The incidence rates of non-Hodgkin lymphoma (NHL) in the United States have almost doubled since the early 1970s, representing one of the largest increases of any cancer. 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 incidence of NHL per 100,000 persons has risen from 8.8 in 1972–1974 to 19.3 in 1995–1999 (all histologic subtypes) in 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. NHL rates have decreased among American males aged 25 to 54 years in the middle to late 1990s (6% to 16% per year), although this may be in part due to improved HIV treatment.

Currently, NHL represents approximately 4% of all cancer diagnoses (4% in males and 4% in females), being the fifth most common cancer in women and the sixth in men. Estimates from the American Cancer Society indicate that in 2008, some 66,120 new cases of NHL will be diagnosed in the United States and approximately 19,160 people will die of this disease.

Epidemiology

Gender The overall incidence of lymphoma is higher in men than in women. The incidence rate (per 100,000 population) between 2000 and 2004 was 40% higher in males (23.2) than in females (16.3). Only thyroid NHL is more common in women than in men.

Age Overall, the incidence of NHL rises exponentially with increasing age. In persons older than age 65, the incidence is 87.2 per 100,000 population. 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. Low-grade lymphomas account for 37% of NHLs in patients between the ages of 35 and 64 years at diagnosis but for only 16% of cases in those younger than age 35.

Race The incidence varies by race, with whites at higher risk than blacks and Asian-Americans (incidence rates increased 40% to 70% in whites compared with blacks). Most histologies, particularly low-grade small lymphocytic and follicular lymphomas, are more common in whites than in blacks. Only peripheral T-cell lymphoma, mycosis fungoides, and Sézary syndrome are more common in blacks than in whites.

Geography 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 (2–3 per 100,000 population). Certain endemic geographic factors appear to influence the development of NHL in specific areas.

HTLV-1–associated NHL Human T-cell lymphotrophic virus-1 (HTLV-1)–associated adult T-cell lymphoma/leukemia (ATLL) occurs more frequently where HTLV-1 is endemic, in southern Japan and the Caribbean, and 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%.

Burkitt lymphoma in Africa The incidence (per 100,000 population) of Burkitt NHL in Africa (Nigeria and Tanzania) is 6 to 8, as compared with 0.1 in the United States. 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.

Immunoproliferative small intestinal disease (α-chain disease) 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.

Peripheral T-cell lymphomas are more common in Europe and China than in North America. They represent 7% to 12% of lymphomas in Western countries.

Disease site Malignant lymphomas 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 80%; extranodal, follicular 9%), are the stomach, skin, oral cavity and pharynx, small intestine, and central nervous system (CNS). Although primary CNS lymphomas are rare, there has been a threefold increase in incidence, even if patients with HIV infection and other types of immunosuppression are excluded.

Survival The 5-year relative survival rate of patients with NHL increased from 28% between 1950 and 1954 to 63% between 1990 and 2003. These improvements in survival occurred mainly in patients with intermediate-high-grade histologies. The potential for cure varies among the different histologic subtypes and is directly related to stage at presentation and response to initial therapy. The natural history (survival rates) for indolent lymphomas has been unchanged from the 1950s to the early 1990s, although a recent analysis from Iowa of Surveillance, Epidemiology, and End Results (SEER) data (1979–1999) shows improving survival rates of patients with follicular lymphoma.

Etiology and risk factors

Chromosomal translocations and molecular rearrangements Nonrandom chromosomal and molecular rearrangements play an important role in the pathogenesis of many lymphomas and correlate with histology and immunophenotype (Table 1). The most commonly associated chromosomal abnormality in NHL is the t(14;18)(q32;q21) translocation, which is found in 85% of follicular lymphomas and 28% of higher grade NHLs. This transloca-tion results in the juxtaposition of the bcl-2 apoptotic inhibitor “oncogene” at chromosome band 18q21 to the heavy-chain region of the immunoglobulin locus within chromosome band 14q32.

The t(11;14)(q13;q32) translocation results in overexpression of bcl-1 (cyclin D1/PRAD 1), a cell-cycle–control gene on chromosome 11q13, and is characteristically associated with mantle cell lymphoma. The t(3;16)(q27;p11) translocation makes the gene for the IL-2 (interleukin-2) receptor a partner of bcl-6, which is expressed in diffuse large cell lymphoma.

Chromosomal translocations involving 8q24 lead to c-myc deregulation and are frequently seen in Burkitt and Burkitt-like lymphomas, including those associated with HIV infection.

Environmental factors also may play a role in the development of NHL.

Occupations Certain workers have a slightly increased risk of developing NHL, including farmers; pesticide applicators; grain (flour) millers; meat workers; wood and forestry workers; chemists; painters; mechanics; machinists; and workers in the petroleum, rubber, plastics, and synthetics industries.

Chemicals that have been linked to the development of NHL include a variety of pesticides and herbicides (2,4-D-organophosphates, chlorophenols), solvents and organic chemicals (benzene, carbon tetra-chloride), wood preservatives, and some components in hair dye. There is evidence that the association between pesticides and NHL risk was limited to t(14;18)-positive NHL cases.

Chemotherapy and radiotherapy Patients who receive chemotherapy and/or radiation therapy are also at increased risk of developing NHL.

Viruses Several viruses have been implicated in the pathogenesis of NHL, including EBV; HTLV-1; Kaposi’s sarcoma-associated herpesvirus (KSHV, also known as human herpesvirus 8, or HHV-8); and hepatitis C virus (HCV). Meta-analyses have shown 13% to 15% HCV seroprevalence in certain geographic regions among persons with B-cell NHL.

EBV is a DNA virus that has been associated with Burkitt lymphoma, particularly in endemic areas of Africa; Hodgkin lymphoma; lymphomas in immunocompromised patients (ie, organ transplantation and HIV infection); sinonasal lymphoma (Asia and South America); and sporadically in other B- and T-cell lymphomas. In contrast to studies performed in European patients, Mexican patients with intestinal lymphomas show a high frequency of EBV positivity; this finding is not limited to T-cell NHLs but rather includes a significant portion of B-cell NHLs. EBV can transform lymphocytes in culture. B lymphocytes from normal EBV-positive subjects have been shown to grow as tumors in mice with severe combined immunodeficiency.

HTLV-1 is a human retrovirus that establishes a latent infection via reverse transcription in activated T-helper cells. A minority (5%) of carriers develop ATLL. An HTLV-1–like provirus has been detected in some patients with mycosis fungoides, although conflicting findings have been reported.

KSHV or HHV-8: KSHV-like DNA sequences are frequently detected in primary effusion lymphomas in patients with HIV infection and in those with multicentric (plasma cell variant) Castleman’s disease.

HCV infection is associated with the development of clonal B-cell expansions and certain subtypes of NHL, particularly in the setting of essential (type II) mixed cryoglobulinemia. HCV may predispose B cells to malignant transformation by enhancing signal transduction upon binding to the CD81 (TAPA-1) molecule.