Medical history and risk for lymphoma: results of a population-based case-control study in Germany

Abstract

Since lymphomas are malignancies of cells of the immune system, associations with disorders characterised by impaired immune functions can be assumed. We investigated the relationship between a history of selected medical conditions and the risk for lymphoma including specified subentities within our population-based case-control study of lymphoma among adults conducted in Germany between 1999 and 2002. Overall, we found decreased risks for a history of repeated diarrhoea, warts, arthrosis, allergies, and appendectomy (at a younger age). Elevated risks for lymphoma correlated with tonsillectomy (at a younger age), whereas null results were found for selected auto-immune disorders in adulthood. Although the numbers are small, most of the results for the subentities corresponded with these findings. These results are compatible with the notion that persistent immunological alterations contribute to the aetiology of lymphoma, but partially inconsistent with the Th1/Th2-shift paradigm.

Introduction

In Germany, lymphomas have one of the highest increases in incidence amongst the different cancer sites, with an annual percent change of approximately 2% in males and 3% in females (1970–1998). In contrast to other cancer sites, this increase has continued until recently [1] (for an update see www.dkfz.de, ‘cancer atlas’). The latest publication of the German cancer registries indicates this level may now have reached a plateau [2]. However, the aetiology remains largely obscure. The few established risk factors, e.g., immune suppression, human immunodeficiency virus (HIV), and some other viral infections, explain only a few of the cases.

Since lymphomas are malignancies of cells of the immune system, associations with disorders characterised by impaired immune functions can be assumed. For immune deficiency syndromes, a strong elevation in lymphoma risk is well established [3]. For auto-immune disorders, such as, e.g., diabetes type 1, multiple sclerosis, rheumatoid arthritis, or Sjögren’s syndrome, indications for a subsequently elevated lymphoma risk have been found. However, with the exception of Sjögren’s syndrome, these are not consistent. Associations with a history of allergies were inconsistent. Some tendency towards a decreased Odds Ratio (OR) was seen in more recent years. A history of infectious diseases which may have affected immune regulation has been considered by several authors, but the results have been conflicting [39], [42], [43].

The aetiology of an increasing incidence of immune-related disorders among children and adults has been discussed in terms of the so-called “hygiene hypothesis”, although the hypothesis was originally confined to childhood leukaemia and allergies. Greaves proposed this explanatory model for acute childhood leukaemia in 1988 [4], [5]. It stated that lack or delayed exposure to common infections, i.e. antigenic challenge, early in infancy might leave the immune system insufficiently prepared for exposure to common viruses some years later leading to inappropriate hypo- or hyper-reactive immune responses.

Independently, Strachan [6] postulated an analogous hypothesis to explain the increasing prevalence of allergies in many countries. Having found a strong inverse correlation between the number of siblings and the prevalence of hayfever, he proposed that declining family sizes and higher standards of household hygiene might be associated with an increased risk of atopic diseases. As early as 1966, Leibowitz and colleagues [7] suggested that multiple sclerosis might be increased among subjects who spent their childhood in homes with high levels of sanitation. In addition, diabetes type I has been related to factors which are constitutive for the hygiene hypothesis [8], [9], [10]. Recent studies indicated that these patterns of early life characteristics might also affect lymphoma risk in adults [11], [12].

Generally, the hypothesis provides an explanatory model for the observation of an increasing prevalence of allergic diseases (asthma, rhinitis and atopic dermatitis) and auto-immune diseases (multiple sclerosis, diabetes type 1 and Crohn’s disease) and a decreasing prevalence of typical infectious diseases (measles, mumps, tuberculosis, rheumatoid fever, hepatitis A) in countries with a so-called “Western” lifestyle [13].

An immunological interpretation of the allergy-related hygiene hypothesis was given within the framework of the Th1/Th2 paradigm. Delayed contact to infectious agents during childhood might lead to an impairment of the Th1/Th2 balance that gives rise to a life-long shift of the system in atopic subjects towards a Th2-type response [14], [15]. Despite less clear evidence for a shift in the Th2-direction in lymphoma, epidemiological findings are increasingly interpreted in terms of this paradigm [11], [16].

In the present paper, we address the role of factors of medical history in the aetiology of lymphoma among adults based on a recently conducted population-based case-control study in Germany and discuss the results in the context of these mechanistic models.