Until recently, carcinomas of the lung were classified into two broad groups: small cell lung cancer (SCLC) and non–small cell lung cancer (NSCLC), the latter including adenocarcinoma, squamous and large cell carcinoma, and large cell neuroendocrine carcinomas. This classification has been recently replaced by a 2015 World Health Organization classification (a simplified version of which is shown in Table 13.6). The reason for this historic division is that virtually all SCLCs have metastasized by the time of diagnosis. Therefore, they are best treated with systemic chemotherapy, with or without radiation therapy. By contrast, NSCLCs are more likely to be resectable and usually respond poorly to conventional chemotherapy. However, therapies are now available that target specific oncoproteins that are found in a subset of NSCLC, mainly adenocarcinomas but also squamous cell carcinomas. Thus, if adequate tissue is available, NSCLC is subjected to molecular analysis to determine if targeted therapy is warranted. In addition, new immunotherapy approaches (checkpoint blockade, discussed in Chapter 6) are now approved for a subset of NSCLC and are being tested in SCLC.
Like other cancers, smoking-related carcinomas of the lung arise by a stepwise accumulation of driver mutations that result in transformation of benign progenitor cells in the lung into neoplastic cells possessing all of the hallmarks of cancer. The sequence of molecular changes is not random but tends to follow a sequence that parallels the histologic progression toward cancer. Thus, inactivation of the putative tumor suppressor genes located on the short arm of chromosome 3 (3p) is a very common early event, whereas mutations in the TP53 tumor suppressor gene and the KRAS oncogene occur relatively late. Certain genetic changes, such as loss of chromosomal material on 3p, are found even in benign bronchial epithelium of smokers without lung cancer, suggesting that large areas of the respiratory mucosa are mutagenized by exposure to carcinogens (“field effect”). On this fertile soil, those cells that accumulate additional mutations ultimately develop into cancer.
A subset of adenocarcinomas (about 10% in whites and 30% in Asians), particularly those arising in nonsmoking women, harbor mutations that activate the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase that stimulates downstream pro-growth pathways involving RAS, PI3K, and other signaling molecules. Of note, these tumors are sensitive to drugs that inhibit EGFR signaling, although the response is often short-lived. EGFR and KRAS mutations (in 30% of adenocarcinomas) are mutually exclusive, as might be expected since KRAS lies downstream of EGFR. Other “targetable” mutations have been described in a low frequency of adenocarcinomas (4% to 6% overall), including mutations that activate other tyrosine kinases, including ALK, ROS1, HER2, or c-MET. Each of these kinases is optimally targeted by a different drug, which has spurred a new era of “personalized” lung cancer treatment, in which the genetics of the tumor guide therapy.