QUESTIONS AND ANSWERS

Cervical cancer is a malignant tumour that arises on the cervix. The cervix is a part of the uterus that is very easily accessible for examination and where any changes can be seen with very simple methods.

Every year in Europe, almost 60,000 women get cervical cancer, and around 30,000 women die from this disease. Cervical cancer most often occurs in younger women, between the ages of 35 and 50. In Serbia, cervical cancer ranks third, after breast cancer and colon cancer, and accounts.

Considering the number of women suffering from cervical cancer, Serbia has been among the first few countries in Europe for several years, with around 1,200 new cases per year. In 2002, Serbia had the highest incidence of cervical cancer (27.3 cases per 100,000) in Europe. For almost two decades, it was at the top of the morbidity table together with Romania, Bulgaria and Lithuania. According to the latest Globocan data from 2022, Serbia is now in eighth place in terms of incidence (13.4 per 100,000 women). However, this incidence is still higher than the average incidence rate in Europe (10.6 per 100,000). The death rate is almost twice as high as the average in Europe and is 6.3 per 100,000 women. In countries that have successfully organized screening, this number is between 1 and 2 per 100,000 women.

There are large varieties in morbidity and mortality from cervical cancer among different parts of Serbia. The latest data from the National Cancer Registry from 2019 show that out of the 18 regions of central Serbia, in the Zaječar, Moravica, Nišava and Kolubara regions, the standardized incidence rates are higher than 20 per 100,000. The highest incidence of even 35.2 per 100,000 women was recorded in Bor region. Once with the highest incidence rate (41.6 per 100,000), the Braničevo region, where the first pilot program of organized screening was successfully implemented, now has an incidence of 13.4 per 100,000. In Vojvodina, the highest incidence of cervical cancer was recorded in Srednje and North Banat District, as well as North Bačka. The average mortality rate in Serbia is 6.5 per 100,000 women and it has not decreased for a long time.^.  

Infection with the Human Papillomavirus is necessary for the development of cervical cancer. This is a widespread sexually transmitted infection which especially affects younger age groups. It is believed that around 80% of people get an HPV infection at least once in their life. The most important thing to know is that this infection in a healthy person is transient, like most other viral infections. Only a small number of women who do not spontaneously eliminate the virus can develop the disease, and this is a consequence of weakened immunity, smoking, hormonal contraception or genetic factors. That is why HPV is considered the most important, but not sufficient factor for the development of cervical cancer.

Cervical cancer develops gradually, from premalignant changes called dysplasia or cervical intraepithelial neoplasia (CIN). This period lasts several years, which gives a lot of time to detect not only malignant disease, but also premalignant changes, which are successfully treated with simple methods. These methods involve removal of part of the cervix, after which it is possible to carry out pregnancy and childbirth normally. This is very important, because cervical cancer most often occurs in younger women, between the ages of 35 and 50. Every fifth woman who is diagnosed with this disease is still in her reproductive period and many of these women want to give birth. Unfortunately, if the disease is not diagnosed at a very early stage, the treatment implies the loss of the possibility of childbirth, the treatment becomes more difficult, and its success is less guaranteed.

Human papillomavirus (HPV) infection is the most common sexually transmitted disease, with a prevalence of 10-11% in the population of women with normal cytological findings. About 80% of sexually active people have had HPV at some point in their lives. The probability of transmission after just 1 intercourse is 60%, unlike HIV where it is only 1-2%. The prevalence of HPV infection is highest in adolescent girls and women under the age of 25, in some populations it reaches 50%. The natural course of the infection is spontaneous elimination, so after 35 years of age the prevalence decreases to below 5%.

HPV positivity does not mean cancer, or even pre-cancer. Most HPV infections are transient and disappear spontaneously within two years in healthy people.

To date, more than 150 types of human papillomavirus have been identified, of which about 40 have a tendency to infect the genital region of both men and women. Genital HPV is usually sexually transmitted and is easily passes from one person to another through any skin-to-skin contact, not just sexual intercourse. In most women who are infected with the HPV virus, the immune system will create antibodies and overcome the viral infection within 6-24 months. Once antibodies to HPV are created, the risk of getting cervical cancer goes back to normal. However, a small number of women still fail to overcome the infection and these women have an increased risk of developing cervical cancer later in life. This happens in cases of weakened immunity, in women who smoke, take hormonal contraception or have such a genetic predisposition that it is difficult to spontaneously eliminate the virus.

HPV infection leads to the appearance of genital warts, as well as premalignant and malignant lesions, primarily in the cervix, but also in other parts of the anogenital region. Genital types of viruses are divided into two large groups:

• Low-risk types (most common HPV 6 and 11) do not integrate into the host's genome. They most often cause benign genital warts (90%) and only in 10% of cases mild grade dysplasia (CIN 1) which is not considered precancerous, and which disappears spontaneously in more than 70% of cases.
• High -risk types (HPV 16,18, 31,33,35,52,58), if it is a long-term infection and additional risk factors are present, can be incorporated into the cell's genome and lead to changes. These types of viruses are found in 50-60% of high-grade lesions (CIN 2 and CIN 3) and 70% of cancers. High-grade changes (moderate and severe dysplasia CIN2 and CIN 3) are considered precancerous. About 30% of these changes can progress to cancer and since there is no test to determine in which women this will happen, severe lesions are removed with small surgical interventions (conization).

Cervical cancer will not develop if there is no long-term HPV infection. In order for HPV infection to lead to cervical cancer, other factors are necessary, the most important of which are smoking, an impaired immune system, taking oral contraceptives, associated other sexually transmitted infections, and genetic factors. The process of carcinogenesis lasts 10-15 years, which gives plenty of time for regular examinations to detect changes.

Defence against the virus is not general, but local, on the cervix. Natural infection causes a weak immune response. The level of natural antibodies is low. Local immunity is impaired by smoking, other infections, oral contraception... This is what the vaccine is based on - it gives a higher titter of antibodies in the blood, and those antibodies pass into the epithelium/cervical mucus, the titter is 10-10,000 times higher IgG than in relation to a natural infection. These are type specific antibodies. The level of antibodies at the age of 9 to 13 years is much higher than after 15 years. HPV cannot be cultivated under artificial conditions and therefore it has been difficult to make a vaccine. The vaccine against infection with human papillomaviruses was introduced in 1991, and since 2006 it has been used in the field. It is important to know that it is a prophylactic vaccine that prevents infection with certain types of viruses for which it was made and has the best effect if it is given before the start of sexual activity. This vaccine cannot cure an existing HPV infection.

It is not easy to obtain the proof of the effectiveness of the vaccine for HPV-related cancers, because of the long period from infection to the onset of cancer, 8-15 (20) years. It is calculated that it can prevent 70% of cervical, 80% of anal, 60% of vaginal, 40% of vulvar and a number of cancers of the oropharyngeal region. For now, it is only a prediction, because there is still no strong scientific evidence that the vaccine prevented the occurrence of all these types of cancer. 

The best way to prevent the development of cervical cancer is regular examination. Regular examinations of women who do not have any symptoms are called screening examinations. The English word screening means preventive medical program that examine the population of apparently healthy people, in order to find those who show early signs of a disease or a predisposition towards the onset of a disease.

The goal of screening for cervical cancer is to reduce the number of cases and deaths from this preventable disease. In addition, early detection and more successful treatment significantly improves the quality of life of women, enables future births, and from an economic point of view, treatment costs are reduced many times over.

Diagnosed in the early stages, cervical cancer is curable. Unfortunately, a large number of our women consult a gynaecologist for the first time when the disease has already developed and when the treatment is difficult and uncertain. Therefore, the most important part of the fight against cervical cancer is the implementation of organized screening. In countries where screening is well organized, such as England, the number of women suffering from and dying from cervical cancer has decreased by more than 80%.

A Pap test is used for screening. This test consists of taking a swab from the cervix, which contains cells from the surface of the cervix. The sample is then sent to a laboratory where it is analysed under a microscope to look for cells that have abnormal changes. Most women have a normal Pap test result. In these women, the risk of cervical cancer is low. A number of women жена има абнормалан резултат Папаниколау теста. This means that cells that show some changes were found in their smear. Any abnormal results require follow-up. Depending on the results, either a repeat Pap test in three to six months, or a colposcopy, a detailed examination of the cervix with a special type of microscope to view the surface of the cervix under magnification, is advised. Some changes that are revealed by additional examinations should be removed so that they do not turn into cancer. A simple treatment that can usually be performed on an outpatient basis is usually sufficient. Such interventions rarely affect a woman's sex life or her ability to have children.

In recent years, countries where cytological screening has been successfully implemented for several decades are now switching to screening with the HPV test for women aged 35 to 65 years. It is considered that, if the HPV test is negative, the risk of cervical cancer is small and that the next test can only be done after 5 years.

However, in Serbia, due to the large number of patients, at the moment, it is not possible to rely on HPV screening only. In addition, screening for women under the age of 30 is still done with cytology as the primary test. Also, it is known that there are 10% of HPV-negative cancers of the cervix, which is why the WHO has included HPV-negative cancers as a special category in the histolgical terminology. For now, it would be ideal to do a co-testing with cytology and HPV test.

Cancer is rarely found in women who go for regular check-ups.

Neither premalignant lesions nor initial cervical cancer give any symptoms which may indicate that something is happening in the body. Therefore, the only way to detect this disease at an early stage of development is a regular gynaecological examination. The basic diagnostic test is the Pap smear. With this test, changes can be detected in the cervical cells, that still do not cause any problems.

All patients who have an abnormal Pap test or a clinically suspicious cervix are referred for colposcopy. Colposcopy can detect changes and determine the place where a biopsy should be taken. A tissue sample is sent for pathohistological examination, which leads to a final diagnosis.

Diagnosed in the early stages, cervical cancer is curable in virtually all cases. The treatment is simple and does not leave any consequences for future life and childbirth.

If cervical cancer continues to develop, symptoms that may appear are:

• Pain in the pelvis
• Bleeding after the intercourse
• Упоран сукрвичав вагинални секрет

If you notice any of these symptoms, you should immediately consult a gynaecologist.

Early detection and treatment of preinvasive cervical changes has led to a significant reduction in both the incidence and mortality from invasive cervical cancer.

It is necessary to explain the importance of taking a cytological swab to a woman, especially one who comes to screening for the first time, and to help her understand what she can expect during taking the swab, when she will be informed about the result and what the next steps could be in the event of an abnormal finding.

A smear for cytological examination is taken with a wooden spatula from the outside of the cervix (ectocervix) and with an endocervical brush from its inside (endocervix) or with a specially designed brush that simultaneously obtains a sample from both parts of the cervix.

An atypical cytological finding indicates the possible presence of a neoplastic lesion which, if not treated, could progress into a life-threatening malignant disease. In women with low-grade lesions, there is a high probability of spontaneous regression, which is why they do not necessarily need treatment. Cytological suspicion of high-grade lesions carries a significant possibility of the existence of severe dysplasia, which has a high risk of progression to cancer. Women with such cytological findings must be immediately referred for further diagnostic and, if necessary, therapeutic procedures.

All patients who have an abnormal Pap test or a clinically suspicious cervix are referred for colposcopy. Its goal is to find out where the atypical cells come from and to find the exact place of the lesion, from which a biopsy is taken. A tissue sample is sent for pathohistological examination, which leads to a final diagnosis and determines the further procedure.

For decades, it was considered that all dysplastic changes of the cervix have malignant potential. Today it is clear that in the spectrum of pathological findings of the cervix - cervical intraepithelial neoplasia (CIN), the line between premalignant and benign lesions can be set between CIN 1 and CIN 2/CIN 3. These two groups of CIN are described as high-grade squamous epithelial lesions ( H-SIL), to distinguish them from low-grade lesions and HPV-induced changes (L-SIL).

Low-grade lesions (L-SIL), are an expression of HPV infection rather than true neoplasia, are most often detected in young women, have a low risk of progression and spontaneous regression in more than two thirds of patients. In these cases, observation without active treatment is the preferred option.

In women with more severe lesions (H-SIL/CIN 2 and 3), there is a significant risk of disease progression to invasive cancer and they should be treated. The only exception to this general rule are women who are pregnant and very young patients with CIN 2, which at this age also has a high potential for spontaneous regression.

Premalignant lesions of the cervix can be treated, depending on the findings, with different techniques based on ablation (destruction of tissue) or excision (removal of tissue).

There is no clearly superior conservative surgical technique for the treatment of CIN. This means that both main treatment modalities: ablative and excisional techniques, have almost the same outcome. There are, however, clearly established criteria for using an ablative or excisional technique and the decision to choose one of them is based on colposcopy.

Ablative techniques are acceptable only when the entire cervix and the entire change is visible and there is no evidence of the existence of an invasive disease, if there is no discrepancy between the cytological, colposcopy and histological findings and when there was no previous treatment.

Excisional techniques are traditionally used knife-conization, laser conization and excision of the transformation zone with a loop. They have an advantage over the ablative approach, because they enable pathohistological verification of changes and insight into the extent of resection (status of resection margins).

Excision should always be used when the changes are not visible in their entirety, if they are large in size and grade, when there is a discrepancy between cytology and colposcopy, and if the woman has previously had treatment.

Even in cases where treatment does not end with this procedure, it still represents an indispensable step in establishing a definitive diagnosis, as it has greater sensitivity and specificity compared to biopsy. This type of intervention has a special value in the treatment of young patients who have not realized or completed their reproductive function. It is of the utmost importance to assess whether operative treatment is really necessary. There is evidence that the treatment of CIN does not negatively affect fertility and the possibility of remaining pregnant but depending on the type and extent of the intervention, it may be associated with a higher frequency of premature rupture of membrane and premature births. Because of all these effects that CIN treatment can have, women who want to give birth should be informed about the possible risks associated with cervical excisional treatment.

The basic methods used in the treatment of cervical cancer are surgery, radiotherapy and chemotherapy. Different combinations of these methods are possible, as well as different timing of their application. The type of treatment is decided on the basis of the stage of the disease, the histological characteristics of the tumour, the age of the patient and her general condition. The decision on treatment is made by a multidisciplinary team (Tumour board) of doctors, which should include gynaecologist-oncologist, pathologist, radiotherapist, medical oncologist and radio diagnostician.

The extent of surgical treatment in early invasive cervical cancer is determined by the stage of the disease. Radical operations are not necessary for microinvasive cancer (a tumour with millimetre dimensions), so for most women who want to preserve the possibility of having children, the treatment ends with conization.

Most patients with early stages of the disease (tumour located only on the cervix) are treated with either radical surgery or radical radiotherapy. It has been proven that both therapeutic modalities are equally effective but differ in the morbidity associated with the treatment. In most centres, surgical treatment is used for this stage of the disease. The standard surgical procedure for invasive cervical cancer is radical hysterectomy with pelvic lymphadenectomy. In the case of small tumours in the first stage of disease, which have favourable histological characteristics, in recent years radical trachelectomy is increasingly used, which removes the entire cervix, but not the body of the uterus, which preserves fertility. Unfavourable prognostic factors (positive lymph nodes, large tumour volume, lymph vascular invasion and others) in patients operated on with early-stage cervical cancer require additional radiation therapy that can improve the prognosis.

The primary therapy for advanced stages (the disease has spread beyond the cervix) is radiation combined with chemotherapy. Surgery has a very limited role in the procedure with advanced cervical cancer. It is used for the removal of enlarged lymph nodes performed by some centres or remains as an option after neoadjuvant chemotherapy.

Diagnosed in the early stages, cervical cancer is curable. Unfortunately, a large number of our women consult a gynaecologist for the first time when the disease has already developed and when the treatment is difficult and uncertain. Therefore, the most important part of the fight against cervical cancer is the implementation of organized screening. 

Clinic for Gynaecology and Obstetrics

Serbian Clinical Center

Koste Todorovića 26

11000 Beograd