Ronald T. Mitsuyasu
I. INTRODUCTION. Despite great advances in the treatment and survival of individuals infected with the human immunodeficiency virus (HIV), cancer is now one of the leading causes of death in patients with AIDS. In the era of highly active antiretroviral therapy (HAART), patients infected with HIV are living longer than ever, and HAART has greatly reduced the incidence of most of the AIDS-defining cancers, including Kaposi sarcoma (KS), non-Hodgkin lymphoma (including primary central nervous system lymphoma), and invasive cervical carcinoma. Unfortunately, the incidence of other, non–AIDS-defining cancers has increased significantly, and the management of patients who develop malignancies in the setting of HIV remains very challenging.
II. AIDS-RELATED LYMPHOMA
A. Incidence
1. Non-Hodgkin lymphoma (NHL) remains one of the most common AIDS-defining conditions, occurring in approximately 16% of all new cases of AIDS. All age groups and all groups at risk for acquisition of HIV infection are equally likely to develop lymphoma.
2. The incidence of NHL generally tracks with the progressive loss of CD4 lymphocytes. With widespread use of HAART in various areas of the world, resulting in population-wide increases in CD4 cells, the incidence of lymphoma has declined. In this setting, the risk for lymphoma depends on the latest CD4 cell count and not the nadir count.
3. Although the risk of lymphoma has decreased significantly in patients treated with HAART, this decrease in lymphoma has been far less than that seen in KS or the various opportunistic infections, resulting in a relative increase in the occurrence of lymphoma as an initial AIDS-defining illness.
B. Pathology. Most AIDS-related lymphomas are B-cell tumors of high-grade pathologic type. About 60% of patients are diagnosed with immunoblastic lymphoma, plasmablastic or small noncleaved lymphoma; the latter may be Burkitt or Burkitt-like subtypes. In contrast, only 10% to 15% of patients generally with non–HIV-associated lymphoma are diagnosed with one of these more unusual forms of lymphoma. Intermediate-grade, diffuse, large B-cell lymphomas have been reported in 30% to 40%.
Aggressive B-cell lymphomas are expected, but HIV-infected patients also have an increased incidence of low-grade B-cell lymphoma and of various T-cell lymphomas, as well, although they are much less common.
Primary effusion lymphoma (PEL) has also been identified among HIV-infected patients who are also infected with human herpesvirus-8 (HHV-8). PEL is a B-cell neoplasm with the morphologic appearance of an anaplastic or immunoblastic lymphoma. Patients present with malignant serous effusions, usually in the absence of specific mass lesions. Median survival time is in the range of 6 months.
C. Clinical features
1. About 80% of patients with newly diagnosed AIDS-related lymphoma present with systemic B symptoms, consisting of fever, drenching night sweats, and/or weight loss.
2. About 60% to 90% of patients have advanced-stage disease, often presenting in extranodal sites. This occurrence is in sharp distinction to the general lymphoma population, of whom approximately 40% present with extranodal disease.
a. The more common sites of initial extranodal disease include the central nervous system (CNS; about 30% prevalence at diagnosis), gastrointestinal (GI) tract (25%), bone marrow (20% to 33%), and liver (10%).
b. Any anatomic site may be involved, with lymphoma reported in the myocardium, earlobe, gallbladder, rectum, gingiva, and elsewhere.
D. Diagnosis and staging evaluation
1. Biopsy. Immunophenotypic or genotypic studies are often helpful to confirm the monoclonal nature and the histologic subtype of the tumor.
2. Computed axial tomography (CAT) scans. Staging evaluation should begin with CAT scans of the chest, abdomen, and pelvis. Nearly two-thirds of patients with AIDS-related lymphoma have evidence of intra-abdominal lymphomatous disease, which most commonly involves the lymph nodes, GI tract, liver, kidney, and/or adrenal gland. Isolated hepatic or splenic enlargement is not usually seen in the absence of other intra-abdominal findings.
3. Positron emission tomography (PET) scanning is now commonly used in conjunction with CAT scans and can detect more minimal disease activity and may be used posttreatment to differentiate residual active lymphoma from scar and fibrosis. Caution should be taken in the interpretation of PET scans, however, as sites of infection or inflammation, common in the setting of HIV infection, may also yield positive PET scan findings.
4. Bone marrow aspiration and biopsy should be performed.
5. Lumbar puncture (LP). LP should be performed routinely as part of the staging evaluation of patients with AIDS-related lymphoma. About 20% of HIV-infected patients are found to have leptomeningeal involvement even without CNS symptoms. Because prophylactic intrathecal chemotherapy has become an integral part of initial therapy, it is now common practice to inject the first dose of methotrexate or cytosine arabinoside at the time of this initial staging LP in an attempt to prevent isolated CNS relapse. In the presence of active cerebrospinal fluid (CSF) involvement by lymphoma, abnormalities may be relatively minor, with median white cell count of often <10 cells/mL although elevated protein and decreased CSF glucose levels are very often present. Abnormal lymphoma cells are generally clearly recognizable upon cytologic, flow cytometric, or cytogenetic evaluation in those with active disease.
E. Prognostic factors
1. Decreased survival in AIDS-related lymphoma is associated with the following factors:
a. CD4 cells <100/μL
b. Karnofsky performance status <70%
c. Age >35 years
d. Stage IV, especially those with leptomeningeal disease
e. Elevated lactate dehydrogenase in serum
f. Higher IPI scores (2 to 3)
h. Certain subsets of lymphoma (e.g., primary CNS lymphoma, PEL) and perhaps subtypes of DLBCL (e.g., activated B-cell phenotype))
F. Management
1. Use of full-dose chemotherapy regimens. Before the availability of HAART, use of low-dose modifications of standard regimens (such as m-BACOD or CHOP) was advocated because prospective clinical trials indicated that standard-dose regimens were associated with significantly increased toxicity. In the era of HAART, these recommendations are no longer valid.
Studies using full-dose regimens, generally in conjunction with HAART, have shown better outcomes with full-dose and more dose-intensive regimens and with the combined use of rituximab. While responses and progression-free survival were improved with rituximab, especially when used concurrently with the EPOCH regimen, concerns about poorer outcomes due to infectious deaths have resulted in recommendations for greater use of prophylactic antibiotics and hematopoietic growth factors in this population, especially with CD4 < 100 cells/mm3.
2. Antiretroviral therapy may be used simultaneously with multiagent chemotherapy or may be discontinued during chemotherapy administration and then restarted immediately. If used simultaneously with chemotherapy, zidovudine (AZT) should not be incorporated into the antiretroviral regimen because this drug is myelosuppressive. With this exception, however, pharmacokinetic studies have indicated no clinically significant interactions between HAART (including protease inhibitors) and multiagent antilymphoma chemotherapy. Accepted practice now includes the combined use of chemotherapy with HAART, except in the immediate posttransplant setting.
3. Infusional chemotherapy: (R)-EPOCH. A dose-adjusted EPOCH regimen has been used with excellent results. Three of the five drugs are given by continuous IV infusion (CIV). Cycles are repeated every 21 days for a total of six cycles. The specific dose-adjusted regimen for patients with AIDS is as follows:
Rituximab, 375 mg/m2 IV on day 1 (in the R-EPOCH study)
Etoposide, 50 mg/m2/d on days 1 through 4 by CIV
Doxorubicin (Adriamycin), 10 mg/m2/d on days 1 through 4 by CIV
Oncovin (vincristine), 0.4 mg/m2/d on days 1 through 4 by CIV (with no maximum dose)
Prednisone, 60 mg/m2/d PO on days 1 through 5
Cyclophosphamide IV on day 5; 375 mg/m2 if CD4 ≥ 100; 187 mg/m2 if CD4 < 100
a. On subsequent cycles, if the nadir absolute neutrophil count (ANC) was >500 cells/μL, the dose of cyclophosphamide was adjusted in increments of 187 mg/m2 to a maximum dose of 750 mg/m2 IV.
b. Granulocyte colony-stimulating factor was given at a dose of 5 μg/kg/d subcutaneously from day 6 until the ANC was >5,000 cells/μL after the nadir.
c. Intrathecal methotrexate was given at a dose of 12 mg on days 1 and 5 for a minimum of 4 doses prophylactically or until CSF clear of malignant cells in those with active disease.
d. Prophylaxis for Pneumocystis pneumonia was mandated, and prophylaxis against Mycobacterium avium was given to patients with CD4 cells <100/μL.
e. Antiretroviral therapy could be suspended or continued during EPOCH chemotherapy and was reinstituted immediately at the conclusion of the 5-day therapy if held. (Most subjects in the AMC 034 R-EPOCH study remained on HAART during chemotherapy with no increase in toxicities.)
f. Results of EPOCH in AIDS-related lymphoma
(1) In the initial NCI trial, the overall complete remission rate was 74%, including 56% of patients with CD4 cells <100/μL and 87% of patients with CD4 cells >100/μL. With a median follow-up of 56 months, there were only two relapses, and the disease-free survival was 92%. Overall survival at 56 months was 60%, whereas the overall survival of patients with CD4 cells >100/μL at entry was 87%.
(2) In a subsequent randomized, multi-institutional AMC study of concurrent versus sequential R-EPOCH in AIDS-NHL, patients received the same dose-adjusted NCI EPOCH regimen with rituximab administered either concurrently on day 1 of each cycle or weekly for 6 weeks after completing EPOCH therapy. Response rate and 1-year disease-free survival were better in the concurrently treated group (RR: 82% vs. 75% and DFS: 78% vs. 68%). Most patients on study received HAART concurrently along with prophylactic antibiotics and G-CSF with very few infectious complications.
G. Primary CNS lymphoma (PCNSL; see also Chapter 21, Section VIII.C in “Non-Hodgkin lymphoma”)
1. Clinical features. Patients with PCNSL present with far-advanced HIV disease, with median CD4 cells of <50/μL and/or a history of AIDS before the lymphoma. Initial symptoms and signs include seizures, headache, or focal neurologic dysfunction. Isolated subtle changes in personality or behavior may also be seen.
2. Diagnosis. Radiographic scanning reveals mass lesions in the brain, occurring at any site. These masses are likely to be relatively large (2 to 4 cm) and relatively few in number (one to three). Ring enhancement may be seen. No specific radiographic findings on CT scans are characteristic of PCNSL. PET scans or thallium single-photon emission computed tomography (SPECT) scans may provide more specific information in terms of the differentiation of PCNSL from other space-occupying lesions within the brain of HIV-infected patients. Further, because AIDS-related PCNSL is essentially always associated with infection by EBV, determination of latent EBV proteins within the CSF may also be used to diagnose PCNSL. In the case of equivocal results and for definitive diagnosis, brain biopsy is required.
3. Management. Radiation therapy (RT) is associated with complete remission in 20% to 50% of cases, but the median survival time is generally only 2 to 3 months. Although RT may not improve the duration of survival, the quality of life does improve, often dramatically. Use of HAART with antineoplastic therapy has been shown to improve survival. High-dose methotrexate with leucovorin rescue is recommended for the treatment of patients with PCNSL without AIDS and has been used effectively in PCNSL with AIDS.
III. HODGKIN LYMPHOMA
A. Incidence. Hodgkin lymphoma (HL) is not an AIDS-defining condition, although the incidence of HL has increased significantly in HIV-infected patients in recent years. All groups at risk for HIV infection appear equally at risk for HL.
The incidence of HL has increased substantially in the post-HAART era. This is likely due to the fact that the Reed-Sternberg cell (RS), the malignant cell of HL, requires the presence of CD4+ lymphocytes, which provide proliferation and survival signals to the malignant RS cells. With the use of HAART and its associated increased CD4+ lymphocyte counts, HL is now seen with increasing frequency.
B. Biology. An association of HL with EBV has been suggested for years based on epidemiologic data in HIV? patients where approximately half of these patients have presence of clonally integrated EBV within the Reed-Sternberg cells. In the setting of HIV infection, EBV is almost universally present within the malignant RS cells.
C. Clinical features. Patients with underlying HIV infection have different clinical and pathologic manifestations of HL than those expected in patients without HIV disease.
1. Sites of disease. Most HIV-infected patients with HL have widespread extra-nodal disease at diagnosis, with about 80% to 90% presenting with stage III or IV disease. Systemic B symptoms are seen in about 80% to 90% of patients.
Unusual extranodal sites of disease may be seen, including the anus, rectum, and CNS. Bone marrow is involved in approximately 50% to 60% at diagnosis and may be the only site of disease in patients with B symptoms, usually in the setting of peripheral cytopenias.
2. Pathology. Mixed cellularity and lymphocyte depletion subtypes of HL are prominent. Nodular sclerosis and lymphocyte predominant subtypes also occur in the setting of HIV infection.
D. Management. The ABVD regimen (see Appendix D-1) is used most frequently, along with hematopoietic growth factors. The BEACOPP regimen (Appendix D-1), when used with concomitant HAART, has been associated with improvements in response rate and overall survival. Whether this improvement is due to the addition of HAART or to that specific regimen is not known, although HAART is probably the most important factor. The median survival after definitive therapy is about 1 to 2 years in the absence of HAART, as opposed to 80% to 90% 2-year survival of HIV-uninfected patients with HL and those on HAART. An intergroup study of HAART with ABVD with a randomization to continue therapy or intensify to BEACOPP in individuals with persistent disease after two cycles of therapy is currently being conducted in HIV+ and HIV- patients with HL.
IV. KAPOSI SARCOMA
A. Incidence and epidemiology. AIDS-related KS is seen in all HIV risk groups worldwide, with most cases in the United States being in gay or bisexual men. With the advent of effective antiretroviral therapy (HAART), the incidence of KS has fallen dramatically in the United States and other resource-rich countries. This dramatic change in the incidence of disease, coincident with the marked decrease in HIV viral load and improvement in immune function associated with HAART, serves to emphasize the crucial role of immunity in the development and control of KS.
B. Pathogenesis: human herpesvirus-8 (HHV-8)
1. HHV-8 is directly associated with all types of KS, including that associated with HIV, with organ transplantation, and with the classic KS seen in elderly men of Mediterranean descent. HHV-8 infection is a necessary requirement for KS development.
2. The specific mechanisms of HHV-8 transmission are not yet fully understood, although the virus is found at highest titer and greatest frequency in saliva. The salivary transmission of HHV-8 infection would be consistent with the primary mode of transmission of other human herpesviruses, such as EBV.
3. HHV-8 infection is clearly required for development of KS, although the virus itself may not be sufficient for KS to emerge. About 2% to 10% of normal, healthy people in the United States have evidence of antibody to HHV-8, without clinical illness.
4. HHV-8 infection of vascular endothelial cells may result in a change to spindle-cell morphology, with most cells latently infected. A few lytically infected cells within the endothelium express certain genes that have transforming potential, leading to a proliferating angiogenic KS lesion.
C. Pathogenesis: inflammatory cytokines and angiogenic factors. HIV infection induces an inflammatory cytokine response, with secretion of interleukin-6 (IL-6), IL-1, tumor necrosis factor-α, and others. These cytokines serve as growth factors for endothelial cells infected with HHV-8 and may also be operative in changing the morphology of these cells to the typical spindle cell, which characterizes the KS lesion. Further, secretion of angiogenic factors, such as basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and others, by HIV-1–infected mononuclear cells serves to induce the prominent proliferation of vascular tissue that characterizes the KS lesion. HHV-8 itself has genes that encode a viral IL-6 and other proteins that further contribute to the growth and dissemination of the tumor.
D. Clinical features
1. Natural history of disease. Some patients experience slowly progressive disease over many years, whereas others have fulminant, rapidly advancing KS that quickly leads to death.
2. Sites of involvement. The patient with KS usually presents with disease on the skin that may consist of nodular or irregular hyperpigmented lesions. The lesions are generally asymptomatic. Lymphedema may occur and can be profound, occasionally even in the absence of visible skin lesions. Lymphadenopathy, sometimes in the absence of KS lesions on the skin, is also sometimes seen.
Another common site of involvement is the oral cavity, which is sometimes associated with the presence of KS in the lower GI tract. Literally, any visceral organ may be involved, although CNS involvement is rare. KS in the lung is associated with a poor prognosis and has a higher mortality rate and usually mandates immediate chemotherapy.
E. Diagnosis and staging evaluation. An initial biopsy with pathologic confirmation should be obtained. The detection of HHV-8 genes in the tumor assists in the diagnosis. Routine staging is not necessary in the patient with KS. Assessment of visible disease on the skin and oral cavity, a baseline chest radiograph, and determination of the number of CD4 cells in blood should be performed. If the patient has symptoms suggestive of GI involvement (e.g., abdominal pain, weight loss, or diarrhea), endoscopy should be performed. With unexplained abnormalities on chest radiograph, bronchoscopy should be performed; the diagnosis of KS is usually made by visualization rather than biopsy due to the submucosal or parenchymal location of most pulmonary tumors.
F. Prognostic factors. Factors associated with poor prognosis include (1) history or presence of opportunistic infection; (2) presence of systemic B symptoms, consisting of fever, drenching night sweats, or weight loss in excess of 10% of the normal body weight; and (3) CD4 cells <200/μL.
G. Management
1. HAART. Multiple case reports and small series have documented significant regression of KS after HAART therapy alone. The initial treatment of patients with KS should be an effective antiretroviral regimen alone. In patients who have never taken HAART before, the overall response rate of KS to HAART alone is approximately 60% after 6 months of use (with complete remission in 11%) and increases to a 75% response rate at 24 months, with complete remissions seen in approximately 60%. If the KS does not regress despite a reduction in HIV viral load and an increase in CD4 cells, alternative treatment for KS may be considered. Due to possible effects of HIV protease inhibitors (PI) on inhibition of matrix metalloproteinase (MMP-2), down-regulation of bFGF and VEGF and their antiangiogenic effects, many clinicians tend to prefer using PI-containing HAART regimens in patients with HIV and KS.
2. Antiherpetic therapy. In vitro, HHV-8 may be suppressed by ganciclovir, cidofovir, and foscarnet; acyclovir is ineffective. A prospective trial in patients with cytomegalovirus retinitis suggested that KS could be prevented by the use of systemic ganciclovir. However, prospective studies of cidofovir, used in patients with known KS, revealed no efficacy to this anti–HHV-8 approach. Such lack of efficacy may be due to the fact that the majority of KS cells are only latently infected with HHV-8, making this viral target less useful in terms of anti–HHV-8 treatment approaches. Approaches to stimulating HHV-8 lytic gene expression with or without antiherpetic therapy are under investigation.
3. Local therapy. KS is a disseminated disease at the time of diagnosis in patients with AIDS, even though only localized disease may be clinically evident. Thus, the role of local therapy often includes considerations of cosmetic, local control as opposed to “cure.”
Topical 9-cis-retinoic acid (Panretin) is associated with a 30% to 50% response rate and has been licensed for use in cutaneous KS. Individual lesions may be injected with vincristine (0.1 mg) or vinblastine (0.1 mg), or with interferon-α (1 million U), although these modalities are painful and associated with the possibility of secondary infection. Such local injections are not advocated at this time.
Local lesions may also be treated effectively with cryotherapy, laser, or surgical excision. Local radiation may be helpful for rapid control of bulky lesions or to control extensive lymphedema due to locally invasive tumors or extensive lymphadenopathy; however, great care must be taken to avoid undue toxicity, as has been reported in HIV-infected patients after receipt of standard doses and schedules of radiation.
4. Immune response modifiers. Oral 9-cis-retinoic acid may be useful in the therapy of KS, working by means of its ability to downregulate IL-6, which is a growth factor for KS. Interferon-α (1 million to 2 million U/d) is also effective, especially when combined with antiretroviral agents. Of great interest, interferon-α in low doses is known to function as an antiangiogenic factor, which may explain its efficacy in AIDS-related KS. Additional biologic agents that aim to decrease either inflammatory cytokines or angiogenic factors have been studied, with preliminary evidence of some antitumor efficacy. These agents include rapamycin, thalidomide, lenolidomide, and others. The spectrum of available biologic or targeted therapies for KS is expected to change considerably over the next several years.
5. Chemotherapy is indicated for rapidly progressive disease, severe lymphedema, pulmonary involvement, and symptomatic visceral disease. Low doses of doxorubicin (10 mg/m2 IV), bleomycin (10 mg/m2 IV), and vincristine (2 mg IV), given every 2 weeks may result in response rates of 25% to 50%. Liposomal preparations of anthracyclines (Doxil and DaunoXome) have shown greater efficacy with lesser degrees of toxicity and have been licensed for use in KS. Paclitaxel (100 or 135 mg/m2 given IV every 2 to 3 weeks) is also highly effective and has been licensed for this purpose. Other chemotherapeutic agents with some activity in KS include the vinca alkaloids (vincristine, vinblastine, and vinorelbine), bleomycin, and gemcitabine.
V. CERVICAL CANCER
A. Incidence. Cervical cancer is an AIDS-defining diagnosis. Women constitute the fastest growing group of new AIDS cases in the United States. The primary risk factor for HIV infection in these patients is heterosexual transmission, usually from a partner whose HIV status is unknown to the woman.
The precise incidence of cervical carcinoma, while increased statistically when compared with that in HIV- women, is still very low in the United States and other countries in which routine Papanicolaou (Pap) screening is common. The incidence of the precursor lesions (cervical intraepithelial neoplasia [CIN] on biopsy or squamous intraepithelial lesions [SIL] on Pap smear) is unknown, although various large cohort studies of HIV-infected women have indicated a high prevalence of oncogenic HPV strains. HAART has been associated with spontaneous clearing of these precursor lesions. The incidence of invasive cervical carcinoma and of premalignant lesion increased in the era of HAART, most likely due to the increased patient and provider awareness and increased screening.
B. Biologic factors
1. Role of human papillomavirus (HPV). Cervical cancer is associated with prior infection by HPV, usually involving serotypes 16, 18, 31, 33, or 35. Immunosuppression may allow more rapid development of in situor invasive disease in the setting of such HPV infection. Preliminary data indicate that infection by more than one serotype may increase the risk for cervical cancer or CIN. Furthermore, lower CD4+ lymphocyte counts have been associated with greater prevalence of HPV infection among HIV-infected women.
2. Role of HPV vaccine. Recently, an HPV vaccine against serotypes 6, 11, 16, and 18 has been licensed in the United States and is recommended for use in girls and boys from the age of 9 to 26 years for prevention of primary HPV infection. The vaccine has been remarkably effective in inducing immunity against HPV and in decreasing the risk of incident CIN/SIL. The vaccine is composed of viral-like particles (VLPs) and is thus not a “live” viral vaccine in any sense. Safety and immunogenicity studies of the quadrivalent HPV vaccine have been completed in HIV+ men and is completing in HIV+ women, demonstrating good safety and immunogenicity in HPV subtype–negative individuals. Nonetheless, because most HIV-infected women have already been infected by multiple types of HPV, the actual effectiveness of this approach in preventing CIN or invasive cervical cancer will need to be established.
C. Clinical features of cervical cancer in the HIV-infected women are not different from those in uninfected women. Preliminary evidence suggests that HIV-infected women are more likely to have advanced-stage disease, high-grade pathologic type, and relapse after definitive therapy.
D. Management. Because of the aggressive nature of cervical carcinoma in HIV-infected women, it has become extremely important to diagnose such patients early, at the time of precancerous abnormalities on Pap smear or local biopsy. It is recommended that HIV-infected women undergo routine Pap testing every 12 months with evaluation of HPV status as well. Colposcopy and biopsy should be performed in the presence of positive HPV status or any abnormal Pap smear results, including atypia. After definitive ablative therapy for CIN II or III, about half of patients relapse within 1 to 2 years. Thus, continued monitoring and follow-up is required. Invasive cervical cancer is treated based on stage and concurrent conditions and is the same in HIV+ as in HIV-women. Concurrent platinum-based chemotherapy with radiation is generally administered to advanced cases of cervical cancer.
VI. ANAL CARCINOMA
A. Incidence. Although not diagnostic of AIDS, the incidence of HPV-related anal carcinoma is known to be increased in homosexual men, even independent of HIV infection. In HIV+ men in the post-HAART era, the incidence of anal cancer has been estimated to be between 78 and 137 cases per 100,000 patient-years, which is as high as the incidence of cervical cancer in women in the pre-Pap screening era. As in HIV+ women, men with HIV have a greater likelihood of developing both premalignant dysplasia and malignant invasive anal lesions. Anal HPV infection is also quite common in HIV-infected women and also in HIV-infected men without history of homosexual activity.
B. Biologic factors. As with cervical cancer, anal cancer is associated with prior infection by HPV, usually involving serotypes 16, 18, 31, 33, or 35. Most anal cancer in HIV+ men in the United States are due to serotypes 16 or 18. Cytologic abnormalities occur in nearly 40% of patients, especially those with CD4 counts <200 cells/mm3.
C. Clinical features. Most individuals with anal dysplasia or cancer are completely asymptomatic. However, rectal pain, bleeding, discharge, and symptoms of obstruction or a mass lesion found on rectal exam are the most frequent presenting symptoms and signs. Patients with severe immunosuppression (i.e., CD4 < 50/mm3) may present with more advanced and more aggressive disease.
D. Management. Because of the high prevalence of HPV infection and the growing incidence of anal squamous intraepithelial lesions (ASIL) and invasive anal cancer detected in HIV+ men and women, the screening of HIV+ individuals with either yearly anal Pap smears and/or direct visualization via high-resolution anoscopy (HRA) and biopsy is becoming a standard procedure in many HIV practices. Discovery of any grade ASIL on Pap smear or anal intraepithelial neoplasm (AIN) requires HRA and biopsy. For those with AIN II-III, ablative treatment with surgery, electrocautery, or infrared coagulation is generally performed. For these individuals as well as those with AIN I or ASUC, follow-up every 6 months is recommended.
Invasive anal cancer can be controlled effectively with high response rates with chemotherapy (e.g., mitomycin C or cis-platinum with 5-day fluorouracil) and radiation therapy. Patients with lower CD4 counts appear to have a greater likelihood of severe toxicities with treatment and may require colostomy and extensive resection for salvage therapy upon relapse. The role of cetiximab (Eribux) in conjunction with standard chemoradiotherapy is under investigation in both HIV+ and HIV- anal cancer patients as a means of enhancing responses and reducing relapses.
VII. OTHER NON–AIDS-DEFINING MALIGNANCIES
A. Incidence. With improved HIV therapy, patients are living longer and are developing other cancers that are not AIDS defining. A large number of reports from around the world now show that other cancers including Hodgkin lymphoma, anal cancer, lung cancer, liver cancer, head and neck cancers, nonmelanomatous skin cancers, germ cell tumors, myeloid and lymphoid leukemias, squamous cell cancers of various organs, and leiomyosarcoma in pediatric patients are occurring with greater frequency in HIV-infected individuals. Rates of these non–AIDS-defining cancers (NADC) now suggest that these cancers are occurring at higher frequencies than the AIDS-defining cancers in the developed world. Interestingly, the rates of the more common tumors, such as breast, prostate, and colon cancers, do not appear to be higher in the HIV populations.
B. Biologic factors. The reason for this increase incidence of NADC is not completely understood, but greater longevity due to HAART coupled with continued immunosuppression is likely to play a significant role. In addition, more rapid immunologic aging due to continued immune activation by HIV and exposure to potential carcinogens also may be contributing. Even when controlled for the high rate of smoking in the HIV population, the relative risk for lung cancer in HIV appears to be at least two-fold greater in the HIV+ than the general population. Induction of genetic instability or direct involvement of HIV in the expression of oncogenes or inhibition of tumor suppressor genes have also been suggested by several tumor models.
C. Clinical features. While systematic comparisons studies have not yet been performed, individuals with HIV and NADC generally seem to present at a younger age, with more advanced staged tumor at diagnosis and with a greater likelihood of relapse after definitive therapy. Unusual locations and presentations of some of these tumors have also been reported. A high index of suspicion for cancer needs to be maintained in the HIV population, and perhaps more frequent screening for the more common cancers will be required.
D. Management. In the absence of comparative data for many of these cancers, treatment strategies have generally followed the same stage-adjusted approaches as used in individuals not infected with HIV. Appreciation of the greater likelihood and/or severity of drug toxicities, the potential for drug interactions between anticancer agents and drugs used in the management of HIV, and the need to provide supportive treatment and prophylactic antibiotics and growth factors need to be incorporated into the management of the HIV patient with malignancies.
Because of the higher risk of these cancers in people with HIV, a greater focus on prevention of cancer should also be incorporated into the management of the HIV patient. Thus, in addition to yearly cervical and anal Pap screening, more frequent breast and prostate examination, administration of hepatitis and HPV vaccinations, use of sunscreen and avoidance of sun overexposures, and an increased awareness and willingness to pursue suggestive signs and symptoms of cancer should allow us to detect tumors earlier and improve the outcome of cancers in this population.
Suggested Reading
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Chiao E, Dezube BJ, Krown SE, et al. Time for oncologists to opt in for routine opt-out HIV testing? JAMA 2010;304;334.
Crum-Cianflone N, Hullsiek KH, Marconi V, et al. Trends in the incidence of cancers among HIV-infected persons and the impact of antiretroviral therapy; a 20-year cohort study. AIDS 2009;23;41.
Engels EA, Biggar RJ, Hall HI, et al. Cancer risk in people infected with HIV in the United States. Int J Cancer 2008;123;187.
Kuhn L, Wang C, Tasi WY, et al. Efficacy of HPV-based screen-and-treat for cervical cancer prevention among HIV-infected women. AIDS 2010;24;2553.
Simard EP, Pfeiffer RM, Engels EA. Cumulative incidence of cancer among individuals with AIDS in the United States. Cancer 2011;117:1089.
Sparano JA, Lee JY, Kaplan LD, et al. Rituximab plus concurrent infusional EPOCH chemotherapy is highly effective in HIV-associated B-cell non-Hodgkin lymphoma. Blood 2010, 115;3008.
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Wilkin T, Lee JY, Lensing SY, et al. Safety and immunogenicity of the quadrivalent HPV vaccine in HIV-1-infected men. J Infect Dis 2010, 202;146.