Pathological imaging classification of lung cancer I. Pathological imaging on lung cancer diagnosis Traditional pathological imaging combination has two levels, one is based on the pathological diagnosis results as follow-up information to verify the correctness of imaging diagnosis; the other is based on the description of pathological histological morphological features to analyze the characteristics of each pathological type and pathological form on imaging. With the continuous advancement of imaging technology and improvement of resolution and image quality, many image details have become diagnostic points, and the traditional qualitative analysis alone is not enough. In recent years, LDCT has become a common means of lung cancer screening in the population, and lung masses, especially peripheral pulmonary nodules (SPN), revealed by CT thin-section scans have good definition, and CT-enhanced scans and post-processing techniques can provide more high-quality image information. Therefore, it is necessary to do an in-depth pathological image control analysis of various details of the CT presentation of lung masses, which is also called pathological imaging. II. Pathological imaging of the pathological progression process of lung adenocarcinoma Since peripheral type lung adenocarcinoma accounts for about 80% of peripheral type primary lung adenocarcinoma, stage I and stage II usually have no obvious symptoms and are not significantly related to heavy smoking, which is difficult to diagnose by bronchoscopic biopsy and mainly relies on CT diagnosis, pathological imaging recognition of peripheral type lung adenocarcinoma is especially important. The progression of lung adenocarcinoma is basically: adenocarcinoma in situ (AIS) – microinvasive adenocarcinoma (MIA) – adnexal growth adenocarcinoma (LPA) – invasive adenocarcinoma (IAC) [1], and solid growth adenocarcinoma may further develop into large cell carcinoma [5]. In this process, the proportion of the adnexal growth component gradually decreases, the area of solid density on CT gradually increases, and the degree of infiltration is largely consistent with solid density [2, 3, 16]. The site of appearance of the infiltrative zone is random, and the cases of infiltration appearing first in the peripheral area of the tumor are no less than those in the central area. According to data from China, Japan, and Korea, lung adenocarcinoma accounts for 60-64% of all primary lung cancers, and recent case data show that adenocarcinoma in situ and microinfiltrative, adnexal-growing (or lepidic pattern) adenocarcinoma have accounted for the majority of primary adenocarcinomas. In invasive adenocarcinoma, the adnexal growth component (ground glass component on CT) is visible in about 60% of cases, so it is important to identify the adnexal growth component, which is specific not only for tumor characterization but also for staging. The overall volume size is not as important as the size of the solid zone in the prognosis of mixed ground glass nodules [24]. The solid density component of the mixed density ground glass image (mGGO) on CT must also exclude alveolar collapse (solid density areas due to degeneration, which occurs in about 20% of early adenocarcinomas) after excluding blood vessels and obstructing bronchioles and mucinous early adenocarcinoma (about 1-2% of total early adenocarcinoma) [11], leaving essentially an infiltrative component. In view of this pattern of adenocarcinoma progression, it appears that central primary lung adenocarcinoma is an extremely unlikely event, and that invasive adenocarcinoma found on bronchial biopsy usually grows in an intramural infiltrate, rarely forming an intraductal mass, and that pathological histology of bronchial pseudostratified ciliated columnar epithelium is usually present without heterogeneity. Therefore, the so-called central invasive adenocarcinoma is only a peripheral type of lung adenocarcinoma near the central airway that invades the bronchial wall [33]. In adenocarcinoma in situ (AIS) and atypical adenomatous hyperplasia (AAH), the internal structure of the tumor tissue is homogeneous and the thickening of the alveolar septum is very close, usually at 25-40 μm, and the alveolar structure is mostly undamaged and the tumor cells are not densely arranged, so that the amount of air contained in the tumor tissue is relatively constant. The air content of AAH is about 60-70%, and the CT value is between -700 and -600Hu accordingly; the air content of AIS is often 50-60%, and the CT value is usually between -600 and -500Hu; while in microinfiltrating adenocarcinoma (MIA), due to the increase in overall tumor cell and tumor tissue density, the accumulation of exfoliated cells in the tumor alveolar cavity increases, and local air At this time, the boundary between the infiltrating area and the attached growth area (initial area) becomes clearer and clearer, and the infiltrating area gradually replaces the initial area, but the air content of the initial area still reaches about 50%, and the corresponding CT value remains around -500Hu. Estimation of CT values on pathology films is very accurate, with air as -1000Hu, water and soft tissue as 0-40Hu (mean about 30Hu), and fat as about -100Hu, and a more accurate actual CT value can be obtained by doing an average calculation according to the area share, which is consistent with the physics of radiological imaging [4, 10, 17, 19]. In benign tumors, the air content is essentially zero, so the CT values are generally above 0Hu under conditions that exclude volume effects. In squamous and adenosquamous carcinomas, the tumor tissue is essentially free of air content, and CT values are above 0Hu. In daily observation, there is no significant difference between the mediastinal window or the lung window to measure the solid area [12]. 2. Good correspondence of anatomical structures The anatomical structures in the lungs are mainly the pulmonary arteries, pulmonary veins and bronchi. Pathologically, the pulmonary arteries have a very strong companionship with the bronchi of the same level, until the fine bronchi without cartilage and with sparse smooth muscle remain companion. The pulmonary veins almost always travel independently. The diameter of bronchial arterioles is usually about ten times different from the corresponding pulmonary arterioles, and in stage T1 lung cancer their blood supply role is quite limited and their thickening cannot be shown on general imaging. In early stage lung adenocarcinoma, the tumor tissue grows along the alveolar wall against the wall, which basically does not damage the blood vessels and bronchi, and there is no strong pulling force, so there is no possibility of the so-called vascular pulling and twisting entanglement. As for the reason why the blood vessels in the tumor area increase and look like entanglement, it is because the blood supply to the tumor area increases and mainly relies on the pulmonary artery supply, which makes the local pulmonary arteries and veins thicken and the tiny branches that could not be shown can be shown on CT and centered on the tumor area. The intrapulmonary lymph nodes have relatively fixed sites, more often in interlobular fissures and subpleural, shield-shaped or bean-shaped, and are often mistaken for GGO on a 5-mm layer-thick plain film. Thin-layer scans can show clear and smooth borders, with solid density inside. Multiplanar reconstruction (MPR) combined with volume reproduction reconstruction (VR) reconstruction shows better anatomical structures and helps in the CT diagnosis of small pulmonary nodules [22]. 3. pathological imaging correspondence of internal tumor degeneration The first type of degeneration is necrosis. Squamous cell carcinoma is prone to hypoxic necrosis, and this irregular morphology of necrosis has stable CT values with no enhancement, and it is difficult to form dystrophic calcifications due to the limited time of necrosis formation. The second type of degeneration is fibrosis. The growth of tumor tissue exceeds the increase of blood supply, and insufficient oxygen supply makes tumor cells unable to maintain cell structure and function, thus transforming into fibrous tissue with little oxygen demand. In the early stage of lung adenocarcinoma, there is plasma protein leakage in the local alveolar cavity, and the alveolar structure gradually disappears, forming an alveolar collapse zone with fewer histocytes. The complete collapse zone has a clear boundary, and the air content on both sides of the collapse zone differs greatly, and there is a steep increase in CT value from the initial zone to the collapse zone on imaging, which is different from the gradual increase in CT value of microinfiltration, and this sudden change causes the peak concentration of CT value in the tumor area elevated [6, 8, 12, 14]. In invasive adenocarcinoma, the tumor tissue is dense and the onset of fibrotic regression varies, with a large number of epithelial cells undergoing irregular scattered fibrosis, and the central region may fuse into a large area of fibrosis based on scattered fibrosis. On pathological histological sections, the number of cells in the fibrotic areas is higher and a complete morphological transition spectrum from epithelial cells to typical fibroblasts can be seen. Therefore, we believe that fibroblasts originate from epithelial mesenchymal transition (EMT) of tumor cells, and EMT is more pronounced in adenocarcinoma than in squamous carcinoma, and the fibrotic areas are more widely distributed and dispersed. The fibrotic areas within the tumor showed ordinary soft tissue density on CT plain scan and low enhancement on enhancement, and on MRI enhancement showed irregularly distributed low signal areas within the overall apparently high signal tumor area, with the central region being the most obvious. The third degenerative consideration is tumor tissue lymphocytic transformation, which is relatively small in extent and appears inconspicuous. Lymphocytic transformation is more common in adenocarcinoma, where tumor cells eventually evolve into lymphocytes, both T and B lymphocytes. In AIS, scattered mounds of lymphocytic tissue usually reach a diameter of 0,5 to 0,9 mm, resulting in scattered small dot-like high-density shadows seen on CT thin-section scans, which are not difficult to distinguish from small vessel cross-sectional shadows. (1) Malformation tumor: Its tissue composition is cartilage, smooth muscle, bronchial mucosa and a small amount of fibrous tissue, and the arrangement of various tissues lacks regularity, often with several pieces of connected oval cartilage tissue as the core, surrounded and embedded with extruded bronchial mucosa and smooth muscle tissue, and the residual space is often filled with fatty tissue. The tumor is usually small, with shallow lobulated margins and a smooth surface, lacking the ground glass component of air-containing alveoli. The presence of interstitial fatty components shows characteristic hypodense areas around -100Hu. Calcification in malformation tumors occurs only in cartilage components, especially crescent-shaped calcification in the perichondrium area of the cartilage mass, and calcification in the entire cartilage mass showing a round-like or popcorn-like appearance is less common, more often it is a slight calcification that is difficult to identify with the naked eye, which is also more vague on pathological HE stained films and more difficult to determine on CT films, often relying on measured CT values (greater than 100 or 160 Hu) to estimate [21]. (2) Sclerosing pneumocytoma: the tissue origin is dysplastic alveoli, fine bronchi and derived tissues, which overall form a round or oval mass with a smooth surface that is distended and very slow growing, with essentially no internal cartilage and smooth muscle components, resulting in a tumor with a smooth surface and clear borders [27]. The calcification originates from old fibrotic tissue, so the calcified areas have an irregular morphology, and the tumor tissue cells are often abundant, and in addition to the fibrotic areas are richly vascularized and often contain angiomatous areas, so enhanced scans show significant enhancement. The rich blood supply and the absence of normal pulmonary vasculature and bronchus inside the tumor make the vasculature travel close to the mass. Sclerosing pneumocytoma is often surrounded by a cloudy halo area, which is the result of bleeding within the tumor into the surrounding lung tissue [26]. (3) Primary adenocarcinoma of the lung: In a large statistical sample, lung adenocarcinoma accounted for 64% of all primary lung cancers (with histopathological data) and more than 80% of peripheral lung cancers.Since 2011, a multidisciplinary consensus has emerged on the developmental process of lung adenocarcinoma: basically, it is a continuous process from AAH to AIS to MIA to IAC (invasive adenocarcinoma). With the development of infiltration, CT shows corresponding changes in the density, number, border, and size of the solid component within the lesion [14, 15, 25]. The bronchi in the tumor area are also filled or disrupted with the progression of infiltration, and CT shows a positive correlation between the disappearance of inflatable bronchial signs and lymph node metastasis [23]. This understanding is important for understanding the pathologic features of each stage. About half of the invasive adenocarcinomas contain an appendage growth component, which appears on CT as a residual ground glass area, often at the periphery of the tumor, formerly known as the “halo sign”, and as CT resolution improves, the internal and external boundaries of these appendage growth areas can be clearly seen and the CT value of the ground glass area can be accurately measured. Internal solid areas without or tiny, lacking burr and lobulated borders often represent in situ adenocarcinoma [7]. There is some accuracy in distinguishing AIS from MIA based on the density, morphology, margins, size and adjacent tissue changes of the tumor area on CT [20]. In early lung adenocarcinoma, an abundant blood supply also suggests increased malignancy, and CT shows increased vascular shadow and morphological changes in the tumor area positively correlated with the development of infiltration [9]. Most of the originally considered peripheral large cell carcinoma (LCLC) is a solid growth type of invasive adenocarcinoma, and the proportion of large cell carcinoma in lung cancer has decreased from about 12% to 1-2% over the past decade, and many scholars believe that large cell carcinoma is not an independent pathological type [5]. Large cell carcinoma has relatively little internal fibrous tissue, and punctate and irregular necrosis are common, showing a round-like appearance on CT with less external contraction and less pronounced burr, lobulation and pleural traction. For most of the burrs at the lung border of infiltrating adenocarcinoma tumors, according to our observation, pathological histology did not find tumor infiltration to form a sharp and thin protrusion, considering that such burrs are related to the contraction of tumor fibrosis. (4) Carcinoid tumors and other neuroendocrine tumors: typical carcinoid tumors are found in the central lung region of young and middle-aged women, and those growing in large bronchial sites often protrude significantly into the airways and obstruct the bronchi. Large-cell neuroendocrine carcinoma is more common in middle-aged and elderly men, and the tumor is often rounded and contains scattered focal necrosis, which is generally smaller than that of squamous carcinoma. The incidence of atypical carcinoid tumors is low and needs further study due to the lack of multicenter statistical data. Small cell carcinoma has poor cell adhesion, strong tissue infiltration and easy lymph node metastasis compared to squamous carcinoma, and relatively less obstruction to bronchi, and these differences are often shown on CT [30]. (5) Squamous carcinoma: Squamous carcinoma occurs in the bronchial mucosa, and most squamous carcinomas are of central type, and peripheral type squamous carcinoma is often close to the segmental bronchi. Central type squamous carcinoma. Histologically, the nests of squamous carcinoma are larger, and the nests are prone to necrosis and can fuse into pieces, forming irregular large necrotic areas. It can be easily distinguished on CT scan. Peripheral squamous carcinoma is mostly well defined with few deep lobes, few burrs, lack of peripheral ground glass shadow, and bronchial obstruction changes are common, which helps to distinguish it from adenocarcinoma [28, 29]. In the radiological diagnosis of malignant tumors, the determination of mediastinal lymph nodes is of great significance, and an increase in the maximum cross-sectional area and short diameter of lymph nodes often indicates lymph node metastasis [31]. (6) Pathological interpretation of several common CT signs of peripheral type lung adenocarcinoma ①Air bubble sign: it is commonly seen in early stage lung adenocarcinoma, the incidence is around 30-60%, which is formed by the enlargement and fusion of alveoli in the intra-tumor wall growth area. ② pleural traction and pleural depression: both are caused by fiber contraction after tumor growth, which is not found in benign lung tumors. Inflammatory pulmonary nodule scar contraction also leads to pleural traction and depression, the extent of which is often inferior to that of peripheral lung cancer. In interlobular pleura, the tumor’s pulling on the pleura will make the contralateral dirty pleura close to the mass, which rarely forms triangular effusion such as submural pleural effusion. On the well-displayed multiplanar reconstruction map, short transverse lines of increased density shadow between interlobular pleura can often be seen, presumably this is also a kind of tiny effusion. (iii) Spherical sign, spicule sign and clear border of tumor lung: In early non-mucinous lung adenocarcinoma, the adnexal growth component does not jump around and the growth rate is close in all directions, so the overall morphology is close to a round sphere and the border is clear. Clear borders are very useful in differentiating from inflammatory lesions, especially spherical pneumonia. Sometimes tumor growth encounters obstructed lobular septa, forming a straight or even concave border on one side or locally in early adenocarcinoma. Early adenocarcinoma has slightly different marginal growth, forming a blunt-topped bump within 2-3 mm in width and height, like a hilly terrain between plains and mountains, and this tumor lung surface morphology can be shown very well during VR (volume reproduction reconstruction). (4) Vascular entanglement sign: In early lung adenocarcinoma, the blood supply is increased without significant destruction of pulmonary arteries and veins, and the blood vessels in the tumor area are thickened, compared with those that can be shown outside the tumor. In fact, the formation of new blood vessels in the tumor area of early adenocarcinoma is so inconspicuous that it is difficult to be shown on CT. 4. Different types of inflammation have different pathological imaging features 1. granulomatous inflammatory nodules. Among them, tuberculosis is the most common type, young patients are more often seen in the posterior segment of the upper lobe apices and the dorsal segment of the lower lobe, because Mycobacterium tuberculosis has a strong destructive force and a strong vitality, it usually causes necrosis, often a large area of cheese like complete necrosis in the central region of the nodule, there are also strips of multiple necrosis, the necrotic area is the center of the nodule, granulomatous nodules are formed around the necrotic area, so sometimes it is a tuberculosis ball, sometimes it is a stacking type The satellite foci vary in proximity to the main nodule and are often connected to the main nodule. The size of the satellite foci is often around 1-2 mm, thus requiring thin-section scanning and multiplanar reconstruction. Focusing on features such as satellite foci can reduce misdiagnosis [35]. Granulomatous inflammatory nodules, in which necrosis is often small or absent, are proliferation-dominant granulomatous inflammation with predominantly multinucleated phagocytic proliferation and insignificant fibrous contraction, rarely causing pleural traction and pleural depression even in close proximity to the pleura. Asymptomatic cryptococcal pulmonary nodules are not uncommon, which are a focal proliferation-dominated inflammatory disease with insignificant pleural traction [36]. 2, Inflammatory pseudotumors with common chronic inflammatory nodules. These lesions arise from lamellar pneumonia and after incomplete resorption leave areas of fibrous hyperplasia with small amounts of inflammatory cell infiltration with irregular borders, which are relatively easy to absorb in areas surrounded by alveoli and more difficult to absorb if surrounded by truncal structures or lobular septa leaving chronic inflammatory fibrotic tissue that produces sharp angles, straight edges and deep concavities [34] Several models have been used for benign-malignant identification and it is usually considered that age large, well-defined masses, burrs, large nodules and lack of calcification increase the likelihood of malignancy [32]. These several diagnostic models compare benign and malignant lesions as one category each, with the obvious disadvantage that the variation within the benign lesion group is so great that many morphologic features of benign and inflammatory lesions are submerged in generalized statistics.