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

It is a sexually transmitted virus, which develops in mucosa and skin, and is related to Lower Genital Tract cancer: cervix, vagina, vulva and anus.

Currently, the genital infection caused by HPV (HPVI) represents the most common sexually transmitted disease worldwide. In addition to this, recent studies confirm that HPV is the causative agent of cervical cancer.

Approximately 80% of sexually active people have been infected with HPV at some point in their lives.According to epidemiological publications, 300 million HPV-infected women are considered worldwide.

HPV infection is very common. In the United States, every day, 17.000 new cases are presented.

Genital warts (condylomas) caused by HPV are highly polluting. Every year, 32 million new cases are presented worldwide. If you have sexual contact with a condyloma-carrying person, you have a 70% risk of being contaminated.

In developed countries, between 5% and 15% of the female population is HPV-carrying, this incidence in developing countries ranges from 10% to 15%. In Central America, this incidence is between 14% and 17%.

It is worth mentioning that between 5% and 30% of people who have HPVI are infected with two or more types of HPV.

Two years after the initiation of a woman’s first sexual relationship, the possibility of acquiring HPV is 70% and is more frequent during adolescence.

The prevalence of HPV is lower in men than in women. Less than 5% of the male population is a carrier of HPV. HPVI tends to be more transient in men than in women.

Every woman, sexually active, is predisposed to the spread of HPV and, as a result, to developing HPVI. However, the age at which HPV is most frequently acquired is during adolescence, with a peak up to 25 years. From this stage, there is a progressive and gradual descent of the incidence curve, as age increases.

HPV belongs to the Papillomaviridae family. It is a small virus (55nm in diameter), that contain DNA with three genetic regions: the early, identified as E, the late, identified as L and non-coding long control region LCR. The early region comprises 8 genes: E1, E2, E3, E4, E5, E6, E7, E8. The late region comprises two genes: L1 and L2.

Each of these oncoproteins have their own functions in the genesis of the precursor lesions and, as a consequence, in the development of invasive cancer, except the E5 which function only in animals.

Currently, about 200 HPV genotypes have been discovered and each virus has been assigned a number that identifies it, according to its chronological order of discovery. The first types of HPV discovered are 6 and 11, by the German scientist Lutz Gissmann, at the beginning of the 80s. Later, Dr. Gissmann -along with other scientists- discover types 16 and 18.

According to their potential to originate cancer (oncogenic risk), they are classified as high-risk and low-risk HPV.

High-risk HPV: 16,18,31,33,35,39,45,51,55,56,59,66,68.

Low-risk HPV: 6, 11, 26, 44, 54, 61, 70, 73.

The most frequent High-Risk HPVs are types 16 and 18, being responsible for 70% of cervical cancers. These types of viruses cause flat lesions in the cervix.

The most common low-risk HPVs are types 6 and 11, and have an affinity for mucosa and external genitalia skin, and are responsible for 90% of genital warts or condylomas.

With a better understanding of HPV DNA, other types of HPV 16-derived viruses have been discovered. They are called variants (identified by the name of countries or continents), one of which is the Asian-American variant, uncovered by Mexican scientist Jaime Berumen. This type of HPV variations present significant aggression in the genesis of cervical cancer.

Contamination with HPV is directly related to sexual contact. However, HPV needs to be associated with risk factors; To, subsequently, be able to develop HPV infection (HPVI).

FACTORS THAT FAVOR THE DEVELOPMENT OF THE HPVI:

  1. Sexual behavior:
    • Early age of first intercourse
    • Intercourse during adolescence
    • Multiple sexual partners
    • Partner’s promiscuous sexual behavior
  2. Deficient Immune Status:
  • Immunosuppressive disease carrier
  • Prolonged immunosuppressive treatments
  • Organ transplant carrier
  1. Smoking
  2. Multiparity (3 or more deliveries)
  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. High-oncogenic risk HPV

The main HPV transmission mode is direct contact: skin to skin or fluids to fluids contact. It usually happens during sexual intercourse through penetration. A person can be HPV positive after a single sexual contact. Although, more sexual contacts and different people increase the risk of infection. Other contamination forms can occur without penetration, either by oral-genital, manual-genital or genital-genital contact.

There is also non-sexual contamination of HPV types 6 and 11, in the nose and in the conjunctiva. In addition to this,  HPV 16 and 18-E6 gene incidence has been found conjunctival cancer cases.

There are reports that state that HPV can be transmitted through fomites (intimate clothing, sexual objects, or genital hygiene products or items). However, this form of contamination is rare, because HPV usually survives on skin or mucous membranes.

During pregnancy, transmission of HPV may occur, although it is not common. This transmission is known as vertical transmission. Three vertical transmission categories are known: 1-Periconceptional: previous period and immediately after fertilization 2. Prenatal: during pregnancy 3. Perinatal: during childbirth or, immediately, after the birth.

Perinatal transmission directly from mother to child, during childbirth, is the most frequent mode of vertical transmission.

Fortunately, these types of vertical transmission are temporary at most, with recovery during the first year of life. The newborn may develop oropharyngeal, genital area, or conjunctival lesions.

One of the most serious consequences of vertical transmission of HPV is the recurrent respiratory papillomatosis of juvenile onset.

There are also studies that report horizontal transmission, which consists of transmitting to infants or children, by hand, towels, during bathing with infected water, saliva or other means of contact. It should be noted that the horizontal transmission is unusual.

Corresponds from the time it takes since the person acquires HPV, to the development of the lesion. It is important to note that there is not a precise (or exact) time for this period due to its variability. It can start after 6 weeks from having acquired HPV, up to months, years and even decades.However, in most cases, the lesions will appear during the first year of HPV infection.

It should be mentioned that, as age increases in a woman, the systemic and local immunity of the cervix decreases, a factor to consider, from the elapsed period between acquiring HPV and the late expression (older) of the lesion of some cases. This stage is known as dormant stage.

The time that elapses since the HPV  contamination and the development of HPVI greatly depends on the immune system integrity of the person who has been infected; Since every woman has different integrity and immune strength.

During sexual contact, HPV penetrates the epithelium of the cervix with its virions (its infecting form) in an area known as the transformation zone. Usually, the cervix needs to be inflamed (glandular eversion), a cervix clinical state that facilitates the penetration of HPV. The virus is directed to the deepest layer of the cervical epithelium (basal layer) and causes the HPVI, subsequently, it will develop in the other layers of the cervical epithelium.

When a woman has contact with HPV, the following clinical scenarios may occur:

  1. To be in contact with HPV and not developing
  2. Having contact with HPV, developing HPVI and subsequently having spontaneous infection regression.
  3. Having contact with Developing HPVI, and subsequently remain in a persistence phase (presence of HPVI in the cervix for 2 years). Then, to enter the progression stage, causing precursor lesions that may have the possibility of becoming invasive cancer.
  • It is not possible to reliably predict which HPV infections will persist and which ones will have regression.

It is noteworthy that the different clinical scenarios presented in the presence of HPV in subsections 1. 2, and  3, depend on the risk factors that each woman carries.

Recent studies have shown that HPV is found in 99.9% of cervical cancer tumors.

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:

  • High-RiskHPV is carcinogenic in humans.
  • HPV is the causative agent of Cervical Cancer.
  • Carcinogenesis, of High-Risk HPV, is based on experimental evidence, which indicates that these viruses interfere with cell proliferation control.

We should bear in mind that HPV “is necessary, but not everything” that is needed to develop cervical cancer. Cervical cancer requires to be associated with the aforementioned risk factors, and it must develop subsequent stages until becoming an invasive cancer.

The mechanism of how HPV causes cancer is very complex; It is generated in its genome, which contains two oncoproteins –E6 and E7-, responsible for disabling p53 and pRb protective cervix oncoproteins, respectively, causing a loss of control, by negative feedback of the oncogenic viral expression (effect known as integration); This being a critical episode in the pathogenesis of cervical neoplasms.

IVPH does not cause symptoms, clinically it manifests with lesions in the stratified epithelium of the cervix, vagina, vulva and anus; Causing a phenomenon known as epithelial tropism (growth).

Lesions caused by HPV are presented in two forms:

  • Flat lesions: Usually in the cervix, and are of High Risk for cancer.
  • Exophytic lesions: Also known as condylomas or warts re present in vagina, vulva, perineum, perianal and rectal area. They have Low Risk of producing cancer.

The easiest way is by means of clinical evaluation when there are exophytic lesions or condylomas. Regularly, the patient is the one who detects them before the doctor, by means of visual inspection or by touch.

Flat lesions, which develop in the cervix and are high-risk, are more difficult to detect and require high-tech evaluation.

Currently, DIGITAL COLPOSCOPY is the ideal method to quickly and accurately detect lesions caused by HPV.

Colposcopy offers many advantages in patients with HPVI:

  • The diagnosis is immediate.
  • A sample is not required.
  • The extent of the lesion can be assessed.
  • It allows for cervix vagina, vulva and anus evaluation.
  • We can select the type of treatment.
  • The patient is involved during the study.

These advantages of Colposcopy are fulfilled as long as it is performed by a Colposcopy Certified Physician, supported by high-tech equipment.

There are also other studies to detect HPVI, such as exfoliative cytology (pap smear), but it has low sensitivity ( the ability of a test to detect an abnormality) and due to this, many studies are reported negative, even when there are HPVIs. The biopsy is another study that is performed and has greater sensitivity. In both studies, an epithelium sample is taken and sent to the laboratory to be evaluated by a pathologist.

There are modern molecular biology tests, including Hybrid Capture II and polymerase chain reaction (PCR)tests. A cervix sample is taken to be processed in the laboratory, for laboratorians to detect HPV DNA. These tests are more precise and have higher sensitivity, but with the disadvantage that they are very expensive.

These molecular tests are very useful in patients over 30 years, mainly for follow-ups of those patients treated for high-risk squamous intraepithelial lesions (CIN II, CIN III, carcinoma in situ).

With the current scientific knowledge of HPV and better accurate diagnostic tests, we can evaluate HPV conditions in various anatomical areas, through the following studies: COLPOSCOPY, VAGINOSCOPY. VULVOSCOPY, HIGH-RESOLUTION ANOSCOPY.

The role of HPV, as a cancer causative agent, in different anatomical areas is: in cervix 99.9%, anus 84%, vagina 70%, penis 47%, vulva 40%, oropharynx 36%, larynx 24% and oral cavity 24%.

Incidence of cancers per anatomical area:

  • Cervical Cancer: 529.000 cases per year
  • Vulvar Cancer: 26.800 cases per year
  • Vaginal Cancer: 200 cases per year
  • Anal Cancer:000 cases per year

When the HPVI is presented in two different anatomical areas simultaneously, It is known as a Multicentric Disease. The presence of these lesions can occur in the cervix, vagina, vulva and anus.

The development of HPVI in each of these anatomical areas increases the risk of cancer development.

In men, usually, the presence of HPV is more transient than in women, since they have an epithelial lining in their genital area that makes it less responsive to HPV and more resilient to developing the infection.  Although, there are men who can develop HPVI, with a maximum age prevalence rate between 30 and 39 years. It should be taken into account that men who have immune system afflictions, do have a high risk of developing HPVI.

HPVI in men may occur at the genital level by flat lesions or exophytic lesions (warts). These may be located in the glans, balanopreputial sulcus, foreskin, penis body, scrotum, pubic and perianal area, and very unusually, in the urethra.

In most cases, it is not necessary. The Colposcopist Physician, who made the HPVI diagnosis is the one who makes the decision of whether or not to test the man. There are indicators set that call for testing or not.

The study to evaluate the genital area of the man, in the cases of HPVI, is called ANDROSCOPY. This must be done by the Colposcopist Physician, who have been trained to carry out the procedure professionally.

The androscopy is carried out, based on scientific knowledge and pre-established methodology, with the help of state-of-the-art technology, allowing us to carry out the diagnosis and treatment in a precise and effective way.

Condom use only partially protects against HPV infection, even when the condom is used correctly. This is because the scrotum, perineum, pubic and anogenital areas, and other surfaces not covered by the condom can be infected.

Although we know that a significant percentage of HPV injuries may have spontaneous regression, there are clinical situations in which the decision to treat HPV-induced lesions is taken:

  1. In our region, most HPV are High-Risk and have the possibility of causing precursor lesions in the cervix, vagina, vulva and anus.
  2. Persistent lesions of certain types of HPV (two or more years in the cervix) have the potential to develop major clinical lesions (CIN II- CIN III) and develop into malignant lesions.
  3. The presence of extensive lesions in the cervix caused by HPV, in most cases have several years. This type of injury is more likely to progress to higher-degree injuries.
  4. The person carrying HPVI is potentially contaminant, mainly those with condylomas, as they will promote the spread of HPV.
  5. In our field, if patients with HPVI are included in a non-treat and only surveillance program; An important group will not comply with follow-ups because our countries do not have well-structured prevention programs that may promote the compliance of this strategy.
  6. The anxiety of the patient (and of the partner) when told this type of infection is present, has important emotional repercussions.

Nowadays, we have the knowledge and cutting-edge technology equipment that allows us to carry out the HPVI  treatment with practical, fast, ambulatory and accessible advantages.

It is worth mentioning that in developed countries they often opt not to treat low-grade squamous intraepithelial lesions (HPVI, CIN I) in favor of performing follow-ups only. However, these countries have well-designed prevention programs with excellent surveillance systems, supported by the socio-cultural aspects of patients. All of the above is very different from the reality of developing countries.

The current knowledge on the development of HPV-related injuries and evaluations with high-tech equipment, allows us to approach the lesions by means of precise and curative treatment, overcoming the disease.

  1. HPV has an affinity for mucosa and skin (it is mucotropic), so the development of HPVI is limited to the epithelium and not the blood, offering a favorable advantage for its eradication.
  2. The epithelium where the HPVI develops is very thin, so lesions are located superficially, allowing us to eradicate them in all their extent and depth.
  3. Currently, there is precise knowledge about the histological (epithelial) development of HPVI. In addition, we have the cutting-edge equipment and modern techniques, which allow us an innocuous (without hurting) and precise therapeutic approach (extension and depth).

Consistent studies have reported that evaluations in post-treatment patients, from lesions caused by HPV, have been free of disease (with negative findings of HPV DNA). It has been suggested that when there is a residual injury from HPV infection, after the procedure, is because the lesion was not completely eliminated due to improper treatment.

Throughout history, various procedures and drugs have been used to treat HPVI lesions: cryotherapy (frostbite), electrocution (burning) and caustics (acids), scalpel cones (cervix cutting), and hysterectomy (removal of the uterus). With the latest knowledge and new technologies advancement, all these procedures are currently obsolete.

Today, we have cutting-edge equipment, such as electrosurgical generators and adequate anesthesia, which allows us to perform ambulatory procedures, with excellent results. (see Electrosurgery icon).

To treat HPV-caused lesions, electrosurgery is currently the most modern and effective procedure.

The treatment approach with this technology is with done high precision, both in extension and in depth, allowing us to eradicate lesions in their entirety.

It should be noted that the success of electrosurgery, requires that it must be professionally carried a Certified Colposcopist Physician with appropriate experience and skill. To perform this procedure pre-established requirements are required. See Electrosurgery icon.

When women or partners are diagnosed HPVI positive, usually a difficult situation is created, generating many questions that may cause an emotional impact on one or both. This emotional disturbance tends to be greater in women.

The Colposcopist Physician is also trained to face this kind of situations and to have the disposition to provide advice for both. This orientation should be carried out in a professional way and must be based on knowledge and expertise in the subject, with the aim of providing counseling to completely overcome this situation, and conserve the marital and family integrity.

After Electrosurgery, the cervix recovers its anatomical and histological characteristics and its normal functions. However, three different clinical situations may manifest in the patient:

  • REINFECTION:

The protective immunity caused by HPV, after infection, is not complete or permanent, as is the case with other viruses. So, for future reference, the patient is still exposed to new HPV infections (reinfection). There are 14 types of high-risk HPV that can infect the lower genital tract, contaminate at different times, and cause cancer.

Monogamous sexual behavior (fidelity) in the couple is the fundamental basis for preventing reinfection.

  • RESIDUAL INFECTION:

It is the manifestation of HPV infection in any control over the course of the 12 months after receiving treatment.

  • RECURRENT INFECTION:

It is the presence of HPV infection, after the first follow-up year, since receiving treatment.

  • In most residual infection and recurrent infection cases, they occur in patients who were not treated by certified personnel or with obsolete and improvised procedures.
  • We must bear in mind that immunosuppressed patients are more likely to develop reinfection, residual infection, or recurrent infection.

There are currently two HPV vaccines. These vaccines are prophylactic ( to prevent or 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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