Thyroid cancer

Introduction to thyroid cancer Thyroid cancer (thyroidcarcinoma) is the most common thyroid malignancy. It is a malignant tumor derived from thyroid epithelial cells. Most of the thyroid cancer originates from follicular epithelial cells. According to the pathological type, it can be divided into papillary carcinoma (60%). Follicular adenocarcinoma (20%), but the prognosis is good, follicular adenocarcinoma tumors grow faster, moderately malignant, easy to pass blood transport, undifferentiated cancer has a poor prognosis, the average survival time is 3 to 6 months . Papillary carcinoma is more common in thyroid cancer. basic knowledge The proportion of sickness: 0.01% Susceptible people: no specific population Mode of infection: non-infectious Complications: respiratory failure

Causes of thyroid cancer

Radioactive damage (19%):

Irradiation of the thyroid gland of the experimental mouse with X-rays can promote thyroid cancer in the animal. Experiments have shown that 131I can change the metabolism of thyroid cells, the nuclear deformation, and the synthesis of thyroxine is greatly reduced. Visible radiation on the one hand causes abnormal division of thyroid cells, leading to cancer; on the other hand, the thyroid gland is destroyed and no endocrine can be produced, and the resulting secretion of thyroid stimulating hormone (TSH) can also promote thyroid cell carcinogenesis. Clinically, many facts indicate that the occurrence of thyroid is related to the role of radiation. It is particularly noteworthy that thyroid cancer is particularly prevalent in children undergoing upper mediastinal or cervical radiation therapy due to thymic enlargement or lymphoid adenoid proliferation during infancy, because children and adolescents have proliferated cells and radiation. It is an additional stimulus that tends to trigger the formation of its tumor. The chances of developing thyroid cancer after receiving cervical radiation therapy in adults are rare.

Iodine deficiency (25%):

Excessive iodine or iodine deficiency in iodine and TSH can alter the structure and function of the thyroid gland. For example, the prevalence of thyroid cancer in the endemic goiter in Switzerland is 2% higher than that of non-prevalence such as Berlin. Conversely, high-iodine diets are also susceptible to thyroid cancer. Iceland and Japan are the countries with the highest levels of iodine, and the rate of thyroid cancer is higher than in other countries. This may be related to factors that stimulate TSH to stimulate thyroid hyperplasia. Experiments have shown that long-term TSH stimulation can promote thyroid hyperplasia, formation of nodules and cancer.

Other thyroid lesions (20%):

Clinically, there are reports of thyroid adenocarcinoma, chronic thyroiditis, nodular goiter or some toxic goiters, but the relationship between these thyroid diseases and thyroid cancer is still difficult to confirm. Taking thyroid adenoma as an example, the vast majority of thyroid adenomas are follicular, only 2 to 5% are papilloma; if thyroid cancer is transformed from adenoma, most of them should be follicular, but the actual More than half of the upper thyroid cancer is head-shaped cancer, and the incidence of thyroid adenoma cancer is also small.

Genetic factors (10%):

About 5-10% of medullary thyroid carcinoma has a clear family history, and often combined with pheochromocytoma and other sputum, it is speculated that the occurrence of such cancer may be related to chromosomal genetic factors.

Family factors and thyroid cancer

Thyroid cancer is less common as an independent familial syndrome, but it can be used as part of familial syndrome or hereditary disease. A small number of families have a tendency to have multifocal well-differentiated thyroid cancer, thyroid cancer and familial colon polyposis ( Such as Gardner syndrome), including colon adenomatous polyps with soft tissue, with fibromatosis most, combined with fibrosarcoma, is an autosomal dominant genetic disease, caused by mutations in the APC gene located on chromosome 5q21 ~ q22, the latter is A signal protein involved in the regulation of cell proliferation, under the stimulation of TSH, a few people can develop cancer, thyroid cancer.

Pathogenesis

Molecular biology

Advances in molecular biology have shown that the transformation of human normal cells into malignant tumor cells has accumulated a variety of molecular biological changes, including initiation, resulting in cell growth independent of normal growth regulation, or normal regulation of cells. Reaction, eventually malignant transformation of cells, thyroid cancer has a variety of oncogenes and tumor suppressor gene abnormalities, gene amplification and other pathways activate, so that normal cells are transformed into growth-controlled malignant cells, must have the participation of other genes, cells Malignant transformation usually has several expressions of these genes, or gene mutations and amplification occur simultaneously. This section discusses molecular biological changes in thyroid cancer.

(1) trk, trk, trk) is located in the q31 region of chromosome 1, encoding a cell surface receptor of a nerve growth factor belonging to a receptor tyrosine kinase, such as a Trk-T1 oncogene conjugated with TPP to activate The expression of the trk oncogene can be found in papillary thyroid carcinoma.

The met(7q31) gene has 120 kb, including 21 exons separated by 20 introns, a transmembrane receptor tyrosine kinase, metephropathy in various cancerous tissues, but thyroid follicular The expression in cancer is only 25%.

The original recognition of the ret proto-oncogene is due to its ability to efficiently transform cultured NIH3T3 fibroblasts. It is a dominant transforming oncogene that plays a role in the development of medullary thyroid carcinoma and papillary thyroid carcinoma, including 20 The phenotype, about 30 kb in length, encodes a transmembrane tyrosine kinase receptor, and is expressed by the extracellular ligand binding region, the neural crest cells, and the genitourinary system. The system, which regulates neural crest cell proliferation, MEN) type 2, is activated by gene rearrangement in papillary thyroid carcinoma.

In 1987, Fusco found that 25% of thyroid papillary carcinomas and their metastatic lymph nodes have conversion sequences in DNA transfection experiments, which are considered to be new oncogenes and named PTC (representing thyroid papillary carcinoma), resulting in coding The ret gene of the tyrosine kinase is produced by juxtaposition with the 5' end sequence of one of the various unrelated genes, so it is called ret/PTC oncogene. According to the difference of the collocated sequence, at least 7 ret/ have been identified. PTC oncogenes, such as ret proto-oncogenes, D10S170 (H4) gene rearrangement (ret/PTC1) on the same chromosome, ret proto-oncogene and RI gene rearrangement on chromosome 17 (ret/PTC2), ret primary cancer The rearrangement of the gene and the RFG/ELE1 gene located in the same chromosomal region (ret/PTC3) is the most common mode of activation. It was found that the ELE1 gene and the ret proto-oncogene tyrosine kinase coding region are linked to the 5' end of other genes. The encoded protein exhibits phosphorylation activity and is activated by the formation of a dimer with its physiological ligand GDNF.

Ret/PTC gene-encoded dimeric protein-mediated ret kinase activation, ret/PTC oncogene also has a transforming effect on cultured thyroid cells, indicating that ret gene mutation is associated with tumorigenesis initiation, ret/PTC oncogene The expression is almost exclusively in papillary thyroid carcinoma, the incidence rate is 5% to 44%, and the ret/PTC positive expression rate of thyroid papillary carcinoma in children associated with the Chernobyl nuclear accident is as high as 67% to 87%, and Most of them are RET/PTC3, and the difference in incidence may reflect the geographical area.

There is no significant difference in the pathological features of thyroid papillary carcinoma or trk oncogene expressing ret/PTC oncogene. It is possible that trk functions similarly to ret/PTC, but not in ret/PTC and TRK. In typical papillary thyroid carcinoma, it may be that other receptor tyrosine kinases or their downstream signaling molecules cause corresponding nuclear changes, and patients with multiple mucosal neuroma have almost the 918th retinoin gene. Sub-mutation, in the sporadic MTC, the incidence of codon mutation at position 918 of the ret proto-oncogene can reach 33% to 67%, but not in the DNA of normal cells, which may occur just in the receptor tyrosine. The catalytically active site of the acid kinase, mutation at codon 918 of the ret proto-oncogene may indicate a poor prognosis.

(2) ras gene: The name of the ras gene is derived from the prefix of rat sarcoma, which was isolated from the retrovirus of rat sarcoma in 1964 and located in Kirstern of the short arm of chromosome 12 (12p). K)-ras and neuroblastoma(N)-ras located on the short arm of chromosome 1 (1p1), which are composed of 4 exons and 5 introns respectively. The encoded proteins are 21kD protein p21ras. It consists of 188-189 amino acid residues, is immobilized on the inner side of the cell membrane, has GTPase (GTPase) activity, and is a member of the large family of G proteins. Although it is a small molecule, it is different from the G protein with a trimer structure. It has the function of regulating cell growth and differentiation, is an intracellular signal transduction, and transmits growth signals to cells. When p21ras binds to GTP, it is activated. After GTP hydrolysis, p21ras binds to GDP in an inactive state.

The ras oncogene passes through the 12th, changes the GTP binding or GTPase activity of the p21 protein, and isolates the H-ras oncogene with dominant activation. The 12th codon of H-ras changes from normal -GGC-(glycine) -GTC-(valine), the mutant H-ras is exactly the same as the oncogene VH-ras in Harveg sarcoma virus. This amino acid change affects the spatial conformation of p21ras, which reduces the GTPase activity by 1000-fold, while the p21ras protein is at The activation state combined with GTP causes cell malignant transformation, so the normal product becomes a carcinogenic product, and ras oncogene mutation is found in various human malignant tumors.

The role of ras protein in the signal transduction process of normal thyroid follicular cell proliferation is still unclear. Whether it is a benign thyroid adenoma or a malignant differentiated or undifferentiated carcinoma, there is a point mutation in the ras oncogene, indicating that The ras oncogene mutation occurs in the early stage of thyroid follicular cell tumor formation. The mutant ras interacts with other oncogenes to transform normal adult thyroid follicular cells, stop differentiation, proliferate, reduce iodine, and express thyroid gland. Oxidase, even in the tissue culture medium, forms a cell clone similar to thyroid tumor. The mutation of ras gene is associated with thyroid follicular carcinoma. The mutation rate of ras gene detected in radiation-related thyroid tumor can reach 60%.

(3) myc gene: members of the myc gene family include c-myc, a nuclear transcription factor protooncogene, a protein encoding 439 amino acid residues, the product of which is a protein of 456 amino acid residues, and the encoded product is 364 amino acids. The protein of the residue is a nuclear transcriptional regulator. The myc protein can be structurally divided into a transcriptional activation region, a non-specific DNA binding region, a nuclear target sequence, an alkaline region, a helix-loop-helix and a leucine zipper region, and a base. The sex region follows the spiral-loop-helix and can be combined with special chromosomal DNA sequences to regulate the transcription process, regulate cell growth, and have the chromosomal gene translocation of myc gene in the body tumor, which is regulated by various substances. The regulatable gene is also a gene that allows cells to proliferate indefinitely and promote cell division. The c-myc gene is also involved in apoptosis.

High levels of c-myc mRNA can be found in differentiated thyroid cancer and thyroid undifferentiated carcinoma, which is 3 to 11 times higher than normal thyroid tissue, and c-myc specific antisense oligodeoxynucleotide blocks c- Myc protein synthesis can also significantly reduce the growth rate of adenocarcinoma cells.

(4) TSH receptor and gsp gene: highly differentiated thyroid follicular cells have polyiodine, TSH-thyroid follicular cell membrane TSH receptor-G protein-cAMP, which produces a cascade-like cascade of regulation, and G protein has at least There are 20 subtypes, and the subunit Gi protein of the inhibitory G protein reduces cAMP.

TSH receptor gene mutation or gsp gene mutation has been found in benign and malignant thyroid tumors. TSH receptor gene mutation or gsp gene mutation is closely related to thyroid hyperfunction adenoma, resulting in TSH-like effect in thyroid follicular cells. , Gs gene codon 201 mutation, CGT (arginine) TGT (cysteine), decreased endogenous GTPase activity, adenylate cyclase activity, equivalent to TSH chronic stimulation, mutant TSH The receptor gene or gsp gene itself does not cause tumors. The pathological stimulation caused by the mutation may inhibit the regulation of normal cell proliferation, but it needs to cooperate with other gene mutations, especially the differentiated thyroid carcinoma with higher basal adenylate cyclase activity. For example, the role of mutant TSH receptor and gsp gene in the development of thyroid carcinoma remains to be further explored in thyroid cancer with hyperthyroidism.

(5) RB gene: RB gene belongs to tumor suppressor gene and is a susceptibility gene of retinoblastoma. It is located in the 13q14 region of chromosome 13 and has 27 exons and 26 introns. The DNA is about 200kb long. The gene-encoded phosphorylated protein product Rb protein, with a molecular weight of about 110kD, regulates the cell cycle, inhibits excessive cell proliferation, and the Rb protein is non-phosphorylated. Once the cell enters proliferation (G2, S, M phase), the Rb protein is mainly Phosphorylated form exists, inhibits cell proliferation, is involved in Cyclin D1 (CD1), and the main variant of RB gene abnormality is deletion. Mutated RB protein loses the function of binding to homonuclear ligands, cell differentiation The response of the signal is blocked, resulting in unrestricted cell growth and tumor formation in the body.

In thyroid papillary carcinoma and thyroid follicular carcinoma, the incidence of abnormalities such as RB gene deletion or mutation can reach 54%, while the incidence of RB gene deletion or mutation in thyroid undifferentiated cancer can reach 60%. 4 to 5 times.

(6) p53 gene: p53 gene is one of the most important tumor suppressor genes. The incidence of p53 point mutation in thyroid undifferentiated carcinoma is high. It is thought that p53 protein which causes tumor formation or cell transformation is a product of p53 gene mutation. It is a tumor-promoting factor that eliminates the function of normal wild-type p53. Mutant p53 protein plays an important role in tumor formation. It is about 20 kb in length and consists of 11 exons and 10 introns and is transcribed into 2.5 kb mRNA. The encoded product is composed of 393 amino acid residues, a nuclear phosphoprotein p53 with a molecular weight of 53 kD, and a basic region of amino acid residues 319 to 393 at the C-terminus. The normal p53 protein is easily hydrolyzed in cells, and the half-life is 20 min. The mutant p53 protein has a half-life of 1.4 to 7 hours. The biological function is a checkpoint for DNA damage in the G1 phase. It is involved in the regulation of cell growth, monitoring and maintaining the integrity of the genome of the cell. If the DNA is destroyed, the p53 protein accumulates and makes the cell The cycle is paused in the late G1, but not in the S phase, thus avoiding the replication of damaged DNA, and there is enough time for the damaged DNA to be repaired, then p53 can pass the programmed cell death or Apoptosis triggers cell suicide, removes damaged cells, prevents the production of cells with cancerous mutations, and when DNA is exposed to external environmental carcinogens, DNA damage cannot be repaired, genetic instability, mutation accumulation, rearrangement Accelerate and promote the transformation of cells into cancer cells, with 175 different types of tumors with different types of mutations.

In thyroid cancer, the major altered form of p53 gene is a little mutated, the incidence of p53 gene abnormalities can reach 25%, and the incidence of p53 gene alteration in thyroid undifferentiated cancer can be as high as 86%.

(7) p16 gene: p16 gene, also known as multiple tumor suppressor 1 (MTS1), located on chromosome 9 9p21, consisting of two introns and three exons, encoding a protein with a molecular weight of 16kD (p16), located in the nucleus, is one of the key enzymes acting on the cell division cycle, directly involved in the regulation of the cell cycle, negatively regulates cell proliferation and division, inhibits cell growth and division, and prevents cancer from occurring. Inhibiting the catalytic activity of CDK4, thereby inhibiting cells from G1 into S phase, inhibiting cell growth and division, and causing loss of function such as mutation, can not inhibit CDK4, and finally cause cells to enter malignant proliferation and accelerate tumorigenesis.

Studies have found that the presence of p16 gene deletion in thyroid cancer cell lines, the expression of p16 protein in thyroid cancer tissue is significantly lower than that of thyroid tumor, and the expression of p16 protein decreases with the increase of malignant degree of thyroid cancer, suggesting that p16 protein can be used as clinical Determining the prognosis of thyroid cancer, the deletion of p16 gene in thyroid cancer is not a frequent event.

(8) nm23 gene: tumor infiltration, including tumor cells detached from the primary tumor, into the extracellular matrix, tumor metastasis is related to the transfer gene activation or metastasis suppressor gene inactivation, is a combination of a variety of metastasis-related genes and metastasis-inhibiting genes As a result of the action, the expression of the nm23 gene was decreased in the highly metastatic tumor, and the expression intensity in the low metastatic cell line was 10-fold higher than that in the high metastatic cell line, indicating that the product encoded by nm23 has a function of inhibiting tumor metastasis.

There are two nm23 genes in the human genome, namely nm23-H1, and nm23-H2, all of which are located at 17q21.3, encoding a 17kD protein consisting of 152 amino acids, nm23 protein and nucleoside diphosphate kinase (NDDK). The amino acid sequence is highly homologous, the homology of nm23-H1 is 89%, and the homology of nm23-H2 is 97%. NDPK is widely present, which transfers the phosphate group of 5' NTP to 5'NDP. Protein activation, which is involved in the polymerization of functional microtubules and G-protein-mediated signaling, on the one hand may cause abnormal microtubule polymerization and cause spindle abnormalities during meiosis, resulting in the formation of chromosome aneuploidy in cancer cells, Promote the development of tumors, on the other hand, may affect the cytoskeleton and cause cell movement, thus participating in the invasion and metastasis process and development process, regulated by two independent regulatory systems, wherein the level of nm23-H1 mRNA is related to cancer cell metastasis More closely, it is currently believed that although nm23 is not necessarily a transcriptional stimulator of myc, it is at least an important regulatory gene of myc, nm23 can induce the expression of myc, and the loss of nm23-H1 contributes to the permanent survival of cells.

Studies have found that the intensity of nm23-H1 immunohistochemical staining is irrelevant to the age of onset of papillary thyroid carcinoma, but the immunological activity of nm23-H1 significantly affects distant metastasis and survival in patients with thyroid follicular carcinoma. Curve, therefore, nm23-H1 can be considered as a prognostic factor for thyroid follicular carcinoma.

(9) Fas/FasL gene: Fas/FasL gene is a superfamily member of apoptosis-related gene, TNF) receptor. TNF is a kind of cytokine mainly produced by activated macrophages, which is cytotoxic. The partial composition: signal peptide, FasL) is a 40kD protein. FasL binds to Fas to initiate death signal, leading to apoptosis, which is a three-dimensional symmetrical structure perpendicular to the cell membrane. The structurally complementary binding of the two leads to the intracellular delivery of Fas. The key to the death signal is the Fas/FasL-mediated apoptosis.

Fas and FasL are expressed in various subtypes of thyroid cancer, and are significantly higher than thyroid adenoma and nodular goiter. Therefore, the expression of Fas and FasL genes may be related to the occurrence and development of thyroid cancer.

(10) bcl-2 gene: bcl-2 gene is opposite to TNF family. Bcl-2 gene can prevent cells from entering apoptosis process. It has been found that many proteins belong to bcl-2 family and can be divided into two types, one class. It is an anti-apoptotic bcl-2 family, mainly Bcl-2, mainly including Bax.

Bcl-2 protein expression may be associated with the occurrence of thyroid tumors. Both benign and malignant tumors of the thyroid have high levels of bcl-2 expression, while normal tissues express less bcl-2, along with the clinical stage of thyroid cancer. The progress of infiltration, the positive rate of bcl-2 was significantly decreased, and the positive rate of bcl-2 in undifferentiated carcinoma was significantly lower than that in differentiated type.

(11) Angiogenesis factor: The growth of tumor is divided into a slow growth phase without blood vessels and a rapid proliferation phase with blood vessels. Angiogenesis is a key link to promote tumor growth. Tumor invasion and metastasis is a complex multi-stage process, and angiogenesis is In the multi-step process of tumor invasion and metastasis, they play an important role, such as primary tumor proliferation, metastatic cancer, and so on.

The process of angiogenesis involves a series of morphological and biochemical changes associated with regulation between angiogenic factors and angiogenesis inhibitors, at least 15 angiogenesis inhibitors, and angiogenic factors including vascular endothelial growth factor (VPF/). VEGF).

Fibroblast growth factor is a mitogen and chemokine that has strong effects on vascular endothelial cells. The level of bFGF in blood of tumor patients can be maintained at a high level, and it is related to the degree of malignancy of thyroid cancer. The expression of bFGF is not thyroid cancer. Events that occur frequently.

(12) MMPs and FAK: During the infiltration and metastasis of tumor cells, the degradation of extracellular matrix (ECM) plays an important role. MMPs) are a group of zinc ion-dependent endopeptidases, of which MMP- 2 The selective degradation of intercellular matrix components and the degradation of the main component of the basement membrane type IV collagen, FAK) is a key enzyme in the process of integrin-mediated signal transduction, can induce the expression of MMPs gene, in normal cells It may promote cell adhesion and inhibit the growth of anchored cells. Overexpression of FAK can cause cells to surpass this growth inhibition and cause cancer cells to lose growth inhibition and proliferate.

The expression of MMP-2 and FAK may be associated with papillary thyroid carcinoma. The positive expression rate and positive intensity of MMP-2 and FAK in papillary thyroid carcinoma are significantly higher than those in adjacent tissues of thyroid cancer.

(13) Sodium/iodine symporter: Sodium iodide symporter (NIS) is a transmembrane glycoprotein, NIS protein consists of 643 amino acids, molecular weight 70-90kDa, later NIS of human thyroid gland It has also been successfully cloned, such as salivary gland, NIS protein promotes the transport of iodine into thyroid cells, NIS protein increases in thyroid tissue of Graves disease, TSH increases thyroid cells expressing NIS protein, 61.6% expresses NIS protein, while undifferentiated carcinoma does not. The expression of NIS protein indicates that NIS expression is inversely proportional to the degree of differentiation of thyroid cancer. It occurs in differentiated thyroid cancer in children and adolescents. When NIS expression is high, the tumor recurrence rate is low. Inducing thyroid cancer tissue to express NIS, radioactive iodine can be used. Radiation Therapy.

(14) Pax8-PPAR1: Pax is a paired-type homeobox, which belongs to the homeobox gene in vertebrates. It has been successfully screened to isolate 9 different mouse Pax genes ( Paxl-9), a homologous box protein that is closely related to the development of the nervous system, acts as a peroxisome proliferator activater receptor gamma 1, PPAR1, a subtype of nuclear transcription factor It has various regulatory effects such as regulation of cytokine production and promotion of epithelial cell growth. The thyroid follicular carcinoma has a chromosomal translocation in which the DNA-binding domain of Pax8 gene and the A to F domain of PPAR1 gene fuse with each other, encoding a fusion oncoprotein. Pax8-PPAR1, the detection of PPAR1 mRNA or PPAR1 protein contributes to the diagnosis of thyroid follicular carcinoma, and can reduce the need to remove benign thyroid tumors to exclude malignant lesions, although the detection rate of PPAR1 protein is in thyroid follicular carcinoma. It is 35% to 63%, but it is also 55% in follicular thyroid tumors. Therefore, the significance of Pax8-PPAR1 in the diagnosis of thyroid follicular carcinoma still needs to be further improved. Confirmed.

(15) Telomerase: There are telomeres at the end of the chromosome of human normal somatic cells. The length of telomeres is repeated with each chromosome, and the telomere is shortened to a certain extent. The cells stop dividing and go to death, which can be changed continuously. Short telomeres act as a repair to complement telomere deletions due to chromosomal replication, maintain telomere integrity, and extend cell life.

In addition to protecting telomeres, telomerase in organisms is also closely related to cancer. The incidence of telomerase and undifferentiated carcinoma is higher than that of thyroid papillary carcinoma. Analysis of telomerase activity to distinguish thyroid nodules Malignant, limited value in the diagnosis of thyroid cancer, and found that the expression of human telomerase reverse transcriptase (hTERT) is related to thyroid cancer, and is positively correlated with the degree of malignancy and infiltration of thyroid cancer. Pre-FNAC detection of hTERT expression is of added value in the diagnosis of thyroid cancer and contributes to the choice of surgical treatment.

In conclusion, early changes in papillary or follicular carcinoma of thyroid follicular epithelial cells may be caused by mutations in the ret or ras gene, and abnormalities in one or more of the mechanisms of cell cycle regulation may play an important role in tumor development. Role, and the occurrence of p53 mutations is closely related to the transformation of differentiated cancer to undifferentiated carcinoma (as shown in Figure 1), ret, and by which way it is a problem to be elucidated.

2. Pathology

According to the histopathological features of thyroid cancer, there are generally four types.

(1) papillary carcinoma: a malignant tumor originating from the thyroid gland, accounting for 50% to 89%. It is the first peak before or after 20 or 30 years old. Bilateral nodules, hard texture, irregular borders, poor mobility, no obvious discomfort, so the average duration of treatment has reached 5 years, even more than 10 years, small diameter can be less than 1cm, hard Sometimes it can not be touched, often due to metastasis to the cervical lymph nodes, even at the time of autopsy, pathological sections can be confirmed as thyroid cancer, often due to long course of disease, cystic changes, resulting in difficulty in swallowing, puncture can extract yellow liquid, easily misdiagnosed as Cysts, late metastasis, easy to invade lymphatic vessels, so early cervical lymph node metastasis, especially in children, mainly in bilateral cervical lymph nodes, swollen lymph nodes can not be discovered for many years, late can also be transferred to the upper mediastinum or sputum Lower lymph nodes, mass puncture and lymph node biopsy help to establish the diagnosis.

Under the microscope, the tumor tissue is mostly composed of papillary nodes, the size of the nipple is more than 3 grades, and the outer layer is monolayer or multi-layered square cancer cells, which are evenly distributed and resemble a ground glass type, which is characterized by this type (Fig. 2).

(2) Follicular carcinoma: refers to thyroid cancer with follicular differentiation and no papillary structure. Its malignancy is higher than that of papillary carcinoma, accounting for about 20% of thyroid cancer, second only to papillary Cancer ranks second, especially in women over 40 years old, mostly solid, can undergo degenerative changes, including hemorrhage, often similar to benign follicular adenoma, and is not easy to distinguish, even in pathological frozen sections, diagnosis There are certain difficulties, diversity changes, tissue similar to normal thyroid, can also be a poorly differentiated change of follicles and gel-like substances, with envelope and vascular invasion (Figure 3), such as eosinophils It can be diagnosed as eosinophilic adenocarcinoma, which is a clear cell carcinoma, which is easy to infiltrate into the periphery. It is moderately malignant. The main metastatic route is the transfer of blood to the lungs and bones.

(3) medullary carcinoma: originated from thyroid C cells (ie, parafficular cells), is a moderate malignant tumor, accounting for 3% to 8% of thyroid malignant tumors, but in the same cancer The cancer cells in the nest have the same shape, no nipple and follicular structure, and their classification is mainly from the European Cancer Research and Treatment Organization (EORTC), the National Thyroid Cancer Treatment Collaborative Research Group (NTCTCS) and thyroid cancer surveillance. %, the average age is about 50 years old, the cancer is often single, mostly confined to one side of the thyroid, the texture is hard, the edge is clear, the length of the disease is long (several months to more than 10 years), the lymph node metastasis, the often metastatic part is Cervical lymph nodes can produce compression symptoms and metastatic masses. They can reappear when recurrence and metastasis. Family members can be screened by CT. People have used ret gene mutation analysis to diagnose the disease and screen high-risk subjects in family members.

Girelli summarized the medical records of 78 cases of medullary thyroid carcinoma from 1969 to 1986 in Italy. The results were: ages 15 to 89 years, mean 45 years old, male to female ratio: 1:2.9, 3 cases were family type non-MEN type, 3 cases were MEN2A type, 2 cases of MEN2B type, 34 cases of death (4 cases died of other diseases unrelated to this disease), 22 cases of survivors survived for 10 to 24 years, the length of survival is mainly related to tumor Staging is closely related to the age at the time of treatment. Early treatment has a good effect, while abnormal patients relapse in different periods after surgery. The higher the blood CT level, the earlier the recurrence, but 30% of patients only have blood CT. Elevated (individually 15 years) without recurrence of lesions.

(4) Undifferentiated carcinoma: clinically including giant cell carcinoma and small cells and other types of malignant thyroid cancer (squamous cell carcinoma), which is the most malignant thyroid tumor, and the disease progresses. Rapid, early local lymph node metastasis, or invasion of the recurrent laryngeal nerve, trachea or esophagus, and often through the blood to the lungs, accounting for about 5% of thyroid cancer, but in a short period of time, the mass rapidly increased, and rapid local infiltration , forming a bilateral diffuse thyroid mass, the mass is large and hard, the boundary is unclear, and it is fixed with the surrounding tissue, accompanied by tenderness, and is also easy to spread to the distant blood.

Thyroid cancer prevention

1. Try to avoid X-rays of head and neck in childhood.

2. Maintaining a happy spirit and preventing emotional internal injuries is an important aspect of preventing the occurrence of this disease.

3. For water and soil factors, pay attention to diet adjustment, and often eat kelp, in fact, it may also be another predisposing factor for certain types of thyroid cancer.

4. Patients with thyroid cancer should eat nutritious food and fresh vegetables to avoid fatty.

5. Avoid the use of estrogen, because it plays a role in the development of thyroid cancer.

6. For thyroid proliferative diseases and benign tumors should go to the hospital for positive.

7. Postoperative thyroid cancer, active use of Chinese and Western medicine prevention and treatment is an effective way to improve the efficacy.

8. Actively exercise and improve disease resistance.

Thyroid cancer complications Complications, respiratory failure

The tumor rapidly enlarges, compresses the trachea, infiltrates the esophagus and recurrent laryngeal nerve and causes difficulty in breathing.

Thyroid cancer symptoms Common symptoms Goiter Thyroid nodules Increased food intake Increased dyspnea Dysphagia Thyroid enlargement Lymph node puncture has grass... Hot nodular carcinoid syndrome dysphagia

The early clinical manifestations of thyroid cancer are not obvious. Patients or family members and doctors accidentally found that the thyroid gland has a hard and uneven mass, and there are many unconscious symptoms. The neck mass is often an asymmetric lumps, and the thyroid nodule mass can be gradually increased. With swallowing up and down activities, and can be invaded by the trachea and fixed, the mass is easy to produce compression symptoms earlier, such as accompanied by hoarseness, poor breathing, difficulty swallowing, or local tenderness and other compression symptoms, when the jugular vein is compressed, can occur Signs of lateral venous engorgement and facial edema are one of the characteristics of thyroid cancer, such as lung metastasis and bone metastasis, and even pathological fractures, while the neck should be carefully examined for thyroid gland.

Papillary thyroid carcinoma

Papillary thyroid carcinoma is generally small, and the development changes slowly, but there may be metastasis in the early stage. The lesions that are often found first may be metastases. The benign masses are more common before the age of 40, and may not progress in 20 to 30 years. Patients over 50 to 60 years of age progress faster.

Papillary thyroid carcinoma is a low-grade malignant tumor, the most common pathological type of thyroid cancer, accounting for 60% to 70% of thyroid cancer in adults and 70% of thyroid cancer in children, especially in children, about 2 /3 cases of papillary thyroid carcinoma are actually mixed tumors, and different proportions of follicular carcinomas can be found in their lesions. The natural course of these patients is similar to papillary carcinoma, and the current classification criteria will Some patients are classified as papillary carcinoma.

(1) Characteristics of the onset: The peak age of onset is 30 to 50 years old, and the female patient is 3 times that of male patients. Among the thyroid cancer caused by external rays, 85% is papillary carcinoma, and the course of coexistence of human and cancer can be long. After several years to a dozen years, even after lung metastasis, you can still carry tumors to survive.

(2) Clinical manifestations: Papillary thyroid carcinoma is a progressively enlarged neck mass. The mass is painless and may be inadvertently discovered by the patient or physician. Therefore, the time of treatment is usually late, and it is easily misdiagnosed as benign lesions. There may be varying degrees of hoarseness, and patients with papillary thyroid carcinoma have no changes in thyroid function, but some patients may develop hyperthyroidism.

In the neck examination, the characteristic manifestation is an asymmetrical mass in the thyroid gland. The texture is hard, the edges are more fuzzy, and the surface of the tumor is uneven. The mass can be swallowed. If the tumor invades the trachea or surrounding tissue, The mass is more fixed.

(3) Metastatic characteristics: When lymph node metastasis occurs in papillary thyroid carcinoma, it is mostly confined to the thyroid region. On the clavicle, a few cases may have axillary lymph node metastasis. In some cases, sentinel lymph node enlargement above the thyroid isthmus may occur. Regional lymph node metastasis occurred in % of patients.

A small number of cases are metastasized through the blood line, mainly for pulmonary metastasis. Several tumor nodules can be formed in the lungs or the whole lungs can be snowflake-shaped. The patient can maintain relatively normal lung function for 10 to 30 years and become a thyroid gland. The only source of thyroxine in the body after resection, resulting in obstructive and restrictive lung disease, distant metastasis can also occur in bones and so on.

2. Thyroid follicular carcinoma

The development of follicular carcinoma is also slow, characterized by rapid dissemination of blood, more distant metastasis, and can reach bone tissue and lung. Because its tissue cytology approximates thyroid follicular structure, it can have iodine absorption function. Therefore, a small number of patients can The performance is hyperthyroidism, the rate of 131I is increased, and when the advanced tumor develops, the superior vena cava compression syndrome can also be caused. The reliable indicators for diagnosing thyroid follicular carcinoma are vascular and capsule invasion, and distant metastasis. The case of complete resection of the lesion is approximately 1/2 to 2/3.

(1) Characteristics of the disease: It can occur at any age, but there are more middle-aged and elderly people. The peak age of the disease is 40-60 years old. There is obvious lymph node metastasis or distant metastasis, even when the biopsy of distant bone metastasis is performed. Get a diagnosis.

(2) Clinical manifestations: The first manifestation of most patients is a thyroid mass, the tumor grows slowly, the texture of the mass is medium, the boundary is unclear, the surface is not smooth, the thyroid activity is better, and the tumor invades the tissue adjacent to the thyroid. After the fixation, the performance is hoarse, some patients may have metastatic symptoms, such as the femur.

(3) Metastatic characteristics: Because thyroid follicular carcinoma invades blood vessels more, local invasion and distant metastasis can occur. Compared with papillary thyroid carcinoma, lymph node metastasis occurs in the neck and mediastinum. 8% to 13%, other organs, such as the brain, bladder and skin can also be involved, less osteogenic changes, can be used after oral radionuclide iodine, radiotherapy by internal irradiation, and even excessive secretion of thyroid hormone.

3. Thyroid medullary carcinoma

Thyroid C cells originate from neural crests, and are associated with adrenal medulla cells, the so-called APUD cells (amine precursor uptake and decarboxylation cells). Most medullary thyroid carcinomas are associated with the RET oncogene located on chromosome 10, q11.2.

(1) Characteristics and classification of the disease: The disease is highly malignant and can be metastasized through the bloodstream. The medullary thyroid carcinoma can be divided into four types.

1 scattered hair: 70% to 80%, non-genetic, no similar diseases in the family, will not be passed on to the offspring, no other endocrine gland lesions, the ratio of male to female incidence is about 2:3, and there is Codon mutations have a poor prognosis.

2 Familial type: refers to patients with family genetic predisposition, but not associated with other endocrine glands, the age of high incidence is 40 to 50 years old, and the genetic mutation pattern is the same as MEN2A.

3MEN2A: MEN is multiple endocrine neoplasia syndrome (MEN), which is related to medullary thyroid carcinoma is MEN2A and MEN2B, including bilateral medullary thyroid carcinoma or C cell hyperplasia, so the incidence of men and women is similar, high incidence The age is 30 to 40 years old and involves 609 of exon 10 and 11 of the RET gene.

4MEN2B: including bilateral medullary thyroid carcinoma, and malignant), but rarely involving the parathyroid gland, the incidence rate of men and women is similar, the high-risk age is 30 to 40 years old, in almost all cases can be found in the 16th exon of RET gene The 918th codon was mutated.

(2) Clinical manifestations: Most patients in the first visit, the main manifestations are painless hard solid nodules of the thyroid, local lymphadenopathy, and sometimes lymphadenopathy becomes the first symptom, such as with heterologous ACTH, can produce different Symptoms, serum calcitonin levels are significantly increased, which is the biggest feature of the disease, so calcitonin becomes a diagnostic marker, more than 0.6ng / ml, should consider C cell proliferation or medullary carcinoma, due to calcitonin The regulation of blood calcium levels is far less powerful than that of parathyroid hormone, as well as ganglionoma or mucosal neuroma, which is MEN.

At the time of physical examination, the thyroid mass is solid, the boundary is unclear, and the surface is not smooth. The family and MEN2 patients can be bilateral thyroid masses, and the masses have better activity. After the late invasion of adjacent tissues, they are more fixed, such as hoarseness.

(3) metastatic characteristics: the early stage of medullary thyroid carcinoma invades the lymphatic vessels of the thyroid gland, and quickly metastasizes to other parts of the gland and lymph nodes in the neck. It can also metastasize to the lungs through distant metastasis and transfer to the lungs. It is associated with the lack of capsules in medullary carcinoma.

4. Undifferentiated thyroid cancer

(1) Characteristics of the disease: Undifferentiated thyroid cancer is a highly malignant tumor, accounting for 2% to 3% of thyroid cancer. It is also reported that 5% to 14%, the age of onset is more than 65 years old, and young people are less common. The thyroid undifferentiated carcinoma of follicular cells can also be divided into giant cells, which are mostly giant cells and spindle cells. Differentiated and undifferentiated carcinomas, including follicular adenomas, can also be present in the same case. Metastatic cancer of the biceps muscle, although cervical lymph node dissection and biceps resection, lung metastasis still died.

(2) Clinical manifestations: Most patients showed progressive neck masses, accounting for 64% to 80%, but there was no thyroid enlargement before the onset, the mass was hard and rapidly increased; 2 thyroid enlargement, may be accompanied There is a distant metastasis; 3 has a history of thyroid mass for many years, but the thyroid mass suddenly increases rapidly and becomes hard as a stone; 4 there is untreated DTC, which increases rapidly after a period of time, accompanied by Regional lymph nodes are enlarged.

(3) Metastatic characteristics: Due to the high degree of malignancy of thyroid undifferentiated carcinoma, the disease develops very rapidly, invading surrounding tissues and organs, such as the trachea, and even forming a mass in the trachea and esophagus, leading to respiratory and swallowing disorders. 90% of patients with cervical lymph node metastasis, 25% of patients with tracheal involvement, and 50% of patients who have undergone lung metastasis through the bloodstream.

5. Rare thyroid cancer

(1) thyroid lymphoma: the incidence of thyroid lymphoma is low, accounting for less than 5% of primary thyroid tumors, mainly non-Hodgkin's lymphoma, the ratio of male to female patients is (2 ~ 3): 1, in addition to rapid increase In addition to large thyroid masses, the disease is often accompanied by obvious local symptoms such as hoarseness, difficulty breathing, and difficulty swallowing. Non-Hodgkin's lymphoma is a multicentric tumor that grows in the reticuloendothelial system, so the incidence of liver is from 0 to 60%, 30% to 70% of patients with HT.

(2) Thyroid metastasis: The malignant tumors in other parts of the body can be transferred to the thyroid gland, such as breast cancer, including 3 cases of lung cancer, which have obvious primary tumor symptoms.

(3) thyroid squamous cell carcinoma: thyroid squamous cell carcinoma is rare, accounting for about 1% of thyroid malignant tumors, and the incidence rate in the population is about 2% to 3%, mainly from Japan, or it can be a widespread thyroid papillary carcinoma. Can also be derived from the thyroid gut tube or cleft palate, part of the primary thyroid squamous cell carcinoma with carcinoma showing thymus-like element (CASTLE), from ectopic thymus or cleft palate sac residual tissue, The prognosis is good, the age of onset is more than 50 years old, no obvious gender difference, early symptoms of invasion and compression of surrounding organs, that is, hoarseness, late invasion of both sides of the leaves, hard texture, fixed, unclear border, accompanied by trachea Compression, cervical lymphadenopathy, poor prognosis, the current treatment is to remove the tumor as much as possible plus radical surgery or radiation therapy.

Thyroid cancer examination

Laboratory inspection

Biochemical examination

Serum biochemical tests contribute to the diagnosis and postoperative follow-up of thyroid cancer.

(1) Determination of thyroglobulin (TG): TG value >10ng/ml is abnormal, such as simple goiter, serum TG can be found elevated, so TG can not be used as a tumor marker for qualitative diagnosis, or There is residual thyroid, but the thyroid is no longer present after 131I treatment. There should be no more TG. If radioimmunoassay is found, it is found that TG is elevated, indicating that there may be recurrence or metastasis of thyroid cancer in vivo. TG can be more specific. Tumor markers, used for postoperative dynamic monitoring, to understand whether there is recurrence or metastasis of thyroid cancer in the body, and there are still thyroid residues, then the detection of TG can only be used as a reference, rather than the effectiveness of the former, so as not to interfere with the test results.

(2) Determination of calcitonin: The content of calcitonin in normal human serum and thyroid tissue is very small, the level of calcitonin in radioimmunoassay is 0.1-0.2 ng/ml, most >50 ng/ml, serum calcitonin is obvious Elevation is positive, normal people do not have this reaction, but calcitonin is far less effective in regulating blood calcium levels than parathyroid hormone, so serum calcium levels are mostly normal, and patients have no X-ray findings of bone resorption, such as serum drop. Calciton returned to normal, indicating that the tumor was completely removed; if the serum calcitonin is still high, it indicates that there is still residual tumor or metastasis, which helps to detect tumor recurrence early, improve the therapeutic effect and increase the survival rate.

(3) thyroid function test: thyroid cancer patients should be tested for thyroid function, including plasma PBI, serum T3.

2. Pathological examination of thyroid cancer

For acupuncture examination, it may spread to cancer, so it is not recommended to be widely used. It is best to perform open thyroid tissue biopsy, which is conducive to diagnosis and differential diagnosis.

Use a fine needle to puncture the thyroid mass, draw a small amount of cells and smear, and perform cytological examination (FNAC). The general diagnosis rate is 5% to 79%. Puncture under the guidance of B-ultrasound can improve the diagnosis rate, but it is fast, sometimes Within half an hour, there is a result. When the nucleus has inclusion bodies, it can diagnose thyroid papillary carcinoma, which can be used as FNAC of cervical lymph nodes. If the structure of papillary carcinoma is found, thyroid papillary carcinoma can be considered, and it can be judged as follicular tumor. But can not identify benign or malignant.

3. Genetic diagnosis

FNAC and B-ultrasound can confirm the diagnosis of thyroid tumors. The cytological evidence provided by FNAC is the best way to diagnose thyroid cancer before surgery. The accuracy of FNAC depends on good training. By detecting different gene expression of thyroid tumor cells, It is possible to judge the benign and malignant thyroid mass.

Among all non-genetic tumors, the first-degree relatives of thyroid cancer have the highest prevalence, which can be as high as 8.6%, suggesting that the pathogenesis of thyroid cancer involves abnormalities of certain genes, or abnormalities of signal transduction factors and one or several There are no good biomarkers for thyroid cancer, and there are no good biomarkers for diagnosis or prognosis. When 8 cases of thyroid papillary carcinoma were detected, 8 of them had increased expression of 24 genes (>2 times), including with papillary Cancer-related MET, there are some genes that were previously thought to be unrelated to thyroid cancer, such as CIT-ED1; there are 8 genes with reduced expression, mainly genes related to thyroid function (such as TPO) and tumor suppressor genes (such as BCL2). It is considered that the candidate gene for gene diagnosis is N33, and further research is needed to detect carcinoembryonic fibronectin of thyroid papillary carcinoma and undifferentiated carcinoma by aspiration biopsy RT-PCR (ABRP). (oncofetal fibronectin, OnfFN) mRNA expression, found that the sensitivity of preoperative diagnosis can reach 96.9%, specificity reached 100%, but not found in adjacent normal thyroid tissue and other thyroid lesions, and Onf Unlike normal fibronectin, FN has a carcinoembryonic group (IIICS group), which can be found in the oral cavity, and has OnfFN/TG>0.1 in papillary thyroid carcinoma and undifferentiated carcinoma, and benign thyroid disease and thyroid follicular adenocarcinoma. OnfFN/Tg<0.06 can be a more objective and accurate diagnosis method before surgery.

The RET proto-oncogene encodes a transmembrane tyrosine kinase receptor, and RET rearranges to form a dimeric fusion gene RET/PTC, which is commonly found in radiation-induced thyroid cancer. There are at least 15 forms of RET rearrangement, RET/PTC1 and RET. /PTC3RET/PTCRET

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diagnosis

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Differential diagnosis

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