Due to the influence of many factors, the global incidence of malignant tumors shows a continuous increase, and it is speculated that the global incidence of malignant tumors will increase by 50% by 2020, not only that, the number of deaths from malignant tumors is also rapidly increasing worldwide [1], and in developing countries such as China, this trend will be more obvious and has a significant trend of youthfulness. Therefore, it is more urgent to strengthen the research on the prevention and treatment of malignant tumors, to accurately and objectively evaluate the biological behavior and prognosis of tumors, and to formulate treatment plans. Classification, grading and staging are the three most important indicators for evaluating the biological behavior and diagnosis of tumors, among which grading and staging are mainly used to evaluate the biological behavior and prognosis of malignant tumors. In recent decades, thanks to the breakthroughs in life science and medical technology, the detection of targets related to individualized tumor therapy and the clinical application of individualized therapeutic drugs including targeted therapy have not only improved the detection rate of early stage tumors, but also significantly improved the prognosis of many tumors. The clinical value and significance of traditional tumor staging, grading and staging have also changed to different degrees. This paper intends to analyze the biological basis and clinical value of tumor typing, grading and staging in order to provide more accurate molecular biological information for individualized tumor treatment, guide the formulation of individualized treatment plans and monitor the efficacy. Department of Dermatology, Guangdong Dermatology Hospital, He Renliang I. Pathological classification of malignant tumors (typing) Although the debate on stem cell theory and dedifferentiation theory of tumor origin is still going on, the fact that tumors can occur in all organs, tissues and cells of the body is undeniable. The degree of similarity or proximity of tumor cells to their tissues of origin to normal tissues is an important diagnostic basis for the pathological classification (staging) of tumors, e.g., keratinizing squamous carcinoma showing a discrete degree of keratinization, adenocarcinoma with secretory function, melanoma capable of synthesizing melanin, synovial sarcoma with bidirectional differentiation features, etc. Therefore, the pathological staging of tumors is an important parameter that best reflects the biological behavior and morphological characteristics of tumor-derived tissue cells. For example, mucinous carcinoma (indolent cell carcinoma or mucinous carcinoma) originating from the digestive tract is more prone to lymph node metastasis and has a worse prognosis than ductal carcinoma, while mucinous carcinoma of the breast has a good prognosis. In terms of tumor cell differentiation, hypodifferentiated tumors have stronger invasive metastatic ability and higher malignancy than highly differentiated tumors. Currently, WHO tumor staging criteria are the accepted tumor staging scheme, and malignant tumors are usually staged according to the dominant component staging principle, i.e. the main histological type of the tumor (>50% of the tissue structure) is used for staging diagnosis. However, heterogeneity is one of the important histological features of malignant tumors, and many malignant tumors (e.g. colorectal cancer and gastric cancer) have different degrees of multi-directional differentiation or coexistence of different histological types, and the heterogeneity of tumors also determines the complex clinical biological behavior and prognosis of malignant tumors. Obviously, the WHO tumor staging method according to the dominant component staging principle will undoubtedly ignore the highly heterogeneous histological features of malignant tumors to some extent, and conceal the influence of secondary histological types on the biological behavior and prognosis of malignant tumors; at the same time, the pathological histological diagnosis is also easily influenced by the microscopic morphological manifestations of malignant tumors and the subjective judgment of pathologists, and there is inevitably some staging inconsistency. The histological diagnosis of malignant tumors is also susceptible to different microscopic morphological manifestations and subjective judgments of pathologists, so there is inevitably some staging inconsistency. In addition, even tumors with the same typing, grading and staging show completely different therapeutic responses and prognosis due to differences in their molecular phenotypes. It can be seen that the malignancy staging scheme according to the dominance principle has certain limitations in reflecting the histological characteristics, biological behavior and prognosis of tumors, and does not meet the requirements for refinement of tumor diagnosis in individualized tumor treatment. Therefore, on the basis of traditional tumor pathological staging, it is urgent to vigorously promote molecular staging of tumors with molecular phenotype detection as the core tumor diagnosis [2-8]. II. Classification of tumors Differentiation (cell differentiation) refers to the process of gradual development from embryonic infantile cells to mature normal cells. Tumor cell differentiation refers to the process of gradual evolution and maturation of tumor cells. Heterozygosity (atypia) [9] is an important histological feature of malignant tumors, which is essentially a morphological manifestation of the degree of tumor differentiation, reflecting the different degrees of morphological differences between tumor tissues in terms of tissue structure and cell morphology and the normal tissue cells from which they originate. The magnitude of this tumor tissue heterogeneity can be expressed by the grading of the tumor (G). Currently, a concise three-stage scheme is most commonly used: grade I (G1), i.e., well-differentiated (called “highly differentiated”), where the tumor cells are close to the corresponding normal tissue of origin and have low malignancy; grade III (G3), where the cells are less differentiated (called “poorly differentiated”). Grade II (G2), with tissue heterogeneity between grade I and grade III, is highly malignant. The concise three-level grading scheme is mostly used for grading the heterogeneity of differentiated malignant tumors, such as adenocarcinoma and squamous carcinoma. In addition, some scholars call some malignant tumors that do not show differentiation tendency as undifferentiated tumors, which belong to grade IV (G4) and are highly malignant. In practice, the grading of tumors is mainly based on parameters such as the size of tumor tissue structure and cellular heterogeneity, the number of nuclear division images or proliferation indices, the extent of necrosis, and invasive status in microscopic HE-stained sections [9-12]. And the best differentiated region is used to determine the histological origin of the tumor (staging), while the worst differentiated region is used to determine the grade of the tumor. It can be seen that the grading of malignant tumors reflects the internal characteristics of the tumor, and has great reference value for objectively assessing the degree of differentiation and biological behavior of the tumor and predicting the prognosis. Generally speaking, the higher the tumor grade, the worse the prognosis, but it is not completely consistent [13]. However, due to the complexity and heterogeneous characteristics of tumor tissue structure, different types of tumors (e.g. adenocarcinoma, squamous carcinoma, renal cell carcinoma, breast cancer, etc.) have their different structural characteristics and grading criteria, and lack of quantitative indicators, in addition, due to the influence of the adequacy of sampling and subjective differences in the interpretation of diagnostic criteria and heterogeneity, all of them affect the objectivity, accuracy and In addition, the objectivity, accuracy and reproducibility of tumor grading are affected to varying degrees by the adequacy of sampling and subjective differences in the interpretation of diagnostic criteria and heterogeneity. Therefore, it is an inevitable trend of tumor grading to streamline the grading parameters, reduce the grading levels, simplify the grading criteria, and enhance the quantifiable parameters and clinical operability and reproducibility. In the past decades, remarkable progress has been made here thanks to the outstanding contributions of experts and scholars in different fields. For example, the concept of grading intraepithelial neoplasia by simplifying 3 grades into two high and two low grades has undoubtedly provided a worthy success in histological grading of tumors. And the detection of nuclear division and proliferation indices (e.g. Ki-67) [14] provides reliable quantifiable parameters for the diagnosis and grading of malignant tumors, among which the value of Ki67 as a quantifiable parameter for evaluating the proliferative activity of tumor cells is increasingly accepted and widely used in tumor grading. In addition, the Gleason scoring system for prostate cancer proposed by Gleason et al. according to the structural heterogeneity of the gland [15,16] also provides a more reasonable and quantifiable grading scheme for the grading of prostate cancer and is widely used. The authors also proposed a new histological grading-scoring scheme for gastric and colorectal cancers by combining the WHO staging principles of gastric and colorectal cancers and their degree of differentiation, biological behavior, and invasive metastatic ability [17,18]. Tumor classification by immunological scoring also provides a new method for quantitative staging and grading[19] . The staging of tumor is determined based on the size of the primary tumor, the depth and extent of infiltration, whether the adjacent organs are involved, whether there are local and distant lymph node metastases, and whether there are hematogenous or other distant metastases, etc. Its essence is to reflect the degree of invasion and metastasis of the tumor, which is an important indicator to evaluate the invasion and metastasis of malignant tumor, the degree of disease progression, regression and prognosis. It is an important indicator to evaluate the scope of malignant tumor invasion and metastasis, disease progress, regression and prognosis. Accurate tumor staging is not only a reliable indicator to accurately predict the biological behavior and prognosis of malignant tumors, but also provides clinicians with accurate basis for patient stratification and management, and is a basic prerequisite for selecting adjuvant treatment options and improving treatment effects. Among the many tumor staging schemes 1929 Dukes staging system proposed by The International American Joint Committee on Cancer (AJCC) is now widely accepted and recognized as a system that can reflect the progress of malignant tumors and judge the prognosis. The TNM staging system (TNM staging system) is now widely accepted and recognized as the most reliable independent index to reflect the progression of malignant tumors and determine the prognosis. In 2010, the seventh edition of TNM staging (AJCC-7) [20] was also published. The visual and microscopic interpretation of the size and extent of primary tumor infiltration (T), local lymph node (N) involvement and tumor metastasis in distant organs and tissues (M) are the three directly evaluable parameters for performing TNM staging of tumors. Among them, lymph node detection has a direct impact on the accuracy of malignant tumor staging [21-23], and obtaining sufficient lymph nodes is a prerequisite to ensure accurate staging. Therefore, the minimum number of lymph nodes required for reliable staging is recommended for different tumors in the seventh edition of the AJCC TNM staging [24], for example, at least 10-14 lymph nodes are recommended for reliable lymph node staging in colorectal cancer. Although the T, N, and M reading thresholds in TNM staging vary among tumors, in general, the larger the number, the more advanced the disease and the worse the prognosis. It is well known that the biological behavior and invasive metastatic ability of malignant tumors depend on their specific histological type (or immunophenotype) and differentiation degree, which means that the histological type (or immunophenotype) and differentiation degree of tumors are the decisive factors that really affect TNM staging. Therefore, in-depth exploration of the histological typing (or immunophenotype) and grading of malignant tumors and comprehensive detection of the extent of tumor invasion and metastasis are fundamental to accurate TNM staging. Unlike tumor histological typing and grading, which are intrinsic parameters of tumor characteristics, tumor staging is an external parameter describing tumor characteristics, which not only depends on the histological type and grading of the tumor, but also is obviously influenced by subjective and social factors such as the early and late appearance of clinical symptoms caused by the tumor, the patient’s clinical tolerance, the patient’s economic status, the level of medical insurance and the patient’s consultation time. It can be seen that the time of patient consultation also determines the TNM stage of tumor to a great extent. The relationship between tumor staging, grading and staging It was previously believed that TNM staging is an independent indicator of malignant tumor progression and prognosis, and is also the main basis for deciding the scope of surgical resection, surgical modality and reasonable adjuvant treatment plan, while the clinical value of tumor histological type and grading is not clear [13,25]. However, this is not the case, and the influence of histological type and grading of malignant tumors on their invasive metastatic ability and tumor prognosis is gradually being recognized: as mentioned earlier, tumor staging and grading are intrinsic and essential features of tumors: tumor staging depends on the morphological similarity between tumor tissue cells and normal tissue cells, and tumor grading depends on the degree of differentiation of tumor-derived tissues, both of which are reflective of the degree of differentiation, structure, and grade of tumor-derived tissue cells. Both are important parameters reflecting the differentiation degree, structural characteristics and biological behavior of tumor-derived cells. The staging of tumor is based on the size of primary tumor and the extent of infiltration, local lymph nodes and distant organs, and the extent of tissue involvement, which are clinically observable parameters reflecting the invasive metastatic ability of tumor. The TNM staging of tumors not only depends on the specific tumor histological type (or molecular phenotype) and degree of differentiation, but is also significantly influenced by the time of patient consultation. In short, tumor staging describes the origin of the tumor, tumor grading describes the degree of differentiation, and tumor staging and grading determine the unique biological behavior and invasive metastatic capacity of different tumor types, which in turn determines the TNM stage of the tumor. TNM stage reflects the degree of progression of malignant tumors and predicts the point in time when patients reach the expected end of life. Therefore, strengthening the study of histological typing, grading and immunophenotyping of malignant tumors is the key to accurately determine the degree of tumor progression, prognosis and clinical treatment plan. However, with the development of molecular biology technology, gene sequencing, fluorescence in situ hybridization, immunohistochemistry, Real-time PCR, etc., and the advent of post-genomic era, the understanding of tumor has been deeply penetrated to the molecular level. Genetic mechanisms such as gene mutations, deletions or overexpression, chromosomal instahility (CIN), microsatellite instability (MSI) and the CpG Island Methylator phenotype (CIMP), have been developed. The CpG Island Methylator phenotype (CIMP), protein phosphorylation and other epigenetic mechanisms have been elucidated [25-33], and a series of molecular targets related to personalized tumor therapy have been discovered and a large number of tumor-specific targeted therapeutic drugs have been released one after another, which not only provide new indicators for prognosis prediction and guiding treatment of malignant tumors, but also provide new solutions for the treatment of malignant tumors to a certain extent [34 ], but also change the clinical significance of traditional tumor pathological staging, grading and staging and patient prognosis at different levels. For example, highly malignant poorly differentiated or undifferentiated colorectal cancers show good clinical course due to the presence of MSI-H, and colorectal cancer patients with high expression of epidermal growth factor receptor (EGFR) and mutations in KRAS and BRAF have significantly improved prognosis compared to the previous ones due to the use of targeted therapeutic agents and neoadjuvant regimens. the detection of Her-2 gene and the use of Herceptin have completely changed the Her-2-positive breast cancer patients’ prognosis was completely changed by the use of Herceptin. It can be seen that the era of individualized tumor treatment has arrived [35,36], and traditional tumor typing, grading and staging can no longer meet the needs of individualized tumor treatment. Therefore, on this basis, it is undoubtedly the development direction and efficacy monitoring of malignant tumor typing, grading and staging to improve the level of tumor molecular typing diagnosis, provide more accurate molecular biological information for individualized tumor treatment, and guide the formulation of individualized treatment plans. The development direction and goal of malignant tumor typing, grading and staging [37, 38]. In conclusion, tumor typing, grading and staging are important parameters to evaluate the biological behavior and invasive metastatic ability of tumors and the degree of clinical progression, among which tumor typing and grading are intrinsic parameters to reflect the origin of tumors and their biological behavior and invasive metastatic ability, and tumor staging is a detectable index to reflect the invasive metastatic ability and the degree of clinical progression of tumors, which not only depends on the histological type and grading of tumors, but also It not only depends on the histological type and grade of the tumor, but also on the clinical symptoms and time of consultation. 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