Faculty of Medicine

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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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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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Small and large cell neuroendocrine carcinomas of the uterine cervix. A report of 10 cases.
(Springer, 2005-08)
Kubelka-Sabit, Katerina
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Plaseska-Karanfilska, Dijana
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Prodanova, Irina
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Yashar, Genghis
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Hadzi-Nicheva, Biljana
BACKGROUND: Small (SCC) and large cell (LCC) neuroendocrine carcinomas of the uterine cervix are rare and highly aggressive neoplasms. Their association with the integration of human papilloma virus (HPV) DNA of the types 16 or 18 has been documented in many studies. AIMS: The purpose of this study is to present the clinical, histopathological, immunohistochemical characteristics and the presence of HPV DNA in ten cases of SCCs and LCCs of the uterine cervix. METHODS: Seven patients with primary SCCs and three patients with LCCs of the uterine cervix were diagnosed at our department between 1989 and 2004. Clinical data were retrieved from the patients’ files and included age, recurrence and survival. Routinely processed operative and/or biopsy specimens were used for immunohistochemical stains and hybridization procedures. Primary antibodies against several epithelial, neuroendocrine, mesenchimal and proliferative markers were included. The presence of HPV DNA was assessed by conventional in situ hybridization (ISH) using probes for HPV 16/18 and 31/33/51 and polymerase chain reaction (PCR), using three primers (MY09/11, GP5+/GP6+, E6). Six of the patients were surgically treated. Postoperatively, four received chemo and/or radiotherapy, two rejected further treatment and one patient was lost to follow-up. The other four patients underwent conservative treatment due to advanced disease. RESULTS: The patients’ age ranged from 25 to 71 years. Histologically, the tumors showed trabecular, nesting or a sheet-like pattern, with areas of necrosis and frequent mitoses. Their neuroendocrine nature was confirmed by diffuse positive immunostaining for neuron-specific enolase and low-molecular weight cytokeratins. Focal positivity for chromogranin, synaptophysin and S100, together with pancytokeratin and EMA, was evident in the majority of the tumors. Their aggressive potential was confirmed by high Ki-67 proliferative index (50-90%). HPV types 16/18 were found in 4 tumors using ISH, and HPV 16 in additional 3, using PCR (type 16). 3 of the patients developed distant metastases and died 7-48 months after receiving partial or full treatment, while 6 are alive and without evidence of disease after 4-38 months. CONCLUSIONS: SCCs and LCCs are highly aggressive neoplasms. However, early diagnosis and combined therapy may improve survival in some patients. Although mainly a morphologic diagnosis, immunohistochemistry may help in the diagnosis of SCC and LCC.
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Ki-67 expression in the invasion front as an additional independent significant prognostic factor influencing reccurence in early stage cervical carcinomas.
(Springer, 2005-08)
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Prodanova, Irina
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Kubelka-Sabit, Katerina
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Yashar, Genghis
INTRODUCTION: The attempts to determine the prognostic significance of biological markers and their relation to human papillomavirus (HPV) infection in cervical cancer have yielded controversial results. AIMS: The aims of this retrospective study were to correlate alterations of cell proliferation, growth, differentiation and apoptosis regulatory proteins in early stage cervical carcinomas with HPV infection, histopathological and clinical parameters, and to estimate their prognostic significance. METHODS: Expression of Ki-67, p53, mdm-2, bcl-2, c-erbB-2, EGFR protein, as well as estrogen and progesterone receptors was evaluated by immunohistochemistry in operative specimens of 83 patients with early stage cervical carcinoma. The results were assessed semiquantitatively in the surface area, center and invasion front of each tumor as a percentage of the immunostained cells and/or intensity of immunostaining for each protein. The presence of HPV was assessed by conventional in situ hybridization (ISH) technique and catalyzed reporter deposition signal amplification ISH using mixed biotinylated probes to identify types 6/11, 16/18 and 31/33 or 31/33/51. RESULTS: In our case series 73 patients had a tumor limited to the uterine cervix less than 4 cm in diameter (pT1b1), while 10 patients had larger neoplasms belonging to pT1b2 category. Pelvic lymph node involvement was found in 20 patients. During the follow-up period (range, 65 -181, mean, 121 months) recurrences were observed in 9 patients. The 5, 10 and 15-year disease-free survival rate was 92.7%, 90.8% and 86.6%, respectively. Among the 18 variables pelvic lymph node involvement (P=0.0008), tumor diameter (P=0.035), depth of stromal invasion (P=0.029), histotype (P=0.0009), grade (P=0.056), HPV DNA presence (P=0.056), HPV type (P=0.043), as well as bcl-2 (P=0.035), mdm-2 (P=0.051), EGFR (P<0.0001), and Ki-67 (P=0.031) expression in the tumor’s invasion front were identified as important predictive indicators of recurrence in the univariate analysis. Independent significant prognostic factors for disease-free survival in multivariate analysis were the histotype, HPV DNA presence and Ki-67 expression. CONCLUSIONS: The invasive front of carcinomas proved to be the most important area for tumor prognosis. In addition to the detection of HPV presence and morphological parameters, Ki-67 evaluation could be used in selecting appropriate therapeutical approaches in patients with early stage cervical cancer.
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Ovarian mucinous cystadenoma with murale nodule of poorly differentiated squamous cell carcinoma. Report of a case
(Blackwell Publishing Ltd., 2008-10)
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Prodanova, Irina
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Kubelka-Sabit, Katerina
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Zografski, George
Background. Mural nodules associated with mucinous and serous tumors of the ovary may represent a reactive process, a benign tumor, or a malignant neoplasm. Thus, the prognosis of the ovarian tumor can be dramatically modified by the presence of this nodule. We report the clinicopathologic and immunohistochemical findings of a case of a mural nodule of anaplastic squamous cell carcinoma associated with ovarian mucinous cystic tumor. Case report. The patient was a 66-year-old postmenopausal woman (gravida 1, para 1) with a 6-month history of increasing abdominal fullness. An abdominal ultrasound revealed a multilocular left ovarian cyst with a solid component. After total abdominal hysterectomy and bilateral salpingo-oophorectomy, the diagnosis of a mucinous cystadenoma with a focus of FIGO stage IC anaplastic carcinoma in the left ovary was made. The patient received six courses of chemotherapy; 3 months after completing chemotherapy, she developed rectosygmoidal wall metastases. Despite rectosygmoid resection and additional chemotherapy and radiotherapy, the disease persisted in the pelvis and the patient died 14 months after initial operation. The primary tumor nodule as well as metastatic rectosygmoid tumors were studied by conventional and immunohistochemical methods. Results. The left ovarian tumor measured 8.5 x 8 x 6 cm. On cut sectioning, it was multilocular with a solid 4.5 x 4 x 3 cm mural nodule. Microscopically, the cyst wall was predominantly lined with benign mucinous epithelium, with rare foci of endometriosis found in smaller locules. The solid area of the mural nodule showed nests of spindle or polygonal highly malignant cells with admixed inflammatory cells. Necrosis and hemorrhage were also present. The ovarian capsule was invaded by the pleomorphic tumor cells. In favor of a diagnosis of anaplastic carcinoma were poor circumscription of the nodule with lymph-vascular involvement and absence of a prominent inflammatory reaction with multinucleated giant cells of the epulis type. In addition, the metastatic rectosygmoid tumor showed poorly differentiated squamous cell carcinomatous features. Immunohistochemically, the atypical cells of the nodule as well as a metastatic tumor were uniformly positive for epithelial markers such as pan-cytokeratin, high-molecular weight cytokeratin, cytokeratin 7 and epithelial membrane antigen, negative for carcinoembryonic antigen and focally weakly positive for vimentin. Many of these cells were also immunoreactive for p53 (80-90%) and Ki-67 (40-50%). Conclusion. The occurrence of ovarian mucinous cystic tumor with mural nodule of poorly differentiated squamous cell carcinoma is evidently very uncommon, because we have not found a similar case in the literature. The malignant nodules composed of sarcoma or anaplastic carcinoma such as in our case are associated with an unfavourable outcome and must be distinguished from other sarcoma-like nodules that may also occur in the wall of mucinous ovarian tumours. Therefore, the implementation of strict morphologic criteria supplemented by immunohistochemistry aids in the sometimes difficult differential diagnosis among these types of mural nodules.
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Malignant perivascular epithelioid cell tumor of the uterus with aggressive behaviour: A case report
(Blackwell Publishing Ltd., 2008-10)
Prodanova, Irina
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Kubelka-Sabit, Katerina
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Background. The perivascular epithelioid cell tumor (PEComa) is recognized by the World Health Organization as a mesenchymal neoplasm showing at least partial morphological and immunohistochemical evidence of a putative perivascular epithelioid cell differentiation. This family of tumors includes angiomyolipoma (AML), lymphangioleiomyomatosis (LAM), clear cell sugar tumor of the lung and distinctive clear cell tumors at various other anatomic sites. Occasionally, PEComas are associated with the tuberous sclerosis complex (TSC). Because non-AML/non-LAM PEComas are extremely rare and their nature and prognostic factors undefined, we present a case of uterine PEComa with obviously aggressive behavior. Case report. A 55-year-old (gravida-2, para-2) presented with a large uterine mass palpated during a routine gynaecological examination. The patient did not have any stigmata or family history of TSC, and had no history of melanoma. A transvaginal ultrasound revealed an enlarged uterus with a heterogeneous mass which size was estimated at 9 x 9 cm. The clinical impression of the lesion was a leiomyoma. Total abdominal hysterectomy with bilateral salpingo-oophorectomy and omentectomy was performed 9 months later, and the pathohistological diagnosis was malignant PEComa of the uterus with metastases in the omentum. Three months after the surgical intervention the patient is still receiving adjuvant chemotherapy and there is no evidence of recurrence. Results. The uterine body was enlarged and measured 12 x 14 x 8 cm, with lobulated surface. Within the myometrium there was a poorly demarked gray-ten nodular tumor occupying the fundus, anterior and posterior walls with focally hemorrhagic areas and necrosis on cut surface. The largest diameter of the tumor was 14 cm. In the adipose tissue of the omentum there were numerous nodular tumor masses whose diameters ranged from 1 to 3 cm. Histologically, the tumor demonstrated a tongue-like growth pattern and was composed of large epithelioid cells with clear or eosinophilic cytoplasm, partially arranged around blood vessels The nuclei were mainly round, centrally located, and vesicular, with moderate to severe pleomorphism and hyperchromatism. Extensive cellular atypia, including bizarre multinucleated giant cells with large nuclei and nucleoli, was present as well. Mitotic count was high (15 per 50 HPFs), with prominent coagulative tumor necrosis. The microscopic examination of the nodular tumors from the omentum exhibited the same morphological features. Immunohistochemically, the tumor cells showed positivity for HMB-45 and smooth muscle actin while they were negative for cytokeratins, carcinoembryonic antigen, S-100 protein, CD-10, caldesmon and desmin. Immunoreactivity for vimentin was inconspicuous. The estrogen and progesterone receptors were also negative. A proliferative index of 30% was noted with Ki-67 immunostaining. The morphology and immunohistochemical profile of the lesions was consistent with PEComa. Conclusion. Due to the fact that a vast majority of PEComas has a benign course of disease or is considered to be of uncertain malignant potential, we present this case with evident aggressive behaviour since we believe that the histological features of this tumor can serve as a model for defining of the criteria for potentially malignant PEComas.
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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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Epithelioid trophoblastic tumor initially misinterpreted as uterine smooth muscle tumor with vaginal and sigmoid colon metastases
(Macedonian Association of Anatomists and Morphologists, 2005)
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Prodanova, Irina
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Veljanoska-Petreska, Slavica
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Kubelka-Sabit, Katerina
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Jashar, Dzengis
The epithelioid trophoblastic tumor (ETT) is a rare trophoblastic neoplasm with a wide spectrum of differential diagnoses and unpredictable clinical behaviour. A 43-year-old woman underwent hysterectomy for an intramural uterine nodule initially misinterpreted as smooth muscle tumor. Subsequently, 91 and 113 months later, two recurrences were discovered: at the vaginal stump and in the sigmoid colon. The histological and immunohistochemical findings of the primary and the metastatic tumors were consistent with the diagnosis of ETT. Therefore, immunohistochemistry could help in confirming the diagnosis of ETT. In these patients, subsequent to primary surgical treatment, a careful and prolonged follow-up is warranted.
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Common blue nevus of the uterine cervix - A report of 16 cases
(Macedonian Association of Anatomists and Morphologists, 2005)
Kubelka-Sabit, Katerina
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Hadzi-Nicheva, Biljana
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Grncharovska, Zlata
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Prodanova, Irina
Blue nevus is uncommon pigmented lesion of the skin that rarely appears in the different mucoses, such as cervix or vagina. Sixteen cases of cervical blue nevi were diagnosed in our department in a five-year period (2000-2004). Localized in the stroma of the cervical canal, predominantly in the posterior lip, the lesions measured 0.1-2 cm. Prussian blue stain excluded the presence of hemosiderin and Masson-Fontana, S100 and HMB-45 stains confirmed the melanocytic nature of the lesions. Our findings are similar to those published in several studies. The recognition of this obscure lesion prevents its misinterpretation as siderosis or malignant melanoma.
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Evaluation of combined bcl-2/mdm-2 immunohistochemical expression as a prognostic factor in early stages of invasive cervical carcinomas
(Springer, 2007-08)
Prodanova, Irina
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Kubelka-Sabit, Katerina
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BACKGROUND: The present study was designed to evaluate the immunohistochemical expression of apoptosis regulating proteins (bcl-2, mdm-2 and p53) in correlation with proliferation (Ki-67), human papillomavirus (HPV) infection and other histopathological and clinical parameters in early stage cervical carcinomas and the estimation of their prognostic significance. Special attention was given to combined bcl-2/mdm-2 immunophenotypes in predicting the recurrence of the disease. METHOD: The subject of this study was a series of 83 surgically treated patients with cervical carcinoma confined to the uterine cervix (pT1b1/1b2), who subsequently received complete radiotherapy. The presence of HPV DNA was determined by the conventional method of in situ hybridization (ISH) and catalyzed reporter deposition signal amplification ISH. The immunostaining was performed using avidin-biotin-peroxidase complex method and the expression of the biological markers was semiquantitatively evaluated as the percentage of immunostained cells. RESULTS: During the clinical follow-up (mean 120.7, range 4.4-181 months) a relapse was diagnosed in 9 (10.8%) patients and the expected 5-, 10- and 15- year disease-free survival was 92.7%, 90.8% and 86.6%, respectively. The results of the univariate analysis indicate that significant predictive indicators for recurrence are: lymphonodal status, maximal tumor diameter, depth of stromal invasion, histological type and HPV DNA presence and type. Immunohistochemical markers showed the following correlations: increased expression of Ki-67 (P=0.031) and bcl-2 negativity (P=0.047) correlated with poor disease-free survival, while mdm-2 positivity showed borderline significance (P=0.051) and p53 expression had no influence on disease-free survival. Additional evaluation of combined bcl-2/mdm-2 expression showed that cases with bcl-2+/mdm-2- and bcl-2-/mdm-2+ immunophenotype had better survival (P=0.048) compared to bcl-2+/mdm-2+ and bcl-2-/mdm-2- phenotype. In the multivariate analysis, histological type, HPV DNA presence and the expression of Ki-67 have been selected as the most significant independent prognostic parameters (P=0.0024). CONCLUSION: The evaluation of combined bcl-2/mdm-2 immunohistochemical expression provides more relevant information for the prediction of the recurrence of the disease than their individual expression. However, neither individual expression of bcl-2 and mdm-2 nor their combined immunohistochemical expressions are independent predictors of prognosis in early stages of invasive cervical carcinomas.

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