Faculty of Medicine

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Case report of insular carcinoid arising from mature cystic teratoma.
(Austin Publishing Group, 2022-12)
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Sejfullai, Siandra
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Shabani, Nezhla
Primary ovarian Neuroendocrine Tumors (NETs) develop in pure form or in association with other tumors, mainly teratomas. Teratomas are the most common type of ovarian germ cell tumor. They are divided into three categories: mature (cystic or solid, benign), immature (malignant), and monodermal or highly specialized. Most teratomas are cystic and composed of mature adult-type tissues; they are better known as dermoid cysts. The Mature Cystic Teratoma (MCT) accounts for more than 95 percent of all ovarian teratomas and is almost invariably benign. Mature cystic teratomas contain mature tissue of ectodermal (e.g, skin, hair follicles, sebaceous glands), mesodermal, and endodermal origin. They are bilateral in 10 to 17 percent of cases. Malignant transformation occurs in 0.2 to 2 percent of mature cystic teratomas. Mature teratomas with malignant transformation comprise 2.9 percent of all malignant OGCTs. The most common malignant change in a dermoid cyst is squamous cell carcinoma, followed by adenocarcinoma and carcinoid tumor. The prevalence of Primary Ovarian Carcinoids (POC) is merely 0.1% in ovarian neoplasms and 1% in carcinoid tumors. POC was classified into trabecular, strumal, mucinous, and insular types, among which the latter is the most prevalent type and the only 1 associated with Carcinoid Syndrome (CS.) We report an extremely rare case of insular carcinoid tumor arising from a mature cystic teratoma with typical clinical manifestation.
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A new familial mutation in the SRY gene (Arg133Gly)
(Macedonian Academy of Sciences and Arts, 2006-09)
Plaseska-Karanfilska, Dijana
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Noveski, Predrag
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Kuzevska, Klementina
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Mutations in the testis-determining gene SRY result in XY sex reversal with pure gonadal dysgenesis (PGD). Most of the SRY mutations affect the HMG domain of SRY which plays a central role in DNA binding and bending activity of SRY. The arginine at codon 133 is conserved in the SRY gene of all studied species. It is part of the basic C-terminal region of the HMG box, which was proposed to provide nuclear localization signal. A de novo Arg133Trp mutation was described in two unrelated patients with pure gonadal dysgenesis. Impaired nuclear localization of SRY was proposed as a cause of organogenesis failure for mutations affecting Arg133. Here we describe a novel mutation that affects codon 133 of the SRY gene, resulting in an arginine to glycine substitution in the protein. It was detected in a 17 years old girl with primary amenorrhea, non-mosaic 46,XY karyotype and bilateral gonadoblastoma. The Arg133Gly mutation in the SRY gene was also detected in patient’s father, who is a phenotipically normal male. However, the mutation was not found in the SRY gene of 90 other males, thus excluding the possibility of a common polymorphism. Our report of familial Arg133Gly mutation suggests that replacement of Arg 133 of the SRY is not sufficient for impaired organogenesis and emphasizes the importance of modifier genes in the sex determination pathway.
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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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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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