ABNORMAL PAP SMEAR OVERVIEW

High grade cervical squamous intraepithelial lesion (HSIL, also called high grade cervical intraepithelial neoplasia) is the name given to moderately to severely abnormal-appearing cells on a Pap smear (also called a cervical cytology test). Any woman with HSIL requires further evaluation to determine if cancerous cells are present. While only about 2 percent of women with HSIL have invasive cancer, up to 20 percent of women with HSIL will eventually develop cancer if the abnormality is not treated.

Atypical glandular cells (AGC) is the name given to abnormal appearing glandular cells on a cervical cytology test. Glandular cells line the opening in the cervix (picture 1). AGC is a relatively uncommon result, although it always requires further evaluation. AGC can be caused by benign conditions, such as cervical polyps, or more serious conditions, such as cancer of the cervix, uterine lining (endometrium), ovary, or fallopian tube.

This topic review discusses the management of women with high grade squamous intraepithelial lesions (HSIL) and glandular abnormalities (AGC) of the cervix. Management of atypical squamous cells (ASC-US and ASC-H) and low grade squamous intraepithelial lesions (LSIL) is discussed separately. (See "Patient information: Management of atypical squamous cells (ASC-US and ASC-H) and low grade cervical squamous intraepithelial lesions (LSIL) (Beyond the Basics)".)

Cervical cancer screening tests are also discussed in a separate topic review. (See "Patient information: Cervical cancer screening (Beyond the Basics)".)

HIGH-GRADE SQUAMOUS LESION (HSIL)

HSIL refers to moderate to severe precancerous changes of the cells of the cervix. Approximately 2 percent of women with HSIL on a Pap smear are found to have invasive cervical cancer when they undergo further evaluation and another 20 percent of women with HSIL will develop cervical cancer over a period of several years if they are not treated. However, if the precancerous lesion is removed or destroyed, cervical cancer can usually be prevented.

Evaluation of HSIL — All women with high-grade (HSIL) on Pap smear should have one of the following:

• Colposcopy of the cervix, including biopsy of any abnormal areas and endocervical curettage (ECC). Management after colposcopy depends upon the results. (See 'Colposcopy' below.)
  
  If the healthcare provider is unable to see the entire cervix during colposcopy, surgical removal of the abnormal area is recommended (eg, loop electrosurgical excision, conization). (See "Patient information: Treatment of precancerous cells of the cervix (Beyond the Basics)".)
• Alternatively, the woman and her provider may decide to remove the abnormal area at the time of the initial colposcopy. This is called "see and treat". (See "Patient information: Treatment of precancerous cells of the cervix (Beyond the Basics)".) This option is not recommended for adolescents and pregnant women. (See 'Special populations' below.)

COLPOSCOPY

Colposcopy is an office procedure that allows a clinician to closely examine the cervix. It is commonly performed after an abnormal Pap smear. Colposcopy is performed while the woman lies on an examination table, similar to a routine pelvic examination. A speculum is used to view the cervix, and the viewing device (called a colposcope) remains outside the woman's body (picture 1).

The colposcope magnifies the appearance of the cervix. This allows the clinician to better see the location and size of any abnormalities, and also to see any changes in the capillaries (small blood vessels) on the surface of the cervix. Capillary changes are not detected by cervical cytology or human papillomavirus (HPV tests), but are important signs of the severity of cervical abnormalities.

During colposcopy, a small piece of the abnormal area can be removed (biopsied). Anesthesia (numbing medicine) is not needed because the biopsy causes only mild discomfort or cramping.

Women with HSIL or AGC usually require a biopsy of the inner cervix during colposcopy; this is called endocervical curettage (ECC). Endocervix refers to the inner cervix and curettage means scraping. Pregnant women should not have ECC because it may disturb the pregnancy.

Management of HSIL after colposcopy — Most women with HSIL results on a Pap smear will have a biopsy of any abnormal-appearing areas during colposcopy. The biopsy samples are sent to a pathologist, who determines if there is any evidence of precancerous changes, termed cervical intraepithelial neoplasia (CIN). These changes are categorized as being mild (CIN 1) or moderate to severe (CIN 2 or 3).

The following management strategies apply to non-pregnant women who are 21 years-old or older. Management of adolescents and pregnant women is discussed separately (see 'Special populations' below).

CIN 2 or 3 — If the healthcare provider is able to see the entire cervix during colposcopy and the biopsy shows CIN 2 or 3, treatment to remove (excise) the abnormal area is recommended to prevent cancer.

Delaying treatment (eg, watching and waiting) is not recommended for women age 21 or older with CIN 2 or 3, given the high risk of progression to cancer. (See "Patient information: Treatment of precancerous cells of the cervix (Beyond the Basics)".)

CIN 1 or less preceded by HSIL — Colposcopy can miss a significant number of seriously abnormal CIN lesions. If a woman has HSIL but the colposcopy/biopsy do not show a high grade lesion, the woman and her provider need to decide what else should be done to make sure a serious lesion has not been missed. The following options are available:

• Close monitoring, including cervical cytology and colposcopy at 6 and 12 months. At these visits, the provider must be able to see the entire cervix during colposcopy and a test of the inner cervix (called endocervical curettage) must be negative. This may be the preferred approach for younger women who would like to preserve their ability to carry a pregnancy in the future.
  
  If these tests are negative, the woman may return to once yearly testing.
  
  If either test show persistent HSIL, a treatment to remove the abnormal area is recommended. (See "Patient information: Treatment of precancerous cells of the cervix (Beyond the Basics)".)
• Remove the abnormal area. Excision is recommended because it can both treat any abnormal areas and determine with certainty what abnormality was present. (See "Patient information: Treatment of precancerous cells of the cervix (Beyond the Basics)".)
• In some cases, a healthcare provider will request an expert review of the woman's cytology and biopsy. This generally involves sending the cervical cytology and biopsy slides to an outside pathologist who is expert in evaluating abnormal Pap smears. If the expert feels that the woman has moderate to severe changes, a treatment to remove the abnormal area may be recommended. If the pathologist feels that there are mild to moderate changes, the woman and her provider may elect to monitor these changes with cervical cytology and colposcopy every six months.

SQUAMOUS CELL CARCINOMA

Squamous cell carcinoma is the medical term for cervical cancer. Women with this result require a biopsy, which is usually performed with colposcopy (see 'Colposcopy' above).

If the biopsy confirms that cancerous cells are present, treatment is strongly recommended. The diagnosis and treatment of early stage cervical cancer is discussed in a separate article. (See "Patient information: Cervical cancer treatment; early stage cancer (Beyond the Basics)".)

GLANDULAR CELL ABNORMALITIES (AGC)

Glandular cells develop from the inside of the cervix (called the endocervical canal). Glandular cells can also come from the endometrium (lining of the uterus), the fallopian tube, or the ovary (figure 1).

Evaluation — All women with atypical glandular cells (AGC) require further testing, including HPV testing, colposcopy, cervical biopsy, endocervical curettage, and often endometrial biopsy. This is because 10 to 40 percent of women with atypical glandular cells have a precancerous or cancerous abnormality.

These tests are usually performed in a single visit.

• HPV testing is done by sweeping the surface of the cervix with a brush, which is then placed into a vial containing a liquid preservative. The vial is sent to a laboratory for evaluation.
• Colposcopy, cervical biopsy, and endocervical curettage are described above (see 'Colposcopy' above).
• Endometrial biopsy is performed by inserting a thin instrument through the vagina into the uterus to obtain a small sample of endometrial tissue. The tissue is then sent to a pathologist, who examines it with a microscope. The biopsy can be performed in a healthcare provider's office without anesthesia.

Management after colposcopy

• If all of these tests are normal and the initial cervical cytology test showed AGC-NOS (not otherwise specified), follow-up recommendations depend on the HPV status. If the HPV test was positive (or unknown), a repeat cervical cytology smear and HPV test are recommended at six months. If the HPV test was negative, the cervical cytology smear and HPV test should be repeated at 12 months. If either is positive, a repeat colposcopy with biopsies is recommended. If both tests are negative, the woman may return to routine screening.
• If all of these tests are normal and the initial cervical cytology test showed AGC-favor neoplasia or adenocarcinoma in situ, a treatment to remove (excise, not ablate) the abnormal area is recommended. (See "Patient information: Treatment of precancerous cells of the cervix (Beyond the Basics)".)

SPECIAL POPULATIONS

Pregnant women — The evaluation and management of pregnant women is different from non-pregnant women because of the risk that treatment to remove abnormal cervical tissue could lead to significant bleeding or preterm labor or delivery. Cervical biopsy is performed only as necessary in pregnant women.

If a pregnant woman has a Pap smear with high-grade intraepithelial lesion (HSIL) or atypical glandular cells (AGC), a colposcopy should be done. If a biopsy is performed, the results are managed as follows:

• CIN 2 or 3 – If the biopsy confirms CIN 2 or 3, the woman and her provider can choose to repeat the cervical cytology and colposcopy later during the pregnancy (three to four months later) or after the woman delivers her baby (six or more weeks after delivery). Treatment to remove the abnormal area is not recommended during pregnancy unless invasive cancer is suspected.
  
  The reason for this recommendation is that CIN 2 or 3 is caused by precancerous changes that have the potential to become cancerous when untreated. This is a slow process that takes many months to years. As long as the abnormality is monitored, it is not necessary to remove the area (and increase the risk of preterm delivery or miscarriage) until after delivery.
• CIN 1 – After a cervical cytology report showing HSIL, if a pregnant woman's colposcopy and biopsy show CIN 1, a repeat Pap smear and colposcopy should be done six weeks after the woman delivers her baby.
  
  The reason for this recommendation is that cervix appears somewhat different during pregnancy, which can make it difficult to determine if an area appears abnormal due to pregnancy or due to precancerous changes. Evaluating the area after delivery allows the provider to determine with more certainty if treatment is needed.

Adolescents — Cervical cancer screening is recommended starting at age 21 years. In this discussion, adolescents refers to age 20 or younger. In adolescents, abnormal cervical cytology is often approached differently because, in this age group, there is a good chance that mild abnormalities will resolve over time, without treatment. There is a high rate of HPV infection in this group, but a very low rate of cervical cancer.

If a Pap smear is performed in someone who is age 20 or younger, the recommendations are:

• HSIL – Colposcopy should be done. Treatment may be needed, but it should not be done before the results of biopsies are known. If the results of
• AGC – The management of AGC in adolescents is the same as in other women.

Management after colposcopy differs somewhat in adolescents from women age 21 or older. The next steps depend upon the results of biopsies that were done during colposcopy. Biopsies may show a precancerous condition of the cervix called cervical intraepithelial lesion (CIN). These changes are categorized as being mild (CIN 1) or moderate to severe (CIN 2 or 3).

• CIN 2 or 3 – CIN 2 or 3 is usually treated by removing the abnormal area. There are different methods for this, which are referred to as a cone biopsy or loop electrosurgical excision procedure (also referred to as LEEP, loop, or LLETZ). In adolescents, another option is close observation by repeating the Pap smear and colposcopy every six months for up to two years. If two consecutive tests show that the abnormality has resolved, the adolescent may return to Pap smears every 12 months.
  
  If the abnormality worsens or if the provider is unable to see the entire cervix during colposcopy, a treatment to remove the abnormal area is recommended. (See "Patient information: Treatment of precancerous cells of the cervix (Beyond the Basics)".)
  
  The advantage of watchful waiting is that it may allow the abnormality time to heal and potentially avoid the need for an excisional treatment. The disadvantage is that a greater number of follow up visits may be needed, depending upon whether the area improves or worsens over time. If the abnormality worsens or does not resolve, an excisional treatment may eventually be needed.
• CIN 1 – Repeat Pap smear at 12 months.

WHERE TO GET MORE INFORMATION

Your healthcare provider is the best source of information for questions and concerns related to your medical problem.

This article will be updated as needed on our web site (www.uptodate.com/patients). Related topics for patients, as well as selected articles written for healthcare professionals, are also available. Some of the most relevant are listed below

Patient level information — UpToDate offers two types of patient education materials.

The Basics — The Basics patient education pieces answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.

Patient information: Cervical cancer (The Basics)
Patient information: Pap tests (The Basics)

Beyond the Basics — Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are best for patients who want in-depth information and are comfortable with some medical jargon.

Patient information: Management of atypical squamous cells (ASC-US and ASC-H) and low grade cervical squamous intraepithelial lesions (LSIL) (Beyond the Basics)
Patient information: Cervical cancer screening (Beyond the Basics)
Patient information: Treatment of precancerous cells of the cervix (Beyond the Basics)
Patient information: Cervical cancer treatment; early stage cancer (Beyond the Basics)

Professional level information — Professional level articles are designed to keep doctors and other health professionals up-to-date on the latest medical findings. These articles are thorough, long, and complex, and they contain multiple references to the research on which they are based. Professional level articles are best for people who are comfortable with a lot of medical terminology and who want to read the same materials their doctors are reading.

Cervical adenocarcinoma in situ
Cervical cancer in pregnancy
Cervical cancer screening tests: Techniques and test characteristics of cervical cytology and human papillomavirus testing
Cervical cytology: Evaluation of atypical and malignant glandular cells
Cervical cytology: Evaluation of atypical squamous cells (ASC-US and ASC-H)
Cervical cytology: Evaluation of high-grade squamous intraepithelial lesions (HSIL)
Cervical cytology: Evaluation of low-grade squamous intraepithelial lesions (LSIL)
Cervical intraepithelial neoplasia: Definition, incidence, and pathogenesis
Cervical intraepithelial neoplasia: Management of low-grade and high-grade lesions
Epidemiology of human papillomavirus infections
Preinvasive and invasive cervical neoplasia in HIV-infected women
Screening for cervical cancer: Rationale and recommendations

The following organizations also provide reliable health information [1-3].

• National Library of Medicine

     (www.nlm.nih.gov/medlineplus/healthtopics.html)

• National Cancer Institute

     (www.nci.nih.gov)

• American Society for Colposcopy and Cervical Pathology

     (www.asccp.org)

ACKNOWLEDGMENT

The authors and editors would like to recognize Dr. Christine Holschneider, who contributed to previous versions of this topic review.