A prevalent infection;
a disease that can develop over time

The development of cervical cancer has long been associated with infections by certain high-risk genotypes of human papillomaviruses (HPV). Though HPV is prevalent throughout the human population, the overwhelming majority of HPV infections are transient.1

However, persistent infection with high-risk genotypes (hrHPV), especially 16 and 18, can sometimes trigger oncogenic processes. In a small percentage of these cases, cervical cancer occurs when abnormal cells develop and become invasive.1

When cervical cancer progresses and metastasizes before it is detected, it can be fatal within 5 years for as many as 90% of patients.4

Progression from HPV infection to early dysplasia to invasive cancer occurs slowly — typically over more than 10 years. While the peak age of HPV infection is in the late teens and early 20s, the median age at diagnosis of cervical cancer is age 45 to 50.2

Routine conventional or liquid-based Pap cytology and/or HPV testing is usually effective at detecting disease at pre-cancerous or early stages, allowing treatment before the onset of invasive cancer.3

The cervix: susceptible to disease

The cervix is composed of fibrous, muscular, and elastic tissue and is lined by the squamous epithelium and the columnar epithelium.5

  • Outer surfaces of the ectocervix (the visible part of the cervix) are lined with squamous epithelial tissue.5

Squamous epilthelium

  • The surface of the endocervix, a spindle-shaped, flattened canal at the neck of the uterus, is lined with a single layer of columnar epithelial cells, which secrete mucin.5

Columnar epithelium


The area where cervical squamous epithelium and columnar epithelium meet is referred to as the squamocolumnar junction. The location of this moves in association with growth, puberty, and menopause.5

Over time, columnar tissue is replaced by squamous epithelium. The region between the location of the original (childhood) squamocolumnar junction and location of the post-puberty functional quamocolumnar junction is termed the transformation zone.5

 

Transformation zone

cervical_transformation_zone

The transformation zone moves higher into the cervical canal as women age, making it increasingly difficult to obtain an adequate sample for the screening of abnormal cells.4

Abnormal tissue growth in the cervix usually begins at the transformation zone, and the types of dysplasia that may lead to cancer remain in this area.5

How cervical carcinogenesis occurs

The development of cervical cancer occurs in 4 main stages6:

  1. Infection with high-risk HPV (hrHPV)
  2. Persistence of infection
  3. Progressive dysplasia
  4. Invasive cancer

Use the figure to explore the development of cervical cancer.

Watch a video about the molecular mechanisms of HPV infection and oncogenesis

HPV_infection_and_development_of_cervical_cancer

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Adapted with permission from Woodman et al. Nat Rev Cancer. 2007;7(1):13.1

1. Infection

prevlance_of_hrHPV_genotypesInfection with a hrHPV generally occurs through sexual activity, where the virus is introduced to the cervical area from an infected partner. Numerous studies have found HPV DNA in 95% to 100% of cervical cancer cases.3,7

The virus is introduced into basal cells of the cervical epithelium. When these cells reproduce, they contain copies of HPV.1

More than 100 HPV genotypes have been identified, along with approximately 30 mucosal genotypes. HPV genotypes 16 and 18 are most often implicated as causative agents of cervical pre-cancer. However, a number of other high-risk genotypes are also of concern, including 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68.1

2. Persistence

The second step in progression to cervical cancer is persistence of HPV infection. Most HPV infections are transient and only 10% to 15% will potentially progress to pre-cancer. However, in women whose infections persist, the presence of hrHPV may cause progressive abnormalities in cervical cells.1,9

3. Progressive dysplasia

Progressive dysplasia usually begins in what is known as the transformation zone. HPV-infected cells may undergo transformation. Over time, in a transforming HPV infection, the tissue may progress through mild, moderate, and severe types of dysplasia.1,2

These traditionally have been referred to as cervical intraepithelial neoplasia 1, 2, and 3 (CIN 1, CIN 2, and CIN 3). More recent terminology refers to CIN 1 as low-grade squamous intraepithelial lesion (LSIL) and CIN 2 or CIN 3 lesions as high-grade squamous intraepithelial lesions (HSIL).10

4. Invasive cancer

In some cases, abnormal cervical cells undergo malignant transformation, where they become able to migrate and grow beyond the cervical epithelium — to deeper tissue layers in the cervix, to adjacent tissues in the uterus and vagina, and potentially to lymph nodes, the pelvic wall, and vital organs in other areas of the body.1

Types and characteristics of cervical dysplasia11

Lesion % typically
regress
% typically
persist
% progress
to CIN 3
% progress
to invasive cancer
CIN 1 60 30 10 1
CIN 2 40 40 20 5
CIN 3 33 <55 >12

While mild dysplasia (CIN 1, or LSIL) usually regresses, women with moderate-to-severe dysplasia (CIN 2/ CIN 3, or HSIL) are at substantial risk of dysplasia persisting and progressing to invasive cancer.

Types of cervical cancer

Because of the long course of disease and the opportunity to detect the development of pre-cancerous lesions, routine screening is the foundation of cervical cancer prevention.2

Cervical cancer is diagnosed when a tissue sample reveals that malignant cells have invaded beneath the epithelium and through the basal membrane into the fibrous layer of cervical tissue.1

The most prevalent type of invasive cervical cancer is called squamous cell carcinoma, which originates in squamous cells of the ectocervix (about 75% to 80% of cases).3

Adenocarcinoma, which originates in columnar/glandular cells of the endocervix, occurs in 10% to 20% of cases.3

Following diagnosis, diagnostic imaging is used to determine the extent to which disease has spread. The likelihood of survival is related to stage of disease.4

HPV and oncogenesis