Cancers of the anus, brain, lung, HD, and leukaemias, in addition to AIDS-defining cancers (KS, NHL, and ICC), have been found in our study to be significantly increased in PWHA.
As in previous studies (Franceschi et al, 1998a
; Sitas et al, 2000
; Grulich et al, 2002
; Frisch et al, 2001
), the group of NADCs, which showed the most consistent excess in PWHA was lymphohaematopoietic cancers. HD risk, among PWHA, was more than 10-fold increased in every strata of gender, age, and HIV-exposure category. An association between HD and HIV infection is, hence, well established (Dal Maso and Franceschi, 2003
). An excess of leukaemias and myeloma is also suggested by our present findings.
Histological confirmation was available for almost all HDs (43 out of 45), myelomas (three out of three), and leukaemias (10 out of 13) in our study. A misdiagnosis of NHL as other haemolymphopoietic neoplasms cannot be totally ruled out because the classification of haemolymphopoietic neoplasms in PWHA is especially difficult (Carbone, 2002
). Some leukaemias might be leukaemoid transformations of AIDS-related NHL. The SIR for lymphoid leukaemia was not significantly greater than the one for myeloid leukaemia, in agreement with the findings by Frisch et al (2001)
in the United States.
As in previous reports (Andrieu et al, 1993
; Serraino et al, 1993
), the most common subtype of HD in PWHA was mixed cellularity type. Nodular sclerosis type (i.e. the commonest HD type in the general population of an age comparable to PWHA) was relatively rare. Besides being more aggressive and more frequently involving bone marrow, HD in PWHA seems to be associated with EBV more often than in the general population (Tirelli et al, 2000
Other cancers whose SIRs were found to be consistently elevated in PWHA are those associated with HPV infection (IARC, 1995). In contrast to KS and NHL, ICC has been an AIDS defining disease only since 1993 (Ancelle Park, 1993
). We were, therefore, able to observe some ICC cases prior to AIDS and noticed that, although SIR peaked in the AIDS period as for all other sites and types, some excess was present years before AIDS. A similar time pattern was found for anal cancer, whose overall SIR (34) was well comparable to the one seen for ICC. Three additional cases of cancer of the vulva, penis, and uterus (not otherwise specified) further support the possibility that HIV-induced immune impairment facilitates the persistence of HPV infection (Palefsky et al, 1999
; Ahdieh et al, 2000
): progression into pre-malignant (Sun et al, 1997
) and, ultimately, in the lack of early detection, invasive cancer. As suggested also by studies where preinvasive lesions of the cervix and anogenital tract were included (Frisch et al, 2000
), the control of HPV infections seems to be impaired in HIV-positive women and men years before a diagnosis of AIDS. Early events in HPV carcinogenesis are probably affected to a greater extent than late ones (i.e. invasiveness). The SIR for cancer of the cervix and anus was marginally greater but not restricted to specific HIV exposure categories (i.e. IDUs and homosexual and bisexual men, respectively). Since HPV and HIV share a sexual route of transmission, it has been considered difficult to disentangle their independent contribution to the increase in risk of anogenital cancer in PWHA (Mandelblatt et al, 1999
). A majority of sexually active women (Woodman et al, 2001
) and men (Franceschi et al, 2002
), however, at some point in their lifetime are infected by HPV. Therefore, factors that enhance the probability of HPV infection becoming persistent and progress into premalignant and malignant lesions are crucial (IARC 1995
). In particular, a lack of cytotoxic T-lymphocyte to the early (E) oncoprotein six antigen is associated with persistence of HPV infection (Tindle, 2002
Nonmelanomatous skin cancer showed a three-fold excess in PWHA in our previous report (Franceschi et al, 1998a
), whereas a somewhat lower SIR (1.5; 95% CI: 0.8–2.5) emerged from our present update. Misclassification with KS seems unlikely, since all nonmelanomatous skin cancers in PWHA were histologically confirmed (seven squamous-cell and seven basal-cell carcinomas). The report of nonmelanomatous skin cancer to CRs is, however, incomplete (Levi et al, 1995
; Parkin et al, 1997
) and the corresponding SIR must be interpreted cautiously. No data on nonmelanomatous skin cancer are available from North American (Frisch et al, 2001
) and Australian (Grulich et al, 2002
) record linkage studies. Gallagher et al (2001)
reported a 10-fold increased SIR of cancer of the lip in New York State and several authors (Frisch et al, 2001
; Grulich et al, 2002
) showed a two- to- four-fold increased risk. Interestingly, skin cancer in our study affected more frequently older PWHA than any other NADC.
Cancers of the lung and brain are found to be consistently increased among PWHA, but masses of non-neoplastic origin or attributable to NHL are common in the lung and brain at AIDS diagnosis. These masses may be misdiagnosed as cancer of the lung or brain, particularly in the absence of histological confirmation. Interestingly, lung cancer showed the most marked variation by HIV transmission group among NADCs. As in Serraino et al (1997)
, lung cancer seemed restricted to IDUs, among whom smoking levels are much higher than in the general population.
Hepatocellular carcinoma is another cancer type aetiologically related to viruses (i.e. hepatitis B and C viruses) that, in turn, share the same route of transmission of HIV and have a high prevalence in PWHA (Smukler and Ratner, 2002
). However, our present study showed only a moderate excess (SIR=1.9) of HCC in agreement with other authors (Frisch et al, 2001
; Gallagher et al, 2001
; Grulich et al, 2002
). It is possible that, until recently, PWHA have not survived long enough to allow the carcinogenic effect of hepatitis viruses to manifest (Deuffic et al, 1999
Standardised incidence ratios were above unity for a few additional cancer types (i.e. stomach, rectum, and ovary), but corresponding CI were broad, due to the relatively small number of cases observed.
No reduction in the SIR of NADCs emerged in Italy after the introduction of HAART. Our present study is based, however, on too short a period after HAART to allow any conclusion.
Since a large number of NADCs occurs before AIDS, the major strength of such methodology is represented by the access to a large number of person-years of observation both before and after AIDS (Franceschi et al, 1998b
; Goedert et al, 1998
). The number of PWHA and of cancer diagnoses may be underestimated on account of incompleteness of reporting to either AIDS or CRs or of missed linkages. However, the completeness of RAIDS and Italian CRs had been shown to be satisfactory and the linkage procedures we used had been validated (Conti et al, 1997
; Ajdacic-Gross et al, 2001
; Dal Maso et al, 2001a
). The problem of migration of PWHA out of CR areas should be less severe in Italy than elsewhere, as population mobility is comparatively low and HIV and cancer treatments are available free of charge in all Italian regions (Franceschi et al, 1998b
). As already reported (Biggar et al, 1996
), SIRs for all cancer sites or types are exaggerated in the months immediately before and after AIDS by an increased medical surveillance and some cancers would have been otherwise found later. Our present SIRs in the post-AIDS period are therefore underestimates and this hampers the evaluation of trends in cancer risk by immune status. Cancer excesses were also found, however, prior to AIDS diagnosis, for ICC, cancer of the anus, and HD.