Lung adenocarcinoma is a type of lung cancer, accounting for 40% to 50% of the total lung cancer. What we often say about lung ground glass shadow (English abbreviation is GGO, not limited to size) and ground glass nodules (English abbreviation is GGN, within 3 cm) are divided into benign infection lesions and malignant tumors. Most of the malignant tumors are lung adenocarcinoma .
There is a saying that lung adenocarcinoma is not too serious. To be more precise, the timing of surgery and whether lung adenocarcinoma metastasis determines the severity of this disease: is surgically removed before the lung adenocarcinoma metastasis is successful, and the patient can obtain a fundamental cure; and after the metastasis is successful, the operation faces a survival period of varying time .
Today, let’s talk about how lung adenocarcinoma can achieve successful metastasis step by step.
"Seed-Soil" classic theory
Without seeds, nature has no possibility of nurturing life; but only seeds, without suitable soil conditions, seeds cannot grow.
Specific tumor metastasis cells are like seeds, and they tend to transfer to appropriate soil, i.e., specific target organs. Only when the soil is suitable for seed growth will the transfer occur successfully.
If the seeds successfully take root and sprout in the soil, that is, the tumor metastasized cells are planted and grown under the target organ microenvironment, and they become metastases.
So, what conditions do suitable soil need to meet? This "soil" requires the assistance of endothelial cells , inflammatory cells, fibroblasts and the complex signaling network regulation, and the soil environment also has special conditions, such as hypoxia environment, medical treatment impacts, etc.
The role of "seed" and "soil" is also mutual: metastatic cells (seeds) are very smart. They bring some growth factor and related cells to help them transfer and grow better; after reaching distant organs, they can also transform and rebuild the microenvironment to promote the thriving growth of metastatic foci; even before entering the target organs, they can release exosome vesicles, carry corresponding genetic information to the target organs, and first modify the microenvironment to create a good "soil" for the successful transfer.
"Quantity and Quality" popular theory
If the metastasis of lung adenocarcinoma wants to form a scale, the necessary condition is the "Quantity and Quality" of the "seed".
number refers to the amount of tumor metastasized cells, that is, the number of cells entering the blood vasculature system (vasculature, lymphatic vessel) and the corresponding target organ. The more the number, the more cells that are successfully planted.
determines the number of "seeds" of lung adenocarcinoma. The macro indicators currently tried to use are tumor imaging examinations, such as tumor diameter, density, solid component proportion (CTR), etc., and the micro indicators are the numerical values of circulating tumor cells (CTC) and ctDNA fragments.
mass refers to the level of tumor cell metastasis ability, that is, the strength of cell viability entering the blood vasculature and corresponding target organs. The stronger your ability, the higher your chances of survival, and the greater your hope of success in planting. For example, small cell lung cancer has extremely high metastasis ability and good quality, and it is easy to achieve successful metastasis when the lesions are very small.
determines the quality of lung adenocarcinoma "seeds". From a macro perspective, it mainly refers to malignant signs such as lobe division, burrs, and vascular aggregation in tumor imaging. Microscopic indicators depend on the pathological subtype after surgery. Among them, the three subtypes, micro-papillary, solid growth type, and complex gland type, have good quality, high ability, easy transfer, and stronger survivability; the adherent subtype has poor quality and low ability, not easy transfer, and weaker survivability. There are also indicators for reference in terms of gene hierarchy. For example, Kras gene mutations often indicate an increase in the probability of recurrence and metastasis, and c-MET gene mutations often indicate an increase in the risk of vascular infiltration.
The metastasis path of each stage
The development of lung adenocarcinoma is divided into preinvasion stage , microinvasive adenocarcinoma (MIA) and invasive adenocarcinoma (IA). It generally develops inertly and grows gradually. The specific duration between each stage has not been clarified.
It is worth mentioning that the pre-invasion stage of is listed as a benign stage , including atypical adenomatoid hyperplasia (AAH) and carcinoma in situ (AIS). Previous theories suggest that the tumor cells cannot enter the blood vasculature and distant target organs. However, in recent years, it has been reported that circulating tumor cells (CTCs) have been detected in patients with carcinoma in situ. Some analysts believe that it may be related to the deformation movement of tumor cells breaking through the link between cells.
Microinvasive adenocarcinoma (MIA) is classified as early lung adenocarcinoma. This stage is super early, only affecting the matrix within the surrounding 5 mm range, and there is no invasion of vascular and lymphatic vessels.
Currently, it is believed that although cancer metastatic cells of carcinoma in situ and micro-invasive adenocarcinoma can enter the blood vasculature, since the number of is very small and is not comparable to invasive adenocarcinomas in which a large number of cancer metastasized cells enter the blood, the probability of forming metastases is extremely low. It can be said with certainty that in the microscopic world, there are very few "seeds" that enter the blood vasculature and target organs. The probability of survival is extremely low, almost zero . Therefore, the survival period of this type of patients that can be seen clinically is very long, and the probability of recurrence for ten years is 100%.
The cancer cells of invasive adenocarcinoma (IA) invade the surrounding matrix more than 5 mm range. If they invade blood vessels and lymph vessels, they have the opportunity to enter the blood vasculature and target organs in large quantities in groups. Therefore, invasive adenocarcinoma is classified as a high-risk stage and surgical resection is recommended. Even so, there is no need to be afraid of , because during this stage, even if a large number of cancer cells enter the body, they will face blood shear force, unfamiliar harsh environment, and fierce attacks from immune cells . The probability of being able to survive is also very low.
However, in the long-term confrontation, the development of one growth and the other, if the "seeds" of cancer cells continue to drift with appropriate mass and quantity, and the number and quality of metastatic cells continue to improve, then under the long-term interaction between the "seeds" of cancer cells and the "soil" of the target organ, the days of successful metastasis may also come in the right time, place, and "cancer" and one day.
clinical discovery confirms the popular science theory
After many surgeries were completed in clinical practice, we found that even invasive adenocarcinoma, patients with smaller diameter and ground glass still have a good prognosis. However, lung adenocarcinomas with large diameter, high proportion of solid components or pure solid density often have poor prognosis of . Metastasis often occurs in patients with mixed ground-glass adenocarcinoma and pure solid density adenocarcinoma with larger lesions and high proportion of solid components. Especially in patients with adenocarcinoma with pure solid lesions and lobular and burr signs, metastasis is more common, and the prognosis is worse as the size increases. No relevant metastatic lesions are often observed in pure ground-glass nodules. These discoveries of the macro world and the popular science theories of the micro world are mutually verified and supported each other.
The lung adenocarcinoma cell manifested by ground glass shadow and ground glass nodules, its metastasis success depends on the number and quality of cancer cells. When the two reach a certain peak, in the long-term confrontation with the human body's physical, chemical and immune system, it overcomes the constraints of physical and chemical factors, evades the sanctions of the immune system, transforms the "soil" suitable for its survival, and continuously reproduces to form tiny lesions visible to imaging. This is the path to metastasis of lung adenocarcinoma.
Looking forward to the future, cutting-edge liquid biopsy technology and gene sequencing technology can screen out better quantitative indicators, allowing patients with lung adenocarcinoma to prepare for the future. After evaluation, the risk of metastasis can be predicted in advance, and the lesion can be removed before successful metastasis, achieving fundamental cure.
text|Trium Surgery Department of Shanghai Pulmonary Hospital Zhao Xiaogang
Editing | Luan Zhaolin
Review | Wu Weihong
