Molecular biomarkers are finding wider application in the medical sciences, particularly oncology. A number of clinically validated biomarkers are currently used in practice for diagnosis, prognosis, patient identification, and to predict or assess treatment response.
Such gains have only recently made their way to cervical cancer screening, which is largely rooted in practices and protocols that have begun to change to encompass more current technologies.
As a result, definitive, actionable information is not always available for clinicians during screening for precancerous cervical disease. This is particularly the case with inconclusive Pap cytology or co-testing results (normal Pap cytology/positive HPV DNA), which are not easily resolved using established screening modalities.1
What are equivocal cytology results?
Understanding equivocal cytology
Introduced in the 1940s, Pap cytology came into widespread use in the 1960s and 1970s, and remains the mainstay of cervical cancer prevention today. However, the morphologic evaluation of cervical cytology is a subjective science, even with newer liquid-based collection technologies. Differences in interpretation and interobserver reproducibility are common. Even when correctly identified, some results do not conclusively indicate the presence of or potential for pre-cancerous disease.4-6
High-risk HPV (hrHPV) testing is used adjunctively to triage ASC-US (atypical squamous cells of undetermined significance) Pap cytology results. By itself, a hrHPV test result cannot be meaningfully correlated to pre-cancerous disease. hrHPV testing provides useful information for clinicians; however, in combination with certain cytology results, this testing only marginally improves clinical decision making.7,8
Uncertainty remains in three key cytologic scenarios: atypical squamous cell of undetermined significance (ASC-US), low-grade squamous intraepithelial lesions (LSIL), and in co-testing patients with normal (negative) cytology who are positive for hrHPV. Other cytologic findings that need to be resolved include atypical squamous cells, which cannot exclude high-grade squamous intraepithelial lesion (ASC-H) and atypical glandular cells (AGC).
What is clinical accuracy in cervical cancer screening?
Understanding clinical accuracy
The overall clinical accuracy of a test or procedure takes into account its sensitivity and specificity. In the clinical setting, these terms refer to the following3:
- Sensitivity refers to the percentage of people who have a given condition who are identified by the test as positive for the condition. Sensitivity measures the proportion of actual disease a test can correctly identify; a highly sensitive test is key to obtaining a strong negative predictive value (NPV)9
- A test with low sensitivity can result in substantial rates of false-negative results
- Pap cytology is highly specific, but not very sensitive
- Specificity refers to the percentage of people who do not have a given condition who are identified by the test as negative for the condition. Specificity measures the proportion of negatives a test can correctly identify; a highly specific test is key to obtaining a strong positive predictive value (PPV) 9
- A test with low specificity can result in substantial rates of false-positive results9
- High-risk HPV (hrHPV) testing is highly sensitive, but not very specific
The optimal cervical cancer screening triage strategy9
- Uses a test with high sensitivity and NPV to rule out those women who can safely return to routine screening
- Uses tests with high specificity and PPV to help determine those women who would benefit from immediate colposcopy or diagnostic follow up
Biomarker-based testing can fill some of the gaps left by cytology and other screening technologies. An approach is currently available that incorporates qualitatively testing for the co-expression of two important proteins: p16INK4a (also referred to as p16) and Ki-67. These proteins are expressed and have clinical value in both cytologic and histologic samples, and are backed by a growing body of clinical evidence.2,3