In this issue

Director's Corner by David G. Poplack, M.D.

New Therapies in Pediatric Cancer
by Stacey Berg, M.D.

Ependymoma: A Review
by Patricia Baxter, M.D. and Murali Chintagumpala, M.D.

HIV-Related Malignancies
by Parth Mehta, M.D. and Brigitta U. Mueller, M.D.

Nasopharyngeal Carcinoma
by Chrystal U. Louis, M.D., M.P.H., Helen E. Heslop, M.D. and
Stephen Gottschalk, M.D.
 

HIV-Related Malignancies by Parth Mehta, M.D. and Brigitta U. Mueller, M.D.
	Dr. Parth Mehta		Dr. Brigitta U. Mueller

Infection with the human immunodeficiency virus (HIV) is currently the greatest scourge of man worldwide. The World Health Organization (WHO) estimates that 39.5 million people were living with HIV infection worldwide in 2006.¹ The associated morbidities are numerous and among the extensive list are a variety of malignancies termed HIV-Related Malignancies or HRM. This article will cover the epidemiology of HRM in general and then proceed to delve deeper into the HRM that occur with some frequency in HIV-infected children. This will include a discussion of pathogenesis, clinical presentation, and an overview of their treatment.

Epidemiology
The 2006 WHO/UNAIDS Global Update reveals a staggering 650,000 new cases of HIV/AIDS in children worldwide with countries as small as Botswana having 32,000 children under the age of 15 years affected.² The incidence of malignancies in children with HIV infection has been estimated to range from 66 per 100,000 in the United States to as high as 418 per 100,000 in Italy per year.⁴ The CDC Surveillance Report of 1996 indicated that 2 percent of 7,629 children reported to the CDC with AIDS had cancer as the AIDS-defining illness.⁵ This is likely an underestimate of the real incidence as only the initial AIDS-defining illness is being reported. Putting this in perspective, the (underestimated) value of 2 percent of children having HRM translates to about 14,000 cases of HRM in children per year.

The incidence of HRM has declined in the West considerably with the advent of Highly Active Anti-Retroviral Therapy (HAART). For example, the incidence of Kaposi Sarcoma (KS) was estimated at 2500 per 100,000 in the years 1990 to 1995 in patients with a CD4 count of 0-94 cells/mm3, while the same incidence in the era of HAART for the same CD4 category is estimated at 500 per 100,000.⁶ This astounding drop in KS incidence is clearly a result of HAART, a treatment that is still relatively inaccessible to children in developing countries where the overwhelming majority of the world’s new cases are occurring.

The two most prevalent HRM are KS and Non-Hodgkin Lymphoma (NHL). Their incidence is dependent on CD4 counts. In the pre-HAART era in the US KS occurred in 2500 and NHL in 1500 per 100,000 for a CD4 category of 0-94 cells/mm3, decreasing to 500 cases per 100,000 each for CD4 counts over 500 cells/mm3.⁶ The other major HRM is cervical cancer (200 per 100,000 in the US).⁶ One interesting HRM that was first recognized in the mid-1990s is leiomyosarcoma (LMS).⁷

Over the last few years, a shift has occurred regarding the treatment of HRM. While previously considered to be a symptom of end-stage HIV infection with minimal or no chance for cure (due to concurrent organ compromise), it is now clear that many of these malignancies can be approached with a curative intent, as long as HIV infection can be controlled. Recovery of CD4 counts and a decrease in the viral load remain important primary goals in the treatment of a patient with an HRM.

To summarize, the incidence of HIV/AIDS infection worldwide remains staggering and therefore the incidence of HRM, while a small percentage of the total cases, will continue to rise and a proper understanding of these cancers, their pathogenesis, and therapy is essential.

Kaposi Sarcoma
Kaposi’s sarcoma was first described in 1872 by the Hungarian physician Moritz Kaposi as a disease of “multiple idiopathic pigmented hemangiosarcomas” affecting mainly men older than 40 years of age. In the era of HIV/AIDS, KS became the first AIDS-defining cancer, initially noted in men who have sex with men. In the US, it is the AIDS-defining illness in less than 1 percent of children under age 13 years, increasing to 3 percent in the adolescent years.[4] In areas where the prevalence of infection with HIV and human herpes virus 8 (HHV8, see below) is higher, these numbers are dramatically increased. In Zambia, for example, KS accounts for almost 20 percent of all childhood cancers!^8,9

Pathology and pathogenesis
Histologically KS is a proliferation of spindle cells surrounded by reticulin and collagen fibers with vascularization.³ The pathogenesis of KS has been linked to HHV-8,³ and has been shown to be present in children with KS as well.¹⁰ The pathogenesis of KS depends strongly on angiogenesis as Vascular Endothelial Growth Factor and its receptor Flt-1 have been demonstrated in AIDS KS lines.11 Cytokines are also involved in KS, specifically bFGF, IL-1, IL-6, and oncostatin M, all sustaining KS growth.¹²

Clinical Presentation
Kaposi’s sarcoma has been described in children as young as 6 months of age, although the median age of presentation is 33 months of age in children with vertically-acquired HIV-infection.¹³ Two major manifestations are described, the cutaneous form (Figure 1) and the lymphadenopathic form. Cutaneous lesions are purple or brown in color, plaque-like or nodular, often with edema secondary to venous congestion and can occur anywhere on the skin or oral mucosa (Figure 2). The lymphadenopathic form can involve any lymph node areas and is associated with rapid progression, especially when organ involvement occurs. Cutaneous lesions must be differentiated from bacillary angiomatosis, angiosarcoma, and hemangiomas.³ A skin biopsy is recommended, especially where there is any uncertainty. A fine-needle aspiration or biopsy is always indicated to evaluate lymph node involvement as patients with HIV infection have a greater risk of co-infection with Mycobacterium tuberculae (Mtb) and lymph node involvement may actually represent extra-pulmonary TB!

Treatment
The rate of remission in KS has dramatically improved with the advent of HAART. In the pre-HAART era, 5-year survival was 25 percent where in the HAART era this has increased to 75 percent.14 Local therapy for isolated or minimal cutaneous lesions is often successful when employing excision, cryotherapy, or intralesional vincristine sulfate.³ Systemic therapy is indicated for extensive cutaneous involvement and lymphadenopathic KS. Response rates of 40 percent to 80 percent have been demonstrated with liposomal doxorubicin at 20 mg/m2 every 2 or 3 weeks for six cycles.15 One older study compared dactinomycin + vincristine vs. both plus imidazole carboxamide (DTIC) and demonstrated 94 percent CR with DTIC compared to 55 percent CR without it.¹⁶ Various other agents including paclitaxel and liposomal All-Trans Retinoic Acid have been attempted without much success. However, experimental therapy with angiogenesis-inhibitors is being explored and is expected to be promising given what is known about the pathogenesis of KS.

Lymphomas
The spectrum of HIV lymphoid malignancies spans lymphoproliferative disease (LPD) like lymphoid interstitial pneumonitis (LIP) to high-grade NHL and CNS lymphoma as well as Hodgkin’s disease. NHL is the most common HRM ^17,18 and usually presents as an extra-nodal high-grade B cell lymphoma, although T cell malignancies can be seen as well. One study from Malawi demonstrated that over 50 percent of cancers in children with HIV infection were lymphomas.¹⁹

Pathology and pathogenesis
Large-cell lymphomas (LCL) are more frequent in children with HIV infection: 43 percent of NHL is of large cell histology in HIV+ children compared to 20 percent in the general pediatric population.⁷

Rare instances of clonal cell lines with HIV expression have been reported, but the consensus is that HIV is not directly responsible for the transformation of B cells.²⁰ However, Epstein-Barr virus (EBV) is implicated in HIV NHL and LPD, and mutations in the EBV protein LMP-1 are thought to play a role in the pathogenesis.21 Furthermore, cytokine release secondary to HIV infection is the likely mechanism of lymphoma development as prolonged cytokine exposure results in lymphoid proliferation with eventual chromosomal aberrations leading to frank malignancy. Cytokines implicated include IL-6, IL-10, interferon- and TNF among others.^22,23

Clinical Presentation
The presentation of HIV-associated NHL and LPD is as varied as those in non-HIV-infected patients. Extra-nodal involvement is frequent and includes the GI tract, liver, lungs, CNS, and bone and bone marrow.^24-26 Signs and symptoms of disease are related to the underlying organ involved and can include dyspnea, pleuritic pain and cough for the respiratory tract, or abdominal pain, jaundice and hepatomegaly for liver involvement. Systemic (B) symptoms of fever, night sweats, and weight loss are common and can make differentiation of lymphoma from TB or symptomatic HIV disease difficult.

Treatment
The therapies used in HIV NHL in children have been varied including CHOP regimens, BACOD, and ABVD or some combination in small case series. The results were poor with median survival of 6 months. The experience in adults in the pre-HAART era has been equally disappointing.^27-30 However, metanalyses of these various regimens revealed cyclophosphamide and methotrexate to be most active, while the escalation of dosing of doxorubicin, prednisone, and vincristine were insignificant.^31-34

Conventional therapy for NHL still consists of a CHOP-like regimen, however, the experience above has led to the use cyclophosphamide and methotrexate at high dose rates with successful treatment of children along with well-tolerated toxicity (NCI protocol).


Leiomyosarcoma
Leiomyosarcoma (LMS) is a unique HRM as it is otherwise exceedingly rare in the pediatric population. One case series from the National Cancer Institute reported LMS as the second most common HRM representing 17 percent of patients.⁷ Interestingly, the presence of EBV has been demonstrated in these tumors, and EBV has been isolated in high titers from LMS in pediatric patients with HIV infection.³⁵

Clinically, these tumors often present within the GI tract, although they can be found anywhere in the body from lungs, spleen, and even intracranially.^7,36 The disease course is variable, depending on the rapidity of tumor growth. Surgery remains the preferred treatment, as LMS, like many sarcomas, are not very responsive to radiation or chemotherapy. However, when chemotherapy is required for aggressive metastatic disease, the standard regimen employed is VAC (vincristine, actinomycin, cyclophosphamide) often alternating with VAdriaC (adriamycin in place of actinomycin). Ifosfamide and etoposide can be used as another alternating regimen. The course of therapy is generally 6 months to 1 year.

Cervical Cancer
Cervical cancer is the second most common cancer in women worldwide and the risk for HIV+ women is nine times greater than for HIV- women. The CDC classification denotes cervical dysplasia and carcinoma in situ as category B symptoms. Interestingly, the incidence of cervical cancer is completely unrelated to the CD4 count.⁶ This is likely due to the high incidence of cervical cancer in general, although a trend towards an increase with lower CD4 count would still be expected.

The pathogenesis of cervical cancer is linked to human papillomavirus, HPV, which is isolated from the overwhelming majority of cervical cancer cases tested. Types 16 and 18 are responsible for about two-thirds of cases. Of interest, a new vaccine is available to cover these serotypes, which ought to decrease the incidence of cervical cancer.³⁷ However, it is possible the serotype distribution may shift with more cases being caused by alternate HPV types.

The mainstay of care for cervical cancer is screening and prevention using the Papanicolaou (Pap) smear to allow for early detection of cervical cancer and hence more effective therapy. Given the increased risk of cervical cancer in HIV+ women, it is recommended that a Pap smear be performed biannually rather than annually for the first year after HIV diagnosis and then yearly if two initial smears are negative. (US Public Health Svc)

Treatment of lesions is dependent on the extent of disease where dysplasia and in situ lesions can often be treated with local therapy. Any abnormal Pap smear should be followed by colposcopy examination of the cervix, vagina, and vulva to assess the extent of disease and to screen for other genital tract dysplasias for which HIV+ women are at increased risk. Persistent low-grade lesions and all high-grade lesions should be treated with excision by laser or electrosurgical cautery (LOOP) or ablation with laser or cryotherapy.^38-40

Anal Cancer
Anal cancer is uncommon, however the incidence is increasing in the population at risk, particularly those infected with HPV and HIV. The NCI estimated 4,000 cases of anal cancer in 2004.⁴¹ The incidence is 35 times greater in men who are receptive for anal intercourse as compared to the general population in the United States. It is not limited to men, however, and women who practice anoreceptive intercourse as a means to maintain virginity, for example, are also considered to be at high risk. About 85 percent of patients with anal cancer were found to have HPV infection as well.⁴² The association between AIDS and anal cancer is strong, although it is currently not categorized as an AIDS-defining illness. Individuals tend to have persistent HPV infection and high viral loads, contributing to the development of cancer.⁴³

The pathogenesis of anal cancer is felt to be equivalent to that of cervical cancer where HIV likely interacts and affects the oncogenicity of HPV leading to malignant change.

The therapy of anal cancer is combined-modality treatment with chemotherapy and radiation. The majority of patients will have clinical regression. Peddada, et al demonstrated that 100 percent of HIV+ patients achieved complete remission with radiation (30 Gy in 15 fractions) along with 5-fluorouracil (1g/m2 on days 1-4 & 29-32) and mitomycin (10 mg/m2 bolus) on day 1.⁴⁴

Summary
The most common HRM are KS and NHL, however, cervical cancer and anal cancer represent two common and pathogenetically related cancers in special populations. The management of these cancers requires optimization of anti-retroviral therapy along with chemotherapy. The immunosuppression of HIV infection and chemotherapy can be difficult to manage and requires close monitoring to ensure a successful outcome.

About the Authors
Parth S. Mehta, M.D., is an instructor of Pediatrics at Baylor College of Medicine and completed fellowship at the Texas Children’s Cancer Center in June 2006. He is also currently a Pediatric AIDS Corp doctor with Baylor International Pediatric AIDS Initiative (BIPAI) in Botswana where he is caring for children with HIV and HIV-related hematological problems and malignancies.
Dr. Mehta’s research interests are in the areas of international oncology, rural hematology and oncology, and HIV-related hematological and oncological problems, as well as the molecular biology of neuroblastoma. He is currently the pediatric hematologist/oncologist for the country of Botswana and the BIPAI network that is active in seven countries in Africa.

Brigitta U. Mueller, M.D., M.H.C.M., is a professor of Pediatrics at Baylor College of Medicine and serves as Director of the Division of Clinical Operations at the Texas Children’s Cancer Center and Director of the Texas Children’s Sickle Cell Center (TCSCC).
Dr. Mueller’s research interests are in the study of the pathogenesis and treatment of sickle cell disease, vascular tumors and HIV-related malignancies. Dr. Mueller is also actively involved in making hospitals and clinics a safe environment for patients and staff and is serving as the Chief Safety Officer for the Cancer Center.

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