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Altered Clinical Course of Malignant Melanoma in HIV-Positive Patients
Lori K. E. Rodrigues, MD;
Barbara J. Klencke, MD;
Kirsten Vin-Christian, MD;
Timothy G. Berger, MD;
Richard I. Crawford, MD;
James R. Miller III, PhD;
Carlos M. M. Ferreira, MD;
Mehdi Nosrati, BS;
Mohammed Kashani-Sabet, MD
Arch Dermatol. 2002;138:765-770.
ABSTRACT
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Objective To determine whether the natural history of melanoma is different in
patients who test positive for human immunodeficiency virus (HIV) compared
with matched control subjects.
Design Retrospective cohort analysis.
Setting Ambulatory care at 2 university-affiliated medical centers.
Patients Each HIV-positive melanoma patient (n = 17) was randomly matched with
2 HIV-negative patients (HIV status unknown, but without risk factors for
HIV) based on the melanoma subtype, tumor thickness, Clark level, tumor location,
and sex and age of the patient.
Main Outcome Measures Disease-free survival and overall survival of HIV-positive and HIV-negative
melanoma patients were compared using a matched-pairs analysis. CD4 cell counts
were recorded at the time of melanoma diagnosis and disease recurrence.
Results Melanoma patients who were HIV positive had a significantly shorter
disease-free survival (P = .03) and overall survival (P = .045) compared with HIV-negative melanoma patients by matched-pairs
analysis. There was an inverse relationship between CD4 cell counts and time
to first melanoma recurrence.
Conclusions The natural history of malignant melanoma in HIV-positive patients is
more aggressive compared with matched HIV-negative melanoma patients. Altered
immune response and comorbid disease may play a role in the poor clinical
outcome of HIV-positive patients. These findings have important implications
in the management of melanoma in the setting of HIV disease.
INTRODUCTION
THE IMMUNE suppression associated with human immunodeficiency virus
(HIV) infection may affect the incidence or clinical behavior of a malignant
tumor. Patients with acquired immunodeficiency syndrome (AIDS) have been shown
to be at greatly increased risk for some cancers, such as Kaposi sarcoma,
primary central nervous system lymphoma, non-Hodgkin lymphoma, and cervical
cancer.1-2 Cutaneous nonmelanoma
neoplasms, such as basal cell carcinoma and squamous cell carcinoma, have
also been noted frequently in those with HIV infection.3-6
One study5 suggested that these skin tumors
have a more aggressive behavior. The relative risk of a few types of malignancies,
such as human papilloma virus–related cancers (eg, anal, penile, and
vulvar), Hodgkin disease, and lung cancer, is slightly elevated, although
these are not yet designated as AIDS-defining cancers.7
Reports of concurrent melanoma and HIV lead some to speculate that there
may be an increased risk of melanoma.8 A few
case reports suggest a poor clinical outcome of melanoma in the setting of
HIV disease,8-10
whereas others make no comment about outcome.11
Further studies are needed to confirm these results because existing epidemiologic
data address the issue of incidence rather than the natural history of the
disease.
In this retrospective study, we review the clinical course of 17 HIV-positive
patients with melanoma. The presentation and clinical behavior of melanoma
in HIV-positive patients are compared with sex- and age-matched HIV-negative
patients (HIV status unknown, but without risk factors for HIV disease). We
report a reduced disease-free and overall survival in HIV-positive melanoma
patients compared with matched controls.
PATIENTS AND METHODS
Twenty-six HIV-positive patients with melanoma were initially seen at
the University of California, San Francisco, and St Paul's Hospital, Vancouver,
British Columbia. Seventeen HIV-positive patients were ultimately evaluated
in our study. The remainder of the patients were excluded for the following
reasons: 5 because we were unable to locate the melanoma pathology reports
(the patients' medical records were kept by physicians who have since changed
practices or retired); 1 did not have an invasive melanoma; 2 presented with
metastatic disease from an unknown primary melanoma; and in 1 case there was
a discrepancy between the dates of diagnosis and death. Approval was obtained
from the Committee on Human Research at the University of California, San
Francisco, to conduct the study. Formal application was not required by the
Ethics Review Committee at St Paul's Hospital for a retrospective review of
medical records. Information about a patient's history of HIV and melanoma
was obtained by medical chart review. Information regarding the melanoma included
pathology reports, risk factors, and treatment. Information regarding the
HIV history included dates of first diagnosis, CD4 cell counts, medications,
and the presence of opportunistic infections.
Each HIV-positive melanoma patient was matched with 2 HIV-negative patients
(HIV status unknown, but without risk factors for HIV disease) based on the
melanoma subtype, tumor thickness, Clark level, sex and age of the patient,
and, when possible, anatomic location of the primary tumor. Controls were
randomly selected from the University of California, San Francisco, Melanoma
Center data set on the basis of the tumor and patient characteristics mentioned.
This data set included patients with a primary melanoma and with 2 years of
follow-up or who had documented first relapse. Disease-free survival and overall
survival for HIV-positive and HIV-negative melanoma patients were recorded
and, when available, the cause of death was noted.
The Wilcoxon matched-pairs, signed rank test and the binomial sign test
were used to determine the statistical significance of the overall survival
and time to first recurrence between the HIV-positive and HIV-negative patients.
Kaplan-Meier analysis was used to assess disease-free and overall survival
for the cohort of HIV-positive and HIV-negative patients. The relationship
between CD4 cell counts (at initial diagnosis of melanoma) and tumor thickness
was examined using regression analysis. The relationship between CD4 cell
counts and disease-free survival was also examined. The HIV-positive patients
were split into 2 groups: those with low (below the median) and those with
high (above the median) CD4 cell counts. Separate Kaplan-Meier curves were
produced for low and high CD4 cell counts, with respect to disease-free survival,
and the significance of the difference between those 2 curves was tested by
the generalized Wilcoxon test and by the log-rank test.
RESULTS
All 17 HIV-positive melanoma patients were men between ages 31 and 75
years, with a mean age of 42 years (Table
1 and Table 2). Subtypes
of melanoma included superficial spreading (8), nodular (4), desmoplastic
(2), and lentigo maligna (1). Two melanomas were not otherwise classified.
Melanoma tumor thickness ranged from 0.4 to 8.0 mm, with a mean tumor thickness
of 1.92 mm. One patient had histologic evidence of ulceration; 4 patients
did not have ulceration. Twelve melanoma biopsy specimens were not evaluated
for the presence or absence of ulceration.
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Table 1. Summary of the Melanoma Characteristics, Dates of Disease
Diagnoses, CD4 Cell Counts, Number of Antiretroviral Medications, and Status
for Each HIV-Positive Study Patient*
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Table 2. Clinical and Histologic Characteristics of Melanoma Patients
by Human Immunodeficiency Virus (HIV) Status
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Three patients had a melanoma located on the head and neck region, 12
on the trunk, and 2 on the extremities. The CD4 cell count at the time of
melanoma diagnosis was available for 12 patients; the values were between
119/µL and 960/µL, with a mean of 436/µL.
Fifteen of the 17 HIV-positive patients had a wide excision of their
melanoma. One patient was lost to follow-up after the initial biopsy. Documentation
of a reexcision was not found in his medical record. Another patient had widespread
metastatic disease at melanoma diagnosis and a wide excision was not performed.
The nodal status of the HIV-positive patients was largely determined
by clinical examination, because the sentinel lymph node biopsy procedure
has only recently entered widespread use. One patient presented with palpable
axillary lymphadenopathy confirmed as melanoma. Three patients had histologically
negative lymph nodes determined by sentinel lymph node biopsy. The remaining
HIV-positive patients had no evidence of lymphadenopathy by clinical examination.
None of the HIV-positive patients underwent elective lymph node dissection.
Baseline staging studies including a chest x-ray examination and blood
work (complete blood cell count with differential, liver function tests, and
lactate dehydrogenase measurements were performed in all but 2 HIV-positive
patients). Elevated liver function test results were noted in 3 patients.
One patient with a lactate dehydrogenase level almost twice the upper limit
of normal had liver metastasis on computed tomographic scanning. Another patient
had an elevated lactate dehydrogenase level and concurrent hepatitis C infection.
Follow-up examinations were recommended at a minimum of every 6 months,
with surveillance chest x-ray examinations and laboratory studies (complete
blood cell count and liver function tests) performed when indicated. One HIV-positive
melanoma patient with elevated liver function test results at baseline was
followed up and is alive without evidence of recurrent disease. Three patients
did not follow through with their physician visits and were lost to follow-up.
Eleven HIV-positive melanoma patients had comorbid illnesses, such as Pneumocystis carinii pneumonia, hepatitis B or C, Mycobacterium avium complex, herpes simplex infection,
central nervous system toxoplasmosis, or cryptococcus and cytomegalovirus
infection by the time of their death. There were no reported cases of Kaposi
sarcoma.
Ten of the 17 HIV-positive patients were undergoing antiretroviral therapy
at the time of melanoma diagnosis (Table
1). Two patients were receiving a single antiretroviral agent, and
the remaining 8 patients were undergoing highly active antiretroviral therapy
(HAART). The 2 patients who received single-drug treatment for HIV disease
are dead; 1 patient died of AIDS and the other of metastatic melanoma and
AIDS. The HIV-positive patients who were treated with HAART are alive and
currently without evidence of recurrent melanoma. Two patients who received
HAART had recurrent disease that was surgically resected and treated with
adjuvant therapy. One patient received interleukin 2 and postoperative radiation;
the second patient was treated with interferon alfa, which he was unable to
tolerate. Seven HIV-positive patients were not treated for HIV disease. Three
patients died of metastatic melanoma and 1 died of metastatic melanoma and
AIDS. Three patients were lost to follow-up. However, it is likely that 1
of these patients died of metastatic melanoma because he had axillary, mediastinal,
and liver masses detected by computed tomographic scanning.
Thirty-four control patients were included in our study, and their clinical
and histologic characteristics are summarized in Table 2. All patients were men between ages 28 and 77 years, with
a mean age of 47 years. Melanoma subtypes included superficial spreading (19),
nodular (9), desmoplastic (4), and lentigo maligna (2). The average tumor
thickness was 2.01 mm, with a range of 0.35 to 8.00 mm. Fourteen patients
had histologic evidence of ulceration, 19 did not have ulceration, and 1 patient's
ulceration status was unknown. Melanoma was located on the head and neck in
10 patients, on the trunk in 21, and on the extremities in 3. There were fewer
HIV-positive patients with head and neck melanomas compared with HIV-negative
patients. The discrepancy was due to a lack of HIV-negative patients with
desmoplastic and lentigo maligna melanoma located in the same anatomic region
as the HIV-positive patients. Therefore, the cases were matched with controls
from the database with similar histologic features but located on the head
and neck. Given the potentially more aggressive behavior of melanomas located
in the head and neck, this selection criterion would worsen the survival results
for the controls, thereby masking a survival difference between the 2 groups.
All patients had wide excision of their melanomas.
DISEASE-FREE SURVIVAL
Fourteen HIV-positive patients and 18 matched HIV-negative melanoma
patients had a median follow-up of 48 months (range, 3-155 months) and were
included in the final analysis. Patients were followed up at least every 6
months or more closely if they presented with a thick melanoma or had evidence
of metastatic disease. Radiographic and laboratory studies were performed
at least annually and more frequently when clinically indicated. Seven (50%)
of 14 HIV-positive patients developed metastatic melanoma compared with 12
(67%) of 18 HIV-negative patients when followed up for a median of 48 months.
The percentage of HIV-negative patients who had a melanoma relapse is higher
than one would expect for this cohort because they were selected from a data
set that was skewed toward relapses. The HIV-positive patients had a reduced
disease-free survival compared with the HIV-negative patients (Figure 1). This reduction in disease-free survival showed a trend
toward statistical significance when the 2 Kaplan-Meier survival plots were
compared under the assumption that the 2 samples were drawn independently
of one another (P = .06, 1-tailed log-rank test).
However, when HIV-positive and HIV-negative patients were matched using the
variables described, a Wilcoxon matched-pairs, signed rank test showed the
reduction in disease-free survival to be significant (P = .03, 1-tailed). The median disease-free survival was 16 months for
HIV-positive patients compared with 42 months for HIV-negative patients.
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Figure 1. Kaplan-Meier analysis comparing
disease-free survival in human immunodeficiency virus–positive and matched
human immunodeficiency virus–negative controls (P = .03).
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OVERALL SURVIVAL
The overall survival of HIV-positive melanoma patients was significantly
reduced when compared with matched HIV-negative melanoma patients (Figure 2; P = .002,
1-tailed log-rank test; P = .045, 1-tailed Wilcoxon
matched-pairs, signed rank test). Seven of 14 HIV-positive patients died during
follow-up compared with 9 of 18 HIV-negative patients. The median overall
survival was approximately 2.8 years for HIV-positive patients vs 6.4 years
for HIV-negative patients. The cause of death in the HIV-positive patients
was due to metastatic melanoma in 3 (43%) of 7 cases. Only 1 HIV-infected
patient died of AIDS-related illness in the absence of metastatic melanoma.
Three died of metastatic melanoma and concurrent AIDS.
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Figure 2. Kaplan-Meier analysis comparing
the overall survival in human immunodeficiency virus–positive cases
and matched human immunodeficiency virus–negative controls (P = .045).
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CD4 CELL COUNTS
There was no association between CD4 cell counts and tumor thickness
in HIV-positive melanoma patients at the time of melanoma diagnosis (Figure 3).
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Figure 3. Relationship between CD4 cell
count at melanoma diagnosis and corresponding tumor thickness.
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The association between initial CD4 cell counts and overall survival
in HIV-positive melanoma patients was not statistically significant. However,
patients with lower CD4 cell counts seemed to have shorter overall survival
compared with patients with higher CD4 cell counts.
Seven HIV-positive melanoma patients had CD4 cell counts measured at
the time that their melanoma metastasized. Patients with higher CD4 cell counts
had a significantly prolonged time to melanoma relapse determined by a regression
scale (P = .04).
COMMENT
At least 22 cases of melanoma associated with HIV disease have been
reported in the literature. Many of these case reports suggest that the natural
history of melanoma in HIV-positive patients is more aggressive and associated
with a poorer prognosis compared with HIV-negative patients. Our study supports
the suggestions of previous reports by demonstrating a significantly shorter
disease-free survival and overall survival for HIV-positive patients with
melanoma.
Our study design controlled for differences in clinical and histologic
characteristics (by matching variables such as tumor thickness, melanoma subtype,
Clark level, and patient age and sex) between HIV-positive and HIV-negative
patients to eliminate factors that may influence overall melanoma prognosis.
Despite this, the clinical course of melanoma in HIV-positive patients was
more rapidly progressive than that of the matched pairs. The aggressive nature
of the melanomas may be secondary to factors such as an altered host immune
response to tumor due to immunodeficiency and comorbid illnesses. In our study,
HIV-positive patients with a more severe immune deficiency (as evidenced by
CD4 cell counts) experienced an earlier relapse of their melanoma. Although
an inverse relationship between CD4 cell counts at melanoma diagnosis and
tumor thickness has been reported,12 this relationship
was not observed in our study. In fact, the HIV-positive patients had a relatively
high median CD4 cell count at the time of melanoma diagnosis; this might suggest
that there is no significant influence of HIV disease on tumor initiation.
The median overall survival for HIV-positive patients in this study
was shorter (2.8 years) compared with HIV-negative patients (6.4 years). At
least 40% of the HIV-positive patients died of metastatic melanoma and almost
30% died as a result of metastatic melanoma and AIDS, even though 8 patients
had concurrent opportunistic infections at the time of death. Most deaths
were observed in the HIV-positive patients who were not treated for HIV or
received only single-agent antiretroviral therapy. This suggests that immune
reconstitution with HAART may improve the prognosis of malignant melanoma
in HIV-positive individuals.
Although the exact mechanism of how HIV disease affects melanoma is
unknown, several lines of evidence point to the effects of immune modulation
on the biology of melanoma. Currently, interferon alfa-2b and interleukin
2 are immunotherapeutic agents approved by the Food and Drug Administration
for the treatment of melanoma. Several phase 3 clinical trials evaluating
the efficacy of tumor vaccines in the adjuvant therapy of melanoma are under
way. In addition, the incidence of melanoma is 2- to 4-fold higher in organ
transplant patients undergoing immunosuppressive regimens.13-16
Finally, a few studies suggest that defects in humoral and cell-mediated immunity
may contribute to melanoma progression. Work by Werkmeister et al17 and Pandolfi et al18
suggests that an increased suppressor cell activity against T and B cells
or the loss of HLA-A2 expression results in ineffective immune surveillance.
Heppner and colleagues19 detected blocking
antibodies that can decrease cell-mediated tumor activity in patients with
melanoma. Lane and coworkers20 found abnormal
B-cell activation and immunoregulation in patients with AIDS compared with
controls.
In addition to the apparently altered clinical course of melanoma in
the setting of HIV infection, the impact of HIV on melanoma incidence is also
controversial. Some studies report an increased incidence of melanoma in HIV-infected
individuals. A prospective study of 1000 patients with HIV disease noted as
much as a 100-fold higher incidence of melanoma compared with the general
population.21 Despite this, epidemiologic studies
using cancer and AIDS registries or other prospective cohort studies have
not demonstrated a significantly increased incidence of melanoma.7, 22-25
Beral et al7 formed an international collaboration
of epidemiologists to address the risk of AIDS-defining cancers and non–AIDS-defining
cancers in HIV-infected patients. Using primary data, 20 prospective cohort
or case-control studies of HIV-infected individuals, representing 90% of the
world's literature on AIDS malignancy, were analyzed to determine the risk
of AIDS-defining cancers and 15 other non–AIDS-defining cancers. The
meta-analysis showed a relative risk of 0.9 (99% confidence interval, 0.4-1.6)
for melanoma in those with AIDS compared with controls.
In conclusion, this study suggests that HIV-positive melanoma patients
have a more aggressive clinical course of melanoma, as evidenced by a shorter
disease-free and overall survival compared with matched HIV-negative melanoma
patients. Our findings may have several implications regarding the management
of HIV-positive melanoma patients. These patients may be candidates for sentinel
lymph node biopsy at a lower tumor thickness than that used for HIV-negative
melanoma patients. These patients should undergo closer surveillance to detect
the presence of metastatic disease. Our results suggest that patients undergoing
HAART may have an improved clinical outcome. Therefore, initiation of HAART
should strongly be considered in HIV-positive patients with malignant melanoma.
Finally, the role of adjuvant immunotherapy, such as interferon alfa or interleukin
2, should be explored in this cohort given its potential beneficial effects
on melanoma and HIV infection.
AUTHOR INFORMATION
Accepted for publication August 7, 2001.
Corresponding author and reprints: Mohammed Kashani-Sabet, MD, University
of California, San Francisco, Melanoma Center, UCSF Comprehensive Cancer Center,
1600 Divisadero St, San Francisco, CA 94115 (e-mail: kashanisabet{at}orca.ucsf.edu).
From the Melanoma Center, Cutaneous Oncology Division (Drs Rodrigues,
Miller, Ferreira, and Kashani-Sabet and Mr Nosrati), Department of Dermatology
(Drs Rodrigues, Vin-Christian, Berger, and Kashani-Sabet), Hematology/Oncology
Division, Department of Internal Medicine (Dr Klencke), Cutaneous Oncology
Program, University of California, San Francisco, Cancer Center; and the Department
of Dermatology, St Paul's Hospital, Vancouver, British Columbia (Dr Crawford).
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