Non-Hodgkin lymphoma (NHL) is the sixth most commonly diagnosed cancer in both men and women in the United States. In 2015, it is estimated that there will be 71,850 new cases of NHL (39,850 men and 32,000 women) and 19,790 deaths from NHL. The disease represents approximately 4.3% of all cancer diagnoses (4.7% in males and 4% in females). Notably, incidence rates of NHL almost doubled between 1970 and 1990 but have stabilized since the late 1990s among general populations. Some of this increase may be artifactual, resulting from improved diagnostic techniques and access to medical care, or directly related to the development of NHL in 25- to 54-year-old men with human immunodeficiency virus (HIV) infection. However, additional factors must be responsible for this unexpected increase in frequency of NHL that has been observed throughout the United States.
The increases have been more pronounced in whites, males, the elderly, and those with NHL diagnosed at extranodal sites. Similar findings have been reported in other developed countries. In the United States, incidence rates increased significantly during 2002-2011 for marginal zone lymphoma (average 1.7% per year), mantle cell lymphoma (MCL) (1.7% per year), adult T-cell leukemia/lymphoma (6.6% per year), and natural killer (NK)/T-cell lymphoma (3.5% per year) but decreased for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (−1.4% per year).
Sidebar: Analysis of pre-diagnosis blood specimens for evidence of t(14;18) in patients with follicular lymphoma revealed that progression to follicular lymphoma may occur up to 20 years later in apparently healthy individuals carrying this marker. Investigators estimated that for individuals with a high frequency of peripheral blood t(14;18), the risk of developing follicular lymphoma may be as high as 23-fold that of controls. This marker of risk was present many years before diagnosis in patients. (Roulland S et al: J Clin Oncol 32:1347-1355, 2014).
The overall incidence of lymphoma is higher in men than in women. The age-adjusted incidence rate between 2007 and 2011 was about 45% higher in males (23.9 per 100,000) than in females (16.3 per 100,000). Although the overall NHL incidence rates remained unchanged during 2002-2011 among men and women, rates for marginal zone lymphoma and adult T-cell leukemia/lymphoma (ATLL) increased significantly in men, and to a lesser degree, in women.
The incidence of NHL overall and of most histologic subtypes rises exponentially with increasing age. In persons older than 65, the incidence was 91.6 (112.3 males and 76.9 females) per 100,000 persons in 2007-2011. Except for high-grade lymphoblastic and Burkitt lymphomas (the most common types of NHL seen in children and young adults), the median age at presentation for all subtypes of NHL exceeds 50 years.
The incidence of NHL varies by race/ethnicity, with non-Hispanic whites (20.6 per 100,000 persons) at higher risk than blacks (14.3 per 100,000), Asian/Pacific Islanders (13.4 per 100,000), and Hispanics (17.7 per 100,000) during 2007-2011. Most histologies, particularly low-grade small lymphocytic and follicular lymphomas, are more common in whites than in blacks. Only peripheral T-cell lymphoma (PTCL), mycosis fungoides, and Sézary syndrome are more common in blacks than in whites.
NHL is most common in developed countries, with the United States having the highest rate worldwide. The lowest NHL rates are found in eastern and south central Asia (2 to 3 per 100,000 population). Certain endemic geographic factors appear to influence the development of NHL in specific areas. Human T-cell lymphotropic virus-1 (HTLV-1)-associated ATLL occurs more frequently where HTLV-1 is endemic, in southern Japan and the Caribbean, and it occurs sporadically in Brazil, sub-Saharan Africa, the Middle East, and the southeastern United States. The seroprevalence in southwest Japan is 16%, although the lifetime risk of ATLL for these persons is 2% to 6%.
The incidence of Burkitt NHL in Africa (Nigeria and Tanzania) is 6 to 8, compared with 0.4 in the United States. Further, the clinical features of Burkitt lymphoma in Africa differ from those of cases reported to the American Burkitt Lymphoma Registry. Etiologic endemic factors include malaria as a source of chronic B-cell antigenic stimulation and Epstein-Barr virus (EBV)-induced immortalization of B lymphocytes. Heavy-chain disease is a disorder of B-lymphoid cells characterized by diffuse thickening of the small intestine due to a lymphoplasmacytic infiltrate with secretion of incomplete IgA heavy chains. Pathologically, it is a mucosa-associated lymphoid tissue (MALT) lymphoma of the small bowel. This clinicopathologic entity is rarely encountered in individuals other than those of Mediterranean ethnic origin.
Follicular lymphomas are more common in North America and Europe but are rare in the Caribbean, Africa, China, Japan, the Middle East, and Latin America. PTCLs are more common in Europe and China than in North America. They represent about 4% of lymphomas in the United States.
The NHLs are a heterogeneous group of neoplasms that usually arise or present in lymphoid tissues, such as lymph nodes, spleen, and bone marrow, but they may arise in almost any tissue. The most frequent sites for extranodal lymphomas, which constitute about 20% to 30% of all lymphomas (peripheral T-cell NHL, 70% to 80%; follicular, 8% to 10%), are the stomach, skin, oral cavity and pharynx, small intestine, and central nervous system (CNS). Although primary CNS lymphomas are rare (3% to 4% of CNS), there has been a threefold increase in incidence from the 1960s to the mid-1990s, even if patients with HIV infection and other types of immunosuppression are excluded. However, there has been an overall decline in the incidence of primary CNS lymphomas in the United States since 1995, driven mainly by the changing incidence in young and middle-aged men. The rate has continued to increase in men older than 65 and in women. Each of these sites may be involved singularly (ie, primary extranodal lymphoma) or as secondary extranodal sites concomitantly with other systemic disease.
The potential curability of NHL varies among the different histologic subtypes and is related in part to stage at presentation. The 5-year relative survival rate of patients with NHL increased from 47% between 1975 and 1977 to approximately 71% between 2004 and 2010. These improvements in survival occurred mainly in patients with intermediate- to high-grade histologies. The natural history (survival rates) for indolent lymphomas was unchanged from the 1950s to the early 1990s; however, recent Surveillance, Epidemiology, and End Results (SEER) and other data have shown improved overall survival rates for patients with follicular lymphoma.
Sidebar: Investigators from the International Lymphoma Epidemiology Consortium (InterLymph) pooled individual-level data from 17,471 NHL patients and 23,096 controls in 20 case-control studies to estimate the associations between 11 NHL subtypes and self-reported medical history, family history of hematologic malignancy, lifestyle factors, and occupation. In the 11 associated monographs, they identified common risk factors among subtypes as well as risk factors that appeared distinct among individual subtypes, suggesting both subtype-specific and shared underlying mechanisms (Morton LM, et al: J Natl Cancer Inst Monogr. 2014:130-144, 2014).