Atypical Squamous Cells of Undetermined Significance

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. 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. 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. 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. 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. 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. 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. 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. 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. Although it has been previously hypothesized that alpha-1 antitrypsin deficiency may be a genetic predisposition, this has not been confirmed. 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. The long-standing diagnosis model has been cytology using the Papanicolaou smear (Pap test) and biopsy, with more recent advances including liquid-based cytology. Other methods of diagnosis include HPV DNA test and colposcopy. 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. In other regions, when cervical screening programs were initially implemented, opportunistic Pap smear tests were used, but the coverage rates were still notably low. 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. This activity improves the understanding of ASC-US, its clinical implications, and the management strategies for ASC-US diagnosis.