Human papillomavirus (HPV) test compared to the Papanicolaou (Pap) test to screen for cervical cancer

Review question
We assessed studies comparing two tests to screen for cervical cancer: the HPV test (Human papillomavirus test) and the Pap test otherwise known as cervical smear or Papanicolaou test. The aim was to find out which test detects precancerous changes of the cervix more accurately.

Background
The HPV and the Pap tests are tests that a doctor performs to check for the development of cervical cancer or precancerous changes to the cells of the cervix (called lesions). These lesions can develop into cervical cancer within about 10 to 20 years. The HPV test checks whether a woman has an HPV infection which may lead to cervical cancer. If the HPV test is positive, it may mean that there are precancerous changes in the cervix. There are many types of HPV tests. One of them is called the HC2 test. The Pap test checks for whether cells in the cervix are abnormal. Abnormal cervical cells that are tested as ‘low grade to high grade’ may mean that there are precancerous changes in the cervix that may lead to cervical cancer. One type of Pap test is ‘conventional cytology' and another is 'liquid-based cytology'. Depending on the test, if it is positive a woman may need to have the cervix examined or could receive surgery to have the precancerous lesion removed.

Study characteristics
We searched for all relevant studies up to November 2015. Forty studies compared the HPV test to the Pap test on over 140,000 women between 20 to 70 years old who attended for their routine cervical screening. The studies examined which test can detect precancerous cervical changes which are called cervical intraepithelial neoplasias (CIN 2 and CIN 3).

Quality of the evidence
There were enough studies with enough women in them to allow us to draw conclusions. However, some of the results from the studies were different from each other. For example, tests were more accurate in studies in Europe than in Asia or Central or South America. Overall, the quality of the evidence was moderate to high.

Key results
A perfect test would correctly say if a woman has precancerous changes or if a woman does not. But most tests are not perfect.

This review found that for every 1000 women screened, around 20 women will have precancerous changes. The HPV test will correctly identify 16 of these women (but will miss 4 women). The Pap test will identify 12 of the women (but will miss 8 women). The women who are missed could develop cervical cancer.

For every 1000 women screened, there will be 980 women who will not have precancerous changes. The HPV test will correctly identify 879 women (but 101 women will be incorrectly told that they have a lesion). The Pap test will correctly identify 951 women (but 29 will be incorrectly told that they have a lesion). Women who are incorrectly told that they have a lesion may have their cervix examined or may receive surgery unnecessarily.

Authors' conclusions: 

Whilst HPV tests are less likely to miss cases of CIN 2+ and CIN 3+, these tests do lead to more unnecessary referrals. However, a negative HPV test is more reassuring than a negative cytological test, as the cytological test has a greater chance of being falsely negative, which could lead to delays in receiving the appropriate treatment. Evidence from prospective longitudinal studies is needed to establish the relative clinical implications of these tests.

Read the full abstract...
Background: 

Cervical cancer screening has traditionally been based on cervical cytology. Given the aetiological relationship between human papillomavirus (HPV) infection and cervical carcinogenesis, HPV testing has been proposed as an alternative screening test.

Objectives: 

To determine the diagnostic accuracy of HPV testing for detecting histologically confirmed cervical intraepithelial neoplasias (CIN) of grade 2 or worse (CIN 2+), including adenocarcinoma in situ, in women participating in primary cervical cancer screening; and how it compares to the accuracy of cytological testing (liquid-based and conventional) at various thresholds.

Search strategy: 

We performed a systematic literature search of articles in MEDLINE and Embase (1992 to November 2015) containing quantitative data and handsearched the reference lists of retrieved articles.

Selection criteria: 

We included comparative test accuracy studies if all women received both HPV testing and cervical cytology followed by verification of the disease status with the reference standard, if positive for at least one screening test. The studies had to include women participating in a cervical cancer screening programme who were not being followed up for previous cytological abnormalities.

Data collection and analysis: 

We completed a 2 x 2 table with the number of true positives (TP), false positives (FP), true negatives (TN), and false negatives for each screening test (HPV test and cytology) used in each study. We calculated the absolute and relative sensitivities and the specificities of the tests for the detection of CIN 2+ and CIN 3+ at various thresholds and computed sensitivity (TP/(TP + TN) and specificity (TN/ (TN + FP) for each test separately. Relative sensitivity and specificity of one test compared to another test were defined as sensitivity of test-1 over sensitivity of test-2 and specificity of test-1 over specificity of test-2, respectively. To assess bias in the studies, we used the Quality Assessment of Diagnostic test Accuracy Studies (QUADAS) tool. We used a bivariate random-effects model for computing pooled accuracy estimates. This model takes into account the within- and between-study variability and the intrinsic correlation between sensitivity and specificity.

Main results: 

We included a total of 40 studies in the review, with more than 140,000 women aged between 20 and 70 years old. Many studies were at low risk of bias. There were a sufficient number of included studies with adequate methodology to perform the following test comparisons: hybrid capture 2 (HC2) (1 pg/mL threshold) versus conventional cytology (CC) (atypical squamous cells of undetermined significance (ASCUS)+ and low-grade squamous intraepithelial lesions (LSIL)+ thresholds) or liquid-based cytology (LBC) (ASCUS+ and LSIL+ thresholds), other high-risk HPV tests versus conventional cytology (ASCUS+ and LSIL+ thresholds) or LBC (ASCUS+ and LSIL+ thresholds). For CIN 2+, pooled sensitivity estimates for HC2, CC and LBC (ASCUS+) were 89.9%, 62.5% and 72.9%, respectively, and pooled specificity estimates were 89.9%, 96.6%, and 90.3%, respectively. The results did not differ by age of women (less than or greater than 30 years old), or in studies with verification bias. Accuracy of HC2 was, however, greater in European countries compared to other countries. The results for the sensitivity of the tests were heterogeneous ranging from 52% to 94% for LBC, and 61% to 100% for HC2. Overall, the quality of the evidence for the sensitivity of the tests was moderate, and high for the specificity.

The relative sensitivity of HC2 versus CC for CIN 2+ was 1.52 (95% CI: 1.24 to 1.86) and the relative specificity 0.94 (95% CI: 0.92 to 0.96), and versus LBC for CIN 2+ was 1.18 (95% CI: 1.10 to 1.26) and the relative specificity 0.96 (95% CI: 0.95 to 0.97). The relative sensitivity of HC2 versus CC for CIN 3+ was 1.46 (95% CI: 1.12 to 1.91) and the relative specificity 0.95 (95% CI: 0.93 to 0.97). The relative sensitivity of HC2 versus LBC for CIN 3+ was 1.17 (95% CI: 1.07 to 1.28) and the relative specificity 0.96 (95% CI: 0.95 to 0.97).

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