[Clinical recommendations for diagnosing, treatment and monitoring of patients with ovarian cancer -- Croatian Oncology Society and Croatian Society for Gynecology and Obstetrics as Croatian Medical Association units and Croatian Society of Gynecological Oncology]. / Klinicke upute za dijagnostiku, lijecenje i pracenje bolesnica oboljelih od raka jajnika hrvatskoga onkoloskog drustva i hrvatskog drustva za ginekologiju i opstetriciju hrvatskoga lijetnickog zbora te hrvatskoga ginekoloskoonkoloskog drustva.

Ovarian cancer together with fallopian tube represents the fifth most common female cancer in the Republic of Croatia. Epithelial ovarian cancer, serous subtype, encompasses most of malignant ovarian neoplasms. Less common are various non-epithelial ovarian malignancies. A special group consists of epithelial carcinomas of low malignant potential with clinically indolent flow, good prognosis and no invasion, and primary cancer of the peritoneum and fallopian tube cancer. Clinically, these malignant tumors are generally asymptomatic in early stages, and usually diagnosed in advanced stages. The diagnosis is confirmed by pathological examination, and occasionally, cytological findings after completing diagnostic procedures. Multidisciplinary team makes treatment decisions, taking into account age, general condition and comorbidities of the patient and characteristics of the tumor itself, including disease stage, histological type and grade of the tumor. The principles of treatment of primary peritoneal and fallopian tube cancer are based on the principles of treatment of epithelial ovarian cancer involving surgery, chemotherapy, immune and hormone therapy, and symptomatic-supportive care throughout the treatment. Less common histological types have a different treatment approach being more frequently diagnosed in the early stages of the disease, have more indolent flow, so in these patients conservative surgeries with the goal of preserving fertility are more often employed. The following text presents the clinical guidelines in order to standardize the procedures and criteria for the diagnosis, management, treatment and monitoring of patients with ovarian carcinoma, fallopian tube and primary peritoneal cancer in the Republic of Croatia.

Future perspectives of personalized oncology.

Based upon an individual's molecular make-up, personalized molecular medicine provides information regarding the origin of disease, its treatment and progression, while personalized molecular pharmacology advises on drug prescription and patient response to it, thus ensuring drug effectiveness and preventing drug toxicity or lack of response. Interindividual differences in drug responses are mostly due to structural variation in parts of genome, e.g. in genes participating in drug metabolism, transport or targeting. However, a wide variety of diseases and accompanying health conditions, including patient's therapy or drug response, also have epigenetic or epigenomic etiology. High priority for personalized oncologic research stems from inter/intraindividual tumor heterogeneity provoked by gradual acquisition of multiple random, or programmed mutations and rearrangements as well as epigenetic alterations or by stochastic fluctuations in cell components, all in tight feedback interaction with tumor's environmental or therapy conditions. Natural selection subsequently shapes inter/intraindividual tumor heterogeneity by promoting clonal expansion of cells that have acquired advantageous mutations for tumor population. Hence, the main rationale of personalized molecular oncology should focus on treating disease by relying on relevant structure and state of patient's whole molecular network (genome/transcriptome/RNome/proteome/metabolome/metabonome) in interaction with its unique environmental conditions, thus implying right therapy for the right patient at the right dose and time. The future of personalized oncology should therefore rely on the methods of systems biology applied in cytology and pathology in order to develop and utilize the efficient and effective diagnostic, prognostic and predictive biomarkers, consequently providing the molecular information on tumor origin, its potential for metastasis, adequate therapy, tumor specific therapy responsiveness, and the probability of its recurrence.

Diagnosis of visceral leishmaniasis by fine needle aspiration cytology of an isolated cervical lymph node: case report.

A 61-year-old woman presented with an isolated, painless, slightly enlarged right laterocervical lymph node without any other signs and symptoms of disease. Laboratory test including hematological and biochemical parameters were normal. A cervical ultrasonography demonstrated one lymph node (10 mm) on the right laterocervical side and one small reactive lymph node on the left laterocervical side. The fine needle aspiration (FNA) smears revealed a polymorphic population of cells composed of lymphocytes, histiocytes, epitheloid cells, plasma cell, tingible body macrophages and macrophages infiltrated with Leishmania amastigotes. Treatment was initiated with Stiboglukonat Na (Pentostam) and led to a full recovery.

Correlation Between E-cadherin Immunoexpression and Efficacy of First Line Platinum-Based Chemotherapy in Advanced High Grade Serous Ovarian Cancer.

To analyze correlation between immunoexpression of E-cadherin and efficacy of first line platinum-based chemotherapy in patients with advanced-stage high-grade serous ovarian carcinoma. The expression of E-cadherin was analyzed immunohistochemically in formalin-fixed, paraffin-embedded samples from 98 patients with advanced-stage high-grade serous ovarian cancer and related to clinical features (stage according to the International Federation of Gynecology and Obstetrics (FIGO) and residual tumors after initial cytoreductive surgery), response to platinum-based chemotherapy (according to Response Evaluation Criteria in Solid tumors (RECIST 1.1 criteria)), platinum sensitivity (according to platinum free interval (PFI) as platinum-refractory, platinum-resistant and platinum-sensitive) and patients progression free survival (PFS) and overall survival (OS). E-cadherin immunostaining was positive in 74 and negative in 24 serous ovarian carcinomas. E-cadherin immunoreactivity was not associated with FIGO stage, residual tumor after initial cytoreductive surgery and number of chemotherapy cycles. Positive E-cadherin expression predict significantly better response to first line platinum-based chemotherapy (p < 0.001) and platinum sensitivity (p < 0.001). Moreover, positive E-cadherin expression predict significantly longer PFS (p < 0.001) and OS (p < 0.001). The multivariate analysis for OS showed that positive E-cadherin expression is predictor to platinum sensitivity (p < 0.001) and longer OS (p = 0.01). Positive E-cadherin expression seems to be a predictor of better response to first line platinum-based chemotherapy, platinum sensitivity and favorable clinical outcome in patients with advanced-stage serous ovarian cancer. Negative E-cadherin expression was shown to be significant, independent predictor of poorer PFS and OS. E-cadherin as a marker has predictive and prognostic value.

P53, MAPK, topoisomerase II alpha and Ki67 immunohistochemical expression and KRAS/BRAF mutation in ovarian serous carcinomas.

BACKGROUND: We investigated the immunohistochemical expression of p53, MAPK, topoisomerase II alpha (topoII alpha) and Ki67 in ovarian serous carcinomas (OSCs) along with mutational analysis for KRAS and BRAF. METHODS: Eighty one cases of OSCs were reviewed and examined immunohistochemically using antibodies against p53, MAPK, topoII alpha and Ki67. Staining was evaluated as a percentage of immunopositive cells with cut-off levels at 10% for p53 and topoII alpha, and 5% for MAPK. The Ki67 immunoexpression was assessed by means of Olympus Image Analysis System as a percentage of immunopositive cells in 1000 tumor cells. KRAS and BRAF mutational analysis was performed on 73 available microdissected samples. RESULTS: Of 81 cases of OSCs 13.6% were of low-grade and 86.4% were of high-grade morphology. In the high-grade group there was a significantly higher immunoexpression of p53 (P < 0.001) and topoII alpha (P = 0.001), with Ki67 median 56.5 vs. 19 in low-grade group (P < 0.001). The difference in immunoexpression of active MAPK between low- and high-grade group was also significant (P = 0.003). MAPK positive immunostaining was detected in 63.6% of low-grade vs. 17.1% of high-grade OSCs. The frequency of KRAS mutation was significantly higher in low-grade as compared to high-grade group (P = 0.006). None of the samples had BRAF mutation. In addition, we detected positive MAPK immunoexpression in 13/59 samples with wild-type KRAS, suggesting that activation of MAPK pathway is not ultimately related either to KRAS or BRAF mutation. Seven morphologically high-grade samples (11.7%) showed both KRAS mutation and p53 immunopositivity. CONCLUSIONS: Although this study is limited by its humble number of low-grade samples, our data fit the proposed dualistic pathway of ovarian carcinogenesis. Mutational analysis for KRAS and BRAF discloses some possible interactions between different tumorigenic pathways of low- and high-grade carcinomas. Immunohistochemical staining for MAPK was not sufficiently sensitive, nor specific, to precisely predict the KRAS mutation. However, it appears to be quite reliable in ruling out a KRAS mutation if the staining is negative. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9283563368804632.

c-erbB-2, p53, and nm23 proteins as prognostic factors in patients with epithelial ovarian carcinoma.

AIM: To demonstrate immunohistochemical expression of p53, c-erbB-2, and nm23 proteins in ovarian cancer and to establish their correlation with such predictive factors as clinical stage, grade, and vascular invasion. The effect of protein overexpression on patients' overall survival was also assessed. METHOD: We performed immunohistochemical analysis of formalin-fixed, paraffin-embedded specimens from 80 ovarian carcinomas, using the anti-nm23, p53, and c-erbB-2 monoclonal antibodies. Immunohistochemical results were scored semiquantitatively. All patients were staged according to the criteria of the International Federation of Gynecology and Obstetrics (FIGO) staging system (I-IV). Carcinomas were graded as low- or high-grade, according to the modified grading system recommended by Shimatzu and Silverberg. For univariate analysis, survival time was analyzed by Kaplan-Meier method, and the log-rank test was used to assess the differences between the groups. For multivariate analysis, Cox proportional hazard regression model was used to examine several parameters simultaneously. RESULTS: Univariate analysis showed that advanced clinical stage (p<0.001); positive staining for nm23 (p<0.001), p53 (p=0.021), and c-erbB-2 (p=0.003) protein; high histological grade (p<0.001); and vascular invasion (p=0.006) were associated with shorter overall survival. Multivariate analysis revealed only clinical stage as an independent prognostic parameter (p=0.014). Multivariate analysis for early-stage disease showed that only the presence of vascular invasion was significantly associated with shorter survival (p=0.008), whereas none of the parameters analyzed for the advanced-stage disease showed independent predictive value for prognosis. CONCLUSION: The overexpression of p53, nm23, and c-erbB-2 proteins was associated with other parameters characteristic of aggressive tumors, such as advanced clinical stage, high grade, and/or presence of vascular invasion. However, this overexpression had no independent prognostic value either for overall survival or survival corrected by clinical stages.