Fig. 6.34 Possible evolution of EBV-induced Burkitt lymphoma.
Burkitt lymphoma is endemic, concomitant infections such as malaria impair immune competence, allowing sustained B-cell proliferation. Eventually, cytotoxic T cells eliminate most of the EBV-infected B cells, but a small number survive. It appears that lymphoma cells emerge from this residual population only with the acquisition of specific mutations, most notably translocations that activate the MYC oncogene. It should be noted that in nonendemic areas 80% of these tumors are unrelated to EBV, but virtually all endemic and sporadic tumors possess the t(8;14) translocation or other translocations that dysregulate MYC. Thus, although sporadic Burkitt lymphomas are triggered by mechanisms other than EBV infection, they appear to develop through similar oncogenic pathways.
The oncogenic role played by EBV is more direct in EBV-positive B-cell lymphomas in immunosuppressed patients. Some individuals with AIDS or who receive immunosuppressive therapy for preventing allograft rejection develop EBV-positive B-cell tumors, often at multiple sites. These proliferations are polyclonal at the outset but can evolve into monoclonal neoplasms. In contrast to Burkitt lymphoma, the tumors in immunosuppressed patients usually lack MYC translocations and uniformly express LMP-1 and EBNA2, which, as discussed, are antigenic and can be recognized by cytotoxic T cells. These potentially lethal proliferations can be subdued if T cell function can be restored, as may occur with withdrawal of immunosuppressive drugs in transplant recipients.
Nasopharyngeal carcinoma also is associated with EBV infection. This tumor is endemic in southern China, in some parts of Africa, and in the Inuit population of the Arctic. In contrast to Burkitt lymphoma, 100% of nasopharyngeal carcinomas obtained from all parts of the world contain EBV. The integration site of the viral genome is identical (clonal) in all of the tumor cells within individual tumors, excluding the possibility that EBV infection occurred after tumor development. The uniform association of EBV with nasopharyngeal carcinoma suggests that EBV has a central role in the genesis of the tumor, but (as with Burkitt lymphoma) the restricted geographic distribution indicates that genetic or environmental cofactors, or both, also contribute to tumor development. Unlike Burkitt lymphoma, LMP-1 is expressed in nasopharyngeal carcinoma cells and, as in B cells, activates the NF-κB pathway. NF-κB, in turn, upregulates the expression of factors such as VEGF and matrix metalloproteases that may contribute to oncogenesis.
The relationship of EBV to the pathogenesis of Hodgkin lymphoma, yet another EBV-associated tumor, is discussed in Chapter 12.
HPVisassociatedwithbenignwarts,aswellascervicalcancer.
TheoncogenicityofHPVisrelatedtotheexpressionoftwoviraloncoproteins,E6andE7,whichbindtothep53andRBtumorsuppressors,respectively,neutralizingtheirfunction.
E7fromlow-riskstrainsofHPV(whichgiverisetobenignwarts).
EBVisimplicatedinthepathogenesisofBurkittlymphomas,lymphomasinimmunosuppressedpatients,Hodgkinlymphoma,uncommonT-cellandNK-celltumors,nasopharyngealcarcinoma,asubsetofgastriccarcinoma,andrarelysarcomas.