title: A novel immunohistochemical method for estimating cell cycle phase distribution in ovarian serous neoplasms: implications for the histopathological assessment of paraffin-embedded specimens.
abstract: We have investigated whether immunohistochemical markers can identify differences in cell cycle phase distribution in ovarian serous neoplasms, including borderline tumours of different grades. Sections of normal ovary (n=18), serous cystadenoma (n=21), borderline serous tumours (n=21) and serous cystadenocarcinoma (n=15) were analysed by immunohistochemistry using markers of cell cycle entry (Mcm-2) and cell cycle phase, including cyclin D1 (mid-to-late G1), cyclin A (S phase), cyclin B1 (G2 phase) and phosphohistone H3 (mitosis). Double-labelling confocal microscopy confirmed marker phase specificity and phase estimations were corroborated by flow cytometry. On progression from normal ovary through serous cystadenoma and borderline tumours to cystadenocarcinomas, expression of Mcm-2 (P<0.0001), cyclin D1 (P=0.002), cyclin A (P<0.0001), cyclin B1 (P<0.0001) and phosphohistone H3 (P<0.0001) increased, paralleled by an increase in the S-phase fraction (cyclin A : Mcm-2 ratio; P=0.002). Borderline tumours of increasing grade also showed increased Mcm-2 and cyclin A expression, together with an increase in the S-phase fraction. Immunohistochemistry can be used to estimate cell cycle phase distribution in ovarian serous neoplasms, giving results similar to flow cytometric analysis and enabling direct assessment of tumour heterogeneity. Immunohistochemical estimates of the S-phase fraction may identify serous borderline tumours likely to exhibit malignant progression and/or select serous cystadenocarcinomas likely to respond to adjuvant therapy.
authors.affiliation: MRC Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 2XZ, UK. ian.scott@hutchison-mrc.cam.ac.uk
authors.forename: I S
authors.initials: IS
authors.lastname: Scott
authors.forename: T M
authors.initials: TM
authors.lastname: Heath
authors.forename: L S
authors.initials: LS
authors.lastname: Morris
authors.forename: S M
authors.initials: SM
authors.lastname: Rushbrook
authors.forename: K
authors.initials: K
authors.lastname: Bird
authors.forename: S L
authors.initials: SL
authors.lastname: Vowler
authors.forename: M J
authors.initials: MJ
authors.lastname: Arends
authors.forename: N
authors.initials: N
authors.lastname: Coleman
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000032:analysis* / Q000096:biosynthesis; D002471:Cell Transformation, Neoplastic; D018284:Cystadenocarcinoma, Serous / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D018613:Microscopy, Confocal; D010051:Ovarian Neoplasms / Q000473:pathology*; D011230:Precancerous Conditions; D013048:Specimen Handling
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins