Faculty of Medicine

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Predictive value of estrogen receptors evaluated by immunocytochemical analysis in breast cancer patients
(Gustav Fischer, 1997-09)
Yashar, Genghis
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Ivkovski, Ljube
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Zografski, George
BACKGROUND: The determination of estrogen receptor (ER)status is valuable in selecting the appropriate therapy and predicting prognosis for patients with invasive breast carcinoma. OBJECTIVE: The aim of our study was to assess the predictive value of ER status evaluated preoperatively by immunocytochemical analysis and compared with recurrence rate, clinical and histopathological features in 52 patients with breast carcinoma. MATERIALS AND METHODS: Fifty-two aspirates obtained by fine-needle-aspiration biopsy (FNAB) were prepared as cytospin samples for ER-immunocytochemical analysis (ER-1CA). Cytospin slides were stained using a standard procedure with horseradish peroxidase-antiperoxidase (PAP) method, utilising monoclonal antibody to ER (H222SP, ER-ICA kit, Abbott Laboratories, USA). The assessment of staining was scored in a semiquantitative fashion incorporating the intensity and the distribution of stained cells and the values were designated as IS-CYTOSCORE. All the patients underwent radical mastectomy with axillar lymphadenectomy during the period from September 1990 to March 1992 and were staged according to the postoperative pTNM classification of UICC (1987) guidelines. During the follow-up period (range, 2-75 months, mean 32) recurrences were observed in 25 (48%) patients.ER status was correlated to recurrence rate, age of the patients, type of the breast carcinoma, tumor size, grade of histologic differentiation, desmoplastic reaction, elastosis, necrosis and calcifications. The comparison was made by cross-classification and statistical significance determined by χ2 and Fisher's exact test. RESULTS: ER status was positively detected in 28 (53.8%) patients. There is significant association between ER status and age of the patients (p = 0.02), the type of the breast carcinoma (p = 0.018), and the recurrence rate (p = 0.012). Eighteen out of 26 (70%) patients 50 years or older, were positively related to ER status. In 22 (42.3%) lobular carcinomas, ER status was positive in 16 (73%) patients, compared with 30 (57.7%) ductal carcinomas, with ER status positive for 12 (40%) patients, only. Recurrences were observed in 16 (64%) patients with ER- breast carcinomas and 9 (36%) patients with ER+ breast carcinomas. Less important histopathological features as elastosis and calcifications, demonstrated statistically significant positive relation with ER status (p = 0.004 and p = 0.005, respectively). No significant association was found between the ER status and other histopathological characteristics. CONCLUSION: Our results suggest that recurrences, age of the patients and the lobular type of breast carcinoma are positively correlated with ER status. These data are consistent with the results of other similar studies. On the other hand, the stage of the disease as well as the grade of histologic differentiation and lymph node involvement, demonstrated no significant association with ER status as expected. A small number of cases studied and the heterogeneous stages included, could explain some of the differences between our data and the results from other studies. Semiquantitative ER-1CA, as fast and simple method, is especially useful in determination of ER status in recurrent, metastatic and small-sized breast carcinomas. The great advantage of ER-ICA is in a possibility of ER status preoperative determination, and repeating the procedure, if necessary. Despite the good performances, some inherent difficulties must be noted: subjectivity in scoring and detection by antigenicity of ER. Therefore, ER status quantitative assessment by using Cell-Analysing-System (CAS) and concomitant quantitative measurements of progesterone receptor status, should be of additional benefit.
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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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Postoperative TNM classification of breast cancer. Implications for further treatment (1989-1995)
(University of Niš Faculty of Medicine and the Department of the Serbian Medical Society Niš, 1996-06)
Yashar, Genghis
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This study includes 1403 postoperative breast cancer specimens elaborated in our laboratory over the period of last 7 years. The average age of the patients is 54.36 years (range 22-90) and the majority are in the age groups of 41-50 and 51-60 (55.95%). The size of the primary tumour (longest diameter) belongs mostly to the category of T2 (primary tumor 2-5 cm). There are 831 cases in this group or 59.23%. Metastatic spread in the regional lymph nodes is absent in 541 cases (38.56%) and in 278 cases (19.81 %) metastatic deposits are encountered in N1biv category (bigger than 2 cm, in the greatest diameter). The most common type of breast cancer is ductal carcinoma which is present in 649 cases (46.26%). Grade of histologic differentiation is mostly moderate (G2) with 864 cases (61.58%). The majority of the patients are in the stage II of the disease (IIA +IIB = 953 cases or 67.97%). In comparision to the similar studies found in the available references it is obvious we have fewer patients in the stage I but the same number in stage II where the disease is more advanced. This means that examination and diagnosis of the breast cancer is for a step later than the degree when usually more agressive therapy is needed considering the percent of the patients in the higher stages of the disease.
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Endometrial adenocarcinoma occuring in young women
(Hellenic Division of International Academy of Pathology, 2003-05)
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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Background: Endometrial adenocarcinoma (EA) primarily occurs in postmenopausal women. Only 1-8% of the cases are diagnosed in women under forty years of age, while this neoplasm is extremely rare in the third decade. Hysterectomy with bilateral salpingo-oophorectomy and pelvic lymphadenectomy (HSOPL) is the treatment of choice for older or patients with invasive EA. However, in young women with non-invasive well-differentiated EAs, who wish to preserve their fertility, conservative treatment with progestins can be tried. Aims: The purpose of this retrospective study is to present the clinical and morphologic characteristics, as well as the immunohistochemical profile of 3 cases of well-differentiated EAs, that occurred in women in their third decade of life. Since the neoplasms were non-invasive, an attempt to preserve their fertility has been made. Methods and patients: Six of the 1081 cases (0.5%) of EA diagnosed at the Department of Histopathology and Clinical Cytology in the last 14-year period (1989-2002), occurred in patients younger than 35 years. Three of them (1.4%, 3/206), have been diagnosed in the last two years (2001-2002). The youngest of the last three patients (age 21), had a genetic abnormality (45X/47XXX) and experienced prolonged and heavy uterine bleedings that required explorative curettage. The second patient (age 25) had a history of diabetes and infertility. The neoplasm was found in the endometrial biopsy that was taken for evaluation of the endometrial response to hormonal stimulation. In the third patient (age 27) the neoplasm was an accidental finding in the cervical curettage material that was submitted to our department, for histopathologic reevaluation of the previously diagnosed moderate dysplasia of the epithelium of the uterine cervix. The materials, obtained either by dilatation and curettage (3 cases) or HSOPL (one case), were submitted to our department and were routinely processed. Standard hematoxylin and eosin (H&E) stained slides were prepared from paraffin blocks, whereas additional histochemical (PAS, alcian blue, azan, silver by Jones) and immunohistochemical stains (estrogen-ER, progesterone-PgR, p53, Ki-67) were performed on selected paraffin blocks that contained the neoplastic tissue. Results: In the curettage materials of the three patients, fragments of endometrial polyp were identfied, that contained areas of simple, complex and atypical hyperplasia. In each of these cases, only few small (1-3-millimetre in diameter) foci of well-differentiated EA were detected. Fragments of functional endometrium were also present. All three patients had hormone (ER, PgR) responsive neoplasms, whereas Ki-67 proliferative index was significantly higher in the neoplastic tissue (30-40%), compared to the zones of atypical hyperplasia (10-20%). The suppressor gene protein product p53 was negative in all three EAs. Subsequent dilatation and curettage to remove the residual parts of the polyp was performed in two of the patients. Conservative 5-6-month treatment with progestins led to regression of the disease in all patients, documented by endoscopy and curettage in two patients. As for the youngest patient, clinical decision for HSOPL has been made, and multiple sections of the operative material did not show any residual EA. Conclusions: Even though extremely rare, EAS may occur in asymptomatic patient and/or in young women without clinical evidence of polycystic ovary disease. In these patients careful histopathologic evaluation of the curettage material is essential, in order to select the ones to whom conservative fertility-preserving treatment can be offered.
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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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Detection of human papillomavirus in early stage cervical carcinoma: Comparison of conventional and catalysed reporter deposition in situ hybridization.
(Blackwell Publishing, 2002-10)
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Kubelka-Sabit, Katerina
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Yashar, Genghis
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Prodanova, Irina
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Zografski, George
Introduction: Recently, alternative techniques have been developed to overcome the sensitivity limitation of conventional in situ hybridization (ISH), by signal amplification, which can be performed in diagnostic laboratories without the need for expensive equipment. Aims: The purpose of this study was to compare the efficiency and applicability of catalyzed reporter deposition (CARD) ISH, with those of conventional ISH in detection of human papillomavirus (HPV) in early stage cervical carcinomas. Material and Methods: Seventy-seven routinely processed specimens previously tested by conventional streptavidin-biotin-alkaline phosphatase ISH (PathoGene, Enzo Diagnostics), were reexamined by CARD-ISH performed by a biotinyl-tyramide-based detection system (GenPoint, DAKO). ISH was performed using commercial mixed biotinylated probes for HPV 6/11, 16/18, and 31/33/51 or 31/33. Discussion and Conclusion: The application of CARD-ISH increased the HPV detection rate from 33.8% (26/77) to 58.4% (45/77), the signal intensity, as well as the number of positive cells. CARD-ISH detection also enabled demonstration of multiple HPV infection in four cervical carcinomas. Diffuse and mixed staining patterns were more prevalent in conventional ISH, while a dot signal pattern presumably indicating viral integration, was highly predominant among CARD-ISH positive cases. CARD-ISH proved to be simple, fast, sensitive and effective at detecting low-copy of HPV in 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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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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Malignant diffuse peritoneal leiomyomatosis: A case report
(Expansion Scientifique Publications, 1998-10)
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Ivkovski, Ljube
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Yashar, Genghis
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Veljanovska, Slavica
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Vuzevski, Vojislav
Diffuse peritoneal leiomyomatosis (DPL) is a rare condition characterized by the presence of multiple abdominal smooth muscle nodules. Malignant transformation appears to be extremely rare. This report presents the eighth case with proven malignancy. The patient is a 43 year old, Caucasian, non-pregnant female, with no history of hormonal therapy, presented with a few months old history of intermittent and increasing right lower abdominal pain. In October 1996, explorative laparatomy was performed. Innumerable subperitoneal gray-white masses with firm to rubbery consistency, varying in size from 0.2 to 11.5 cm, were found scattered over the parietal peritoneum, omentum and mesentery. Several of these nodules were removed. Their microscopic appearance was variable. Most of the lesions appeared to consist of subperitonel nodules of benign-appearing smooth muscle cells. Nevertheless, some of them showed malignant characteristics, marked cellularity, and numerous mitoses. Immunohistochemical and ultrastuctural studies proved the smooth muscle origin of the tumors. During the next few months the abdominal tumors increased in size and the patient's condition progressively deteriorated. A second laparotomy was performed in March 1997. More than 40 nodules were removed together with a small bowel segment where inflammatory fistula was found. After receiving three courses of chemotherapy, the patient refused further treatment. In December 1997, the patient was admitted to the hospital with acute abdominal pain due to ileus, and the third laparotomy was performed. This additional case indicates that DPL has a low, but definite malignant potential, and suggests that meticulous examination of histologic material and careful follow up are required.
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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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