It turns out that the metastatic path of lung adenocarcinoma is like this

The following article is from the Popular Health Magazine, author Zhao Xiaogang

Popular Health Magazine .

"Public Health" magazine is supervised by the National Health Commission and sponsored by Health Newspaper. Its mission is to promote health science knowledge and disseminate health information.

This is the 4064th article of Da Yi Xiao Hu

Lung adenocarcinoma is a type of lung cancer, accounting for 40% to 50% of all lung cancers. The ground-glass opacities (GGO, not limited to size) and ground-glass nodules (GGN, less than 3 cm) we often talk about in the lungs are divided into benign infection lesions and malignant tumors , among which the vast majority of malignant tumors are lung adenocarcinomas .

There is a saying that lung adenocarcinoma is not a very serious cancer. A more accurate statement is that the timing of surgery and whether lung adenocarcinoma metastasizes determine the severity of the disease: if surgery is performed before lung adenocarcinoma metastasizes successfully, the patient can be cured; if surgery is performed after metastasis, the patient will face different survival periods .

Today, let’s talk about how lung adenocarcinoma achieves successful metastasis step by step.

The classic theory of "seed-soil"

Without seeds, nature would have no possibility of nurturing life; but if there are only seeds but no suitable soil conditions, the seeds cannot grow.

Specific tumor metastatic cells are like seeds, they tend to migrate to suitable soil, that is, specific target organs. Only when the soil is suitable for seed growth can metastasis occur successfully.

If the seeds successfully take root and sprout in the soil, that is, the tumor metastatic cells are implanted and grow in the microenvironment of the target organ, they become metastatic foci.

So, what conditions does suitable soil need to have? This "soil" requires the assistance of endothelial cells, inflammatory cells, fibroblasts and the regulation of complex signal transduction networks. In addition, the soil environment also has special conditions, such as hypoxic environment and medical treatment effects.

The interaction between "seeds" and "soil" is also mutual: metastatic cells (seeds) are very smart, they carry certain growth factors and related cells to help them metastasize and grow better; after reaching distant organs, they can also transform and rebuild the microenvironment to promote the healthy growth of metastatic lesions; even before entering the target organ, they can release exosome vesicles, carrying the corresponding genetic information to the target organ, transforming the microenvironment first, and creating a good "soil" for successful metastasis.

Popular Science Theory of "Quantity and Quality"

If the metastasis of lung adenocarcinoma is to expand on a large scale, the necessary conditions are the "quantity and quality" of the "seeds".

The quantity refers to the volume of tumor metastatic cells, that is, the number of cells that enter the blood vascular system (vessels are lymphatic vessels) and the corresponding target organs. The greater the quantity, the greater the number of cells that can be successfully implanted.

To determine the number of lung adenocarcinoma "seeds", the macroscopic indicators currently being tried are tumor imaging examinations, such as tumor diameter, density, and solid component ratio (CTR), etc., and the microscopic indicators are the values ​​of circulating tumor cells (CTC) and ctDNA fragments.

Quality refers to the ability of tumor cells to metastasize, that is, the ability of cells to enter the blood vascular system and the corresponding target organs. The stronger the ability, the higher the probability of survival and the greater the hope of successful implantation. For example, small cell lung cancer has a very high metastatic ability and good quality, and it is easy to achieve successful metastasis when the lesion is very small.

To judge the quality of lung adenocarcinoma "seeds", from a macroscopic point of view, the main reference is to the malignant signs such as lobulation, burrs, and vascular aggregation in tumor imaging. Microscopic indicators depend on the postoperative pathological subtype. Among them, the three subtypes of micropapillary type, solid growth type, and complex glandular type are of good quality, high ability, easy to metastasize, and stronger survival ability; the wall-attached subtype is of poor quality, low ability, not easy to metastasize, and weaker survival ability. There are also indicators for reference at the genetic level. For example, Kras gene mutations often indicate an increased probability of recurrence and metastasis, and c-MET gene mutations often indicate an increased risk of vascular infiltration.

The path to transfer at each stage

The development of lung adenocarcinoma is divided into the pre-invasive stage , microinvasive adenocarcinoma (MIA) and invasive adenocarcinoma (IA). It generally develops indolently and grows gradually, and the specific duration between each stage is still unclear.

It is worth mentioning that the pre-invasive stage is classified as a benign stage , including atypical adenomatous hyperplasia (AAH) and carcinoma in situ (AIS). Previous theories believed that the tumor cells could not enter the blood vascular system and distant target organs. However, in recent years, there have been reports that circulating tumor cells (CTCs) have been detected in patients with carcinoma in situ. Some analysts believe that this may be related to the deformation and movement of tumor cells breaking through the connection between cells.

Microinvasive adenocarcinoma (MIA) is classified as early lung adenocarcinoma. This stage is ultra-early and only involves the stroma within 5 mm around it, without invasion of blood vessels or lymphatic vessels.

It is currently believed that although the cancer metastasis cells of carcinoma in situ and microinvasive adenocarcinoma can enter the blood vascular system, their number is very small . No matter how high the quality is, they cannot be compared with invasive adenocarcinoma with a large number of cancer metastasis cells entering the blood, so the probability of forming metastasis is extremely low. It can be said with certainty that in the microscopic world, the number of "seeds" of carcinoma in situ and microinvasive adenocarcinoma that enter the blood vascular system and target organs is very small, and the probability of survival is extremely low, almost zero . Therefore, the clinical survival of such patients is very long, and the probability of no recurrence in ten years reaches 100%.

Invasive adenocarcinoma (IA) cancer cells invade the surrounding stroma more than 5 mm. If they invade blood vessels and lymphatic vessels, they have the opportunity to enter the blood vascular system and target organs in large numbers. Therefore, invasive adenocarcinoma is classified as a high-risk stage, and surgical resection is recommended. Even so, there is no need to be afraid , because at this stage, even if a large number of cancer cells enter the body, they will face the shear force of blood flow, the unfamiliar harsh environment, and the fierce attack of immune cells, and the probability of survival is also very low .

However, in the long-term confrontation and development of one thing growing while the other shrinks, if the cancer cell "seeds" continue to drift with appropriate quality and quantity, and the number and quality of metastatic cells continue to increase, then under the long-term interaction between the cancer cell "seeds" and the target organ "soil", the day of successful metastasis may also come one day when the time, place, and "cancer" are right.

Clinical findings confirm popular science theories

After completing many surgeries in the clinic, we found that even for invasive adenocarcinoma, patients with a small diameter and ground-glass components still have a good prognosis . However, lung adenocarcinomas with a large diameter, a high proportion of solid components, or pure solid density often have a poor prognosis . Metastasis often occurs in patients with mixed ground-glass adenocarcinomas and pure solid density adenocarcinomas that show larger lesions and a high proportion of solid components on CT. Especially in patients with adenocarcinomas with pure solid lesions combined with lobulation and spiculation signs, metastasis is more common, and the prognosis becomes worse as the size increases. Pure ground-glass nodule adenocarcinomas are often not observed to have related metastatic lesions. These discoveries in the macroscopic world confirm and support each other with the popular science theories in the microscopic world.

The success of lung adenocarcinoma cells, which are manifested by ground-glass opacities and ground-glass nodules, depends on the quantity and quality of cancer cells . When the two reach a certain peak, they overcome the constraints of physical and chemical factors in the long-term confrontation with the human body's physical, chemical, and immune systems, evade the sanctions of the immune system, and transform into a "soil" suitable for their own survival, and continue to multiply to form tiny lesions visible in imaging. This is the path of lung adenocarcinoma metastasis.

We expect that in the future, cutting-edge liquid biopsy technology and gene sequencing technology will be able to screen out better quantitative indicators, allowing lung adenocarcinoma patients to prepare in advance. After evaluation, the risk of metastasis can be predicted in advance, and the lesion can be removed before it successfully metastasizes, achieving a fundamental cure.

Text | Zhao Xiaogang, Department of Thoracic Surgery, Shanghai Pulmonary Hospital

Editor | Luan Zhaolin

Review | Wu Weihong

This article is reproduced from the WeChat public account of "Pulmonary and Chest Surgery"