Why do so many people get lung nodules? Can they be prevented?

Lung nodules is a very popular medical term on the Internet recently. Suddenly, it seems that many people have been diagnosed with lung nodules, and there are various speculations about why they "get" lung nodules. So what are lung nodules? What causes lung nodules? Are lung nodules harmful to the body? What should I do if I find a lung nodule? Do I need treatment? How can I prevent it? ... This article will answer all non-clinical questions about lung nodules.

Written by Zhou Yebin (PhD, University of Alabama at Birmingham)

1

Pulmonary nodules: findings from medical imaging

The lungs are a key component of the human respiratory system and a very important organ. Ordinary people may have heard of many lung diseases, which are very scary. For example, the epidemic that has been looming over our heads for the past three years is called "COVID-19". Lung cancer is even more common. It is the cancer with the highest incidence and the highest number of deaths in China. According to a study, China is expected to have nearly 900,000 new cases of lung cancer in 2022, and about 700,000 people will die from lung cancer. These two figures account for 20% and 30% of all cancers respectively [1] .

What is lung cancer? It is the uncontrolled growth of cancer cells in the lungs. Many people are extremely afraid of lung nodules because of this. If a nodule grows on a healthy lung, will it turn into lung cancer in the future? Many lung nodules are found because of lung cancer screening, which makes people even more afraid: I am here for early screening for lung cancer, can this finding be a good thing?

Here, we have to state the conclusion first: there is no need to panic about lung nodules.

Pulmonary nodules refer to round or irregular lesions with a diameter of less than 3 cm in the lungs, which appear as opaque shadows on medical images such as CT. The diameter definition here is very critical. Once it is larger than 3 cm, it is considered a lung mass.

There are two points to note when referring to the definition of lung nodules. First, lung nodules themselves are not a disease, nor do they absolutely correspond to a certain disease . Pathologically speaking, it is indeed an abnormal proliferation of lung tissue; but in practice, lung nodules are a kind of "imaging abnormality", which is an imaging abnormality observed by medical imaging methods as tissue proliferation, and does not correspond to a specific disease. Second, because lung nodules are by definition very small tissue proliferation, even if the mechanism behind it is terrible, such as cancer (in fact, most of them are not), it will be discovered at a very early stage, and there will be many options and room for maneuver in treatment.

As a medical imaging finding that cannot absolutely correspond to a specific disease, lung nodules can be caused by many reasons. When ordinary people hear that they have been diagnosed with lung nodules, they feel very scared and don’t know what to do. In fact, the medical community is also very troubled by lung nodules, because the diagnosis is equivalent to the discovery of a phenomenon. If you don’t know the reason behind the phenomenon, it is difficult to deal with it and it is not easy to explain to patients.

So what can we do? The medical community's approach is to combine risk control with the exploration of causes. What does this mean?

Imagine if a person undergoing a physical examination is told that he has lung nodules, what would he want to know? Of course, he would want to know “why do I have lung nodules” and “is it dangerous?” If the doctor only tells you that it is not dangerous but cannot explain the reason, many people may still find it difficult to rest assured.

But doctors think differently: there are many potential causes of lung nodules, and in specific cases, some causes are difficult to rule out or confirm, so it is more important to find out the causes of lung nodules that are most harmful to health. For example, if it is an early stage cancer, then the cause behind the lung nodule is very dangerous, so it is necessary to find out whether it is cancer. But if it is a scar left by a past lung infection, then there is no need to be particularly sure.

It can be said that after excluding all diseases that are truly dangerous to the human body, there is no need to investigate the cause of lung nodules in a particular case. This is "combining risk control with cause investigation."

2

Pulmonary nodules are not the only ones that can cause tumors

As mentioned above, lung nodules can have many causes, and treatment needs to be combined with the actual health risks represented by each cause. We can take a general look at what causes lung nodules.

Medical imaging of lung nodules is usually done on X-rays or CT scans. The principles of the two are similar, and different tissue densities will result in differences in these images. Everyone knows that X-rays can show human bones because the density of bones is different from that of the surrounding muscle tissue. The reason why lung nodules can be seen on imaging is similar. The tissue density at the location of the nodule is different from that of normal lung tissue, so it appears as "alien" on the image. To ask what causes lung nodules is actually to ask what conditions may lead to abnormal tissue density in the lungs.

A very common cause is infection. When an infection occurs in the lungs, an inflammatory response will occur, which will cause changes in tissue density. After the infection subsides, "scars" may also be left behind. The classic example of lung nodules after infection is tuberculosis: tuberculosis infection can cause a type of inflammation called granulomatous infections in the lungs, that is, the human immune system cannot completely eliminate the tuberculosis bacilli, causing a long-term inflammatory response. In this case, macrophages will surround the site of inflammation and form a granuloma [2]. In imaging, this granuloma will appear as a lung nodule.

Obviously, tuberculosis can cause granulomatous inflammation, but not all granulomatous inflammation is tuberculosis. Other bacteria and fungi can also cause granulomatous inflammation. In addition, some parasitic infections can also cause pulmonary nodules, the most typical of which are echinococcosis caused by the larvae of the genus Echinococcus and paragonimiasis caused by Paragonimus westermani [3].

In summary, we can summarize that infection and the inflammatory response caused by infection can cause lung nodules.

Inflammatory responses are not only triggered by infection. Some autoimmune diseases, such as rheumatoid arthritis and granulomatous vasculitis, can also cause inflammation[3] . There is also a disease called sarcoidosis, also known as sarcoidosis, which can also cause abnormal aggregation of inflammatory cells and form granulomas. The cause of this disease has not yet been fully clarified [3].

Although the above are either inflammation or infection, there are many specific causes of inflammation and infection. However, most people who encounter lung nodules should not worry about these, but whether it is a tumor.

Tumors in the lungs can also show abnormalities in imaging. But tumors can be divided into many types. It can be benign, which means that the tumor is an abnormal proliferation of tissue that stays in place and will not invade surrounding tissues or metastasize to distant sites. Of course, there are also malignant tumors, that is, cancer. However, tumors found in the lungs are not necessarily primary to the lungs, but may be cancers from other places. The abnormal imaging observed in the lungs is that cancer cells have metastasized to the lungs.

3

Risk level and classification of pulmonary nodules

There are so many reasons that can cause lung nodules. Which ones should we worry about? Or if we find lung nodules, which causes should we be particularly vigilant about?

Nowadays, most people find that they have lung nodules when they undergo medical imaging examinations when they have no symptoms. In other words, the lung nodules found on the imaging are the only abnormality in the body. If a person has an autoimmune disease, a parasitic infection, or is in the stage of a serious bacterial or fungal infection, how could he have no other symptoms except lung nodules?

When you go to the doctor because of these symptoms, the doctor will judge that "you have XXX symptoms, and the image shows nodules in the lungs, which may be XXX disease", rather than "The image shows lung nodules, the cause needs to be investigated."

Therefore, if we are a normal healthy person and detect lung nodules during screening, the causes of lung nodules we are actually facing are mainly ① scars left by past infections and inflammations, ② or current mild inflammation and infection, ③ benign tissue hyperplasia, and ④ potential malignant tumors. Among these, the only ones that really pose a serious threat to health and that we need to find a way to identify are malignant tumors.

This is why the current medical treatment for lung nodules is to exclude tumors. In addition, the definition of lung nodules is that the size does not exceed 3 cm, and the presence of lung nodules alone is often not an advanced malignant tumor. Based on the idea of ​​excluding lung tumors, the medical community has further subdivided lung nodules, and based on different subdivisions, it is determined whether it is necessary to exclude and how to exclude.

The classification of lung nodules is based on "what can be seen in medical images": one is the appearance of the nodule, and the other is the size of the nodule. The tissue density of lung nodules is different from that of normal lung tissue. This difference can also have different manifestations, resulting in different appearances of specific images. The differences in appearance caused by differences in lung nodule density lead to three categories [4]:

1. Solid nodules : All nodules are of soft tissue density, with a relatively uniform density, and the images of blood vessels and bronchial tubes inside are obscured;

2. Ground glass nodule (GGN): The image of the nodule is blurred, and the density is slightly higher than the surrounding lung parenchyma, but the outlines of the blood vessels and bronchi inside are still visible;

3. Part-solid nodule : A nodule that contains both ground glass density and solid soft tissue density, that is, the density is uneven.

Many people may have heard of the name "ground glass nodules" and feel deeply frightened. Some people even equate them with lung cancer. In fact, according to the malignancy probability of the three types of nodules, partially solid nodules > ground glass density nodules > solid nodules. In the United States, which was one of the earliest lung cancer screening sites, a study showed that 63% of partially solid nodules, 18% of ground glass density nodules, and 7% of solid nodules were malignant [5]. However, most lung nodules are solid nodules with the lowest malignancy probability.

In addition to judging the appearance, the size of the nodule should also be considered. The larger the nodule, the higher the risk of malignancy, and the smaller the nodule, the more likely it is to be harmless. Lung nodules that are 5-10 mm are called small nodules, and those that are less than 5 mm are called micronodules.

The medical community has also analyzed the probability of malignancy of lung nodules by adding various lung cancer risk factors. The most widely used model, which is also recommended in the Chinese lung nodule diagnosis and treatment guidelines, is a model developed by the Mayo Clinic in the United States. This model includes six independent factors for predicting lung cancer, namely ① age, ② smoking history, ③ history of thoracic malignant tumors before the nodule is discovered, ④ nodule diameter, ⑤ nodule spicule characteristics, and ⑥ nodule location [6]. The model formula finally calculates the probability of malignancy, which is divided into three types: low (<5%), medium (5% - 65%), and high (<65%).

Based on the type, size and probability of malignancy of lung nodules, the medical community also has corresponding treatment recommendations. For example, for lung nodules accidentally discovered in ordinary healthy people, there is a commonly used Fleischner Society Guidelines internationally, and there is also an expert consensus on the diagnosis and treatment of lung nodules in China.

According to the Fleischner Society Guidelines, no follow-up examination is required for lung nodules smaller than 6 mm with a low probability of malignancy. However, this is for lung nodules that are accidentally discovered in the general population (many of the nodules found in physical examinations now belong to this category). If the patient is in a high-risk group, such as a person with a history of smoking, more active follow-up examinations are required [7].

Figure 1. The 2017 Fleischner Society Guidelines recommend the management of incidentally discovered pulmonary nodules in the general population.

The consensus on the diagnosis and treatment of lung nodules in our country is consistent with the Fleischner Society Guidelines in principle, but there are some differences in details. For example, the size limit recommended for tracking ground glass nodules is 5 mm, and the limit for solid nodules and partially solid nodules is 8 mm. The follow-up management is also more proactive. For non-solid nodules, even if they are smaller than the above size limits, there is also a recommendation for further imaging tracking [6].

Figure 2. Chinese Expert Consensus on the Diagnosis and Treatment of Pulmonary Nodules (2018 Edition) - Management recommendations for non-solid nodules

4

More common than you think

Since the diagnosis and treatment of lung nodules are closely linked to lung cancer screening, many people are terrified by the discovery of lung nodules, thinking that the presence of lung nodules means danger. Even if it is not lung cancer now, it is likely to develop into lung cancer in the future. In fact, the commonness of lung nodules is far beyond the imagination of most people. Previous studies abroad have shown that in the general population, the proportion of single lung nodules detected by CT scan is 2%-24%. For people at high risk of lung cancer, this proportion can be as high as 17%-53%[3]. Now that CT is getting more and more accurate, the detection rate may be even higher. Some studies have used more precise CT imaging, and the detection rate of lung nodules has even exceeded 60%[5]. In the United States, the number of people diagnosed with lung nodules each year is as high as 1.6 million, and 30% of chest CT scans will find lung nodules[7].

The incidence of lung nodules increases with age, with a detection rate of 0.4 cases per 1,000 people per year for people aged 18-24 years and as high as 20.3 cases for people aged 85-89 years[7]. This may be partly because older people undergo more CT scans and are more likely to have lung nodules detected. However, in a study of people aged 55-74 years who underwent low-dose spiral CT (LDCT) examinations, the lung nodule detection rate was 24.3% for those aged 55-59 years and 34% for those aged 70-74 years, which also showed a trend of increasing detection rates with age[7]. In addition to age, smoking history and the amount of smoking are positively correlated with the detection rate of lung nodules.

In recent years, the equipment of domestic medical institutions has become better and better. Some physical examination institutions have added medical imaging to physical examination items, so that lung nodules are often found in large numbers during unit physical examinations. In 2020, several hospitals in Zhejiang Province conducted statistics on the detection rate of lung nodules during physical examinations. The detection rate of several hospitals was over 20%, and one hospital even reached 37% [8]. One hospital conducted age-specific statistics and found that from January to August 2020, among the people who underwent lung CT for physical examinations, half of the people over 60 years old had lung nodules larger than 3 mm, and almost one-third of those under 60 years old had lung nodules larger than 3 mm.

However, very few lung nodules are truly malignant. Currently, LDCT is the main method for lung cancer screening. The earliest evidence that this screening method can help reduce lung cancer mortality was provided by the 2011 report of the National Lung Screening Trial (NLST). The NLST study recruited more than 50,000 people with high risk factors for lung cancer between 2002 and 2004. Half of the subjects underwent annual LDCT examinations, while the other half underwent traditional chest X-rays. After three rounds of annual examinations, 24.2% of the people in the LDCT group had abnormal images, but 96.4% were false positives; the detection rate of chest X-rays was much lower, at only 6.9%, but the false positive rate was still 94.5%[9].

These data mean that the vast majority of lung abnormalities, such as lung nodules, detected by imaging screening are not malignant and there is no need to worry. It should also be noted that the NLST screening was conducted in a high-risk population for lung cancer. This population has such a high false positive rate. If this is extended to the general population, the problem of false positives will be even more prominent. Later studies abroad have basically shown that more than 95% of lung nodules detected by LDCT screening are small nodules less than 10 mm, and more than 95% of these small nodules are benign [5].

Therefore, it is not surprising to find lung nodules during a physical examination. If they are detected, it is important to know that the vast majority of lung nodules are not cancer and there is no need to panic. Even the ground glass nodules or partially solid nodules that may scare people are mostly not malignant tumors, but inflammation, hemorrhage, and tissue fibrosis[5]. Ground glass nodules occur more frequently in Asians, and Asian countries are more concerned about them. However, according to follow-up data from South Korea, 37% of ground glass nodules and 48% of partially solid nodules will shrink or disappear within three months, which means that these nodules are likely caused by inflammation[10].

5

Is it meaningful to screen for lung nodules?

At this point, everyone should understand that the purpose of physical examination for lung nodules is to screen for lung cancer, but the efficiency of this screening is very low. Most positive results are false positives from the perspective of lung cancer screening and do no actual harm to the body. So, since the screening efficiency is so low, is it still necessary to check?

Our screening is to use LDCT to screen for early lung cancer, but many of the results are in the form of lung nodules. So the question of whether screening is necessary depends on whether it can help early detection and early treatment of lung cancer and whether it can reduce lung cancer mortality. The most critical evidence in this regard is the 2011 NSLT report from the United States mentioned above. In this report, LDCT screening did have a high false positive rate, but it detected more early lung cancer cases than traditional chest X-rays, ultimately reducing the mortality rate by 20%[9].

This provides a very sufficient basis for early screening of lung cancer. However, it is also true that the screening efficiency is low and the false positive rate is very high. Therefore, early screening of lung cancer still needs to be done, but when doing it, we must also be vigilant about the efficiency issue and not further reduce the already low efficiency.

The NSLT study was conducted in a high-risk population for lung cancer. Based on this, early lung cancer screening in the United States is also recommended only for high-risk populations. my country's recommendations also refer to these international studies. For example, the 2018 Chinese Expert Consensus on the Diagnosis and Treatment of Lung Nodules limits the screening population to a high-risk population for lung cancer, specifically defined as those aged ≥40 years with any of the following risk factors: (1) smokers or former smokers ≥20 pack-years (or 400 cigarettes-years), the latter of whom have quit smoking less than 15 years ago; (2) those with a history of environmental exposure or high-risk occupational history (such as exposure to asbestos, beryllium, uranium, radon, etc.); (3) those with chronic obstructive pulmonary disease, diffuse pulmonary fibrosis, or a history of tuberculosis; (4) those with a history of malignant tumors or a family history of lung cancer [6].

In recent years, with the development of economic level, LDCT lung cancer early screening has been included in the scope of physical examination benefits of some commercial insurance or companies, but some people who undergo screening may not belong to the high-risk group. Blindly expanding the screening population when the efficiency of lung cancer early screening is not high will only make the false positive problem more serious.

Many people are easily attracted by the marketing slogan of "early detection and early treatment", but they do not notice that although the dose of LDCT is lower than that of conventional CT, it still has non-negligible radiation. Overdiagnosis based on false positives is also likely to lead to overtreatment, which not only wastes medical resources but also brings unnecessary anxiety to the examinees. With the popularization of LDCT and other projects in physical examinations in recent years, the domestic medical community needs to consider conducting prospective studies to confirm the efficiency of early screening for lung cancer in reality.

As for those who are diagnosed with lung nodules during physical examinations, it is important to understand that most of them are harmless benign nodules and there is no need to be overly anxious. As we mentioned in the previous article, there will be different follow-up management recommendations based on the size, type, and probability of malignancy of the nodules. Most follow-up tracking starts with re-examination after a period of time. This is because malignant tumors have their own growth patterns, and comparing imaging results at intervals can help determine whether lung nodules are really likely to be malignant tumors. Some lung nodules that are more likely to be malignant can also be checked for cancer risks using other technologies such as PET imaging.

6

Can lung nodules be prevented?

Some readers may ask: Lung nodules still have the risk of being malignant tumors. Is there any way to prevent lung nodules? Wouldn’t it be more reassuring if we didn’t even have lung nodules? This is really impossible to prevent. There are so many causes of lung nodules, many of which cannot be prevented, such as infection and inflammation. Who can guarantee that they will never get infected or inflamed? We should not aim to get a negative medical imaging test, but should consider issues that are truly related to health. Nowadays, diagnosis and treatment of lung nodules are part of early screening for lung cancer. Instead of thinking about preventing lung nodules, it is better to consider how to prevent lung cancer that can really endanger life. From a personal perspective, quitting smoking and drinking is the most effective way to prevent lung cancer. In addition, air pollution can also lead to an increase in the incidence of lung cancer. From a social perspective, maintaining a good ecological environment (including air quality) is also a way to reduce lung cancer [11].

Lung nodules have also become the subject of online rumors recently, such as the recent rumor that "lung nodules appeared after receiving the COVID-19 vaccine". In fact, the immune response induced by the vaccine has nothing to do with the formation of lung nodules in terms of mechanism. In the previous article, we also cited the example of lung nodule detection in Zhejiang in 2020. At that time, there was no COVID-19 vaccine, but many people were still diagnosed with lung nodules.

What we need to worry about more is the biggest risk factor for lung cancer - tobacco. China is currently the world's largest tobacco producer and consumer. One in every three cigarettes consumed in the world is lit in China. There are 300 million Chinese smokers today, accounting for one-third of the world's total smokers. 26.6% of people over the age of 15 in China are smokers. Even among non-smoking Chinese citizens, 700 million people - including 180 million children - are exposed to secondhand smoke[12]. If the tobacco problem is not solved, lung cancer will remain the most common and deadly cancer in China for the foreseeable future, and this cannot be changed by early screening or "prevention" of lung nodules.

References

[1] https://journals.lww.com/cmj/Fulltext/2022/03050/Cancer_statistics_in_China_and_United_States,.11.aspx

[2] https://pubmed.ncbi.nlm.nih.gov/8816144/

[3] https://www.ncbi.nlm.nih.gov/books/NBK556143/

[4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5973458/#:~:text=%E8%82%BA%E7%BB%93%E8%8A%82( pulmonary%20nodule,%E6%88%96%E4%B8%8D%E6%B8%85%E6%99%B0%E7%9A%84%E7%97%85%E7%81%B6%E3%80%82

[5] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2797465/

[6] http://www.syradiology.com/uploads/file/20181128/1543369702981214.pdf

[7] https://jamanetwork.com/journals/jama/fullarticle/2788136

[8] http://www.zchospital.com/index.php/Xw/detail/cCode/101/id/540

[9] https://pubmed.ncbi.nlm.nih.gov/21714641/

[10] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630533/

[11] https://www.cancerresearchuk.org/about-cancer/causes-of-cancer/air-pollution-radon-gas-and-cancer/how-can-air-pollution-cause-cancer

[12] https://www.who.int/china/health-topics/tobacco

Produced by: Science Popularization China

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