Department of Pathology, Thoracic Oncology Service, Department of Medicine, and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, NY 10065, USA.
Clin Cancer Res. 2012 Feb 15;18(4):1167-76. doi: 10.1158/1078-0432.CCR-11-2109. Epub 2012 Jan 6.
There is persistent controversy as to whether EGFR and KRAS mutations occur in pulmonary squamous cell carcinoma (SQCC). We hypothesized that the reported variability may reflect difficulties in the pathologic distinction of true SQCC from adenosquamous carcinoma (AD-SQC) and poorly differentiated adenocarcinoma due to incomplete sampling or morphologic overlap. The recent development of a robust immunohistochemical approach for distinguishing squamous versus glandular differentiation provides an opportunity to reassess EGFR/KRAS and other targetable kinase mutation frequencies in a pathologically homogeneous series of SQCC.
Ninety-five resected SQCCs, verified by immunohistochemistry as ΔNp63(+)/TTF-1(-), were tested for activating mutations in EGFR, KRAS, BRAF, PIK3CA, NRAS, AKT1, ERBB2/HER2, and MAP2K1/MEK1. In addition, all tissue samples from rare patients with the diagnosis of EGFR/KRAS-mutant "SQCC" encountered during 5 years of routine clinical genotyping were reassessed pathologically.
The screen of 95 biomarker-verified SQCCs revealed no EGFR/KRAS [0%; 95% confidence interval (CI), 0%-3.8%], four PIK3CA (4%; 95% CI, 1%-10%), and one AKT1 (1%; 95% CI, 0%-5.7%) mutations. Detailed morphologic and immunohistochemical reevaluation of EGFR/KRAS-mutant "SQCC" identified during clinical genotyping (n = 16) resulted in reclassification of 10 (63%) cases as AD-SQC and five (31%) cases as poorly differentiated adenocarcinoma morphologically mimicking SQCC (i.e., adenocarcinoma with "squamoid" morphology). One (6%) case had no follow-up.
Our findings suggest that EGFR/KRAS mutations do not occur in pure pulmonary SQCC, and occasional detection of these mutations in samples diagnosed as "SQCC" is due to challenges with the diagnosis of AD-SQC and adenocarcinoma, which can be largely resolved by comprehensive pathologic assessment incorporating immunohistochemical biomarkers.
关于肺鳞状细胞癌（SQCC）中是否存在 EGFR 和 KRAS 突变，一直存在争议。我们假设，报告的变异性可能反映了由于不完全采样或形态重叠，病理区分真正的 SQCC 与腺鳞癌（AD-SQC）和低分化腺癌存在困难。最近开发了一种可靠的免疫组织化学方法，用于区分鳞状与腺状分化，这为在病理上同质的 SQCC 系列中重新评估 EGFR/KRAS 和其他可靶向激酶突变频率提供了机会。
95 例经免疫组织化学验证为ΔNp63(+) / TTF-1(-)的切除 SQCC 进行 EGFR、KRAS、BRAF、PIK3CA、NRAS、AKT1、ERBB2/HER2 和 MAP2K1/MEK1 的激活突变检测。此外，对 5 年内常规临床基因分型中罕见的 EGFR/KRAS 突变“SQCC”患者的所有组织样本进行了病理重新评估。
对 95 例生物标志物验证的 SQCC 进行筛查，未发现 EGFR/KRAS [0%；95%置信区间（CI），0%-3.8%]、4 例 PIK3CA（4%；95% CI，1%-10%）和 1 例 AKT1（1%；95% CI，0%-5.7%）突变。对临床基因分型中发现的 EGFR/KRAS 突变“SQCC”（n=16）进行详细的形态学和免疫组织化学重新评估，结果 10 例（63%）病例重新分类为 AD-SQC，5 例（31%）病例重新分类为形态上类似 SQCC 的低分化腺癌（即具有“鳞状”形态的腺癌）。1 例（6%）病例无随访。
我们的研究结果表明，EGFR/KRAS 突变不会发生在纯肺 SQCC 中，在诊断为“SQCC”的样本中偶尔检测到这些突变，是由于 AD-SQC 和腺癌的诊断挑战所致，通过综合病理评估结合免疫组织化学标志物可在很大程度上解决这些问题。
