Familial Aggregation of Non-Hodgkin's Lymphoma (NHL). A Case Report

In Western countries there has been a large and mainly unexplained rise in incidence of non-Hodgkin's lymphoma (NHL) in recent years [1]. Several aetiological factors for NHL are known, including genetic and environmental or occupational factors. Familial aggregation of lymphoproliferative malignancies (malignant lymphoma and lymphatic leukaemia) has been reported repeatedly but accounts for only a small proportion of lymphoma cases. Most of the familial cases are sibling pairs either alone or in combination with other affected relatives. A population-based study in Israel among first-degree relatives of patients with lymphomas showed that only 0.7% of the lymphoma patients had a history of lymphoma in one or more relatives [2]. In some families, a pre-existing immune deficiency has been described [3–5]. No histological subtype appears to predominate in familial cases.

Here, a family in which all three living male siblings of Asian descent developed NHL is presented.

Risk of NHL has been found significantly increased in relatives of people with haematological malignancies, especially among siblings, although the absolute risk is small [2, 6, 7]. It has been estimated that the absolute lifetime risk for a first-degree relative of an NHL case of developing NHL is 3.6% (compared with a population risk of 2.1%) and higher if the index case had an aggressive subtype of NHL [8]. Aggregation of NHL seems to be stronger for siblings and for male relatives and among relatives of early-onset (<50 years) NHL cases [9]. With the exception of chronic lymphocytic leukaemia and indolent lymphoma, most affected families present with diverse lymphoproliferative and other haematological malignancies [10]. This diversity is not completely unexpected as lymphoma and leukaemia have common cellular origins, and some types have common genetic somatic changes or share common aetiological factors. Histological subtypes do appear to have an effect on familial risk. A recent study using the Swedish Family-Cancer Database calculated standardized incidence ratios (SIRs) for histopathology-specific subtypes of NHL in offspring with NHL whose parents or siblings were affected with different types of lymphoproliferative malignancies. A family history of NHL significantly increased the risk for NHL (SIRparent = 1.8; SIRsibling = 1.9) and for diffuse large B-cell lymphoma (SIRparent = 2.3), follicular lymphoma (SIRsibling = 2.3), and B-cell lymphoma not otherwise specified (NOS) (SIRsibling = 3.4). For a parental history of histopathology-specific concordant cancer, the risks were significantly increased for diffuse large B-cell lymphoma (SIR = 11.8), follicular NHL (SIR = 6.1), plasma cell myeloma (SIR = 2.5), and chronic lymphocytic leukaemia (SIR = 5.9) [11].

In general, familial aggregation of lymphoproliferative malignancies may be coincidental or may be caused by (combinations of) shared genetic and environmental risk factors. In rare cases, familial aggregation is associated with rare hereditary tumour syndromes such as Li-Fraumeni syndrome or hereditary immunodeficiency syndromes. Apart from those cases occurring in families meeting the criteria of Li-Fraumeni (like) syndrome, constitutional p53 mutations are rare in cases of familial aggregation of lymphoma [12]. Some multiple-case families have been found to have various types of immune deficiency disorders [3, 4]. The immunological disorders range from X-linked lymphoproliferative syndrome and ataxia telangiectasia to subtle laboratory findings like a disturbance in T cell function, decreased T cell number, or increased immunoglobulins. In other families risk factors are unclear. An argument in favour of genetic predisposition playing a role is the fact that various investigators have demonstrated that anticipation is present in familial NHL [13, 14]. Anticipation is a phenomenon characterised by an increase in severity of clinical symptoms or a decrease in the age of onset in successive generations. A possible non-genetic explanation is that the parents and children have been simultaneously exposed to a causative environmental agent, the difference in age of onset reflecting the generational difference. However, this does not explain cases in families who did not live together and cases where parents were diagnosed with NHL many years after their children were.

A population-based case-control study in the United States showed that certain non-genetic risk factors, including exposure to a chlorinated hydrocarbon pesticide, plywood, fibreboard or particleboard and history of liver diseases (other than hepatitis or cirrhosis) (OR = 6.5, 95% CI: 1.2-36.2), increased the risk of NHL in patients with a family history of haematological malignancies compared to patients without such family history [15]. Another study could not confirm that a family history of cancer modifies the association of agricultural exposures with NHL [16] and a more recent study showed no evidence that aetiological associations varied between familial NHL and nonfamilial NHL cases [7]. In general, it is therefore still difficult to pinpoint interactions between shared inherited and environmental risk factors with respect to NHL development.

In the present family, no signs of impaired immunity were present; however, neither cancer predisposing germline gene mutations nor exposure to viruses or environmental carcinogens can be excluded. All three affected brothers may have been exposed to possible carcinogenic materials during work, and all three were smokers. Tobacco use has been suggested to increase the risk of NHL, but the results of epidemiological studies have been inconsistent [17]. The combined effects of genetic susceptibility and tobacco use could possibly lead to NHL. At diagnosis, one brother had indolent lymphoma and two had aggressive lymphoma of follicle centre cell origin. It is possible that this was a transformed lymphoma, which originated also from an indolent lymphoma, but this could not be substantiated by available clinical and morphological data. The leukaemia of case 2 could have been secondary to chemotherapy or could have been a second primary haematological malignancy, which would then again suggest possible predisposition.

In conclusion: in this case report we have presented a quite remarkable clinical finding in three male siblings who developed malignant lymphoma. All of them are still alive. Shared genetic or environmental risk factors, or combinations of these, remain to be identified in this family.