Topoisomerase IIα expression in mantle cell lymphoma: a marker of cell proliferation and a prognostic factor for clinical outcome

Abstract

Mantle cell lymphoma (MCL) is a malignant lymphoma associated with a relatively aggressive clinical course and a median overall survival time of 3-4 years. Treatment usually consists of combination chemotherapy, often including topoisomerase (topo) inhibitors such as doxorubicin, etoposide and mitoxantrone. Topo IIa is an enzyme that is needed whenever uncoiling of DNA is necessary during the cell cycle. The enzyme is a marker of cell proliferation. We analyzed the expression of topo IIa in relation to Ki-67 and the clinical outcome in patients with MCL. Biopsy specimens from 95 untreated patients enrolled in two multicenter trials (1975)(1976)(1977)(1978)(1979)(1980)(1981)(1982)(1983)(1984)(1985) were investigated immunohistochemically with monoclonal antibodies against topo IIa (Ki-S4) and Ki-67 (Ki-S5). Patients with low (0-10%) topo IIa expression had a median overall survival time of 49.0 months, compared to 17.0 months for patients with high (more than 10%) topo IIa expression. The Kaplan-Meier analysis showed a significant difference in the overall survival time related to the percentage of topo IIa (Po0.001) and Ki-67 (Po0.001) positive tumor cells. Multivariate Cox regression analysis revealed the expression of topo IIa as the most important prognostic factor (Po0.001) in MCL superior to the international prognostic index (IPI), the Ki-67 index and other clinical characteristics.

Minichromosome maintenance protein 6, a proliferation marker superior to Ki-67 and independent predictor of survival in patients with mantle cell lymphoma

“…For these reasons, it is useful to confirm results based on gene expression profiling on the protein level with, for example, by immunohistochemistry. In a previous study, we studied topoisomerase IIa expression by immunohistochemistry and were able to confirm the results from Rosenwald et al (Schrader et al, 2004). Since mRNA expression of MCM2, was reported to be associated with bad prognosis (Rosenwald et al, 2003), we evaluated MCM protein expression by immunohistochemistry in MCL.…”

“…The expression level ranged from 12.0 to 95.6%, with a median of 64.6% and a mean of 61.0% ( Figures 1A and B). We retrieved data on Ki-67 expression from our previous investigation on the same collection of samples (Schrader et al, 2004). As expected, the MCM6 index was significantly higher than the Ki-67 index (Figure 2, Po0.0001), with a mean for Ki-67 of 19.8%, compared to 61.0% for MCM6.…”

“…These data are in line with others (Ramnath et al, 2001;Helfenstein et al, 2004), indicating that the ratio of MCM6-and Ki-67-positive cells is larger in MCL than the Ki-67 expressing cells. Blastoid variants usually have a more aggressive clinical behaviour than classical types, and the proliferation indices in the blastoid subtypes are usually higher (Schrader et al, 2004). To our surprise, there were no significant differences in MCM6 expression (P ¼ 0.27) between the different cytological subtypes.…”

“…The immunohistochemical investigation was performed as described previously (Schrader et al, 2004). All sections were stained with antibodies against CD3 (dilution 1 : 20) (DAKO, Hamburg, Germany), CD5 (dilution 1 : 25) (Novocastra, Newcastle, UK), CD20 (dilution 1 : 5) (DAKO), CD23 (dilution 1 : 20) (Novocastra), …”

Immunohistochemical detection of cdc2 is useful in predicting survival in patients with mantle cell lymphoma

“…3 For the biologic markers, high proportion of cells positive for Ki67 has been found to correlate with worse clinical outcome. 4,6,7 In addition, genetic alterations in p53 [8][9][10] and loss of p27 11 are associated with worse clinical outcome. While these biologic markers have been shown to be useful in predicting survival, these assays have not be carried out in most routine diagnostic pathology laboratories.…”