Clinical Features. When first detected, CLL/SLL often is asymptomatic. The most common signs and symptoms are nonspecific and include easy fatigability, weight loss, and anorexia. Generalized lymphadenopathy and hepatosplenomegaly are present in 50% to 60% of patients. The leukocyte count may be increased only slightly (in SLL) or may exceed 200,000 cells/µL. Hypogammaglobulinemia develops in more than 50% of the patients, usually late in the course, and leads to an increased susceptibility to bacterial infections. Less commonly, autoimmune hemolytic anemia and thrombocytopenia are seen.
The course and prognosis of CLL/SLL are highly variable and depend on the disease stage and genetic findings. For example, the presence of abnormalities in the TP53 tumor suppressor gene is associated with an overall survival of less than 30% at 10 years, whereas isolated abnormalities of chromosome 13q are associated with an overall survival that is not significantly different from that of the matched general population. Insights into the molecular pathogenesis of CLL/SLL has led to development of effective new drugs that variously inhibit BCR signaling (e.g., by targeting BTK) or BCL2 function. However, cure may only be achieved with hematopoietic stem cell transplantation, which is reserved for relatively young patients who fail conventional therapies. A small fraction of tumors transform to aggressive tumors resembling diffuse large B cell lymphoma (Richter transformation); after transformation occurs, the median survival is less than 1 year.
This relatively common tumor constitutes 40% of the adult NHLs in the United States. Like CLL/SLL, it occurs much less frequently in Asian populations.
Greater than 85% of follicular lymphomas have a characteristic (14;18) translocation that fuses the BCL2 gene on chromosome 18 to the IgH locus on chromosome 14. This chromosomal rearrangement results in the inappropriate “overexpression” of BCL2 protein, which you will recall is an inhibitor of apoptosis that contributes to cell survival (Chapters 1 and 6). Whole genome sequencing of follicular lymphomas has identified additional mutations in genes encoding histone-modifying proteins in about one-third of cases, suggesting that epigenetic changes also contribute to the genesis of these tumors.
Fig.12.16A ).Mostcommonly,thepredominantneoplasticcellsareso-called“centrocytes”,cellsslightlylargerthanrestinglymphocytesthathaveangular“cleaved”nucleiwithprominentindentationsandlinearinfoldings(
Fig.12.16B ).Thenuclearchromatiniscoarseandcondensed,andnucleoliareindistinct.Thesecentrocytesaremixedwithvariablenumbersofcentroblasts,largercellswithvesicularchromatin,severalnucleoli,andmodestamountsofcytoplasm.Inmosttumors,centroblastsareaminorcomponentoftheoverallcellularity,mitosesareinfrequent,andsinglenecroticcells(cellsundergoingapoptosis)arenotseen.Thesefeatureshelptodistinguishfollicularlymphomafromfollicularhyperplasia,inwhichmitosesandapoptosisareprominent.Uncommonly,largecellspredominate,ahistologicpatternthatcorrelateswithamoreaggressiveclinicalbehavior.
Immunophenotype. These tumors express B cell markers such as CD20 and the germinal center B cell markers CD10 and BCL6; of note, BCL6 is a transcription factor that is required for the generation of germinal center B cells.