What Is an Epithelial Cell Abnormality? Types & Causes

An epithelial cell abnormality is any structural or behavioral change in the cells that line your body’s surfaces and organs, detected when those cells look different from normal under a microscope. The term comes up most often after a cervical screening test (Pap smear), where a standardized system called the Bethesda System sorts abnormalities into specific categories. But epithelial cells line far more than the cervix: your skin, airways, digestive tract, and urinary system are all covered by epithelium, and abnormalities can develop in any of those tissues. What makes the concept worth understanding is that most epithelial cell abnormalities are not cancer, yet some of them can progress toward cancer if left unchecked.

Why Epithelial Cells Matter

Epithelial cells form the body’s frontline barriers. In the lungs, they work with mucus and junctions between cells to trap and clear pathogens and pollutants without triggering unnecessary inflammation.¹ In the skin, specialized squamous epithelial cells assemble a tough outer structure called the cornified cell envelope, reinforced with cross-linked proteins and lipids that keep water in and harmful agents out.² In the alveoli of the lungs, stem-like epithelial cells continuously differentiate and replace damaged cells to maintain normal architecture.³

Because epithelial tissues are exposed to the outside world constantly and turn over rapidly, they are especially vulnerable to damage. Chronic irritation, infection, or genetic errors during that turnover can push cells away from their normal appearance and behavior. That deviation is what a pathologist calls an epithelial cell abnormality.

What Pathologists Actually Look For

When a sample of cells arrives in the lab, the pathologist examines features visible under a microscope. The key markers include how dark the nuclei stain (hyperchromasia), whether the nuclei look crowded or overlap, whether the nuclei have irregular shapes, the ratio of nucleus size to overall cell size, the texture of the genetic material inside the nucleus, and whether the cells are dividing at an unusually high rate.⁴ None of these features alone is definitive. Pathologists weigh them together, grading each on a scale, to decide whether a sample looks benign, mildly atypical, or clearly abnormal.

Tobacco use offers a concrete example of how external agents push these cellular features in the wrong direction. Studies comparing oral mucosa cells from tobacco users and non-users found that cytological atypia appeared only in the tobacco-exposed group, with significantly higher nuclear area measurements in both smokers and users of smokeless tobacco products.⁵ Those enlarged, busier nuclei are early signs of the kind of cellular disruption that screening is designed to catch.

Squamous Cell Abnormalities on a Pap Smear

The Bethesda System is the classification most people encounter through cervical screening. Under the heading “Epithelial Cell Abnormality: Squamous,” it arranges findings along a spectrum. The mildest category, ASC-US (atypical squamous cells of undetermined significance), means the cells look slightly off but not clearly abnormal. A step up is ASC-H (atypical squamous cells, cannot exclude a high-grade lesion), which tells the clinician the changes are more concerning. Beyond the equivocal categories sit two defined grades of squamous intraepithelial lesion: LSIL (low-grade) and HSIL (high-grade). At the far end of the spectrum is invasive squamous cell carcinoma.⁶

LSIL usually reflects a transient viral infection and frequently clears on its own. HSIL signals deeper disruption of the epithelium that is more likely to persist and, without treatment, has a real chance of progressing. The equivocal categories exist because biology does not always sort neatly: some cells just look ambiguous, and the system is designed to flag those cases for closer follow-up rather than ignore them.

Glandular Cell Abnormalities

Not all epithelial cells are squamous. The cervix also has glandular (columnar) epithelial cells, and abnormalities in those cells get their own Bethesda category: atypical glandular cells (AGC). AGC is less common than squamous abnormalities but tends to be taken more seriously because glandular lesions are harder to see on colposcopy and carry a higher risk of underlying significant disease.

A large retrospective study of over 1,100 women with AGC cytology found that roughly 28% of those who were positive for high-risk HPV had high-grade lesions or worse, and among women 40 and older who tested negative for high-risk HPV, the risk of endometrial neoplasia was still elevated.⁷ The combination of AGC with certain HPV genotypes (types 16, 18, or 45) is a particularly strong warning sign for cervical adenocarcinoma or its precursor. Though this combination appears in less than one tenth of one percent of screened women, its predictive power is striking.⁸ AGC results generally trigger more aggressive workup than squamous abnormalities of similar grade, often including endometrial sampling in addition to colposcopy.

How HPV Drives Cervical Abnormalities

Human papillomavirus is the engine behind the vast majority of cervical epithelial cell abnormalities. High-risk HPV strains produce two proteins, E6 and E7, that effectively disable the cell’s built-in brakes on growth. E7 binds to and neutralizes the retinoblastoma protein (pRb), which normally prevents the cell from entering the DNA-copying phase of its cycle prematurely.⁹ Meanwhile, E6 targets p53, the protein responsible for pausing the cell cycle to repair DNA damage or triggering cell death when damage is too severe. By degrading p53, E6 removes the cell’s main safety net against accumulating dangerous mutations.¹⁰

With both growth restraints disabled, infected epithelial cells can keep dividing even when they should not. That uncontrolled proliferation is what shows up under the microscope as LSIL or HSIL. In most people, the immune system eventually clears the infection and the abnormal cells along with it. When the virus persists, the abnormal growth can deepen through the layers of the epithelium and, over years, invade underlying tissue.

Not All Abnormalities Progress

One of the most important things to understand about epithelial cell abnormalities is that the pathway from a mild abnormality to cancer is not inevitable. Roughly 10% of low-grade squamous intraepithelial lesions progress to high-grade lesions within two years; the majority resolve on their own.¹¹

Even moderate-grade abnormalities (classified histologically as CIN2) frequently regress without treatment. A prospective cohort study found that about 64% of CIN2 lesions regressed completely during surveillance, while about 16% progressed to CIN3 or worse.¹² Another study of HPV-positive women with CIN2 found a similar regression rate of 61%, with most regression happening within the first two to three years. Progression in that study was significantly linked to HPV 16/18 infection and to cytology results suggesting a high-grade lesion.¹³

This is why clinical guidelines for CIN2 increasingly allow for active surveillance, especially in younger women who may want to preserve fertility. If the lesion is going to clear on its own in the majority of cases, immediate excision carries procedural risks that not every patient needs to accept. The decision hinges on the individual’s HPV genotype, age, cytology severity, and comfort with monitoring.

Biomarkers That Help Pathologists Decide

Because visual interpretation under a microscope involves judgment calls, laboratories often use supplementary stains to improve accuracy. Two of the most widely used biomarkers in cervical pathology are p16 and Ki-67. The p16 protein accumulates when HPV’s E7 oncoprotein disrupts normal cell-cycle control, so strong, diffuse p16 staining in a tissue sample is a reliable sign of high-risk HPV activity. Ki-67 marks cells that are actively dividing. When pathologists use both stains together, their diagnostic accuracy for distinguishing true dysplasia from look-alike benign changes improves significantly.¹⁴

These markers matter most in borderline cases. A biopsy that looks like it might be CIN1 or CIN2, where the grading could go either way, benefits from p16 staining to clarify whether a high-risk HPV strain is genuinely driving the process. That distinction changes follow-up recommendations and can spare a patient unnecessary procedures.

Epithelial Abnormalities Beyond the Cervix

Cervical screening generates most public awareness about epithelial cell abnormalities, but the concept applies across the body wherever epithelial tissues face chronic insult.

Airway Epithelium

In the lungs and bronchial tree, chronic cigarette smoke exposure can cause the normal columnar epithelium to transform into squamous epithelium, a process called squamous metaplasia. Animal and cell-culture studies have shown that cigarette smoke activates signaling pathways that suppress the genes maintaining normal airway cell identity, leading to both hyperplasia (excess cell growth) and replacement of the airway lining with a cell type that does not belong there.¹⁵ Squamous metaplasia in the airways is considered a precancerous change when it persists, and it has been confirmed in chronic smoke-exposure models.¹⁶

Gastrointestinal Epithelium

In the esophagus, chronic acid reflux from gastroesophageal reflux disease (GERD) can trigger a transformation of the normal squamous lining into columnar, intestinal-type epithelium, a condition called Barrett’s esophagus. Roughly 10 to 15% of people with GERD develop Barrett’s, and the sequence from metaplasia to dysplasia to adenocarcinoma is one of the clearest examples of how epithelial abnormalities can escalate.¹⁷

In the stomach, infection with the bacterium Helicobacter pylori drives a similar chain. More than 80% of gastric cancers are attributed to H. pylori, and the tissue changes follow a recognizable sequence: loss of acid-producing cells, metaplasia, dysplasia, and eventually cancer if the infection persists unchecked for years or decades.¹⁸

Skin

Actinic keratosis is the skin’s version of an epithelial cell abnormality. Caused primarily by cumulative UV radiation damage, actinic keratoses are rough, scaly patches where keratinocytes have begun growing abnormally. They are now widely regarded as a chronic skin condition rather than isolated events. When actinic keratoses resist treatment, squamous cell carcinoma of the skin develops in close to 30% of cases over several years.¹⁹

A Common Thread Across Organs

A useful vocabulary for understanding these changes across different organs comes from pathology’s distinction between metaplasia, hyperplasia, dysplasia, and neoplasia. Metaplasia is when one normal tissue type converts to another normal type with different properties (as in Barrett’s esophagus). Hyperplasia means more cells than usual without a change in tissue organization. Dysplasia refers to abnormal cell multiplication with features pointing toward malignancy, but confined to the epithelium itself. Neoplasia is new tissue formation driven by excessive, autonomous cell growth.²⁰ These are not rigid stages every abnormality marches through. Many cases of metaplasia never become dysplasia, and many cases of mild dysplasia regress entirely. But the terms help clinicians communicate where a given abnormality sits along the spectrum between normal and malignant.

Treatment Approaches for Cervical Abnormalities

Management of cervical epithelial cell abnormalities depends on the severity. ASC-US and LSIL typically lead to repeat screening or HPV testing; if the abnormality persists, colposcopy and biopsy follow. For HSIL, two approaches have been compared. A “see-and-treat” strategy performs excision at the time of the initial colposcopy visit, eliminating the waiting period. A three-step strategy separates the colposcopy, biopsy, and treatment into distinct visits. In a study of over 500 patients with HSIL cytology, there was no difference in final pathology outcomes between the two approaches.²¹ The practical advantage of see-and-treat is that it reduces clinic visits and the window during which a patient is waiting anxiously for results. The loop electrosurgical excision procedure (LEEP) remains the most common excisional method used in these cases.²²

HPV Vaccination and Its Impact on Abnormality Rates

Vaccination against HPV is changing the landscape of cervical epithelial abnormalities at the population level. CDC surveillance data from five U.S. sites tracking cervical precancers from 2008 to 2022 found that among screened women aged 20 to 24, rates of CIN2 or worse dropped by 79%, and CIN3 or worse dropped by 80%. Among women aged 25 to 29, the decline in CIN3 or worse was 37%.²³ The larger decline in younger women reflects the fact that they were more likely to have been vaccinated before exposure to the virus. These numbers represent a genuine reduction in disease, not just a change in screening practices. They are among the strongest evidence that preventing the viral infection prevents the downstream epithelial cell abnormalities.

The Emotional Weight of an Abnormal Result

Getting a call or letter about an abnormal Pap smear can be genuinely distressing. In a study of 590 women, nearly 69% reported feeling anxious after learning of an abnormal result, and about 26% described outright panic. Even after a conversation with their physician, over half still felt worried and only about a quarter felt reassured.²⁴ A separate study found that the strongest predictor of psychological distress before diagnostic procedures was low satisfaction with the information and support patients had received. For women over 40, worry about cancer and about the impact on sexual health were additional independent contributors to distress.²⁵

The takeaway from this research is not that screening causes harm. It is that how results are communicated matters enormously. An abnormal Pap smear is a common finding, especially in younger women with active HPV infections, and the overwhelming majority of these abnormalities will never become cancer. Clinicians who take the time to explain what a specific result actually means, and what it does not mean, can measurably reduce their patients’ distress.

Artificial Intelligence in Screening

One developing area is the use of AI systems to assist pathologists in identifying abnormal cervical cells. A “cytologist-in-the-loop” AI approach tested on Pap smear slides achieved a sensitivity of about 89% on its own. When integrated into a triage workflow, the system reduced the overall slide-reading workload by more than a third without missing any abnormal squamous cases. Compared to junior cytologists working independently, the AI-assisted workflow had substantially higher sensitivity (about 82% versus 53%) and higher specificity.²⁶ A separate prospective study found that when AI assisted cytopathologists, sensitivity improved by about 13 percentage points compared to pathologists working alone.²⁷

These systems are not replacing human judgment. The gains come from the AI pre-screening slides to flag suspicious cells, so the human reviewer spends less time on clearly normal samples and more time on ambiguous ones. In settings where experienced cytopathologists are scarce, this kind of tool could make high-quality screening accessible to far more people.