HPV test is a virology test, not for predicting cancer
Sin Hang Lee, Milford Hospital
19 August 2009
Since Dr. Castle wrote this Commentary from an office in the authoritative National Cancer Institute of the United States (NCI) and the Commentary was published in a peer-reviewed international scientific journal, his opinions will unfortunately influence many health care policy makers whose decisions will in turn affect the welfare of many women worldwide. The undersigned felt obligated to comment on this Commentary.
Under an academic title, the Commentary promotes a generation of less specific HPV tests which may refer more women to unnecessary colposcopic biopsies than the Digene hc2 HPV test due to cross-reactivity with non-target HPV types. The Commentary endorsed these HPV tests “despite the cross-reactivity to these weakly carcinogenic or non-carcinogenic HPV genotypes”. By its “definition”, cross-reactivity is a good thing because “it may indirectly increase the reassurance following a negative HPV test i.e. the negative predictive value of an HPV test for cervical precancer and cancer”, and the only bad thing is when “the tradeoff of more false positives for greater reassurance may not be acceptable if the local infrastructure cannot manage the screen positives”. The Commentary addressed the issues of clinical sensitivity, specificity and negative predictive value (NPV) of the commercial HPV test kits available now and under development in the pipeline of the manufacturing companies. It justified introduction of “a generation of HPV tests (even some that are not now in clinical trials but too far along in the formulation phase to alter)” that “will be slightly less specific than what might otherwise be achieved.” However, the Commentary did not mention even once the positive predictive value (PPV) of these virology DNA tests, using precancer or cancer histopathology as the endpoint for evaluation in a real-life population, e.g. among women who receive their regular gynecological care rendered by board-certified gynecologists in private practice in the US. The sad truth is that the NCI does not have any HPV testing ppv data on the non-Hispanic white majority living in the US where the cervical cancer prevalence rates range from <1 to 7 per 100,000 women from one local population to another. The data presented in Figure 1 of the Commentary were based on data collected from various parts of the world, including most regions where the cervical cancer prevalence rates are known to be exceedingly high. It is a common knowledge that a laboratory test developed in population with high disease prevalence will lose its acceptable ppv when applied to populations with a low disease prevalence rate.
The undersigned has been practicing diagnostic cancer pathology and clinical microbiology at the hospital laboratory bench for more than 50 years. Since each test result generated at the bench may have serious impacts on the well-being of a patient, the expected ppv of all cancer tests, e.g. an intra-operative frozen section diagnosis, is 100%. The expected ppv for identification of a microbe in clinical specimens as the causative agent of an infection is also 100%. The Commentary endorsed converting a virology test to a cancer test with a >95% false positive rate [1] and a <5% ppv, which is unprecedented in laboratory medicine. It overemphasized the benefit of the high clinical sensitivity of the commercial HPV screen test kits in detecting more precancer or cancer at the expense of specificity, without mentioning the ppv of these tests. Based on this argument, any test, HPV or not, that refers all tested women blindly to colposcopic biopsy will have a 100% clinical sensitivity in detecting biopsy-proven precancer or cancer. However, this is not the traditional way to practice cancer pathology.
The Commentary endorsed a “once-in-a-lifetime low-cost and rapid HPV testing” for low-resource settings of the world while pointing out the fact that this “will need sufficient numbers of highly-trained colposcopists to handle the clinical volume of screen positives, which could approach 10-15% of the population in many location.” Since more than 95% of hc2 HPV test referrals for cervical biopsies are unnecessary [1], if this recommendation were implemented in a low-resource setting like Sichuan, China with a population of about 100 million, there would be 10 million or more women to undergo unnecessary cervical biopsies in that province alone. The downstream unnecessary expenses to cover the colposcopy, histotechnology, and the pathology professional services for 10 million 4-quadrant cervical biopsies resulting from this “low-cost and rapid HPV testing” would be enormous, let alone the cost in human suffering associated with the psychological and physical trauma of an invasive procedure. Previously, Dr. Castle stated on record that “the medical community should emphasize persistence of cervical HPV infection, not single-time detection of HPV, in management strategies and health messages [2].” Unfortunately, this Commentary was not formulated on the basis of the last statement.
Sin Hang Lee, M.D., F.R.C.P.(C)
References 1. Stout NK, Goldhaber-Fiebert JD, Ortendahl JD, Goldie SJ. Trade-offs in cervical cancer prevention: balancing benefits and risks. Arch Intern Med 2008, 168: 1881-1889. 2. Rodríguez AC, Schiffman M, Herrero R, Wacholder S, Hildesheim A, Castle PE, Solomon D, Burk R; Proyecto Epidemiológico Guanacaste Group. Rapid clearance of human papillomavirus and implications for clinical focus on persistent infections. J Natl Cancer Inst 2008, 100: 513-517.
Competing interests
Dr. Sin Hang Lee is a pathologist at Milford Hospital, Milford, CT and the director of Milford Medical Laboratory. Dr. Lee receives a fixed salary from the hospital which charges fees for cancer biopsies and HPV testing. Dr. Lee is also the president and a shareholder of HiFi DNA Tech, LLC (www.hifidna.com), a company specialized in transferring the Sanger DNA sequencing technology to community hospital laboratories to increase specificity of DNA tests.
HPV test is a virology test, not for predicting cancer
19 August 2009
Since Dr. Castle wrote this Commentary from an office in the authoritative National Cancer Institute of the United States (NCI) and the Commentary was published in a peer-reviewed international scientific journal, his opinions will unfortunately influence many health care policy makers whose decisions will in turn affect the welfare of many women worldwide. The undersigned felt obligated to comment on this Commentary.
Under an academic title, the Commentary promotes a generation of less specific HPV tests which may refer more women to unnecessary colposcopic biopsies than the Digene hc2 HPV test due to cross-reactivity with non-target HPV types. The Commentary endorsed these HPV tests “despite the cross-reactivity to these weakly carcinogenic or non-carcinogenic HPV genotypes”. By its “definition”, cross-reactivity is a good thing because “it may indirectly increase the reassurance following a negative HPV test i.e. the negative predictive value of an HPV test for cervical precancer and cancer”, and the only bad thing is when “the tradeoff of more false positives for greater reassurance may not be acceptable if the local infrastructure cannot manage the screen positives”. The Commentary addressed the issues of clinical sensitivity, specificity and negative predictive value (NPV) of the commercial HPV test kits available now and under development in the pipeline of the manufacturing companies. It justified introduction of “a generation of HPV tests (even some that are not now in clinical trials but too far along in the formulation phase to alter)” that “will be slightly less specific than what might otherwise be achieved.” However, the Commentary did not mention even once the positive predictive value (PPV) of these virology DNA tests, using precancer or cancer histopathology as the endpoint for evaluation in a real-life population, e.g. among women who receive their regular gynecological care rendered by board-certified gynecologists in private practice in the US. The sad truth is that the NCI does not have any HPV testing ppv data on the non-Hispanic white majority living in the US where the cervical cancer prevalence rates range from <1 to 7 per 100,000 women from one local population to another. The data presented in Figure 1 of the Commentary were based on data collected from various parts of the world, including most regions where the cervical cancer prevalence rates are known to be exceedingly high. It is a common knowledge that a laboratory test developed in population with high disease prevalence will lose its acceptable ppv when applied to populations with a low disease prevalence rate.
The undersigned has been practicing diagnostic cancer pathology and clinical microbiology at the hospital laboratory bench for more than 50 years. Since each test result generated at the bench may have serious impacts on the well-being of a patient, the expected ppv of all cancer tests, e.g. an intra-operative frozen section diagnosis, is 100%. The expected ppv for identification of a microbe in clinical specimens as the causative agent of an infection is also 100%. The Commentary endorsed converting a virology test to a cancer test with a >95% false positive rate [1] and a <5% ppv, which is unprecedented in laboratory medicine. It overemphasized the benefit of the high clinical sensitivity of the commercial HPV screen test kits in detecting more precancer or cancer at the expense of specificity, without mentioning the ppv of these tests. Based on this argument, any test, HPV or not, that refers all tested women blindly to colposcopic biopsy will have a 100% clinical sensitivity in detecting biopsy-proven precancer or cancer. However, this is not the traditional way to practice cancer pathology.
The Commentary endorsed a “once-in-a-lifetime low-cost and rapid HPV testing” for low-resource settings of the world while pointing out the fact that this “will need sufficient numbers of highly-trained colposcopists to handle the clinical volume of screen positives, which could approach 10-15% of the population in many location.” Since more than 95% of hc2 HPV test referrals for cervical biopsies are unnecessary [1], if this recommendation were implemented in a low-resource setting like Sichuan, China with a population of about 100 million, there would be 10 million or more women to undergo unnecessary cervical biopsies in that province alone. The downstream unnecessary expenses to cover the colposcopy, histotechnology, and the pathology professional services for 10 million 4-quadrant cervical biopsies resulting from this “low-cost and rapid HPV testing” would be enormous, let alone the cost in human suffering associated with the psychological and physical trauma of an invasive procedure. Previously, Dr. Castle stated on record that “the medical community should emphasize persistence of cervical HPV infection, not single-time detection of HPV, in management strategies and health messages [2].” Unfortunately, this Commentary was not formulated on the basis of the last statement.
Sin Hang Lee, M.D., F.R.C.P.(C)
References
1. Stout NK, Goldhaber-Fiebert JD, Ortendahl JD, Goldie SJ. Trade-offs in cervical cancer prevention: balancing benefits and risks. Arch Intern Med 2008, 168: 1881-1889.
2. Rodríguez AC, Schiffman M, Herrero R, Wacholder S, Hildesheim A, Castle PE, Solomon D, Burk R; Proyecto Epidemiológico Guanacaste Group. Rapid clearance of human papillomavirus and implications for clinical focus on persistent infections. J Natl Cancer Inst 2008, 100: 513-517.
Competing interests
Dr. Sin Hang Lee is a pathologist at Milford Hospital, Milford, CT and the director of Milford Medical Laboratory. Dr. Lee receives a fixed salary from the hospital which charges fees for cancer biopsies and HPV testing. Dr. Lee is also the president and a shareholder of HiFi DNA Tech, LLC (www.hifidna.com), a company specialized in transferring the Sanger DNA sequencing technology to community hospital laboratories to increase specificity of DNA tests.