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Newfoundland Public Health Laboratory, Department of Health, Division of Community Medicine, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland, A1B 3T2 Canada [S. R.]; Departments of Oncology and Epidemiology, McGill University, Montreal, Quebec H2W 1S6 Canada [E. L. F.]; Departments of Pathology and Obstetrics and Gynecology, McGill University and the Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, H3T 1E2 Canada [A. F.]
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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There are many reasons for the pitfalls of cervical cancer screening systems, including cervical sampling errors and laboratory errors in screening and interpretation. Pap cytology is based on highly subjective interpretation of morphological alterations and is also dependent on optimally collected samples. Also, the highly repetitive nature of the work of screening many Pap smears leads to fatigue, which invariably causes errors in interpretation. In addition, false-positive cytology results lead to unnecessary and frequently invasive procedures in a fairly large number of women, which in turn result in increased patient anxiety and costs.
The high cost of screening and the resulting unnecessary follow-up procedures have led international health agencies such as the WHO and the Union Internationale Contre le Cancer to recommend increasing screening intervals from annual to every 3 years. However, extending screening intervals prompts the serious concern of interval cancers related to false-negative Pap smears that will not be revealed upon repeated screening. Such cases pose important medical, financial, and legal implications; the latter being a particularly acute problem in the United States, where false-negative Pap tests are among the most frequent reasons for medical malpractice litigation.
This state of affairs elicited interest from the medical technology industry for developing new tests with adequate sensitivity and specificity for detecting clinically significant cancer precursors. One such method is HPV3 testing via viral DNA detection, based on the rationale that there is now consensus to regard cervical cancer and its precursors a disease caused by sexually transmitted, high-risk HPV genotypes (6) . The objective of this study was thus to determine and compare the effectiveness of HPV DNA testing and cervical cytology for the detection of cervical disease in a primary screening capacity.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Pap Cytology.
Conventional Pap smears were processed and read in one of four
regional, accredited cytology laboratories. For colposcopy referral
purposes, a positive Pap smear was considered to be any abnormality
ranging from ASCUS to SILs and invasive cancer. Pap smears were
evaluated in accordance with the Bethesda classification system.
HPV Testing.
The HPV DNA assays were carried out independently of the Pap smear
screens at the Newfoundland Public Health Laboratory using the Hybrid
Capture assay (Digene, Inc., Beltsville, MD). Specimens were collected
and processed in accordance with the manufacturer’s instructions. The
first generation Hybrid Capture (HC-I) tube assay was used to test all
subjects admitted until September 30, 1997. For those admitted on or
after October 1, 1997, the second generation Hybrid Capture (HC-II)
microtiter assay was used, also strictly according to the
manufacturer’s instructions. Only the high-risk HPV DNA probe mixture
was used in the study. For HC-I, this probe included the high oncogenic
risk HPV types 16, 18, 31, 33, 35, 45, 51, 52, and 56. The HC-II
high-risk HPV mixture contained four additional HPVs, 39, 58, 59, and
68. A positive HPV test was defined as that with relative light
units:positive controls ratios of 1.0 or greater, implying that the
cervical specimen contained one or more of the above oncogenic HPVs.
Statistical Analysis.
The study’s objective was to compare the diagnostic performance of
cytology and HPV testing and to assess whether the combination of the
two tests provided a gain in screening efficacy with respect to that of
Pap cytology alone. Sensitivity, specificity, PPVs, and NPVs and their
95% CIs were calculated using standard formulae. Calculations were
performed for three different definitions (cutpoints) of positive
cytology: ASCUS or worse, LSIL or worse, and HSIL. In addition,
computations of indexes included two different definitions of cervical
disease: CIN-I or worse and CIN-II/III or worse. The latter definitions
were based on two different gold standards for ascertaining disease: a
stringent one based on the histological examination alone, and a
liberal one, in which the colposcopical diagnosis was considered if no
histology was available.
For the combination testing, we considered a positive result when either cytology or HPV testing resulted positive. Such combination testing always yields a gain in sensitivity but a loss in specificity (relative to cytology) that is attributable to chance alone. Therefore, to measure the true improvement in screening efficacy, we compared the indexes of the combination testing against expected values obtained after correcting the sensitivity and specificity of cytology for the contribution of a hypothetical, random adjunct test that had the same positivity as HPV testing in the same population (7) .
Method for Correcting for Verification Bias.
Having the disease outcome determined in a random sample of women who
tested negative simultaneously for Pap and HPV allowed us to derive
more valid estimates of sensitivity and specificity for the two
screening tests. However, to prevent the effect of verification bias,
an adjustment procedure was necessary. This bias is caused by the fact
that only a fraction of the women testing negative by both tests
(
10%) and a much larger proportion of those with at least one test
positive (100% as specified in the protocol) were referred for
colposcopical verification, which decreases the relative proportions of
negative subjects within the disease case and non-case series. Given
the prevalence of cervical lesions and the rate of positive Pap and HPV
results in our population, the bias causes a falsely elevated
sensitivity and a falsely decreased specificity.
As an illustration of the impact of the verification bias, we may consider a hypothetical situation in which a single test with 80% sensitivity and 67% specificity were applied to a population of 1000 subjects with 10% disease prevalence. With complete verification of the disease status, the frequencies of true positives, true negatives, false positives, and false negatives would be: 80, 600, 300, and 20, respectively. If verification is randomly restricted to 80% of those testing positive and 10% of those testing negative, the screening table frequencies become, respectively, as above: 64, 60, 240, and 2. Using this sample to compute the above indexes yields 97% for sensitivity and 20% for specificity, values that do not represent the true performance of this hypothetical test. It is noteworthy that the PPV (21%) and NPV (97%) are not affected by the verification bias; the same estimates are obtained with either the complete or the restricted table frequencies.
We adjusted for verification bias in a dual test situation by
correcting the frequencies of test results by adding to them the
proportion of unverified subjects with the same test result who had the
same lesion grade. This was done as follows. Denote the frequency of
subjects in each combination of test results and lesion category by
FCHL, where the subscripts C, H, and L
indicate the results for cytology and HPV, and the lesion status,
respectively. Subscript values for cytology denote negative (0), ASCUS
(1)
, LSIL (2)
, or HSIL+ (3)
results. For HPV, there are two possible
results: negative (0) and positive (1)
, and for lesion status: negative
(0), CIN-I (1)
, or CIN-II/III (2)
. Let
UCH be the frequency of unverified
subjects in each combination of C and H. To compensate for the
verification bias the adjusted frequency for each combination was
calculated as follows:
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To use this formula, one has to assume that for each subset of women with a given combination of cytology and HPV results, the distribution of lesion grades among those not referred for colposcopy (and thus with unverified lesion status) is the same as for those with lesion grade ascertained by colposcopy. This is a plausible assumption because the Pap and HPV test results were the only criteria determining referral for colposcopy, and thus women without colposcopic results are likely to have the same prevalence of lesion categories as those in the same stratum represented by the combination of Pap and HPV result. The same assumption is not tenable for histological verification because the decision to biopsy is conditional also on the clinician’s impression during the colposcopic examination.
Any estimates of sensitivity and specificity that were based on the actual frequency tables cross-classifying test result and presence of disease without the above correction were considered to be relative estimates for the purposes of test comparisons.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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shows the frequency distribution of screening cytology results and HPV
positivity by selected characteristics. In general, HPV and lesion
rates decreased with age but there was considerable heterogeneity among
the 10 clinics concerning the prevalence of HPV and lesions. Likewise,
laboratories varied somewhat in terms of lesion and HPV prevalence,
with the St. John’s laboratory having the highest HPV and lesion
prevalence of all four testing sites. Just over 69% of the
population was tested by HC-I and 31% with HC-II.
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Table 2
shows the distribution of cytology and HPV results according to the
final lesion diagnosis either by histology alone or histology
complemented with the colposcopical result. Both subsets displayed the
same trends of increasing likelihood of a higher lesion grade given a
worse cytological diagnosis or HPV positivity. There was one woman
found to have an invasive squamous cell carcinoma, and she was positive
both by cytology (scored as HSIL) and by HPV.
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shows the relative diagnostic indexes based on the histological
diagnoses alone. HPV testing had a significantly greater relative
sensitivity than cytology in any of the three severity cutpoints
(ASCUS, LSIL, or HSIL) for detecting CIN of any grade as well as
CIN-II/III or worse lesions. Expectedly, the relatively greater
sensitivity of HPV testing was accompanied by appreciably lower
relative specificity than most severity cutpoints for cytology.
Overall, the rate of combined correct diagnoses (true-positive plus
true-negative frequencies) for any grade lesions was higher for HPV
testing (68.8%; 95% CI, 60.3–76.1) than for any cytological cutpoint
(ASCUS, 52.3%; LSIL, 51.6%; HSIL, 44.5%, with non-overlapping 95%
CIs with respect to the HPV test). However, the accuracy rate for HPV
testing was relatively lower for CIN-II/III or worse lesions (60.2%;
95% CI, 51.5–68.2) than for most cytological cutpoints: ASCUS,
51.6%; LSIL, 68.0%; and HSIL, 78.1%. The PPV and NPV for HPV testing
were greater than those for all cutpoints of cytology for detecting any
grade of cervical disease. For CIN-II/III or worse lesions, however,
the PPV of HPV testing was comparable with that of cytology with an
LSIL cutpoint.
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shows the effect of combining HPV testing to cytology as a screening
tool using histology as the only gold standard. In addition to the
relative index estimates and associated 95% CIs, the expected value
for each parameter is also shown, assuming the addition to the
respective cytological cutpoint of a random adjunct test that mimicked
the contribution by HPV testing by producing the same rate of
positivity in this sample as HPV testing did, i.e., 58.6%.
Adding HPV testing to cytology increased the relative sensitivity of
all its severity cutpoints significantly for any grade lesions
or CIN-II/III because all of the expected values were lower than the
95% CIs for the estimates. The test combination of cytology at an LSIL
cutpoint and HPV positivity detected most cases (83%) of CIN and all
CIN-II/III cases. In general, addition of HPV testing to cytology also
avoided the loss in relative specificity that was expected when adding
a second (random) adjunct test, although the differences were
significant only for LSIL and HSIL as cutpoints for diagnosing any
grade lesions. NPVs were >95% for HSIL in all combinations at the
expense of a <50% PPV.
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shows the diagnostic indexes for cytology, HPV, and their combination
using the diagnostic definition based on histology supplemented by the
colposcopical result. Two sets of results are shown: with and without
correction for colposcopy verification bias. The uncorrected (relative)
estimates for individual tests did not differ substantially from those
calculated using histology alone (Table 3)
, the relative sensitivity of
HPV testing for detecting both any-grade lesions or CIN-II/III was
greater than that of any cytology cutpoint, and its relative
specificity was comparable with the ASCUS criterion of positivity.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In addition, as is the case with most investigations comparing screening modalities, the gold standard for disease could not be obtained for all subjects under investigation because of the impossibility of referring for colposcopy and eventually biopsy all cases presumed free of disease by the screening tests. Although our protocol established that participating physicians should have favored colposcopic-guided histological confirmation whenever either of the screening tests was positive, colposcopies were performed in only 80% of the referred cases and, among these, biopsies were taken in 40%. Although colposcopy is not considered to be a diagnostic gold standard, it performs well in predicting invasive cancer and its high-grade precursors (8) . Our colposcopists were clearly influenced by the screening results in deciding whether to biopsy, with almost three times as many women being biopsied when either screening result was positive than when none was. However, the particular combination of cytology and HPV test results did not seem to influence the biopsy rate: 40% for Pap+/HPV-, 42% for Pap-/HPV+, and 39% for Pap+/HPV+. Our estimates of screening performance would have been severely biased if colposcopy and biopsy rates had been differential with respect to the screening test with a positive result. This did not happen because physicians were equally likely to refer for colposcopy (and colposcopists were equally likely to perform a biopsy) Pap+/HPV- subjects as they were Pap-/HPV+ ones.
Our choice of a random, "control" group of women referred for colposcopy with both tests being negative enabled us to compute absolute estimates of sensitivity and specificity for Pap and HPV. However, because of the different rates of colposcopy referral given the joint test results, our estimates of screening performance had to be corrected for verification bias. Referral rates were 91% if both tests were positive, 75–77% if either the HPV or the Pap test was positive, and 8% if both tests resulted negative. Such verification bias could be eliminated by adjusting the diagnostic indexes on the basis of the expected lesion distribution among those with missing colposcopical diagnoses. Because physicians were also influenced by the knowledge of the cytological lesion grade, we adjusted the frequencies for each combination of cytological cutpoint and HPV test status to ensure improved control of the verification bias.
As expected, the corrected sensitivity estimates were invariably lower than the uncorrected ones for all combinations, whereas the corrected specificity estimates were higher than the respective unadjusted values. Although inferences about differences in test performance could be made with the relative, uncorrected values, the appropriate assessment of the anticipated screening efficacy of the two tests and their combination can only be made using the bias-free estimates. An important caveat is the fact that the correction procedure is not valid for the histological diagnoses because the colposcopist’s decision to biopsy is based not only on the screening test results but also on the visual impression of the cervix during the colposcopy. However, given that the results with histology-only and histology-colposcopy diagnoses were comparable in most test and lesion combinations, it is plausible to assume that our corrected estimates using the augmented (by colposcopy) diagnoses may have reflected the true screening performance of Pap and HPV tests had histological diagnoses been available for our entire sample. The fact that our study sample was approximately representative of all cervical cancer screening activity in the province supports the generalizability of our findings to the female population of Newfoundland, which experiences higher rates of invasive cervical cancer than the average for Canada (9) .
As an individual screening test to detect cervical cancer precursors, HPV testing performed relatively well compared with cytology. The sensitivity of HPV testing was greater than that of cytology in any of the severity cutpoints, regardless of the lesion grade being detected and of the disease ascertainment approach. The higher sensitivity of HPV testing was penalized by a higher false-positive rate than cytology, particularly when the latter had positivity defined at the LSIL cutpoint or higher. This was especially true for the detection of CIN-II/III or worse lesions. Overall, HPV testing was more accurate than any cytology cutpoint at detecting or ruling out any grade lesions but it performed worse than cytology for diagnosing CIN-II/III, regardless of the gold standard for lesions.
The addition of HPV testing to cytology produced substantial gains in sensitivity without imposing a large penalty on specificity in all combinations of lesion grade and diagnostic approach. Using histologically confirmed lesions, the LSIL/HPV+ combination detected all cases of CIN-II/III while missing only 17% of all-grade CIN. Although this was obtained at the expense of false-positive rates of 49% for all-grade CIN and 59% for CIN-II/III, the loss in specificity was significantly lower than that expected by chance if cytology had been augmented by a non-informative test. In population-based terms (bias-corrected estimates), a dual negative result using the combination of LSIL/HPV+ would imply virtual certainty in correctly ruling out an CIN-II/III (99%) and 74% for ruling out all-grade lesions.
Another approach for assessing the potential impact of combination testing in primary screening is by gauging sensitivity against the proportion of women who would have been referred for colposcopy because of a positive result. The latter is the best indicator of the overall burden that the screening program would place in the public health system. An economically liberal practice that has gained acceptance in North America is to refer for colposcopy all ASCUS or worse abnormalities, which in our population accounted for 9.2% of all women. This management approach would have resulted in an appallingly low sensitivity of 40% (56% before correction) for CIN-II/III. A combination testing policy of referring any LSIL or worse abnormalities or HPV-positive cases would have required 12.3% of colposcopical examinations (an extra 3% of referrals), but the sensitivity for detecting CIN-II/III would have increased to 76% (97% if uncorrected).
The above findings suggest thus that one is less likely to miss
clinically significant lesions when both cytology and HPV results are
simultaneously negative in women attending a screening program. If our
findings are corroborated by additional studies in other populations,
double testing may indeed allow screening intervals to be substantially
longer than currently recommended, while keeping an acceptable margin
of safety against the development of cervical cancer. It has been
speculated that patients who have been negative for both high-risk HPV
types and cytology have a greatly decreased risk for developing HSIL as
compared with those who had negative smears alone
(10, 11, 12)
. The expense of a double screening approach can
be absorbed by the reduction in cost associated with increased
screening intervals (11
, 13
, 14)
. Such a reduction in cost
would also offset the extra expense of referring for colposcopy women
with latent HPV infection (HPV-positive test in cytologically negative
women). Indeed, Cuzick and Sasieni (11)
have calculated
that if the screening interval for women over the age of 30 years could
be extended from every 3 years to 5 years, 30 million pounds/year
could be saved in the United Kingdom screening program, which is
currently estimated to cost 130 million pounds/year.
HPV testing in a screening capacity should only be used in women after
the age of 30 years (11
, 15)
. Indeed, at this age, the
prevalence of latent HPV infections including those with high-risk
oncogenic types is low (15
, 16)
. Primary screening via HPV
testing in young women would lead to detection of a high number of
cases either without lesions or with low-grade lesions with high
spontaneous regression rates (15)
. On the other hand,
those of ages between 30 and 50 years tend to have persistent,
high-risk HPV type infections with progression potential to high-grade
lesions (11
, 15
, 17, 18, 19)
whose incidence peaks between
ages 30 and 35 years. As an illustration, in the present study the
bias-corrected sensitivity of HPV testing to detect CIN-II/III was 62%
among women <30 years and 82% among women 
30 years. Similarly, the
bias-corrected specificity was 87 and 94% for the same age strata,
respectively.
In conclusion, the results of the present study indicate that HPV testing can have an important role in primary screening for cervical cancer either as an adjunct tool to augment existing Pap cytology programs or as a standalone test. The hybrid capture technology for detecting HPV DNA has been proven to be reproducible, is simple to perform at relatively low cost, and does not require the extensive training that conventional cytological screeners must be subjected to. In addition, it is expected that HPV testing will eventually be automated and performed by relatively unskilled personnel. Data on the role of HPV testing using self-obtained cervicovaginal samples in screening for cervical carcinoma and its precursors have recently become available, a feature which may improve compliance over current screening program (20 , 21) . These conditions make it a serious contender for use in a screening program in the third world (21 , 22) , wherein lies the heaviest burden of cervical cancer incidence and mortality.
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Acknowledgments |
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Footnotes |
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1 This study was partially supported by grants
from the Newfoundland Cancer Treatment and Research Foundation and from
the Memorial University of Newfoundland. This study was approved by the
Human Investigation Committee, Faculty of Medicine, Memorial University
of Newfoundland, and by the institutional review boards of
collaborating centers. E. L. F. is the recipient of a Distinguished
Scientist Award from the Medical Research Council of Canada. 
2 To whom requests for reprints should be
addressed, at Department of Oncology, McGill University, 546 Pine
Avenue West, Montreal, Quebec, H2W 1S6 Canada. Phone: (514) 398-6032;
Fax: (514) 398-5002; E-mail: eduardof{at}oncology.lan.mcgill.ca
3 The abbreviations used are: HPV, human
papillomavirus; ASCUS, atypical squamous cells of undetermined
significance; HSIL/LSIL, high/low-grade squamous intraepithelial
lesion(s); CIN-I and CIN-II/III, cervical intraepithelial neoplasia
grades I and II/III, respectively; HC-I/II, first/second generation
Hybrid Capture; PPV, positive predictive value; NPV, negative
predictive value; CI, confidence interval.
Received 2/29/00; revised 7/ 7/00; accepted 7/26/00.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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