Biggar RJ, Frisch M, Goedert JJ, for the AIDS–Cancer Match Registry Study Group . Risk of Cancer in Children With AIDS. JAMA. 2000;284(2):205-209. doi:10.1001/jama.284.2.205
Author Affiliations: Viral Epidemiology Branch, National Cancer Institute, Bethesda, Md (Drs Biggar, Frisch, and Goedert); and Department of Epidemiology Research, Danish Epidemiology Science Center, Statens Serum Institut, Copenhagen, Denmark (Dr Frisch).
Context Population-based data on cancers associated with acquired immunodeficiency
syndrome (AIDS) in children are lacking.
Objective To determine risk of pediatric AIDS-associated cancers.
Design, Setting, and Participants Using records from 11 locations in the United States for varying periods
between 1978 and 1996, we linked data for children aged 14 years and younger
at AIDS diagnosis to local cancer registry data.
Main Outcome Measures Cancer frequency and, in the 2-year post–AIDS onset period, cancer
incidence and relative risk (RR; measured as standardized incidence ratio),
by cancer type.
Results Among 4954 children with AIDS, 124 (2.5%) were identified as having
cancer before, at, or after AIDS onset, including 100 cases of non-Hodgkin
lymphoma (NHL), 8 of Kaposi sarcoma (KS), 4 of leiomyosarcoma, and 2 of Hodgkin
disease; there were 10 other or unspecified cancers. Expected numbers for
all cancers identified in the study sample, based on population rates (using
area-specific registry data), were less than 1. In the first 2 years after
AIDS diagnosis (5485 person-years), NHL incidence was 510 per 100,000 person-years
(RR, 651; 95% confidence interval [CI], 432-941). Median time for developing
NHL after AIDS diagnosis was 14 months (range, 3-107 months). The most common
type of NHL was Burkitt lymphoma. However, the risk of primary brain lymphoma
(91 per 100,000 person-years) was especially high (RR, 7143; 95% CI, 2321-16,692),
and 4 cases were diagnosed more than 2 years (range, 37-98 months) after AIDS
onset. Leiomyosarcomas also tended to occur several years after AIDS onset,
with 3 of the 4 cases occurring 33 to 76 months after AIDS diagnosis, whereas
KS was reported only at or within 2 years of AIDS diagnosis. Hodgkin disease
risk was also significantly increased (RR, 62; 95% CI, 2-342).
Conclusions The spectrum of AIDS-associated pediatric cancers resembled that seen
in adults, with the addition of leiomyosarcoma. Both primary brain lymphomas
and leiomyosarcomas tended to occur in children surviving several years after
AIDS onset. Because the expected numbers of these cancers in this population
were less than 1 and because of the small numbers of some types of observed
cancers, the RR estimates are imprecise and caution is warranted in their
Cancers are well known to occur in excess in persons with acquired immunodeficiency
syndrome (AIDS). These tumors include, prominently, Kaposi sarcoma (KS), a
cancer occurring especially in homosexual men with AIDS, and non-Hodgkin lymphoma
(NHL), which has similar incidence in all groups regardless of the route of
exposure to human immunodeficiency virus (HIV).1
In adults, invasive cervical cancer is considered an AIDS-defining disease,
and other cancers such as Hodgkin disease, anal cancer, and testicular cancer
have been linked to AIDS.2 Children with AIDS
are at lower risk of cancer than are adults, and they constitute only a small
fraction of persons with AIDS. Thus, studies of cancer in children have mainly
involved case series.3- 5
We sought to provide a population-based overview of the spectrum of malignancies
in children with AIDS.
We linked cancer registry data to 366,034 cases of AIDS in 11 areas.
These areas were included because they had a relatively high AIDS incidence
and cancer registry coverage of the same population. We evaluated only data
obtained during the periods when both registry bases were considered complete,
which varied by registry: the states of New York (January 1981–December
1994), Massachusetts (January 1982–December 1995), Connecticut (November
1980–September 1995), New Jersey (January 1979–December 1996),
Florida (January 1981–December 1995), and Illinois (January 1980–December
1995); and the urban areas of Seattle, Wash (January 1983–June 1996),
San Francisco, Calif (January 1980–September 1995), Los Angeles, Calif
(March 1978–February 1996), Atlanta, Ga (May 1980–December 1994),
and San Diego, Calif (January 1988–December 1995). Most data were from
an era before highly active antiretroviral therapies became widely used. Between
1988 and 1990, AIDS–cancer linkages in 50,050 persons in New Jersey,
California, Florida, and Atlanta, Ga, were evaluated using similar methods,2,6,7 but there were too few
children to analyze pediatric cancer risk.
To perform linkage, we used AutoMatch, versions 3.0 and 4.1 (MatchWare
Technologies, Inc, Burtonsville, Md), which weighted the likelihood of subject
matching on the basis of identical or near-identical information. By order
of priority, we included, when available, social security number, last name,
first name, middle name or initial; the soundex codes for the last name, first
name, and middle name or initial; birth and death dates; race; sex; and home
address. Further details of the matching procedures, confidentiality protection,
and analysis approaches are provided elsewhere.2,6,7
Expected numbers of cancers were computed from data in the geographic
areas where the AIDS cases occurred, except for Illinois, where rates from
National Cancer Institute Surveillance, Epidemiology, and End Results Registries
in Iowa and Detroit were substituted because we did not have histology-specific
information. Coding was based on the International Classification
of Diseases for Oncology, Second Edition.8
The KS analyses excluded data from Florida because of concern about diagnostic
accuracy. While AIDS registries identified Hispanics, cancer registries did
not have data specific to this group. Therefore, expected cancers for Hispanics
were based on rates for whites, on the assumption that most Hispanics would
be classified as white in cancer registry data. Cancer reports were accepted
from either AIDS or cancer registry data. When in conflict, cancer registry
information about histology was preferentially accepted as likely to be more
accurate. However, after noting a significant dearth of information about
NHL sites in the cancer registry data, we accepted the NHL localization as
primary brain lymphoma from either the AIDS or the cancer registry.
Children were followed up from birth or up to 5 years before their AIDS
diagnosis to the date of death or last complete cancer registry information,
whichever came first. Nine children had AIDS-defining cancer diagnoses (8
NHL, 1 KS) recorded in the cancer registry before AIDS was diagnosed (median,
6.5 months; range, 1-14 months). Following standardized procedures,2,6,7 the date of AIDS onset
was moved back to that date, since these were within 5 years of another AIDS
diagnosis. Screening of donated blood for HIV antibodies became routine in
early 1985. To avoid linkages occurring because children became HIV infected
via transfusions related to their cancer, we excluded all tumors occurring
prior to 1985 unless the tumor occurred at or after another AIDS diagnosis.
The AIDS onset period was defined as 6 months before to 3 months after
the precise date given to the AIDS diagnosis to accommodate slight variations
in timing of receipt of cancer reports by the AIDS or cancer registries. Cancer
incidence could not be evaluated during the AIDS period because most of the
observed cancers (58 cases of NHL and 4 cases of KS) were AIDS-defining. The
appropriate denominator for cancer incidence data in this group would be HIV-infected
children, but we did not have such data. However, children with AIDS are,
by definition, HIV-infected, and therefore we could use the population of
children without the specific cancer under study who were followed into the
post-AIDS onset period as the population at risk of developing that cancer.
Cancer incidence rates per 100,000 person-years were therefore calculated
for a 2-year period after AIDS diagnosis (defined as 4 through 27 months after
AIDS onset). Expected cancers were calculated as the sum of the products of
population incidence and person-time in the strata of age (≤4, 5-9, and
10-14 years), sex, and race (whites, blacks, Hispanics, and other or unknown).
Relative risk (RR) calculations (RRs were measured as standardized incidence
ratios) were based on dividing the observed by the expected number of cancer
cases for the 2 years after AIDS onset, and 95% confidence intervals (CIs)
were calculated based on the Poisson assumption.9
Because cases of cancer in children with AIDS contribute to the contemporaneous
background rates, RRs are conservative. Comparisons of frequencies were made
by χ2 methods and Fisher exact (2-tailed) tests. Descriptive
statistics are reported as mean (SD).
Overall, 4954 children aged 14 years and younger at AIDS diagnosis were
identified in the linkage areas during times when both AIDS and cancer registries
were complete. New York contributed the largest number of cases (39.8%), followed
by Florida (24.1%), and New Jersey (14.6%). By sex, 51.2% were boys; and by
race, 60.6% were black, 23.5% were Hispanic, 15.1% were white, and 0.8% were
of other or unknown race. The mean (SD) age at AIDS onset was 2.7 (3.6) years,
but 36.9% of children were in the first 12 months of life, and a further 18.6%
were 13 to 24 months old, so that the median age was 1 year (interquartile
range: 1-4 years). Transmission was predominately via exposure to an infected
mother (90.4%) or contaminated blood or blood products (7.3%). The latter
category includes children with hemophilia.
Among these children, 124 (2.5%) were identified as having cancer either
pre-AIDS, at AIDS onset, or post-AIDS. By type, there were 100 cases of NHL
(81%), 8 of KS (6%), 4 of leiomyosarcoma (3%), and 2 of Hodgkin disease (2%);
there were 10 other or unspecified types (8%) (Table 1). One child may have had 2 cancers, ie, immunoblastic lymphoma
(IBL) followed 4 years later by Burkitt lymphoma (BL). Only the first cancer
is further considered. Cancer was more frequent in boys (2.9%) than girls
(2.0%) (P=.04). By race, cancer was less frequent
in blacks (1.9%) than in whites (3.1%; P=.06) and
Hispanics (3.4%; P=.01). The mean (SD) age at AIDS
diagnosis for children who developed cancer was 3.6 (3.7) years (median, 2
years), and the mean (SD) age at which they developed cancer was 4.5 (3.7)
years (median, 3 years). Cancer risk was not significantly related to HIV-exposure
category after adjusting for age and sex.
The distribution of cancers by time from AIDS onset is given in Table 1. During the 2 years after AIDS
diagnosis, 5485 person-years of observation were accrued for 3753 children
(mean, 17.5 months). During this period, 36 cancers occurred vs 0.89 expected
(RR, 40; 95% CI, 28-56). The cancer incidence was 656 per 100,000 person-years
in this period (Table 2). Incidence
was higher in boys than girls, and this pattern was also seen in the general
Among the 100 cases of NHL, 34 were BL, including Burkitt-like lymphomas,
19 were IBL, 23 were primary brain lymphomas (without regard to histology),
and 24 were unspecified NHL. Only 35% were recorded in both AIDS and cancer
registries, whereas 37% were only in the AIDS registry data and 28% were only
in the cancer registry data. Brain sites were often (61%) reported only in
the AIDS registry data, which did not provide histology information for brain
The cases of NHL occurred in a broad range of ages, from younger than
1 year to age 13 years, but the average age at AIDS diagnosis was 3 to 3.5
years for all histologic subtypes. Most cases of NHL (n=58) were concurrent
with AIDS onset (Table 1). The
median time for developing NHL after AIDS was 14 months (range, 3-107 months).
However, the late occurrence of 4 cases of primary brain lymphoma (37, 38,
40, and 98 months after AIDS onset) represented a notably longer time to onset
than for other specified NHL subtypes. In the 2 years following AIDS diagnosis,
the NHL incidence was 510 per 100,000 person-years and the RR was 651 (95%
CI, 432-941) (Table 2). Regarding
histology, BL was the most common type.
Overall, NHL incidence rose as the age at AIDS diagnosis increased (unpublished
data from study). The incidence in boys was higher than in girls (660 vs 345
per 100,000 person-years), but because background incidence rates for NHL
are higher in boys, RRs were similar (604; 95% CI, 359-957; and 675; 95% CI,
309-1282, respectively). The incidence in blacks (450 per 100,000 person-years)
was slightly lower than either whites (480) or Hispanics (551), a pattern
also generally seen in each NHL subtype (unpublished data from study). Because
the background incidence rate for primary brain lymphoma was lower than for
BL or IBL, the RR of primary brain lymphoma (7143; 95% CI, 2321-16,692) was
much higher than for BL (656; 95% CI, 292-1245) and IBL (815; 95% CI, 297-1774).
Eight children were diagnosed with KS. Four cases were identified at
the time of AIDS diagnosis, and 4 occurred 5 to 15 months after AIDS onset.
In these subjects, the average age at AIDS onset and KS diagnosis were 5.6
years and 6.0 years, respectively. Five children with KS were boys. Route
of HIV exposure was mother-to-child in 6 cases and via blood or blood products
in 2 cases. In 1 instance, the mother was known to have been exposed to HIV
by a bisexual partner (P=.09 for risk association).
The incidence of KS in the 2 years after AIDS onset was 97 per 100,000
person-years, being higher in boys (136) than in girls (52) and higher in
whites (150) than in blacks (89) or Hispanics (86). Incidence rates (per 100,000
person-years) were lowest in young children with AIDS, being 33 in those younger
than 5 years, 284 in 5- to 9-year-olds, and 260 in 10- to 14-year-olds. The
RR was not calculated because all KS reports involved children with AIDS.
Two children with AIDS, both Hispanic boys aged 4 and 9 years, were
diagnosed with Hodgkin disease. The incidence (based on 1 case) was 18 per
100,000 person-years in the 2 years after AIDS diagnosis, and the RR was 62
(95% CI, 2-342) (Table 2).
One boy and 3 girls were diagnosed as having leiomyosarcoma. Three were
blacks and 1 was of other or unknown race. At AIDS diagnosis, they were in
the first year of life, and aged 1, 1, and 6 years, and at cancer diagnosis
they were in the first year of life, and aged 4, 7, and 9 years, respectively.
Three children had a notably long period between AIDS and cancer: 33, 33,
and 76 months. No case fell within the 2 years after AIDS diagnosis used to
assess the incidence and RR. However, finding 3 cases more than 2 years after
AIDS onset, when a relatively lower proportion would have still been in follow-up,
implies a very high late risk. Based on 2 cases occurring from 2 to 5 years
after AIDS onset, the RR for this time period was 1915 (95% CI; 232-6915).
We identified 10 children with other or unspecified cancers in cancer
registry data. Three cancers occurred in the 2 years after AIDS onset (RR,
4; 95% CI, 1-11). One cancer was a mediastinal ganglioneuroblastoma diagnosed
in 1990, 45 months before AIDS onset. The others were diagnosed as malignant
histiocytosis, fibrous histiocytoma, and neurofibrosarcoma (3, 4, and 41 months
after AIDS onset, respectively). One cancer was a fusiform or spindle cell
tumor of the liver (diagnosed 40 months after AIDS onset). Five were unspecified
cancers. One, an ill-defined connective tissue tumor of the limb, occurred
7 months before AIDS onset; 3 tumors (with origins in oral cavity, brain,
and lymph node) occurred in the 2 years after AIDS onset; and 1 (origin in
lung) occurred 70 months after AIDS onset.
One case of leukemia was observed, but histologically, the cells were
Burkitt-like, and the case was assigned to the BL group. Two other cases of
leukemia occurred in the period before 1985, both several years before AIDS
onset. Those cases were excluded because the HIV infection might have been
caused by blood products given as part of clinical care for the leukemia.
No other case of leukemia was seen, but only 0.7 cases were expected among
children with AIDS in the entire time span from 5 years before to 5 years
after AIDS diagnosis.
In this study we assessed cancer risk in 4954 children with AIDS, which
is approximately 70% of the 6948 children (younger than 14 years) reported
as having AIDS to the Centers for Disease Control and Prevention (CDC) through
1995.10 The distributions by age, sex, race,
and risk groups were similar to those reported to the CDC.10
Therefore, our study population closely reflected the profile of pediatric
AIDS cases in the United States.
Most cancers occurring in children with AIDS were NHL, but excesses
of KS, Hodgkin disease, and leiomyosarcoma were significant. Overall, 2.5%
of children with AIDS developed cancer, which is lower than the proportion
seen in adult AIDS patients.1,2
Cancer incidence was higher in boys than girls (P=.04)
and higher in whites (P=.06) and Hispanics (P=.01) than in blacks, largely because most cancers were
NHL. In a prior study, we found similar demographic patterns for NHL in adults
with and without AIDS.1 The only other population-based
examination of cancer risk in children with AIDS compared European and US
data for NHL and KS at AIDS onset, using proportional rather than incidence-based
analysis techniques.5 Investigators with that
study noted a higher proportion of NHL cases in boys, whites, and older children.
In our study, NHLs occurred more frequently and leiomyosarcomas less
frequently than in case series reports, which may be biased toward presenting
unusual cases. Among NHLs, BL was the most common histological subtype, as
previously reported in children.1,11
However, IBL cases were also frequent, although we note that for 10 of 19
cases, the diagnosis came only from the AIDS rather than the cancer registry.
Hence, if some of these IBL diagnoses not confirmed by cancer registry evaluation
were really BL, a higher proportion of NHLs may be BL than we credited.
About a quarter of the lymphomas were primary brain lymphomas. Among
children without HIV infection, primary brain lymphomas are rare. The relatively
high frequency of primary brain lymphoma late in the course of AIDS suggests
a high incidence in children with prolonged or profound immunosuppression.
Typically, primary brain lymphomas in persons with AIDS have high or intermediate
grade histologies,12,13 but in
this study histologies were usually not recorded for primary brain lymphomas.
The profile of leiomyosarcomas also showed a higher frequency in the
late follow-up period, again suggesting a strong role for prolonged or advanced
immunosuppression. Proportionately, leiomyosarcomas constituted 3% of all
cancers, which was considerably lower than the 17% reported in the largest
case series, which included both leiomyosarcomas and leiomyomas.4
Cancer registries do not collect data on benign soft tissue sarcoma. Referral
bias in case series may also contribute to this proportional difference.
The etiology of KS probably involves infection with human herpesvirus
8, a virus with a high prevalence in homosexual and bisexual men.14 Children infected via transmission from mothers who
were in turn infected by a bisexual man are thought to be at increased risk
of KS,15 but only 1 of 8 KS cases in this study
had such an exposure. None of the children with KS became HIV infected by
sexual routes. The excess of Hodgkin disease in the children with AIDS was
based on only 1 case occurring in the 2 years following AIDS onset, but it
is statistically significant and is concordant with the excess of Hodgkin
disease reported in adults with AIDS.2
The occurrence of other or unspecified cancers was increased 3.6-fold,
but this finding was not statistically significant. There was no increase
in the risk of leukemia or cancers at common pediatric sites, such as kidney
or brain (other than lymphoma). Ewing sarcoma and rhabdomyosarcoma have been
described in children with AIDS16 but were
not seen in this study. Mucosal-associated lymphoid tissue tumors have also
been described in children with AIDS,4 but
the cancer registry data were insufficiently detailed for documentation of
In summary, NHLs dominate the profile of cancers occurring in children
with AIDS, with BL being the most common specific type. The highest RR was
for primary brain lymphoma, and a high proportion of these cancers occurred
several years after AIDS onset when subjects were likely to have had prolonged
or profound immunosuppression. Leiomyosarcomas also had a late onset pattern.
Kaposi sarcoma and Hodgkin disease risks were also increased. The risks of
other pediatric cancers were not increased. Thus, AIDS-related immunosuppression
does not result in an increase in risk for all cancers in children. Rather,
as in adults, the increased risk is limited to a few types that also occur
excessively in adults with AIDS, as well as leiomyosarcoma. If children with
AIDS survive longer with better therapies, both the risks of cancer and the
profile of types could change.