+, TIA-1+ and frequently stained CD3 epsilon+. Tumor cells were frequently stained positively with monoclonal antibodies (mAbs) for T lymphocytes, but were negative for T-cell receptor (TCR) beta and delta chain expression. In situ hybridization analysis using an Epstein-Barr virus-encoded early RNA 1 (EBER-1) probe revealed positive signals in 13 of the 15 cases examined. Southern blotting analysis for clonality of the Epstein-Barr virus (EBV) genome in 12 positive cases confirmed the presence of monoclonal proliferation in 7 cases. The pattern of TCR gamma chain gene rearrangement was examined by PCR analysis of DNA from tumor tissues by the denaturing gradient gel electrophoresis method. The results demonstrated no clonal rearrangement in any of the 21 cases examined, including 7 cases with proven clonal proliferation of EBV-infected cells, indicating the absence of T-cell clones. Our findings strongly suggested that nasal T-cell lymphoma is in fact a NK cell lymphoma.     

病毒与淋巴瘤

病毒感染是导致机体发生淋巴瘤的主要病因之一.研究发现爱泼斯坦巴尔病毒（EBV）、人免疫缺陷病毒（HIV）、丙型肝炎病毒（HCV）和乙型肝炎病毒（HBV）等均是通过不同途径及机制感染机体,导致淋巴瘤的发生发展.对于病毒感染所致淋巴瘤的研究将有利于阐明淋巴瘤发生的分子机制,并对进一步探索有效的治疗方案具有重要意义.