INTRODUCTION
Patients infected with human immunodeficiency virus (HIV) are at significantly increased risk of developing a malignancy compared with the general population. HIV contributes to the development of cancer through immunosuppression promoting the tumorigenic effects of coinfecting oncogenic viruses. HIV infection also induces immune dysregulation causing chronic B-cell stimulation and cytokine activation that contributes to the initiation of malignancies. AIDS-defining malignancies include Kaposi sarcoma (KS), primary central nervous system lymphoma (PCNSL), non-Hodgkin lymphoma (NHL), and invasive cervical cancer. In addition, patients with HIV infection are also at increased risk of developing certain non-AIDS-defining malignancies.1 Introduction of highly active antiretroviral therapy (HAART) has resulted in a significant change in the epidemiological and clinical profile of cancers in HIV-infected patients by decreasing the mortality associated with opportunistic infections and by improving the longevity of the patients. Although a significant decrease has been reported in certain AIDS-defining malignancies, such as KS, in the developed world, as patients live longer with chronic HIV infection, malignancy is becoming an important cause of morbidity and mortality.2 Immune reconstitution following HAART and advances in chemotherapy and supportive care has resulted in improved outcomes of cancers in HIV infected patients compared to the pre-HAART era.3
KAPOSI SARCOMA
GENERAL PRINCIPLES
Epidemiology
KS is the most common HIV-related malignancy. The incidence of KS is approximately 15 times greater in men than in women. It is most common in homosexual or bisexual men. Since the introduction of HAART, the incidence of KS has declined markedly in HIV-infected patients. The standardized incidence ratio for KS compared to the general population fell from 22,100 to 3640. However, KS continues to be a problem of epidemic proportion in the parts of the world where HIV remains untreated.
Pathophysiology
KS-associated herpes virus, human herpes virus 8 (HHV-8), infection is found in all forms of KS. HHV-8 infection is transmitted by sexual contact, but it is also found in the saliva of infected patients. KS lesions are histologically characterized by neoangiogenesis and proliferating spindle-shaped cells admixed with an inflammatory infiltrate of lymphocytes, plasma cells, and macrophages. The malignant spindle-shaped cells are thought to be derived from HHV-8 infected circulating endothelial precursors. HHV-8 and HIV infection act synergistically to produce cytokines, growth factors, anti-apoptotic signals, and angiogenic factors, which stimulate KS spindle cell growth and create an environment necessary to develop and sustain the tumor.4
DIAGNOSIS
Clinical Presentation
The clinical presentation of KS varies from minimal to fulminant disease. AIDS-related KS is generally an aggressive cancer resulting in serious morbidity and mortality. Although no organ is spared from involvement with KS, the most commonly involved sites are skin, mucous membranes, lymph nodes, gastrointestinal tract, and lungs.
The cutaneous lesions are typically multifocal, plaque like or papular, and pinkish to violaceous in color, although they may evolve into nodules and ultimately ulcerate.
Lymph node involvement can cause lymphedema. Internal disease can present with vague symptoms and can occur in the absence of mucocutaneous manifestations.
Gastrointestinal involvement can cause abdominal pain or bleeding.
Pulmonary involvement by KS may cause interstitial infiltrates or hemorrhagic effusions, resulting in cough and/or dyspnea.
Diagnostic Testing
Diagnosis is established by biopsy of lesions; bronchoscopy or esophagoduodenoscopy may be necessary for internal involvement. Serology for anti-HHV-8 antibodies is not central to the diagnosis.
TREATMENT
It is important to note that KS is not considered a curable malignancy. The treatment decisions are based on the presence and extent of symptomatic and extracutaneous manifestations.
Optimization of HAART therapy is the first line of therapy.
Local therapy is used for bulky lesions or for cosmesis. Therapeutic options for local treatment include topical alitretinoin, intralesional chemotherapy with vinblastine, radiation therapy, laser therapy, and cryotherapy.
Individuals with more advanced or progressive disease are treated with systemic chemotherapy. First-line chemotherapeutic drugs are liposomal anthracyclines such as doxorubicin and daunorubicin. Paclitaxel is a second-line agent. High-dose interferon-alpha therapy can be used for patients following immune reconstitution, but it is associated with significant side effects. Targeted therapy including VEGF inhibitors, KIT and PDGFR inhibitors, and mTOR inhibitors are being investigated in clinical trials.
PROGNOSIS
The AIDS Clinical Trials Group classifies patients with AIDS-related KS into good- and poor-risk groups based on tumor burden, CD4 counts, and the presence of systemic illness. However, in the post-HAART era, the CD4 count is less important.5 Advanced age and associated AIDS-defining illnesses also affect the outcome of patients with KS.
HUMAN IMMUNODEFICIENCY VIRUS–RELATED LYMPHOMAS
GENERAL PRINCIPLES
Epidemiology
HIV-associated lymphomas constitute the second most common type of malignancy encountered in patients with HIV infection. Systemic NHL is the most common type, although the greatest increase in risk over the general population seems to be with primary central nervous system lymphoma (PCNSL). Approximately 10% HIV patients develop NHL. It appears to be more common in males than in females. Introduction of HAART significantly decreases the incidence of a subset of NHL, such as immunoblastic lymphoma and PCNSL.6
Pathophysiology
Various pathogenic mechanisms are attributed to development of lymphoma in HIV, including HIV-induced immunosuppression, chronic antigenic stimulation, genetic abnormalities, cytokine dysregulation, dendritic cell impairment, and viral infections associated with Epstein–Barr virus (EBV) and HHV-8.7
NON-HODGKIN LYMPHOMA
GENERAL PRINCIPLES
HIV-related NHLs are a heterogeneous group of tumors. More than 95% of the tumors are derived from B cells. Notable differences between HIV-related lymphoma and NHL in the general population include propensity for advanced disease, presence of B symptoms, extranodal disease including bone marrow involvement, leptomeningeal disease, and disease in unusual locations.
Diffuse large B-cell lymphoma (DLBCL) is the most common HIV-related lymphoma. It is divided into centroblastic and immunoblastic types. The immunoblastic type is more characteristic of HIV infection and is more frequently associated with EBV infection (90%) compared to the centroblastic type (30%). Overexpression of Bcl-6, a proto-oncogene product, is usually associated with centroblastic and not immunoblastic DLBCL.
Burkitt lymphoma accounts for 30% of HIV-related lymphoma. Thirty to forty percent of HIV-related Burkitt lymphomas in Western countries are associated with EBV infection, and c-MYC activation is involved in all cases.
PCNSL represents a distinct extranodal presentation of DLBCL in HIV infection. It is usually of the immunoblastic type and is associated with severe immunosuppression (CD4 count <50) and universal EBV infection. Its involvement is usually confined to the craniospinal axis, without any systemic involvement. Its prognosis is extremely poor.
Primary effusion lymphoma represents <5% of HIV-related lymphomas. It is associated with HHV-8 infection and frequent coinfection with EBV. It is an aggressive tumor and morphologically varies from the immunoblastic to the anaplastic type. It is of B cell origin but does not express B cell antigens.
Plasmablastic lymphoma is a subtype that typically involves the oral cavity and jaw. It is highly associated with EBV infection and lacks HHV-8 infection. The tumor consists of large plasmablast cells with the morphological features of immunoblasts, but the immunophenotypic features of plasma cells.
DIAGNOSIS
Since many other HIV-associated diseases, including various infections, can mimic the clinical and imaging features of lymphoma, biopsy is typically needed for diagnosis. The staging workup includes CT of the chest, abdomen, and pelvis and bone marrow evaluation. Because CNS involvement is common, MRI of the brain and lumbar puncture for cerebrospinal fluid (CSF) analysis should be considered for all patients with HIV-related lymphoma.
The workup of a brain mass requires special consideration. CNS imaging cannot reliably differentiate between CNS lymphoma and toxoplasmosis. A solitary lesion is more likely to be lymphoma. If brain biopsy is hazardous, PCR for CSF EBV DNA is 80% sensitive and almost 100% specific for PCNSL and, hence, could substitute for a diagnostic biopsy.
TREATMENT
With the use of HAART and anticipated immune restoration, standard-dose chemotherapy is the standard of care in patients with HIV-related NHL. Concurrent HAART and chemotherapy regimens CHOP (cyclophosphamide, vincristine, doxorubicin, and prednisone) or CDE (cyclophosphamide, doxorubicin, and etoposide), or dose-adjusted EPOCH (etoposide, prednisone, doxorubicin, cyclophosphamide, and vincristine) without highly active antiretroviral therapy (HARRT) have proven to be effective and tolerable.
If HAART is used with chemotherapy, zidovudine should be avoided due to an increased risk of myelosuppression. Also, caution should be exercised with didanosine, stavudine, and zalcitabine, which may potentiate vincristine-induced neuropathy.
The role of rituximab in AIDS-related lymphoma remains unclear. Rituximab should not be given to DLBCL patients with CD4 <50 due to high risk of infection.
Prophylactic intrathecal methotrexate may be delivered at the time of initial CSF analysis to reduce the risk of leptomeningeal disease, particularly in patients with Burkitt lymphoma, Burkitt-like lymphoma histology, bone marrow, paranasal or paraspinal involvement, or EBV virus coinfection.
PCNSL is treated with high-dose methotrexate chemotherapy and/or whole-brain irradiation.
Select patients with relapsed or refractory lymphoma can be considered for high-dose chemotherapy with stem cell support.
PROGNOSIS
Poor prognostic factors include low CD4 counts (<100), elevated lactate dehydrogenase, poor performance status, presence of extranodal disease, prior AIDS-defining illness, advanced stage, and aggressive histology of lymphoma.
HODGKIN LYMPHOMA
Clinical features of HIV-associated Hodgkin lymphoma include a high frequency of B symptoms, advanced-stage disease, a higher incidence of bone marrow involvement, and universal EBV coinfection. Histological subtypes most often seen are mixed cellularity and lymphocyte depleted. Although chemotherapy outcomes are improving in the post-HAART era, the prognosis is significantly worse than that for HIV-negative patients. Timing of HAART therapy again remains inconclusive. Chemotherapy regimens that have been studied include ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), and the Stanford V regimen (doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, prednisone), and involved field radiation for initial bulky disease.
CERVICAL CANCER
HIV infection is a strong risk factor for cervical cancer independent of the usual demographic and behavioral risk factors for cervical cancer. HIV-positive women have significantly increased rates of cervical intraepithelial neoplasia compared to HIV-negative individuals, and the incidence of cervical intraepithelial neoplasia increases with the severity of immunosuppression. However, there has been no convincing evidence to show increased invasive cervical neoplasm in HIV-infected individuals compared to HIV-negative women. HIV-positive patients are more likely to be infected with the oncogenic human papilloma virus (HPV) strains 16, 18, and 31 and, also, with multiple HPV subtypes compared to HIV-negative individuals. HPV infection is more persistent in HIV-positive patients and correlates with the severity of immunosuppression.8
The Centers for Disease Control recommends two Pap smears at a 6-month interval for any woman newly diagnosed with HIV. If both are negative, a Pap smear should be repeated annually.
HIV-positive patients with cervical cancer have more intractable disease and have a higher relapse rate compared to the HIV-negative group. Restoring immune function with HAART may improve the treatment outcome.
OTHER CANCERS
In large database studies of linked HIV and cancer registries, several other cancers have been shown to be increased in incidence compared to that in the general population: invasive anal carcinoma (an HPV-associated illness), multiple myeloma, leukemia, lung cancer, and malignancies of the oral cavity, lip, esophagus, stomach, liver, pancreas, larynx, heart, vulva, vagina, kidney, and soft tissues. Multiple myeloma in HIV-infected individuals occurs at a younger age and has a more aggressive clinical picture. The most common epithelial neoplasms seen in the general population—breast cancer, colon cancer, and prostate cancer—do not appear to occur more frequently in HIV-infected patients. In contrast to the adult malignancies, the clinical pathology and optimal therapy of AIDS-related malignancies in children are unclear.
REFERENCES
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