Results

Table 1 gives selected information on the interviewed cases and controls, and table 2 the distribution by gender, age and the diagnostic categories of the cases.

A previous paper has been devoted to the association between peptic ulcer and gastric NHL.42

Table 3 shows odds ratios (OR) and 95% confidence intervals (CI) for selected diseases (those with at least five cases exposed). The analyses are shown according to both the conservative criterion of analysing only the subjects who were able to recall the date of first diagnosis (A), and to a broader criterion of inclusion (B). The differences between the two criteria are marginal; only for herpes labialis and chicken pox, as expected, there is a large discrepancy between the two criteria, but this does not affect the risk estimates. Statistically significant OR, after exclusion of unknown dates, were observed for hay fever (associated with a protective effect), infectious mononucleosis and hepatitis.

Table 4 gives the age adjusted OR and 95% CI for each diagnostic category within haematolymphopoietic malignancies. A statistically significant association is evident only for lupus erythematosus and NHL (OR=8.4; 95% CI 1.6, 45). A negative association with hay fever is suggested; this is statistically significant for HD and myeloid leukaemia.

Table 5 describes the data for infectious mononucleosis (IM). As in the previous table, we have excluded subjects who were not able to locate the onset of IM in time. A relative risk of about four was found for both NHL and HD. A positive association was detected between a higher educational level and the risk of NHL or HD among the subjects who reported previous IM.

Other confirmatory findings from our study concern a history of hepatitis and of tuberculosis and the risk of NHL and lymphocytic leukaemia (table 6). Also HD was increased among subjects who reported tuberculosis. In addition, tuberculosis as the cause of death in the mother was strongly associated with NHL (OR=2.8; 95% CI 1.1, 6.9; based on 15 cases and 6 controls), while the association with father's tuberculosis was weaker (OR=1.7; 0.7, 3.9; based on 13 cases and 8 controls). No similar association was detected with HD.

Our study does not confirm previous suggestions concerning NHL and diabetes (table 6). We have considered different latency periods between the onset of diabetes and the risk of NHL, but no association was found. Also tonsillectomy and adenoidectomy showed no relation with any of the diseases included in our study (table 6).

Table 7 suggests that a history of malaria increases the risk of lymphatic leukaemias and of “low grade” B cell malignancies (according to the Working Formulation), two categories partially overlapping. The risk is associated, in fact, only with malaria at young age. Malaria was endemic in several Italian areas until the end of the second world war.

Finally, one interesting finding was the observation of four cases of poliomyelitis among NHL patients, one among HD and one among myeloid leukaemia patients, compared with none among the controls (Fisher's exact test for NHL+HD, p=0.03, one tail). These cases had no peculiar distribution by histological findings or anatomic site. They lived in different towns, there was no evident link among them, and no reasonable suspicion of recall bias.

Estimates were not modified or confounded by residence (urban/rural), education or centre.

Discussion

The incidence of NHL is increasing in Western societies, while HD, leukaemias and myelomas are stable.1 NHL have been associated with immunosuppression, particularly among patients who have had a transplant and HIV carriers. It can be hypothesised that exposure to mild immunosuppressants can also increase the risk of NHL.44 45 Some viruses—namely, EBV—have been implicated in the aetiology of NHL and HD.

We have conducted a large study on haematolymphopoietic malignancies and medical history. Merits of our study are the large sample size, the population design (with controls randomly drawn from the general population), the low refusal rate, and the overall good quality of interviews, collected by trained interviewers. The main limitation is related to the nature of the information on previous diseases, exclusively based on interviews with no objective clinical data. However, the methods we used to limit recall bias (see Methods section) reassure us about the credibility of the findings. Despite the multiple comparisons, the low number of statistically significant associations is rather suprising.

Our study confirms an association of NHL and HD with IM. Interestingly, the association is stronger among subjects belonging to higher social groups, defined on the basis of education. We cannot rule out that this finding is attributable to recall bias—that is, more accurate recall of IM infection by subjects belonging to higher social groups. In fact, it is probable that more educated people have physicians or researchers among their friends, and may be more receptive to speculations about causes. A similar finding has been reported for the association between gastric NHL and peptic ulcer (infection with H pylori); in that case recall bias is highly unlikely.42 For both conditions (peptic ulcer and IM), the infectious agent is extremely common: 90% of adults living in Western societies are immunised against EBV; about 40–45% of Italians are immunised against H pylori.42Some late event associated with higher social class could trigger the development of gastric NHL or, respectively, lymphnodal NHL. It can be speculated that early H pylori or EBV infection creates local immunological protection, while late infection—more typical of higher social groups—would entail an increased risk of lymphoma.

Chronic infections can increase the risk of cancer.46 47Several mechanisms have been proposed for this finding. In particular, it has been speculated that chronic infections increase the production of oxygen radicals that cause oxidative DNA damage.46 This mechanism might explain the association we have found between tuberculosis and NHL and HD, and between NHL and hepatitis (we do not have information, however, about the clinical characteristics and course of hepatitis). The association between parental death from tuberculosis and NHL is more difficult to explain.

Malaria has been identified as a risk factor for Burkitt's lymphoma in African children, particularly in interaction with EBV. To the best of our knowledge, an association between malaria and lymphatic malignancies has not been reported before from Western countries. Malaria causes a chronic immunosuppressive state8 but it could also act by the formation of reactive oxygen species and DNA damage.

An unexpected finding was the observation of five lymphomas (four NHL, one HD), one case of myeloid leukaemia and no controls who had had poliomyelitis (p=0.03, one tail exact test, for NHL+HD). This observation is unlikely to be attributable to recall bias, as poliomyelitis is a very severe disease. It might shed light on still unknown relations between viral infections and lymphomas. HD has an age distribution that is similar to that of poliomyelitis, and a similar pathogenetic process has been invoked (the so called polio model for HD).34

Finally, we did not confirm the role of diabetes in NHL aetiology, as reported recently by some researchers but not by others. The lack of an association cannot be explained by severe pitfalls. Our study was population-based, the response rate was particularly high and the vast majority of interviews were conducted face to face by trained personnel. Random misclassification because of inaccuracies in the recall of the disease history is possible, although diabetes is a condition that is usually well known to the patients.