The widespread utilization of routine cervical cancer screening has greatly enhanced physicians’ ability to detect cancerous and precancerous changes of the cervix. In the United States, the incidence of cervical cancer fell approximately 70% from 1950-1970, followed by an additional 50% drop from 1970-2000. [1, 2] These declines likely resulted from implementation of cervical screening programs and an increase in the availability of screening to populations that previously did not have access to testing.
The most common cervical screening test used worldwide was developed by Dr. George Papanicolaou in 1943 when he described how vaginal cells could be collected and stained as a means of detecting cytologic abnormalities of the uterine cervix.  Although the test, known as the Papanicolaou smear (or Pap smear or Pap test), continues to be the mainstay of identification of cervical cancer and precancerous lesions of the cervix, it is still not being used to full advantage. It is estimated that 50% of women diagnosed with invasive cervical cancer have never had a Papanicolaou test, and 10% have not had a Papanicolaou test in the 5 years prior to diagnosis. Sadly, despite widespread screening and treatment of pre-invasive lesions, there are still approximately 12,000 new cases of cervical cancer in the United States each year and roughly 4,000 annual deaths from the disease. [4, 5]
Worldwide, the human papillomavirus (HPV) has been detected in as many as 99.7% of cervical carcinomas.  Because HPV is implicated in such a high percentage of cervical cancers, a great deal of research has been devoted to characterizing the virus and its role in cervical cancer. HPV is now known to be a small deoxyribonucleic acid (DNA) virus that infects epithelial cells and causes a variety of skin lesions.
To date, more than 100 different types of HPV have been identified, 40 of which may involve lesions of the anogenital tract. Subtypes of the virus can be broadly divided into those that infect stratified squamous epithelium and those that infect mucosal epithelium.
The mucosotrophic types can be further subdivided into low-risk and high-risk types. Of those that affect genital tissues, the low-risk types have been associated with the formation of genital warts. The commonly identified low-risk types include 6, 11, 40, 42, 43, 44, 54, 61, 72, and 81.
The high-risk types are those associated with the formation of intraepithelial neoplasia and include 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 69, and 82. These subtypes are considered oncogenic (cancer causing); they are found in 99% of cervical cancers, with types 16 and 18 being found in 70% of them.
Almost all precancerous and cancer lesions are associated with long-term, persistent HPV infection.  Fortunately, 90% of infections with HPV are thought to clear within 2 years due to a cell-mediated immune response. It is the women who fail to clear the HPV infection who are at risk for cervical dysplasia and subsequent cervical cancer.
All HPV subtypes contain early (E) genes and late (L) genes, which are essential to viral integration and replication. L genes encode viral capsid proteins. E genes are responsible for episomal replication. E proteins made by the viral genome promote the activation of host DNA replication mechanisms that can then be used by the virus during its own replication. This is necessary because the virus enters through a disrupted epithelial barrier and infects replicating basal keratinocytes; it then relies on the differentiation of the keratinocytes to reach the surface and be shed for continued infection. The virus replicates only during terminal differentiation of the superficial keratinocytes, which allows it to be shed into the mucosal lumen. The superficial keratinocytes ultimately are shed with the stratum corneum, so no lytic phase exists in the HPV life cycle, as the apoptotic keratinocytes release the virus during degradation in the mucosal lumen (see the image below).
Viral integration into the host cellular genome is a hallmark of malignant progression. This occurs with E1 and E2 genomes (see the image below). E1 protein has helicase activity for replication, and E2 encodes DNA-binding protein for regulation of transcription. Disruption of E1 and E2 allows for dysregulated downstream genes and the expression of E6 and E7 proteins, which are selectively maintained in virally induced tumors. E6 promotes cell growth by inactivation of the p53-related effects, which control cellular proliferation and apoptosis. E7 forms complexes with pRb and functionally inactivates pRb and related proteins, such as EF2, which leads to transcription growth-related proteins. 
In addition to understanding the intricacies of HPV biology, many researchers have looked at the incidence, prevalence, and clearance of the virus, as well as associated risk factors. In the United States, the overall prevalence of the virus is approximately 25% in screened women aged 14-59 years, with the highest prevalence (44.8%) in women aged 20-24 years. HPV prevalence was noted to be 24.5% in women aged 14-19 years, 27.4% in women aged 25-29 years, 27.5% in women aged 30-39 years, 25.2% in women aged 40-49 years, and 19.6% in women aged 50-59 years. Age, marital status, and the number of lifetime and recent sexual partners have been defined as independent risk factors for HPV detection. [6, 8, 9]
Many factors have been studied for an association with regression, including age, race or ethnicity, clinical site, performance of randomized biopsy, number of years of sexual activity, age of sexual debut, number of lifetime partners, length of hormonal contraception use, incidence of sexually transmitted infections, incidence of bacterial vaginosis, condom use, douching practices, and cigarette use.  The only identified factor associated with regression of HPV infection, however, is the presence of low-risk HPV type. These findings have contributed to the currently recommended screening guidelines for cervical cancer.
As mentioned previously, the advent and widespread implementation of routine cervical cancer screening has greatly enhanced the ability to detect cancerous and precancerous changes of the cervix, leading to a decline in the incidence of and mortality from cervical cancer. The Papanicolaou test has been implemented in countries around the world as a screening strategy, and subsequent reductions in rates of cervical cancer by 50% or more have been seen. [11, 12, 13, 14, 15, 16, 17]
Collection of the Papanicolaou test currently involves sampling the cervix at the transformation zone using a spatula or brush. The transformation zone is where the ectocervix and endocervix meet and dysplasia is most likely to be identified. Since the introduction of the screening test, techniques for sampling cervical cells and analyzing them for dysplastic changes have advanced.
In the conventional Pap test, the cervical sample is transferred to a slide, and a chemical fixative is subsequently applied. While many institutions still use this technique, numerous others use the newer liquid methodologies, which include ThinPrep and SurePath. In these tests, the cervical sample is suspended in a liquid medium and sent to a lab for further processing. Samples go through density gradient sedimentation (SurePath) or filtration techniques (ThinPrep) and are then plated as thin layers on slides.
Once cell collection is complete, the samples are sent to a cytopathologist, who provides a cytologic analysis. The results can be used to triage abnormalities that may require further diagnostic testing, including colposcopy and biopsy of suspicious lesions.
The Papanicolaou test is meant as a screening examination, not as a diagnostic tool. Ideally, this examination would have high sensitivity and specificity, but with the high intraobserver variability that occurs, the reported sensitivity and specificity greatly varies. Sensitivity ranges from 30-87%, and specificity ranges from 86-100%. [18, 19]
In theory, the liquid-based test should have the advantage over conventional collection because of lower incidence of fixation artifact, lower incidence of drying artifact, and less masking of the cellular components. However, studies comparing the 2 techniques have not yielded consistent evidence that the liquid-based test offers significant improvements in sensitivity or specificity, thus both are considered acceptable. [20, 21, 22, 23]
Papanicolaou test results are routinely reported according to the Bethesda system. This was introduced in 1988 and revised in 2001 and 2008, with the hope of standardizing pathology reports and improving their usefulness. The most recent update to the system was done in 2014 and is described below. [24, 25]
The 2014 Bethesda System (Adapted from Nayar/Wilbur 2015) 
Indicate conventional smear (Pap smear) vs. liquid-based preparation vs. other
GENERAL CATEGORIZATION (optional)
NEGATIVE FOR INTRAEPITHELIAL LESION OR MALIGNANCY (When there is no cellular evidence of neoplasia, state this in the General Categorization above and/or in the Interpretation/Result section of the report–whether or not there are organisms or other non-neoplastic findings)
EPITHELIAL CELL ABNORMALITIES
OTHER MALIGNANT NEOPLASMS: (specify)
Provide a brief description of the test method(s) and report the result so that it is easily understood by the clinician.
COMPUTER-ASSISTED INTERPRETATION OF CERVICAL CYTOLOGY
If case examined by an automated device, specify device and result.
EDUCATIONAL NOTES AND COMMENTS APPENDED TO CYTOLOGY REPORTS (optional)
Suggestions should be concise and consistent with clinical follow-up guidelines published by professional organizations (references to relevant publications may be included)
Since high-risk HPV has been implicated in more than 90% of cervical cancers, testing for the virus has been utilized as a screening modality either alone or in concert with Papanicolaou tests. In 2003, the US Food and Drug Administration (FDA) approved Digene Hybrid Capture 2 High-Risk HPV DNA Test, which is meant to identify the presence of 14 high-risk HPV types found in cervical samples. This test was approved for use in conjunction with a Papanicolaou test. It is meant to help to triage cytologic abnormalities that are mildly abnormal and may indicate HPV infection and the need for further and closer follow-up.
In March of 2009, the FDA approved Cervista HPV 16/18, which detects the DNA sequences for HPV types 16 and 18 in cervical cells. Differentiating these HPV types gives health care professionals more information on a patient’s risk of subsequently developing cervical cancer. A positive Cervista 16/18 test result indicates whether HPV type 16 or 18 (or both) is present in the cervical sample.
The FDA also approved the Cervista HPV HR test, which is the second DNA test that detects essentially all of the high-risk HPV types in cervical cell samples. The Cervista HPV HR test uses a method similar to the Cervista HPV 16/18 test to detect the DNA sequences of these HPV types. In women aged 30 years or older or in women with borderline cytology, the Cervista HPV 16/18 test can be used together with cytology and the Cervista HPV HR test to assess risk of cervical disease.
Based on the FDA’s approval of the first HPV genotyping assay in March 2009, the American Society for Colposcopy and Cervical Pathology (ASCCP) released the Management Algorithm for Using HPV Genotyping to Manage HPV High-Risk Positive/Cytology Negative Women 30 Years and Older. These specific guidelines are discussed in detail in the section on management of cytologic abnormalities.
Several studies have compared the outcomes of using HPV testing alone versus using HPV testing used with cervical cytology. HPV testing has been shown to increase the sensitivity of cytology screening; however, it has lower specificity and, consequently, a lower positive predictive value when used as a primary screening test. [26, 27, 28, 29] HPV does improve specificity in women older than age 30 years and when it is used as part of triaging Papanicolaou test results of atypical squamous cells of undetermined significance (ASC-US). 
There is also emerging evidence that primary HPV screening may be a reasonable alternative to cervical cytology screening in women ages 25 years and older. A working group consisting of representative experts from the Society of Gynecologic Oncology, the American Society of Cytopathology, the College of American Pathologists, the American Society for Colposcopy and Cervical Pathology, the American Cancer Society, the American College of Obstetricians and Gynecologists, and the American Society for Clinical Pathology published interim clinical guidance for practitioners utilizing primary HPV screening  . These recommendations are discussed in detail in the section on primary HPV screening.
A study by Lee et al found through self-reporting by health care providers that low-risk HPV testing, HPV cotesting in women younger than age 30 years, and HPV reflex testing for high-grade, abnormal Papanicolaou test results may lead to unnecessary follow-up and increased medical costs without added benefits.  Eliminating low-risk HPV testing in the United States and educating health care providers and patients on appropriate indications for HPV testing are needed in order to deter health care providers from performing such tests when they are unnecessary.
Since the Bethesda classification was outlined in an attempt to standardize screening, research has focused on defining the appropriate follow-up for each of the findings. ASCCP reviewed and published their findings in the 2006 Consensus Guidelines. This publication guided the triaging of cytologic findings and appropriate timing of screening until November of 2009 when the American College of Obstetricians and Gynecologists (ACOG) updated the guidelines.
In 2012, ACOG [32, 33] ; the American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology (ACS/ASCCP/ASCP)  ; as well as the US Preventive Services Task Force (USPSTF)  updated their screening recommendations for cervical cancer in asymptomatic women at average risk.
The 2012 ACOG, ACOG/ASCCP/ASCP, and USPSTF recommend routine screening in all women at age 21 years, regardless of the woman’s sexual behaviors and risk factors. Routine screening is not recommended for those younger than 21 years. [32, 33, 34, 35]
Women who fall into this age group should be screened every 3 years with liquid-based or conventional cytology alone. [32, 33, 34, 35] Routine screening with HPV testing (alone or cotest with cytology) is not currently recommended by major societies for this age group. See section on primary HPV screening for interim guidance in women age 25 and older.
Women aged 30-65 years and older can be screened using cytology alone and cotesting with cytology/HPV. Women who have negative test results on both tests should not be rescreened before 3 years, although ACOG and ACS/ASCCP/ASCP indicate cotesting every 5 years in this age group is preferred. [32, 33, 34] These findings are consistent with testing that shows that 4-6 years after the original screening, women with negative HPV and cytology have a very low rate of cervical intraepithelial neoplasia (CIN) of grade 2 or higher.
The USPSTF does not state a preference between the cytology alone and the cotesting screening strategies but indicates cotesting at 5-year intervals is a reasonable option in women of this age group who prefer a longer screening interval. 
The recommendations are to stop screening once a woman is 65 years old as long as she has had (1) 3 or more documented consecutive negative cytology tests, (2) 2 documented consecutive negative cotest results in the previous 10 years, and (3) no history of CIN 2 or higher, or cancer (ACS/ASCCP/ASCP: ≤20 years). [36, 32, 33, 34, 35]
Women who have a history of CIN-2 or CIN-3 need continued screening for at least 20 years. 
In general, the reported number of abnormal cytologic findings on Papanicolaou tests during pregnancy is 5-8%, which is not significantly different from nonpregnant patients. Management of abnormal cervical cytology in pregnancy should follow the 2012 consensus guidelines. 
For pregnant women over the age of 24 years with ASC-US or LSIL findings, colposcopy is recommended but can be deferred until after delivery.
For pregnant women with ASC-H, HSILs, and AGCs, colposcopy should be performed for all ages. If the lesions are concerning for CIN-2 or -3, these patients should be biopsied. If no lesions are seen on colposcopy, these women should have repeat cytology at 6 weeks postpartum. Endocervical curettage is contraindicated during pregnancy.
The ACS and USPSTF 2012 guidelines did not address special populations (eg, women with a history of cervical cancer, women who were exposed in utero to diethylstilbestrol (DES), women who are immunocompromised) who may require more intensive or alternative screening. ACOG recommends annual screenings for immunocompromised patients, women with history of CIN2, CIN3, or cancer; and women who were exposed to DES in utero. According to the latest ACOG recommendations,  HIV-positive women should be screened with cervical cytology at the onset of sexual activity or age 21 years, whichever comes first, and should undergo annual screening until they have at least 3 consecutive normal annual cytology results. HIV-infected women age 30 years and older can undergo cytology alone or cotesting. Once there are 3 consecutive negative annual cytology results or one negative cotest, screening can be extended to 3 years. Screening should continue for at least 20 years after treatment of CIN2 or more.
Three vaccines have been developed in an effort to combat HPV and its related disease. Routine vaccination is recommended for males and females beginning at age 11-12 years and should be given up to the age of 26 years in those who have not yet been vaccinated.  These vaccines all target HPV types 16 and 18, which account for over 70% of all cervical cancers. Two of the vaccines are also effective against types 6 and 11, which cause 90% of genital warts, and the 9-valent vaccine (approved in 2014) also covers genotypes 31, 33, 45, 52, and 58. These vaccines are now widely available in the United States and have demonstrated greater than 90% efficacy in preventing CIN2 or worse disease in HPV-naïve populations. Cervical cancer screening recommendations for women who have been vaccinated by the HPV vaccine, however, are currently the same as those for women who have not been vaccinated. [40, 41, 42, 43, 44]
Atypical squamous cells (ASC), including those designated as being ASC-US or in the category “cannot exclude high grade” (ASC-H), are an epithelial abnormality diagnosed when the degree of nuclear atypia is not sufficient for the cells to be defined as a squamous intraepithelial lesion (SIL), either low grade or high grade. ASC-H includes atypia that are suggestive of high-grade changes.
Low-grade squamous intraepithelial lesions (LSILs), as defined by the Bethesda system, are suggestive of mild dysplasia or expected CIN-1 on histology and HPV infections with high-risk types. Studies looking at the natural progression of this finding suggest that approximately 50% of these lesions will regress in 24 months, 20% will progress to HSILs, and about 0.2% will progress to cancer in the same time period. [7, 45]
HSILs are lesions consistent with moderate and severe dysplasia, corresponding with CIN-2, CIN-3, and carcinoma in situ on histology. This cytology result indicates a high suspicion for an underlying high-grade lesion. These lesions have a lower likelihood of regression within 24 months, with only 35% regressing, 23.4% persisting, and 1.4% progressing to invasive cancer. [7, 45] Although HPV positivity does affect the time to regression, 90% or more of these lesions will be positive for high-risk HPV, so there is little use in testing for HPV as part of triaging for follow-up care (see the table below).
Regression to Normal at 24 Months
% (Confidence Interval; CI)
Progression to HSIL at 24 Months
Progression to Invasive Cervical Cancer at 24 Months
Atypical glandular cells (AGC) seen on cytologic specimens can be associated with squamous cell and glandular abnormalities, including adenocarcinoma of the cervix or the endometrium. According to the Bethesda classification, these abnormalities can be subdivided into lesions associated with cervical, endocervical, or endometrial atypia.
Some studies have suggested that the use of p16 immunohistochemistry can serve as a surrogate for the differentiation of benign lesions from precancerous ones. A cyclin-dependent kinase-4 inhibitor, p16 is expressed in a limited range of normal tissues and tumors and has been identified as a biomarker for HPV transforming infections. Its use has been initiated because, over time, p16 accumulates in the nucleus and can be detected by immunostaining.
A meta-analysis of 97 studies found that p16 immunostaining can be easily applied to cytologic and histologic samples. Additionally, the proportion of p16-positive smears was noted to rise with the increasing severity of cytologic and histologic abnormality.
However, no standardized methodology exists for what constitutes a p16-positive sample; this is particularly true of cytologic samples; thus, a wide range of positivity is reported among the various studies reviewed. Because of the lack of standardization, no current clinical guidelines exist for the use of p16 in primary cervical cancer screening or in the triage of low-grade Papanicolaou smears. However, with time and more standardization, p16 immunostaining may be incorporated into the triage cervical screening. 
Precancerous lesions of the cervix are referred to as cervical intraepithelial neoplasia (CIN). During cytologic examination, suspicion for underlying CIN is associated with the presence of koilocytes, which are atypical cells with a perinuclear cavitation or halo in the cytoplasm. In addition, dysplastic cells display an increase in the nuclear to cytoplasmic ratio. These changes are thought to reflect infection with HPV, and when they are seen, additional diagnostic steps, including colposcopy and tissue biopsy, are needed to assess for the histologic diagnosis of CIN.
On histology, the changes that indicate intraepithelial neoplasia include enlarged nuclei, increased nuclear-cytoplasmic ratio, increased hyperchromasia, increased nuclear polymorphism, and increased anisokaryosis. As the severity of CIN increases, the number and abnormal configurations of mitotic figures also increase. The lesions are defined by the amount of the squamous epithelium that is dysplastic. Low-grade CIN, or CIN-1, displays dysplastic changes in approximately one third of the thickness of the epithelium. CIN-2 involves one half to two thirds of the thickness, and CIN-3 can show full-thickness involvement.
Lastly, carcinoma in situ is diagnosed when dysplasia is seen throughout the epithelium and resembles cervical cancer but has not invaded into the basement membrane. High-grade lesions, such as CIN-2 and CIN-3, are considered to be true precursors of invasive cancer.
The following section discusses management of abnormal cytology (2012 ASCCP Consensus Guidelines).  Note that the management of women age 21-24 years differs from that of women age 25 years and older due to the natural history of HPV infections, lower incidence of invasive lesions and the higher likelihood of regression in that age group.
Management of women with ASC-US
See the list below:
Women aged 21-24 years with ASC-US
Women aged 20 years or younger with ASC-US or LSIL
Pregnant women with ASC-US
Management of women with ASC-H
See the list below:
Management of women with LSIL
Women aged 25 years or greater with LSIL
Women aged 21-24 years with LSIL
Pregnant women with LSIL
Postmenopausal women with LSIL
Management of women with HSIL
See the list below:
Pregnant women with HSIL
Management of women with AGC
Women with AGC, including ASC-NOS, AGC-favor neoplasia, and AIS
Women with atypical endometrial cells
Management of women with benign endometrial cells found in cervical cytology
See the list below:
Management of women age 30 years and older who are Pap negative and HPV positive
Repeat cytology and HPV DNA testing in 12 months
Another option would be to perform HPV 16 and 18 testing
In 2014, the FDA approved one of the HPV DNA tests (cobasHPV test) for primary screening for cervical cancer in women aged 25 years and older. Although not yet fully endorsed by major societies, a panel of experts co-sponsored by the ASCCP and the Society for Gynecologic Oncologists (SGO) published recommendations for using primary HPV testing for cervical cancer screening.  In the proposed algorithm, women aged 25 years and older would undergo cervical HPV testing for screening, as opposed to cytology. Women who test negative for high-risk HPV should be re-screened no sooner than every 3 years. For women who test positive for high-risk HPV, HPV genotyping is performed, and those who test positive for HPV 16/18 are referred for colposcopy. Those who are high-risk HPV positive but 16/18 negative undergo cervical cytology. Those with negative cytology results are rescreened in 1 year, and those with ASC-US cytology or greater are referred for colposcopy.
The above algorithm appears to be at least as effective as current cytology-based screening guidelines and therefore may be considered as a reasonable alternative. Nonetheless, cytology alone and cotesting, as outlined above, remain the screening modalities recommended by guidelines of major societies.
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Regression to Normal at 24 Months
% (Confidence Interval; CI)
Progression to HSIL at 24 Months
Progression to Invasive Cervical Cancer at 24 Months
Nicole W Karjane, MD Associate Professor, Department of Obstetrics and Gynecology, Virginia Commonwealth University Medical Center
Nicole W Karjane, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, Association of Professors of Gynecology and Obstetrics, North American Society for Pediatric and Adolescent Gynecology
Disclosure: Received income in an amount equal to or greater than $250 from: Merck<br/>Served as Nexplanon trainer for: Merck.
Michel E Rivlin, MD Former Professor, Department of Obstetrics and Gynecology, University of Mississippi School of Medicine
Michel E Rivlin, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Medical Association, Mississippi State Medical Association, Royal College of Surgeons of Edinburgh, Royal College of Obstetricians and Gynaecologists
Disclosure: Nothing to disclose.
Robert P Edwards, MD Professor, Department of Obstetrics, Gynecology and Reproductive Science, University of Pittsburgh School of Medicine; Vice-Chair, Clinical Affairs, Director, Ovarian Cancer Center of Excellence, Magee-Womens Hospital, University of Pittsburgh Medical Center
Robert P Edwards, MD is a member of the following medical societies: American Association for Cancer Research, American College of Obstetricians and Gynecologists, American College of Surgeons, American Medical Association, Society for Reproductive Investigation
Disclosure: Nothing to disclose.
Sarah E Taylor, MD Resident Physician, Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Hospital, University of Pittsburgh Medical Center
Sarah E Taylor, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Medical Association
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Reference Salary Employment
Suzanne R Trupin, MD, FACOG Clinical Professor, Department of Obstetrics and Gynecology, University of Illinois College of Medicine at Urbana-Champaign; CEO and Owner, Women’s Health Practice; CEO and Owner, Hada Cosmetic Medicine and Midwest Surgical Center
Suzanne R Trupin, MD, FACOG is a member of the following medical societies: American Association of Gynecologic Laparoscopists, American College of Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine, American Medical Association, Association of Reproductive Health Professionals, International Society for Clinical Densitometry, and North American Menopause Society
Disclosure: Nothing to disclose.
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