Cervical Cancer

Epidemiology of Cancers: Cervical Cancer

Description
There are 2 main types of cervical cancers;
Squamous cell carcinoma - accounts for 80-90% of all cervical cancers.
Adenocarcinoma - accounts for 10-20% of cervical cancers (and is becoming more common in women born in the last 20-30 years). 

Squamous cell cervical cancer has a distinct precursor detectable by cytologic screening (carcinoma in situ).

Adenocarcinoma, precursor lesions are less well defined and not readily detectable by cytological screening1.

Clinical Symptoms
Carcinoma in situ is commonly asymptomatic.

Invasive cancer of the cervix causes postcoital and spontaneous bleeding, discharge and discomfort during intercourse. In advanced disease, a variety of symptoms occur due to extensive local tumour growth and/or metastasis1.

Human Papillomavirus (HPV)
It has been shown that infection with High Risk HPV is a prerequisite for the development of cervical cancer1. Recent studies have shown that HPV-DNA can be found in 99.7% of all cervical carcinomas, with HPV types 16,18,45 and 31being the most frequent1.

An estimated half of all cervical cancers are associated with HPV 16 and 18. Women who have an HPV infection have an odds ratio of about 70 for the development of high grade cervical abnormalities3. The WHO have declared HPV16 and 18 as carcinogenic agents for humans.

Epidemiology

  • Worldwide cervical cancer is the third most common cancer in women.
  • The World Health Organization (WHO) estimate that 500,000 cases of cervical carcinoma occur worldwide each year, of which > 80% occur in developing countries.  Some of the highest incidence rates have been observed among women in Latin America, southern and eastern Africa and the Caribbean.
  • Worldwide an estimated 250,000 deaths from cervical cancer occur each year.
  • In the UK 2,841 new cases of invasive carcinoma of the cervix were diagnosed in 2002, making it the 12th most common cause of cancer in women2.
  • Since the late 1980s there has been an increase in the incidence rates of carcinoma in situ for women in England and Wales aged <30 and in women aged 30-34 since 19923.
  • However, incidence rates of invasive cervical cancer have generally shown a downward trend for all age groups since 1990. Age-standardised (European) incidence rates have decreased by 56% since 19753.  Much of this decline is likely to reflect the implementation of cervical cancer screening1.
  • Incidence varies by age, with peaks among women in their late thirties. late seventies and early eighties. The peak among women in their seventies and eighties reflect a cohort effect; women born in the 1920s are known to have high rates of invasive carcinoma of the cervix throughout their lives.
  • In 2004, 1,093 deaths from cervical cancer were registered in the UK, giving a European age standardised death rate of 2.8/100,000 females and a crude rate of 3.6/100,000 females3.
  • Mortality rates in 2004 were > 60% lower than they were 30 years earlier. However, age specific trends over a longer time period show differing trends by age and are explained by birth cohort analysis rather than analysis by year of death3. Women born at the end of the nineteenth century and around 1920 have a higher mortality rates for cervical cancer than for previous and subsequent birth cohorts. For women born between the  mid 1920s and mid 1940s mortality rates are lower. In contrast mortality rates are higher among women born after the 1940s, and may be explained by changing sexual behaviour since the 1960s3.
  • Overall, mortality rates for cervical cancer increase with age, with the highest number of deaths occurring in women >75 years. Less than 6% of cervical cancer deaths occur in women <35 years.

Risk Factors

Human Papilloma Virus (HPV)
Infection with specific 'high risk' subtypes of Human papilloma virus (HPV) is the most important risk factor for the development of cervical cancer.

However, the development of cervical cancer depends on a variety of co-factors that modify the risk among HPV-DNA positive women1,2. These include;

  • Young age at first intercourse
  • Multiple sex partners
  • Smoking
  • Multiparity (5+ full term pregnancies)
  • Long term use of oral contraceptives (> 5 years)
  • Previous exposure to other sexually transmitted infections.
  • Infection with HIV.

However, as many of these co-factors are strongly correlated with HPV infection, it is difficult to characterize their role in the development and progression of neoplasia, as well as in the acquisition and persistence of HPV infection1.

Prevention and Screening
The purpose of cervical screening is to reduce the incidence of malignant carcinoma of the cervix by detecting and treating cervical intraepithelial neoplasia (CIN). It is widely accepted that invasive carcinoma of the cervix is preceded bypre-malignant lesions which are benign.

Three different systems are used to classify cervical abnormalities1,3.

  • The WHO system involves histologic classification of cervical dysplasia as mild, moderate or severe, in addition to a separate category for carcinoma in situ (CIS).
  • Cervical intraepithelial neoplasia (CIN) was introduced by Richart to classify cervical lesions into 3 stages;

CIN 1 - mild dysplasia
CIN 2 - moderate dysplasia
CIN 3 - severe dysplasia or CIS

  • The Bethesda system from the United States, which is based on cytology and Pap smear readings, where low-grade squamous intraepithelial lesion (LSIL) corresponds to CIN and high grade SIL (HSIL) includes CIN2 and CIN3.

Screening programmes in the United Kingdom are based on cytological smears (Papanicolaou smears). The treatment of precancerous abnormalities of the cervix had been shown to be highly effective in the prevention of cervical cancer in HPV infectedwomen3.

Currently in the UK all women aged between 25 and 64 are eligible for cervical screening every 3-5 years under the NHS Cervical Screening Programme.

Age 25 - Invitation
Age 25-49 - Every 3 years
Age 49-64 - Every 5 years
Age 65+ - Women who have not been screened since age 50 or have had recent abnormal test.

Since 1998 the NHS Screening programme has operated a call and recall system for all women registered with a GP. 

Liquid-based cytology (LBC)
LBC places samples of cells taken from the cervix in a preservative fluid rather than being spread onto a slide. The advantages of LBC include a reduction in the number of inadequate specimens, improved sensitivity, and a possible reduction in specimen interpretation times.

LBC is currently being piloted in the NHS screening programme and is due for roll out by 2008.

HPV Testing
HPV testing as a primary screening tool has a higher sensitivity for CIN than cytology (86% compared with 60% for all grades of CIN and 93% compared with 73% for CIN2 and CIN3) but a lower specificity especially in young women (< 30 years old) who tend to have transient HPV infections4.

A review of the role of HPV testing with the NHS Cervical Screening Programme concluded that the most plausible role for HPV testing in the NHSCSP may be to guide the management of women with borderline or mildly dyskaryotic smears. As a result, a pilot of high risk HPV type testing is currently being conducted where women with borderline or mild dyskaryosis are being tested for high risk HPV. If found positive women are then referred for colposcopy4.

HPV Vaccines
In June 2006 an HPV vaccine (manufactured by Merck) was licensed by the United States Food and Drug Administration (FDA) for use in females aged 9-26 years. The vaccine protects against 4 types of HPV (including types 16 and 18 which areresponsible for an estimated 70% of cervical cancers) and types 6 and 11 that cause 90% of genital warts.

Development of the vaccine is considered particularly promising for use in developing countries where over 80% of cases occur and where national screening programmes for cervical cancer are absent.

References

  1. Bosch F, Iftner, T, The Aetiology of Cervical Cancer, National Health Service Cervical Screening Programme (HSCSP), Publication No. 22, September 2005. Available online: http://www.cancerscreening.nhs.uk/cervical/publications/nhscsp22.pdf
     
  2. Adami, HO, Hunter D, Trichopoulos D, eds. Textbook of Cancer Epidemiology, Oxford University Press: New York, 2002.
     
  3. Office of National Statistics. Cancer Statistics Registrations: Registrations of cancer diagnosed in 2003, England, Series MB1 No.34. 2005. Available online: http://www.statistics.gov.uk/downloads/theme_health/MB1_34/MB1_34.pdf
     
  4. Cancer Research UK: http://info.cancerresearchuk.org:8000/cancerstats/

Further Resources

NHS Cervical Screening Programme: http://www.cancerscreening.nhs.uk/cervical/index.html
http://www.jostrust.org.uk/links/Downloads-and-Materials/information

© CM Kirwan 2006