AUTHOR: DR. RAMÓN M. BOTACIO P.
Keywords:
HPV: Human Papillomavirus
HPVI: Human Papillomavirus Infection
DNA: Deoxyribonucleic Acid

Cervical cancer, due to its high incidence and mortality rate, is a public health problem in developing countries.  Currently, we have a better understanding of this type of cancer, its risk factors, the natural history of the disease: its onset, causal agent, phases of progression and regression, its different stages, and time of evolution, until its development into invasive cancer. Also, nowadays, we have modern diagnosis methods and timely treatment, making it an avoidable cancer.

Each year, at a global level, 530.000 new cases of cervical cancer are registered; approximately 275.000 of which die that very same year.

On a global scale, 3.4 million years of life are lost annually in the group of women who die before the age of 70 due cervical cancer.

Every death from cervical cancer that occurs before 70 years of age contributes to losing an average of 17 years of potential life.

Eighty-five percent of cervical cancer cases occur in developing countries, being one of the top mortality causes. In developed countries, these cases only correspond to 15%.

In America, 83.000 cases of cervical cancer are registered each year, 36.000 of which die, the same year. In Latin America, as in the Caribbean, it is the second leading cause of death for women in reproductive stage. This is also true in Panama. Although in some of these countries this type of cancer is the first mortality cause.

With the passing of time, the trend of the incidence rate of cervical cancer is lower in developed countries and larger in developing countries. If new effective strategies against this condition are not implemented, it is predicted that by 2040 we will have a million new cases per year.

Cervical cancer occurs in relatively young women, at reproductive age. Worldwide reports describe the age of invasive cancer diagnosis with the following percentages: only 0.2% before 20 years, 14.5% between 20 and 34 years, 26.1% between 35 and 44 years, 23.7% between 45 and 54 years, 20.00% between 57 and 64 years and 9.3% in over 65 years. It is worrying that the number of young women with a diagnosis of cervical cancer increases every year. In INACOLP, the highest incidence group correspond to women between 35 and 45 years of age.

The average age of women dying from cervical cancer is around 44 years in most studies reported worldwide.

With the onset of sexual contact, the woman is at risk of developing a natural history of cervical cancer, because there is the possibility of acquiring HPV (causative agent) during intercourse.However, for HPV to develop cervical cancer, it needs to be associated with other risk factors.

  1. Sexual behavior:
  • Early age of first intercourse
  • Intercourse during adolescence
  • Multiple sexual partners
  • Partner’s promiscuous sexual behavior
  1. Deficient Immune Status:
  • Immunosuppressive disease carrier
  • Patient with organ transplant
  • Immunosuppressive drug use
  1. Smoking
  2. Multiparity (4 or more deliveries antecedents)
  3. Oral contraceptives (consumption for more than 5 years)
  4. Nutritional deficiencies (vitamin A and C, folic acid)
  5. Cervix with glandular eversion (inflamed cervix)
  6. Genetic family history of cancer

In the early 1980s, the German scientist, Dr. Lutz Gissmann, discovered the first papillomaviruses, types 6 and 11; a historical incident for humanity. This discovery allowed him to study the genomic material of HPV to, later -with his teacher- Dr. Harold Zur Hausen, demonstrate that HPV is the causative agent of cervical cancer. They were are awarded a Medicine Nobel Prize for this groundbreaking research.

In 1995, the International Agency for Research on Cancer (IARC), through a research paper on the risk assessment of HPV carcinogenesis in humans, published the following: HPV is the etiologic agent of cervical cancer.

The natural history of cervical cancer begins when a woman acquires HPV during sexual contact. HPV penetrates the epithelium of the cervix with glandular eversion, coated with immature metaplasia (inflamed cervix).

When the HPV penetrates into the cervix, it is directed to the deeper layer (basal layer), and then reproduces in its other three layers. At that time, HPV DNA enters the episomal stage (in a circular or out-of-chromosome form) and then enters into the integration phase (when the HPV DNA is integrated into the host cell DNA).

When HPV is found in the epithelium of the cervix in the integration phase, three characteristics are present so that HPVI may advance to subsequent stages: persistence, which is the presence of HPV in the cervix for 2 years; and progression, which is when the HPV DNA integrates with the DNA of the host cell (in the cervix), with the possibility of advancing to the transformation stage, until causing invasive cancer.

 

The natural history of cervical cancer is characterized by the gradual succession of preinvasive intraepithelial stages and the advancement to the invasive stage and are as follows:

  1. Human Papillomavirus Infection
  2. Grade I cervical intraepithelial neoplasia (mild dysplasia)
  3. Grade II cervical intraepithelial neoplasia (moderate dysplasia)
  4. Grade III cervical intraepithelial neoplasia (severe dysplasia)
  5. Carcinoma in situ
  6. Invasive carcinoma

The concept of cervical intraepithelial neoplasia or dysplasia is represented by alterations in cell proliferation and maturity, resulting in atypical (abnormal) cellular changes. These cellular changes are found within the epithelium of the cervix, protected by the basal membrane (protection layer), which, while remaining intact, prevents it from advancing to the invasive carcinoma stage.

Squamous intraepithelial neoplasia Grade III (CIN III/Carcinoma in situ) has been established as the immediate precursor of invasive cancer.

The time elapsed since the onset of the lesion caused by HPV, until evolving into CIN III/carcinoma in situ is approximately 10 years.

During the stage of CIN III/carcinoma in situ the basal membrane is integrated, when there is rupture of this membrane, the lesion is classified as an invasive stage, with a substantial change in the prognosis and quality of life of the woman. The time required since the beginning of the first HPVI Mild-Lesion Dysplasia until developing into invasive carcinoma ranges between 10 and 20 years.

It is known that when an intraepithelial lesion appears in the cervix, invasive cancer will not always develop. Each woman has a proper protection condition for the advancement or regression of the disease. This protection depends, to a large extent, on the risk factors that each woman are carrying. It is considered that up to 80% of the lesions in the cervix may have regression. However, the remaining 20% of the disease’s progression is caused due to high rates of cervical cancer in developing countries.

There is a worldwide classification of the different stages of the cervical cancer natural history. The classification is a nomenclature that allows for a universal language to identify each stage, through Cytology, Histology and Colposcopy reports.

Currently, world level classification used is the BETHESDA 2001, as follows:

  1. Low-Grade Squamous Intraepithelial Lesion:
  • Human Papillomavirus Infection
  • Grade I cervical intraepithelial neoplasia (mild dysplasia)
  1. High-Grade Squamous Intraepithelial Lesion:
  • Grade II cervical intraepithelial neoplasia (moderate dysplasia)
  • Grade III cervical intraepithelial neoplasia (severe dysplasia)
  • Carcinoma in situ.
  1. Invasive cancer:
  • Squamous cell carcinoma
  • Adenocarcinoma
  • Adeno-scaly

This classification is based on the affection degree in the cervix epithelium thickness:

  1. Grade I Cervical Intraepithelial Neoplasia
  • The lesion implicates a third of the epithelium.
  1. Grade II Cervical Intraepithelial Neoplasia
  • The lesion implicates two-thirds of the epithelium.
  1. Grade III Cervical Intraepithelial Neoplasia
  • The lesion implicates more than two-thirds of the epithelium.
  1. Carcinoma in situ
  • The lesion implicates all the thickness of the epithelium.
  1. Invasive carcinoma:
  • It is when there was rupture of the basal membrane and the lesion implicates the stroma, tissue, blood vessels, and lymphatics and adjacent organs.
  • When the lesion has spread to other organs, it is known as

Usually, during the development of the different stages of the natural history of cervical cancer there are no symptoms (it is asymptomatic); Even when it reaches the stage of invasive cancer, it can remain unnoticed for many years.

When the signs or symptoms are present, it is almost always an advanced invasive cancer. Abnormal vaginal bleeding (bleeding that is not during menstruation) is a common sign of alarm that may occur during or after intercourse, and may be scarce or intermittent, and may be associated with bad odor secretion. In terminal phase (very advanced stage of cancer) there may be considerable vaginal bleeding, severe pelvic or lumbar pain, loss of appetite, weight loss, severe anemia, edema (swollen legs), and bowel and bladder functions endangerment.

Premalignant and malignant changes in the cervix in early stages cannot be seen at first sight. High-tech tests are required to perform timely diagnosis and treatment.

The most accurate method for early detection of small lesions in the cervix is Colposcopy, which must be performed by the Colposcopy Certified Physician who, with knowledge and experience, may diagnose the 5 development stages prior to invasive cancer.

One of the important Colposcopy advantage, backed by knowledge and cutting-edge equipment, is that it allows us to take a complete and reliable sample of the cervix, for the histopathological study to yield accurate results, and corroborate premalignant or malignant lesion diagnosis.

Exfoliative cytology (pap smear) is the most widely used study for the detection of precancerous cells and invasive cancer. It consists of taking a cervix sample, extending it into a glass slide and processing it in a laboratory. However, the sensitivity ( the ability of a test to detect the disease) is low and, often, does not accurately detect abnormal cells.

In order for exfoliative cytology to be effective, the human resource taking and processing the sample is required to be trained and updated, in addition to laboratories meeting quality control requirements and first class required categories. These requirements are usually met by prevention programs of developed countries, with trained personnel, high-tech equipment, and systematic work schemes. In these countries, Pap smears have contributed to lower cervical cancer incidence and mortality.

Currently, there are several modern studies that contribute to the prevention of cervical cancer: liquid-based cytology, molecular biology tests to detect HPV (PCR, Hybrid II capture) and immunohistochemistry, which is an innovative study that can emit a prognosis of precursor lesions that can advance into invasive cancer (p16 – Ki 67).

In 1991, the World Health Organization (WHO) referenced that the most effective strategy to counteract increasements in the incidence of cancers is prevention.

Countries with high rates of cervical cancer incidence and mortality do not have well-structured prevention programs and do not meet proposed goals and aims.

 The main weaknesses of these programs are the following:

  • Not having Cervical Pathology and Colposcopy specialized human resources.
  • Limitation in human resources responsible for processing the cervical pathology sample.
  • Lack of Specialized Reference Centers for the quick and efficient care of patients requiring timely diagnosis and treatment.
  • Reference Centers with shortages of high-tech equipment, instruments, and supplies demanded by procedures and quality control.
  • Failure to update Prevention Norms, which must be structured by colposcopy and cervical pathology trained human resource, which will strengthen the program with standards whose content is scientific and up-to-date.
  • Not having a Systematized Prevention System (organization).

Countries with organized and effective cervical cancer prevention programs have: specialized human resource with working spirit, cutting-edge reference centers, Modern Laboratories and quality control, presenting low incidence and mortality rates.

There are currently two HPV vaccines. These vaccines are prophylactic (to prevent and avoid) and are structured against HPV. Its principle is based in that the woman who has already received the vaccine in due form, when having contact with HPV, will not develop the infection, so she will not present precursor lesions and, as a result, will not develop cervical cancer in the future.

Currently, it is understood that this vaccine can also prevent other types of cancer, such as in the vagina, vulva and anus regions where HPV may produce carcinogenesis.

In 2006, the Food and Drug Administration (FDA) in the United States approved the first HPV vaccine, the TETRAVALENT VACCINE, structured against 4 types of papillomavirus: 16 and 18 (cervical cancer producers), 6 and 11 (genital warts producers). The application scheme for this vaccine is 3 doses: day 0 (first dose), at 2 months (second dose) and at 6 months (third dose).

In 2009, the FDA approved another HPV vaccine, the BIVALENT VACCINE, structured against 2 types of papillomavirus: 16 and 18. The application scheme for this vaccine is 3 doses: day 0 (first dose), at 1 month (second dose) and at 6 months (third dose).

Currently, both vaccines are approved approximately in 100 countries and are included in their cervical cancer prevention programs.

For several years, there have been multiple clinical trials that have analyzed the safety of these vaccines. These studies report that both HPV vaccines are safe and that adverse effects, by vaccine doses, were similar to those found in other vaccines.

Currently, a new vaccine, the NONAVALENT, is already in some countries. It is a prophylactic vaccine, structured against 9 types of papillomavirus: 6, 11, 16, 18, 31, 33, 45, 56 and 58.

The HPV vaccines proposal is a major contribution to the prevention of cervical, vaginal, vulva and anus cancer, and favorable results have already been presented.

The future rests in the elaboration and presentation of prophylactic and therapeutic vaccines against HPV, which will contribute to the prevention and eradication of cancers originated by this virus in a broader way.

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