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1572 Part XI: Malignant Lymphoid Diseases Chapter 95: General Considerations for Lymphomas 1573

the relative risk of death from all causes, from any cancer, or from from patients with ATLL. HTLV-1 is an acquired retrovirus that is
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lymphoma was significantly less in the 22,000 applicators exposed to not related to other known animal retroviruses. HTLV-1 can immor-
chlorpyrifos than in the 33,000 applicators not so exposed. It is pos- talize lymphoid cells in culture and induce malignancy in an infected
sible that subsets of individuals may be susceptible to different expo- human host. The incidence of infection with HTLV-1 in endemic areas
sures based on genetic differences (see “Interaction of Environment and is very high, yet few of these infected patients develop ATLL. HTLV-1
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Genotype” below) Indeed, preliminary studies using single nucleotide also leads to a neurologic disorder called tropical spastic paraparesis.
polymorphism–based analysis have linked lymphomagenesis with Host determinants affect transformation of lymphocytes by HTLV-1,
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normal variations (polymorphisms) in genes involved in apoptosis, and these may be genetic factors. Development of ATLL is associated
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cell cycle regulation, lymphocyte development, and inflammation. 38–40 with infection by the virus. Serum specimens from Japanese patients
In some cases, polymorphic genes have been associated with specific with ATLL are positive for HTLV-1, as are serum samples from ATLL
morphologic subsets of lymphoma. Dark hair dyes have also been patients in the Caribbean, where ATLL is endemic. The highest prev-
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associated with a moderately increased risk of follicular lymphoma in alence of ATLL in Japan is in the southern island of Kyushi, where
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women. A meta-analysis has demonstrated a dose–response relation- 10 to 15 percent of the population has antibody to HTLV-1. On the
ship of NHL with cigarette smoking, with increasing NHL risk in heavy Japanese islands where ATLL is rare, the rate is less than 1 percent.
or long-duration smokers, possibly from a suppressive effect of smoking These and additional data from the Caribbean, the southeastern United
on the immune system. Increased body mass index is associated with States, South America, and Africa indicate that ATLL clusters in regions
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an increased risk of many cancers, 43,44 including lymphoma. 44–47 Indexes where HTLV-1 is prevalent. 60,61 How these regions are linked is not
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above 30 to 35 kg/m (normal = 8.5 to 25 kg/m ) are associated with an known. One hypothesis is that HTLV-1 was brought to the Americas
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increased risk of lymphoma and a worse outcome after treatment. The from Africa by the slave trade and then to the southern islands of Japan
risk factors discussed in this section have not been found uniformly in by trade between Japan and Africa. 61,63
all studies of their association with lymphoma and should be considered Host susceptibility, a shared environmental exposure, or both
provisional associations. In addition, as larger populations of patients contribute to HTLV-1 infection. The prevalence of HTLV-1 antibodies
with lymphoma, stratified by histologic type, are studied, it may become in close family members is three to four times higher than in the cor-
possible to dissect out etiologic relationships of exogenous exposures responding normal population. 63,64 In some instances, cell cultures of
with specific subtypes of lymphoma but not others. antibody-positive, clinically normal patients yield HTLV-1 isolates.
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Small but significant increases in lymphoma are associated with Blood donors are routinely screened for antibodies to HTLV-1 to pre-
radiation exposure. An increased incidence of lymphoma was reported vent transmission by this route.
in survivors of the atomic bombings in Hiroshima and Nagasaki who
were near the hypocenter of the detonation. 48–51 An increased incidence
of lymphomas also has been reported for individuals at the Chernobyl Epstein-Barr Virus
accident site who received radiation equivalent to that of the atomic Some B-cell lymphomas, including Burkitt lymphoma, posttransplanta-
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bomb exposures in Japan. Individuals treated a half century ago tion lymphoma, and HIV-associated lymphomas (immunodeficiency-
with radiation for ankylosing spondylitis also had a small increase in related Burkitt lymphoma, primary central nervous system lymphoma,
lymphoma incidence. The relative risk of lymphoma with high-dose primary effusion lymphoma, the immunoblastic-plasmacytoid type of
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radiation is low and some still question the causal relationship. Sev- DLBCL, and oral cavity plasmablastic lymphoma) may be caused by
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eral studies have found an inverse relationship between an individu- Epstein-Barr virus (EBV; Chaps. 98 and 102). EBV is a DNA virus
al’s exposure to ultraviolet light and lymphoma incidence (especially in the herpesvirus family that first was described in cultured lympho-
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DLBCL). 55 blasts from patients with African Burkitt lymphoma. EBV binds to
the CD21 antigen (also the receptor for the C3d component of com-
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plement) on B lymphocytes. It is capable of transforming B lympho-
INTERACTION OF ENVIRONMENT AND cytes into lymphoblastoid cells that may proliferate perpetually in cell
culture. EBV is present in greater than 95 percent of cases of endemic
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GENOTYPE Burkitt lymphoma and in approximately 20 percent of cases of nonen-
Polymorphic immune gene variations have been identified as significant demic Burkitt lymphoma. 69,70 Malaria is holoendemic in regions where
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factors in the association of organochloride exposure with increased endemic Burkitt lymphoma exists. A three-step process in the devel-
incidence of lymphoma in a large population of patients and matched opment of this lymphoma has been proposed 72,73 : (1) EBV initiates
controls. Associations between all exposures and NHL risk were lim- a polyclonal proliferation of B cells; (2) malaria or other infections
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ited to the same genotypes for interferon-γ, IFNG (C-1615T) TT, and further stimulate the proliferating B cells; and (3) the transform-
interleukin-4, IL4 (5′-UTR, Ex1–168C→T) CC. Associations between ing B cells incur specific reciprocal translocations of chromosome 8
PCB180 in plasma and dust and NHL risk were limited to the same with chromosome 2, 14, or 22, resulting in a clonal expansion of B
genotypes for interleukin-16, IL16 (3′-UTR, Ex22+871A→G) AA, lymphocytes.
interleukin-8, IL8 (T-251A) TT, and interleukin-10, IL10 (A-1082G) Extranodal NK/T-cell lymphoma, nasal type is mostly endemic to
AG/GG. This result indicates that the relation between organochlo- East Asia and is usually associated with EBV infection (Chap. 104). The
rine exposure and NHL risk may be modified by particular variants EBV genome is typically detected in the lymphoma cells. 74,75 Geographic
in immune genes, supporting the concept of a gene-environment inter- localization of extranodal NK/T-cell lymphoma matches the endemic
action for induction of NHL. distribution of EBV, suggesting the role of EBV in lymphomagenesis.

INFECTIOUS AGENTS Human Herpesvirus-8
Human herpesvirus-8 (HHV-8) is associated with Kaposi sarcoma,
Human T-Cell Leukemia/Lymphoma Virus I Castleman disease, and primary effusion lymphoma, found most com-
Adult T-cell leukemia/lymphoma (ATLL) provides the most compelling monly in immunodeficient individuals infected with HIV. 65,76–79 HHV-8
evidence for a viral etiology of lymphoma. Human T-cell leukemia/ is not a ubiquitous virus. It is mainly endemic in areas where classical
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lymphoma virus-1 (HTLV-1) is a C-type RNA tumor virus, isolated or Kaposi sarcoma is of high prevalence, including the Mediterranean

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