Metastasis of lung adenocarcinoma

  Pulmonary ground-glass opacity (abbreviated as GGO, regardless of size) and ground-glass nodules (abbreviated as GGN, within 3 cm) are imaging findings based on ground-glass density changes, including benign infectious lesions and malignant lesions. Tumor division. The vast majority of malignant tumors are lung adenocarcinoma.
  If surgical resection is performed before the successful metastasis of lung adenocarcinoma, the patient can be completely cured; and if the operation is performed after the successful metastasis, the survival time varies. Therefore, the way of metastasis of lung adenocarcinoma is particularly important. How does the lung adenocarcinoma with GGO and GGN as imaging manifestations achieve its successful metastasis step by step?
The classic theory of “seed-soil”

  Without seeds, nature has no possibility to breed life; but only seeds, without suitable soil conditions, seeds cannot grow.
  Specific tumor metastatic cells (seeds) tend to metastasize to specific target organs (soil), and only when the soil is suitable for seed growth can successful metastasis occur. Tumor metastatic cells grow and grow in the target organ microenvironment, that is, become metastatic foci. This “soil” needs the assistance of endothelial cells, inflammatory cells, fibroblasts, etc. and the regulation of complex signal transduction networks, and the soil environment has special conditions, such as hypoxia environment, medical treatment effects, etc.
  The role of “seed” and “soil” is also mutual: the transferred cells (seeds) can carry their own microenvironment (certain growth factors and related cells) to help them better transfer and grow; after reaching distant organs , gradually adapt to the local microenvironment, and even reconstruct the microenvironment to promote the vigorous growth of metastases under the interaction between the metastatic cells and the microenvironment. Even before the tumor metastasis cells have not entered the target organ, they can release some exosome vesicles to carry the corresponding genetic information to the target organ, transform the microenvironment first, and create a good “soil” for the successful transfer to welcome the “seed”. “s arrival.

The popular science theory of “quantity and quality”

  For the “seed” of lung adenocarcinoma to take root and grow vigorously in the “soil”, the necessary conditions are the “quantity and quality” of tumor metastatic cells.
  The number refers to the number of tumor metastatic cells, that is, the number of cells entering the blood vasculature (vessels or lymphatic vessels) and corresponding target organs. The higher the number, the higher the number of successfully planted cells. To determine the number of “seeds” of lung adenocarcinoma, the macroscopic indicators currently tried are tumor imaging examinations, such as tumor cell diameter, density, solid component ratio (CTR), etc., and the microscopic indicators are circulating tumor cells (CTC), ctDNA Fragment value. However, the recognition of these indicators in the industry is not consistent, and the corresponding research is increasing.
  Quality refers to the level of tumor cell metastatic ability, that is, the strength of cell viability into the blood vasculature and corresponding target organs. The stronger the ability, the higher the probability of survival, and the greater the hope of successful planting. For example, small cell lung cancer has extremely high metastatic ability and good quality, and it is easy to achieve successful metastases when the lesions are very small.
  To judge the quality of the “seed” of lung adenocarcinoma, the macroscopic indicators currently tried are malignant signs of tumor imaging such as lobulation, burr, and blood vessel aggregation, and the microscopic indicators are postoperative pathological subtypes. Among them, the three subtypes of micropapillary type, solid growth type, and complex glandular type have good quality, high ability, easy transfer, and stronger viability; the adherent type has poor quality, low ability, and is not easy to transfer. , less survivability. Gene level indicators, such as Kras gene, c-MET gene, EGFR gene, ROS gene, ALK gene, etc. Mutations in the Kras gene often indicate an increased probability of recurrence and metastasis, and mutations in the c-MET gene often indicate an increased risk of vascular invasion.

The transition path at each stage

  Lung adenocarcinomas are classified into pre-invasive stages, minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IA), which generally develop indolently and gradually, and the specific duration between each stage is unclear. It is worth mentioning that the preinvasive stage includes atypical adenomatous hyperplasia (AAH) and carcinoma in situ (AIS), which are classified as precancerous lesions and benign stages.
  Pre-invasive stage (AAH, AIS), classified as benign stage. Previous theories held that the tumor cells were unable to 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 and movement of tumor cells, breaking the connection between cells.
  Minimally invasive adenocarcinoma (MIA) is classified as early-stage lung adenocarcinoma, which is an ultra-early stage, involving only the surrounding stroma within 5 mm without invasion of angiolymphatic vessels. CTCs can also be detected in this patient.
  Although the metastatic cells of carcinoma in situ and minimally invasive adenocarcinoma can enter the blood vasculature, due to the small number, no matter how high the quality, they cannot be compared with the invasive adenocarcinoma with a large number of metastatic cells entering the blood. The probability of metastases is extremely low. It can be said with certainty that in the microscopic world, very few “seeds” of carcinoma in situ and microinvasive adenocarcinoma enter the blood vasculature and target organs, and the probability of survival is extremely low, almost zero. Therefore, in the macroscopic world, the clinically visible patients of this type have a very long survival period, with a 100% probability of no recurrence in ten years.
  Invasive adenocarcinoma (IA) refers to cancer cells that invade the surrounding stroma beyond 5 mm. If they invade blood vessels and lymphatic vessels, they have the opportunity to enter the blood vasculature and target organs in large numbers. Therefore, invasive adenocarcinoma is classified as a high-risk stage, and surgical resection is recommended. At this stage, even if a large number of cancer cells enter the body, they are faced with the shear force of blood flow, the unfamiliar and harsh environment, and the fierce attack of immune cells, and the probability of being able to survive is very low.
  However, in the long-term confrontation, in the development of one and the other, if the “seeds” of cancer cells continue to drift with appropriate quality and quantity, and the number and quality of metastatic cells continue to increase, then the “seeds” of cancer cells and target organs will continue to drift. Under the long-term interaction of “soil”, the day to achieve successful transfer may also come at a certain time, location, and “cancer”.
corroboration of clinical findings

  After completing many surgeries in the clinic, we found that even in invasive adenocarcinomas, patients with smaller diameters and ground-glass components had a good prognosis; lung glands with larger diameters, a high proportion of solid components, or pure solid density Cancer, the prognosis is often poor. Metastases tend to occur in patients with mixed ground glass adenocarcinoma and pure solid density adenocarcinoma with large lesions on CT with a high proportion of solid components. Metastases are more common in adenocarcinoma patients with pure solid lesions with lobulated and spiculated signs, and the prognosis is worse with increasing size. In pure ground-glass nodule adenocarcinoma, associated metastatic lesions are often not observed. These discoveries of the macroscopic world and the popular science theories of the microscopic world confirm and support each other.
  Lung adenocarcinoma cells manifested by ground-glass opacities and ground-glass nodules, the success of their metastasis depends on the quantity and quality of cancer cells. In the confrontation, they overcame the constraints of physical and chemical factors, evaded the sanctions of the immune system, transformed the “soil” suitable for their own survival, and continuously multiplied to form tiny lesions visible on imaging. This is how lung adenocarcinoma metastases.
  Looking forward to the future, cutting-edge liquid biopsy technology and gene sequencing technology can screen out better quantitative indicators, so that lung adenocarcinoma patients can plan ahead. After evaluation, the risk of metastasis can be predicted in advance, and the lesions can be removed before successful metastasis to achieve a fundamental cure.

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