© 1998 by Oxford University Press
Journal of the National Cancer Institute Monographs, No. 23, 31-35,
1998
© 1998 Oxford University Press
Cancers in Human Immunodeficiency Virus-Infected Children
*Correspondence to: Brigitta U. Mueller, M.D., Assistant Professor of Pediatrics, Harvard Medical School, Children's Hospital, HU-215, 300 Longwood Ave., Boston, MA 02115. E-mail: mueller_b{at}a1.tch.harvard.edu
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Abstract |
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 Top Abstract Background and EpidemiologyNon-Hodgkin's LymphomaKaposi's SarcomaSmooth Muscle TumorsMiscellaneous TumorsPresent and Future ChallengesReferences |
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Although the exact incidence of cancers in human immunodeficiency virus (HIV)-infected children is not clear, an excess of non-Hodgkin's lymphomas and soft tissue tumors as well as a multitude of otherwise rare tumors in childhood, such as cervical, thyroid, or pulmonary carcinoma, has been reported. In contrast to the findings in HIV-infected adults, Kaposi's sarcoma is rare in children in industrialized countries but not in children living in the sub-Saharan area. Treatment of the neoplastic disease is often complicated by multiple HIV-associated organ dysfunctions as well as drug interactions and infectious complications secondary to severe immunosuppression. Nonetheless, preliminary results with dose-intensive, but brief, chemotherapeutic regimens have been encouraging, and HIV-infected children who develop cancer are likely to benefit from aggressive treatment combined with adequate supportive care. Furthermore, insights gained from the study and treatment of this very challenging group of patients may benefit other immunocompromised hosts as well as increase our understanding of oncogenesis in general.
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Background and Epidemiology |
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TopAbstractBackground and EpidemiologyNon-Hodgkin's LymphomaKaposi's SarcomaSmooth Muscle TumorsMiscellaneous TumorsPresent and Future ChallengesReferences |
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Worldwide, the Joint United Nations Programme on AIDS [acquired immunodeficiency disease syndrome] (UNAIDS) estimates that 400 000 new human immunodeficiency virus (HIV) infections occurred in children in 1996 and that currently 830 000 children are living with symptoms of HIV/AIDS (UNAIDS Web site). Of the 2.6 million children who were infected since the epidemic began, an estimated 1.4 million have already died. The number of children with HIV infection who develop a cancer is poorly defined. Among the 7629 children diagnosed with AIDS by the end of December 1996, 156 (2.04%) had a cancer as their AIDS-defining diagnosis (1). However, the AIDS definition revised by the Centers for Disease Control and Prevention (CDC) in 1994 lists only a limited number of neoplasms: Kaposi's sarcoma (KS) lesions, primary non-Hodgkin's lymphomas (NHLs) of the central nervous system (CNS), small non-cleaved cell lymphomas, and immunoblastic large-cell NHLs of B-cell or unknown phenotype (2). Leiomyosarcomas are listed under category B of the CDC classification, representing a "moderate" clinical symptom. Furthermore, children who meet the diagnosis of AIDS with another symptom before they develop a tumor will not be registered again. It is therefore clear that the CDC registry will provide only limited information about the true incidence of neoplasms in HIV-infected children.
Among the 156 tumors captured in the CDC AIDS definition in children, there were 50 Burkitt's lymphomas, 48 immunoblastic lymphomas, 30 NHLs of the CNS, and 28 KS lesions. The number of KS cases is probably an overestimation because of initial problems with the pathologic diagnosis (Lindegren ML [CDC]: personal communication). If one takes into account only these numbers, a conservative estimate is that children with HIV infection appear to have at least a 100-fold higher incidence of cancers. In 1996 alone, 10 of 678 children who were newly diagnosed with AIDS received this diagnosis because of an NHL or a KS. This represents an incidence of neoplasms in children with AIDS of 1.47%, compared with healthy, non-HIV-infected children, who develop cancer in approximately 130 cases per million children (0.013%) per year (1,3).
Several efforts have been made to better define the number and range of neoplastic manifestations in HIV-infected children. In a combined, retrospective survey performed by the HIV and AIDS Malignancy Branch of the National Cancer Institute (NCI), Bethesda, MD, and the Children's Cancer Group, 59 tumors were identified in 57 children (Granovsky M [NCI]: personal communication). It is interesting that 42% of these tumors would not have been captured by the CDC classification. These data are very comparable to a prospective survey performed by the Pediatric Oncology Group (4). The tumors observed are often unusual and extremely rare in non-HIV-infected children; they include carcinoma of the thyroid, oat cell tumor of the tracheo-esophageal region, carcinomas of the vagina and cervix, hepatoblastoma, and soft tissue tumors (e.g., leiomyosarcomas), among others (5-8). Several reports from Africa have noted an increased incidence of retinoblastomas, nasopharyngeal carcinomas, and rhabdomyosarcomas, tumors not commonly associated with immune deficiency states (9,10).
There are clear differences between HIV-infected children and
HIV-infected adults. For example, KS is a rare tumor in children
in industrialized countries (United States and Europe), perhaps
with the exception of Haiti and Romania (11). It is interesting that KS is the AIDS-defining
illness in only 3% of adolescents between 13 and 19 years
of age, but this incidence increases to 9% in young adults
between 20 and 24 years of age and to 13% in adults older
than 25 years (1,12). KS is more common in
homosexual HIV-infected men than in heterosexual HIV-infected men
or women. However, there is an increasing incidence of KS among
children living in Africa (9,10,13-15). A
further difference between adults and children with HIV infection
is the increased incidence in children of smooth muscle tumors,
leiomyomas, and leiomyosarcomas (8,16-20)
as well as the high prevalence in children of lymphoproliferative
disorders (Table 1)
(21-24). It is currently not clear whether there is an
increased tendency of these lymphoproliferative disorders to
evolve into a "true," monoclonal cancer with a rapid
and invasive growth pattern.
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Non-Hodgkin's Lymphoma |
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TopAbstractBackground and EpidemiologyNon-Hodgkin's LymphomaKaposi's SarcomaSmooth Muscle TumorsMiscellaneous TumorsPresent and Future ChallengesReferences |
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As indicated above, the CDC classification includes small, non-cleaved cell lymphomas (mainly B-cell phenotype), large-cell lymphomas (immunoblastic and anaplastic tumors), and primary CNS lymphomas.
In non-HIV-infected children, there are two forms of small, non-cleaved cell NHLs (Burkitt's and Burkitt's-like lymphomas). The endemic form, more than 95% of which is associated with Epstein-Barr virus infection, presents typically with jaw tumors and has an especially high prevalence in equatorial Africa. The sporadic form is observed in the United States, Europe, and Asia and is 20- to 100-fold less common than the endemic form (25). Burkitt's lymphoma constitutes about 50% of the childhood lymphomas. It has an annual incidence in children of 76.2 per million in Nigeria compared with 0.3 (U.S. blacks) and 2.0 (U.S. whites) per million in the United States. However, either form is rare compared with an extrapolated annual incidence of more than 4400 cases per million children with AIDS (based on the CDC statistics of three of 678 children diagnosed with AIDS because of a Burkitt's NHL in 1996) (1,12).
In non-HIV-infected children, only about 20% of all NHLs are of the large-cell type, and most of them are of the B-cell phenotype (26). The incidence of large-cell tumors appears to be higher in HIV-infected children, and anaplastic T-cell NHL can occur. Among the 13 HIV-infected children with NHL followed at the NCI, five (38%) had large-cell tumors. Two were immunoblastic B-cell tumors, two were anaplastic T-cell tumors, and one was an anaplastic tumor of non-B, non-T phenotype. Lymphoblastic NHLs, which represent about one third of all NHLs in children in the United States, are predominantly of T-cell origin and do not appear to be more common in the HIV-infected population. They are not included in the CDC AIDS definition.
Although secondary involvement of the CNS is observed, especially in children with bone marrow involvement, it is extremely rare to see a primary CNS lymphoma in the non-HIV-infected child (26). However, it is the AIDS-defining diagnosis in 0.4% of children, constituting 23% of all the NHLs registered for AIDS diagnosis. However, in 1996, only one (10%) of 10 children had a CNS NHL as an AIDS-defining tumor, compared with 230 (22%) of 1030 adults (1). This finding possibly reflects a change in the disease course in children, since CNS NHLs are most prevalent in patients with very low CD4 counts and have often been diagnosed at autopsy. As in adults, the differential diagnosis, especially in the adolescent, has to include cerebral toxoplasmosis. However, we also have observed at least one case of an intracranial lymphoproliferative lesion similar to what has been described in the post-transplant situation. Furthermore, since HIV-infected children are now surviving longer, it has to be kept in mind that brain tumors are the most common solid tumors in otherwise healthy children (3). An empirical treatment for toxoplasmosis may not be warranted in the younger child, since cerebral toxoplasmosis with mass lesion(s) is extremely rare in preadolescent children, and an early biopsy should be considered.
Unusual, extranodal sites of presentation of NHLs are relatively
common in the HIV-infected child (Table 2)
(27-31). Intriguing is the high incidence
of mucosa-associated lymphoid tumors, observed in pulmonary or
gastric mucosa as well as in the parotid, salivary, or lacrimal
glands (29,32,33). These oligoclonal or
monoclonal processes are usually curable by surgical excision
alone and may represent an interface between lymphoproliferative
disorder and cancer. Lymphocytic interstitial pneumonitis is a
common manifestation of pediatric HIV disease, and it is possible
that pulmonary mucosa-associated lymphoid tumors and lymphocytic
interstitial pneumonitis are related (34-37).
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Kaposi's Sarcoma |
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TopAbstractBackground and EpidemiologyNon-Hodgkin's LymphomaKaposi's SarcomaSmooth Muscle TumorsMiscellaneous TumorsPresent and Future ChallengesReferences |
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KS is rarely diagnosed in HIV-infected children from the United States, with the exception of vertically infected children from Haiti or older adolescents (38-42). However, in African countries such as Zambia or Uganda, KS now constitutes almost 20% of all childhood cancers, compared with 6% before 1986, and the male-to-female ratio has changed from 3:1 before the AIDS epidemic to about 1.7:1 at the present time (9,10,15). It is interesting that this more than 40-fold increase in the occurrence of childhood KS, although mainly occurring in HIV-infected children, has also been observed in noninfected pediatric populations. The lymphadenopathic form is most prevalent, and common sites include head and neck (82%), extremities (7%), inguinal (5%), and abdomen (4%). In adults, human herpesvirus type 8 (HHV-8) has been shown to be present in more than 90% of all KS lesions, as well as in AIDS-related body cavity NHLs, lymphomatous effusions without tumor mass, and Castleman's disease (43-46). In the general population of the United States, about 25% of adults have HHV-8-related antibodies, compared with 18% of adolescents and less than 4% of children under 13 years of age (47-51). However, in African countries such as Nigeria or Zaire, the seroprevalence in the population is much higher (56% and 82%, respectively). In a study from Uganda, nine of 18 children with KS were also positive for HHV-8, compared with seven of 22 children with other tumors (9,15).
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Smooth Muscle Tumors |
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TopAbstractBackground and EpidemiologyNon-Hodgkin's LymphomaKaposi's SarcomaSmooth Muscle TumorsMiscellaneous TumorsPresent and Future ChallengesReferences |
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Leiomyomas and leiomyosarcomas are extremely rare in non-HIV-infected children, but at least 18 cases have now been observed in HIV-infected children. While leiomyomas can be incidental findings and can remain clinically indolent, leiomyosarcomas often present as widespread disease. As described for lymphomas, smooth muscle tumors can also occur in unusual locations (e.g., in the lungs, adrenal glands, or skin) (8,16-20,52,53). Leiomyosarcomas from children with HIV infection as well as from patients after receiving a transplant but not from other patients have been shown to be positive for Epstein-Barr virus by in situ hybridization (20,54). Quantitative polymerase chain reaction showed relatively high levels of Epstein-Barr virus in tumor tissue (as many as 4.3 genome copies per cell), and discrete episomal Epstein-Barr virus clones were found in lesions taken from different sites in the same patient, indicating simultaneous emergence of separate clones (20). It is currently unclear whether HIV infection and the associated disturbance in immune surveillance lead to an increased expression of the Epstein-Barr virus receptor or whether Epstein-Barr virus infection of the smooth muscle cells results in increased expression.
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Miscellaneous Tumors |
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TopAbstractBackground and EpidemiologyNon-Hodgkin's LymphomaKaposi's SarcomaSmooth Muscle TumorsMiscellaneous TumorsPresent and Future ChallengesReferences |
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Anal (55,56) and cervical (57,58) carcinomas might be seen in sexually active adolescents, since infection with human papillomavirus, which is known to be associated with the occurrence of these tumors, is frequently acquired by adolescents (59). Hodgkin's disease is more common in adolescents than in younger children and, as in adults, it is possible that a slight increase in the number of this relatively common tumor will be observed in the future (60). Hepatic tumors might become more prevalent, since many HIV-infected children, especially those who are hemophiliacs, are also infected with hepatitis B or C (61-63).
HIV-infected children (like HIV-infected adults) are surviving longer and are in better health, thanks to improved and expanded therapeutic options. It is therefore possible that more children in the future will develop the "normal" pediatric cancers, especially leukemia and brain tumors. While these tumors may not be more common in the HIV-infected child, their diagnosis and therapy will certainly pose unique problems.
Children are being exposed to multiple drugs for the treatment of HIV disease and its complications not only during childhood but also prenatally. To decrease the transmission rate of HIV disease, it is currently recommended that all pregnant HIV-positive women receive zidovudine during pregnancy and birth and that their infants be treated with zidovudine for the first 6 weeks of life (64,65). Recently, studies of the offsprings of mice that had been treated with zidovudine during the last trimester (66) revealed an increased risk of developing liver and lung tumors as well as tumors of the reproductive organs. Olivero et al. have demonstrated that zidovudine is incorporated into the DNA of newborn mice and monkeys, as well as into the nuclear DNA of cord blood samples drawn from children whose mothers had been treated with the drug. In January 1997, the National Institutes of Health (Bethesda, MD) convened a panel to review these studies and, although acknowledging the validity of the findings, also recognized that the benefit of preventing transmission of HIV disease in the vast majority of children currently outweighs the potential concerns of carcinogenicity. However, the panel also strongly emphasized the need for careful, long-term follow-up of all children exposed in utero to antiretroviral therapy, including those children who are not HIV infected.
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Present and Future Challenges |
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TopAbstractBackground and EpidemiologyNon-Hodgkin's LymphomaKaposi's SarcomaSmooth Muscle TumorsMiscellaneous TumorsPresent and Future ChallengesReferences |
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There are several dilemmas that the physician who is treating HIV-infected children is facing. First, as mentioned, the scope of the problem, including the exact incidence and spectrum of tumors, is not well defined. It may be necessary in the future to adapt the CDC definition, and it clearly remains important to use the AIDS malignancy registries as well as to publicize unusual cases in order to capture the (potentially very broad and unexpected) spectrum of pediatric AIDS-related tumors.
Second, the treating physician is faced with diagnostic dilemmas. Atypical symptoms and courses can occur, unusual cancers may be encountered, and the differential diagnosis is often confusing because of similar presentations of opportunistic infections (e.g., CNS lesion and toxoplasmosis or fever and night sweats in disseminated Mycobacterium avium complex infection). Furthermore, even if a child is successfully treated for one tumor, he or she remains at risk for another cancer as long as the immunosuppression continues.
Thirdly, there are therapeutic dilemmas. Children are often followed by an infectious disease specialist who has no oncology experience or at a cancer center that has no HIV experience, and an inter-disciplinary approach appears certainly more advantageous. Furthermore, there are currently no standardized treatment guidelines or protocols available for HIV-infected (or otherwise immune compromised) children who develop a cancer. Many of these children have unique problems, such as pre-existing organ damage, especially diminished bone marrow reserves, and concurrent opportunistic infections, and they are also receiving multiple drugs (antiretroviral and other) that might lead to potentially dangerous drug interactions. However, there is increasing evidence that children with HIV infection, despite the multiple problems involved, are able to tolerate even intensive chemotherapy (at least for limited periods of time) and can be cured of their cancer without acceleration of their underlying disease (31,67-69). One such example is the dose-intensive protocol currently used by the NCI for the treatment of NHL in immunocompromised children (31). A combination of cytoxan (day 1) and methotrexate (day 10) is given for three cycles as soon as the absolute neutrophil count reaches 500 cells/mm3. Seven of nine patients achieved a complete remission, and no patient died during or as a result of chemotherapy.
In summary, there are many unsolved problems to be addressed regarding the epidemiology, etiology, diagnosis, and therapy of cancers occurring in HIV-infected children. Knowledge gained in studying these questions not only will benefit the affected children but also will further our understanding of oncogenesis and of the interactions between viral infections and the immune system, and shorter but still effective therapies might benefit the nonimmune compromised cancer patient as well.
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TopAbstractBackground and EpidemiologyNon-Hodgkin's LymphomaKaposi's SarcomaSmooth Muscle TumorsMiscellaneous TumorsPresent and Future ChallengesReferences |
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  E. Chiappini, L. Galli, P.-A. Tovo, C. Gabiano, C. Lisi, C. Giaquinto, O. Rampon, G. C. Gattinara, G. De Marco, P. Osimani, et al. Cancer Rates After Year 2000 Significantly Decrease in Children With Perinatal HIV Infection: A Study by the Italian Register for HIV Infection in Children J. Clin. Oncol., January 1, 2007; 25(1): 97 - 101. [Abstract] [Full Text] [PDF]
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