Due to the influence of many factors, the global incidence of malignant tumors has shown a sustained elevation, 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 rising globally [1], and in developing countries, such as our country, this trend will be more pronounced, and there is a significant trend of rejuvenation. 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. Tumor classification, grading and staging are the three most important indicators for evaluating the biological behavior and diagnosis of tumors, of which grading and staging are mainly used for the assessment of the biological behavior and prognosis of malignant tumors. In recent decades, thanks to the breakthrough progress in life science and medical technology, the detection of targets related to individualized tumor therapy and the clinical application of individualized therapeutic agents, including targeted therapy, have not only improved the detection rate of early tumors to a large extent, but also significantly improved the prognosis of many tumors. The clinical value and significance of traditional tumor typing, grading and staging have also changed to different degrees. In this paper, we would like 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 treatment of tumors, and to guide the formulation of individualized treatment plans and monitoring of therapeutic efficacy. He Renliang, Department of Dermatology, Guangdong Provincial Dermatology Hospital, Guangdong Province, China I. Pathological Classification of Malignant Tumors (Staging) Although, the debate on the stem cell theory and dedifferentiation theory on the origin of tumors is still going on, the fact that tumors can occur in all organs and 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., keratinized squamous carcinomas show a disproportionate degree of keratinization, adenocarcinomas have a secretory function, melanomas are capable of synthesizing melanin, and synovial sarcomas have bi-directional differentiation characteristics, etc. Therefore, the pathological typing of tumors is an important parameter that best reflects the biological behavior and morphological characteristics of the tissue cells from which the tumor originates. Tumors of different tissue types have different biological behaviors and invasive and metastatic abilities. For example, mucinous carcinomas from the digestive tract are more prone to lymph node metastasis and have a poorer prognosis than tubular adenocarcinomas, whereas mucinous carcinomas of the breast have a good prognosis. In terms of tumor cell differentiation, low-differentiated tumors have stronger invasive and metastatic ability and higher degree of malignancy than high-differentiated tumors. Currently, the WHO tumor typing standard is the accepted tumor typing scheme, and the typing of malignant tumors is usually carried out according to the principle of predominant component typing, i.e., typing and diagnosis are based on the main histological type of the tumor (>50% of the tissue structure). However, heterogeneity is one of the important histological features of malignant tumors, and many malignant tumors (e.g., colorectal and gastric cancers, etc.) have varying degrees of multidirectional differentiation or coexistence of different histological types, and the heterogeneity of tumors also determines the complex clinical biological behaviors and prognosis of malignant tumors. Obviously, the WHO tumor typing method in accordance with the principle of dominant component typing will undoubtedly ignore the highly heterogeneous histological characteristics of malignant tumors to a certain extent, and conceal the influence of secondary histological types on the biological behavior and prognosis of tumors; at the same time, histological diagnosis of malignant tumors is susceptible to the influence of microscopic morphology of the many different malignant tumors as well as the subjective judgment of the pathologist, and there is a certain degree of inconsistency in the typing process. At the same time, the histologic diagnosis of malignant tumors is susceptible to different microscopic morphologic manifestations and subjective judgment of pathologists, which inevitably leads to a certain degree of inconsistency in staging. In addition, even tumors with the same typing, grading and staging show completely different therapeutic responses and prognoses due to differences in their molecular phenotypes. It can be seen that the malignant tumor typing scheme according to the principle of dominance has certain limitations in reflecting the histological characteristics, biological behavior and prognosis of tumors, and cannot meet the requirements for tumor diagnostic refinement in the individualized treatment of tumors. Therefore, on the basis of traditional tumor pathology typing, it is urgent to vigorously promote the molecular typing diagnosis of tumors with tumor molecular phenotype detection as the core [2-8]. Secondly, tumor grading differentiation (celldifferentiation) refers to the process of gradual development from naïve cells at the time of embryo to mature normal cells. Tumor cell differentiation is the process of gradual evolution of tumor cells to maturity. 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 and the normal tissue cells from which they originate in terms of tissue structure and cellular morphology. The magnitude of this tumor tissue heterogeneity can be expressed by the grading (G) of the tumor. Currently, a concise three-level scheme is most commonly used: grade I (G1), i.e., well-differentiated (called “hyperdifferentiated”), with tumor cells close to the corresponding normal tissue of origin and with a low degree of malignancy; grade III (G3), with less differentiated cells (called “hypofractionated”), with tumor cells close to the corresponding normal tissue of origin; and grade III (G3), with tumor cells with a lower degree of differentiation (called “hypofractionated”). Grade III (G3), less differentiated cells (called “hypo-differentiated”), tumor cells are differentiated from the corresponding normal tissue of origin, poorly differentiated, and highly malignant; Grade II (G2), with tissue isoforms between grades I and III, has an intermediate degree of malignancy. The concise three-level grading scheme has been mostly used to grade the heterogeneity of differentiated malignant tumors, such as adenocarcinoma and squamous carcinoma. In addition, there are scholars who 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 determined based on the size of the tumor tissue structure and cellular heterogeneity, the number of nuclear schizophrenic images or proliferation indices, the extent of necrosis, the invasive status, and other [9-12] parameters in the HE-stained sections under the microscope. And the histological origin (typing) of the tumor is determined by the best differentiated area, while the grade of the tumor is determined by the worst differentiated area. It can be seen that the grading of malignant tumors reflects the internal characteristics of the tumor, which is of 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 not completely consistent [13]. However, due to the complexity and heterogeneity of tumor tissue structure, different types of tumors (e.g., adenocarcinomas, squamous carcinomas, renal cell carcinomas, breast carcinomas, etc.) have different structural characteristics and grading criteria, and lack of quantitative indicators, in addition to the impact of the degree of adequacy of sampling and the subjective differences in the diagnostic criteria and heterogeneity of the interpretation of the different types of tumors, which all differently affects the objectivity, accuracy, and reproducibility of the tumor grading. Reproducibility. Therefore, streamlining grading parameters, reducing grading levels, simplifying grading criteria, and enhancing quantifiable parameters and clinical operability and repeatability are the inevitable trends in tumor grading. Over the past decades, remarkable progress has been made here thanks to the excellent contributions of experts and scholars in different fields. For example, the grading concept of simplifying 3 grades into two higher and lower grades in the grading of intraepithelial neoplasia has undoubtedly provided a worthwhile and successful experience in the histological grading of tumors. And the detection of nuclear division and proliferation index (e.g., Ki-67) [14] provides reliable quantifiable parameters for the diagnosis and grading of malignant tumors, among which Ki67, as a quantifiable parameter for evaluating the proliferative activity of tumor cells, has become increasingly accepted and widely used for its value 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 reasonable quantifiable grading scheme for 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 for gastric and colorectal cancers and their degree of differentiation, biological behavior, and invasive and metastatic ability [17,18]. Tumor classification by immunological scoring also provides a new method for quantitative typing and grading [19]. Tumor staging is based on the size of the primary tumor, the depth and extent of infiltration, and whether it involves adjacent organs, with or without local and distant lymph node metastasis, with or without hematogenous or other distant metastases, etc. Its essence is to reflect the degree of invasive metastasis of the tumor, and it is an important indicator for evaluating the scope of invasive metastasis of malignant tumors, the degree of progression of the course of the disease, the regression and prognosis. It is an important indicator for evaluating the extent of invasion and metastasis of malignant tumors, regression and prognosis. Accurate tumor staging is not only a reliable indicator for accurately predicting the biological behavior and prognosis of malignant tumors, but also provides clinicians with an accurate basis for patient stratification and management, as well as a basic prerequisite for selecting adjuvant therapeutic options and improving therapeutic effects. Among the many tumor staging programs Dukes staging in 1929, the TNM staging system (TNMstagingsystem) proposed by TheInternationalAmericanJointCommitteeonCancer(AJCC) is now widely accepted and recognized to reflect the progression of malignant tumors and determine the prognosis of malignant tumors. In 2010, the seventh edition of TNMstaging (AJCC-7) [20] was also published. And the visual and microscopic interpretation of the size and infiltration range of the primary tumor (T), local lymph node (N) involvement and tumor metastasis in distant organs and tissues (M) are the three direct evaluable parameters for performing tumor TNM staging. 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, for colorectal cancer, at least 10-14 lymph nodes are recommended for reliable lymph node staging. Although, the T, N, and M interpretation thresholds in TNM staging vary for different tumors, but, 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 types (or immunophenotypes) and degree of differentiation, which means that the histological types (or immunophenotypes) and degree of differentiation of tumors are the determining factors that really affect the TNM staging. Therefore, in-depth exploration of the histological typing (or immunophenotyping) and grading of malignant tumors and comprehensive detection of the extent of tumor invasion and metastasis are the fundamentals of accurate TNM staging. Unlike tumor histological typing and grading, which are intrinsic parameters of tumor characteristics, tumor staging is an external parameter that describes the characteristics of the tumor, which not only depends on the histological type and grading of the tumor, but is also obviously affected by subjective and social factors, such as the early or late emergence of clinical symptoms triggered by tumors, the clinical tolerance of patients, the economic status of the patients, the level of medical insurance and the time of patients’ visits to the clinic. It can be seen that the consultation time of patients also determines the TNM stage of the tumor to a considerable extent. The relationship between tumor typing, grading and staging has been considered that TNM staging is an independent indicator to reflect the progression of malignant tumors and determine the prognosis, and it is also the main basis for deciding the scope of surgical resection, surgical modalities, and reasonable adjuvant treatment options, while the clinical value of the tumor’s histological type and grading is not clear [13,25]. However, this is not the case in reality, and the influence of histological type and grading of malignant tumors on their invasive and metastatic ability and tumor prognosis is being gradually recognized: as mentioned earlier, tumor typing and grading are intrinsic and essential features of tumors: tumor typing relies on the morphologic similarity between tumor tissue cells and normal tissue cells, and tumor grading relies on the degree of differentiation of the tissue from which the tumor originates, which both reflect the degree of differentiation and structure of the tissue cells from which the tumor originates. The grading of tumor depends on the degree of differentiation of the tissue from which the tumor originates, both of which are important parameters reflecting the degree of differentiation, structural characteristics and biological behavior of the tissue cells from which the tumor originates. Tumor staging is based on the size and infiltration range of the primary tumor, local lymph nodes and distant organs, and the range of tissue involvement, and is a clinically observable parameter reflecting the invasive and metastatic ability of the tumor. The TNM staging of a tumor depends not only on the specific tumor histological type (or molecular phenotype) and the degree of differentiation, but is also significantly influenced by the time of the patient’s visit to the clinic. In short, tumor typing describes the origin of the tumor, tumor grading describes the degree of differentiation of the tumor, and tumor typing and grading determine the biological behavior and invasive and metastatic ability of different types of tumors, which in turn determines the tumor’s TNM stage, which reflects the degree of progression of malignant tumors and predicts the time at which the patient reaches 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 the development of clinical treatment plans. However, with the development of molecular biology technology, gene sequencing, fluorescence in situ hybridization, immunohistochemistry, Real-time PCR and other technologies are widely used and the advent of post-genomicera, the understanding of tumors has been deepened to the molecular level. Genetic mechanisms such as gene mutation, deletion or overexpression as well as chromosomalinstahility (CIN), microsatellite instability (MSI), and CpG island methylation (CpGIslandMethylation) have been recognized. TheCpGIslandMethylatorphenotype (CIMP), protein phosphorylation and other epigenetic mechanisms have been elucidated [25-33], a series of molecular targets related to personalized treatment of tumors have been discovered successively, and a large number of tumor-targeted therapeutic drugs have been marketed one after another, which not only provide new indicators for prognosis prediction of malignant tumors and guidance of treatment, but also provide a certain degree of guidance for the treatment of malignant tumors. To a certain extent, they provide new solutions for the treatment of malignant tumors [34], and also change the clinical significance of traditional tumor pathology typing, grading, and staging and the prognosis of patients at different levels. For example, highly malignant poorly differentiated or undifferentiated colorectal cancers show a favorable 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 genes such as KRAS and BRAF also have a significantly improved prognosis compared with the previous one due to the use of targeted therapeutic agents and neoadjuvant treatment regimens.The detection of the Her-2 gene and the use of hesperidin have completely changed the prognosis of Her-2 positive breast cancer patients’ prognosis. It can be seen that the era of individualized treatment of tumors has come [35,36], and traditional tumor typing, grading and staging can no longer meet the needs of individualized treatment of tumors, therefore, on the basis of this, to improve the diagnostic level of molecular typing of tumors, to provide more accurate molecular biological information for individualized treatment of tumors, to guide the development of individualized treatment plans and monitoring of the effectiveness of the treatment will undoubtedly be the development direction of the typing of malignant tumors, The development direction and goal of malignant tumor typing, grading and staging will undoubtedly be the development direction and goal of malignant tumor typing, grading and staging [37, 38]. In conclusion, tumor typing, grading and staging are important parameters for evaluating the biological behavior and invasive metastatic ability of tumors and the degree of clinical progression, in which tumor typing and grading are intrinsic parameters that respond to the source of the tumor and its biological behavior and invasive and metastatic ability, and tumor staging is a detectable indicator that reflects the invasive and metastatic ability of the tumor and the degree of clinical progression, which not only depends on the histological type and grading of tumors, but is also It is not only dependent on the histologic type and grading of the tumor, but also obviously limited by the clinical symptoms and consultation time of the patients. 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