Improved prognostication in soft tissue sarcoma: Independent information from vascular invasion, necrosis, growth pattern, and immunostaining using whole-tumor sections and tissue microarrays

Department of Oncology, Lund University Hospital, SE-221 85 Lund, Sweden.
Human Pathlogy (Impact Factor: 2.77). 10/2005; 36(9):994-1002. DOI: 10.1016/j.humpath.2005.07.008
Source: PubMed


In 140 mixed primary soft tissue sarcomas with a median follow-up of 6 years, the prognostic importance of tumor size, tumor depth, grade, necrosis, vascular invasion, and peripheral growth pattern (pushing versus infiltrating) was evaluated on whole-tumor sections. Immunohistochemical expression of Ki-67, p53, cyclin A, bcl-2, beta-catenin, CD44, and P-glycoprotein was determined using tissue microarray from the peripheral growth zone. Local recurrences developed in 17% of the patients and correlated with necrosis, vascular invasion, and cyclin A expression. No local recurrence developed in tumors with a pushing growth pattern, regardless of tumor grade and depth. Metastasis developed in 39% of the patients. Vascular invasion was identified in 36% of the tumors and was the strongest prognostic factor for metastasis with a hazard ratio of 3.5. Growth pattern and tumor necrosis were also strong prognostic factors for metastasis, whereas malignancy grade, tumor size, and tumor depth did not have any independent prognostic value. Immunostaining showed independent prognostic information for Ki-67, beta-catenin, CD44, and P-glycoprotein. The results indicate that whole-tumor sections could facilitate identification of vascular invasion, necrosis, and peripheral growth pattern and that immunohistochemical profiling from the growth zone also provides independent prognostic information for metastasis in soft tissue sarcoma.

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    • "Although, there are some controversies [3], most studies have shown that nuclear expression of β-catenin is associated with the progression of human cancers. In human sarcomas, nuclear expression of β-catenin predicted poor prognosis of synovial sarcoma [46], [47]. Our results have also indicated that the expression of β-catenin and cyclin D1 are significantly associated with shorter OS and EFS by univariate analysis. "
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    ABSTRACT: Recently, the roles of SIRT1 and deleted in breast cancer 1 (DBC1) in human cancer have been extensively studied and it has been demonstrated that they are involved in many human carcinomas. However, their clinical significance for soft-tissue sarcomas has not been examined. In this study, we evaluated the expression and prognostic significance of the expression of SIRT1, DBC1, P53, β-catenin, cyclin D1, and KI67 in 104 cases of soft-tissue sarcomas. Immunohistochemical expression of SIRT1, DBC1, P53, β-catenin, and cyclin D1 were seen in 71%, 74%, 53%, 48%, and 73% of sarcomas, respectively. The expression of SIRT1, DBC1, P53, β-catenin, and cyclin D1 were significantly correlated with advanced clinicopathological parameters such as higher clinical stage, higher histological grade, increased mitotic counts, and distant metastasis. The expression of SIRT1, DBC1, P53, β-catenin, cyclin D1, and KI67 were significantly correlated with each other and positive expression of all of these predicted shorter overall survival and event-free survival by univariate analysis. Multivariate analysis revealed the expression of SIRT1 as an independent prognostic indicator for overall survival and event-free survival of sarcoma patients. In conclusion, this study demonstrates that SIRT1- and DBC1-related pathways may be involved in the progression of soft-tissue sarcomas and can be used as clinically significant prognostic indicators for sarcoma patients. Moreover, the SIRT1- and DBC1-related pathways could be new therapeutic targets for the treatment of sarcomas.
    PLoS ONE 09/2013; 8(9):e74738. DOI:10.1371/journal.pone.0074738 · 3.23 Impact Factor
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    • "Malignant tumors are showing necrosis and uncontrolled cell proliferation that is related to a nuclear antigen called Ki-67, a nonhistone nucleoprotein in proliferating cell nuclei. This polypeptide accumulates from G1 -phase to mitosis [7-10]. The role of Ki-67 in the human genome has not been identified but Ki-67 antigen-positive cells have given a more accurate indication of proliferating cells compared to that of PCNA (Proliferating Cell Nuclear Antigen) positive cells in many cancers as PCNA is detectable in almost all quiescent cells adjacent to some tumors. "
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    ABSTRACT: The prognosis for many cancers could be improved dramatically if they could be detected while still at the microscopic disease stage. It follows from a comprehensive statistical analysis that a number of antigens such as hTERT, PCNA and Ki-67 can be considered as cancer markers, while another set of antigens such as P27KIP1 and FHIT are possible markers for normal tissue. Because more than one marker must be considered to obtain a classification of cancer or no cancer, and if cancer, to classify it as malignant, borderline, or benign, we must develop an intelligent decision system that can fullfill such an unmet medical need. We have developed an intelligent decision system using machine learning techniques and markers to characterize tissue as cancerous, non-cancerous or borderline. The system incorporates learning techniques such as variants of support vector machines, neural networks, decision trees, self-organizing feature maps (SOFM) and recursive maximum contrast trees (RMCT). These variants and algorithms we have developed, tend to detect microscopic pathological changes based on features derived from gene expression levels and metabolic profiles. We have also used immunohistochemistry techniques to measure the gene expression profiles from a number of antigens such as cyclin E, P27KIP1, FHIT, Ki-67, PCNA, Bax, Bcl-2, P53, Fas, FasL and hTERT in several particular types of neuroendocrine tumors such as pheochromocytomas, paragangliomas, and the adrenocortical carcinomas (ACC), adenomas (ACA), and hyperplasia (ACH) involved with Cushing's syndrome. We provided statistical evidence that higher expression levels of hTERT, PCNA and Ki-67 etc. are associated with a higher risk that the tumors are malignant or borderline as opposed to benign. We also investigated whether higher expression levels of P27KIP1 and FHIT, etc., are associated with a decreased risk of adrenomedullary tumors. While no significant difference was found between cell-arrest antigens such as P27KIP1 for malignant, borderline, and benign tumors, there was a significant difference between expression levels of such antigens in normal adrenal medulla samples and in adrenomedullary tumors. Our frame work focused on not only different classification schemes and feature selection algorithms, but also ensemble methods such as boosting and bagging in an effort to improve upon the accuracy of the individual classifiers. It is evident that when all sorts of machine learning and statistically learning techniques are combined appropriately into one integrated intelligent medical decision system, the prediction power can be enhanced significantly. This research has many potential applications; it might provide an alternative diagnostic tool and a better understanding of the mechanisms involved in malignant transformation as well as information that is useful for treatment planning and cancer prevention.
    BMC Genomics 02/2008; 9 Suppl 1(Suppl 1):S23. DOI:10.1186/1471-2164-9-S1-S23 · 3.99 Impact Factor
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    • "Some of the targeted genes of the APC–b-catenin–Tcf pathway have been identified in vitro [15] [16] [17] [18], and cyclin D1 is one of them [18]. Expression and mutations of b-catenin in soft tissue sarcomas (STSs) including spindle cell sarcomas (SCSs) and pleomorphic sarcomas has also been described [19] [20] [21]; however, the expression pattern of b-catenin in SCS except synovial sarcoma (SS) is almost always observed as nuclear staining [20] [22] [23]. b-catenin accumulation in STS has been shown to correlate with tumor progression as assessed by proliferative activity or poor prognosis [19] [20] [21]; however, it remains unclear whether these proliferative advantages are caused by the activation of the aforementioned target genes. "
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    ABSTRACT: Nuclear beta-catenin staining in soft tissue sarcomas (STSs) has been shown to correlate with tumor progression as assessed by proliferative activity or poor prognosis. Frequent activation of Wnt signaling pathway has been also shown in synovial sarcoma (SS), suggesting a specific role of this pathway in SS. We examined roles of nuclear beta-catenin staining within soft tissue sarcomas. Immunohistochemical detection of nuclear beta-catenin accumulation correlated with cyclin D1 overexpression in spindle cell and pleomorphic sarcomas (P = .037), and the expression of these proteins evenly distributed throughout each section. In some cases, strong beta-catenin nuclear staining was observed in highly pleomorphic and mitotic cells. Furthermore, tumors with nuclear beta-catenin accumulation showed statistically significant increasing cyclin D1 mRNA expression level compared with those without (P = .023). Cyclin D1 mRNA expression levels were statistically higher in tumors with cyclin D1 overexpression than in tumors without (P = .037), suggesting that cyclin D1 overexpression is due to transcriptional activation. However, these correlations could not be detected in SS. In biphasic SS, beta-catenin nuclear staining was observed in spindle cells, whereas cyclin D1 nuclear staining was seen in glandular areas where beta-catenin kept membranous expression. Mutations in exon 3 of the beta-catenin gene and in the mutation cluster region of adenomatous polyposis coli gene were absent in this series of cases. Thus, cyclin D1 could be considered as one of the targets of the nuclear beta-catenin in spindle cell and pleomorphic sarcomas. A possible association between beta-catenin accumulation and spindle cell morphogenesis may exist in SS.
    Human Pathlogy 07/2006; 37(6):689-97. DOI:10.1016/j.humpath.2006.01.017 · 2.77 Impact Factor
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