The WHO classification of lymphoid neoplasms ( 12.7 ) considers the morphology, cell of origin (determined by immunophenotyping), clinical features, and genotype (e.g., karyotype, presence of viral genomes) of each entity. As is evident, the diagnostic entities are numerous. We will focus our discussion on a subset that are particularly clinically important or pathogenically illustrative:
Table 12.7 WHO Classification of Lymphoid Neoplasms
Mycosis fungoides/Sézary syndrome Peripheral T cell lymphoma, unspecified
NK, Naturalkiller;WHO, WorldHealthOrganization.aEntriesinitalics areamongthemostcommonlymphoidtumors.
Together these neoplasms constitute more than 90% of the lymphoid tumors seen in the United States.
The salient features of the more common lymphoid leukemias, non-Hodgkin lymphomas, and plasma cell tumors are summarized in
Table 12.8 and are discussed in the following sections. We will then cover Hodgkin lymphoma and finish by briefly mentioning a few uncommon entities with distinctive clinicopathologic features.
Acute lymphoblastic leukemia/lymphomas (ALLs) are neoplasms composed of immature B (pre-B) or T (pre-T) cells, which are referred to as lymphoblasts. About 85% are B-ALLs, which typically manifest as childhood acute “leukemias.” The less common T-ALLs tend to present in adolescent males as thymic “lymphomas.” There is, however, considerable overlap in the clinical behavior of Band T-ALL; for example, many T-ALLs present with or evolve to a leukemic picture. Because of their morphologic and clinical similarities, the various forms of ALL will be considered here together.
ALL is the most common cancer of children. Approximately 2500 new cases are diagnosed each year in the United States, most occurring in individuals younger than 15 years of age. ALL is almost three times as common in whites as in blacks and is slightly more frequent in boys than in girls. Hispanics have the highest incidence of any ethnic group. B-ALL peaks in incidence at about the age of 3, perhaps because the number of normal bone marrow pre-B cells (the cell of origin) is greatest very early in life. Similarly the peak incidence of T-ALL is in adolescence, the age when the thymus reaches its maximum size.
Many chromosomal aberrations seen in ALL dysregulate the expression and function of transcription factors that are required for the normal differentiation of B and T cell progenitors. Up to 70% of T-ALLs have gain-offunction mutations in NOTCH1, a gene that is essential for T cell differentiation, whereas a high fraction of B-ALLs has loss-of-function mutations in genes that are required for B cell differentiation, such as PAX5. These varied mutations appear to promote maturation arrest and increased self-renewal, a feature of immortalized cells, which, as mentioned, is one of the hallmarks of cancers.
In keeping with the multistep origins of cancer, mutations in transcription factor genes are not sufficient to produce ALL, and aberrations that drive cell growth, such as mutations that increase tyrosine kinase activity and RAS signaling, also are common. Ongoing deep sequencing of ALL genomes is rapidly filling in the remaining gaps. Early returns suggest that fewer than 10 mutations are sufficient to produce full-blown ALL; hence, compared to solid tumors, ALL is a genetically simple tumor.