Genetic Abnormalities in Lymphoid Malignancies

ABSTRACT

• Lymphoid neoplasms accounted for about 90,000 new cases of cancer in 2001 (making them the fourth most common cancer). Lymphoid malignancies include acute and chronic forms of leukemia, entities that manifest as solid tumors generally classed as either Hodgkin disease or non-Hodgkin lymphomas, and plasma cell tumors. They have been increasing in incidence at an approximate rate of 5 percent per year since the 1950s. The etiologies are largely unknown.

• More than 90 percent of lymphoid neoplasms are derived from B lymphocytes (all plasma cell tumors, 99 percent of Hodgkin disease, 85 percent of non-Hodgkin lymphomas, 95 percent of chronic lymphoid leukemias, and 80 percent of acute lymphoid leukemias). The World Health Organization (WHO) Classification of Tumors of Lymphoid Tissues defines discrete clinicopathologic entities based on histology, cell surface phenotype, genetic abnormalities, and clinical features. While there are 43 named entities in this classification, the 10 most common diseases account for about 90 percent of the cases.

• Acute lymphoid leukemias are associated with several common chromosomal translocations. Chronic lymphoid leukemia is associated with trisomy 12 (20 percent) and deletions of chromosome 13q14 (up to 50 percent). Hodgkin disease is characterized by aneuploidy, but no consistent clonal genetic abnormality has been detected. Non-Hodgkin lymphomas of B cell origin frequently have characteristic chromosomal translocations that involve the immunoglobulin genes [for example, t(14;18)(q32;q21) in follicular lymphoma, t(11;14)(q13;q32) in mantle cell lymphoma, and t(8;14)(q24;q32) in Burkitt lymphoma], and those of T cell origin often have translocations involving the T cell receptor loci on chromosomes 7 and 14 attached to a variety of partners. Plasma cell tumors have been difficult to study but often show evidence of errors occurring during heavy chain switch recombination and contain gains and losses of multiple chromosomal segments. Lymphoid tumors tend to accumulate genetic damage over time. The lymphoid follicle is the site of somatic mutation to generate antibody diversity, and tumors derived from the lymphoid follicle are characterized by ongoing mutation in immunoglobulin and nonimmunoglobulin genes.

• At least three human viruses are lymphomagenic: Epstein-Barr virus, human T cell lymphotropic virus (HTLV) I, and human herpesvirus (HHV)-8. Many individuals are infected with Epstein-Barr virus worldwide, yet the incidence of Epstein-Barr virus-related lymphoma is low. Similarly, of the many people in endemic areas infected with HTLV I, few develop lymphoid malignancy. Less is known about the epidemiology of HHV-8. A fourth virus, human hepatitis C virus, is associated with lymphoplasmacytic lymphoma, but the relationship is complex and viral products are not found in the tumor cells.

• Lymphomas of mucosa-associated lymphatic tissue (MALT) appear to be initiated by chronic antigenic stimulation, and they retain dependence on the initial stimulating antigen even after evidence of a clonal malignancy develops. The most common MALT lymphoma occurs in the stomach as a consequence of Helicobacter pylori infection. More than half of these gastric MALT lymphomas are cured by eradication of the bacterium even though the tumor cells contain clonal immunoglobulin gene rearrangements. In those not responding ...