Familial aggregation and heterogeneity of non-Hodgkin lymphoma in population-based samples.

The importance of genetic factors in the etiology of non-Hodgkin lymphoma (NHL) is suggested by case-control and cohort studies. Most previous studies have been too small to estimate accurately risks of specific categories of lymphoproliferative malignancies in relatives of NHL cases or to quantify the contribution of NHL case characteristics to familial risk. We have overcome sample size limitations and potential recall bias by using large databases from Sweden and Denmark. Diagnoses of lymphoproliferative malignancies were compared in 70,006 first-degree relatives of 26,089 NHL cases (including 7,432 with subtype information) versus 161,352 first-degree relatives of 58,960 matched controls. Relatives of NHL cases were at significantly increased risk for NHL [relative risk (RR), 1.73; 95% confidence interval (95% CI), 1.39-2.15], Hodgkin lymphoma (RR, 1.41; 95% CI, 1.0-1.97), and nonsignificantly for chronic lymphocytic leukemia (CLL; RR, 1.31; 95% CI, 0.93-1.85). No increased risk was found for multiple myeloma among case relatives. Findings with respect to siblings compared with parents and offspring or with respect to age at diagnosis of proband were inconsistent. In both populations, relatives of cases with an aggressive NHL subtype were at substantially increased risk of NHL (combined RR, 3.56; 95% CI, 1.80-7.02). We conclude that NHL has an important familial component, which is shared with Hodgkin lymphoma and CLL. We estimate that the absolute lifetime risk for a first-degree relative of an NHL case to develop NHL is 3.6% (compared with a population risk of 2.1%) and higher if the index case had an aggressive subtype of NHL.     

Nephrotic syndrome and acute renal failure in non-Hodgkin lymphoplasmacytic lymphoma

Two patients with lymphoplasmacytic lymphoma, and monoclonal proteins of IgM in one, and IgG and lambda light chains in the second patient, nephrotic syndrome and acute renal failure are reported. A 58-year-old man previously treated for pre-B acute lymphoblastic leukemia, developed 3 years later nephrotic syndrome as a complication of lymphoplasmacytic lymphoma and high-paraprotein IgM kappa type. Immunofluorescent analysis of kidney biopsy showed extensive IgM and light kappa chain deposits, which caused membranoproliferative glomerulonephritis. Treatment with cyclophosphamide was ineffective and patient died 2 months later. The second patient is a 42-year-old female diagnosed with lymphoplasmacytic lymphoma and paraprotein IgG lambda type. The course of the disease was fulminant with developing nephrotic syndrome and fatal acute renal failure. Immunofluorescent and light microscopic studies of kidney biopsy showed signs of immunotactoid glomerulonephritis with deposits of IgG and C3. Hemodyalises and cytostatic therapy were without response and she died after 45 days.     

Familial occurrence of carcinoid tumors and association with other malignant neoplasms.

Carcinoid tumors are generally thought to be sporadic, except for a small proportion that occur as a part of multiple endocrine neoplasia syndromes. Data regarding the familial occurrence of carcinoid as well as its potential association with other neoplasms are limited. A chart review was conducted on patients indexed for malignant carcinoid tumor of the gastrointestinal tract seen at the Mayo Clinic between 1988 and 1996. A survey of family history of malignancies and personal history of other tumors was mailed to all eligible patients. Data for 245 patients were analyzed. Observed rates of carcinoids and other malignancies were compared with Surveillance, Epidemiology, and End Results data. Estimates of the cumulative probability for first-degree relatives developing a carcinoid tumor were calculated. Nine (3.7%) patients with carcinoid tumor had at least one first-degree relative with the same malignancy. The rate of carcinoid tumor in first-degree relatives of probands was higher (P < 0.0001) than expected based on the Surveillance, Epidemiology, and End Results population data. Cumulative probability in a first-degree relative for developing a carcinoid was calculated to be 1.5% at age 80. There was an increased risk for developing a carcinoid tumor among first-degree relatives of patients with carcinoid. Neither patients with carcinoid nor their first-degree relatives had an increased incidence of other malignancies.     

Familial aggregation of Hodgkin lymphoma and related tumors

BACKGROUND: The importance of genetic factors in the etiology of Hodgkin lymphoma (HL) has been suggested by family and population studies. However, the spectrum of malignancies associated with common genetic etiology and the effects of gender and age on familial risk have not been established. METHODS: Diagnoses of lymphoproliferative malignancies were compared in 15,799 first-degree relatives of 5047 patients with HL versus 32,117 first-degree relatives of 10,078 control probands from Sweden and in 7185 first-degree relatives of 2429 patients with HL versus 27,434 first-degree relatives of 8,495 control probands from Denmark using marginal survival models. RESULTS: The risk of HL in relatives of patients with HL was increased significantly in both populations, with relative risks of 3.47 (95% confidence interval [95% CI], 1.77-6.80) in Sweden and 2.55 (95% CI, 1.01-6.45) in Denmark and a pooled estimate of 3.11 (95%CI, 1.82-5.29). In Sweden, risks for relatives of patients also were increased significantly for chronic lymphocytic leukemia and non-Hodgkin lymphoma (in males). Relative risks were higher in males compared with females and in siblings of patients compared with parents and offspring of patients. Relatives of patients with earlier-onset disease were at higher risk for HL. CONCLUSIONS: HL has an important familial component, which is stronger in families of affected individuals age < 40 years, in males, and in siblings, and it is shared with some (but not other) lymphoproliferative malignancies. The cumulative lifetime risks are very small, however, for the development of HL de novo or in first-degree relatives of affected patients.     

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.     

Familial aggregation of nasopharyngeal carcinoma and other malignancies. A clinicopathologic description.

Nasopharyngeal carcinoma (NPC) occurred in five members in three generations of a white American family of Scandinavian descent. Six other family members had malignancies including malignant melanoma, malignant lymphoma, squamous cell carcinoma of the tongue, adenocarcinoma of the colon, and asynchronous bilateral in situ and invasive ductal carcinomas of the breast. There was also a history of autoimmune disorders and exposure to smoke, fumes, and chemicals in some family members. Regression analysis revealed a significant covariate risk for exposure to smoking, alcohol ingestion, dust, salted or spicy foods, and poorly ventilated conditions. According to segregation analysis, the susceptibility to nasopharyngeal carcinoma and other malignancies in this family was transmitted as an autosomal codominant characteristic. A specific histocompatibility antigen (HLA) haplotype of A1-B37-DR6 was associated with a predisposition for NPC, but no linkage was identified. Laboratory studies in selected family members did not reveal significantly elevated levels of Epstein-Barr virus antibodies or serum carcinoembryonic antigen. No specific karyotypic abnormalities were identified with peripheral blood chromosome analysis. This family was an example of apparent autosomal codominant susceptibility to NPC and other malignancies. The relationship of malignancy to the HLA haplotype of A1-B37-DR6, autoimmune disorders, and cytogenetic abnormalities was intriguing but not defined clearly.     

Polychlorinated biphenyls and non-Hodgkin lymphoma.

Several epidemiologic studies suggest that polychlorinated biphenyl (PCB) levels measured in peripheral blood or adipose tissue are related to increased risk of non-Hodgkin lymphoma (NHL) and, therefore, may be at least partially responsible for the rising incidence of NHL unrelated to HIV infection in recent decades. Case-control studies that measured PCBs in blood, adipose tissue, or household carpet dust, at the time of diagnosis, have observed elevated NHL risk associated with concentrations of either total PCBs or of specific congeners. Similar associations have been found in a number of prospective cohorts. These associations do not seem to be due to confounding by other organochlorines or by other known NHL risk factors. These results support evidence of PCB carcinogenicity from animal studies. However, interpretation of the epidemiologic evidence is limited by the wide range in measurement precision across congeners and by the moderate to high correlation among many congeners. Occupational cohort studies provide very limited support for a relationship between PCBs and NHL. In conclusion, there is mounting evidence of a relationship between certain PCBs and risk of NHL, but important questions remain, especially regarding the magnitude, timing, and causality of that relationship.     

Sun exposure and non-Hodgkin lymphoma.

It was initially hypothesized that sun exposure might cause non-Hodgkin lymphoma (NHL) on the following grounds: its incidence was increasing in parallel with that of cutaneous melanoma; its risk was increased in those with a history of melanoma or other skin cancer; sun exposure causes immune suppression; and immunosuppression for other reasons is associated with an increased risk of NHL. The association of NHL with prior skin cancer has been found consistently in subsequent studies, but results of ecological analyses have only partially supported this hypothesis. Contrary to it, three recent studies of NHL in individuals found that risk decreased, generally by 25% to 40%, across categories of increasing total or recreational, but not occupational, sun exposure. One study, thus far reported only in abstract, showed the opposite. Production of vitamin D from sun exposure offers a plausible mechanism for protection against NHL by sun exposure. A recent study has found a reduced risk of NHL in people with a high dietary intake of vitamin D. Results of additional studies in individuals and a planned original-data meta-analysis of case-control studies should help to resolve the present conflicting results on sun exposure and NHL.     

Association of aspirin and other non-steroidal anti-inflammatory drug use with incidence of non-Hodgkin lymphoma

Non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, seem to have chemopreventive properties against several types of cancer, particularly colon cancer. Persons with rheumatoid arthritis, an autoimmune disease for which NSAIDs are used commonly, have been reported to be at lower risk of colon cancer but at elevated risk of non-Hodgkin lymphoma (NHL), raising the possibility that NSAIDs may be a risk factor for NHL. We evaluated the association of use of NSAIDs, arthritis history, and risk of NHL in a prospective cohort of 27,290 postmenopausal women from the state of Iowa. The frequency of use of aspirin and of other NSAIDs excluding aspirin (e.g., ibuprofen), as well as a physician diagnosis of rheumatoid arthritis (RA) or osteoarthritis (OA), were self-reported on a questionnaire mailed in 1992. The incidence of NHL was ascertained through annual linkages to the Iowa SEER Cancer Registry. Relative risks (RR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards regression. Through 7 years of follow-up, 131 cases of NHL were identified. Compared to women who did not use either aspirin or other non-aspirin NSAIDs, women using aspirin exclusively (RR = 1.71; 95% CI = 0.94-3.13), non-aspirin NSAIDs exclusively (RR = 2.39; 95% CI = 1.18-4.83), or both types of drugs (RR = 1.97; 95% CI = 1.06-3.68) were at increased risk of NHL. A diagnosis of RA (RR = 1.75; 95% CI = 1.09-2.79), but not OA (RR = 1.06; 95% CI = 0.67-1.68), was associated with risk of NHL, but the positive association of use of aspirin and other NSAIDs with NHL was independent of RA history. Multivariate adjustment for other NHL risk factors only attenuated slightly these associations, whereas exclusion of cases occurring during the first 2 years of follow-up strengthened the associations. These data suggest that use of NSAIDs, either aspirin or other non-aspirin NSAIDs, are associated positively with risk of NHL, and that this association is independent of RA history.     

Advances in the epidemiology of HIV-associated non-Hodgkin's lymphoma and other lymphoid neoplasms.

The spectrum of HIV-related lymphoid malignancies certainly includes non-Hodgkin's lymphoma (NHL; i.e., chiefly large-cell lymphoma and Burkitt's lymphoma), primary lymphoma of the brain (PBL) and, possibly, Hodgkin's disease (HD). Since the mid-1990s, several epidemiological studies have led to better quantification of the burden of lymphomas in HIV-infected populations. AIDS surveillance data from 17 western European countries show that between 1988 and 1997 a total of 7,148 AIDS cases had NHL as the AIDS-defining illness. The yearly number of cases rose steadily from 1988 to 1995 but declined thereafter. As a percentage of AIDS-defining illnesses, NHL increased from 3.6% in 1994 to 4.9% in 1997. Percent increases were observed in different strata by area, age group, sex and HIV-transmission group. To estimate relative risk (RR) of NHL and other lymphoid neoplasms in unselected HIV-seropositive populations, records of population-based cancer registries and AIDS registries were linked in the United States, Italy and Australia. RRs for NHL in adults with HIV/AIDS ranged between 14 (for low-grade NHL) to over 300 (for high-grade NHL). For HD, the RR was approximately 10. Limited findings from studies based on death certificates and cohorts of HIV-seropositive persons were consistent with those from registry linkage studies. In developing countries, the risk of HIV-associated NHL appears to be much lower than in developed countries, but under-ascertainment and earlier death from other AIDS manifestations may explain the lack of HIV-associated lymphomas in Africa.     

High incidence of other neoplasms in patients with low-grade gastric MALT lymphoma

BACKGROUND: Low-grade gastric MALT lymphoma is an uncommon tumour for whicha close association with chronic Helicobacter pylori infectionhas been suggested. However, given the rarity of MALT lymphomaof the stomach despite the high prevalence of H. pylori infection,it seems plausible that genetic host factors might play a fundamentalrole in gastric lymphomagenesis. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 83 patientswith low-grade gastric MALT, all of whom resided in a geographicarea (southern Switzerland and northern Italy) where the incidenceof gastric tumours appears to be uncommonly high. RESULTS: One or more additional cancers were observed in17 of 83 patients(20%, 95% CI 12% to 31%) for a total of 23 tumours. Of these,5 were diagnosed prior to, 12 con-comitantly with, and 7 afterthe gastric MALT lymphoma. Eleven patients had a single additionalsolid tumour (13%, 95% CI 7% to 22%); 3 patients had non-Hodgkin'slymphoma and one had Hodgkin's disease. Multiple additionalcancers were present in 3 cases. Nine of 83 patients have diedand 8 of them of a second cancer. CONCLUSIONS: Unexpectedly an extraordinarily large number of patients withother malignancies was observed in this series. The reasonsfor this finding are still unknown, but genetic alterationsare speculated to play an important role. stomach, MALT lymphoma, non-Hodgkin's lymphoma, solid tumours, second neoplasms     

Benzene exposure and risk of non-Hodgkin lymphoma.

Exposure to benzene, an important industrial chemical and component of gasoline, is a widely recognized cause of leukemia, but its association with non-Hodgkin lymphoma (NHL) is less clear. To clarify this issue, we undertook a systematic review of all case-control and cohort studies that identified probable occupational exposures to benzene and NHL morbidity or mortality. We identified 43 case-control studies of NHL outcomes that recognized persons with probable occupational exposure to benzene. Forty of these 43 (93%) studies show some elevation of NHL risk, with 23 of 43 (53%) studies finding statistically significant associations between NHL risk and probable benzene exposure. We also identified 26 studies of petroleum refinery workers reporting morbidity or mortality for lymphomas and all neoplasms and found that in 23 (88%), the rate of lymphoma morbidity or mortality was higher than that for all neoplasms. A substantial healthy-worker effect was evident in many of the studies and a comprehensive reevaluation of these studies with appropriate adjustments should be undertaken. Numerous studies have also reported associations between benzene exposure and the induction of lymphomas in mice. Further, because benzene is similar to alkylating drugs and radiation in producing leukemia, it is plausible that it might also produce lymphoma as they do and by similar mechanisms. Potential mechanisms include immunotoxicity and the induction of double-strand breaks with subsequent chromosome damage resulting in translocations and deletions. We conclude that, overall, the evidence supports an association between occupational benzene exposure and NHL.     

Occupation and the risk of non-Hodgkin lymphoma.

Although thus far no occupational agents have been classified as established causes of non-Hodgkin lymphoma (NHL), employment as a farmer, teacher, dry cleaner, meat worker, printer, or wood worker has been associated with elevated risk in the peer-reviewed literature. We conducted several meta-analyses to assess risk in these occupations and industries from articles published in MEDLINE up to August 1, 2006. The summary risk estimates suggest a homogeneous excess risk for NHL among workers in the printing industry [relative risk (RR), 1.86; 95% confidence interval (95% CI), 1.37-2.52] and wood workers (RR, 1.15; 95% CI, 1.00-1.31). Considerable heterogeneity but elevated risks were found for farmers (RR, 1.11; 95% CI, 1.05-1.17), especially in animal husbandry (RR, 1.31; 95% CI, 1.08-1.60), and teaching (RR, 1.47; 95% CI, 1.34-1.61). An increased risk was absent for employment in the meat processing industry (RR, 0.99; 95% CI, 0.77-1.29). These results suggest that although excess risk is found for employment in the printing industry, wood processing industry, teaching, and farming, it is unlikely that occupation represents a major risk factor for NHL in most populations. At present, no conclusive evidence of causal relations between occupations and increased NHL risk exists; this can be ascribed to methodologic problems in studying the link between NHL risk and occupation, including heterogeneity of disease and exposure circumstances and low statistical power. Implementing state-of-the-art exposure assessment technologies, including biomarker-based assessment, and aiming to identify susceptible subgroups can increase the statistical power enough to analyze etiologically relevant NHL subtypes and provide clues on possible causal agents in future studies. These goals can be best attained within the framework of large-scale, international collaborative projects.     

Cytogenetic characteristics of childhood non-Hodgkin lymphoma.

Cytogenetic studies were performed successfully on 24 patients with non-Hodgkin lymphoma (NHL) who were younger than 15 years of age. Of these, 22 patients (92%) had abnormal clones. With respect to histologic findings, 3 (25%) of the 12 patients with lymphoblastic lymphoma had 14q11 translocations and 2 (17%) had t(9;17) (q34;q23). Four (80%) of the five patients with small non-cleaved cell lymphoma had t(8;14)(q24;q32). With respect to immunologic findings, four (44%) of the nine patients with T-cell lymphoma had abnormalities consisting of 14q11 and 7q36 translocations, in which the T-cell receptor genes resided. Three (33%) of the patients with T-cell lymphoma had t(9;17)(q34;q23). However, three (43%) of the seven patients with B-cell lymphoma had t(8;14) (q23;q32), and two (29%) of the patients with B-cell lymphoma had an extra i(11q) chromosome with a resultant 11q tetrasomy. Non-T-cell non-B-cell lymphomas, which occurred in 21% of all patients, showed various chromosomal abnormalities. This study demonstrated that, in childhood NHL, karyotype correlates closely with immunophenotype, clinical features, and histologic findings.     

Malignant lymphoma of lymphoplasmacytic/lymphoplasmacytoid and immunoblastic types

Sixty-four patients with extranodal non-Hodgkin's lymphomas of lymphoplasmacytic/lymphoplasmacytoid (LP) and immunoblastic (IBS) types were reviewed. The criteria distinguishing the latter from the former was a presence of basophilic and prominent nucleoli in a vast majority of the tumor cells. The numbers of LP and IBS types were 34 and 30, respectively. Intervals from appearance of tumors to initial treatment in LP and IBS were 15.7 +/- 25.3 and 6.0 +/- 12.3 months, respectively (p less than 0.1). Histologically LP had a low mitotic count (p less than 0.001) and contained a larger number of mast cells (p less than 0.05) than IBS. Proliferating cells in 4 patients with LP type had nuclei with a slightly irregular indentation similar to those of intermediate lymphocytic lymphoma. Follow-up study revealed the LP type to have a much more favorable prognosis than the IBS type (p less than 0.001) though 3 patients with LP showed unfavorable prognosis. Tumor cells in these tumors had a small to medium-sized, often convoluted nucleus. The present results showed that the distinction of LP and IBS by their morphology of nucleoli was prognostically meaningful. Furthermore it is suggested that tumors of the LP type are heterogeneous.     

Severe aplastic anemia associated with paroxysmal nocturnal hemoglobinuria and lymphoplasmacytic lymphoma

An unusual case of aplastic anemia presenting in association with lymphoplasmacytic lymphoma and paroxysmal nocturnal hemoglobinuria is discussed. An insult to the hematological stem cell compartment may result in multiple pathological entities, potentially influencing our approach to the treatment of hematological clonal disorders.     

Obesity, diet and risk of non-Hodgkin lymphoma.

Non-Hodgkin lymphoma (NHL) represents a group of heterogeneous diseases that significantly vary in their causes, molecular profiles, and natural progression. In 2007, there will be approximately 59,000 newly diagnosed NHL cases in the United States and over 300,000 cases worldwide. Although new therapeutic regimens are minimizing the number of deaths related to NHL, causes for the majority of lymphomas remain undetermined. Recent studies suggest that dietary factors may contribute to the rising rates of NHL. This review will summarize epidemiologic reports that have studied the relationship between obesity, physical activity, and diet and risk of NHL. Based on a number of case-control and prospective cohort studies, overweight/obesity probably increases the risk of NHL, whereas moderate physical activity may reduce risk. Several studies support an inverse association between intakes of vegetables and NHL risk, particularly for the consumption of cruciferous vegetables. This may relate to the induction of apoptosis and growth arrest in preneoplastic and neoplastic cells, two important actions of isothiocyanates found in cruciferous vegetables. Studies also suggest that fish intake may be inversely associated with risk of NHL, although findings have not been entirely consistent. This may relate to the high organochlorine content in some fish that could override a protective effect. High consumption of fats, meat, and dairy products also may increase lymphoma risk. The accumulated scientific evidence concerning the associations between obesity, diet, and NHL suggests several identified modifiable risk factors that might be recommended to decrease lymphoma risk.     

Treatment of non-Hodgkin lymphoma

Preliminary results of new therapies in the areas of cytotoxic agents and immunotherapy for advanced indolent lymphomas have been encouraging. Long-term follow-up on high-dose therapy suggests a potential role for this modality in this group of lymphomas. In aggressive lymphomas, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) continues to hold ground as first-line therapy when compared against other regimens. Several studies reinforce past findings that patients with chemosensitive relapse are better candidates for high-dose therapy. In relapsed or refractory disease, selected compounds appear to have activity as single agents and others have shown activity in combination therapy. Despite high treatment-related mortality rates, allogeneic transplantation in relapsed aggressive lymphoma warrants further investigation. Last, as patients are surviving longer, complications of therapy are having to be addressed.