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HUMAN PAPILLOMA VIRUS [HPV] AND ITS ROLE IN FEMALE CANCERS.

INTRODUCTION

For the purpose of this article the focus will be on the relevance of HPV and cancers of the female genital tract and specific cancer of the cervix.

A brief review on the HPV itself, diagnosis, prevention and its role in the aetiology of cervix cancer, as well as treatment, will be given.

The burden of HPV as one of the most common viral infections on this planet is well known.

Up to 50% of the female population in third world countries will be infected by the papilloma virus in their lifetime.

The frequency of HPV infections is highest among woman younger than 25 because of early age of sexually activity started.

The clearance of the virus before the age of 30 is well known and therefore the majority of women infected will not develop cervical carcinoma or established pre-cancerous lesions.

Cervix cancer still remains one of the most common female cancers in the world and especially in developing countries where screening for the prevention of cervix cancer as well as vaccination programs remain inadequate.

HPV as a cause of cancers of the vulva, vagina, upper respiratory tract and throat, tonsils and penile cancers as well as anal cancer is well established.

It is also known to be the cause of benign disease such as skin warts and anal-genital warts.

There are up to 200 serotypes of HPV viruses. In terms of cervical cancer it is classified as low risk viruses and high risk viruses responsible for cervix cancer and its precursors.

Until the early 80’s, the aetiology of cervix cancer was unknown and unproven.

Thanks to the research of the 2008 Nobel Prize winner, Dr Harald Zur Hausen, of the University of Freiburg, Germany, HPV as the cause of cervix carcinoma was established in 1987.

Zur Hausen started his work in the 1970’s to be able to prove the existence of HPV 16 and 18 as a cause of cervix carcinoma in 70% of cases.  The rest of the so-called high risk HPV viruses as a cause would soon follow.

THE VIRUS

HPV is a small double-stranded DNA virus that is sexually transmitted between male and female. It is the most common sexually transmitted disease in the world.

It belongs to the Papillomaviridae family and is categorized accordingly to Hi risk and Low risk viruses. Numbers 16/18/ 45, 31, 52, 58 and a few others are among the Hi risk viruses that are oncogenic or cancer-causing viruses.

HPV 6 and 11 is responsible for vulva benign warts called Condylomata Acuminata.

The virus targets the so-called transformation zone of the cervix. The transformation zone is the junction between the ectocervix and the endocervix.

The virus infects the metaplastic cells of the transformation zone of the cervix.

HPV DNA is incorporated into the DNA of these cells. The virus then persists in those infected cells.

Persistence of the virus is dependent upon a weakened immune response, the HPV type and the viral load and cofactors such as sexual activity and smoking.

HPV DNA integration into the nucleus of the host cell leads to the expression of E6 and E7 onco-proteins that leads to an increased risk of disease.  Progression of these persistently infected cells/epithelium leads to cervical pre-cancer that are called high grade intra-epithelial neoplasia [CIN2/3].

After the CIN3 stage of this premalignant condition, invasion through the basement membrane will lead to invasive cervical cancer after many years or even decades in some cases.

It is important to understand that there is no anti-virus drug available to eradicate HPV infection. Prevention is through vaccination at an early age and through practising safe sex. Elimination of the virus can take place by means of the patient’s own immune system.

The window of opportunity for cervical cancer prevention is therefore vast, and in my opinion probably the most preventable cancer in the female population.

This is possible as demonstrated in first world countries such as Sweden where vaccination protocols and strict effective screening protocols and treatment of pre-malignant lesions are followed.

SCREENING FOR PRE-MALIGNANT AND MALIGNANT LESIONS OF THE CERVIX.

Since the 1950’s it has been proven that Pap smears can reduce the incidence of cervix carcinoma by more than 50%.

The sensitivity of the Pap smear to identify premalignant lesions and HPV infection of the cervix depend on the quality of the smear taken by the health worker and whether the ectocervix and endocervix cells are sampled.  It also depends on the training and expertise of the Cytologist.

Identification of HPV infection is determined on the detection of koilocytes cells as described by Zur Hausen.  It is important to remember that most HPV infections will be asymptomatic even for premalignant lesions up to stage CIN3 as caused by the virus.

Post coital vaginal bleeding might be a nonspecific sign of a high grade lesion or infiltrative carcinoma.  Once pelvic pain, foul smelling vaginal discharge or abnormal vaginal bleeding is present the patient might already have an infiltrative carcinoma of the cervix.

Only genital warts caused by HPV 6 and 11 will generally be clearly visible by the patient.

Table 1

The data is from a USA study that shows how the incidence of cervical carcinoma was reduced by Pap smears screening alone.It is estimated that a total of 105 000 cancers were prevented given the prevalence of 15 per 100 000 patients.In previous years with an incidence of 30 per 100 000 patients it was estimated that 492 000 cases were prevented with Pap smears alone.

Summary of overall changes in cervical cancer incidence and cases prevented:

 

Annual cancer incidence (cases per 100,000
women)
Estimated cases prevented
Three
decades ago
(1976–1978)
Current
(2007–2009)
Change From baseline
incidence
From pre-
screening
incidence
Early-stage cancer incidence 9.8 4.9 −4.9 84,544 N/A
Late-stage cancer incidence 5.3 3.7 −1.6 20,647 N/A
Cases prevented over 3 decades: 105,000 492,000

The aim of screening programs is to detect premalignant lesions, CIN2 to CIN3 as caused by HPV.  To detect precancerous lesions it is the ideal in terms of treatment and 100% cure to prevent infiltrative cancer.

Once infiltrative disease is diagnosed, the cure with more complex treatments depends upon the stage of cervical cancer.The morbidity and mortality are determined by the stage of the disease classified from stage 1 to stage 4.

Screening for HPV infection with a more sensitive test namely PCR is propagated since 2014. It can be used as the primary screen method to identify the patient with a HPV infection from the age of 25 and those that already has a High grade lesion.

Very often the cytology will be normal but the HPV PCR is positive on the same sample for High grade viruses such as HPV 16 or 18.  This can be so because the virus has not yet changed the cells to CIN2 – 3 or the koilocytes cells were not identified by the cytologist.  PCR screening is freely available in private practice in RSA and in first world countries such as the USA.

As previously said, in a significant proportion of patients the virus will disappear spontaneously.

To identify the patient where the virus persists [especially HPV 16 and 18] or where other High risk viruses are present, will lead to further testing to identify a possible CIN2 to CIN3 lesion.

This is done by means of Colposcopy in the office of a Gynaecologist.  Abnormal lesions fromCIN1 to CIN3 are identified by using a 5% acetic acid solution on the cervix or Lugol’s iodine. Under magnification the abnormal area is identified and a small biopsy is taken.This is then sent to a pathologist that will confirm it as a low grade or high grade lesion.

Treatment in the form of a LLETZ cone biopsy is usually done for high grade lesions under general anaesthesia or under local anaesthesia in some settings.

These patients need yearly follow up for life to detect any recurrence of a lesion.

PREVENTION IS BETTER THAN CURE– HPV VACCINES

In this age of vaccination and the prevention of cervix cancer and premalignant lesions this has further been made possible by the development of HPV vaccines.

The diagram above clearly demonstrates the advantages of early vaccination.  Age 12 or earlier vaccination leads to a High antibody response that will protect girls and women once they start sexual activity.  It has also proven beyond doubt that HPV vaccines protect against the development of high grade lesions of the cervix.  Screening in vaccinated women still needs to continue as per protocol.

Apart from preventing infiltrative carcinoma, vaccination also reduces colposcopy examinations, the need to do biopsies and invasive procedures such as cone biopsies of the cervix.

Since 2006 HPV vaccines have been developed.

  • Cervarix and Gardasil are the main groups available.
  • Cervarix protects against HPV 16 and 18 and can be given to girls aged 15 or earlier in 2 doses.
  • Cervarix has a 91% efficacy if given to women after the age of 25, lasting at least 7 years.
  • Gardasil protects against HPV 16 and 18 as well as type 6 and 11, responsible for genital warts.
  • Gardasil 9-valent vaccine is now available to protect against 9 strains of the HPV.
  • Cervarix and Gardasil 9 gives the same protection against HPV 16 and 18 that last for at least 10 years.

CONCLUSION

Since introduction in 1941 of the Pap smear, originally developed by Georgios Papanikolaou, the incidence of Cervix carcinoma was drastically reduced.

However due to limitations in screening programs, the less than optimal sensitivity of the Pap test, still thousands of women dies yearly due to this disease.

Lack of education and information to the female population results in ignorance and avoidance of being part of the screening programs.

Opportunities missed such as screening not done by primary health care workers or screening not done at the 6 weeks post-partum visit, contributes to this problem.

Over the years I have seen patients that presents with less and more advanced infiltrative cervical carcinoma with good and bad outcome.

Most of them never had a Pap smear and all of these patients had one thing in common, namely a diseases that was potentially completely preventable.  All of them had a pre-malignant lesion for many years that was 100% curable.

With the introduction of primary HPV screening and widely accepted HPV vaccination programs in first world countries the incidence will further decrease.

In third world countries with lack of resources this will be difficult to obtain.

Dr. Louis L. Du Toit

Gynaecologist/Obstetrician

Emuleni Medi-Clinic

Block A

Vanderbijlpark

Gauteng

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