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Overview of AIDS-defining malignancies in HIV infection

Author Section Editor Deputy Editor
Scot C Remick, MD, FACP Bruce J Dezube, MD Michael E Ross, MD

Last literature review version 18.2: Maio 2010 | This topic last updated: Agosto 7, 2009
INTRODUCTION — HIV-infected individuals have an increased propensity to develop malignancy [1,2]. The
spectrum of neoplasia in these patients is changing, especially in developed portions of the world, where the
widespread use of highly active antiretroviral therapy (HAART) has limited the immunosuppression associated with
HIV for prolonged periods in most patients.

The occurrence of an unusually high number of cases and an aggressive clinical course for Kaposi's sarcoma (KS)
was noted early in the AIDS epidemic, and KS was included as an AIDS-defining illness in early case definitions
from the Centers for Disease Control and Prevention (CDC) [3]. Non-Hodgkin lymphoma (NHL) and invasive
cervical carcinoma were subsequently added as AIDS-defining conditions during revisions of the CDC case
definition in 1985 and 1993, respectively.

The effect of HAART and the pathogenesis of malignancy in patients with HIV is reviewed here, along with a
discussion of the AIDS-defining malignancies (KS, NHL, and cervical cancer). The non-AIDS-defining malignancies
are discussed separately. (See "Overview of non-AIDS-defining malignancies in HIV infection".)

PATHOGENESIS

Immunosuppression — The development of neoplasia in HIV-infected patients is similar to that observed in solid
organ transplant recipients who receive chronic immunosuppressive agents, as well as in patients with profound
cell-mediated immune deficiencies. (See "Development of malignancy following solid organ transplantation" and
"Lymphoproliferative disorders following solid organ transplantation".)

Progressive immunologic deterioration is the hallmark of untreated HIV infection, and this immunologic decline is
associated with an increased incidence of AIDS-defining malignancies [4]. In contrast, there does not appear to be
the same correlation between immune compromise and the incidence of other malignancies. (See "Overview of
non-AIDS-defining malignancies in HIV infection", section on 'Incidence'.)

Role of the HIV virus — The pathogenesis of HIV-associated neoplasia is complex. Although the HIV virus is not
generally considered oncogenic [5,6], a direct pathogenic role for HIV infection has been suggested by the
following observations:

Components of the HIV viral genome have been incorporated into the fur gene complex on chromosome 15 in
some cases of HIV-associated non-B cell malignant lymphomas [7].

The HIV tat gene protein product appears to be a growth factor for KS [8,9]. (See "AIDS-related Kaposi's
sarcoma: Epidemiology and pathogenesis".)

Other viruses — Other viruses that may be implicated in the development of some malignancies in HIV-infected
persons include the Epstein Barr virus (EBV), human papillomavirus (HPV), human herpesvirus (HHV)-8, hepatitis
B, and hepatitis C.

EBV infection — The EBV genome has been detected within tumor cell nuclei, and EBV appears to be involved
in the pathogenesis of Hodgkin lymphoma (HL). (See "The role of Epstein-Barr virus in Hodgkin lymphoma".)

Reed-Sternberg (RS) cells in HIV-associated HL display a phenotype consistent with post germinal center B cells in
contrast to RS cells in HL of the general population, which express transcription factors consistent with germinal
center B cells [10]. In addition, RS cells of HIV-associated HL express the EBV-encoded latent membrane protein 1
which may contribute to modulation of the phenotype [10]. (See "Virology of Epstein-Barr virus".)

HL is not an AIDS-defining malignancy, but its incidence is markedly increased in HIV-infected people. The clinical
manifestations and potential treatment of HL in this setting are discussed separately. (See "Overview of non-AIDS-
defining malignancies in HIV infection", section on 'Hodgkin lymphoma'.)

HHV-8 infection — In the United States and Europe, HIV-related KS is predominantly seen among men who
have sex with men but only rarely in injection drug users. This observation reflects the seroprevalence of HHV-8,
the virus linked to KS. The incidence of KS rose during the initial years of the AIDS epidemic, but has
subsequently declined in association with the widespread use of HAART. (See 'Effect of HAART' below.)

The endemic form of KS was relatively common in men residing in sub-Saharan Africa prior to the HIV epidemic, at
least partially attributable to the widespread presence of human herpesvirus-8 infection [11]. Since then, the
incidence of KS has risen dramatically in both sexes and has remained elevated [12-14].

The role of HHV-8 in tumorigenesis, its epidemiology, and its transmission are discussed elsewhere. (See
"Epidemiology and transmission of human herpesvirus 8 infection" and "Disease associations of human herpesvirus
8 infection".)

HPV infection — The relationship of HPV-associated cervical dysplasia and neoplasia to HIV infection may be
due to lifestyle risks for acquiring both viruses and attributes of and host responses to these viruses. HIV-infected
patients may be unable to clear oncogenic strains of HPV due to T cell deficiency. There is a significant relationship
between the risk of persistent HPV infection and the degree of immunosuppression. (See "HIV and women" and
"Virology of human papillomavirus infections and the link to cancer" and "Preinvasive and invasive cervical
neoplasia in HIV-infected women".)

The relationship between HPV infection and cervical neoplasia was illustrated in one series of 309,365 American
patients with HIV infection or AIDS, in whom the relative risk for in situ HPV-associated neoplasia (ie, squamous
intraepithelial lesions [SIL]) increased over time, suggesting that the gradual loss of control over HPV-infected
keratinocytes was related to advancing immunosuppression [15]. However, the incidence of invasive squamous cell
cancers did not increase with advancing immunosuppression in HIV, which suggests that late-stage cancer invasion
was not influenced by immune status.

Hepatitis B — HIV-infected patients frequently have concomitant hepatitis B (HBV) infection and are more
likely to develop chronic HBV [16]. To date, there has not been a documented increase in the incidence of
hepatocellular carcinoma or lymphoma in patients coinfected with HIV and HBV infection [17-19]. (See
"Epidemiology, clinical manifestations, and diagnosis of hepatitis B in the HIV-infected patient" and "Epidemiology
and etiologic associations of hepatocellular carcinoma".)

Hepatitis C — Subjects with HIV infection are frequently coinfected with hepatitis C virus (HCV).

Coinfection with HCV and HIV is associated with an increase in the incidence of both cirrhosis and hepatocellular
carcinoma. (See "Overview of non-AIDS-defining malignancies in HIV infection", section on 'Hepatocellular
carcinoma'.)

Initial studies do not indicate an increased risk of B-cell lymphoma with HCV infection complicating HIV disease
[19,20], despite the known association of HCV and lymphoma in the setting of mixed cryoglobulinemia. (See
"Extrahepatic manifestations of hepatitis C virus infection", section on 'Lymphoma'.)

EFFECT OF HAART — The era of highly active antiretroviral therapy (HAART) began in 1996 with the availability
of the protease inhibitors. In most patients, HAART causes both an immunologic response (manifested by a
sustained elevations in CD4 lymphocyte counts) and a virologic response (nearly complete suppression of HIV viral
replication). Both immunologic and virologic responses are important in achieving at least partial immune
restoration, thus decreasing the incidence of opportunistic infections, reducing the risk of developing NHL or KS,
and prolonging survival [21,22]. (See "Selecting antiretroviral regimens for the treatment naive HIV-infected
patient".)

Since the widespread introduction of HAART, the incidence of KS and NHL has declined in HIV-infected patients,
and is inversely proportional to the CD4 lymphocyte count [23-30]. (See "AIDS-related Kaposi's sarcoma:
Epidemiology and pathogenesis" and "AIDS-related lymphomas: Epidemiology, risk factors, and pathobiology".)

The impact of immunosuppression on the incidence of KS and NHL since the introduction of HAART is illustrated by
the following examples:

Data from United States AIDS and cancer registries were analyzed for 325,516 adults with AIDS prior to the
introduction of HAART (1990 to 1995) and following HAART's widespread utilization (1996 to 2002) [25]. Over
these two periods, the incidence of KS significantly decreased (1839 versus 335 per 100,000 person-years) as did
the incidence of NHL (1066 versus 390 per 100,000 person-years).

The Swiss HIV cohort study analysis of 7304 patients confirmed a substantial decrease in the incidence of KS
and NHL among patients treated with HAART, although the incidence of both remained elevated compared with the
general population [30]. In contrast, the use of HAART did not decrease the incidence of cervical cancer, HL, or
other non-AIDS defining malignancies, whose incidence is linked to lifestyle factors (ie, smoking, hepatitis B and C,
papillomavirus infection) rather than HIV-induced immunosuppression.

Another consequence of HAART is a changing pattern in the causes of death in HIV-infected patients. Before the
introduction of HAART, malignancies accounted for fewer than 10 percent of all deaths among HIV-infected patients
[31,32]. By contrast, in a French study that included 64,000 HIV-infected patients who received follow-up in the
year 2000 (964 of whom died), death was due to malignancy in 28 percent [33].

This increased risk of dying from cancer in HIV-infected patients in the HAART era may be due to the chronicity of
HIV infection (largely an effect of HAART), the oncogenic role of other viruses (eg, HHV-8, EBV, HPV, hepatitis B
and C viruses) in causing non-AIDS defining malignancies, and/or the aging of the HIV-infected population. (See
'Other viruses' above and "Overview of non-AIDS-defining malignancies in HIV infection".)
KAPOSI'S SARCOMA — KS is a low-grade soft tissue sarcoma of vascular origin that is associated with infection
with human herpesvirus (HHV)-8 (also known as the KS-associated herpesvirus). KS is primarily a disease of
men; early in the HIV epidemic, KS was noted in 20 to 30 percent of HIV-infected men who have sex with men.
(See "AIDS-related Kaposi's sarcoma: Epidemiology and pathogenesis".)

Infection with HHV-8 precedes and is predictive of the development of KS. In a study of 800 men, 400 of whom
were HIV-positive, the 10-year probability of developing KS was approximately 50 percent in those who were
seropositive for both HIV and HHV-8 [34]. (See "Disease associations of human herpesvirus 8 infection".)

AIDS-related KS has a variable clinical course, ranging from an asymptomatic incidental finding to explosive
growth resulting in significant morbidity and mortality. Skin involvement is characteristic but extracutaneous
spread is common, particularly to the oral cavity, the lungs and the digestive tract. (See "AIDS-related Kaposi's
sarcoma: Clinical features and treatment" and "Pulmonary involvement in HIV-associated Kaposi's sarcoma".)

A staging system for KS classifies patients into a good- or poor-risk group according to the parameters of tumor
extent (T), immune status (I) and the severity of systemic illness (S) (table 1). (See "AIDS-related Kaposi's
sarcoma: Clinical features and treatment".)

The major goals of treatment for AIDS-related KS are symptom palliation, prevention of disease progression, and
shrinkage of tumor to alleviate edema, organ compromise, and psychological stress. Although there are no
randomized trials, observational studies provide strong evidence that the natural history of KS has changed since
the introduction of HAART; immune reconstitution due to control of the HIV infection is the most likely explanation
for this altered prognosis. Highly active antiretroviral therapy (HAART) is recommended for virtually all patients
with AIDS-related KS.

The need for treatment beyond HAART and the choice among the various options depend upon the extent of
disease, the rapidity of tumor growth, the HIV-1 viral load, the CD4 cell count, and the patient's overall medical
condition. Locally directed therapy is often used to palliate symptoms caused by a specific tumor or to treat
cosmetic disfigurement. Systemic therapy is used for more extensive disease but injury to an immune system that
is already severely compromised should be avoided whenever possible.

The treatment of KS is discussed separately. (See "AIDS-related Kaposi's sarcoma: Clinical features and
treatment".)

NON-HODGKINS LYMPHOMA

Systemic NHL — The incidence of systemic NHL increases with worsening immunosuppression in AIDS patients.
Approximately 70 to 90 percent of these NHL are intermediate or high-grade and almost all are diffuse large B cell
(immunoblastic variant) or Burkitt's-like lymphomas [35]. (See "AIDS-related lymphomas: Epidemiology, risk
factors, and pathobiology".)

As in North America and Europe, the incidence of NHL in sub-Saharan Africa has increased, but rates remain
substantially lower than those observed in developed countries [11,36]. The lower incidence may reflect poor
ascertainment of cases due to lack of diagnostic equipment or qualified medical personnel or death from competing
causes associated with HIV infection [36].

Approximately two-thirds of HIV-positive patients with systemic NHL present with extranodal disease. The
gastrointestinal tract is involved in 45 percent and the bone marrow, liver and lung are involved in approximately
20 to 30 percent of patients. Lymphomatous meningitis occurs in 3 to 20 percent of patients with systemic NHL,
and can be asymptomatic in up to 25 percent. For this reason, examination of cerebrospinal fluid (CSF) should be
routinely performed in these patients. (See "AIDS-related lymphomas: Epidemiology, risk factors, and
pathobiology".)

A tissue biopsy is required to establish a histologic diagnosis, although fine needle aspiration cytology is often of
value. Once the diagnosis is confirmed, the extent of disease involvement is determined by staging procedures,
which should include lumbar puncture for CSF cytology, bone marrow examination, and computed tomographic
(CT) scanning of the chest, abdomen, and pelvis. CT and MRI are the primary modalities to evaluate the brain;
thallium-201 scanning or single-photon emission computed tomography (SPECT) may also be useful. PET scanning
is also often incorporated into the initial staging evaluation.

The treatment and prognosis of lymphoma in HIV-infected patients is discussed separately. (See "AIDS-related
lymphomas: Clinical manifestations, diagnosis, and staging of systemic lymphoma" and "AIDS-related lymphomas:
Treatment of systemic lymphoma".)

CNS lymphoma — Primary central nervous system (CNS) lymphomas are more common in HIV-infected patients
than in the non-HIV-infected population (approximately 15 versus 1 percent of all lymphomas). The majority of
primary CNS lymphomas are large cell or large cell immunoblastic types of B-cell origin.

The incidence of primary CNS lymphoma rises with prolonged survival from HIV-1 infection and is associated with
a greater degree of immunosuppression than systemic NHL, as is manifested by a CD4 count less than 50/microL.
Primary CNS lymphoma thus is only rarely an AIDS-defining malignancy. (See "AIDS-related lymphomas:
Epidemiology, risk factors, and pathobiology".)
Epidemiology, risk factors, and pathobiology".)

The treatment and prognosis for patients with primary CNS lymphoma are discussed separately. (See "AIDS-
related lymphomas: Primary central nervous system lymphoma".)

Primary effusion lymphoma — Primary effusion lymphoma, a specific subtype of non-Hodgkin lymphoma, has
been linked to infection with HHV-8. This B-cell lymphoma is characterized by its predilection for body cavities
such as the peritoneal, pleural, and pericardial spaces, and is known as primary effusion lymphoma or body cavity
based lymphoma.

Primary effusion lymphoma originates on serosal surfaces, and most affected patients present with a symptomatic
serous effusion containing high-grade, malignant lymphocytes, but with no detectable mass lesion. The diagnosis
of PEL is usually made based upon a cytologic examination of the effusion which almost always contains malignant
cells. The key diagnostic criterion is the presence of HHV-8 in the nuclei of the malignant cells.

Patients with primary effusion lymphoma have a poor prognosis. Mean overall survival is less than three months
without treatment and approximately six months with chemotherapy. However, with the use of highly active anti-
retroviral therapy (HAART), some patients can have more extended survival.

Primary effusion lymphoma is discussed in detail separately. (See "AIDS-related lymphomas: Primary effusion
lymphoma".)

Castleman's disease — Castleman's disease is an uncommon lymphoproliferative disorder, first described in

1956, which is associated with HHV-8 infection.

Systemic features of Castleman's disease include fever, splenomegaly, hepatomegaly, and massive
lymphadenopathy. Castleman's disease is associated with HHV-8, and can be observed in both HIV-negative and
positive patients. All of the variants of Castleman's disease may be associated with HHV-8 infection (unicentric or
multicentric disease and hyaline vascular or plasma cell variant).

The clinical features and management of Castleman's disease are discussed separately. (See "Castleman's
disease".)

CERVICAL CANCER — A close association exists between infection with oncogenic HPV and malignancies of the
anogenital tract, including the cervix, anus, vulva, penis, and perianal skin. This association has been most
thoroughly studied for diseases of the uterine cervix. The vast majority of cervical cancers are thought to be
caused by HPV infection. (See "Virology of human papillomavirus infections and the link to cancer".)

A higher than expected rate of invasive and preinvasive cervical neoplasia has been reported in HIV-infected
women [37,38]. In an early series of HIV-infected women with invasive cervical cancer, therapy failed to control or
eradicate the tumor, and all died with a mean survival of 10 months [37]. Based upon these findings, the CDC in
1993 added moderate and severe cervical dysplasia as an early symptomatic HIV condition (category B) and
invasive cervical cancer as an indicator condition in the case definition of AIDS (category C). (See "Preinvasive and
invasive cervical neoplasia in HIV-infected women" and "The stages and natural history of HIV infection".)

The incidence of both cervical dysplasia and neoplasia is significantly increased in HIV-infected women, and the
prevalence of cervical intraepithelial neoplasia (also called cervical squamous intraepithelial lesions) ranges
between 30 and 40 percent [15,38]. (See "Cervical cancer screening tests: Techniques for cervical cytology and
human papillomavirus testing".)

SUMMARY — HIV-infected individuals have an increased propensity to develop malignancy, including both AIDS-
defining malignancies (Kaposi's sarcoma [KS], cervical cancer, and non-Hodgkin lymphoma [NHL] including
systemic NHL, CNS lymphoma, primary effusion lymphoma, and Castleman's disease), as well as a number of non-
AIDS-defining malignancies. (See 'Pathogenesis' above and "Overview of non-AIDS-defining malignancies in HIV
infection".)

Immunosuppression from HIV infection appears to play an important role in the development of both KS and NHL.
The widespread use of highly active antiretroviral therapy (HAART) has prevented severe immunosuppression for
prolonged periods in most HIV-infected individuals in the United States and Europe. This has been associated with
substantial decreases in the incidence of KS and NHL, and a relatively better prognosis in response to treatment
than in the pre-HAART era. (See 'Immunosuppression' above and 'Effect of HAART' above.)

In areas such as sub-Saharan Africa, where HAART is not as widely used, there has not been a corresponding
decrease in the incidence of these tumors.

As patients have survived longer with AIDS, the frequency of non-AIDS-defining malignancies has increased
compared to the non-HIV-infected population, and cancer deaths have accounted for an increasing fraction of the
deaths in HIV-infected individuals. (See "Overview of non-AIDS-defining malignancies in HIV infection".)

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GRAPHICS
 Staging classification for AIDS-related KS

Poor risk (any of the

Good risk (all of the following) following)
Tumor, T T0: Confined to skin and/or lymph nodes and/or minimal oral T1:Tumor-associated edema or
disease (non-nodular KS confined to palate) ulceration
Extensive oral KS
Gastrointestinal KS
KS in other non-nodal viscera

Immune I0: CD4 cell count >200/!L* I1: CD4 cell count <200/!L
system, I

Systemic S0: No history of OI or thrush• S1: History of OI and/or thrush

illness, S
No "B" symptoms" "B" symptoms present
Karnofsky performance status >70 Karnofsky performance status <70
Other HIV-related illness (eg,
neurologic disease, lymphoma)

* A CD4 lymphocyte cut-off of 150 !L may be more discriminatory. (Krown, SE, Testa, MA, Huang, J. AIDS-
related Kaposi's sarcoma: prospective validation of the AIDS Clinical Trials Group staging classification.
AIDS Clinical Trials Group Oncology Committee. J Clin Oncol 1997; 15:3085.)
• OI is opportunistic infection.
" "B" symptoms are unexplained fever, night sweats, <10 percent involuntary weight loss, or diarrhea
persisting more than two weeks. Adapted from: Krown, SE, Metroka, C, Wernz, JC. Kaposi's sarcoma in the
acquired immune deficiency syndrome: a proposal for uniform evaluation, response, and staging criteria.
AIDS Clinical Trials Group Oncology Committee. J Clin Oncol 1989; 7:1201.

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