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Seminar
890
www.thelancet.com Vol 370 September 8, 2007
Human papillomavirus and cervical cancer
Mark Schiff man, Philip E Castle, Jose Jeronimo, Ana C Rodriguez, Sholom Wacholder
Summary
Cervical cancer is the second most common cancer in women worldwide, and knowledge regarding its cause and
pathogenesis is expanding rapidly. Persistent infection with one of about 15 genotypes of carcinogenic human
papillomavirus (HPV) causes almost all cases. There are four major steps in cervical cancer development: infection of
metaplastic epithelium at the cervical transformation zone, viral persistence, progression of persistently infected
epithelium to cervical precancer, and invasion through the basement membrane of the epithelium. Infection is
extremely common in young women in their fi rst decade of sexual activity. Persistent infections and precancer are
established, typically within 5–10 years, from less than 10% of new infections. Invasive cancer arises over many years,
even decades, in a minority of women with precancer, with a peak or plateau in risk at about 35–55 years of age. Each
genotype of HPV acts as an independent infection, with diff ering carcinogenic risks linked to evolutionary species.
Our understanding has led to improved prevention and clinical management strategies, including improved screening
tests and vaccines. The new HPV-oriented model of cervical carcinogenesis should gradually replace older
morphological models based only on cytology and histology. If applied wisely, HPV-related technology can minimise
the incidence of cervical cancer, and the morbidity and mortality it causes, even in low-resource settings.
Burden of cervical cancer
There were about 500 000 incident cases of and
275 000 deaths due to cervical cancer worldwide in 2002,
equivalent to about a tenth of all deaths in women due to
cancer.1 The burden of cervical cancer is disproportionately
high (>80%) in the developing world.2 Not only is cervical
cancer the most prevalent and important cancer in
women in several developing countries, but also the
societal importance of the disease is accentuated even
further by the young average age at death, often when
women are still raising families. Cases are often detected
at late stages due to non-existent or inadequate screening,
and the standard treatment options are often absent or
unaff ordable. Promising approaches to cervical cancer
prevention have resulted from our new understanding
that almost all cases are caused by persistent infection
with about 15 genotypes of human papillomavirus
(HPV).3,4 We review recent advances and current issues
regarding HPV and cervical cancer.
The cervical transformation zone
Cervical cancer usually arises from a ring of mucosa
called the cervical transformation zone (fi gure 1). For
reasons that we do not understand, persistent HPV
infections cause cancers mainly at the transformation
zones between diff erent kinds of epithelium (eg, cervix,
anus, and oropharynx).2 Illustrating the importance of
the transformation zone, cancer-associated
(carcinogenic) HPV infections are equally common in
cervical and vaginal specimens;5 however, cervical cancer
is the second most common tumour in women
worldwide, whereas vaginal cancer is exceedingly rare.2
The position of the cancer-susceptible transformation
zone is dynamic, gradually shifting over years towards,
and into, the endocervical canal6 as stratifi ed squamous
epithelium replaces the mucus-producing glandular
epithelium.7
Prevention of cervical cancer after abnormal screening
results depends on the destruction or excision of the
Lancet 2007; 370: 890–907
Division of Cancer
Epidemiology and Genetics,
National Cancer Institute,
National Institutes of Health,
Department of Health and
Human Services, Bethesda, MD,
USA (Prof M Schiff man MD,
P E Castle PhD, J Jeronimo MD,
A C Rodriguez MD,
Prof S Wacholder PhD)
Correspondence to:
Prof Mark Schiff man, Division of
Cancer Epidemiology and
Genetics, National Cancer
Institute, National Institutes of
Health, Department of Health
and Human Services, Bethesda,
MD 20892, USA
schiff mm@mail.nih.gov
Search strategy and selection criteria
We searched the Cochrane Library (2000–07) and Medline
(1980–2007) with the terms “human papillomavirus”, “HPV”,
“CIN”, “cervix cancer”, “cervical carcinoma”, “cervical
neoplasia”, “cervix cancer”, “cervix carcinoma”, and “cervix
neoplasia”. We largely selected publications from the past
5 years, but chose some commonly referenced, important
older publications. Review articles and book chapters are
cited to provide readers with additional details and
references. Our reference list was modifi ed on the basis of
comments from peer reviewers. We searched for papers in
English, Spanish, and French.
Figure 1: The cervical transformation zone
The cervical transformation zone is a ring of active squamous metaplasia where the stratifi ed squamous epithelium
of the ectocervix progressively undermines and replaces the glandular epithelium of the endocervix. For unclear
reasons, metaplastic tissue is especially susceptible to the carcinogenic potential of persistent HPV infections.
Seminar
www.thelancet.com Vol 370 September 8, 2007
891
entire transformation zone epithelium, not specifi c
precancerous lesions; this method is eff ective in about
80–95% of cases.8,9 The site of a biopsy showing cervical
precancer is not necessarily the exact site of subsequent
cancer development but rather is evidence of a fi eld of
increased risk. Therefore, exfoliative cytological and
virological measurements of the transformation zone
can sometimes predict cancer risk even when
histopathology from a colposcopically derived biopsy
does not confi rm the presence of a precancer.10
Histopathology
In poorly screened populations, squamous cell
carcinomas constitute most cases of cervical cancer. In
regions with good cervical cancer screening
programmes, the proportion of adenocarcinomas is
increased (15–20%) compared with unscreened
populations, presumably because they arise from the
poorly sampled glands of the canal or from poorly
recognised precursor lesions.11 Beyond the relative
increase, absolute rates of cervical adenocarcinomas
are thought to have increased in various countries over
the past two to three decades,12,13 for uncertain reasons.
Infection with a carcinogenic HPV is a necessary cause
of both squamous cell carcinoma and adenocarcinoma.
However, the distribution of carcinogenic HPV types
and variants detected in these two histopathological
types (eg, adenocarcinoma is more strongly linked with
HPV18) and the roles of non-viral cofactors (eg, smoking
and parity) diff er.14,15
Basics of HPV virology
Papilloma (wart) viruses have co-evolved with animal
hosts over millions of years and the life cycle of each
genotype of HPV is tied closely to the diff erentiation of
its specifi c epithelial target (eg, sole of foot, non-genital
skin, anogenital skin, anogenital/oropharyngeal
mucosa).16 The relations between HPV genotypes can be
expressed in the form of phylogenetic trees based on
DNA sequence and protein homologies, which serve as
unifying tools in understanding HPV classifi cation and
behaviour.17 HPV16 and HPV18 are the two most
carcinogenic HPV types, and are responsible for 70% of
cervical cancer and about 50% of cervical intraepithelial
neoplasia (CIN) grade 3 (CIN3);18 by contrast, HPV6 and
HPV11 are responsible for about 90% of genital warts.
When we refer to HPV infection in this Seminar, we
are referring to the genetically related group of genotypes
that are linked to cancer risk—ie, the carcinogenic
types—unless specifi ed. For cytopathology, we refer to
the 2001 Bethesda System19 and for histopathology, we
use the WHO classifi cation.20
The human papillomavirus genome codes for only eight
genes (fi gure 2).21 E6 and E7 are the primary HPV
oncoproteins. Each has numerous cellular targets,21–23 with
p53 and retinoblastoma tumour suppression protein (pRB)
being the most important. E6 inhibition of p53 blocks
apoptosis, whereas E7 inhibition of pRB abrogates cell-
cycle arrest. E7 is the primary transforming protein. Both
proteins are expressed at low levels during the infectious
process. At some still undefi ned point in progression to
Epidermis
Dermis
Suprabasal
Virus release
Granular
Cornified
Basal
Cutaneous
Virus assembly/
virus release
Genome
amplification
Genome maintenance/
cell proliferation
Genome maintenance
Mucosal
Viral DNA
E1, E2, E4, E5
E6, E7
E4
L2
L1
HPV16
LCR
2000
1000
P670
7156
7000 7904/1
6000
5000
4000 3000
PAL P97
PAE
E2
E4
84
E2
#4
E2
#3
E1 E2
#2
E2
#1
SP1 TATA P97
E5
L2
L1
E6
E7
E1
Figure 2: The HPV genome and its expression within the epithelium
The HPV genome consists of about 8000 bp of single-stranded, circular DNA. There are eight open reading frames and an upstream regulatory region. HPV genes are
designated as E or L according to their expression in early or late diff erentiation stage of the epithelium: E1, E2, E5, E6, and E7 are expressed early in the
diff erentiation, E4 is expressed throughout, and L1 and L2 are expressed during the fi nal stages of diff erentiation. The viral genome is maintained at the basal layer of
the epithelium, where HPV infection is established. Early proteins are expressed at low levels for genome maintenance (raising the possibility of a latent state) and
cell proliferation. As the basal epithelial cells diff erentiate, the viral life cycle goes through success stages of genome amplifi cation, virus assembly, and virus release,
with a concomitant shift in expression patterns from early genes to late genes, including L1 and L2, which assemble into viral capsid. L1 is the major capsid protein
while L2 serves as the link to the plasmid DNA. Adapted from Doorbar.21
Seminar
892
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precancer, E6 and E7 expression is deregulated by either
genetic or epigenetic changes, leading to their over-
expression in the full-thickness epithelial lesion.
Development of cervical cancer
Cervical cancer arises via a series of four steps—HPV
transmission, viral persistence, progression of a clone of
persistently infected cells to precancer, and invasion—that
can be reproducibly distinguished and which provide a
rational starting point for any discussion of optimum
prevention eff orts (fi gure 3). Backward steps occur also,
namely clearance of HPV infection and the less frequent
regression of precancer to normality. The molecular
virology underlying HPV persistence, progression, and
invasion is not well understood, but this causal model is
supported by epidemiological and laboratory data and
does not require unreliable morphological distinctions
like histological CIN grade 1 (CIN1) or cytological atypical
squamous cells of undetermined signifi cance (ASC-US)
analogous to borderline dyskaryosis.25,26
HPV transmission
Anogenital HPV infections are transmitted mainly by
skin-to-skin or mucosa-to-mucosa contact.27,28 The
probability of infection per sexual act is not known but is
clearly high,27 with no known diff erence between HPV
types. Because of their common transmission route,
HPV types tend to be transmitted together,29,30 resulting
in a high proportion (20–30%) of concurrent infections
with several diff erent types when women in the general
population are sampled.31 Men are also often infected
with several HPV types concurrently, implying that a
sexual act could transmit several types at once.
Independent of type, infecting viral particles reach the
germinal cells in the basal layer presumably via tiny
tears to the mucosa.4 Male circumcision might decrease
male HPV infection and carriage, possibly due to the
toughness of keratinised epithelium, thereby reducing
transmission.32 Penetrative sexual intercourse is not
strictly necessary for transmission and HPV types can
apparently be transferred to the cervix from original
infection at the introitus.33
Most women in the world are probably infected with at
least one if not several types of HPV during their sexual
life.34 Total exposure is diffi cult to measure because DNA
detection is usually transient and serology is not accurate.35
Thus, a substantial proportion of HPV DNA negative,
seronegative women have nonetheless been exposed.
While looking for uncommon, signifi cant cervical
lesions, pathologists and clinicians encounter a huge
assortment of abnormalities that are minor or, even more
commonly, equivocal (fi gure 4). Many millions of women
are diagnosed every year with such abnormalities.37 An
aggressive management approach cannot be justifi ed
because almost all abnormalities clear without
treatment.38 However, these abnormalities cannot be
ignored because most precancers and cancers are
diagnosed in women with equivocal or mildly abnormal
cytological fi ndings.39
Only about a third of women with HPV infections
detectable by DNA testing have recognised cytopathology.
Normal cervix
Infection
HPV-infected cervix Precancerous lesion Cancer
Transient infection HPV viral persistence
Clearance
Progression
Regression
Invasion
Figure 3: Major steps in the development of cervical cancer
Top row shows cytology, bottom row colposcopy. The major steps in cervical cancer development can be
understood best in relation to age at fi rst sexual intercourse as a proxy for age at fi rst infection. The typical age of
cervical HPV infection is similar to other sexually transmitted infections, with a large peak rapidly following average
age of sexual initiation. This average age of HPV infection varies by culture, aff ecting average ages of subsequent
stages. Incident HPV infection is best measured by molecular tests. Cross-sectionally, most HPV infections show no
concurrent cytological abnormality. About 30% of infections produce concurrent cytopathology, usually
non-classical (equivocal) changes. Most HPV infections clear within 2 years; the 10% that persist for 2 years are
highly linked to precancer. Detection of precancers is delayed by their initially small size and the typically low
sensitivity of screening methods. Precancers are usually detected around age 25–30 years (about 10 years after
sexual debut) in regions with cytological screening. Adapted from Schiff man and Castle.24
ModNOSReactive
Squamous atypia
Negative
LSIL HSIL
SIL
ASC-H
NILM
Negative KA CIS
Mild Sev CA
Dysplasia
2NOSReactive
Squamous atypia
NegativeNegative KA 1 3 CA
CIN
CA
ASC-US
Bethesda
2001
Increasing cancer risk
I II III IV V
CIN
nomenclature
Dysplasia
nomenclature
Papanicolaou
classification
Figure 4: Comparative classifi cations of HPV-related microscopic abnormalities
To discuss HPV infection and cervical cancer with colleagues from other settings requires understanding the many
diff erent terms used. Equivocal interpretations of ASC-US (atypical squamous cells of undetermined signifi cance)
and ASC-H (atypical squamous cells, cannot rule out high-grade squamous intraeptithelial lesions) are noted with
stippling, the amount and colour of which suggests the expected frequencies within the diff erential diagnosis.
Adapted from Sherman.36
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893
Cytological abnormalities are less sensitive for detection
of HPV than molecular testing. HPV16 and related types
are most likely to produce high-grade squamous
intraepithelial lesions; by contrast HPV18 (the second
most common type in cancers) causes a disproportionately
low fraction of such lesions.40,41 A lack of HPV18-induced
high-grade squamous intraepithelial lesions could
explain, at least in part, the poor performance of screening
for endocervical or glandular lesions and the increased
proportion of adenocarcinoma, which are associated with
HPV18,11,42 in well-screened populations.
In longitudinal studies of cytologically normal adult
women who are HPV DNA positive at enrolment, the
cumulative risk of incident equivocal and minor
cytological abnormalities rises to a high level (about
25–50% of smears) 1–2 years after enrolment and declines
thereafter, returning to baseline (<5% of smears) at about
4 years.43,44 The smaller cumulative risk of precancer and
cancer continues to rise for as long as we have been able
to observe prospectively (≥15 years), suggesting that a few
women remain persistently infected.45,46 How often
precancer arises from an evident mild lesion versus an
equivocal lesion or cytologically normal, HPV-infected
tissue is not known.
HPV clearance versus persistence
Most cervical HPV infections (with cytological
abnormality or not) are cleared or suppressed by
cell-mediated immunity within 1–2 years of exposure47
(fi gure 5). The most persistent HPV types tend to be the
most common.17 This correspondence is to be expected
because prevalence equals incidence multiplied by
duration (ie, persistence). The prevalence of diff erent
types of HPV is modifi ed by diff erential censoring due to
detection and treatment, which are more common for
lesions caused by HPV16 than other types.
With longer HPV persistence of a given type, the
probability of subsequent clearance over a fi xed interval
decreases and the risk of precancer diagnosis increases.30
However, the average persistence of some non-
carcinogenic types (eg, HPV61) can also be long.17
Prevalent infections detected in cross-sectional screening
persist longer in older women than in younger women,
probably because they are more likely to represent
infections already of long duration.48 The median time to
clearance of HPV infections detected during screening
studies is 6–18 months.30 There is no accepted defi nition
of clinically important persistence, but follow-up
strategies targeting abnormalities lasting more than
about 1 year (and especially 2 years) seem to distinguish
infections and associated lesions posing greater risk to
the patient from transient infections.49 The small
proportion (about 10%) of carcinogenic infections
persisting for several years is strongly linked to a high
absolute risk of diagnosis of precancer.17
Ongoing cohort studies with up to 10 years of follow-up
data have shown that, after clearance, the same HPV type
can occasionally re-appear.50 Whether infections resolve
by complete viral clearance or by maintenance of a latent
state in the basal-cell epithelium, in which the virus
replicates at extremely low levels without full viral
expression, is unclear. The appearance of many HPV
infections among immunosuppressed HIV-positive
individuals suggests that latency is a possibility.51 In
populations with secondary peaks of HPV infection—eg,
post-menopausal women—re-emergence from latency
due to senescence of cell-mediated immune control
could have a role, as well as new sexual partners (of the
women or their partners) or cohort eff ects. However,
older women with a long period without cytological signs
of HPV infection show very small risk of subsequent
cervical cancer, suggesting that re-activation from latency
typically does not cause harm.52
Progression to cervical precancer
In terms of histopathology, precancer includes the fairly
reliable morphological diagnoses of CIN3, severe
dysplasia or dyskaryosis, or carcinoma in situ (fi gure 6).
In precancer, undiff erentiated cells with fi xed genetic
abnormalities have replaced almost the full thickness of
the cervical epithelium.53 To discuss what lesions do not
represent precancer is also important for diagnostic
specifi city. CIN grade 2 (CIN2) is heterogeneous: it is
sometimes produced by non-carcinogenic types of HPV
and, therefore, is equivocal in cancer potential.54 CIN1 is
an insensitive histopathological sign of HPV infection,
and is not precancer. Careful study of cases of
0
06
10
20
30
40
50
60
70
80
90
100
Time (months)
Percentage
12 18 24 3630 42 48 54 60 66 72 78 84
Progressed
Persisted
Cleared
Figure 5: Average clearance, persistence, and progression of carcinogenic HPV infections
Carcinogenic HPV infections detected by DNA testing tend to resolve quickly within a year of detection. Details
vary by population, cytological status, and age, but this diagram of 777 infections found at enrolment visits of a
large population-based cohort study (Guanacaste, Costa Rica; unpublished data) illustrates a typical pattern. Over
time, the risk of a precancer diagnosis rises while the probability of eventual clearance among the still-persistent
infections falls. Among women with no fertility concerns, treatment for carcinogenic infections, especially with
HPV16 (the type most linked to risk of precancer and cancer), that persist beyond an appropriate period of
watchful waiting (eg, 12–24 months), might be justifi ed.
Seminar
894
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histologically confi rmed CIN1 have revealed that such
lesions actually represent a lower risk of progression to
cervical cancer than does interpretation of cytological
low-grade squamous intraepithelial lesions.10 Diagnosis
of CIN1 incorporates the errors of placement, processing,
and interpretation of colposcopically guided biopsy,
although such a diagnosis is poorly reproduced even
when made on the basis of large tissue specimens.26 For
any given type of carcinogenic HPV, diagnosing CIN1
does not predict meaningfully higher risk of CIN3 than
does negative biopsy.10
The lag time between infection and appearance of the
fi rst microscopic evidence of precancer can be
surprisingly short, often within 5 years.55 In fact,
histological precancer has been diagnosed within 2 years
of sexual debut.33,56,57 The biological meaning and clinical
importance (ie, risk of invasion) of these early precancers
are unknown. The average age of diagnosis of precancer
varies from 25 to 35 years and depends both on the
average societal age at fi rst intercourse, which can
serve—with notable exceptions such as early sexual
abuse—as a crude proxy for fi rst exposure to HPV, and
on the intensity of screening. Screening by HPV testing
can promptly detect precancers that would otherwise
grow slowly to the point of detection by less sensitive
methods like cytology and colposcopic impression.58
However, more sensitive screening will also classify as
abnormal more lesions and infections that would clear
without treatment.
The risk factors for persistence and precancer have not
been disentangled. HPV type is the strongest factor that
aff ects the absolute risks of viral persistence and of
progression to precancer given viral persistence.17,45
HPV16 is remarkably carcinogenic, with an absolute risk
of a precancer diagnosis approaching 40% after 3–5 years
of persistent infection.17,46,59 The total risk of precancer for
a woman carrying several HPV types is increased
compared with women infected with any one of the HPV
types she carries, but it is not clear whether her risk is
greater than the sum of the risks posed by individual
HPV types.31
Viral load measurements are not clinically useful.
Levels detectable only by PCR (eg, below the threshold
of detection of the commercially available Hybrid
Capture 2 [Digene Corporation, Gaithersburg, MD,
USA]) are associated with microscopic normality and
with low risk of subsequent precancer or cancer, but
increasingly high viral loads do not imply increasing
prospective risk,60 except for HPV16.61,62 The amount of
HPV DNA measured in scrapes of the cervical
epithelium is a complex sum of the number, size, and
grade of the HPV-associated lesions,63 and therefore the
meaning of viral load is ambiguous. Some of the highest
viral loads can be attributed to recently acquired minor
lesions producing large amounts of virus, analogous to
benign warts.
Risk of cervical cancer is mainly a function of HPV
infection and lack of eff ective screening. External factors
(apart from screening) are minor compared with the
extremely high primary risks of the most carcinogenic
HPV types. Smoking,64 multiparity,65 and long-term use
of oral contraceptives66 can double or triple the risk of
precancer and cancer among women infected with
carcinogenic types of HPV. The role of chronic
infl ammation, especially due to coinfection with
Chlamydia trachomatis, is less certain.67 Further, there has
been no confi rmation of a role for any one micronutrient
in observational studies and supplementation trials,68
although there is some evidence of a possible protective
association between higher folate and the risk of
precancer.68 Among HPV-infected women, low
socioeconomic status might remain a risk factor for
precancer even when recent medical care is taken into
account.69 Interestingly, a preliminary association
between condom use and decreased persistence or
progression has been seen in a few studies.70,71 The
mechanisms of action for HPV cofactors (whether
immune, genotoxic, or hormonal) are not well
understood.
Poorly understood cellular immune responses strongly
aff ect whether an infection is ultimately cleared or
persists to pose a risk of precancer. Eff orts to identify
specifi c subsets of T cells responsible for clearance
remain inconclusive.47 Epidemiological studies in diverse
populations have shown the human leucocyte antigen
DRB1*1301 to be protective.72 In addition to acquired
immune responses, innate immune responses—the fi rst
line of mucosal defence—could also have an important
role.73
HPV infection in people living with HIV/AIDS has
been addressed in detail elsewhere.51,74,75 In brief, HIV
Certainty of cervical cancer
Figure 6: What defi nes precancer?
Heterogeneity in biology (and defi nition) still exists in precancer, even as it remains the prime target of screening
programmes and preventive treatment as well as the scientifi c surrogate for cancer risk. As the functional
defi nition of precancer has expanded to include smaller and less serious lesions due to diffi culties distinguishing
the true cancer precursors, the risk (predictive value) of the diagnosis of precancer as a surrogate for predicting
invasive cancer has declined. These changes can alter the eff ect and assessment of prevention programmes. The
most certain surrogate for invasive cancer is full-thickness carcinomas in situ; however, many CIN3 lesions
detected by screening are very small and less certain to pose an eventual risk of invasion. Nonetheless, CIN3 shares
virtually the same HPV type spectrum and causal cofactors as cancer. By contrast, CIN2 can be caused by HPV types
rarely found in cancer, and has a sizeable regression potential. Thus, CIN2 represents equivocal precancer, but it is,
nonetheless, treated in some regions to provide a safety margin against cancer risk. Molecular markers to defi ne
precancer would be helpful, but prospective validation showing risk of invasion would not be ethical.
Seminar
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895
status, defi ned by CD4+ T-cell counts and HIV viral load,
strongly aff ects the early natural history of HPV.
HIV-positive individuals experience increased HPV
prevalence and persistence, and decreased viral clearance
compared with HIV-negative individuals for types other
than the uniquely persistent and carcinogenic type
HPV16. HIV-infected individuals are often infected with
more HPV types than are non-infected individuals,
suggesting type diff erences in the success of immune
suppression.76 The probability of invasion is not strongly
aff ected by HIV. Highly active antiretroviral therapy
(HAART) does not seem to aff ect HPV natural history or
to reduce the risk of cervical precancer and cancer;
however, the relation between such therapy and risk is
perhaps confounded because HIV-infected women on
HAART are living longer and allowing the cervix to have
prolonged exposure to carcinogenic HPV in the context
of relative immunosuppression.
Invasive cervical cancer
In unscreened populations, the peak risk of invasive
cervical cancer occurs earlier than for most adult cancers,
peaking or reaching a plateau from about 35 to 55 years
of age.77 This distribution is due to the fact that cervical
cancers originate mainly from HPV infections
transmitted sexually in late adolescence and early
adulthood. The average time between HPV infection and
establishment of a (small) precancer seems to be much
shorter than the average duration of precancer growth
leading to invasion. There are many more precancers
than cancers, suggesting that only a minority invade. The
precise magnitude and timing of risk of invasion, if
precancers were left untreated, will remain unknown
because contemporary cohort studies, in which treatment
of precancer is mandated, cannot study invasion
ethically.78 Crude estimates from early studies of large
precancers suggested a 20–30% risk of invasion over a
5–10-year time frame.79,80
Apart from age, risk factors for invasion are unknown
except for viral type; in particular, HPV16, HPV18, and
HPV45 are found in a higher fraction of cancers than in
precancers than are other HPV types.18 The integration of
the HPV genome into the host genome is associated with
invasive cancer and might be an important biomarker
distinguishing HPV infection from precancer.81 However,
integration might not be necessary to cause invasion,
since not all women with invasive cancers have
measurable integration.82,83 Continued transcriptional
activity of the HPV oncogenes is needed to maintain the
cancer.84
Prevention of cervical cancer
Risk as a guiding principle of prevention strategies
The steps in cervical cancer pathogenesis can guide
prevention and management. Short-term risk of CIN3 is
a scientifi cally valid, ethically justifi ed surrogate for
long-term cancer risk, and can be estimated in prospective
studies and clinical trials. To base clinical decisions on
knowledge of risk of such lesions makes sense; the
clinical response should be uniform irrespective of what
clinical test is used to defi ne risk85 (panel 1). For example,
fi nding HPV16 on an HPV DNA test conveys slightly
higher risk of subsequent CIN3 than does cytologicial
identifi cation of low-grade squamous intraepithelial
lesions.44 The best way to predict individual risk is to use
the risk estimate from a large stable group of women
with similar characteristics.
Panel 1: Replacing clinical protocols with risk stratifi cation
Total cost and total benefi t are the key statistics needed to assess and compare old and
new technologies for screening and diagnosis. For public-health programmes like
screening and management of very common abnormalities, the costs and benefi ts should
be described on a population basis: for example, the number of cases of disease or death
averted and the total cost—ie, fi nancial and iatrogenic medical consequences—summed
over all women receiving the test. These integrated costs and benefi ts, and therefore
prioritisation of who will receive the tests, will vary with the indication for the screening
and with geography, age, and sexual behaviour. Sensitivity and specifi city without
weighting by frequency of disease are not enough to capture integrated costs and
benefi ts adequately. By contrast, positive predictive value, which is the probability of
disease among women testing positive, and negative predictive value, which is a measure
of the reassurance of no disease among women testing negative, are expressed in terms
of population risks and are helpful.
There are several corollaries of thinking in terms of risks. First, there should be no
distinction between a clinical and a molecular test. For example, the utility of a
colposcopic examination, a Pap test, and an HPV test should be compared on an even
footing on the basis of performance and cost. Second, for a test with fi xed sensitivity
and specifi city, the clinical or population subset with the higher risk of disease should
have higher priority for intervention, given equal cost. Third, no one-dimensional
comparison of tests or programmes, like an odds ratio or even a risk diff erence, can
capture the information needed to choose between them. Finally, the
cost eff ectiveness of a programme is measured by comparison with alternative
programmes, including no programme. Thus, visual inspection with acetic acid could
be cost eff ective in a resource-poor area where there is no alternative programme in
place, despite its low accuracy.
Adoption of a-priori thresholds based on risk for deciding who needs closer surveillance,
colposcopy, and treatment will aid clinicians in making decisions that maximise the
health benefi t to women. For example, a society might decide that women at less than
2% absolute risk of precancer within the subsequent 2–3 years are normal and can stay in
regular interval screening, women with a 2–9% risk should be re-screened in a year,
women with a 10–39% risk need intensive colposcopic assessment immediately, and
women with 40% or greater risk need immediate treatment. The choices of such cutoff
points, once accepted, could guide management as new risk biomarkers are validated.85
There are a few implications of strategies based on absolute risk. First, no screening
strategy is effi cient among young women, who have very high prevalence of HPV infection
and of its cytological signs, both of which are very likely to clear without intervention.
Strategies to prevent the rare but sometimes fatal rapidly invasive cancers among young
women require screening and aggressive management of huge numbers of ultimately
normal young women; prevention strategies in regions seeking a nearly perfect level of
prevention can be so expensive that the entire programme is no longer cost eff ective.
Second, using HPV testing to detect very low viral loads and marginally carcinogenic types
(eg, HPV53) should be avoided to preserve the predictive value of a positive test.86
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Primary prevention of HPV infection
There is some evidence that health education program-
mes that promote abstinence, conscientious condom
use, or both, could reduce the risk of cervical cancer at
the population level.87 However, mutual abstinence until
marriage is far from universal, and even strict condom
use is not completely protective against HPV
transmission because the male anogenital skin is not
completely covered.88 Thus, the development of HPV L1
virus-like-particle (VLP) vaccines is a potentially major
advance in prevention of cervical cancer. These vaccines
are based on the self-assembly of recombinant L1 protein
into non-infectious capsids that contain no genetic
material.89 Intramuscular injection of the vaccine induces
high titres of neutralising antibody, more than 50 times
the titres induced by natural infection.90 Protection at the
cervix against the same types in the VLP vaccine is
probably mediated by antibodies transudated into the
secretions that bathe the epithelium, serum antibodies
directly exudated at the site of microscopic trauma
thought to be involved in transmission, or both91
(Schiller J, National Cancer Institute, Bethesda, MD,
USA; personal communication).
Two VLP vaccines have been developed for primary
HPV vaccination. Gardasil (Merck and Co, Bluebell, PA,
USA) has gained regulatory approval in several countries.
Cervarix (GlaxoSmithKline, Rixensart, Belgium) has
been approved in Australia, is pending approval in the
European Union, and applications for approval have
been submitted to regulatory agencies in the USA and
other countries.92 Both vaccines target HPV16 and
HPV18; Gardasil, which includes a standard alum
adjuvant, also targets HPV6 and HPV11.92 Cervarix uses a
new proprietary adjuvant intended to boost
immunogenicity. In populations of young adult women
without known exposure to the target types, both vaccines
have shown near perfect effi cacy against HPV infection
and related cytological and histological endpoints for up
to 5 years.93–97
Important questions remain (panel 2). For example,
the regulatory approval for Gardasil was predicated on
rather short-term effi cacy data for 15–26-year-old women
and data showing good antibody titres after vaccination
for 9–15 year olds. At present, girls aged 11–12 years are
being targeted in the USA, before entry to middle school.
Several jurisdictions are considering mandatory
vaccination for 11–12-year-old girls, but this is
controversial, especially regarding cost-eff ectiveness
analyses (table 1).98 Ideally, to ensure that a vaccination
programme will protect young women through the age
of greatest risk of HPV exposure, we would know that
durability will be 10–15 years or greater or that boosting
will be safe and eff ective; waiting for certainty, however,
would reduce the benefi t for the cohorts of girls born
between about 1995 and early 2005.
The value of universal vaccination in the upper age
range, 19–26 years, is even more controversial.99,100
Women who have had several sexual partners and have
already been exposed to the target types are at least
partly immune and cannot be distinguished from
unexposed women by DNA testing, because both
groups will be negative and serology is not reliable or
accurate as a biomarker of past exposure and protective
immunity.101,102 As women age, they are more likely than
younger women to have established monogamous
relationships that reduce future risk. The vaccines do
not treat existing infections or lesions,103,104 and
cross-protection against other HPV types is partial95 or
non-existent.103 Therefore, the current HPV vaccines are
most certain to yield the greatest public-health benefi t
(population eff ectiveness) in girls at an age before most
have begun sexual activity. At a certain, still-undetermined
age that might vary by region, screening might be more
cost eff ective than vaccination if a trade-off is considered.
We believe that broad recommendations for widespread
vaccination in adult women should await independent,
population-based eff ectiveness trials and cost-utility
assessments.
Panel 2: Important questions regarding the new
HPV16/18 vaccines
1 What is the duration of protection and the total eff ect on
cancer incidence?
2 Are boosters safe and eff ective if needed?
3 Do the vaccines provide cross-protection against a few
related types, as previously suggested?
4 What is the effi cacy of fewer than three doses of vaccine,
as will sometimes occur in vaccination programmes?
5 Does the vaccine prevent infection in men, and reduce the
transmissibility of HPV from men to their partners?
6 When immunity wanes and incident infections occur, are
the natural history of HPV16 and HPV18 infections and
the related risks for precancer and cancer the same as in
unvaccinated women who typically acquire infections by
these types as young women?
7 What will be the eff ect of HPV vaccination on compliance
with screening programmes, which are needed for
prevention of the 30% of cancers against which the
vaccines do not provide protection?
8 How great will the negative eff ect be of the reduced
prevalence of HPV16 and HPV18 in post-vaccinated
populations on the clinical performance and cost-
eff ectiveness of screening assays and diagnostic
procedures?
9 Will prevention of infection with HPV16 or HPV18 alter
the natural history of other carcinogenic types and the
number of cervical cancers they cause?
10 Do these vaccines protect against other HPV-related
cancers such as oropharyngeal and anal cancers?
11 In developing countries, where 80% or more of cervical
cancer occurs, who can aff ord to get vaccinated, even with
tiered pricing, in view of competing health priorities?
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897
Multivalent vaccines (which target an expanded range
of types) and diff erent approaches to produce immunising
HPV proteins are being tested.105 The eff ect of expanding
the number of types on vaccine price and safety are
unclear, as is the acceptability of the current vaccine once
there is public awareness that a broader-spectrum vaccine
is coming. One alternative to achieve broad-spectrum
protection that is being explored is vaccination with L2,
the minor capsid protein, which has been shown to elicit
cross-neutralising protection (albeit weaker responses
than the L1 VLP vaccines).106 The ideal would be a low-cost,
single-dose, needle-free pan-HPV vaccine that is stable
without refrigeration. Alternatively, there is evidence that
carrageenan, an inexpensive polysaccharide used in a
wide spectrum of human-use products, including vaginal
lubricants, potentially blocks HPV infection in a mouse
challenge model.27
Screening
Cervical cancer prevention, as practised in high-resource
regions, includes: screening; triage of equivocal results;
colposcopically guided biopsy of abnormal screening
results; decision whether to treat; treatment; and
post-treatment follow-up (including eventual return to
routine screening intervals if appropriate). Cervical
cancer prevention programmes vary widely by country
and could be radically improved by new technologies.
Whichever validated screening method is chosen,
broad coverage and full follow-up of abnormalities are
the key requirements for reducing the incidence of
cervical cancer by screening. Screening in the absence of
a treatment programme is unethical. The appropriate
programme for a given setting (when to begin, the proper
intervals between screens, when to stop) depends on
aff ordability, diff ering societal demands for protection
against cancer risk, and desire to prevent iatrogenic
complications among women who are at low risk of
cervical cancer. However, a few principles follow from
the established fact that the cause of cervical cancer is
persistence of sexually transmitted HPV infection of the
transformation zone. Screening women within 5–10 years
of fi rst sexual intercourse, when the risk of fi nding
benign HPV infections is very high but risk of cancer is
vanishingly low,107 cannot be cost eff ective. Similarly, it is
not cost eff ective to screen women after total hysterectomy
for reasons unrelated to cancer108 or older women with
For mandatory vaccination Against mandatory vaccination
Do we have enough information to
promote a major public-health
mandate?
Many vaccination programmes are implemented
before long-term durability and safety data are
available. Implementation will create the needed
vaccinated cohort to permit assessment
Because screening is a good alternative to vaccination, no
mandatory programme should be promoted until strong
supportive data are already available to permit integration of
vaccination and screening
Population benefi t of vaccination
overlaid on screening
Making vaccination mandatory would increase
coverage of prevention among the poorly screened,
highest-risk population that would benefi t most
from vaccination
Further reductions in incidence and mortality (already low in the
USA) would be diffi cult to achieve. Adding vaccination to
screening might even reduce compliance with screening because
women might falsely assume that they are protected
Urgency of mandate If we delay, cohorts of girls will miss the benefi ts of
vaccination
It is better to proceed slowly, accumulate more data and public
acceptance based on voluntary vaccinations, and to move to
mandates when public-health benefi t is established
Safety Good safety profi le to date Rare eff ects can not be ruled out until many more girls are
vaccinated
Known durability Established durability of about 5 years with
sustained serotitres for HPV16
Peak risk of sexual exposure lasts for more than 10 years after
suggested mandatory vaccination age
Trends in protection in years after
vaccination
No evidence for decreasing effi cacy over 5 years HPV18 serotitres fall within 2–3 years of vaccination with
Gardasil,96 which might herald a subsequent decrease in
protection
Feasibility of boosting One unpublished, small study suggests good
antibody response to booster among young adult
women
General lack of large-scale evidence, and lack of well-formulated
strategies regarding how and when boosting could be done.
Lack of data on the safety of boosting. No serology assay widely
available for monitoring if titres proved predictive
Choice of vaccine Gardasil is already approved in many countries Cervarix is approved in Australia and might be approved
elsewhere within a year. Weighing its relative benefi ts might
make sense. Are the two vaccines interchangeable and
compatible?
Impending development of second-
generation vaccines with more types,
longer durability, or lower cost
It is best to start now and replace or boost with
newer vaccines when available
Especially for lower-resource regions, second-generation
vaccines could reduce number of doses, need for boosting, and
cost
Ethical and family issues There is no evidence that vaccination would
promote sexual activity. Parents could opt out
Vaccination might encourage onset of sexual activity and deny
the parents their right to choose
Cost-eff ectiveness Analysis assuming lifelong durability already
indicates cost-eff ectiveness at current prices
Unknowns include durability, need for boosting, integration
with screening schedules, and possibly reduced performance of
screening tests. Strain on public-health resources
Table 1: Arguments for and against mandatory HPV vaccination of girls before the average age of sexual debut
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repeated negative cytology, HPV tests, or both, assuming
endocervical sampling is adequate.52
The development and implementation of organised
and eff ective cytology-based cervical cancer screening—
eg, Papanicolaou (Pap) tests—for detection and treat-
ment of precancerous lesions and earlier stage, treatable
cancers has led to signifi cant decreases in the incidence
and mortality of cervical cancer.109 The eff ect of cytology
programmes has been best documented from ecological
correlations of cervical cancer with screening activities in
populations, mainly in Nordic countries. Many early
screening programmes targeted the peak ages of cervical
cancer risk and produced decreases in incidence confi ned
mainly to women aged 30–70 years.110 When screening
coverage is extended to younger and older women, rates
at all ages decrease, although cost per cancer averted
rises, as seen in US Surveillance and End Result (SEER)
data.111 A fraction of the earliest cases of cervical cancer
are probably rapid onset;112 their shorter time of
development permits fewer rounds of screening that
could detect precancerous lesions.
The success of well-established cytology programmes
in detecting cervical precancer and treatable cancer is
attributable to repeated, fairly insensitive screening of
women during the slow progression from incident HPV
infection to easily diagnosed precancer (5–10 years) and
from precancer to cancer (typically ≥10 years).113,114 The
need for repeated screening cycles makes cytology-based
cervical cancer screening programmes expensive.
Further substantial, cost-eff ective improvements in
cytology programmes could be diffi cult to achieve,
although automated screening of liquid-based cytology
might someday prove itself.115 In choosing between
cytology techniques, there is no convincing evidence that
liquid-based cytology is more accurate than conventional
pap smears, especially when adjunctive HPV testing is
done.116,117 Nonetheless, liquid-based cytology might
reduce the proportion of inadequate smears,118,119 especially
in settings where conventional smears are prone to
air-drying (eg, the tropics) or where widespread cervical
infl ammation is a problem. Although not abnormal, an
inadequate smear can similarly increase anxiety of
women.120
Assays for HPV have been introduced to improve the
effi ciency and maximise the sensitivity of cervical cancer
screening. There is convincing evidence that testing for
carcinogenic HPV DNA is cost eff ective and sensitive for
detection of precancerous lesions in women with
equivocal cytology,114,121,122 is more sensitive but less specifi c
than cytology-based methods for primary cervical cancer
screening,45,114,117,123,124 can be added usefully to the follow-up
of women post-colposcopy when precancer is not found,125
and can guide assessment of cure post-treatment.126 Most
importantly, testing negative for carcinogenic HPV
provides greater reassurance against cervical precancer
and cancer than does cytology-based methods. The
greater reproducibility of current tests for carcinogenic
HPV types127 is an added advantage over cytology. In the
USA, HPV testing to triage equivocal cytology is
commonly used. HPV is also approved in primary
screening in women 30 years and older, who are past the
peak of self-limited infections, and in whom the positive
predictive value is higher than in younger women.128 The
International Agency for Research on Cancer has
Panel 3: Why HPV16 deserves individual consideration in
prevention programmes
1 HPV16 causes half the cases of cervical cancer worldwide
and is the major carcinogenic type in almost every country
surveyed133
2 HPV16 is the most common carcinogenic type in the
general population, accounting for about 20% of
infections among cytologically normal women,134
20% among women with equivocal lesions,133 and 26%
among those with mild abnormalities133
3 Although HPV16 is no more likely to cause cytological
abnormalities than other carcinogenic types,40 it
disproportionately causes changes suggesting precancer
and accounts for about 45% of those severe
interpretations133
4 Prospectively, HPV16 persists longer on average than any
other type and persistence is highly associated with
precancer (about 40% of women with persistent HPV16
are diagnosed within 5 years with precancer)17
5 HPV16 is the main HPV type that causes other anogenital
and oropharyngeal cancers that are not common enough
to merit screening but might be prevented by an eff ective
vaccine135
Proportion of cervical
cancers caused
Cumulative total
HPV16 54·6% 54·6%
HPV18 15·8% 70·4%
HPV33 4·4% 74·8%
HPV45 3·7% 78·5%
HPV31 3·5% 82·0%
HPV58 3·4% 85·4%
HPV52 2·5% 87·9%
HPV35 1·8% 89·7%
HPV59 1·1% 90·8%
HPV56 0·8% 92·2%
HPV51 0·7% 92·9%
HPV39 0·7% 93·6%
HPV73 0·5% 94·1%
HPV68 0·5% 94·6%
HPV82 0·2% 94·8%
No type identifi ed 5·2% 100%
Data adapted from reference 18.
Table 2: Proportion of cervical cancer caused by the carcinogenic
HPV types
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899
endorsed the use of carcinogenic HPV testing alone as
an option in primary cervical cancer screening.109
At least four assays indicating current infection give
roughly similar results when used to assay the major
carcinogenic HPV types as a pool: Hybrid Capture 2;
the MY09/MY11 primer set and its improvements like
PGMY; the GP5+/GP6+ primer set; and SPF10/LiPA
PCR-based methods.123,129,130 Only Hybrid Capture 2 is
approved in the USA by the Food and Drug
Administration (FDA); it does not provide individual
typing information. Two PGMY-based systems have
been submitted for FDA approval, one of which is a
pooled test like Hybrid Capture 2, while the other
provides genotyping. We believe that only completely
standardised assays should be used for routine practice
because standardisation is, with sensitivity, the major
advantage of HPV testing.131 Without rigorous
standardisation, subtleties of HPV tests can greatly
aff ect analytical performance.132
HPV16 is by far the most important HPV type
worldwide, and its eff ect is refl ected in all aspects of
cervical cancer prevention (panel 3). If we could eliminate
HPV16 infection or reliably identify and destroy all its
cytopathological or colposcopic manifestations, we could
prevent up to half of cervical cancer cases.2 Table 2 shows
the relative importance of diff erent HPV types. An
important goal is to improve specifi city of HPV testing
while maintaining its clinical sensitivity. Possible
advances include type-specifi c detection of HPV16 and
HPV18, which has been shown to identify women at the
greatest risk of developing precancer and cancer.136
Detecting persistence of these most carcinogenic HPV
types would be an even more specifi c marker of clinically
important infections, theoretically, but clinical use of
genotyping will require robust assays and workable
clinical protocols. Other promising screening assays
under development detect carcinogenic HPV E6/E7
mRNA137 and p16INK4a.138
Cervical-vaginal self-collection permits the use of
molecular testing outside clinical settings with clinical
sensitivity for precancer and cancer that seems as good
as cervical cytology but lower than clinician-directed
specimen collection.139,140 The degree of sensitivity might be
suffi cient if self-collection encourages and permits
otherwise unscreened women to be screened.141
Importantly, HPV testing can be too analytically
sensitive. HPV is not a disease per se, and any molecular
detection of HPV is worthwhile only as part of a cervical
cancer prevention programme. Moreover, benign
infection is very common, creating a tension between
positive and negative predictive values. The cutoff points
of positivity must aim for clinical sensitivity, defi ned as
the detection of CIN3 or worse until the next screening,
while attempting to minimise the detection of
insignifi cant infections or traces of viral DNA. The
detection of some benign infections is unavoidable, but
the types targeted must be restricted to clearly
carcinogenic types to prevent non-specifi city that could
aff ect thousands of women falsely labelled as being at
risk of cancer.
Diagnosis of abnormalities found on screening
Historically, colposcopically directed biopsies have been
the clinical reference standard for diagnosing precancer
or even to make fi ner distinctions such as CIN grade 1, 2,
or 3.142 However, the choice of biopsy site and the
histopathological diagnosis of resultant biopsies tend to
be variable and subjective.143 Clinicians rely on colposcopy
to determine the presence or absence of epithelial lesions,
fi nd the area of the cervix with the highest degree of
disease, and direct the biopsy for histological diagnosis.
Colposcopic assessment also provides information about
location and extent of disease, which is important for
planning treatment.
Although the sensitivity of screening has improved
considerably in the past decade, colposcopy has not
advanced, given the weak correlations between visual
changes and disease severity and lack of reproducibility
among assessors.144 Even highly experienced assessors
have false negative colposcopy rates as high as 20–40% in
patients with a histological diagnosis of precancer.145,146 Two
factors aff ect this false negative rate: fi rst, CIN3 lesions
missed by colposcopy are smaller and involve fewer
quadrants of the cervix than do lesions that are detected
visually;147 and second, patients with precancer related to
non-HPV16 carcinogenic types are more likely to have
equivocal visual lesions.144 Therefore, the use of colposcopy
might be even more limited when HPV testing and
vaccination become more widely used.
Colposcopic sensitivity increases signifi cantly if more
than one non-random biopsy is taken, irrespective of
training or expertise of the assessor.146,148 More studies are
needed to determine whether the additional biopsies
should be taken only from apparent lesions, from areas of
minor epithelial changes, or even from seemingly normal
quadrants of the cervical epithelium.
Treatment of cervical precancer and invasive
cancer
The eff ect of behavioural factors on the clearance of HPV
or precancer is poorly understood. However, consideration
of smoking is always important for reasons of public
health. There is some evidence that smoking cessation
promotes resolution of HPV-induced cytopathology.149
Genotoxic smoke constituents are secreted at high levels
into the cervical mucus.150 Enhancement of cellular
immunity is also probably involved. In any case, it makes
sense to encourage women with precancerous screening
abnormalities to stop smoking in the context of a broader
programme for prevention of smoking-related cancer and
health problems.
At present, the usual practice for treatment of precancers
is to treat the entire transformation zone of women
diagnosed with equivocal (CIN2) or more defi nite (CIN3)
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precancer, not just the identifi ed lesions.151 There is some
international variation in the treatment threshold, and
consideration of age and desired family size is common
and appropriate. The presence of a lesion indicates that the
entire transformation zone is at risk and colposcopists
cannot ascertain the site of worst pathology with certainty.
In many countries, hysterectomy is no longer acceptable
as a primary treatment option for precancers, and
fertility-sparing treatments such as cone-shaped excision
and cryotherapy are the fi rst options for intraepithelial
lesions of the cervix. Loop electrosurgical excision
procedure (LEEP) or large loop excision of the
transformation zone (LLETZ) has become the most
popular procedure because it can be done as an outpatient
with local anaesthesia and because it removes only a small
amount of cervical stroma. Although taking the minimum
amount of tissue is the goal, recent reports show that
women who undergo LEEP/LLETZ are at increased risk
compared with the general population for premature
deliveries.152 Cold-knife cone is still used when more
extended tissue removal is required.
Cryotherapy with nitrous oxide, a low-cost ambulatory
treatment, is almost as eff ective as ambulatory excisional
procedures to treat small precancerous lesions.153
Cryotherapy is widely used in low-resources areas mainly
because it can be provided without local anaesthesia or
electricity. One noteworthy drawback is the typical weeks of
recovery marked by discharge with some possibility of
infection. Carbon dioxide is often used as an alternative gas
to nitrous oxide because it is less expensive and easier to
fi nd in remote areas; however, technical improvements are
needed to overcome serious defi ciencies such as blockage
of equipment154 and poor depth of tissue necrosis.155
While CIN2 is a poorly reproducible diagnosis (fi gure 7)
and the accuracy of colposcopic biopsy itself is in some
doubt, we might soon be able to treat the transformation
zone based on more exact virological assessment of risk.
Specifi cally, if a carcinogenic HPV type persists for a
number of years in an older woman for whom fertility
issues are not important, the risk posed by LEEP might be
warranted to address the possibility that a precancer is
being missed by colposcopy. The use of a molecular test to
guide treatment will require extremely careful study
(panel 1) and we suggest it for discussion, not immediate
adoption.
Cytology and HPV testing are useful to assess cure
after treatment by LEEP. Women successfully treated
usually test HPV negative. Those testing HPV-negative
4–6 months after LEEP have no appreciable risk of
recurrent CIN2 or worse within the subsequent couple
of years, although the relevant studies have lasted only
around 2 years, so for how long negative tests after
LEEP can be interpreted in this way is not clear. Those
testing positive must be monitored more closely,
although the proper immediate management must be
individualised.126,157
Any proposed outpatient non-surgical method must
work very well, because excisional procedures are 90–95%
eff ective with minimal side-eff ects. Current HPV vaccines
do not treat existent HPV infections or precancerous
lesions. A better understanding of the molecular
underpinnings of HPV and cervical carcinogenesis could
lead to the rational design and development of an array of
targeted, lower-morbidity non-surgical treatments such as
therapeutic vaccines, topical immunotherapies (eg,
imiquimod and resiquimod for treatment of condyloma),
and topical chemotherapies (eg, siRNA and apoptosis
inducers).
There is a pressing need to educate health profes sionals
and the public regarding the natural history of HPV as we
move towards HPV-based prevention strategies. As
evidenced by the recent alarmist reaction to a report that
HPV is very common in the general US population,158
many still confl ate the one-time detection of HPV DNA
with high risk of cervical cancer (unpublished data).
Unwarranted psychosocial damage can follow detection of
HPV.159 Many women would probably still prefer to be
notifi ed of a mildly abnormal Pap than of an HPV infection
because the connection between abnormal Paps and
sexual behaviours was previously not well understood,
although the two test results address the same biological
processes.
We have yet to agree as a health community on the full
set of messages that should accompany HPV screening. It
is not clear which health professional will have the time,
training, and interest to lead the education eff ort in
diff erent regions, especially as messages change following
the advent of vaccination. A critical example of an
Normal
0
ASC CIN1/LSIL
Clinical centre pathology diagnosis
CIN2 CIN3
10
20
30
40
50
60
70
80
90
100
QC pathology biopsy diganosis (%)
CIN3
CIN2
CIN1/LSIL
ASC
Normal
Figure 7: A comparison of community pathology biopsy diagnoses to quality control pathology review
diagnoses
Comparison of biopsy diagnoses made by clinical centre pathologists (community diagnosis)156 with biopsy
diagnoses rendered by the expert quality control pathology.54 Patterned bars highlight the proportion of
agreement for a given community diagnosis. Note that many biopsies diagnosed as CIN2 by the clinical centre
pathologist, the threshold for excisional treatment in many countries, were not called CIN2 on expert review.
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901
educational issue is what to tell women with normal
cytology and a positive HPV test. We propose that patients
should be informed that although HPV exposure is
extremely common, almost all infections go away within a
year or two; many are gone within 6 months. Patients
should make sure that they get retested, and if the infection
does not clear, then they will need a full examination
(colposcopy with multiple biopsies) and possibly treatment
to prevent precancer and later risk of cancer.
Two important advances in the treatment of invasive
cancer deserve brief mention. Radical hysterectomy has
been the preferred treatment for stage I cases, but during
the past few years, minimally invasive surgery has become
an option for young women with small tumours who
desire fertility. Currently there are enough data to conclude
that radical vaginal trachelectomy with laparoscopic pelvic
lymphadenectomy is a safe procedure with an acceptable
recurrence rate (4%). In one study, pregnancies occurred
in 31 (43%) of 72 treated patients and 36 (72%) of
50 pregnancies reached the third trimester.160
Radiotherapy is still the best choice for stage II–IV
patients, but several randomised studies have shown
improvement of survival with concurrent chemotherapy.161
Cisplatin seems to be the best drug for advanced
squamous carcinoma as a single agent or in combination
with other cytotoxic drugs. The optimum treatment of
adenocarcinoma is less clear.
Fitting prevention strategies into available
resources and existing programmes
New cervical cancer prevention methods must be
introduced with consideration of added value and added
cost. Otherwise, the rich could easily be over-treated, while
the poor at higher risk are neglected. For example, the
addition of HPV testing to cytology for screening, if
repeated every year, cannot be cost eff ective and will lead
to excessive interventions.162 Similarly, new preventive
vaccines, if adopted with high acceptance, rationally must
lead to less frequent screening to be cost eff ective.163 Wit h
less HPV16 and HPV18, the predictive value of positive
screens will fall as the number and relative proportion of
important lesions decreases, and the marginal gain in
reassurance from negative screens will decrease as
well.113,164 In general, regional planners must decide which
prevention strategies do well, and which additions (or
replacements) are most worthwhile.
To reach their potential, new cervical cancer pre vention
methods will need to be accessible and aff ordable to
women who are currently underserved and at the greatest
risk. The average cost per year of life saved with
cytology-based screening programmes in countries where
it has been successful is higher than most resource-limited
countries’ annual gross per head income.
Cervical cancer screening programmes requiring one
to three interventions in a woman’s lifetime are the
most cost eff ective; more visits (common in
high-resource regions) have a notably reduced
cost-eff ectiveness.165 High programme coverage and
immediate, eff ective treatment of positive cases (to
minimise loss to follow-up) are crucial to achieve a
reduction in cervical cancer mortality. Other factors
that increase cost include the woman’s time
requirement, need for transportation and the availability
and cost of treatment of cancer cases. The relative
importance of each of the diff erent factors varies by
country; thus programme selection has to be adjusted
accordingly.166
One of the least expensive, easiest, and most widely
assessed screening approaches is visual inspection with
acetic acid or with Lugol’s solution. Visual inspection
with acetic acid has been better studied, and its
sensitivity estimates vary considerably (40–90%), partly
due to lack of technique standardisation but also to the
use of diff erent gold standard methods.167–170 Additionally,
the technique provides instant results that, if combined
with treatment options such as cryotherapy, allows for
1-day see-and-treat schemes that decrease the overall
cost of screening programmes substantially. Despite its
low sensitivity, specifi city, and predictive values when
used as a stand-alone test, in scarce-resource areas
visual inspection with acetic acid is a realistic screening
method when the only alternative is no screening.171
We face an important challenge to apply HPV-based
technology widely at low cost. The eff ect on cancer of
vaccines against HPV infection will not be felt until
about 20–30 years after a countrywide programme is
introduced.163 The introduction of such programmes
will probably require the involvement of donors like
WHO, the Pan American Health Organisation, the
GAVI Alliance, or the Bill & Melinda Gates Foundation
to make vaccines available and aff ordable.
Like HPV vaccines, existing HPV tests are
unaff ordable and need to be done in specialised
laboratories. A new HPV DNA test has been developed
for low-resource regions by the Program for Appropriate
Technology in Health (PATH) through a grant from the
Gates Foundation. This test will provide results within
a few hours with sensitivity and specifi city similar to
current commercially available tests, but at a cost of
under US$5.172 Additionally, there are few infrastructure
and reagent requirements, making HPV testing a
practical possibility as a stand-alone screening method.
Validation studies are currently underway.
We believe that a logical prevention strategy in regions
with scarce resources would combine vaccination before
sexual debut (if reduced cost or donated vaccine is
available) and screening at an optimum age around
35 years with cryotherapy of all HPV-positive women
except for those needing expert care—eg, for obvious
cancers.24 Region-specifi c age rates of HPV prevalence
should be considered to guide the ages of vaccination and
screening. Combining vaccination and screen-and-treat
strategies would reduce overall HPV endemicity and
provide lasting population benefi t.
Seminar
902
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Future directions
There are a number of important, active research topics
that will soon aff ect clinical management of cervical
HPV and precancer: the average risk and timing of
clearance versus persistence of each type of HPV; the
risk and timing of diagnosis of precancer given
persistence of each of the types; the eff ect, if any, of age
at infection on these rates of clearance, persistence,
and progression; the risk, if any, of occasional
re-appearance of an HPV type via reinfection or latency,
if such a state exists for HPV, following initial clearance;
the origin and signifi cance of age-specifi c HPV
prevalence curves that diff er by region; the unique
carcinogenicity of HPV16, including its molecular
mechanism and natural history; the occult nature of
HPV18 infection and related lesions and the increased
importance of HPV18 in the development of
adenocarcinoma; the validation of new molecular
markers with better predictive values than CIN2
diagnoses for distinguishing between HPV infections
with and without concurrent precancer and, among
those without concurrent precancer, distinguishing
those that are most likely to become precancer in the
next 5 years; the immune response that prevents HPV
reinfection and the response that underlies HPV
clearance, including genetic infl uences on the success
of these responses; and HPV natural history in immuno-
suppressed individuals.
The advent of highly effi cacious prophylactic vaccines
against HPV16 and HPV18 has irrevocably changed the
landscape of research into cervical cancer prevention.
No-one can predict how quickly we can move towards the
goal of a vaccine that protects against all carcinogenic
HPV types, with a safe and inexpensive, universally
applicable route of delivery. However, each improvement
in vaccines will force a reconsideration of the whole
prevention eff ort, relative to resources. Based on the
current vaccines, some new clinical directions are already
evident.
Although approval of the Merck vaccine has proceeded
rapidly in many countries, actual adoption has been
irregular by country and, at least in the USA, by state.
Mandatory vaccination, catch-up vaccination of older
girls and young women, and vaccination of boys remain
controversial issues. The protection off ered by two rather
than three doses of vaccine is being determined, which
will aff ect cost. The trade-off s from the quadrivalent
coverage of the Merck vaccine and the novel adjuvant of
the GSK vaccine will be considered in cost-eff ectiveness
analyses once more longer-term, type-specifi c effi cacy
data are released.
The use of HPV testing for primary screening will
certainly increase, but the relative roles of cytology and
HPV testing (alone or combined) will vary by country
for years to come. We predict that HPV genotyping,
fi rst for HPV16, will eventually enter clinical practice as
an important prognostic biomarker, and hope that its
introduction is preceded by clear validation of reliable
typing assays and useful follow-up algorithms. Once
genotyping is reliable, type-specifi c viral persistence
will immediately become an appealing and powerful
prognostic biomarker. The discussion will shift to
proper time intervals for defi ning persistence. Even if
data demonstrate high risk in women with persistent
infections in the absence of clearly diagnosed precancer,
excisional treatment based on molecular tests alone will
probably be very controversial and adopted as policy
only in societies favouring aggressive clinical
management.
Successful, widespread vaccine programmes will
motivate reconsideration of optimum screening
techniques and strategies. It is evident that the most
clear-cut cytopathological and colposcopic abnormalities
are caused by HPV16. The predictive values of screening
protocols including HPV testing depend to a major extent
on the risks associated with HPV16. Screening protocols
will need to change with time as the population prevalence
of HPV16 is gradually reduced.
Improvements in diagnosis will need to be made to
match the improvements in screening. Colposcopically
directed biopsy, in which the clinician targets the most
abnormal lesion, is not suffi ciently reliable or accurate to
diagnose precancer in women referred by the combination
of HPV testing and cytology. To foster better diagnosis
for clinical practice and as a reference standard of disease,
there is an urgent need for clinical trials to assess how
biopsies should be taken to improve sensitivity and the
reassurance of a negative colposcopic examination.
Otherwise, the benefi ts of improved screening will not be
fully realised.
Developing a simple and safe treatment for persistent
HPV infection, including small precancerous lesions,
would be an important breakthrough of immediate
importance worldwide. We can now reliably and
sensitively detect infection with carcinogenic types of
HPV to identify women at risk of cervical cancer, but
viral clearance is too common to justify immediate
treatment, especially at younger ages. In some regions,
for women past the peak ages of HPV prevalence, the
most eff ective screening-based prevention strategies
mandate immediate rather than delayed treatment
(which results in losses to follow-up). Immediate
treatment requires safe, inexpensive, simple destruction
of the transformation zone and surrounding epithelium
(or an equivalently safe and simple non-surgical
approach). Finding a treatment better than the current
forms of cryotherapy and loop excision should be a high
priority.
We project that improved vaccines, screening tests,
and management strategies will continue to emerge
without evident end. New vaccine candidates and
molecular biomarkers will supplant the prevention
tools we have discussed. How quickly the institutions
supporting cervical cancer prevention can react to
Seminar
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903
evolving opportunities is unclear. For example, recent
studies of visual inspection with acetic acid indicate
some benefi t in detection of cervical cancers and large
precancers. Adoption of this technique could reduce
the incidence of, and mortality due to, cervical cancer in
very low-resource regions. However, any large
prevention eff ort based on this technique should take
into account further improvements such as inexpensive
HPV testing, which will be available within a few years.
To frame and disseminate public-health messages at
this pace is diffi cult, even when the change represents
advances.
Conclusions
Much of the cervical cancer problem can be solved with
existing or soon-to-be available technology, suffi cient will,
and modest resources. There is an enlarging repertoire
of options for cervical cancer prevention for regions with
varying needs and values, based on innovative technology
and clear understanding of cervical carcinogenesis.
Because of the importance of the problem and the
feasibility of ameliorating it, we hope to see a major
decrease in the numbers of women aff ected with this
cancer within our lifetimes.
Confl ict of interest statement
ACR is supported by an appointment to the Senior Fellowship Program
at the National Institutes of Health (NIH). The programme is
administered by the Oak Ridge Institute for Science and Education
through an interagency agreement between the US Department of
Energy and the NIH. The other authors are supported by the
Intramural Research Program of the National Cancer Institute, NIH,
and the US Department of Health and Human Services. None of the
authors has a personal fi nancial confl ict of interest to report. The
National Cancer Institute has a clinical trials agreement with
GlaxoSmithKline (Rixensart, Belgium) in which we are autonomously
assessing their bivalent prophylactic HPV vaccine. The company will
be provided the data as part of their effi cacy demonstration, while we
will independently analyse and publish the fi ndings. The bulk of
funding for this large trial, apart from the provision of vaccine and
components required for the vaccine’s regulatory approval, is provided
by the National Cancer Institute.
Acknowledgments
We are grateful for important contributions from Allan Hildesheim and
Diane Solomon.
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