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Abstract

Women with HIV infection have an increased risk of developing certain malignancies. These malignancies are commonly human papillomavirus (HPV)-related, reflecting the high rate of coinfection with HPV in women with underlying HIV infection. These women also have a high incidence of premalignant HPV-related changes, such as high-grade squamous intraepithelial lesions as diagnosed on Pap smears and cervical intraepithelial neoplasia on cervical biopsy. Screening recommendations for HIV-infected women reflect the need for vigilance in detecting and treating these lesions early. In addition, recent interest has focused on the use of cervical cancer screening, employing HPV-testing techniques, and on HPV vaccination in younger women to prevent initial infection and the subsequent development of cervical and other HPV-related cancers. The incidence of other types of malignancies, such as Hodgkin's and non-Hodgkin's lymphoma, is also increased in HIV-infected individuals. When these lymphomas occur, they tend to be of advanced stage and high-grade histologies. The advent of highly active antiretroviral therapy has been associated with a marked decrease in the incidence of some of these cancers. The use of therapy has been associated with marked improvement in response rates and overall survival of affected patients.

Keywords

Epidemiology of HIV-related cancers

Patients with HIV infection have a statistically significant increase in the risk of developing certain cancers, such as Kaposi's sarcoma (KS), high-grade B-cell and non-Hodgkin's lymphoma (NHL) and invasive cervical cancer (ICC), all of which are considered to be AIDS-defining conditions. Interestingly, each of these malignancies has been associated with an infectious organism, including human herpes virus type 8 in the case of KS, Epstein–Barr virus in approximately 30% of cases of AIDS-related lymphoma [1] and human papillomavirus (HPV) in cases of ICC [2,3]. Aside from cervical cancer, HPV has also been associated with other malignancies, such as anal carcinoma [4 –8], some head and neck cancers [9 –11] and even an unusual type of squamous cell carcinoma of the conjunctiva, reported in patients from Africa [12].

HPV & HIV

Human papillomavirus infection is more common among women infected with HIV than in their HIV-negative counterparts, with HPV infection reported in approximately 58% of a large group of HIV-infected women studied as part of the Women's Interagency HIV Study (WIHS), ongoing since 1994 [13]. Interestingly, the average age of these dually infected women was 30–40 years, indicating that HPV is more likely to be persistent in the setting of HIV infection, or that HPV viral reactivation may occur [14]. Aside from the high prevalence of cervical HPV infection, a subsequent WIHS study found that among HIV-infected women with cervical HPV infections, approximately 73% had also documented HPV infection in the anal region [7,8].

With the high prevalence of HPV in both cervical and anal regions of HIV-infected women, the potential for development of malignancy in these areas is clear. A retrospective linkage study of the US AIDS Registry with the National Cancer Registry was performed in an attempt to ascertain the precise risk of HPV-related cancers among HIV-infected persons, when compared with population-based controls [4]. While the risk of HPV-associated cancers was statistically elevated, the level of increase differed among anatomic sites, age, ethnic groups and degree of immunosuppression from HIV. While age did not change the risk, certain ethnic groups such as Hispanic women were at even greater risk (relative risk [RR]: 8.5; 95% CI: 4.5–14.5). Furthermore, an inverse association between higher risk of cervical cancer and lower CD4 counts was found; the RR of developing cervical cancer was twofold greater in patients with CD4 counts of less than 100 cells/mm³. Invasive anal cancers were also increased in women with AIDS, with a RR of 6.8 (95% CI: 2.7–14), which was even higher in Whites than in Blacks or Hispanics. These data would indicate that HPV-related malignancies are more likely to occur in the setting of immunosuppression, with differing levels of risk in different ethnic groups.

It is worth noting that the increased risk of these HPV-related cancers in the setting of HIV may involve a constellation of factors, in addition to the increased prevalence of HPV. Thus, the presence of HIV-related immunosuppression [15], the persistence of HPV infection over time [16,17], the increased likelihood of other behavioral factors, such as smoking among HIV-infected women [2,18], and/or the presence of other coinfections may also serve to predispose HIV-infected persons to the increased risk of these HPV-related cancers.

Multiple epidemiologic studies have demonstrated that HPV infection is widespread among sexually active women. In this regard, increased numbers of sexual partners and earlier onset of sexual activity are associated with a higher risk of sexually transmitted infections, including HPV [19]. Between 1966 and 1987, a tenfold increase in genital warts was documented in the USA, and there are estimated to be 1.8 million new HPV infections in the USA per year. Multiple studies have suggested a strong association between HIV and the likelihood of coinfection by HPV [7,13,20,21]. The WIHS, a prospective study of 2066 HIV-infected women and their HIV-negative controls, evaluated the prevalence of HPV infection and found that HIV-infected women with CD4 counts of less than 200 cells/mm³ were at the highest risk, with HPV infection documented in 70% of these women. The risk was also increased among women with CD4 counts greater than 200 cells/mm³, but with HIV viral loads over 20,000 viral copies/ml, consistent with the hypothesis that HIV, per se, may impart increased risk, above and beyond the role of immunosuppression. Other risk factors for HPV infection were found in equal proportions among the 569 HIV-negative and 2066 HIV-infected women, including race, younger age and smoking.

Hormonal influences may also affect the risk of contracting genital HPV infection. This may be due to the attenuation of the immune response to HPV by hormones, for example, genital condylomas increase in size during the last trimester of pregnancy. Furthermore, the rate of detection of asymptomatic HPV infection is higher in pregnant women. Hormones may bind to specific receptors in HPV-infected cells and, thereby, influence the progression from HPV infection to malignancy [22,23].

Two studies have shown an association between HPV-related genital warts and the presence of HIV infection. In addition, once infected, HIV-positive women may have more persistent HPV infections. This may be due in part to the effects of the HIV tat protein on increasing E2-dependent HPV 16 transcription [24]. The immunosuppression from HIV and subsequent altered immunologic surveillance may lead to further HPV replication and also to higher rates of progression to HPV-associated neoplasia [24].

In women coinfected with HIV and HPV, there is a risk of more extensive HPV-related disease, a higher rate of recurrence and an accelerated risk of progression to malignancy [24,25].

HPV & cervical cancer

The various genotypes of HPV cause diverse types of epithelial tissue lesions. Different genotypes of HPV are trophic for specific tissues, such as the oral cavity or the urogenital tract. There are approximately 100 different types of HPVs [26]. The pathogenicity of the virus depends on the molecular type. For example, types 6 and 11 are associated with genital warts, benign cervical changes or low-grade cervical dysplasia. Types 16 and 18 are associated with higher-grade cervical dysplasia or ICC. The HPV viral genes E6 and E7, which are integrated and dysregulated within the host genome, transcribe proteins that can bind and inactivate the host p53 and Rb proteins. These are tumor suppressors, which, when inactivated, lead to dysregulated cell growth and potential malignancy.

Nomenclature: CIN & squamous intraepithelial lesion

Papaniculou (Pap) screening can identify women with suspicious cervical lesions that may require further evaluation. After documenting an abnormal Pap smear, a formal colposcopy with biopsy should be performed in order to determine, most carefully, the stage of infection or disease. Different pathologic staging systems are employed for cervical Pap smears and for biopsies. The Bethesda classification system differentiates Pap smear cytologic categories into low-grade squamous intraepithelial lesion (LGSIL), which often demonstrates either a reactive lesion – consistent with HPV infection or inflammation – or cervical intraepithelial neoplasia (CIN) I (i.e., mild dysplasia) on cervical biopsy. A second Pap smear category is termed high-grade squamous intraepithelial lesion (HGSIL), and may be consistent with either CIN II (moderate dysplasia) or CIN III (severe dysplasia or carcinoma in situ) on cervical biopsy (Table 1) [27]. The Bethesda classification system also includes the category of atypical squamous cells of uncertain significance (ASCUS). This category is somewhat controversial in terms of its malignant potential, although patients with ASCUS may have CIN on cervical biopsy.

Table 1.

Correlation of pathologic classification systems: Pap smears and cervical biopsies.

Pap smear results	Associated biopsy results
	CIN I	CIN II Rare	CIN III
LGSIL	Common	Rare
HGSIL	Not seen	Common	Common
ASCUS	Occasional	Not seen	Not seen

ASCUS: Atypical squamous cells of unknown significance; CIN: Cervical intraepithelial neoplasia; HGSIL: High-grade squamous intraepithelial lesion; LGSIL: Low-grade squamous intraepithelial lesion.

Natural history & therapy of CIN/squamous intraepithelial lesion in HIV-infected women

Low-grade squamous intraepithelial lesion on Pap smear or CIN I on biopsy is expected to resolve spontaneously in over 50% of cases in HIV-negative women [28,29]. In the remaining individuals, CIN I may progress to CIN II (HGSIL on Pap), which may then progress to CIN III and then further to ICC. The purpose of Pap screening then, is to identify and treat precursor lesions in order to prevent invasive cancer. A fivefold increase in squamous intraepithelial lesions in HIV-infected women has been reported in a study of 4119 women followed in an outpatient clinic in Senegal [30]. Furthermore, women with high-risk genotypes of HPV or with coinfection by HIV-1 were more likely to have HGSIL or ICC than HIV-negative women. Among the HIV-positive women, higher plasma HIV RNA levels and lower CD4 counts were associated with high-risk HPV infection (types 16 or 18), in addition to more advanced degrees of cervical abnormalities. A prospective cohort study in urban clinics in NY, USA, evaluated 328 HIV-infected and 325 HIV-uninfected women, none of whom had evidence of squamous intraepithelial lesions at study entry [31]. After over 36 months of follow-up, one in five HIV-infected women developed biopsy-confirmed CIN. Another cohort study from a clinic in Bronx, NY, USA, also demonstrated a higher rate of squamous intraepithelial lesions in women with both HIV and HPV infections. In this cohort of 96 women, the rate of squamous intraepithelial lesions was 52% for women with both HPV and HIV infection versus 9% for dually uninfected women. The rate of squamous intraepithelial lesions in HPV-infected, HIV-negative women has been reported to be 15% in a large series [31].

Treatment of these various precursor lesions will be determined by the histologic grade of disease and by the extent of the lesion after colposcopic evaluation. Patients with ASCUS or CIN I most often do not require treatment; nonetheless, if HIV infected, these women should be followed very closely, with re-evaluation by Pap smear and colposcopy after 6 months. Many practitioners are uncomfortable with simple observation of ASCUS, LGSIL or CIN I in HIV-infected women, because of the increased likelihood of progression; in these instances, ablative therapy is often performed for these early precursor lesions. In HIV-infected women with CIN II and III, therapy is indicated in order to prevent subsequent invasive disease. Therapeutic options are similar to those employed in HIV-negative women, including cryotherapy, laser vaporization or loop electric excision procedure. None of these regimens has been demonstrated to be superior to the other [32,33], and no specific method of ablation has been recommended for HIV-infected women, per se. However, despite effective ablation in HIV-infected women, recurrence rates in the range of 40–60% have been reported [34,35]. The frequency of recurrence is related to the underlying immune status and the severity of disease [34,35]. Thus, women with CD4 counts of less than 500 cells/mm³ are at a 50% or greater risk of recurrence when compared with women with higher CD4 cell counts [35].

Invasive cervical cancer

In 1993, the definition of AIDS was revised to include women with ICC [36,37]. However, this decision was somewhat controversial at the time, as the incidence of cervical cancer was not yet increased among HIV-infected women. Nonetheless, the high prevalence of HPV coinfection and the increasing incidence of CIN/squamous intraepithelial lesion in HIV-infected women was of concern, strongly suggesting that the risk of cervical cancer would rise over time. In fact, as shown in subsequent epidemiologic studies, a statistically increased risk of ICC has been demonstrated among HIV-infected women [38,39].

The staging system for cervical cancer is based on clinical and pathologic criteria [40]:

Stage I disease is limited to the cervix;

Stage II disease extends beyond the cervix to the upper two-thirds of the vagina or the parametrial tissue;

Stage III extends to the pelvic side wall, the lowest third of the vagina or the pelvic lymph nodes;

Stage IV disease indicates presence of distant metastases, or invasion of the bladder or rectum.

Treatment options are based on the stage of disease (Table 2).

Table 2.

Staging system for cervical cancer.

Stage	Definition
I	Limited to cervix
IA	Preclinical: diagnosed by microscopy
IB	Tumor>5 mm in depth or >7 mm in horizontal spread
II	Disease extends beyond cervix to upper two-thirds of vagina or parametrium
IIA	Involves upper two-thirds of vagina
IIB	Extends into parametrial tissue
III	Involves the lowest one-third of vagina or pelvic sidewall; or hydronephrosis
IIIA	Involves the lowest one-third of vagina
IIIB	Involves the pelvic sidewall
IV	Extensive local spread or metastasis
IVA	Involves the bladder or rectal mucosa
IVB	Distant metastasis

Patients with stage IA disease, as diagnosed by microscopic findings, tend to have a good prognosis, with treatment usually consisting of hysterectomy. Pelvic lymph-node dissection is not considered necessary for these patients. Stage IB or IIA disease can be treated with either radiotherapy or surgery. The recommended surgery is more extensive than that recommended for stage IA disease, consisting of a radical hysterectomy with pelvic lymph-node dissection. Radiotherapy usually consists of external-beam pelvic radiation and intracavitary treatment with a radioisotope. Patients with more advanced disease, including stage IIB, III and IVA, are also treated with radiotherapy. Platinum-based multiagent chemotherapy may be used for metastatic or recurrent disease [40].

HIV-infected patients treated with surgery usually have a similar course when compared with HIV-negative patients in terms of complications, although the infection rate may be increased. By contrast, radiation therapy is less well tolerated in the HIV-infected patient and may lead to lymphopenia and depressed T-cell function, which further worsens the already compromised immune function. Chemotherapy may be utilized as clinically indicated, but the close monitoring of hematologic indices is needed.

The clinical presentation of cervical cancer in HIV-positive women tends to be more aggressive than is usual, with many patients presenting with advanced-stage disease [36,37,41]. Diagnosis is often delayed as many of the systemic signs of cancer, such as unexplained weight loss, low-grade temperatures and/or lymphadenopathy, may initially be attributed to the underlying HIV, or another infection. In a study of 16 HIV-seropositive women with ICC, comparisons were made with 68 seronegative women. The HIV-infected women were more likely to have high-grade tumors, lymph-node involvement and squamous cell pathology. While the stage of cervical cancer did not correlate with CD4 levels, the CD4 status did influence treatment outcome. Patients with CD4 counts of over 500 cells/mm³ demonstrated a more favorable response to treatment. Nonetheless, the median survival for the HIV-infected women was only 9 months and, ultimately, more women died from cervical cancer than from AIDS [37].

Effect of highly active antiretroviral therapy on CIN or invasive cervical carcinoma

While several studies have indicated that highly active antiretroviral therapy (HAART) may be associated with regression of cervical precursor lesions [42,43], the incidence of ICC has not declined in the era of HAART [38].

Screening recommendations

Given the high prevalence of HPV infection and increased rates of squamous intraepithelial lesions and ICC seen in HIV-infected women, a comprehensive screening program is warranted. The sensitivity and specificity of Pap smears appear to be similar in HIV-infected and -uninfected women. The US CDC has developed provisional recommendations for screening in HIV-infected women to include a Pap smear as part of the initial evaluation. If the Pap smear is normal, the examination should be repeated in 6 months. If this repeat Pap smear is normal, then annual Pap smears and gynecologic examinations are suggested. If the initial Pap smear is abnormal, including findings of ASCUS, colposcopy is recommended.

However, based upon the role of HPV in the pathogenesis of cervical cancer, screening strategies are also changing at present, with recommendations for HPV screening along with cytologic assessment [44]. The implementation of HPV DNA testing leads to earlier detection of advanced CIN lesions [45 –47]. HIV-negative women with no evidence of infection by carcinogenic HPV genotypes may now defer repeat Pap cytologic screening to every 3 years [46]. The Population-Based Screening Study Amsterdam (POBASCAM) trial in HIV-negative women confirmed the safety of extending screening intervals in HIV-negative women who were screened negative by HPV testing [44 –46]. The increased likelihood of acquiring HPV or reactivating existing HPV in the setting of HIV requires a more careful and frequent evaluation in these women, and similar guidelines for less frequent screening of HIV-infected women have not been suggested. An ongoing study is currently evaluating the role of HPV testing in HIV-positive women with ASCUS. In HIV-negative women, HPV testing is used to triage women with ASCUS; oncogenic HPV genotype-positive women are sent for immediate colposcopy, while HIV-negative women without oncogenic HPV infection undergo repeat Pap smear in 12 months. Whether this strategy will be validated in HIV-infected women is unknown.

Additional concepts for the prevention of cervical cancer in HIV-negative women include: a strategy involving vaccination to prevent HPV in young women prior to the age of sexual activity and secondary screening for the carcinogenic types of HPV in older women who have already been exposed. In areas with limited resources, proposed new models of screening focus on reaching women at the peak time of risk of precancerous conditions. For example, screening women at 35 and 40 years of age with current HPV DNA tests that target the 13 HPV types associated with carcinoma can achieve more cost-effective reductions in cancer than conventional cytologic screening [44].

Vaccination against HPV

In June 2006, the US FDA approved an HPV vaccine to prevent cervical cancer [48]. This genetically engineered vaccine is derived from viral capsid antigens using a single structural viral protein (L1) encompassed in a framework of virus-like particles (VLPs). Vaccination of animals with these VLPs stimulated the production of high titers of antibody. Randomized, placebo-controlled trials using vaccines containing L1 VLP HPV genotypes in humans have demonstrated that the vaccines were safe and effective in protecting women from HPV infection and also from developing CIN. A quadrivalent (HPV types 6, 11, 16 and 18) vaccine (Gardasil®) was approved by the FDA in 2006. A bivalent vaccine (HPV types 16 and 18; Cervarix®) was approved in 2007 [48 –50].

Multiple unanswered questions remain in terms of the use of these HPV vaccines in the general population as well as in HIV-infected women. Thus, recommendations on the age at which to vaccinate differ. It would be preferable to vaccinate before the age of sexual activity, although this may be seen as socially controversial [50]. If one waits to vaccinate, sexual exposure to HPV may already have occurred [51]. Furthermore, achieving compliance with wide-spread vaccination in adolescents and young women can be challenging. In addition, the duration of protection from these vaccines remains unknown. Hence, there is variation in the recommendations offered by the American Cancer Society, the American College of Obstetrics and Gynecology and the CDC. For older women with prior HPV infection, the role of vaccination is unknown. Theoretically, the vaccine could provide protection against the HPV types that are not already acquired.

The recommendations for HPV vaccination in HIV-infected women have not yet been made. Since most of these women have previously been infected with HPV, the potential efficacy of this approach in preventing ICC is questionable. Furthermore, HIV-infected women may not be able to mount an appropriate immune response to the vaccine owing to their underlying immuno-compromise. Specific studies of the HPV vaccines in HIV-infected women are currently underway; results of these studies are awaited with interest.

Anal dysplasia & anal cancer

Epidemiology of anal cancer

Anal cancer is rare in the general population with an incidence of less than 1 per 100,000 in the USA. By contrast, in HIV-positive individuals the incidence is greatly increased. A multisite cohort study assessed the prevalence and risk factors for anal intraepithelial neoplasia (AIN) in HIV infected women [52 & Hessol N, Unpublished Data]. Low-grade AIN was present in 12%, and high-grade AIN in 9% of HIV-infected women. A population-based study of approximately 309,365 HIV-positive patients with invasive or in situ anal cancer compared the incidence of anal cancer with age-matched seronegative men and women. The risk of invasive or in situ anal cancer in HIV-positive women was increased, with a RR of 134-fold higher than that observed in the HIV-negative women. Furthermore, in HIV-positive women over the age of 40 years, the RR was 2.6-fold higher than in HIV-negative women. While the RR appears extremely high in the under 30 years age group, these data are somewhat misleading, since the actual number of cases in this age group was quite small [52]. Similar to the situation with cervical dysplasia and ICC, HPV infection is a major risk factor for AIN and anal cancer. In one large, WIHS study of HIV-infected women, anal HPV infection was more frequent than cervical infection, indicating the need for close follow-up of these individuals over time. While no studies of anal HPV progression over time have yet been conducted in HIV-infected women, similar studies in HIV-infected men have indicated a statistically increased risk of progression of existing anal precursor lesions, when compared with HIV-negative controls. In the WIHS cohort study of HIV-infected women, the major risk factor for low-grade AIN was anal HPV infection with both oncogenic and nononcogenic genotypes of HPV. High-grade AIN was associated with infection with oncogenic types of HPV [Hessol N, Unpublished Data]. The incidence of high-grade AIN was 5–9-times higher in HIV-infected women with infection by oncognenic genotypes of HPV than in non-HPV-infected HIV-positive women [Hessol N, Unpublished Data]. Unfortunately, the use of HAART has not been associated with a decrease in the incidence of anal cancer [53]. In fact, as patients are less likely to die of AIDS-related infectious complications, there is speculation that the incidence of anal cancer and other malignancies will continue to increase. Interestingly, the increased incidence of HPV-related anal and other cancers is not only observed in HIV-induced immunosuppression, but in HIV-negative organ-transplant recipients as well, who are immunosuppressed iatrogenically in an attempt to prevent graft rejection [54].

Screening recommendations

Anal Pap smears are performed in a similar fashion to cervical Pap smears, and can detect abnormal cytology; although the anal Pap smear may be less likely to predict anal biopsy results. Thus, anal Pap smears may be less accurate in regards to the degree of dysplasia present. Routine anal screening guidelines have not been standardized, but the CDC currently recommend that an anal screening program should be incorporated into the routine health maintenance for HIV-infected men and women. One proposed option includes a yearly anal cytology assessment for HIV-positive individuals. If the cytology is normal, continued annual screening is suggested. If any atypical cells are detected, including ASCUS, anoscopy with biopsy is suggested [52]. However, these guidelines may be limited by the need for training a greater number of physicians in performing high-resolution anoscopy and biopsy, and in training additional pathologists who are experienced in evaluating the specimens. Furthermore, it will be important for these screening tests to be office based, to maximize patient compliance with screening and follow-up.

Treatment of anal dysplasia

The treatment of choice for low-grade dysplasia may include close observation without treatment, since some of these lesions resolve spontaneously. Alternatively, use of infrared coagulation, laser ablation, electrocautery, trichloracetic acid or surgical excision may be employed [55 –57]. Various protocols are currently ongoing in order to determine optimal modes of treatment for these precursor lesions.

Treatment of invasive anal carcinoma in HIV-infected men or women

Combined chemotherapy (mitomycin C and 5-fluorouracil) together with radiation is considered to be the standard therapy for invasive anal carcinoma in HIV-negative patients, and these modalities are also used in HIV-infected individuals. Early results suggest equivalent response and survival rates in HIV-positive and -negative patients [58,59].

HPV-associated head & neck (oral) cancers

The AIDS Cancer Registry group has reported an increased incidence of oral cancer in HIV-and HPV-coinfected men, with a relative twofold increased risk. This risk was not observed in women in the cohort [4]. Nonetheless, HPV-related oral cancers are expected to continue to increase over time. These tumors are often located in the tonsils or base of the tongue, and are associated with improved prognosis when compared with HPV-negative head and neck cancers. History of oral sex is a risk factor for these cancers, as is concomitant HPV genital infection [9 –11]. In contrast to the situation in HPV-negative head and neck cancers, where cigarette smoking is associated with increased risk, this is not the case in HPV-positive oral cancers, where a history of marijuana smoking may be associated with increased risk [60].

AIDS-related lymphoma

Epidemiology of lymphoma

High-grade B-cell NHL has been classified as an AIDS-defining illness since 1985. Between 1982 and 1990, the incidence rates of NHL increased by 800% among men aged 20–59 years in San Francisco, CA, USA, heralding the epidemiologic trend seen in subsequent national and international registry studies [54]. Overall, studies have suggested that patients with HIV infection have a 60–600-fold increased risk of developing NHL and a 7–20-fold increased risk of Hodgkin's lymphoma (HL) [61,62]. Since the advent of HAART, there has been a significant decline in the incidence of certain types of NHL in HIV-infected individuals, specifically, primary CNS lymphoma and immunoblastic lymphoma. However, the incidence of other genotypess of NHL remains elevated when compared with population-based expectations. It is worth noting that the incidence of HL has further increased in the era of HAART, while that of NHL continues to fall. Therefore, the epidemiology of HL differs from that of AIDS-related lymphoma [63]. In HL, the incidence increases with increasing CD4 cell count, while the incidence of AIDS-related lymphoma decreases in the setting of higher CD4 cells [63,64]. In the widespread use of HAART, HIV-positive patients are now living longer, with decreased risk of developing AIDS-related opportunistic infections. In this setting, AIDS-related lymphoma has become one of the more common of the initial AIDS-defining diagnoses. Furthermore, with longer survival rates observed in the aging population, it is expected that lymphoma, HL and various non-AIDS-defining cancers will become more prominent as causes of morbidity and mortality in HIV-infected women and men.

Presentation & treatment of AIDS-related lymphoma

Patients with AIDS-related lymphoma typically present with widespread stage IV disease, involving one or more extra-nodal sites of disease, such as bone marrow, liver and/or GI tract. CNS involvement may also be seen, occurring either as primary CNS lymphoma or in the setting of systemic lymphomatous disease, CNS involvement usually involves lymphoma cells within the cerebrospinal fluid, diagnosed in approximately 10–20% of patients. In addition to symptoms related to actual sites of lymphomatous involvement, systemic ‘B’ symptoms are also common, present in over 50% at diagnosis and consisting of fever of unknown origin, drenching night sweats and/or weight loss in excess of 10% of normal bodyweight. Since these symptoms may also occur as a consequence of HIV itself, or of various opportunistic infections, the actual diagnosis of lymphoma may be delayed [65]. Women are less likely than men to develop HIV-negative, de novo lymphoma, and the same relationship appears to be true in patients with AIDS-related lymphoma.

The initial treatment for patients with AIDS-related lymphoma includes multiagent chemotherapy. Prior to the advent and widespread use of HAART, treatment results were poor, and the median survival was approximately 6 months [66]. Despite the potential for drug interactions, several investigators have now demonstrated that HAART may be given safely, when given simultaneously with multiagent chemotherapy [67]. In the era of HAART, the survival of patients with AIDS-realted lymphoma has increased appreciably, and now approaches that of patients with de novo lymphoma [68,69]. The etoposide, prednisone, vincristine, cyclophosphamide and adriamycin (EPOCH) regimen, consisting of a 4-day continuous infusion of etoposide, doxorubicin, vincristine and cyclophosphamide along with oral prednisone, has resulted in a 74% complete remission rate, and an over-all survival of 60% at an actual follow-up of approximately 5 years. Of the patients who achieved complete remission, 92% remained free of disease over this follow-up period [68]. Interestingly, in patients who do experience relapse after initial response, high-dose chemotherapy followed by autologous stem cell transplantation has resulted in 83% long-term, disease-free survival, with results quite consistent with those reported in patients with HIV-negative lymphoma [70].

Hodgkin's lymphoma in the setting of HIV

Although HL is not considered to be an AIDS-defining condition, the incidence of this malignancy is statistically increased in HIV-infected patients, when compared with population expectations. Of further interest, the incidence of HL has increased in the era of HAART [63]. This surprising finding, in contrast to AIDS-related lymphoma – which has decreased in the HAART era – is related to the fact that the malignant cell in HL, the Reed–Sternberg cell, requires a certain mileau in order to survive and proliferate. This mileau consists of CD4 lymphocytes, which produce multiple cytokines and growth factors required for the continued survival of the Reed–Sternberg cell. With increasing CD4 cells as a consequence of HAART therapy, the overt expression of HL is allowed to occur [62,71].

Patients with HIV-related HL most often present with systemic B symptoms, including fever, drenching night sweats and/or weight loss, often in the setting of pancytopenia and bone marrow involvement, which occurs in 50–60% of patients at diagnosis. Other extra-nodal sites may also be involved.

The optimal therapy of HL associated with HIV has not yet been defined. Nonetheless, standard regimens are commonly employed. When used together with HAART, survival rates have improved considerably [72].

Kaposi's sarcoma

Kaposi's sarcoma was considered to be one of the first AIDS-defining diagnoses, and is now known to be caused by the human herpes virus, type 8 (HHV-8). While prominent in men who have sex with men, KS is remarkably uncommon among women, either in the setting of HIV or in patients with other forms of KS, including organ transplant patients, African patients from endemic areas of the continent and classical KS, occurring in elderly men of Mediterranean background. While KS has been described in women, the disease is clearly unusual [61].

Breast cancer

Epidemiology of breast cancer in HIV-infected women

Breast carcinoma has been reported in both HIV-infected men and women. Nonetheless, a meta-analysis of seven observational studies did not demonstrate an increased incidence of breast cancer above that observed in HIV-negative men and women, and a recent large, linkage study has confirmed the fact that breast cancer is not increased among HIV-infected individuals [73,74]. However, since women with HIV are living longer as a result of HAART and better supportive care, it is unknown whether the incidence of breast cancer will increase. Furthermore, HIV-infected women are less likely to undergo routine screening mammography, which may ultimately play a role in later diagnosis and more advanced disease at presentation of breast cancer.

Presentation & treatment of breast carcinoma in HIV-infected women

No prospective therapeutic trials for treatment of breast cancer in HIV-infected women have been published. However, using the paradigm from AIDS-related lymphoma, it is expected that standard therapy should be employed, especially in the setting of HAART.

Conclusion

Women with HIV infection remain at risk for malignancy. The majority of these malignancies are HPV driven and reflect the high incidence of coinfection with HIV and HPV. Thus, the incidence of high-grade cervical dysplasia and ICC are increased in HIV-infected women with concomitant HPV infection. Treatment of these conditions is a challenge as the recurrence rates are high. Therefore, efforts are equally directed to the prevention of HPV and screening of women at risk. The cervical cancer vaccine in the HIV-negative setting has been shown to be effective in the protection against certain high-risk HPV subtypes. However, it is not known whether HIV-positive women would be able to mount an adequate immune response to derive the same protection. Anal dysplasia also remains a concern, but screening remains a challenge owing to the inaccuracy of anal Pap smears in regards to the degree of dysplasia present, indicating the need for high-resolution anoscopy in addition to anal Pap smears. Certain non-HPV-related cancers, such as HL and NHL, are also of greater incidence in HIV-infected men and women. These lymphomas tend to present with advanced-stage aggressive disease and require multiagent chemotherapy. The combination of chemotherapy and HAART has led to improved response rates and overall survival for these patients. At present, breast cancer does not appear to be increased in HIV-infected women. However, this may be in part due to less frequent screening. One can postulate that as HIV-infected women live longer, these cancers and others that increase in incidence with age will be seen in the HIV-positive population.

Executive summary

Epidemiology

AIDS-defining cancers include high-grade B-cell lymphoma, Kaposi's sarcoma and invasive cervical cancer (ICC). The incidence of Hodgkin's lymphoma is also statistically increased in HIV-infected patients, as is the risk of anal cancer, although these latter two cancers are not considered to be AIDS defining.

With the widespread use of highly active antiretroviral therapy (HAART), the incidence of AIDS-related lymphoma has decreased, although the incidence of lymphoma remains increased over population-based expectations, and now serves as one of the most common of the initial AIDS-defining diagnoses. By contrast, the incidence of Hodgkin's lymphoma has increased in the era of HAART, while the incidence of ICC remains largely unchanged.

HPV infection in HIV

The vast majority of HIV-infected women have been infected with human papillomavirus (HPV), and, in contrast to HIV-negative women, HPV remains persistent in these individuals.

HPV infection may be found more commonly in the anal region than in the cervix in HIV-infected women.

Two HPV vaccines have recently been licensed in the USA against several genotypes of HPV, including HPV 16 and 18, which are associated with development of cervical cancer. While efficacious in preventing HPV infection and cervical precursor among HIV-negative women, prospective trials in HIV-infected women have not yet been completed and currently, no recommendations can currently be made in terms of the use of these vaccines in HIV-infected women.

HPV & cervical precursor lesions or invasive cancer

Specific oncologic genotypes of HPV (predominantly HPV types 16 and 18) are associated with cervical dysplasia and ICC, in both HIV-positive and -negative women.

Cervical precursor lesions are increased fivefold among HIV-infected women, with approximately 20% of HIV-infected women with normal Pap smear and colposcopy results at baseline developing such lesions within a follow-up of 3 years.

Cervical precursor lesions are treated similarly among HIV-positive and -negative women with similar results, although HIV-infected women are statistically more likely to experience relapse, occurring in approximately 50% of women.

Advanced clinical presentation of ICC is expected in HIV-infected women. Therapy is the same as that for HIV-negative women, although results are worse, with a median survival of less than 1 year.

AIDS-related lymphoma & Hodgkin's lympoma

Advanced stage and presence of systemic ‘B’ symptoms, including fever, drenching night sweats and/or weight loss are common at diagnosis.

HAART may be used safely with multiagent chemotherapy, and has led to a marked prolongation in survival in affected patients. More than 50% of these patients may now be curable using combination chemotherapy.

High-dose chemotherapy and autologous stem cell transplant may lead to long-term, disease-free survival in patients who have relapsed after initial response.

Breast cancer

The incidence of breast cancer is not increased in HIV-infected women, although vigilance will be required to confirm these data. Screening mammography should be encouraged among HIV-infected women. Treatment for breast cancer is similar among HIV positive and -negative women.

Conclusion

The specific characteristics of HIV-related disease in women have been carefully reviewed. Non-Caucasian women are most likely to be infected, as are women of lower socioeconomic background. The efficacy of HAART is equivalent among men and women. While the various opportunistic infections and other HIV-related disorders are similar among men and women, this is not the case with HIV-related malignancies.

Future perspective

Patients with HIV are living longer owing to use of HAART, associated with an approximate 75% decrease in mortality since these antiretroviral agents were introduced in 1996.

Despite the fact that various opportunistic infections as well as non-Hodgkin's lymphoma and Kaposi's sarcoma have decreased substantially in HAART-treated patients, additional malignancies continue to increase in the HAART era, such as anal cancer and Hodgkin's lymphoma. Furthermore, the incidence of cervical cancer has remained unchanged. As HIV-infected women age, it is expected that additional malignancies will continue to be significant causes of morbidity and mortality in these individuals.

It will be important to assure access to low-cost screening programs (for HPV and breast cancer), to smoking cessation programs and to education about the long-term risks associated with malignancy. In addition, vaccination strategies for HPV prevention in HIV-infected women will be exceedingly important, and results of ongoing studies are awaited with great interest.

Future perspective

The mortality from HIV infection has greatly decreased since the advent of HAART. As patients with HIV infection live longer, malignancy will continue to be a major cause of mortality. While certain cancers such as KS and NHL have decreased in incidence, the incidence of cervical cancer and HL remains unchanged. While patients can now tolerate more intense therapy for these cancers including – in certain cases – high-dose chemotherapy and autologous stem cell transplant, ultimately, more effort must be directed to prevention and screening. Results of studies of the HPV vaccine in HIV-positive women are of great interest, and better access to comprehensive cervical cancer, anal cancer and breast cancer screening programs are needed.

Footnotes

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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Malignancies in Women with HIV Infection

Abstract

Keywords

Epidemiology of HIV-related cancers

HPV & HIV

HPV & cervical cancer

Nomenclature: CIN & squamous intraepithelial lesion

Natural history & therapy of CIN/squamous intraepithelial lesion in HIV-infected women

Invasive cervical cancer

Effect of highly active antiretroviral therapy on CIN or invasive cervical carcinoma

Screening recommendations

Vaccination against HPV

Anal dysplasia & anal cancer

Epidemiology of anal cancer

Screening recommendations

Treatment of anal dysplasia

Treatment of invasive anal carcinoma in HIV-infected men or women

HPV-associated head & neck (oral) cancers

AIDS-related lymphoma

Epidemiology of lymphoma

Presentation & treatment of AIDS-related lymphoma

Hodgkin's lymphoma in the setting of HIV

Kaposi's sarcoma

Breast cancer

Epidemiology of breast cancer in HIV-infected women

Presentation & treatment of breast carcinoma in HIV-infected women

Conclusion

Future perspective

Footnotes

References