| 51. |
|
|
| 52. |
- Fernebro, Josefin, et al.
(författare)
-
Standardizing evaluation of sarcoma proliferation - higher Ki-67 expression in the tumor periphery than the center
- 2007
-
Ingår i: APMIS : acta pathologica, microbiologica, et immunologica Scandinavica. - : Wiley. - 1600-0463. ; 115:6, s. 707-712
-
Tidskriftsartikel (refereegranskat)abstract
- Soft tissue sarcomas often present as large and histopathologically heterogenous tumors. Proliferation has repeatedly been identified as a prognostic factor and immunostaining for Ki-67 represents the most commonly used proliferation marker. There is, however, a lack of consensus on how to evaluate Ki-67 staining regarding optimal cut-off levels, selection of tumor areas, and the number of tumor cells to evaluate. We assessed the impact of targeting peripheral versus central tumor areas using tissue microarray-based staining for Ki-67 throughout the tumor diameter in 25 leiomyosarcomas. In 18/25 tumors, Ki-67 expression was higher in the tumor periphery. If 10% staining tumor nuclei was used as cut-off and the maximal Ki-67 staining section in the tumor periphery was considered, 21/25 tumors would have been classified as highly proliferative compared to 14/25 if the tumor center had been analyzed. Similar results were obtained also when higher cut-off levels were used and if the mean expression rather than the maximal expression was considered and the differences were neither caused by necrosis nor by hypoxia (assessed as HIF-1 alpha expression). Our findings suggest that the determination of proliferation in soft tissue sarcomas should be standardized for clinical application of Ki-67 as a prognostic marker.
|
|
| 53. |
- Francis, Princy, et al.
(författare)
-
Diagnostic and prognostic gene expression signatures in 177 soft tissue sarcomas: hypoxia-induced transcription profile signifies metastatic potential.
- 2007
-
Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Background Soft tissue sarcoma (STS) diagnosis is challenging because of a multitude of histopathological subtypes, different genetic characteristics, and frequent intratumoral pleomorphism. One-third of STS metastasize and current risk-stratification is suboptimal, therefore, novel diagnostic and prognostic markers would be clinically valuable. We assessed the diagnostic and prognostic value of array-based gene expression profiles using 27 k cDNA microarrays in 177, mainly high-grade, STS of 13 histopathological subtypes. Results Unsupervised analysis resulted in two major clusters – one mainly containing STS characterized by type-specific genetic alterations and the other with a predominance of genetically complex and pleomorphic STS. Synovial sarcomas, myxoid/round-cell liposarcomas, and gastrointestinal stromal tumors clustered tightly within the former cluster and discriminatory signatures for these were characterized by developmental genes from the EGFR, FGFR, Wnt, Notch, Hedgehog, RAR and KIT signaling pathways. The more pleomorphic STS subtypes, e.g. leiomyosarcoma, malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma and dedifferentiated/pleomorphic liposarcoma, were part of the latter cluster and were characterized by relatively heterogeneous profiles, although subclusters herein were identified. A prognostic signature partly characterized by hypoxia-related genes was identified among 89 genetically complex pleomorphic primary STS and could, in a multivariate analysis including established prognostic markers, independently predict the risk of metastasis with a hazard ratio of 2.2 (P = 0.04). Conclusion Diagnostic gene expression profiles linking signaling pathways to the different STS subtypes were demonstrated and a hypoxia-induced metastatic profile was identified in the pleomorphic, high-grade STS. These findings verify diagnostic utility and application of expression data for improved selection of high-risk STS patients.
|
|
| 54. |
|
|
| 55. |
- Halvarsson, Britta, et al.
(författare)
-
Clinicopathologic factors identify sporadic mismatch repair-defective colon cancers.
- 2008
-
Ingår i: American Journal of Clinical Pathology. - 1943-7722. ; 129:2, s. 238-244
-
Tidskriftsartikel (refereegranskat)abstract
- Identification of sporadic mismatch repair (MMR)-defective colon cancers is increasingly demanded for decisions on adjuvant therapies. We evaluated clinicopathologic factors for the identification of these prognostically favorable tumors. Histopathologic features in 238 consecutive colon cancers were linked to MMR status based on immunostaining and BRAF mutation status.MMR defects were identified in 22.7% of the tumors, with 46 classified as sporadic. When the clinical parameters of age, sex, and proximal tumor location were combined with the morphologic features with the highest relative risks (RRs), eg, mucinous differentiation (RR, 9.0), tumor-infiltrating lymphocytes (RR, 7.5), absence of necrosis (RR, 7.5), and expanding growth pattern (RR, 5.0) into a 7-factor index, the presence of at least 4 features identified the MMR-defective tumors with 92.3% sensitivity and 75.3% specificity and excluded 61.5% of the tumors from MMR testing. This clinicopathologic index thus successfully selects MMR-defective colon cancers.
|
|
| 56. |
- Halvarsson, Britta, et al.
(författare)
-
Loss of mismatch repair protein immunostaining in colorectal adenomas from patients with hereditary nonpolyposis colorectal cancer.
- 2005
-
Ingår i: Modern Pathology. - : Elsevier BV. - 1530-0285 .- 0893-3952. ; 18:8, s. 1095-1101
-
Tidskriftsartikel (refereegranskat)abstract
- Colorectal adenomas occur at younger age, at increased frequency and have a greater tendency for malignant transformation in patients with hereditary nonpolyposis colorectal cancer (HNPCC). We performed immunostaining for the mismatch repair proteins MLH1, PMS2, MSH2 and MSH6 in 35 colorectal adenomas from 26 patients with HNPCC and identified loss of immunostaining in 23/35 (0.66) adenomas. Loss of mismatch repair protein immunostaining was particularly frequent in large (>5 mm) (14/16) and proximally located (13/15) adenomas, whereas the gene mutated - MLH1 or MSH2 - and the type of mutation did not seem to affect the results. We conclude that loss of mismatch repair protein immunostaining is detected at a lower rate in adenomas than in carcinomas associated with HNPCC. Adenomatous tissue can thus be used for immunostaining of mismatch repair proteins in clinical investigations of HNPCC, but whereas loss of immunostaining may pinpoint the gene affected and thereby guide mutation analysis, retained staining cannot exclude that the adenoma developed as part of the syndrome due to reduced sensitivity. However, the analysis has a greater chance of being informative if large and proximally located adenomas are selected.
|
|
| 57. |
|
|
| 58. |
- Halvarsson, Britta, et al.
(författare)
-
Phenotypic heterogeneity in hereditary nonpolyposis colorectal cancer: identical germline mutations associated with variable tumor morphology and immunohistochemical expression.
- 2007
-
Ingår i: Journal of Clinical Pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 60:7, s. 781-786
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Hereditary non-polyposis colorectal cancer (HNPCC) is associated with high risks for colorectal and endometrial cancer, young age at onset and an increased risk of multiple primary tumours. Colorectal cancer in HNPCC is characterised by poor tumour differentiation, an expanding growth pattern, and a pronounced lymphocytic reaction with tumour-infiltrating lymphocytes. Aims and METHODS: The mutation spectrum in HNPCC is diverse and in order to clarify whether the HNPCC tumour phenotype is influenced by the underlying genetic alteration, 29 colorectal cancers and 12 adenomas from 24 individuals in two HNPCC families were morphologically and immunohistochemically characterised. RESULTS: The tumour morphology as well as the immunohistochemical expression of beta-catenin varied extensively within the families as well as between synchronous/metachronous colorectal cancers from the same individual. Poor tumour differentiation, an expanding growth pattern, and tumour-infiltrating lymphocytes occurred at higher frequencies in proximal tumours, whereas distal colorectal cancers often lacked distinct HNPCC-associated morphological features. CONCLUSIONS: The clinical, morphological and immunohistochemical variability observed within these families indicates that other mechanisms than the underlying germline mutation influence the HNPCC phenotype. Since morphological features linked to HNPCC are less frequent in distal cancers, it may be particularly relevant to obtain family history and age of onset in these tumours in order to identify individuals with HNPCC.
|
|
| 59. |
- Halvarsson, Britta, et al.
(författare)
-
The added value of PMS2 immunostaining in the diagnosis of hereditary nonpolyposis colorectal cancer.
- 2006
-
Ingår i: Familial Cancer. - : Springer Science and Business Media LLC. - 1389-9600 .- 1573-7292. ; 5:4, s. 353-358
-
Tidskriftsartikel (refereegranskat)abstract
- dentification and characterization of the genetic background in patients with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome is important since control programmes can in a cost-effective manner prevent cancer development in high-risk individuals. HNPCC is caused by germline mismatch repair (MMR) gene mutations and the genetic analysis of HNPCC therefore includes assessment of microsatellite instability (MSI) and immunohistochemical MMR protein expression in the tumor tissue. MSI is found in >95% of the HNPCC-associated tumors and immunostaining using antibodies against the MMR proteins MLH1, MSH2, and MSH6 has been found to correctly pinpoint the affected gene in about 90% of the cases. The PMS2 antibody was the most recently developed and we have in a clinical material assessed the added value of PMS2 immunostaining in 213 patients with suspected hereditary colorectal cancer. All 119 MSS tumors showed retained expression for all four antibodies and PMS2 did thus not identify any underlying MMR defect in these cases. However, PMS2 immunostaining contributed to the characterization of the MMR defect in a subset of the MSI tumors. Concomitant loss of MLH1 and PMS2, which functionally interact in the MutL alpha complex, was found in 98% of the tumors from patients with germline MLH1 mutations. Among the 12 MSI-high tumors with retained expression of MLH1, MSH2 and MSH6, 8 tumors showed loss of PMS2 staining, and mutations in MLH1 were identified in 2 and mutations in PMS2 in 3 of these individuals. In summary, isolated loss of PMS2 was found in 8% of the MSI-high tumors in our series, including 8/12 previously unexplained MSI-high tumors, in which mutations either in MLH1 or in PMS2 were identified in five cases.
|
|
| 60. |
|
|
