The prognostic impact of cyclin dependent kinase inhibitors p21WAF1, p27Kip1, and p16INK4/MTS1 in adenocarcinomas of the uterine cervix: an immunohistochemical evaluation of expression patterns in population-based material from 142 patients with international federation of gynecology and obstetrics stage I and II adenocarcinoma.
BACKGROUND
The authors assessed the prognostic significance of abnormal cyclin dependent kinase inhibitor (CDKI) expression in adenocarcinomas of the uterine cervix.


METHODS
Population-based, archival material from patients with International Federation of Gynecology and Obstetrics (FIGO) Stage I and II cervical adenocarcionmas from 2 5-year periods (1976-1980, n = 82 patients; 1986-1990, n = 142 patients) was examined for expression of p21(WAF1), p27(Kip1), and p16(INK4/MTS1) using immunohistochemical techniques.


RESULTS
Rates of tumors with low levels of nuclear expression of p27 and p16 were lower during the period 1976-1980 (P < 0.01), suggesting bias due to unbuffered formalin. Analyses that were restricted to patients from 1986-1990 showed positive associations between all three CDKIs (P < 0.05). Low p16 expression was associated with higher FIGO stage (P = 0.01), age older than 55 years (P = 0.01), and deep invasion (P = 0.003). No significant associations with stage, age, or histopathologic parameters were found for p21 or p27. Significant associations with tumor differentiation were not seen for any CDKI. Kaplan-Meier plots showed diverging survival curves for p21 and p27 expression, but the differences were not significant. In multivariate analysis, low p27 expression and high p16 expression were strong predictors of a poor prognosis (p27: < 40% nuclear staining; P = 0.001; hazard ratio, 3.18; p16: < 40% nuclear staining; P < 0.001; hazard ratio, 0.16). Low p27 expression was of prognostic significance only if it was analyzed together with p16 expression. Further evaluation indicated that patients with different phenotypic p27/p16 combinations may have different outcomes.


CONCLUSIONS
Aberrant expression patterns of CDKIs were predictors of prognosis for patients with FIGO Stage I or II cervical adenocarcinoma. Analysis of CDKI expression in this patient group may prove clinically useful.
Alfsen
G Cecilie
GC
Department of Pathology, The Norwegian Radium Hospital, Oslo, Norway. g.c.alfsen@labmed.uio.no
Reed
Wenche
W
Sandstad
Berit
B
Kristensen
Gunnar B
GB
Abeler
Vera M
VM
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016213:Cyclins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D011379:Prognosis; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000473:pathology
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases