There are several malignancies that may be associated with HIV infection but
are not considered AIDS-defining malignancies (Table 2 and
Table 3). Several
large observational studies have found varying degrees of association of these
malignancies with HIV. Interestingly, many of these malignancies are associated
with viruses other than HIV, raising the question of whether direct and indirect
effects of HIV predispose seropositive individuals to virally induced
malignancies. Although the true association of many of these malignancies to HIV
infection remains to be determined, reports of advanced stage at diagnosis and
unusually aggressive clinical courses are consistent. Minimally, it seems that
the natural history of many malignancies may be altered by HIV infection. Two of
the possible HIV-related malignancies, Hodgkin’s lymphoma and anal neoplasia,
There are significant data indicating that Hodgkin’s disease should be
considered an AIDS-associated malignancy. Several studies have shown that
HIV-infected individuals have approximately a five- to ninefold increased risk
for Hodgkin’s disease.[5,23,43,44] Most recently, Biggar and colleagues
reported a significant increase in the relative risk of Hodgkin’s disease when
comparing the pre-AIDS period to the post-AIDS period in their analysis of
366,000 AIDS cases matched to tumor registries in the United States, suggesting
a role for immunosuppression.
The impact of HAART on the epidemiology and clinical course of Hodgkin’s
disease associated with HIV infection remains to be determined. In a recent
meta-analysis of over 20 cohort or case-control studies, Beral et al did not
find a significant change in the incidence rates for Hodgkin’s disease
(relative risk = .77; 99% CI: .32-1.85).
The clinical presentation of Hodgkin’s disease is distinctive in patients
with HIV infection.[5,44] Seropositive individuals are more likely to have
unfavorable histologies than seronegative individuals.[5,22,44] Several series
have reported mixed-cellularity histology in 40% to 45% and lymphocyte depletion
in 20% to 25% of HIV-related Hodgkin’s disease cases.[46,47] This contrasts
HIV-negative individuals with Hodgkin’s disease in whom mixed cellularity is
found in 15% to 30% and lymphocyte-depleted histology in less than 1% of
cases. Clonal Epstein-Barr virus can be detected in 80% to 100% of cases of
Hodgkin’s disease occurring in the setting of HIV infection, compared to only
25% to 50% of HIV-negative Hodgkin’s disease cases.[44,47]
Advanced stage at diagnosis is characteristic of Hodgkin’s disease arising
in the setting of HIV infection. Data from the pre-HAART era demonstrate 80% to
90% of patients presenting with stage III or IV disease, contrasting with
approximately 30% of seronegative patients presenting with advanced Hodgkin’s
disease.[44,46,48,49] The usual contiguous pattern of spread seen in
HIV-negative patients with Hodgkin’s lymphoma is often not observed in
HIV-infected patients. The median CD4 count at diagnosis is 275 to 306
Prior to the HAART era, the outcomes for HIV-infected individuals with
Hodgkin’s disease were significantly worse than for seronegative patients.
Complete response rates of 50% were typical for HIV-associated Hodgkin’s
disease, compared to a 90% complete response rate in HIV-negative Hodgkin’s
disease. The median survival of patients with HIV-associated Hodgkin’s disease
was 12 to 15 months, contrasting with a median survival of 12 years in
seronegative individuals. Intercurrent opportunistic infections were a
significant cause of morbidity and mortality in patients with HIV infection and
Hodgkin’s disease. Treatment delays and dose reductions secondary to
myelosuppression frequently complicated the treatment of HIV-associated Hodgkin’s
The best regimen for HIV-related Hodgkin’s disease remains to be
determined. To date, ABVD (doxorubicin [Adriamycin], bleomycin [Blenoxane],
vinblastine, dacarbazine [DTIC-Dome]) and ABVD alternating with MOPP
(mechlorethamine, vincristine [Oncovin], procarbazine [Matulane], prednisone)
seem to be better tolerated than MOPP. The Stanford V regimen
(mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide,
prednisone) is currently under investigation in HIV-associated Hodgkin’s
disease.[50,51] Patients with good-prognosis localized disease may be candidates
for an abbreviated course of chemotherapy followed by involved-field
radiotherapy, as in the seronegative population.
Given the significant percentage of HIV-infected patients with Hodgkin’s
disease that die from AIDS-related complications during chemotherapy, it is
likely that the use of HAART in conjunction with chemotherapy will result in
At present, anal cancer is not considered an AIDS-defining malignancy.
Numerous studies report an association between receptive anal intercourse and
anal cancer.[52,53] The incidence of anal cancer in men with a history of
receptive anal intercourse was estimated to be 35 per 100,000 person-years,
prior to the AIDS epidemic. This rate is similar to the incidence of
cervical cancer in women prior to the introduction of Pap smear screening.
Recent estimates of the incidence rates of anal cancer in HIV-positive men are
70 to 80 per 100,000 person-years.[26,54] It remains unclear whether the
observed increased frequency in the HIV-infected population is merely a
consequence of confounders such as increased frequency of receptive anal
intercourse, tobacco use, and history of sexually transmitted diseases
(especially anal condylomata), or representative of an interaction between
immunosuppression and anal neoplasia. Table 4 lists several large observational
studies with discordant findings regarding an association between HIV infection
and anal cancer.[26,55-57] Several of these studies compared HIV-positive men to
the general populationa significant confounder.
Anal dysplasia in HIV-infected individuals is a recently recognized problem.
Evidence suggests that its pathogenesis and natural history is analogous to that
of cervical dysplasia, with potential subsequent risk for progression to anal
cancer. Palefsky et al found that anal HPV infection is nearly universal in a
cohort of San Francisco men who report a history of sex with men. Moreover,
the presence of oncogenic subtypes (HPV 16 and 18) and infection with multiple
subtypes were more common in HIV-positive men than HIV-negative men. The
risk of progressive disease correlated with infection with multiple HPV
genotypes. The presence of dysplasia, particularly high-grade dysplasia, was
more common in seropositive men than seronegative men. Furthermore, the relative
risk of dysplasia was inversely correlated with CD4 count.
Possible interactions between HIV and HPV include immune dysfunction,
abnormal cytokine expression, and transactivation of HPV genes by HIV-secreted
proteins.[30,60] Defective cellular immunity may allow persistence of HPV
infection, a critical step in the development of dysplasia. Indeed, HIV-infected
individuals are more likely to have persistent HPV infection than seronegative
individuals. Preliminary data from Strickler et al suggest that cellular
responses to HPV-16 E6 or E7 peptides were less common in HIV-positive
individuals than in HIV-negative persons. Furthermore, such cellular
responses were less likely to occur in individuals with more advanced HIV
disease. In addition, HIV-positive individuals are more likely to be
infected with multiple oncogenic HPV subtypes.
Interactions between HIV-infected cells and HPV-infected keratinocytes may
occur via aberrant expression of cytokines or growth factors that modulate HPV
gene expression.[54,60] Evidence suggests that the HIV-1 encoded tat protein can
increase the expression of HPV oncoproteins E6 and E7. Subsequent inactivation
of tumor suppressor genes (p53 and Rb) by these peptides leads to abnormal
proliferation, which may be an early step in oncogenesis.
It is unclear if the clinical course of anal neoplasia is significantly
different in HIV-infected individuals compared to HIV-negative individuals.
There is some evidence that progression to high grade dysplasia is increased in
the setting of HIV infection.[54,59]
Impact of HAART
The impact of HAART on anal neoplasia is unclear.
Theoretically, improved immune function would result in decreased persistence of
HPV and decreased incidence of dysplasia. However, early data suggest that HAART
does not seem to effect the regression of high-grade squamous intraepithelial
lesions. Palefsky reported that 57% of a cohort of 28 HIV-infected men with
high-grade squamous intraepithelial lesions did not experience regression of
their dysplasia while on HAART. This raises the concern that the incidence
of anal cancer may paradoxically increase in the setting of lengthened survival
of HIV-infected individuals on HAART.
There is a high incidence of recurrent dysplasia in both HIV-positive and
HIV-negative individuals. It is not known if HAART will impact the treatment
outcomes. Treatment of anal dysplasia in the setting of HIV infection is
controversial. Low-grade lesions can be followed clinically with serial anoscopy
and biopsy. High-grade lesions in HIV-infected individuals with preserved immune
function can be treated with surgical excision or laser ablation if the
dysplasia is limited. Those with extensive disease or advanced immunosuppression
may be managed with close clinical follow-up and biopsy of any suspicious
The recommendations for treatment of anal cancer in the setting of HIV are
the same as for individuals without HIV infection, namely, combination
chemoradiotherapy. The opportunity for curative treatment demands aggressive
treatment in many HIV-infected individuals. Individuals with lower CD4 counts
(below 200 cells/µL) may have more complications of therapy (skin toxicity,
myelosuppression, opportunistic infections) resulting in treatment interruptions
and, occasionally, less than optimal dose intensity.[52,61] Hoffman and
colleagues reported that four of eight patients with CD4 counts below 200
cells/µL died from complications of AIDS during treatment with combination
chemotherapy (cisplatin or mitomycin [Mutamycin]) and radiotherapy. The
authors reported that the median duration of disease control in eight patients
with CD4 counts below 200 cells/µL was 13.5 months, compared to a median
duration of 24 months in those with CD4 counts above 200 cells/µL (n = 9). Thus,
the beneficial effects of HAART on CD4 counts may translate into less toxicity
and improved outcomes for HIV-positive patients with anal cancer.
The epidemiology of malignancies in HIV-infected individuals is changing in
the HAART era. Specifically, several of the AIDS-defining malignancies are
decreasing in frequency. In addition, improved immune function, decreased viral
replication, and better supportive care may contribute to improved outcomes.
Further studies are needed to evaluate the impact of HAART on the clinical
presentation, treatment, and outcomes of HIV-related malignancies. Such
information will facilitate the development of standard screening and treatment
recommendations for HIV-infected individuals with cancer.
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