van Houten Viola M M, Tabor Maarten P, van den Brekel Michiel W M, Kummer J Alain, Denkers Fedor, Dijkstra Janny, Leemans René, van der Waal Isaäc, Snow Gordon B, Brakenhoff Ruud H
Department of Otolaryngology/Head and Neck Surgery, Vrije Universiteit Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
J Pathol. 2002 Dec;198(4):476-86. doi: 10.1002/path.1242.
In total, 10-30% of patients with head and neck squamous cell carcinoma (HNSCC) develop local recurrences despite seemingly adequate tumour resection. This may result from minimal residual cancer (MRC): small numbers of tumour cells left behind in the surgical margins, undetectable by routine histopathology. In recent studies, p53 mutations have been considered as selective and sensitive DNA markers of cancer cells. There are two potential problems in using mutated-p53 DNA as a marker. Firstly, p53 mutations occur early in progression and might therefore detect unresected precursor lesions besides tumour cells. Secondly, DNA is a very stable biomolecule that might lead to false-positive results. These two potential problems have been evaluated in this study. Fifty patients with a radical tumour resection were included, of whom 30 showed a p53 mutation in the primary tumour. Histopathologically tumour-free surgical margins were quantitatively analysed for mutated p53 by molecular diagnosis (plaque assay) and subsequent (immuno)histopathology. p53 mutated DNA was detected in the surgical margins of 19/30 patients. Immunohistochemistry confirmed the presence of small tumour foci in 2/19 mutated p53-positive cases. In 7/19 cases, the tumour-specific p53 mutation was found in unresected dysplastic mucosal precursor lesions. Moreover, in a number of cases small p53-immunostained patches were detected, but the mutations found were never tumour-related. By screening contralateral exfoliated cells and plaque assays on RNA it was shown that detection of mutated-p53 DNA is prone to false-positive results. In conclusion, using p53 mutations as a marker, both MRC and unresected mutated p53-positive mucosal precursor lesions are detected within surgical margins. Molecular assessment of surgical margins using p53 mutations enables the selection of HNSCC patients at high risk for tumour recurrence, but tumour RNA seems at present to be a more specific biomolecule for analysis than tumour DNA.
总体而言，10%至30%的头颈部鳞状细胞癌（HNSCC）患者尽管肿瘤切除看似充分，但仍会发生局部复发。这可能是由于微小残留癌（MRC）所致：手术切缘遗留少量肿瘤细胞，常规组织病理学无法检测到。在最近的研究中，p53突变被认为是癌细胞的选择性和敏感性DNA标志物。将突变型p53 DNA用作标志物存在两个潜在问题。首先，p53突变在疾病进展早期就会出现，因此除了肿瘤细胞外，可能还会检测到未切除的前驱病变。其次，DNA是一种非常稳定的生物分子，可能导致假阳性结果。本研究对这两个潜在问题进行了评估。纳入了50例接受根治性肿瘤切除的患者，其中30例原发性肿瘤显示p53突变。通过分子诊断（噬菌斑测定）和随后的（免疫）组织病理学对组织病理学上无肿瘤的手术切缘进行p53突变的定量分析。在30例患者中的19例手术切缘检测到p53突变DNA。免疫组织化学证实19例p53突变阳性病例中有2例存在小肿瘤灶。在19例中的7例中，在未切除的发育异常黏膜前驱病变中发现了肿瘤特异性p53突变。此外，在一些病例中检测到小的p53免疫染色斑块，但发现的突变与肿瘤无关。通过筛查对侧脱落细胞和RNA噬菌斑测定表明，检测突变型p53 DNA容易出现假阳性结果。总之，以p53突变为标志物，在手术切缘内可检测到微小残留癌和未切除的p53突变阳性黏膜前驱病变。利用p53突变对手术切缘进行分子评估能够筛选出肿瘤复发高危的HNSCC患者，但目前肿瘤RNA似乎是比肿瘤DNA更具特异性的分析生物分子。
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