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The causal relation between human papillomavirus and cervical cancer

The causal relation between human papillomavirus and cervical cancer

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Published by Alberto
The causal role of human papillomavirus infections in
cervical cancer has been documented beyond
reasonable doubt. The association is present in virtually
all cervical cancer cases worldwide. It is the right time
for medical societies and public health regulators to
consider this evidence and to define its preventive and
clinical implications. A comprehensive review of key
studies and results is presented.
The causal role of human papillomavirus infections in
cervical cancer has been documented beyond
reasonable doubt. The association is present in virtually
all cervical cancer cases worldwide. It is the right time
for medical societies and public health regulators to
consider this evidence and to define its preventive and
clinical implications. A comprehensive review of key
studies and results is presented.

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Published by: Alberto on Mar 16, 2010
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The causal relation between human papillomavirus andcervical cancer
F X Bosch, A Lorincz, N Muñoz, C J L M Meijer, K V Shah
 J Clin Pathol 
The causal role of human papillomavirus infections incervical cancer has been documented beyondreasonable doubt. The association is present in virtuallyall cervical cancer cases worldwide. It is the right timefor medical societies and public health regulators toconsider this evidence and to define its preventive andclinical implications. A comprehensive review of keystudies and results is presented.
During the 1990s, epidemiological studies, sup-portedbymoleculartechnology,providedevidenceon the causal role of some human papillomavirus(HPV) infections in the development of cervicalcancer. This association has been evaluated underall proposed sets of causality criteria and endorsedby the scientific community and major reviewinstitutes. The finding is universally consistent,and to date there are no documented alternativehypotheses for the aetiology of cervical cancer.HPV has been proposed as the first ever identi-fied, “necessary cause” of a human cancer. Inpractical terms, the concept of a necessary causeimplies that cervical cancer does not and will notdevelop in the absence of the persistent presenceof HPV DNA.Cervical cancer is still the second most com-mon cancer in women worldwide,although it is atheoretically preventable disease.In developed parts of the world,and in popula-tions where cytology based programmes areestablished, it would be beneficial to add HPVtesting to the screening protocol.HPV testing wasshown by several studies, including one ran-domised trial, to be of help in solving theambiguous cases generated by cytology reading.In populations where cytology programmes areeither not in place or are not efficient,HPV testingshould now be considered and evaluated as analternative test for primary screening.Prevention of exposure to high risk HPV typesby vaccination may prove to be the most efficientand logistically feasible preventive interventionfor cervical cancer. At this stage of development, regulatory agen-cies are requested to evaluate the scientificevidence and weigh its implications in relation tocosts, public health investments, and policy. Thisis a subjective evaluation that could be guided bya careful description of the most relevant studiesand findings.
 A major discovery in human cancer aetiologyhas been the recognition that cervical cancer is arare consequence of an infection by somemucosatropic types of HPV. In public healthterms, this finding is equally important as thediscovery of the association between cigarettesmoking and lung cancer, or between chronicinfections with hepatitis B virus (HBV) or hepa-titis C virus and the risk of liver cancer.Moreover,as in the HBV disease model, intense efforts arecurrently going into the development and testingof vaccines that may prevent the relevant HPVinfections, and presumably, cervical cancer.By the year 2000, the epidemiological evidenceincluded a large and consistent body of studiesindicating, beyond any reasonable doubt, strongand specific associations relating HPV infectionsto cervical cancer. The observations have beenreported from all countries where investigationshave taken place. Studies include prevalence sur- veys, natural history investigations, case–controlstudies and, more recently, a randomised inter- vention trial. Natural history and follow up stud-ies have clearly shown that HPV infectionpreceded the development of cervical cancer byseveral years and confirmed that sexual transmis-sion is the predominant mode of HPV acquisition.These studies satisfied, in biological terms, thelong known clinical and epidemiological observa-tions that cervical cancer displayed the profile of asexually transmitted disease (STD). Case–controlstudies, case series, and prevalence surveys haveunequivocally shown that HPV DNA can bedetected in adequate specimens of cervical cancerin 90–100% of cases, compared with a prevalenceof 5–20% in cervical specimens from womenidentified as suitable epidemiological controls.The association has been recognised as causalin nature by several international review partiessince the early 1990s, and the claim has beenmade that this is the first necessary cause of ahuman cancer ever identified.
AF, attributable fraction; ASCUS,atypical squamous cells of undetermined significance; CI,confidence interval; CIN, cervical intraepithelial neoplasia;EBV, Epstein-Barr virus; GP, general primer; HCV, hepatitisC virus; HIV, human immunodeficiency virus; HPV, humanpapillomavirus; HSIL, high grade squamous intraepitheliallesion; HSV-2; type 2 herpes simplex virus; IARC,International Agency for Research on Cancer; IBSCC,international biological study on cervical cancer; OC, oralcontraceptive; OR, odds ratio; ORF, open reading frame;Pap, Papanicolaou; PF, protective fraction; PCR,polymerase chain reaction; RB, retinoblastoma; RR,relative risk; STD, sexually transmitted disease; Th1, Thelper cell type 1See end of article forauthors’ affiliations
Correspondence to:Dr F X Bosch,Epidemiology and CancerRegistry Unit (SERC),Catalan Institute ofOncology (ICO), HospitalDuran i Reynals, Gran Viakm 2,7, L’Hospitalet deLlobregat, 08907Barcelona, Spain;x.bosch@ico.scs.esAccepted for publication22 January 2002
The implications of the recognition that, in the absence of  viralDNA,cervicalcancerdoesnotdevelop,areofconsiderablepractical importance. On the one hand, the concept of riskgroups comes into focus.High risk women can now be sharplyredefined as the group of persistent HPV carriers. Operatively,this represents substantial progress from previous versions of thehighriskgroupthatidentifiedwomenbytheirexposuretoaconstellationofilldefinedfactors(lowsocioeconomicstatus,high number of sexual partners, smoking, use of oral contra-ceptives, history of STDs, and any combination of the above).Most of these factors are now viewed either as surrogates of HPV exposure or as relevant cofactors given the presence of HPV DNA. On the other hand, if indeed HPV is a necessarycause of cervical cancer, the implication is that specificpreventive practices targeting some putative non-HPV relatedcervical cancer cases are no longer justified. Finally, technol-ogyis now available to screen HPV DNA positive women in thegeneral population. Therefore, the final consideration on thenature of the association between HPV and cervical cancer isof considerable public health relevance. Research at the popu-lation level has largely accomplished its task by providing anexhaustive body of evidence. It is now time for public healthinstitutions to evaluate these achievements,consider the costsand benefits involved, and apply this knowledge to theirguidelines, recommendations, and policy.
Research in relation to the aetiology of cervical cancer hasmade substantial progress in the past two decades, both inscientific and operational terms. For decades, the epidemio-logical profile of women with cervical cancer was recognisedas suggestive of a sexually transmitted process, and severalinfectious agents were proposed over the years includingsyphilis, gonorrhea, and type 2 herpes simplex virus (HSV-2).The development of technology to test for the presence of HPV DNA in cellular specimens in the early 1980s and themultidisciplinary collaboration within the field made possiblethe establishment of a definite aetiological role for HPV incervical cancer. Evidence is also accumulating for HPVinvolvement in a considerable proportion of cancers of the vulva, vagina, anal canal, perianal skin, and penis. The associ-ation of HPV with cervical cancer has provided the back-ground and the justification for improving screening pro-grammes and for developing HPV vaccines.Figure 1 is a schematic view of the time scale of thisdynamic process. It includes an indication of the resultsobtained as technology evolved in sensitivity expressed as theper cent of cervical cancer cases that were found to contain viral DNA.The figure also indicates the types of HPV tests that were predominantly used and an estimate of the periods in which the key types of studies were initiated.Figure 2 displays the approximate number of scientificpapersidentifiedbyMedlinesearchesonHPVandonHPVandcervical cancer, and the number of research abstractspresented at the major annual papillomavirus conferences(http://www.ipvsoc.org). The 1980s generated a rapidlyincreasing number of publications on HPV DNA prevalence incervical cancer and reports on validation of the availabledetection methods. The 1990s produced the key results of case–control and cohort studies, and beginning in the late1990s there was an increasing number of publications on theclinical uses of HPV testing in screening and triage.
Epidemiological studies are essential to establish the associ-ationbetweenriskfactorsandcancerandtoqualifythenatureof the association. Traditionally, these include case series,case–control studies, cohort studies, and intervention studies.Comparisons of exposure between patients with cervicalcancer and their relevant controls were initially establishedusing questionnaires. Most studies conducted before theavailability of HPV DNA detection systems identified as keyrisk factors several variables related to the sexual behaviour of the women and of their sexual partners. The most frequentlyreported risk factors included the number of sexual partners,an early age at first intercourse, or any previous STD.
Once the relevant biomarkers were validated, in this casethe presence of HPV DNA in exfoliated cervical cells,it becamepossible to advance over questionnaire based studies andestablish biologically sound comparisons between patientsand controls. In epidemiological terms, these comparisons would analyse cervical cells from women with cervical cancerand from otherwise comparable women without cervical can-cer (case–control studies), or from cohorts of women testedfor viral DNA (cohort studies). To characterise the linkbetween HPV and invasive cervical cancer, case–control stud-ies proved to be the key study design and the only ones ethi-cally acceptable in human populations. Typically in such astudy and at the time of fieldwork, controls are selected tomatch the age distribution of the cases and,as much as possi-ble,the general characteristics of the cases (place of residence,socioeconomic status, health plan, etc). To characterise theassociation, all study participants are requested to comply with a questionnaire to assess their individual exposure to anyknown or suspected risk factor for the disease. Theinformation is then used to estimate the odds ratios (ORs) of disease related to any given exposure. Multivariate analyseshave the ability to compare (through statistical adjustment)strictly equivalent groups of women in relation to any of theexposures of interest. The adjusted differences (ratios) in the
Figure 1
Evolution of epidemiological research on humanpapillomavirus (HPV) and cervical cancer in the past two decades.FISH, filter in situ hybridisation; GP-PCR, general primer PCR; HCI–II, hybrid capture first and second generation; PCR, polymerasechain reaction; SH, Southern blot hybridisation; TS-PCR, type specificPCR.
HPV DNA incervical cancer30–60%19801990200075%95%99%HPV-DNA testsTypes of studiesSHTimeHC IFISH, TS-PCRHPV in triageCohortCase controlPrevalenceHPV in screeningHPV in casesHPV vaccines Phase IIIITrialsHC II/GP-PCR
Figure 2
Scientific publications on human papillomavirus (HPV)identified by Medline and the number of research abstractspresented at the annual Papillomavirus International Conferences.
YearNumber of HPV related publicationsPublications on HPV and cervical cancerAbstracts at the HPV Annual Conferences
HPV and cervical cancer 245www.jclinpath.com
prevalence in HPV markers between cases and controls arethen obtained after having eliminated the effects of any otherdifferences in exposure. Likewise, comparisons of cases andcontrols in relation to other variables of interest will provideestimates of the relevance of other factors (oral contraceptives(OCs) or smoking) and identify the variables that merelyreflect HPV exposure (surrogate variables). When the technology to detect HPV DNA in samples of DNA extracted from exfoliated cervical cells became available,it was relatively easy to show that most of the sexualbehaviour variables were in fact surrogate measures of HPVexposure, reflecting the predominant pathway of acquisitionof HPV. As methods became more sensitive, the parametersthat merely expressed the probability of HPV (or any otherSTD) infection, such as number of sexual partners, becamestatistically irrelevant.
Causality in public health requires a judgment based on sci-entific evidence from human and experimental (animal)observations. As such, only the latter may benefit from themost stringent criteria of causality; that is, the repeatedinduction of the disease by exposure to the relevant agent(s)compared with the “spontaneous” occurrence of the samedisease in unexposed and yet comparable groups of animals. Allcausalassociationsofhumancancershavebeenrecognisedbased on educated judgment of the results of epidemiologicalstudies at the level already available for HPV and cervical can-cer. Final proof can only be confirmed by intervention(preventive) trials, in which a reduction of the disease burden(incidence or mortality) is observed following the introduc-tion of a preventive practice in strictly controlled conditions.These studies typically include as controls populations to whom the existing standard of preventive care is beingoffered.Table1displayssomeofthecriteriathathavebeenproposedto evaluate the nature of the associations encountered by epi-demiological studies. This is particularly relevant whencausality is being proposed because,as a consequence,preven-tive or clinical recommendations are made.In addition to the criteria listed in table 1, some additionalcontributions might be worth discussing. In 1976, Evansreviewed the history of the causality criteria in infectious dis-ease models and adapted the early postulates of Henle-Kochto both the viral origin of acute diseases and to the relationbetween viral infections and cancer.
The human models thatinspired most of the latter included two examples: Epstein-Barr virus (EBV) infections and Burkitt’s lymphoma, andHSV-2 viral infections and cervical cancer.The technology that wasdiscussedwaslargelybasedonantibodydetectionandthestudies involved were seroepidemiological surveys and case–control studies. Antibody measurements were the methods of choice for the assessment of exposure. Evans proposed a uni-fied scheme for causation that included most of the criteriamentioned in table 1.
In 1976, Rothman
introduced theconcepts of “necessary and sufficient causes”. This model isuseful to accommodate the growing evidence of the multifac-torial origin of human cancer in many instances. Finally, sev-eral authors have defined criteria to evaluate the findings of molecular technology that provided the basis of the studies of HPV and cervical cancer.
16 17
Because of its wider acceptance,we will discuss in detail thecriteria proposed by Hill, and its version adopted by the Inter-national Agency for Research on Cancer (IARC) monographprogramme, in addition to the model on necessary and suffi-cient causes proposed by Rothman in 1995.
In brief, the criteria proposed by Hill
as summarised byRothman
include the following:Hill suggested that the following aspects of an associationshould be considered when attempting to distinguish causalfrom non-causal associations: (1) strength, (2) consistency,(3) specificity, (4) temporality, (5) biological gradient, (6)plausibility,(7) coherence,(8) experimental evidence,and (9)analogy.
By “strength of association”,Hill means the magnitude of theratio of incidence rates. Hill’s argument is essentially thatstrong associations are more likely to be causal than weakassociations because if they were the result of confounding orsome other bias,the biasing association would have to be evenstronger and would therefore presumably be evident. Weakassociations, on the other hand, are more likely to beexplained by undetected biases. Nevertheless, the fact that anassociation is weak does not rule out a causal connection.
Consistency refers to the repeated observation of an associ-ation in different populations under different circumstances.
The criterion of specificity requires that a cause should lead toa single effect,not multiple effects.However,causes of a giveneffect cannot be expected to be without other effects on anylogical grounds. In fact, everyday experience teaches usrepeatedly that single events may have many effects.
Table 1
Epidemiological considerations important for causal inference
Lilienfeld (1959)
Sartwell (1960)
Hill (1965)
Surgeon General (1964)
and Susser (1973)
MacMahon and Pugh(1970)
IARC (1995)
Magnitude of effect Strength of association Strength of association Strength/magnitude ofassociationStrength/magnitude ofassociationStrength of associationConsistency Replication Consistency Consistency Consistency ConsistencySpecificity Specificity SpecificityTemporality Temporality Temporality Temporality TemporalityDose response Dose response Biological gradient Dose response Dose response Dose responseBiological mechanism Biological plausibility Biological mechanisms MechanismsBiologicalreasonablenessBiological coherence Biological coherence Consonance with existingknowledgeExperimentation Experimental Experimental Experimentalevidence (intervention) (intervention)AnalogyExclusion of alternativeexplanationsAdapted from Weed 1995.
246 Bosch, Lorincz, Muñoz, et alwww.jclinpath.com

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