Prevalence of hepatitis C infection in patients with non-Hodgkin's lymphoma in South Florida and review of the literature

The etiology of non-Hodgkin's lymphoma is unknown in the majority of the cases. Although Epstein - Barr virus, human T-cell leukemia-lymphoma virus and human herpes virus-8 have been established as casual agents in the pathogenesis of specific types of lymphoma, the role of hepatitis C virus (HCV) in lymphomagenesis remains controversial, with marked geographic variability. We conducted an epidemiologic study to evaluate the prevalence of hepatitis C virus infection in patients with lymphoma in South Florida. Ninety consecutive patients with lymphoma and 96 consecutive control patients with solid tumors were tested for HCV. HCV infection was detected in 2 patients with NHL (2.2%) and in 4 control patients (4.1%). Our study does not support the association between HCV and lymphoma in South Florida, US.     

Characterization of T-cell non-Hodgkin's lymphoma and its association with Epstein-Barr virus in Pakistani patients

This study analyzes the prevalence of T-cell non-Hodgkin's lymphoma (T-NHL) in a major referral center of Pakistan and its association with Epstein-Barr virus (EBV). Ninety-two cases of T-NHL were characterized on the basis of morphology, immunohistochemistry and genetic features. The prevalence of T-NHL was 22.2% of the total NHLs diagnosed during the eight years period (1992-1999). Polymerase chain reaction (PCR) technique was used to assess T-cell clonality in paraffin-embedded tissues of known T-NHL. Amplifiable DNA was isolated from all the cases, which were further studied for T-cell receptor (TcR)-beta, gamma, delta, and IgH chain gene rearrangements. Out of 92 cases 51 cases showed clonal product and 33 demonstrated polyclonal smear for beta, gamma, or delta chain genes, respectively, whereas 8 cases exhibited IgH chain gene rearrangement for FR2 region. This study demonstrated frequent presence of EBV in T-NHL (55.4%) by PCR, which were further tested for the localization of the virus by in situ hybridization (ISH). The extent of polymorphism in EBV genome was studied by single stranded conformation polymorphism (SSCP) technique for Bam HI E, K, N and Z regions. Hypervariability in Bam HI K, and N regions was noticeably higher compared to E or Z regions. In conclusion, our study demonstrated that the prevalence of T-NHL in Pakistan is slightly higher to that reported for Western communities. In addition, the frequency of EBV genome in T-NHL is intermediate as compared to other studies. No association was established between EBV variants differentiated on the basis of sequence heterogeneity in Bam HI K, N, E and Z regions with the manifestation of different subsets of T-NHL.     

Prevalence of hepatitis C infection in patients with non-Hodgkin's lymphomas

Several studies have suggested an association between hepatitis C virus (HCV) and low-grade B-cell non-Hodgkin's lymphomas. The results, however, have been controversial. Italian and Japanese studies have reported a 40% prevalence rate, but the data were not confirmed by English and Canadian studies. We evaluated the prevalence of HCV infection in 109 patients with non-Hodgkin's lymphomas, and compared it with a control group composed of 67 patients with Hodgkin's disease and 31 patients with chronic lymphocytic leukemia. The prevalence of HCV infection was also determined in blood donors. HCV infection was detected using second and third generation anti-HCV ELISA. Positive results were additionally confirmed using Inno-LIA AbIII and/or RNA-HCV by PCR. Immunohistochemical stains were used to determine B or T cell lineage when the morphological analysis was not sufficient for lymphoma classification. HCV infection was detected in 9% of patients with non-Hodgkin's lymphomas, in 2% of patients in the control group (p=0.036), and in 1.2% of blood donors. There was no difference in the prevalence of HCV infection between patients with B or T cell lymphomas. Blood transfusions or previous surgeries, both risk factors for HCV infection, were detected in 90% of the patients with a positive anti-HCV test, in average 17 and 36 years before the diagnosis of lymphoma, respectively. Seventy percent of the patients with non-Hodgkin's lymphomas and a positive anti-HCV test presented evidence of chronic liver disease when the lymphoma was diagnosed. This study suggests the presence of an association between HCV infection and non-Hodgkin's lymphomas in Brazil.     

Aggressive sino-nasal non-Hodgkin's lymphoma diagnosed in Nottinghamshire, UK, between 1987 and 1996

In the 10-year period 1987 to 1996, 24 patients were diagnosed with aggressive non-Hodgkin's lymphoma of the nasal cavities or paranasal sinuses. The disease occurred in a relatively elderly population of median age 72 years (range 42 to 96) with a male predominance (male 15; female nine). The histology on review was mostly of the large B-cell subtype (21 patients); peripheral T-cell subtype (one), anaplastic large cell of T-cell type (one) and T/natural killer cell nasal lymphoma (one). The disease was localized in 20 patients (Stage IEA). The overall survival at 5 years was 40% (95% confidence interval (CI) 19-61); at 10 years it was 33% (95% CI 12-54). The cause-specific survival (excluding deaths from causes other than lymphoma) at 5 years and 10 years was 62% (95% CI 39-86).     

Induction of interleukin-6 by hepatitis C virus core protein in hepatitis C-associated mixed cryoglobulinemia and B-cell non-Hodgkin's lymphoma.

PURPOSE: Chronic hepatitis C carries the risk to develop mixed cryoglobulinemia (MC) and B-cell non-Hodgkin's lymphoma (B-NHL), possibly because viral antigens stimulate the host's inflammatory response via extracellular pattern recognition receptors (PRR). To clarify this issue, we studied whether recognition of hepatitis C virus (HCV) proteins by PRR is involved in the pathogenesis of HCV-associated MC or B-NHL. EXPERIMENTAL DESIGN: Peripheral blood mononuclear cells of patients with HCV-associated B-NHL (n = 12), MC (n = 14), uncomplicated hepatitis C (n = 12), and healthy volunteers (n = 12) were incubated with the recombinant HCV proteins E2, core, and NS3 to study induction of cytokine production, stimulation of B-cell proliferation, and immunoglobulin secretion. In addition, serum levels of interleukin-6 (IL-6) were measured by ELISA. RESULTS: HCV core was the only studied protein, which induced production of IL-6 and IL-8 in CD14(+) cells. IL-6 induction was mediated via Toll-like receptor 2 (TLR2) and lead to increased B-cell proliferation in vitro. TLR2 expression on monocytes and IL-6 serum concentrations were increased in all groups of HCV-infected patients compared with healthy controls and were highest in MC (P < 0.05). CONCLUSIONS: Increased secretion of IL-6 via stimulation of TLR2 by HCV core protein may play a role in the pathogenesis of hepatitis C-associated MC and B-NHL.     

Aggressive and indolent non-Hodgkin's lymphoma: response assessment by integrated international workshop criteria

Until recently, response assessment in patients with lymphoma was primarily performed by computed tomography (CT). Based on CT, International Workshop Criteria (IWC) were developed and widely used. Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) is a more sensitive and specific imaging technique for the detection of residual disease in lymphoma, and Revised Integrated International Workshop Criteria (IWC + PET) were recently proposed by the members of the International Harmonization Project (IHP), which combine both imaging techniques. We determined whether these new IWC + PET-criteria, can more accurately predict outcome compared to IWC-criteria in aggressive and indolent non-Hodgkin's lymphoma (NHL), and therefore correlated IWC and IWC + PET response with time-to-next-treatment (TNT) in 69 patients with NHL. We demonstrated that IWC + PET-guidelines are highly recommended over IWC-guidelines for patients with potentially-curable and routinely FDG-avid lymphoma. In contrast, no additional value of IWC + PET was demonstrated in a small group of patients with incurable histological subtypes.     

鼻腔鼻窦非霍奇金淋巴瘤免疫表型及其与EB病毒感染的关系

背景与目的:鼻腔鼻窦非霍奇金淋巴瘤(non-Hodgkin's lymphoma,NHL)的患病率和免疫表型组成具有地域性差异.本研究探讨中国广州地区57例鼻腔鼻窦NHL免疫表型及其与EB病毒(Epstein-Barr virus,EBV)感染的关系.方法:收集2000年4月1日至2006年10月31日中山大学肿瘤防治中心病理科57例鼻腔鼻窦NHL标本.免疫组化染色确定免疫表型,EBER原位杂交及PCR检测EBV感染情况.结果:在同期诊断的1 412例NHL中,71例(5.03%)发生于鼻腔鼻窦,其中仅有57例适用于本研究.57例鼻腔鼻窦NHL患者中,男性38例,女性19例,年龄3～75岁,中位年龄50岁;44例(77.19%)为鼻型NK/T细胞淋巴瘤,其中37例(84.09%)为EBV /CD56 NK细胞肿瘤,7例(15.91%)为EBV /CD56-细胞毒性T细胞表型;11例(19.30%)为B细胞淋巴瘤,其中6例为弥漫大B表型,2例为Burkitt(Burkitt样)淋巴瘤(EBV ),1例为髓外浆细胞瘤(EBV ),1例为MALT淋巴瘤(EBV-),1例为小淋巴细胞性淋巴瘤(EBV-);2例(3.51%)为外周T细胞淋巴瘤(EBV-).37例适用DNA检测的病例中,25例(67.57%)感染缺失型LMP1(del-LMP1)EBV株,12例(32.43%)感染野生型LMP1(wt-LMP1)EBV株.结论:鼻腔鼻窦NHL最常见的类型为鼻型NK/T细胞淋巴瘤,可进一步分为EBV /CD56 NK细胞及EBV /CD56-细胞毒性T细胞表型.NK/T细胞淋巴瘤均感染了EBV,EBV株主要为del-LMP1型.     

Epstein-Barr virus antibody patterns preceding the diagnosis of non-Hodgkin's lymphoma.

Immunosuppressed patients who develop non-Hodgkin's lymphoma (NHL) have abnormal antibody responses against the Epstein-Barr virus (EBV) prior to the diagnosis of malignancy. To see if this is also true of "spontaneous" cases in the general population, we undertook a collaborative serologic case-control study. From 4 serum banks containing specimens from over 240,000 persons, 104 subjects were identified for whom a blood specimen had been stored an average of 63 months before diagnosis of NHL, and 259 controls matched for age, sex, ethnic group and date of serum collection. The relative risks (RR) for subsequent development of NHL associated with elevated levels of IgG and IgM antibodies against viral capsid antigen were 2.5 (95% confidence interval = 1.1-5.7) and 3.2 (1.3-7.5), respectively; these associations increased with age at diagnosis. For the nuclear antigen, the distribution of titers for cases was more restricted than that of controls, with fewer cases having either elevated or low titers, RR = 0.5 (0.2-1.4) and 0.5 (0.2-1.2), respectively. Cases had significantly lower antibody titers against the cytomegalovirus, RR = 0.4 (0.2-0.9). These findings suggest that, at least for some patients, NHL is preceded by an enhanced level of endogenous immunosuppression with resultant EBV activation. This observation supports the role of EBV either directly in the development of NHL or as a primary marker of immune dysfunction.     

乙型肝炎病毒感染与非霍奇金淋巴瘤相关性的研究

目的:通过比较非霍奇金淋巴瘤(NHL)患者与肺癌患者乙型肝炎病毒(HBV)感染率的差异,进一步探讨HBV感染与NHL之间的关系.方法:回顾性分析2000-01-2009-02在浙江省肿瘤医院住院治疗的1 279例NHL患者和随机抽取同期住院的1 340例肺癌患者HBV抗原抗体表达情况,并判断其差异性.结果:NHL患者HBsAg阳性率较肺癌患者差异有统计学意义(χ2=13.30,P=0.000),其HBsAg、HBeAb和HBcAb及HBsAg、HBeAg和HBcAb阳性率均明显高于肺癌患者(χ2=4.60,P=0.032;χ2=45.09,P=0.000);两组之间抗体阳性率差异均无统计学意义.同时B细胞性NHL患者的HBsAg阳性率明显高于肺癌患者(χ2=22.18,P=0.000);而T细胞性NHL患者与肺癌患者的HBsAg阳性率差异无统计学意义,χ2=1.03,P=0.309.在NHL两亚型之间,B细胞性NHL患者的HBsAg阳性率明显高于T细胞性NHL患者(χ2=5.06,P=0.024).结论:NHL患者HBV感染率明显高于肺癌患者,B细胞性NHL患者的感染率高于T细胞性NHL;提示HBV持续感染可能在NHL尤其在B细胞性NHL发病中起重要作用;为制定NHL的防治策略提供了参考依据.     

Clinicopathologic characteristics of follicular lymphoma in hepatitis C virus-infected patients

Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma. It has been hypothesized that chronic hepatitis C virus (HCV) infection stimulates IGH-BCL2 clone proliferation, leading to development of FL. Furthermore, regression of FL after antiviral treatment without chemotherapy has been reported in HCV-infected patients. To clarify the relationship between HCV and FL, we compared the prevalence of IGH-BCL2 translocation and other clinicopathologic characteristics between HCV-infected and HCV-uninfected FL patients and determined the impact of HCV eradication on the oncologic outcomes of HCV-infected FL patients. The study included HCV-infected patients (cases) with FL seen at our institution during 2004-2018. Cases were matched with HCV-uninfected FL patients (controls) according to year of lymphoma diagnosis, sex, and hepatitis B serology. We studied 19 cases and 57 controls. More cases than controls had splenic involvement of FL (26% vs 5%, P = 0.02), higher histologic grade (grade 3 in 56% vs 24%, P = 0.01), absent or weak CD10 expression (42% vs 11%, P = 0.005), and absent BCL2 expression (33% vs 4%, P = 0.004). Compared to controls, cases had a lower rate of detection of IGH-BCL2 translocation (31% vs 68%, P = 0.02). Finally, cases with a sustained virologic response (virologic cure of HCV) had a better 10-year overall survival rate than did cases not treated with antivirals or controls (P = 0.001). In conclusion, HCV-infected patients with FL have unique clinicopathologic characteristics including improved overall survival with HCV eradication. The pathogenesis of FL in HCV-infected patients seems unrelated to antiapoptotic effect of IGH-BCL2 rearrangement.     

Identification of human herpesvirus 6-specific DNA sequences in two patients with non-Hodgkin's lymphoma

Human herpesvirus 6 (HHV-6) is a recently discovered virus which has not been causally linked to any particular disease. In order to investigate the possible role of this virus in the pathogenesis of lymphoid malignancies, we examined tissue samples from 117 patients for the presence of HHV-6-specific DNA sequences. Two cases of non-Hodgkin's lymphoma were found to be positive. One patient had a T cell lymphoma and a preceding history of angioimmunoblastic lymphadenopathy; the other had a B cell lymphoma occurring in the context of Sj?gren's syndrome. HHV-6 has been isolated previously from a patient with angioimmunoblastic lymphadenopathy, and viral sequences have been identified in another patient with Sj?gren's syndrome and B cell lymphoma. The relationship between HHV-6 and these conditions therefore warrants further investigation.     

HBV感染与非霍奇金淋巴瘤的关系

背景与目的:文献报道乙型肝炎病毒(hepatitis B virus,HBV)感染率在非霍奇金淋巴瘤(non-Hodgkin's lymphoma,NHL)患者中较同一地区的非原发性肝癌实体瘤患者和普通人群高,但HBV和NHL之间的关系尚无定论.本研究旨在对比同一地区NHL患者与结直肠癌患者HBV的感染率.方法:比较109例NHL患者和128例结直肠癌患者乙型肝炎病毒表面抗原(HBsAg)的阳性率,并与普通人群对照,通过卡方检验判断有无统计学意义.结果:NHL患者HBsAg阳性率(40.4%)明显高于结直肠癌患者(14.1%)及当地普通人群(约17.3%),有统计学意义(P＜0.01);以结直肠癌患者作参照组,HBsAg阳性者患NHL的优势比为2.87,95%可信区间为1.830～4.502.结论:NHL患者的HBsAg阳性率高于结直肠癌患者和普通对照人群.     

Distinctions between endemic and sporadic forms of Epstein-Barr virus-positive Burkitt's lymphoma

Tumour cell lines were established in vitro from 16 cases of Epstein-Barr (EB) virus genome-positive Burkitt's lymphoma (BL), 7 of "endemic" origin (i.e. from holoendemic malarial areas of Africa and of New Guinea) and 9 of "sporadic" origin (i.e. from outside such high-incidence areas). All the BL cell lines thus established were monoclonal by immunoglobulin isotype expression and displayed a characteristic chromosomal translocation, t(8:14) or t(8:22), confirming their malignant origin. Clear differences observed between the individual BL cell lines appeared to be related to their endemic or sporadic status. All 7 endemic cell lines began growth as a carpet of single cells, often with small, loose clumps appearing in later passage. Whilst 3 lines of sporadic origin displayed a similar pattern to the above, the majority of sporadic lines grew as large, tight clumps of cells from the first passage onwards. These differences in growth pattern were reflected by differences in cell surface phenotype, as defined in indirect immunofluorescence tests using a panel of monoclonal antibodies (MAbs) specific for B-lineage-associated antigens. BL cell lines could be classified into 3 separate groups on the basis of their reactivity with 6 particular antibodies (MHM6, AC2, Ki-1, Ki-24, J5 and 38.13). All 7 endemic BL cell lines and 2 of the 3 sporadic BL cell lines which began growth as single cells showed a group-I cell-surface phenotype (MHM6, AC2, Ki-1, Ki-24 negative; J5, 38.13 positive) in early passage. In contrast, all 6 sporadic BL cell lines which began growth in large clumps displayed a distinct group-II phenotype (MHM6, AC2, Ki-1 positive/negative; Ki-24, J5, 38.13 positive); in later passage most of these sporadic lines progressed to a group-III phenotype (MHM6, AC2, Ki-1, Ki-24 positive; J5, 38.13 negative) without loss of those immunoglobulin and chromosomal markers identifying the cells' malignant origin. These clear differences between endemic BL cell lines on the one hand and the majority of sporadic BL cell lines on the other suggest that endemic BL arises from a more restricted range of progenitor B cells than does the sporadic form of the disease.     

Frequency and significance of anemia in non-Hodgkin's lymphoma patients

Objectives: Retrospective evaluation of anemia frequency and its prognostic value in patients with different subtypes of non-Hodgkin's lymphoma and comparison with other clinical characteristics.Patients and methods: Anemia was defined as a hemoglobin value less than or equal to 12 g/dl for all men and women over 50 years of age, and less than or equal to 11 g/dl for women under 50 years of age. The study included 1077 adult lymphoma patients treated between 1980 and 1995 with the following histologic subtypes: 127 patients with small lymphocytic or lymphoplasmacytoid, 62 with marginal zone, 50 with mantle-cell, 208 with follicular, 104 with T-cell lymphoma, 426 with diffuse large-cell and, finally, 73 patients with other high-grade lymphomas.Results: Anemia was present in 341 patients (32%). It was an adverse prognostic factor (P <; 0.0001) for overall survival (OS) and progression-free survival (PFS) but not for relapse-free survival (RFS). When patients with and those without bone marrow involvement were considered separately, anemia remained an adverse factor. Anemia was significantly associated with shorter PFS in small lymphocytic or lymphoplasmacytoid, mantle cell, diffuse large cell and high-grade lymphomas and with shorter OS in all histologic subgroups except marginal zone lymphoma. In multivariate analysis, anemia was a significant prognostic factor for OS and PFS for the population as a whole (P = 0.0001 and P = 0.0048, respectively) and in patients with bone marrow involvement (P = 0.007 and P = 0.005, respectively) but not in patients without bone marrow involvement. Finally, the addition of anemia to the International Prognostic Index led to an improvement for OS (P = 0.0004) and PFS (P = 0.0004).Conclusions: Anemia is an important adverse prognostic factor for the outcome of lymphoma patients, particularly in some histologic subgroups and in patients with bone marrow involvement.     

非霍奇金淋巴瘤预后因素的初步分析

目的:初步分析非霍奇金淋巴瘤患者临床病理因素与预后的关系.方法:回顾性分析我院70例非霍奇金淋巴瘤患者的性别、年龄、ECOG评分、恶性程度、临床分期、最大肿瘤直径、结外受累部位数、有无B症状、LDH、β2微球蛋白、疗效及肿瘤进展时间(TTP)等.应用SAS 8.2统计软件分析各临床病理因素与预后的关系.结果:单因素分析显示,年龄(P=0.040)、ECOG评分(P=0.032)、临床分期(P=0.033)、最大肿瘤直径(P=0.028)、结外受累部位数(P=0.000)、血清乳酸脱氢酶(LDH,P=0.041)和疗效(P=0.000)是影响TTP的单个因素.多因素分析显示,ECOC评分(P=0.046)、临床分期(P=0.035)、最大肿瘤直径(P=0.021)、结外受累部位数(P=0.007)和疗效(P=0.000)影响TTP的独立预后因素.结论:ECoG评分、临床分期、最大肿瘤直径、结外受累部位数、疗效等许多临床病理因素影响着患者的预后.     

Second lung adenocarcinoma after combination chemotherapy in two patients with primary non-Hodgkin's lymphoma.

We report a rare complication of a secondary malignant solid tumor in two patients with non-Hodgkin's malignant lymphoma who developed lung adenocarcinoma after treatments with combination chemotherapies. The first was a case of primary malignant lymphoma of the cervical spinal cord which had been previously treated with radiation to the spinal lesion and combination chemotherapies and entered complete remission. The patient was further treated for relapse with autologous bone marrow transplantation preconditioned with high-dose chemotherapy. Lung adenocarcinoma developed 5.5 years after the initial diagnosis. The second case of malignant lymphoma of lymph nodes did not respond to conventional combination chemotherapies and did not enter remission. Lung adenocarcinoma developed 1 year after the initial diagnosis. The two patients died of lung carcinoma. The clinical profiles of these cases are presented and the causal relationship of primary malignant neoplasms to the second malignant neoplasms is discussed.     

Kaposi's sarcoma in two lymphoma patients with hepatitis B and other infections

Kaposi's sarcoma developed in two lymphoma patients previously treated by chemotherapy and chemoirradiation. The histologic picture in the two cases showed a non-Hodgkin's lymphoma with multifocal epithelioid histiocytic reaction. Both patients had Hepatitis-B surface antigen and other infections due to herpes and streptococcus. The European Jewish origin of the two patients, the previous chemotherapy, and their infective state tend to support more the hypothesis of predisposing factors in the occurrence of Kaposi's sarcoma than a coincidental association.     

Mitoxantrone-containing combination chemotherapy in patients with non-Hodgkin's lymphoma

Thirty-one patients with advanced non-Hodgkin's lymphoma were entered in a trial of a four-drug combination of mitoxantrone, cyclophosphamide, vincristine, and prednisolone (MCOP). This trial was intended to test the efficacy of substituting mitoxantrone for adriamycin in the CHOP combination, and to evaluate tumor response in patients who had received anthracycline antibiotic therapy. Of 31 patients, 25 were fully evaluated for tumor response and toxicity. There were 7 responses (4 complete, 3 partial) among 9 patients who had received radiation alone or chemotherapy not containing anthracycline antibiotics, whereas there were 7 responses (3 complete, 4 partial) in 16 patients who had been given anthracycline-containing chemotherapy. Median duration of response was 11+ weeks (range; 5 to 43+ weeks). The major toxicity was myelosuppression, although patients tolerated this well. This study suggested that mitoxantrone is not fully cross-resistant with anthracycline antibiotics and that MCOP is an effective regimen in patients with previously treated non-Hodgkin's lymphoma. However, when salvage chemotherapy for CHOP-failure is intended, cyclophosphamide and vincristine in MCOP should be further substituted by other agents such as etoposide and cis-platinum.     

Modified CHOP therapy in patients with non-Hodgkin's lymphoma

From July 1983 to December 1989, 31 previously untreated patients with non-Hodgkin's lymphoma were treated with modified CHOP regimen (cyclophosphamide 300 mg/m2 on day 1, aclacinomycin 40 mg/m2 on day 1, vincristine 0.7 mg/m2 on day 1 and prednisolone 40 mg/m2 on days 1-5). The therapy was repeated at 2-week intervals. The complete response rate was 66.7% for clinical stage (CS) II according to the Ann Arbor criteria, 60.0% for CS III and 33.3% for CS IV, respectively. The 5-year survival rate was 100% for CS II, 36.6% for CS III and 34.6% for CS IV, respectively. Clinical effects of modified CHOP regimen were almost the same as those of other therapies including adriamycin from the standpoint of 5-year survival rate. On the other hand, the myelosuppression accompanying modified CHOP therapy was not severe. Only one patient had a white blood count below 1,000/microliters during 6 courses of the therapy. It is thought that this regimen is useful to enhance the quality of life of patients because of no severe complications such as myelosuppression.