Article on Springer


Current Obstetrics and Gynecology Reports
© Springer Science+Business Media New York 2014
10.1007/s13669-014-0083-x
Management of HPV and Associated Cervical Lesions (C-H Lai, Section Editor)
Diagnosis and Management of Precancerous Cervical Lesions
Melinda S. Auer1 and David G. Mutch2
(1)Department of Obstetrics and Gynecology, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
(2)Judith and Ira Gall Professor of Gynecologic Oncology, Division of Gynecologic Oncology, Washington University School of Medicine, 4911 Barnes-Jewish Hospital Plaza, St. Louis, MO 63110, USA

Melinda S. Auer
Email: auerm@ccf.org

David G. Mutch (Corresponding author)
Email: mutchd@wudosis.wustl.edu
Published online: 6 May 2014
Abstract
Over the past five decades, the Pap smear for cervical cancer screening has become standard of care across the United States and other countries, and its implementation in the routine gynecologic examination has dramatically reduced the rates of invasive cervical cancer. As we have come to understand the nuances of this routine screening and are increasingly better able to identify precancerous cervical lesions, we have also developed improved screening and treatment modalities. This progress has led to ever-changing diagnostic and management guidelines. Over the last several years, the American Society for Colposcopy and Cervical Pathology (ASCCP) has revised its guidelines for cervical cancer screening and issued new recommendations for treatment and management of cervical dysplasia. In addition, investigators across the world are exploring improved methods of screening, treatment, and identification of precancerous cervical lesions. Such methods include optimizing HPV testing, genotyping HPV and identifying associations with cervical dysplasia, and optimizing the timing and efficacy of treatment. This article will review and critically evaluate the literature published within the past year with regard to the diagnosis and management of precancerous cervical lesions.
Keywords HPV testing Pap smear Cervical cancer Genotyping HPV Management of HPV and associated cervical lesions Cervical dysplasia Precancerous cervical lesions Review
Introduction

Cervical cancer is no longer one of the leading causes of death among women in the United States and other countries that have adopted the practice of routine screening. However, it is still a significant cause of morbidity and mortality, with 12,710 women diagnosed with cervical cancer in 2011, ultimately leading to 4,290 deaths in the United States alone [1]. Furthermore, it remains one of the leading causes of cancer morbidity and mortality worldwide. Globally, it is estimated that cervical cancer is the third leading cancer diagnosis, with 500,000 new cases of cervical cancer diagnosed annually, resulting in approximately 280,000 deaths each year [2].
Infection with the human papillomavirus has been identified as the primary risk factor for the development of cervical dysplasia and progression to invasive cancer. Papillomaviruses are double-stranded DNA viruses with predilection for replication in epithelial cells. Over 40 subtypes of HPV are known to infect the genital tract, 13 of which are associated with cancer [3]. HPV 16 and 18 are the two subtypes most strongly associated with cervical cancer. Persistent HPV 16 infection in particular is an extremely strong predictor of development of CIN 3 and cervical cancer, and has been identified as a class I carcinogen by the IARC [1]. Cervical carcinogenesis begins with HPV infection and progresses with the expression of E6 and E7 oncogenes; the E6 oncoprotein alters cellular differentiation, while E7 reactivates cellular proliferation, ultimately stimulating the replication of malignant cells [1, 2, 4–7]. Inactivation of tumor suppressor genes such as p53 and Rb by viral oncogenes also results in uncontrolled cellular proliferation, leading to the development of dysplasia and cancer [1, 2, 4–7]. Knowledge of the pathophysiology of HPV infection and its role in the progression to cervical dysplasia is essential for appropriate management of precancerous cervical lesions, and lends itself to opportunities to develop more sensitive diagnostic tools.
In addition to HPV infection, a variety of risk factors have been identified in cervical carcinogenesis, although research is still ongoing to determine the exact relationship between each risk factor, HPV infection, and development of premalignant changes. HPV infection is generally transmitted through sexual contact; thus it is widely accepted that earlier age at first intercourse and number of sexual partners confer an elevated risk of cervical dysplasia and cancer [1, 3, 8]. A recent study published in Gynecologic Oncology assessed the relationship between each individual risk factor and development of CIN 2+. It was demonstrated that the number of lifetime sexual partners was associated with an increased risk of cervical cancer and CIN 3, compared to CIN 2 [8]. It was also noted that delaying sexual activity until after age 19 was associated with a decreased risk of CIN 3 [8]. Additionally, increasing parity has been associated with an increased risk of CIN 3, with the strongest correlation in patients with more than three live births [8]. A significant correlation has been established between tobacco use and the development of cervical dysplasia and cancer; current smoking confers a greater risk than history of smoking, and increased pack-years has been shown to be associated with an increased risk of CIN 3 [1, 8]. Oral contraceptive use compared to intrauterine devices or no method of hormonal contraception has demonstrated an increased risk of cervical carcinogenesis. Oral contraceptive use may confer an elevated risk of CIN 3 versus CIN 2, and long-term (>10 years) use of oral contraceptives is also associated with increased risk of cervical dysplasia and cancer [8, 9], although the exact mechanism behind this relationship is still unclear [9, 10]. One hypothesis involves hormone recognition sites and their role in the replication of the HPV genome during infection. HPV DNA contains sites of hormonal recognition within its transcription region, and potentiation of viral replication with hormonal stimulation has been identified in in-vitro cells [1]. Additionally, long-term oral contraceptive use may lend itself to riskier sexual behavior, decreased condom use, and the possibility of higher numbers of sexual partners, all of which are associated with the acquisition of HPV infection [1, 3, 8].
As researchers further investigate the underlying mechanisms and risk factors associated with cervical cancer, screening and treatment strategies are continually being revised. Pap smears still remain the primary screening modality, but HPV testing is becoming more widely accepted as an adjuvant screening tool. Early diagnosis of precancerous cervical lesions begins with cytology, and appropriate and timely management of these lesions is a critical component in the continued reduction in morbidity associated with cervical dysplasia and cancer.
Screening for Precancerous Cervical Lesions and Invasive Cancer

Since the advent of Pap smear screening in the United States in the 1950s, the annual incidence of invasive cervical cancer has fallen dramatically. In 2012, the ASCCP revised guidelines for cytology screening, with changes primarily involving age at initial screening, frequency of screening, and the role of HPV testing in screening and follow-up of abnormal Pap smears and dysplasia. The updated guidelines recommend initiation of screening at age 21, which differs from the previous recommendation of screening initiation within three years of first intercourse [11•, 12]. Other changes include reflex HPV testing at three-year intervals in patients between the ages of 21 and 29 years and co-testing in patients aged 30–65 years [11•, 12]. Co-testing for HPV is not indicated in patients younger than 30 secondary to the prevalence of transient HPV infection in this age population, with a high rate of infection regression and low incidence of cervical cancer [11•, 12]. Based on the prevalence of transient HPV infection in young patients, co-testing would increase the number of abnormal screening tests and could result in non-indicated and invasive testing in patients with low risk of cervical cancer [11•, 12]. It is important to keep in mind that the longer screening intervals are only applicable as long as the cervical cytology does not indicate further evaluation.
The Role of HPV Testing – Screening and Post-Treatment Follow-Up

Current practice utilizes HPV testing as a triage test in conjunction with cervical cytology to assess the need for further evaluation such as colposcopy and closer follow-up, both as a screening test as well as post-treatment surveillance. According to the updated ASCCP guidelines, HPV co-testing is now the preferred method of screening for cervical cancer in patients over 30 years of age with no history of abnormal cytology. The rationale behind this is that the addition of HPV testing may increase the sensitivity of Pap screening, since the sensitivity of cytology alone can range between 50 % and 70 % due to both poor reproducibility and interpretation errors of conventional cytology [2, 13]. The addition of HPV testing is proposed to increase the sensitivity of cervical cancer screening and identify patients with high-risk HPV subtypes 16/18 that have a greater chance of progression to cervical dysplasia. In addition to screening purposes, cytology and HPV co-testing is also becoming a cornerstone of post-treatment follow-up for patients with a history of cervical dysplasia [2, 13, 14]. A retrospective study published in Cancer Cytopathology collected data on 243 cases of ASCUS and LSIL cytology specimens, and performed HPV testing to demonstrate the relationship between positive high-risk HPV testing and cervical neoplasia. Of patients with ASCUS, 37 % were positive for HPV 16/18, while 33 % of LSIL specimens were HPV 16/18-positive [14]. Of the patients with ASCUS/(+) HPV 16/18, 28 % demonstrated at least CIN 2 on histologic specimens with a positive predictive value of 43 %, while 32 % of women with LSIL/(+) high-risk HPV demonstrated CIN 2+ [14]. These results support the correlation between high-risk HPV and the development of cervical dysplasia, even in low-grade cytology specimens, and also demonstrate the sensitivity of high-risk HPV DNA testing. Utilizing HPV testing in both screening and post-treatment modalities can help stratify those lesions at higher risk of progression to dysplasia and invasive disease.
Three HPV DNA tests are currently approved by the Food and Drug Administration – Hybrid Capture 2, Cervista HPV-HR (Hologic), and cobas HPV test. The HC2 test is most commonly utilized in clinical practice and contains probes for 13 types of high-risk HPV. Unfortunately, the HC2 test alone has significantly lower sensitivity than cytology screening alone, and also does not determine specific HPV types in its specimens [2, 15, 16]. The ATHENA trial utilized the cobas HPV test, which allows for specific genotyping of both HPV 16 and 18, noting that HPV testing alone was more sensitive but less specific for detecting CIN 3+, and ultimately recommending use of HPV testing as a primary screening tool in addition to the more specific liquid cytology [2]. PCR amplification of HPV DNA is another method of detecting high-risk HPV subtypes, but is not routinely used due to the length of time required for specimen processing and risk of contamination [2, 17]. The theory behind PCR amplification suggests that by quantifying the amount of viral DNA, a relationship between the amount of virus and risk of dysplasia and invasive cancer can be established [2, 17]. Detection of HPV mRNA using the NucliSENS easyQ HPV assay was proven to be a reliable method of HPV identification, with sensitivity reaching 81 % and 83 % in low-grade and high-grade lesions, respectively [18, 19]. The same study demonstrated negative predictive values up to 89 % in low-grade lesions, along with positive predictive values up to 97 % in high-grade lesions [18]. This assay is potentially more sensitive and specific in identifying clinically relevant lesions, as it detects the oncogenic activity of E6 and E7 HPV oncoproteins and may help to predict which lesions are more likely to progress based upon the oncogene activity [19]. While the mRNA assay is a promising development in the area of HPV detection, it is still not widely used, and further investigation is needed before it becomes an accepted mode of HPV testing [18, 19].
Diagnosis and Management of Cervical Dysplasia in the General Population

The 2012 ASCCP guideline revisions also included management of cervical neoplasia and pre-invasive cervical disease. In general, unless persisting for longer than 24 months, CIN 1 can be treated with conservative management and co-testing. CIN 2 remains the threshold for treatment among women aged 30–65 years. Refer to Table 1 for a summary of the updated guidelines.
Table 1
Summary of updated ASCCP guidelines for pre-invasive cervical lesions in women ages 30-65 [11•, 12]
Grade of Dysplasia
Initial Management
CIN 1
• CIN 1 with low-grade cytology
 ◦ Co-testing at 12 months
 ◦ If persistent for >24 months, can continue follow-up or treatment
• CIN 1 with high-grade cytology
 ◦ Diagnostic excisional procedure or conservative management recommended
 ◦ Co-testing at 12 and 24 months if observation
 ◦ Excision recommended if repeat high-grade cytology at either 12 or 24 months
• CIN 1 on endocervical sample
 ◦ Treatment or conservative management per ASCCP guidelines for CIN 1
 ◦ If conservative management chosen, repeat co-testing with repeat endocervical sampling at 12 months
CIN 2
• Treatment recommended
 ◦ Ablation or excisional procedure acceptable if adequate colposcopy
 ◦ Excisional treatment advised if inadequate colposcopy, CIN 2+ on endocervical sample, or ungraded CIN
 ◦ Post-treatment follow-up consists of co-testing at 12 and 24 months; if negative, repeat testing in 3 years
• Patients treated for CIN 2+ require 20 years of routine screening regardless of age
CIN 2/3
• See treatment for CIN 2
CIN 3/CIS
• See treatment for CIN 2
AIS
• Women who have completed childbearing
 ◦ At least diagnostic excisional procedure, but hysterectomy preferred treatment
• Women who have not completed childbearing
 ◦ Diagnostic excisional procedure
 ◦ If (+) margins, re-excision recommended
 ◦ Re-evaluation at 6 months with co-testing and endocervical sampling
Colposcopy with biopsies remains the accepted standard for diagnosis of precancerous cervical lesions. Unfortunately, the reliability and reproducibility of colposcopy largely depends upon the skill of the colposcopist and number of biopsies performed [20•, 21]. Standardization of colposcopy and obtaining the appropriate number of biopsies remains a primary consideration in improving the diagnosis of precancerous cervical changes. An article in Obstetrics & Gynecology recently assessed the validity of three pathognomonic non-gradable criteria suggested for colposcopy standardization [20•]. These criteria, identified as either present or absent, include the “inner border,” a dull white area inside a less opaque acetowhite area; the “ridge sign,” an opaque lesion directly adjacent to the squamocolumnar junction that resembles a mountain ridge; and the “rag sign,” an opaque acetowhite area at the squamocolumnar junction that becomes abraded and eroded upon manipulation, revealing either an underlying erosion or denuded epithelium [20•]. Of 234 patients with only the ridge sign, 123 demonstrated high-grade CIN, whereas 90/234 patients with the rag sign were diagnosed with high-grade CIN [20•]. Results of this study showed that of the 234 patients with high-grade neoplasia, 182 (77.8 %) had at least one of three pathognomonic signs; 114 (49.5 %) had one sign, 58 (24.7 %) had two signs, and 10 patients (4.2 %) had all three pathognomonic signs present [20•]. Based on the results of this study, it is reasonable to suspect high-grade neoplasia in patients that demonstrate any combination of the three colposcopic findings.
Conflicting reports regarding the number and location of cervical biopsies during colposcopy also complicate its reproducibility. Some physicians support directed biopsies of colposcopic lesions, while others support the random four-quadrant approach [21]. Evidence has demonstrated that biopsies taken from areas of acetowhite changes and the appearance of high-grade lesions can increase the diagnosis of CIN 3+ by 38 % compared to random biopsies [21]. Despite the increased yield of CIN diagnosis when biopsies are site-specific, one targeted biopsy may still miss the area of greatest dysplasia, and therefore multiple biopsies of suspected lesions are recommended [21]. Identification of acetowhite changes on colposcopy has greater than 90 % sensitivity in detecting CIN 2+ lesions over the subsequent two years; specificity of biopsies from acetowhite lesions ranges from 67–74 %, as most women with acetowhite changes do not have high-grade disease [21]. Despite the low specificity of directed biopsies, it is still recommended that biopsies from acetowhite areas are collected, while biopsies of normal-appearing cervical epithelium should be avoided [21]. Notwithstanding the number and location of biopsies, biopsy and histopathologic diagnoses do not always correlate. In a study out of Serbia in which histology specimens from 130 patients were reviewed and the congruence between biopsy and excisional specimens were examined, the general consensus revealed that most biopsy specimens under-diagnosed cervical dysplasia, particularly in CIN 2+ specimens [22]. When CIN 2 was diagnosed on punch biopsy, the excisional specimen demonstrated CIN 3 in 33 % of cases, whereas biopsy specimens labeled as CIN 3 were actually diagnosed as invasive cancer in 17 % of cases [22]. Nevertheless, in the event that suspicious lesions are identified after abnormal cytology and HPV testing, directed biopsies should still be collected in order to diagnose precancerous cervical lesions.
One of the more novel approaches to diagnosing and identifying high-grade cervical lesions utilizes the isolation of tumor suppressor genes within the HPV genome. p16 is a tumor suppressor gene that functions as a cyclin-dependent kinase inhibitor that regulates cell cycle proliferation by inhibiting transition through the G1 phase of the cell cycle [6, 23, 24]. p16 is expressed at low levels in normal cells, but is considerably overexpressed in the majority of precancerous and cancerous cervical lesions [6, 23, 24]. In a secondary analysis of the New Technologies for Cervical Cancer Screening (NTCC) study, results demonstrated that testing for p16 expression in HPV-positive women resulted in both high sensitivity and specificity for diagnosis of cervical neoplasia [23]. In addition, a research group out of China examined the utility of detecting IMP3 expression in women with a spectrum of cervical changes ranging from normal to invasive squamous cell carcinoma. IMP3 is part of the insulin-like growth factor mRNA-binding protein family that is typically only expressed in placental, lymph nodes, and endocervical mucosa, but has been identified in numerous malignancies [24]. In one study, 98 cases with histologic diagnoses ranging from normal cervical tissue to invasive squamous cell carcinoma were pooled, and staining for both p16 and IMP3 was performed on all samples. The concordance rates between cytologic and histologic specimens ranged from 60–88 %, and so interpretation of immunostaining was analyzed for both cytology and histology specimens [24]. p16 was detected in 29.7 % cases of LSIL, 72.2 % cases of HSIL, and 100 % cases of carcinomas, while IMP3 staining was noted in 8.1 % of LSIL specimens, 25 % of HSIL, and 84 % of carcinomas [24]. As compared to cytology, histologic specimens demonstrated both increased sensitivity and specificity when stained for p16 and IMP3, and the combination of immunostaining for CIN 1 demonstrated a sensitivity and specificity of 81.4 % and 96.5 %, respectively [24]. For CIN 2/3, the sensitivity and specificity when staining for both p16 and IMP3 was 71.9 % and 88.9 %, while the sensitivity for detecting carcinoma was 92 % [24]. In general, the results of this study demonstrated that the majority of CIN 1 diagnoses were associated with p16-/IMP3- staining patterns, CIN 2/3 were associated with p16+/IMP3-, and squamous cell carcinomas were noted to have p16+/IMP3+ immunostaining [24] The study showed a high frequency of p16 staining in high-grade and cancerous lesions and much lower staining in low-grade lesions, supporting the utility of this diagnostic tool in differentiating low-grade from high-grade lesions diagnosed on liquid-based cytology specimens.
Treatment of Precancerous Cervical Lesions

Based on the revised ASCCP guidelines, the threshold for treatment of precancerous lesions in women aged 30–65 years is the histologic diagnosis of CIN 2 or greater. Treatment options for precancerous cervical lesions are generally grouped into ablative or excisional procedures. Ablative procedures include cryotherapy and laser ablation, and are typically reserved for lower-grade lesions that do not involve the endocervical tissue [21, 25•]. Excisional procedures include the loop electrosurgical excision procedure (LEEP) and cold-knife conization. While large-loop excision of the transformation zone and laser conization are occasionally performed, the majority of physicians utilize LEEP or cold-knife conization, and so for the purposes of this review, only cold-knife cone and LEEP will be analyzed. The excisional procedures are generally preferred for cases with endocervical involvement, higher-grade dysplasia, and the need for a histologic specimen, but these procedures are not without risk. Table 2 summarizes the various treatment options and reviews both the advantages and disadvantages of ablative versus excisional procedures, and in particular, compares LEEP versus cold-knife conization and cryotherapy versus laser ablation. In a recently published Cochrane Review in which procedures for treatment of cervical neoplasia were critically analyzed, no significant difference in residual disease was noted between cryotherapy and laser ablation, particularly when a double-freeze method of cryotherapy was used [25•]. Laser ablation was associated with reduction of vasomotor symptoms and malodorous discharge compared to cryotherapy. In LEEP versus cold-knife conization, there was no significant difference in residual disease, as well as primary hemorrhage and cervical stenosis rates, among studies [25•]. The choice of procedure for treating patients with cervical dysplasia should be tailored to individual case and physician skill.
Table 2
Summary of ablative and excisional treatments for cervical dysplasia [21, 25•, 26, 27]
Procedure
Indications
Limitations
Advantages
Excisional – LEEP
• CIN 1 preceded by HSIL or ASC-H (versus conservative management)
• Persistent CIN 1 for >24 months
• CIN 2+ on biopsy specimen with endocervical involvement, inadequate colposcopy (transformation zone not completely visualized), or ungraded CIN
• AIS in patients who desire future fertility
• Margins often obscured due to cautery effect
• Increased risk of cervical stenosis
• Increased risk of miscarriage, preterm labor
• Elevated bleeding risk intraoperative or postoperative
• Less blood loss than cold-knife conization
• Shorter operating times compared to CKC
• Able to be performed in outpatient clinic setting
• Lower cost
Excisional – Cold-knife conization
• See indications for LEEP
• Increased risk of hemorrhage and infection compared to LEEP
• Increased risk of preterm labor, miscarriages, adverse pregnancy outcomes
• More technically challenging than LEEP
• Cannot be performed in-office
• Clean margins with no cautery effect
• Samples more tissue than LEEP
• Provides intact specimen including ectocervix and endocervix (during LEEP, most specimens are separate)
Ablative – Cryotherapy
• Low-grade lesions without endocervical involvement
• Entire lesion must be visualized on colposcopy
• No specimen for histologic examination
• Limited to cases without endocervical involvement
• Not recommended for high-grade CIN2+ lesions
• Cryotherapy probe must cover entire lesion
• No risk of preterm labor, miscarriage, or adverse pregnancy outcomes
Ablative – Laser ablation
• Same as for cryotherapy
• Lesion may extend into vaginal fornix
• See limitations of cryotherapy
• No risk of preterm labor, miscarriage, or adverse pregnancy outcomes
Diagnosis and Management of Cervical Dysplasia in Special Populations

While the guidelines for screening, diagnosis, and management of cervical dysplasia generally cover the majority of patients who will be affected, certain patient populations require their own set of guidelines. These special populations include adolescents and patients aged 21–24 years, pregnant women, and patients aged ≥65 years who are nearing the cessation of routine pap screening. According to the updated ASCCP guidelines, Pap screening begins at age 21 regardless of sexual activity and ceases at age 65, although some adolescents are incidentally screened and are found to have abnormal cytology, along with older patients who are nearing of Pap screening cessation. Pregnancy can also complicate the management plan of cervical dysplasia due to the risk of miscarriage, preterm labor, and hemorrhage associated with biopsies and excisional treatment modalities. The ASCCP specifically references these patient populations and reviews the new guidelines for diagnosis and treatment of cervical dysplasia.
Adolescents and Patients 21–24 Years of Age

The new 2012 ASCCP guidelines differ from the 2006 guidelines in that screening of patients younger than 21 years is no longer recommended, regardless of timing of first sexual activity. The new guidelines for cervical dysplasia also support conservative management of CIN 1, whereas management of CIN 2/3+ is similar to that for the general population. The same guidelines generally apply to patients between the ages of 21 and 24, as the HPV infection is common, and early dysplastic changes are typically transient in nature and confer an overall low risk of progression to severe dysplasia and invasive cancer. The annual incidence of cervical cancer among U.S. women 21–24 years of age is 1.4/100,000, requiring approximately 55,000 Pap smears for every cervical cancer diagnosis in this age group [11•]. It has been noted that HPV infection is most common in teenagers and patients in their early 20s, with incidence of up to 60 % over a three-year period and a lifetime risk of HPV infection of up to 80 % [12]. In retrospective studies, resolution of HPV infections, on average, in patients younger than 21 years of age occurs in eight months, or with reduction in viral load to undetectable levels in 85–90 % of women between 8 and 24 months [12]. The resolution and clearance of HPV infection in adolescents and young women is thought to be associated with vigorous immune response to HPV infection.
A study recently published in the Journal of Pediatric and Adolescent Gynecology investigated the incidence of precancerous lesions identified in patients under the age of 21 to determine whether the updated ASCCP guidelines would ultimately miss cases of dysplasia in younger patients. The study identified a total of 681 cases with cervical dysplasia greater than CIN2+ and AIS between the years of 2008–2010; results demonstrated that 70 % of the subjects were identified as having CIN 2, while CIN 2/3 and CIN 3 were found in 13.5 % and 16.2 % of study subjects, respectively [28]. Adenocarcinoma in situ was identified in only 1 of 681 cases [28]. Despite the high number of CIN 2 identified, the results do not contradict the updated ASCCP guidelines for patients younger than age 21, given the fact that CIN 2 often regresses, and the chances of progression to invasive disease are very low [28]. Although the study did identify several cases of CIN 3, the number needed to screen in this age group in order to identify one case of CIN 3 would not support routine screening [28]. In addition to high rates of infection clearance in this age group, the more conservative route of management of early cervical dysplasia is also favored due to the potential negative outcomes on future fertility, particularly when excisional procedures are used.
In general, treatment of CIN 1 is not recommended in women of any age, but this is particularly the case in young women between the ages of 21 and 24 years as well as adolescents who have been incidentally screened. For young women with CIN I after cytologic diagnosis of ASC-US or LSIL, repeat cytology in 12 months is recommended; if ASC-H or HSIL is demonstrated, colposcopy is advised [11•, 12, 29]. If cytology at 24 months after initial CIN diagnosis reveals ASCUS+, colposcopy is also recommended [11•]. Two negative consecutive Pap smears are required before a patient can return to routine screening. In young women with CIN 1 after ASC-H or HSIL on cytology, observation with concurrent cytology and colposcopy for two years at six-month intervals is recommended [11•, 12, 29]. If at any point a high-grade lesion is identified on colposcopy, or if HSIL persists for over a year, biopsy of suspicious lesion is recommended, and if HSIL persists for over 24 months without histologic diagnosis of CIN 2+, excisional procedure is recommended [11•]. Excisional procedures such as LEEP or cold-knife cone are considered acceptable in this age group only if colposcopy is unsatisfactory, or CIN 2+ or ungraded CIN is found on endocervical sample during follow-up evaluations of CIN 1 [11•, 12, 29].
In young women, initial conservative management of CIN 2/3 with cytology and colposcopy is generally acceptable, although treatment at time of diagnosis is also considered an acceptable option. In women with a diagnosis of CIN 2-3, treatment or observation for 12 months, with cytology and colposcopy at six-month intervals, is acceptable [11•, 12, 29]. If at any point during observation the lesion worsens on colposcopy, if HSIL persists for over a year, or if a high-grade colposcopic lesion persists for over 12 months, repeat biopsy is recommended [11•]. Treatment, whether ablative or excisional, is recommended if colposcopy is inadequate, CIN 3 is identified, or if CIN 2 or CIN 2/3 persists for over 24 months [11•, 12, 29]. Patients may return to routine screening after two negative Pap smears in addition to a negative co-test after one year [11•]. For patients treated for cervical dysplasia, screening follows the guidelines for the particular grade of dysplasia as outlined by ASCCP.
Pregnancy

Due to the risks such as pregnancy loss, preterm contractions and/or labor, and hemorrhage associated with current excisional procedures, cervical dysplasia in pregnancy, regardless of age, is generally observed unless invasive cancer is suspected or diagnosed. CIN 1 can be managed conservatively during pregnancy and can be re-evaluated as early as six weeks post-partum. In pregnant patients with CIN 2+ but without evidence of invasive cancer, serial colposcopic and cytologic examinations can be performed at intervals of no less than 12 weeks [11•, 12]. Biopsy of lesions is recommended only if appearance of the lesion worsens on colposcopy or if repeat cytology suggests invasive cancer [11•, 12]. A diagnostic excisional procedure should be performed in pregnancy only if invasive carcinoma is suspected [11•, 12].
Women Aged 65+

Per the ASCCP guidelines, women with no history of cervical dysplasia or invasive cancer may discontinue Pap screening at age 65. However, for patients aged 65 years or older who demonstrate cytologic findings of ASCUS+, regardless of HPV, these results should be considered abnormal, and repeat co-testing at one year is recommended [11•, 12]. Treatment of higher-grade lesions follows the ASCCP guidelines as outlined for the general population.
Conclusions

As more research is conducted and technology continually improves, the guidelines for cervical cancer screening will likely continue to change. With newer testing modalities, including HPV testing, the diagnosis of precancerous cervical lesions will become increasingly sensitive. It is vital that clinicians stay updated on the most current recommendations for cervical cancer screening, as well as management of precancerous cervical lesions, so that patients can continue to receive the best available care.
Compliance with Ethics Guidelines
Conflict of Interest
Melinda S. Auer declares that she has no conflict of interest.
David G. Mutch has received grants from NIH, NCI, Lilly, and Genentech.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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About garyskeete

ASHWORTH MEDICINE-Professional Medical Assisting, Doctor of Science,Legal Assistant Diploma BSc Criminal Justice
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