Dissecting lymphoma incidence to inform epidemiologic and clinical research

Over the last half century, the age-adjusted incidence of non-Hodgkin lymphoma (NHL) has more than tripled [1,2]. Although some portion of this “epidemic” of NHL can be attributed to human immunodeficiency virus (HIV), the causes of most cases of NHL in the general population remain unknown. In the 1950s, when the NHL epidemic began, the myriad forms of NHL were lumped together and treated as a single disease – both clinically and in the research community. Following the advent of the molecular era and introduction of the World Health Organization (WHO) Classification of Tumours of the Hematopoietic and Lymphoid Tissues [3,4], the more than 92 000 cases of NHL (including lymphoid leukemias) diagnosed in the United States in 2012 were classified into more than 40 different subtypes, according to morphological, immunophenotypic, genetic and prognostic features [5]. In clinical practice today, many of these subtypes are treated differently. In the research community, distinct NHL subtypes are also increasingly recognized as potentially having different underlying causes, and tracking of the incidence patterns of NHL subtypes has grown correspondingly complex.

What can be gained from detailed examination of the incidence of NHL subtypes? Underneath the most basic benefits (e.g. quantifying the burden of NHL over time) lie tantalizing clues to clinical and etiologic research. One such example is presented in this issue of the journal, in which Aschebrook-Kilfoy et al. [6] track the incidence of mantle cell lymphoma, a rare B-cell lymphoma characterized by CCND1 translocation that was first officially recognized as part of the Revised European-American Lymphoma (REAL) classification in the 1990s [7]. The authors confirm earlier reports of increasing mantle cell lymphoma incidence over the last two decades, but record for the first time that the magnitude of the increase varies according to specific patient characteristics. The most striking increases in incidence have occurred among older, white males – further increasing the predominance of mantle cell lymphoma in these individuals compared with younger individuals, females and non-whites in the United States.

Evaluating incidence by specific patient characteristics such as age at diagnosis, race/ethnicity or sex can provide a range of valuable information. Recognition that the incidence of primary mediastinal B-cell lymphoma peaks during the third and fourth decades of life in a pattern similar to that of nodular sclerosing Hodgkin lymphoma [8] foreshadowed the more recent discovery of similar molecular characteristics and comparable efficacy of specific treatments between these entities [9]. Striking differences in the incidence of specific NHL subtypes by race and ethnicity have spurred the investigation of inherited susceptibility to NHL. For example, the lower prevalence of certain genetic risk factors for chronic lymphocytic leukemia (CLL) in Asians [10] likely plays a key role in explaining why the incidence of CLL is more than four times higher in Caucasians in the United States compared with Asian Americans [11]. The explanation for the predominance of most – but not all – lymphoma subtypes among men [11] remains unknown. Studies of hormonal factors have yielded inconsistent results [12,13], suggesting that uncovering the reasons for the sex difference in lymphoma should be a priority for future etiologic research.

Investigation of the incidence trends for specific subtypes can also provide insight into clinical practices in the general population. The steady decline in the incidence of NHLs without a specified subtype in the United States over the last several decades [11] quantifies the improved diagnostic accuracy gained by introducing the REAL classification in the 1990s [7] followed by the WHO classification in 2001 [3,4]. However, this decline was least evident in older individuals and those with HIV [14], suggesting that improved diagnostic assessment may be warranted in specific patient populations, particularly in scenarios where a more accurate diagnosis will impact treatment selection. Pairing incidence data with population-based survival data can also serve as an indicator for access to medical care and changes in treatment practices, exemplified in a recent study demonstrating higher incidence of multiple myeloma in blacks than in whites, but greater improvements in survival for whites over time [15].

As the classification of NHL subtypes continues to evolve, detailed investigations of the incidence of newly recognized NHL subtypes should continue to provide clues to the causes of NHL as well as valuable benchmarks for clinical advances in the diagnosis and treatment of NHL. In particular, comparisons among the numerous subtypes defined by molecular characteristics, such as germinal center versus activated B-cell type diffuse large B-cell lymphoma, may help to clarify which entities should truly be considered distinct diseases.

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