Genetic study on mode of tumor spread from colorectal metastasis in the liver -standardization of surgical procedure

为了阐明结直肠癌肝转移的最合理手术方式，我们进行了遗传学和组织学研究。采用遗传学诊断方法，对肝实质内肿瘤和Glisson's进行了研究。还研究了K-ras和p-53突变对肝切除术后患者生存率的影响。自1996年至2002年，58例大肠癌肝转移患者接受了62次肝切除术。采用突变等位基因特异性扩增法检测取自肿瘤、周围肝实质和肿瘤附近Glisson蒂的组织样本的K-ras和p-53突变。该队列随访至2004年1月，并分析患者生存率。在62组肝转移瘤标本中，39例K-ras和/或p53基因突变阳性。2.0%（4/199）的大肠癌转移灶周围肝实质内存在微转移灶，且微转移灶位于肿瘤边缘4 mm以内，经Glisson蒂的微转移灶较常见（14.3%：3/21），但也局限于距肿瘤边缘较短的范围（≤ 5 mm）。两种基因均无突变的患者3年生存率为94%，而wither基因突变的患者3年生存率为67%（p=0.177 logrank）。K-ras基因突变患者的3年生存率明显低于无突变患者（P=0.045）。手术切缘2 mm似乎是临床上可接受的最低要求，切缘相关复发风险约为5%。转移灶中的K-ras突变与肝切除术后患者预后不良有关。

To clarify most reasonable procedures for the surgical resection of colorectal liver metastases, we have conducted a genetic and histological study. Using a genetic diagnosis, tumor supread inside the hepatic parenchyma and Glisson's were investigated. Impact of K-ras and p-53 mutations on patient survival after liver resection was also studied. From 1996 through 2002,58 patients underwent 62 liver resections for hepatic metastasis from colorectal cancer. Tissue samples taken from the tumor, the surrounding liver parenchyma, and Glisson's pedicle near the tumor were tested for K-ras and p-53 mutations using the mutant allele-specific amplification method. This cohort was followed up until January 2004, and patient survival was analyzed. Of the 62 sets of samples from liver metastases, 39 were positive for K-ras and/or p53 gene mutations. Micrometastases in the liver parenchyma surrounding colorectal metastases were present in 2.0% (4/199) of tested samples and were located within 4 mm from the tumor border.Micrometastases via Glisson's pedicle were more common (14.3%:3/21), but they were also confined to a short range from the tumor edge (【less than or equal】 5mm). Three-year survival rate of patients without mutations of either gene was 94% while that of patients with mutation of wither gene was 67% (p=0.177 logrank). Three-year survival rate of patients with K-ras mutation had significantly poor prognosis comapring to that of patients without mutation (p=0.045).Micrometastases around the liver tumors are not common and most are confined to the immediate vicinity of the tumor border. Surgical margin of 2 mm appears to be a clinically acceptable minimum requirement with an approximately 5% risk of margin-related recurrence. K-ras mutation in the metastatic lesion was related to a poor patient outcome after liver resection.