From Oncogenic HPV to Cervical Cancer

Most HPV infections resolve through normal immune responses, after a period ranging from a few months to three years (Ho et al 1998; Moscicki et al 1998; Giuliano et al 2002). It is only when infection with oncogenic HPV types becomes persistent that the development and progression of cervical cancer may occur. (Bosch et al 2002).

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The continued presence of the virus may lead to the development of abnormal cells. HPV must reach the nucleus of the basal cell to cause infection but only oncogenic HPV types persist in the basal cell nucleus. However, only one HPV type per basal cell is allowed to enter the nucleus therefore replication shows monoclonal infection in that cluster of cells.

(Reference: Solomon D et al. JAMA 2002;287:2114-9)

Regression of lesions can occur at all stages of the disease.  However, regression is less likely when neoplastic cells have started to form at the CIN II stage.

CIN III is a higher grade pre-cancerous lesion of the squamous epithelium involving severe dysplasia. Eventually, persistent infection with oncogenic HPV can develop into cancer.

Usually, patients with cervical cancer do not experience symptoms and present only once the cancer has started to invade neighbouring areas (Conway 1996). The progress from neoplasia (intraepithelial dysplasia) to cervical cancer may take many years (in some cases up to 10-20 years from initial infection to cervical cancer (Burd 2003)), though sometimes it can be as short as 2 years (Holowaty et al 1999). Invasive cervical cancer is one possible end result of persistent infection with oncogenic HPV types.

Adenocarcinomas, which can be harder to detect during screening unless a brush or similar instrument is employed, may account for up to 20% of cervical cancer cases (Ferlay et al 2004; Duarte-Franco and Franco 2004). This form of cervical cancer tends to occur in the glandular cells lining the endocervical canal. The prognosis of adenocarcinoma is less favourable than the more common squamous cell carcinoma (Sherman et al 2005).

Cervical pre-cancer progression: CIN I

Appearance

CIN I, which can arise from either low-risk or oncogenic HPV infection in approximately 25% of cases (Unger and Barr 2004), is the lowest and earliest grade of pre-cancer. CIN I is a typically flat lesion containing the abnormal squamous epithelial cells that may be visible on inspection of the cervix.

Cytology

Mild dysplasia is a term for the microscopic changes of CIN I. This includes changes in the shape and size of the cells and changes in the size and appearance of the cell nuclei. Koilocytosis will also be present. The presence of LSIL, koilocytosis, koilocytic atypia, CIN I or mild dysplasia all mean that an HPV infection is present.

Probability of regression or progression

Based on a study of the natural history of HPV in 187 adolescent women aged 13-22 years with LSIL, the probability of regression of the LSIL, or progression to HSIL was (Moscicki et al 2004):

• Regression at 12 months: 61%
  
• Regression at 36 months: 91%
  
• Progression to HSIL: 3%

This means that the probability of the CIN I lesions developing to a more serious state is small and that they are more likely to regress to a more normal condition.


Cervical cancer disease progression: CIN II

Appearance

A cervix displaying CIN II may show more abnormal areas than a cervix showing CIN I.

Cytology

CIN II is also called moderate dysplasia. These changes are more severe than those seen in cells from a cervix with CIN I and they may be seen on microscopic examination of cervical cells. For example, there are more abnormal nuclei, especially in the more immature cells.

Risk of progression

Based on a review of the post-1950 literature that examined the natural history of CIN as a whole without taking account of the type of HPV causing it (Östör 1993), the probability of regression or progression from CIN II is:

• Regression: 43%
  
• Persistence: 35%
  
• Progression: 22%
  
• Progression to invasive cancer: 5%

These figures show that CIN II is a more serious condition than CIN I. The risk of progression has increased compared with CIN I, and the likelihood of regression is lower.

Currently, CIN II is usually treated with surgical excision or destruction whereas CIN I is often followed at regular intervals to establish whether it resolves spontaneously.


Cervical cancer disease progression: CIN III

Appearance

CIN III is the more severe pre-cancerous lesion of squamous epithelium involving severe dysplasia and carcinoma in situ.

Cytology

Microscopic examination of cells from a CIN III cervix shows severe nuclear abnormality in immature basal cells. Keratinisation or cornification may be present at the surface or in isolated cells inside the epithelium. Koilocytosis may also be observed in surface cells.

Risk of invasion

Based on a review of the post-1950 literature that examined the natural history of CIN as a whole without taking account of the type of HPV causing it (Östör 1993), the probability of regression or progression from CIN III overall is:

• Regression: 32%
  
• Persistence: <56%
  
• Progression to invasive cancer: >12%

These figures show that CIN I is almost twice as likely as CIN III to regress to a less serious level. In addition, the risk of CIN III progressing to invasive cervical cancer is further increased compared with CIN I or CIN II (Östör 1993).

Cervical cancer disease progression: carcinoma in situ

Once the disease has progressed to CIN III the disease may become clinically obvious and the woman may begin to experience symptoms such as bleeding and discharge, especially after sexual activity.

Invasive cancer

Several growth patterns are possible and are often visible on speculum examination.

• Early lesions may present as rough, reddish, granular areas that bleed on touch.
  
• More advanced cancers can be superficially invasive and grow into the lumen of the vagina as a mushroom or proliferating, bulging cauliflower-like growth.
  
• Others may grow inwards distorting the cervix, without much visible surface growth result, although the cervix may appear grossly enlarged, irregular and barrel-shaped, with a rough, papillary or granular surface.
  
• Symptoms may include vaginal discharge, bleeding and possible cramping.

Cervical screening is still the best method of preventing and identifying cervical cancer but it does not prevent infections with HPV, the necessary cause of Cervical Cancer