Correlation of human papilloma virus infection with cytology, colposcopy and histopathological examination of the bioptic tissue in low- and high-grade intraepithelial lesions.

INTRODUCTION: It is now believed that the majority of cervical cancer is preceded by long-term infection with high-risk types of the human papilloma virus (HPV). The presence of HPV high-risk types (HR-HPV) in the cells of intraepithelial change multiplies the possibility of its progressive development to high-grade cervical precancer and invasive disease. AIM: This study examined the correlation of HPV infection with cytology, colposcopy, and histopathological examination of the bioptic tissue in low- and high-grade cervical lesions. MATERIALS AND METHODS: This research was conducted as a study section. Data collection was performed during a ten-year period, at the University Clinic of Gynecology and Obstetrics - Narodni Front in Belgrade (Serbia). The basic set included 1,927 patients. Colposcopy, cytology, histopathology, and HPV test verification was made in all patients. Statistical analysis was performed using the SPSS program, version 17.0. Contingency tables were used to assess the degree of correlation of variables and chi-square test was used to determine the level of statistical significance in this study. A p value < 0.05 was considered statistically significant. RESULTS: Among 1,927 women studied, 635 (32.95 %) had abnormal cytological findings and among these, 272 (42.83%) were HR-HPV positive. There was a statistical difference between colposcopic and cytological findings in patients with HR-HPV (x2 = 35.33, p = 0.000). There was also a statistically significant difference between histophatological and colposcopical findings in patients with HR-HPV (x2 = 10,171, p = 0.001). Only HR-HPV types 16 and 18 showed a statistical significance compared to histopathological findings, unlike other HR-HPV. An important finding was that the authors found an abnormal colposcopy in 93.30% patients with low-grade intraepithelial neoplasia and 68.05% patients with low-grade squamous intraepithelial lesion (LSIL) had normal cytology and was 70.15 % HR-HPV negative. CONCLUSION: The findings imply that among high-grade intraepithelial neoplasias, the authors found a high presence of HPV type 16 and 18, and a statistical significant presence of HPV 16 in low-grade intraepithelial neoplasia, unlike other HR-HPV types in low-grade intraepithelial findings. The authors found a significant statistical correlation with abnormal cytology and presence of HPV type 16 in both groups (LSIL and high-grade squamous intraepithelial lesion (HSIL). The authors also found an abnormal colposcopy in 93.30% of patients with low-grade intraepithelial neoplasia, while 68.05% of patients with LSIL had normal cytology and were HR-HPV negative in 70.15% of the cases.

Primary double invasive cervical carcinoma, squamous cell carcinoma and adenocarcinoma--case report.

A case of 56-year old women with double primary invasive cervical carcinoma, squamous cell carcinoma and endometrioid adenocarcinoma is presented. The patient was subjected to radical abdominal hysterectomy with pelvic and paraaortic lymphadenectomy. Surgery was followed by radiotherapy. Since the treatment the patient has been doing well and is free of any signs of relapse of the disease.

Distribution of high-risk HPV types in Yugoslav women with cervical neoplasia.

PURPOSE: The purpose of this study was to determine the frequency of high-risk types of human papillomavirus (HPV) infection, namely type 16, 18, 31 and 33, among Yugoslav women diagnosed with different grades of squamous intraepithelial lesion (SIL), as well as to investigate the relationship between HPV infection and age, parity, age at first intercourse, number of sexual partners and residence of the patients, all of which are considered risk-factors. PATIENTS AND METHODS: DNA was isolated from cervical swabs of 72 women using phenol/chloroform/isoamylalcohol extraction. Detection of HPV DNA in patients' genomic DNA was performed using the polymerase chain reaction (PCR) method with type-specific primer pairs, and amplification products were analyzed using 2% agarose and 10% polyacrylamide gel electrophoresis. RESULTS: Thirty out of 72 (41.7%) patients with cervical intraepithelial neoplasia (CIN) were HPV-positive and 8 of them were double positives. HPV31 was the most frequent high-risk HPV type in this group of patients (13.9%). Eighty percent of the high-grade SIL (HSIL) patients were HPV-positive and 38.8% of the low-grade SIL (LSIL) patients were HPV-positive. Compared to HPV-negative women, the HPV-positive ones were younger, had started sexual activity earlier, and overall had more sexual partners. CONCLUSION: Our study showed that oncogenic HPV types are responsible for the transition of LSIL to HSIL, and for its further progression to an invasive carcinoma of the cervix. Thus, HPV typing should become a widely used method for identifying women with increased risk for developing HSIL and invasive cervical cancer. We also concluded that sexual behavior is connected with the frequency of HPV infection. Henceforth, introduction of prophylactic measures could reduce the incidence of HPV infected women in our country.

[Detection of human papillomaviruses in cervical intraepithelial neoplasms]. / Otkrivanje virusa humanih papiloma u intraepitelinim neoplazijama grlica materice.

Over the period 1994-1998 1000 patients suffering from intraepithelial cervical lesions (SIL) were examined for the presence of Human Papilloma Virus (HPV) infection. Today it is completely acknowledged that certain types of these viruses play a key role in the onset and evolution of these diseases. The study showed that SIL of the cervix appears in very young women. The highest incidence was found in age groups 24-28 years (21.10%) and 29-33 years (19.10%). Thus, over 40% of the entire study group patients was under 34 years of age. Histological analysis of tissue samples showed that 79.30% of patients had lesions of low histological grade (LSIL), while in 20.70% of them the disease progressed to a high histological level (HSIL). Detection of Human Papilloma Virus Infection revealed negative results in 34.90% of patients, 17.80% were 6/11 positive (non-oncogenic type), and in 47.30% oncogenic types were found (16, 18, 31, 33). This finding in the LSIL group was exceptionally important since it influenced the approach to treatment. Oncogenic types of viruses were detected in 34.30% of LSIL lesions; it indicates a high progression potential of pathological changes.

[Effect of certain aspects of female sexual behavior on the development of cervical intraepithelial neoplasia]. / Uticaj nekih parametara sekusualnog zivota zene na pojavu intraepitelinih neoplazija grlica materica.

The paper presents results of investigation of certain parameters of female sexual activity and their effect on the appearance of squamous intraepithelial cervical lesions (SIL). This correlation was investigated in the context of Human Papilloma Virus (HPV) infection, in view of the role attributed to certain types of these viruses in the appearance and development of cervical SIL. Research was done on 1000 patients suffering from low histological grade (LSIL) or high histological grade (HSIL) intraepithelial cervical neoplasms. It transpired that such lesions were most frequent in women in the second, third and fourth decade of life, and that one third of pathological lesions was a function of age. Human Papilloma Virus infection was detected in 65% of patients. The frequency of HPV negative results or presence of non-oncogenic types of viruses (6 and 11) was significantly higher in LSIL type lesions, while the frequency of detection of oncogenous HPV types (16, 18, 31 and 33) was significantly higher in more severe stadiums of the disease. Of the investigated parameters of sexual activity, early onset of such activity and several sexual partners proved to be significant. The number of parturitions and abortions did not appear to be significant risk factors for the onset and development of these diseases.

[The role of insulin-like growth-factor binding proteins in normal and polycystic ovaries]. / Uloga vezujucih proteina za faktore rasta slicne insulinu u normalnom i u policisticnom ovarijumy.

The insulin-like growth factor binding proteins are single chain polypeptides, that can bind insulin-like growth factors, but not insulin. They can serve as autocrine or paracrine regulators of the actions of insulin-like growth factor. The human granulosa cells produce insulin-like growth factor-II but not insulin-like growth factor-I, while the human theca cells produce insulin-like growth factor-I and II. Polycystic ovarian syndrome is a disorder which is characterised by hyperandrogenism and anovulation. In polycystic ovarian syndrome there is a disorder of follicular development, with the accumulation of antral follicles within the ovary which fail to respond appropriately to endogenous follicle-stimulating hormone. Significance is given to insulin-like growth factor binding proteins, which have an inhibitory action on follicle-stimulating hormone. No differences were found in the total level of insulin-like growth factor binding proteins follicular profiles between women with polycystic ovarian syndrome and without it. Serum insulin-like growth factor binding protein-I levels are lower in polycystic ovarian syndrome with hyperinsulinaemia, probably as a consequence of insulin-mediated suppression of insulin-like growth factor binding protein-I. Consequently, serum free insulin-like growth factor-I levels are higher. This alteration may cause an excessive thecal androgen production. The alterations in the insulin-like growth factor-insulin-like growth factor binding proteins axis may be one of several mechanisms that help to sustain the steady state of anovulation and follicular dysmaturation that are characteristic of this syndrome.

[The national program for the early detection and treatment of premalignant and malignant diseases of the lower genital system in women]. / Nacionalni program ranog otkrivanja i lecenja premalignih i malignih bolesti donjeg dela genitalnog organa zene.

Lower genital tract malignancies are often seen in our female population; their detection is often delayed and treatment fails frequently. Latest scientific data on their etiology and newer methods of their detection and treatment in the early stages opens roads in the field of primary and secondary prevention and for the effective therapy, as well. In order to improve current status of the women's health in this field, on October 10, 1995 year, the Section for cervical pathology and colposcopy in addition to Yugoslav Association of Gynecologists and Obstetricians (UGOJ), has been established. One of the most important aims of the Section is introduction of premalignant and malignant diseases of female lower genital tract. So far, the Section has: 1. Submitted the Program proposal to the Ministry of Health of Serbia; on the basis of that proposal, on April 10, 1996 year, the Ministry issued: "Expert instruction for the conduction of assignments aimed at early detection of the cancer of the uterine cervix". In that act obligatory for all health institutions, that have gynecology depts, all activities and goals for National Program introduction are prescribed. 2. The Yugoslav School for pathology of the cervix, vagina, vulva and colposcopy, opened in 1996, year, under the patronage of the Ministry of Health of the Republic Serbia provides the theoretical and practical training for the Program carriers and medical doctors receiving their training in gynecology and obstetrics. The first generation, the School attendees consisted of 149 doctors from the entire country. 3. Creation and submission of a draft common Health Form intended for the computerized and professional use, to provide for more efficient introduction of the National Program. The Form, should be introduced by the Health Ministry as an Official Health Document, to be used by all OBG institutions. 4. Submitted proposal of the activities and tasks in the field of Program realisation according to Health institutions' profiles. 5. Creation of the draft Protocol for actual activities and procedures in order to provide for an early detection and treatment of premalignant and malignant diseases of the female lower genital tract. Having the future mandatory character of this Protocol, the Section will divulge it to the professional audience. 6. Created a project of the National program and submitted it at the beginning of 1996 year, to the Republic Bureau of Health protection, with a request for its financial support in that program. In addition to the activities mentioned, the section management undertook and is taking measures for faster achievement of the aim-of the National Program introduction. Official Health institutions are assigned responsibilities of the Program introduction, the funding and a resolve all the legal, organisational and financial issues. Results that we are expected from this Program include introduction of the primary and secondary measures aimed at disease prevention; early detection of the diseases and its treatment; reduction of the numbers of cases in the advanced stages; significant improvement of gynecological status, and reduction of costs of the treatment of advanced stages of disease. The results should stimulate all, and become must for all subjects involved in the National Program realisation. The Program introduction into the daily OBG practice is a prerequisite of already well established practice in a number of countries, saving life and limb of most women affected by the lower genital tract malignancies.

[Chlamydia trachomatis and acute pelvic inflammatory disease]. / Chlamydia trachomatis i akutna pelvicna inflamatorna bolest.

The incidence of Chlamydia trachomatis infection in women with acute pelvic inflammatory disease has been studied. Chlamydia trachomatis was isolated in 20 (35.71%) of 56 examined women. In all women with positive isolation, the infection was also confirmed serologically.

The E2 region of HPV 16 in relation to different types of cervical lesions.

The presence of the E2 region of HPV 16 was determined by the polymerase chain reaction in biopsy samples with different histopathological diagnoses. The absence of the E2 gene was observed in 17 of 30 cases examined. The E2 deletions were not confined exclusively to invasive carcinomas or to integrated viral forms. In the majority of cases, the course of cervical lesions was consistent with the state of the E2 gene.

Human papillomavirus DNA in distant metastases of cervical cancer.

Eighteen distant metastases from cervical cancer to the extrapelvic abdomen, extraabdominal lymph nodes, vulva, suburethral region, skin, and breast in 17 patients were analyzed by Southern blot hybridization under nonstringent and stringent conditions for the prevalence of human papillomavirus (HPV) type 11, 16, 18, 31, 33, and 35 DNA. Fourteen metastases in thirteen patients were HPV-positive. Thirteen tumors contained HPV-16 and one HPV-related sequences with varying copy number. In 9 of 11 cases, where the corresponding primary tumor could be studied, HPV positivity and type were identical. Two HPV-negative primary lesions had HPV-positive metastases; in three cases differences in restriction pattern or copy number were revealed. The HPV status showed no clear association with age of the patient, latency period between primary tumor and metastasis, histological findings, therapy, and clinical course of the disease after metastasis. The rather conserved presence of HPV DNA in distant metastases of cervical carcinoma underlines the importance of these viruses also for the maintenance of the malignant state.

[Human papilloma viruses and genital neoplasias]. / Humani virusi papiloma i genitalne neoplazije.

The article deals with the problem of genital infections caused by human papilloma viruses, and their possible influence on oncogenic process. Also a review of earlier examinations of malignant disease in the lower genital tract and the risk faktors that contribute to its genesis, is given. Potential role of human papilloma viruses, that has been recently pointed out, is processed from the aspect of their frequency in genital neoplasias and from biological, pathogenetical and clinical viewpoints. Also a survey of diagnostical methods and their possibilities in revealing genital infections with specific types of viruses, as well as prognostic analysis of such infections, are presented. Taking into account the importand role of viruses in development malignant disease of the lower genital tract, the article especially analyzed preventive measures of infections, their early detection and therapeutic possibilities. On the basis of researches of numerous authors and on the basis of previous author's work on this problem, modern attitudes about this very current question are presented.

[Use of the CO2 laser in the treatment of pathologic changes in the vulva, vagina and uterine cervix]. / Primena CO2-lasera u lecenju patoloskih promena vulve, vagine i grlica materice.

In the period from April 1987 to April 1990, 230 patients with pathological changes of the vulva, vagina and cervix uteri were treated with the CO2-laser. The diagnosis and pretreatment stages of the diseases were confirmed by the cytodiagnostic, colposcopic and histopathological results of the biophysics. In most cases, DNA-hybridization of human papilloma viruses confirmed their virus etiology. Twenty patients had peak condyloma of the vulva and vagina, 34 had benign cervical diseases, 65 were at the premalignant and 111 in the first stages of malignant cervical disease. Vaporizations, conical or cylindrical excisions were performed depending on the nature of disease and its localisation. The average age of operated patients was 30.6 years and the average parity 0.69. Operations were performed using analgesia and in rare cases total anesthesia. After the excision treatment, the tissue was checked histo-pathologically according to the principle of series. The complications were very rare. After operation, postoperative control was performed after 3.9 and 15 months, and later once a year. The results have shown that one treatment was sufficient in 80% of patients for curing vulvar and vaginal disease and 20% patients needed repeat because of the condyloma that relapsed. After the first treatment, benign and premalignant cervical diseases were cured in 100% of cases. In 95.4% operated patients at the first stages of cervical malignant diseases, the excisional treatment was final and in 4.6% needed an additional radical therapy because of a higher stage of lesion found by the conular histo-pathological analysis. There were no relapses relating to the cervix.

[Cervical maturation using Prepidil gel in pregnancy termination in primigravidas]. / Maturacija grlica preparatom Prepidil gel pre namernog prekida trudnoce kod prvorotki.

The study investigated the possibility of pharmacological servical ripening induced by Dinoprostone (Prepidil Gel--Upjohn Co) prior to therapeutic abortion in primigravida. The study concerned patients-volunteers choosen by random. 73 patients were divided into two groups with the same average age, term of gestation, cervix consistency and passage through the cervical canal before the application of gel. In the first group therapeutic abortion was carried out 6 hours after the application of gle into cervical canal, and in the second group--4 hours after the gel application. Cervical maturation, testified by its consistency and spontaneous cervical ripening, was equal in both groups (average delta Hegar I was 7.32 and delta Hegar II--7.02), and it enabled medical procedure only with the local anaesthesia with 2% hylocein in 82% ob pregnant women. In a fifth of patients ob both groups it was necessary to do additional mechanical dilatation, which was easily performed due to the already soft cervix; these patients were also administered 1 ampulla ob Fortral I.V. In both groups during the action of Dinoprostone there were no significant changes either in blood pressure or in body temperature. More expressed uterine activity, followed by initial and incompleted abortions, were more frequent in patients of the first group (3529%) than in those from the second group (17.95%) in which only contractions occurred (33.33%). The rate of gastrointestinal side effects was 29.41% in the first group and 41.03% in the second group. There was no uterine complication during the activity of Dinoprostone as well as during and after medical procedure.

[The role of human papillomaviruses among the risk factors for cervical carcinoma]. / Mesto humanih papiloma virusa medu faktorima rizika cervikalnog karcinoma.

In a prospective study, risk factors of the development of cervical carcinoma in 210 diseased and 100 healthy subjects were investigated. Special attention was paid to metaplastic changes in the portio vaginalis cervics and to human papilloma virus which are considered responsible for the development of these changes. It has been found that metaplasias are favoured by adolescence, chronic irritative processes in the cervix (pathologic discharge recorded in 51.9% of the diseased and 38% of the healthy), cervical lacerations (33.8%:9%), and a prolonged use of hormonal contraception (37.1:15%), all relationships being statistically significant. The factors statistically significant for the development of infection with human papilloma virus proved to be early sexual life (16.2% of the diseased and 6% of the healthy), a great many changes in sexual partners (6.7%:1%), unreliable sexual devotion of the male partner (56.2%:42%), the use of non-barrier contraception methods, and inadequate sexual hygiene. It has not been found that some other factors (profession, number of marriages, nationality, and the like) have an important effect on cervical changes.

Carcinoma of the cervix uteri and risk factors.

A prospective study included 210 patients and 100 healthy individuals in whom risk factors for the onset of malignant disorders of the cervix uteri were investigated. The following parameters were analyzed: age, profession, religious affiliation, former pregnancies, chronic irritative process on the cervix uteri, socio-economic status, heredity, contraceptive usage, smoking, sexual life and presence of the human papilloma viruses in the injured and healthy cervix. The results of the research emphasized the relevant risk factors for the genesis of the disease. They are presented in an original sheme. The central place in the pathogenesis of the disease is taken by the existing metaplasia on the portio vaginalis uteri and its contact with definite types of human papilloma viruses. The risk factors that contribute to the genesis of metaplasia and cervical infection by human papilloma viruses proved to be of great importance for the appearance of disorder. The adolescent period, the chronic irritative process on the portio vaginalis and the long-term use of hormonal contraceptives influence the genesis of metaplasia. Early sexual life, the changing of sexual partners, the sexual life of male partners, poor sexual hygiene, and the use of nonbarrier contraceptive devices favour the development of human papilloma viral infections of the cervix uteri.

[Human papillomavirus types and cervical neoplasia]. / Tipovi humanih papiloma virusa i cervikalne neoplazije.

The pathological cells of the cervix uteri were examined for the presence of some types of human papilloma viruses (HPV) by DNA-hybridization and by the Southern blot method. Different degrees of neoplasia were found in the majority of these pathological changes of the uterus. The control group of patients included in the study had normal clinical, cytological and colposcopical results. Two parameters were identical both in the examined and the control patients. Types 6/11 were found in neither of the groups examined. The control patients had types 16/18 HPV in 8.3% of cases, while the frequency of these types was much higher in the examined group; it depended on the phase of the disease. These types were not detected in pathological lesions of CIN I; 40% of patients with CIN II had them, and 7.3% of patients with CIN III were positive to types 16/18 HPV. The majority (75%) of the examined samples of invasive neoplastic cervical lesions were positive to the presence of HPV 16/18.