Epidemiology and etiology of non-Hodgkin lymphoma--a review

The etiology of non-Hodgkin lymphoma, as well as its global dramatic rise in incidence during the past decades, remains largely unexplained. However, there is increasing awareness that this group of malignancies may entail not only clinical, morphological and molecular heterogeneity, but also considerable variations in terms of etiologic factors. In this review, epidemiologic patterns are summarized as well as current evidence of associations between various known or suspected risk factors for non-Hodgkin lymphoma overall or for any of its subtypes. Central pathogenetic mechanisms include immunosuppression, especially in relation to T-cell function and loss of control of latent EBV infection, and chronic antigen stimulation. Some degree of familiar aggregation also implies a role for genetic susceptibility. A number of recent investigations of non-Hodgkin lymphoma etiology will hopefully lead to a better understanding of the causes of these malignancies.     

Cigarette smoking and risk of non-Hodgkin lymphoma subtypes among women

Previous studies of the relationship between cigarette smoking and non-Hodgkin lymphoma (NHL) have yielded conflicting results, perhaps because most studies have evaluated the risk for all NHL subtypes combined. Data from a population-based case-control study conducted among women in Connecticut were used to evaluate the impact of cigarette smoking on the risk of NHL by histologic type, tumour grade, and immunologic type. A total of 601 histologically confirmed, incident cases of NHL and 718 population-based controls provided in-person interviews. A standardised, structured questionnaire was used to collect information on each subject's current smoking status, age at initiation, duration and intensity of smoking, and cumulative lifetime exposure to smoking. Our data suggest that cigarette smoking does not alter the risk of all NHL subtypes combined. However, increased risk of follicular lymphoma appears to be associated with increased intensity and duration of smoking, and cumulative lifetime exposure to smoking. Compared with nonsmokers, women with a cumulative lifetime exposure of 16-33 pack-years and 34 pack-years or greater experience 50% increased risk (OR=1.5, 95% CI 0.9-2.5) and 80% increased risk (OR=1.8, 95% CI 1.1-3.2), respectively, of follicular lymphoma (P for linear trend=0.05). Our study findings are consistent with several previous epidemiologic studies suggesting that cigarette smoking increases the risk of follicular lymphoma. This research highlights the importance of distinguishing between NHL subtypes in future research on the aetiology of NHL.     

Smoldering mantle cell lymphoma

Background

Mantle cell lymphoma (MCL) is an aggressive disease, with poor prognosis and a limited survival. However, some patients with indolent MCL can survive beyond 7~10 years. These patients remain largely asymptomatic and can be in observation for a long time without any treatment. The process of “wait and watch” leaves these patients with the potential risk of evolution to classic, aggressive MCL. On the other hand, early treatment for these patients may not impact overall survival but rather affects the quality of life. Therefore, it is essential to clearly identify this type of indolent MCL at the time of diagnosis.

Results

Reported findings of indolent presentation of MCL include: lack of B symptoms, normal serum lactic dehydrogenase (LDH) and β2-microglobulin levels (β2M), low MCL-International Prognostic Index (MIPI) score, maximum tumor diameter less than 3 cm, spleen size?<?20 cm, positron emission tomography/computerized tomography with the Standard Uptake Value max <6, Ki-67 less than 30%, with some particular immunophenotype, such as CD5 and CD38 negative, markedly increased CD23 positive lymphocytes proportions, high expression of CD200, kappa light chain restriction, without C-myc, TP53 and NOTCH1/2 mutations, non-blastoid/pleomorphic histology, and no tumor growth on reevaluation every 2~3 months (followed for at least 6 months). Imaging evaluation may only be performed in the presence of disease-related symptoms or organ involvement. Meanwhile, if novel nodal or extranodal lesion is found, biopsy is mandatory to exclude lymphoma.Common clinopathological forms of indolent presentations include monoclonal B lymphocytosis with t (11; 14); “indolent leukemic” presentation of MCL with involvement of peripheral blood, bone marrow involvement, splenomegaly, and minimal lymphadenopathies and in situ lymphoma (often found in lymph nodes removed for other reasons, and in gastrointestinal biopsies).

Conclusions

Considering these distinct indolent clinical presentations with particular features in cytology and gene mutational status, we propose to include these MCL clinical presentations under the umbrella of “Smoldering Mantle Cell Lymphoma”.

     

Bortezomib in mantle cell lymphoma

Mantle cell lymphoma (MCL) represents 6% of non-Hodgkin lymphomas, but is one of the most active fields of clinical investigation. Unfortunately, there is still no standard or curative therapy in MCL. Front-line therapy appears to benefit from intensification either through high-dose therapy with stem cell transplant consolidation or dose-intense chemotherapy with hyperfractionated cyclophosphamide, vincristine, adriamycin/doxorubicin and dexamethasone/rituximab. Most patients still relapse and a multitude of novel agents are currently being tested in this setting, including proteasome inhibitors with bortezomib (the first of its class and the first US FDA-approved drug for MCL), mTOR inhibitors, Bcl-2 inhibitors, antiangiogenesis agents and histone deacetylase inhibitors among others. An obvious effort is needed to enroll patients on clinical trials, the design of which might benefit from pharmacogenomics and a better understanding of MCL biology and its diversity.     

套细胞淋巴瘤的免疫治疗

套细胞淋巴瘤(MCL)是一种恶性侵袭性非霍奇金淋巴瘤,以出现t(11;14)(q13;q32)以及细胞周期蛋白D1(Cyclin D1)过度表达为特征,预后很差.近年来,生物学、遗传学以及免疫学的发展推动了MCL的免疫治疗.单用利妥昔单抗的疗效有限,但将其与其他化疗方案如CHOP(环磷酰胺联合多柔比星、长春新碱、泼尼松)、hyperCVAD/MTX-Ara-C(高剂量环磷酰胺联合长春新碱、多柔比星、地塞米松与甲氨蝶呤或阿糖胞苷交替)、FCM(氟达拉滨联合环磷酰胺、米托蒽醌)等联合之后,无论作为MCL的一线治疗还是挽救治疗,疗效均有明显改善.利妥昔单抗用于维持治疗或与自体造血干细胞移植联合后可延长缓解持续时间.此外,替伊莫单抗以及妥司莫单抗、异基因造血干细胞移植、供者淋巴细胞输注、树突状细胞、独特型疫苗联合等,其他的免疫治疗如沙利度胺和雷利度胺联合利妥昔单抗在复发性或难治性MCL中也取得了一定进展.     

Smoking and risk of non-Hodgkin lymphoma subtypes in a cohort of older women

Although non-Hodgkin lymphoma (NHL) has not been considered to be a smoking-related malignancy, recent investigations suggest otherwise. We evaluated this association in a cohort of 37,336 women, aged 55-69 years, who reported in a mailed questionnaire in 1986 information regarding smoking history as well as demographic, medical history and dietary factors. Cancer and mortality experience through 1996 was determined by linkage to the Iowa Cancer Registry and other databases; there were 200 incident cases of NHL during the 380,231 total person-years of follow-up. Compared to never smokers, former (age-adjusted RR = 1.0; 95% CI 0.8-1.5) and current smokers (age-adjusted RR = 1.0; 95% CI 0.7-1.5) were not at elevated risk of NHL, and there was no trend with pack-years smoked (Ptrend = 0.3). Multivariate adjustment for other NHL risk factors did not alter these findings. Age-adjusted analysis by NHL subtype revealed a suggestive positive association of smoking with follicular NHL [(RRformer = 1.3; 95% CI 0.6-2.8), (RRcurrent = 1.8; 95% CI 0.8-3.8)], which strengthened after multivariate adjustment [(RRformer = 1.6; 95% CI 0.7-3.4), (RRcurrent = 2.3; 95% CI 1.0-5.0)]; there was no association for diffuse or small cleaved-cell NHL. Our study findings, which are consistent with other recent investigations, suggest that smoking may be associated with an increased risk of follicular NHL.     

Epidemiology of non-Hodgkin lymphoma in Connecticut. 1935-1988.

BACKGROUND. During the past decades, there have been reports of increases in the incidence and mortality rates due to non-Hodgkin lymphoma (NHL) in many parts of the world. The risk factors responsible for the increasing incidence are largely unknown. This study provided an overview of the incidence pattern of NHL in Connecticut and generated hypotheses for additional investigation. METHODS. This study was based on all the NHL cases reported to the Connecticut Tumor Registry (CTR) between 1935 and 1988. Crude, age-adjusted, and age-specific incidence rates of NHL were calculated for each sex. Age-adjusted incidence rates were calculated by the direct method standardized to the 1970 United States standard million population. The data are presented by calendar year and cohort year of birth to examine the secular trends and birth cohort effects. Racial information was not coded before 1957 and is of uncertain validity until the early 1970s; therefore, racial analysis was restricted to 1970-1988. Analyses by histologic subtypes and by anatomic sites were restricted to the last 3 decades (1960-1988) because more accurate classification systems were used during this time. RESULTS. A total of 11,326 newly diagnosed cases of NHL were included in the study. Of them, 5866 (52%) were diagnosed in men and 5460 (48%) were diagnosed in women. The study results indicated that the incidence rate of NHL has been increasing during the past decades for men and women, whites and blacks, nodular NHL and diffuse NHL, disease originating from lymph nodes and disease originating from other sites, and in all age groups, especially the older age groups. Birth cohort examination did not show any indication of a decline or levelling off in incidence rates among recent birth cohorts. Age-specific incidence rates in both sexes suggested that the rates increase with age, with a sharp increase beginning at 50 years of age and peaking at 80 years of age. Men had a 30% higher incidence rate than women, and whites had approximately 1.5 times the age-adjusted incidence rate of blacks. CONCLUSIONS. The results indicated that the incidence rate of NHL has been increasing in Connecticut during the past decades and is likely to continue to rise in the coming years. Analytical epidemiologic studies are needed to examine the risk factors that might account for the increase in NHL.     

Circulating immune markers and risks of non-Hodgkin lymphoma subtypes: A pooled analysis

Although prediagnostic circulating concentrations of the immune activation markers soluble CD27 (sCD27), sCD30 and chemokine ligand-13 (CXCL13) have been associated with non-Hodgkin lymphoma (NHL) risk, studies have been limited by sample size in associations with NHL subtypes. We pooled data from eight nested case-control studies to investigate subtype-specific relationships for these analytes. Using polytomous regression, we calculated odds ratios (ORs) with 95% confidence intervals (CIs) relating study-specific analyte tertiles to selected subtypes vs controls (n = 3310): chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 623), diffuse large B cell lymphoma (DLBCL; n = 621), follicular lymphoma (FL; n = 398), marginal zone lymphoma (MZL; n = 138), mantle cell lymphoma (MCL; n = 82) and T cell lymphoma (TCL; n = 92). We observed associations with DLBCL for elevated sCD27 [OR for third vs first tertile (OR_T3) = 2.2, 95% CI = 1.6-3.1], sCD30 (OR_T3 = 2.0, 95% CI = 1.6-2.5) and CXCL13 (OR_T3 = 2.3, 95% CI = 1.8-3.0). We also observed associations with sCD27 for CLL/SLL (OR_T3 = 3.3, 95% CI = 2.4-4.6), MZL (OR_T3 = 7.7, 95% CI = 3.0-20.1) and TCL (OR_T3 = 3.4, 95% CI = 1.5-7.7), and between sCD30 and FL (OR_T3 = 2.7, 95% CI = 2.0-3.5). In analyses stratified by time from phlebotomy to case diagnosis, the sCD27-TCL and all three DLBCL associations were equivalent across both follow-up periods (<7.5, ≥7.5 years). For other analyte-subtype comparisons, associations were stronger for the follow-up period closer to phlebotomy, particularly for indolent subtypes. In conclusion, we found robust evidence of an association between these immune markers and DLBCL, consistent with hypotheses that mechanisms related to immune activation are important in its pathogenesis. Our other findings, particularly for the rarer subtypes MZL and TCL, require further investigation.     

Physical activity and the risk of non-Hodgkin lymphoma subtypes: A pooled analysis

Non-Hodgkin lymphoma (NHL) is composed of a heterogeneous collection of subtypes with considerable differences in genetics, biology and aetiology. Studies to date on physical activity and NHL risk have not had sufficient sample size to evaluate whether associations differ by subtype. We pooled data from nine case-control studies to examine the association between moderate-to-vigorous intensity physical activity (MVPA) and risk of NHL overall and by subtype (diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukaemia/small lymphocytic lymphoma, marginal zone lymphoma and mature T-cell lymphoma). A total of 5653 cases and 9115 controls were included in the pooled analysis. Physical activity was harmonised across nine studies and modelled as study-specific tertiles. Multinomial logistic regression was used to estimate the association between physical activity and NHL, adjusting for confounders. The overall odds of NHL was 13% lower among participants in the most active tertile of MVPA compared to the least active tertile (adjusted odds ratio = 0.87, 95% CI = 0.80, 0.95). Similar decreases were observed across NHL subtypes. In summary, in this pooled analysis of case-control studies, physical activity was associated with a modest risk reduction for each NHL subtype examined and with overall NHL.     

套细胞淋巴瘤治疗进展

套细胞淋巴瘤是具有独特生物学、病理和临床特征的B细胞恶性肿瘤，占非霍奇金淋巴瘤5%~10%，大多数患者诊断时即为晚期。套细胞淋巴瘤具有侵袭性淋巴瘤的侵袭性和惰性淋巴瘤的难治愈性特征，患者预后较差。近年来随着大剂量化疗、自体造血干细胞移植及新药研究的进展，患者生存期得到明显延长。     

Burkitt transformation of mantle cell lymphoma

The associated poor prognosis and potentially aggressive behavior of mantle cell lymphoma and its blastoid variants make differentiation from other non-Hodgkin B-cell lymphomas especially important. We present a case of mantle cell lymphoma with a marked leukemic component, which demonstrated both a typical nodular mantle cell pattern and Burkitt lymphoma within a single lymph node removed at the time of splenectomy. The presence of CD5, CD10, and Bcl-1 co-expression by immunohistochemistry and detectable t(11;14) and cMYC gene rearrangement by FISH analyses in the Burkitt region support a transformation of mantle cell lymphoma over a concomitant malignancy. A limited number of mantle cell lymphomas demonstrating dual t(11;14) and chromosome 8q24 cMYC gene rearrangements have been previously reported in the literature. They demonstrate an extremely aggressive course with a very poor prognosis. Although the accelerated terminal phase of this patient's clinical course mirrors these previous published cases; none have described the combined morphologic and immunophenotypic features of Burkitt lymphoma reported here. This case provides further support for the aggressive nature of these lymphomas and demonstrates the utility of flow cytometry, immunohistochemistry, and cytogenetic techniques in avoiding potential errors in their diagnosis, prognosis, and treatment.     

Biology and therapy of mantle cell lymphoma

PURPOSE OF REVIEW: Mantle cell lymphoma is an aggressive non-Hodgkin's lymphoma characterized by the t(11;14) chromosomal translocation and overexpression of cyclin D1. Constituting approximately 5 to 8% of all non-Hodgkin's lymphomas, it carries the poorest prognosis among non-Hodgkin's lymphoma subtypes. Standard and effective treatment approaches have yet to be established. RECENT FINDINGS: Several recent insights regarding the molecular pathogenesis and prognostic biomarkers have been realized by way of comparative genomic hybridization, cDNA microarray, and proteomic analysis. Clinical trials using chemotherapy plus rituximab have shown improved response rates, including complete remissions, but without cure in most cases, indicating a clear need for new treatment approaches. Novel therapies for relapsed disease using the proteasome inhibitor bortezomib, thalidomide plus rituximab, the cyclin inhibitor flavopiridol, or inhibitors of the mammalian target of rapamycin (mTOR) have shown encouraging clinical responses. Stem cell transplantation, including nonmyeloablative approaches, are being incorporated into therapeutic regimens and show promise in both the front-line and relapsed/refractory settings. SUMMARY: This review summarizes recent advances in the biology, pathogenesis, and therapy of mantle cell lymphoma and identifies ongoing areas of clinical investigation and new treatment approaches.     

套细胞淋巴瘤治疗研究进展

套细胞淋巴瘤(MCL)是一种独特的B细胞非霍奇金淋巴瘤,其生物学行为具有侵袭性,恶性程度高,临床进展快,对常规治疗反应差,接受标准治疗后缓解期较短,至今依然被认为是一种不可治愈的淋巴瘤类型.第59届美国血液学会(ASH)年会报告中,涵盖了MCL新靶点的研发、耐药机制的研究、临床试验方案的优化等方面研究进展.文章结合会议报道对MCL治疗研究进展进行综述.     

Biology and management of mantle cell lymphoma

Mantle cell lymphoma is a distinct subtype and accounts for approximately 5 to 10% of non-Hodgkin lymphomas. The malignant cells express pan B-cell markers, including CD19, CD20 and CD22, and the T-cell marker CD5, whereas CD10 and CD23 expression are usually absent. By cytogenetic analysis, the t(11;14)(q13;q32) translocation is commonly observed, resulting in overexpression of cyclin D1. This entity often combines some unfavorable clinical features of the indolent and aggressive lymphoma subtypes, as it is generally incurable and relatively aggressive. It is most commonly observed in men 50 to 70 years of age and is characterized by disseminated disease, usually involving lymph nodes, bone marrow, and spleen. Frequently, there is extranodal involvement including the gastrointestinal tract. These tumors are incurable with the currently available therapeutic options, with usual time to progression after chemotherapy of approximately 1 year. Newer chemotherapy regimens (including stem cell transplantation) and monoclonal antibody-based therapies have shown limited evidence of additional benefit. Overall, the prognosis for patients with mantle cell lymphoma remains poor, and novel strategies are needed.     

Epidemiology of non-Hodgkin lymphomas and other haemolymphopoietic neoplasms in people with AIDS

HIV-infected individuals have a high risk of developing non-Hodgkin lymphoma (NHL). In Europe, the prevalence of AIDS with a concurrent NHL diagnosis increased from 3.6% to 5.4% between 1994 and 2000. In population-based record linkages between cancer registries and AIDS registries in the USA, Italy, and Australia, the relative risks of NHL in people with AIDS ranged between 15 for low-grade and T-cell NHL and 400 for high-grade NHL. The corresponding relative risk of Hodgkin's disease was about 10, whereas the risks for multiple myeloma and leukaemias were in the range 2 to 5. Since the introduction of highly active antiretroviral therapy in the more developed countries (1996), most studies have suggested a decline in the incidence of some types of NHL, most notably the primary brain form. In studies from Africa, the risk of HIV-associated NHL is about ten times less than that in the more developed countries, but underascertainment and earlier death from other AIDS-related illnesses may explain the relative lack of HIV-associated lymphomas.