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Introduction Thyroid cancer is the most common malignant tumor of the head, neck and endocrine system
.
Globally, the incidence of thyroid cancer continues to rise, becoming one of the fastest-growing malignant tumors
.
1
Data show that China’s thyroid cancer will continue to grow at a rate of 20% per year2, which has attracted widespread attention from the society and the medical community
.
Yimaitong invited Professor Liu Zhiyan, Director of the Department of Pathology, the Sixth People's Hospital of Shanghai Jiaotong University, to share with us the important value and significance of pathological diagnosis and genetic testing in the diagnosis and treatment of thyroid cancer
.
Professor Liu Zhiyan, Ph.
D.
in Japan, visiting scholar at the University of Michigan, Director of the Department of Pathology, Shanghai Jiaotong University Sixth People’s Hospital, and supervisor of master students.
Member of the Head and Neck Section of the Chinese Society of Pathology.
Member of the Thyroid Professional Committee of the Oncology Branch of the Chinese Medical Association Member of the Thyroid Professional Committee of the Chinese Society of Clinical Oncology Standing Member of the Thyroid and Parathyroid Committee of the Chinese and Western Medicine Association Chinese Journal of Pathology Newsletter Member of the International Thyroid Society Member of the International Cell Society The new version of the guidelines emphasizes subtype stratification, focusing on genetic testing.
Whether it is preoperative assessment of thyroid cancer, recurrence risk stratification and clinical diagnosis and treatment, pathological diagnosis is of great value
.
Compared with the "Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Persistent/Relapsed and Metastatic Differentiated Thyroid Cancer (2019 Edition)"3, the CSCO Expert Committee on Thyroid Cancer (hereinafter referred to as the expert group) in the "CSCO Guidelines for the Diagnosis and Treatment of Differentiated Thyroid Cancer" (2021 Edition)” (hereinafter referred to as the “New Guide”) detailed the recommended levels of pathological examinations at different stages, detailed descriptions of the thyroid fine needle aspiration (FNA) cytology Bethesda diagnostic system and its clinical treatment specifications, and emphasized the thyroid The importance of histological types and subtypes of cancer
.
Different subtypes of thyroid cancer have different degrees of aggressiveness, and there are differences in treatment options and prognosis
.
According to the 2017 WHO classification of thyroid tumors, the expert group classified malignant tumors derived from thyroid follicular epithelial cells into differentiated thyroid cancer, poorly differentiated cancer, and undifferentiated cancer.
Among them, differentiated thyroid cancer can be divided into many types, such as thyroid.
The precise classification of papillary carcinoma (PTC), follicular thyroid carcinoma (FTC) and eosinophilic carcinoma provides an important reference for subsequent treatment plan formulation and prognosis evaluation
.
In addition, the "New Guide" emphasizes that genetic testing is an important part of pathological diagnosis and is of indispensable significance
.
Preoperative molecular marker detection of FNA samples can increase the diagnosis rate of thyroid cancer and provide a reference for the formulation of surgical plans
.
After surgery, comprehensive genetic testing helps clinicians assess the patient’s risk of recurrence and guide the formulation of scientific and individualized treatment plans
.
For advanced patients, genetic testing helps to accurately identify the beneficiaries of targeted drugs
.
Exploring the meaning of genes and finding a better solution for thyroid cancer diagnosis and treatment.
The prerequisite for precise treatment is accurate diagnosis.
BRAF, RAS, and RET genes are key genes in the MAPK and PI3K-AKT signaling pathways.
These genes are mutated or rearranged in the thyroid.
It plays an important role in the occurrence and development of cancer.
In addition, mutations in the TERT promoter and mutations in the TP53 gene also play an important role in the progression of thyroid cancer
.
Ultrasound and ultrasound-guided FNA are the preferred methods for distinguishing benign and malignant thyroid nodules, but there are still situations in which this method cannot be differentiated and diagnosed in clinical applications
.
Therefore, in the "Chinese Standards for Diagnosis and Treatment of Thyroid Cancer (2018 Edition)", thyroid cancer molecular marker detection (such as BRAF V600E mutation, RAS mutation, RET/PTC rearrangement, etc.
) is considered to help improve the determination of benign and malignant by FNA.
The diagnosis rate of thyroid nodules
.
In addition to auxiliary diagnosis, genetic testing has important guiding significance in the risk stratification of thyroid cancer recurrence and the formulation of treatment plans
.
Studies have shown that BRAF/RAS and TERT promoter double mutations have a synergistic effect, which is more aggressive than single-gene BRAF or RAS or TERT mutations in thyroid cancer4
.
Not only that, genetic mutations (such as BRAF mutations, etc.
) can affect the efficacy of iodine therapy in patients
.
In addition, in the "New Guide", for advanced, aggressive, and life-threatening thyroid tumors (unresectable recurrent/persistent lesions, soft tissue, bone, and central nervous system metastasis), the expert group recommends the application of genomic testing.
Detection of gene mutations, DNA mismatch repair (dMMR), microsatellite instability (MSI), and tumor mutation burden (TMB) with guiding significance, to identify the advantageous groups that benefit from treatment and optimize treatment plans
.
For example, patients with BRAF mutant anaplastic thyroid cancer can choose dabrafenib combined with trametinib, and patients with ALK fusion mutant thyroid cancer can choose crizotinib
.
Not only that, screening specific gene mutations through genetic testing, such as RET gene mutations, helps to screen for hereditary MTC and guide preventive treatment
.
With the deepening of research, the advancement of genetic testing technology, and the updating of relevant guidelines and consensus, genetic testing has received more and more attention in the management of the entire diagnosis and treatment of thyroid cancer
.
At present, the commonly used detection methods in clinical practice mainly include first-generation sequencing, fluorescent quantitative PCR (RT-PCR) and second-generation sequencing (NGS)
.
The RT-PCR method has the advantages of simple operation, short detection time, and relatively high sensitivity
.
Therefore, this method is often used to detect BRAF V600E gene mutations, RAS gene mutations, and RET gene rearrangements
.
However, the disadvantage of the RT-PCR method is that the method needs to design primer probes based on known mutation types, and it is difficult to cover and detect all possible mutation types
.
The NGS detection technology that has emerged in recent years has high throughput, can detect multiple variants of multiple genes in parallel, has a wide detection range, and has the advantages of discovering unknown gene variants.
However, the method is relatively complicated to operate, such as data analysis and data interpretation.
There are multiple challenges
.
Therefore, Professor Liu Zhiyan suggested that clinicians and pathologists should strengthen communication between departments, and comprehensively consider specific genetic testing methods according to application scenarios and purposes
.
The "fortress" of precision diagnosis and treatment of thyroid cancer-targeting RET gene genetic testing provides a way to understand the meaning of genes, but among the vast array of genes, which genes need to be focused on in the diagnosis and treatment of thyroid cancer? Whether it is a malignant tumor derived from thyroid follicular epithelial cells or a malignant tumor derived from C cells, the RET gene plays an important role and is the "fortress" for the diagnosis and treatment of thyroid cancer
.
In PTC, RET gene rearrangement is one of the most common genetic changes
.
The incidence of RET/PTC rearrangement in sporadic PTC is 15%-20%, especially in ionizing radiation and children’s PTC4
.
Among them, RET/PTC1 rearrangement is the most common, accounting for about 60%-80% of all RET/PTC rearrangements
.
Professor Liu Zhiyan said that RET/PTC rearrangement is one of the very specific markers in the diagnosis of PTC
.
However, it should be noted that RET/PTC rearrangement can also occur in benign lesions, such as Hashimoto's thyroiditis
.
RET/PTC1 rearrangement is related to the typical nuclear characteristics of PTC, while RET/PTC3 rearrangement often occurs in lesions dominated by follicular structure
.
Therefore, the application of genetic testing can effectively assist pathologists in morphological judgments of thyroid cancer cells
.
Unlike PTC, the common gene mutation in MTC is a point mutation in the RET gene
.
About 50% of sporadic MTCs are accompanied by RET gene mutations, especially the mutation at codon 918 is the most common
.
Hereditary MTC accounts for about 20%-25% of MTC, and its genetic basis is a point mutation in the RET gene
.
Professor Liu Zhiyan believes that if you encounter MTC patients during clinical diagnosis and treatment, the germline mutations and somatic mutations of the RET gene should be detected, which will help the patient's accurate diagnosis and genetic screening, and guide the patient's family members for preventive treatment
.
In addition, RET-targeted drug pratinib was approved by the U.
S.
Food and Drug Administration (FDA) for the treatment of thyroid cancer in December 2020, and pratinib was used to treat advanced or metastatic RET gene mutation-positive MTC and RET The indications of gene fusion-positive thyroid cancer have been included in the priority review by the National Food and Drug Administration (NMPA), and it is expected to benefit Chinese patients in the near future
.
Therefore, RET genetic testing will help identify the populations with advantages of pratinib and guide the formulation of precise targeted treatment programs
.
Under the background of precision diagnosis and treatment, the role of pathologists has quietly changed.
Professor Liu Zhiyan said that diagnosis and treatment of thyroid cancer has entered the era of precision medicine
.
Under the multidisciplinary diagnosis and treatment (MDT) model, the role of pathologists is no longer limited to assisting clinicians in diagnosing the disease, but throughout the entire diagnosis and treatment of thyroid cancer, assisting clinicians in formulating precise and personalized diagnosis and treatment plans by providing accurate pathological diagnosis information , To assess the prognostic recurrence risk
.
Approval Number: NPM-CN-TC-007-20210928 Reference Materials 1.
National Comprehensive Cancer Network (NCCN) Guidelines for Thyroid Cancer 2021.
2 Edition 2.
Thyroid Cancer Treatment Standards (2018 Edition) 3.
Chinese Society of Clinical Oncology (CSCO) ) Guidelines for the diagnosis and treatment of persistent/recurrent and metastatic differentiated thyroid cancer (2019 edition) 4.
Luo Dingyuan, Liao Jianwei.
Guangdong expert consensus on gene detection and clinical application of thyroid cancer (2020 edition)[J].
Chinese Journal of General Surgery (Electronic Edition) , 2020, 14(03):161-168.
.
Globally, the incidence of thyroid cancer continues to rise, becoming one of the fastest-growing malignant tumors
.
1
Data show that China’s thyroid cancer will continue to grow at a rate of 20% per year2, which has attracted widespread attention from the society and the medical community
.
Yimaitong invited Professor Liu Zhiyan, Director of the Department of Pathology, the Sixth People's Hospital of Shanghai Jiaotong University, to share with us the important value and significance of pathological diagnosis and genetic testing in the diagnosis and treatment of thyroid cancer
.
Professor Liu Zhiyan, Ph.
D.
in Japan, visiting scholar at the University of Michigan, Director of the Department of Pathology, Shanghai Jiaotong University Sixth People’s Hospital, and supervisor of master students.
Member of the Head and Neck Section of the Chinese Society of Pathology.
Member of the Thyroid Professional Committee of the Oncology Branch of the Chinese Medical Association Member of the Thyroid Professional Committee of the Chinese Society of Clinical Oncology Standing Member of the Thyroid and Parathyroid Committee of the Chinese and Western Medicine Association Chinese Journal of Pathology Newsletter Member of the International Thyroid Society Member of the International Cell Society The new version of the guidelines emphasizes subtype stratification, focusing on genetic testing.
Whether it is preoperative assessment of thyroid cancer, recurrence risk stratification and clinical diagnosis and treatment, pathological diagnosis is of great value
.
Compared with the "Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Persistent/Relapsed and Metastatic Differentiated Thyroid Cancer (2019 Edition)"3, the CSCO Expert Committee on Thyroid Cancer (hereinafter referred to as the expert group) in the "CSCO Guidelines for the Diagnosis and Treatment of Differentiated Thyroid Cancer" (2021 Edition)” (hereinafter referred to as the “New Guide”) detailed the recommended levels of pathological examinations at different stages, detailed descriptions of the thyroid fine needle aspiration (FNA) cytology Bethesda diagnostic system and its clinical treatment specifications, and emphasized the thyroid The importance of histological types and subtypes of cancer
.
Different subtypes of thyroid cancer have different degrees of aggressiveness, and there are differences in treatment options and prognosis
.
According to the 2017 WHO classification of thyroid tumors, the expert group classified malignant tumors derived from thyroid follicular epithelial cells into differentiated thyroid cancer, poorly differentiated cancer, and undifferentiated cancer.
Among them, differentiated thyroid cancer can be divided into many types, such as thyroid.
The precise classification of papillary carcinoma (PTC), follicular thyroid carcinoma (FTC) and eosinophilic carcinoma provides an important reference for subsequent treatment plan formulation and prognosis evaluation
.
In addition, the "New Guide" emphasizes that genetic testing is an important part of pathological diagnosis and is of indispensable significance
.
Preoperative molecular marker detection of FNA samples can increase the diagnosis rate of thyroid cancer and provide a reference for the formulation of surgical plans
.
After surgery, comprehensive genetic testing helps clinicians assess the patient’s risk of recurrence and guide the formulation of scientific and individualized treatment plans
.
For advanced patients, genetic testing helps to accurately identify the beneficiaries of targeted drugs
.
Exploring the meaning of genes and finding a better solution for thyroid cancer diagnosis and treatment.
The prerequisite for precise treatment is accurate diagnosis.
BRAF, RAS, and RET genes are key genes in the MAPK and PI3K-AKT signaling pathways.
These genes are mutated or rearranged in the thyroid.
It plays an important role in the occurrence and development of cancer.
In addition, mutations in the TERT promoter and mutations in the TP53 gene also play an important role in the progression of thyroid cancer
.
Ultrasound and ultrasound-guided FNA are the preferred methods for distinguishing benign and malignant thyroid nodules, but there are still situations in which this method cannot be differentiated and diagnosed in clinical applications
.
Therefore, in the "Chinese Standards for Diagnosis and Treatment of Thyroid Cancer (2018 Edition)", thyroid cancer molecular marker detection (such as BRAF V600E mutation, RAS mutation, RET/PTC rearrangement, etc.
) is considered to help improve the determination of benign and malignant by FNA.
The diagnosis rate of thyroid nodules
.
In addition to auxiliary diagnosis, genetic testing has important guiding significance in the risk stratification of thyroid cancer recurrence and the formulation of treatment plans
.
Studies have shown that BRAF/RAS and TERT promoter double mutations have a synergistic effect, which is more aggressive than single-gene BRAF or RAS or TERT mutations in thyroid cancer4
.
Not only that, genetic mutations (such as BRAF mutations, etc.
) can affect the efficacy of iodine therapy in patients
.
In addition, in the "New Guide", for advanced, aggressive, and life-threatening thyroid tumors (unresectable recurrent/persistent lesions, soft tissue, bone, and central nervous system metastasis), the expert group recommends the application of genomic testing.
Detection of gene mutations, DNA mismatch repair (dMMR), microsatellite instability (MSI), and tumor mutation burden (TMB) with guiding significance, to identify the advantageous groups that benefit from treatment and optimize treatment plans
.
For example, patients with BRAF mutant anaplastic thyroid cancer can choose dabrafenib combined with trametinib, and patients with ALK fusion mutant thyroid cancer can choose crizotinib
.
Not only that, screening specific gene mutations through genetic testing, such as RET gene mutations, helps to screen for hereditary MTC and guide preventive treatment
.
With the deepening of research, the advancement of genetic testing technology, and the updating of relevant guidelines and consensus, genetic testing has received more and more attention in the management of the entire diagnosis and treatment of thyroid cancer
.
At present, the commonly used detection methods in clinical practice mainly include first-generation sequencing, fluorescent quantitative PCR (RT-PCR) and second-generation sequencing (NGS)
.
The RT-PCR method has the advantages of simple operation, short detection time, and relatively high sensitivity
.
Therefore, this method is often used to detect BRAF V600E gene mutations, RAS gene mutations, and RET gene rearrangements
.
However, the disadvantage of the RT-PCR method is that the method needs to design primer probes based on known mutation types, and it is difficult to cover and detect all possible mutation types
.
The NGS detection technology that has emerged in recent years has high throughput, can detect multiple variants of multiple genes in parallel, has a wide detection range, and has the advantages of discovering unknown gene variants.
However, the method is relatively complicated to operate, such as data analysis and data interpretation.
There are multiple challenges
.
Therefore, Professor Liu Zhiyan suggested that clinicians and pathologists should strengthen communication between departments, and comprehensively consider specific genetic testing methods according to application scenarios and purposes
.
The "fortress" of precision diagnosis and treatment of thyroid cancer-targeting RET gene genetic testing provides a way to understand the meaning of genes, but among the vast array of genes, which genes need to be focused on in the diagnosis and treatment of thyroid cancer? Whether it is a malignant tumor derived from thyroid follicular epithelial cells or a malignant tumor derived from C cells, the RET gene plays an important role and is the "fortress" for the diagnosis and treatment of thyroid cancer
.
In PTC, RET gene rearrangement is one of the most common genetic changes
.
The incidence of RET/PTC rearrangement in sporadic PTC is 15%-20%, especially in ionizing radiation and children’s PTC4
.
Among them, RET/PTC1 rearrangement is the most common, accounting for about 60%-80% of all RET/PTC rearrangements
.
Professor Liu Zhiyan said that RET/PTC rearrangement is one of the very specific markers in the diagnosis of PTC
.
However, it should be noted that RET/PTC rearrangement can also occur in benign lesions, such as Hashimoto's thyroiditis
.
RET/PTC1 rearrangement is related to the typical nuclear characteristics of PTC, while RET/PTC3 rearrangement often occurs in lesions dominated by follicular structure
.
Therefore, the application of genetic testing can effectively assist pathologists in morphological judgments of thyroid cancer cells
.
Unlike PTC, the common gene mutation in MTC is a point mutation in the RET gene
.
About 50% of sporadic MTCs are accompanied by RET gene mutations, especially the mutation at codon 918 is the most common
.
Hereditary MTC accounts for about 20%-25% of MTC, and its genetic basis is a point mutation in the RET gene
.
Professor Liu Zhiyan believes that if you encounter MTC patients during clinical diagnosis and treatment, the germline mutations and somatic mutations of the RET gene should be detected, which will help the patient's accurate diagnosis and genetic screening, and guide the patient's family members for preventive treatment
.
In addition, RET-targeted drug pratinib was approved by the U.
S.
Food and Drug Administration (FDA) for the treatment of thyroid cancer in December 2020, and pratinib was used to treat advanced or metastatic RET gene mutation-positive MTC and RET The indications of gene fusion-positive thyroid cancer have been included in the priority review by the National Food and Drug Administration (NMPA), and it is expected to benefit Chinese patients in the near future
.
Therefore, RET genetic testing will help identify the populations with advantages of pratinib and guide the formulation of precise targeted treatment programs
.
Under the background of precision diagnosis and treatment, the role of pathologists has quietly changed.
Professor Liu Zhiyan said that diagnosis and treatment of thyroid cancer has entered the era of precision medicine
.
Under the multidisciplinary diagnosis and treatment (MDT) model, the role of pathologists is no longer limited to assisting clinicians in diagnosing the disease, but throughout the entire diagnosis and treatment of thyroid cancer, assisting clinicians in formulating precise and personalized diagnosis and treatment plans by providing accurate pathological diagnosis information , To assess the prognostic recurrence risk
.
Approval Number: NPM-CN-TC-007-20210928 Reference Materials 1.
National Comprehensive Cancer Network (NCCN) Guidelines for Thyroid Cancer 2021.
2 Edition 2.
Thyroid Cancer Treatment Standards (2018 Edition) 3.
Chinese Society of Clinical Oncology (CSCO) ) Guidelines for the diagnosis and treatment of persistent/recurrent and metastatic differentiated thyroid cancer (2019 edition) 4.
Luo Dingyuan, Liao Jianwei.
Guangdong expert consensus on gene detection and clinical application of thyroid cancer (2020 edition)[J].
Chinese Journal of General Surgery (Electronic Edition) , 2020, 14(03):161-168.
