23. 08. 11. - Cervical cancer - Information for women
Cancro del collo dell'utero - Informazioni per le donne
1. State of affairs in Croatia
In 2001 Croatia had the population of 4.4 million people, including 2.3 million women. Cervical cancer is the eighth most common cancer type among women in Croatia and it is estimated that out of 350 women diagnosed, 100 die every year.
(Znaor A, Babić D, Čorušić A, Grce M, Mahovlić V, Pajtler M, Šerman A. Prijedlog ranog otkrivanja raka vrata maternice u Hrvatskoj, Liječnički Vjesnik, 2007 – Proposal for Early Detection of Cervical Cancer in Croatia, Croatian Medical Journal 2007)
Having said that, the incidence of cervical cancer in Croatia decreased from 26 to 14/100,000 between the years 1970 and 2004. This trend can be attributed to cervical screening programme being implemented in Croatia since 1953, when the first laboratory for gynaecologic cytology (Pajtler M, et al., 2007) was founded in Zagreb. However, if we compare Croatian statistics with the ones in European countries with organized screening programmes, there is still plenty of room for improvement.
The screening for cervical cancer in Croatia is covered by the national health insurance for all women above 18 years of age. Cervical screening is currently done using conventional cytology methods (cervical smear test, i.e. Pap test). In 2005, the Croatian Health Insurance Institute recorded 574,290 Pap smears.
(Pajtler M, Audy-Jurković S, Kardun-Skelin I, Mahovlić V, Vrdoljak Mozetić D, Ovanin-Rakić A. Organisation of Cervical Cytology Screening in Croatia: Past, Present and Future. Coll. Antropol. 31 (Suppl 2) (2007) 47-54.)
2. What is cervical screening?
Screening is a process of identification of individuals within the group of people who are at increased risk of developing certain diseases or who are at an asymptomatic, early stage of disease. The purpose of screening is to take appropriate actions to prevent disease or to make treatment more successful. Cervical cancer can develop when cervical cells become abnormal and start to grow uncontrollably. At first the changes are slight and most of them disappear spontaneously and without treatment. Sometimes the abnormal cells do not disappear and if they are not found and removed, they can develop into cervical cancer. The screening helps us prevent the development of cervical cancer by identifying women who have abnormal cervical cells at an early stage. This method can also identify women who already suffer from cervical cancer. If a woman has abnormal cells, further tests can show whether treatment is required. In fact, most of the abnormal cells disappear spontaneously and treatment is required only if that does not happen or the cells are markedly abnormal.
3. What is Pap test or cervical smear?
Pap test is a cytological analysis of type, morphology and abnormality of cervical cells. Cervical smear can be taken by your primary gynaecologist or in gynaecology clinics. During vaginal examination, a speculum is inserted into the patient’s vagina to allow access to the cervix and a sample for the test is collected with a small wooden spatula and a brush.
→ the first smear is taken from posterior wall of vagina and spread onto a glass slide
→ the second smear is taken from exocervix and spread onto a glass slide
→ the third smear is taken from the cervical canal with a brush, the so called cytobrush and spread onto a glass slide as well
The glass slide is then sprayed with a fixative and sent to a laboratory for cytology. In the laboratory specimen is prepared in a way which makes it easier to tell the difference between normal and abnormal cells. The cells are examined under a microscope by the experts, cytologists, who look for abnormalities. If abnormal cells are found, they will be categorized according to the grade of abnormality.
4. How accurate is Pap smear?
Even a lege artis interpretation of the cell sample relies on subjective judgement of a cytologist and therefore the accuracy of a Pap test can vary. However, the accuracy of this method still lies at 75 - 80% and in combination with colposcopic and histological methods the accuracy increases to 95%. This cytological staining procedure was invented some fifty years ago by the American scientist of Greek origins, Georgios Papanicolau, and the test was named after him. Provided that the changes are detected in an early phase, the treatment is simple, relatively easy and minimally invasive.
5. What is abnormal Pap smear? What is CIN?
Cervical dysplasia is a term used to describe abnormal cells detected via a Pap test and it implies different degrees of changes of cervical cells, nuclear abnormalities (dyscariosis) and atypical features such as shape, size and staining intensity, as well as altered epithelial maturation. A degree of dysplasia is detected in 2-5% of women. The malignant potential of the changed cells is 10-15%, whereas in cases of most severe grades, CIN 3 or CIS (carcinoma in situ), the risk of developing cancer is 30-50%.
→ Mild dysplasia - CIN 1
This is the mildest degree of dysplasia. The Pap smear shows epithelial dyscariosis: cytoplasm is differentiated and intact and nuclei slightly enlarged and of irregular shape, exhibiting hypercromasia and granulated chromatin. The abnormal cells make up for one-third of the epithelium. In 70% of the cases of mild cervical dysplasia, spontaneous regression is expected within the period of one year.
→ Moderate dysplasia - CIN 2
Moderate dysplasia stands for dyscariosis of surface and middle epithelial cells. Up to two-thirds of the epithelium is affected by histological changes, with the basal cell layer enlarged due to the high rate of mitotic activity and increase in number of cells with atypically looking nuclei.
→ Severe dysplasia - CIN 3
In cases of severe dysplasia or CIN 3 more than two-thirds of epithelial cells are affected by the changes. The Pap smear shows dyscariotic cells in surface, middle and inner layers of cervical epithelium. According to histological classification of dysplasia, CIN 3 is the equivalent of CIS (Carcinoma in situ). This is an early form of carcinoma characterized by dyscariotic changes in all cell layers, which means irregular composition of epithelium and disturbed cell maturation cycle. Histologically speaking, CIS differs from invasive cancer inasmuch that the basement membrane, the membrane dividing epithelium and connective tissue with blood and lymph vessels underlying the epithelium, is preserved intact in the case of CIS.
The Pap test results may include the term squamous intraepithelial lesion (SIL), which describes dysplastic cervical cells. SIL can be low-grade (LGSIL), corresponding to CIN 1, and high-grade (HGSIL), corresponding to both CIN 2 and CIN 3.
Results can also indicate atypical squamous or glandular cells (ASCUS or AGCUS), with the degree of abnormality which does not meet the criteria for CIN, SIL or dysplasia. In 5-10% of women with ASCUS Pap smear result, further tests reveal a high-grade SIL or, in rare cases, invasive cancer. Special attention has to be paid to ASC-H (abnormal squamous cells, high-grade SIL not excluded). Colposcopy and further treatment are mandatory in this case.
6. What is HPV?
It is estimated that some 60-80% of women will be infected with a human papillomavirus (HPV) at some point in their lifetime. HPV infection is a sexually transmitted disease. At least 80%, if not 100% of the girls between 18 and 25 years of age are exposed to HPV through sexual contact, while only about 30% of them develop symptoms of infection. The reason for that is spontaneous clearance of the virus: overt symptoms can be cleared by the immune system itself, but this process depends heavily on the strength of the immune system of the infected person.
Although HPV infections normally go away quickly, persistent infection with high-risk HPV types can lead to cervical cancer. Out of 1,000,000 women infected with high-risk HPV type, 100,000 or 10% of them will develop precancerous lesions, while in 1600 or 16% of them the infection will progress to invasive cancer. The weakening of the immune system due to chronic emotional or any other type of stress, poor diet, alcohol and smoking can influence changes in immune response and thereby contribute to reactivation of the virus. HPV infection is limited to epithelial cells only and there is no immunologic memory in the process, which means that previous infection does not provide immunity against re-infection. There are more than 300 known HPV strains, with new ones being discovered every day, and more than 40% of them can infect the mucosa the respiratory and digestive tracts and anogenital region.
Infection with high-risk HPV strains can lead to development of cervical cancer with relative risk from 80 to 130. This is why it is extremely important to carry out HPV tests and typizations - in combination with cytological examination these considerably increase sensitivity and predicative value of cervical screening. Low-risk HPV types (6, 11, 41, 43, 44) cause genital warts (condylomata accuminata), which are sexually transmitted and contagious. High-risk HPV types (16, 18, 31, 35, 39, 45, 51, 52, 56) are dangerous since they are accompanied by the appearance of abnormal cells on the surface of the cervix (cervical dysplasia), but at the same time they are not followed by any other symptoms.
7. What is colposcopy?
Colposcopy is a Greek word which literary means inspection of the vagina. This is a diagnostic method developed by Hans Hinselmann and introduced into clinical practice in 1925. Its accuracy lies at approximately 60% and 85%, but in combination with a Pap test it increases to as much as 98-99%. Colposcopic procedure is an excellent diagnostic addition to the cytological one. It enables a reliable localization and insight into distribution of pathological epithelial lesions as well as directed biopsy of suspicious area.
Colposcopy is performed with the woman lying on her back, legs in stirrups, and never during the menstrual period.
The standard instrument for sample collection, the adaptable speculum, is used: it is inserted into the vaginal canal in order to medically observe the vagina and inner portion. The procedure is neither more uncomfortable nor painful than a standard gynaecologic examination.
Three percent acetic acid is applied to the exocervical and vaginal mucosa, which can cause slight burning. Pursuant to that, iodine solution, the so called Lugol’s solution, is applied to improve visualization of changes under the light of a colposcope, enlarged by 4-40 x. If the patient is allergic to iodine solution, this part of colposcopy is to be left out. The green filter of the colposcope facilitates visualization of the blood vessel patterns and their interpretation.
During the colposcopy, the doctors can decide on locations from which tissue samples for further pathohistological diagnostics will later be taken or they can do it as a part of the procedure. There are women who experience some pain, but normally of slight intensity, since exocervix is poorly innervated. Possible bleeding can be stopped by applying liquid haemostatic agents or gauze pads which are removed two hours after the procedure. Results of pathohistological analysis of tissue samples are usually to be expected in 7-10 days’ time.
8. How to treat dysplasia?
Although research indicates that for major part abnormalities in the Pap test disappear spontaneously and without treatment, even in cases when test results show high-risk HPV, the composition of the cell layers can change quickly. This is why it is very important to have regular Pap tests.
The prevailing attitude in CIN treatment is that it should be as minimally invasive as possible and conducted in a way so as to bring dysplasia under control as early as possible with no significant or permanent consequences. The first step is examination of cervix for viruses and bacteria and the treatment of the lingering infection. In case of high-risk HPV infection, it is necessary to conduct colposcopy, sometimes even biopsy. As a contribution to standardization of diagnostics and treatment of women with CIN in Croatia and its harmonization with most recent insights of the medical science, the following manual was published in 2001: Ljubojević N et al. Improved National Croatian Diagnostic and Therapeutic Guidelines for Premalignant Lesions of the Uterine Cervix with Some Cost Benefit Aspects, Coll Antropol 2001; 25 (2): 467-474
There exists a wide range of treatments of condyloma and low-grade cervical dysplasia:
- Some good results have been obtained in treatment with low-doses of natural interferon, with rate of success up to 80%. The main aim of local treatment with interferon is to inhibit penetration of the virus into the genome of uninfected mucous cells of vagina and cervix.
- Condyloma can be surgically removed: with a scalpel or laser, as well as by means of cryotherapy and electrotherapy.
- Warts can be treated with Podophyllinum, chemical resin derived from fruit of white hawthorn, from the group of herbal cytostatic agents. The condition is mostly treated by 3-5% alcohol solution of podophyllinum or podofilox (Condylox), a very similar medication, which can be applied to external condyloma by the patient, at home, following the doctor’s instructions.
- A new medication in condyloma treatment is Imiquimod (Aldara), which acts as an immune response modifier. Among its antiviral and antineoplastic effects, stimulation of the cellular division of immune system is the most important one.
The following approach in diagnosis and treatment of high grade SIL is recommended:
- In case of progression and/or persistence of changes, diagnostic (oftentimes together with therapeutic) conization is indicated. Conization is performed with a scalpel or electrosurgical loop (LLETZ). In the case of persistent and severe dysplasia, conization is currently the preferred modality to treat CIN 3 and CIS, as well as CIN 2 which remains unchanged for longer than 12 months. Of course, only after the histological analysis of the cone, the final diagnosis can be made.
- If the diseased tissue has not been removed completely, re-conization or hysterectomy (removal of the uterus) can be performed.
Both 1) and 2) depend on age and parity of patients.
9. Vaccine
There are two types of vaccines on Croatian market: bivalent and quadrivalent.
The quadrivalent vaccine protects against high-risk HPV types 16 and 18 and low-risk types 6 and 11.
The bivalent vaccine is indicated to prevent the HPV types 16 and 18.
HPV 16 and 18 together are alone responsible for 70 % of the cases of cervical cancer, while HPV 6 and 11 cause 90% of benign genital warts (condyloma). The remaining 30% (every third case) is caused by some of the remaining strains of high-risk HPV. Therefore vaccination does not provide full protection against cervical cancer.
Prepared by:
Dražan Butorac, MD, specialist in gynaecology and obstetrics and
Professor Goran Grubišić, MD, PhD, specialist in gynaecology and obstetrics
