What Does Epithelial Cell Abnormality Mean?

An epithelial cell abnormality is a finding on a cytology report, most commonly a Pap smear, indicating that the thin layer of cells lining the cervix (or another organ) looks different from normal under a microscope. It does not mean you have cancer. In most cases, it signals changes that range from mildly unusual to precancerous, and the specific category on your report determines what happens next. The term comes from the Bethesda System, a standardized way of reporting cervical cytology results that groups abnormal findings into clinically meaningful tiers, each with its own level of concern and its own recommended follow-up.

How Cervical Cytology Results Are Reported

When a lab examines your Pap smear, it classifies the result using the Bethesda System, which was designed so that every category carries clear clinical meaning backed by worldwide consensus.¹ The broadest result is NILM, which stands for “negative for intraepithelial lesion or malignancy” and essentially means everything looks normal. When the result is not NILM, it falls into the “epithelial cell abnormality” bucket. Within that bucket, abnormalities are split into two main streams depending on which type of cervical cell is affected: squamous cells (the flat cells covering the outer cervix) and glandular cells (the column-shaped cells lining the cervical canal). Squamous abnormalities are far more common, but glandular findings carry their own set of concerns.

Squamous Cell Abnormalities, From Mildest to Most Serious

The squamous side of the Bethesda System arranges findings along a spectrum. At the mild end sit the “atypical squamous cells” categories, and at the serious end sits invasive squamous cell carcinoma. Understanding where your result lands on that spectrum matters far more than whether the report says “abnormal.”

ASC-US

ASC-US, or atypical squamous cells of undetermined significance, is the single most common epithelial cell abnormality. It means some cells looked slightly off but not clearly precancerous. One study of nearly 1,800 Pap smears found ASC-US in roughly 7 percent of all samples.² The cells fall into this category precisely because they are ambiguous: they might reflect a low-grade HPV infection, inflammation, hormonal changes, or even just a suboptimal sample. The positive predictive value of ASC-US for a truly high-grade lesion is low. In one analysis, only about 4 percent of women with ASC-US who went on to biopsy turned out to have a significant precancerous change.³ That said, ASC-US results do persist in many women: in one follow-up study, about three-quarters of women with ASC-US still had the same finding on a repeat test, and a meaningful number of them were eventually found to harbor low-grade precancerous changes at a higher rate than women with consistently normal smears.²

ASC-H

ASC-H, or atypical squamous cells where a high-grade lesion cannot be excluded, sounds similar to ASC-US but carries substantially more weight. The pathologist sees features that raise real concern about a high-grade precancerous lesion but cannot say so definitively from the smear alone. In the same study referenced above, the positive predictive value for a significant precancerous change jumped to 40 percent in women with ASC-H, a tenfold increase over ASC-US.³ Because of that higher risk, ASC-H typically triggers an immediate referral for colposcopy and biopsy rather than a wait-and-retest approach.

LSIL

LSIL, or low-grade squamous intraepithelial lesion, means the cells show clear but mild changes usually caused by an HPV infection. It roughly corresponds to what pathologists once called “mild dysplasia.” The changes are considered low-grade because they affect only the surface layers of the cervical lining and, in the majority of cases, resolve on their own as the immune system clears the virus. The risk of a high-grade finding hiding behind an LSIL result is around 21 percent on biopsy.⁴ That number is high enough to warrant follow-up but low enough that many guidelines recommend surveillance rather than immediate treatment for younger women.

HSIL

HSIL, or high-grade squamous intraepithelial lesion, is the most concerning precancerous category. It means the abnormal cells are more severe, involving deeper layers of the cervical tissue, and without treatment the risk of progression to cervical cancer is real. HSIL on cytology has the highest agreement with what a biopsy ultimately confirms: in one study, the concordance rate was about 86 percent, far higher than for any other abnormal category.⁵ HSIL always warrants prompt colposcopy and biopsy, and treatment usually follows.

LSIL-H

Some labs use an additional term, LSIL-H, which means a smear that looks mostly low-grade but contains a few cells suspicious for a high-grade lesion. Research shows the risk of a high-grade finding on biopsy for LSIL-H is about 40 percent, roughly double that of plain LSIL and close to the risk seen with ASC-H.⁴ Women with LSIL-H also carry high-risk HPV types at rates strikingly close to those seen with HSIL. One study found high-risk HPV in 92 percent of LSIL-H cases compared with 91 percent in HSIL, and HPV 16 specifically was detected in 36 percent of LSIL-H cases.⁶

Glandular Cell Abnormalities

When the abnormal cells come from the glandular lining of the cervical canal (or occasionally from the uterine lining), the report will say AGC, or atypical glandular cells. AGC is less common than squamous abnormalities but can be more consequential. The overall risk that an AGC finding is hiding a high-grade cervical or endometrial lesion is around 21 percent.⁷ Glandular abnormalities are also harder for pathologists to interpret than squamous ones. When the AGC is further categorized as “not otherwise specified” (AGC-NOS), the agreement between the Pap result and what a biopsy shows is low, meaning the smear alone is not a reliable predictor. When the AGC is categorized as “favor invasive lesion,” the predictive value is much higher.⁸ High-risk HPV testing with genotyping helps sort out which AGC patients are at genuine risk and which are not.⁷ Because glandular abnormalities can originate from the endometrium (uterine lining) as well as the cervix, the workup for AGC often includes endometrial sampling in addition to colposcopy, particularly in women over 35 or those with abnormal bleeding.

What Causes These Abnormalities

The leading driver of epithelial cell abnormalities on Pap smears is persistent infection with high-risk strains of human papillomavirus (HPV). HPV produces viral proteins that disrupt normal cell-cycle controls, and higher levels of these viral proteins are associated with more severe cytological abnormalities.⁹ HPV 16 is the most potent strain, and its presence in HSIL and LSIL-H findings is consistently higher than in lower-grade results.

HPV is not the only cause, though. Chronic irritation from intrauterine devices, chemical irritants, infections with bacteria or yeast, hormonal shifts (especially around menopause), and reparative tissue changes can all produce cervical cell changes that mimic HPV-related abnormalities on a Pap smear.¹⁰ This is one reason ASC-US is so common: inflammatory or hormonal changes can push cells into looking mildly atypical without any underlying precancerous process. It also explains why HPV co-testing has become so important. A mildly abnormal Pap smear plus a negative HPV test is reassuring in a way that the Pap smear alone cannot be.

What Happens After an Abnormal Result

Your follow-up depends on which category your result falls into and, increasingly, on whether you tested positive for high-risk HPV. The general framework used across many screening programs works like this: ASC-US and LSIL are typically managed with a repeat Pap smear in six to twelve months or HPV triage testing, with colposcopy reserved for results that persist or worsen. ASC-H, HSIL, and AGC trigger direct referral for colposcopy and biopsy.¹¹

Colposcopy involves looking at the cervix through a magnifying instrument after applying a vinegar-like solution that highlights abnormal areas. If a suspicious area is seen, a small tissue sample (biopsy) is taken and sent for histological examination. It is worth knowing that the Pap smear and the biopsy do not always agree. One large analysis found overall concordance between cytology and biopsy of about 51 percent, with Pap smears overestimating severity about 35 percent of the time and underestimating it about 14 percent of the time.⁵ Overestimation was most common in ASC-US, meaning many women referred for biopsy after an ASC-US result will find out their tissue looks normal or only mildly changed. Underestimation was most common in LSIL, so some women with an LSIL smear turn out to have a higher-grade lesion on biopsy. These imperfections are one reason screening programs rely on repeat testing and follow-up rather than a single result.

Do Abnormal Cells Progress or Go Away on Their Own

This is the question that causes the most anxiety, and the answer is genuinely reassuring for most people. Low-grade abnormalities clear on their own the majority of the time. In a long-term surveillance study of women with persistent LSIL, about 57 percent achieved complete clearance, and no cases of invasive cervical cancer were observed during follow-up periods extending up to six years. Progression to a high-grade lesion (CIN3) occurred in roughly 9 percent, with most of those cases appearing within the first two years.¹² Women who were positive for HPV 16 had a somewhat higher progression rate than those without it.

Even high-grade lesions can regress, particularly in younger women. A retrospective study of women aged 30 or younger found that about 47 percent of CIN3/HSIL cases regressed, including a third that regressed completely, over a median of roughly eight months. Among women with the less severe CIN2/HSIL designation, the regression rate was even higher at about 63 percent, and no invasive carcinoma was observed.¹³ These findings are part of the reason many guidelines now favor active surveillance over immediate treatment for CIN2 in younger women who want to preserve fertility. The trade-off, of course, is that surveillance requires reliable follow-up, and not every patient can guarantee that.

Treatment When It Is Needed

When a biopsy confirms a high-grade lesion and the decision is made to treat, the most common procedure is a loop electrosurgical excision procedure (LEEP), which uses a thin heated wire to remove the abnormal tissue from the cervix. LEEP is effective, and most recurrences appear within the first three years. Women who remain recurrence-free at the three-year mark can generally return to routine screening intervals.¹⁴ If the edges of the removed tissue still show abnormal cells (a “positive margin”), the decision about what to do next depends on the patient’s age, whether she wants to have children, and how reliably she can return for follow-up. Options range from close monitoring to a repeat excision or, in some cases, hysterectomy.¹⁵

The Emotional Side of an Abnormal Result

If you feel anxious after getting an abnormal Pap result, you are in large company. Research consistently finds that the period between receiving the result and having a colposcopy is especially distressing. A qualitative study described this waiting period as “the land of the unknown,” finding that most women were confused about what their result actually meant, did not know what a colposcopy was before being referred for one, and went online only to find worst-case scenarios and information that did not resolve their confusion.¹⁶ Anxiety was a prominent factor in women older than 40 with abnormal results, often intertwined with worry about cancer, general health, and sexual relationships.¹⁷ The strongest correlate of lower distress was satisfaction with the information and support received from other people, which underscores the value of a healthcare provider who takes the time to explain what the result actually means rather than simply handing over a referral slip.

Epithelial Cell Abnormalities Beyond the Cervix

The cervix gets the most attention, but epithelial cells line many organs, and abnormal-looking epithelial cells can show up in cytology samples from elsewhere in the body.

In urine cytology, atypical squamous cells can signal urothelial (bladder) malignancy. One study found that urine samples classified as “atypical” were associated with a confirmed diagnosis of urothelial cancer in about 68 percent of cases on follow-up biopsy, with over half of those being high-grade tumors.¹⁸ Another analysis found that high-grade squamous atypia in urine carried a 92 percent risk of high-grade malignancy on histologic follow-up.¹⁹ The significance of atypical cells in urine is therefore quite different from the cervical context, where most mild abnormalities resolve. In the bladder, atypical findings tend to carry higher stakes.

In the mouth, cytology brushings can reveal epithelial cell abnormalities too. Researchers have applied Bethesda-style classification to oral smears, finding ASC-US in 45 percent and ASC-H in 2 percent of samples taken from potentially malignant oral lesions, with a significant association between those findings and HPV positivity.²⁰ Deep-learning tools are now being tested on oral cytology samples and can distinguish precancerous from benign lesions with high accuracy, pointing toward a future where a simple brush biopsy could screen for oral cancer the way a Pap smear screens for cervical cancer.²¹

In the lungs, sputum cytology has long been used to look for atypical bronchial epithelial cells. A large cohort study of heavy smokers found that moderate or worse cytological atypia in sputum was associated with roughly three times the risk of developing lung cancer compared with normal sputum, independent of age, sex, and amount smoked.²² One practical limitation is that sputum samples contain very few epithelial cells relative to immune cells, which has driven efforts to develop enrichment techniques that concentrate the relevant cells before analysis.²³

In the bile ducts, brushing cytology during endoscopy can detect atypical glandular cells that raise concern for cholangiocarcinoma (bile duct cancer). However, false positives occur, particularly in patients with primary sclerosing cholangitis, a chronic inflammatory condition that produces degenerative cell changes mimicking cancer.²⁴

Biomarkers That Sharpen the Picture

One limitation of traditional cytology is that it relies on how cells look, and looks can be deceiving. A growing arsenal of molecular biomarkers is helping clinicians distinguish the abnormal cells that matter from the ones that do not. The most clinically advanced of these is p16/Ki-67 dual staining. Under normal conditions, p16 (a protein that slams the brakes on cell division) and Ki-67 (a marker of active cell division) should not appear together in the same cervical cell. When they do co-express, it signals that HPV has hijacked the cell’s growth controls, and it predicts the presence of high-grade cervical lesions with both high sensitivity and high specificity.²⁵ In practice, p16/Ki-67 staining can be applied to the same liquid-based cytology sample already collected during screening, making it a useful add-on when a Pap result is ambiguous.

How Artificial Intelligence Is Changing Screening

Cytology has always been labor-intensive: a trained professional examines cells on a slide, one sample at a time. Artificial intelligence is beginning to change that. AI systems trained on hundreds of thousands of cervical cytology images can flag abnormal slides with high sensitivity, reducing time per sample and removing some of the subjectivity that comes with human interpretation.²⁶ A systematic review and meta-analysis found that AI outperformed experienced colposcopists when assessing colposcopic images for cervical abnormalities.²⁷ AI-based primary cytology screening shows high sensitivity, though specificity remains somewhat variable across studies.²⁸ That variability matters because low specificity means more false positives, which means more unnecessary colposcopies and biopsies. As the technology matures, the expectation is that AI will work alongside human screeners rather than replacing them, handling initial triage and flagging the slides that warrant a closer look.