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The biology of HPV infections: understanding the progression to cervical cancer.

Human papillomavirus (HPV) is responsible for virtually all cervical cancers worldwide and has been proposed as the first "necessary cause" of a human cancer ever identified. (1) (Please visit to read references for this article.) In recent years, tremendous strides have been made in understanding the biology of HPV infections and the progression to cervical cancer, as well as the unique differences between each of the HPV virus types, including the 14 high-risk HPV (hrHPV) genotypes linked to cervical cancer.

HPV life cycle

Infection with HPV is opportunistic, and the virus gains access to the basal cell layer following micro-abrasions along the squamous epithelium. (2) Here, HPV is maintained in the dividing basal cells as low-copy episomal DNA, (3) and the dividing basal cells provide a reservoir of infected cells for the overlaying virus-producing tissue. It is within these upper cell layers that the virus initiates stages of its life cycle: inducing host cell replication and division to produce multiple copies of viral DNA, forming the viral capsid, viral assembly, and finally, release of the virus. (4)

For all HPV genotypes, the very first step of this life cycle process, which occurs almost immediately upon cellular exit from the basal layer, is the expression of E6/E7 mRNA, whose protein products force these cells to replicate and divide when they normally would not. (5) As a result, these infected cells are now driven to produce multiple copies of the virus (2-log increase), (3) and the cell division leads to an accrual of more infected cells that, in turn, also replicate and divide. This abnormal cell expansion marks the first appearance of abnormal tissue, leading to changes in the structural appearance of the epithelial tissue.

The magnitude of the abnormal growth or how far these basal-like cells over-grow into the epithelial layers is used to classify the degree of the HPV-related lesion. Abnormal cell growth in the lower 1/3 of the epithelium is categorized as cervical intraepithelial neoplasia 1 (CIN1); 2/3 of the way from the basal layer as CIN2; and ultimately, when the disorganization extends past 2/3 and reaches the full depth of the epithelium, as CIN3. (6)

Disease progression and genotyping recommendations

The viral E6 and E7 proteins drive cell proliferation and cell cycle re-entry in order to allow genome and viral amplification. Those intracellular activities lead to an accumulation of HPV-infected cells following unscheduled cell division, which results in an expansion of lesion size and a rise in viral genome copy-numbers. Functional differences between the E6 and E7 proteins produced by the high- and low-risk HPV types center on their ability to associate with and effect regulators of cell cycle and replication. (7) Whereas E6 and E7 from low-risk HPV genotypes may only associate with their cellular targets, those from the high-risk HPV genotypes will also mediate the degradation of these targets, resulting in a more extensive cellular modification. (8) Both E6 and E7 proteins have multiple cellular targets--the identity of these differs between low-risk and high-risk HPV as well as among high-risk HPV types. (9) Thus, it is the unique function of the E6/E7 proteins that dictates the malignant potential of each individual viral genotype.

A clear distinction exists between the level of disease associated with the high-risk and low-risk HPV genotypes: the former are clearly linked to high-grade cervical disease and cervical cancer; the latter are only found within low-grade and benign lesions. (10,11) Even among the hrHPV genotypes, there is variation between prevalence, persistence, virulence, and association with cervical cancer. Of these factors, virulence, or the demonstrated rapid progression to high-grade disease and high association with cervical cancer, is perhaps the most significant when ranking HPV genotypes in terms of associated risk. For example, HPV 16 has both the greatest tendency to persist and the highest probability of progression, with HPV18, 31, and 33 having the next-highest risk of progression. The remaining hrHPV genotypes, on the other hand, are associated with low absolute risks of CIN3+ that last for years, (12) which may warrant less aggressive follow-up.

For cervical cancer screening, HPV genotyping protocols are typically designed to enable clinicians to most effectively triage women at the highest immediate risk for high-grade disease and cancer. (13) Because they are the most oncogenic, HPV 16 and HPV 18 have been consistently proposed as the types that would warrant separate detection as a triage for a hrHPV-positive result or concurrently with a pooled hrHPV test (14) due to the higher immediate risk of CIN3+, (15-19) the lasting and rapidly increasing risk for progressing to a high-grade lesion following an initial positive result, (12,20,21) and the high association of these with both squamous cell carcinoma and adenocarcinoma. (22-23)

Progression vs. regression

It is clear that not all infections will progress to high-grade disease, and numerous studies have demonstrated that a higher CIN grade correlates with a greater risk that the lesion will progress to an even higher grade or to invasive cervical cancer. (24) The likelihood of progression also depends greatly on the HPV genotype associated with the infection. (12,20) Conversely, spontaneous regression to a lower-grade disease during follow-up studies is highly probable, (24) and most infections will clear on their own within a few years. (25)

The factors that drive the process of progression, regression, and clearance are still relatively unknown--although certain hrHPV genotypes are much more likely to progress to high-grade disease than others, (12 20) and resolution and regression of HPV-associated lesions largely involves specific immune responses and T-cell mediated processes. (26,27) Because regression of a lesion and clearance of an HPV infection could take months or even years (12,25) and depend on an immune response, current molecular HPV assays are incapable of differentiating between a progressing lesion and lesions that are destined to regress.

Evaluating HPV test performance

HPV testing is not strictly a baseline test: positive results not only provide indication of underlying risk at the time of testing but also possible risk over the subsequent 3-to-5-year screening interval.

Hence, a single assessment of histologically confirmed disease via colposcopy at the time of testing is not an accurate assessment of "true" or "false" HPV test positivity. (21) The most significant limitation of this strategy is that it assumes that high-grade lesions, if present, will be found upon colposcopy. CIN3 lesions, in particular, are initially tiny and difficult to detect visually, and current colposcopic procedures, which rely solely on directed biopsies (only sampling visible lesions), are only 60% sensitive for CIN3+ detection. (28) Positive HPV tests that appear to be false positive when judged against baseline colposcopic biopsy actually tend to predict elevated risk of subsequent CIN3+ and thus reflect a true positive result. (21) This means that one cannot simply designate that a positive HPV test is a "false" positive at baseline: the lesion may simply not have been found or sampled at the time of colposcopy. It also does not negate the fact that the woman may still be at an elevated risk for a high-grade lesion.

Only a long-term cumulative incident risk (CIR) measurement accurately assesses long-term cancer risk associated with either a positive or negative screening test. CIR provides a probability of a given event occurring and is able to address two critical questions: (1) did the test accurately predict women at risk for developing high-grade lesions following a positive result over the given time interval; and, more importantly, (2) did the negative result accurately predict that a woman was at low risk for high-grade disease and cervical cancer within the same interval? Thus, an HPV assay should have a low CIR over several years following a negative result; for assays aimed at enhancing risk assessment, the CIR should be significantly higher following a positive result when evaluated against a comparator benchmark.

Julia Engstrom-Melnyk, PhD, is Scientific Affairs Manager in the Medical and Scientific Affairs group at Roche Diagnostics Corporation.
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Title Annotation:Clinical issues; Human papillomavirus
Author:Engstrom-Melnyk, Julia
Publication:Medical Laboratory Observer
Geographic Code:1USA
Date:Apr 1, 2014
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