Diffuse large B-cell lymphoma with overexpression of cyclin e substantiates poor standard treatment response and inferior outcome.
OBJECTIVE
Gold standard to predict survival and stratify patients for risk-adapted therapy in diffuse large B-cell lymphoma (DLBCL) is the international prognostic index, although it does not consider the molecular heterogeneity of DLBCL. Deregulation of cyclin E (CCNE) is a strong predictor of poor prognosis in some neoplastic diseases. In tumor cells, it induces chromosomal instability with an increased rate of aneuploidy/polyploidy.


METHODS
We analyzed in this retrospective study the prognostic value of immunohistochemical CCNE expression on a validated tissue microarray containing 101 de novo DLBCLs and, in 9 cases, the CCNE-induced chromosomal instability as assessed by cytometry.


RESULTS
Forty-six of 98 evaluable DLBCLs expressed CCNE in a mean proportion of 20 +/- 29% of tumor cells; 38 cases expressed CCNE in >/=20% of tumor cells. CCNE-positive samples were aneuploid compared with near tetraploidy in CCNE-negative cases. Multivariate analysis showed CCNE expression in >/=20% of tumor cells to be an international prognostic index-independent, Adriamycin-based treatment-independent, and BCL2-independent prognostic factor for poor disease-specific survival. CCNE expression in >/=80% of tumor cells was associated with dismal short-term prognosis. CCNE expression in >/=50% of tumor cells emerged as an independent predictive factor for standard CHOP treatment resistance.


CONCLUSIONS
CCNE expression assessment is easy on paraffin-embedded tissue. The high prognostic value of CCNE expression in DLBCL may be the basis for future prospective trials. In addition, a high CCNE expression hints at the presence of a possible target for individualized cancer therapy.
Tzankov
Alexandar
A
Institutes of Pathology, Medical University of Innsbruck, Innsbruck, Austria. Alexander.Tzankov@i-med.ac.at
Gschwendtner
Andreas
A
Augustin
Florian
F
Fiegl
Michael
M
Obermann
Ellen C
EC
Dirnhofer
Stephan
S
Went
Philip
P
D000368:Aged; D002869:Chromosome Aberrations; D019927:Cyclin E / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D008297:Male; D011237:Predictive Value of Tests; D011379:Prognosis; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D015996:Survival Rate; D046888:Tissue Array Analysis / Q000379:methods; D016896:Treatment Outcome
D019927:Cyclin E