Epidemiologic studies have identified the association of cervical neoplasia with sexual activity. The initial study suggests this relationship is more than 150 years old. The sexually transmitted agent that could be related to the initiation or promotion of cervical neoplasia has been sought for many years. Essentially every substance found in the genital tract has been implicated over the years. These have included sperm, smegma, spirochetes, Trichomonas, fungus, and more recently herpes simplex virus type II (HSV-2) and human papilloma virus (HPV). During the 1970s, HSV-2 was studied extensively in an attempt to develop a possible etiologic link. These endeavors mainly used case-control studies, which showed a significant higher prevalence of HSV-2 in cancer cases compared with controls. These studies encountered problems with crossreactivity between HSV-1 and HSV-2 and standardization of assays. It could not be determined if the infection with the virus preceded the cancer. When controlled for highrisk factors, many studies found no difference among patients and controls in the prevalence of HSV-2 antibody. Most investigators today do not consider HSV-2 to be a serious candidate as an etiologic agent for cervical neoplasia, although some have postulated that it may in some way be a cofactor.

Since the mid-1970s, there has been an explosion of information concerning HPV. It was actually in the mid- 1970s when zur Hausen suggested that HPV was a likely candidate as a sexually transmitted agent that may result in genital tract neoplasias. Later in that decade, Meisel published a series of articles that described a new virus-induced condylomatous lesion of the cervix. Although koilocytosis had previously been described, these workers noted the presence of intranuclear HPV in koilocytotic cells associated with CIN. In contrast to the long-identified typical cauliflower condyloma, it was noted that HPV also produced a flat, white lesion, best recognized colposcopically, that was thought to be a precursor of cervical neoplasia. The development of immunoperoxidase techniques that can identify the HPV confirmed these original observations. Subsequently, HPV has been isolated from genital lesions; with the use of hybridization techniques, the HPV DNA can be typed.

To date, about 120 different types of HPV have been isolated and characterized (Table 1–1). The identity of a new subtype has usually been based on the description of the DNA genome compared with the known HPV prototypes. A new type must share less than 50% DNA homology to any known HPV. Classification depends on the composition of DNA. About 30 HPV types primarily infect the squamous epithelium of the lower anogenital tracts of both males and females. So-called low-risk types (6, 11, 42, 43, 44) are mainly associated with benign lesions such as condyloma, which rarely progress to a malignancy. The high-risk types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58) are detected in intraepithelial and invasive cancers. More than 85% of all cervical cancers are said to contain high-risk HPV sequences. In benign precursor lesions, the HPV DNA is episomal (has extra chromosomal replication). In cancers, the DNA is integrated into the human genome. All HPVs contain at least seven early genes (E1-7) and two late genes (L1 and L2).
The integration usually occurs in the E1/E2 region, resulting in disrupting gene integrity and expression. These open reading frames encode DNA-binding proteins that regulate viral transcription and replication. With HPV-16 and 18, the E2 protein represses the promoter from which the E6 and E7 genes are transcribed. Because of integration, the E6 and E7 genes are expressed in HPV-positive cervical cancer. It appears that E6 and E7 are the only viral factors necessary for immortalization of human genital epithelial cells. These two oncoproteins form complexes with host regulatory proteins such as p53 and pRB (retroblastoma susceptibility gene). High-risk HPV E6, upon binding with p53, causes rapid degradation of the protein, thus preventing p53 normal function from responding to DNA damage induced by radiation or chemical mutagens. Without this binding, increased levels of p53 growth arrest of cells may occur, which allows repair of damaged DNA to take place or apoptosis (programmed cell death) to occur. E7 protein may bind to several cellular proteins, including pRB. This interaction may inactivate pRB and push the cell cycle into the S phase and induce DNA synthesis. Other regulatory genes such as c-myc may also be involved. Other factors are obviously important, because only a small percentage of women infected with high-risk HPV develop cancer. HPV-immortalized human keratinocyte cell lines will only be manifest in nude mice, for instance, after transfection with additional oncogenes such as ras. In humans, the immunologic response may contribute to this very complicated scenario.

HPVs carry their genetic information within a cellular double-stranded DNA molecule. Infections caused by these viruses are usually not systemic but result in local infections manifest as warty papillary condylomatous lesions. HPV-infected cells contain both the fully formed viral particles and their DNA. Replication of the virus occurs only in the cell nuclei, in which DNA synthesis is low. Mature HPV particles are never found in replicating basal or parabasal cells but are found in the koilocytotic cells in the superficial layer. HPV, like HSV-2, may also have a latent intranuclear form in which only fragments of the viral DNA are expressed.

Characterizations of the HPV types suggest about 40 of these can cause genital disease. These have been divided into high-risk HPV types of which 16 and 18 are the most common, probably high-risk (types 26, 53 and 66) or lowrisk types with 6 and 11 being the most common. These appear to be sexually transmitted. (Fig. 1–1). Although HPV types 16 and 18 are the types most commonly isolated in cervical cancer, not all infections with type 16 and 18 progress to cancer. Reeves reported one of the largest studies of both cervical cancer and controls, and HPV- 16/18 were seen in 62% of 759 cancer patients, whereas HPV-6/11 were identified in 17%. More interesting is that only 7% of 1467 randomly selected, age-matched controls were found to have HPV 6/11, whereas 32% of controls tested positive for HPV-16/18. The crude and adjusted relative risk of cervical cancer associated with HPV-16/18 or HPV-6/11 were similar. Other studies suggest that HPV-16/18 may be present in as many as 80% of the normal population. This proportion of HPV positivity in the normal population varies depending on the geographic area evaluated. Meanwell evaluated 47 cancer patients, 66% of whom had HPV-16, compared with 35% of 26 controls. After controlling for age, he found no significant difference between cases and controls with regard to the frequency HPV-16 was identified.

Initially, it was suggested that in all cancers the HPV DNA was integrated, whereas in CIN lesions the HPV DNA was episomal. This suggested the role of a more virulent type of HPV (i.e., 16/18). More recently, an increased number of cancers with episomal HPV DNA have been reported. Integration has been noted in CIN lesions; therefore, it appears that integration is not a constant finding in cancers. Although integration of HPV-16 has been demonstrated, the importance of this finding in the development of cancer has not been determined. An interesting study from Greenland and Denmark evaluated the incidence of HPV and HSV-2 in the normal population of these two countries. The cumulative incidence rate of cervical cancer in Greenland is 5.6 times higher than it is in Denmark. A total of 586 women in Greenland and 661 from Denmark were investigated. The total HPV-16/18 rate was 13% in Denmark, compared with 8.8% in Greenland; and the age-adjusted prevalence rate in Greenland was only 67% of Denmark’s. HPV-6/11 prevalence was similar in the two populations (6.7% and 7.5%). The authors noted a much higher proportion of women in Greenland with HSV-2 antibodies than of those from Denmark (68.2% vs 30.9%). They also noted a higher number of sexual partners in Greenland (22% with 40 or more) compared with Denmark (0.3%). Cancer screening was similar in the two areas. Although the authors suggested that these data should be interpreted with caution and that other, similar studies need to be done, the observed HPV-16/18 infection rate in Greenland (compared with the cancer incidence in Greenland compared with Denmark) is an interesting observation.

HPV-18 may be more virulent than HPV-16 and may be a prognostic factor. Kurman and associates noted a deficit of HPV-18 in CIN compared with cancer, whereas there was no significant difference in the distribution of HPV-16 in CIN compared with cancer. These authors postulated that this deficit of HPV-18 in CIN could represent a rapid transit time through the preinvasive phase. Obviously, this is conjecture at this time. Walker noted that patients with cervical cancer and HPV-18 had a worse prognosis than did similar-staged patients with HPV-16. One other study noted that the prognosis was worse in patients with cervical cancer if no HPV subtype was identified than if any HPV type was present. Today it is generally accepted that type 18 is more frequently associated with adenocarcinoma of the cervix and type 16 with squamous cancer. There also appears to be a difference in sexual behavior and reproductive risk factors between the two histotypes. There is a positive association of high gravidity and squamous cancer and an inverse association with adenocarcinoma. Age of first intercourse and number of sexual partners is of greater risk for squamous carcinoma than adenocarcinoma.

Over the last several years, many studies worldwide attempted to characterize HPV DNA with regard to specific types and correlate these findings with the cervical neoplastic process. Although the laboratory evidence of the role of HPV DNA in the carcinogenesis was being established, the epidemiologic studies were lacking. Many studies that used testing that was considered appropriate just a few years ago are today considered inadequate because of the test’s insensitivity in light of current technology. For many years, the Southern blot analysis for HPV DNA was considered to be the gold standard. Because it is very laboratory and personnel intense, as well as difficult to replicate between different laboratories, other techniques were developed. The filter in situ hybridization and dot blot test were developed; the latter was used in the commercially available Vira Pap/Vira Type kits. Both techniques were insensitive. The HPV Profile kit was developed to increase the number of HPV types tested (from 7–14) but is labor intense and uses radiolabeling. This was introduced in 1993 but was replaced by hybrid capture, which is said to have greater sensitivity, requires less time and uses a chemiluminescence substrate instead of radiolabeling.

The hybrid capture second generation (HC2) is Food and Drug Administration (FDA) approved for HPV testing of the cervix. Both high- and low-risk HPV types can be identified but require separate ribonucleic acid (RNA) probes. Testing for low-risk types is not usually recommended. The high-risk probe can identify 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68. A semiquantitative measure of the viral load can be obtained based on the intensity of light emitted by the sample. In many instances, more than one subtype may be present. With our current knowledge, should HPV typing be offered or suggested as part of our routine screening or even as a triage? This question implies that we know the answer to several other questions (e.g., the incidence or prevalence in the “normal” population; what affects the positive rate; which technique is considered to be the gold standard; whether HPV DNA detection can predict future cervical neoplasia). Some investigators have stated that HPV DNA is ubiquitous and endemic. The most common method of transmittal appears to be sexual; however, nonsexual transfer is not rare. Jenison found that 28–65% of children younger than 10 years old had antibodies HPV-6, 16, or 18 fusion proteins, and 20% had (PCR) detection of HPV-6 or 16 in oral mucosa.

The prevalence of HPV DNA detection appears to increase during pregnancy, and transmission from the mother to the child during delivery is accepted as a possible transfer mechanism. Although the prevalence of HPV DNA does appear to be related to sexual activity, detection of the DNA has been found in co-ed virgins. It appears that HPV DNA is detected most often in women without evidence of CIN in the 15–25 age range. The one-time prevalence of HPV DNA depends on the assay used. One study of adolescents and young women using the dot blot hybridization technique found 9–11% positive, whereas another study of similar women using PCR found HPV DNA in 33%. Studies of sexually active adolescents noted that detection of HPV DNA varied from 15–38%.

The HPV detection rate was usually higher in women with more sexual partners; however, one study noted that the rate decreased significantly as the number of sexual partners increased (> 10 partners). The rate of detection did not correlate with the years of sexual activity. These usually decreased with age when other factors were controlled. Limited data are available on longitudinal studies of HPV DNA detection de Villiers found that approximately 9% of women of all ages with normal cytology had HPV DNA present on first testing. This rate increased to 26% if repeat testing was done over a 5-year period. The actual rate is probably higher because they used a less sensitive technique (filter in situ hybridization). Mao and associates evaluated 516 sexually active university students (18 to 24 years old). They collected genital specimens for HPV testing every 4 months for up to 4 years. During the study, over 4000 study visits were completed and at about 20% of the visits HPV positivity other than 6 and 11 was noted. Only 5% were positive for 6 and 11. Except for those with 6 and 11, all other HPV subtypes identified, the women were asymptomatic.

Ho et al followed 608 college women at 6-month intervals for 3 years. The accumulative 30- month incidence of HPV infection was 43%. The increased risk was associated with younger age, increased number of vaginal sex partners, high frequency of vaginal sex and partners with an increase of sexual partners. The median duration of new infections was 8 months. The persistence of HPV for 6 months was related to older age, type of HPV as well as multiple subtypes of HPV. The risk of an abnormal Pap smear increased with persistent HPV infection, particularly high-risk types.

Woodmar and associates recruited 2001 women, 15–19 years old, who had recently become sexually active. They took cervical smears every 6 months. In 1075 women who were cytologically normal and HPV negative at recruitment, the accumulative risk for any HPV infection was 44%. The accumulative 3-year risk of a different HPV type than present initially was 26%. 246 had abnormal smears and 28 progressed to high-grade CIN. This risk was highest in women who were positive for HPV-16 but 40% tested negative for HPV and another 33% tested positive for 1st time only at the visit as the abnormal smear. Five women who progressed to high grade CIN consistently tested negative for HPV.

Moscicki followed a small group of HPV DNA-positive women for longer than 2 years with several visits in which HPV DNA using both PCR and dot blot technique were tested. Twelve of 27 tested positive for HPV-16/18. More than half of the women had negative results spontaneously (defined as two or more negative test results) for the original HPV type detected during the first visit. The data suggested that the number of virions decreased over a relatively short period and that the infection was presumed terminated. When a new HPV type was identified, most reported acquiring a new sexual partner since the last visit. This probably reflects a new infection and not reactivation. Rosenfeld found that > 50% of young urban patients tested positive for HPV at either an initial visit or at follow-up 6–36 months later using the Southern blot test. Therefore, the prevalence and incidence of HPV DNA appear to vary greatly, depending on age, sexual activity, the number of times tested, and the laboratory technique used. More than one million people are estimated to seek medical attention each year in the USA because of virus-induced lesions. The incidence, therefore, appears to be quite high for finding HPV DNA in the female genital tract. Even with the high-risk HPV types, infections commonly cause only mild transient cytologic changes and rarely lead to significant CIN or invasive cancer. Therefore, the use of routine screening utilizing HPV DNA probes does not appear to be clinically indicated in the young patient. HPV testing has been evaluated as an adjunct to primary cervical screening. Cuzick and associates obtained HPV testing for types 16, 18, 31, and 33 using a semiquantitative type-specific PCR test. In 1980, their study was done on evaluable women who had never been treated for CIN and who had not had an abnormal Pap smear during the previous 3 years.

Cytologic abnormality or high concentrations of HPV were obtained in 11.6% (231 patients) and 81 (4%) had CIN II or III, respectively. The positive predictive value (PPV) of HSIL cytology in identifying CIN II or III was 66%. HPV testing detected 61 cases of CIN II or III (sensitivity 75% and PPV of 42%). Of the 81 cases of CIN II or III, cytology was negative in 33 and 20 had no evidence of any of the HPV types tested. Although sensitivity and PPV were noted, specificity and the negative predictive value (NPV) were not. It has been suggested that in patients with an abnormality, HPV DNA typing may be used as a triage method to determine who may need further investigation. This is particularly true for patients with ASCUS or LSIL, because those with HSIL will most always be evaluated with a colposcopy. Goff evaluated the Vira Type kit in patients with ASCUS. Of 171 patients, 19% had detectable HPV DNA and 85% were of the high-risk HPV types. Only 6 of 28 patients with atypia and high-risk HPV types had CIN; none had CIN III.

The authors thought that available HPV typing was not clinically useful in identifying patients who should have a colposcopy. Sedlacek reached similar conclusions in 334 women referred for evaluation of abnormal cytology. He could not demonstrate a relationship between the HPV type and the high-grade biopsy proven CIN using the Southern blot technique. On the other hand, using PCR with consensus primers or semiquantitative PCR suggests a significant correlation of highrisk HPV types with CIN II and III. Hatch evaluated The Hybrid Capture kit in 311 patients who were referred for evaluation of abnormal cytology. Fifty percent of LSIL, 26% of HSIL, and 44% of those with invasive cancers were HPV-DNA negative. The test missed one-third of histologic LSIL and HSIL in patients with LSIL on cytology. In the ASCUS group, the ability of the test to identify histologic HSIL noted a sensitivity of 60%, a specificity of 68%, and a PPV of 35%. With these results, most clinicians would not want to rely on this test to predict which patient may have significant cervical neoplasia, particularly invasive disease.

In a study of 1128 women referred with an abnormal Pap smear, Kaufman and associates repeated the Pap smear, obtained a sample for HPV testing (Profile kit), and did a colposcopy. They performed 1075 colposcopic-directed biopsies and endocervical curettages (ECCs). HPV DNA was identified in 488 women. Positivity of HPV increased as the severity of the referral Pap smear increased (ASCUS 25%; HSIL 44%), and this also correlated with biopsy results (HPV in CIN I 39%; CIN III 59%). The detection of highrisk HPV DNA in women with any degree of SIL on the referral Pap smear poorly predicted biopsy-proven CIN III. Sensitivity of HPV to predict CIN II and III with LSIL on a Pap smear was only 58%; specificity was 68%; and PPV was 22%. If HPV had been used as the only triage in patients with LSIL on Pap, > 40% of women with confirmed CIN II or III would not have had a colposcopy or biopsy. In a follow-up study of these same patients with CIN II or III, the authors evaluated HPV testing using a PCR technique that is the most sensitive for the HPV tests. The PCR appeared to be more sensitive than the Profile, but the PPV was similar (21.7% and 22.8%). Approximately one quarter of the patients with negative results on biopsies were HPV-positive and almost one half of patients with CIN II or III were HPV-16-negative. When PPV and NPV were evaluated, combined triage did not improve on either HPV testing or cytology alone. Cost analysis was performed, and repeat cytology was better in identifying CIN II or III with half the cost of HPV testing. The authors thought that at present the use of these tests should be restricted to the research arena and should not be used in routine clinical practice.

In evaluation of 537 women with a referral Pap of CIN I, colposcopy and HPV typing (PCR) were done along with a repeat Pap. Based on a repeat Pap and colposcopy impression, 142 women were presumed to have CIN II or a worse lesion. In the group with CIN I, 45% tested positive for HPV and 52% tested positive in the CIN II category. In the latter group, HPV positivity among women younger than 22 years of age and with a history of current cigarette smoking in people 22 years or older were significant predictors of patients with CIN II or III. The authors believed that the age limitation would limit the usefulness of HPV screening. Most authors have noted a decrease in HPV positivity with age, even though more severe lesions appear in older patients. Manos and colleagues evaluated the use of HPV testing compared with repeat Pap smears in women with an ASCUS Pap. Of 973 patients with ASCUS and a definitive histologic diagnosis, 65 (6.7%) women had HSIL or cancer. The HPV test was positive using capture II method in 89.2%, and the repeat Pap smear was abnormal in 76.2% (not statistically significant). Triage based on HPV typing alone or on a repeat Pap smear would only refer a similar number of patients for colposcopy (39%). False-positive results for HPV testing and repeat Pap smears were similar when the histology was normal.

In a report from Italy, 221 patients with Pap smears showing minor atypia were evaluated with HPV testing, cervicography, and repeat cytology. In a multivariate analysis, only cytology and cervicography retained an association with histologic diagnosis of CIN II–III. The HPV test did not influence the decision for a biopsy nor was it associated with a histologic diagnosis. A prospective study of biopsy-proven CIN I was evaluated with regard to risk factors for progression. Of 163 women, 13 (8%) progressed to CIN III; 43% regressed; and 49% persisted. All progression occurred in women who tested positive for HPV DNA and who had an immature abnormal transformation zone on the initial evaluation. In addition, women who complained of vaginal discharge on enrollment increased the risk of progression. None of the CIN I patients with HPV DNA-positive test results progressed. Although all the patients who progressed tested HPV-positive, 89 (90%) who were HPV positive did not progress.

In a clinical opinion, Kaufman and Adams reviewed the current status of HPV testing in predicting the presence of HSIL or cancer in patients with ASCUS or LSIL cytology. Using the profile and hybrid capsule tests for HPV to identify CIN II or III, sensitivity varied from 55–93%. In the studies with the highest sensitivity, the specificity ranged from 24–67% and PPV ranged from 17–28%. To date, no data suggest that HPV testing has or will decrease morbidity and mortality from invasive cancer. Their opinion indicated that presently HPV testing has little clinical value to the practitioner. The use of HPV typing to predict progression of CIN has been suggested. In a study by Gaarenstoom, HPV 16 presence was significantly related to progression of CIN—29% vs 0% in HPV-negative lesions. All patients had colposcopically directed biopsies but were followed without being treated. PCR with a primer was used to identify HPV. In 1993, a diagnostic and therapeutic technology assessment (DATTA) was performed by the American Medical Association. Three questions were asked. Is HPV DNA testing an effective method of guiding therapy in:

1. women with atypical Pap smears;
2. LSIL, and
3. a condylomatous cervical lesion identified at colposcopy whose histologic diagnosis is indeterminate?

The scientific literature was reviewed, and a panel from the obstetric-gynecologic, pathology, oncology, infectious disease, and preventive medicine community was asked to answer the three questions. Sixty percent, 62%, and 55%, respectively, thought that HPV DNA testing was investigational with regard to the three questions posed. Only 22%, 15%, and 17% thought that HPV DNA testing may be “promising”, and a similar group noted that it had “doubtful” effectiveness.

Recently cell proliferation pathways have been evaluated in regards to HPV. This has led to evaluation of genes and growth factors. Data has suggested that the progression of CIN to cancer can lead to an upregulation of epidermal growth factor receptor (EGF-R). This upregulation is common to all squamous cell cancers; however in cervical cancer, EGF-R upregulation leads to a specific up regulation of insulin-like growth factor-II (IGF-II). IGF-I but not IGF-II levels are elevated in other gyn cancers as well as breast and prostate cancers. It has been suggested that IGF-II levels could be used as a monitor for CIN as well as cervical cancers post therapy. Increased serum IGF-II levels in cervical cancer are accompanied by a significantly reduced level of serum IGF-binding protein-3 (IGF-BP3). IGF-BP3 appears to be a cell regulatory and pro-apoptotic agent and an increase in its level offers an excellent prognosis for cervical cancer regression through its downregulating effects on EGF-R, IGF-II and vascular-endothelial growth factor (VEGF). VEGF-B is known to be elevated during metastatic spread of many cancers. A reduction in IGF-BP3 levels have been observed upon treatment with VEGF in HPV-positive and negative cell lines. VEGF-C has been found to be significantly elevated in women with persistent cervical cancer or HSIL and appears to be effective in early diagnosis of metastatic cervical cancer. VEGFC appears to be unique to cervical cancer in that it interacts with IGF-II and IGF-BP3 through EGF-R. Interestingly, VEGF-C is upregulated by nicotine in cervical cancer cell lines. This translational research may lead not only to a better understanding of cervical cancer and its precursors but may also increase our ability to predict which CIN may progress as well as monitor cervical cancer post treatment and identify persistence or recurrence at an earlier time than currently available.

It has been suggested that the sexual partners of women with CIN and HPV infection should be treated to control the infectious process among women. Campion evaluated 140 women who presented for treatment of biopsy-proven CIN. As a control group, 280 females matched for age and disease severity (two control patients for each study patient) were identified. HPV typing was performed on each control and case. The atypical T-Z was destroyed with the laser in each. Repeat HPV typing was done at 6 months. In the study group, the current sexual partners were evaluated and all HPV lesions were treated. The male partners of the control group were not treated. The primary cure rate of CIN was the same in the two groups (92% study vs 94% control group). The importance of controlling disease in the male sexual partner may be overemphasized.

It is now generally accepted that the virus itself cannot be eliminated with any known therapy. Therefore is there any benefit from knowing HPV subtypes that relates to clinical management? There probably is not. Not only is HPV commonly found in as many as 80% of normal (non- CIN) patients, but after treatment for CIN, HPV was found in 100% of 20 females with CIN who were successfully treated with laser.

Riva and associates treated 25 women with koilocytotic atypia, CIN, vaginal intraepithelial neoplasia (VAIN), or vulval intraepithelial neoplasia (VIN). All patients had laser therapy of the cervix, vagina, and vulva in continuity. Morbidity was significant. Histologic persistence of subclinical HPV infection was documented in 88% of patients after treatment. Neither treatment of male sexual consorts nor sexual abstinence significantly improved treatment outcome. HIV and cervical neoplasia Human immunodeficiency virus (HIV) infection is an ever-increasing disease affecting all our citizens. Initially thought to be limited to homosexual males and intravenous (IV) drug users, more and more women are being diagnosed with HIV and acquired immunodeficiency virus (AIDS). An estimated 850,000–950,000 persons in the USA are living with HIV including 180,000–220,000 who do not know they are infected. In 2003, the estimated number of AIDS was 43,171 of which 11,498 cases are in females. Eighty percent of women who contract AIDS are in the reproductive age group. Approximately 25% acquire these infections during adolescence, and over three-fourths of female cases in 2003 were contracted by heterosexual transmission. In women, early manifestations of the disease are often gynecologic, such as chronic yeast infections, pelvic inflammatory disease, genital warts, and herpes. On January 1, 1993, the Centers for Disease Control and Prevention (CDC) expanded the case definition of AIDS to include HIV-positive women with invasive cervical cancer. This inclusion remains controversial, because it apparently was based on preliminary data. These data suggested that in HIV-positive patients, there was a high incidence of CIN, Pap smears were unreliable, and other diagnostic procedures (i.e., colposcopy) should be part of routine evaluation of these patients.

It is well recognized that immunodeficiency predisposes to development of neoplasia in congenital disorders such as Wiskott–Aldrich syndrome, in which the incidence of cancer may be increased 10,000-fold. Renal transplant patients appear to be at increased risk for lower genital tract neoplasia. Cervical neoplasia has been reported to range from 5–40%, and anogenital neoplasia is reported 9 to 14 times greater in these patients compared with controls. It is not surprising, therefore, to see an increased incidence of cancers in HIV-positive patients. Kaposi sarcoma and non-Hodgkin’s lymphoma are the most commonly seen cancers in patients with AIDS. Squamous cell carcinomas of the anogenital tract and oral cavity have been reported with increased frequency. Spinillo noted in 75 HIV-positive women that 22 (29%) had CIN. Sun evaluated in a cross-sectional study of 344 HIV-positive and 325 HIV-negative women. HIV-positive women were more likely to have HPV-DNA of any type, HPV-16 or 18, or more than one HPV type than HIV-negative patients. The HIV-positive patients with HPV DNA were more likely to have CIN than were HPV-infected, HIV-negative women. Essentially, all studies noted a much higher rate (up to tenfold) of CIN in HIV-positive women compared with controls. Maiman noted that 39% of HIV-positive patients but with normal cytology had CIN.

He suggested in these women that Pap smears should be done every 6 months and that they should have a routine baseline colposcopy or cervicography. Subsequently, several large studies representing several hundred patients noted only a false-negative Pap smear rate of 10–19%. Wright noted that the Pap smear failed to detect abnormalities in only 0.8% of 398 HIV-positive women who actually had highgrade CIN. The CDC currently recommends that all HIVpositive women have a Pap smear (Table 1–2). If the result is normal, repeat the smear in 6 months then annually thereafter as long as the Pap smear is normal. If the first Pap has severe inflammation with reactive squamous cells, the smear should be repeated in 3 months. In patients with ASCUS or any degree of SIL, further evaluation (colposcopy) appears warranted. Not only are HIV-positive patients at greater risk for CIN, but also the severity of the disease appears to be related to T cell function.

HIVpositive patients with CIN have absolute T cell counts and T4:T8 ratios of about one half of those HIV-positive patients without CIN. Wright noted in an evaluation of 398 HIV-positive and 357 HIV-negative patients that CIN was independently associated with HPV infections (odds ratio [OR] 9.8), HIV infection (OR 3.5), CD4+ T lymphocyte count

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