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Clinical Cancer Research Vol. 5, 2830-2835, October 1999
© 1999 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Prognostic Relevance of p53 Alterations and Mib-1 Proliferation Index in Subgroups of Primary Liposarcomas1

Regine Schneider-Stock2, Anke Ziegeler, Carsten Haeckel, Dagmar-S. Franke, Janusz Rys and Albert Roessner

Department of Pathology, Otto-von-Guericke University, 39120 Magdeburg, Germany [R. S. S, A. Z., C. H., D-S. F., A. R.], and Department of Pathology, Oncologic Center, 31-115 Cracow, Poland [J. R.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
For prognostic analyses of p53 alterations (p53 gene mutations + p53 immunopositivity) and Mib-1 proliferation index, we investigated 42 primary malignant lipomatous tumors for which complete clinical data and a long follow-up were available. p53 gene mutations were investigated by PCR-single strand conformation polymorphism-sequencing analysis, and immunohistochemistry was used to determine p53 protein expression and Mib-1 proliferation index. We found a mutation frequency of 14.3%. Nine liposarcomas (21%) were p53 immunopositive, and 11 (26.2%) had at least one p53 alteration. In myxoid liposarcomas, p53 alterations are not relevant to the presence or absence of round cell components. Pleomorphic liposarcomas showed a significantly higher proliferation index and more p53 alterations than myxoid or well-differentiated variants (P < 0.001). When the Cox’s regression analysis tumors of grade III histology (P = 0.005) was performed, the pleomorphic subtype (P = 0.016) and liposarcomas of retroperitoneal localization (P = 0.015) showed a significantly poorer prognosis. Moreover, we found that p53 alterations and high proliferation index correlated significantly with reduced overall survival. Their prognostic value seemed to be higher in myxoid than in pleomorphic liposarcomas. The metastasis-free survival was reduced in patients who had liposarcomas with p53 alterations (P = 0.171) or elevated proliferation index (P < 0.016), reflecting a more aggressive behavior. In conclusion, the determination of p53 alterations and/or Mib-1 proliferation index is useful for assessing the prognosis of patients with liposarcomas and may especially be helpful in dividing different prognostic groups for patients with myxoid variants.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
It is generally accepted that p53 mutations in human malignant tumors are often related to a poor prognosis (1 , 2) . In soft tissue tumors, there was a correlation between the overexpression of p53 and MDM2 proteins in the same tumor and poor survival (3 , 4 , 5) . Taubert et al. (6) reported that patients with nonframeshift mutations had a considerably poorer prognosis. Moreover, p53 overexpression alone was found to be associated with a poor clinical outcome (7 , 8) . In contrast to these findings, Nakanishi et al. (9) and O’Reilley et al. (10) found no correlation between p53 overexpression and patients’ survival. This discrepancy can be explained by the fact that different soft tissue tumor entities were included in these investigations. Prognostic statements, however, should be made for single entities. Thus, liposarcomas (as a single entity), constituting ~15% of soft tissue tumors, are characterized by an outstandingly wide morphological variety. In the recent publications of Dei Tos et al. (11 , 12) , Pilotti et al. (13) , and Schneider-Stock et al. (14, 13, 14, 15, 16) , different genetic patterns in the different histological subtypes of liposarcomas have already been discussed. The fact that the specific t(12;16) chromosome translocation has been confirmed recently in myxoid liposarcomas (17) corroborates the concept that myxoid liposarcoma represents an entity biologically different from well-differentiated or pleomorphic liposarcomas. General consensus has been reached that localization, tumor size, histological subtype, and hence, the grade of malignancy, are prognostic factors in liposarcomas (18) . To date, only a few authors have demonstrated a correlation between p53 overexpression and worse event-free survival or patient survival in single entities, such as in rhabdomyosarcoma (19) , chondrosarcoma (20) , and osteosarcoma (21) . Despite the growing number of cytogenetic (22) and molecular biological findings in liposarcoma, data on the prognostic significance of p53 alterations (p53 mutations and p53 protein expression) in a larger group, especially on the association with histological subtypes, are not available.

Thus, a cohort of 42 primary malignant lipomatous tumors was analyzed in a retrospective study. The Mib-1 proliferation index was determined additionally, because a high proliferation index was shown to correlate with poor clinical outcome and reduced survival in patients with soft tissue sarcomas (7 , 23) . Using Cox’s regression model, we estimated the prognostic significance of p53 alterations and Mib-1 proliferation index.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Tumors.
We investigated a total of 42 primary malignant lipomatous tumors. Tumors were collected at the Medical Faculty of the Otto-von-Guericke University, Magdeburg, between 1983 and 1997. The tumor group consisted of 42 primary tumors. Nine liposarcomas were snap frozen, and 33 tumors were formalin-fixed and paraffin-embedded. All liposarcomas were histopathologically reclassified according to Mentzel and Fletcher (24) . The grading system proposed by Trojani et al. (25) was used. There were 10 pleomorphic, 19 myxoid (13 classical low grade, 6 with round cells), and 13 well-differentiated (8 WD-lipoma-like and 5 WD-sclerosing) tumors. There were 25 men (mean age, 52.7 years; range, between 19 and 82 years) and 17 women (mean, 53.8 years; range, between 15 and 83 years). The median follow-up period was 36 months.

DNA Preparation.
DNAs from frozen tumor tissues were prepared by standard phenol-chloroform extraction (26) . For DNA preparation from paraffin blocks, three 10-µm sections were cut on a microtome. After deparaffinization, sections were incubated for 48 h at 55°C in 100 µl of digestion buffer [10 mM Tris-hydrochloric acid (pH 8.3), 1 mM EDTA, and 0.5% Tween 20] and 8 µl of proteinase K (20 mg/ml; Promega Corp., Madison, WI). DNA was isolated by phenol-chloroform extraction and a final purification step using spin columns (Qiagen, Santa Clarita, CA). This procedure minimized background smear in PCR.

p53-PCR-Single Strand Conformation Polymorphism-Screening.
The conserved regions of the p53 gene (exons 5–8) were investigated. The oligonucleotide primers and annealing temperatures are described elsewhere (27) . The PCR products were detected on ultrathin polyacrylamide gels (0.3–0.45 mm thick, and 8–15%, depending on the fragment length to be separated) at 15°C for ~2.5 h in horizontal electrophoresis (Multiphor; Pharmacia/Biotech). DNA fragments were visualized using a modified silver-staining protocol according to Budowle et al. (28) . The single strand conformation polymorphism technique served as prescreening for mutations. A 4.5-µl sample of the PCR product and 4.5 µl of 100% formamide buffer (0.05% bromphenol and 0.05% xylencyanol) were denatured at 98°C for 5 min, subsequently chilled on ice, and applied to a 0.5x MDE gel (Mutation Detection Enhancement/AT Biochem). Electrophoresis was performed at 10°C for 2 h, and gels were silver-stained according to the method of Goldmann and Merril (29) .

PCR products showing mobility shifts of their single strands were directly sequenced on an automated fluorescence sequencer (373A; Perkin-Elmer Cetus, NJ or ALF Express, Pharmacia Biotech, Uppsala, Sweden).

Mib-1 Proliferation Index/p53 Immunohistochemistry.
The Mib-1 proliferation index and p53 protein expression were evaluated immunohistochemically as described elsewhere (16) . Briefly, after 15 min of deparaffinization, sections were dehydrated and immersed in sodium citrate (pH 6.0) for 3 x 10 min in a microwave oven, followed by incubation with primary antibody anti-Ki-67 (Mib-1; Oncogene Science, Uniondale, NY) and murine monoclonal antibody DO1 (Oncogene Science) in a dilution of 1:30 and 1:50, respectively, for 60 min. The alkaline phosphatase/anti-alkaline phosphatase technique was used for staining.

Positive Mib-1 nuclear reaction was evaluated as an index: the ratio of the positive-stained nuclei to the total number of tumor cells by examining 40 high-power fields in representative areas with ~1000 cells. A Mib-1 proliferation index >10% was judged to be highly proliferative according to Nawa et al. (20) in chondrosarcomas.

Only a distinct nuclear immunoreaction in >5% of tumor cells was judged as positive for p53.

Statistical Analysis.
For statistical evaluation, frequency of p53 gene mutations and p53 immunopositivity were added, and the combined parameter was defined as "p53 alterations" according to Casey et al. (30) . To assess the association between clinicopathological variables and parameters investigated (p53 alterations and Mib-1 proliferation index), Fisher’s exact test (two-tailed) was used. Prognostic analysis (grading, tumor localization, histological subtype, and tumor size) started with designing the cumulative survival functions according to Kaplan-Meier. The log-rank test was used to estimate the differences in survival between the groups of patients. The Cox’s regression model was applied to estimate the risk ratios in 95% confidence intervals. P < 0.05 was considered statistically significant. Statistical analyses were done using SPSS software (SPSS, Inc.; program version 7.5 for Windows, 1996).


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
p53 Alterations and Mib-1 Proliferation Index.
Of 42 primary malignant lipomatous tumors, 9 (21%) were p53 immunopositive, 6 cases (14.3%) showed p53 gene mutations, 11 (26.2%) had at least one p53 alteration, and 8 tumors (19%) had a Mib-1 proliferation index >10%.

p53 mutation data are given in Table 1Citation . The majority of p53 mutations were missense mutations in exons 6–8. A base substitution occurred at a polymorphic site in codon 213, and this case was defined as tumor without p53 alteration in the prognostic analysis. One nonsense mutation (codon 271) was found in a pleomorphic liposarcoma. As expected, these two latter tumors were negative for p53 immunohistochemistry. All other tumors showing p53 mutations at CpG islands (codons 245, 248, and 273) and the codon 214 mutation were p53 immunopositive. The codon 250 mutation (p53 immunonegative) seems to be not relevant for the establishment of functional p53 protein conformation. Five of nine cases were immunopositive for the p53 protein without detectable mutation.


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  		Table 1 p53 alterations in primary liposarcomas

 
Table 2Citation summarizes data obtained by a comparison between the Mib-1 index and p53 alterations and the various clinicopathological factors of liposarcomas. Pleomorphic liposarcomas showed a significantly higher proliferation index as well as more p53 alterations than myxoid or well-differentiated variants (P < 0.001). Liposarcomas with retroperitoneal localization showed significantly more p53 alterations (P < 0.05).


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  		Table 2 Association between p53 alterations/Mib-1 proliferation index and various clinicopathological factors in primary liposarcomas

 
Survival Analysis.
The 5-year survival rate for the 42 patients with primary liposarcomas was 68.95%. Tumors of grade III histology (P = 0.005), the pleomorphic subtype (P = 0.016), and lesions of retroperitoneal localization (P = 0.015) showed a significantly poorer prognosis. Thus, we confirmed the prognostic significance of these factors (18) in liposarcomas showing the accuracy of sampling and classification of the patient group.

Patients who had tumors with a high proliferation index or p53 alterations had a more unfavorable prognosis, compared with low proliferating tumors or tumors without any p53 alteration. The 5-year survival rate in patients with p53-positive tumors (46.1%) or high proliferation index (37.5%) was worse than in those with p53-negative liposarcomas (76.7%; P = 0.023) or low proliferating tumors (74.3%; P = 0.003). Performing the univariate Cox’s regression analysis, we found a strong correlation between p53 alterations as well as high proliferation index and overall survival in liposarcomas (Table 3Citation ; Fig. 1, A and BCitation ). In the multivariate analysis, only tumor localization (P = 0.001) and tumor grade (P = 0.04) were independent prognostic factors.


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  		Table 3 Prognostic significance of p53 alterations and Mib-1 proliferation index in primary liposarcomas using Cox’s regression model

 


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  		Fig. 1. Kaplan-Meier overall survival curves for patients with liposarcomas according to p53 alterations (A) and Mib-1 proliferation index (B). Patients who have p53 alterations or a high proliferation index show a significantly poorer prognosis than those with p53-negative tumors (P = 0.023) or low proliferating tumors (P = 0.003). p53 alterations also significantly correlated with overall survival in 19 patients with myxoid liposarcomas (P = 0.013). The p53-positive group in patients with myxoid liposarcomas (C) shows a poorer prognosis than the p53-negative group.

 
Analyzing the histological subtypes of liposarcomas separately, we found a different prognostic relevance of investigated parameters. Whereas patients who had myxoid tumors with p53 alterations died in a significantly shorter time after tumor resection (7 months versus 74 months) and showed a significantly reduced overall survival (40% versus 71.4%; Fig. 1CCitation ), there were no differences for pleomorphic liposarcomas (Table 3)Citation . Because of the low number of cases in the Mib-1 >10% group (n = 2), we could not estimate the prognostic relevance of proliferation index in myxoid liposarcomas (Table 3)Citation . Nevertheless, both patients having myxoid liposarcomas with Mib-1 index >10% died of the disease 2 and 8 months after tumor resection, respectively. The only patient with a p53-immuno-positive tumor of the well-differentiated subtype in the retroperitoneal space died of the disease 38 months after tumor resection and had developed one recurrent tumor as well as lung and liver metastases.

Clinical data revealed that 9 of 42 (21.4%) patients developed metastases. The metastasis-free survival time was reduced in patients having primary tumors with p53 alterations [12.3 (p53+) versus 44.8 (p53-) months; P = 0.171] or elevated proliferation index [0 (Mib-1>10%) versus 34.3 (Mib-1<10%) months; P = 0.016]. There were no significant differences in the recurrence-free survival.


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The prognostic relevance of p53 alterations and Mib-1 proliferation index in soft tissue tumors has been reported by Cordon-Cardo et al. (3) , Drobnjak et al. (7) , O’Reilley et al. (10) , Wurl et al. (4 , 5) , and deAnta et al. (2) . However, a larger group of liposarcoma patients, for whom complete clinical data, a long follow-up, and data on p53 alterations and Mib-1 proliferation index are available, has not been subjected to prognostic analysis thus far. Considering the parameter "p53 alterations," we measured a dysregulated p53 protein by p53 gene mutation and p53 immunopositivity. We found five p53-immunopositive tumors without a detectable p53 gene mutation. Because the p53 antibody used recognizes wild-type overexpression and mutant protein, we also retrieved deregulated p53 caused by interactions with multiple other factors such as the mdm2 oncoprotein (31) , binding to viral oncoproteins (32) , or changes at the transcriptional level. Also, mutations might have occurred outside the conservative regions of the p53 gene.

Data from our study confirmed that also in liposarcomas, p53 alterations and a high proliferation index correlate strongly with pathological variables of poor clinical outcome and reduced survival. Also, Mousses et al. (33) found that the p53 status is related to the histopathology of liposarcomas. In their studies, p53 alterations were predominantly observed in pleomorphic variants. In our study, there was no difference in the frequency of p53 alterations between the pure myxoid and the more round cell variants, supporting findings of DeiTos et al. (12) . Thus, p53 alterations do not seem to be useful markers for characterizing tumor progression in myxoid liposarcoma. Sprogoe-Jakobsen and Holund (34) described that Mib-1 index and p53 status are indicators for determination of malignancy in smooth muscle neoplasms (myxoid leiomyosarcomas versus leiomyomas). In contrast, by investigating a group of 70 patients with soft tissue tumors including 11 liposarcomas, Nakanishi et al. (9) found no correlation between p53 protein expression and survival of patients. Moreover, there was no correlation between overall survival and p53 or Mib-1 proliferation index in 44 extrauterine leiomyosarcomas (10) and in malignant fibrous histiocytomas (35) .

Using Cox’s regression model, we were the first to show that in liposarcomas, p53 alterations (p53 mutations and p53 protein expression) and Mib-1 proliferation index were associated with poor prognosis. Moreover, their prognostic value was higher in myxoid than in pleomorphic liposarcomas. Patients who had myxoid liposarcomas with p53 alterations or a high Mib-1 proliferation index showed a shorter overall survival. This indicates that myxoid liposarcomas contain two different subgroups in terms of prognosis and that these two groups can be distinguished by Mib-1 index or p53 alteration detection. Obviously, p53 alterations and Mib-1 index are associated with a more aggressive clinical behavior in myxoid liposarcomas. Interestingly we found no statistical difference between the two groups (p53+ or Mib-1 >10% versus p53- or Mib-1 <10%) in pleomorphic liposarcomas. This result supports the findings of Drobnjak et al. (7) , who investigated 141 high-grade sarcomas and found no difference in context of p53 status versus survival in contrast to significant associations in a mixed group of 174 soft tissue tumors. In accordance with Kawai et al. (8) , we found shorter metastasis-free survival in patients who had primary liposarcomas with p53 alterations or a high proliferation index. This fact reflects the more aggressive clinical behavior of these tumors. Recently, Heslin et al. (36) described that Mib-1 index is an prognostic molecular marker that predicts distant metastases in high grade extremity soft tissue tumors.

In conclusion, the present study demonstrates that determination of p53 alterations and/or Mib-1 proliferation index is a useful procedure for assessing the prognosis of liposarcoma patients, and moreover, for establishing different prognostic groups for patients with myxoid variants.


   ACKNOWLEDGMENTS
 
We thank Simone Staeck for excellent technical assistance.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by the Deutsche Krebshilfe, Germany (10-1074 SchnI) and the Rudolf-Bartling Foundation, Hanover, Germany. Back

2 To whom requests for reprints should be addressed, at Otto-von-Guericke University, Department of Pathology, Leipziger Strasse 44, 39120 Magdeburg, Germany. Phone: 0049-391-6715060; Fax: 0049-391-6715818; E-mail: Regine.Schneider-Stock{at}medizin.uni-magdeburg.de Back

Received 4/19/99; revised 8/ 2/99; accepted 8/ 2/99.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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