Pathogenesis Micrograph showing an ALK positive<unk> . ALK immunostain. Micrograph showing a ROS1 positive<unk> . ROS1 immunostain. Large scale studies such as The Cancer Genome Atlas (TCGA) have systematically characterized recurrent somatic alterations likely driving lung<unk>  initiation and development. Gene mutations and copy number alterations Since smoking is a strong mutagenic factor, lung<unk>  is one of the tumor types with the highest number of mutations. Common somatic mutations in lung<unk>  affect many oncogenes and tumor suppressor genes, including TP53 (mutated in 46% of cases), EGFR (27%), KRAS (32%), KEAP1, STK11 and NF1. EGFR and KRAS mutations tend to appear in a mutually exclusive fashion. KRAS mutations are associated with smoking habits, whereas EGFR mutations occur more frequently in females, people of Asian ethnicity and never-smokers. Copy number amplifications in oncogenes such as TERT, MDM2, EGFR, MET, and MYC have been reported, as well as deletions of tumor suppressor genes such as CDKN2A. Frequent alterations occur in genes belonging to the receptor tyrosine kinase pathway, of which EGFR is the most prominent example. This pathway is involved in cell proliferation and survival and it is often deregulated in cancer. As a consequence, targeted therapies have been developed to inhibit mutant pathway components. Chromosomal rearrangements Three membrane associated tyrosine kinase receptors are recurrently involved in fusions or rearrangements in<unk> s: ALK, ROS1, and RET, and more than eighty other translocations have also been reported in<unk> . In ALK rearrangements, the most common partner gene is EML4. EML4-ALK fusions tend to occur in tumors that do not carry EGFR or KRAS mutations and have also a lower frequency of TP53 mutations. ALK and ROS fusions offer opportunities for targeted therapies with tyrosine kinase inhibitors. Pathophysiology The respiratory tract can be divided into two main components: the conducting airways and the gas exchange airways. The gas exchange airways are made of alveoli, small microscopic air sacs that are responsible for the exchange of oxygen and carbon dioxide during normal breathing. Alveoli are composed of two cell types, type I and type II pneumocytes. Type I pneumocytes cover 95% of alveolar surfaces, and are not able to regenerate. Type II pneumocytes are more common, making up 60% of the cells within alveolar epithelium, but constitute only 3% of the alveolar surface. There are several factors that contribute to the transformation of normal alveolar epithelium into dysplastic, or pre-cancerous, lesions.<unk>  develops in a step-wise progression as type II pneumocytes undergo consecutive molecular changes that disrupt normal cell regulation and turnover. Atypical adenomatous hyperplasia (AAH) is considered a pre-cancerous lesion, and is thought to further progress to<unk>  in situ and invasive<unk> . The lesions of AAH are <5 mm, can be single or multiple, and have a ground glass appearance on CT imaging. As more genetic mutations and dysregulation of normal cell signaling pathways accumulate, AAH can progress to<unk>  in situ (AIS). AIS lesions are classified as small tumors <3 cm with abnormal type II pneumocyte cell growth that is limited to the alveolar spaces i.e. without invasion into the stroma, pleura, or vasculature. This type of growth is termed "lepidic" and is characteristic of<unk>  in its earliest stages.
Adenocarcinoma of the lung
Giant-cell carcinoma of the lung
Sarcomatoid carcinoma of the lung
Acinic cell carcinoma of the lung
Squamous-cell carcinoma of the lung
Non-small-cell lung carcinoma
Pulmonary sclerosing pneumocytoma
Epithelial-myoepithelial carcinoma of the lung