Etiology of Cervical Intraepithelial Neoplasia

CERVICAL INTRAEPITHELIAL NEOPLASIA

Etiology

Cervical cancer and CIN are caused by human papillo-mavirus (HPV). Of the approximately 80 types of HPV, about 30 infect the anogenital tract. Approximately 15 of these types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82) are associated with cancer and are known as high-risk HPV types. The majority of cervical cancers are caused by just four of these high-risk HPV types: 16, 18, 31, and 45. Low-risk HPV types are not associated with cancer. However, low-risk types 6 and 11 are associ-ated with genital warts (condylomata acuminata) and with low-grade squamous intraepithelial lesions.

HPV infects the cells of the cervix. The size and shape of the cervix change depending on age, hormonal status, and number of children (parity). In reproductive-age women, the cervix measures 7–8 mm at its widest point. The upper part of the cervix that opens into the endome-trial cavity is called the internal os; the lower part that opens into the vagina is called the external os. The exte-rior portion of the cervical canal is called the exocervix, and the interior cervical canal is called the endocervical canal. The walls of the endocervical canal contain numerous folds and plicae.

The histology of the cervix is complex (Fig. 43.1, A and B). Overlying the fibrous stroma of the cervix is the cervical epithelium, a meshwork of cells. The epithe-lium is of two types: columnar (glandular) and stratified non-keratinizing squamous epithelia. The columnar epithe-lium consists of a single layer of mucus-secreting cells that are arranged into deep folds or crypts. The area where the two types of epithelia meet is called the squamocolumnarjunction (SCJ). The SCJ is clinically important, as it isthe site where over 90% of lower genital tract neoplasias arise. During childhood, the SCJ is located just inside the external os. Under the influence of hormones and the acidification of the vaginal environment during puberty, subcolumnar cells undergo metaplasia, a process of trans-formation. The metaplasia of these cells causes the SCJ to “roll out,” or evert, from its original position inside the external os to a position on the enlarged cervical surface. Columnar epithelium is also rolled onto the cervical sur-face, where it is exposed to vaginal secretions, irritants, and a changing hormonal milieu. The area between the original SCJ and the active SCJ is called the transforma-tion zone (TZ). As metaplasia continues, the metaplasticepithelium covers and eventually becomes indistinguish-able from the original squamous epithelium.  

Glands within the columnar epithelium may become trapped dur-ing this metaplastic activity by squamous epithelium, caus-ing Nabothian cysts. These cysts are not considered pathologic, but a normal consequence of the dynamic his-tology of the cervix.

The metaplastic cells within the TZ represent the newest and least mature cells in the cervix, and it is thought that they are the most vulnerable to oncogenic change. The rate of metaplasia is highest during adolescence and early pregnancy. During perimenopause, the new SCJ recedes upward into the endocervical canal, often out of direct visual contact (Figure 43.1C).

HPV infection of cervical cells may or may not result in neoplastic change. Most HPV infections are transient, indicating that the host’s immune system is able to eradi-cate the virus before it can cause neoplastic changes in cer-vical cells. It is likely that several as-yet unidentified host or environmental factors act as cofactors. If the HPV DNA is not integrated into the host genome, encapsulated virions are produced that are expressed morphologically as “koilocytes.” If HPV DNA is integrated into the host DNA, the expression of the cell’s regulatory genes may be altered, leading to the transformation of the cells into intraepithelial lesions or cancer.