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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. This particular classification refers to abnormal cytologic changes that suggest a squamous intraepithelial lesion but are qualitatively and quantitatively less than those of a definitive squamous intraepithelial lesion diagnosis. Based on the patient's age and the estimated risk of possible underlying neoplastic lesions, an ASC-US result requires further follow-up by performing repeat cytology and human papillomavirus tests to guide the management of potential precancerous or cancerous cervical lesions. This activity enhances clinicians' knowledge and skills in treating patients with ASC-US results, reducing the risk of progression to cervical cancer while avoiding unnecessary procedures. Participants gain insights into the pathophysiology and clinical significance of ASC-US, current screening and diagnostic guidelines, and risk stratification. The activity also highlights the role of an interprofessional healthcare team in improving care for patients with AS-CUS results. Objectives: Differentiate atypical squamous cells of undetermined significance from other cytological abnormalities to accurately interpret Papanicolaou smear results. Screen patients using appropriate evidence-based guidelines, including human papillomavirus testing, to identify risk factors for cervical cancer. Select appropriate treatment and follow-up pathways based on patient risk stratification and test results. Collaborate with the interprofessional healthcare team to ensure comprehensive evaluation and treatment of patients with atypical squamous cells of undetermined significance. Access free multiple choice questions on this topic.

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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] 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] 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]

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] 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] 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]

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] 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]

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] 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]

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] 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]

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]

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 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]

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.

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.

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]