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

INTRODUCTION — Cervical intraepithelial neoplasia (CIN) is a premalignant condition of the uterine cervix. 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.

CIN may be low-grade or high-grade. Patients 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" and "Human papillomavirus infections: Epidemiology and disease associations" 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, 2001, and 2015. In this system, different terminology is used for cytologic (on Pap test) and histologic (on biopsy) findings [1-4]. Cytologic findings are described with the term "squamous intraepithelial lesion (SIL)" and histologic changes are 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).

Due to the poor reproducibility of CIN 2, CIN 2 and 3 are often classified together as an entity known as CIN 2,3. 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 [5,6]. 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 2019 American Society of Colposcopy and Cervical Pathology guidelines for the evaluation and management of cervical cytologic and histologic abnormalities [7].

Terminology for cytologic squamous cell abnormalities is discussed separately. (See "Cervical cancer screening: The cytology and human papillomavirus report", section on 'Intraepithelial cell abnormalities'.)

INCIDENCE — The estimated annual incidence in the United States of CIN among patients 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 patients 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'.)

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]. (See "Virology of human papillomavirus infections and the link to cancer".)

HPV infection is necessary for development of cervical neoplasia, but since the vast majority of patients 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 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 and HPV vaccination status [12,26-28]. Sequential infection with different HPV subtypes and concurrent infection with more than one HPV subtype is common [29,30]. 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) [31,32]:

●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) [31,33,34]. 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, 18, 31, 33, 45, 52, and 58, are strongly associated with high-grade lesions (CIN 2,3) and progression to invasive cancer, although they may also be associated with low-grade lesions. HPV 16 and 18 have the highest risk of developing CIN 3 or greater and account for 25 percent of low-grade lesions, 50 to 60 percent of high-grade lesions, and 70 percent of all cervical cancers [35,36].

•The greater association of precancer/cancer with HPV 16 compared with other oncogenic types was illustrated in a study of patients with low-grade lesions and HPV 16 [37]. The two-year cumulative absolute risk of developing CIN 3 or worse was higher in patients with HPV 16 infection than in those with other high-risk subtypes (30 to 40 percent versus 8 to 10 percent).

•HPV 18 has also been shown to have a disproportionately high cancer risk; in a study of HPV genotyping, the immediate risk of CIN 3 or worse was higher in patients with HPV 18 infection and negative cytology compared with those with other high-risk, non-HPV 16, 18 subtypes (3.0 percent versus 1.3 percent) [35].

●The HPV subtypes associated with squamous cell carcinoma differ somewhat from those associated with adenocarcinoma and are discussed elsewhere. (See "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis", section on 'Histopathology'.)

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 in resource-rich settings".)

Age and persistence — Most cervical HPV infections are transient and occur in young patients. Persistent infection with oncogenic HPV subtypes is a key factor in development of high-grade cervical lesions [38-45] and cervical cancer [43-45], while clearance of HPV infection predicts regression of CIN [46].

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 [37-40,47-49]. Transient infections are particularly common in young patients in whom the average duration of a newly diagnosed HPV infection is 8 to 13 months [40,48,50]. It is unclear whether HPV-positive patients 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 female participants aged 14 to 59 years (n = 1921); the overall prevalence was 26.8 percent [51]. 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 patients in their teens and twenties, 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 [36,52]. (See "Human papillomavirus infections: Epidemiology and disease associations".)

The reason HPV persists in some patients and not in others is poorly understood. A persistent HPV infection is variably defined as one that is present for at least 6 to 12 months. The longer that HPV persists within the cervix, the higher the risk for the development of CIN. In one prospective population-based cohort study, 21 percent of patients with highly oncogenic HPV infections persisting over 12 months developed CIN 2 or worse over 30 months of follow-up [40]. However, even for patients who develop CIN, the lesion most commonly is cleared. In an analysis of patients 13 to 24 years of age with CIN 2, 38 percent had regression within one year, 63 percent by year 2, and 68 percent by year 3 [53].

The likelihood of persistence is related to several factors:

●Older age – 50 percent of high-risk HPV infections persist in patients older than 55 years of age compared with a 20 percent rate of persistence in patients under age 25 [36].

●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), 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 [30].

●High oncogenic HPV subtype – High-oncogenic-risk HPV subtypes are more likely to persist than low oncogenic types [48]. (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 patients who have not had any sexual relationships [54].

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 patients will have acquired a genital HPV infection by age 50 [55].

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 "Human papillomavirus infections: Epidemiology and disease associations".)

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 patient's 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 [56]. 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 patients.

●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) [57]. On average, these changes occur two to eight months after the patient is first infected [58]. The cytologic findings are also the cytologic characteristics of low-grade squamous intraepithelial lesions (LSIL) and atypical squamous cells of undetermined significance (ASC-US); 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 [59-61]. In most patients, 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 [58].

●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, high-grade lesions and cancer may develop [62].

An important factor in the early stages following infection is the patient's susceptibility to oncogenic HPV types, which is determined by the host's immune system [63]. 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 [64,65]. 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 [66,67]. (See "Virology of human papillomavirus infections and the link to cancer", section on 'Molecular pathogenesis'.)

COFACTORS IN PATHOGENESIS

Immunosuppression

●HIV infection – The incidence of CIN is increased in patients with HIV [68-71]. The increased risk of CIN appears related to the greater prevalence of human papillomavirus (HPV) infection in these patients (64 percent versus 27 percent in patients without HIV infection). (See "Preinvasive and invasive cervical neoplasia in patients with HIV infection".)

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) [71-73]. This was illustrated in a longitudinal study that found patients with HIV were more likely to be repeatedly HPV-positive over a six-year period than patients 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/microL than in those with CD4 counts more than 200/microL (93 versus 48 percent) [71].

In addition, cervical cancer is one of the most common acquired immunodeficiency syndrome (AIDS)-related malignancies in patients [74].

●Immunosuppressive therapy – Patients with chronic conditions requiring long-term immunosuppressive therapy are at increased risk of developing CIN [75,76]. This association has been described in transplant recipients and patients with systemic lupus erythematosus [77-80].

Cigarette smoking — Cigarette smoking and HPV infection have synergistic effects on the development of CIN and cervical cancer [81-87]. 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 [85]. The cumulative exposure to cigarette smoking (as measured by pack-years smoked) is strongly related to the risk of CIN [88]. In another study of HPV-positive patients, the risk of cervical cancer in smokers was two- to fourfold that of nonsmokers [82].

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 [89,90] and decrease local immunity [91,92]. Impaired host immunity may then allow persistence of oncogenic virus.

Herpes simplex virus and chlamydia — Infection with chlamydia [93-95], herpes simplex virus [96-98], or other sexually transmitted infections may be a surrogate marker of exposure to HPV rather than a causal factor itself (table 3) [99]. Alternatively, these infections may modulate host immunity, thereby facilitating persistence of oncogenic HPV [100,101].

Oral contraceptives — Long-term use of oral contraceptives has been implicated as a cofactor that increases the risk of cervical carcinoma in patients who are HPV-positive [87]. 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 [102]. (See "Combined estrogen-progestin contraception: Side effects and health concerns", 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 [103,104]. 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 [105,106]. 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 [107].

One review found that high parity increased the risk of squamous carcinoma of the cervix among HPV-positive patients [108]. There are few data regarding the role of marijuana smoking in CIN. The only study was performed in patients with HIV infection and suggested no increase in the burden of cervical HPV infection [109].

PREVENTION

Primary prevention — The primary approach to prevention of CIN is vaccination against oncogenic human papillomavirus (HPV) infection. This is discussed in detail separately. (See "Human papillomavirus vaccination".)

Use of HPV vaccination in patients with a current or prior HPV infection or CIN is discussed in detail separately. (See "Cervical intraepithelial neoplasia: Management", section on 'HPV vaccination in patients with CIN'.)

Although HPV is a sexually transmitted infection, condoms are only partially protective. (See "Cervical intraepithelial neoplasia: Management", section on 'Management of sexual partners'.)

Secondary prevention — Secondary prevention is aimed at cervical cancer rather than CIN itself. For patients with CIN, appropriate monitoring and treatment are used to prevent progression to malignant disease. (See "Cervical intraepithelial neoplasia: Management" and "Cervical intraepithelial neoplasia: Choosing excision versus ablation, and prognosis and follow-up after treatment", section on 'Follow-up after treatment'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cervical cancer screening, prevention, and management".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Management of a cervical biopsy with precancerous cells (Beyond the Basics)" and "Patient education: Follow-up of low-grade abnormal Pap tests (Beyond the Basics)" and "Patient education: Follow-up of high-grade or glandular cell 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 high-grade 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 patients with CIN, appropriate monitoring and treatment are used as secondary prevention of cervical cancer. (See 'Primary prevention' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Christine H Holschneider, MD, who contributed to an earlier version of this topic review.