review ARTICLE J Bras Patol Med Lab, v. 52, n. 4, p.

238-245, August 2016

Cervical cancer screening:

10.5935/1676-2444.20160040
from Pap smear to future strategies
Triagem de câncer do colo uterino: do teste de Papanicolaou a estratégias futuras

Cristina Aparecida T. S. Mitteldorf

Hospital Sírio Libanês, São Paulo, Brazil.

abstract
Previously, the screening for detection of cervical cancer was performed by simple cervicovaginal sample collected by the physician whenever
the patient attended the medical consultation, and soon it was established as the annual “Pap smear”. Since then, an elementary test has
evolved into a complex process with multiple algorithms for the identification of invasive disease. The detection of human papillomavirus
(HPV) has become part of the new screening recommendations, resulting in major changes in the guidelines. This review intends to
emphasize the most important topics that are part of cervical cancer screening, including cervical cytology and HPV detection, and
to discuss particular aspects of cervical cancer in Brazil. Despite the great benefits achieved by the cervical cancer screening programs
with cytology and HPV test, there are still important issues to be discussed and improved in defining future strategies, including simplicity
and possible application in different socioeconomic contexts, definition of the best test or tests to be applied and recommended interval,
minimizing possible harms. After the establishment of screening algorithms well defined by leading organizations, management protocols
should be disseminated among physicians and patients by education programs.

Key words: cervical cancer; cervical cancer prevention; molecular diagnostic methods; vaginal smears; HPV DNA tests.

Introduction of early uterine cancer. In one year, it was found 54 cases of cancer
in 639 women, 51 of them correctly diagnosed by cytology and six
detected exclusively by Pap smear(3).
Although the observation of cells was the first and original
approach to the study of human diseases in the 19th century, the The implementation of a very simple and effective screening
development of cytology as a diagnostic modality, as it is known test was followed by a dramatic decrease in mortality rate related
today, followed the fundamental contribution of Dr. George to cervical cancer in different populations(4-13).
Nicolas Papanicolaou, who first reported in 1928 that malignant
Over the past 30 years, the widespread routine cervical cancer
cells from the cervix can be identified in vaginal smears. His work
cytology screening has contributed to a 50% reduction in the
in collaboration with the gynecologist Herbet Traut provided
a detailed description of the cytology of the female genital tract incidence of cervical cancer in the United States. As demonstrated
and the basis of the discovery of unsuspected occult cancer in by the data, proper screening may effectively prevent cervical
asymptomatic patients, published many years later. Although cancer, since 50% of women diagnosed with cervical cancer
initially their observations were received with skepticism by had never undergone cervical cytology testing and another 10% had
both pathologists and clinicians, many confirmed their findings not received screening in the five years preceding their diagnosis(14).
subsequently, and cervical smears were embraced as a routine Cervical cancer is very rare among screened women(15).
screening test for preinvasive lesions of the cervix, since then Cervical cytology is reported according to the Bethesda system,
known as “Pap smear” or “Pap test”(1, 2). which was introduced in 1988. The principles of the reports include
The first cervical cancer screening clinics were established in clear, uniform, and reproducible terminology, reflecting the most
the 1940s, when a number of women were screened for detection current understanding of cervical neoplasia. It was revised in

First submission on 09/05/16; last submission on 10/07/16; accepted for publication on 11/07/16; published on 20/08/16

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 Cristina Aparecida T. S. Mitteldorf

1999, 2001 and the last updated version occurred in 2014, which intraepithelial lesions (LSIL and HSIL) by LBC preparations,
includes an assessment of the specimen adequacy, whether there is a systematic review did not confirm that LBC is more accurate
evidence of lesions and the severity of the lesions(16). than conventional smears, but has an equivalent performance.
Even so, LBC is gradually replacing the conventional cytological
preparations, because it presents many other clear advantages,
Human papillomavirus including the possibility of aliquoting for the hrHPV test(22).
Cervicovaginal cytology is clearly far from being a perfect
Most cervical cancers develop from infected cells with high- screening test. In a systematic review, it was shown to have a sensitivity
risk human papillomavirus (hrHPV), originated from the of only 51% (ranging from 30% to 87%) and a specificity of 98%
squamocolumnar junction. The causal link was described by Dr. (ranging from 86% to 100%), although methodological quality and
Harald zur Hausen, who won the Nobel prize in 2008 for isolating frequency of histological abnormalities varied greatly, and only 12 of
the human papilloma virus (HPV) types 16 and 18 from cervical the 94 studies with less biased estimates were analyzed(23).
cancer tissue(17).
Furthermore, there is a significant interobserver variability
HPV is among the most powerful human carcinogens and has in the interpretation of cytology, contributing to variations in
been implicated not only to cervical cancer, but also to cancers sensitivity and specificity rates. We must not forget that the
at several sites. HPV infection is the most common sexually interpretative variability is also significant for histological
transmitted infection worldwide, mainly in low- and middle- specimens, even among well-trained observers demonstrated in
income countries(18). Apparently hrHPV is a necessary but not a cervical biopsies, as well as many other sites and organs(24).
sufficient condition for almost all cervical cancers. The risk of
preinvasive lesions and invasive cancer of the cervix is strongly A meta-analysis found that about 29% of failures to avoid
associated with persistent infection with hrHPV, especially type invasive cervical cancer can be attributed to false-negative cytology.
16. Fortunately, most HPV infections in human are harmless, The authors examined 42 studies from 1950 to 2007, and the most
and cause no lesion. Due to the interaction between host and the common failure of the process was history of poor screening: 54%
pathogen, the majority of infected women will clear the virus and of women had inadequate screening intervals and 42% had never
the precancerous lesions will regress. Only about 1% of low-grade been screened. It should be emphasized that the proportion of Pap
lesions (CIN1) and 12% of high-grade lesions (CIN3) will progress smears originally reported as normal and that, after review, were
and become invasive if left untreated(19). classified as false-negatives, or those normal cases that were not
reviewed, but simply assumed to be false-negative, varied greatly
Since the causal link between cervical cancer and hrHPV among studies. Sampling errors may have contributed to at least
infection was established, much effort has been devoted to the some of the cases not reviewed(25).
study of prevention and identification of HPV infection. Currently
vaccination against carcinogenic strains of HPV is commercially
available, but even in some developed countries the vaccination HPV test
uptake has been slow(19, 20).

The detection of HPV deoxyribonucleic acid (DNA) may be

Papanicolaou test – “Pap smear” accomplished by several molecular methods, particularly including
signal-amplification (Hybrid Capture® assay) and polymerase
chain reaction (PCR) based methods. The Hybrid Capture® system
In use for more than 50 years, the Pap test in its original is designed to detect HPV divided into high- and low-risk groups,
preparation, also called “conventional cervical smear (CS) without genotyping individual virus, demonstrating high sensitivity
method for cytology collection”, is still acceptable for screening and specificity for hrHPV. The PCR-based techniques are highly
purposes(21). It remains as an alternative for cervical cancer sensitive and specific but, besides being a labor-intensive procedure,
screening due to its simplicity and low cost.
it also presents some drawbacks, such as false negative results. Real-
The liquid based cytology (LBC) was approved by the US time PCR assay is a rapid, reproducible and reliable diagnostic tool,
Food and Drug Administration (FDA) in 1996 as an alternative which has the additional advantages of detecting very small viral
to conventional cervicovaginal smear. Although several studies concentrations and different targets simultaneously, as well as to
showed an increased detection of low- and high-grade squamous determine the viral load(26).

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 Cervical cancer screening: from Pap smear to future strategies

Initially, the hrHPV test was recommended as a reflex testing Although the cobas® HPV test has been approved, it was
of atypical squamous cells of undetermined significance (ASC-US) stressed that it has limited sensitivity (27% for women equal to
to screen patients to colposcopy. The sensitivity for detecting CIN3 or older than 50 years, 36% for women equal to or older than
or greater by hrHPV test was 96.3% compared to 44.1% of cytology 40 years, 53% for women equal to or older than 30 years, and
by one repeat with a screening threshold of HSIL or greater(27). 58% for women equal to or older than 25 years), which is much
lower than that observed with the cotesting in women equal to or
In 2004, the National Institute of Health, the National Cancer
older than 30 years, perhaps because of suboptimal performance
Institute, the American Society for Colposcopy and Cervical
of cytology(21, 29, 42). Negative HPV rates in patients with invasive
Pathology (ASCCP) and the American Cancer Society (ACS)
cervical cancer varied among authors and seemed to increase
agreed to expand the use of hrHPV as a cotesting(28, 29).
with time before cancer diagnosis, perhaps due to the smaller size
The joint recommendation released in 2012 advocates HPV of lesions or lower viral titers during earlier periods(42). Another
testing to be used in conjunction with routine cytology, as well arguable point is the use of CIN2 or/and CIN3 or worse as the right
as a reflex testing in women aged 30 to 65 years(14, 21). A woman endpoint for evaluating cervical screening algorithm, since it does
with a negative result for both hrHPV and cytology has a lower not reflect cancer risk accurately(16, 42).
risk of developing CIN2 or CIN3 in the next four to six years(14).
The cotesting increases the detection of CIN2 or greater lesions at
baseline and significantly decreases the detection rates of CIN2/ Screening guidelines
CIN3 or greater lesions at subsequent screening compared to
cytology alone(30).
Screening recommendations proposed by several societies
The ATHENA trial demonstrated that 10% of women who tested and private organizations have been published and are reviewed
positive for HPV 16 and/or 18 had high-grade cervical neoplasia periodically when new evidence suggests that a change may be
(CIN2 or worse) that was not detected by cytology(31). Many other necessary. Previous established guidelines showed considerable
studies have documented that HPV testing has a greater sensitivity variation prior to 2012.
and reproducibility with increased negative predictive values
The current American guidelines for cervical cancer screening
compared to cytology(32-38). The data presented by these studies
were created in 2012 as a joint recommendation of the ACS, ASCCP
endorsed the idea of hrHPV test as a primary screening test, replacing
and the American Society for Clinical Pathology (ASCP), which
cytology as screening women for colposcopy, advocated by many.
were accepted and promoted by the ACOG, in association with US
In 2014, the FDA approved the cobas® HPV test for primary Preventive Service Task Force (USPSTF). The benefit was defined
screening of cervical cancer in women aged 25 or older, by as more detection of CIN3 or worse at baseline and reduction in
detection of hrHPV genotypes, at intervals equal to or greater than CIN3 or worse detection at subsequent rounds of screening. The
three years(39). harm was defined as an increase in number of colposcopy(14, 21, 43).
Interim guidelines for primary hrHPV screening were Some reviews on cervical cancer screening guidelines
developed by representatives from the Society of Gynecologic present a summary from major organizations recommendations
Oncology, the American Society of Cytopathology, and the College and the reader will find more detailed information(44).
of American Pathologists, in addition to American Congress of The current main guidelines recommendations are the following:
Obstetricians and Gynecologists (ACOG), and all groups authoring
• cervical cancer screening should begin at 21 years of age,
the 2012 screening guidelines(40).
regardless of age of coitarche or vaccination status, with cervical
In the Quest Diagnostics Health Trend study, which enrolled cytology tests exclusively until 30 years of age (either with
more than 250,000 women, the HPV/Pap cotesting identified conventional or liquid-based cytology), every three years;
more women whose cervical biopsy result revealed a finding of
• for women from 30 to 65 years of age, cotesting with cytology
CIN3 or greater than HPV-only testing (98.8% versus 94%). The
and HPV test every five years is preferred, although cytology
data showed that up to 19% of women with cancer may be missed
screening every three years is acceptable;
when they are screened using HPV testing only; HPV/Pap cotesting
misses 5.5% of cancer cases, and Pap alone, 12.2%. The authors • screening should be discontinued for women over 65 years of
concluded that cotesting in women aged 30-65 is the most effective age at low risk, with no history of cervical intraepithelial neoplasia
screening test for detecting cervical cancer(41). (CIN) grade 2 or greater, with negative results in prior screening;

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 Cristina Aparecida T. S. Mitteldorf

• screening should be discontinued for women of any age who In 2014, the Ministry of Health of Brazil launched the National
have total hysterectomy and have no history of cervical cancer or Immunization Program through a quadrivalent HPV vaccine
precancerous condition. (subtypes 6, 11, 16, and 18) for girls between 9-13 years old(57).
Adherence to guideline recommendations is quite variable. A recent study evaluated the cervical cancer screening program
Many clinicians continued to suggest annual Paps, as recommended in Brazil from 2006 to 2013 using the Information System of Cervical
by ACOG, although current guidelines advocated against annual Cancer Screening (Sistema de Informação do Câncer de Colo de
screening, since no advantage is observed in relation to Pap tests Útero [SISCOLO]), created by the Department of Informatics of the
performed every two or three years. Physicians believe that patients Public Health System (Departamento de Informática do Sistema
were uncomfortable with less frequent testing and if they extend Único de Saúde [DATASUS]), which contains information on all Pap
the screening intervals, patients would not return annually just for tests collected in the public health system, and was implemented for
the clinical examination(45). the management and monitoring of the cervical cancer screening
program(58). A decreasing trend in the rates of LSIL and HSIL was
observed, as well as lower numbers of positive cytological diagnosis
Cervical cancer in Brazil and an increased rate of rejected exams. The positivity rates and
the frequency of unsatisfactory cases were lower than expected. The
According to the 2016/2017 estimates, Brazil will register next authors suggest that actions should be taken by the government
year 300,800 cases of cancer among women(46). More than 16,000 to improve the effectiveness of cervical cancer control in Brazil,
new cases of cervical cancer are expected in 2016(47). Cervical cancer through more funding for internal quality control during both the
remains as the third leading cause of cancer-related mortality pre-analytical and the analytical phase(59).
among women for decades, without any improvement(48). Albeit Brazil, like many other countries in Latin America, has
Currently, the Brazilian program to cervical cancer control is a cytology-based screening program, they often have problems
based on population screening and vaccination, used together as with quality and/or delays in follow-up care(60).
complementary actions and coordinated by the Brazilian National
Cancer Institute (Instituto Nacional de Câncer José Alencar Gomes
da Silva [Inca]), an agency of the Ministry of Health of Brazil Future strategies
facing national integrated actions for the control and prevention
of cancer(49). The screening method is the Pap test or Pap smear The best screening algorithm remains a matter of debate.
for women between 25 to 64 years old, or sexually active women;
this test is provided annually (or once every three years after two Primary HPV screening is an attractive option to health service
normal tests) and it is followed by colposcopy for HSIL, carcinoma, because the results are not subject to inter-observer variation.
or persistent LSIL or ASC-US. However, it requires equipments, reagents, personnel, training,
quality control and accreditation. This scenario is far from the
LBC was also incorporated as the standard method of
real world in different populations, even in developed countries,
evaluating cervical samples in Brazil, largely replacing CS. Some
considering that many women will be screened or may never be
Brazilian studies have demonstrated a better performance of LBC
screened at all.
compared to CS, with lower rates of unsatisfactory specimens and
higher sensitivity(50-52). A more recent study critically analysed We must remember the fact that the system for cervical
218,594 cases collected in a public health service in the state of cancer screening with both the Pap test and the HPV test is already
São Paulo and observed positivity of 5.7% versus 3%, respectively, working in many practices. There is no reason to disrupt such an
in LBC and CS; unsatisfactory preparations were present in 0.3% operative scheme that is working successfully without adequate
and 3% of the cases, respectively(53). However other groups have evidence of additional benefit of primary HPV screening. Further
observed similar performances between the methods, finding no data are needed on the actual benefits and costs and the impact on
significant diferences(54, 55). the use of colposcopy and other diagnostic tests(61).
In 2012, a Quality Management Manual for Cytopathology Supporters of primary HPV screening claim that this method
Laboratory was published by Inca and the Ministry of Health of not only finds more CIN3 or worse than cytology or cotesting does,
Brazil, in order to improve the quality and reliability of cytological but also find them earlier; moreover, the positive predictive value
test(56). of the primary HPV screening algorithm was greater than that

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 Cervical cancer screening: from Pap smear to future strategies

one of cytology. In contrast, those who advocate cotesting believe After well defined, screening algorithms were established by
this approach detects more disease than the HPV test alone and leading organizations; management protocols should be
emphasize that the performance of this new algorithm has not disclosed among physicians and patients through education
been assessed in routine clinical use. The focus of the debate programs, integrated into a multidisciplinary team, with
about the best screening algorithm to detect cervical cancer is the participation of all professionals involved in women’s
much more complex, since it may involve reducing costs rather health, ensuring not only a more effective diagnosis, but also
than maximizing protection, not only by decreasing the number an appropriate treatment and monitoring, connecting the
of tests, but also by increasing the screening intervals(41). primary, secondary and tertiary levels of health. In Brazil,
In some practices, where access to cytological examination is the new recommendations are being finalized and will soon be
limited, primary HPV testing may allow to provide screening for published by Inca, Ministry of Health of Brazil.
the patients, which had not been previously possible(61).
Several studies support that HPV testing is feasible in low-resource
Conclusion
setting as a tool for cervical cancer screening. The incorporation of
new technologies, adapted for low- and middle-income countries
may be part of future programs for early diagnosis and control of 1) Cervical cytology, including conventional smear and
the disease. Although the best screening strategy in this context is liquid based cytology, is a successful method for cancer screening
still a work in progress, perhaps HPV testing can be applied using a and is still recommended as the exclusive test for women 21 to 29
self-obtained vaginal samples that will allow first-line screening years of age; 2) since HPV was established as the main causative
and triaging of HPV-positive women during a single visit, agent of cervical cancer, its detection improved screening
defining management and eventually treatment(62). sensitivity; 3) cotesting, hrHPV test used in association with
In summary, despite the great benefit that the cervical cytology, is recommended for women 30 to 64 years of age, since
cancer screening programs achieved through the use of it is the most effective screening method for detecting cervical
cytology and HPV testing, there are still important issues cancer; 4) the sole routine clinical use of HPV testing, or primary
to be discussed and improved in defining future strategies, HPV testing, is still a matter of debate, but, perhaps, it may prove
including simplification and possible application in different to be an option for strategic screening in countries with limited
socioeconomic contexts, definition of the best test or tests to resources, as new tests are becoming faster, automated and cost-
be applied and interval recommendation, minimizing harms. effective.

resumo
Inicialmente, a triagem para detecção do câncer de colo uterino era feita por meio de uma simples amostra cervicovaginal colhida
pelo médico, sempre que o paciente comparecia à consulta médica; logo se estabeleceu como “exame de Papanicolaou” anual. Desde
então, um teste elementar evoluiu para um processo complexo, com múltiplos algoritmos para identificação de doença invasiva. A
detecção do papilomavírus humano (HPV) tornou-se parte das novas recomendações de triagem, resultando em grandes mudanças
nas diretrizes. Esta revisão pretende enfatizar os tópicos mais importantes que fazem parte do rastreamento do câncer de colo do
útero, incluindo citologia cervical e detecção do HPV, bem como discutir aspectos particulares do câncer de colo do útero no Brasil.
Apesar dos grandes benefícios alcançados pelos programas de rastreamento do câncer de colo uterino por meio do uso da citologia
e do teste de HPV, existem ainda pontos importantes a serem discutidos e melhorados na definição de estratégias futuras, como
simplicidade e possível aplicação em diferentes contextos socioeconômicos, definição do melhor teste ou testes a serem aplicados
e intervalo recomendável, minimizando possíveis danos. Após o estabelecimento de algoritmos de rastreamento bem definidos
pelas principais organizações, protocolos de manejo devem ser divulgados entre médicos e pacientes por programas de educação.

Unitermos: neoplasias do colo do útero; prevenção de câncer de colo uterino; técnicas de diagnóstico molecular; esfregaço vaginal;
testes de DNA para HPV.

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Corresponding author

Cristina Aparecida T. S. Mitteldorf

Rua Dona Adma Jafet, 91, 3º subsolo, bloco C; Bela Vista; CEP: 01308-050, São Paulo-SP, Brasil; e-mail: crismittel@terra.com.br.

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