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CHAPTER 95 translocations (e.g., t[11;14]), immunocytochemical markers (e.g., cyclin D ),
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GENERAL CONSIDERATIONS and the specific tissue location (e.g., mucosa-associated lymphatic tissue).
Although most lymphomas arise without an evident cause, human T-cell
FOR LYMPHOMAS: leukemia/lymphoma virus I (HTLV-1), Epstein-Barr virus, hepatitis C virus,
and human herpes virus-8 infections, as well as infections with the bacteria
EPIDEMIOLOGY, ETIOLOGY, Helicobacter pylori and, perhaps, Chlamydophila psittaci, either are estab-
lished as causal (e.g., HTLV-1) or have very strong associations with lym-
phoma incidence (hepatitis C virus), suggesting their role in causation.
HETEROGENEITY, AND HIV is permissive by inducing severe immunodeficiency and setting the
stage for an Epstein-Barr virus–induced or human herpes virus-8–induced
PRIMARY EXTRANODAL lymphoma. These relationships may vary by geographic area. Several
occupational and industrial exposures are suspected of being related to
DISEASE lymphoma incidence, for example, organochlorines, phenoxyacid herbi-
cides, and others, but these associations have not been established with
scientific certainty. At present, the estimated attributable risk of lymphoma
from all suspected exogenous factors together is relatively small in propor-
Oliver W. Press and Marshall A. Lichtman* tion to the number of annual cases, leaving most cases without an apparent
cause. There are wide discrepancies in the incidence of specific lymphoma
subtypes in different geographic regions (e.g., follicular lymphoma is very
SUMMARY common in the United States and very uncommon in East Asia). Primary
extranodal lymphoma may involve virtually any tissue or organ. Depending
Lymphomas are a heterogeneous group of malignancies that originate from on the site, important functional abnormalities may ensue (e.g., bilateral adrenal
neoplastic transformation of lymphocytes that have undergone mutations gland replacement and hypoadrenocorticism, hypothalamic–pituitary
that confer growth and survival advantages compared to their normal involvement and diabetes insipidus). Multidrug chemotherapy combina-
cellular counterparts. These neoplasms usually originate in lymph nodes or tions in conjunction with lymphocyte-specific monoclonal antibody therapy
lymphatic tissue in other sites (extranodal lymphoma), and can be localized form the foundation of current treatment paradigms for most lymphomas,
or widespread at the time of diagnosis. Men are affected more frequently though radiotherapy and surgical excision continue to play limited roles in
than women and the risk of acquisition of most lymphomas increases log- selected circumstances, depending on the site and histopathology.
arithmically with age. Classification systems have considered the likely
lymphoid progenitor that corresponds to the phenotype (immunotype)
and genotype of the malignant cells in the transformed clone. The specific
pathologic diagnosis is usually established by the appearance of the histo-
pathology in tissue sections, the immunophenotypic profile of CD antigens DEFINITION AND HISTORY
expressed on affected lymphocytes, specific cytogenetic findings, especially Lymphomas are a heterogeneous group of malignancies of B cells,
T cells, and, rarely, natural killer (NK) cells that usually originate in
the lymph nodes, but may affect any organ of the body. Lymphoma
previously was referred to as lymphosarcoma and its two major sub-
types designated reticulum cell sarcoma and giant follicular lymphoma
(Brill-Symmers disease). In 1966, Rappaport published a classifica-
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Acronyms and Abbreviations: ALCL, anaplastic large cell lymphoma; ALK, ALCL tion system based on the patterns of lymphoma cell growth, size, and
tyrosine kinase gene; ATLL, adult T-cell leukemia/lymphoma; CBC, complete blood shape that attempted to correlate morphology with clinical outcome.
count; CRu, complete remission unconfirmed; CT, computed tomography; DLBCL, The classification proved to have some inaccuracies, such as the term
diffuse large B-cell lymphoma; EBV, Epstein-Barr virus; FDG,2-fluorodeoxyglu- histiocytic lymphoma to describe lymphoid tumors of large transformed
cose; HHV-8, human herpesvirus-8; HL, Hodgkin lymphoma; HTLV-1, human T-cell lymphocytes that were not derived from the monocyte-macrophage
leukemia/lymphoma virus-1; iFISH, interphase fluorescence in situ hybridization; Ig, lineage. Nonetheless, the Rappaport classification was an important
immunoglobulin; IWG, International Working Group; MALT, mucosa-associated lym- milestone and became the most widely used classification in the United
phatic tissue; NCCN, National Cancer Center Network; NHL, non-Hodgkin lymphoma; NK, States. In 1974, Lukes and Collins proposed another classification sys-
natural killer; PET, positron emission tomography; R-CHOP, rituximab-cyclophosphamide, tem, which incorporated morphology with immunologic subtype, that
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hydroxydoxorubicin, vincristine (Oncovin), and prednisone; REAL, revised European- was endorsed by the Committee on Nomenclature. Another scheme,
American classification of lymphoid neoplasm; RNA-seq, ribonucleic acid sequenc- the Kiel classification, introduced by Karl Lennert and colleagues, had
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ing; SEER, Surveillance, Epidemiology, and End Results; TCE, trichloroethylene; TCR, been more popular in Europe. By the 1970s at least six classifications of
T-cell receptor; WHO, World Health Organization. lymphoma had been published, and the major ones included two in the
United States, one in continental Europe, and one in the United Kingdom.
There was no success in reaching a consensus classification that could
be used worldwide. A National Cancer Institute study showed that there
was poor reproducibility among different pathologists looking at the
* Kenneth A. Foon was a coauthor of this chapter for the 8th edition of Williams same slides and trying to classify the case of lymphoma using any exist-
Hematology and significant portions of that chapter have been retained. ing scheme. In 1982, a Working Formulation sponsored by the National

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