title: P53, MAPK, topoisomerase II alpha and Ki67 immunohistochemical expression and KRAS/BRAF mutation in ovarian serous carcinomas.
abstract: 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.
  The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9283563368804632.
authors: Department of Pathology, Forensic Medicine and Cytology, Clinical Hospital Center Split, School of Medicine, University of Split, Split, Croatia. dinkasundov@gmail.com
authors: Dinka
authors: D
authors: Sundov
authors: Ana
authors: A
authors: Caric
authors: Ivana
authors: I
authors: Mrklic
authors: Dijana
authors: D
authors: Gugic
authors: Vesna
authors: V
authors: Capkun
authors: Irena Drmic
authors: ID
authors: Hofman
authors: Branka Petric
authors: BP
authors: Mise
authors: Snjezana
authors: S
authors: Tomic
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000032:analysis*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D002277:Carcinoma / Q000737:chemistry / Q000235:genetics / Q000473:pathology; D016009:Chi-Square Distribution; D004252:DNA Mutational Analysis; D004250:DNA Topoisomerases, Type II / Q000032:analysis*; D004268:DNA-Binding Proteins / Q000032:analysis*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis*; D042282:Microdissection; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis*; D009154:Mutation; D060787:Neoplasm Grading; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000737:chemistry / Q000235:genetics / Q000473:pathology; D010051:Ovarian Neoplasms / Q000737:chemistry / Q000235:genetics / Q000473:pathology; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D016159:Tumor Suppressor Protein p53 / Q000032:analysis*; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C117307:KRAS protein, human; D019394:Ki-67 Antigen; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D004250:DNA Topoisomerases, Type II
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