Cervical intraepithelial neoplasia: Terminology, incidence, pathogenesis, and prevention

Author
Jason D Wright, MD
Section Editor
Barbara Goff, MD
Deputy Editor
Sandy J Falk, MD, FACOG
Disclosures: Jason D Wright, MD Grant/Research/Clinical Trial Support: Genentech [Ovarian cancer
(Bevacizumab). Consultant/Advisory Boards: TheVax Genetics [Human papillomavirus (Therapeutic human
papillomavirus vaccine)]. Barbara Goff, MD Nothing to disclose. Sandy J Falk, MD, FACOG Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed
by vetting through a multi-level review process, and through requirements for references to be provided to support the
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All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Jun 2015. | This topic last updated: May 06, 2014.
INTRODUCTION Cervical intraepithelial neoplasia (CIN) is a premalignant condition of the
uterine cervix [1]. The ectocervix (surface of the cervix that is visualized on vaginal speculum
examination) is covered in squamous epithelium, and the endocervix, including the cervical canal, is
covered with glandular epithelium. CIN refers to squamous abnormalities. Glandular cervical
neoplasia includes adenocarcinoma in situ and adenocarcinoma. (See "Cervical cytology:
Evaluation of atypical and malignant glandular cells" and "Cervical adenocarcinoma in
situ" and "Invasive cervical adenocarcinoma".)
Screening for cervical cancer includes cervical cytology and testing for oncogenic subtypes of
human papillomavirus (HPV). Follow-up of abnormalities in screening tests with colposcopy and
cervical biopsy may result in a diagnosis of CIN or cervical cancer [2].
CIN may be low-grade or high-grade. Women with low-grade CIN have minimal potential for
developing cervical malignancy, while those with high-grade lesions are at high risk of progression
to malignancy.
The definition, incidence, and pathogenesis of CIN are reviewed here. The management of CIN and
the epidemiology and virology of HPV infection are discussed separately. (See "Cervical
intraepithelial neoplasia: Management of low-grade and high-grade lesions" and "Epidemiology of
human papillomavirus infections" and"Virology of human papillomavirus infections and the link to
cancer".)
TERMINOLOGY Historically, premalignant squamous changes of the cervix were described as
mild, moderate, or severe cervical dysplasia. In 1988, a new terminology system was introduced,
the Bethesda system, which was then revised in 1991 and 2001. In this system, different
terminology was used for cytologic (on Pap test) and histologic (on biopsy) findings [3-5]. Cytologic
findings were described with the term "squamous intraepithelial lesion (SIL)" and histologic changes
were described with the term "cervical intraepithelial neoplasia (CIN)." The term CIN has three
degrees of severity (figure 1 and picture 1):

CIN 1 is a low-grade lesion. It refers to mildly atypical cellular changes in the lower third of
the epithelium. Human papillomavirus (HPV) cytopathic effect (koilocytotic atypia) is often
present.
CIN 2 is considered a high-grade lesion. It refers to moderately atypical cellular changes
confined to the basal two-thirds of the epithelium (formerly called moderate dysplasia) with
preservation of epithelial maturation. As noted below, there is considerable variability in this
category.
CIN 3 is a high-grade lesion. It refers to severely atypical cellular changes encompassing
greater than two-thirds of the epithelial thickness and includes full-thickness lesions (previous
terms were severe dysplasia or carcinoma in situ).
In 2012, the Lower Anogenital Squamous Terminology (LAST) project of the College of American
Pathology and the American Society for Colposcopy and Cervical Pathology published changes in
the terminology used to describe HPV-associated squamous lesions of the anogenital tract [6,7]. In
the LAST system, histologic cervical findings are described using the same terminology as cytologic
findings, as follows (figure 1):
CIN 1 in the previous terminology system is referred to as low-grade squamous intraepithelial
lesion (LSIL).
CIN 2 is stratified according to p16 immunostaining to identify precancerous lesions. CIN 2
has poor reproducibility and is likely a heterogeneous mix that includes lesions that could be
called CIN 1 or 3. Specimens that are p16-negative are referred to as LSIL and those that are
p16-positive are referred to as high-grade squamous intraepithelial lesions (HSIL).
CIN 3 is referred to as HSIL.
In this topic, CIN terminology is used because that terminology is used in the 2012 American
Society of Colposcopy and Cervical Pathology guidelines for the evaluation and management of
cervical cytologic and histologic abnormalities [2].
Terminology for cytologic squamous cell abnormalities is discussed separately. (See "Cervical and
vaginal cytology: Interpretation of results", section on 'Terminology for squamous cell
abnormalities'.)
INCIDENCE The estimated annual incidence in the United States of cervical intraepithelial
neoplasia (CIN) among women who undergo cervical cancer screening is 4 percent for CIN 1 and 5
percent for CIN 2,3 [8]. High-grade lesions are typically diagnosed in women 25 to 35 years of age,
while invasive cancer is more commonly diagnosed after the age of 40, typically 8 to 13 years after
a diagnosis of a high-grade lesion. (See "Invasive cervical cancer: Epidemiology, risk factors,
clinical manifestations, and diagnosis", section on 'Epidemiology and risk factors'.)
PATHOGENESIS
Role of human papillomavirus Human papillomavirus (HPV) is the major etiologic agent of
cervical precancer and cancer [9,10]. The association between HPV and cervical neoplasia is so
strong that most other behavioral, sexual, and socioeconomic covariables have been found to be
dependent upon HPV infection and do not hold up as independent risk factors [9,11].

HPV infection is necessary for development of cervical neoplasia, but since the vast majority of
women infected with HPV do not develop high-grade cervical lesions or cancer, HPV alone is not
sufficient to cause these disorders [12-24].
The two major factors associated with development of high-grade cervical intraepithelial neoplasia
(CIN) and cervical cancer are the subtype of HPV and the persistence of the virus. Environmental
factors (eg, cigarette smoking) and immunologic influences also appear to play a role.
(See 'Cofactors in pathogenesis' below.)
Types There are over 100 HPV types; approximately 40 types are specific for the anogenital
epithelium and have varying potentials to cause malignant change [25]. The distribution of HPV
subtypes in the population varies somewhat by geographic region [12]. Sequential infection with
different HPV subtypes and concurrent infection with more than one HPV subtype is common
[26,27]. Acquisition of one subtype of HPV infection and clearance of another subtype of HPV
infection are independent events.
The HPV type determines the clinical manifestations of the infection and the oncogenic potential
(low or high) of the virus (table 1):
Low-risk types, such as HPV 6 and 11, do not integrate into the host genome and only cause
low-grade lesions (CIN 1) and benign condylomatous genital warts (table 2) [28-30]. Overall,
HPV 6 and 11 account for 10 percent of low-grade lesions and 90 percent of condylomatous
genital warts.
High-risk HPV types, such as 16 and 18, are strongly associated with high-grade lesions
(CIN 2,3), persistence, and progression to invasive cancer, although they may also be
associated with low-grade lesions. HPV 16 and 18 account for 25 percent of low-grade
lesions, 50 to 60 percent of high-grade lesions, and 70 percent of cervical cancers [31]. Highgrade lesions are usually flat, but cancers can be nodular, ulcerative, exophytic, or endophytic.
There are differences in the oncogenic potential of the high-risk HPV subtypes and even among the
variants within a specific subtype [30,32]. The greater association ofprecancer/cancer with HPV 16
compared with other oncogenic types was illustrated in a study of women with low-grade lesions
and HPV 16 [33]. The two-year cumulative absolute risk of developing CIN 3 or worse was
significantly higher in women with HPV 16 infection than in those with infection involving other highrisk subtypes (30 to 40 percent versus 8 to 10 percent).
HPV plays a role primarily in the two most common histologic types of cervical cancer: squamous
cell (69 percent of cervical cancers) and adenocarcinoma (25 percent) [34]. The HPV subtypes
associated with squamous cancer differ somewhat from those associated with adenocarcinoma. In
an international study of over 30,000 cervical cancers, the distribution of HPV subtypes was [35]:
Squamous cell carcinoma HPV 16 (59 percent of cases), 18 (13 percent), 58 (5 percent),
33 (5 percent), 45 (4 percent)
Adenocarcinoma HPV 16 (36 percent), 18 (37 percent), 45 (5 percent), 31 (2 percent), 33
(2 percent)
Testing for high-risk HPV types is discussed separately. (See "Cervical cancer screening tests:
Techniques for cervical cytology and human papillomavirus testing", section on 'HPV
testing' and "Screening for cervical cancer", section on 'HPV testing'.)

Age and persistence Most cervical HPV infections are transient and occur in young women.
Persistent infection with oncogenic HPV subtypes is a key factor in development of high-grade
cervical lesions [36-43] and cervical cancer [41-43], while clearance of HPV infection predicts
regression of CIN [44].
Over 50 percent of new HPV infections are cleared in 6 to 18 months, and 80 to 90 percent will
have resolved within two to five years [33,36-38,45-47]. Transient infections are particularly
common in young women in whom the average duration of a newly diagnosed HPV infection is 8 to
13 months [38,46,48]. It is unclear whether HPV-positive women who become HPV-negative
actually clear the virus from their bodies or retain the virus in an inactive or low-level state.
The age distribution of HPV was illustrated in a study of females aged 14 to 59 years (n = 1921);
the overall prevalence was 26.8 percent [49]. The rate of detection of HPV by age group was: 14 to
19 years (24.5 percent), 20 to 24 years (33.8 percent), 25 to 29 years (27.4 percent), 30 to 39 years
(27.5 percent), 40 to 49 years (25.2 percent), and 50 to 59 years (19.6 percent). Point prevalence is
much lower, peaking at 30 to 50 percent for women in their twenties and thirties, 15 percent at age
26 to 30, 10 percent at age 31 to 35, 5 to 15 percent at age 40 to 60, but then increasing up to 30
percent after age 50 [31,50]. (See "Epidemiology of human papillomavirus infections".)
The reason HPV persists in some women and not in others is unknown. A persistent HPV infection
is variably defined as one that is present for at least 6 to 12 months. In one prospective populationbased cohort study, 21 percent of patients with highly oncogenic HPV infections persisting over 12
months developed CIN 2 or worse over 30 months follow-up [38].
The likelihood of persistence is related to several factors:
Older age 50 percent of high-risk HPV infections persist in women older than 55 years of
age compared with a 20 percent rate of persistence in women under age 25 [31].
Duration of infection The longer an HPV infection has been recognized, the longer it will
take to clear. In the ASCUS-LSIL Triage Study (ALTS) study, 65 percent of infections that had
been observed for at least 18 months persisted for another six months, while 37 percent of
newly observed HPV infections persisted for six months [27].
High oncogenic HPV subtype High oncogenic risk HPV subtypes are more likely to persist
than low oncogenic types [46]. (See 'Types' above.)
After viral infection or administration of the HPV vaccine, a host immune response develops. The
immunologic response to papillomaviruses is still incompletely understood; however, an adequate
antibody response usually prevents reinfection with the same viral type.
Sexual transmission HPV is transmitted through sexual contact. Cervical cancer and its
precursors are almost nonexistent in women who have not had any sexual relationships [51].
HPV infection is endemic among sexually experienced individuals. The risk correlates with the
lifetime number of sex partners, but is relatively high (4 to 20 percent) even in those with one
partner. At least 75 to 80 percent of sexually active women will have acquired a genital HPV
infection by age 50 [52].
HPV infection of the cervix or lower female genital tract is asymptomatic and is only clinically
apparent if genital warts or neoplastic lesions develop.

The epidemiology of HPV infection is discussed separately. (See "Epidemiology of human

papillomavirus infections".)
Cervical transformation zone The transformation zone of the cervix is regarded as the site of
carcinogenesis mediated by infection with oncogenic subtypes of HPV.
The terms "transformation zone" and "squamocolumnar junction" are frequently used
interchangeably in the literature. However, these are two distinct entities. The squamocolumnar
junction is the area in which the squamous epithelium of the ectocervix meets the columnar
epithelium of the endocervix. The cervical transformation zone is a dynamic entity of metaplasia
throughout a womens life and is histologically the area where the glandular epithelium has been
replaced by squamous epithelium. Thus, the squamocolumnar junction is part of the transformation
zone, but the transformation zone comprises a larger area than just the squamocolumnar junction.
Some data suggest that the primary site of carcinogenic HPV-related CIN and cervical cancer is not
the entire transformation zone, but is a small population of cuboidal cells at the squamocolumnar
junction [53]. This group of cells has a unique gene expression profile similar to that found in
squamous and glandular high-grade CIN and carcinomas.
Molecular mechanism HPV infection of the cervix or lower female genital tract is asymptomatic
and is only clinically apparent if genital warts or neoplastic lesions develop.
Clinical scenarios that may ensue following acute HPV infection include:
Latent infection without physical, cytologic, or histologic manifestations. This is the most
common clinical sequelae of HPV infection, occurring in well over 90 percent of infected
women.
Active infection in which HPV undergoes vegetative replication, but not integration into the
genome.
Actively replicating HPV produces characteristic cellular changes such as nuclear
enlargement, multinucleation, hyperchromasia, and perinuclear cytoplasmic clearing (halos)
[54]. On average, these changes occur two to eight months after the woman is first infected
[55]. The cytologic findings are also the cytologic characteristics of low-grade squamous
intraepithelial lesions (LSIL) and atypical squamous cells of undetermined significance (ASCUS); thus, LSIL and HPV-positive ASC-US can be considered cytologic manifestations of
active HPV infection.
Resolution of infection is associated with regression of the cytologic changes. Resolution
appears to be related, at least in part, to formation of HPV antibodies and recruitment of
macrophage natural killer cells and activated CD4+ T-lymphocytes [56-58]. In most women,
the immune response is a dominant process, so the infection remains latent or is suppressed
quickly; however, these antibodies can take months to develop or never develop at all [55].
Neoplastic transformation in which HPV integrates into the human genome. Possible clinical
manifestations of this state include high-grade lesions and cancer. This process occurs years
after the acute infection. (See "Virology of human papillomavirus infections and the link to
cancer".)

HPV is epitheliotropic; once the epithelium is infected, the virus can either persist in the cytoplasm
or integrate into the host genome. When HPV remains in an episomal nonintegrated state, the
result is a low-grade lesion. When the virus becomes integrated into the human genome, highgrade lesions and cancer may develop [59].
An important factor in the early stages following infection is the individual's susceptibility to
oncogenic HPV types, which is determined by the host's immune system [60]. Viral integration into
the host genome results in the disruption of the E1 and E2 open reading frames and therefore, it
also results in loss of the transcriptional regulation of E6 and E7, with resultant overexpression of
these oncoproteins [13]. The HPV E6 protein binds to p53 and induces the cellular degradation of
p53, while E7 interacts with the retinoblastoma protein (Rb), which leads to dissociation of the
transcription factor E2F and promotion of cell cycle progression [61,62]. The disabling of these two
major tumor suppressor genes, p53 and Rb, is thought to be central to host cell transformation
induced by HPV and immortalization of infected cell lines. The presence of extracellular E7 also
activates cervical endothelial cells, resulting in overproduction of interleukins 6 and 8, two cytokines
that are associated with progression of CIN 2,3 to overt malignancy in more than 80 percent of
cancers [63,64]. (See "Virology of human papillomavirus infections and the link to cancer", section
on 'Molecular pathogenesis'.)
COFACTORS IN PATHOGENESIS
Immunosuppression
Human immunodeficiency virus (HIV) infection The incidence of cervical intraepithelial
neoplasia (CIN) is increased in HIV-infected women [65-68]. The increased risk of CIN
appears related to the greater prevalence of human papillomavirus (HPV) infection in these
women (64 percent versus 27 percent in women without HIV infection). (See "Preinvasive and
invasive cervical neoplasia in HIV-infected women".)
The risk of both HPV infection and CIN increases with increasing degrees of
immunosuppression (as measured by lower CD4 counts and higher HIV RNA load) [68-70].
This was illustrated in a longitudinal study that found HIV-infected patients were more likely to
be repeatedly HPV positive over a six-year period than women without HIV infection (79
versus 48 percent) and that a subsequent positive HPV test was more common in those with
CD4 counts less than 200/L than in those with CD4 counts more than 200/L (93 versus 48
percent) [68].
In addition, cervical cancer is one of the most common acquired immunodeficiency syndrome
(AIDS)-related malignancies in women [71].
Immunosuppressive therapy Women with chronic conditions requiring long-term
immunosuppressive therapy are at increased risk of developing CIN [72,73]. This association
has been described in transplant recipients and women with systemic lupus erythematosus
[74-77].
Cigarette smoking Cigarette smoking and HPV infection have synergistic effects on the
development of CIN and cervical cancer [78-84]. Compared with HPV-negative nonsmokers, one
study reported that the risk of CIN 2,3 with smoking alone, HPV infection alone, and both smoking
and HPV infection was approximately twofold, 15-fold, and 66-fold, respectively [82]. The

cumulative exposure to cigarette smoking (as measured by pack-years smoked) is strongly related
to the risk of CIN [85]. In another study of HPV-positive women, the risk of cervical cancer in
smokers was two- to fourfold that of nonsmokers [79].
Breakdown products of cigarette smoke, such as nicotine, cotinine, and nicotine-derived
nitrosamine ketone (NNK) (ie, 4-[methylnitrosamino]-1-[3-pyridyl]-1-butanone), are concentrated in
cervical mucus, where they may induce cellular abnormalities in cervical epithelium [86,87] and
decrease local immunity [88,89]. Impaired host immunity may then allow persistence of oncogenic
virus.
Herpes simplex virus and chlamydia Infection with chlamydia [90-92], herpes simplex virus
[93-95], or other sexually transmitted infections may be a surrogate marker of exposure to HPV
rather than a causal factor itself (table 3) [96]. Alternatively, these infections may modulate host
immunity, thereby facilitating persistence of oncogenic HPV [97,98].
Oral contraceptives Long-term use of oral contraceptives has been implicated as a cofactor
that increases the risk of cervical carcinoma in women who are HPV-positive [84]. However, oral
contraceptive use may be a surrogate marker of exposure to HPV rather than a causal factor. The
excess risk of cervical cancer declines after discontinuation of oral contraceptives, and by 10 years,
returns to the baseline risk in nonusers [99]. (See "Risks and side effects associated with estrogenprogestin contraceptives", section on 'Cervical cancer'.)
Other For the most part, genetic, familial, dietary, and endogenous hormonal factors are not
thought to play a role in development of CIN or cervical cancer [100,101]. Although familial factors
were implicated in some studies of the pathogenesis of squamous cell cervical cancer, familial
aggregation due to shared environmental exposures could not be excluded [102,103]. Several
studies have reported that certain human leukocyte antigen (HLA) types can affect the risk of HPV
acquisition and therefore, may make some patients more susceptible to HPV infection based on a
genetic factor [104].
One review found that high parity increased the risk of squamous carcinoma of the cervix among
HPV-positive women [105]. There are few data regarding the role of marijuana smoking in CIN. The
only study was performed in women with HIV infection and suggested no increase in the burden of
cervical HPV infection [106].
PREVENTION
Primary prevention The primary approach to prevention of cervical intraepithelial neoplasia
(CIN) is vaccination against oncogenic human papillomavirus (HPV) infection. This is discussed in
detail separately. (See "Recommendations for the use of human papillomavirus vaccines".)
Use of HPV vaccination in women with a current or prior HPV infection or CIN is discussed in detail
separately. (See "Cervical intraepithelial neoplasia: Treatment and follow-up", section on 'HPV
vaccination in women with CIN'.)
Although HPV is a sexually transmitted infection, condoms are only partially protective.
(See "Cervical intraepithelial neoplasia: Treatment and follow-up", section on 'Management of
sexual partners'.)

Secondary prevention Secondary prevention is aimed at cervical cancer rather than CIN itself.
For women with CIN, appropriate monitoring and treatment are used to prevent progression to
malignant disease. (See "Cervical intraepithelial neoplasia: Management of low-grade and highgrade lesions" and "Cervical intraepithelial neoplasia: Treatment and follow-up".)
INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The
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Beyond the Basics topics (see "Patient information: Management of a cervical biopsy with
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abnormal Pap tests (Beyond the Basics)" and "Patient information: Follow-up of high-grade
abnormal Pap tests (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
Cervical intraepithelial neoplasia (CIN) is a premalignant condition of the uterine cervix. CIN
refers to squamous abnormalities. Glandular cervical neoplasia includes adenocarcinoma in
situ and adenocarcinoma. (See 'Introduction' above.)
Using the Bethesda system, squamous cervical cytologic findings are described using the
term "squamous intraepithelial lesion (SIL)" and histologic changes with the term "CIN." Using
the Lower Anogenital Squamous Terminology (LAST) system, both cytologic and histologic
findings are described using the term "SIL". CIN has three degrees of severity (figure 1).
(See 'Terminology' above.)
Human papillomavirus (HPV) is the major etiologic agent of cervical precancer and cancer.
The association between HPV and cervical neoplasia is so strong that most other behavioral,
sexual, and socioeconomic covariables have been found to be dependent upon HPV infection
and do not hold up as independent risk factors. (See 'Role of human papillomavirus' above.)
HPV infection is necessary but not sufficient to develop cervical neoplasia. The two major
factors associated with development of high-grade CIN and cervical cancer are the subtype of
HPV and persistent infection. Environmental factors (eg, cigarette smoking) and immunologic
influences also appear to play a role. (See'Types' above and 'Age and persistence' above
and 'Cofactors in pathogenesis' above.)
Low oncogenic risk HPV subtypes, such as HPV 6 and 11, do not integrate into the host
genome and only cause low-grade lesions (eg, low-grade SIL and CIN 1) and benign genital
warts (table 1). (See 'Types' above.)

High oncogenic risk HPV subtypes, such as 16 and 18, are strongly associated with highgrade lesions, persistence, and progression to invasive cancer, but also cause low-grade
lesions. (See 'Types' above and 'Age and persistence' above.)
The primary approach to prevention of CIN and cervical cancer is HPV vaccination. Although
HPV is a sexually transmitted infection, condoms are only partially protective. For women with
CIN, appropriate monitoring and treatment are used as secondary prevention of cervical
cancer. (See 'Primary prevention' above.)
ACKNOWLEDGMENT The authors and editors would like to recognize Dr. Christine
Holschneider, who contributed to previous versions of this topic review.
Use of UpToDate is subject to the Subscription and License Agreement.
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