Molecular analysis of surgical margins in head and neck squamous cell carcinoma patients
Molecular analysis of surgical margins in head and neck squamous cell carcinoma patients
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DOI：
10.1097/00005537-200212000-00003
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发表时间：
2002-12-01
期刊：
影响因子：
2.6
通讯作者：
Stucker, FJ
中科院分区：
文献类型：
--
作者：
Nathan, CAO;Amirghahri, N;Stucker, FJ
目的/假设：手术切缘的分子分析在确定手术切缘中发挥着越来越重要的作用。大多数标记物缺乏有效临床使用的敏感性和适用性。到目前为止，原癌基因eIF 4 E（4 E）在100%的头颈部鳞状细胞癌肿瘤中升高，并且在预测复发方面具有预后价值。在一项回顾性研究中，与p53相比，4 E在边缘的过表达似乎是一个更敏感的复发预测因子。目的是在前瞻性研究中证实这一发现，并比较基质金属蛋白酶-9（MMP-9）与4 E在肿瘤和切缘中的表达。其他目的是确定这些标志物中哪些在预测复发方面具有预后意义，并阐明结合三种分子标志物分析手术切缘是否有任何额外的益处。研究设计.对1998年至1999年间连续接受初次手术切除的头颈部鳞状细胞癌患者进行了前瞻性研究。回顾患者和肿瘤特征，并记录复发时间。方法.石蜡包埋切片的肿瘤和所有组织学无肿瘤的边缘进行了分析的存在或不存在的4 E，p53和MMP-9的免疫组化分析。根据该机构的头颈部癌症方案对患者进行随访，并记录复发时间。结果：98%的肿瘤过表达4 E，65%过表达p53，92%过表达MMP-9。在52例无肿瘤切缘的患者中，4 E、p53和MMP-9的阳性切缘分别为52%、46%和54%。虽然在切缘中4 E和p53表达之间没有显著相关性（P = 0.16），但4 E和MMP-9表达之间存在显著相关性（P = 0.0002）。但当4 E和p53表达于患者的边缘时，仅为过表达者。p53在肿瘤组织中的表达（n = 34），有显著相关性（P = 0.04）。4 E阳性和4 E阴性切缘患者的无病间期也有显著差异（P = 0.003）。p53阳性组与p53阴性组的复发时间差异不显著（P = 0.18），但当MMP-9用作标记物时接近显著性（P = 0.07）。尽管单变量分析显示分期、淋巴结疾病、分级和切缘4 E表达与无病间期显著相关，但在考克斯多元回归分析中，仅切缘4 E表达与无病间期显著相关（P = 0.01）。结论.手术切缘分子分析的时代已经到来。虽然4 E和MMP-9之间存在显著相关性，但与研究充分的肿瘤抑制基因p53和相对新颖的标志物MMP-9相比，4 E的过表达似乎是复发的重要预测因子。
Objectives/Hypothesis: Molecular analysis of surgical margins is playing an increasingly important role in establishing surgical margins. Most markers lack the sensitivity and ease of applicability for effective clinical use. To date, the proto-oncogene eIF4E (4E) is elevated in 100% of head and neck squamous cell carcinoma tumors and is of prognostic value in predicting recurrence. In a retrospective study, 4E overexpression in the margins appeared to be a more sensitive predictor of recurrence when compared with p53. The goal was to confirm this finding in a prospective study and also to compare the expression of matrix metalloproteinase-9 (MMP-9) to 4E expression in tumors and margins. Other objectives were to determine which of these markers have prognostic significance in predicting recurrence and elucidate whether there is any additional benefit to analysis of surgical margins with a combination of the three molecular markers. Study Design. A prospective study was performed on all patients who consecutively underwent primary surgical resection between 1998 and 1999 for head and neck squamous cell carcinoma. Patient and tumor characteristics were reviewed, and time to recurrence was noted. Methods. Paraffin-embedded sections of tumors and all histologically tumor-free margins were analyzed for the presence or absence of 4E, p53, and MMP-9 with immunohistochemical analysis. Patients were followed according to the institution's head and neck cancer protocol, and time to recurrence was noted. Results: Ninety-eight percent of tumors overexpressed 4E, 65% overexpressed p53, and 92% overexpressed MMP-9. Of the 52 patients with tumor-free margins, 52%, 46%, and 54% had positive margins for 4E, p53, and MMP-9, respectively. Although no significant correlation between 4E and p53 expression was seen in the margins (P = .16), a significant correlation between 4E and MMP-9 expression was noted (P = .0002). However, when expression of 4E and p53 in the margins of only the patients who overexpressed. p53 in the tumors was compared (n = 34), there was a significant correlation (P = .04). There was also a significant difference in the disease-free interval between patients with 4E-positive and 4E-negative margins (P = .003). This difference in time to recurrence was not significant for the p53-positive versus the p53-negative group (P = .18) but approached significance when MMP-9 was used as a marker (P = .07). Although the univariate analysis showed that stage, nodal disease, grade, and 4E expression in the margins were significantly associated with disease-free interval, in the Cox multiple regression analysis, only 4E expression in the margin was significantly associated with disease-free interval (P = .01). Conclusions. The era for molecular analysis of surgical margins is here. Although a significant correlation was seen between 4E and MMP-9, overexpression of 4E appears to be a significant predictor of recurrence when compared with the well-studied tumor suppressor gene p53 and a relatively novel marker, MMP-9.