A result of atypical glandular cells (AGC) on a Pap test (also called a Pap smear) means that some of the glandular cells collected from your cervix or uterus look abnormal when examined under the microscope. Glandular cells normally line the inner canal of the cervix (the endocervix) and the inside of the uterus (the endometrium). When these cells look unusual, the result can mean many different things — from harmless changes caused by infection or inflammation to precancerous changes and, less commonly, cancer.
AGC is an uncommon Pap test finding, occurring in less than 1% of all Pap tests, but it carries a meaningfully higher chance of underlying significant pathology than the more common abnormal results, such as ASC-US or ASC-H. For this reason, AGC almost always leads to further investigation. This article will help you understand what AGC means, how it is reported, and what the next steps in your care are likely to be.
What do glandular cells normally do?
Glandular cells line two areas in and around the cervix and uterus. In the endocervix — the inner canal of the cervix — glandular cells produce mucus that protects the cervix and lubricates the canal. In the endometrium — the inner lining of the uterus — glandular cells form the tissue that thickens and sheds during the menstrual cycle. In a normal Pap test, most of the cells seen under the microscope are squamous cells, which cover the outer surface of the cervix, but small groups of glandular cells from the endocervix or endometrium are also common.
- Endocervical glandular cells — Finding small groups of these cells in a Pap test is normal at any age and is often considered a quality indicator showing that the sample reached the transformation zone (the area where most precancerous changes begin).
- Endometrial glandular cells — Finding endometrial cells is usually normal in younger people, especially around the time of menstruation. However, in people over the age of 45 — particularly those who are postmenopausal — the presence of endometrial cells may warrant further evaluation, even when they appear normal.
What causes atypical glandular cells?
Several conditions can cause glandular cells in a Pap test to look abnormal. Many of these causes are not dangerous, but because AGC is also associated with serious conditions, the underlying cause cannot be determined from the Pap test alone:
- Infection — Cervical or uterine infections (including some sexually transmitted infections) can cause reactive changes in glandular cells.
- Inflammation — Inflammation from any cause — including an intrauterine device (IUD), recent intercourse, or prior procedures — can alter the appearance of glandular cells.
- Pregnancy-related changes — Hormonal changes during pregnancy and shortly afterward can produce glandular cell changes that may be read as AGC.
- Prior radiation therapy — Radiation directed at the pelvic area can cause long-lasting changes in the appearance of glandular cells.
- Cervical lesions — Precancerous and cancerous conditions of the cervix, including adenocarcinoma in situ (AIS), HPV-associated endocervical adenocarcinoma, and HPV-independent gastric-type adenocarcinoma, can shed atypical glandular cells onto a Pap test.
- Endometrial lesions — Conditions affecting the lining of the uterus — including atypical endometrial hyperplasia and endometrial cancer — can also produce atypical glandular cells, especially in postmenopausal patients.
- Benign growths — Non-cancerous growths, such as endocervical polyps, can sometimes shed cells that appear atypical on a Pap test.
What does AGC look like under the microscope?
The word atypical is used by pathologists to describe cells that look different from normal, healthy cells. When a pathologist or a specially trained cytotechnologist examines the Pap test sample under the microscope, the glandular cells in an AGC result show changes that go beyond normal reactive changes but are not clearly precancerous or cancerous. Typical microscopic features include:
- Enlarged cells — The atypical glandular cells are larger than the normal glandular cells in the surrounding sample.
- Dark nuclei — The nucleus (the part of the cell that holds the genetic material) appears darker than usual under the microscope, a feature called hyperchromasia.
- Variation in size and shape — The nuclei differ in size and shape from one cell to another, in contrast to the uniform appearance of normal glandular cells.
- Crowded or overlapping groups — The atypical cells may be arranged in tight, three-dimensional clusters in which individual cell outlines are difficult to make out.
When AGC is identified, the pathologist also tries to decide whether the abnormal cells most likely originated from the endocervix or the endometrium. Sometimes this distinction can be made from the appearance and arrangement of the cells. In other cases, the source of the cells cannot be determined, and the report simply states “atypical glandular cells” without specifying the site of origin.
AGC subcategories: not otherwise specified vs. favor neoplastic
The pathology report for an AGC result almost always includes a subcategory that indicates the pathologist’s level of concern about an underlying precancerous or cancerous condition. The Bethesda System — the international reporting framework used for Pap test results — defines the following subcategories:
- Atypical glandular cells, not otherwise specified (AGC-NOS) — The cells look abnormal, but the changes are not specific enough to strongly suggest a precancerous or cancerous process. This is the more common form of AGC. Even so, AGC-NOS still carries a meaningful chance of an underlying significant lesion, and further testing is required.
- Atypical glandular cells, favor neoplastic (AGC favor neoplasm) — The cells show features that worry the pathologist more strongly about a precancerous or cancerous process, but the findings are not definitive enough to make a final diagnosis from the Pap test alone. The chance of finding a significant lesion — including adenocarcinoma in situ or an invasive cancer — is substantially higher with this subcategory than with AGC-NOS.
The report may further indicate whether the atypical cells appear to originate from the endocervix (the cervix) or the endometrium (the uterus), or whether the source is uncertain. This distinction is important because it helps guide subsequent investigations toward the most likely site of the abnormality. When the appearance of the cells meets specific criteria for a precancerous diagnosis, the result is no longer reported as AGC but as adenocarcinoma in situ (AIS) or, when fully malignant features are present, as adenocarcinoma.
What happens after an AGC result?
Because AGC carries a higher chance of an underlying significant lesion than most other abnormal Pap test results, additional testing is recommended in almost all cases. The specific workup depends on the AGC subcategory, the suspected site of origin, your age, and whether you are pre- or postmenopausal. The most commonly recommended investigations include:
- Colposcopy with biopsy — A colposcopy is an examination of the cervix using a magnifying instrument called a colposcope. Any abnormal-looking area is sampled with a biopsy. Colposcopy is recommended for essentially all AGC results.
- Endocervical curettage — A small sample of tissue is collected from inside the endocervical canal, an area that cannot be fully seen even with the colposcope. This is particularly important when the atypical cells are thought to come from the endocervix, since the abnormality may be located higher in the canal.
- Endometrial biopsy — A small sample of tissue is collected from the lining of the uterus using a thin instrument passed through the cervix. Endometrial biopsy is recommended in addition to colposcopy for patients aged 35 and older, for anyone with abnormal uterine bleeding or risk factors for endometrial cancer, and for any AGC result in which endometrial cells are favored as the source.
- HPV testing — Because high-risk HPV is the cause of most cervical glandular precancers and cancers, an HPV test is usually performed alongside the workup. A positive HPV test strengthens the suspicion for a cervical (rather than endometrial) cause. However, a negative HPV test does not eliminate concern: endometrial cancers and some HPV-independent cervical cancers are not detected by HPV testing, and colposcopy and any other recommended investigations are still performed.
- Imaging — In some cases, especially when the abnormal cells are thought to come from the endometrium, or when the workup so far has not provided a clear answer, ultrasound or other imaging studies may be recommended.
The findings from these tests determine the next steps. If a precancerous condition (such as adenocarcinoma in situ or atypical endometrial hyperplasia) is found, treatment is recommended to remove the abnormal area. If invasive cancer is found, you will be referred to a gynecologic oncologist for staging and treatment planning. If no significant lesion is found, close follow-up with repeat Pap and HPV testing is recommended — usually every 6 to 12 months for at least 2 years — because the AGC result indicates a meaningfully increased baseline risk, and a small lesion may not always be apparent on the first round of testing.
Questions to ask your doctor
- Is my AGC result reported as “not otherwise specified” or “favor neoplastic,” and what does the difference mean for me?
- Were the atypical cells thought to come from my cervix, my uterus, or could the source not be determined?
- Was an HPV test also performed, and what was the result?
- Will I need a colposcopy, an endocervical curettage, an endometrial biopsy, or all three?
- Am I considered at higher risk because of my age, menopausal status, or any symptoms I have been experiencing?
- If imaging is recommended, what type and why?
- What are the possible findings on biopsy, and what would each one mean for my treatment?
- What does it mean if my report says “favor neoplasm,” and how does it change the urgency of follow-up?
- What symptoms — such as abnormal bleeding or discharge — should I watch for while my workup is being completed?
- If no significant lesion is found on biopsy, what is my follow-up schedule going to look like?
- How long will I need close surveillance before returning to routine cervical cancer screening?
- Should I consider HPV vaccination if I have not already been vaccinated?
Related articles on MyPathologyReport.com