Tools
Atypical Squamous Cells of Undetermined Significance
Introduction
Atypical squamous cells of undetermined significance (ASC-US) is a term used in the Bethesda system for reporting cervical cytology to describe a category of cervical epithelial cell abnormalities. ASC-US refers to abnormal cytologic changes that suggest a 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 cytologic 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 is a distinctive precursor lesion of cervical squamous cell carcinoma.[2]
Approximately a decade ago, cervical cancer was the third most common cancer in women worldwide and ranked as the first most common cancer in women in 42 low-resourced countries.[3] However, the established link between persistent carcinogenic human papillomavirus (HPV) infection and the development of cervical cancer has paved the way for the advancement of primary and secondary prevention strategies. The currently used preventive measures include primary prevention through HPV vaccination and secondary prevention through cervical screening programs, patient follow-up, and the treatment of precursor lesions.[4]
In developed countries such as the United States, the United Kingdom, and Canada, the widespread availability and access to cervical cancer screening have led to a significant reduction in both the incidence and mortality of cervical cancer.[5][6][7][8] In the United States, the incidence of cervical cancer cases has dropped to 7.7 per 100,000, whereas deaths from invasive cervical cancer have dropped to 2.2 per 100,000 women.[9] A late diagnosis of invasive cervical cancer has a 100% mortality rate. The importance of screening in the prevention of cervical cancer is that precancerous stages are slow-growing and amenable to treatment.[10][11] 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.[5][12] A recent study estimated the worldwide age-standardized incidence rate of cervical cancer to be 13.1 (6.4 for North America) per 100,000 women-years and an age-standardized mortality rate of 6.9 (1.9 for North America) per 100,000 women. In the same study, cervical cancer was ranked as the fourth most common cancer among women worldwide after breast cancer, colorectal cancer, and lung cancer.[13]
Although it has been previously hypothesized that alpha-1 antitrypsin deficiency may be a genetic predisposition, this has not been confirmed.[14] In contrast, ample scientific evidence suggests that certain high-risk HPVs (hrHPVs) cause >90% of cervical cancers, with HPV strain 16 contributing 50% to 73.8% and HPV 18 accounting for 12% to 16.4% of cases.[15][16] The long-standing diagnosis model has been cytology using the Papanicolaou smear (Pap test) and biopsy, with more recent advances including liquid-based cytology.[17][18] Other methods of diagnosis include HPV DNA test and colposcopy.[19][20]
Women who 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 hrHPV. Although the Pap test dates back to the late 1940s, it has not been fully adopted and used in resource-limited settings for several reasons, including its high cost and delays in obtaining results. Very low rates of Pap smears 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 compared to that in Jamaica, or Pap testing does not even exist.[21] In other regions, when cervical screening programs were initially implemented, opportunistic Pap smear tests were used, but the coverage rates were still notably low.[22]
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 SIL (LSIL), high-grade SIL (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. Visual inspection of the ectocervix is the new way of screening, with immediate results and successful treatment of most of the identified precancerous lesions.[23] This activity improves the understanding of ASC-US, its clinical implications, and the management strategies for ASC-US diagnosis.[19][24][25][26]
Etiology
Register For Free And Read The Full Article
Search engine and full access to all medical articles- 10 free questions in your specialty
- Free CME/CE Activities
- Free daily question in your email
- Save favorite articles to your dashboard
- Emails offering discounts
Learn more about a Subscription to StatPearls Point-of-Care
Etiology
Cervical cancer is not a sexually transmitted infection, but it develops from precursor lesions (CIN) that are predisposed by persistent infection with the HPV, a common sexually transmitted pathogen. Over 200 species of HPV have been identified, with 13 high-risk (hrHPV) strains recognized as carcinogenic. Among these, HPV 16 and HPV 18 are responsible for approximately 70% of cervical cancers, with a higher prevalence in women with HIV.[27][28] The ASC-US observed in cervical cytology may be related to HPV infection and neoplasia. ASC-US is just cytologic mimics caused by inflammation, air drying, atrophy with degeneration, and other artifacts. A study of cervical screening programs in the United States showed about 50% of women with ASC-US are infected with hrHPV. In contrast, noninfected women are not at an increased risk of cancer.[2]
Other studies have demonstrated a high prevalence of hrHPV in patients with ASC-US; a study in Brazil analyzed 1340 liquid-based cytology specimens and found that 64% of ASC-US specimens harbored hrHPV.[29] In 2 separate studies, Mai Nishimura reported hrHPV in 81% of patients with ASC-US. In contrast, Ming Guo et al reported a hrHPV 16/18 incidence rate of 37% in their ASC-US patient cohort, whereas a Mexican study found an incidence rate of 11.2%.[30][31][32] In a study conducted in Turkey, 129 women with abnormal Pap smears were screened for hrHPV positivity. Of these, 94 had an ASC-US diagnosis, and 94% of them were infected with hrHPV.[33] Similarly, Liu et al reported a significant correlation between ASC-US/hrHPV positivity, remarkably HPV-16 positivity, and cervical precancerous and cancerous lesions.[34]
Epidemiology
Cervical precancerous lesions are slow-growing and most commonly occur between the ages of 35 and 45. However, they are more frequently observed in women with HIV between the ages of 25 and 35. With the persistence of hrHPV infection over years or decades, the actual cancer peaks after 50.[35] ASC-US was originally described by Papanicolaou as atypical pathology and is a cytological nomenclature.[17] The original laboratory technicians working on cervical cytologic smears reported them simply as normal, atypical, or suspicious/malignant.[17] Therefore, ASC-US represents a mix of various squamous epithelial cells at different stages of transitioning from the lowest risk atypia to the most severe form of precancer, with some harboring the potential to revert to normalcy.[30]
The histological classification known as CIN is a 3-tier grading of CIN corresponding to the number of layers of epithelial cells affected by atypia.[35][36] 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. The modified Bethesda system of cytological classification divides atypical squamous cells into 2 categories—ASC-US and atypical squamous cells-cannot exclude high-grade SIL (ASC-H).[37][38]
ASC-US is a common diagnostic category considered a difficult and grey zone diagnosis between negative and confirmed SIL.[35][38] Follow-up studies of ASC-US cases have identified LSIL and HSIL.[39] According to the Bethesda system, ASC-US and ASC-H are considered lower risk compared to LSIL, which is the equivalent of CIN1 by histology and HSIL (CIN 2/3).[40][35][41][42] Different studies have reported the incidence of ASC-US to be as low as 2.5% in a Japanese study, 4.1% in a US study, 5.8% in another US study, 7.4% in a Bosnia study, and as high as 19.1% in another Japanese study.[30][43][44][45]
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. Chronic cases progress to more severe persistent infections associated with nuclear and cytoplasmic changes. In the presence of hrHPV types 16 and 18, viral genes E6 and E7 are believed to encode viral proteins in the infected squamous cells. These proteins promote the degradation of tumor suppressor gene proteins p53 and Rb, respectively, resulting in malignant transformation.[24][46] A prospective study by M Jahic and E Jahic involving 1784 Pap smears found that, out of 254 abnormal smears, 74% persisted, 8% regressed, and 18% progressed to a more advanced stage.[45] Immunohistochemistry studies have associated the loss of certain capsid proteins in ASC-US specimens with progression to a more severe form of precancer. Ki et al showed that detecting HPV serotypes 16 and 18 in the absence of HPV L1 capsid expression predicted the worsening of precancer.[47]
HIV positivity has also been known to promote HPV persistence and is associated with a higher incidence of ASC-US.[23][48] Furthermore, a low CD4 count and the absence of antiretroviral therapy were associated with the persistence of HPV infection.[10][29][49][50]
In addition, other factors must also be considered to explain the detection of ASC-US, including menopausal atrophic changes of the cervicovaginal tract and infectious and inflammatory changes other than those caused by HPV. Li et al reported that the rate of ASC-US was higher in women older than 50, whereas the rate of CIN2 positivity was lower in this age group compared to younger women. The study also described how other vaginal ecosystem-related infectious and inflammatory changes may increase the false-positive detection rate of ASC-US. Recognizing and considering these additional factors during patient evaluations may help reduce false-positive ASC-US detections and colposcopy referrals.[51]
Histopathology
ASC-US is a cytopathologic term that implies cervical epithelial cell abnormalities described by the Bethesda system for reporting cervical cytology. The term refers to abnormal cytologic changes that suggest SIL but are qualitatively and quantitatively less than those of a definitive SIL diagnosis.[1] The morphologic criteria for ASC-US include cells that resemble superficial or intermediate squamous cells with nuclei 2.5 to 3 times larger than those of normal intermediate squamous cells. These cells also exhibit a slightly increased nucleo-cytoplasmic ratio, minimal hyperchromatism, and irregular chromatin. The cytoplasm may show halo and atypical parakeratosis (dense orangeophilia). These criteria may vary slightly among different laboratories due to differences in slide preparation and staining techniques.[52][53][54][55]
The distinction between a true premalignant lesion and a neoplastic one is based on the number, type, and severity of changes 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.[56] Hyperchromasia and enlargement of nucleoli suggest a progression from mere ASC-US to LSIL/CIN 1 or higher.[57][58] Histologically, the CIN histological classification is a 3-tier CIN grading system corresponding to the number of layers of epithelial cells affected by atypia.[59]
History and Physical
ASC-US is not a clinical diagnosis. A woman receiving an ASC-US report from a Pap test is most often asymptomatic and is most likely identified through population-based screening. Alternatively, some women may present opportunistically with symptoms such as bloody, offensive, and or watery vaginal discharge, lower back pain, or signs of a urinary tract infection.[25] The physical examination evaluates the patient's general health and assesses for possible signs related to pathologies that may underlie the cytologic changes of ASC-US.
As a late diagnosis or advanced invasive cervical cancer has no remedy, it is critical to identify and address risk factors predisposing women to cervical cancer. These risk factors should guide screening decisions for women seeking care.[60] Risk factors for cervical cancer include lower age at sexual debut, multiple sexual partners, and sexually transmitted infections, including hrHPV and HIV. 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.[60] Prolonged and intense smoking has also been linked to an increased risk of developing cervical cancer.[61]
Evaluation
Cervical cancer screening in women between the ages of 21 and 65 is supported by the American College of Obstetricians and Gynecologists, the United States Preventive Services Task Force, and the United States Food and Drug Administration.[59] Studies have shown that regular and consistent screening of women for cervical cancer reduces the invasive incidence of cervical cancer and related mortality.[7] All sexually active women presenting in the outpatient department with gynecologic or perianal symptoms, including abnormal vaginal bleeding, vaginal discharge, dysuria, or vaginal itching, should undergo triage testing.[32][43] For asymptomatic, immunocompetent women aged 21 to 29, cervical cancer screening is recommended every 3 years using cytology alone. For individuals aged 30 to 65, where the persistence of HPV can lead to complications, it is recommended to hrHPV testing alone or co-testing (which includes both hrHPV and cytology) is recommended every 5 years in addition to the option of screening by cytology alone every 3 years.[6][8][62] Screening is not recommended for women younger than 21 because most HPV infections in this age group are transient or resolve spontaneously. Women older than 65 can cease surveillance screening if they have consistently tested negative.
Triage testing involves cytology with Pap test or liquid-based cytology, visual inspection with acetic acid (VIA) combined with colposcopy, HPV DNA testing, or a combination of these methods as recommended in the clinical setting.[32][63] This method is particularly relevant for patients with an ASC-US diagnosis, as it helps to further categorize the ASC-US result into a true NILM, LSIL, or HSIL.[30][43][46][64]
Initially, a speculum vaginal and bimanual pelvic examination is performed. A Pap test is performed alone or with hrHPV DNA assay, or VIA is performed alone or in combination with hrHPV DNA, or hrHPV DNA is carried out alone (primary HPV testing).[62][65] The combination of cytology and HPV DNA testing is advised because HPV DNA testing is more sensitive compared to cytological analysis alone. However, the rare occurrence of HPV-negative/cytology-positive cancers has highlighted the importance of co-testing.[30][43][62][66] Wang et al reported a more efficient approach in triaging women with ASC-US through a combination of HPV16/18/31/33/58 testing.[67]. Similarly, Yang et al explored triage approaches for women with ASC-US in pre- and post-HPV vaccination groups. They reported that combined HPV 16/18 and HPV 33/58 genotyping have the highest specificity and were associated with the lowest colposcopy referral among the unvaccinated and vaccinated groups, respectively.[68] The triage methods for women with ASC-US may also include other techniques based on HPV E6/E7 messenger RNA (mRNA) amplifications and dual staining for p16/Ki-67.[69][70]
VIA involves the application of 3% to 5% dilute acetic acid for 1 min on the ectocervix.[23] Aceto-whitening of ectocervical lesions is caused by the high absorption of acetic acid by protein-rich precancer cells.[71] Proper visualization of the cervix after acetic acid application is facilitated using a handheld bright light or colposcope. VIA studies are reported as VIA-negative, VIA-positive, or suspicious for cancer. For VIA-positive results or suspected malignancy, colposcopy-guided cervical biopsies are performed to confirm the diagnosis.[23][72][73]
Treatment / Management
The variable progression of ASC-US poses a significant 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 executed.[30] A meta-analysis by Melnikow et al found that 68% of ASC-US cases regressed to negative results by 24 months, whereas 7.13 % of ASC-US progressed to a higher-grade SIL in the same period.[74](A1)
The clinical significance of ASC-US increases when 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.[32][62] The term undetermined significance in ASC-US highlights the uncertainty regarding its progression—how much of the ASC-US may resolve to become negative and how much of the ASC-US persists and progresses to become low- or high-grade SIL.[74] The main factors responsible for persistence are not fully understood. However, hrHPV infection is known to persist more in patients with HIV compared to patients without HIV, resulting in a higher incidence of invasive cervical cancer in those with HIV positivity.[23][75](A1)
Management of an initial ASC-US result may involve repeating Pap cytology, performing VIA with colposcopy, or combining these with HPV genotyping (DNA or mRNA) when feasible.[23][76] Persistent ASC-US, including ASC-H, requires a thorough analysis and intervention, including referral for colposcopy.[39][77] Ki et al define ASC-US persistence as the occurrence of ASC-US in 12-month follow-up cytology or in serial ASC-US reports.[47] Studies have shown that HPV DNA testing before colposcopy in women with persistent ASC-US provided improved diagnostic sensitivity compared to a CIN 2 or higher diagnosis.[78] Baena et al studied the effectiveness of immediate colposcopy, cytology, and HrHPV testing in detecting CIN 2 or greater in 2661 women aged 20 to 69 with ASC-US cytology results. Contrary to other studies, they concluded that hrHPV testing was superior in effectiveness and in managing women with ASC-US.[79](B2)
In April 2020, the American Society for Colposcopy and Cervical Pathology (ASCCP) published the 2019 ASCCP risk-based management guidelines for abnormal cervical cancer screening tests and cancer precursors. One of the key changes in the updated management guidelines is that a patient's risk of developing CIN3 or higher—assessed through current test results and their medical history (including any unknown factors)—has become a critical criterion for making recommendations regarding colposcopy, treatment, or surveillance.[26](B3)
In patients younger than 25 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 required after 1 year. If this second cytology result is negative, routine age-based screening is resumed. If HPV testing was performed for a patient with ASC-US and the test was negative, repeat cytology is unnecessary, and routine age-based screening could be directly resumed. Colposcopy is indicated if the first 1-year repeat cytology shows HSIL/ASC-H/AGC/AIS and also if the second 1-year repeat cytology shows ASC-US or more severe lesions.[26](B3)
According to the 2019 ASCCP guidelines, clinicians should start using CIN3+ risk estimates—based on HPV testing or co-testing and past history—when a patient reaches 25 years. Previously, patients aged 25 or older with ASCUS had 2 management options before the recent guidelines update. The first option involved HPV testing (preferred). If the test is positive, colposcopy is performed, whereas If the result is negative, repeat cytology is performed in 3 years. The second option involved repeating the cytology in 1 year. If an abnormality is detected, a colposcopy is performed. If the 1-year repeat cytology is negative, the patient could return to routine age-based screening. However, according to 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 documented history of negative HPV testing or co-testing can now be treated with repeating HPV testing or co-testing at 1 year. Clinicians should treat patients based on new 2019 ASCCP guidelines using the tables of Egemen et al or using an app made available on the ASCCP website.[26][80](B3)
SIL treatment options include ablation methods such as cryotherapy or thermocoagulation, whereas HSIL (CIN 2+) is best treated with procedures such as large loop excision of the transformation zone/loop electrosurgical excision procedure (LLETZ/LEEP) or laser or cold knife conization in cases of AIS.[81][82][83][84][85][86] During cryotherapy, pressurized gas, either carbon dioxide or nitrous oxide, is used to freeze acetowhite lesions 3 to 5 mm deep under normal light or colposcopic guidance.[11] Thermal coagulation is the burning of acetowhite areas depicting precancerous lesions. Both methods cause tissue necrosis with minimal or no systemic complications.[11] Under certain circumstances, a test-and-treat or single-visit approach using VIA and colposcopy is preferred over a Pap test, especially in resource-limited settings.[10][73][76][87][88](A1)
Apart from surgical interventions, certain pharmacological approaches have been used in various randomized controlled trials, with some showing promising outcomes at phase II.[89][90][91][92] In a study by Laccetta and colleagues, 176 patients with ASC-US were treated with topical beta-glucan, and a Pap test was repeated after 6 months. Approximately 63% reverted to a negative Pap test. No adverse effects were reported.[93] 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.[90] In 1996, Manetta 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% regression of CIN1 in some patients.[94] 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.[94](A1)
Differential Diagnosis
ASC-US may encompass a range of underlying pathologies, including NILM, LSIL/CIN 1, HSIL/CIN 2+, or even early invasive cervical carcinoma. On the other hand, ASC-US may be just a cytologic mimic caused by inflammation (cervicitis), air drying, atrophy with degeneration, and other artifacts. Accurate differentiation is best achieved through HPV DNA testing, colposcopy, and biopsy, particularly in cases of persistent ASC-US.[56][65]
Prognosis
In the presence of quality triage studies, most ASC-US diagnoses have a good prognosis.[95][96] The clearance of HPV infection restores the cervical tissues to their normal state. Progression to HSIL/CIN 2+ can be effectively treated using cryotherapy, LLETZ, or conization, offering the patient the potential for complete lifetime elimination of cervical cancer risk.
Complications
Complications of ASC-US may occur due to insufficient follow-up or treatment itself. Although an ASC-US diagnosis may completely resolve on repeat Pap testing, failure to follow up can lead to progression to HSIL/CIN 2+ or invasive cancer, particularly in underserved populations with limited access to comprehensive screening services.[21][74] In resource-limited settings, the presence of unskilled staff increases the risk of overtreatment of ASC-US or LSIL. All treatment modalities carry a minimal risk of complications, including mild pain during the procedure, bleeding, postoperative pain, and vaginal discharge. Performing cryotherapy or LLETZ in the presence of conditions such as cervicitis, bacterial vaginosis, or vaginal trichomoniasis may give rise to significant and malodorous vaginal discharge. Recurrence of the lesion may indicate poor quality treatment resulting from incomplete excision of the lesion or transformation zone. However, 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.[85] The persistence of lesions has also been reported to be higher in patients with HIV compared to immunocompetent individuals.[97]
Postoperative and Rehabilitation Care
Patients treated with cryotherapy and LLETZ/LEEP are typically treated as same-day cases and provided mild oral analgesics, such as ibuprofen, or pain relief. These patients are typically advised to abstain from sexual intercourse for 4 to 6 weeks and to use condoms if abstinence is not maintained. Patients are also advised not to insert tampons and not to douche. Patients who develop malodorous discharge or persistent vaginal discharge beyond 14 days are asked to return to their clinicians for reevaluation and treatment. If signs of postoperative infection exist, endocervical or high vaginal swabs should be sent for culture. Empirical therapy for infection includes doxycycline 100 mg orally twice daily for 7 days and metronidazole 400 mg orally 3 times daily for 7 days.
Deterrence and Patient Education
Full-blown advanced cervical cancer, in women with or without HIV, has 100% 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, such as ASC-US, must be closely monitored and informed to ensure timely follow-up, preventing progression to invasive cervical cancer.
Society must consider the significant human and financial costs associated with treating invasive cancer, including its devastating impact on lives and families, compared to the cost-effectiveness of prevention. Prevention is a less expensive choice. Combined prevention and lifestyle modification, including a delay in sexual debut, reduction of sexual partners, consistent and correct use of condoms, male circumcision, and smoking cessation, can significantly reduce the burden of cervical precancer and cancer.
Pearls and Other Issues
Understanding the clinical implications of ASC-US is essential for effective management and prevention of cervical cancer. Key points to guide decision-making and patient care in cases of ASC-US include the following:
- The coverage for cervical cancer screening in most resource-limited settings is still <35% of the population.
- Women can be screened and followed up for cervical premalignant diseases using the Pap test, VIA with colposcopy, HPV DNA testing, and biopsy.
- At least one cervical cancer screening method can be implemented in any country where cervical screening programs are unavailable. In 1949, Papanicolaou and Traut began performing simple cytology, and today, this has evolved to the more sophisticated molecular DNA testing for HPV.
- Prioritizing and integrating cervical cancer screening into routine care at primary healthcare facilities can significantly reduce new cases of cervical cancer and potentially eliminate 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, which poses a management challenge. Triaging with molecular testing and histology is one way to address this challenge.
- VIA, together with same-day treatment, has been shown to reduce the incidence of invasive cervical cancers.
- All patients with HIV must be prioritized for VIA screening. This simple and cost-effective procedure can be performed as part of a single-visit approach for screening and treatment.
- Large-scale HPV vaccination before the onset of sexual activity may hold the key to the elimination of cervical cancer.
Enhancing Healthcare Team Outcomes
ASC-US management requires a collaborative, patient-centered approach that integrates the skills and contributions of clinicians, advanced practitioners, pharmacists, and other healthcare professionals. This multidisciplinary effort ensures effective care, enhances patient safety, and improves outcomes. Most women receiving an ASC-US diagnosis are asymptomatic. Clinicians at primary care facilities, maternities, general outpatient departments, gynecology, and sexually transmitted infection clinics must be proactive, engage women, create awareness, and screen all sexually active women for cervical precancer and cancer.
Healthcare professionals must understand the interplay of culture, behavior, and socioeconomic status and their relationship to cervical cancer incidence.[21] Community health workers, nurses at immunization clinics, and midwives must be engaged to inform patients and create awareness of the benefits of cervical cancer screening and the dangers of invasive cervical cancer. The diagnosis and treatment of cervical precancer must be performed in collaboration with skilled cytopathologists, gynecologic oncologists, and clinicians specifically trained in cryotherapy, LLETZ, and conization. Efficient coordination involves timely referrals to specialists and follow-up to ensure adherence to recommended screenings. Nurses and care coordinators can schedule follow-up visits, track patient compliance, and provide reminders, promoting adherence to guidelines. Together, healthcare teams can enhance outcomes for patients with ASC-US while ensuring a supportive, safe, and effective care experience.
Finally, prophylactic HPV vaccination in girls aged 9 to 15 has been shown to generate a huge decrease in new HPV infections.[98] Healthcare professionals who care for female children and adolescent girls have ample opportunity to advocate for the scale-up of HPV vaccination across the globe.[98][99]
References
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]
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]
Level 1 (high-level) evidenceArbyn 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]
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]
Level 3 (low-level) evidenceDickinson 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]
Rerucha CM, Caro RJ, Wheeler VL. Cervical Cancer Screening. American family physician. 2018 Apr 1:97(7):441-448 [PubMed PMID: 29671553]
Eddy DM. Screening for cervical cancer. Annals of internal medicine. 1990 Aug 1:113(3):214-26 [PubMed PMID: 2115753]
Level 2 (mid-level) evidenceUS 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]
Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA: a cancer journal for clinicians. 2023 Jan:73(1):17-48. doi: 10.3322/caac.21763. Epub [PubMed PMID: 36633525]
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) evidenceCastle 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]
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]
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) evidencePhilippe P. Is cervical cancer hereditary? Canadian Medical Association journal. 1981 Mar 15:124(6):672-6 [PubMed PMID: 20313553]
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]
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]
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]
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]
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]
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) evidenceAgurto 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]
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]
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]
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) evidenceBukhari 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]
Perkins RB, Guido RS, Castle PE, Chelmow D, Einstein MH, Garcia F, Huh WK, Kim JJ, Moscicki AB, Nayar R, Saraiya M, Sawaya GF, Wentzensen N, Schiffman M, 2019 ASCCP Risk-Based Management Consensus Guidelines Committee. 2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors. Journal of lower genital tract disease. 2020 Apr:24(2):102-131. doi: 10.1097/LGT.0000000000000525. Epub [PubMed PMID: 32243307]
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) evidenceSaraiya 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]
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]
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]
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]
Level 2 (mid-level) evidenceTorres-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]
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]
Liu Q, Zhang T, Chen L, Zhou X, Zhang X, Zheng W, Niu S, Zhou F. Correlation of immediate prevalence of cervical precancers and cancers with HPV genotype and age in women with ASC-US/hrHPV+: a retrospective analysis of 2292 cases. Journal of clinical pathology. 2024 Apr 18:77(5):338-342. doi: 10.1136/jcp-2022-208580. Epub 2024 Apr 18 [PubMed PMID: 36653168]
Level 2 (mid-level) evidenceLiu 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]
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]
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]
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) evidenceSherman 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]
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]
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]
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]
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]
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]
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]
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) evidenceKi 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]
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) evidenceKelly 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) evidenceGeorge 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]
Li B, Dong L, Wang C, Li J, Zhao X, Dong M, Li H, Ma X, Dong Y, Wu M, Yan Y, Fan A, Xue F. Analysis of the related factors of atypical squamous cells of undetermined significance (ASC-US) in cervical cytology of post-menopausal women. Frontiers in cellular and infection microbiology. 2023:13():1123260. doi: 10.3389/fcimb.2023.1123260. Epub 2023 Feb 16 [PubMed PMID: 36875525]
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]
Level 1 (high-level) evidenceStoler 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]
Abramovich CM, Wasman JK, Siekkinen P, Abdul-Karim FW. Histopathologic correlation of atypical parakeratosis diagnosed on cervicovaginal cytology. Acta cytologica. 2003 May-Jun:47(3):405-9 [PubMed PMID: 12789922]
Level 2 (mid-level) evidenceKattoor J, Kamal MM. The gray zone squamous lesions: ASC-US / ASC-H. CytoJournal. 2022:19():30. doi: 10.25259/CMAS_03_10_2021. Epub 2022 Apr 30 [PubMed PMID: 35673698]
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]
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]
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]
Rayner M, Welp A, Stoler MH, Cantrell LA. Cervical Cancer Screening Recommendations: Now and for the Future. Healthcare (Basel, Switzerland). 2023 Aug 11:11(16):. doi: 10.3390/healthcare11162273. Epub 2023 Aug 11 [PubMed PMID: 37628471]
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) evidenceMcIntyre-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]
Level 1 (high-level) evidenceLew 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]
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 4:370(9585):398-406 [PubMed PMID: 17679017]
Level 1 (high-level) evidenceBruno 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]
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) evidenceSchiffman 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]
Wang W, Zhang H, Lin L, Yang A, Yang J, Zhao W, Wang Z, Zhang L, Su X, Wang Z, Wang C, Zhang H, Feng B, Li D, Liu H, Niu X, Wang J, Song J, Li L, Lv W, Zhao C, Hao M. Efficient combination of Human Papillomavirus Genotyping for the triage of women with Atypical Squamous Cells of Undetermined Significance in Chinese rural population: A population-based study. Journal of Cancer. 2021:12(10):2815-2824. doi: 10.7150/jca.55771. Epub 2021 Mar 14 [PubMed PMID: 33854582]
Yang H, Hao Y, Niu M, Zheng J, Jia X, Zhang S, Wang L, Zhang X, Pan Q, Feng X, Qiao Y, Li Z. Comparative study of triage strategies for women with atypical squamous cells of undetermined significance in the post-vaccine era. Frontiers in oncology. 2024:14():1416116. doi: 10.3389/fonc.2024.1416116. Epub 2024 Oct 8 [PubMed PMID: 39439955]
Level 2 (mid-level) evidenceCubaka Ntamushigo J, Motshedisi Sebitloane H. Review of triage strategies for atypical squamous cells of undetermined significance among young women. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. 2025 Feb:168(2):428-435. doi: 10.1002/ijgo.15915. Epub 2024 Sep 13 [PubMed PMID: 39268663]
Bruno MT, Guaita A, Boemi S, Mazza G, Sudano MC, Palumbo M. Performance of p16/Ki67 Immunostaining for Triage of Elderly Women with Atypical Squamous Cells of Undetermined Significance. Journal of clinical medicine. 2023 May 11:12(10):. doi: 10.3390/jcm12103400. Epub 2023 May 11 [PubMed PMID: 37240506]
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:130(6):1218-1225. doi: 10.1097/AOG.0000000000002330. Epub [PubMed PMID: 29112672]
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]
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]
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) evidenceSchlecht 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 3:95(17):1336-43 [PubMed PMID: 12953088]
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) evidenceHirai 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]
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]
Baena A, Agudelo MC, Lopez C, Ramírez AT, Castañeda KM, Bedoya AM, Riveros M, Posada G, Borrero M, Buitrago CA, Suescun D, Gomez LJ, Ochoa JC, Stoler M, Gage J, Castle PE, Sasieni P, Almonte M, Herrero R, Sanchez GI, ASCUS-COL Trial Group. Comparison of immediate colposcopy, repeat conventional cytology and hrHPV testing for the clinical management of ASC-US cytology in routine health services of Medellin, Colombia: The ASCUS-COL Trial. International journal of cancer. 2020 Oct 2:():. doi: 10.1002/ijc.33318. Epub 2020 Oct 2 [PubMed PMID: 33006400]
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]
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]
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) evidenceStaland 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]
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]
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) evidenceDolman 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) evidenceSanghvi 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]
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 3 (low-level) evidenceRader 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) evidenceCho 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) evidenceHefler 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]
Level 1 (high-level) evidenceAshrafian 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) evidenceLaccetta 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]
Level 1 (high-level) evidenceManetta 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]
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) evidenceKisser 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) evidenceYanik 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]
Level 2 (mid-level) evidenceArbyn 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) evidenceMonsonego 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]