HIV infection and malignancy: Management considerations

INTRODUCTION — Individuals living with HIV have an increased propensity to develop malignancy. The occurrence of an extremely high number of cases of Kaposi sarcoma (KS) was noted early in the AIDS epidemic and many of them had an unusually aggressive clinical course. KS was therefore included as an AIDS-defining illness in early case definitions from the Centers for Disease Control and Prevention (CDC). Non-Hodgkin lymphoma (NHL) and invasive cervical carcinoma were subsequently added as AIDS-defining conditions.

Subsequently, the spectrum of neoplasia in patients living with HIV has changed as the use of potent antiretroviral therapy (ART) has become widespread (table 1). The incidence of KS and NHL has decreased markedly, but there has been a relative increase in malignancies that collectively are referred to as non-AIDS-defining cancers (NADCs) compared with the general population. NADCs are a major factor contributing to mortality in people living with HIV. [1]

This topic will review general management considerations for patients with HIV and a malignancy, as well as a discussion of specific malignancies. The epidemiology and pathogenesis of malignancy in people living with HIV are discussed separately. (See "HIV infection and malignancy: Epidemiology and pathogenesis", section on 'Introduction'.)

CLINICAL IMPLICATIONS — Malignancies in patients infected with HIV are often characterized by earlier age at onset, atypical pathology (higher tumor grade), more aggressive clinical behavior, and/or more advanced stage at presentation [2,3]. These features may have implications for screening and treatment, and may contribute to a poorer outcome, with rapid progression, a high rate of relapse, and a worse response to treatment.

Screening and prevention — The increased incidence of selected cancers in patients living with HIV, combined with the younger age of onset and the altered biology, raise the question of whether more aggressive screening is indicated [3-6]. Most cancer screening guidelines do not make separate recommendations for individuals infected with HIV, with the exception of the European AIDS Clinical Society [7].

Unfortunately, routine screening for cancer is less frequent in people living with HIV than in the general population [3]. Clinicians caring for individuals living with HIV should adhere to age-appropriate screening recommendations for the common malignancies and should actively encourage compliance with those guidelines [3,5,8]. Providers should be aware of the new guidelines for lung cancer screening in those at increased risk because of significant smoking. (See "Screening for lung cancer".)

Despite the absence of evidence supporting increased screening in this population, clinicians should be highly vigilant to symptoms suggestive of early disease. In addition to screening, clinicians caring for individuals living with HIV should make every effort to help patients minimize risk factors for cancer. Potential opportunities include:

●Smoking cessation programs (see "Overview of smoking cessation management in adults")

●The use of human papillomavirus (HPV) vaccines (see "Human papillomavirus vaccination")

●Hepatitis B virus (HBV) vaccine and the treatment of hepatitis B infection (see "Hepatitis B virus immunization in adults" and "Hepatitis B virus: Overview of management")

●The treatment of hepatitis C virus (HCV) infection (see "Overview of the management of chronic hepatitis C virus infection")

Treatment

General principles of therapy — Treatment of cancer in individuals living with HIV follows the same general principles as for those not infected with HIV. The diagnosis of cancer should be confirmed pathologically. For patients with early-stage disease, initial management is with curative intent, as is the case for individuals without HIV [3]. However, cancer registry data suggest that patients with HIV infection are less likely to be treated for some malignancies, and this may adversely affect survival rates [9].

Other factors that can complicate the management of malignancy in an individual living with HIV include the following:

●Patients living with HIV frequently have significant comorbidities that result in a poor performance status and affect the response to treatment.

●The presence of reactive lymphadenopathy or other imaging abnormalities not related to the malignancy may complicate accurate tumor staging.

●Individuals living with HIV may be poor surgical candidates because of an increased risk of developing postoperative infections, particularly in those with predominantly late-stage AIDS. Data from patients with early-stage HIV disease found surgical risks were similar to those without HIV infection [10,11].

Chemotherapy — Systemic therapy may be required for metastatic disease or as adjuvant therapy. The use of cytotoxic chemotherapy with antiretroviral therapy (ART) may result in additive cytotoxicity or other drug-drug interactions and may further enhance immunosuppression. The combination of chemotherapy and ART requires a careful consideration of such potential interactions. (See "Systemic therapy for malignancy in patients on antiretroviral medications".)

Safety and efficacy of immunotherapy — Data consistently suggest that checkpoint inhibitor immunotherapy can be used safely and effectively in HIV-positive patients with cancer [12-17].

Checkpoint inhibitor immunotherapy has dramatically improved treatment outcomes for patients with cancer, including antibodies that target cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death-1 receptor (PD-1), and programmed cell death ligand-1 (PD-L1). Although initial immunotherapy trials excluded patients with HIV [18], subsequent studies have investigated the use of these agents in HIV-positive patients, including retrospective observational studies and meta-analyses [12,13,17,18], treatment registries [14], and prospective clinical trials. Clinical trials evaluating inhibitors of PD-1, such as nivolumab [19] and pembrolizumab [15], and PD-L1, such as durvalumab [20], exclusively in HIV-positive patients have reported similar efficacy and immune-mediated toxicities compared with patients without HIV treated with these agents. Additionally, in most studies, immunotherapy did not negatively impact control of HIV disease, including HIV viral load and CD4 counts [12,20]. Further studies investigating other immunotherapy agents in HIV-positive patients are necessary. (See "Principles of cancer immunotherapy" and "Toxicities associated with immune checkpoint inhibitors".)

Prognosis — Patients with HIV infection and cancer may experience higher cancer-specific mortality compared with those who do not have HIV infection, independent of cancer stage or receipt of cancer treatment [21,22]. The largest analysis of cancer-specific mortality is a retrospective review of over 1.8 million patients with cancer, of whom approximately 6500 were infected with HIV [21]. HIV infection was associated with increased cancer-specific mortality for several common non-AIDS-defining cancers: colorectum (adjusted hazard ratio [HR] 1.49), pancreas (HR 1.71), larynx (HR 1.62), lung (HR 1.28), melanoma (HR 1.72), breast (HR 2.61), and prostate (HR 1.57).

The association between HIV infection and cancer-related mortality remained for colorectal, lung, melanoma, and breast cancer even after adjustment for non-receipt of cancer treatment.

Immunosuppression, as it relates to tolerance of cancer treatments [23] and its role in promoting tumor progression, may play a role in the increased cancer-specific mortality observed in patients living with HIV compared with patients without HIV. This serves as another potential rationale for early initiation of antiretroviral therapy. (See "When to initiate antiretroviral therapy in persons with HIV".)

LYMPHOPROLIFERATIVE AND HEMATOLOGIC MALIGNANCIES

Non-Hodgkin lymphoma — Non-Hodgkin lymphomas (NHLs) in patients living with HIV frequently arise in extranodal sites, such as the stomach or esophagus, and may constitute the majority of malignancies seen in those sites. The incidence of NHLs in patients living with HIV has fallen markedly since the introduction of antiretroviral therapy (ART). (See "HIV infection and malignancy: Epidemiology and pathogenesis", section on 'Epidemiology'.)

NHLs that have been designated as AIDS-defining include diffuse large B cell lymphoma, Burkitt’s lymphoma, immunoblastic lymphoma, plasmablastic lymphoma, primary effusion lymphoma, and primary lymphoma of the brain.

The clinical manifestations and management of AIDS-defining NHL, as well as non-AIDS-defining NHL with an increased incidence in individuals living with HIV, are discussed separately. (See "HIV-related lymphomas: Clinical manifestations and diagnosis" and "HIV-related lymphomas: Treatment of systemic lymphoma".)

Hodgkin lymphoma — Hodgkin lymphoma (HL) is among the most common non-AIDS-defining malignancies in the population living with HIV. When compared with adults without HIV, patients with HIV are more likely to have unfavorable histology and more advanced disease at diagnosis [24]. (See "HIV-related lymphomas: Epidemiology, risk factors, and pathobiology", section on 'Hodgkin lymphoma'.)

The clinical manifestations and management of HL in individuals living with HIV are discussed separately. (See "HIV-related lymphomas: Clinical manifestations and diagnosis" and "HIV-related lymphomas: Treatment of systemic lymphoma".)

Plasma cell disorders — Patients living with HIV can present with a range of plasma cell disorders, including reactive plasmacytosis, paraproteinemia, amyloidosis, light chain deposition disease, plasmacytomas, multiple myeloma, and plasma cell leukemia [25-28]. Plasma cell disorders in patients living with HIV tend to occur at a younger age than in the general population, with an average age of 33 years in one study [29]. Epstein Barr virus (EBV) infection may contribute to the development of monoclonal gammopathy in some patients living with HIV [30,31].

Antiretroviral therapy (ART) can resolve monoclonal gammopathy for patients with HIV, particularly those without active hepatitis C coinfection. For example, in one retrospective study including over 1200 patients, 11 percent were found to have abnormal protein bands [32]. Of 77 patients with abnormal bands who were included for further study, 66 percent experienced disappearance of the monoclonal peak at a median follow-up of 6.8 years. Multivariate analysis revealed that disappearance of the monoclonal peak was associated with HIV virologic control (odds ratio [OR] 6.0, 95% CI 1.6-21.9) and the absence of hepatitis C virus replication at the end of follow-up (OR 10.2, 95% CI 2.4-43.7). These results are in contrast to monoclonal gammopathy in patients who do not have HIV, for whom monoclonal protein typically does not resolve. (See "Clinical course and management of monoclonal gammopathy of undetermined significance".)

The demographic characteristics of patients with monoclonal gammopathies were illustrated by a series of 25 patients living with HIV, in which the median age was 50 years [33]. Multivariate analysis found that abnormalities in serum proteins were associated with a younger age, a higher HIV viral load, a more robust immune system (ie, higher CD4 cell count), and hepatitis B and/or C virus coinfection [25,33].

A subset of these patients go on to develop myeloma, plasmacytoma, or lymphoma [25,27]. Extramedullary disease is common in those patients who develop multiple myeloma; such plasmacytomas can be multiple and present in unusual anatomical locations. Plasma cell malignancies may show a plasmablastic morphology, making them difficult to differentiate from plasmablastic lymphoma. Myeloma patients with concomitant HIV infection may have an increased risk of complications, including intractable hypercalcemia, hyperviscosity, cytopenia, and renal failure [25].

Persons living with HIV diagnosed with a plasma cell disorder should be treated similarly to patients without HIV [25,34]. (See "Multiple myeloma: Overview of management".)

Acute myeloid leukemia — Case reports suggested that the incidence of acute myeloid leukemia (AML) is increased in persons living with HIV [35-39]. However, data from the Swiss HIV Cohort study indicate that the overall incidence is similar or only modestly increased [40].

The clinical presentation and biologic features of HIV-related AML are similar to those in persons without HIV, although the occurrence of extramedullary leukemic infiltration (myeloid sarcoma) in this setting is not uncommon.

In general, patients living with HIV with AML can achieve complete stable remission with standard therapy. However, a poor prognosis has been reported, especially with CD4 cell counts <200 cells/mm³. (See "Acute myeloid leukemia: Induction therapy in medically-fit adults".)

With increasing use of chemotherapy for both AIDS-defining cancers and non-AIDS-defining malignancies, treatment-related leukemias may become an increasing issue [41].

Chronic myelogenous leukemia — Chronic myelogenous leukemia (CML) is rare among HIV-positive patients [42]. The clinical presentation of HIV-associated CML is typically more aggressive than patients without HIV. Patients may also experience myelosuppression related to both diseases and therapy [43].

HIV-positive patients with CML may be treated concurrently with ART and tyrosine kinase inhibitors used to treat patients without HIV with CML. This approach can control of both diseases and improve long-term survival [42,43]. (See "Overview of the treatment of chronic myeloid leukemia" and "Systemic therapy for malignancy in patients on antiretroviral medications".)

CUTANEOUS MALIGNANCIES

Kaposi sarcoma — Kaposi sarcoma (KS) is a low-grade soft tissue sarcoma of vascular origin that is associated with infection with human herpesvirus (HHV)-8 (also known as the KS-associated herpesvirus) [44]. Infection with HHV-8 precedes and is predictive of the development of KS (see "HIV infection and malignancy: Epidemiology and pathogenesis", section on 'HHV-8 infection'). KS is primarily a disease of males; early in the HIV epidemic, KS was noted in 20 to 30 percent of men living with HIV who have sex with men. With the widespread use of antiretroviral therapy (ART), the incidence decreased dramatically. (See "HIV infection and malignancy: Epidemiology and pathogenesis", section on 'Epidemiology'.)

AIDS-related KS has a variable clinical course, ranging from an asymptomatic incidental finding to explosive growth resulting in significant morbidity and mortality. Skin involvement is most common (picture 1A-B), but extracutaneous involvement is common, particularly in the oral cavity (picture 2), lungs, and digestive tract. (See "AIDS-related Kaposi sarcoma: Clinical manifestations and diagnosis", section on 'Cutaneous KS' and "AIDS-related Kaposi sarcoma: Clinical manifestations and diagnosis", section on 'Visceral disease'.)

The major goals of treatment for AIDS-related KS are symptom palliation, prevention of disease progression, and shrinkage of tumor to alleviate edema, organ compromise, and psychological stress. Although there are no randomized trials evaluating the effect of ART, observational studies provide strong evidence that the natural history of KS has changed since its introduction; immune reconstitution due to control of the HIV infection is the most likely explanation for this altered prognosis. ART is recommended for virtually all patients with AIDS-related KS. (See "AIDS-related Kaposi sarcoma: Staging and treatment" and "Pulmonary involvement in AIDS-related Kaposi sarcoma".)

The need for treatment beyond potent ART and the choice among the various options depend upon the extent of disease, the rapidity of tumor growth, the HIV-1 viral load, the CD4 cell count, and the patient's overall medical condition. Locally directed therapy is often used to palliate symptoms caused by a specific tumor or to treat cosmetic disfigurement. Systemic therapy is used for more extensive disease, but injury to an immune system that is already severely compromised should be avoided whenever possible.

The approach to therapy and the integration of various treatment options is discussed separately. (See "AIDS-related Kaposi sarcoma: Staging and treatment".)

Basal cell and squamous cell carcinomas — Individuals living with HIV have a two- to threefold increased risk of nonmelanoma skin cancer (basal cell carcinoma [BCC] and squamous cell carcinoma [SCC]) [3,45,46]. Factors associated with the development of cutaneous malignancies included increasing age and being a White person. BCC is substantially more common than SCC in individuals living with HIV [47,48]. This is in contrast to organ transplant recipients, where SCC is more frequent.

Risk factors for BCC and SCC are similar to those in individuals without HIV. However, patients living with HIV with BCC and SCC tend to be younger, have multiple tumors that often arise in areas not exposed to the sun, have an increased rate of recurrence, more commonly experience treatment-associated complications, and seem to have an overall poorer outcome [48]. Unusually aggressive skin carcinomas are a recognized complication of HIV infection [49]. (See "Epidemiology, pathogenesis, clinical features, and diagnosis of basal cell carcinoma", section on 'Risk factors' and "Cutaneous squamous cell carcinoma: Epidemiology and risk factors", section on 'Risk factors'.)

Multiple treatment options are available for BCC and SCC based upon patient-specific factors. BCCs and SCCs in persons living with HIV should be treated as they would in their counterparts without HIV [48]. (See "Treatment and prognosis of basal cell carcinoma at low risk of recurrence" and "Treatment of basal cell carcinomas at high risk for recurrence" and "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma (cSCC)" and "Systemic treatment of advanced basal cell and cutaneous squamous cell carcinomas not amenable to local therapies".)

Melanoma — The incidence of melanoma in patients infected with HIV may be moderately increased compared with the general population (table 1). Melanomas in patients living with HIV are often multiple, frequently metastasize, and are associated with a poor prognosis [50]. Thus, a more extensive search for metastatic disease may be warranted at diagnosis. (See "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites" and "Overview of the management of advanced cutaneous melanoma" and 'Prognosis' above.)

Merkel cell carcinoma — Merkel cell carcinoma is a poorly differentiated neuroendocrine carcinoma arising in the skin, which is etiologically linked with infection with the Merkel cell polyoma virus. The incidence of Merkel cell carcinoma is increased more than 10-fold in persons with HIV infection [51-55]. (See "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma" and "Staging, treatment, and surveillance of locoregional Merkel cell carcinoma".)

Extrapulmonary neuroendocrine neoplasms in people with HIV infection are discussed below. (See 'Neuroendocrine neoplasms' below.)

Conjunctival cancer — SCC of the conjunctiva can present with a range of symptoms from eye irritation or erythema to a plaque or nodular lesion [56]. SCC of the conjunctiva has a high propensity for local invasion into the orbit, and occasionally distant metastases occur. Conjunctival SCC in patients living with HIV occurs much earlier in life than in individuals without HIV and may be particularly aggressive [57,58].

The incidence of conjunctival SCC is significantly elevated in immunosuppressed individuals, including both those with HIV and solid organ transplant recipients [59]. In sub-Saharan Africa, the HIV epidemic has been associated with a dramatic increase in the incidence of conjunctival neoplasia [60,61]. The association of conjunctival SCC with HIV infection in other geographic regions is less well established, although one epidemiologic study has reported an increased incidence in North America as well [62].

Risk factors for SCC of the conjunctiva include age greater than 50 years, high solar ultraviolet radiation exposure, geography (sub-Saharan Africa), and HPV infection [63,64]. The relatively lower incidence in America and Europe has been attributed, at least in part, to the lower solar ultraviolet exposure associated with higher latitudes [65].

In patients living with HIV, the pathologic spectrum of conjunctival involvement includes intraepithelial dysplasia, carcinoma in situ, and invasive SCC, most commonly originating in the limbus (transition zone) of the eye. Aggressive histologic variants may be diagnosed, such as spindle cell carcinoma. A biopsy is required to distinguish leukoplakic lesions ranging from pinguecula to intraepithelial carcinoma (dysplasia, carcinoma in situ), and invasive SCC.

Patients with conjunctival cancer will need to be evaluated for eyelid infiltration, and intraocular and orbital invasion, as well as metastatic disease. Treatment is mainly surgical [66-68]. Other potential therapies include photodynamic therapy or topical treatment with either mitomycin [69,70] or interferon alfa-2b [71] (if available, given the manufacturer has discontinued production). In one case, an African woman with advanced HIV and conjunctival SCC invading her orbit had complete tumor regression from ART alone [72].

GENITOURINARY MALIGNANCIES

Cervical cancer — The incidence of both cervical dysplasia and neoplasia is significantly increased in females living with HIV, and the prognosis is worse compared with females without HIV [73]. The prevalence of cervical intraepithelial neoplasia (also called cervical squamous intraepithelial lesions) ranges between 30 and 40 percent [74,75]. A higher-than-expected rate of invasive and preinvasive cervical neoplasia has been reported in females with HIV [75,76]. Females with HIV are screened more frequently than those without HIV. (See "Screening for cervical cancer in patients with HIV infection and other immunocompromised states" and "Cervical cancer screening tests: Techniques for cervical cytology and human papillomavirus testing".)

In an early series of females living with HIV and invasive cervical cancer, therapy failed to control or eradicate the tumor, and all died with a mean survival of 10 months [76]. A subsequent study of 348 females with cervical cancer, approximately two-thirds of whom had HIV, also suggested that HIV infection increased the risk for death, particularly among those treated with curative intent and despite the use of antiretroviral treatment [73]. Given the poor prognosis of cervical cancer among patients with HIV, the Centers for Disease Control and Prevention (CDC) categorizes moderate and severe cervical dysplasia as an early symptomatic HIV condition and invasive cervical cancer as an indicator condition in the case definition of AIDS. (See "Preinvasive and invasive cervical neoplasia in patients with HIV infection" and "The natural history and clinical features of HIV infection in adults and adolescents".)

A close association exists between infection with oncogenic strains of human papillomavirus (HPV) and malignancies of the anogenital tract, including the cervix, anus, vulva, penis, and perianal skin. The vast majority of cervical cancers are thought to be caused by HPV infection. (See "Virology of human papillomavirus infections and the link to cancer".)

Gestational trophoblastic disease — Although HIV is not an apparent risk factor for gestational trophoblastic neoplasia, these patients tend to present with more advanced disease, and may have a significantly worse prognosis than in females living without HIV infection [77-79]. (See "Hydatidiform mole: Epidemiology, clinical features, and diagnosis" and "Initial management of low-risk gestational trophoblastic neoplasia".)

Prostate cancer — HIV infection does not have a significant effect on the incidence of prostate cancer [45,80-83]. The HIV status does not appear to influence prostate-specific antigen (PSA) levels, clinical presentation, tumor grade or stage, or outcome in males with prostate cancer receiving potent antiretroviral therapy (ART), although rare cases of unusually aggressive prostate cancer have been reported in males living with HIV [81,84-87].

However, patients with prostate cancer and concomitant HIV infection have a worse prognosis than those without HIV infection. In one observational cohort study from the Surveillance, Epidemiology, and End Results (SEER) database of older adult (≥65 years old) cancer patients, those with prostate cancer and HIV (170 patients) experienced higher overall mortality (hazard ratio [HR] 1.58, 95% CI 1.23-2.03), cancer-specific mortality (HR 1.65, 95% CI 0.98-2.79), and rates of relapse or death (HR 1.32, 95% CI 1.03-1.71) relative to prostate cancer patients without HIV (approximately 130,000 patients) [22]. (See "Risk factors for prostate cancer" and 'Prognosis' above.)

The use of radiation therapy does not appear to affect the immune system in these patients [88]. Thus, patients with prostate cancer and well-controlled HIV viremia should be managed similarly to their counterparts without HIV [89]. (See "Initial approach to low- and very low-risk clinically localized prostate cancer" and "Initial management of regionally localized intermediate-, high-, and very high-risk prostate cancer and those with clinical lymph node involvement" and "Overview of systemic treatment for advanced, recurrent and metastatic castration-sensitive prostate cancer and local treatment for patients with metastatic disease".)

Testicular neoplasms — There appears to be a modest increase in the incidence of testicular malignancies in males living with HIV compared with males without HIV [45]. This increased risk is limited to seminomas and does not appear to affect the incidence of nonseminomatous germ cell tumors [90-92]. (See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors".)

Stage at presentation does not appear to be affected by HIV status, and the natural history of testicular neoplasia is similar to that encountered in patients without HIV. There is no evidence that outcome is worse than in males who have seminoma without HIV infection, and long-term survival in males appears to depend upon the status of their HIV infection [93-95]. Management is the same as in males without HIV [2,96].

Bladder cancer — There is no evidence to suggest that the incidence of bladder cancer is significantly increased in people infected with HIV [45]. Nevertheless, symptoms of hematuria, dysuria, and frequency and/or urgency in a patient living with HIV warrant complete evaluation, including a work-up for bladder cancer. (See "Overview of the initial approach and management of urothelial bladder cancer".)

Renal cancer — In a review of the literature that included seven studies and 444,172 individuals living with HIV, the relative risk of renal cell carcinoma (RCC) ranged from 0.8 to 2 [45].

Patients living with HIV with RCC appear to present at a slightly younger age than those without HIV infection [97]. Those diagnosed with early-stage RCC did well after surgical resection, while those who were symptomatic with advanced renal cancer at diagnosis did poorly. (See "Prognostic factors in patients with renal cell carcinoma".)

BREAST CANCER — Adherence to screening recommendations for breast cancer is particularly important in females living with HIV, because of the relatively high frequency of poor prognosis features when breast cancer occurs, even though infection with HIV has at most a minor effect on the incidence of breast cancer (table 1) [45,80,98]. When breast cancer occurs in females living with HIV, there appears to be a propensity for high-grade ductal carcinoma in situ (DCIS), bilateral disease, poorly differentiated carcinomas, and early metastasis [99,100]. (See "Screening for breast cancer: Strategies and recommendations".)

Patients living with HIV with breast cancer should be treated in the same way as their counterparts without HIV with similarly staged disease, particularly when they have CD4 counts >200 cells/mm³ and controlled HIV viral loads [99]. Despite the tendency to present with more advanced disease, aggressive treatment of early breast cancer can result in a favorable outcome [101], though breast cancer specific mortality is higher compared with patients who do not have HIV [22]. (See "Overview of the treatment of newly diagnosed, invasive, non-metastatic breast cancer" and "Overview of the approach to metastatic breast cancer" and 'Prognosis' above.)

GASTROINTESTINAL MALIGNANCIES

Anogenital cancer and premalignant lesions — Human papillomavirus (HPV) infection has been causally linked with premalignant lesions and invasive cancers involving the anus, vulva, vagina, and penis, as well as the cervix [102]. (See 'Cervical cancer' above.)

Malignancies and premalignant lesions in all of these sites are significantly more common in individuals infected with HIV compared with the general population (table 1).

The increased incidence of these lesions may have important implications for screening and the use of HPV vaccine in high-risk population, such as men living with HIV who have sex with men [103]. Management of these lesions follows the same general approach as in people without HIV:

●Anal intraepithelial neoplasia and anal cancer (see "Anal squamous intraepithelial lesions: Epidemiology, clinical presentation, diagnosis, screening, prevention, and treatment" and "Clinical features and staging of anal cancer")

●Vulvar and vaginal intraepithelial neoplasia (see "Vulvar and vaginal intraepithelial neoplasia in patients with HIV infection")

●Carcinoma of the penis (see "Carcinoma of the penis: Clinical presentation, diagnosis, and staging" and "Carcinoma of the penis: Epidemiology, risk factors, and pathology")

Colorectal cancer — Colorectal cancer may occur at a younger age and be more aggressive in patients infected with HIV [104,105]. As an example, in a series of 17 cases, the average age at diagnosis was 43 years and the majority had right-sided lesions [105]. Eight (47 percent) presented with stage IV disease and eight died within 26 months of diagnosis. The increased incidence of right-sided lesions in people living with HIV suggests that colonoscopy is preferable for screening, rather than flexible sigmoidoscopy. (See "Screening for colorectal cancer: Strategies in patients at average risk".)

Although a 2007 review of the literature composed primarily of patients from the prepotent antiretroviral therapy (ART) era did not demonstrate an increase in the incidence of colorectal cancer [45], one study from the United States observed a 2.4-fold increase compared with the population without HIV for the period 2000 to 2003 [80].

An increased incidence of colorectal cancer is also supported by the frequency with which precursor lesions are identified. This was illustrated by a flexible sigmoidoscopy screening study in 2382 patients, including 165 who were living with HIV, in which there was an increased prevalence of adenomas in the HIV population (26 versus 13 percent in subjects without HIV) [106]. Advanced neoplasia (adenomas ≥10 mm, villous histology, high-grade dysplasia, and adenocarcinoma) was also significantly more frequent (7 versus 4 percent).

Patients with colorectal cancer and HIV infection tend to have worsened cancer-specific mortality compared with patients without HIV infection. (See 'Prognosis' above.)

Stomach and esophageal malignancies — There is an increased incidence of both stomach and esophageal malignancies among people living with HIV [107]. These lesions include both carcinomas and non-Hodgkin lymphomas (NHLs).

●In an analysis of almost 600,000 individuals living with HIV, the incidence of both carcinoma of the stomach and carcinoma of the esophagus was significantly increased compared with the general population (standardized incidence ratios [SIRs] 1.44 and 1.69, respectively) [108]. Among those with esophageal cancer, the increase was observed with both adenocarcinoma and squamous cell cancer. The incidence rates relative to the general population remained roughly constant in the pre and post-ART periods.

The management of gastric and esophageal cancers is discussed separately. (See "Early gastric cancer: Treatment, natural history, and prognosis" and "Surgical management of resectable esophageal and esophagogastric junction cancers" and "Management of locally advanced, unresectable and inoperable esophageal cancer".)

●NHLs were frequently observed in addition to carcinomas. Among patients with stomach malignancies, NHLs were almost four times more frequent than carcinomas, and approximately two-thirds of these were diffuse large B-cell lymphomas. Among patients with esophageal malignancies, NHLs constituted about one-third of all cases, and the majority were diffuse large B-cell lymphomas. The relative increase in the incidence of NHL in both the esophagus and the stomach decreased with the introduction of ART. (See 'Non-Hodgkin lymphoma' above.)

Hepatocellular carcinoma — Coinfection with HIV and either the hepatitis B virus (HBV) or the hepatitis C virus (HCV) may be associated with accelerated progression of fibrosis and an increased risk of cirrhosis, end-stage liver disease, and hepatocellular carcinoma (HCC). (See "Epidemiology and risk factors for hepatocellular carcinoma", section on 'Risk factors'.)

In an analysis of over 615,000 individuals infected with HIV, the risk of HCC in individuals who were living with HIV increased progressively over time, beginning prior to the introduction of ART and continuing up to the present (standardized incidence ratio 3.8 compared with the general population) [109]. An increasing incidence of HCC was seen in the population living with HIV and general population; this was attributed to the incidence and prevalence of HCV and to the longer survival in patients living with HIV who were treated with ART [110].

Prevention and/or treatment of infection with hepatitis viruses should be routine whenever feasible [3].

●(See "Epidemiology, clinical manifestations, and diagnosis of hepatitis B in patients living with HIV".)

●(See "Prevention of hepatitis B virus infection in adults with HIV".)

●(See "Treatment of chronic hepatitis B in patients with HIV".)

●(See "Treatment of chronic hepatitis C virus infection in the patient with HIV".)

RESPIRATORY TRACT

Lung cancer — The incidence of lung cancer is increased approximately two- to fourfold for individuals infected with HIV when compared with age- and sex-matched populations [3,40,45,80,111,112]. This relative increase has remained relatively constant before and after the introduction of antiretroviral therapy (ART). There is an increased prevalence of cigarette smoking in the HIV population [113,114], but the risk of lung cancer remains elevated even after correcting for smoking status [115-117].

The clinical features of lung cancer are illustrated by a retrospective series of 75 patients living with HIV with lung cancer, who were compared with patients in the Surveillance, Epidemiology, and End Results (SEER) database [118]. Lung cancer patients living with HIV were significantly younger (median age 50 versus 68 years). Stage and histologic types were similar to the broader lung cancer population.

Retrospective reviews suggest an association between HIV infection and increased lung-cancer-specific mortality. However, aggressive treatment for patients with lung cancer and HIV infection is indicated if the patient's overall medical condition permits [119,120]. (See "Overview of the initial treatment and prognosis of lung cancer" and 'Prognosis' above.)

Head and neck cancer — There is an approximately two- to threefold increase in the incidence of squamous cell carcinoma of the head and neck for individuals infected with HIV, with some variation depending upon the specific site of origin [3,45,80,111]. Other histologic types of cancer may also be increased in the head and neck region, including lymphoepithelial carcinoma of the salivary gland, nasopharyngeal carcinoma, and Merkel cell carcinoma [121,122].

Common sites of involvement include the oral cavity, tonsillar area, and larynx. The majority of males living with HIV with squamous cell carcinoma (SCC) of the head and neck are men who have sex with men [123], and the age at presentation appears to be younger than those not infected with HIV [124].

Between 24 and 40 percent of the head and neck cancers in patients infected with HIV are related to human papillomavirus (HPV), which is not significantly different than in the general population [125]. Patients with HPV-related cancers have a better prognosis than those with tumors that are tobacco-related, as do those with higher CD4 counts [126]. (See "Epidemiology, staging, and clinical presentation of human papillomavirus associated head and neck cancer".)

Treatment of head and neck cancer follows the same principles as that in patients without HIV, although complications are more common in patients living with HIV. (See "Management and prevention of complications during initial treatment of head and neck cancer" and "Management of late complications of head and neck cancer and its treatment" and "Overview of treatment for head and neck cancer" and 'Prognosis' above.)

SARCOMA — Sarcomas are uncommon in patients living with HIV. However, there is a disproportionate increase in leiomyosarcoma among those with HIV infection, potentially related to infection with Epstein Barr virus (EBV) [127]. In one series, leiomyosarcoma accounted for 58 percent of all sarcomas other than Kaposi sarcoma (KS), compared with 17 percent of cases in the Surveillance, Epidemiology, and End Results (SEER) database [128]. There may be multiple smooth muscle tumors, often found in uncommon locations such as the central nervous system (CNS), lung, pericardium, pleura, spleen, adrenal gland, lymph node, and orbit [127,129].

AIDS-associated leiomyosarcomas behave in an aggressive fashion. These tumors tend to recur despite therapy, resulting in poor survival. First-line therapy may include radiation therapy and/or complete local excision. The treatment of localized and metastatic sarcomas is discussed separately. (See "Surgical treatment and other localized therapy for metastatic soft tissue sarcoma" and "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Introduction'.)

NEUROENDOCRINE NEOPLASMS — Extrapulmonary neuroendocrine neoplasms have also been observed in people with HIV infection. These include cases of well-differentiated neuroendocrine tumors in both typical locations [130] and unusual sites [131], as well as the more aggressive poorly differentiated neuroendocrine carcinomas [132]. (See "Clinical characteristics of well-differentiated neuroendocrine (carcinoid) tumors arising in the gastrointestinal and genitourinary tracts" and "High-grade gastroenteropancreatic neuroendocrine neoplasms".)

Merkel cell carcinoma in people with HIV infection is discussed above. (See 'Merkel cell carcinoma' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cervical cancer screening, prevention, and management".)

SUMMARY

●Early in the AIDS epidemic, a dramatic increase in Kaposi sarcoma (KS), non-Hodgkin lymphoma (NHL), and cervical cancer was noted, and these tumors ultimately were classified as AIDS-defining cancers. With the widespread use of potent antiretroviral therapy (ART), there was a dramatic decrease in the incidence of KS and NHL and a significant increase in the incidence of several other malignancies (non-AIDS-defining cancers). (See "HIV infection and malignancy: Epidemiology and pathogenesis", section on 'Epidemiology'.)

●An understanding of the epidemiology and risk factors for these malignancies, in association with the prolonged survival of people living with HIV in the ART era, increases the importance of adherence to cancer screening recommendations and prevention measures. (See 'Screening and prevention' above.)

●Although the biology of malignancy in people living with HIV is often more aggressive than in those without HIV infection, standard treatment is generally indicated and can be associated with a favorable outcome, depending upon the tumor type, stage, and comorbidity. (See 'Treatment' above.)