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There is increased incidence of microsatellite instability (MSI) in patients who develop multiple primary colorectal cancers (CRC), although the association with hereditary nonpolyposis colon cancer (HNPCC) is unclear. This study aims to evaluate the underlying genetic cause of MSI in these patients. Microsatellite instability was investigated in 111 paraffin-embedded CRCs obtained from 78 patients with metachronous and synchronous cancers, and a control group consisting of 74 cancers from patients with a single CRC. Tumours were classified as high level (MSI-H), low level (MSI-L) or stable (MSS). MLH1, MSH2 and MSH6 gene expression was measured by immunohistochemistry. Methylation of the MLH1 promoter region was evaluated in MSI-H cancers that failed to express MLH1, and mutational analysis performed in MSI-H samples that expressed MLH1, MSH2 and MSH6 proteins. The frequency of MSI-H was significantly greater in the multiple, 58 out of 111 (52%), compared to the single cancers, 10 out of 74 (13.5%), Po0.01. Of the 32 patients from whom two or more cancers were analysed, eight (25%) demonstrated MSI-H in both cancers, 13 (41%) demonstrated MSI-H in one cancer and 11 (34%) failed to demonstrate any MSI-H. MSI-H single cancers failed to express MLH1 or MSH2 in seven out of nine (78%) cases and MSI-L/MSS cancers failed to express MLH1 or MSH2 in one out of 45 (2.2%) cases, all cancers expressed MSH6. MSI-H multiple cancers failed to express MLH1 or MSH2 in 21 out of 43 (48%) cases and MSI-L/MSS cancers failed to express MLH1 or MSH2 in four out of 32 (12.5%) cases. MSH6 expression was lost in five MSI-H multiple cancers, four of which also failed to express MLH1 or MSH2. Loss of expression of the same mismatch repair (MMR) gene was identified in both cancers from six out of 19 (31%) patients. Methylation was identified in 11 out of 17 (65%) multiple and three out of six (50%) single MSI-H cancers that failed to express MLH1. Mutational analysis of 10 MSI-H multiple cancers that expressed MLH1, MSH2 and MSH6 failed to demonstrate mutations in the MLH1 or MSH2 genes. We suggest that, although MSI-H is more commonly identified in those with multiple colorectal cancers, this does not commonly arise from a classical HNPCC pathway.

INTRODUCTION Patients with liver metastasis from breast cancer have a poor prognosis, although this may be improved by hepatectomy in a selected group with disease confined to the liver. We evaluate the effectiveness of radiofrequency ablation (RFA) as a cytoreductive strategy in the management of liver metastasis from primary breast cancer.PATIENTS AND METHODS Nineteen patients with hepatic metastasis from primary breast cancer underwent RFA of their liver lesions between April 1998 and August 2004. RESULTS The median age of the patients was 52 years (range, 32-69 years), 8 had disease confined to the liver, with 11 having stable extrahepatic disease in addition. Seven patients with disease confined to the liver at presentation are alive, as are 6 with extrahepatic disease, median follow-up after RFA was 15 months (range, 0-77 months). Survival at 30 months was 41.6%. In addition, 7 patients followed up for a median of 14 months (range, 2-29 months) remain alive and disease-free. RFA failed to control hepatic disease in 3 patients. RFA was not associated with any mortality or major morbidity.CONCLUSIONS Control of hepatic metastasis from breast cancer is possible using RFA and may lead to a survival benefit, particularly in those patients with disease confined to the liver. KEYWORDSLiver metastasis -Radiofrequency ablation (RFA) -Breast cancer