Dr. Renshaw's thoughtful review article1 reminds us of the major ambiguities that remain in assessing the vital issues of overall Papanicolaou (Pap) screening sensitivity, assessing comparative accuracy among individual laboratories, and assessing adherence to “the standard of practice.” Despite the success of the Pap test in decreasing the rate of cervical carcinoma in the U.S. by > 70%, public expectations of 100% effectiveness have never been achieved in any screened population reported to date.2, 3 In essence, potential public “disappointment” with cervical carcinoma screening reflects the gap between the capability of the Pap test to prevent cervical carcinoma and cervical carcinoma deaths and the expectations of the public. The unrealistically high expectations of the public are especially reflected in the legal system, in which lay juries actually serve as the ultimate arbiters of “the standard of practice.” For example, a trial lawyer's newsletter from 1997 recently opined that a claim for medical malpractice against some health care provider almost certainly exists in any case in which a woman develops cervical carcinoma and undergoes a hysterectomy or dies, unless the woman utterly failed to obtain even periodic Pap smears.4 The expectation expressed here is that the Pap test is the equivalent of a cervical carcinoma insurance policy that will pay a substantial dollar benefit if a woman who received any Pap testing, even a woman who underwent screening only periodically, develops cervical carcinoma or dies of cervical carcinoma.

Available evidence clearly indicates that the Pap test has significant limits for effectiveness. For example, to my knowledge all studies published to date have demonstrated that as the frequency of Pap screening decreases from annual testing to less frequent testing, the incidence rates of cervical carcinoma diagnosis and death increase.5–7 Nevertheless, even doubling or tripling the relative risk of developing cervical carcinoma in less frequently screened women still may be discounted as only “small” increases in “absolute risk” and may be believed to be consistent with an “acceptable“ (to whom?) and “low underlying probability of disease.” Epidemiologic model evaluations, which nearly always are taken from a group rather than an individual patient perspective, have argued that “efficient” and “cost-effective” screening programs for cervical carcinoma can add up to only 32.4 days of average life expectancy, compared with a gain in life expectancy of 46 days with the total elimination of cervical carcinoma.8 This type of model evaluation suggests that the last 30% gain in life expectancy is not “efficient.” Individual patients often have a different view, one that is debated within the tort system when outcomes that perhaps are considered acceptable by epidemiologists are judged as unacceptable by the individual patient.9

The effectiveness of the cervical carcinoma screening system varies significantly depending on the sensitivity of screening and the ability to minimize false-negative results in women with undetected, clinically significant precancerous or treatable and curable early malignant lesions.5 As noted by Renshaw,1 relatively few studies historically have assessed the sensitivity of Pap testing reliably by including diagnostic biopsy assessment of a significant proportion of women with negative Pap results to measure the true total prevalence of significant precancerous or early malignant disease.10–15 However, this biopsy gold standard has special significance because it reflects the level of reliable “proof” required clinically in general practice on which to base definitive treatment of clinically significant, potentially progressive, life-threatening disease.16 From this unique biopsy-based perspective, available studies cited by Renshaw suggested that the conventional Pap smear has a sensitivity of only approximately 70% for the detection of clinically significant, high-grade squamous intraepithelial lesions or carcinoma. This detection rate increases to 93–94% in what to my knowledge are the only 2 available similar studies in which liquid-based Pap testing was assessed for screening sensitivity against a biopsy-based reference standard.14, 15 The addition of human papillomavirus (HPV) DNA cotesting with hybrid capture methodology to liquid-based Pap screening increased the sensitivity of cervical carcinoma screening still further in these overseas studies to nearly 100% of high-grade lesions and early malignancies.15, 17 Indeed, in what to my knowledge is the one available biopsy endpoint-based study using Food and Drug administration (FDA)-approved Hybrid Capture II HPV DNA testing (Digene Corp., Gaithesburg, MD) from liquid-based vial fluid,15 virtually 100% of 86 clinically significant high-grade lesions and tumors were detected by cotesting with liquid-based cytology. As noted by Belinson et al.,15 the presumption that type 2 cervical intraepithelial neoplasia-positive (CINII+) lesions would not develop in the 1332 women who were found to test negative using a liquid-based Pap test and direct HPV test was found to be valid. However, the theory that CINII+ lesions would not occur among the 1478 women in whom colposcopic evaluation was negative was not proven valid because 16 of these women were found to have CINII lesions or worse. Because this 100% level of effectiveness reflects actual public expectations, it will be important to determine whether third-party payers and clinical groups support payment for this form of screening, which recently was proposed as the “DNA Pap test” to a supplemental, premarket approval FDA panel. It has been recently noted that although a few cost-effectiveness analyses have been widely regarded as having shaped policy regarding the frequency of cervical carcinoma screening or the age at which it is no longer necessary, any decision must take into account the standard of care, patients' expectations of care (emphasis added), providers' training, and the jurisdiction (country or region).18 Clearly, what patients and the legal system may expect and what payers are willing to pay for may be significantly different.

Nowhere is the dichotomy between expectations and what can be proven to be achievable more relevant than in the area of endocervical glandular neoplasms of the cervix, which currently are reported to represent approximately 25–33%% of cervical malignancies.19, 20 However, among litigated cases of cervical carcinoma, endocervical glandular lesions may represent the majority of cases (up to 80% of litigated cervical carcinoma cases in one published estimate21). Few are aware that available studies of screened populations do not indicate that conventional Pap smear cervical screening is effective at lowering the rate of incidence or death due to endocervical adenocarcinoma in screened versus unscreened populations.22–24 For glandular cervical carcinoma, data regarding improved cervical carcinoma screening efficacy with liquid-based Pap testing25 and the usefulness of adjunctive HPV testing26, 27 should be of considerable significance in addressing patients' previously unachievable expectations.

Furthermore, even in patients with indeterminate atypical squamous cells of undetermined significance (ASCUS), recent studies have suggested that reflex HPV testing from residual vial fluid may be both more sensitive and more cost-effective in detecting clinically significant, undetected, high-grade CINII-III lesions and tumors compared with repeat cytology.28, 29 With The ASCUS/LSIL (low-grade squamous intraepithelial lesion) Triage Study (ALTS) and other data15 indicating that HPV DNA testing is, at a minimum, as equally sensitive in detecting these clinically significant target lesions as immediate 100% colposcopy, recommendations for HPV testing on ASCUS cases logically may be argued to be as effective for facilitating the diagnostic detection of potentially clinically significant progressive disease as recommending colposcopy itself after any level of interpretive Pap test abnormality. Recommendations for Pap reports regarding specific follow-up strategies recently have been shown to increase the likelihood of clinically appropriate follow-up on a statistically significant basis.30 These recent developments make recommendations for HPV DNA testing, either as a primary co-test along with the Pap test or as a recommended adjunctive follow-up test, formidable new options in ongoing efforts to achieve very high levels of cervical screening sensitivity and disease detection. Nearly 100% cervical screening sensitivity, long unrealistically expected by the public, actually may be achievable with existing new technology methods. Therefore, although adherence to a quantifiable standard of practice may be unrealistic to measure, as argued by Renshaw,1 the public is likely to remain difficult to convince that those cases of cervical carcinoma diagnosed in screened patients do not represent examples in which current screening practices have fallen short of the promise of newer cervical screening methods.


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