Extranodal marginal zone lymphoma is an example of a cancer that arises within and is sustained by chronic inflammation. It tends to develop within tissues that are involved by chronic inflammation triggered by autoimmune disorders (such as the salivary gland in Sjögren syndrome and the thyroid gland in Hashimoto thyroiditis) or that are the sites of chronic infection (such as H. pylori gastritis). In the case of H. pylori–associated gastric marginal zone lymphoma, eradication of H. pylori with antibiotic therapy often leads to regression of the tumor cells, which depend on inflammatory cytokines secreted by H. pylori–specific T cells for their growth and survival. Based on these observations, it is supposed that the disease is initiated within the context of a polyclonal immune reaction. With the acquisition of still-unknown initiating mutations, a B cell clone emerges that depends on antigen-stimulated T-helper cells for signals that drive growth and survival. At this stage, withdrawal of the responsible antigen causes tumor involution. As further clonal evolution leads to greater tumor cell autonomy, spread to distant sites may occur. This theme of polyclonal to monoclonal transition during lymphomagenesis is also applicable to the pathogenesis of EBV-induced lymphoma (discussed in Chapter 6).
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MORPHOLOGYTheclonalBcellscharacteristicallyinfiltratetheepitheliumofinvolvedtissues,oftencollectinginsmallaggregatesthatarecalledlymphoepithelial lesions. Insometumorsthetumorcellsaccumulateabundantpalecytoplasmorexhibitplasmacelldifferentiation,featuresthatarecharacteristicbutnotpathognomonic.
Immunophenotype. This is a tumor of mature B cells expressing CD20 and surface immunoglobulin, usually IgM.
Clinical Features. These tumors often present as swelling of the salivary gland, thyroid or orbit or are discovered incidentally in the setting of H. pylori–induced gastritis or an imaging procedure. When localized, they are often cured by simple excision followed by radiotherapy.
Diffuse large B cell lymphoma is the most common type of lymphoma in adults, accounting for approximately 35% of adult NHLs. It includes several subtypes that share an aggressive natural history.
About one-third of diffuse large B cell lymphomas have rearrangements of the BCL6 gene, located on 3q27, and an even higher fraction of tumors have activating point mutations in the BCL6 promoter. Both aberrations result in increased levels of BCL6 protein, an important transcriptional regulator of gene expression in germinal center B cells. Another 30% of tumors have a (14;18) translocation involving the BCL2 gene that results in overexpression of BCL2 protein. Some of these tumors may represent “transformed” follicular lymphomas. The remaining tumors have other diverse driver mutations, such as translocations involving the MYC gene.
MORPHOLOGYTheneoplasticBcellsarelarge(atleastthreetofourtimesthesizeofrestinglymphocytes)andvaryinappearancefromtumortotumor.Inmanytumors,cellswithroundorovalnuclearcontours,dispersedchromatin,severaldistinctnucleoli,andmodestamountsofpalecytoplasmpredominate(
Fig.12.17 ).Inothertumorsthecellshavearoundormultilobatevesicularnucleus,oneortwoprominentcentrallyplacednucleoli,andabundantpaleorbasophiliccytoplasm.Occasionally,thetumorcellsarehighlyanaplasticandincludetumorgiantcellsresemblingRScells,themalignantcellsofHodgkinlymphoma.