ETIOLOGY AND RISK FACTORS

Research has shown that specific risk factors increase a person’s chance of developing lung cancer. Despite the risks involved, it is not always possible to predict precisely why one person develops lung cancer and someone with similar risk factors does not. For example, advanced age and male gender contribute to a higher occurrence of lung cancer, but other risk factors may turn out as more causative.

Smoking

Smoking is by far the number one risk factor for lung cancer. This includes cigarettes, cigars, and vaping. Up to 80%–90% of all cases of lung cancer are caused by current or former smoking. The remaining 10%–20% of cases occur in people who have never smoked (“never smokers”) (ALA, 2020a; CDC, 2021b).

Tobacco contains approximately 7,000 chemicals, many of which are poisons. Seventy of these chemicals are tied to cancers in humans and animals. Eighty to ninety percent of people who contract lung cancer have a history of smoking. A person who has smoked a few cigarettes or smoked for a brief period of time is at higher risk for lung cancer than individuals who have never smoked. Smokers are 15 to 30 times more likely to develop lung cancer than nonsmokers (CDC, 2019a).

PACK-YEARS

A person’s smoking intensity is measured in pack-years. One “pack-year” is defined as smoking approximately one pack (20 cigarettes) per day for one year. Smoking half pack a day for one year is equivalent to 1/2 pack-years, and smoking two packs a day for 10 years is equivalent to 20 pack-years. The higher a person’s number of pack-years, the more likely it is that they will develop conditions such as lung cancer, emphysema, bronchitis, or heart diseases.

CASE

Earlene is a 72-year-old smoker who presented at the clinic with a complaint of almost continuous coughing and shortness of breath (SOB) for 3–4 weeks with no production of sputum. When taking her medical history, the nurse practitioner, Caitlyn, discovers that Earlene has been smoking since age 12, with no significant break in her smoking. When questioned, Erlene tells Caitlyn that she has smoked an average of 10–15 cigarettes a day (or 1/2 to 3/4 pack) for all of those 60 years. The nurse explains the term pack-year to Earlene and tells her that she has a smoking history of 30 to 45 pack-years, which is a significant finding. Caitlyn refers Earlene for follow-up and diagnostic testing.

Exposure to second-hand smoke (the smoke exhaled by another) is a significant risk factor for lung cancer. Exposure to secondhand smoke causes more than 7,300 deaths per year in nonsmokers. Repeated exposure is a chronic irritant that can cause diseases or infections. In the United States 1 out of 4 people, including 14 million children, who don’t smoke are exposed to second-hand smoke. It also contributes to heart disease and stroke in adults (CDC, 2021a).

Tobacco smoke in the air indoors settles on the floor and other surfaces or is released into the air in a process called off-gassing. Residual nicotine and other toxic chemicals build up in the air or on clothing, rugs, furniture, bedding, dust, and vehicle surfaces and mixes with other pollutants, causing a carcinogenic composite. This residue, referred to as third-hand smoke, doesn’t dissipate over time and must be aggressively cleaned or laundered. Children are at risk for the development of lung cancer from third-hand smoke, as they tend to put things in their mouths and touch affected surfaces. Their smaller lungs are especially sensitive to off-gassing (Hayes, 2017).

Vaping, also referred to as electronic or e-cigarettes, has become a common replacement or alternative to smoking conventional cigarettes or marijuana. Electronic cigarettes have been globally popular for the past 15 years. Originally, they were thought to be a reasonable way to reduce or gradually wean oneself from smoking nicotine-based cigarettes. It has since been discovered that e-cigarettes can be equally addicting as regular cigarettes and cause lung injuries, including cancer. They contain propylene glycol, a known lung irritant, and sufficient levels of nicotine to be addictive and carcinogenic (CASAA, 2020).

LUNG CANCER SCREENING

The use of computerized tomography (CT) scanning for lung screening has provided the ability to diagnose very small tumors that can be excised by a segmentectomy. This allows removal of the smallest amount of lung tissue possible and preserves the most pulmonary function. Robotic segmentectomy is more complex than robotic lobectomy depending on the ability to access the tumor with the robotic arms.

The U.S. Preventive Services Task Force recommends yearly lung cancer screening with low-dose CT for people who:

Have a 20 pack-year or more smoking history, and
Smoke now or have quit within the past 15 years, and
Are between 50 and 80 years old
(CDC, 2021d)

Environmental Pollutants

The inhalation of various pollutants, both particles and gases, can contaminate the lungs. Large particles are expelled by coughing or sneezing, but tiny particles remain in the lungs, and even brief exposure to these particles in large enough amounts can cause the development of lung cancer (ALA, 2020b).

Radon gas, a naturally occurring, odorless, tasteless radioactive gas that can become trapped inside of buildings, causes approximately 20,000 cases of lung cancer every year (ALA, 2020a; CDC, 2019a).
Small mineral fibers such asbestos, found in the workplace and in older residences, are known to cause lung cancer, mesothelioma, and other pulmonary disorders, and can be mediated by the use of personal protection equipment such as masks and gloves, reduction of exposure time, and the education of employees regarding safe practices (Vuong, 2020).
Air pollution can cause an increase in the burden of disease from stroke, heart disease, lung cancer, and asthma unless measures are taken in the areas of transport, urban planning, power generation, and industry that reduce air pollution (WHO, 2018).

Occupational Exposures

There are many toxic substances that can lead to lung cancer with prolonged exposure in an occupational environment. Preventative processes and personal protective equipment (PPE) have been developed and introduced to protect workers who experience contact with these substances from developing lung cancer.

Polycyclic aromatic hydrocarbons, including industrial coke, silicon, carbon products, foundry and combustion processes, lubrication oils and engine exhaust emissions, and bitumen in larger exposure amounts, are a health hazard to millions of workers globally (Petit et al., 2019).
Coal dust and other coal mining–related toxins have been associated with an elevated risk of lung cancers and pneumoconiosis (black lung) when inhaled (Green & McGinley, 2019).
Nickel and chromium in welding fumes have been linked to the development of lung cancer in welders (Pesch et al., 2019).
Uranium leads to a high incidence of lung cancer, including from inhaling radon degradation products (RDP), uranium dust, and external gamma rays during uranium mining, and due to exposure when it is processed, refined, or milled for use in nuclear energy (Zablotska et al., 2018).
Arsenic is associated with cancers of the lung, bladder, skin, kidneys, nasal passages, liver, and prostate, which has led the Environmental Protection Agency (EPA) to reduce the maximum contaminant level allowed in public water systems (EPA, 2020).

Family History and Genetics

The risk of having lung cancer is higher if one’s parents, siblings, or children have lung cancer. This may be due to an unexplained familial tendency. There may also be common exposure to carcinogens when family members live or work together (CDC, 2019a).

Ten percent of all cancers have a link to hereditary or genetic traits. The most common genetic cause of lung cancer is epidermal growth factor receptor (EGFR) gene mutations. EGFR accounts for 10% of all small cell cancers, and it is believed that 50% of all lung cancers not caused by smoking are related to EGFR. Other genetic mutations that have recently been determined to cause lung cancer are ALK, ROS1, and BRAF. These findings have driven the direction of pharmacological research for the treatment of lung cancer (Howley, 2019).

When lung cancer is caused by genetic changes, the cancer risk follows an autosomal dominant pattern, which means one copy of the altered gene in each cell will increase a patient’s chance of getting the disease. Patients who inherit this altered gene have an increased risk of cancer. Not all people who inherit mutations in these genes will develop lung cancer, but a small percentage do (NIH, 2020b).

Patients with cancers linked to hereditary or genetic trains are at higher risk for developing multiple cancers. These patients are also more likely to develop cancer at a younger age and to be diagnosed at a more advanced stage (CDC, 2019b).

EPIDERMAL GROWTH FACTORS

The epidermal growth factor receptor (EGFR) protein contributes to cell-signaling pathways that govern a cell’s ability to replicate and continue to live. Mutations in the EGFR gene cause the proteins to be made in larger-than-normal amounts on some types of cancer cells. This causes the cancer cells to replicate more rapidly. Drugs that interfere with epidermal growth factor receptor proteins, such as osimertinib (Tagrisso), are being used in the treatment of some types of cancers to prevent the rapid proliferation of the abnormal cancer cells (NCI, 2020a).

CASE

Dwight is a 47-year-old construction worker who has just been diagnosed with a small NSCLC tumor in his left lower lobe. He has never smoked. During his intake history and physical, it is discovered that his father died at age 38 of lung cancer, as did his paternal grandfather. Dwight told his physician that he did not know how long or how much each family member smoked but that they smoked “all their lives.” When questioned about possible exposure to carcinogenic substances on the job, such as asbestos or radon, Dwight stated that he was not aware of any, but that “it’s certainly possible.”

As part of Dwight’s lung biopsy to definitively diagnose his cancer, the surgeon sends some of the sample to test for EGFR DNA mutation, given the multigenerational family history of lung cancer and Dwight’s own lack of smoking. The test returns as positive. Dwight’s surgeon explains the combination of treatments possible, such as osimertinib and surgery, to treat his NSCLC and connects Dwight with the nurse, who can help him make a follow-up appointment to discuss treatment options further.

HORMONE REPLACEMENT THERAPY AND LUNG CANCER

The research on the possibility of whether there is a relationship between women taking hormone replacement therapy (HRT) after menopause and the occurrence of lung cancer has produced divergent findings. A 2019 meta-analysis of research into this topic discovered that previous findings were inconclusive and that there was not a definitive correlation or causative effect between the use of HRT and lung cancers (Jin & Lang, 2019).

Other Medical Conditions

Several other medical conditions and their treatment modalities may be risk factors for the development of lung cancer. Lung cancer is also often detected during diagnostic testing for these conditions. Such coexisting conditions may precede the appearance of malignant tumors or may be discovered during the testing for the cancerous symptoms.

EMPHYSEMA / CHRONIC BRONCHITIS

With emphysema, the alveoli (air sacs) in the lungs become damaged and their inner walls rupture, causing a decrease in lung surface area, leading to hypoxia. This compromises exhalation, causing air to become trapped in the chest (Mayo Clinic, 2020a). The severe airway obstruction experienced in emphysema makes a person two to three times as likely to develop lung cancer. Certain phenotypes of emphysema (e.g., centrilobular) are associated with a greater incidence of lung cancer. Parastatal emphysema has proved to be less likely to coexist with lung cancer (Gonzales et al., 2019).

Chronic bronchitis is the condition of limited or obstructed airflow due to chronic inflammation. It presents as excessive coughing with sputum production for a period of three months or more in at least two consecutive years.

BRONCHIECTASIS

Bronchiectasis is a pulmonary condition that causes the airways to become inflamed and scarred in the presence of excessive sputum. The most common symptoms are dyspnea, productive cough, hemoptysis, wheezing, chest pain, clubbing, weight loss, fatigue, and pulmonary infection. Bronchiectasis is commonly associated with smoking, the most common cause of lung cancer. Bronchiectasis may be present in 10%–15% of patients with lung cancer (Sanchez-Carpintero Abad et al., 2020).

SOLID ORGAN TRANSPLANT

In a study of 463 patients who received lung transplantation over a period of 25 years, the relationship between lung transplantation and lung cancer was explored. There were 19 patients in the study who were found to have lung cancer. The majority of the cancers were found in the explanted lung (lung to be removed) or the lung not needing transplantation. Only 3 of the 19 positive cases were found to have malignant tumors in the transplanted lung.

Only 2.37% of the patients in the study were found to have lung cancer in transplanted, explanted, or unaffected lungs. They also determined that the life expectancy of the patients in the study without lung cancer was an average of 8.1 years. Those patients with lung cancer had an average life expectancy of 5–6 years (Chatron et al., 2019).

Following lung transplantation, cancer is the second most common cause of death (17.3%) in the 5–10 year postoperative period. Patients who have had solid organ transplantation (SOT) are placed immediately on large-dose immunosuppressive therapy to prevent organ rejection. Lung transplant recipients are given even more immunosuppressants than other organ transplant recipients. This reduces the effectiveness of antitumor immune surveillance, causing the increased percentage of cancer of the lung post lung transplantation (Shtraichman & Ahya, 2020).

TUBERCULOSIS

Tuberculosis is one chronic lung disease that complicates the course of lung cancer. It is likely that chronic inflammation in the lungs due to tuberculosis could cause clastogenic activity (or mutation or the breakdown of hormones) in the DNA of the bronchial epithelial tissue. Another possibility is lateral gene transfer; since Mycobacterium tuberculosis (MTb) is an intracellular organism, bacterial DNA could assimilate to bronchial epithelial tissue and cause a tumor to form neoplastic transformation (Molina-Romero et al., 2019).

LEUKEMIA / LYMPHOMA

Chemical air pollutants such as NO₂ and CO and industrial substances such as styrene have been proven to cause both lung cancer and leukemia, sometimes both at the same time in the same patient. Occasionally, exposure to these types of chemicals may cause an increase the mortality of lung cancer and leukemia (Christensen et al., 2017; Dehghani et al., 2017).

It is not uncommon for patients to have a combination of lung cancer and lymphoma. One such condition is anaplastic lymphoma kinase (ALK)–rearranged advanced non-small cell lung cancer (Song et al., 2020).

The therapies used to treat leukemia and lymphoma, particularly among children, may have the late, secondary effect of causing lung cancer as an adult. A systematic review of the long-term effects of extended radiation therapy, particularly in the cases of Hodgkin lymphoma and childhood cancers, proved to cause an increased risk of primary cancers secondary to the side effects of the original cancer treatments. The increased risk occurred in the development of breast and lung cancers (Journy et al., 2019).