Lung cancer tends to develop slowly, though there are very aggressive types of lung cancer that grow and metastasize rapidly (Hayabuchi 1983; Lozic 2010; Cooper 2000; Alberts 2002). The transformation of healthy lung tissue into cancerous tissue occurs at the cellular level as DNA is damaged by various possible mechanisms, including environmental carcinogens such as those found in tobacco smoke, with the likelihood of cancer development dependent upon each individual’s genetic predisposition. Prolonged DNA insults eventually lead to disruption of signaling pathways that control cellular growth in lung tissue. Once genes and pathways that control cellular growth are sufficiently damaged, malignancy emerges (Horn 2013a; Sato 2007).
Researchers have identified numerous molecular changes that drive lung cancer development, many of which have become targets of biologic drugs designed to destroy cancerous cells or arrest their growth. Several gene mutations have been associated with lung cancer, but two have been particularly well studied (Davidson 2013; Horn 2013a):
- KRAS – Mutations in the KRAS gene primarily occur among smokers with adenocarcinomas;
- EGFR – Mutations in the EGFR gene are more common in patients who never smoked, women, and Asians.
Both genes control cellular growth, so mutations in these genes can cause cells to grow and divide rapidly and continuously, eventually leading to tumor formation (Horn 2013b; Bacchi 2012; Martinsson 2010; Sunaga 2011; Yoon 2010).
Types of Lung Cancer
The types of lung cancer include non-small cell lung cancer (NSCLC), which is the most prevalent; small cell lung cancer (SCLC), which accounts for 15-20% of lung cancers in the United States; as well as some rare neuroendocrine tumors accounting for less than 5% of cases (Horn 2013a; Mayo Clinic 2014; NCI 2014e; Skirecki 2009). NSCLC and SCLC are further classified based on their pathology (NCI 2013a; NCI 2013c; Horn 2013b). The type of cancer helps determine the treatment used as well as the prognosis.
Non-small cell lung cancer. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, arising from the bronchial surface epithelium or bronchial mucous glands (Bunn 2008; O'Hanlon 2013). It tends to grow and spread to other sites (metastasize) more slowly than SCLC. The 5-year survival rate for NSCLC is 18%, compared to 6% for SCLC (ACS 2013a; A.D.A.M. 2013a).
- Adenocarcinoma. Adenocarcinoma is the most common type of lung cancer in the United States and Japan. It predominantly occurs in smokers, although never-smokers may also develop this form. This type typically develops in the mid-lung zone and periphery of the lung. Patients with solid and micropapillary adenocarcinomas (many small tumor loci) tend to have a worse prognosis (Horn 2013a).
- Squamous cell carcinoma. Squamous cell carcinoma is strongly associated with smoking (Herbst 2008) and typically occurs within the central part of the lung (Horn 2013a).
- Large cell carcinoma. Large cell carcinoma usually occurs in the periphery of the lung and accounts for less than 10% of lung cancers (Horn 2013a).
Small cell lung cancer. Small cell lung cancer (SCLC) arises from neuroendocrine cells in the lungs and is sometimes referred to as oat-cell carcinoma because of the flatness and small oval shape of the cancer cells (O'Hanlon 2013). SCLC accounts for 15-20% of lung cancer cases (Skirecki 2009). SCLC is more aggressive than NSCLC, with the cells dividing more rapidly, although it is generally more responsive to chemotherapy and radiation therapy. However, the potential for metastasis and the rate of recurrence after treatment are both high, and overall survival rate is poor (ACS 2013a; A.D.A.M. 2013a; NCI 2013c).
Neuroendocrine tumors of the lung. SCLC is a type of neuroendocrine cancer and there are three other less common neuroendocrine tumor types: typical carcinoid, atypical carcinoid, and large cell neuroendocrine carcinoma. The first two are less common in smokers and generally less aggressive, while the latter is more likely to be seen in smokers and carries a worse prognosis (Horn 2013b; ACS 2013b; Rekhtman 2010).
Lung Cancer among Never Smokers
Rates of lung cancer in never smokers vary depending on gender, ethnicity, and geographic location. Approximately 40% of females in Asia diagnosed with lung cancer are never smokers, while about 10% of males diagnosed with lung cancer in Western countries never smoked (Pallis 2013a; Larsen 2011). A study published in 2012 found that the increased risk of lung cancer in never-smoking women in Asia was linked to three genetic alterations that are prevalent in this population – a mutation on chromosome 10 and two separate mutations on chromosome 6 (Lan 2012). Lung cancer in never smokers generally displays a different profile of mutations and molecular changes than those which occur among smokers (Larsen 2011).
Risk factors for lung cancer among never smokers include exposure to secondhand smoke, hormonal and genetic factors, air pollution, radon exposure, and occupational exposure to carcinogens (Pallis 2013a; Brennan 2011; CDC 2006; Kligerman 2011; Cohen 1995). Never smokers diagnosed with lung cancer are more likely to have adenocarcinomas. Several reports have demonstrated a better survival rate compared with smokers (Pallis 2013a).
There are striking differences in the pathophysiology and biology of lung cancer in patients who never smoked compared to patients who ever smoked. A small study found, on average, a 10-fold higher rate of genetic mutations in smokers with lung cancer compared to never smokers (Govindan 2012). Moreover, comparisons of the 2 groups showed marked differences in the profile of mutations. For instance, overexpression of epidermal growth factor receptor (EGFR) is more common in lung cancer among never smokers (Pallis 2013a; Larsen 2011).
In addition to differences in the genetic profiles of smoking-associated lung cancers and those not associated with smoking, there are also differences in the location of these tumors within the lung. Smoking-related cancerous lesions, whether SCLC or NSCLC, most often develop in the central airway of the lungs, while most lung cancers in never smokers develop in the distal airways (Usuda 2010; Gonzalez 2012; Samet 2009; Larsen 2011; Brambilla 2009).