A low-grade squamous intraepithelial lesion (LSIL) is a finding on a Pap test that indicates mildly abnormal cell changes on the surface of the cervix. This result is not a diagnosis of cancer; rather, it suggests cellular alterations classified as low-grade dysplasia. The vast majority of LSIL cases are directly attributable to infection with the Human Papillomavirus (HPV), a common sexually transmitted virus. However, an LSIL result is a cytological interpretation based on the appearance of cells under a microscope, and this appearance can be mimicked by several biological and physiological processes unrelated to HPV. These non-HPV factors can cause cellular changes that appear atypical to the pathologist, leading to an LSIL classification or a related ambiguous result, such as Atypical Squamous Cells of Undetermined Significance (ASC-US). Understanding these alternative causes is important because they often resolve spontaneously or require simple treatment for the underlying issue, rather than management for a persistent precancerous lesion.
Non-HPV Infections and General Inflammation
Infections caused by pathogens other than HPV are a frequent cause of cellular changes that resemble LSIL, a phenomenon known as reactive atypia. The resulting inflammation can directly alter the appearance of squamous cells, making them look abnormal during a Pap test. This reactive process occurs because the immune response causes cervical cells to swell and their nuclei to enlarge, mimicking the architectural changes characteristic of true low-grade dysplasia.
Several common non-HPV infections trigger this inflammatory response. Bacterial Vaginosis (BV), an imbalance in the vaginal flora, causes inflammation that leads to abnormal cell presentation. Pathologists may observe “clue cells,” which are epithelial cells heavily coated with bacteria, alongside an increase in inflammatory white blood cells in the smear. Similarly, a yeast infection caused by an overgrowth of Candida fungi creates irritation that can lead to cellular changes misinterpreted as a precancerous lesion.
Another common culprit is the parasite Trichomonas vaginalis, which causes the sexually transmitted infection trichomoniasis. The intense inflammation resulting from this infection causes significant cellular swelling and nuclear changes that can easily be mistaken for LSIL on cytology. The cellular abnormality is a temporary reaction to the infection or irritation, not a result of true dysplastic changes, and the atypical appearance typically clears once the underlying infection is successfully treated.
Hormonal Shifts and Atrophic Changes
Hormonal changes, particularly a decrease in estrogen levels, can significantly influence the appearance of cervical cells, leading to results that mimic LSIL or ASC-US. This is most commonly observed in post-menopausal women, a condition referred to as cervical or vaginal atrophy. The decline in estrogen causes the cervical and vaginal linings to become thinner and less mature.
The lack of estrogen results in the shedding of cells from the deeper, basal layers of the epithelium, known as parabasal cells. These immature cells are naturally smaller, have a higher nuclear-to-cytoplasmic ratio, and possess denser nuclei compared to the mature surface cells. This combination of features—small cells with relatively large, dense nuclei—is a key characteristic of atypia.
The appearance of these atrophic parabasal cells can be visually confusing, causing them to be misclassified as low-grade squamous lesions. This change is a result of cellular shrinkage and a lack of maturation due to hormone withdrawal. The cellular appearance is benign and reversible, often improving with the temporary use of topical estrogen therapy, which helps to mature the cervical epithelium.
Cellular Repair and Metaplastic Processes
The cervix is a dynamic organ constantly undergoing cellular renewal, and the process of rapid healing or transformation can generate cells that appear atypical. Squamous metaplasia is the normal biological process where the glandular cells lining the endocervical canal are replaced by protective squamous cells, specifically at the transformation zone. This zone is particularly prone to cellular turnover and repair.
When the cervix is irritated, such as after procedures like cryotherapy or due to chronic irritation, the repair process accelerates. Rapidly regenerating repair cells can appear disorganized and may exhibit features like enlarged nuclei and prominent nucleoli as they rush to heal the tissue. These features are also common in true LSIL, leading to a diagnostic overlap.
The immaturity of these newly formed metaplastic cells can cause them to be mistaken for dysplastic cells. These atypical repair cells are a benign finding related to regeneration, not HPV-driven precancer. Their appearance under the microscope necessitates careful evaluation to avoid over-diagnosis. The pathologist must distinguish between the uniform, open chromatin pattern of benign repair cells and the darker, irregular chromatin typically seen in true LSIL.