Causes and Risk Factors of Small Cell Lung Cancer

The causes and risk factors for small cell lung cancer differ somewhat from other types of lung cancer. While smoking is more strongly associated with small cell than non-small cell lung cancer, other risk factors, such as radon exposure in the home and asbestos exposure on the job, are very important as well.

While our understanding of the genetics of lung cancer is in its infancy, there are some hereditary mutations that may increase risk. In addition, the transformation of non-small cell lung cancer to small cell lung cancer is now being seen more often in people treated with EGFR inhibitors.

Studies that look at lung cancer risk do not always separate out the different types of lung cancer. That said, this article will explore some of the common risk factors that have been identified, as well as general risk factors for the disease.

Common Causes

The precise causes of small cell lung cancer are uncertain, though several risk factors have been identified. Small cell lung cancer usually develops after a series of mutations leads to the uncontrolled growth of a cell.

These mutations may be caused by a number of factors, including exposure to tobacco smoke or elevated radon levels in the home, or as "accidents" that occur during the normal division of cells. Even when the DNA in cells is damaged, however, proteins produced by DNA repair genes (tumor suppressor genes) often repair the damage or eliminate the abnormal cell.

Small cell lung cancer is most often considered a "multifactorial disease," meaning that many factors may work together to either increase or decrease the risk of cancer developing. This is the reason that some people may be heavy smokers throughout their lives, yet never develop cancer. At the same time, people who have never smoked can and do sometimes develop small cell lung cancer.

Lifestyle Risk Factors

A list of risk factors for small cell lung cancer begins with smoking, but it's important to recognize other causes as well. In addition, the combination of smoking and some of these causes can be more than additive in raising risk.

Smoking

Smoking is the strongest risk factor for small cell lung cancer, and most (but not all) people with it have a current or past history of smoking. A study performed in the United States found that only 2.5% of small cell lung cancers were found in people who had never smoked.

The role of smoking, however, may vary based on sex. A 2012 study looked at differences in small cell lung cancer based on sex. The incidence was similar in both sexes (the cancer was actually slightly more common in women in this particular study), yet, while only 2.1% of the men claimed to be lifelong nonsmokers, 24.1% of the women had never smoked.

A 2015 study in Korea, however, found that 13% of people with small cell lung cancer had never smoked, and the authors note that the diagnosis of small cell lung cancer in people who have never smoked (known as never-smokers) is becoming increasingly common.

As the number of people who smoke declines in the United States, and the incidence of lung cancer in never-smokers increases, this may become more common here as well.

Former Smokers Are at Risk as Well

It's important to note that "smoking" refers to both people who smoke and those who have quit, even those who may have quit decades ago. At the current time, there are more former smokers than current smokers who are diagnosed with the disease.

According to one study, the risk of lung cancer persists long after a person quits smoking—even 35 years after quitting.

Heavy Smokers Are at Greater Risk

Both the duration of smoking and the amount of smoking are important with regard to small cell lung cancer. The disease is more common in people who are classified as heavy smokers (or heavy former smokers) or who have a high number of pack-years of smoking (a number calculated by multiplying the number of packs smoked per day by the number of years smoked).

Secondhand smoke has also been cited as a risk factor for lung cancer in general (all types combined), but it is uncertain what role it plays in small cell lung cancer specifically.

Radon

Radon exposure in the home is considered to be a strong risk factor for lung cancer overall and has been cited as the second leading risk factor for the disease after smoking.

Radon gas occurs from the normal decomposition of granite beneath homes, and it becomes trapped after entering homes. Exposure may also occur via radon in the water supply or even granite countertops.

Often thought of as a risk factor for lung cancer in never-smokers (especially lung adenocarcinoma), radon exposure appears to be very important in small cell lung cancer as well. A 2012 study looked at the role of radon among different types of lung cancer. Lung cancer types that were found to have the highest risk associated with radon exposure were large cell lung cancer (a type of non-small cell lung cancer) and small cell lung cancer. A 2017 study confirmed this link. It noted that some people with small cell lung cancer had extremely high radon concentrations in their homes.

A 2018 review looked at this further. It observed that small cell lung cancer is the type of lung cancer most tightly related to radon exposure in the home.

Radon exposure appears to be an important risk factor for small cell lung cancer in people who smoke, but has been implicated in small cell lung cancer in never-smokers as well.

In a study looking specifically at never-smokers with lung cancer, the only obvious risk factor was that the average radon concentration in homes of the people with lung cancer was higher than for a control group of people who did not have small cell lung cancer.

Asbestos

Exposure to asbestos is not only a cause of mesothelioma, but also increases the risk of lung cancer.

In a 2017 study, asbestos exposure was associated with a doubling of the risk of all the major subtypes of lung cancer (including small cell lung cancer) in current smokers. For never-smoking women, there was no association between asbestos exposure and lung adenocarcinoma or squamous cell carcinoma, but a strong association with small cell lung cancer.

Never-smokers who had higher than average exposure to asbestos appeared to be at greater risk than former or current smokers (2.75 times the risk), especially for small cell lung cancer.

Other Occupational Exposures

There are a number of occupational exposures that are associated with an increased risk of lung cancer overall, though relatively few studies have separated out the different types (such as small cell lung cancer) when reporting results.

With regard to lung cancer overall, the exact role of on-the-job exposures as a cause is unknown, but it is often quoted that these exposures are responsible for roughly 10% of lung cancers.

Looking at small cell lung cancer specifically, an older study found that people who work in blue-collar and service occupations are roughly two to three times more likely to develop small cell lung cancer, likely due to these exposures.

Causes and Risk Factors for Lung Cancer in General

There are many other potential and known risk factors for lung cancer overall, though the majority of research has not separated out the subtypes to know how important the exposures might be for small cell lung cancer.

Some factors that are associated with an increased risk of lung cancer overall include:

• Air pollution
• Radiation to the chest (such as for Hodgkin disease and breast cancer)
• Some lung conditions such as COPD and asthma
• Some non-lung-related medical conditions such as rheumatoid arthritis (there is some evidence that both scleroderma and interstitial pneumonitis are risk factors for small cell lung cancer in never-smokers )

Genetics

Little is known about the role of genetic predisposition in small cell lung cancer, though this will likely change in the near future.

Gene mutations found in small cell lung cancer tumors are most often acquired mutations, or mutations that are acquired after birth in the process of a cell becoming a cancer cell. Mutations in two tumor suppressor genes in particular are very common. Tumor suppressor genes are genes that code for proteins that repair damaged DNA in cells. (As a point of reference, the BRCA genes are also tumor suppressor genes.)

When DNA is damaged, but not repaired (or if the cell is not eliminated), there is a greater likelihood that it will develop into a cancer cell. The RB1 is mutated in around 90% of these tumors, with the TP53 gene estimated to be mutated in 75% to 90% of these tumors.

While hereditary mutations are thought to be involved in a small minority of these tumors, there is some link. It has been found that people who have survived familial retinoblastoma (a rare tumor that begins in the retina of the eye during early childhood) are more likely to develop small cell lung cancer.

Familial retinoblastoma is related to a mutation in the RB1 gene. The risk is also elevated in people who have hereditary mutations in the TP53 gene, a condition referred to as Li-Fraumeni syndrome.

Transformation of Non-Small Cell Lung Cancer

Small cell lung cancer is now occurring more frequently in people who have been treated for non-small cell lung cancer with an EGFR mutation (EGFR positive lung cancer). The transformation of non-small cell lung cancer to small cell lung cancer usually occurs as a resistance mechanism by which the tumor evades treatment with EGFR inhibitors.

In other words, a tumor that had been controlled with drugs that target the EGFR mutation mutates so that it can bypass the inhibition and continue to grow.

Risk Factors in Never-Smokers

Looking at small cell lung cancer in people who have never smoked is helpful when looking for other risk factors for the disease, both in never-smokers and people who smoke or have smoked.

When small cell lung cancer occurs in never-smokers, it tends to occur at a younger age (young adults with lung cancer) and often has a different mutational profile (the types of mutations in the cancer cells differ from the types of mutations in cancer cells of people who have never smoked).

As noted above, exposure to both radon and asbestos is associated with an increased risk of small cell lung cancer in never-smokers.

Different types of mutations tend to be associated with different causes and risk factors. For example, some mutations have been found to be more prevalent in people who have had high radon exposure, and other mutations are more common in people who have been heavy smokers. The science is very young, but further research into the types of mutations seen in small cell lung cancer may help identify important causes or risk factors in the future.

Overall, the incidence of small cell lung cancer appears to be decreasing—likely related to lower smoking rates. That said, the proportion of never-smokers with the disease appears to be increasing.

The connection between radon exposure and small cell lung cancer is of concern for both never-smokers and smokers, as radon levels in homes appear to be increasing, according to a 2019 study. This comes at a time when the overall risk of lung cancer in never-smokers is also increasing. Whether these two are related is unknown, but it is a reminder that everyone should test their home for radon.

A Word From Verywell

It is extremely important to look at the potential causes and risk factors for small cell lung cancer. Lung cancer (all types combined) is currently the leading cause of death of both men and women in the United States and around the world. And as noted, unlike the decrease in incidence related to smoking cessation, the risk in never-smokers is increasing.

Yet, while looking at causes is important, if you or a loved one is currently living with the disease, the causes are less important. If it is your loved one who has been diagnosed with small cell lung cancer, what they need from you is love and caring, not an analysis of why they may have the disease.

And if you are living with small cell lung cancer yourself, it doesn't matter why you developed the disease. Absolutely everyone deserves compassion, kindness, and the best medical care available, whether they've smoked heavily or never smoked.