Niskogradusni serozni karcinom jajnika (LGSOC) manje je agresivan i ima bolji klinički ishod u usporedbi s visokogradusnim seroznim karcinomom jajnika (HGSOC). Kirurško liječenje s pokušajem ...maksimalne citoredukcije važno je i opravdano zbog relativne kemorezistencije ovog tumora. Stadije bolesti IA-IB trebalo bi klinički pratiti nakon primarne citoredukcije, dok su kliničko praćenje, kemoterapija ili hormonska terapija predložene mogućnosti za stadije bolesti IC-IIA. Bolesnice stadija IIB-IV liječe se kemoterapijom sastavljenom od karboplatina i paklitaksela tijekom 6 ciklusa koju slijedi hormonska terapija, najčešće inhibitorima aromataze, ili pak samom hormonskom terapijom do progresije bolesti ili neprihvatljive
toksičnosti. Kirurško liječenje, kemoterapija i hormonska terapija također se koriste za bolesnice s povratom bolesti. U tijeku su klinička istraživanja ciljanom terapijom, posebno s inhibitorima mitogenom-aktiviranih proteinskih kinaza (MEK) i inhibitorima kinaza ovisnih o ciklinu (CDK). Dodatna istraživanja genomike LGSOC-a, u cilju boljeg definiranja aktivacije genskih mutacija uključenih u karcinogenezu, neophodna su radi poboljšanja prognoze ove zloćudne bolesti.
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.
Rak jajnika i jajovoda, odnosno adneksa, i primarni rak potrbušnice jest šesta po učestalosti zloćudna bolest žena i najsmrtonosniji ginekološki tumor u Hrvatskoj. Histološki je rak jajnika, jajovoda ...i potrbušnice najčešće epitelnog podrijetla, i to seroznog podtipa. Rjeđi su različiti neepitelni tumori jajnika kao i presadnice u jajnike. Posebnu skupinu čine karcinomi niskog zloćudnog potencijala označeni neinvazivnošću, klinički indolentnim tijekom i dobrom prognozom. Klinički su karcinomi u ranim stadijima razvoja uglavnom asimptomatski, tako da se najčešće dijagnosticiraju u kasnijim, uznapredovalim stadijima bolesti. Dijagnoza se potvrđuje patohistološkim nalazom, a iznimno nalazom citološkog bloka nakon provedene dijagnostičke obrade. O liječenju i praćenju bolesnica odlučuje multidisciplinarni tim uzimajući u obzir osobitosti bolesnice (dob, opće stanje i komorbiditete) kao i obilježja samog tumora (stadij bolesti, histološki tip i stupanj zloćudnosti tumora, status homologne rekombinacije, odnosno gena BRCA 1 i 2 kao i odgovor na prethodno liječenje i popratnu toksičnost ako se radi o povratu bolesti). Liječenje primarnog raka jajnika, jajovoda i potrbušnice temelji se na kirurškom liječenju, sistemskoj primjeni kemoterapije, imunoterapije, ciljane terapije i hormonske terapije kao i suportivno-simptomatskih mjera tijekom cijelog liječenja. Terapijski pristup se razlikuje kod rjeđih neepitelnih histoloških tipova ovih tumora jer se češće dijagnosticiraju u ranim stadijima bolesti, imaju indolentniji tijek, drugačiju biologiju bolesti kao i osjetljivost na sistemsko liječenje. U tekstu koji slijedi predstavljene su obnovljene i nadopunjene kliničke upute s ciljem standardizacije postupaka i kriterija postavljanja dijagnoze, liječenja te praćenja bolesnica s rakom jajnika, jajovoda i potrbušnice u Hrvatskoj. Prvo izdanje smjernica za dijagnozu, liječenje i praćenje bolesnica s rakom jajnika objavljeno je 2013. godine.1
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.
...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.
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.
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.
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9283563368804632.
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.
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.
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.
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.
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.
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.
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