The Washington Manual of Oncology, 3 Ed.

AIDS-Associated Malignancies

Lee Ratner

GENERAL CARE OF THE PATIENT WITH HIV AND CANCER

 I. GENERAL. A malignancy develops in about 20% of patients with human immunodeficiency virus (HIV) during their lifetime, and is often the first clinical evidence of HIV infection. It is also responsible for 28% of AIDS patients’ deaths. The most common malignancies in this patient population are non-Hodgkin’s lymphoma, Kaposi’s sarcoma, and anogenital carcinoma. The incidence of other malignancies is also increased in HIV-infected patients, including Hodgkin’s lymphoma (HL), lung cancers, multiple myeloma, testicular tumors, hepatocellular carcinomas (HCCs), and childhood sarcomas. The frequency of non-AIDS–defining cancers has increased significantly over the last 15 years, and has been attributed to expansion of the HIV-infected population and aging. Most of these malignancies are associated with oncogenic viruses, including Epstein–Barr virus (EBV), human herpesvirus-8 (HHV8), and human papilloma viruses (HPV). When CD4 cell counts drop below 200 cell/mL, HIV-infected patients tend to experience greater toxicity with chemotherapy. Dose modifications and dose delays are common in this setting. Often, personalized dose modifications in lower performance status patients may be chosen by treating physicians. Providers need to be cognizant of any drug–drug interactions of highly active antiretroviral therapy (HAART) with antitumor therapies as well as supportive medications. Regular discussion between medical oncologists, infectious disease specialists, and radiation and surgical oncologists are essential. Maximizing nutritional status can assist in minimizing toxicity and accelerating recovery from therapy. Social work assistance is invaluable for these patients, who often have other financial, social, and personality difficulties.

1. DIAGNOSTIC STUDIES FOR HIV INFECTION should be considered in patients who are not known to be HIV infected, but who develop a malignancy that occurs at increased frequency with HIV infection. Many patients with HIV infection are unaware of their risk factors or deny their existence. HIV testing is recommended to all individuals presenting with aggressive B-cell lymphomas, Kaposi’s sarcoma, or anogenital carcinomas, as well as individuals with any malignancy who have higher than average risk for HIV (i.e., IV drug abusers, homosexuals or bisexuals, individuals with large numbers of sexual partners, and individuals from countries in Africa, southeast Asia, or parts of the Caribbean where HIV is especially prevalent). Appropriate pre- and posttesting counseling services should be available for these individuals. The screening HIV test is an enzyme-linked immunosorbent assay (ELISA), which, if positive, is confirmed by Western blot or plasma HIV RNA assay. The rapid, point-of-care, HIV antibody tests are an acceptable alternative to the ELISA and are in wide use. If HIV is diagnosed concurrently with such a malignancy, additional clinical evaluation of their HIV infection may be indicated. Plasma HIV RNA and CD4 should be determined during the evaluation of HIV-associated malignancies. However, it is important to recognize that chemotherapy can cause wide fluctuations of the CD4 count that may not be an accurate measurement of the immune status.

 III. HAART will usually be recommended as concurrent therapy for the malignancy, and, in some cases, prophylaxis for opportunistic infections (OIs). Although issues of drug interactions and excessive toxicity must be considered, there is now considerable evidence supporting the concurrent use of HAART in all HIV-1-infected individuals.

1. HAART regimens include the use of at least three antiretroviral agents with nucleoside- or nucleotide-reverse transcriptase inhibitors (zidovudine, didanosine; didexoycytidine, stavudine, lamivudine, abacavir, and tenofovir emtricitabine) combined with nonnucleoside-reverse transcriptase inhibitors (nevirapine, delaviridine, efavirenz, rilpivirine, etravirine, and protease inhibitors (PIs); indinavir, ritonavir, nelfinavir, saquinavir, amprenavir, lopinavir plus ritonavir, atazanavir, tipranvir, fosamprenavir, and darunavir), fusion inhibitors (T-20, maraviroc), or integrase inhibitors (raltegravir, dolutegravir, and elvitegravir). Several nucleoside combination pills are available, including Combivir (zidovudine plus lamivudine), Epzicom (lamivudine plus abacavir), Trizivir (zidovudine plus lamivudine plus abacavir), or Truvada (tenofovir plus emtricitabine). A triple nucleoside regimen without a nonnucleoside or PI or integrase inhibitor or entry inhibitor is not appropriate. Combination pills that provide appropriate HAART combinations include Atripla (efavirenz plus tenofovir plus emtricitabine), Complera (rilpivirine plus tenofovir plus emtricitabine), and Stribild (elvitegraivr plus cobicistat plus tenofovir plus emtricitabine).
2. Benefits of HAART include a lower incidence of development of HIV-associated malignancies, especially primary CNS lymphoma and Kaposi’s sarcoma. Moreover, with HAART the onset of malignancies in individuals is at a higher level of CD4, there is improved tolerance of full-dose chemotherapy, improved response rates and duration of responses, and improved survival during treatment of their malignancy. Pharmacokinetic studies have suggested that metabolism and clearance of several cytotoxic chemotherapeutic agents is not affected by HAART, but caution is still recommended when high doses of chemotherapy are utilized, for example, during stem cell transplantation studies. Several antivirals are inducers and/or inhibitors of cytochrome Cyp3A4, including PIs, elvitegravir (component of Stribild), and, to a lesser extent, nonnucleoside-reverse transcriptase inhibitors. Thus, adverse interactions may occur with targeted chemotherapeutic agents that are also Cyp3A4 inhibitors or inducers (e.g., dasantinib, imatinib, nilotinib, erlotinib, gefitinib, everolimus, sunitinb, sorafenib, and pazopanib).
3. Specific recommendations for combining HAART with chemotherapy include avoiding the nucleoside analog zidovudine, in light of excessive neutropenia and anemia. Moreover, the PI atazanavir, which causes hyperbilirubinemia in almost one-third of patients, can also be problematic when anthracyclines or vinca alkaloids are utilized. Some authors have also suggested that HAART regimens, including PIs, may be associated with more myelosuppression when combined with chemotherapy than those lacking PIs, although this remains controversial. Caution is recommended in the use of antiretrovirals associated with neurotoxicity (e.g., didanosine, stavudine, and dideoxcytidine) together with chemotherapy regimens including vinca alkaloids, especially in individuals with preexisting HIV-associated neuropathy. PIs commonly cause gastrointestinal (GI) toxicities. It should also be recognized that nucleoside inhibitors may cause lactic acidosis, abacavir may cause a multisystem hypersensitivity reaction, emtricitabine occasionally causes hyperpigmentation of the palms and soles, etravirine causes a rash, nevirapine may cause liver toxicity, and efavirenz is frequently associated with central nervous side effects. Atazanavir, ritonavir-boosted lopinavir, and saquinavir are associated with prolongation of the QT interval, as are anthracyclines, arsenic trioxide, dasatinib, lapatinib, nilotinib, sunitinib, and tamoxifen. Therefore, because of the potential for sudden death, these combinations should be avoided. Well-tolerated regimens for a HAART-naïve patient who will receive chemotherapy would be Truvada (300 mg tenofovir plus 200 mg emtricitabine) once daily with Sustiva (600 mg) once daily, or Truvada once daily with raltegavir (400 mg) twice daily. A preferred initial PI-based regimen for a HAART-naive patient is ritonavir (100 mg)-boosted darunvair (800 mg) once daily with Truvada once daily.
4. Initiation of HAART therapy should be accompanied by liver function tests; amylase and lipase as baseline values since several antiretrovirals (e.g., didanosine) can cause pancreatitis; an HIV genotype test to identify drug-resistant mutations; fasting glucose and lipid profile since PIs may cause dyslipidemias and glucose intolerance; a serologic tests for syphilis, hepatitis A, B, and C viruses, toxoplasmosis, cytomegalovirus (CMV) assays; glucose-6-phosphate dehydrogenase testing in case dapsone will be needed; cervical Papanicolaou smear, opthalmalogy examination, and anal and cervical screening for HPV if available; and tuberculin skin test, chest radiography, and an electrocardiogram since HIV may be associated with cardiomyopathy. Vaccinations for influenza, hepatitis A and B viruses, and Streptococcus pneumonia should also be considered.
5. Optimal care of the HIV-infected patient should be done in collaboration with an infectious disease specialist. During active treatment, repeat HIV RNA levels should be assessed, and after completion of therapy, both HIV RNA and CD4 counts should be obtained.

 IV. PROPHYLAXIS FOR OPPORTUNISTIC INFECTIONS (OIs) is also indicated in individuals with depressed CD4 count. Since chemotherapy can also transiently affect the CD4 count, it has been suggested that OI prophylaxis recommendations be expanded in individuals receiving chemotherapy. Thus, if it is anticipated that the CD4 count will decline below 200/mm,³ prophylaxis for Pneumocystis jiroveci pneumonia (PCP) is recommended with bactrim thrice weekly, or in allergic patients, dapsone or atovaquone. If the CD4 count is anticipated to decline below 50/mm³, prophylaxis for Mycobacterium avium intracellulare (MAI) is also indicated with weekly azithromycin. In individuals with prior OI, who have a CD4 count above these cut-off values and have discontinued prophylactic antibiotics, resumption of prophylactic antibiotics concurrent with chemotherapy may be indicated. Special attention is also recommended in evaluating possible clinical signs of OI in the HIV-positive patient receiving chemotherapy as follows: (1) any CD4 count: oral and esophageal Candidiasis, Mycobacteria including tuberculosis, bacterial pneumonias, histoplasmosis, or coccidiomycosis, (2) CD4 <100: MAI, Toxoplasma, encephalitis, and (3) CD4 <50: CMV retinitis, pneumonitis, or colitis, or progressive multifocal leukoencephalopathy.

1. EVALUATION OF ANEMIA IN AN HIV-POSITIVE PATIENT WITH A MALIGNANCY should consider causes other than chemotherapy or antiretrovirals, and should also include other causes of decreased erythropoiesis including (1) drugs (e.g., trimethoprim-sulfamethoxazole, ganciclovir, and dapsone), (2) nutritional deficiency of iron, folate, or vitamin B12, (3) effects of uncontrolled HIV on bone marrow stromal cells, (4) OIs (e.g., parvovirus, atypical or typical mycobacteria, or histoplasmosis, and (5) preexisting conditions (e.g., sickle cell disease or thalassemia). Alternatively, causes of erythrocyte loss should also be considered, including (1) hemolysis due to thrombotic thrombocytopenic purpura, glucose-6-phosphate dehydrogenase deficiency, autoimmune hemolytic anemia, or drug-induced hemolysis, (2) GI bleeding that may complicate lymphoma, Kaposi sarcoma (KS), or enteric infections due to CMV, Candida, or parasites, or (3) hypersplenism associated with infection, lymphoma, or cirrhosis that may complicate hepatitis B or C virus infections.

 VI. EVALUATION OF NEUTROPENIA IN AN HIV-POSITIVE PATIENT WITH A MALIGNANCY should consider causes other than chemotherapy or antiretrovirals. These include causes of decreased myelopoiesis from drugs (e.g., ganciclovir, trimethoprim-sulfamethoxazole, pentamidine, rifabutin, and dapsone), nutritional deficiencies (e.g., folate or vitamin B12 deficiency), infections (e.g., uncontrolled HIV, atypical or typical mycobacteria, histoplasma), or bone marrow involvement by the malignancy (e.g., lymphoma, multiple myeloma). Increased loss of neutrophils may occur with autoimmune neutropenia or hypersplenism. Granulocyte colony stimulating factor (G-CSF) has been shown to be safe and effective in HIV-infected patients, although there is controversy about the use of granulocyte–macrophage colony stimulating factor (GM-CSF), which can potentiate HIV replication in macrophages.

 VII. EVALUATION OF THROMBOCYTOPENIA IN AN HIV-POSITIVE PATIENT WITH A MALIGNANCY should consider causes other than chemotherapy or antiretrovirals. Causes of decreased thrombopoiesis include (1) drugs (e.g., trimethoprim-sulfamethoxazole, pyrimethamine, ganciclovir, fluconazole, and clarithromycin), (2) nutritional deficiency (e.g., folate or vitamin B12), (3) infection (e.g., uncontrolled HIV, mycobacteria, histoplasma, or Bartonella henselae), or (4) bone marrow involvement by lymphoma. Causes of decreased platelet survival include (1) immune thrombocytopenic purpura from HIV infection or autoimmune conditions, (2) thrombotic thrombocytopenic purpura, or (3) hypersplenism.

ACQUIRED IMMUNODEFICIENCY SYNDROME-ASSOCIATED DIFFUSE LARGE B-CELL LYMPHOMAS (DLBCL)

 I. CLINICAL PRESENTATION

1. Non-Hodgkin’s lymphomas (NHL) are 100- to 200-fold more frequent in HIV-positive individuals than the general population, and occur in 5% to 10% of HIV-infected individuals. HIV-DLBCL accounts for about 5% of all DLBCL cases in the United States. AIDS-associated lymphomas are generally aggressive B-cell malignancies that present at an advanced stage with extranodal involvement in more than two-thirds of individuals.
2. Pertinent history should include performance status, duration of HIV infection, treatment of OIs, and current antiretroviral regimen.
3. B symptoms, such as fever, night sweats, and weight loss in excess of 10% of the normal body weight, are very common, but should be attributed to AIDS-associated lymphoma only after the exclusion of OIs. Extreme fatigue from anemia caused by bone marrow involvement may be seen.
4. Lymph node enlargement may be asymptomatic or associated with pain or obstructive symptoms. This should be differentiated from persistent generalized lymphadenopathy (PGL) due to HIV replication or other AIDS-related OIs. Splenomegaly is commonly present, and may be related to the cause of lymphadenopathy.
5. GI involvement causing anorexia, nausea, vomiting, hemorrhage, change in bowel habits, or obstruction occurs in 10% to 25% of patients. Jaundice and abdominal discomfort may be due to lymphomatous hepatic or pancreatic involvement.
6. CNS or meningeal involvement resulting in seizures, altered mental status, and neurological defects occurs in 10% to 30% of patients. Other causes of neurological defects in this patient population should also be considered, such as HIV-associated encephalopathy.
7. Pleural or pericardial effusions may cause dyspnea and chest discomfort.
8. The physical examination should include careful examination and measurements of enlarged lymph nodes, spleen, and liver. Pulmonary and cardiac examinations may reveal pleural or pericardial effusions. A thorough neurological examination should be done to determine the presence of meningismus or focal neurological defects.
9. DIAGNOSTIC WORKUP AND STAGING
10. Pathology. Definitive diagnosis of AIDS-associated NHL is made with the identification of lymphoma in lymph node biopsies or other tissues (bone marrow, cerebrospinal fluid (CSF), pleural fluid, and liver), in an HIV-infected individual. DLBCL is characterized by large noncleaved cells that usually express cell surface pan-B-cell marker, CD20, and lymphocyte common antigen, CD45, but not CD3. The transcription factor Bcl-6 is expressed in the centroblastic subtype but not the immunoblastic subtype. In contrast, the immunoblastic subtype is typically characterized by CD138 expression as well as EBV latent membrane protein-1 (LMP-1). Centroblastic DLBCL is thought to arise in the germinal center (GC), whereas immunoblastic DLBCL is a post-GC lymphoma. GC B-cell-like type DLBCL is considered when CD10 is expressed in >30% of the malignant tumor cells, or if cells are CD10−, BCL6+, and IRF4/MUM1−. All others are considered to be activated B-cell-like type or non-GC types. Cytogenetics or FISH should be performed for MYC translocations, since these variants have a poor outcome with CHOP therapy.
11. Laboratory tests. Complete blood counts may reveal anemia, leukopenia, or thrombocytopenia, even if there is no marrow involvement. Serum chemistries may show abnormalities in liver function tests, elevated lactate dehydrogenase (LDH), calcium, or uric acid. Electrolytes and creatinine should also be monitored during therapy.
12. Radiology/procedures
13. Computed tomography (CT) scan of the chest, abdomen, and pelvis with a CT or an MRI scan of the brain is necessary for the staging of AIDS-related NHL. Special attention should be given to mesenteric adenopathy, a site not usually affected in PGL.
14. PET scans are helpful in distinguishing adenopathy due to lymphoma that generally shows significant uptake of fluorodeoxyglucose (FDG) from that associated with PGL or OIs, which show less intense FDG uptake. Alternatively, gallium scanning may be useful for this purpose. PET or gallium scans are useful to detect residual disease after therapy, and to distinguish fibrosis from refractory tumor.
15. Bone marrow aspiration and biopsies reveal bone marrow involvement in approximately 20% of patients, and may be associated with increased risk of CSF involvement.
16. Lumbar puncture should be performed and CSF sent for cytological examination. Cell count and protein may be normal or elevated, whereas glucose may be low. Analysis of CSF by flow cytometry or for EBV DNA by polymerase chain reaction (PCR) may predict lymphomatous meningitis.
17. The Ann Arbor staging for NHL also is used for AIDS-related NHL. Prognostic factors correlating with poor survival in patients with AIDS-related NHL include stage IV disease, Karnofsky performance status less than 70%, CD4 count less than 100/mm³, elevated LDH, and history of OIs before lymphoma diagnosis.

 III. THERAPY

1. m-BACOD (methotrexate, bleomycin, doxorubicin, vincristne, and dexamethasone) was used in AIDS-DLBCL patients in the pre-HAART era. Given in a low-dose regimen, this resulted in 41% complete remissions and median survival of 35 weeks, whereas standard dose m-BACOD with GM-CSF resulted in 52% complete remissions with a median survival of 31 weeks and more grade 3 toxicity (70% vs. 51%). Since the demonstration in the HIV-negative population that m-BACOD was similar in efficacy to CHOP, the m-BACOD regimen has not been routinely utilized in AIDS-DLBCL.
2. CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) given at the same doses as in the HIV-negative patient population together with HAART and G-CSF is feasible and effective (J Clin Oncol2001;19:2171). In a nonrandomized study, this therapy resulted in a complete response (CR) rate of 30% when given in low doses, and 48% when full doses were provided. The chemotherapy had no adverse effect on HAART activity. Moreover, HAART with a PI, indinavir, had no effect on doxorubicin clearance and only a 1.5-fold reduction in cyclophosphamide clearance, which did not translate into excessive neutropenia.
3. R-CHOP was not significantly more effective than CHOP in AIDS-NHL (CR rates of 58% and 47%, respectively) in one study, but was significantly more toxic (14% and 2% serious treatment-related toxicities). The increase in mortality with R-CHOP compared with CHOP, in this randomized study, was primarily due to infectious deaths, particularly in individuals with CD4 lymphocyte counts <50/mm³. However, subsequent trials using prophylactic quinolone antibiotics for individuals with <100 CD4 cells/mm³ obviated this complication. Moreover, a meta-analysis of trials using various different forms of chemotherapy with or without rituximab found a reduced risk of lymphoma recurrence and death from any cause with the addition of rituximab to combination chemotherapy (Blood 2013;122:3251).
4. CDOP (cyclophosphamide, liposomal doxorubicin, vincristine, and prednisone) in combination with rituximab resulted in a 47% CR rate in a study of 40 patients.
5. The infusional dose-adjusted (DA) EPOCH regimen (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) with growth factor support resulted in complete remission in 74% of 39 patients, with 60% disease-free survival at 53 months. In this trial, antiretrovirals were withheld during chemotherapy, and after reinstitution of HAART, CD4 cells recovered by 12 months and viral load decreased below baseline by 3 months. Important features of this regimen are that it utilizes 5 days of oral prednisone (60 mg/m²/day), a 4-day infusion of etoposide (50 mg/m²/day), vincristine (0.4 mg/m²/day up to 2 mg total), and doxorubicin (10 mg/m²/day), and day 5 cyclophosphamide, followed by G-CSF or Neulasta. Cycle 1 cyclophosphamide dose is 375 mg/m² for patients with CD4 <100 and 750 mg/m² for patients with CD4 ≥100. In subsequent cycles, the cyclophosphamide dose is increased by 187 mg/m² each cycle up to a maximum of 750 mg/m² if grade 3 or 4 neutropenia or thrombocytopenia has not occurred, and decreased by 187 mg/m² each cycle if one of these complications has occurred. Thus, monitoring of the CBC at days 8, 10, and 12 of each cycle is necessary for guiding subsequent therapy. Concurrent use of rituximab plus EPOCH resulted in a 73% CR in one study, and 5-year progression-free (PFS) and overall survivals (OS) of 84% and 68%, respectively, in another study.
6. Short-course EPOCH-RR regimen includes rituximab given on days 1 and 5 of each cycle. To determine the number of cycles of therapy, all patients undergo restaging with CT and FDG-PET after the second treatment cycle, and each cycle until achieving CR or no further tumor shrinkage. The criteria for stopping therapy after a minimum of 3 cycles of therapy is that there is less than 25% reduction in bidimensional tumor products compared with the previous interim CT scan and the standardized uptake values on FDG-PET have decreased at least 50% compared with the pretreatment FDG-PET. With 5 years of follow-up, PFS and OS were 84% and 68%, respectively, and 79% of patients only required 3 treatment cycles.
7. CDE (cyclophosphamide, doxorubicin, and etoposide) is an alternative infusional regimen that has resulted in CR rates of 46% to 86%, but grade 3 or 4 neutropenia and thrombocytopenia in 75% and 55% of participants, respectively.
8. ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisolone) is an alternative intensive regimen used primarily in Europe. In one study, the 5-year OS was 51% for good-risk patients.

 I. Indications for CNS prophylaxis in AIDS-DLBCL are not well defined. Bone marrow involvement has been suggested as increasing the likelihood of CNS relapse, as well as paraspinal, paranasal, epidural, testicular, or widespread systemic involvement. When CNS prophylaxis is provided, the usual recommendation is 4 weekly treatments of either intrathecal cytarabine (50 mg) or methotrexate (12 mg).

 J. Lymphomatous meningitis should be treated with intrathecal cytarabine or methotrexate 2 to 3 times weekly via Omaya reservoir until the CSF is clear of malignant cells, then weekly for 4 weeks, and then monthly. The duration of therapy remains poorly defined, but is often given for 6 to 12 months. Alternatively, liposomal cytarabine (Depocyt) can be given with a 5-day course of decadron 4 mg bid with each treatment, on weeks 1 and 3 for induction, on weeks 5, 7, 9, and 13 for consolidation, and weeks 17, 21, 25, and 29 for maintenance. In patients failing to respond to intraventricular chemotherapy, CSF flow studies can be performed after instilling radioisotope to identify possible blockade.

1. Radiotherapy may be given as palliation to bulky, rapidly enlarging, organ compressing, or CNS lesions or as consolidation to patients with localized lymphoma after chemotherapy.
2. Duration of first-line therapy for AIDS-DLBCL should be 3 to 8 cycles, unless there is severe toxicity or lymphoma progression. This should include 1 to 2 cycles after obtaining a CR. For patients with stage I disease and good prognostic characteristics, 3 cycles of therapy followed by involved field radiation is appropriate therapy.
3. Salvage chemotherapy regimens for AIDS-associated lymphomas are not highly effective (response rates of 10% to 25%) with most patients relapsing within months, as in the HIV-negative population. This includes the use of rituximab with etoposide and high-dose cytosine arabinoside and cisplatin (ESHAP), mitoguazone, or a combination of etoposide, mitoxantrone, and prednimustine. The use of rituximab with ifosfamide, carboplatin, and etoposide (R-ICE) is a reasonable choice for a salvage regimen, but trials in AIDS patients have not yet been reported. There is little reported experience with dexamethasone, cisplatin, cytarabine (DHAP), mesna, ifosfamide, mitoxantrone, etoposide (MINE), or carmustine, etoposide, cytarabine, melphalan (miniBEAM) regimens in this patient population.
4. Autologous stem cell transplantation has also been utilized for refractory or relapsed AIDS-associated lymphomas, particularly in the HAART era. In individuals with a good performance status, lacking severe immune compromise, stem cell collections were successful in 80% to 100% of cases, and graft failure was rare. Long-term survivors have been reported from such studies, but the number of patients in each series remains low. In one study of 68 patients from 20 institutions, including 16 patients in first CR and 44 patients in CR more than 1, partial remission, or chemotherapy-sensitive relapse, and 8 patients with chemotherapy-resistant disease, nonrelapse mortality was 30% at 24 months. Only anecdotal reports have appeared thus far for the use of allogeneic transplants in HIV-infected individuals.

 IV. COMPLICATIONS

1. Complications of disease. Rapidly enlarging tumors may compromise airways and other vital organs. Significant hepatic dysfunction, hypercalcemia, and CNS relapse may occur. OIs and other AIDS-related illnesses are causes for morbidity and mortality in patients with AIDS-NHL; thus, PCP and mycobacterial prophyalxis should be continued during active lymphoma therapy, if indicated.
2. Complications of therapy
3. Lymphocytotoxic chemotherapy may cause depletion of CD4 and total lymphocyte counts, increasing the risk of severe myelosuppression and infections. Potential interactions with chemotherapy and HAART may produce substantial and unexpected toxicity that may require dose delay or reduction, possibly compromising optimal antilymphoma therapy.
4. Intrathecal chemotherapy may cause chemical arachnoiditis that is relatively acute, subacute neurological deficits occurring within days to weeks, or chronic encephalopathy occurring over weeks to months.
5. Cardiomyopathy may occur after the use of doxorubicin, particularly in individuals receiving cumulative doses of more than 550 mg/m², but may occur at lower cumulative doses in individuals who received chest radiotherapy, or have other cardiac disorders, such as HIV-associated cardiomyopathy.
6. Virus reactivation is a potential complication of rituximab-based therapies, particularly HBV, HCV, and JCV. Monitoring HBV and HCV levels during therapy is indicated in individuals with chronic persistent infections. Antiviral therapy is recommended for high-risk HBV-positive patients.
7. FOLLOW-UP. During treatment, intervening history, physical examination, CBC, chemistries, and LDH should be obtained prior to the initiation of each cycle of therapy, and as clinically indicated. With DA-EPOCH-R, more frequent measurements of CBC are required to guide the dose level for the subsequent cycle. After completion of therapy, for patients in complete remission, follow-up visits and laboratory studies are required every 1 to 3 months for 1 year, every 2 to 4 months during the second year, and then every 3 to 6 months. CT scans are usually performed every 3 to 6 months for 2 years. It is important to remember that these patients are at risk for relapse of their AIDS-NHL or development of a second AIDS-NHL.

 VI. BACKGROUND

1. EBV infection occurs in nearly 50% of AIDS-associated DLBCL. In these cases, latency type 3 antigens are expressed, including EBV nuclear antigens 1 and 2 (EBNA-1 and 2), latent proteins (LP) 3A and 3C, as well as latent membrane protein-1 (LMP-1). Immunohistochemical stains for LMP-1 or in situ hybridization for EBV-associated RNAs (EBERs) are often used to identify EBV in pathological samples.
2. Chronic antigen induction of polyclonal B-cell expansion and cytokine deregulation (especially interleukins 6 and 10) during HIV infection may also contribute to transformation.

 VII. CURRENT FOCUS OF RESEARCH. Current studies of AIDS-DLBCL are evaluating (1) the combination of vorinostat with DA-EPOCH-R chemotherapy for first-line therapy, (2) the safety and efficacy of antiviral and antitumor activity of bortezomib combined with R-ICE in subjects with relapsed or refractory disease, and (3) the safety and activity of DA-EPOCH therapy with or without rituximab in c-Myc positive diffuse large B-cell lymphoma. Future trials will (1) compare CHOP with oral chemotherapy with concomitant antiretroviral therapy in patients with HIV-associated lymphoma in sub-Saharan Africa, and (2) evaluate ibrutinib in patients with relapsed or refractory B-cell NHL or in first-line therapy in combination with chemotherapy. There is also considerable interest in examining the effects of allogenic stem cell transplantation with or without CCR5-depleted cells on HIV reservoirs.

ACQUIRED IMMUNODEFICIENCY SYNDROME-ASSOCIATED BURKITT-LIKE LYMPHOMAS

 I. CLINICAL PRESENTATION. Burkitt-like lymphoma (BL) accounts for 15% to 40% of AIDS-NHL cases. AIDS-BL accounts for about 20% of all BL cases in the United States. The clinical presentations of AIDS-BL patients are similar to those of HIV-negative patients in terms of histology, disease stage, and proportion with bone marrow and CNS involvement.

2. DIAGNOSTIC WORKUP AND STAGING. The pathology of AIDS-BL is characterized by a population of small noncleaved lymphocytes, typically exhibiting a “starry-sky” appearance and a cohesive growth pattern, but atypical variants are noted with medium-sized cells with plasmacytoid differentiation or with nuclear pleomorphism. The tumor cells are generally CD101 and CD201 and usually express proliferation antigen Ki67 on almost 100% of malignant cells, transcription factor Bcl-6, and, uncommonly, antiapoptosis protein Bcl-2. These tumors are classified as high-grade lymphomas. Molecular diagnostic or cytogenetic studies can be used to confirm the presence of the 8;14 translocation or the variant location 2;8 or 8;22, all of which involve a translocation of myc with an immunoglobulin locus.

 III. THERAPY

1. CHOP therapy was used for AIDS-associated BL, prior to the development of HAART, and responses were similar to those of AIDS-associated DLBCL. However, with HAART therapy, AIDS-BL may have a worse prognosis than AIDS-DLBCL when treated in the same fashion, suggesting a need for more aggressive therapy in this setting.
2. R-hyper-CVAD is a regimen of hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, and rituximab given in alternating cycles with high doses of both cytosine arabinoside and methotrexate, followed by leucovorin for a total of 8 cycles. Antibiotic prophylaxis is provided with a quinolone, fluconazole, and valganciclovir, together with standard prophylactic regimens for PCP, MAI, and CMV, where indicated. In a single-center study, 9 of 11 patients achieved CRe, and 1 patient PR. Grade 3 or 4 myelosuppression occurred in all patients, and fever or infection during 35% of chemotherapy cycles. Six of seven patients given HAART concurrently with chemotherapy remained in CR for a median of 29 months.
3. R-CODOX-M/IVAC (cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine) was used for the treatment of 14 HIV-positive patients, of whom 63% had CRs, with a 2-year disease-free survival of 60%. Grade 3 or 4 toxicities included anemia (100%), neutropenia (88%), thrombocytopenia (75%), mucositis (75%), neutropenic fever (63%), sepsis (38%), neuropathy (38%), and nephrotoxicity (24%). In a study of 34 AIDS-BL patients with R-CODOX-M/IVAC, 1-year overall survival was 83%.
4. DA-EPOCH-R was utilized in 30 subjects with BL, including 13 individuals with AIDS-BL who received 3 to 6 cycles of therapy, including 1 cycle after obtaining complete remission, resulting in PFS and OS in 12 of these 13 subjects at a median of 36 months of follow-up (New Engl J Med 2013;369:1915). This regimen is generally better tolerated than R-Hyper-CVAD or R-CODOX-M/IVAC.
5. Prophylactic intrathecal chemotherapy with methotrexate or cytosine arabinoside should be given to all AIDS-BL patients, generally 4 to 6 weekly doses of therapy in patients who do not have positive CSF cytology.

 IV. COMPLICATIONS. The risks of myelosuppression, tumor lysis syndrome, and neurotoxicity are higher for AIDS-BL patients given more intensive therapies, such as R-Hyper-CVAD or R-CODOX-M/IVAC, than for AIDS-DLBCL patients given R-CHOP.

1. FOLLOW-UP is as described for AIDS-DLBCL patients.

 VI. BACKGROUND. AIDS-BL is associated with EBV infection in 80% of cases. However, the pattern of latency differs from that of AIDS-DLBCL, with expression of EBNA-1 but not LMP1 or EBNA2. As in BL not associated with HIV, translocations between immunoglobulin genes and myc are uniformly present. Mutational inactivation of tumor suppressor protein p53 is also prevalent.

 VII. CURRENT FOCUS OF RESEARCH. A confirmatory study of the results with DA-EPOCH-R for AIDS-BL is planned.

ACQUIRED IMMUNODEFICIENCY SYNDROME-ASSOCIATED PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMAS

 I. CLINICAL PRESENTATION. Primary central nervous system lymphoma (PCNSL) usually presents in severely immunocompromised individuals with CD4 counts less than 50/mm³. AIDS-PCNSL accounts for about 13% of all PCNSL cases in the United States. Thus, with widespread use of HAART, the incidence of AIDS-associated PCNSL has declined significantly. Typical presentations are with confusion, memory loss, lethargy, or focal neurological signs. Patients may also present with seizures, headaches, memory loss, or dementia.

1. DIAGNOSTIC WORKUP AND STAGING
2. Differential diagnosis includes systemic lymphomas with CNS involvement, toxoplasmosis, HIV encephalopathy, progressive multifocal leukoencephalopathy, and other infections associated with viral, fungal, or mycobacterial infections. Some investigators have suggested that in patients with serological evidence of prior toxoplasma exposure, a 14-day course of antitoxoplasmosis therapy may be indicated to assess response. However, given the other diagnostic modalities available, this approach is rarely utilized now, and the delay in therapy resulting from this approach is potentially risky.
3. Diagnostic workup should include chest, abdomen, and pelvis CT scans in order to exclude systemic lymphoma. Body PET scans may be indicated as well in selected cases. If these scans are negative, it is unclear whether or not bone marrow biopsy is needed, since the yield of positive results in this setting may be very low. Patients should undergo slit-lamp ophthalmologic exam to exclude concurrent intraocular lymphoma.
4. Brain MRI or CT scan typically shows multifocal disease. However, lesions are typically larger and fewer than those associated with Toxoplasma encephalitis. Lesions may be ring enhancing and are often associated with edema and shift of normal brain structures, and may be found at any location in the brain.
5. Brain PET or single-photon emission computer tomography (SPECT) is helpful in distinguishing PCNSL from other HIV-associated brain lesions, such as toxoplasmosis, which exhibit less uptake of FDG.
6. Brain biopsy is the gold standard for diagnosis, but tumor location and other factors may preclude this procedure. CT-guided stereotactic brain biopsies can produce diagnostic rates with acceptable morbidity, comparable to that of open brain biopsy.
7. CSF EBV PCR is a sensitive (80%) and specific (99%) test for AIDS-associated PCNSL, since EBV infection is uniformly associated with this condition. For patients with positive CSF EBV PCR and PET or SPECT scans showing intense uptake in the brain lesion, biopsy may be obviated. Pathology is typically a diffuse large B-cell lymphoma, usually of the immunoblastic subtype, with angiocentric distribution.

 III. THERAPY for PCNSL should also include HAART, which significantly improves survival.

1. Whole brain radiotherapy alone was used in the pre-HAART era, since the median survival of patients presenting with PCNSL was only 1 to 3 months as a result of OIs. Typically, 4,000 cGy is used in fractions of 267 cGy each. Cranial irradiation alone results in a 53% rate of tumor regression and slightly improved survival compared with untreated individuals. Because of the multifocal nature of AIDS-PCNSL, radiation should be directed to the whole brain and meningeal fields to the level of the second cervical vertebra without spinal irradiation. In patients with poor performance status, who are severely immune compromised, and/or patients with multidrug-resistant HIV infection, this may be the most appropriate therapy. Autopsy studies showed that patients who did not receive radiotherapy died of lymphoma progression, whereas those that did receive radiotherapy died of OIs.
2. High-dose methotrexate (2.5 to 3.5 g/m² every 14 days) with leucovorin rescue was reported to produce a CR of 50%, a median OS of 10 months, and improved quality of life. For patients with a good performance status, who are not severely immunocompromised and are responding to HAART therapy, a chemotherapy regimen including high-dose methotrexate may be appropriate, followed by cranial irradiation, as in the HIV-negative PCSNL population. However, recent studies have questioned the need for cranial irradiation in those individuals who achieve complete remission with chemotherapy. High-dose methotrexate therapy requires careful monitoring of methotrexate levels and adjustment of leucovorin doses if delayed methotrexate clearance is found. Methotrexate should not be used in individuals with a third space fluid collection.
3. High-dose cytosine arabinoside added to high-dose methotrexate has been reported in a small randomized phase 2 trial to improve response rates in HIV-negative PCNSL, although there were higher rates of myelosuppression and neutropenic infections.
4. Steroids are used to limit edema, but the impact on survival is unclear.
5. Rituximab has been reported to play a role in CNS lymphomas not associated with AIDS, when given systemically, but there are only anecdotal reports of its use for AIDS-PCNSL. Intrathecal rituximab remains investigational.
6. Other agents (e.g., temozolomide, topotecan, procarbazine, vincristine, and ifosfamide) and stem cell transplantation remain to be evaluated in AIDS-associated PCNSL.

 IV. COMPLICATIONS

1. Complications of PCNSL include ocular lymphoma that may involve the vitreous, uvea, or retina, and is usually bilateral. Bilateral ocular irradiation, or high-dose cytarabine or methotrexate, which penetrate the vitreous, may be given. Leptomeningeal lymphoma can be treated with intrathecal methotrexate or cytarabine via Ommaya reservoir.
2. Complications of therapy of AIDS-associated PCNSL are coincident OIs and neurological toxicity from whole brain radiotherapy.
3. FOLLOW-UP should be performed monthly in the first year after completion of therapy, with MRI brain scans performed every 3 months and less often thereafter.

 VI. BACKGROUND. AIDS-PCNSL occurs in 2% to 11% of HIV-infected patients, representing a 3,600-fold higher incidence of this disease, compared with that of the general population. Latent EBV-infected cells develop into malignant clones in the relatively immunoprivileged CNS, secondary to decreased immunosurveillance resulting from HIV-related T-cell depletion.

ACQUIRED IMMUNODEFICIENCY SYNDROME-ASSOCIATED PRIMARY EFFUSION LYMPHOMAS

 I. CLINICAL PRESENTATION

8. Primary effusion lymphomas (PELs) account for 1% to 5% of HIV-NHL. PEL presents 200-fold less commonly in HIV-negative patients, including elderly individuals or organ transplant recipients. In the HIV-positive patients, these lymphomas are uniformly associated with HHV8.
9. Classical presentations of PEL are ascites, pleural effusion, or pericardial effusions without infiltrative growth patterns or tumor masses. Some cases of PEL extend into tissues underlying serous cavities, including the nodes, omentum, mediastinum, and lung. Other cases of HHV8-positive solid lymphomas are extracavitary variants of PEL.
10. PEL occurs primarily in homosexual men and late stages of HIV infection (mean CD4 count 98/mm³). In one study, 64% of patients had previous manifestations of AIDS. PEL commonly occurs in patients with previous manifestations of HHV-8 infection, such as Kaposi’s sarcoma or Castleman’s disease.
11. DIAGNOSTIC WORKUP AND STAGING
12. Diagnostic thoracentesis, pericardiocentesis, or paracentesis is usually required to diagnose patient with PEL.
13. PEL is classified as a stage IV NHL.
14. Pathology of PEL usually demonstrates plasma cell differentiation as shown by expression of CD138 or syndecan-1. The cells typically express leukocyte common antigen, CD45, EMA, and activation antigens, HLA-DR, CD23, CD25, CD30, CD38, CD70, and CD77. However, they are usually negative for T- and B-cell markers, including CD20, although clonal immunoglobulin gene rearrangements are present. Although the large, pleomorphic malignant cells may resemble Reed–Sternberg (RS) cells, they are CD15 negative.

 III. THERAPY

1. CHOP therapy was generally ineffective in the pre-HAART era (Nador Blood 1996;88:645). However, now that HAART is available, the CHOP regimen is an appropriate choice of therapy for these patients, if they have adequate performance and immune status. Rituximab is not recommended for use in these lymphomas, which are typically CD20 negative. There are also anecdotal reports of use of other combination chemotherapy regimens for PEL, as described for DLBCL. Other regimens, such as DA-EPOCH, may be effective for PEL.
2. HAART alone has been reported to be effective for AIDS-PEL, according to anecdotal reports.
3. Major prognostic factors for response are good performance status and preexisting use of HAART therapy. In a study using a variety of treatment regimens, of which CHOP was the most common, OS was greater than 3 years in 32% of patients.

 IV. BACKGROUND. AIDS-associated PELs are uniformly associated with HHV8 infection and frequent coinfection with EBV. It is unclear why PEL arises in body cavities, but there is evidence that viral Bcl-2 is activated by hypoxia, which may contribute to lymphoma development.

ACQUIRED IMMUNODEFICIENCY SYNDROME-ASSOCIATED HODGKIN’S LYMPHOMAS

 I. CLINICAL PRESENTATION. HL is 10- to 25-fold increased in incidence in the HIV-positive population compared with the HIV-negative population.

1. At diagnosis, 74% to 92% of HIV-HL patients present with advanced disease, with frequent extranodal involvement, including the bone marrow, liver, and spleen, but mediastinal involvement is uncommon. Moreover, 70% to 96% of patients have B symptoms. Bone marrow involvement is present in 40% to 50% of patients, and is the first indicator of disease in 20% of cases. In contrast to the HIV-negative population, noncontiguous nodal spread of lymphoma is common, for example, liver without splenic involvement or lung without mediastinal node involvement.
2. Median CD4 count at presentation is in the range of 275 to 300/mm³.
3. DIAGNOSTIC WORKUP AND STAGING
4. Lymph node enlargement may be due to HIV or HL, and PET scans may be helpful in distinguishing the etiology. Other coincident causes of lymph node enlargement should also be excluded, such as mycobacterial or cytomegalovirus infection or NHL.
5. Pathology shows the mixed cellularity subtype as the most common variant in HIV-infected individuals, as well as an increased frequency of the lymphocyte-depleted subtype compared with HIV-negative HL. LMP-1 is expressed in almost all cases in the RS cells. RS cells are typically CD15+CD30+CD45−.
6. Staging evaluation is as described by AIDS-DLBCL except that brain MRI/CT scans and lumbar puncture may be omitted unless there are neurological symptoms. Pulmonary function tests should be performed prior to the use of bleomycin.

 III. THERAPY

1. Full-dose chemotherapy regimens are recommended, combined with HAART and G-CSF. However, it should be recognized that G-CSFs increase the likelihood of bleomycin pulmonary toxicity, and thus the fewest possible doses of CSFs should be utilized.
2. ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) given with G-CSF support is the most commonly used regimen, given at the same doses as in the HIV-negative population. In the pre-HAART era, this regimen resulted in a CR of 42%. In the post-HAART era, CR rates of 87% and 91% have been reported in separate studies. Recent studies show that HIV infection does not adversely affect the overall survival or event-free survival for individuals with HL treated with ABVD (J Clin Oncol 2012;30:4056).
3. EBVP (epirubicin, bleomycin, vinblastine, and prednisone) resulted in a CR rate of 74%, with grade 3 or 4 leukopenia in 32% of patients.
4. The Stanford V regimen (doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, and prednisone) resulted in a complete remission rate of 81%, 3-year overall survival of 51%, and disease-free survival of 68%. This regimen maintains or increases the dose intensity of individual drugs, but reduces the cumulative doses of bleomycin and doxorubicin compared with ABVD, and may reduce the incidence of pulmonary or cardiac dysfunction.
5. The BEACOPP regimen (cyclophosphamide, doxorubicin, etoposide, procarbazine, prednisone, bleomycin, and vincristine) resulted in CR in all 12 treated patients and 83% 2-year survival, but grade 3 or 4 leukopenia in 75% of cases.
6. Risk-adapted therapy was utilized in a study of HIV-associated HL. Subjects with early-stage favorable disease received 2 to 4 cycles of ABVD plus involved field radiation, whereas patients with early-stage unfavorable disease received 4 cycles of BEACOPP or a combination of 4 cycles of ABVD, followed by involved radiotherapy if disease was >5 cm or residual disease >2 cm. Patients with advanced disease received 8 cycles of BEACOPP. CRs occurred in 96% of subjects, and 2-year progression-free survival was 92%, and 2-year OS was 91%.
7. Salvage therapy studies have not been reported in AIDS patients. However, patients relapsing more than 12 months after obtaining an initial complete remission may be candidates for treatment with one of the first-line regimens described earlier. Patients relapsing in a shorter period of time may be candidates for similar salvage approaches as described for AIDS-DLBCL patients. The role of brentuximab in salvage therapy remains to be defined in HIV-associated HL.

 IV. COMPLICATIONS of the disease or treatment are as described for AIDS-DLBCL with the addition of possible pulmonary fibrosis resulting from use of bleomycin. This complication, characterized by acute pneumonitis with fever, congestion, cough, and dyspnea, occurs most commonly after doses of more than 200 to 400 U/m², but may occur at lower doses when chest radiotherapy is also utilized.

 V. FOLLOW-UP should be as described for AIDS-associated diffuse large B-cell lymphomas.

 VI. BACKGROUND. EBV has been identified in 80% to 100% of HIV-HL cases compared with about 50% in the HIV-negative population. The RS cells of HL from HIV-negative patients are generally derived from GC B cells, whereas those of HIV-HL patients are derived from post-GC B cells.

 VII. CURRENT FOCUS OF RESEARCH. Current research is focusing on the possible substitution of brentuximab for bleomycin in the ABVD regimen, given the excellent response rate of brentuximab in relapsed HIV-negative HL, but significant pulmonary toxicity when bleomycin and brentuximab are used concurrently. Other research is examining the use of stem cell transplantation, either autologous or allogeneic, in the treatment of HIV-HL, as well as therapeutic strategies targeting EBV infection.

ACQUIRED IMMUNODEFICIENCY SYNDROME-ASSOCIATED ANAL CARCINOMAS

 I. CLINICAL PRESENTATION

1. HIV-infected individuals have a 30- to 120-fold higher rate of anal carcinoma than HIV-negative individuals. These squamous cell carcinomas result from high-risk HPV infections. These malignancies are not clearly associated with immune suppression, occur in individuals with a wide range of CD4 counts, and are not considered AIDS-defining illnesses. The incidence of anal cancers appears to have increased since the introduction of HAART, although clinical features and overall survival have not changed.
2. The most common clinical presentations are pain or bleeding. However, larger tumors may interfere with anal sphincter function and lead to incontinence.
3. Clinical examination will identify a mass, and the size and position within the anal canal or anal margin should be documented. Rectal examination may detect enlarged perirectal lymph nodes.
4. Proctosigmoidoscopy should be done in all of these patients.
5. A thorough gynecological examination should be done in women, especially if the tumor is situated in the anterior anal canal or if the perineum is involved. Evidence of vaginal mucosal involvement suggests that rectovaginal fistula might develop during treatment. If pelvic examination cannot be performed due to pain, this examination should be done under anesthesia.
6. DIAGNOSTIC WORKUP AND STAGING
7. Screening strategies for anal or cervical dysplasia are based on CD4 count and the local expertise.
8. Pathology shows that distal anal tumors tend to be keratinized, whereas more proximal tumors are nonkeratinized and referred to as cloacogenic or basaloid. However, the clinical behavior of both types of tumors is similar.
9. Differential diagnosis includes other rare tumors arising in the anal canal that need to be distinguished from squamous cell carcinoma including adenocarcinomas of the anal ducts or glands, melanomas, clear cell sarcomas, and neuroendocrine tumors.
10. Staging evaluations should include endoanal ultrasonography, CT, MRI, or PET.
11. Prognosis depends on sex, tumor stage, nodal status, and response to chemoradiation. Patients with well-differentiated tumors have a more favorable outcome than those with poorly differentiated cancers.

 III. THERAPY is generally with concurrent chemotherapy with radiotherapy.

1. Chemotherapy options may include fluorouracil and mitomycin, as in the HIV-negative patient population, fluorouracil alone, or fluorouracil with cisplatin. Local control rates are 80% to 90% for tumors less than 4 cm, and 70% to 85% for larger tumors. The addition of mitomycin to fluorouracil improves local control and disease-free survival. HIV-infected patients with CD4 counts greater than 200/mm³ generally tolerate therapy similar to that of the HIV-negative patient population, although the rate of local skin/mucous membrane toxicity and bone marrow suppression may be higher in HIV-positive than in HIV-negative individuals. Individuals with CD4 counts less than 200/mm³ may tolerate chemotherapy less well, and consideration should be given for withholding or reducing the dose of mitomycin.
2. Recurrent or residual disease is associated with substantial morbidity, associated with poor wound healing and wound infections or sinuses. Salvage therapy for recurrent local disease in selected cases may include inguinofemoral lymph node dissection, pelvic exenteration, or additional radiotherapy if the region has not received the maximum tolerated doses.
3. Distant metastatic disease is managed with palliative intent, and active chemotherapy agents include cisplatin and fluorouracil. Resection of isolated metastases in the liver or lung may be considered in select cases.

 IV. COMPLICATIONS. Late complications of chemoradiotherapy occur in 3% to 16% of patients after 3 to 10 years, and include necrosis of the anus, especially with more than 60 Gy external radiotherapy or after interstitial implants. Other complications include neurogenic bladder, urethral stenosis, small bowel damage, cytopenia, intractable diarrhea, and radiation-induced sarcoma. These complications are more common in patients with CD4<200/mm³ (J Clin Oncol 2008;26:2550).

1. FOLLOW-UP of treated patients involves digital rectal examination and proctoscopy every 2 months for 1 year, every 3 months in the second year, and then every 6 months thereafter. If persistent thickening is present after 3 months, follow-up CT or MRI exams and/or biopsies may be indicated.

 VI. BACKGROUND. Anogenital squamous cell carcinomas are uniformly associated with HPV infection, particularly high-risk strains 16, 18, 31, and 35. The HPV E6 protein binds tumor suppressor protein p53 and promotes its degradation, abrogating its cell cycle arrest and apoptosis functions. The HPV E7 protein binds retinoblastoma family proteins, p105, p107, and p130, and promotes cell cycle transition into the S phase.

 VII. CURRENT FOCUS OF RESEARCH is examining the efficacy of vaccines in preventing acquisition of high-risk HPV strains. Moreover, vaccines expressing epitopes of HPV E6 or E7 are also being examined as therapeutic vaccines. The use of infrared coagulation for treatment of high-grade squamous intraepitheal neoplasia of the anal canal is also being studied. In addition, the role of cidofovir against HPV for high-grade perianal dysplasia will be investigated.

ACQUIRED IMMUNODEFICIENCY SYNDROME-ASSOCIATED KS

 I. CLINICAL PRESENTATION

1. KS occurs 500- to 10,000-fold more commonly in HIV-positive individuals than in the general population. Although occurring more commonly in patients with <200 CD4 lymphocytes/mm³, the CD4 count at presentation can be quite variable, and KS may be the first manifestation of AIDS.
2. Clinical presentation depends on the site and degree of KS involvement. Manifestations of disease may range from asymptomatic innocuous cutaneous macules to life-threatening visceral lesions. The clinical course of KS is also highly variable, with rapid increase in the number and size of lesions in some patients over the course of weeks to months, or indolent lesions gradually shrinking over years.
3. Pertinent history should include a description of all areas of initial KS involvement, lesion duration and rates of progression, oral lesions, GI and pulmonary lesions, presence of KS-associated edema, and other KS-associated symptoms, AIDS-defining illnesses, other sexually transmitted diseases, OIs, and past and current antiretroviral treatment.
4. Physical examination includes evaluation of performance status, complete evaluation of the skin, oral cavity, and lymph nodes, with assessment of the chest, abdomen, and neurological assessment, and genital and rectal examinations. Baseline measurements of at least five indicator lesions, description of whether lesions are flat or raised, and determination of the number of lesions per area (i.e., left leg, torso, head, and neck) are necessary for later assessment of rate of progression and response to therapy. Photographs or drawings of sites of KS involvement are helpful for follow-up evaluations.
5. Cutaneous manifestations. Typically, KS presents with pigmented skin lesions, from a few millimeters to several centimeters in size, that may be flat or raised, with a pink to purple or brown color. These lesions tend to be painless and nonpruritic, although bleeding and superficial infection or cellulitis may occur. Visceral KS can occur without skin manifestations.
6. Facial KS typically involves the nasal, periorbital, or conjunctival areas. These may be cosmetically unappealing and cause anxiety and social stigmatization.
7. Oral KS occurs in 30% of patients, and often involves the hard and soft palates, and occasionally the gums, tongue, tonsils, and pharynx. The lesions may be macular, nodular, or exophytic, causing dysphagia, odynophagia, or speech difficulties.
8. Genital KS is characterized by irregular erythematous patches on the foreskin or shaft of the penis.
9. KS of the feet may cause pain and ambulation difficulties.
10. Lymphedema may occur because of dermal and lymphatic involvement of KS, resulting in a nonpitting, sometimes woodlike edema of the lower extremities and genitals, sometimes disproportionally more severe than the degree of KS involvement. Skin breakdown may cause weeping, ulceration, and subsequent superimposed bacterial infections.
11. Nodal KS may present with painless lymph node enlargement, caused by focal or total replacement with KS. This should be differentiated from lymphoma, mycobacterial, or HIV lymphadenitis.
12. Visceral manifestations most often affect the lungs and GI tract.
13. Pulmonary KS affects 40% of KS patients and is usually associated with dyspnea without fever, cough, or hemoptysis. This may be progressive, debilitating, and rapidly fatal if left untreated.
14. GI KS occurs anywhere in the GI tract in 40% of patients at diagnosis, and is generally asymptomatic, although bleeding, obstruction, or enteropathy can occur.
15. Other visceral organs, such as spleen, bone marrow, liver, heart, and pericardium, may be involved with KS. However, CNS involvement with KS is highly unusual.
16. DIAGNOSTIC WORKUP AND STAGING
17. Diagnosis of KS should be confirmed in all patients by biopsy on at least one occasion. Differential diagnosis of pigmented skin lesions in HIV-infected patients includes ecchymosis, nevi, melanoma, Bartonella henselae-associated skin lesions, and dermatofibromas.
18. Clinical Evaluations
19. Evaluation of cutaneous disease includes counting the number of lesions if <50, or the number of lesions on a single portion of the body, measurement of biperpendicular diameters of five lesions, description of the color of the lesions, and whether they are raised or flat, whether there is tumor-associated edema, and photographic documentation of the lesions.
20. Evaluation of mucosal lesions should include description of the size of the lesions and their site of involvement.
21. Evaluation of visceral disease should be directed primarily at assessing pulmonary and GI tract lesions. Patients should have a baseline and at least annual chest radiograph, or, if indicated, chest CT. If GI bleeding, vomiting, pain, or other abdominal symptoms are present, upper or lower endoscopy should be strongly considered.
22. Pathology. The diagnosis of KS is made by biopsy and histological examination of cutaneous lesions, enlarged lymph nodes, or visceral tissues. Typical pathology shows a proliferation of spindle cells that may express endothelial markers such as PECAM-1 (CD31), CD34, LYVE1, podoplanin (D2-40), and FLI1 and KS herpes virus (KSHV, HHV8) markers such as LANA, mixed with endothelial cells, fibroblasts, inflammatory cells, and extravasated erythrocytes. Similar histological findings are present in non-AIDS–related KS.
23. Radiology and endoscopic procedures
24. A baseline chest radiograph is done for all patients with KS to exclude pulmonary KS and other cardiopulmonary disorders associated with HIV infection. Localized or diffuse interstitial reticulonodular infiltrates with mediastinal prominence may be seen in patients with pulmonary KS, and should be differentiated from lymphoma or PCP and other typical (i.e., bacterial) and atypical pneumonias (i.e., mycobacterial, CMV, or histoplasma pneumonias). KS may also present with alveolar infiltrates, pleural effusion, or isolated pulmonary nodules. KS lesions are generally thallium or PET positive and gallium negative, in contrast to pulmonary infections.
25. Bronchoscopy may reveal endobronchial erythematous KS-like lesions even with radiologically normal studies. Because transbronchial biopsies have poor histologic yield, a presumptive diagnosis of pulmonary KS can be made on the basis of dyspnea without fever, chest radiograph, and bronchoscopic findings after exclusion of other disease processes.
26. Staging of KS utilizes the AIDS Clinical Trials Group (ACTG) classification system, which characterizes patients as good risk or poor risk, on the basis of their tumor burden (T), immune function (I), and presence of systemic illness (S). T0 denotes good-risk KS confined to skin and/or lymph nodes and/or minimal oral disease, whereas T1 poor-risk lesions are associated with symptomatic lymphedema, tumor ulceration, extensive oral disease, and/or visceral involvement. Immune function is categorized according to whether the CD4 count is < or ≥150/mm³. S0 is defined as no history of OIs, B symptoms, other HIV-related illness, and Karnofsky score of at least 70%. Good-risk KS patients are T0I0S0.
27. Prognosis in the HAART era is largely determined by the T and S stages, whereas in the era of HAART use, CD4 count does not have a significant impact on survival. The 3-year OS is 88% for individuals with T0S0, 81% for T0S1 patients, 80% for T1S0 patients, and 53% for T1S1 patients.
28. Morbidity from KS is associated with painful lesions in the mouth or on the soles of the feet, lymphedema, symptoms associated with visceral KS, or psychological disturbances resulting from the cosmetic effects of KS lesions.
29. Mortality from KS is associated primarily with pulmonary KS and less commonly with hemorrhage from GI lesions.

 III. THERAPY

1. Patients with good-risk or asymptomatic and stable poor-risk KS may be offered local or systemic therapy.
2. Local therapies include electron beam radiotherapy, topical 9-cis retinoic acid (Panretin Gel), intralesional injections or iontophoresis of vinblastine (0.1 mL of 0.1 mg/mL) or 3% sodium tetradodecyl sulfate (0.1 to 0.3 mL), cryotherapy, laser coagulation therapy, or surgical excision. Despite the effectiveness of these procedures, there are several possible complications. Radiotherapy may result in chronic residual lymphedema, postirradiation telangiectasias, woody skin changes, and reappearance of KS after treatment. It is more toxic for mucosal than skin lesions. Panretin gel can cause local inflammation and lightening of the skin, resulting in inadequate cosmetic results. Photodynamic therapies can result in moderate pain and photosensitivity for a number of weeks after treatment. Intralesional injections cause necrosis or sclerosis of mucocutaneous lesions, which may be quite painful. Cryotherapy can result in hypopigmented areas, particularly troublesome for dark-skinned individuals. Surgical excision is not optimal for large lesions due to reappearance of KS at the margins.
3. HAART therapy alone produces a response rate of about 80% in patients with T0 lesions, but responses are unusual in patients with T1 lesions. This approach is more likely to be effective in patients naïve to HAART who have previously poorly controlled HIV, and who will be compliant with subsequent use of HAART. The time to response is 3 to 9 months. PI-based and nonnucleoside reverse transcriptase inhibitor-based HAART regimens have been verified to be similarly effective. It should be noted that progressive KS may also develop in patients who have recently initiated HAART, attributed to an immune reconstitution syndrome.
4. Thalidomide has been reported to produce responses in 30% to 50% of patients, at doses of 100 to 1,000 mg/day (200 mg/day is the usual maximal tolerated dose), but is complicated by fatigue, constipation, neuropathy, xerostomia, neutropenia, orthostatic hypotension, risk of birth defects, and, less commonly, hyper- or hypoglycemia, hypothyroidism, tremor, elevated serum transaminases, or thrombosis. The use of other thalidomide analogs, such as lenalidomide and pomalidomide, is currently under investigation.
5. Interferon-α produces responses in about 30% of patients, when used in high doses, >20 mU/m² three times per week, but fewer responses at lower doses when used alone, although responses at low doses are improved when combined with PIs. Interferon-α can result in neutropenia, flulike symptoms, and depression. The use of pegylated interferon for KS has not been reported.
6. Patients with poor-risk symptomatic visceral KS or rapidly progressive KS should be treated with HAART combined with chemotherapy or investigational agents. Pharmacological doses of systemic corticosteroids should be avoided, since this can cause marked acceleration of KS.
7. Liposomal anthracyclines are the most appropriate initial therapy, and either liposomal doxorubicin (Doxil, 20 mg/m² IV every 2 to 3 weeks) or daunorubicin (DaunoXome, 40 mg/m² IV every 2 to 3 weeks) results in response rates of 25% to 90%. Grade 3 or 4 adverse effects include myelosuppresion (36%), nausea and vomiting (15%), anemia (10%), and hand-foot syndrome. The incidence of extravasation injury, mucositis, nausea, alopecia, and cardiomyopathy with liposomal anthracyclines is lower than that with nonliposomal anthracyclines.
8. Paclitaxel 100 mg/m² q 2 to 3 weeks is generally considered the most effective and best-tolerated second-line agent, although some oncologists recommend it as first-line therapy for life-threatening KS. Response rates of 59% to 71% have been reported, with a median duration of response of more than 10 months. Myelosuppresion (grade 3 or 4 in 35%), alopecia, neuropathy, and hypersensitivity reaction are the major toxicities. Liposomal paclitaxel (xyotax) and abraxane have not been studied in AIDS-KS.
9. Oral etoposide may be useful as a third-line agent, given at a dose of 50 mg/day for 7 days of each 14-day cycle. In a trial of 36 patients, the response rate was 36%, with a median duration of response of 25 weeks. This therapy was complicated by grade 3 or 4 neutropenia in 36% of patients.
10. Vinorelbine has a 43% response rate in patients with one or more prior systemic therapies for KS, but is associated with myelosuppression.
11. Alternative chemotherapy regimens that may be considered include bleomycin, docetaxel, or a combination of doxorubicin, bleomycin, and vincristine.
12. Duration of therapy depends on individual patients. Generally, chemotherapy is given until a plateau in the response has been achieved, and then doses of therapy can be discontinued or given less frequently. Chronic chemotherapy can be associated with limiting cumulative treatment-related toxicities.

 IV. COMPLICATIONS

1. Complications of AIDS-KS. Although visceral KS, especially GI and pulmonary KS, may prove fatal, AIDS-related immunosuppression and OIs remain the major cause of morbidity and mortality in patients with KS. Superimposed bacterial, fungal, and parasitic infections in ulcerated, weeping lesions are not uncommon. Severe dyspnea from pulmonary KS and hemorrhage from GI involvment of KS also may be seen.
2. Complication of therapy. The use of HAART with systemic anti-KS therapy, such as paclitaxel, may potentially cause profound toxicity in some patients with AIDS-KS. The metabolism of paclitaxel, docetaxel, and anti-HIV PIs involves cytochrome P450 3A4 isoform.
3. FOLLOW-UP. The frequency of follow-up may vary from every 2 weeks to every 6 months, depending on the stage of disease, rate of disease progression or regression, and the type of therapy. During follow-up visits, indicator lesions should be measured, the number of KS lesions in indicator regions should be counted, and the character of the lesions described. Repeat photographs and follow-up chest radiographs should be performed as clinically indicated.

 VI. BACKGROUND

1. KS develops in HIV-negative individuals, including older men primarily of Eastern European, Mediterranean, and/or Jewish descent, individuals undergoing immunosuppression (e.g., associated with bone marrow or organ transplantation), and young males in equatorial Africa, as well as in HIV-infected individuals. AIDS-associated KS occurs in individuals who are homosexual or bisexual and very rarely, if at all, in other HIV risk groups. The incidence of AIDS-KS has decreased significantly with the use of HAART in the United States. However, in other parts of the world with limited access to HAART, KS incidence continues to increase.
2. Pathogenesis of KS is thought to involve expression by the spindle cells of cytokines such as interleukin-6, basic fibroblast growth factor, vascular endothelial growth factor (VEGF), matrix metalloproteinases, tumor necrosis factor-α, oncostatin-M, platelet-derived growth factor, and interferon-γ.
3. HHV8, also designated KSHV, is thought to be the etiologic agent of this disorder, with primarily latently infected cells contributing to the development of this disorder. A small proportion of cells with lytic HHV8 replication may also contribute to disease pathogenesis. HHV8 is present in AIDS-KS, as well as KS developing in HIV-negative populations. Several viral genes implicated in the pathogenesis of KS include those encoding homologs of antiapoptosis proteins Bcl-2 and an inhibitor of Fas-mediated apoptosis, interleukin-6, cyclin D, interferon-regulatory factors, chemokines, and G protein-coupled receptors. Serologic tests for HHV8 are not yet routinely available. The median time for KS development in HHV8-positive, HIV-1-infected individuals is estimated to be about 10 years. HHV8 is thought to be transmitted sexually, although concentrations of virus in semen appear to be very low. Blood-borne transmission is thought to occur, but inefficiently. Mother-to-child transmission also occurs, which is primarily through saliva.

 VII. CURRENT FOCUS OF RESEARCH

1. Antiangiogenic agents have been extensively studied in AIDS-associated KS. This includes thalidomide, as well as several agents studied in phase I and II trials, including fumagillin analog TNP-470, a VEGF receptor inhibitor SU5416, antiangiogenic dipeptide IM862, bevacizumab, lenalidomide, and ephrin and Notch pathway inhibitors. The matrix metalloproteinase inhibitor, COL-3, a tetracycline analog, resulted in a 44% response rate for a median duration of more than 25 weeks in a cohort of 17 patients. This therapy was complicated by headache, photosensitivity, or rash. An inhibitor of collagen synthesis, halofuginone, is also undergoing clinical study in AIDS-KS. Interleukin 12 has also been shown to be a potent inhibitor of angiogenesis, perhaps through induction of inducible protein 10, and clinical trials are underway with this agent. An antisense oligonucleotide to VEGF mRNA will also be studied in AIDS-KS. There is also evidence that antiretroviral PIs may function as angiogenesis inhibitors.
2. Inhibitors of growth factor receptor signaling were studied, including imatinib, as an inhibitor of platelet-derived growth factor and c-kit receptors. In a trial of 10 individuals given 600 mg/day, 5 exhibited a PR, but grade 3 or 4 diarrhea, depression, or neutropenia occurred in 8 patients. Other studies are based on the mediators of signaling pathways, including phosphatidyl inositol 3-kinase, serine-threonine kinase Akt, extracellular receptor kinase Erk, nuclear factor kappa B, target of rapamycin (TOR), and cyclin D.
3. Cell-differentiating retinoids have also been used systemically in AIDS-KS patients. Oral 9-cis-retinoic acid (alitretinoin or Panretin) resulted in a 37% response rate, but almost half of the patients discontinued treatment because of headache or skin toxicity. Hypertriglyceridemia and subclinical pancreatitis have also been reported with retinoids, including alitretinoin. There are no reports of the use of bexarotene for AIDS-KS.
4. Anti-HHV8 therapy with cidofovir or foscarnet has been reported in anecdotal or retrospective studies. For example, time to KS progression was prolonged in patients treated with foscarnet compared with patients treated with ganciclovir (211 days vs. 22 days). Histone deacetylase inhibitors, such as butyrate and valproic acid, and nuclear factor kappa B inhibitors (e.g., bortezomib), which have been shown to induce lytic gene expression of HHV8, are being evaluated in clinical trials.

OTHER ACQUIRED IMMUNODEFICIENCY SYNDROME-ASSOCIATED MALIGNANCIES

Although a number of other malignancies may be more frequent among HIV-positive than among HIV-negative individuals, treatment approaches are generally similar, especially if virus load is well controlled and CD4 is not profoundly depressed.

 I. HCC is about fivefold more common in HIV-positive individuals than in the general population, primarily because of a higher rate of persistent hepatitis B and C virus infection. However, higher rates of alcohol abuse, nonalcoholic steatohepatitis, and diabetes may contribute to HCC development in HIV-positive individuals. Screening for active HBV and HCV infection is recommended for all HIV-positive individuals. Hepatitis B vaccine should be provided to all individuals who are not immune to HBV. Antiviral treatment is recommended for individuals with persistent infection and evidence of liver disease. Screening for HCC in patients with cirrhosis is recommended every 6 months with ultrasound. Treatment of HCC in HIV-positive patients, with transplantation, TACE, or sorafenib (depending upon the stage), is similar to that in HIV-negative individuals. However, outcomes of transplantation for HCC may be worse in HIV-positive individuals, in terms of HCV and HCC recurrence.

2. LUNG CANCERS occur 2.5- to 5-fold more commonly in HIV-positive individuals than in the general population, and are the most frequently diagnosed non-AIDS–defining malignancy in this population. Lung cancer risk is unrelated to level of HIV-induced immunosuppression.

 III. LIP CANCERS occur 3.1-fold more commonly in HIV-infected patients than in the general population. Some of these cancers may be HPV related.

 IV. CERVICAL CANCERS occur threefold more commonly in HIV-infected women than in the general population. Pap smears are recommended at the time HIV is diagnosed, and repeated at least once within 6 months if normal. If the initial or follow-up Pap smear shows severe inflammation, a repeat study should be performed in 3 months. If a Pap smear shows squamous intraepithelial lesions or atypical squamous cells of undetermined significance, colposcopic examination and, if indicated, biopsies should be performed. High-risk HPV infections are found more commonly in sexually active HIV-infected women than in women not infected with HIV. When cervical cancer presents in an HIV-infected woman with CD4<500/mm,³ it appears at a younger age and with more advanced disease, and it is associated with a worse outcome than in women without HIV infection. The incidence and therapeutic response of cervical cancer, however, appears unchanged by HAART therapy. The use of radiation therapy combined with chemotherapy may also be less well tolerated in HIV-infected women than in women lacking HIV. As for HIV-negative patients, early-stage, nonbulky cervical tumors respond well to surgical intervention, and for more advanced tumors, the standard of care is concomitant chemoradiotherapy with cisplatin.

3. PENILE CANCER occurs 3.9-fold more commonly in HIV-positive individuals than in the general population.

 VI. OTHER. Higher rates of testicular seminomas, multiple myeloma, multicentric Castlemans’s disease, nonmelanotic and melanotic skin cancer, prostate carcinoma, brain tumors, leukemia have also been described in HIV-infected individuals than in the general population.

SUGGESTED READINGS

Ammari ZA, Mollberg NM, Abdelhady K, et al. Diagnosis and management of primary effusion lymphoma in the immunocompetent and immunosuppressed hosts. Thoracic Cardiovasc Surg 2013;61:343–349.

Antman K, Chang Y. Kaposi’s sarcoma. N Engl J Med 2000;342:1027–1038.

Barta SK, Xue X, Wang D, et al. Treatment factors affecting outcomes in HIV-associated non-Hodgkin lymphomas: a pooled analysis of 1546 patients. Blood 2013;122:3251–3262.

Clark MA, Hartley A, Geh JI. Cancer of the anal canal. Lancet Oncol 2004;5:149–157.

Dunelavy K, Pittaluga S, Shovin M, et al. Low-intensity therapy in adults with Burkitt’s lymphoma. New Engl J Med 2013;369:1915–1925.

Dunleavy K, Wilson WH. How I treat HIV-associated lymphoma. Blood 2012;119:3245–3255.

Kaplan LD. Management of HIV-associated Hodgkin lymphoma: how far we have come. J Clin Oncol 2012;30:4056–4058.

Martis N, Mounier N. Hodgkin lymphoma in patients with HIV infection: a review. Curr Hematol Malig Rep 2012;7:228–234.

Oehler-Janne C, Huguet F, Provencher S, et al. HIV-specific differences in outcome of squamous cell carcinoma of the anal canal: a multicentric cohort study of HIV-positive patients receiving highly active antiretroviral therapy. J Clin Oncol 2008;26:2550–2557.

Pria AD, Hayward K, Bower M. Do we still need chemotherapy for AIDS associated Kaposi’s sarcoma? Expert Rev Anticancer Ther 2013;13:203–209.

Ratner L, Lee J, Tang S, et al. Chemotherapy for human immunodeficiency virus-associated non-Hodgkin’s lymphoma in combination with highly active antiretroviral therapy. J Clin Oncol 2001;19:2171–2178.

Rudek MA, Flexner C, Ambinder RF. Use of antineoplastic agents in patients with cancer who have HIV/AIDS. Lancet Oncol 2011;12:905–912.

Spano J-P, Costagliola D, Katlama N. AIDS-related malignancies: state of the art and therapeutic challenges. J Clin Oncol 2008;26:4834–4842.

Yarchoan R, Tosato G, Little RF. AIDS-related malignancies—the influence of antiviral therapy on pathogenesis and management. Nat Clin Pract 2005;2:406–415.