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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 135Neoplasms in Acquired Immunodeficiency Syndrome

, MD.

Immunodeficiency is associated with an increased risk of malignancy in the setting of multiple etiologies. The risk is variable, dependent on the severity and extent of the immunologic abnormality, and is not restricted to those individuals considered to have a lack of immune reactivity.1 Rather, an increased incidence of lymphoid neoplasms may also be observed in the context of conditions typically regarded as those of excess immunologic stimulation. These include entities such as Sjögren’s syndrome and Whipple’s disease. The immunologic activation that these conditions represent suggest that a common theme among lymphomas in the context of immune dysfunction is the inability to control pathogenic conditions that serve as an ongoing immune stimuli. Thus, immune activation coupled with immunodeficiency may be the most conducive setting for the emergence of immunodeficiency-related tumors. Indeed, the relative risk of lymphoid malignancy is greatest in conditions associated with profound immune stimulation and immune defects such as multiple organ transplantation, human leykocyte antigen (HLA)–mismatched bone marrow transplant with lymphocyte-depleted grafts, and acquired immunodeficiency syndrome (AIDS).2–11,12

The spectrum of the tumor types seen in the context of immunodeficiency extends beyond that of lymphoma but remains quite limited. There appears to be little interaction between the conditions that predispose to the emergence of epithelial malignancies seen in the general population and immunodeficiency. Rather, immunodeficiency tumors represent a narrow subset of neoplasms, some of which are seen with only very low incidence in the general population. For example, primary central nervous system (PCNS) lymphoma and Kaposi’s sarcoma are extremely rare entities in all but the immunodeficient population, where they compose a large proportion of tumors. In addition, the incidence of specific tumor types does vary according to the immunodeficient state. Non-Hodgkin’s lymphoma is a common theme among all the immunodeficiencies, yet in AIDS, there is a broader spectrum of histologic subtypes than are seen in any other immunodeficiency. Kaposi’s sarcoma is uniquely increased in human immunodeficiency virus (HIV) –related immunodeficiency, particularly in subgroups within the HIV-infected population. Cutaneous tumors are common in many immunodeficient states, but the increase in squamous cell tumors of the skin is higher in the post-solid-organ-transplantation population than in those with HIV-related immunodeficiency. In the latter, papillomavirus-related squamous cell neoplasia of the urogenital tract predominates (Table 135.1).

Table 135.1. Tumor Types with Increased Incidence in HIV Disease.

Table 135.1

Tumor Types with Increased Incidence in HIV Disease.

Shared among the tumors related to immunodeficient states is the frequent association with an infectious pathogen. The presence of Epstein-Barr virus (EBV) in immunodeficiency-related lymphomas is well known and likely due to the direct stimulation that virus provides to B-cell proliferation. In the absence of effective immunologic targeting of cells expressing EBV latency gene products, the overgrowth of cells may proceed unchecked, with the subsequent emergence of a transformed cell. This model for the direct ability of viruses to induce cell proliferation is a paradigm that may be applied to papillomavirus-related tumors as well. However, the model is less easily applied to the Kaposi’s–sarcoma-associated herpesvirus (KSHV)-related tumors. The tumors associated with KSHV are more varied and are of less clear pathophysiologic relationship to viral gene products—issues that will be discussed in greater depth in sections that follow. In general, the tumors that do emerge in immunodeficiency are those in which a secondary pathogen can be implicated (Table 135.2). In that sense, the concept of inadequate immunologic control provides a unifying mechanism, and the tumors may be considered as opportunistic malignancies, much the way in which specific infections are considered opportunistic infections. Indeed, the opportunistic malignancies of the immunocompromised patient represent the overlap between infectious diseases and oncology and provide unique insight into the intersection of immune function and tumor development.

Table 135.2. Secondary Virus Infections Associated with AIDS-Related Malignancies.

Table 135.2

Secondary Virus Infections Associated with AIDS-Related Malignancies.

Epidemiology

The spectrum of tumors in the context of HIV-1 infection varies on the basis of risk group and is substantially affected by the use of potent or highly active anti-retroviral therapy (HAART).

Pre-HAART

The use of HAART is largely restricted to the developed world and did not become available until 1996, with the introduction of the protease-inhibitor class of anti-HIV medications. Widespread use of protease inhibitors rapidly occurred in the United States, Western Europe, and Australia, altering the death rate and complication rate of HIV disease.13 The spectrum of opportunistic diseases also changed,14 with an impact on malignant disease, discussed below. Given the lack of access to HAART in much of the developing world, the unclear durability of HAART efficacy, and the number of patients unable to take or having failed HAART, the profile of AIDS-related malignancies in the pre-HAART era is still of considerable importance.

One of the first manifestations of the AIDS epidemic was the cluster of cases of a rare malignancy among homosexual men in United States coastal cities. That tumor, Kaposi’s sarcoma (KS), was identified as an AIDS-defining illness with the first attempt at classifying the immunodefiency syndrome by the Centers for Disease Control.15 The prevalence of KS was documented as approximately 20% early in the AIDS epidemic but clearly was noted to be highest among patients whose risk factor for HIV transmission was men having sex with men.16 KS prevalence was substantially lower in the groups infected by blood products or through parenteral drug use.17 Subsequent behavioral studies indicated that specific types of sexual practice, including promiscuity and oral-fecal contact,18 had the highest risk and substantiated the impression that KS might be a manifestation of a secondary, transmissible pathogen. Indeed, it was strong epidemiologic data that galvanized efforts to identify a pathogen and which led to the molecular cloning of KSHV.19

The second most common malignancy, which was recognized in 1984 to be increased among young homosexual men, was non– Hodgkin’s lymphoma. This disease was added to the list of AIDSdefining complications in the first revision of the CDC criteria for AIDS. It was noted that the lymphomas that occurred in this population were generally of high-grade histology and followed extremely aggressive clinical courses. Unlike KS, this complication was much more broadly based in the risk groups for HIV infection. All groups had a high relative risk estimated to be approximately 60-fold above that of the general population.18,20,21 Subsets of infected individuals have been noted to have somewhat greater or lesser risk, such as the hemophiliac population, in which at least one study has noted an increased risk.18,22 Similarly, it has been noted that risk among intravenous drug users (IVDUs) or those from the Caribbean basin may be lower, but concern about confounding issues of care and surveillance complicate that analysis. However, the potential for important co-factors of lymphomagenesis within these subsets remains, and attention to this possibility may yield important information about the process of lymphocyte transformation.

The third most common oncologic complication of HIV disease is anogenital squamous cell neoplasms. These are invariably associated with human papillomavirus (HPV) infection of oncogenic serotype.23,24 The impact of anti-retroviral therapy on these neoplasms is at present unclear, but with the improved survival of patients with HIV disease, it is considered likely that HPV-related neoplasms will become increasingly problematic.

Post-HAART

The introduction of HAART has resulted in profound and dramatic changes in the nature of HIV disease.13 The inexorable decline in immune function and its attendant ravaging secondary infections and tumors in many cases is stopped and indeed reversed when combination therapy with protease inhibitors is introduced. The improvement in those patients with advanced disease has led to widespread use of the agents, including among those individuals who have recently acquired HIV-1 infection. The result has been a precipitous decline in the rate of death from AIDS in populations with access to the medications. While death and debility from AIDS has decreased dramatically, there has not been a similar decline in new cases of HIV infection. Therefore, the total population with HIV infection in the West is rising, and those infected are living longer; globally, the epidemic goes unabated. Some changes in the epidemiology of malignancies in HIV infection have been immediately evident since HAART was introduced, but the impact of longer periods of more modest immune dysfunction or even of the anti-retroviral drugs themselves remains to be fully defined.

An observation immediately evident in the clinical care of patients with advanced HIV disease was the regression of KS following successful HIV suppression on HAART. The impact on new cases of KS was also rapidly noticeable, and epidemiologic data have substantiated the magnitude of those clinically apparent effects. Multiple studies from sites in the United States, Europe, and Australia have indicated the widespread decline in KS, with estimates of decline in incidence as high as 80-fold.25–27

As with KS, changes in the incidence of primary central nervous system (CNS) lymphoma are dramatic. Although this complication of far-advanced HIV disease was much less common than KS and documentation of its decline was therefore less well documented, the impact in clinical terms has been comparable in magnitude. Centers previously seeing new cases monthly are now seeing them annually. This is a complication of severe immune suppression that, like the post-transplantation setting, is virtually uniformly associated with EBV detectable in tumor tissue. In general, the EBV latency genes expressed in these tumors are type III or those of lymphoproliferative disease (EBNA1-6, LMP1, and LMP2).28,29 These and other features distinguish PCNS lymphoma from other AIDS-related lymphomas and may be the basis for clear differences in the impact of HAART.

The incidence of systemic AIDS-related lymphomas appears to be much more modestly affected by the introduction of HAART.30 In one study, an increase was noted during the same interval in which a decline of KS was pronounced.31 However, the picture emerging from several studies is that the incidence of systemic lymphomas is diminished, but that the extent of reduction is not nearly as dramatic as that of KS.25,27,30 Whether there are certain subsets of systemic lymphomas that are particularly altered, such as those associated with EBV or KSHV, is as yet unclear. The lack of a reduction similar in proportion to that of KS may reflect a more complex pathophysiology in which simple control of an infectious pathogen may be insufficient to reverse B-lymphocyte proliferation.

Kaposi’s Sarcoma

It was the announcement of clustered cases of KS in Los Angeles that made headlines and first brought the AIDS epidemic to public awareness in 1982. Previously, KS was regarded as a tumor that generally had an indolent course in elderly men of Mediterranean extraction but which could be problematic in the context of immunosuppressive medication for organ transplantation. It was this latter association that helped focus attention on an immune alteration spreading among subcommunities in urban centers. Recognized as a common entity among homosexual men infected with HIV-1 but not among groups with other risk factors for HIV infection (such as blood product exposure),17,32 it was long suspected as being related to a second co-factor.33 A number of potential culprits were examined; none proved tenable until the recent identification of KS-associated herpesvirus (KSHV), also termed human herpesvirus-8 (HHV-8). This virus was first recognized through the use of a genetic comparison of tissues from individuals with and without KS. A DNA fragment was consistently noted that had partial homology with other members of the gammaherpesvirus family.19 This subset of the herpesviruses includes several viruses with oncogenic potential such as EBV, associated with a number of tumors and herpesvirus simirii associated with the ability to transform T cells. Due to the company KSHV kept and the high frequency of detectable signature DNA sequences in KS lesions, this virus rapidly and justifiably became the focus of investigation for a pathophysiologic basis of KS.

Viral Epidemiology

KSHV is a 165-kb double-stranded DNA virus33 with features strongly supporting its causative role in clinical KS. There are data indicating that KSHV infection precedes tumor formation,33,34 that populations with high seroprevalence for KSHV are also those with a high incidence of KS,32 and that the virus infects cell types within tumors.33

The definition of prior exposure to KSHV depends upon documentation of antibodies specifically reactive against the virus. To date, there is not an agreed-upon standard for defining prior exposure, but a number of serologic and demographic studies have been performed, using selected tests. Among the tests with high specificity for KSHV is an analysis for antibodies directed against the latency-associated nuclear antigen (LANA) encoded by open reading frame 73 (ORF 73) of the KSHV genome. This antigen appears to be a serodominant antigen with reactivity demonstrated to be of high specificity although the sensitivity is only about 80% in HIV-infected populations with clinical KS.32 With this method, the prevalence of KSHV infection has been estimated to be at least 1 to 2% in the United States blood donor population, compared with 2% in hemophiliacs, 3 to 4% in HIV-positive women,35 and 25 to 30% in HIV-positive homosexual men.36 A whole-virus lysate has also been used to develop an enzyme-linked immunosorbent assay (ELISA) screening method with increased sensitivity,37 with which it has been estimated that 92% of patients with KS (regardless of HIV-infection status) and 11% of healthy blood donors may have had prior KSHV exposure. Other assays with even higher sensitivity have approximated KSHV seroprevalence at 25% in nonselected individuals from the U.S. population and at 90% among HIV-infected homosexual men.38

Evaluation of populations around the world has demonstrated a correlation of KSHV infection with the development of KS. Endemic KS was first noted in the Mediterranean basin, and studies of populations from that region have noted a high prevalence of KSHV by either polymerase chain reaction (PCR) analysis of peripheral blood DNA or serologic assays. One study of healthy individuals and non-KS dermatology patients in Italy demonstrated that 24% were positive for KSHV by PCR analysis.39 Among family members of individuals with KS (predominantly endemic KS) in Sardinia, 39% were noted to be positive by serologic testing, compared with 11% of age- and sex-matched controls.40 The higher prevalence among family members suggests a potential vertical or paravertical transmission route in addition to the sexual transmission suspected from the HIV epidemic.

In sub-Saharan Africa, it has been documented that children contract KS with a frequency not seen among HIV-infected pediatric populations in the United States or Western Europe. This may be due to the high frequency of infection among pregnant women. In one study, approximately 40% of pregnant women in Zambia had anti-LANA antibodies, including all the mothers of children with KS.41 Another Zambian study showed the overall infection rate in the 14-to-84-year-old population to be 58% and to increase linearly with age.42 Detailed mechanisms of transmission within these populations remain to be elucidated.

The much-suspected role of sexual transmission has been convincingly demonstrated in a longitudinal study of men in San Francisco followed over a 10-year period. Among exclusively heterosexual men, no KSHV seropositivity was detected; however, among homosexual or bisexual men, the incidence of seroconversion was linearly related to the number of male sexual-intercourse contacts.36 Men who had more than 250 sexual partners in the preceding 2 years had a seropositivity rate of 65%.

Clinical Manifestations

KS characteristically appears as pigmented macular-papular lesions on mucocutaneous surfaces (Figs. 135.1andFigs. 135.2 ). It is typically violaceous or erythematous in hue and may be associated with an ecchymotic halo. Typically, the lesions are multifocal and do not have a predictable order or pace of progression. Lesions may present as solitary nodules or plaques but may also occur in clusters or simultaneously in multiple well-segregated sites. While classic or endemic KS often favor the lower extremities, the pattern of involvement is much less predictable in the setting of HIV infection. Virtually any mucocutaneous site may be involved. On the face, the ears and nose are often affected, resulting in profound disfigurement. In addition to the disabling cosmetic effects of KS, lesions do occasionally become thick, uncomfortable plaques and can ulcerate with possible superinfection. Lesions are not generally destructive, however. The integument or mucous membrane overlying a lesion is most often intact, and deep invasion into muscle or bone generally does not occur.

Figure 135.1. Cutaneous Kaposi’s sarcoma in a Caucasian patient with advanced HIV disease.

Figure 135.1

Cutaneous Kaposi’s sarcoma in a Caucasian patient with advanced HIV disease. The violaceous plaques on the chest are of characteristic appearance. These lesions have entirely resolved on paclitaxel chemotherapy and anti-retroviral medication. (more...)

Figure 135.2. Kaposi’s sarcoma in an African American male with HIV-1 infection.

Figure 135.2

Kaposi’s sarcoma in an African American male with HIV-1 infection. Skin tone can make the lesions less readily distinguishable from other cutaneous processes and quite distinct from the appearance in lighter-skinned individuals.

Edema often accompanies KS either locally or at a dependent site distal to KS lesions (Fig. 135.3). The edema can marked, with profound compromise of extremity mobility or occasionally with periorbital, peripubic, or genital edema. Two mechanisms are thought to contribute to the development of edema. One is the involvement of lymphatic vessels or lymph nodes with KS, thereby causing a mechanical obstruction to lymphatic flow. The other is the elaboration of permeability factors by KS lesions. The vessels that compose a KS lesion are themselves leaky with extravasation of plasma proteins and cells into surrounding soft tissue. In addition, the vascular endothelial growth factor (VEGF) produced by KS lesions can alter the integrity of surrounding otherwise-normal vessels, increasing their permeability and thus, their contribution of fluid to interstitial fluid. The increased demand on lymphatic drainage and the compromised egress of lymph results in thickened skin locally and frank edema distally.

Figure 135.3. Lower extremity involvement by Kaposi’s sarcoma can result in marked edema and limited mobility.

Figure 135.3

Lower extremity involvement by Kaposi’s sarcoma can result in marked edema and limited mobility. This patient had pedal edema that had limited response to chemotherapy despite marked improvement in the circumferential Karposi’s sarcoma. (more...)

Involvement of organs other than lymph nodes occurs frequently. The most common site is the gastrointestinal (GI) tract, where mucosal-based lesions are commonly observed in the course of endoscopic procedures. The physiologic significance of these lesions is often minimal, however. Most patients will be unaware of GI involvement, and serendipitous observation of a mucosal KS lesion should not trigger a reflex to undertake aggressive therapy. However, there are some individuals for whom GI KS can be a symptomatic and even life-threatening complication. Massive bleeding has been observed, as has intussusception.

Pulmonary involvement may take several forms. Pleural-surface studding with KS lesions can result in pleural effusions, which are often bloody but which do not have a characteristic set of diagnostic findings or cytologic abnormalities. Bronchial mucosa may be involved and, like GI mucosal surfaces, may be incidentally noted during bronchoscopic examination. The lesions are generally not destructive, but depending upon location, they may be responsible for bronchial irritation, coughing, and hemoptysis. Involvement of the parenchyma of the lung occurs and is arguably the most serious complication of KS, as it is associated with life-threatening respiratory compromise and a high mortality rate if unsatisfactorily treated.43 Radiographically, involvement often takes the appearance of peribronchiolar cuffing on computed tomography (CT). Pathologically, this infiltration may extend into fine interstitial tissue and affect airspace function. This results in either a patchy or diffuse reticulonodular appearance on x-rays. The diagnosis of KS involvement of the lung is often difficult to firmly establish short of parenchymal thoracoscopic or open biopsy. Bronchoscopy is useful in assessing alternative infectious explanations for clinical findings and may identify mucosal lesions. However, mucosal lesions do not necessarily coincide with parenchymal infiltration, and transbronchial biopsy is often unrevealing. Nuclear medicine scans have been shown to be of some usefullness, with a negative gallium scan and a positive thallium scan reported to have a high specificity for pulmonary KS.44,45 In some circumstances, the use of a therapeutic trial may also be helpful in establishing a presumptive diagnosis. If thorough microbiologic evaluation has been unrevealing, the chemotherapeutic agents discussed below have been well tolerated and associated with high rates of response, such that their use in select patients may be justified as a test for chemotherapy responsiveness of a parenchymal infiltrate. Such a strategy is generally reserved for those patients in whom (a) there is a diagnosis of KS already established from involvement of other sites, (b) there are no symptoms suggesting infection, or (c) aggressive assessment for infection has been negative and there are no other contraindications to cytotoxic chemotherapy.

In addition to lung, GI tract and lymph nodes, special sites of concern are areas of the upper airway. Involvement of the mucosa of the mouth, sinuses, pharynx, and larynx can result in distortion of soft tissues such that airway compromise or alteration of food ingestion can occur. These are lesions that generally respond rapidly to therapy and do not invade deeper structures. Therapeutic approaches will be discussed below.

Given the common occurrence of involvement beyond the readily apparent skin or oral mucous membranes, extensive staging evaluations are often considered. While the bulk of tumor does have some influence on prognosis, other characteristics of overall status of the patient’s immune and general health dictate prognosis to a greater extent46 (Table 135.3). The staging performed then is often based on clinical presentation, with radiographic studies limited to a chest x-ray unless symptoms dictate otherwise. If localizing symptoms do suggest organ involvement, then more extensive radiographic and procedural interventions are appropriate, but they cannot be recommended routinely. Criteria for staging do include assessment of the underlying HIV infection, and all patients should have a careful history regarding medications, other complications of HIV infections, and documentation of the CD4 count in the blood.

Table 135.3. Staging Classification for AIDS-Related Kaposi’s Sarcoma.

Table 135.3

Staging Classification for AIDS-Related Kaposi’s Sarcoma.

Establishing the diagnosis of KS generally depends upon simple punch biopsy of the skin or a snip biopsy of mucosal surfaces. The CDC criteria for an AIDS-defining diagnosis of KS do not require histologic confirmation if assessment is by an experienced clinician. However, biopsy is recommended, given the differential diagnosis for nonblanching lesions resembling KS,47 such as bacillary angiomatosis (usually due to Bartonella infection, with increased frequency in advanced HIV infection patients), hematoma, purpura, sarcoid plaques, lichen planus, pyogenic granuloma,48 mycosis fungoides, secondary syphilis, pityriasis rosea, drug-related erythema multiforme, prurigo nodularis, nevi, vascular lesions of the phakomatoses, epithelioid hemangioendothelioma, angiosarcoma, melanoma, and basal cell carcinoma.

Pathology and Pathogenesis

The histologic appearance of KS belies its unclear association with the term “sarcoma.” No monomorphic array of mesenchymally derived cells is seen. Rather, the lesions are composed of endothelial cells lining ectatic vascular spaces surrounded by spindle cells of variable extent admixed with mononuclear immune cells and extravasated red blood cells. It is the red blood cells that provide the pigment to KS lesions and their breakdown that leads to the ecchymotic halo seen in actively growing lesions. The hemosiderin deposited locally yields a pigmented lesion that may remain even after effective therapy reverses the proliferative spindle and endothelial cell components. Cutaneous lesions are generally within the dermis. Deep invasion to muscle is generally not seen.

The origins of the endothelial and spindle cell components remain controversial. Recent reports have indicated that the endothelial cells of KS lesions express the VEGF-C receptor characteristic of lymphatic endothelium49 and do not have detectable nitric oxide synthase, generally present in vascular endothelium.50 The finding that the spindle cell expresses the mannose-binding receptor and CD68 suggests that the origin may be a macrophage-like cell type, perhaps emanating from the sinuses of secondary lymphoid organs and circulating in the blood before ultimately assuming its role in a KS lesion.51

The difficulty in defining the cell of origin emanates from its complex histology and the limitations of the available in vitro or in vivo models. In vitro culture has been established for some cell types, and outgrowth of cell lines has been documented although the relationship to the primary disease process is unclear. In vivo transplantation of KS tissue into immunodeficient mice has resulted in tumors, but these are of murine origin. The potential for cytokine elaboration driving lesion development was hypothesized, and studies have extensively characterized cytokine production by KS lesions.52–55 The cytokines, particularly VEGF and basic fibroblast growth factor (bFGF), may play a role in the paracrine or autocrine sustenance of KS. Antibodies to bFGF have been shown to block the proliferation of KS cells and to prevent them from entering the S phase of the cell cycle, even in the presence of exogenous growth factors like the IL-6–IL-6R complex, IL-1β, TNF-α, and oncostatin M.56 But exogenous growth factors do not completely explain the phenotype and growth potential of KS cells, which have been shown to overexpress the antiapoptotic bcl-2 gene independently of any factors contained in conditioned medium from these cells.57

HHV-8 appears necessary for the induction of KS and is found in KS lesions regardless of whether the underlying context is HIV disease, organ transplantation, or endemic KS. However, the specific mechanism by which the virus participates in the oncogenic process is unclear and does not readily fit into paradigms established by other virus-related neoplastic disease. The latent genes implicated in EBV-induced transformation do not have homologues in KSHV. The genes of Herpesvirus saimiri (HVS), which are known to transform cells, have homology only in the genome of a KSHV gene, K1, that is capable of transforming an immortalized cell line.58 However, this gene is not expressed in the latent phase of the KSHV life cycle. Similarly, a chemokine receptor-like KSHV gene product, ORF 74, is constitutively activated and is capable of transforming cells when transduced as a single gene, but it is also a lytic-phase gene.59 Two other gene products K9 (a homologue of the interferon regulatory factor family) and K12 (with no clear gene family homology) are capable of transforming cell lines when transduced but are not expressed in latent phase.60–63 The lack of clear association with the latent phase would argue that these gene products are not transforming in cis, but whether they may transform in trans cannot be excluded. A number of other mechanisms, including those that may be capable of acting at a distance, have been raised as possibilities for KSHV. These include the chemokine-related gene products, vMIP-I (K6) and vMIP-II (K4), or the interleukin-6 homologue, K2. Each of these has been shown to be capable of interacting with cognate receptors on target cells, either acting as agonists (K2 and K6) or antagonists (K4).64,65 Finally, there are KSHV gene products that have antiapoptotic effects, and that may enhance tumorigenicity. ORF 16 encodes a bcl-2-related gene product,66 and ORF 71 (K13l) encodes a functional member of the Fas-associated death domain-like IL-1β-converting enzyme-inhibitory protein (FLIP) family of anti-apoptotic genes.67 The vFLIP of KSHV protects cells from Fas-mediated cell death and can enhance tumor progression of cell lines transplanted in vivo. Thus, KSHV encodes a range of gene products with potential for altering the growth, death, and immunologic characteristics of infected cells. Which of these will be shown to play a dominant role in oncogenesis is not clear, but investigation into the process will no doubt lead to new insights into viral-induced tumors and will potentially open new avenues for therapeutic attack.

The prevalence of KS in populations that are HIV-infected, have undergone solid organ transplantation, are elderly and of Mediterranean extraction, or live in economically disadvantaged parts of tropical Africa suggests that expression of a KS disease phenotype requires a degree of immunosuppression. The advent of HAART for HIV infection treatment offers dramatic support to a central role for immune suppression: complete remissions of cutaneous68 and pulmonary KS are well recognized in the context of increases in CD4 count and declines in HIV load induced by HAART.69

Retrospective analysis of the incidence of KS among HIV-infected patients receiving antiherpesvirus medications has suggested a direct role of replicating KSHV in the pathologic process. In several studies, there was a decline in KS in the context of patients treated with ganciclovir70–72 or foscarnet.73 In one such treatment program, it was shown that those patients who received systemic ganciclovir had a lower incidence of KS compared with those in whom the drug was delivered by intraocular implant.70 Therefore, suppression of replicating virus appears to lower the risk of KS. While transformation is generally associated with the latent phase of herpesvirus infection, control of the lytic phase (the only time at which the antiherpesvirus medications have known activity) may limit the potential for transformation.

Control of virus by immunologic means also appears to be highly relevant to the risk of developing KS. It has long been known that there is an increased risk of KS in the context of multiple types of immunologic deficiency. The recent definition of epitopes of the virus that are recognized by cytotoxic T lymphocytes will allow for further definition of this important point and potentially lead to vaccine strategies. While HIV-induced immunodeficiency is only one type of immune abnormality that may predispose to KS, the relative risk among the population co-infected with HIV and KSHV is strikingly high, and this has suggested the potential for interaction between the two viruses in the development of tumor. The tat gene product of the HIV-1 genome has been of particular interest and has been shown to affect KSHV replication itself74 as well as alter cytokine (IL-6)75 or cytokine receptor expression in target cells and lead to a proangiogenic effect.76 Additive effects of HIV-1 and KSHV may thereby particularly increase the potential for development of KS.

Treatment

Treatment of KS should be guided by the impact of the tumor on the patient.77 The adage that KS is “a tumor that people die with rather than from” was generally applied to the endemic KS seen in the elderly. However, variability in the course of HIV-infected patients with KS and the lack of clear association of tumor control with mortality suggests that aggressive therapy may not always be an appropriate response to the diagnosis of KS. This is particularly true among patients with advanced HIV disease or untreated HIV disease. In that setting, the toxicity of cytotoxic therapy may be daunting, and the potential therapeutic effect of anti-HIV medications is considerable. Suppressing HIV replication is associated with a rise in CD4 count, with attendant improvement in immunologic function, and also reduction in whatever the direct contribution of HIV to the pathophysiology of KS might be. The net result is a high frequency of clinical improvement among patients with established KS and, at times, complete eradication, simply by the introduction of anti-retroviral therapy. Therefore, for patients in whom the impact of KS is not threatening, a therapeutic trial of anti-retroviral therapy alone is appropriate first-line therapy (Fig. 135.4). In patients in whom a more aggressive “up-front” approach is warranted, attention to optimizing anti-HIV therapy is also a crucial parameter in the overall management of their oncologic care. Anti-HIV therapy is regarded as an important component of KS treatment for all patients with AIDS-associated KS. However, it should be recognized that not all patients will experience an improvement in their KS with anti-HIV medications, and that the improvement is generally slow, often noted only after 4 to 8 weeks of therapy. For those patients who have not had an improvement in KS by 12 weeks after initiation of anti-HIV therapy, it is unlikely that their disease will be controlled by that intervention alone.

Figure 135.4. Treatment schema for patients with Kaposi’s sarcoma.

Figure 135.4

Treatment schema for patients with Kaposi’s sarcoma. HAART = highly active antiretroviral therapy; IFN-α = interferon-alpha; IL = interleukin; VBL = vinblastine; XRT = radiation therapy.

In contrast to anti-retroviral drugs, antiherpesvirus medications have a less clear role in the management of KS. While the studies mentioned above do indicate an impact of certain anticytomegalovirus drugs on KS, the overall impact is modest and does not offset the considerable toxicity and cost of these therapies. Antiherpesvirus agents currently available, therefore, cannot be recommended as anti-KS therapy at this time.

Local Antitumor Chemotherapy

Therapies directed at KS tumors can be divided into either local or systemic therapies. The selection of a local therapy may be influenced by certain factors, such as the extent and location of the lesions (eg., small, singular lesions on the trunk or on an extremity) and the rapidity of clinical change (eg., indolent development of new lesions over months rather than weeks). The standard options for local therapy are liquid nitrogen, intralesional injection of vinblastine, radiation therapy, and recently, topical 9-cis-retinoic acid cream. Photosensitizing agents are currently being tested, and intralesional interferon-alpha has been reported to be active, but the former is still investigational, and the latter may more appropriately be considered systemic therapy.

For patients who have a small number of lesions and who are unresponsive to anti-HIV medications or who require more rapid improvement than the anti-HIV medications may offer, intralesional injection of vinblastine is a reasonable first-line approach. In particular, palatal or buccal mucosa lesions respond promptly to intralesional vinblastine,19 although rarely is such therapy durable for more than a few months, and the discomfort of injection may be considerable. In general, we use vinblastine at 0.1 to 0.4 mg/mL, injecting approximately 0.1 to 0.2 mL into a 1-cm2 lesion; it may be admixed 1:1 with xylocaine to reduce local discomfort. Local reaction is generally modest, but skin breakdown can occur, and regrowth of lesions is common.

Topical 9-cis-retinoic acid cream has recently received approval by the U.S. Food and Drug Administration for treatment of cutaneous KS. A randomized placebo-controlled trial in 82 patients demonstrated a six-fold higher response rate in the retinoic acid–treated group compared with placebo.78 The difficulty with this medication is its potential for inducing a possibly troubling local reaction when applied to normal skin. Patients must therefore be counseled to be fastidious in their application of the cream exclusively to affected skin. Even with such care, some patients develop local reactions that may be troubling; however, for patients who tolerate the compound, it may be a desirable alternative. Of note, the same compound appears to be active when given systemically. In open-label trials, tumor response was noted in approximately 37% of patients.79,80 Headache, dry skin, hyperlipidemia, and pancreatitis may, however, complicate use of this medication.

Radiation Therapy

Radiation therapy using either orthovoltage or electron beam may be useful for some patients.81 The response rate is high, as shown by a French study of 643 patients with AIDS-associated KS in whom a complete response rate of 92% was noted when 20 Gy was delivered over 2 weeks, followed 2 weeks later by 10 Gy over 1 week.82 For patients with a limited number of lesions or with large plaquelike lesions, this may be an effective approach.83 Modifications in dose schedule may reduce the complexity for patients, as in the experience from one center using a single 8-Gy dose in which a 77% response was observed.84 Tolerance of therapy is generally good; however, caution must be used when targeting mucous membranes. The sensitivity of patients with AIDS to mucositis from radiation therapy appears to be heightened, and severe, debilitating complications can occur.

Systemic Antitumor Chemotherapy

Type I interferons have long been used for the treatment of KS, with theoretic appeal because of their antiviral, antiproliferative, antiangiogenic, and proimmunologic activities.85 Whether interferons affect KSHV replication has not been well defined at this time, but interferon-alpha can decrease HIV-1 replication and may thereby alter the production of HIV tat.86 Interferons also have been demonstrated to alter cytokine profiles that may participate in KS development. For example, circulating levels of soluble TNF receptor and IL-1-receptor antagonist have been shown to be increased,87,88 and bFGF production by tumor cell lines to be decreased.89,90 Thus, interferons may be considered a pathophysiologically based therapy for KS, yet their use is affected by a number of considerations. As a single agent, interferon-alpha has antitumor effect but generally requires doses (> 9 million units/day or three times weekly) that are difficult to tolerate. When used in combination with zidovudine (azidothymide [AZT]), lower doses of interferon may be used. Interferon-alpha-2 has been shown to induce remission of KS in a dose-dependent fashion when given in combination with AZT, with 31% of 54 patients responding to 8 million units given daily subcutaneously,85 although doses as low as 2 million units have been shown to have activity. Interferon therapy is most effective in those with relative preservation of immune function and is therefore generally reserved for those with ≥ 100 CD4 cells/mm3. The use of interferon is limited by its slow onset of action (a median time to response of 10 weeks in some studies) and the frequency of troubling side effects. Most prominent are flulike symptoms initially, with depression and fatigue common after prolonged use.

Cytotoxic chemotherapy for KS is appropriate for advanced symptomatic KS, particularly for those patients with edema, extensive mucocutaneous disease, and pulmonary or symptomatic GI involvement. Combination therapies of bleomycin and vincristine91 or doxorubicin, bleomycin, and vincristine92 have been shown to be active, with tumor responses reported over a wide range (57 to 88%).93 The definition of response to chemotherapy in KS has historically been more ambiguous than with most other tumors because of the limitations of the bidimensional measurement in KS. KS can undergo complete regression of identifiable tumor on histology, yet the region of hyperpigmentation may not change in size. What does change is the nodularity of the lesion, the color characteristics (from a violaceous or salmon color to a gray-brown hemosiderin stain), and when present initially, associated edema. Thus, responses in the older literature are difficult to assess, while more recent studies have benefited by the introduction of standard response criteria initially defined within the AIDS Clinical Trials Group (ACTG) and more recently refined by a joint effort of the AIDS Malignancy Consortium, the National Cancer Institute, and the U.S. Food and Drug Administration (FDA).

Combination cytotoxic therapy with doxorubicin, bleomycin, and vincristine has served as a standard for comparison with newer treatment regimens. While combined doxorubicin, bleomycin, and vincristine has a substantial response rate, side effects are common, most prominently nausea, alopecia, fatigue, peripheral neuropathy, acral cyanosis, and Raynaud’s phenomenon.94 These toxicities can be quite debilitating in a patient population on numerous other medications and often dealing with numerous other medical problems. The impetus for an active but more easily tolerated treatment program has therefore been particularly acute in KS. The liposomal encapsulated chemotherapy agents have provided that option and have a number of characteristics that are appealing for use in KS. The leaky vasculature composing KS lesions predisposes to deposition of the drug, and lesion concentrations of drug have been shown to be almost an order of magnitude higher than in noninvolved tissue.95 Further, the side-effect profiles of these agents are more favorable. Two recent phase III studies, with roughly 250 HIV-related KS patients each, found a 25% response rate to this triple therapy or to bleomycin plus vincristine; this finding compared to 46% and 58% for liposomal doxorubicin in the two studies, respectively.96,97 In contrast, a large randomized study comparing the doxorubicin-bleomycin-vincristine combination to liposomal daunorubicin found the liposomal drug to have less toxicity, but the tumor response rate was equivalent and not as high as that found for liposomal doxorubicin.98 Whether liposomal doxorubicin is truly superior to liposomal daunorubicin is unclear and is the subject of an ongoing clinical trial. These liposomal agents are different in their liposomal composition as well as their anthracycline and have different kinetic profiles. The longer half-life of liposomal doxorubicin may account for its differential activity and association with the hand-foot syndrome, not seen with the currently formulated liposomal daunorubicin. Many practitioners use these agents interchangeably for first-line therapy of patients with advanced, symptomatic KS, although current FDA approval for liposomal doxorubicin is only for use in refractory or relapsed KS.

The taxane tubulin stabilizer, paclitaxel, has emerged as a highly active, well-tolerated agent for KS. In a phase I trial involving 28 patients, a major response was observed in 71%,99 including those previously treated with anthracyclines. This treatment appears to have both profound activity and highly durable responses. Tumor breakthrough is relatively rare, and patients can tolerate low-dose paclitaxel (100 mg/m2 every 2 weeks) extremely well. In a phase II study, the response rate was 59%, with a longer duration of response than had been seen with any other therapy.100 Some patients have received this therapy for over 2 years at our center and have maintained excellent tumor control. As with other agents, the antitumor effect is rapidly lost if the drug is stopped unless intervening improvement in immunologic function has occurred and can contribute to tumor control.

The highly vascular nature of KS lesions and their ready accessibility to study have made KS a candidate disease for assessment of antiangiogenesis agents. A number of clinical trials involving a range of different agents have occurred or are under way. The agent thalidomide has a number of properties, including inhibiting angiogenesis, and has been assessed in early-phase studies in patients with KS. A phase II trial of 13 patients demonstrated a partial response in 4 patients, and the drug was generally well tolerated over a 52-week period.101 Fumigillin (TNP-470) was well tolerated in a study of 38 patients but had poor activity.102 The membrane metalloproteinase inhibitor col-3 and the dipeptide IM-862, as well as inhibitors of VEGF signaling pathways, have all been shown to have antiangiogenic activity in animal models and are currently being tested in KS. It is envisioned that these agents may play a role for patients with relatively early-stage disease to prevent progression or to maintain a remission induced by a cytotoxic agent.

The viral process underlying KS and the relationship of the disease to immune function also suggests that immunologic approaches may ultimately have therapeutic value. A number of recent reports have defined epitopes within KSHV gene products that are recognized by cytotoxic T lymphocytes.103,104 Definition of whether reactivity to certain epitopes associates with protection from disease will pave the way for the development of vaccine or adoptive cell therapies of the future.

Non–Hodgkin’s Lymphoma (NHL)

Lymphoproliferation occurs in the context of immunodeficiency of many different types. It is a common complication of individuals born with congenital abnormalities of T-cell function, those receiving immunosuppressive medications for organ transplantation, and those with HIV infection. The common theme among these is the role of EBV going unchecked in its ability to induce B-cell proliferation. However, the minority of AIDS-related lymphomas resemble the lymphoproliferative disease of the congenital or post-transplantation setting. AIDS-related lymphoma is a complex set of tumors with challenging clinical scenarios. It has been and remains the most lethal complication of HIV infection, demanding new approaches and new understanding of the pathophysiology underlying it.14

Epidemiology

The association of NHL with HIV infection was evident within the first half-decade of the AIDS epidemic, when an unusual number of lymphomas among young men became evident in cancer registries in California. The first revision of the definition of AIDS by the U.S. Centers for Disease Control in 1987 included NHL, and it has remained an important and devastating manifestation of HIV-induced immunosuppression. Unlike KS, in which select subsets of HIV-infected individuals have a unique risk, NHL is more uniformly distributed among risk groups for HIV, with little variation. What variation is present may be attributable partly to issues of care.

The risk for NHL among HIV-infected individuals is in part determined by the level of immunosuppression, with higher risk noted among those with low CD4 cell counts. However, specific subsets of lymphoma have a stronger association with severe immunosuppression than do others. The occurrence of PCNS lymphoma is restricted to those with very advanced immunodeficiency, as is the primary effusion lymphoma (PEL) subset of systemic lymphomas. These manifestations of profound immune dysfunction appear to have decreased in incidence since the advent of HAART. Among the non-PEL systemic lymphomas, the immunoblastic histologic subset appears to occur more commonly in those with more profound immunosuppression, whereas the small noncleaved-cell Burkitt tumors are often seen in a group with more preserved immune function.105 The median CD4 counts in most treatment reports of systemic lymphoma are in the range of 50 to 189 cells/mm3, with the small-cell group having a median CD4 count of 193. In contrast, reports of patients with PCNS lymphomas demonstrate a profound CD4 count depression (30 cells/mm3 in one study).106 Thus, NHL may occur across a broad range of contexts in HIV disease, including those with virtually no other manifestations of immunosuppression. Possible underlying, unrecognized HIV infection should be considered in any person presenting with a highly aggressive lymphoma.

Pathology and Pathogenesis

The development of lymphoma among HIV-infected patients is virtually always associated with transformation of a B cell, a cell type that HIV itself is unable to infect. Thus, HIV does not play a direct role in the development of most AIDS-related lymphoma (ARL); rather, it provides the background immunosuppression either for transforming viruses or for proliferative triggers for B cells to go unabated. The rare exception to this is a small subset of tumors of T-cell origin.

T-cell malignancies in HIV infection are uncommon but include a spectrum of clinicopathologic entities.107–115 In one subset, the HIV genome has been identified either in the T cells or in tumor-associated macrophages. Definition of the HIV chromosomal integration site revealed a preferential localization to a region upstream of the c-fes proto-oncogene, a finding that suggests a direct role for HIV in tumor pathogenesis.116

While HIV may not be present in any but the rare T-cell malignancy, other viruses often are present. Most particularly, EBV is common in a subset of systemic lymphomas and virtually all primary CNS lymphomas. The biology by which this gammaherpes virus exerts its effects are being unraveled through molecular analyses and perhaps is most clearly defined for the PCNS lymphomas and post-transplantation lymphoproliferative diseases. In that context, specific expression of latent virus genes are characteristic of a so-called type III pattern. These genes include theLMP1 and LMP2 and EBNA1 through EBNA6. The LMP1 gene has been extensively studied as a potentially direct mediator of B-cell proliferation and has been shown to interact with the tumor necrosis factor receptor (TNFR) –signaling pathway.117,118 It has been recently shown that this gene is expressed in primary tumor tissue from patients with post-transplantation lymphoproliferative disease (PTLD) and ARL and is associated with activation of NF-kB.119

LMP1 is a six-transmembrane-spanning molecule with a cytoplasmic carboxy terminus capable of interacting with the TNFR II-associated factors (TRAFs) that mediate downstream transcription factor activation.118,120–123 Aggregation of the cytoplasmic domains of LMP1 mimic activated TNFR II and thereby provide a stimulus resembling constitutively activated receptor.124 The activated pathways are similar to those of the TNFR family member CD30, involving the transcriptional regulators NF-kB and c-jun.124,125 Potential downstream targets of these regulators are the pro-proliferative cytokines, interleukin-6 (IL-6) and IL-10.

A number of mutations within the carboxy terminus of LMP1 have been noted, and there are some data to support the possibility that these are associated with ARL or HIV-related Hodgkin’s disease.123,126–128 However, other studies have indicated that the frequency of such mutations is no greater among those with lymphoproliferative disease than it is among patients in an unaffected control group.126 The concept that molecular evolution of persistant EBV infection may lead to alteration in the malignant potential of select latently infected B cells is an appealing hypothesis that remains speculative at this time.

The proportion of tumors associated with EBV has been variably reported, ranging between 33 to 67%.129–131 This finding leaves a large fraction of systemic ARLs without a clear association with an oncogenic virus; among these, a small proportion is linked to KSHV. The clinicopathologic entity, primary effusion lymphoma (PEL), is typically seen in those patients with profound immunosuppression and presents as fluid without tumor mass in the involved body cavity.132,133 The tumor cells generally do not express B-, T-, or even hematopoietic-cell surface markers (they are CD45, CD3, CD19 negative). Molecular analysis of the cells demonstrates that they have undergone immunoglobulin gene re-arrangement consistent with an origin in the B-cell lineage. All such tumors identified to date include the KSHV genome, and some have evidence of EBV co-infection.134,135

The ability of KSHV to infect B cells in vitro has been shown whereas the impact of that infection has been difficult to discern in vitro. No clear association of virus infection with altered B-cell growth kinetics, such as is observed with EBV, has been noted with KSHV. However, the close clinical and pathologic relationship of KSHV to PEL is compelling evidence for a direct relationship between KSHV and B-cell oncogenesis mediated by mechanisms not yet understood.

Among the possible contributions of viruses to malignant transformation is alteration in the immunologic reactivity to neoplastic cells. Mechanisms include the ability of EBV EBNA1 to alter antigen-processing pathways and thereby potentially mask EBV-infected cells from cytotoxic T lymphocytes (CTL) reactivity.136–138 While the specific details of the mechanism remain to be elucidated, it appears that KSHV exerts a similar effect on infected transformed cells. In addition, viral gene products may be elaborated by infected cells and may impact immune effector cells. For example, EBV encodes a viral IL-10 homologue (BRCF-1) with biologic activity mimicking that of endogenous IL-10.139–141 Cell lines and tumors from AIDS patients and animal models of ARL have indicated that IL-10 is produced,139,141–144 and that it potentially exerts an inhibitory influence on the T-helper-cell (TH-1) response. IL-10 potently suppresses interferon-gamma and IL-2 production by effector cells of the TH-1 response and is a B-cell mitogen.140

Other cytokines potentially participating in altered reactivity to malignant cells include IL-6, which, in addition to serving as a proliferative stimulus to B cells, may act to alter cell sensitivity to immune killing. Specifically, IL-6 has been shown to reduce the ability of EBV-positive cells to be lysed by antigen-specific CTL from HIV-1-positive individuals.145 IL-6 levels have been noted to be elevated in the serum of patients with AIDS and may be associated with the development of NHL.146

The CD40 and CD40 ligand (CD40L) interaction has also been hypothesized to participate in the development of HIV-related lymphomas. Activation of this TNF-receptor family pathway has been shown to alter the proliferation, differentiation, and survival of B cells that serve as a key mechanism of interaction of the B- and T-cell-mediated immune mechanisms. The infection of microvascular endothelial cells from the bone marrow and CNS has been shown to result in altered CD40 signaling that up-regulates adhesive interactions with B cells and possibly explains the potential for extranodal lymphoma in HIV-infected individuals.147

Chemokine pathways may also contribute to the unique susceptibility of HIV-infected patients for lymphomagenesis. Patients with a genetic variant in the CXC chemokine, stroma-derived growth factor-1 (SDF-1), have an excess risk of developing the Burkitt’s-lymphoma subtype of ARL.148 This chemokine is a known B-cell mitogen for B cells, and by exerting chemokinetic effects, may thereby contribute to a proliferative stimulus for patients with the genetic variant. The presence of this variant has been suggested to possibly provide a method of identifying those patients with increased risk for lymphoma although the potential for this risk factor remains speculative at this time.

Genetic mutations in the tumor cells have been well characterized and are related to the specific histologic subtype. Large cell lymphomas exhibit a Bcl-6 re-arrangement in approximately 33% of cases, a c-myc re-arrangement in 40%, and a p53 mutation in 25%.149 In contrast, the small cell lymphomas seen in AIDS have c-myc re-arrangements but not Bcl-6 and rarely have p53 mutations.150–153 The presence of EBV is variably associated with either the c-myc or Bcl-6 re-arrangements in the small and large cell lymphomas, respectively.150–153 The finding that re-arranged c-myc gene juxtaposes with the immunoglobulin gene heavy chain switch region152,154–157 suggests that the malignant event is occurring proximate to the time of immunoglobulin class switching. This relatively late event in B-cell ontogeny is indicative of transformation in a relatively mature B cell.

The tumor types seen can be broadly categorized as large cell, immunoblastic, and small cell. Among the small noncleaved cell tumors are the subtypes called Burkitt’s lymphoma (BL) and Burkitt-like lymphoma (BLL). The BLL subtype more closely resembles the large cell phenotype. Characteristics that distinguish BLL from BL include a higher frequency of EBV, CD39, CD70, and CD11a. While BL is often found in a patient population with higher CD4 counts, the BLL patients have been noted to have lower counts similar to the large cell subsets.158,159

Clinical Setting

Lymphoma in the context of HIV infection may be broken down into two major groups: those with PCNS lymphoma presenting with parenchymal brain disease alone or those with systemic lymphoma who may or may not also have CNS involvement. Among the patients with systemic lymphoma, there is a rare subset of individuals presenting without a mass lesion but rather with PEL, as noted above. All of these groups represent B-cell neoplasms of high grade with a very aggressive pace of disease.

PCNS lymphoma is generally a manifestation of far advanced immunosuppression. Mean CD4 counts are ≤ 30 cells/mm3, there is commonly a previous history of an AIDS-defining complication, and the EBV genome is invariably present in the tumor.106 Histologically, these tumors have an immunoblastic appearance and express a type III pattern of EBV latent gene products.160 The clinical approach to these patients is detailed in a later section.

Systemic lymphomas may occur in a much earlier stage of HIV disease although there remains an association of incidence with more advanced immunosuppression. This situation is particularly true of PEL, which is an end-stage complication of HIV-induced immunosuppression and which has been observed in other types of immunosuppression, including that associated with organ transplantation.161 The common sites of involvement with this tumor are the peritoneum, the pleural space, and the pericardium.162 Involvement of the bone marrow has been observed with progressive disease, and at least one report documents the development of a mass lesion with immunochemical characteristics of PEL.163 The approach to this patient population is a staging process similar to any systemic NHL, including the evaluation of the CNS. Whether a distinct approach to therapy should be undertaken is unclear at this point, as standard treatment regimens generally have had unfavorable outcomes.

Systemic ARL, which is not PEL, is quite distinct from lymphoma outside the context of HIV. Involvement of extranodal sites is the rule rather than exception, occurring in up to 95% of patients, and is frequently the site of diagnostic biopsy.3,5,7,151,164,-177 Lymphoma restricted to extranodal sites may be seen in up to 56% of patients.177 Particular sites of involvement are favored by specific histologic types. Among those patients with small noncleaved histology, bone marrow and meningeal disease occurs in approximately one quarter, while large cell tumors favor the GI tract and brain parenchyma. A summary of the sites of involvement reported in three series is presented in Table 135.4 and indicates the frequency of involvement of the most common sites: bone marrow, CNS, GI tract, and the liver.

Table 135.4. Sites of Extranodal Involvement for AIDS High-Grade B-Cell Lymphomas.

Table 135.4

Sites of Extranodal Involvement for AIDS High-Grade B-Cell Lymphomas.

Clinical Manifestations

AIDS-related lymphomas are generally extremely aggressive, high-grade lymphomas of B-cell origin. However, lymphoproliferative disease in AIDS may include a number of entities, including infrequent T-cell malignancies. Large granular lymphocyte disease, large cell or anaplastic T-cell lymphoma, Sézary syndrome, and angiocentric T-cell proliferation have been reported.107–113,115,178, Pathologic and pathogenetic variability in these rare tumors is broad. Some have integrated HIV-1, as previously noted,113,116 some have integrated human T-cell leukemia/lymphoma virus (HTLV-1),114 and some have integrated EBV in a subset with oropharyngeal T-cell lymphoma.

Multicentric Castleman’s disease or angiofollicular lymph node hyperplasia has been reported in patients with advanced HIV disease.179 This process often presents with fever, peripheral adenopathy, weight loss, hepatosplenomegaly, pulmonary symptoms, and anemia or pancytopenia. Both the hyalin-vascular and plasma cell subtypes of Castleman’s disease have been reported in AIDS. KSHV is found in the involved nodes, and there is a high prevalence of co-incident or subsequent Kaposi’s sarcoma.132,179–181 This lymphoproliferative process is regarded as a KSHV-related neoplasm that is aggressive with poor outcome, although responses to chemotherapy have been reported.179

Plasma cell disorders are increased in the setting of HIV infection and are also fairly heterogeneous. Plasmablastic lymphomas of the oral cavity182 with frequent absence of typical lymphoid markers, such as CD45 (leukocyte common antigen) or CD20, have been noted. Extramedullary plasmacytomas and overt multiple myeloma with paraprotein specific for HIV antigens have been reported.183,184 The clinical course of these disorders is highly variable, and the clinical approach should be based on standard guidelines for these diseases outside the context of HIV infection.

Clinical Approach

Evaluation of patients with ARL follows staging procedures for other types of NHL, with several caveats specific to the HIV-infected population. First, the frequent involvement of the CNS mandates a more thorough assessment of the CNS, including an imaging study of the brain and sampling of the CSF. Second, the potential for co-incident opportunistic infection must be kept in mind when evaluating a patient with “B symptoms.” Microbiologic evaluation is particularly important for that population with CD4 counts < 200 cells/mm3 in whom the risk for opportunistic disease is increased and is a necessity for those with < 50 cells/mm3. Depending on the clinical scenario, particular concern should be paid to the possible presence of active Pneumocystis carinii, Cytomegalovirus, Toxoplasma gondii, Mycobacterium avium complex, Mycobacterium tuberculare, and Cryptococcus. Third, assessment of the status of the HIV disease is critical in defining the therapeutic approach. CD4 cells should be measured as well as plasma HIV RNA, and a detailed history of previous anti-retroviral therapy and opportunistic disease should be obtained. Those patients for whom NHL represents a manifestation of end-stage, treatment-refractory HIV disease should be regarded with palliative intent. In contrast, the patient with viral suppression on HAART may have an open-ended prognosis from HIV-1 infection, and the emphasis should be on curing the lymphoma—a concept not realistically considered in the pre-HAART era but of substantial importance since the availability of HAART in 1996. Experience with long-term ARL survivors now free of any clinical evidence of HIV disease emphasizes the importance of that perspective. Selecting a regimen appropriate for the patient involves weighing where the patient may lie in the continuum of HIV disease.

Prognostic Factors

Prognosis in patients with ARL has generally been poor, but with the advent of HAART, the improved prognosis from HIV-1 itself, as well as the improved tolerance of chemotherapy, are expected to substantially alter long-term results. Factors that have been indicative of higher risk have been variably reported, based on the specific clinical trial. The largest experience, with 192 patients and comparing the m-BACOD regimen with the modified m-BACOD regimen, identified a CD4 count of < 100 cells/mm3, age > 35 years, intravenous drug use and stage III/IV disease as independent prognostic indicators.185 Overall survival in the setting of one or none of these factors was 46 weeks; of two factors, 44 weeks; and of 3 or 4 factors, 18 weeks.

The International Prognostic Index186 has been applied to patients with ARL and has been shown to be predictive in at least one study of 46 patients.187 Other studies have also identified an increase in lactate dehydrogenese (LDH)188 or age > 40 years as factors independent of CD4 cell counts. Prior AIDS-defining illness, Karnofsky performance status, and the presence of extranodal disease have also been reported to be predictive of risk.106,171,189–191 Kaplan and colleagues also noted that the presence of polyclonality was a favorable indicator, particularly in the absence of EBV in the tumor and a CD4 count of > 300 cells/mm3.190 Remarkably, only a single study has shown the small noncleaved-cell histology to be of prognostic importance, and histologically guided therapies have generally not been applied to this population. However, the use of regimens tailored for Burkitt’s tumor histology is likely to be developed in the future.

Treatment

Low-Dose Therapy

Early in the AIDS epidemic, the aggressive nature of the lymphomas observed was met with an aggressive clinical approach to therapy. The result was severe toxicity and frequent treatment-related death. As prophylactic therapy for opportunistic infections has improved, and with the advent of growth factors, the tolerability of chemotherapy has also improved. However, given the overall poor prognosis of patients with HIV-1 infection and the frequent necessity of concurrent treatment for other opportunistic illnesses, there was an effort to identify a low-intensity antitumor regimen. This effort resulted in the modified m-BACOD regimen,166 which is being tested in a phase III trial comparing it directly with the full-dose regimen.191 The modified m-BACOD was essentially half dose (Table 135.5), and the full-dose regimen was given with concurrent granulocyte-macrophage colony-stimulating factor GM-CSF. Surprisingly, the results revealed no statistically meaningful differences in the incidence of complete remission (50% versus 46%), relapse after complete remission (19% versus 23%), time to progression (22 weeks versus 28 weeks), overall median survival (31 weeks versus 34 weeks), death from AIDS (20 patients versus 12 patients), and death from lymphoma (24 patients versus 36 patients). The major difference between the two arms of the trial was that grade 4 neutropenia occurred with greater frequency in patients receiving the standard-dose regimen despite the fact that all such patients received GM-CSF as a part of their treatment program. The utility of this regimen has been called into question, however, with the better tolerability of full-dose regimens in the era of HAART and the demonstration in the non-HIV-infected population that a regimen of cyclophosphamide, hydroxydaunomycin, Oncovin, and prednisone (CHOP) is at least as effective as m-BACOD, with fewer side effects.192 For those patients in whom advanced HIV disease precludes use of full-dose chemotherapy, a modified m-BACOD or CHOP regimen may be appropriate. However, use of the modified regimens in patients with retroviral control cannot be advocated without further definition of equivalent control of the lymphoma.

Table 135.5. Commonly Used Therapy Regimens for AIDS-Related Lymphoma.

Table 135.5

Commonly Used Therapy Regimens for AIDS-Related Lymphoma.

Standard-Dose Therapies

For patients with control of HIV-1, the options are those of standard chemotherapy regimens such as CHOP (see Table 135.5), in which response rates slightly lower than that of the uninfected population have been observed.

European investigators have evaluated more chemotherapy-intensive regimens for patients with AIDS lymphoma. French-Italian Cooperative Group tested the LNH84 regimen in 140 patients and observed a complete remission rate of 65%, with a relapse rate of 24%.193 A follow-up study of patients with CD4 count >100 cells/mm3, no prior AIDS-defining illnesses, and good performance status has been conducted comparing CHOP chemotherapy with ACVB (doxorubicin 75 mg/m2 on day 1, cyclophosphamide 1.2 mg/m2 on day 1, vindesine 2 mg/m2 on day 1, bleomycin 10 mg on days 1–5, prednisolone 60 mg on days 1–5) with granulocyte colony–stimulating factor (G-CSF) support. Preliminary results indicate that hematologic toxicity was more severe in the ACVB arm, but that a higher response rate was seen.194 Further analysis of this data is required before firm conclusions can be drawn. However, the potential for dose-intensive regimens for those in this patient population with good prognostic factors is suggested and needs to be further explored.

Continuous-infusion regimens have also been tested for patients as first-line therapy. The cyclophosphamide-doxorubicin-etoposide (CDE) regimen (cyclophosphamide 800 mg/m2, doxorubicin 50 mg/m2, etoposide 240 mg/m2, all per day for 4 days), to which dideoxy inosine (ddI) was added, resulted in a complete response rate of 58% with a median response duration exceeding 18 months in a phase II trial.195 A follow-up study using this approach is ongoing at present, and a comparison of this regimen with standard regimens such as CHOP is anticipated.

Similarly, a trial employing the infusional EPOCH regimen has given very encouraging early indications of activity, with a 70% complete response rate in a small phase II trial.196

Standard Cytotoxic Chemotherapy plus Antiretroviral Therapy

The idea of combining anti-retroviral and antitumor therapy has advocates who suggest that the ability of the immune system to participate in combating the malignancy will be maximized by suppressing HIV-1 replication. This view is balanced by the view of those who regard the viral infection as a secondary priority in the setting of life-threatening tumor growth and believe that adding the potential risks of drug-drug interaction does not justify the combining these two groups of agents. This dichotomous opinion is reflected in two recent clinical trials. One study involved the use of a set triple drug, protease inhibitor-containing regimen in combination with CHOP chemotherapy and assessed clinical outcomes and pharmacologic parameters. The other involved a trial of continuous-infusion chemotherapy (adjusted EPOCH) in which anti-retroviral therapy was held and viral and immune outcomes were measured in addition to tumor responses.

The trial of CHOP plus indinivir, d4T, and 3TC was conducted by the United States National Cancer Institute–supported AIDS Malignancy Consortium and involved a cohort of patients receiving low-dose CHOP and a subsequent cohort receiving full-dose CHOP plus the same anti-retroviral regimen. The preliminary results of this study indicated that the combination did not result in unexpected severe or more-frequent toxicities. Pharmacologic analysis tested the possibility both of antineoplastic drugs affecting protease inhibitor levels and of antiviral therapies altering cytotoxic drug metabolism. No alterations in levels of indinivir or doxorubicin were noted, although a reduction in cyclophosphamide clearance of approximately 50% was observed.197

The United States National Cancer Institute conducted a trial of infusional chemotherapy in which all anti-retroviral therapies were held during cancer treatment.196 While these data are preliminary, the results suggest that holding antiviral therapy results in a rise in HIV RNA during cancer chemotherapy, that reverts to entry levels when antivirals are resumed. Whether either maintaining or holding anti-retroviral drugs affects long-term outcomes is not known, but the short-term consequences of holding such therapy appear to be acceptable, and combining select antivirals and antitumor therapy appears not to be associated with unacceptable adverse events.

High-Dose Therapy or Combined-Modality Therapy

Efforts to improve the currently poor outcome for patients with ARL have included the addition of immunotoxins to enhance tumor killing. While this combination was reasonably well tolerated, activity of the immunotoxin was limited, and the outcomes were not sufficiently different from concurrent chemotherapy-alone trials to merit further pursuit. With the availability of the humanized anti-CD20 antibody (rituximab) and its apparent activity even for high-grade B-cell malignancies, the concept of combined immunoglobulin and standard cytotoxic chemotherapy is being reconsidered. A multi-center randomized phase III trial testing CHOP versus CHOP plus rituximab is currently under way.

Bone marrow transplantation in patients with HIV disease has been reported; however, these reports antedate protease inhibitor combination therapy regimens. In 1989, an allogeneic bone marrow transplantation in a patient with ARL was reported by Holland and colleagues.198 Cyclophosphamide (50 mg/kg/d on days 9 through 5) and total-body irradiation (300 cGy/d on days 4 through 1) were given, followed by allogeneic bone marrow transplantation and intermediate-dose AZT (1.33 mg/kg IV q4h). Bone marrow engraftment occurred by day 17, and complete chimerism was documented by PCR analysis. (The patient died 47 days after transplantation because of relapsed tumor; HIV could not be detected by PCR analysis in autopsy tissue.) In a population of 12 patients in Marseilles who were HIV-seropositive at some point during care for their autologous or allogeneic bone marrow transplantation, 2 were known to be seropositive at the time of transplantation, and no untoward problems with myeloablation or engraftment were reported.199

A single HIV-positive patient treated with allogeneic transplantation for aplastic anemia (cyclophosphamide and total body irradiation (TBI) were used in unspecified doses) was reported to experience cryptosporidiosis and cerebral toxoplasmosis post transplantation with normal engraftment.200 Other reports have similarly noted engraftment, but have noted progressive underlying neoplasia or HIV disease, when allogenic transplantation has been attempted.201–206

A single patient received BEAM chemotherapy and autologous transplantation for relapsed AIDS lymphoma.207 The patient recovered blood counts and was discharged on day 24. He subsequently developed opportunistic infections but was reported to be alive and in complete response at 20 months post transplantation. Ongoing trials using autologous stem cell transplantation are encouraging regarding tolerability, but overall outcomes remain to be defined.208 These studies are being conducted in conjunction with gene modification of stem cells to protect against HIV-1 infection at our center and others.

CNS Prophylaxis

The role of CNS prophylaxis has been much debated. While early studies indicated a very high incidence of CNS involvement or relapse (8 of 12 patients in one study168), the usefulness of routine CNS prophylaxis has never been rigorously studied in this patient population. Approach to this issue is very center-dependent, and some centers treat all patients with four weekly doses of intrathecal ara-C or methotrexate. The practice at our center is to reserve this treatment for patients who have small noncleaved-cell histology or bone marrow, testicular, or Waldeyer’s ring involvement.

Supportive Care

All patients should receive prophylaxis for opportunistic infections. Regardless of the CD4 count at entry, reductions in CD4 counts can be expected during chemotherapy, and Pneumocystis carinii prophylaxis is generally used. The therapies standardly used in advanced HIV disease are applied to this population.

Growth factor use is often required, given the noted increased sensitivity to myelotoxic injury in patients with HIV disease. A single randomized trial of CHOP versus CHOP plus GM-CSF found a significant difference in the incidence of fever and neutropenia and days of hospitalization in the cohort receiving prophylactic growth factor.173 This trial antedated the use of protease inhibitors, which has generally improved patients’ tolerance of chemotherapy. Therefore, many practitioners use guidelines similar to those for other patients receiving chemotherapy when deciding about growth factor use.209

The use of growth factors in the HIV-1-infected population has been of some concern due to the potential for growth factor stimulation of HIV-1 replication.210,211 This issue has been raised particularly for GM-CSF, in which direct activation of the HIV-1 transcriptional control regions has been documented in vitro. Data regarding the increase in viral load in vivo, however, has been conflicting. Some studies have demonstrated a rise in markers of viral load (HIV p24 at the time of these studies),173,212 and others show either no increase or a transient increase.213–215 The trial involving GM-CSF and CHOP observed an increase in HIV-1 p24 that was noted in the early cycles but that by the end of the trial was not different compared with controls. The data with G-CSF use are similarly conflicting. G-CSF does not have effects on inflammatory cytokine release or notable induction of HIV-1 in vitro seen with GM-CSF but has been shown to induce increases in HIV RNA in half the patients receiving it at doses sufficient for stem cell mobilization.216 These increases were transient and returned to baseline following cessation of the growth factor. The long-term consequences of growth factor use and its relationship to control of virus replication by anti-retroviral drugs are not presently known. Concerns regarding long-term consequences generally do not discourage use of growth factors in the context of patients with otherwise strong indications for their benefit.209

Primary CNS Lymphoma

A brain mass in the context of HIV infection can be caused by a number of infectious and neoplastic processes and thereby poses a substantial diagnostic challenge. Most commonly seen in AIDS patients are Toxoplasma gondii abscess, PCNS lymphoma, mycobacterial or bacterial abscess, and progressive multifocal leukencephalopathy (PML). Criteria for distinguishing between these entities remains imperfect without tissue sampling, but for those patients in whom biopsy is not possible or is refused, certain parameters can raise or lower the likelihood of a lymphoma diagnosis, and the use of PCR analysis has greatly improved the reliability of a diagnosis without histologic confirmation.

In general, PCNS lymphoma, PML, and toxoplasmosis are complications of far advanced immunosuppression with CD4 counts of ≤ 50 cells/mm3. This patient population is often on trimethoprim/sulfamethoxazole prophylaxis for Pneumocystis, which provides excellent protection against Toxoplasma. For those patients in whom a Toxoplasma antibody titer is negative and who have been on such prophylaxis, the liklihood of a lymphoma diagnosis in the setting of a CNS mass lesion has been documented to be 74%.217 Additional information can be gained from PCR analysis for the EBV genome in CSF samples. Among patients with a focal brain lesion and AIDS, a positive finding for EBV by PCR had a sensitivity of 80% and a specificity of 100% for PCNS lymphoma in one large study.218

Radiographic features more suggestive of lymphoma include central location, lack of multi-focality, and size > 2 cm.167,219 In addition, a lesion that crosses the midline is highly likely to be a neoplastic process. Single photon emission computed tomography (SPECT) or positron emission tomography (PET) can also help distinguish lymphoma from abscess, and the combination of one of these imaging techniques with a positive DNA PCR for EBV is used by some centers to find sufficient evidence for initiation of therapy. If these tests do not clearly delineate the process and a biopsy is not feasible, empiric anti-Toxoplasma therapy has often been used as a diagnostic as well as therapeutic tool. Initiation of sulfadiazine or clindamycin with pyrimethamine generally halts the progression by 5 days and results in clinical or radiographic improvement by 14 days.220 For those in whom these milestones are not met, the likelihood of toxoplasmosis is low.

Therapy for PCNS lymphoma remains very limited and with poor outcome. Radiation therapy has been the mainstay of care, with response rates ranging from 60 to 79%, but durable remissions are uncommon.167,221,222 Alternative approaches such as high-dose methotrexate have limited experience in this population, but reports of small trials have been encouraging.223 Combining cytotoxic chemotherapy and radiation therapy has been tested, with disappointing effect on the tumors and unacceptable toxicity. While the EBV genome is associated with PCNS lymphoma, it is generally noted to be in latent phase and therefore unlikely to be sensitive to lytic-phasespecific antiviral agents. Nonetheless, limited experience with the use of ganciclovir in combination with zidovudine and IL-2 has suggested antitumor activity.224 The ultimate use of these agents or other EBV-directed genetic225 or chemical226 manipulations awaits careful assessment in clinical trial. The overall poor outcome for these patients strongly argues for the encouragement of patients to participate in clinical protocols testing novel approaches.

The use of steroids in this patient population has engendered concern because of the potential worsening of immunosuppression. There is an absence of data regarding this point, but the opportunity to reduce edema and mass effect should not be avoided out of concern for immunosuppression. Rather, the tapering of steroids should be as rapid as is tolerated, and vigilance regarding the development of concurrent infection should be maintained. In the era preceeding HAART, death was as commonly due to secondary events as to tumor.227 For those patients who present with PCNS lymphoma and have not been receiving HAART, initiating anti-retroviral therapy should be considered a priority, as anecdotal reports have emerged of long-term survivors among the group gaining control of HIV-1.228

Hodgkin’s Disease

While not an AIDS-defining tumor, Hodgkin’s disease (HD) is increased in frequency in HIV disease and in the number of unique characteristics distinguishing it from HD outside the context of AIDS.

Epidemiology

The relative risk of Hodgkin’s disease in patients infected with HIV-1 is estimated to be 2.5- to 8.5-fold above that of the uninfected population.229–234 Several analyses of cancer registries have confirmed this increase, including a linkage analysis of cancers and AIDS surveillance data collected by registries in several regions of the United States.21 A 7.6-fold increased relative risk of HD was observed in patients with AIDS. In Australia and Italy, similar types of analyses have indicated up to an 18.3-fold increase in the relative risk of HD.233–235 The risk of HD appears to be uniformly increased across the risk groups for HIV infection, independent of age or gender.235 Despite the increase in relative risk in the HIV-infected population, the overall magnitude of the problem is still relatively small compared to that of NHL.

Pathology and Pathogenesis

HD in the context of HIV infection has pathologic features that distinguish it from the seronegative population. In particular, there is a much higher frequency of the mixedcellularity subtype, with a corresponding reduction in the relative proportion of patients with nodular sclerosis histology.189 The overall frequency of mixed-cellularity or lymphocyte-depleted histology was found to be two-thirds of the cases in the HIV-1-positive context compared with only 29% in uninfected patients.189

In addition, the presence of EBV in Hodgkin’s disease tissue is markedly increased in HIV-infected individuals. Estimates ranged from 80 to 100% in contrast to the HIV-negative population.236–238 Of note, expression of the EBV LMP1, but not EBNA2, latency genes is in a type 2 pattern.238 Thus, the EBV genome is identified with high frequency in HIV-infected HD and is considered likely to play an etiologic role.

In addition to the presence of EBV, there are other molecular characteristics of HD unique to the HIV-infected population. While the transcription factor Bcl-6, expressed in germinal-center B cells, is present on Reed-Sternberg cells from both HIV-1-infected and uninfected individuals, syndecan-1 (a proteoglycan associated with the post-terminal center) is restricted to the HIV-1-positive population.239,240 Therefore, the post-germinal-center B cell may be the cell of origin in HIV-1-related HD, as opposed to the germinal-center cell of origin presumed to be the source of Reed-Sternberg cells in the uninfected population.

Clinical Features

HD in patients with HIV is typically of advanced stage and associated with B symptoms.241 Stage III or IV disease has been documented in 91% of patients with HIV-associated HD at the time of diagnosis, compared with 46% in individuals without HIV.124 Like ARL, the location of HD in the setting of HIV-1 infection is often extranodal, involving the bone marrow in up to 50% of patients.242–244 Other sites include the tongue, rectum, skin, and lung,241 and extranodal disease may be the site of presentation. Staging strategies should be the same as those in HD patients outside the context of HIV-1, with particular attention to possible microbiologic explanations for B symptoms.

Treatment

The clinical treatment approach to patients with HD in the setting of HIV infection is similar to that in other contexts, and radiation therapy, chemotherapy, or combined radiation and chemotherapy should be applied as appropriate for stage, similar to guidelines for treatment outside the setting of HIV infection. The underlying level of immunosuppression and overall performance status of the patient must be considered before embarking on these therapies, and in general, prophylaxis for Pneumocystis carinii is provided. Treatment complications, including myelosuppression and opportunistic infections, may be expected to be more severe among patients with advanced AIDS. However, cure of HD is a realistic aim in the setting of HIV infection, and antitumor therapy dose attenuation should be contemplated only in patients with advanced AIDS or who have demonstrated intolerance to the standard-dose regimens.

Squamous Cell Neoplasia

The issue of human papillomavirus–related disease is an increasing concern in the HIV epidemic for several reasons, including (1) the increasing frequency of women infected by HIV, (2) the rampant progression of HIV disease in parts of the world where there is already a high incidence of cervical cancer and limited screening for cervical disease, and (3) the extension in overall survival of HIV-infected individuals. The nature of the abnormalities is fairly broad in scope and includes anogenital, conjunctival, oropharyngeal, and cutaneous neoplasia.

Epidemiology

The increased frequency of squamous cell neoplasia in HIV-infected individuals has been documented in a number of studies. The single AIDS-defining disease among the HPV-related tumors is that of invasive cervical carcinoma, which has not been shown generally to be of increased frequency in AIDS. Rather, intraepithelial neoplasia (IEN) of both the uterine cervix and the anus is increased. Homosexual HIV-infected men have a particularly high incidence of squamous cell abnormalities and an increased risk of anal cancer.245

Pathology and Pathogenesis

The association of specific subtypes of HPV with a potential for epidermal cell transformation has been long established, and the frequency of HPV-16, -18, and -19, is reported to be increased in HIV-infected individuals.246 The frequency of multiple subtypes of HPV has also been assessed and found to be markedly increased in the HIV-infected population (73% of HIV-1-infected homosexual men compared with 23% of uninfected homosexual men).246,247 The incidence of high-grade IEN of the anus has been estimated to be as high as 48% among HIV-1-positive homosexual men over a 4-year interval and was associated with the presence of mulitple HPV subtypes, persistent anal infection, and high-level infection with oncogenic HPV subtypes.248 Screening for IEN among HIV-1-infected homosexual men has demonstrated a prevalence of high-grade anal IEN (or carcinoma in situ) of 36% compared with 7% of HIV-1-negative homosexual men.249 Most often, these lesions on the anus and uterine cervix are not solitary sites but rather represent one of multiple areas of dysplasia and are therefore difficult to satisfactorily treat,250 particularly on the anus. Patients with a history of high-grade IEN may often have recurrence following attempts at excision, cryotherapy, or topical treatment because of the ubiquitous nature of the HPV infection locally and the tendency of that virus to continue to have effects on local tissue.

A critical issue in evaluating the magnitude of this problem is the risk of progression of IEN to frank invasive cancer. This issue remains ill defined and highly controversial. If the risk is estimated at 1% or above, cost-benefit analyses have indicated that ongoing screening is justified.251 The lack of large increases in the frequency of invasive anogenital cancer among HIV risk groups suggests that the risk is relatively small. However, the potential for frank invasion is not zero, and therefore, vigilance among patients with HIV disease is warranted.

The risk of some opportunistic neoplasms is clearly diminished in the context of aggressive therapy for HIV and suppression of HIV replication. There have been conflicting reports of whether HPV-related tumors are among those responsive to improved anti-HIV therapy. Some reports have indicated that some individuals may experience improvement in HPV-related neoplasia,252 while others indicate otherwise.253 At present, the complete suppression of HIV should not be regarded as fail-safe defense against the development of HPV-related tumors.

Clinical presentation

HPV disease may present anywhere along the continuum of condyloma acuminatum to invasive anal cancer. Patients who have anal dysplasia may or may not have symptoms associated with it. Our practice among patients with a history of high-grade anal dysplasia is to perform an anoscopic examination and possible biopsy, even if the diagnostic lesion is on the anal verge, to assess for possible invasive disease out of the external examination field. Some centers, including our own, are initiating anal Pap evaluation for HIV-infected individuals, but this approach is highly controversial.

For women with HIV infection, the standard practices and recommendations for cervical screening are to be followed, with increased vigilance for those with severe immunosuppression. For HIV-infected women with CD4 counts of < 200 cells/mm3, the recommendation is for Pap smears to be performed semi-annually.

Treatment

Treatment guidelines for dysplasia and carcinoma of the uterine cervix are well defined and should be followed in the setting of HIV infection. Management of anal disease is less clear.

For patients with invasive carcinoma of the anus, treatment guidelines recommending a combination of chemotherapy and radiation therapy should be followed; this treatment has been reasonably well tolerated in the HIV-infected population.254–256 There is a distinct increased sensitivity to mucosal injury with radiation in HIV disease, and therefore, close interaction of the medical and radiation oncologist is essential. If patients have very advanced HIV disease failing anti-retrovirals, a conservative approach to management of the malignancy may be warranted, but this requires case-by-case assessment.

The ambiguity of risk for invasion if high-grade IEN or carcinoma in situ is diagnosed has led to considerable variability in treatment practices for these patients. Our practice has been to surgically remove any lesions identifiable to the eye but not to attempt wide excisions. For those patients with recurrent anal warts or with tissue discoloration seen with HPV disease, imiquimod cream has been useful and is generally well tolerated. For lesions within the anal canal, satisfactory topical therapy is not available, and vigilant monitoring is the general approach.

Lesions on other sites are generally approached with similar principles. For invasive disease, resect, and use standard guidelines for care. For noninvasive disease, excise overt lesions locally, and attempt topical therapies such as imiquimod or 5-fluorouracil.

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