Cervical intraepithelial neoplasia (CIN)

by Jason Wasserman MD PhD FRCPC
March 28, 2022


What is cervical intraepithelial neoplasia?

Cervical intraepithelial neoplasia (CIN) is a pre-cancerous, sexually transmitted disease caused by infection with a virus called human papillomavirus (HPV). It is called pre-cancerous because over time it can change into a type of cervical cancer called squamous cell carcinoma. CIN is divided into three levels – CIN1, CIN2, and CIN3 – and the risk of developing cancer is lowest with CIN1 and highest with CIN3.

Another name for CIN1 is low-grade squamous intraepithelial lesion (LSIL). Similarly, CIN2 and CIN3 are often grouped under the name high-grade squamous intraepithelial lesion (HSIL). The World Health Organization (WHO) now recommends using the terms LSIL and HSIL when describing pre-cancerous changes in the cervix but many pathologists will also include the corresponding CIN level in the pathology report.

How do pathologists make the diagnosis of cervical intraepithelial neoplasia?

The diagnosis of CIN is typically made after a small sample of tissue is removed from the cervix during a procedure called a biopsy. The diagnosis can also be made after part or all of the cervix is removed for other reasons. The tissue sample is then sent to a pathologist who examines it under a microscope.

How do pathologists grade cervical intraepithelial neoplasia?

When examined under the microscope, the squamous cells in the epithelium on the surface of the cervix looks abnormal. Pathologists divide CIN into three levels – CIN1, CIN2, and CIN3 – based on the amount of the epithelium that has been replaced by the abnormal squamous cells. Your pathology report should include the type of CIN seen (for example CIN1) and for larger tissue samples, whether CIN was seen at the margin of the tissue (see below for more information about margins).

Cervical intraepithelial neoplasia 1 (CIN1)

In CIN1, the abnormal cells are found mostly in the lower one-third of the epithelium and abnormal cells called koilocytes are often seen. Koilocytes are larger than normal squamous cells and the nucleus of the cell (the part that holds the genetic material) is often hyperchromatic (darker) and irregular in shape. A clear space may be seen around the nucleus. Pathologists describe this space as a ‘halo’ because it looks like a ring surrounding the nucleus. Some koilocytes may have more than one nucleus. These cells are called binucleated or multinucleated. Koilocytes look abnormal because they have been infected by HPV. An increased number of mitotic figures (dividing cells) may also be seen. Another name for CIN1 is low-grade squamous intraepithelial lesion (LSIL). The risk of developing cancer with CIN1 is low and for most women, the condition will resolve over time without treatment.

Cervical intraepithelial neoplasia 2 (CIN2)

In CIN2, the abnormal cells are found mostly in the lower two-thirds of the epithelium. The abnormal cells are hyperchromatic (darker) and they lack the maturation that is normally seen as the squamous cells move towards the surface of the epithelium. As a result, the cytoplasm (body of the cell) is small compared to the nucleus (the part that holds the genetic material) and it looks less pink. An increased number of mitotic figures (dividing cells) are typically seen and some of these mitotic figures may be dividing in an abnormal way that results in an unequal distribution of genetic material between the two new cells. Pathologists call this cell an atypical mitotic figure. Another name for CIN2 is high-grade squamous intraepithelial lesion (HSIL). The risk of developing cancer with CIN2 is higher than with CIN1 but lower than with CIN3.

Cervical intraepithelial neoplasia 3 (CIN3)

In CIN3, abnormal cells are found throughout the entire epithelium (from the top to the bottom). The abnormal cells are hyperchromatic (darker) and they lack the maturation that is normally seen as the squamous cells move towards the surface of the epithelium. As a result, the cytoplasm (body of the cell) is small compared to the nucleus (the part that holds the genetic material) and it looks less pink. An increased number of mitotic figures (dividing cells) are typically seen and some of these mitotic figures may be dividing in an abnormal way that results in an unequal distribution of genetic material between the two new cells. Pathologists call this cell an atypical mitotic figure. Another name for CIN3 is high-grade squamous intraepithelial lesion (HSIL). The risk of developing cancer with CIN3 is high and most women are offered treatment to remove the abnormal tissue.

What is p16?

Cells infected with high-risk types of human papillomavirus (HPV) produce large amounts of a protein called p16 and increased p16 is commonly seen in CIN2 and CIN3. For this reason, pathologists perform a test called immunohistochemistry that allows them to see p16 inside cells. Pathologists use the term positive or reactive to describe cells that show increased amounts of p16. A positive result supports the diagnosis of CIN2 or CIN3 and helps exclude other conditions that can look like CIN2 and CIN3 under the microscope.

What is a margin?

A margin is any tissue that has to be cut by the surgeon in order to remove the tumour from your body. If you underwent a surgical procedure to remove the entire tumour from your body, your pathologist will examine the margin closely to make sure there are no abnormal cells at the cut edge of the tissue. Margins are not described after a biopsy.

The number and type of margins will depend on the type of procedure performed to remove the tumour from your body. Typical margins include:

  • Endocervical margin – This is where the cervix meets the inside of the uterus.
  • Ectocervical margin – This is the bottom of the cervix, closest to the vagina.
  • Stromal margin – This is the tissue inside the wall of the cervix.

A margin is considered positive when CIN is seen at the edge of the cut tissue. Finding CIN at the margin increases the risk that the CIN will grow back in that location.

Margin

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