Faculty of Medicine

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Axillary lymph node metastases in early (pT1) breast carcinomas: Most of the common prognostic factors lack predictive value.
(University of Ioannina, 2003-09)
Yashar, Genghis
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Ivkovski, Ljube
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Zografski, George
Introduction: Axillary lymph node status is an important prognostic feature for patients with breast cancer, but the diagnostic and therapeutic value of axillary lymph node dissection in early breast carcinomas has been questioned. Aim: The purpose of this retrospective study was to determine whether routine biological tumor markers, in addition to conventional clinical and histopathological features can predict axillary lymph node metastases in early breast carcinomas (pT1). Material and methods: Data from 90 patients with pT1 breast cancer who underwent radical mastectomy or lumpectomy with axillary lymph node dissection between January 2000 and April 2003 were investigated. The association between axillary lymph node status and several clinicopathological factors (age, size, tumor grade, histological type), as well as immunohistochemical expression of estrogen and progesterone receptors (ER/PgR), Ki-67 and p53, were analyzed. Hormone receptor status, Ki-67 and p53 expression were assessed by immunohistochemistry and the results were evaluated by performing the standardized scoring system. Results: From the total of 90 patients, 35 (396) were with axillary lymph node metastases. Among the factors studied only the tumor size appeared to correlate with the incidence of lymph node involvement, but this was not statistically significant (p=0.07). Axillary lymph node involvement was present in 4 (286) of the 19 patients with primary tumors <1cm (pT1a+pT1b), compared with 31 (44%) of the 71 with tumors >1cm (pT1c). Hormone receptor status, proliferative activity (Ki-67), and p53 expression were not predictors of nodal involvement in early breast carcinomas. Conclusion: Therefore, biological tumor markers as well as most of the common prognostic clinicopathological factors are not reliable predictors of lymph node metastasis in early breast carcinomas.
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HER2/neu expression in correlation with p53 and Ki-67 immunoreactivity and clinicopathological parameters in breast cancer patients.
(Blackwell Publishing, 2002-10)
Yashar, Genghis
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Ivkovski, Ljube
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Kraleva, Slavica
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Prodanova, Irina
Introduction: Although the role of HER2/neu status is still unsettled, its determination is valuable in selecting breast carcinoma patients for adequate Herceptin therapy. Aims: The purpose of this study was to evaluate the association among HER2/neu, p53 and Ki-67 immunoreactivity, as well as clinicopathological parameters (tumour size, histopathologic grade, nuclear grade, tumour type. lymph-node status and age) in breast cancer patients. Materials and methods: HER2/neu, p53 and Ki-67 expression was determined in 169 post-operative stage I-III (UICC. 1997) breast cancer patients using the standardized DAKO HercepsTest and by immunoperoxidase technique. respectively. The results were evaluated by performing the standardized scoring system. Discussion and conclusion: HER2/neu expression was positive in 66 patients (37%). There was no association between HER2/neu expression and p53 or Ki-67 immunoreactivity as well as any clinicopathological parameter, while the values of Ki-67 and p53 were strongly interrelated (P < 0.001). Ki-67 was also in significant correlation to tumour size, lymph-node involvement and tumour type (P<0.001), while p53 was only related to patients' age (P <0.01). These results indicate that HER2/neu is an independent prognostic marker in differentiating a subgroup of high-risk breast cancer patients. Additional studies are required to adjust HER2/neu testing results to clinical outcome.
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Association between Her2/neu expression and hormon receptor status in breast cancer patients.
(2002-06)
Yashar, Genghis
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Kraleva, Slavica
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Vasev, Nikola
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Ivkovski, Ljube
Determination of HER2/neu expression by immunohistochemistry is mandatory for application of Herceptin® therapy in breast cancer patients. The purpose of this study was to investigate the association between HER2/neu expression and hormone receptor status, as well as with other clinicopathological parameters in breast cancer patients. HER2/neu, p53 and Ki-67 expression was determined in 169 postoperative stage I-III (UICC, 1997) breast cancer patients using the standardized DAKO HercepsTest® and immunoperoxidase technique, respectively. The results of HER2/neu immunoreactivity were evaluated by performing the standardized scoring system (0 = negative, 1+ = weakly positive, 2+ = positive, 3+ = strongly positive staining), while ER and PgR were scored in a semiquantitative fashion (ER-ICA and PR-ICA). The results from HER2/neu expression were correlated to hormonal receptor status and clinicopathological parameters (tumor size, histopathologic grade, nuclear grade, histologic type of the tumor, lymph node status and patient age). Statistical significance was determined with χ2 and Fisher’s exact test. HER2/neu expression was positive in 66 patients (37%). There was no significant association between the values of HER2/neu and ER/PgR status, or with any other clinicopathological parameter. ER status significantly correlated with PgR status (p<0.01), tumor size (p<0.01), lymph-node involvement (p<0.01) and tumor type (p<0.01). PgR status was related to the histopathologic grade (p<0.01), lymph-node status (p<0.01), tumor type (p<0.01) and patient age (p<0.01). HER2/neu is a relatively new promising marker in predicting the response to target specific therapy. However, its predictive value remains a complex and inconclusive subject. According to our results, the prognostic potential of HER2/neu seems to be independent from hormone receptor status and any other clinicopathological parameter in breast cancer patients.
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Expression of p53 and Ki-67 immunoreactivity in breast cancer patients.
(Institute of Oncology, Sremska Kamenica, Yugoslavia, 2001-03)
Yashar, Genghis
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Kubelka, Katerina
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Zografski, George
The aim of this study is to investigate the association between p53, Ki-67 expression and hormone receptor status as well as clinicopathological parameters in breast cancer patients. The study group consists of 146 breast cancer patients (stage I to stage III, according to the postoperative TNM classification of UICC, 1997 guideline system) who underwent radical mastectomy with axillary lymphadenectomy between January 1998 and March 2000. The expression of p53, Ki-67, estrogen receptor (ER) and progesterone receptor (PgR) has been evaluated by using standard immunoperoxidase technique. The scoring system has been performed for determination the results of p53 and Ki-67 immunoreactivity. The semiquantitative ER-ICA and PR-ICA scoring system has been used for assessment of staining for ER and PgR. The results from p53 and Ki-67 expression were correlated to hormon receptor status, and to clinicopathological parameters. Statistical significance was determined with x2 test. Strong correlation was found between the values of p53 and Ki-67 (p<0.00001), p53 and ER (p=0.0004), Ki-67 and ER (p=0.0006) as well as ER and PgR (p<0.0001). p53 and Ki-67 expressed additional correlation to the age of the patients (p=0.01). No correlation was found between p53, Ki-67, ER as well as PgR and lymph node involvement or the stage of the disease. The preliminary results of our study suggest that determination of p53 and Ki-67 expression associated to hormone receptor status and some clinicopathological parameters could be helpful in standardizing the protocols for further treatment of breast cancer patients. However, additional investigations with long term follow-up of the patients are needed to clarify the prognostic significance of p53 and Ki-67 immunoreactivity
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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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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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Immunohistochemical study of phyllodes tumor of the breast
(Springer, 1999-09)
Yashar, Genghis
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Kubelka, Katerina
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Zografski, George
Phyllodes tumor ('PT) is a rare, fibroepithelial breast neoplasm with unpredictable prognostic and controversial therapeutic aspects. Aims: The aim of this retrospective study is to evaluate Ki-67 and CD34 antigen expression, as well as estrogen (ER) and progesterone receptor (PgR) status in stromal cells, as additional diagnostic criteria in assessing different types of PT. Methods: Routinely processed, formalin-fixed and paraffin-embedded surgical specimens from 47 cases of PT were stained by immunoperoxidase technique using Ki-67, CD34, ER and PgR monoclonal antibodies. On the basis of histopathological criteria proposed by Azzopardi, 6 malignant, 12 borderline and 29 benign PT have been evaluated. The mean size of the tumour was 9.4 cm (range 2.8-20 era). During the follow-up period (mean 50, range 2-127 months), recurrences were observed in 8 patients (17%). Results: The proliferating index determined by Ki-67 antigen expression was significantly different between histologically benign PT (19%), borderline PT (25%) and malignant PT (50%). There was a difference of the human progenitor cell CD34 antigen expression in malignant PT (50%), borderline PT (50%) and benign PT (30%). As expected, the stromal cells in various types of PT were mostly ER negative and PgR positive. Conclusions: Our preliminary results suggest that CD34 positivity and high proliferative index of Ki-67 antigen in stromal cells are more frequently associated with high grade PT. Therefore, the immunohistochemical features could provide better discrimination between different PT types. The prognostic implications of these observations should be evaluated in additional studies.
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Immunohistochemical expression and prognostic significance of DCC (deleted in colon cancer), p53 protein and proliferative marker Ki-67 in colorectal colon cancer.
(Springer, 2005-05)
Yashar, Genghis
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Prodanova, Irina
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Kubelka-Sabit, Katerina
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Objectives: The objective of this study was to evaluate the immunohistochemical expression of Deleted in colon cancer (DCC), p53 protein and proliferating index Ki-67 in correlation with various clinico-pathological (age, sex, tumor status, lymph node involvement, localization, tumor diameter, grade of differentiation, histological type) and biomolecular parameters (loss of heterozygosity of the long arm of chromosome 18 and microsatellite instability) in colorectal cancer patients. In addition, the prognostic significance of their influence on overall survival (OS) was also estimated. Methods: A retrospective analysis of 100 patients with colorectal cancer who underwent large bowel resection with regional lymphadenectomy was conducted in the period between 1995 and 2000. All the patients were in stage II and stage III of the disease according to the postoperative TNM classification of UICC (1997) guidelines. The immunohistochemical expression of protein products of the DCC, p53 tumor suppressor genes and Ki-67 proliferating index were semi-quantitatively evaluated. Biomolecular analyses for the loss of heterozygosity of the chromosome 18q and microsatellite instability were performed with the Polymerase chain reaction (PCR) technique. Results: In our case series, 57 (57%) patients were in stage II, and the remaining 43 (43%) patients in stage III of the disease. During the follow-up period (mean 53, range 5-97 months), 41(41%) patients died of the disease. The expected 5-year OS rate was 58.6%. In the univariate analysis, tumor status, lymph node involvement, sex, age, tumor grade, p53 protein expression and Ki-67 proliferating index were parameters with prognostic significance related to OS (p<0.05). Among these variables, in the multivariate analysis the tumor status and Ki-67 proliferating index were selected as independent and significant prognostic factors related to OS (p=0.0019). According to the value of the prognostic index (PI) defined by Cox regression model, the patients were categorized in two distinct risk groups. The 5-year OS rate of the low- and high-risk group patients was 65.0% vs. 29.4% (p=0.001). The 5-year OS for stage II was 71.1% vs. 40.0% (p=0.05) and for stage III of the disease it was 54.8% vs. 25.0% (p=0.03), respectively. Conclusions: These data indicate that defining prognostic groups in each stage of the disease allow an exact and objective selection of colorectal cancer patients with different death risk. Therefore, the prognostic index (PI) as an indicator of the patient’s place in the prognostic spectrum could be a sound basis for an appropriate planning.
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Ovarian cellular fibromas: A cliniopathological and immunohistochemical analysis of 10 cases.
(Springer, 2007-08)
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Prodanova, Irina
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Kubelka-Sabit, Katerina
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Zografski, George
BACKGROUND: Traditionally, cellular fibroblastic tumors of the ovary were classified as either cellular fibroma (CF) or fibrosarcoma. A recent study suggests that cellular fibromatous neoplasms with bland cytology and elevated mitotic counts are associated with favourable prognosis and should be diagnosed as "mitotically active cellular fibroma" (MACF) rather than fibrosarcoma. In addition to clinicopathological features, immunohistochemistry may aid in further differentiating between CF and MACF, but its role has not been analyzed so far. METHOD: We retrospectively analyzed the clinicopathological and immunohistochemical features of 10 cases of ovarian cellular fibroblastic tumors diagnosed either as CF or fibrosarcoma in the last seven years. Patient records and archival pathology specimens were reviewed and immunohistochemistry was performed using pan-cytokeratin, EMA, vimentin, inhibin-alpha, calretinin, CD10, CD99, alpha-smooth muscle actin (SMA), desmin, S-100, c-kit, estrogen (ER), progesterone receptor (PR), p53, bcl-2, and MIB-1 antibody. RESULTS: Utilizing criteria proposed by Irving et al. the tumors were reclassified as CF (0-3 MFs/10 HPFs, n=5) and MACF (>4 MFs/10 HPFs, n=5). The mean age of patients with CF and MACF was 44 and 36 years, respectively. All tumors were unilateral, and the mean tumor size of CFs was 6.0 cm and 13.3 cm for MACFs. The majority of the tumors were solid; four of them had a cystic component, while ovarian surface rupture was present in one CF and one MACF. All tumors consisted of cellular, intersecting bundles of spindle cells showing slight or moderate pleomorphism. The mean highest mitotic count was 2.3 MFs/10 HPFs for CF, and 7.6 MFs/10 HPFs for MACFs. Follow-up of 4 to 79 months (mean 38 months) was available in 9 patients and was uneventful in all cases. One patient with MACF died 15 days following the operation as a result of the intercurrent disease. Immunohistochemical analyses showed that spindle cells in majority of the tumors were immunoreactive for vimentin, alpha-SMA, inhibin-alpha, calretinin, PR, and bcl-2. All tumors were negative for pan-cytokeratin, EMA, CD10, CD99, c-kit, ER, and p53, while one CF was positive for S-100, and one MACF showed positivity for desmin. In addition, the MIB-1 labeling index (LI) in MACFs was higher (mean 14.4%, range 10-25%), than that in CF (mean 5.6%, range 3-10%). CONCLUSION: Our results confirm the immunophenotypic similarity between ovarian fibromas and cellular fibromatous neoplasms, and suggest that the use of MIB-1 LI may help in differentiating between CF and MAFC.

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