Atypical Squamous Cells of Undetermined Significance

Cornelia O. Ndifon; Ghaith Al-Eyd; Charles J. Dunton

Atypical Squamous Cells of Undetermined Significance

Earn CME/CE in your profession:

Free Review Questions

Continuing Education Activity

Atypical squamous cells of undetermined significance (ASC-US) is a category of cervical epithelial cell abnormalities described by the Bethesda system for reporting cervical cytology. It refers to abnormal cytologic changes that are suggestive of the squamous intraepithelial lesion (SIL) but are qualitatively and quantitatively less than those of a definitive SIL diagnosis. Based on the patient's age and the estimated risk of possible underlying neoplastic lesions, an ASC-US report requires further follow-up by doing repeat cytology and HPV tests to guide the management of potential precancerous/cancerous cervical lesions. This activity reviews the evaluation and management of ASC-US and highlights the role of the interprofessional team in this process.

Objectives:

Explain the term "ASC-US" and identify its etiology.
Describe the diagnostic workup tests used to evaluate a patient with a cervical cytology report of ASC-US.
Outline the management of a patient with a cervical cytology report of ASC-US, based on the most recent practice guidelines.
Explain the importance of collaboration and communication among the interprofessional team to ensure a thorough evaluation and management of a patient with a cervical cytology report of ASC-US.

Introduction

Atypical squamous cells of undetermined significance (ASC-US) is a term used to report a category of cervical epithelial cell abnormalities described by the Bethesda system for reporting cervical cytology. It refers to abnormal cytologic changes that are suggestive of the squamous intraepithelial lesion (SIL) but are qualitatively and quantitatively less than those of a definitive SIL diagnosis.[1] The clinical significance of ASC-US is based on the fact that this cytology finding is suggestive of a varying degree of SIL. Nearly 10% to 20% of patients with ASC-US prove to have a varying degree of cervical intraepithelial neoplasia (CIN), which are distinctive precursor lesions of cervical squamous cell carcinoma.[2]

About a decade ago, cervical cancer was the third most common cancer in women worldwide, and it was ranked as the first most common cancer in women in 42 low-resourced countries.[3] However, the explained link between persistent infection with carcinogenic human papillomavirus (HPV) and the development of cervical cancer has paved the way for the advancement of primary and secondary prevention of this type of cancer. The currently used preventive measures include primary prevention by HPV vaccination and secondary prevention through cervical screening programs, patient's follow-up, and treatment of precursor lesions.[4]

In developed countries such as United States, United Kingdom, and Canada, widespread availability and access to cervical cancer screening have led to a significant reduction in both incidence and mortality from cervical cancer.[5][6][7][8] In the United States, the incidence of cervical cancer cases has dropped to 7.4 per 100,000, while deaths from invasive cervical cancer have dropped to 2.8 per 100,000 women.[9][10][11] A late diagnosis of invasive cervical cancer has a 100 percent mortality rate. The importance of screening in the prevention of cervical cancer is that precancerous stages are slow-growing and amenable to treatment.[12][13] Active screening and treatment of women for precancerous lesions, particularly in developing countries, have a very high chance of total elimination of deaths from cervical cancer.[14][5] A more recent study estimated the worldwide age-standardized incidence rate of cervical cancer to be 13·1 (6.4 for Northern America) per 100,000 women-years and an age-standardized mortality rate of 6·9 (1.9 for Northern America) per 100,000. In the same study, cervical cancer was ranked as the worldwide fourth most common cancer among women after breast cancer, colorectal cancer, and lung cancer.[15]

Though it has been previously theorized that alpha-1 antitrypsin deficiency may be a genetic predisposition, this is not yet confirmed.[16] Rather, ample scientific evidence suggests that certain high-risk Human papillomaviruses (hrHPV) cause over 90% of cervical cancers, with 50 to 73.8% attributed to HPV 16 strain and 12 to 16.4 % attributed to HPV 18.[17][18] The long-standing model of diagnosis has been by cytology using the Papanicolaou smear (Pap test) and biopsy, and most recently by liquid-based cytology (LBC).[19][20] Other methods of diagnosis include HPV DNA test and colposcopy.[21][22]

Women that have ever been sexually active are at risk of developing cervical cancer; however, there are women with a greater risk profile than others. Risk factors commonly associated with the development of cervical cancer include younger age at sexual debut, multiple concurrent sexual partners, chronic intense smoking, HIV infection, and persistent infection with high-risk HPV. Though the Pap test dates back to the late 1940s, it has not been fully adopted and utilized in resource-limited settings for several reasons, including high cost and delay in getting results. Very low rates of Pap smear have been reported in resource-limited countries, including Jamaica at 15% and Nicaragua at 20% national coverage. In some Asian and African countries, Pap testing rates are even lower, or it does not even exist, compared to Jamaica.[23] In other countries, at the time when cervical screening programs were not implemented, opportunistic Pap smear screening tests were used instead, but the rate was also remarkably low.[24]

Visual inspection of the ectocervix is the new way of screening, with immediate results and successful treatment of most of the identified precancerous lesions.[25] Negative cervical cytology is reported as "negative for intraepithelial lesion or malignancy" (Negative/NILM). Squamous cell abnormalities that can be detected by cervical cytology include ASC-US, atypical squamous cells-high-grade cannot be excluded (ASC-H), low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial session (HSIL), and invasive squamous cancer. Glandular cell abnormalities include atypical glandular cells (AGC), including endocervical and endometrial cells (not otherwise specified or favor neoplastic), endocervical adenocarcinoma in situ (AIS), and adenocarcinoma. This activity will improve the understanding of what ASC-US is and the implications and management of ASC-US diagnosis.[26][27][21][28]

Etiology

Cervical cancer is not a sexually transmitted infection, but it develops from precursor lesions (CIN) that are predisposed by a persistent infection with a common sexually transmitted pathogen, the HPV. There are over 200 species of human papillomavirus. Researchers have identified 13 hrHPV viral strains that cause human cancers, of which HPV 16 and HPV 18 cause about 70 percent of cervical cancers, and more so in HIV-infected women.[29][30] The atypical squamous cells seen in cervical cytology may be related to HPV infection and neoplasia. They are just cytologic mimics caused by inflammation, air drying, atrophy with degeneration, and other artifacts. One study of the U.S. cervical screening programs showed about 50% of women with atypical squamous cells are infected with HrHPV. In contrast, the other noninfected women are not at increased cancer risk.[2]

Other studies have demonstrated a high prevalence of hrHPV in patients with ASC-US; one study in Brazil analyzed 1,340 liquid-based cytology specimens and found out that 64% of ASC-US specimens harbored hrHPV.[31] In two separate studies, Mai Nishimura reported identifying hrHPV in 81 % of patients with ASC-US. In contrast, Ming Guo and colleagues reported a hrHPV 16/18 incidence rate of 37% in their ASC-US patient cohort, while one Mexican study found an incidence rate of 11.2 percent.[32][33][34] In another study in Turkey, 129 women with abnormal Pap smears were screened for hrHPV positivity, 94 had ASC-US diagnosis, and 94% of those had a hrHPV.[35]

Epidemiology

Cervical precancer lesions are slow-growing and are commonest between the ages of 35 and 45 years but can be seen more frequently in HIV-positive women between the ages of 25 and 35. With the persistence of hrHPV infection over the years or decades, actual cancer peaks after the age of 50 years.[36] We call ASC-US today originally described by Papanicolaou as atypical pathology, and it is a cytological nomenclature.[19] The original laboratory technicians who worked on smears reported them simply as normal, atypical, or suspicious/malignant.[19] ASC-US, therefore, represents a mix of squamous epithelial cells at different stages of transitioning from the lowest risk atypia to the worst form of precancer, with some harboring the potential to revert to normalcy.[32]

The histological classification known as cervical intraepithelial neoplasia or CIN is a three-tier grading of CIN that corresponds to the number of layers of epithelial cells affected by atypia.[36][37] The CIN classification replaces the dysplasia terminology, with CIN 1, CIN 2, and CIN 3 being equivalent to mild dysplasia, moderate dysplasia, and severe dysplasia, respectively. The dysplasia descriptions are, however, no longer in use. There modified Bethesda system of cytological classification divides atypical squamous cells (ASC) into atypical squamous cells of undetermined significance (ASC-US), and atypical squamous cells-high-grade cannot be excluded (ASC-H).[38][39]

ASC-US is a common diagnostic category considered to be a difficult and grey zone diagnosis between negative and a confirmed SIL.[36][39] Follow-up and further analyses of ASC-US results have not only identified LSIL cells but HSIL also.[40] By the Bethesda system, ASC-US/ASC-H taken together is of lesser risk compared to LSIL, which is the equivalent of CIN1 by histology and HSIL (CIN 2/3).[41][36][42][43] Different studies have reported the incidence of ASC-US to be as low as 2.5% in one Japanese study, 4.1% in one US study, 5.8% in another U.S. study, 7.4% in Bosnia, and as high as 19.1% in another Japanese study.[32][42][44][45][46]

Pathophysiology

Atypical squamous cells that are related to an underlying SIL are associated with HPV infection. Following the initial acquisition of hrHPV, there is an inflammatory response that resolves after a short time. The chronic cases progress to more severe persistent infection associated with nuclear and cytoplasmic changes. In the presence of hrHPV 16 and 18, the viral genes E6 and E7 are thought to encode viral proteins in the infected squamous cells that promote the degradation of tumor suppressor gene proteins p53 and Rb respectively, resulting in malignant transformation.[26][47] Mahira Jahic and Elmir Jahic did a prospective analysis of 1,784 Pap smears and found that, out of 254 abnormal smears, overall, 74% persisted, 8% regressed, and 18% progressed to the worse stage.[46] Studies using immunohistochemistry have associated the loss of certain capsid proteins in ASC-US specimens with progression to a more severe form of precancer. Eun Young Ki and colleagues showed that detection of HPV serotypes 16 and 18 in the absence of HPV L1 capsid expression predicted worsening of precancer.[48] HIV positivity has also been known to promote HPV persistence and associated with a higher incidence of ASC-US.[25][49] Furthermore, a low CD4 count and not being on antiretroviral therapy were associated with the persistence of HPV infection.[50][49][31][51][46][47][12]

Histopathology

ASC-US is a cytopathology term that implies cervical epithelial cell abnormalities described by the Bethesda system for reporting cervical cytology. It refers to abnormal cytologic changes that are suggestive of SIL but are qualitatively and quantitatively less than those of a definitive SIL diagnosis.[1] The morphologic criteria of ASC-US include cells that have the shape and size of superficial or intermediate squamous cells with enlarged nuclei 2.5 to 3 times the area of those of normal intermediate squamous cells, slightly increased nucleo-cytoplasmic ratio, with minimum hyperchromatism and irregular chromatin. The cytoplasm may show halo and atypical parakeratosis (dense orangeophilic). These criteria may vary slightly among different laboratories due to differences in slide preparation and staining techniques.[52][53][54] The distinction between a true premalignant lesion and a neoplastic one is based on the number, type, and severity of change both in the nucleus and cytoplasm. An ASC-US smear may also show mitosis, blurring of cytoplasmic borders, binucleation, and corneal pearls. Other histologic changes include squamous epithelial giant cells and parakeratosis.[55] Hyperchromasia and enlargement of nucleoli suggest a progression from a ‘mere’ ASC-US to LSIL/CIN 1 plus.[56][57] Histologically and as described earlier, the CIN histological classification is a three-tier grading of CIN that corresponds to the number of layers of epithelial cells affected by atypia.

History and Physical

ASC-US is not a clinical diagnosis. A woman receiving an ASC-US report from Pap test is most often asymptomatic and is most likely identified through a population-based screening. Alternatively, she may present with bloody, offensive, and or watery vaginal discharge, lower backache, or signs of urinary tract infection and be diagnosed opportunistically.[27] The physical examination evaluates the general health of the patient and checks for possible signs related to pathologies that may underlie the cytologic changes of ASC-US.

Considering that a late diagnosis or advanced invasive cervical cancer has no remedy, it is important to consider the risk factors that predispose women to develop this cancer and use that as a guide to determine the screening status of women in their care.[58] Risk factors for cervical cancer include lower age at sexual debut, multiple sexual partners, and sexually transmitted infections, including hrHPV and HIV. Also, women who have never had an initial Pap test were observed to present with a more severe form of a precancerous lesion or full-blown cancer.[58] Prolonged and intense smoking has also been linked to an increased risk of developing cervical cancer.[59]

Evaluation

Cervical cancer screening in women between the age of 21 and 65 years is supported by the American College of Obstetricians and Gynecologists (ACOG), American Cancer Society (ACS), U.S Preventive Services Task Force (USPSTF), and the U.S. Food and Drug Administration (FDA).[6][14] Studies have shown that regular and consistent screening of women for cervical cancer reduces invasive cervical cancer incidence and deaths.[7] Any sexually active woman presenting in the outpatient department with gynecologic or perianal symptoms, including abnormal vaginal bleeding, vaginal discharge, dysuria, or vaginal itching, should undergo triage testing.[44][34] Immunocompetent and asymptomatic women between the ages of 21 and 29 are to be screened once every three years by cytology alone. In the older age groups of 30 to 65 years, where HPV persistence may spell problems, HrHPV testing alone or co-testing (HrHPV and cytology) is also recommended every 5 years in addition to the option of screening by cytology alone every 3 years.[8][6][60] Screening is not recommended for women below age 21 because most HPV infections are transient or clear completely. Women older than 65 years can cease surveillance screening if they have consistently been previously negative.

Triage testing involves cytology with Pap test or LBC, visual inspection with acetic acid (VIA) plus colposcopy, HPV DNA, or any combination as recommended in the setting where one works.[34][61][34] Triage testing is specifically relevant to a patient with an ASC-US diagnosis because it enables further delineation of an ASC-US result into a true NILM, LSIL, or HSIL.[62][44][32][47]

Initially, a bimanual and speculum vaginal examination is done. Either Pap test is done alone or together with hrHPV DNA assay, or VIA is done alone or in combination with hrHPV DNA, or hrHPV DNA is done alone (primary HPV testing).[60][63] The combination of cytology and HPV DNA testing is advocated for because HPV DNA testing is more sensitive than cytological analysis alone. At the same time, however, the very infrequent occurrence of HPV negative/cytology-positive cancers has highlighted the importance of co-testing.[64][44][32][60]

Visual inspection with acetic acid involves the application of 3% to 5% dilutes acetic acid for one minute on the ectocervix.[25] Aceto-whitening of ectocervical lesions is caused by the high absorption of acetic acid by protein-rich precancer cells.[65] Good visualization of the post-application cervix is achieved with a handheld bright light or colposcope. VIA studies are reported as VIA-negative, VIA-positive, or suspicious for cancer. Colposcopy-guided cervical biopsies are usually done for VIA positive and suspicious for cancer patients.[66][67][25]

Treatment / Management

The variable progression following the diagnosis of ASC-US poses a management challenge. There is a possibility of overtreatment, and at the same time, also the risk of progression to higher grade precancerous lesions or even invasive cancer with conservative treatment, especially if close follow-up is not carried out.[32] J Melnikow and colleagues found, in a meta-analysis, that 68% of ASC-US regressed to normal by 24 months, while 7.13 % of ASC-US progressed to a worse grade SIL in the same period.[68]

The diagnosis of ASC-US begins to gain clinical significance when it is associated with a positive hrHPV diagnosis. Both reflex HPV DNA testing and co-testing have reported a high incidence of hrHPV in ASC-US specimens.[60][34] The 'U' in ASC-US stands for 'undetermined' significance because it is unclear how much of the ASC-US may resolve to become negative and how much would persist and progress to become low- or high-grade squamous intraepithelial lesion.[68] Also, the main factors responsible for persistence are not fully understood, though hrHPV infection is known to persist more in HIV positive patients compared to HIV negative patients, resulting in a higher incidence of invasive cervical cancer in HIV positive patients.[69][25]

An initial ASC-US may warrant no further management except to repeat Pap cytology alone or do an acetic acid-guided visual inspection (VIA) with colposcopy or in combination with HPV genotyping (DNA or mRNA) where feasible.[70][25] Persistent ASC-US, including ASC-H, calls for a thorough analysis (triaging) and intervention, including referral for colposcopy.[40][10] Eun Young Ki and colleagues define ASC-US persistence at 12-month repeat cytology or serial ASC-US reports.[48] Studies have shown that HPV DNA testing prior to colposcopy in women with persistent ASC-US provided improved diagnostic sensitivity compared to a CIN 2+ diagnosis.[71]

The American Society for Colposcopy and Cervical Pathology (ASCCP) has recently published (in April 2020) the 2019 ASCCP risk-based management guidelines for abnormal cervical cancer screening tests and cancer precursors. One of the essential changes from prior management guidelines is that patient's risk of CIN3+, determined by current test results and past history (including unknown history), has become a key factor on which recommendations of colposcopy, treatment, or surveillance are based.[28]

In patients younger than 25 years with LSIL, ASC-US HPV-positive, or ASC-US without HPV testing, repeat cytology at 1 year is preferred, and if the result is NILM/ASC-US/LSIL, another repeat cytology is needed in 1 year, after that if the result is negative, then routine age-based screening is resumed. If HPV testing was first done for a patient with ASC-US, and the test was negative, there would be no need for the repeat cytology described above, and routine age-based screening could be directly resumed. Colposcopy is indicated if the first one-year repeat cytology shows HSIL/ASC-H/AGC/AIS, and also when the second one-year repeat cytology shows ASC-US or more severe lesions.[28]

As per the new 2019 ASCCP guidelines, practitioners should start using CIN3+ risk estimates (based on HPV testing/co-testing and past history) when a patient reaches the age of 25 years. Previously (before the recent guidelines update), patients aged 25 years and older with ASCUS have two management options, one option is to do HPV testing (preferred), and if the test is positive, colposcopy is indicated, while patients with negative HPV test will have repeat cytology in three years. The second option is to repeat the cytology in one year, and if an abnormality is detected, then colposcopy is indicated. If the one-year repeat cytology is negative, then the patient can return to routine age-based screening. But per the new guidelines, a colposcopy can be deferred for certain patients if they have only minor screening abnormalities indicating HPV infection, provided that the risk of having CIN3+ is low. For example, a patient who tested HPV positive with low-grade cytologic abnormalities (LSIL/ASC-US), and has a past history of documented negative screening HPV test or co-test, can now be managed by repeating HPV testing or co-testing at 1 year. Practitioners can start managing their patients based on these new 2019 ASCCP guidelines using the tables of Egemen et al. or by using an app or website that will be designed and made available at the ASCCP website.[28][72]

SIL treatment options include ablation methods such as cryotherapy or thermocoagulation, while HSIL (CIN 2+) is best treated by large loop excision of the transformation zone/loop electrosurgical excision procedure (LLETZ/LEEP) or laser or cold knife conization in cases of adenocarcinoma in-situ (AIS).[73][74][75][76][77][12][78] During cryotherapy, pressurized gas, either carbon dioxide or nitrous oxide, is used to freeze acetowhite lesions that are 3 to 5 mm deep under normal light or colposcopic guidance.[13] Thermal coagulation is the burning of acetowhite areas depicting precancerous lesions. Both heat and cold coagulation cause tissue necrosis with minimal or no systemic complications.[13] Under certain circumstances, a test and treat or single visit approach with VIA and colposcopy showed to be preferred to Pap test, particularly in resource-limited settings.[79][80][70][77][66][74][67][12]

Apart from surgical interventions, certain pharmacological approaches have been employed under various randomized controlled trials (RCTs), with some showing promising outcomes at phase II.[81][82][83][84] In one study done by G Laccetta and colleagues, 176 patients with ASC-US were treated with topical beta-glucan, and Pap test repeated after 6 months. Sixty-three percent reverted to a negative Pap test. No side effects were reported.[85] Cho et al. studied the effects of 1 to 1.5 g of oral poly-gamma-glutamic acid daily in 195 patients; and reported an HPV clearance rate of 44% in 85 patients with hrHPV.[82] In 1996, Manetta A and colleagues investigated the effects of a daily oral dose of beta carotenes in patients diagnosed with CIN 1 and 2. After 12 months of treatment, they reported as high as 60 percent regression of CIN1 in some of the patients.[86] Some other studies did not show positive effects on CIN lesions. Research conducted at the Medical College of Wisconsin explored the effects of 400 mg of daily oral celecoxib in 63 patients with CIN3. There was no positive change in the severity of the disease.[86]

Differential Diagnosis

ASC-US could represent different pathologies NILM, LSIL/CIN 1, HSIL/CIN 2+, or even early invasive cervical carcinoma. On the other hand, ASC-US could be just a cytologic mimic caused by inflammation (cervicitis), air drying, atrophy with degeneration, and other artifacts. True differentiation is best achieved with HPV DNA testing, colposcopy, and biopsy, particularly in persistent ASC-US.[55][63]

Prognosis

In the presence of quality triage studies, most ASC-US diagnoses have a good prognosis.[87][88] Clearance of HPV infection returns the cervical tissues to normal. Still, progression to HSIL/CIN 2+ can be treated either by cryotherapy, LLETZ, or conization methods, and the patient stands a chance of complete lifetime elimination of the possibility of cancer.

Complications

Complications of ASC-US may arise from inadequate follow-up or the lack of it, or they may result from treatment in general. An ASC-US diagnosis may completely return to normal on repeat Pap test, but generally, an ASC-US diagnosis that is not followed up may worsen to HSIL/CIN 2+ or invasive cancer in underserved populations with limited or no access to comprehensive screening services.[23][68][23] In resource-limited settings, with unskilled staff, there is a risk of overtreatment of ASC-US/LSIL. All forms of treatment carry a very small risk of complications, ranging from mild pain during the procedure to bleeding, postoperative pain, and brownish vaginal discharge. Doing cryotherapy or LLETZ in the presence of cervicitis, bacterial vaginosis, or vaginal trichomoniasis may give rise to severe and malodorous vaginal discharge. Recurrence of the lesion may indicate poor quality treatment resulting from incomplete excision of lesion or transformation zone, though the presence of HPV is a stronger predictor of treatment failure. Preterm births have been reported to complicate the conization of the cervix in patients with CIN 2+ or AIS.[77] The persistence of lesions has also been reported to be more in HIV-infected patients compared to immunocompetent individuals.[89]

Postoperative and Rehabilitation Care

Patients treated with cryotherapy and LLETZ/LEEP are usually managed as day cases and are given mild oral analgesics such as ibuprofen. They are usually instructed to avoid sex for 4 to 6 weeks and to use condoms where abstinence fails. Patients are also advised not to insert tampons and not to douche. Those who develop malodorous discharge and or persistent vaginal discharge beyond 14 days are asked to return to the physician for reevaluation and treatment. Where signs of postoperative infection exist, endocervical or high vaginal swabs can be sent for culture, and the woman treated empirically with doxycycline 100 mg orally two times daily for seven days and metronidazole 400 mg orally three times a day for seven days.

Deterrence and Patient Education

Full-blown advanced cervical cancer, whether in HIV-positive or negative women, has 100 percent mortality. All women should be made aware of the importance of regular screening and the availability of the HPV vaccine. Patients with nonspecific cervical abnormalities like ASC-US must be educated and closely monitored, so they do not fall through the cracks and later appear with invasive cervical cancer. Weigh the costs of screening for hrHPV and treating invasive cancer with attendant grave consequences on human lives and families; versus prevention. We should choose prevention over cure because it is a less expensive choice. Combined prevention and lifestyle modification, including delay in sexual debut, reduction of sexual partners, consistent and correct use of condoms, male circumcision, and smoking cessation, would go a long way to reduce precancer and cancer.

Pearls and Other Issues

The coverage for cervical cancer screening in most resource-limited settings is still below 35 percent of the population.
Women can be screened and followed up for cervical pre-malignant diseases, usually by Pap test, and also by VIA with colposcopy, HPV DNA, and biopsy.
It is possible to do at least one cervical cancer screening method in any country in the world where cervical screening programs are not available. In 1949, Papanicolaou and Traut began doing simple cytology, and today we have evolved to the more sophisticated molecular DNA testing for HPV. There should be no excuse for not doing cervical cancer screening.
Prioritizing and integrating cervical cancer screening in the daily management of women in primary healthcare facilities would go a long way to reducing new cases of cancer and possible elimination of deaths from invasive cervical cancer.
ASC-US diagnosis is an abnormal finding that requires a further evaluation from 6 months after the initial result but not later than 12 months.
An ASC-US diagnosis may mean NILM or true precancer and hence poses a management challenge, which needs to be addressed by triaging with molecular testing and histology.
VIA (visual inspection with acetic acid), together with same-day treatment, has been shown to reduce the incidence of invasive cervical cancers.
All patients with HIV must be prioritized to have a visual inspection with acetic acid. This is a simple and cheap procedure delivered as a screening and treating procedure or single visit approach.
Large-scale HPV vaccination before the onset of sexual activity may hold the key to the elimination of cervical cancer.

Enhancing Healthcare Team Outcomes

Most women who would receive an ASC-US diagnosis are asymptomatic. Healthcare workers at primary care facilities, maternities, general outpatient departments, gynecology, and sexually transmitted infection (STI) clinics, need to be proactive, engage women, create awareness, and screen all sexually active women for cervical precancer. Healthcare professionals need to understand the interplay of culture, behavior, and socioeconomic status and their relationship to cervical cancer incidence.[23] Community health workers, nurses at immunization clinics, and midwives must be engaged to inform patients and create awareness on the benefits of cervical cancer screening and the dangers of invasive cervical cancer. The diagnosis and treatment of cervical precancer must be done in collaboration with skilled cytopathologists, gynecologic oncologists, and doctors specifically trained in cryotherapy, LLETZ, and conization. Finally, prophylactic HPV vaccination in girls 9 to 15 years has been shown to have a huge decrease in new HPV infections.[90] Healthcare professions attending to female children and adolescent girls have ample opportunity to advocate for the scale-up of HPV vaccination across the globe.[90][91]

Details

References

[1]

Tewari R, Chaudhary A. Atypical Squamous Cells of Undetermined Significance : A Follow up Study. Medical journal, Armed Forces India. 2010 Jul:66(3):225-7. doi: 10.1016/S0377-1237(10)80042-5. Epub 2011 Jul 21 [PubMed PMID: 27408306]

[2]

ASCUS-LSIL Traige Study (ALTS) Group. Results of a randomized trial on the management of cytology interpretations of atypical squamous cells of undetermined significance. American journal of obstetrics and gynecology. 2003 Jun:188(6):1383-92 [PubMed PMID: 12824967]

[3]

Arbyn M, Castellsagué X, de Sanjosé S, Bruni L, Saraiya M, Bray F, Ferlay J. Worldwide burden of cervical cancer in 2008. Annals of oncology : official journal of the European Society for Medical Oncology. 2011 Dec:22(12):2675-2686. doi: 10.1093/annonc/mdr015. Epub 2011 Apr 6 [PubMed PMID: 21471563]

[4]

IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Human papillomaviruses. IARC monographs on the evaluation of carcinogenic risks to humans. 2007:90():1-636 [PubMed PMID: 18354839]

[5]

Dickinson JA, Stankiewicz A, Popadiuk C, Pogany L, Onysko J, Miller AB. Reduced cervical cancer incidence and mortality in Canada: national data from 1932 to 2006. BMC public health. 2012 Nov 16:12():992. doi: 10.1186/1471-2458-12-992. Epub 2012 Nov 16 [PubMed PMID: 23158654]

[6]

Rerucha CM, Caro RJ, Wheeler VL. Cervical Cancer Screening. American family physician. 2018 Apr 1:97(7):441-448 [PubMed PMID: 29671553]

[7]

Eddy DM. Screening for cervical cancer. Annals of internal medicine. 1990 Aug 1:113(3):214-26 [PubMed PMID: 2115753]

[8]

US Preventive Services Task Force, Curry SJ, Krist AH, Owens DK, Barry MJ, Caughey AB, Davidson KW, Doubeni CA, Epling JW Jr, Kemper AR, Kubik M, Landefeld CS, Mangione CM, Phipps MG, Silverstein M, Simon MA, Tseng CW, Wong JB. Screening for Cervical Cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2018 Aug 21:320(7):674-686. doi: 10.1001/jama.2018.10897. Epub [PubMed PMID: 30140884]

[9]

Sawaya GF, Huchko MJ. Cervical Cancer Screening. The Medical clinics of North America. 2017 Jul:101(4):743-753. doi: 10.1016/j.mcna.2017.03.006. Epub 2017 Apr 21 [PubMed PMID: 28577624]

[10]

Hirai CM, Kaneshiro B, Hiraoka MK. The Effect of the 2012 ASCCP Consensus Guideline for Abnormal Cervical Cytology on Resident Colposcopy Training. Hawai'i journal of medicine & public health : a journal of Asia Pacific Medicine & Public Health. 2018 Jan:77(1):3-6 [PubMed PMID: 29333334]

[11]

Wender RC, Brawley OW, Fedewa SA, Gansler T, Smith RA. A blueprint for cancer screening and early detection: Advancing screening's contribution to cancer control. CA: a cancer journal for clinicians. 2019 Jan:69(1):50-79. doi: 10.3322/caac.21550. Epub 2018 Nov 19 [PubMed PMID: 30452086]

[12]

D'Alessandro P, Arduino B, Borgo M, Saccone G, Venturella R, Di Cello A, Zullo F. Loop Electrosurgical Excision Procedure versus Cryotherapy in the Treatment of Cervical Intraepithelial Neoplasia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Gynecology and minimally invasive therapy. 2018 Oct-Dec:7(4):145-151. doi: 10.4103/GMIT.GMIT_56_18. Epub 2018 Sep 26 [PubMed PMID: 30306032]

Level 1 (high-level) evidence

[13]

Castle PE, Murokora D, Perez C, Alvarez M, Quek SC, Campbell C. Treatment of cervical intraepithelial lesions. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. 2017 Jul:138 Suppl 1():20-25. doi: 10.1002/ijgo.12191. Epub [PubMed PMID: 28691333]

[14]

Committee on Practice Bulletins—Gynecology. ACOG Practice Bulletin Number 131: Screening for cervical cancer. Obstetrics and gynecology. 2012 Nov:120(5):1222-38 [PubMed PMID: 23090560]

[15]

Arbyn M, Weiderpass E, Bruni L, de Sanjosé S, Saraiya M, Ferlay J, Bray F. Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis. The Lancet. Global health. 2020 Feb:8(2):e191-e203. doi: 10.1016/S2214-109X(19)30482-6. Epub 2019 Dec 4 [PubMed PMID: 31812369]

Level 3 (low-level) evidence

[16]

Philippe P. Is cervical cancer hereditary? Canadian Medical Association journal. 1981 Mar 15:124(6):672-6 [PubMed PMID: 20313553]

[17]

Zhen S, Lu JJ, Wang LJ, Sun XM, Zhang JQ, Li X, Luo WJ, Zhao L. In Vitro and In Vivo Synergistic Therapeutic Effect of Cisplatin with Human Papillomavirus16 E6/E7 CRISPR/Cas9 on Cervical Cancer Cell Line. Translational oncology. 2016 Dec:9(6):498-504. doi: 10.1016/j.tranon.2016.10.002. Epub 2016 Oct 28 [PubMed PMID: 27816686]

[18]

Yang L, Yang H, Wu K, Shi X, Ma S, Sun Q. Prevalence of HPV and variation of HPV 16/HPV 18 E6/E7 genes in cervical cancer in women in South West China. Journal of medical virology. 2014 Nov:86(11):1926-36. doi: 10.1002/jmv.24043. Epub 2014 Aug 11 [PubMed PMID: 25111286]

[19]

LINDSAY S. The Papanicolaou-Traut method of cancer diagnosis; its use as a routine pathologic laboratory procedure. California medicine. 1949 May:70(5):413-6 [PubMed PMID: 18126374]

[20]

Austin RM, Onisko A, Zhao C. Enhanced Detection of Cervical Cancer and Precancer Through Use of Imaged Liquid-Based Cytology in Routine Cytology and HPV Cotesting. American journal of clinical pathology. 2018 Oct 1:150(5):385-392. doi: 10.1093/ajcp/aqy114. Epub [PubMed PMID: 30137189]

[21]

Wright TC, Stoler MH, Behrens CM, Sharma A, Zhang G, Wright TL. Primary cervical cancer screening with human papillomavirus: end of study results from the ATHENA study using HPV as the first-line screening test. Gynecologic oncology. 2015 Feb:136(2):189-97. doi: 10.1016/j.ygyno.2014.11.076. Epub 2015 Jan 8 [PubMed PMID: 25579108]

[22]

Gustavsson I, Aarnio R, Myrnäs M, Hedlund-Lindberg J, Taku O, Meiring T, Wikström I, Enroth S, Williamson AL, Olovsson M, Gyllensten U. Clinical validation of the HPVIR high-risk HPV test on cervical samples according to the international guidelines for human papillomavirus DNA test requirements for cervical cancer screening. Virology journal. 2019 Aug 22:16(1):107. doi: 10.1186/s12985-019-1216-7. Epub 2019 Aug 22 [PubMed PMID: 31438976]

Level 1 (high-level) evidence

[23]

Agurto I, Arrossi S, White S, Coffey P, Dzuba I, Bingham A, Bradley J, Lewis R. Involving the community in cervical cancer prevention programs. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. 2005 May:89 Suppl 2():S38-45 [PubMed PMID: 15823265]

[24]

Al Eyd GJ, Shaik RB. Rate of opportunistic pap smear screening and patterns of epithelial cell abnormalities in pap smears in ajman, United arab emirates. Sultan Qaboos University medical journal. 2012 Nov:12(4):473-8 [PubMed PMID: 23275844]

[25]

Anderson J, Wysong M, Estep D, Besana G, Kibwana S, Varallo J, Sun K, Lu E. Evaluation of Cervical Cancer Screening Programs in Côte d'Ivoire, Guyana, and Tanzania: Effect of HIV Status. PloS one. 2015:10(9):e0139242. doi: 10.1371/journal.pone.0139242. Epub 2015 Sep 25 [PubMed PMID: 26405784]

[26]

Smith ER, George SH, Kobetz E, Xu XX. New biological research and understanding of Papanicolaou's test. Diagnostic cytopathology. 2018 Jun:46(6):507-515. doi: 10.1002/dc.23941. Epub 2018 Apr 16 [PubMed PMID: 29663734]

Level 3 (low-level) evidence

[27]

Bukhari MH, Saba K, Qamar S, Majeed MM, Niazi S, Naeem S. Clinicopathological importance of Papanicolaou smears for the diagnosis of premalignant and malignant lesions of the cervix. Journal of cytology. 2012 Jan:29(1):20-5. doi: 10.4103/0970-9371.93213. Epub [PubMed PMID: 22438612]

[28]

Spin label studies on the interactions of bovine adrenodoxin with NADPH-adrenodoxin reductase and with cytochrome P-450scc., Miura R,Sugiyama T,Yamano T,, Journal of biochemistry, 1979 May [PubMed PMID: 32243307]

[29]

Clifford GM, Tully S, Franceschi S. Carcinogenicity of Human Papillomavirus (HPV) Types in HIV-Positive Women: A Meta-Analysis From HPV Infection to Cervical Cancer. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2017 May 1:64(9):1228-1235. doi: 10.1093/cid/cix135. Epub [PubMed PMID: 28199532]

Level 1 (high-level) evidence

[30]

Saraiya M, Kwan A, Cooper CP. Primary HPV testing: U.S. women's awareness and acceptance of an emerging screening modality. Preventive medicine. 2018 Mar:108():111-114. doi: 10.1016/j.ypmed.2017.12.007. Epub 2017 Dec 23 [PubMed PMID: 29277414]

[31]

Oliveira GG, Oliveira JMDSC, Eleutério RMN, Barbosa RCC, Almeida PRC, Eleutério J Jr. Atypical Squamous Cells: Cytopathological Findings and Correlation with HPV Genotype and Histopathology. Acta cytologica. 2018:62(5-6):386-392. doi: 10.1159/000489386. Epub 2018 Jun 13 [PubMed PMID: 29898441]

[32]

Nishimura M, Miyatake T, Nakashima A, Miyoshi A, Mimura M, Nagamatsu M, Ogita K, Yokoi T. Clinical Significance of Atypical Squamous Cells of Undetermined Significance among Patients Undergoing Cervical Conization. Asian Pacific journal of cancer prevention : APJCP. 2015:16(18):8145-7 [PubMed PMID: 26745052]

[33]

Guo M, Gong Y, Wang J, Dawlett M, Patel S, Liu P, Bevers TB, Sneige N. The role of human papillomavirus type 16/18 genotyping in predicting high-grade cervical/vaginal intraepithelial neoplasm in women with mildly abnormal Papanicolaou results. Cancer cytopathology. 2013 Feb:121(2):79-85. doi: 10.1002/cncy.21240. Epub 2012 Dec 5 [PubMed PMID: 23225501]

[34]

Torres-Ibarra L, Cuzick J, Lorincz AT, Spiegelman D, Lazcano-Ponce E, Franco EL, Moscicki AB, Mahmud SM, Wheeler CM, Rivera-Paredez B, Hernández-López R, León-Maldonado L, Salmerón J, FRIDA Study Group.. Comparison of HPV-16 and HPV-18 Genotyping and Cytological Testing as Triage Testing Within Human Papillomavirus-Based Screening in Mexico. JAMA network open. 2019 Nov 1:2(11):e1915781. doi: 10.1001/jamanetworkopen.2019.15781. Epub 2019 Nov 1 [PubMed PMID: 31747033]

[35]

Beyazit F, Sılan F, Gencer M, Aydin B, Paksoy B, Unsal MA, Ozdemir O. The prevelance of human papillomavirus (HPV) genotypes detected by PCR in women with normal and abnormal cervico-vaginal cytology. Ginekologia polska. 2018:89(2):62-67. doi: 10.5603/GP.a2018.0011. Epub [PubMed PMID: 29512809]

[36]

Liu L, Wang D, Dong H, Jin C, Jiang L, Song H, Jin C, Wang T, Shi C, Yang L, Wang Y. Characteristics of carcinogenic HPV genotypes in North China Plain and the association with cervical lesions. Medicine. 2019 Sep:98(37):e17087. doi: 10.1097/MD.0000000000017087. Epub [PubMed PMID: 31517830]

[37]

Gu J, Fu CY, Ng BK, Liu LB, Lim-Tan SK, Lee CG. Enhancement of early cervical cancer diagnosis with epithelial layer analysis of fluorescence lifetime images. PloS one. 2015:10(5):e0125706. doi: 10.1371/journal.pone.0125706. Epub 2015 May 12 [PubMed PMID: 25966026]

[38]

Thrall MJ, Pambuccian SE, Stelow EB, McKeon DM, Miller L, Savik K, Gulbahce HE. Impact of the more restrictive definition of atypical squamous cells introduced by the 2001 Bethesda System on the sensitivity and specificity of the Papanicolaou test: a 5-year follow-up study of Papanicolaou tests originally interpreted as ASCUS, reclassified according to Bethesda 2001 criteria. Cancer. 2008 Jun 25:114(3):171-9. doi: 10.1002/cncr.23538. Epub [PubMed PMID: 18454461]

[39]

Nayar R, Wilbur DC. The Bethesda System for Reporting Cervical Cytology: A Historical Perspective. Acta cytologica. 2017:61(4-5):359-372. doi: 10.1159/000477556. Epub 2017 Jul 11 [PubMed PMID: 28693017]

Level 3 (low-level) evidence

[40]

Sherman ME, Solomon D, Schiffman M, ASCUS LSIL Triage Study Group. Qualification of ASCUS. A comparison of equivocal LSIL and equivocal HSIL cervical cytology in the ASCUS LSIL Triage Study. American journal of clinical pathology. 2001 Sep:116(3):386-94 [PubMed PMID: 11554167]

[41]

Dankai W, Khunamornpong S, Siriaunkgul S, Soongkhaw A, Janpanao A, Utaipat U, Kitkumthorn N, Mutirangura A, Srisomboon J, Lekawanvijit S. Role of genomic DNA methylation in detection of cytologic and histologic abnormalities in high risk HPV-infected women. PloS one. 2019:14(1):e0210289. doi: 10.1371/journal.pone.0210289. Epub 2019 Jan 4 [PubMed PMID: 30608989]

[42]

Wright TC Jr, Stoler MH, Parvu V, Yanson K, Eckert K, Kodsi S, Cooper CK. Detection of Cervical Neoplasia by Human Papillomavirus Testing in an Atypical Squamous Cells-Undetermined Significance Population: Results of the Becton Dickinson Onclarity Trial. American journal of clinical pathology. 2019 Jan 1:151(1):53-62. doi: 10.1093/ajcp/aqy084. Epub [PubMed PMID: 30189049]

[43]

Nayar R, Wilbur DC. The Pap test and Bethesda 2014. Cancer cytopathology. 2015 May:123(5):271-81. doi: 10.1002/cncy.21521. Epub 2015 May 1 [PubMed PMID: 25931431]

[44]

Fujiwara H, Suzuki M, Morisawa H, Sayama M, Kimura K. The Impact of Triage for Atypical Squamous Cells of Undetermined Significance with Human Papillomavirus Testing in Cervical Cancer Screening in Japan. Asian Pacific journal of cancer prevention : APJCP. 2019 Jan 25:20(1):81-85 [PubMed PMID: 30678384]

[45]

Stoler MH, Wright TC Jr, Sharma A, Apple R, Gutekunst K, Wright TL, ATHENA (Addressing THE Need for Advanced HPV Diagnostics) HPV Study Group. High-risk human papillomavirus testing in women with ASC-US cytology: results from the ATHENA HPV study. American journal of clinical pathology. 2011 Mar:135(3):468-75. doi: 10.1309/AJCPZ5JY6FCVNMOT. Epub [PubMed PMID: 21350104]

[46]

Jahic M, Jahic E. Diagnostic Approach to Patients with Atypical Squamous Cells of Undetermined Significance Cytologic Findings on Cervix. Medical archives (Sarajevo, Bosnia and Herzegovina). 2016 Jul 27:70(4):296-298 [PubMed PMID: 27703293]

[47]

Zhan X, Wang S, Wu X, Qiu X, Li F, Zeng Y, Chen Z. [The role of HPV E6/E7 mRNA combined with P16/ki67 immunocytochemistry in the diagnosis of atypical squamous cells of undetermined significance(ASCUS)]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology. 2018 Oct:34(10):937-941 [PubMed PMID: 30554588]

Level 2 (mid-level) evidence

[48]

Ki EY, Park JS, Lee A, Kim TJ, Jin HT, Seo YB, Gen Y, Park MY, Lee SJ. Utility of human papillomavirus L1 capsid protein and HPV test as prognostic markers for cervical intraepithelial neoplasia 2+ in women with persistent ASCUS /LSIL cervical cytology. International journal of medical sciences. 2019:16(8):1096-1101. doi: 10.7150/ijms.31163. Epub 2019 Aug 6 [PubMed PMID: 31523171]

[49]

Chalermchockcharoenkit A, Chayachinda C, Thamkhantho M, Komoltri C. Prevalence and cumulative incidence of abnormal cervical cytology among HIV-infected Thai women: a 5.5-year retrospective cohort study. BMC infectious diseases. 2011 Jan 7:11():8. doi: 10.1186/1471-2334-11-8. Epub 2011 Jan 7 [PubMed PMID: 21211065]

Level 2 (mid-level) evidence

[50]

Kelly H, Weiss HA, Benavente Y, de Sanjose S, Mayaud P, ART and HPV Review Group. Association of antiretroviral therapy with high-risk human papillomavirus, cervical intraepithelial neoplasia, and invasive cervical cancer in women living with HIV: a systematic review and meta-analysis. The lancet. HIV. 2018 Jan:5(1):e45-e58. doi: 10.1016/S2352-3018(17)30149-2. Epub 2017 Oct 26 [PubMed PMID: 29107561]

Level 1 (high-level) evidence

[51]

George NB, Baldassari JH, Pérez Taveras DA, José Fernández M, Concepción Robledo M. The utility of pap cell block preparations with liqui-PREP™ cell pellets to clarify the cytological diagnosis of atypical squamous cells of undetermined significance and atypical glandular cells. Diagnostic cytopathology. 2017 Jun:45(6):520-525. doi: 10.1002/dc.23707. Epub 2017 Mar 24 [PubMed PMID: 28342244]

[52]

Solomon D, Davey D, Kurman R, Moriarty A, O'Connor D, Prey M, Raab S, Sherman M, Wilbur D, Wright T Jr, Young N, Forum Group Members, Bethesda 2001 Workshop. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA. 2002 Apr 24:287(16):2114-9 [PubMed PMID: 11966386]

[53]

Stoler MH, Schiffman M, Atypical Squamous Cells of Undetermined Significance-Low-grade Squamous Intraepithelial Lesion Triage Study (ALTS) Group. Interobserver reproducibility of cervical cytologic and histologic interpretations: realistic estimates from the ASCUS-LSIL Triage Study. JAMA. 2001 Mar 21:285(11):1500-5 [PubMed PMID: 11255427]

[54]

Enzymatic cleavage of the O2'-butyryl ester bond of N6, O2'-dibutyryl cyclic AMP and its possible involvement in the action of cyclic AMP derivatives in vivo., Nakamura H,Watanabe T,Kakiuchi S,Wada H,, Journal of biochemistry, 1979 May [PubMed PMID: 12789922]

[55]

Aoyama C, Liu P, Ostrzega N, Holschneider CH. Histologic and immunohistochemical characteristics of neoplastic and nonneoplastic subgroups of atypical squamous lesions of the uterine cervix. American journal of clinical pathology. 2005 May:123(5):699-706 [PubMed PMID: 15981809]

[56]

Mariuzzi G, Santinelli A, Valli M, Sisti S, Montironi R, Mariuzzi L, Alberti R, Pisani E. Cytometric evidence that cervical intraepithelial neoplasia I and II are dysplasias rather than true neoplasias. An image analysis study of factors involved in the progression of cervical lesions. Analytical and quantitative cytology and histology. 1992 Apr:14(2):137-47 [PubMed PMID: 1590897]

[57]

Ratree S, Kleebkaow P, Aue-Aungkul A, Temtanakitpaisan A, Chumworathayi B, Luanratanakorn S. Histopathology of Women with “Atypical Squamous Cells Cannot Exclude High-Grade Squamous Intraepithelial Lesion” (ASC-H) Smears. Asian Pacific journal of cancer prevention : APJCP. 2019 Mar 26:20(3):683-686 [PubMed PMID: 30909664]

[58]

Dunyo P, Effah K, Udofia EA. Factors associated with late presentation of cervical cancer cases at a district hospital: a retrospective study. BMC public health. 2018 Oct 3:18(1):1156. doi: 10.1186/s12889-018-6065-6. Epub 2018 Oct 3 [PubMed PMID: 30285699]

Level 2 (mid-level) evidence

[59]

McIntyre-Seltman K, Castle PE, Guido R, Schiffman M, Wheeler CM, ALTS Group. Smoking is a risk factor for cervical intraepithelial neoplasia grade 3 among oncogenic human papillomavirus DNA-positive women with equivocal or mildly abnormal cytology. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2005 May:14(5):1165-70 [PubMed PMID: 15894667]

[60]

Lew JB, Simms KT, Smith MA, Hall M, Kang YJ, Xu XM, Caruana M, Velentzis LS, Bessell T, Saville M, Hammond I, Canfell K. Primary HPV testing versus cytology-based cervical screening in women in Australia vaccinated for HPV and unvaccinated: effectiveness and economic assessment for the National Cervical Screening Program. The Lancet. Public health. 2017 Feb:2(2):e96-e107. doi: 10.1016/S2468-2667(17)30007-5. Epub 2017 Feb 7 [PubMed PMID: 29253402]

[61]

Sankaranarayanan R,Esmy PO,Rajkumar R,Muwonge R,Swaminathan R,Shanthakumari S,Fayette JM,Cherian J, Effect of visual screening on cervical cancer incidence and mortality in Tamil Nadu, India: a cluster-randomised trial. Lancet (London, England). 2007 Aug 4; [PubMed PMID: 17679017]

Level 1 (high-level) evidence

[62]

Bruno MT, Ferrara M, Fava V, Barrasso G, Panella MM. A prospective study of women with ASCUS or LSIL pap smears at baseline and HPV E6/E7 mRNA positive: a 3-year follow-up. Epidemiology and infection. 2018 Apr:146(5):612-618. doi: 10.1017/S0950268818000250. Epub 2018 Feb 21 [PubMed PMID: 29465024]

[63]

Luu HN, Dahlstrom KR, Mullen PD, VonVille HM, Scheurer ME. Comparison of the accuracy of Hybrid Capture II and polymerase chain reaction in detecting clinically important cervical dysplasia: a systematic review and meta-analysis. Cancer medicine. 2013 Jun:2(3):367-90. doi: 10.1002/cam4.83. Epub 2013 Apr 21 [PubMed PMID: 23930214]

Level 1 (high-level) evidence

[64]

Schiffman M, Kinney WK, Cheung LC, Gage JC, Fetterman B, Poitras NE, Lorey TS, Wentzensen N, Befano B, Schussler J, Katki HA, Castle PE. Relative Performance of HPV and Cytology Components of Cotesting in Cervical Screening. Journal of the National Cancer Institute. 2018 May 1:110(5):501-508. doi: 10.1093/jnci/djx225. Epub [PubMed PMID: 29145648]

[65]

Liu AH,Walker J,Gage JC,Gold MA,Zuna R,Dunn ST,Schiffman M,Wentzensen N, Diagnosis of Cervical Precancers by Endocervical Curettage at Colposcopy of Women With Abnormal Cervical Cytology. Obstetrics and gynecology. 2017 Dec; [PubMed PMID: 29112672]

[66]

Basu P, Taghavi K, Hu SY, Mogri S, Joshi S. Management of cervical premalignant lesions. Current problems in cancer. 2018 Mar-Apr:42(2):129-136. doi: 10.1016/j.currproblcancer.2018.01.010. Epub 2018 Jan 11 [PubMed PMID: 29428790]

[67]

Tai YJ, Chen YY, Hsu HC, Chiang CJ, You SL, Chen CA, Cheng WF, Taiwan Cervical Cancer Control Task Force. Risks of cervical intraepithelial neoplasia grade 3 or invasive cancers in ASCUS women with different management: a population-based cohort study. Journal of gynecologic oncology. 2018 Jul:29(4):e55. doi: 10.3802/jgo.2018.29.e55. Epub 2018 Mar 20 [PubMed PMID: 29770625]

[68]

Melnikow J, Nuovo J, Willan AR, Chan BK, Howell LP. Natural history of cervical squamous intraepithelial lesions: a meta-analysis. Obstetrics and gynecology. 1998 Oct:92(4 Pt 2):727-35 [PubMed PMID: 9764690]

Level 1 (high-level) evidence

[69]

Schlecht NF,Platt RW,Duarte-Franco E,Costa MC,Sobrinho JP,Prado JC,Ferenczy A,Rohan TE,Villa LL,Franco EL, Human papillomavirus infection and time to progression and regression of cervical intraepithelial neoplasia. Journal of the National Cancer Institute. 2003 Sep 3; [PubMed PMID: 12953088]

[70]

Fokom Domgue J, Futuh B, Ngalla C, Kakute P, Manjuh F, Manga S, Nulah K, Welty E, Schmeler K, Welty T. Feasibility of a community-based cervical cancer screening with "test and treat" strategy using self-sample for an HPV test: Experience from rural Cameroon, Africa. International journal of cancer. 2020 Jul 1:147(1):128-138. doi: 10.1002/ijc.32746. Epub 2019 Nov 9 [PubMed PMID: 31633801]

Level 2 (mid-level) evidence

[71]

Bruno MT, Coco A, Di Pasqua S, Bonanno G. Management of ASC-US/HPV positive post-menopausal woman. Virology journal. 2019 Mar 28:16(1):39. doi: 10.1186/s12985-019-1145-5. Epub 2019 Mar 28 [PubMed PMID: 30922353]

[72]

Egemen D, Cheung LC, Chen X, Demarco M, Perkins RB, Kinney W, Poitras N, Befano B, Locke A, Guido RS, Wiser AL, Gage JC, Katki HA, Wentzensen N, Castle PE, Schiffman M, Lorey TS. Risk Estimates Supporting the 2019 ASCCP Risk-Based Management Consensus Guidelines. Journal of lower genital tract disease. 2020 Apr:24(2):132-143. doi: 10.1097/LGT.0000000000000529. Epub [PubMed PMID: 32243308]

[73]

Wyse A, Seah WA, O'Neill J, Byrne P. The use of cold coagulation for the treatment of cervical intraepithelial neoplasia. Irish medical journal. 2017 May 10:110(5):565 [PubMed PMID: 28737306]

[74]

Hoffman SR, Le T, Lockhart A, Sanusi A, Dal Santo L, Davis M, McKinney DA, Brown M, Poole C, Willame C, Smith JS. Patterns of persistent HPV infection after treatment for cervical intraepithelial neoplasia (CIN): A systematic review. International journal of cancer. 2017 Jul 1:141(1):8-23. doi: 10.1002/ijc.30623. Epub 2017 Feb 27 [PubMed PMID: 28124442]

Level 1 (high-level) evidence

[75]

Staland B. Treatment of premalignant lesions of the uterine cervix by means of moderate heat thermosurgery using the SEMM coagulator. Annales chirurgiae et gynaecologiae. 1978:67(3):112-6 [PubMed PMID: 686641]

[76]

Langell A, Pickett T, Mangum C, Chen J, Langell J. Thermal Coagulation Device for Treating Cervical Dysplasia. Surgical innovation. 2019 Apr:26(2):149-152. doi: 10.1177/1553350618819521. Epub 2018 Dec 20 [PubMed PMID: 30569837]

[77]

Kyrgiou M, Athanasiou A, Kalliala IEJ, Paraskevaidi M, Mitra A, Martin-Hirsch PP, Arbyn M, Bennett P, Paraskevaidis E. Obstetric outcomes after conservative treatment for cervical intraepithelial lesions and early invasive disease. The Cochrane database of systematic reviews. 2017 Nov 2:11(11):CD012847. doi: 10.1002/14651858.CD012847. Epub 2017 Nov 2 [PubMed PMID: 29095502]

Level 1 (high-level) evidence

[78]

Dolman L, Sauvaget C, Muwonge R, Sankaranarayanan R. Meta-analysis of the efficacy of cold coagulation as a treatment method for cervical intraepithelial neoplasia: a systematic review. BJOG : an international journal of obstetrics and gynaecology. 2014 Jul:121(8):929-42. doi: 10.1111/1471-0528.12655. Epub 2014 Mar 6 [PubMed PMID: 24597779]

Level 1 (high-level) evidence

[79]

Sanghvi H, Limpaphayom KK, Plotkin M, Charurat E, Kleine A, Lu E, Eamratsameekool W, Palanuwong B. Cervical cancer screening using visual inspection with acetic acid: operational experiences from Ghana and Thailand. Reproductive health matters. 2008 Nov:16(32):67-77. doi: 10.1016/S0968-8080(08)32401-X. Epub [PubMed PMID: 19027624]

[80]

Phongsavan K, Phengsavanh A, Wahlström R, Marions L. Safety, feasibility, and acceptability of visual inspection with acetic acid and immediate treatment with cryotherapy in rural Laos. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. 2011 Sep:114(3):268-72. doi: 10.1016/j.ijgo.2011.03.009. Epub 2011 Jul 12 [PubMed PMID: 21752376]

Level 2 (mid-level) evidence

[81]

Rader JS, Sill MW, Beumer JH, Lankes HA, Benbrook DM, Garcia F, Trimble C, Tate Thigpen J, Lieberman R, Zuna RE, Leath CA 3rd, Spirtos NM, Byron J, Thaker PH, Lele S, Alberts D. A stratified randomized double-blind phase II trial of celecoxib for treating patients with cervical intraepithelial neoplasia: The potential predictive value of VEGF serum levels: An NRG Oncology/Gynecologic Oncology Group study. Gynecologic oncology. 2017 May:145(2):291-297. doi: 10.1016/j.ygyno.2017.02.040. Epub 2017 Mar 10 [PubMed PMID: 28285845]

Level 1 (high-level) evidence

[82]

Cho HW, Park YC, Sung MH, Park JS, Kim TJ, Seong SJ, Cho CH, Lee JK. Short-term clinical and immunologic effects of poly-gamma-glutamic acid (γ-PGA) in women with cervical intraepithelial neoplasia 1 (CIN 1): A multicenter, randomized, double blind, phase II trial. PloS one. 2019:14(6):e0217745. doi: 10.1371/journal.pone.0217745. Epub 2019 Jun 20 [PubMed PMID: 31220105]

Level 1 (high-level) evidence

[83]

Hefler LA, Grimm C, Speiser P, Sliutz G, Reinthaller A. The cyclooxygenase-2 inhibitor rofecoxib (Vioxx) in the treatment of cervical dysplasia grade II-III A phase II trial. European journal of obstetrics, gynecology, and reproductive biology. 2006 Apr 1:125(2):251-4 [PubMed PMID: 16188370]

[84]

Ashrafian L, Sukhikh G, Kiselev V, Paltsev M, Drukh V, Kuznetsov I, Muyzhnek E, Apolikhina I, Andrianova E. Double-blind randomized placebo-controlled multicenter clinical trial (phase IIa) on diindolylmethane's efficacy and safety in the treatment of CIN: implications for cervical cancer prevention. The EPMA journal. 2015:6():25. doi: 10.1186/s13167-015-0048-9. Epub 2015 Dec 21 [PubMed PMID: 26693258]

Level 1 (high-level) evidence

[85]

Laccetta G, Carrone A, Burratti M, Mancino P. Effect of the treatment with β-glucan in women with cervical cytologic report of atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesions (L-SIL). Minerva ginecologica. 2015 Apr:67(2):113-20 [PubMed PMID: 25668505]

[86]

Manetta A, Schubbert T, Chapman J, Schell MJ, Peng YM, Liao SY, Meyskens FJ Jr. beta-Carotene treatment of cervical intraepithelial neoplasia: a phase II study. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 1996 Nov:5(11):929-32 [PubMed PMID: 8922303]

[87]

Xu L, Verdoodt F, Wentzensen N, Bergeron C, Arbyn M. Triage of ASC-H: A meta-analysis of the accuracy of high-risk HPV testing and other markers to detect cervical precancer. Cancer cytopathology. 2016 Apr:124(4):261-72. doi: 10.1002/cncy.21661. Epub 2015 Nov 30 [PubMed PMID: 26618614]

Level 1 (high-level) evidence

[88]

Kisser A, Zechmeister-Koss I. A systematic review of p16/Ki-67 immuno-testing for triage of low grade cervical cytology. BJOG : an international journal of obstetrics and gynaecology. 2015 Jan:122(1):64-70. doi: 10.1111/1471-0528.13076. Epub 2014 Sep 11 [PubMed PMID: 25208923]

Level 1 (high-level) evidence

[89]

Yanik EL, Napravnik S, Cole SR, Achenbach CJ, Gopal S, Olshan A, Dittmer DP, Kitahata MM, Mugavero MJ, Saag M, Moore RD, Mayer K, Mathews WC, Hunt PW, Rodriguez B, Eron JJ. Incidence and timing of cancer in HIV-infected individuals following initiation of combination antiretroviral therapy. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2013 Sep:57(5):756-64. doi: 10.1093/cid/cit369. Epub 2013 Jun 4 [PubMed PMID: 23735330]

[90]

Arbyn M, Xu L, Simoens C, Martin-Hirsch PP. Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors. The Cochrane database of systematic reviews. 2018 May 9:5(5):CD009069. doi: 10.1002/14651858.CD009069.pub3. Epub 2018 May 9 [PubMed PMID: 29740819]

Level 1 (high-level) evidence

[91]

Monsonego J. [Prevention of cervical cancer (II): prophylactic HPV vaccination, current knowledge, practical procedures and new issues]. Presse medicale (Paris, France : 1983). 2007 Apr:36(4 Pt 2):640-66 [PubMed PMID: 17350792]