Faculty of Medicine

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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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Her2/neu expression in breast cancer patients - Correlation with estrogen and progesterone receptor status, p53 and Ki-67 immunoreactivity and clinicopathological parameters
(Institute of Oncology, Sremska Kamenica, Yugoslavia, 2002-09)
Yashar, Genghis
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Prodanova, Irina
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Vasev, Nikola
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Kraleva, Slavica
Although the role of HER2/neu status is still unsettled, its determination is valuable in selecting breast carcinoma patients for adequate Herceptin¨ therapy. The purpose of this study was to investigate the association between HER2/neu expression with estrogen (ER) and progesterone (PgR) receptor status, p53 and Ki-67 immunoreactivity, as well as with other clinicopathological parameters in breast cancer patients. HER2/neu, ER/PgR status, p53 and Ki-67 expression was determined in 169 postoperative stage I-III (UICC, 1997) breast cancer patients using the standardized DAKO HercepsTest¨ and by the immunoperoxidase technique, respectively. The results were evaluated by performing the standardized scoring system. The values of HER2/neu expression were correlated to ER/PgR status, p53 and Ki-67 immunoreactivity and to clinicopathological parameters (tumor size, histopathologic grade, nuclear grade, tumor type, and lymph node status and patients’ age). The statistical significance was determined with c2 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, p53 or Ki-67 immunoreactivity, neither with any other clinicopathological parameter. ER is associated with PgR, tumor size, tumor type and lymph node status (p<0.01); PgR with histopathologic grade, tumor type and lymph node status (p<0.01) and Ki-67 with p53 immunoreactivity, tumor size and patients’ age (p<0.01). The results of the current study 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 the clinical outcome.
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Uterine myxoid leiomyosarcoma arising in a leiomyoma - A case report.
(Institute of Oncology, Sremska Kamenica, Yugoslavia, 2002-09)
Hadzi-Nicheva, Biljana
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Prodanova, Irina
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Yashar, Genghis
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Kubelka, Katerina
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Grncharovska, Zlata
Myxoid leiomyosarcoma of the uterus (MLU) is a very rare neoplasm. We report a case of MLU arising from a pre-existing leiomyoma. Between 1989 and 2001, 45 uterine leiomyosarcomas were diagnosed in our laboratory and MLU was established in one case only (2.1%). Subtotal hysterectomy was performed on a 56-year woman with clinical diagnosis of a uterine myoma. The histopathological processing included hematoxylin-eosin, histochemical and immunohistochemical staining of selected specimens. Macroscopically, the uterus measured 15 x 12 x 11 cm, with an indistinctly circumscribed multi-nodular tumorous mass 10.5 cm in diameter, and infiltrative satellite nodules in the surrounding myometrium. The morphology of the neoplasm showed a leiomyoma with distinct degenerative changes, necrosis and hemorrhage. In some areas the cells were round or oval with a vacuolated cytoplasm, slight atypia and rare mitoses. The mitotic count was 1-3 cells/10 HPF. Due to the presence of an abundant mucoid substance, these areas appeared as hypocellular. The additional processing confirmed the smooth muscular origin of the neoplasm (Masson trichrome, azan, desmine, alfa-smooth muscle actin and vimentine positive). The areas of the myxomatose nodules were characterized with hormone independence (estrogen and progesterone receptors negative), high proliferative activity (Ki-67 - 30%) and the presence of p53 protein product (45%). The areas of the pre-existing leiomyoma showed hormone dependence, low proliferative activity and absence of p53 protein product. Additional immunostaining is useful in supporting a diagnosis of MLU in myxoid uterine smooth-muscle tumors with a low mitotic rate.
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Lipoleiomyoma of the uterus: Immunohistochemical analysis of 11 cases.
(Institute of Oncology, Sremska Kamenica, Yugoslavia, 2002-09)
Prodanova, Irina
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Hadzi-Nicheva, Biljana
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Yashar, Genghis
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Kubelka, Katerina
The histogenesis of uterine lipoleiomyomas (UL), which are commonly considered to be rare tumors, has not been fully clarified. The purpose of this study is to ascertain the actual incidence of UL, and to establish the origin of the lipomatous component in UL. Out of the total of 812 uterine smooth muscle neoplasms diagnosed over the period between May 2001 and May 2002, 11 were UL (1.4%). The tissue samples from all cases were routinely processed, and the lipid content was histochemically demonstrated with Oilred-O. This method was performed in areas, which were macroscopically suspected to contain fatty tissue. Selected sections were immunostained. Ten leiomyomas and one smooth muscle neoplasm of uncertain malignant potential, with various amounts of the lipomatous component were identified. In three tumors the lipomatous component consisted of mature lipocytes. In eight tumors, the perivascularly localized focal areas of cells with pale abundant cytoplasm similar to smooth muscle cells or to fibrocytes containing cytoplasmatic lipid droplets were found. Immunohistochemically, the cells in the perivascular areas were positive for S-100 protein, desmin, vimentin, neuron specific enolase, alpha 1-antitrypsin, CD 34 and collagen IV and were negative for alpha-smooth muscle actin. Additionally, these cells and mature lipocytes were negative for estrogen and progesterone receptors. Our results suggest that UL are not rare neoplasms and that lipomatous differentiation in leiomyomas can be found more frequently than expected. Immunohistochemical results indicate that lipomatous cells, as well as smooth muscle cells, derive from multi-potential undifferentiated mesenchymal cells.
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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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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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Benign and malignant pigmented lesions of the female genital tract (FGT). Report of 15 cases.
(Springer, 2001-09)
Kubelka, Katerina
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Yashar, Genghis
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Prodanova, Irina
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Ivkovski, Ljube
Introduction: Benign and malignant pigmented lesions (PL) of the FGT are uncommon, predominantly affecting the vulva. Methods: We report the clinical and pathological features of the 15 PL of the FGT retrieved in a 12-year, retrospective analysis at our Department. Patient records and archival pathology specimens of 7 benign and 8 malignant PL of the FGT, were reviewed. Results: The mean age of all patients was 47 (range, 28-67). Three patients had vulvar nevi (2 intradermal and 1 dysplastic), while blue nevi ranging 2-10 mm in diameter were accidentally discovered in the endocervix of the hysterectomy specimens in four other patients. Vulvar primary malignant melanomas (PMMs) were uncommon (4 cases), comprising 2.5% of female PMMs and 4.3% of all vulvar malignancies diagnosed between 1989 and 2000. Contrary to other studies, all vulvar PMM in our series were of nodular type, ranging 3-13 mm in depth according to Breslow and III-IV level according to Clark. Within the same period, two patients with malignant PL of the uterine cervix were detected, accounting for 0.13% of all females with malignant cervical neoplasms. One of them had a PMM diagnosed in advanced clinical stage (FIGO III), and the other patient had an unusual pigmented squamous cell carcinoma in liB postoperative stage. There were also 2 cases of delayed unilateral ovarian metastases of cutaneous PMM. The diagnosis in all cases of non-vulvar pigmented lesions was confirmed by immunohistochemistry. Conclusions: Although uncommon, PL especially those affecting rare localizations must be considered as diagnostic possibility in FGT.
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Myoepithelial carcinoma of the breast arising in adenomyoepithelioma. A case report.
(Springer, 2001-09)
Yashar, Genghis
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Ivkovski, Ljube
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Kubelka, Katerina
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Zografski, George
Introduction: Adenomyoepithelioma (AME), and especially myoepithelial carcinoma (MC), the malignant variant of this tumor, is a rare breast neoplasm. This report comprises the pathological features of a breast MC arising in AME with an aggressive clinical course. Case report: A 48-year old woman with a palpable mass in the right breast was admitted in November 1998. A month later following FNAB, surgical excision was performed. During the follow-up period of 17 months, until the patient's death, two local recurrences developed. Despite the aggressive chemotherapy, administrated after the first recurrence, subsequently bone, pulmonary and brain metastases appeared. Results: The primary tumor was an ovoid, white-grey, encapsulated mass measuring 4x3,5x1,5 cm. Microscopically, this biphasic tumor was composed of rare tubules surrounded by interlacing bundles of spindle cells exhibiting mild atypia. It was initially classified as a benign phyllodes tumor. The immunohistochemical analyses performed after the second recurrence proved the myoepithelial origin of the neoplasm (S-100, cytokeratin and alpha-SMA positive cells), with a high mitotic index (11 MF/10 HPF), and an immunophenotype indicating aggressive biological potential (steroid receptor negative, 50% Ki-67 and 30% p53 positive cells). Therefore, it was reclassified as MC arising in spindle cell type of AME. Conclusion: The histopathological diagnosis of AME could be very difficult, especially when a distinction from other spindle cell breast neoplasms must be done. Immunohistochemistry is essential to confirm the diagnosis, having in mind the reported pathological characteristics and the immunohistochemical profile of recurrent and malignant tumors of this type.
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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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Paravaginal female adnexal tumor of probable Wolffian origin. A case report
(Springer, 1999-09)
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Yashar, Genghis
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Kubelka, Katerina
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Zografski, George
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Stavrik, George
Female adnexal tumor of probable Wolffian origin (FATWO) is a rare neoplasm originating from mesonephric remnants. Approximately 50 cases have been reported, predominantly arising in broad ligament, mesosalpinx, ovarian hilus, and periadnexal region. Aims: The aim of this report is to present the clinical and pathological features of a FATWO occurring in paravaginal area. So far, there have been only two cases reported to occur at this site. Case report: The patient is a 23-year old, nuliparous female, presented with a painless fixed paravaginal tumor. In August 1995, explorative laparatomy was performed. Encapsulated ovoid, tumor, located between urinary bladder and vagina, tightly fixed to vaginal wall connective tissue, was found. The uterus and both adnexa appeared unremarkable. The tumor was removed and biopsy sample from left ovary was taken. The patient had had an uneventful post-operative course and she remained well, without evidence of recurrence, 42 months after laparatomy. Results: The tumor was a solid ovoid mass with smooth surface, measuring 6.7 x 5 x 3.7 cm. On sectioning, the neoplastic tissue was solid, soft, butter yellow in colour; multiple cysts varying up to 3 cm in diameter and hemorrhagic foci were also present. Microscopically, it was well circumscribed and surrounded by fibrous capsule, composed of tumor cells arranged in different patterns: solid, closely packed tubules, and microcystic. The histochemical and immunohistochemical features of the tumor were identical to other cases of FATWO reported in the literature. Conclusions: Although the majority of these tumors are benign, a few cases have shown definite low malignant potential, with metastases and recurrences developing after at least 6 to 16 years following radical surgery. The presented case indicates that in spite of the unusual location, FATWO must be recognized, ensuring a careful and prolonged follow-up.

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