Faculty of Medicine

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Capecitabine as Second and Third-line Chemotherapy in the Treatment of Platinum-refractory Epithelial Ovarian Cancer
(Elsevier, 2011-09)
Veljanoska, Slavica
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Arsovski, Oliver
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Background: The aim of the study was to evaluate the value of Capecitabine (Xelode) in treatment of epithelial ovarian cancer, after failure of initial chemotherapy. Response rates to first-line chemotherapy in women with ovarian cancer are high but most patients relapse and need further treatment. Recurrent disease is incurable, however, many patients can obtain good palliation from further treatment. Material and Method: The study included 20 patients with epithelial ovarian cancer treated initially with cytoreductive surgery and followed by chemotherapy treatment: 14 patients received platinum/paclitaxel therapy and 6 patients received platinum/cyclophosphamide therapy. Progression of disease was manifested with hepatic metastases in 11 patients (55%), lung metastases in 2 (10%) and an increase in serum CA125 in 5 patients (25%). Comparison of the value of serum CA125 before and after treatment was taken as an indicator of response to chemotherapy. The treatment schedule consisted of oral capecitabine 1250mg/m2 administrated twice daily for 14 days, followed by 7-day rest period. Treatment was administrated orally within 30 min of breakfast and dinner, and swallowed with approximately 200ml of water. The cycle was repeated every 21 days. Results: 18 patients (80%) received 6 courses chemotherapy with Capecitabine, 4 (20%) did not achieve the planned 6 courses of chemotherapy due to deterioration of their general condition. In 10 patients (50%) deceased value of CA125 was observed, in 8 (40%) value was unchanged, and in 2 (10%) an increase of serum CA125 was noted. All 20 patients were evaluable for safety. Capecitabine was very well tolerated, with the most common clinical adverse events being nausea and diarrhoea, neither of which occurred with grade 3 or 4 intensity. Conclusions: Capecitabine has demonstrated promising activity and a favorable safety profile in the treatment of platinum-refractory epithelial ovarian cancer. The safety and convenience advantages afforded to patients over current i.v. options make capecitabine an ideal agent for administration in the outpatient setting, potentially freeing them from the burden of i.v. therapy.
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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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Follicular variant of papillary thyroid carcinoma arising in struma ovarii: A case report
(Macedonian Association of Pathology, 2016-09)
Stojkoska, Elena
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Qerimi, Adelina
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Ognenoska-Jankovska, Biljana
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Objective: Struma ovarii is a rare form of ovarian mature teratoma and is the most common type of monodermal teratoma (3% of all ovarian teratomas). 5-10% of such tumors are malignant with papillary carcinoma as the most common type (70%) while 26% of them are a follicular variant of papillary thyroid carcinoma (FVOPTC). We report a case of FVOPTC arising in struma ovarii focusing on the clinical, histopathological and immunohistochemical features. Material and Methods: A 29-year old nulliparous female underwent laparoscopic surgery of a 7 cm a large right ovarian cyst, diagnosed by ultrasound. Clinically and biochemically she was euthyroid with normal serum TSH level, and without previous significant medical or gynecological history. Results: Grossly, a laparoscopically obtained material consisted of 8x3 cm fragment of cyst wall measuring 0.2 to 0.6 cm in thickness with a focus of 5 mm large grayish-white tumor. Histology of the cyst wall showed thyroid tissue characteristic of cystic struma ovarii while the tumor showed typical nuclear features of papillary thyroid carcinoma with follicle formation and minimal presence of papillary structures typical for FVOPTC arising in thyroid tissue. Immunohistochemical staining showed positive expression for thyroglobulin, TTF-1, and cytokeratin-19 in the tumor cells. Conclusions: FVOPTC arising in struma ovarii is difficult to assess because it is a rare tumor with about 60 published cases and lacking standard criteria for diagnosis. Thus, the morphological criteria for the diagnosis of this tumor are based on classical criteria for primary thyroid carcinoma. Prognostically, FVOPTCs measuring less than 2 cm arising in struma ovarii are considered as low-risk lesions with a low rate of recurrence and metastasis.
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Ovarian Leydig cell tumor (hilus cell tumor): A case report
(Macedonian Association of Pathology, 2016-09)
Qerimi, Adelina
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Stojkoska, Elena
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Ognenoska-Jankovska, Biljana
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Trajanova, Milka
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Objective: Leydig cell tumor is a rare ovarian tumor that belongs to the group of sex-cord stromal tumors. They produce testosterone leading to hyperandrogenism. As a subtype of steroid cell tumors of the ovary characterized by the presence of Reinke crystals, it comprises 19% and affects mainly young women. Material and Methods: A 24-year old nulliparous patient clinically presented with hirsutism, oligomenorrhea, and infertility. Ultrasonography showed a left ovarian tumor mass with the greatest diameter of 4.3 cm. The patient underwent a laparoscopic tumorectomy followed by gradual withdrawal of the symptoms at the first check-up after 6 months follow-up. Results: The laparoscopically obtained material consisted of 15 yellow to orange-tanned, soft and solid fragments with a diameter ranging from 0.5 to 5.5cm. Microscopically, the tumor was solid, relatively well-circumscribed, and composed of cellular areas with clustering of nuclei separated by eosinophilic anuclear zones. Some of the tumor cells had scant and others abundant eosinophilic or clear cytoplasm with lipid-rich, oil Red O-positive vacuoles and oval, hyperchromatic or bizarre nuclei. Mitotic figures were scarce, while Reinke crystals were found after a prolonged search. Immunohistochemically, tumor cells showed diffuse positivity for vimentin, focal for cytokeratin AE1/AE3, alfa-smooth muscle actin, S100, CD99, calretinin, inhibin-alpha, melan A, CD56 and were steroid hormone receptor negative. Conclusions: Although idiopathic hirsutism and other benign androgen excess disorders like polycystic ovarian syndrome are common, the presence of an ovarian mass in younger patients should raise suspicion of Leydig cell tumor or other steroid cell tumors. This case confirms that Reinke crystal quest should always be tenacious.
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Ovarian cellular fibromas: A cliniopathological and immunohistochemical analysis of 10 cases.
(Springer, 2007-08)
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Prodanova, Irina
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Kubelka-Sabit, Katerina
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Zografski, George
BACKGROUND: Traditionally, cellular fibroblastic tumors of the ovary were classified as either cellular fibroma (CF) or fibrosarcoma. A recent study suggests that cellular fibromatous neoplasms with bland cytology and elevated mitotic counts are associated with favourable prognosis and should be diagnosed as "mitotically active cellular fibroma" (MACF) rather than fibrosarcoma. In addition to clinicopathological features, immunohistochemistry may aid in further differentiating between CF and MACF, but its role has not been analyzed so far. METHOD: We retrospectively analyzed the clinicopathological and immunohistochemical features of 10 cases of ovarian cellular fibroblastic tumors diagnosed either as CF or fibrosarcoma in the last seven years. Patient records and archival pathology specimens were reviewed and immunohistochemistry was performed using pan-cytokeratin, EMA, vimentin, inhibin-alpha, calretinin, CD10, CD99, alpha-smooth muscle actin (SMA), desmin, S-100, c-kit, estrogen (ER), progesterone receptor (PR), p53, bcl-2, and MIB-1 antibody. RESULTS: Utilizing criteria proposed by Irving et al. the tumors were reclassified as CF (0-3 MFs/10 HPFs, n=5) and MACF (>4 MFs/10 HPFs, n=5). The mean age of patients with CF and MACF was 44 and 36 years, respectively. All tumors were unilateral, and the mean tumor size of CFs was 6.0 cm and 13.3 cm for MACFs. The majority of the tumors were solid; four of them had a cystic component, while ovarian surface rupture was present in one CF and one MACF. All tumors consisted of cellular, intersecting bundles of spindle cells showing slight or moderate pleomorphism. The mean highest mitotic count was 2.3 MFs/10 HPFs for CF, and 7.6 MFs/10 HPFs for MACFs. Follow-up of 4 to 79 months (mean 38 months) was available in 9 patients and was uneventful in all cases. One patient with MACF died 15 days following the operation as a result of the intercurrent disease. Immunohistochemical analyses showed that spindle cells in majority of the tumors were immunoreactive for vimentin, alpha-SMA, inhibin-alpha, calretinin, PR, and bcl-2. All tumors were negative for pan-cytokeratin, EMA, CD10, CD99, c-kit, ER, and p53, while one CF was positive for S-100, and one MACF showed positivity for desmin. In addition, the MIB-1 labeling index (LI) in MACFs was higher (mean 14.4%, range 10-25%), than that in CF (mean 5.6%, range 3-10%). CONCLUSION: Our results confirm the immunophenotypic similarity between ovarian fibromas and cellular fibromatous neoplasms, and suggest that the use of MIB-1 LI may help in differentiating between CF and MAFC.
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Ovarian clear cell adenocarcinoma arising in association with endometriosis: a clinicopathological study of 20 cases
(Springer, 2014-09)
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Ognenoska-Jankovska, Biljana
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Veljanoska-Petreska, Slavica
Objective: The objective of the study was to determine clinicopathological features of the ovarian clear cell adenocarcinomas (OCCA) arising in association with endometriosis. Method: We retrospectively compared 20 cases of endometriosis-associated clear cell adenocarcinoma (EACCA) with 35 cases of clear cell adenocarcinoma without endometriosis (CCAWE) diagnosed at our department between 2000 and 2013, using Student’s t-test and chi-square test to analyze the data. Results: The median age in EACCA group was 50 versus 58 years in CCAWEgroup (P=0.0007), and the prevalence of postmenopausal status was significantly higher in EACCA cases (55 % vs. 17.1 %; P=0.0035). Grossly, in the EACCA group the tumours were predominantly unilocular cysts containing solitary or multiple nodules in the inner surfaces (80 % vs. 31.4 %), while CCAWE were more frequently multilocular cystic tumours (P=0.0005). The EACCA patients tended to have smaller (median size 11 vs. 13 cm) and early-stage tumours (FIGO stage I and II combined; 85 % vs. 68.6 %), although the differences were not statistically significant. In 17 patients EACCA were arising within endometriosis, with atypical endometriosis present in 6 cases, while in the remaining 3 OCCA were adjacent to endometriosis on the same ovary. Conclusion: Patients with EACCA are typically premenopausal and younger, with a tendency to have smaller in size, early-stage tumours usually presenting as unilocular cysts.
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Clinicopathological and immunohistochemical analysis of 23 cases of ovarian cellular fibroma
(Springer, 2013-09)
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Ognenoska-Jankovska, Biljana
Objective: To define clinicopathological characteristics and immunohistochemical markers helpful in differentiating between cellular fibroma (CF) and mitotically active cellular fibroma (MACF). Method: Patient records and archival pathology specimens of 23 ovarian cellular fibromas diagnosed and followed between 2000 and 2012, were reviewed and immunohistochemistry was performed. Results: The mean age of patients with CF (n=15) and MACF (n=8) was 55 and 37 years, respectively. All tumours were unilateral, with a mean tumour size of 8.6 cm for CFs and 12.9 cm for MACFs. In all tumours, most of the cells showed mild or moderate nuclear atypia. The mean highest mitotic count was 2.0 MFs/10 HPFs for CF, and 7.2 MFs/10 HPFs for MACFs. The majority of the tumours were immunoreactive for vimentin, alpha-SMA, WT-1, inhibin-alpha, calretinin, CD56, melan-A, PR, and bcl-2, and negative for pan-cytokeratin, EMA, CD117, ER, and p53. A few tumours were also positive for S100, desmin, CD10, and CD99. In addition, the MIB-1 labeling index (LI) in MACFs was higher (mean 16.9 %, range 12–25 %), than that in CFs (mean 5.9 %, range 3–9 %). Conclusion: Our results confirm the clinicopathological differences and the immunophenotypic similarity between ovarian fibromas and cellular fibromas, and suggest that the use of MIB-1 LI may help in differentiating between CF and MAFC.
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Malignant melanoma metastatic to the ovaries: a clinicopathological and immunohistochemical study of four cases
(Wiley-Blackwell, 2012-10)
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Veljanoska-Petreska, Slavica
Introduction: Ovarian involvement with malignant melanoma (MM) is extremely rare often leading to a misdiagnosis of ovarian cancer. We present the clinicopathological and immunohistochemical features of four cases of ovarian metastatic MM diagnosed at our Department over a 23-year period (1989–2011). Materials and Methods: The patients’ age ranged from 28 to 72 (mean 49.5) years. All presented with a pelvic mass and a past history of MM (three cutaneous, one anorectal), although at the time of the histopathological evaluation it was known in only two cases. The interval between the primary and ovarian MM ranged from 3 to 72 months. The initial treatment was surgery, followed by chemoimmunotherapy in three of them. One patient died of an unrelated cause 29 months following surgery with metastatic disease, while the other three died from metastatic disease within 41 days, 15 months, and 10 years, respectively. Two of these patients had lymph node metastases previously and all three had synchronous metastases at other sites at the time of the surgery. Results: The ovarian tumors were unilateral, varied in size from 14 to 25 cm, and only two were grossly pigmented. Histologically, they were composed of large epithelioid cells with eosinophilic cytoplasm, small cells, spindle-shaped cells, or a combination. The predominant architectural patterns were nodular in one, and diffuse in the other three tumors. Immunostains for S-100, HMB-45, and melan-A were positive in all tumors tested. Conclusion: The presented cases illustrate the clinical variability and unpredictable biologic behavior of ovarian metastatic MM and emphasize the value of immunohistochemistry in establishing the diagnosis.
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Ovarian serous tumor with mural nodule of sarcomatoid carcinoma and reactive changes.
(Springer, 2009-09)
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Veljanovska, Slavica
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Zografski, George
Background Serous ovarian tumors with mural nodules are very infrequent, with only a dozen of cases described, including four cases of sarcomatoid carcinoma. We report a first case of a mural nodule with features of both sarcomatoid carcinoma and prominent sarcoma-like reactive changes associated with ovarian serous cystic tumor. Methods A 52-year-old woman underwent left salpingooophorectomy and partial omentectomy because of a cyst. Forty-five months previously a total abdominal hysterectomy with right salpingo-oophorectomy and left ovarian resection had been performed. Postoperatively the patient received full-dose chemotherapy and is clinically free of disease at 76 months’ follow-up. Results Within the wall of the largest locule of the left ovarian multilocular cyst, 12.5 cm in diameter that had ruptured at operation, there was a 4x4x1.5 cm nodule. The smaller locules were lined with benign serous epithelium, while the largest locule had morphology of a serous borderline tumor with small foci of superficial invasion. The mural nodule was composed of carcinomatous nests intermingled with pleomorphic mononuclear cells, multinucleated giant cells, histiocytes and other inflammatory cells. The luminal epithelium and underlying pleomorphic cells were diffusely positive for cytokeratin and epithelial membrane antigen, and focally positive for vimentin. Benign spindle cells and multinucleated giant cells were vimentin positive. The ovarian capsule was not invaded. Conclusion(s) This study confirms the usefulness of immunohistochemistry in distinguishing variant forms of mural nodules in cystic ovarian tumors. It further suggests that malignant nodules in serous tumors do not necessarily carry a poor prognosis.
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Androgen Secreting Steroid Cell Tumor of the Ovary Represented with Postmenopasal Bleeding and Extensive Hirsutism
(Scientific Foundation SPIROSKI, 2013-12-15)
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Introduction: Steroid cell tumors of the ovary present less than 0.1% of all ovarian tumors and belong in the group of sex cord-stromal tumors. Case description: We present a case of 69-year-old woman investigated because of postmenopausal bleeding, a 5-year history of excessive hirsutism, baldness and acne. The evaluation revealed elevated serum testosterone, but ultrasound detected a 2 cm mass of the left ovary. The patient underwent hysterectomy and bilateral adnexectomy. The histopathology diagnosis was steroid cell tumor, not otherwise specified. Postoperative chemotherapy was administered at the discretion of the radio-oncologist. At the last follow-up 48 months after surgery, the hirsutism was completely resolved, the serum testosterone was within the normal range and there was no evidence of recurrence. Conclusion: In adult patients with hirsutism and elevated serum testosterone a possibility of a presence of an ovarian steroid cell tumor should be considered. Surgery is the main treatment of such patients.

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