CANCER PREVENTION INSTITUTE OF CANADA

Last updated: 15-Jan-2007

Human Papillomavirus

Globally, cervical cancer is the second most common female cancer (only exceeded in prevalence by breast cancer). As indicated in the table above, there is virtually a one-to-one connection between cervical cancer cases and the detection of HPV DNA. As Walboomers et al. concluded in 1999, “the presence of HPV in virtually all cervical cancers implies the highest worldwide attributable fraction so far reported for a specific cause of any major human cancer.”[1] In short, HPV has been proposed as the first-ever necessary cause of a human cancer identified by researchers.[2],[3]

For completeness, it is important to note that HPV types have been implicated in a number of other cancers, including other anogenital carcinomas, e.g., of the vulva or penis,[9] and various nongenital mucosal and cutaneous diseases, e.g., oropharyngeal and lung carcinomas and certain skin cancers.[10],[11],[12],[13] In the latter case, UV radiation is known to be a co-factor.[14] A particularly significant cancer related to HPV in high-risk male populations is squamous cell anal carcinoma.[15] Aside from lesions and full cancers, the other main disorders associated with HPV are different types of genital warts.

Taken as a group, anogenital HPV is the most common sexually transmitted infection.[16] The lifetime risk of contracting such an infection is about 80%.[17]

Transmission of the Agent

The primary mode of HPV transmission is sexual intercourse. Studies show that the number of recent sexual partners is significantly associated with the incidence of HPV infection.[18],[19] Limited research has concluded that the virus can be passed through fomites (substances or articles that hold and convey infection, e.g., handkerchief) or skin contact, but this remains very debatable; no evidence of such transmission has been found in the case of genital lesions, the precursor to cancer.[20] A final transmission route implicated as plausible is non-penetrative sexual activity (including oral sex).[21] Although the whole area of transmission is subject to ongoing study, the basic understanding is that HPV infections are “easily transmitted.”[22]

As Arena et al. have noted, “the data reported in the literature on the relationship between HPV and pregnancy are highly discordant.”[23] Although earlier studies suggested the possibility of “vertical transmission” of HPV from mother to infant during delivery, more recent research has concluded that this route of viral spread is very low-risk.[24],[25] Even when the virus is found in newborns, it often seems to clear after a few months.[26] The first report has recently been made of fetal cervical HPV infection through intrauterine exposure.[27]

Co-factors and Correlates

HPV infection is very common, but mostly transient. The fact that, even in women with persistent HPV infection, only a certain fraction will eventually develop cervical cancer indicates that the virus, though necessary, is not always a sufficient cause. Co-factors seem to be involved in at least some cervical carcinogenesis.[28] For example, risk for cervical cancer developing with HPV infection increases twofold when the woman is or has been a smoker;[29] recently, evidence for the effect of passive smoking has also been reported.[30],[31] In fact, some research suggests that exposure to cigarette smoke may be required as a carcinogen to advance HPV-infected cells toward high-grade neoplasms.[32] The crucial biological impact appears to be the oxidant load created through smoking, though this remains a matter of investigation.[33],[34]

There is evidence that the presence of other sexually transmitted agents, cervical inflammation, multiple births (known as multiparity), and long-term oral contraceptive use all correlate with progression towards cervical cancer.[35],[36],[37],[38] Although a causal relationship is unproven, herpes simplex virus-2 may act in conjunction with HPV to create cervical cancer (perhaps multiplying the risk of developing the main types of cervical cancer up to 2 or 3 times).[39] HIV (with its associated immune suppression) and Chlamydia trachomatis are also on the list of potential co-factors.[40],[41],[42],[43],[44]

The most recent research has called into question how much birth and contraception experience actually influence cervical cancer rates.[45],[46] A 2003 systematic review further concluded that “there was no evidence for a strong positive or negative association” between HPV infection and use of oral contraceptives.[47] In sum, it is probably best to say the connection between oral contraceptives, HPV and cervical cancer remains a fluid area of research.[48] As for the case of multiple births, if its association with cervical cancer risk holds up, then a general decline in parity might partly explain the decrease in cervical cancer in many industrialized countries.[49]

Finally, there is consistent evidence that higher intakes of fruit and vegetables are protective against cervical cancer, as well as weaker indications of a similar role for specific dietary ingredients (e.g., vitamins C and E, lycopene, and folate).[50],[51],[52],[53] The main proposal for the function of dietary co-factors is an antioxidant protective mechanism.[54]

Natural History and Carcinogenesis

This section will focus on the main HPV-related cancer of interest to public health, namely, cervical cancer. This type of cancer arises through three carcinogenic steps. First, HPV infection of the cervix occurs, primarily as a result of sexual intercourse. The effect of infection on cervical cells is quite variable. Whatever the impact, most infections tend to resolve over a one- to two-year period.[55] The next step, progression to a precancerous state, happens in a small percentage of cases. The crucial factor is the persistence of HPV as opposed to clearance of the virus. Persistence is due mostly to some capability of the virus to suppress or evade the body’s natural immune system.[56],[57]

The modal time between HPV infection (most often in late teens or early 20s) and the peak of precancer development is 7 to 10 years. This places the typical age of women with precancerous lesions at about 30 years. The final step is full-blown, invasive cancer, which may take another 10 years to develop; between one third and two-thirds of women with precancer will move on to this end-point. In sum, this generic, prolonged natural history confirms the basic understanding that rapidly invasive cancers among young women are rare events.[58]

Preventive Interventions

As outlined above, there are three approaches to preventing cancer with an infectious origin: limiting exposure to the pathogen in the first place; interrupting the establishment of infection; and stopping full cancer development once infection is present. We will look at each of these approaches in turn.

Early Primary Prevention

The most “full-proof” way to eliminate the risk for future genital HPV infections is to refrain from genital contact with another person. The next most certain approach is to only be sexually active within a long-term, mutually monogamous relationship with an uninfected partner.[59] Indeed, reducing the number of potentially risky sexual partners by any means is clearly a preventive measure. These sort of proactive “partner management” interventions become important in light of the fact that preventing transmission through condom use has not been demonstrated (though condoms may protect against the development of genital warts and lesions).[60],[61]

The literature related to the prevention of sexually transmitted infections (STIs) is extensive. To avoid an overly lengthy document, we will confine our description of this sort of early primary prevention to a few notable programs.

Population-Based Interventions to Reduce Sexually Transmitted Infection (STI). The relevant review by the Cochrane group restricted itself to randomized controlled trials where, by definition, the unit of randomization was either a community or treatment facility (not individuals). These stringent criteria yielded only 5 qualifying studies, all based in developing countries and none focusing on HPV per se. The interventions in population-based programs include: education and media campaigns aimed at promoting safer sexual behaviour; improved STI treatment services; integration of case-finding into routine health care; and mass treatment of persons in at-risk communities, even if they are asymptomatic. The programs reviewed, which may have limited applicability in developed countries anyway, were for the most part unsuccessful in reducing STI incidence rates. Only one study showed a significant decrease in gonorrhoea and syphilis (which, for our purposes, will be taken as proxies for HPV infection) and an increase in condom use (with the latter being of limited application to HPV prevention anyway, given current information).[62] A 2005 systematic review of interventions to prevent STIs examined three of the same community-based studies identified by Cochrane, including the one trial that showed some success. All the included population-level studies were based in the same African communities covered by Cochrane.[63] There apparently has been no population-level experimental research in developed countries, even though it is acknowledged that, to have maximum impact, STI interventions will likely need to be applied to whole populations.[64]

Individual and Group Approaches to STI Control. The bulk of the 41 studies identified in the 2005 review noted above dealt with individual approaches; a smaller number looked at group-based programs. A large percentage of the projects showed significant success. [65] For instance, a third of the 9 group-based programs in the review involved counselling and skills building that led to significant decreases in STI transmission. One study showed counselling focused on skills training (8.6% incidence over 12 months) was superior to a health education model (15.4%).[66] The most recent literature has supported the efficacy of cognitive-behavioural group interventions for STI control.[67]

Another review from 2002 found 8 interventions designed to reduce STI incidence; 5 of them showed significant success, including individual counselling, mass communications regarding risk reduction, and multiple-component motivation and skills education.[68]

A Cochrane review originally completed in 2000 confirmed that health promotion directed at women can reduce sexual risk behaviours, especially with respect to increased use of condoms for vaginal intercourse.[69] However, we have already noted the limited protection of condoms against HPV. In fact, none of the studies included in the review focused on the control of cervical cancer as an end-point.

Summing up STI prevention, it was acknowledged in 2002 that “the evidence based for many interventions is sparse and randomised trials of interventions are in their early days.”[70]

Despite the fact that not contacting and subsequently contracting HPV would be 100% effective in preventing cervical cancer, it is possible that the advent of an HPV vaccine will create some complacency around such behavioural interventions, as well as other approaches to controlling cervical cancer. This would possibly be a backwards step, especially given the Centers for Disease Control’s 2004 position statement; they maintained that an effective HPV vaccine should not replace other prevention strategies.[71]

Primary Prevention

The one-to-one association of cervical cancer and HPV infection has two practical implications: the development of a vaccine and enhanced screening programs based on HPV testing.[72] The development of a vaccine has had a clearer rationale and, in fact, has progressed further at this point. The vaccine story, though chronologically a later development than conventional cervical cancer screening, must logically come first; it represents a primary approach to prevention, whereas detecting the presence of cancer is already part of a secondary strategy.

Many challenges exist in the development of a vaccine. Because of the multiplicity of HPV types which are oncogenic, there is motivation to make any vaccine polyvalent. However, this adds development and manufacturing expense, so the balancing act becomes one of targeting those viral types which cause the greatest proportion of cancer. Once a strategy has been set, there still must be vigilance against the “potential epidemiological shift of HPV disease to currently less frequent types and variants.”[74]

There have been several studies exploring either preventive or therapeutic HPV vaccines in humans. The trial by Koutsky et al. has provided the most conclusive evidence to date that HPV vaccination will be both safe and effective.[75] The main objectives of this double-blind, placebo-controlled, randomized trial were:[76]

• determine whether an HPV-16 vaccine would prevent persistent infection.

• estimate the impact of the vaccine on the incidence of cervical neoplasia.[77]

• assess the immunogenicity (i.e., ability to create an immune response) and tolerability of the vaccine.

The observed efficacy rate against cancer development was 100%. These encouraging results were matched by a very low rate of adverse events with the vaccine (less than 1%). As well, the vaccine not only prevented the development of disease, but also seems to prevent “its causative agent from residing in the genital tract where it can infect new sexual partners.”[78] The main caveat emerging from this study was evidence that vaccination against one type of HPV will not protect against infection by another. Another limitation is that the vaccine does not appear to reverse infection or cervical neoplasia once it is present.

The results of the only other phase III trial were reported in November, 2004. It studied the effect of a bivalent vaccine protecting against HPV-16 and HPV-18; adding HPV-18 has the potential for eliminating another 10% of total cervical cancer cases.[79] On an intention-to-treat basis, the vaccine was 95% efficacious against persistent infection and 93% against cytological abnormalities and lesions. In addition to these results, the vaccine was shown to be safe, well-tolerated and highly immunogenic.

Several other studies have reported on earlier stages of vaccine testing. The phase II data from a quadrivalent vaccine published in May, 2005, were very promising.[80] Over two and a half years of follow-up, the vaccine reduced the combined incidence of persistent infection from HPV-6, HPV-11, HPV-16, or HPV-18—as well as related genital disease including new cervical pre-cancers and genital warts—by 90%. The phase III trial of this vaccine is now under way. Several other vaccines are in the pipeline that will be targeting even higher numbers of HPV subtypes.

As one or more of these vaccines move towards licensing in the next few years, several questions remain open:

• Who should be vaccinated, and when? Some argue that the key population should be girls before they are sexually active, but since HPV causes a variety of cancers in men and women, a case can be made to vaccinate everyone.[81],[82]

• How long does the protection last?

• How polyvalent should a widely-used public health vaccine be? For example, if women were vaccinated against five HPV types (16, 18, 31, 33, and 45), it would reduce cervical cancer risk by 85%.[83] Another consideration is mortality; one study showed that cervical cancer patients with HPV-18 or -45 are more likely to die from their disease.[84]

• How effective and cost-effective would a vaccination program be over the long-term, especially compared to current screening strategies?

There are two routes to answering the last question. The first is to compare the results from highly successful hepatitis B vaccination programs (see the next major section of this report). The second is mathematical modeling of disease progression and the impact of a vaccine. An example of the latter is offered by Taira et al.[85] Their model estimated HPV prevalence and infection rates for the population overall, by age group, by level of sexual activity and by gender. The conclusion was that administering an HPV-16/18 vaccine to 12 year old girls would reduce cervical cancer cases by almost 62%, with a cost-effectiveness ratio of $14,583 per QALY.[86]

HPV Testing. There is a lot of debate concerning the potential usefulness of augmenting (or even replacing) conventional cytological screening (see under secondary prevention below) for cervical cancer with an HPV DNA test. As one study noted, “the extreme rarity of HPV-negative cancers reinforces the rationale for HPV testing in addition to, or even instead of, cervical cytology in routine cervical screening.”[87] Additional pressure to consider alternatives comes from the challenges and deficiencies of current routine screening methods (see below). However, the extra cost of HPV testing is viewed by some as being prohibitive.

In April, 2005, the American College of Obstetricians and Gynecologists released a practice bulletin that acknowledges the high sensitivity of detecting HPV DNA in terms of ruling out cervical cancer.[88] If HPV is not present, women can be reassured with a high level of certainty that they are cancer-free. Using the test in the opposite direction is where the problems begin, i.e., deciding whether a detected HPV infection (even high risk types) but without cervical abnormality should be followed and treated (and, if so, when and how).[89] The cost of any additional surveillance (in about 4 to 6% of the screened population) adds to the already higher expense of HPV testing.[90] On the other hand, women with normal cytology and negative for high-risk HPV types can be screened less frequently; cost-effectiveness and modeling studies suggest that this fact could offset increased costs with HPV testing and thus make the procedure attractive from a public health perspective.[91] A comprehensive review of the literature up to 2005 confirmed that adding HPV testing to conventional screening would “likely” be cost-effective, though it also acknowledged that “further research is needed into the practicalities of implementing such a policy.”[92]

Another potential area of usefulness for HPV testing is rapid intermediate evaluation of precancer treatments (see under secondary prevention below).[93],[94],[95] An alternate approach to tracking the development of disease and the effectiveness of therapy is surveillance of molecular biomarkers associated with the natural history of HPV-related carcinogenesis.[96]

Avoiding Co-factors. Women who smoke do not seem to clear an HPV infection as quickly as non-smokers. Smoking is a risk co-factor for cervical cancer (as well as many other cancers, of course); but, in the case if cervical cancer, it is possible that this relationship is not necessarily a causative one (e.g., smokers perhaps having more sexual partners, on average). For this reason, it cannot be assumed that not smoking (or cessation) will automatically reduce the risk of HPV infection developing into cancer. While no specific studies were found which evaluated that particular issue, it is of significance in terms of secondary prevention that smoking does seem to decrease the effectiveness of precancer treatments.[97]

Conservative Treatment. The therapeutic approaches to a detected HPV infection are limited, though some new directions are being explored. In fact, in the absence of coexistent cellular changes, treatment is generally not recommended for subclinical genital HPV infection diagnosed by colposcopy,[98] biopsy, acetic acid application, or the detection of HPV by laboratory tests. The diagnosis of subclinical genital HPV infection is often not definitive, and no therapy has yet been identified that can eliminate infection.[99],[100] This was confirmed in the only systematic review located, which dates back to 2000 and was not published in a top-tier journal.[101] Nonetheless, the results there (which mainly looked at laser therapy) can be added to earlier conclusions that effective antiviral therapies for subclinical HPV infection are not yet available.[102]

Research continues in this area. Reversing the assessment of earlier studies,[103] recombinant human interferon gamma has shown good results in effecting regression of precancer cells and sometimes complete remission of HPV infection.[104] As well, one study suggested that the highly active antiretroviral therapy used with human immunodeficiency viral infection and AIDS can have a positive effect on cervical precancer regression (the impact on HPV clearance was not reported).[105] The quest is for a targeted antiviral, rather than simply the induction of non-specific inflammation which in turn generates a “bystander immune response.”[106] Antivirals for HPV are especially important for the large population of immunosuppressed individuals who will mostly likely not benefit from immunotherapies.

A new approach is the potential use of therapeutic vaccines to control HPV infection or associated lesions. The main targets shaping vaccine development have been the key oncoproteins responsible for malignant transformation.[107] Mostly, results from small phase I trials have been variable.[108] If the promise seen in some early results is eventually fulfilled, then these therapeutic agents may play a role in both primary and secondary prevention of cervical cancer.

The last statement underlines the fact that therapies for HPV often overlap with those for the various precancer and early cancer stages which may lead to full invasive cervical cancer. The object of therapy is a “moving target” throughout the natural history of HPV disease. Somewhere we pass from primary prevention related to controlling HPV infection per se, through intermediate stages of precancerous development, and finally to a point where advanced precancer or early cancer is clearly in place. For our purposes, we will treat the latter stages as cases requiring secondary prevention; once detected through screening, the transformed cells and lesions become candidates for treatment, which usually is some form of ablation[109] through surgery or other means (see below).

Rounding out the conservative approaches to HPV infection, both dietary nutrients (e.g., retinoids, related to vitamin A, and beta-carotenes) and a topical medication called cidofovir have been investigated, with mixed-to-promising results.[110],[111] Nonsteroidal anti-inflammatories and gene therapies are also in an early stage of investigation.[112],[113] Finally, an experimental treatment of HPV infection, photodynamic therapy, has shown variable efficacy.[114]

Secondary Prevention

Screening. Chronologically, conventional cervical cancer screening (the backdrop for future decisions about HPV tests) has a longer history than the development of vaccines or HPV DNA testing, but logically it belongs at this point in the discussion. Cancer screening is designed to detect the presence of precancerous cells or lesions and then prompt preventive measures. By identifying the precursor lesions associated with HPV infection, screening programs based on cytology[115] have reduced the incidence of invasive cervical cancer. One case study, a report in the UK, concluded that cervical cancer screening has prevented an epidemic that would have killed about 1 in 65 British women born since 1950, or about 6,000 deaths per year. In sum, at least 100,000 women born between 1951 and 1970 have been spared premature death in that country.[116] Even with such dramatic statistics, cost-effectiveness analyses of such programs have produced variable results. In countries where an abnormal test result can lead to substantial resources being invested in management, the cost per life year saved may run into many thousands of dollars.[117]

The most common screening test that goes beyond a regular gynecologic examination is the so-called Pap smear, the name being a shortened form of its originator, GN Papanicolaou.[118] He published results concerning the correlation between abnormalities in scraped cells and cervical cancer in a cornerstone paper in 1941. The aim, and the eventual result, of a simple screening test was to save “millions of women who would otherwise discover their cancer of the cervix uteri at a non-curable stage.”[119] As described earlier, precursor lesions usually appear a considerable length of time before a carcinoma; thus early detection and prompt management can lead to effective prevention of the disease.

An abnormal Pap smear can be treated in a variety of ways, from conservative monitoring over a period of months to see if it returns to normal, to cryosurgery that freezes and destroys infected cells, to other procedures that excise problem tissue (see below).

The main strategic issues with Pap smears are:

• Identifying the most efficient age cut-offs and frequency of routine testing.

• Focusing on organized or opportunistic screening.[120]

• Introducing automatic scanning devices.[121]

• As noted earlier, how and when to integrate HPV DNA testing. The most common proposal is a primary Pap test with an adjunctive HPV test, especially if the cytological examination provides equivocal results.[122]

• Establishing the best protocol for monitoring tissue status after precancer intervention. A meta-analysis of the literature suggested that a double negative (i.e., no abnormality in Pap smear or HPV DNA test) at 6 months and then again at 24 months is sufficient to allow the person to return to a routine testing protocol.[123]

Despite the amazing track record of Pap smears, the motivation to also move towards HPV testing and / or vaccinations has emerged due to the high false-negatives seen in conventional testing. The false-negative rate with Pap smears ranges from 5 to 30%.[124] This results in, for example, about half of the cervical cancer cases in the US (representing about 7,000 women per year) occurring in those who are routinely screened. Cervical adenocarcinomas[125] in younger women are especially hard to prevent.[126] All of this uncertainty has prompted a large amount of litigation and huge awards. False positives are also a concern, given that the vast majority of HPV infections resolve spontaneously; of course, this challenge would also apply to the newer HPV tests.

We may be at the limit of human ability to derive appropriate and consistent information from the microscopic examination of Pap specimens. Thus efforts to increase the sensitivity of the test have focused more on the collection, handling and processing of specimens. So called thin layer (or liquid-based) technology involves collecting material with a soft brush and then rinsing it into a special fluid preservative; from there, a thin-layer slide can be prepared which offers several improvements in terms of the quality of the cytological examination. This method has the advantage of providing material for any subsequent HPV DNA test as well.[127]

Resisting Critics / Increasing the Use of Screening. Whatever the risk, inconvenience and cost of false negatives, there is a tragic irony developing around looking for a “perfect” Pap smear: it may become too good to be affordable. The cost of more specialized specimen collection and preparation, computerized rescreening and malpractice insurance could mean the loss of an inexpensive, widely available Pap smear, which “will undoubtedly lead to increased cervical carcinoma.”[128] The fact is that more women experience the development of cancer because of the failure to have a regular Pap smear than because of errors in cytodiagnosis.[129]

The Cochrane review of interventions to encourage cervical screening identified the following approaches:[130]

• invitations to women who are not overdue (letters, telephone calls, etc.)

• reminders to those overdue

• education (materials, home visits, etc.)

• counselling

• risk factor assessment

• improvements in screening methods

• economic incentives.

In all, 35 studies were identified in the review (27 being randomized controlled trials). The only extensive and strong evidence was for invitation letters; there was limited support for educational interventions.

Surgery and Other Forms of Ablation. It becomes a matter of judgment as to when to categorize surgery and other means of dealing with precancerous situations as interventions which truly have left behind the “world of prevention” and entered the arena of full cancer management. One way to enable a categorization of required interventions is the grading system that has been adopted to describe a Pap smear diagnosis. In the US, two levels of CIN (more generally known as squamous intraepithelial lesions, or SILs) are recognized: low-grade and high-grade; in contrast, the Europeans distinguish 3 levels of precancerous development.[131] High-grade SILs of the cervix require treatment because of their potential to progress to invasive cancer. One of the “advantages” of such cervical lesions is that they are localized, allowing for excision or other ablative therapies to be highly effective. Once we have entered this level of response, we are no longer treating HPV infection per se, though effective treatment of SIL usually means that HPV is also cleared from the site.[132] Targeted antiviral therapies need to be developed in order to reduce the risk of recurrence after ablation.

Types of local destruction or excision used with high-grade SILs include:[133]

• cryotherapy

• cold coagulation

• electrodiathermy

• CO2 laser

• cone biopsy (laser or knife)

• loop diathermy, or loop electrosurgical excision procedure (LEEP)

The Cochrane review of these approaches noted that there is “no obviously superior surgical technique” for treating SIL. The LEEP did seem to offer the least morbidity and the most reliable specimens for evaluating success of the treatment.[134] A very recent study of the cold-knife section technique showed it was very effective, with low morbidity and little adverse consequences for childbearing.[135] This is in stark contrast to the most invasive treatment for high-grade SIL or full cancer, namely, hysterectomy.

Much like subclinical infection (discussed above under primary prevention), the treatment of low-grade SILs is a complex matter, and varies widely across jurisdictions.[136] The approaches fall into three categories: surveillance (but this misses the small number of women who are at risk for disease progression); routine ablation (this tends to overtreat, for most infections and associated lesions are self-limiting); and selective ablation (this depends on triage through something like the new HPV DNA test). In the near term, the best improvement in any management protocol would be the clinical adoption of proven immunotherapies, such as a vaccine.[137] As noted earlier, interferon has shown some effectiveness against low-grades SILs, though it still offers inferior results compared to surgery.[138]

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[77] An abnormal cell growth that may progress to cancer.

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[79] Harper DM, Franco EL, Wheeler C et al. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. The Lancet. 2004; 364(9447): 1757-65.

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[86] Quality-adjusted life-year, a standard measure of improved health which takes into consideration delayed mortality as well as reduced morbidity.

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[88] Summary available at http://investor.digene.com/phoenix.zhtml?c=82439&p=irol-newsArticle_Print&ID=695453&highlight=. Accessed June 2005.

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[98] Visual examination of the cervix and vagina using a lighted magnifying instrument.

[99] See the CDC website at http://www.cdc.gov/STD/treatment/6-2002TG.htm#SubclinicalGenitalHPV Infection. Accessed June 2005.

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[109] The removal or destruction of a body part or tissue or its function. Ablation may be performed by surgery, hormones, drugs, lasers, radiofrequency, heat, freezing, or other methods.

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[115] The examination of cellular structure.

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[118] Alternate terminology includes PAP Test, Papanicolaou smear, cervical smear, cervical/vaginal cytology.

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[125] A cancer that develops in the lining or inner surface of an organ. As opposed to, for instance, cancer in squamous epithelial cells.

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