In the present work we have detected an increased risk of both salivary gland and nasopharyngeal carcinoma among individuals with AIDS compared to the general population. Our results agree with some previous reports, but not all.20-24
The lack of consistency among studies could be attributed to the rarity of these tumors.
The presence of substantially increased cancer risk in people with AIDS compared to the general population can suggest an important role for immunosuppression and an associated viral etiology. Our finding of markedly elevated risk for lymphoepithelial carcinoma of the salivary gland in the setting of HIV-induced immunosuppression thus points to an underlying viral etiology, and EBV is an attractive candidate.
The oropharyngeal compartment is a central component of EBV persistence within individuals, and oropharyngeal shedding of EBV is the primary mechanism of transmission in the human population. Although it is unclear whether EBV persists in epithelial cells in the oropharynx or transiently shuttles between lymphocytes and oropharyngeal epithelial cells, EBV is associated with a variety of epithelial neoplasms including nasopharyngeal carcinoma and lymphoepithelial carcinomas of stomach, salivary gland, lung, and thymus.2
The EBV association in lymphoepithelial carcinomas of the stomach and thymus is independent of race and geographical origin,2
but the association of EBV with lymphoepithelial carcinoma of the salivary gland and lung appears to be more frequent in Asian and Inuit populations. 2, 11-16
Following the first description of EBV association with salivary lymphoepithelial carcinoma,26
numerous studies have documented the presence of EBV within lymphoepithelial carcinoma tumor cells (). These studies suggest a nearly universal presence of the virus in salivary gland lymphoepithelial carcinomas from endemic areas, such as the Arctic region, southeastern China, and Japan.27-31
Data from other populations are sparse,32-36
with available results suggesting perhaps more variable detection of EBV.19
Published studies may overestimate the prevalence of EBV infection in these tumors, because some investigators may only have reported EBV positive cases. In addition, the majority of the studies were small and examined the expression of only a restricted set of two viral genes that encode non-translated small RNAs (EBER-1 and EBER-2) using in situ
hybridization.10, 26-31, 36-43
Fewer studies evaluated the expression of additional viral latency associated genes, although both latency patterns I (seen also in Burkitt lymphoma) and II (seen in Hodgkin lymphoma and nasopharyngeal carcinoma) have been detected in salivary gland lymphoepithelial carcinomas.9, 32, 33, 41, 44-49
Studies reporting detection Epstein Barr virus in salivary gland lymphoepithelial carcinoma
While this study examined salivary gland cancers in HIV-infected people, the occurrence of EBV-related salivary gland cancers has also been described among other patients with disturbed immunity, such as chronic autoimmune disorders.33
Furthermore, EBV has also been implicated in HIV-related sialadenitis, a chronic inflammatory condition of the salivary gland.50
Of note, chronic or autoimmune sialadenitis has been reported to precede development of salivary gland carcinoma.51-53
The increased risk of squamous cell carcinomas of both salivary gland and nasopharynx might be attributed to tobacco or alcohol use, which are common in HIV-infected people and linked to other cancers of the head and neck.54
Also, HPV is etiologically implicated in a subset of head and neck squamous cell carcinomas, specifically those arising in the oropharynx and tonsil. 55-57
HPV has also been detected in nasopharyngeal carcinomas 58
and was found more commonly in squamous cell nasopharyngeal carcinomas arising in U.S. whites than among Asians.59
The observation of only moderately increased risk for non-keratinizing carcinoma of the nasopharynx, which is etiologically associated with EBV in other settings, is perhaps because U.S. and Asian populations differ in genetic predisposition, age at initial EBV infection, or other factors.
This study is the first to provide a detailed examination focusing on the risk of salivary gland and nasopharyngeal cancers, including data on specific subtypes of these cancers, in HIV-infected people. Epidemiologic assessment of rare cancers is greatly facilitated by database linkages such as provided in the HIV/AIDS Cancer Match Study. Our large sample size allowed calculation of stable SIR estimates, although the number of cases for most histologic subtypes was still small. We did not have a sufficient number of cases to examine risk of these cancers according to demographic characteristics or CD4 count. The small number of cases may also partly explain why we did not demonstrate a decline in cancer risk among people with AIDS diagnosed in 1996 or after, as has been demonstrated for other virus-related cancers.60
Finally, while we could not adjust for differences in smoking or alcohol use between our subjects and the general population, it is unlikely that the approximately 40-fold risk for lymphoepithelial carcinoma of the salivary gland could be entirely explained by such differences.
In summary, our findings point to an elevated risk of salivary gland and nasopharyngeal carcinoma in HIV-infected people and suggest that immunosuppression or oncogenic viral infections play a role in their etiology. Appraisal of tumor tissues for the presence and functional characteristics of EBV, HPV, and other viruses will be required to confirm this hypothesis.