Abeloff's Clinical Oncology, 4th Edition

Part II – Problems Common to Cancer and its Therapy

Section H – Special Populations

Chapter 69 – HIV-Associated Malignancies

Richard F. Ambinder,Nina D. Wagner-Johnston

SUMMARY OF KEY POINTS

Incidence • Non-Hodgkin's lymphoma, Hodgkin's lymphoma, and Kaposi's sarcoma (KS) all occur with increased incidence in human immunodeficiency virus (HIV)-infected patients. • KS occurs in HIV-infected patients who also are infected with KS herpesvirus (KSHV). Outside of Africa and some Mediterranean populations, KS occurs mainly in men who have sex with men. • Lymphoma (non-Hodgkin's and Hodgkin's) occurs in all HIV risk groups. These neoplasms tend to be aggressive and extranodal and to manifest at an advanced stage. Burkitt's and Hodgkin's lymphomas tend to occur in patients with higher CD4+ counts (typically greater than 200/mm3), whereas primary central nervous system lymphoma tends to occur in patients with very low CD4+ counts (typically less than 50/mm3). Etiology and Pathogenesis • KS is always associated with KSHV; immunocompromise, inflammatory cytokines, and perhaps the HIV TaT protein contribute to pathogenesis. • Lymphoma in HIV-infected patients is associated with Epstein-Barr virus (EBV) in approximately half of the cases; immunocompromise, chronic antigen stimulation, and perhaps inflammatory cytokines and chemokines contribute to pathogenesis. Evaluation of Patients with Kaposi's Sarcoma • Determination of CD4+ T-cell count and HIV load is the first step in evaluation. • Biopsy is indicated to confirm diagnosis. • Computed tomography (CT) scan of chest and abdomen also is indicated. • Gastrointestinal endoscopy is performed if clinically indicated Treatment of Kaposi's Sarcoma • Highly active antiretroviral therapy (HAART) and treatment of opportunistic infections sometimes are associated with regression of KS. • If disease is symptomatic or rapidly progressive, or with visceral involvement, systemic therapy with liposomal anthracycline or paclitaxel is instituted; all patients should be receivingPneumocystis prophylaxis. Hematopoietic growth factors and antifungal and antiherpesvirus prophylaxis or treatment also are appropriate for most patients receiving cytotoxic chemotherapy. • If disease is indolent and antiretroviral therapy has just been initiated or major changes have been made, observation may be appropriate. • For a few lesions, topical therapy, injection of lesions, or radiation therapy may be adequate treatment. • For systemic disease, interferon, thalidomide, or experimental therapy should be considered. Evaluation of Patients with Lymphoma • Determination of CD4+ T-cell count and HIV load is the first step in evaluation. • Assessment for signs of tumor lysis also is indicated. • Extranodal presentations of lymphoma are common, as are constitutional symptoms (especially with Hodgkin's lymphoma). • Staging for systemic lymphoma should include testing lactate dehydrogenase levels; imaging of chest, abdomen, and brain; bone marrow biopsy; and lumbar puncture. • Positron emission tomography (PET) scans with fluorodeoxyglucose (FDG) labeling should be interpreted with extreme caution because HIV infection, inflammation associated with opportunistic infection, and immune reconstitution syndrome all are associated with FDG activity. Treatment of Lymphoma • Allopurinol and hydration constitute the first step in treatment, even before staging is complete. • Chemotherapy (with cyclophosphamide, hydroxydaunomycin (doxorubicin), vincristine (Oncovin), and prednisone (CHOP) plus rituximab or etoposide, Oncovin, doxorubicin, cyclophosphamide, and prednisone (EPOCH) plus rituximab for non-Hodgkin's lymphoma, and doxorubicin (Adriamycin), bleomycin, vincristine, and dacarbazine (ABVD) or the Stanford V regimen for Hodgkin's lymphoma) is standard treatment. • Intrathecal prophylaxis is appropriate for patients with Burkitt's or Burkitt's-like lymphoma, for patients with bone marrow involvement of non-Hodgkin's lymphoma, and for patients with EBV-associated non-Hodgkin's lymphoma. Either cytarabine or methotrexate can be used for this purpose. Cytotoxic Therapy for Cancer • Pneumocystis prophylaxis is given regardless of CD4+ count. • Antifungal and antiherpesvirus infection prophylaxis or treatment also is indicated. • In HAART-naive patients, antiretroviral therapy should be initiated shortly after cytotoxic chemotherapy begins when associated nausea is controlled. • Patients with relapsed lymphoma may be appropriate candidates for high-dose therapy with stem cell rescue.

INTRODUCTION

In 1981, the first cases of Pneumocystis carinii pneumonia in gay men were reported.^[1] Shortly thereafter, KS, primary central nervous system lymphoma, and Burkitt's lymphoma also were recognized in gay men. In 1983 human immunodeficiency virus (HIV-1) was cultured from the lymph node of a patient.^[2] The origins of the HIV/AIDS (acquired immunodeficiency syndrome) epidemic remain obscure, but by 2006, the impact of the epidemic was staggering. Nearly 40 million people worldwide were infected with HIV, and the annual death rate was approximately 3 million, making HIV the fourth leading cause of death worldwide.^[3] In North America, approximately 1.4 million people are infected, and almost half a million have died. Among patients with access to antiretroviral therapy, however, AIDS-related mortality has dramatically declined. This chapter reviews aspects of HIV infection and the diagnosis and management of KS, AIDS-associated lymphoma, and Hodgkin's lymphoma.

HIV INFECTION

The virus is transmitted sexually, parenterally, and vertically.^[4] Worldwide, heterosexual transmission is most common. Condoms reduce the risk of transmission, and male circumcision reduces the risk of female-to-male HIV transmission.^[5] The highest risk of sexual transmission is associated with receptive anal intercourse. In the United States, men who have sex with men are the largest HIV risk group. Injection drug use also is a major contributor to the epidemic. Health care workers are at risk, but barrier precautions, safer needle devices, attention to safe practices, and related technical innovations have reduced exposure.^[6]

HIV is associated with a spectrum of disease from asymptomatic to profoundly immunocompromised. HIV RNA levels are important predictors of the rate of progression, whereas CD4⁺ T-cell counts are markers of immunologic status. In patients who do not receive treatment, the plasma HIV load reaches a fairly constant level within about 6 months of primary infection. The host cytotoxic T-cell response is one determinant of this “set point.” Some diseases are specifically associated with low CD4⁺ T-cell counts. For example, Pneumocystis pneumonia typically occurs in patients with counts of less than 200 cells/mm³, and primary brain lymphoma typically is diagnosed in patients with counts of less than 50 cells/mm³.^[7]

A variety of constitutional signs and symptoms are common in HIV-infected patients, even in the absence of opportunistic infection or malignancy. These include anorexia, nausea, vomiting, and weight loss. Persistent fever, however, always requires a search for opportunistic infections. Typically this investigation involves a chest radiograph, sinus CT scan, blood cultures for bacteria and atypical mycobacteria, and serum cryptococcal antigen test. Neurologic problems include AIDS dementia complex, HIV myelopathy, and various peripheral neuropathies.

Opportunistic infections that commonly occur in HIV-infected patients include Pneumocystis pneumonia (the agent of which is now called Pneumocystis jiroveci), chronic sinusitis, oral and esophageal candidiasis, herpes simplex infections, shingles, cytomegalovirus retinitis, and enterocolitis associated with Campylobacter, Salmonella, Shigella, adenovirus, cytomegalovirus, or any of various protozoans (Cryptosporidium, Entamoeba histolytica, Giardia, and others). A variety of infections manifest in the central nervous system, including toxoplasmosis, progressive multifocal leukoencephalopathy, and cryptococcal meningitis. Skin infections with molluscum contagiosum and dermatophytic fungi also are common. Several of these infections can be prevented with appropriate prophylaxis^[8] ( Table 69-1 ).

Table 69-1 -- Prophylaxis of Opportunistic Infections

CD4+ T-Cell Count	Indicated Prophylaxis
Less than 200/mm3	Pneumocystis pneumonia (PCP)[*] prophylaxis with TMP-SMX, dapsone, or aerosolized pentamidine.
Less than 100/mm3	Toxoplasmosis prophylaxis in patients who are seropositive for Toxoplasma gondii. TMP-SMX administered for PCP prophylaxis also protects against toxoplasmosis. A variety of other agents are available for use in patients not receiving TMP-SMX.
Less than 50/mm3	Mycobacterium avium complex (MAC) infection prophylaxis. The drug of choice is either clarithromycin (daily) or azithromycin (weekly).

TMP-SMX, trimethoprim-sulfamethoxazole.

*	I.e., Pneumocystis jiroveci infection.

Antiretroviral therapy generally is recommended for all patients with acute HIV infection or within the first 6 months after seroconversion. ^{[9] [10] [11]} In addition, antiretroviral therapy is recommended for all patients with symptomatic AIDS, thrush, or unexplained fever and patients with CD4⁺ T-cell counts below 200/mm³. For asymptomatic patients with CD4⁺ T-cell counts above 200/mm³, many clinicians would initiate therapy only in those with higher viral loads. Drugs approved for the suppression of viral replication include nucleoside analog reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, and an inhibitor of fusion of the viral envelope with CD4⁺ T cells.^[12] In parallel with the treatment of chemotherapy-responsive malignancies, combination antiretroviral therapy with two or more agents appears to be the most effective way to suppress viral replication and to reduce the emergence of resistant virus. Use of non-nucleoside reverse transcriptase inhibitors is associated with rapid mutations to high-level resistance, so these agents should never be used alone. Use of protease inhibitors sometimes is associated with lipodystrophy, a disorder associated with fat redistribution. The only available envelope fusion inhibitor, enfuvirtide, is a parenteral drug and approved solely for resistant virus. A convenient guide to the medical management of HIV infection, which is updated regularly, can be found at the Johns Hopkins AIDS Service website (http://hopkins-aids.edu/publications/publications).

KAPOSI'S SARCOMA

Epidemiology

Before AIDS, KS was a rare disease recognized in older men of Eastern European or Mediterranean descent, in parts of Africa where it often occurred in children, and in organ transplant recipients.^[13]Among AIDS patients, KS is the most common cancer. The risk of development of KS for an HIV-infected patient in the pre-HAART era was estimated to be greater than 1000 times the risk in the HIV-uninfected population.^[14] With antiretroviral therapy, the incidence has diminished substantially. ^{[15] [16]} The risk of KS is not evenly distributed among HIV risk groups. KSHV, also referred to as human herpesvirus-8 (HHV-8), is a required cofactor.^[13] In contrast with most human herpesvirus infections, which are ubiquitous, KSHV infection is uncommon in most populations worldwide. Rates of infection are higher in central and southern Africa and intermediate in Mediterranean and Eastern European countries.

Men who have sex with men are at especially high risk for acquiring KSHV infection.^[17] Sexual transmission may be inferred from several studies, but the precise mode of transmission remains poorly understood. By contrast, patients who acquire HIV infection through nonsexual blood-borne exposure (from intravenous drug use or transfusion of blood or blood products) are at lower risk for KSHV infection and for the development of KS. Among persons who are seropositive for KSHV and HIV, the sequence of exposure is an important risk factor for the development of KS.^[18] When KSHV seroconversion follows HIV seroconversion, the risk of developing KS is higher. Presumably this reflects the impact of HIV on establishing an effective primary immune response to KSHV.

Pathogenesis

KS lesions are composed of spindle-shaped cells between collagen bundles, neovascular slit-like spaces, extravasated erythrocytes, hemosiderin-laden macrophages, and an infiltrate of plasma cells, lymphocytes, and other inflammatory cells.^[19] Spindle cells show nuclear pleomorphism in the later stages. Lesions begin in the dermis and progress from macular to plaque to tumor stage. In the early macular stage, spindle cells form irregular slits and clefts. Nuclear atypia and mitoses are absent. In the plaque stage, the entire dermis is involved, and extravasated erythrocytes and hemosiderin-laden macrophages appear. With progression to the tumor stage, spindle cells come to predominate. Nuclear atypia and mitoses are present.

Spindle cells probably are of lymphatic endothelial origin. KS may begin as a polyclonal inflammatory lesion and only sometimes progress to clonal neoplasia. Immunohistochemistry and in situ hybridization studies show that KSHV is present in spindle cells and some of the cells of the inflammatory infiltrate. KSHV is invariably present in KS lesions.^[20] Electron microscopy shows evidence of viral production in some cells in KS lesions ( Fig. 69-1 ), but spindle cells generally are latently infected ( Fig. 69-2 ). Several viral genes are implicated in aspects of regulation of cellular growth, apoptosis, immune regulation, and angiogenesis.^[21] Curiously, many of the genes with functional properties suggesting that they may play a role in transformation are lytic cycle genes and are not expressed in most of the spindle cells of KS lesions. These include the viral interferon regulatory factors (v-IRFs), an antiapoptotic protein viral Bcl-2 (v-Bcl-2), viral interleukin 6 (v-IL-6), a G protein-coupled receptor (GPCR), and K1, a transmembrane glycoprotein with transforming properties. The viral proteins that are expressed in latently infected spindle cells are LANA (latency-associated nuclear antigen), a nuclear protein required for maintenance of the viral episome; v-CyC, a cyclin-D homolog that may disrupt usual pathways of cell cycle inhibition; and v-FLIP (viral FLICE-like inhibitory protein—FLICE being Fas-associated protein with death domain [FADD]-like interleukin-1α–converting enzyme), an antiapoptotic protein that blocks death signals and may induce survival signals. KSHV LANA may recruit de novo DNA methyltransferases, an integral feature in the development of cancer.^[22] The molecular biology of the virus and its role in transformation are discussed further in Chapter 11 .

Figure 69-1 Electron micrograph showing herpesvirus particles budding from spindle cells in a Kaposi's sarcoma lesion. (Courtesy of Jan Orenstein.)

Figure 69-2 Kaposi's sarcoma herpesvirus (KSHV) antigens in spindle cells of a nodular KS lesion. Immunohistochemical studies show punctate nuclear LANA (brown spots) in many cells, with v-GPCR expression (red cytoplasm) in a few scattered lytic cells with nuclei that are devoid of LANA. LANA, latency-associated nuclear antigen; v-GPCR, viral G protein-coupled receptor; v-IL-6, viral interleukin-6.

The immune system seems to play a determining role in the pathogenesis of KS. In organ transplant recipients, reduction or withdrawal of immunosuppression is often associated with tumor regression.^[17]The virus itself expresses a number of genes that modify immune function. Viral genes modulate the actions of interferon and downregulate the display of major histocompatibility complex (MHC) class I and natural killer (NK) cell receptor ligands. ^{[23] [24] [25]} Cytotoxic T-cell responses to viral lytic antigens are readily detected in KSHV-seropositive individuals but are diminished in HIV-infected persons.

Cytokine dysregulation associated with HIV infection may specifically enhance the proliferation of this neoplasm. In vitro interleukin-6, tumor necrosis factor-a, interleukin-1β, interleukin-8, and various chemokines will stimulate proliferation of KS-derived cells. The HIV TaT protein may activate the RAS/ERK MAPK and JAK/STAT pathways, leading to lytic cycle replication of KSHV. ^{[26] [27]}Opportunistic infections often precede the presentation or an exacerbation of KS. Although both phenomena may reflect a deterioration of underlying immune status, several investigators have suggested that altered cytokine and inflammatory mediator production in association with opportunistic infection may have a direct impact on KS pathogenesis.^[28]

Clinical Aspects

KS lesions typically arise on the skin or mucous membranes as flat deep purple plaques ( Fig. 69-3 ). These plaques may progress to form nodules. Many parts of the body may be involved, and the clinical problems associated with KS vary as a function of location. Lesions generally are not pruritic or painful (except occasionally when they involve the plantar surface of the feet). The most frequent sites of disease are the skin, mucous membranes, lymph nodes, and gastrointestinal tract. Skin lesions most commonly appear on the legs and face (especially the nose and ears) and often are symmetrically distributed. The oral hard palate also is commonly involved. KS virtually never involves brain parenchyma.

Figure 69-3 Kaposi's sarcoma lesions. A, Plaque lesion. B, Nodular lesions. C, Near-symmetrical distribution of lesions on the trunk. Lesions are circled. D, Lesions on the hard palate.

KS lesions have a distinctive appearance that is highly suggestive with regard to diagnosis. Other entities, however, occasionally are confused with KS. Among them is bacillary angiomatosis, a benigndisease associated with a slow-growing, fastidious, gram-negative bacillus and treated with antibiotic therapy.^[29] Bacillary angiomatosis often is associated with systemic symptoms such as fever, chills, and headache. Therefore, a biopsy generally is indicated to confirm the diagnosis. This most commonly is a punch biopsy of a skin lesion, but at times lymph node biopsy, transbronchial or other endoscopic biopsy, or pleural biopsy is required. Once the diagnosis has been established, visualization of a characteristic lesion by bronchoscopy without biopsy or characteristic CT findings (flame-shaped hemorrhages) generally are regarded as adequate to diagnose pulmonary KS ( Fig. 69-4 ). Gallium scan may be useful in differentiating pulmonary KS from Pneumocystis pneumonia, because the inflammatory infiltrates in Pneumocystis pneumonia are gallium-avid and KS lesions are not. On the other hand, KS lesions usually are thallium-avid.

Figure 69-4 Computed tomographic scan of the chest shows a nodular lesion with characteristic flame-like appearance adjacent to the right upper bronchus. (Courtesy of Elliot Fishman.)

Lesion location is an important determinant of symptoms. Facial lesions are particularly likely to be cosmetically disturbing. Lesions of the lower extremities often lead to lymphatic obstruction with painful edema. Pulmonary lesions often are associated with dyspnea (but rarely with hemoptysis). Gastrointestinal lesions may be associated with pain, cramping, diarrhea, and bleeding or may be entirely asymptomatic.

Staging and Prognosis

Standard tumor-node-metastases (TNM) staging has not proved particularly useful for KS, partly because KS is a multicentric disease and partly because the status of HIV disease is of overriding importance. The AIDS Clinical Trials Study Group (ACTG) developed a staging system specifically for KS occurring in HIV-infected persons.^[30] Devised in the era before the introduction of HAART, this system classified patients as “good risk” or “poor risk” according to the extent of tumor (confined to skin or minimal disease versus edema, ulcers, and extensive oral, visceral, or gastrointestinal invasion), immune status as measured by CD4⁺ T-cell count (≥200/mm³, <200/mm³), and evidence of HIV-associated systemic symptoms; it proved to be a reasonable predictor of survival. When the ACTG staging system was re-evaluated in patients receiving HAART, immune status was no longer associated with an increased risk of death, even when the CD4⁺ cutoff point was lowered to 100/mm³ or less.^[31]

Suppression of HIV replication with antiretroviral therapy sometimes is associated with remission. ^{[32] [33]} It has been noted that some protease inhibitors have direct antiangiogenic effects, but regimens that do not include protease inhibitors appear equivalent with regard to clinical outcome of antiretroviral-naive HIV-infected patients with KS.^[34] KSHV copy number does not correlate well with clinical response in patients receiving liposomal doxorubicin.^[35]

Therapy

Management of HIV and Opportunistic Infection

HAART has profoundly altered the survival of patients with KS. The Multicenter AIDS Cohort Study showed an 81% reduced risk of death for patients with KS who received HAART.^[33] The only form of KS clearly implicated in directly causing the death of patients is pulmonary KS. In the era before HAART, KS was associated with a 90% mortality rate attributable to disease progression. In patients receiving HAART, KS is associated with a 47% mortality rate.^[36]

The impact of antiviral therapy may be multifaceted. Restoration of immune function must be of major importance, but antiviral therapy also may reduce exposure to HIV proteins such as TaT and a variety of inflammatory cytokines associated with opportunistic infections also thought to play a role in KS progression. Thus, therapy begins with ensuring that the antiretroviral regimen has been optimized and that opportunistic infections have been treated ( Box 69-1 ). In the absence of rapidly progressing disease (more than 10 new lesions in the past month), lymphedema, or symptomatic visceral or cosmetically disfiguring disease, it often is appropriate to wait several months to assess the full impact of the initiation of antiretroviral therapy before systemic therapies are instituted.

Box 69-1

Treatment of Kaposi's Sarcoma

• Treatment with liposomal anthracycline: Liposomal doxorubicin is administered at a dose of 20 mg/m2 intravenously every 2 to 3 weeks. Granulocyte colony stimulating factor (G-CSF) is used as needed. Once a maximum response is attained, treatment is discontinued. • Treatment with paclitaxel: Paclitaxel is administered at 100 mg/m2 infused over 3 hours every 2 weeks. G-CSF is routinely used. Once a maximum response is attained, treatment is discontinued. • Treatment with interferon-a: Therapy begins at 1 million units/per day, with dose escalation as tolerated up to 9 million units per day over a period of 2 months. Interferon treatment is associated with flu-like symptoms of fevers, chills, myalgias, and fatigue. These symptoms typically diminish and tolerance improves with time. Night-time administration and adjuvant use of acetaminophen and nonsteroidal anti-inflammatory medications improve the tolerability of the regimen. Patients who respond or whose disease is stable are continued on treatment until disease progression.

Systemic Therapy

Interferon-α is active in a subset of patients.^[37] The mechanism of action may involve antiviral, immune modulatory, antiproliferative, or antiangiogenic properties. Uncertainties with regard to mechanism notwithstanding, interferon-α has demonstrated beneficial activity in the treatment of KS. In combination with protease inhibitor-based antiretroviral therapy, interferon can be safely administered at 5 million IU per day.^[38] Dose-limiting toxicities are neutropenia and malaise. Time to interferon response of 8 to 12 weeks precludes its use in patients with very symptomatic or aggressive disease. On the other hand, responses often are long-lasting, particularly complete responses (CRs). This period is longer than the response duration typically associated with cytotoxic chemotherapy. Furthermore, even patients with widespread disseminated disease can have complete clinical responses.

Although a variety of single agents and combinations of agents have been studied in the past, single-agent therapy with a liposomal anthracycline or with paclitaxel is now the standard of care. Liposomal formulation of anthracyclines leads to altered pharmacokinetic profiles. Thus, liposomal doxorubicin has a prolonged plasma half-life and achieves increased concentration in tumor tissues and decreased concentration in normal tissues.^[39] In phase III trials, liposomal doxorubicin and liposomal daunorubicin have been shown to be at least as effective as and less toxic than combination regimens including nonliposomal anthracyclines. ^{[40] [41]} Liposomal anthracyclines generally are well tolerated, with myelosuppression as the major limiting toxicity. A “hand-foot” syndrome occasionally is seen and often responds to steroids.^[42] Alopecia is rare, and cardiotoxicity is very rare.

Paclitaxel is an active agent for treatment of refractory KS. ^{[43] [44] [45]} In an initial trial, patients with advanced KS received 135 mg/m², escalated to 175 mg/m² every 3 weeks. The response rate was 71.4%. Responses were seen in all four assessable patients who had previously received anthracycline therapy for KS and in patients with pulmonary KS. In a subsequent study, patients in whom one or more chemotherapy regimens, including combination chemotherapy and chemotherapy with liposomal daunorubicin, had failed to provide benefit, received treatment with paclitaxel 100 mg/m² every 2 weeks.^[45] Of these patients with poor prognosis, in whom the median CD4⁺ T-cell count was 5/mm³, 53% responded. The same regimen in treatment-naive patients yielded an overall response rate of 70%. Alopecia, nausea, vomiting, myalgias, and myelotoxicity often requiring growth factor support are common toxicities.

Thalidomide also shows activity against KS. ^{[46] [47]} Regimens studied include daily doses of 100 mg for 8 weeks, dose escalation beginning at 200 mg daily to tolerance, and treatment with 200 to 600 mg daily. ^{[48] [49]} Sedation, depression, fever, rash, and neurologic toxicity have all been reported. The antineoplastic activity of thalidomide is poorly understood. Thalidomide inhibits tumor necrosis factor (TNF) production, alters T-cell response, and modulates T_H1 cytokine production. Although only a minority of patients respond, its oral availability and toxicity profile make it an attractive alternative for patients who do not require immediate responses and in patients who cannot tolerate myelosuppressive regimens.

Several other agents have been reported to have promising results. Administration of interleukin-12 to patients whose KS was progressing despite antiretroviral therapy led to partial response or CR in 71% of patients in a phase I pilot study.^[50] Two oral therapies have also been reported to be active against KS in small series: Imatinib induced regression of tumor in HIV-infected patients,^[51] whereas substitution of rapamycin therapy for other immunosuppression modalities was associated with regression in renal transplant recipients.^[52]

Local Therapies

Local therapies are appropriate for patients with a few lesions and slowly progressive disease. For example, a patient with maximally suppressed HIV-1 infection and indolent but cosmetically disturbing facial lesions may benefit from local treatment. Local therapy avoids immunosuppression associated with cytotoxic chemotherapy but does nothing to interrupt or slow systemic progression and the appearance of new lesions. Alitretinoin (9-cis-retinoic acid) is administered as a topical gel.^[53] Four to 8 weeks of therapy typically are required before responses are seen. Responses occur even in patients with low CD4⁺ T-cell counts. Irritation at the site of gel application is common. Intralesional injections with vinblastine, interferon, and sodium tetradecyl sulfate all have a high response rate, but regrowth is common. ^{[54] [55]} Similarly, liquid nitrogen is effective for the treatment of small lesions, particularly on the face.^[56] Radiation therapy is an effective and widely used local treatment. ^{[56] [57] [58] [59]}Response rates generally are between 80% and 90%. A variety of dosing schedules have been used. In a randomized study, three radiation regimens were compared: 8 Gy delivered in 1 fraction, 20 Gy in 10 fractions, and 40 Gy in 20 fractions. Each treatment scheme led to flattening of lesions. As might be expected, the highest dose was associated with the greatest chance for complete clearing of lesions and the longest duration of benefit. Thus, single fractions are most appropriate for patients with very short life expectancy and to provide symptomatic rather than cosmetic relief. The conjunctiva, oral pharynx, and other sensitive tissues require different doses and fractionation schemes than those used with most cutaneous lesions.

Antiherpesvirus Agents

In vitro ganciclovir and foscarnet are active in inhibiting lytic KSHV replication.^[60] Several studies have demonstrated a decreased incidence of KS in patients with HIV who received either ganciclovir or foscarnet regimens but not acyclovir. ^{[61] [62] [63] [64]} Thus, of potential interest to researchers is the possibility that agents with similar in vitro activity may block the development of KS. By contrast, these agents appear to have no activity in the treatment of established KS.^[65] Presumably, the resistance of established KS to such treatments reflects the predominantly latent state of the viral genome in tumors.

LYMPHOMA

Epidemiology

Both non-Hodgkin's and Hodgkin's lymphomas occur with increased incidence in patients with HIV infection, although the increase in non-Hodgkin's lymphomas is much greater, and only aggressive B-cell non-Hodgkin's lymphomas have been formally recognized as AIDS-defining illnesses. In contrast with the situation with KS, lymphomas occur in all HIV-infected populations and show no marked predilection for men who have sex with men or other particular risk groups. Early data from cancer and AIDS registries in the United States showed that the relative risk of development of non-Hodgkin's lymphoma within 3.5 years of another AIDS diagnosis was 165-fold compared with that in persons without AIDS.^[66] Particular types of lymphoma showed a much more dramatic increase in incidence. Thus, brain lymphoma was increased 3600-fold in comparison with the general population.^[67] The risks for high-grade diffuse immunoblastic and Burkitt's lymphomas were increased 652-fold and 261-fold, respectively. The risk for Hodgkin's lymphoma in HIV-infected persons is increased 5- to 10-fold. ^{[68] [69] [70]}

With HAART, the overall incidence of lymphoma is decreasing, with the most marked decrease occurring in primary brain lymphoma. ^{[71] [72] [73] [74]} The length of time with HIV infection before diagnosis of lymphoma is increasing, as is the CD4⁺ T-cell count at the time of diagnosis. Of interest, the incidence of Hodgkin's lymphoma has increased in the past decade beginning with the availability of HAART. ^{[68] [75] [76]}

Histology and Pathogenesis

The spectrum of lymphomas in the general population includes indolent and aggressive, follicular and diffuse, B- and T-cell tumors, and Hodgkin's and non-Hodgkin's histologic types. In patients with HIV infection, the increased incidence of lymphomas is mainly an increase in aggressive B-cell tumors with diffuse architecture and in Hodgkin's lymphoma. ^{[73] [77]} Diffuse immunoblastic, Burkitt's (and Burkitt's-like), and diffuse large B-cell lymphomas each account for approximately one third of the total of non-Hodgkin's lymphomas. Polymorphic lymphoproliferative disorders such as those seen in transplant recipients also have been described.^[78] Surface markers characteristic of B cells (CD19, CD20, CD22) generally are expressed, with the notable exception of primary effusion lymphomas. The latter often exhibit an indeterminate phenotype with expression of lymphoid activation markers.^[77] Mixed cellularity is the most common Hodgkin's lymphoma subtype in the HIV-infected population, whereas lymphocyte-predominant Hodgkin's lymphoma is quite rare. ^{[70] [79] [80] [81]}

The Epstein-Barr virus (EBV) genome is present in approximately half of lymphomas that arise in HIV-infected patients. In contrast with KSHV, EBV is a ubiquitous virus. EBV has a tropism for B lymphocytes and mediates growth transformation of primary B cells into long-term-proliferating lymphoblastoid cell lines. It is associated with lymphoma across the spectrum of immunocompromised patients, including patients with congenital immunodeficiency and transplant recipients. The molecular biology of the virus and its role in transformation are discussed further in Chapter 11 . Particular anatomic sites and particular histologic types are especially likely to be EBV-associated. Primary brain lymphomas and lymphomas with central nervous system involvement are virtually always EBV-positive in patients with AIDS ^{[82] [83] [84]} ( Fig. 69-5 ). Lymphomas with immunoblastic features, primary effusion lymphomas, plasmablastic oral lymphomas, and Hodgkin's lymphoma usually also are EBV-associated. ^{[77] [79]} Curiously, although EBV was discovered in African Burkitt's lymphoma and nearly 100% of endemic Burkitt's lymphomas are EBV-associated, AIDS-associated Burkitt's or Burkitt's-like lymphoma is the histologic type least frequently associated with EBV (20% to 30%).^[77]

Figure 69-5 In situ hybridization demonstrating the presence of Epstein-Barr virus (EBV) RNA in brain lymphoma. Tumor cells are clustered around a vessel.

Burkitt's lymphomas occur earlier in the course of HIV disease than do diffuse immunoblastic or diffuse large cell lymphomas.^[73] In one series, the median CD4⁺ T-cell count in patients with Burkitt's lymphoma was 270/mm³, whereas it was 99/mm³ for diffuse immunoblastic and diffuse large cell lymphomas.^[85] Among patients with lymphoma as an AIDS-defining event, Burkitt's lymphoma accounted for 47% of lymphomas occurring as the first manifestation of AIDS, whereas it accounted for only 13% of non-Hodgkin's lymphomas that developed after another AIDS-related event. Isolated extranodal lymphomas were histologically diffuse immunoblastic or large cell types (97%) and were associated with a median CD4⁺ T-cell count of 70/mm³. Primary central nervous system lymphomas represent the extreme end of this spectrum and are associated with a particularly low CD4⁺ T-cell count.^[83] It has been suggested that HAART has changed the character of lymphomas occurring in HIV-infected patients, with a shift away from lymphomas of postgerminal center origin.^[86]

Clinical Aspects

Advanced stage, extranodal disease, and constitutional symptoms frequently are seen in patients with HIV-associated lymphoma. ^{[87] [88] [89]} Approximately 90% of patients have some extranodal involvement, and in 30%, all disease is extranodal. The gastrointestinal tract is a particularly frequent site of extranodal involvement. Sites not generally involved by lymphoma, such as heart, common bile duct, and rectum, exhibit such involvement in patients with AIDS. Similarly, brain and skin may be involved by Hodgkin's lymphoma at presentation in HIV-infected patients. Pleural, pericardial, or peritoneal cavities may harbor lymphomatous effusions in the absence of any “solid” tumor mass.

Constitutional symptoms are much more common in association with lymphoma in HIV-infected patients than in other patients. As in patients with KS, the presence of such symptoms in patients with lymphoma should prompt a search for opportunistic infections. In contrast with the KS situation, however, even after opportunistic infections are excluded, constitutional symptoms are common. Biopsy is required for the diagnosis of lymphoma, with the possible exception of primary central nervous system lymphoma, as discussed later.^[90] CT or magnetic resonance imaging (MRI) of the chest and abdomen often is useful in identifying lesions likely to yield diagnostic material. Gastrointestinal tract lesions occasionally will be detected only by endoscopy. Persistent generalized lymphadenopathy is common in patients with HIV infection, but asymmetrically enlarged nodes should always be biopsied. A finding of benign hyperplasia on biopsy and examination of an enlarged node does not exclude the possibility of lymphoma elsewhere, and several biopsies may be required to establish a diagnosis. Even in the absence of cytopenias, bone marrow biopsy sometimes will yield a diagnosis ( Fig. 69-6 ). Bone marrow-only presentations of Hodgkin's lymphoma are not uncommon.

Figure 69-6 Plasma cell leukemia in a patient with human immunodeficiency virus infection. A, Peripheral blood smear. B, Aspirate. C, Bone marrow biopsy.

The location of the pathologic lesion is important in determining the type of biopsy to be performed. Lesions in the brain or other organs devoid of lymphoid tissue are adequately assessed by needle biopsy. Lymph nodes are best assessed by excisional biopsy, which allows assessment of architecture. Failure to identify a clonal population by flow cytometry or other molecular diagnostic techniques does not exclude lymphoma. Clonality could not be demonstrated in a sizable percentage of lymphomatous lesions in a San Francisco series; whether its absence reflected technical artifact or distinctive pathogenesis was not clear.^[91]

Staging of non-Hodgkin's lymphomas in patients with AIDS requires that the brain be imaged by MRI or CT. In addition, in patients with EBV-positive tumors and in patients with Burkitt's, Burkitt's-like, or immunoblastic lymphomas, a diagnostic lumbar puncture is indicated. An initial dose of an appropriate agent for prophylactic intrathecal chemotherapy (cytosine arabinoside or methotrexate) often is administered at the time of the diagnostic lumbar puncture.

Although brain lymphomas are common in patients with HIV infection, toxoplasmosis is the most common cause for an intracranial mass lesion.^[92] Ring-enhancing unifocal or multifocal lesions arecommon in both diseases. Yet biopsy sometimes is associated with morbidity and even death, particularly in patients with lymphoma.^[93] Thus, rather than prompt biopsy of suspicious lesions, empirical treatment for presumed toxoplasmosis is standard in seropositive patients. Biopsy is pursued only if a patient fails to respond to toxoplasmosis therapy or if evidence of progression is observed over a 2-week therapeutic trial.

A variety of approaches to differentiate neoplastic from non-neoplastic lesions have been explored. ^{[94] [95] [96] [97] [98]} Recent studies of diffusion-weighted MRI have shown significant overlap in apparent diffusion coefficients between lymphoma and toxoplasmosis lesions, thereby limiting its utility in distinguishing between the two entities. ^{[99] [100]} PET with [¹⁸F]fluoro-2-deoxyglucose (FDG) seems promising in accurately differentiating between lymphoma and infectious intracranial lesions, although the literature is not recent and includes relatively few cases.^[101] Single-photon emission computed tomography (SPECT) with thallium 201 generally correctly identifies patients with primary central lymphoma but occasionally mislabels patients with infectious lesions as having such neoplasms. ^{[96] [97] [98]}

A nonradiographic approach to diagnosis of primary brain lymphoma involves polymerase chain reaction (PCR) assay for EBV DNA in cerebrospinal fluid. ^{[102] [103]} Although PCR analysis occasionally will detect EBV DNA in cerebrospinal fluid in other settings, such as acute infectious mononucleosis with neurologic manifestations, viral DNA rarely is detected in the cerebrospinal fluid of HIV-infected patients without lymphoma.

The established International Prognostic Index (IPI) factors of age, tumor stage, lactate dehydrogenase level, together with Eastern Cooperative Oncology Group (ECOG) performance status and number of extranodal sites, are confirmed to be significant vari-ables in AIDS-related non-Hodgkin's lymphoma in the era of HAART. ^{[104] [105]} Failure to attain complete remission also has been shown to predict shorter survival. CD4⁺ cell counts below 100/mm³ also were prognostic for poor outcome when analyzed prospectively; of interest, however, in a retrospective analysis, CD4⁺ counts less than 100/mm³predicted shorter survival only in the pre-HAART era. The response to antiviral therapy has emerged as the most important prognostic factor.^[74]

Therapy

Patients with HIV infection often have very aggressive, rapidly proliferating tumors. Attention to the possibility of tumor lysis syndrome with prompt assessment of renal function, serum electrolytes, and hyperuricemia is critical. Patients should always be started on allopurinol and aggressively hydrated, even before the staging evaluation is complete ( Box 69-2 ). Rapid assessment and treatment can be critically important in patients with aggressive lymphomas.

Box 69-2

Treatment of Non-Hodgkin's Lymphoma

• Treatment is with standard-dose CHOP: cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2), vincristine (Oncovin; 1.4 mg/m2), prednisone (100 mg/day for 5 days)—repeated every 3 weeks. A maximum of six cycles are given. Granulocyte colony stimulating factor is routinely prescribed. Dose adjustments are made for toxicity. • Patients with Epstein-Barr virus-associated lymphoma, except Hodgkin's lymphoma, or with Burkitt's or Burkitt's-like lymphoma receive intrathecal prophylaxis with 12 mg of methotrexate and 100 mg of hydrocortisone administered five times during the first two cycles of systemic chemotherapy. • Patients with lymphomatous meningitis receive whole-brain irradiation and intrathecal chemotherapy (three times per week until clear; the interval of treatments is then tapered to once a week for a month and then once a month for a total of 6 months), until the cerebrospinal fluid (CSF) demonstrates clearance of lymphoma.

Before the routine use of Pneumocystis prophylaxis and hematopoietic growth factors, lymphoma regimens in AIDS patients were associated with a high treatment-related mortality rate.^[106] A randomized trial of standard versus reduced-dose therapies showed that reduced-dose therapies did not compromise overall or disease-free survival but were associated with a decrease in the percentage of patients in whom severe toxicities developed.^[107] In profoundly immunocompromised patients, the antitumor effects of cytotoxic chemotherapy had to be balanced against associated myelosuppressive and immunosuppressive effects. With the advent of improved prophylaxis of opportunistic infections, highly effective antiretroviral therapy, and perhaps some change in the character of the tumors emerging in such patients, the outlook for these patients has improved significantly.

A first question addressed in the era of HAART was the safety of the combination of antiretroviral therapy and cytotoxic chemotherapy. Data from retrospective series and from trials combining cytotoxic chemotherapy regimens with antiretroviral regimens have been published. ^{[108] [109]} Although some interactions have been reported with altered clearance rates of serum concentrations of cyclophosphamide, doxorubicin, and indinavir, adverse interactions have been modest, with the exception of regimens that include zidovudine. Additional studies have suggested increased toxicity with the combination of chemotherapy and some of the protease inhibitors, known potent inhibitors of the cytochrome P-450 system. When saquinavir was combined with an infusional regimen of cyclophosphamide, doxorubicin, and etoposide (CDE), mucositis was observed in 67% of patients, a significantly higher rate than that seen with didanosine plus CDE. ^{[108] [110]} Decreases in day 10 and day 14 neutrophil counts in patients receiving CDE with protease inhibitor-containing HAART compared with those who received HAART without protease inhibitors also are described, with grade 3 and 4 infections requiring hospitalization occurring in 48% versus 25% of patients, respectively.^[111] Infusional regimens have attracted a great deal of interest. CDE administered as a 96-hour infusion combined with HAART has yielded impressive results in a multi-institutional study.^[112] Of 98 analyzable patients, those who received the infusional therapy and HAART had a median overall survival time of almost 14 months, whereas those who received the same infusional therapy and only a single antiretroviral agent (didanosine) had a median survival time of approximately 7 months. Combination of the regimen with rituximab yielded a CR rate of 70% and a significant increase in estimated overall survival rate (64% at 2 years).^[113] This study and another trial evaluating rituximab combined with CHOP (i.e., cyclophosphamide, vincristine, doxorubicin, and prednisone) chemotherapy have raised concerns that rituximab may increase the risk of severe and life-threatening infection.^[114] Further evaluation of this strategy should proceed with caution. A different continuous infusion regimen used in a single-institution study also yielded impressive results.^[86] The EPOCH chemotherapy regimen (i.e., cyclophosphamide, doxorubicin, etoposide, vincristine, and prednisone) given by continuous infusion yielded a 92% disease-free survival time of 53 months. These survival outcomes represent a dramatic improvement over what was reported in cooperative group trials from the pre-HAART era. Whether the improved survival reflects changing pathogenesis of lymphoma in HIV-infected patients, improved antiretroviral therapy following lymphoma therapy, the use of continuous infusion, or the particular choice of agents is not clear.

One of the complexities of infusional chemotherapy relates to possible metabolic interactions with antiretroviral agents. The possibility of important, possibly adverse interactions led the investigators studying one of the infusional therapies to not initiate antiretroviral therapy until the conclusion of cytotoxic chemotherapy.^[86] Viral load increased modestly during therapy and plateaued between cycles 4 and 6. At 3 months after starting or restarting antiretroviral therapy, viral loads declined to below baseline. There was no evidence that therapy led to the emergence of antiviral resistance. To the contrary, resistance mutations became transiently undetectable during therapy. CD4⁺ T-cell counts decreased but recovered to baseline within 6 to 12 months. Pneumocystis prophylaxis probably should be administered to all patients undergoing intensive chemotherapy regardless of CD4⁺ T-cell count, whereas Mycobacterium avium complex prophylaxis is administered only to patients with CD4⁺ T-cell counts below 50/mm³.^[87]

Most patients with HIV infection and Hodgkin's lymphoma present with advanced-stage disease. Thus, combination chemotherapy is virtually always the mainstay of therapy ( Box 69-3 ). The ABVD regimen (i.e., doxorubicin, bleomycin, vinblastine, and dacarbazine) was studied by the AIDS Clinical Trials Group in the era before HAART.^[115] With the advent of HAART, the CR rate has nearly doubled. In a recent retrospective series of 62 patients with advanced Hodgkin's lymphoma treated with ABVD and HAART, 54 (87%) achieved a CR with 5-year event-free survival (EFS) and overall survival (OS) probabilities of 71% and 76%, respectively.^[116] The Stanford V regimen^[117] with concomitant HAART was evaluated in a phase II study. Of 59 patients subjected to this regimen, 81% achieved a CR. At a median follow-up of 17 months, the estimated 3-year disease-free survival (DFS) and OS rates were 51% and 68%, respectively.^[118]

Box 69-3

Treatment of Hodgkin's Lymphoma

• Treatment is with standard-dose ABVD—doxorubicin (Adriamycin; 25 mg/m2), bleomycin (10 units/m2), vinblastine (6 mg/m2), dacarbazine (375 mg/m2)—administered on days 1 and 15. • A maximum of six cycles are given. G-CSF is routinely prescribed. • Dose adjustments are made for toxicity.

A variety of salvage therapies have been evaluated, often with disappointing results.^[88] ESHAP (etoposide, methylprednisolone, cisplatin, and high-dose cytarabine) chemotherapy is a commonly used regimen.^[119] Increasingly, high-dose therapy with autologous peripheral stem cell transplantation is being used as consolidation. ^{[120] [121]} Time to engraftment, infectious complications in the post-transplantation period, and conditioning regimen complications are similar to those seen in patients without HIV infection. High-dose therapy with peripheral stem cell transplantation is rapidly becoming established as the appropriate salvage strategy for patients with chemotherapy-responsive relapse of either Hodgkin's or non-Hodgkin's lymphoma.

What should be regarded as “standard therapy” for AIDS-associated lymphoma? Except in the most immunocompromised patients, standard-dose lymphoma therapy including doxorubicin is appropriate. Among the chemotherapy regimens that might be considered as standard are CHOP, CDE, and EPOCH. Rituximab has been almost universally added to these regimens. ^{[113] [114] [122] [123]} One study suggested that rituximab therapy may be associated with an increased incidence of fatal bacteremia, but this has not been confirmed by other studies.^[114] The optimal integration of antiretroviral therapy with chemotherapy remains uncertain, but long-term lymphoma-free survival can be achieved with concomitant or delayed antiretroviral therapy. Patients who experience relapse and are in good condition are appropriate candidates for salvage and may benefit from high-dose therapy with stem cell rescue or other aggressive interventions.

Whole-brain radiation therapy has been the mainstay of treatment for brain lymphomas ( Box 69-4 ). ^{[124] [125]} Retrospective studies show tumor responses, improvement in quality of life, and longer survival with treatment, but long-term survival is rare. Small series with high-dose methotrexate or ganciclovir and zidovudine have been reported. ^{[126] [127] [128]} In a retrospective analysis of the impact of HAART on survival in patients with primary central nervous system lymphomas, 6 of 7 patients who received HAART were alive, versus 0 of 18 patients who received no treatment, at a median follow-up time of 667 days (P = 0.0007).^[129]

Box 69-4

Approach to Patients with AIDS-Associated Brain Lymphoma

• In the presence of characteristic lesion(s) on magnetic resonance imaging and thallium or positron emission tomography studies, detection of Epstein-Barr virus DNA by polymerase chain reaction assay in cerebrospinal fluid is diagnostic of brain lymphoma. In patients in whom lumbar puncture is contraindicated, brain biopsy is required for diagnosis. • Treatment is with radiation therapy.

OTHER MALIGNANCIES IN PATIENTS WITH HIV INFECTION

With HAART, the spectrum of malignancies in HIV-infected patients has been changing.^[130] Non-AIDS-defining cancers have been reported with increased incidence, including those most common in the general population (lung cancer, colon cancer, skin cancers) as well as multiple myeloma and related plasma cell disorders, anal cancer, and cervical cancer. Lung and colon cancers may be indistinguishable from those appearing in the general population. Plasma cell dyscrasias in this population are quite distinctive, however. They are EBV-associated and often manifest with visceral or leukemic involvement.^[131] Although cervical cancer has been recognized by the Centers for Disease Control and Prevention as an AIDS-defining illness, an excess of cervical cancer attributable to HIV infection remains to be conclusively demonstrated. ^{[87] [132]} Some evidence, however, suggests that HIV-infected women with cervical cancer are more likely than non-HIV-infected women to have advanced disease at presentation and exhibit a higher recurrence rate. Furthermore, cervical intraepithelial neoplasia occurs more frequently in women with HIV infection. Anal cancer occurs with a 40- to 80-fold excess in people with AIDS compared with the general population. Receptive anal intercourse also is a well-established risk factor for this cancer, and the relative contributions of HIV infection and behavior have not been fully defined. Leiomyosarcomas in visceral organs occur with dramatically increased frequency in patients with HIV infection, particularly pediatric patients, but remain rare. The approach to treatment of these disorders does not differ from that in the non-HIV-infected population or has yet to be defined, although clearly, cognizance of the special risks associated with chemotherapy is important.

CURRENT OUTLOOK

With an improved prognosis for patients with HIV infection as a result of advances in supportive care and antiretroviral therapy, the neoplastic complications of HIV infection grow in importance. In the early days of the epidemic, the treatment of malignancies with curative intent might have been regarded as only marginally important in patients who were otherwise doomed to a short survival by virtue of their retroviral infection. For an increasing number of patients, however, HIV infection is most appropriately viewed as a chronic disease that requires a collaborative and multidisciplinary effort on the part of primary care and subspecialty providers, and the nihilism of the past should be replaced by a cautious optimism. It is now clear that durable remissions will translate into long-term survival in patients whose HIV load can be suppressed to very low or undetectable levels. The challenge that remains is to further develop specific therapies for HIV-associated malignancies and to integrate these approaches with the growing armamentarium of antiretroviral therapies.

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