Faculty of Medicine

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Human papilloma virus DNA presence in early stage cervical carcinomas: Correlation with other prognostic factors and recurrence rate
(Gustav Fischer, 1997-09)
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Ivkovski, Ljube
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Yashar, Genghis
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Stavrik, George
BACKGROUND: Although the role of human papillomavirus (HPV) in cervical carcinogenesis is reasonably well established, the attempts to determine the prognostic value of presence or absence of detectable human papillomavirus DNA and HPV type in cervical carcinoma have yielded conflicting results. OBJECTIVE: The objective of our study was to assess the prognostic significance of the presence of HPV DNA by exploring the relationship of HPV presence to the recurrence rate and clinical and histopathologic features of 92 patients with cervical carcinoma..In this report the preliminary results of a larger programme aimed to search for the prognostic factors in a fairly homogenous population of patients with early stage cervical carcinomas who underwent abdominal hysterectomy with pelvic lymphadenectomy as primary therapy, followed by postoperative adjuvant pelvic radiotherapy, are presented MATERIALS AND METHODS: Routinely processed formalin-fixed paraffin-embedded cervical carcinoma surgical specimens were examined for the presence of HPV DNA by in situ hybridization technique using mixed biotinylated probes to identify HPV types 6/11, 16/18 and 31/33/51 (Enzo Diagnostics, New York). Clinical data and histopathologic features of these patients were analyzed retrospectively to determine their relation to presence or absence of HPV DNA. All the patients were staged according to the postoperative TNM classification of UICC (1987) guidelines. In our case series the tumor was limited to cervix in 48 (52.2%) patients, while local extension to vagina and parametrial tissues was found in 10 (10.9%) and 34 (36.9%) patients, respectively. Pelvic lymph node involvement was found in 25 (27.2%) patients. During the follow-up period (range, 2-87, mean, 35 months), recurrences were observed in 13 patients. Variables were compared by cross-classification and statistical significance was determined by χ2 and Fisher`s exact test. RESULTS: HPV DNA was detected in 41 (44.6%) cervical carcinoma specimens. The prevalence rate of different HPV types was 37% (34) for HPV 16/18, 6.5% (6) for HPV 31/33/5, while HPV type 6/11 was detected only in one case of verrucous carcinoma. Recurrence rate was significantly higher in patients with HPV DNA negative cervical carcinomas (P=0.02). Among the HPV DNA positive patients with cervical carcinoma the recurrence rate was 4.9% (2 cases), compared to 21.6% (5 cases) for the HPV DNA negative group. Various clinical and histopathologic features of the patients with cervical carcinomas (tumor extent, grade, presence of regional lymph nodal metastases, number of positive lymph nodes, histologic subtype, maximum depth of cervical stromal invasion, maximal tumor diameter, longitudinal endocervical involvement, proportionate longitudinal endocervical involvement, tumor-cervix area quotient, maximal and minimal sagittal tumor area, parametrial involvement, vaginal involvement, lymph-vascular space invasion, peri- and intra-tumoral lymphocytic infiltration, surgical margins involvement, age) were also correlated with the presence of HPV DNA. No statistically significant association was found between the presence of HPV DNA and 17 other clinical and histopathologic variables. On the other hand recurrence rates were significantly related to tumor extent (P=0.0001), presence of regional lymph nodal metastases (P=0.0002), maximal tumor diameter (P=0.14), proportionate longitudinal endocervical involvement (P=0.007), maximal sagittal tumor area (P=0.038), parametrial involvement (P=0.0001), vaginal involvement (P=0.03), and lymph-vascular space invasion (P=0.0023). CONCLUSIONS: The preliminary results of our study are consistent the observations reported by several other authors. The presence of HPV DNA appeared to be related to recurrence rate and unrelated to various histopathologic characteristics of well-known prognostic significance. However, having in mind the limited number of cases studied, as well as a lower sensitivity of in situ hybridization technique, an analysis of larger series, as well as introducing a more sensitive technique like PCR assay, will be necessary to determine whether the presence of HPV DNA and HPV type should be considered when developing treatment strategies and assessing prognosis in patients with early stage cervical carcinomas.
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Prognostic significance of the HPV status in early stage cervical carcinoma
(Macedonian Academy of Sciences and Arts, 2006-09)
Kubelka-Sabit, Katerina
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Prodanova, Irina
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Yashar, Genghis
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Zografski, George
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Aims: In order to evaluate their prognostic significance, the parameters of the human papilloma virus (HPV) status were correlated to the lympho-nodal and tumor status, maximal diameter, minimal thickness of uninvolved stroma, histologic type, grade of differentiation, lympho-vascular space invasion, degree of lymphocytic inflammatory stromal reaction at the invasion front, age and the disease-free survival (DFS) of the patients with early stage invasive cervical carcinomas. Material and methods: 77 cases of cervical carcinomas, limited to the uterus, surgically treated and postoperatively irradiated, were selected for this retrospective study. HPV DNA status (presence and HPV type, type of hybridization signal and number of positive cells per sample) was evaluated using sensitive in situ hybridization detection kit with catalyzed signal amplification with biotinylated probes for types 6/11, 16/18 and 31/33 or 31/33/51. Results: The presence of HPV DNA was detected in 45 (58.4%) cases. Thirty-two (71.1%) showed positivity for HPV type 16/18, 8 (17.8%) for 31/33, whereas multiple infection was detected in (8.9%) 4 cases. Dot hybridization signal was found in 31 (68.9%), diffuse in 2 (4.4%) and mixed in 12 (26.7%) cases. More than five positive nuclei per sample were found in 37 (82.2%) of the cases. Only the presence of HPV was associated with absence of regional lymph node involvement, presence of moderate/abundant lymphocytic infiltration and longer 5 and 10-year DFS. Conclusions: According to our results, more extensive studies are needed to assess the real prognostic influence of the other parameters of HPV status in early stage cervical carcinomas.
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Small and large cell neuroendocrine carcinomas of the uterine cervix. A report of 10 cases.
(Springer, 2005-08)
Kubelka-Sabit, Katerina
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Plaseska-Karanfilska, Dijana
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Prodanova, Irina
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Yashar, Genghis
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Hadzi-Nicheva, Biljana
BACKGROUND: Small (SCC) and large cell (LCC) neuroendocrine carcinomas of the uterine cervix are rare and highly aggressive neoplasms. Their association with the integration of human papilloma virus (HPV) DNA of the types 16 or 18 has been documented in many studies. AIMS: The purpose of this study is to present the clinical, histopathological, immunohistochemical characteristics and the presence of HPV DNA in ten cases of SCCs and LCCs of the uterine cervix. METHODS: Seven patients with primary SCCs and three patients with LCCs of the uterine cervix were diagnosed at our department between 1989 and 2004. Clinical data were retrieved from the patients’ files and included age, recurrence and survival. Routinely processed operative and/or biopsy specimens were used for immunohistochemical stains and hybridization procedures. Primary antibodies against several epithelial, neuroendocrine, mesenchimal and proliferative markers were included. The presence of HPV DNA was assessed by conventional in situ hybridization (ISH) using probes for HPV 16/18 and 31/33/51 and polymerase chain reaction (PCR), using three primers (MY09/11, GP5+/GP6+, E6). Six of the patients were surgically treated. Postoperatively, four received chemo and/or radiotherapy, two rejected further treatment and one patient was lost to follow-up. The other four patients underwent conservative treatment due to advanced disease. RESULTS: The patients’ age ranged from 25 to 71 years. Histologically, the tumors showed trabecular, nesting or a sheet-like pattern, with areas of necrosis and frequent mitoses. Their neuroendocrine nature was confirmed by diffuse positive immunostaining for neuron-specific enolase and low-molecular weight cytokeratins. Focal positivity for chromogranin, synaptophysin and S100, together with pancytokeratin and EMA, was evident in the majority of the tumors. Their aggressive potential was confirmed by high Ki-67 proliferative index (50-90%). HPV types 16/18 were found in 4 tumors using ISH, and HPV 16 in additional 3, using PCR (type 16). 3 of the patients developed distant metastases and died 7-48 months after receiving partial or full treatment, while 6 are alive and without evidence of disease after 4-38 months. CONCLUSIONS: SCCs and LCCs are highly aggressive neoplasms. However, early diagnosis and combined therapy may improve survival in some patients. Although mainly a morphologic diagnosis, immunohistochemistry may help in the diagnosis of SCC and LCC.
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Ki-67 expression in the invasion front as an additional independent significant prognostic factor influencing reccurence in early stage cervical carcinomas.
(Springer, 2005-08)
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Prodanova, Irina
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Kubelka-Sabit, Katerina
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Yashar, Genghis
INTRODUCTION: The attempts to determine the prognostic significance of biological markers and their relation to human papillomavirus (HPV) infection in cervical cancer have yielded controversial results. AIMS: The aims of this retrospective study were to correlate alterations of cell proliferation, growth, differentiation and apoptosis regulatory proteins in early stage cervical carcinomas with HPV infection, histopathological and clinical parameters, and to estimate their prognostic significance. METHODS: Expression of Ki-67, p53, mdm-2, bcl-2, c-erbB-2, EGFR protein, as well as estrogen and progesterone receptors was evaluated by immunohistochemistry in operative specimens of 83 patients with early stage cervical carcinoma. The results were assessed semiquantitatively in the surface area, center and invasion front of each tumor as a percentage of the immunostained cells and/or intensity of immunostaining for each protein. The presence of HPV was assessed by conventional in situ hybridization (ISH) technique and catalyzed reporter deposition signal amplification ISH using mixed biotinylated probes to identify types 6/11, 16/18 and 31/33 or 31/33/51. RESULTS: In our case series 73 patients had a tumor limited to the uterine cervix less than 4 cm in diameter (pT1b1), while 10 patients had larger neoplasms belonging to pT1b2 category. Pelvic lymph node involvement was found in 20 patients. During the follow-up period (range, 65 -181, mean, 121 months) recurrences were observed in 9 patients. The 5, 10 and 15-year disease-free survival rate was 92.7%, 90.8% and 86.6%, respectively. Among the 18 variables pelvic lymph node involvement (P=0.0008), tumor diameter (P=0.035), depth of stromal invasion (P=0.029), histotype (P=0.0009), grade (P=0.056), HPV DNA presence (P=0.056), HPV type (P=0.043), as well as bcl-2 (P=0.035), mdm-2 (P=0.051), EGFR (P<0.0001), and Ki-67 (P=0.031) expression in the tumor’s invasion front were identified as important predictive indicators of recurrence in the univariate analysis. Independent significant prognostic factors for disease-free survival in multivariate analysis were the histotype, HPV DNA presence and Ki-67 expression. CONCLUSIONS: The invasive front of carcinomas proved to be the most important area for tumor prognosis. In addition to the detection of HPV presence and morphological parameters, Ki-67 evaluation could be used in selecting appropriate therapeutical approaches in patients with early stage cervical cancer.
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Potential prognostic significance of apoptosis related oncogenes: p53, bcl-2 and mdm-2 in early stage cervical carcinoma
(2003-09)
Prodanova, Irina
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Yashar, Genghis
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Kubelka-Sabit, Katerina
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Zografski, George
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Introduction: Evaluations of expression of apoptosis related oncogenes are being increasingly called upon in an attempt to better understand the carcinogenesis of cervical carcinoma and to provide possible prognostic information. The aim of this study was to analyze the expression of bcl-2, p53 and mdm-2 oncoproteins and cellular proliferative marker Ki-67 in early stage cervical carcinoma, with an emphasis on their association with human papillomavirus (HPV) infection, recurrence rate and lymph node status. Material and methods: Using immunohistochemistry, 69 radical hysterectomy specimens with cervical carcinoma (pT1b1/pT1b2) were studied. Evaluation of expression of p53, bcl-2, mdm-2 and Ki-67 was performed in surface area, center and invasion front of the neoplasms. The HPV presence was determined by CARD in situ hybridization. Results and conclusion: In the invasion front bcl-2 was expressed in 31 (45%), p53 in 37 (53%) and mdm-2 in 33 (47%) cases. HPV infection was detected in 40 (58%) cases. Carcinomas with a higher Ki-67 labeling index were more frequently HPV positive than HPV negative (82.5% vs 17.5%, p<0.01). No association was found between p53, mdm-2 or Ki-67 and either lymph node status or recurrence rate. Negative staining for bcl-2 was associated only with the presence of lymph node metastasis (74% vs 26%, p=0.05), and not with the recurrence rate. Significant correlation among expression of bcl-2, p53, mdm-2 oncoprotein and Ki-67 values was also observed. These results suggest that further study of a larger series is needed to confirm whether bcl-2, either alone or in combined evaluation with other markers, could be a useful marker to identify more aggressive behavior in early stage cervical carcinoma.
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Iimmunohistochemical expression of c-erbb-2 in early stage cervical carcinoma: Correlation with human papillomavirus infection and prognosis.
(Springer, 2003-09)
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Yashar, Genghis
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Kubelka-Sabit, Katerina
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Prodanova, Irina
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Zografski, George
Introduction: The attempts to determine the prognostic significance of c-erbB-2 oncoprotein expression (OPE) and its relation to human papillomavirus (HPV) infection in cervical cancer have yielded controversial. The aim of this study was to evaluate the patterns of c-erbB-2 OPE in early stage cervical carcinoma and to assess its prognostic value by exploring its relationships to various clinicopathological characteristics, HPV status and recurrence rate. Materials and methods: Radical hysterectomy specimens from 71 cervical carcinoma patients (pT1b1/1b2) were investigated immunohistochemically for c-erbB-2 presence. The c-erbB-2 score (range: 0-400) was determined in the surface area, center and invasion front of each carcinoma. CARD in situ hybridization was used for HPV detection. Results and conclusion: Strong c-erbB-2 OPE was detected in 21, 20, and 32 cases in the invasion front, center and surface area of the tumor, respectively. There was a significant difference in positive staining rate of c-erbB-2 between squamous cell, mixed carcinomas and adenocarcinomas (23%, 50% vs 83%, p=0.005). C-erbB-2 OPE was significantly higher in carcinomas with abundant than in tumors with less abundant peri-tumoral lymphocytic infiltration (36.5% vs 10.5%, p=0.032). In HPV positive carcinomas (41), c-erbB-2 was detected more frequently in type 31/33 versus type 16/18 lesions (75% vs 18.8%, p=0.002). No association was found between c-erbB-2 expression and recurrence rate, lymph node metastasis or any other clinicopathological variable investigated (age, tumor diameter, depth of invasion, grade, vascular invasion). Therefore, immunostaining for c-erbB-2 is unlikely to be of use as a prognostic indicator in early stage cervical carcinomas, while further study is warranted to examine relationships between HPV infection and c-erbB-2 OPE.
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Determination of estrogen, progesterone receptor and ki-67 immunoreactivity in early stage cervical carcinoma: Association with human papillomavirus infection and prognosis.
(Springer, 2003-09)
Yashar, Genghis
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Prodanova, Irina
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Kubelka-Sabit, Katerina
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Zografski, George
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Introduction: The predictive values of estrogen (ER) and progesterone receptor (PgR) status and cell proliferation kinetics in cervical carcinomas are still unsettled. The purpose of this study was to clarify the associations among ER/PgR status and Ki-67 expression and to determine their relationship to human papillomavirus (HPV) infection, recurrence rate and other clinicopathologic parameters (age, tumor diameter, depth of invasion, histotype, grade, vascular involvement, inflammatory infiltrate, lymph node status) in early stage cervical carcinomas. Materials and methods: ER, PgR and Ki-67 immunostaining was performed in 72 cervical carcinoma radical hysterectomy specimens (pT1b1/pT1b2). ER/PgR staining was scored in a semiquantitative fashion, while to evaluate the cell proliferation, the Ki-67 labelling index (LI) was assessed in the surface area, center and invasion front of each tumor. HPV status was determined by CARD in situ hybridization. Results and conclusion: ER positivity was detected in 11 (15%), while PgR positivity in 14 (20%) carcinomas. ER/PgR values were in correlation with Ki-67 LI in all three tumors' compartments (p<0.01). In contrast to ER/PgR status, Ki-67 LI was strongly associated with HPV infection (p<0.01). No relationship was found between PgR or Ki-67 immunoreactivity and either recurrence rate or any other clinicopathological variable investigated. Nevertheless, reduced ER expression was significantly associated with larger tumor diameter (p=0.04) and poor differentiation (p=0.03), as well as lymphovascular involvement (p=0.04) and lymph node metastases (p=0.02). These results suggest that ER, PgR and Ki-67 expression are closely related to neoplastic cell proliferation, probably induced by HPV infection. Their determination may provide additional prognostic information in early stage cervical carcinomas.
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Blood vessel invasion and inflammatory stromal reaction at the invasion front as additional significant prognostic factors in surgically treated patients with cervical carcinoma.
(Springer, 2001-09)
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Yashar, Genghis
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Veljanoska, Slavica
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Kubelka, Katerina
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Prodanova, Irina
Introduction: The objective of this study was to evaluate the prognostic significance of 23 clinical and histopathological variables in relation to disease-free (DFS) and overall survival (OS) in patients with early stage cervical carcinomas. Methods: A retrospective analysis of 237 patients with cervical carcinoma, undergoing radical hysterectomy and postoperative irradiation between 1988 and 1997 was conducted. The operative specimens were subjected to detailed and uniform histopathological work-up. The patients were staged according to the postoperative TNM classification of UICC (1997) guidelines. Mean follow-up time was 57 (18-124) months. Results: The 5 and 10-year OS rate was 80.8%, while DFS rates at 5 and 10 years were 76.8% and 75.5%, respectively. In multivariate analysis, blood vessel invasion, pelvic lymph node metastases, tumor diameter, inflammatory stromal reaction at the invasion front, and minimum thickness of uninvolved cervical stroma/parametrial extension, were independent and significant variables. The prognostic index, as an indicator of the patient's place in the prognostic spectrum, defined by the Cox regression model, was able to categorize the patients into three distinct risk groups. The 5-year DFS and OS rates of the low-, intermediate-, and high-risk groups were 97.5%, 86.3%, and 43.8%, vs. 98.8%, 84.5%, and 45.3%, respectively (P<0.0001). Conclusions: The prognostic index could be a sound basis for an appropriate planning of the following therapeutical strategy for the surgically treated patients with cervical carcinoma. The postoperative TNM classification should be modified, incorporating the blood vessel invasion and the inflammatory stromal reaction at the invasion front, as additional significant prognostic factors.
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Common blue nevus of the uterine cervix - A report of 16 cases
(Macedonian Association of Anatomists and Morphologists, 2005)
Kubelka-Sabit, Katerina
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Hadzi-Nicheva, Biljana
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Grncharovska, Zlata
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Prodanova, Irina
Blue nevus is uncommon pigmented lesion of the skin that rarely appears in the different mucoses, such as cervix or vagina. Sixteen cases of cervical blue nevi were diagnosed in our department in a five-year period (2000-2004). Localized in the stroma of the cervical canal, predominantly in the posterior lip, the lesions measured 0.1-2 cm. Prussian blue stain excluded the presence of hemosiderin and Masson-Fontana, S100 and HMB-45 stains confirmed the melanocytic nature of the lesions. Our findings are similar to those published in several studies. The recognition of this obscure lesion prevents its misinterpretation as siderosis or malignant melanoma.
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Evaluation of combined bcl-2/mdm-2 immunohistochemical expression as a prognostic factor in early stages of invasive cervical carcinomas
(Springer, 2007-08)
Prodanova, Irina
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Kubelka-Sabit, Katerina
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BACKGROUND: The present study was designed to evaluate the immunohistochemical expression of apoptosis regulating proteins (bcl-2, mdm-2 and p53) in correlation with proliferation (Ki-67), human papillomavirus (HPV) infection and other histopathological and clinical parameters in early stage cervical carcinomas and the estimation of their prognostic significance. Special attention was given to combined bcl-2/mdm-2 immunophenotypes in predicting the recurrence of the disease. METHOD: The subject of this study was a series of 83 surgically treated patients with cervical carcinoma confined to the uterine cervix (pT1b1/1b2), who subsequently received complete radiotherapy. The presence of HPV DNA was determined by the conventional method of in situ hybridization (ISH) and catalyzed reporter deposition signal amplification ISH. The immunostaining was performed using avidin-biotin-peroxidase complex method and the expression of the biological markers was semiquantitatively evaluated as the percentage of immunostained cells. RESULTS: During the clinical follow-up (mean 120.7, range 4.4-181 months) a relapse was diagnosed in 9 (10.8%) patients and the expected 5-, 10- and 15- year disease-free survival was 92.7%, 90.8% and 86.6%, respectively. The results of the univariate analysis indicate that significant predictive indicators for recurrence are: lymphonodal status, maximal tumor diameter, depth of stromal invasion, histological type and HPV DNA presence and type. Immunohistochemical markers showed the following correlations: increased expression of Ki-67 (P=0.031) and bcl-2 negativity (P=0.047) correlated with poor disease-free survival, while mdm-2 positivity showed borderline significance (P=0.051) and p53 expression had no influence on disease-free survival. Additional evaluation of combined bcl-2/mdm-2 expression showed that cases with bcl-2+/mdm-2- and bcl-2-/mdm-2+ immunophenotype had better survival (P=0.048) compared to bcl-2+/mdm-2+ and bcl-2-/mdm-2- phenotype. In the multivariate analysis, histological type, HPV DNA presence and the expression of Ki-67 have been selected as the most significant independent prognostic parameters (P=0.0024). CONCLUSION: The evaluation of combined bcl-2/mdm-2 immunohistochemical expression provides more relevant information for the prediction of the recurrence of the disease than their individual expression. However, neither individual expression of bcl-2 and mdm-2 nor their combined immunohistochemical expressions are independent predictors of prognosis in early stages of invasive cervical carcinomas.

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