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Detailed information about Familial hereditary tumors: Thyroid cancer.
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Detailed information about Familial hereditary tumors: Thyroid cancer.
Thyroid cancer is the most common malignant tumor of the endocrine system.
Familial hereditary thyroid cancers include hereditary medullary thyroid carcinoma (HMTC) and familial non-medullary thyroid carcinoma (FNMTC) .
Hereditary medullary thyroid carcinoma
Medullary thyroid carcinoma (MTC) is a malignant tumor derived from thyroid parafollicular cells (C cells), accounting for about 5% of thyroid malignant tumors. The role of calcin gene-related peptide. Therefore, MTC is also considered as one of neuroendocrine tumors.
25%~30% of MTC is HMTC . According to the ATA guidelines, HMTC can be divided into multiple endocrine neoplasia type 2A (MEN2A) and multiple endocrine neoplasia type 2B (MEN2B).
MEN2A HMTC can be divided into 4 types according to the difference in clinical manifestations: classic MEN2A, MEN2A with cutaneous lichen amyloidosis (CLA), MEN2A with Hirschsprung’s disease (HD), familial MTC (FMTC).
MEN2B type is characterized by MTC complicated with mucosal multiple neuromas , usually onset in infancy , and has high invasiveness, and lymph node and even distant metastasis can occur in the early stage.
Familial non-medullary thyroid carcinoma
Non-medullary thyroid carcinoma (NMTC) includes papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC) and anaplastic thyroid carcinoma (ATC) and other malignant tumors originating from thyroid follicular epithelial cells, accounting for about 90% of all TCs. %, of which PTC is the most common pathological type. 5% to 10% of NMTC patients show familial aggregation.
FMNTC was defined as having 2 or more NMTC patients among first-degree relatives and excluding the history of head and neck radiation exposure. FMMTC can be divided into 2 categories:
- Familial tumor syndromes with non-thyroid tumors as the main manifestation, including familial adenomatous polyposis (FAP), Cowden syndrome, etc., and FMNTC may be the first manifestation in such genetic syndromes;
- Non-syndromic, patients in one affected family are characterized by the development of NMTC without other endocrine tumors or diseases. The biological behavior of FMNTC is highly aggressive, such as early age of onset, high proportion of multifocal and bilateral disease, local infiltration, high lymph node metastasis rate, high recurrence rate, and short disease-free survival.
Risk assessment and genetic testing
About 95% of HMTC is caused by mutations in the RET gene. 95% of MEN2A patients have mutations in the RET gene at codons 609, 611, 618, and 620 of exon 10 and codon 634 of exon 11. 95% of MEN2B patients carry the M918T mutation in exon 16 of the RET gene, and less than 5% of MEN2B patients carry the A883F mutation in exon 15.
According to the ATA guidelines, the aggressive risk of HMTC patients is divided into highest risk (HST), high risk (H), and intermediate risk (MOD) according to the RET gene mutation site, as shown in Table 1.
The specific causative gene for FMNTC has not been found, so it is impossible to risk stratify patients with FMNTC according to the variation characteristics of a specific gene. In the study of Chinese FNMTC families, it was found that different FNMTC families have different tumor susceptibility gene variants, including APC, MSH6, BRCA1/2 genes, etc.
The risk of TC caused by different gene mutations is different. For example, about 1/4 of the patients with PTEN germline mutation are associated with TC, and the age of onset is early, and the rate of FTC is high.
The aforementioned susceptibility gene variants are also associated with the development of other tumors, suggesting an increased risk of developing a second tumor. For example, FMNTC patients with MSH6 pathogenic variants are at increased risk of developing colorectal and endometrial cancer.
3. Eligible people
Clinically, 1% to 7% of sporadic MTC patients actually have the genetic background of HMTC, so genetic screening of sporadic cases can further clarify the disease type. MTC gene screening can help to identify specific types of HMTC in family members, and to carry out risk stratification according to different mutation sites, and to formulate targeted treatment strategies.
Given the high incidence of NMTC (especially PTC), many sporadic non-medullary thyroid carcinomas (SNMTCs) may also have familial aggregation.
Compared with SMNTC, patients with FMNTC have an increased risk of developing a second tumor and may be a cause of death. Therefore, screening of genetic susceptibility genes in NMTC patients with family history is helpful for the identification of FNMTC and SMNTC, and also helps to evaluate the clinical prognosis and secondary tumor risk of NMTC.
Expert panel opinion: RET gene screening is recommended for the following populations :
- MTC patients with family history and their first-degree relatives;
- Patients themselves and their parents with MEN2B manifestations in childhood or infancy;
- Patients with lichen amyloidosis of the skin;
- Hirschsprung disease patients;
- Patients with adrenal pheochromocytoma;
- Those with SNMTC who are willing to be tested.
Tumor susceptibility gene screening is recommended for NMTC patients with a family history and their first-degree relatives.
4. Detection of genes
1) HMTC: RET gene mutation is the main molecular etiological basis for the pathogenesis of MTC.
2) FNMTC: The specific pathogenic gene of FNMTC has not yet been found. Syndromic FMNTC is associated with known tumor susceptibility genes, such as APC gene is the causative gene of FAP syndrome.
In the study of non-syndromic FNMTC causative genes, DICER1, FOXE1, PTCSC2, POT1, TCO, NMTC1 and other genes have been found to be related to the susceptibility of FNMTC. , 6q and 12q mutations are related, but all lack reproducibility.
FMNTC has no hot spot gene mutation, and involves many genes. Therefore, extensive polygenic screening can be considered for FMNTC.
Expert Group Opinion: For germline RET gene testing in suspected HMTC patients or high-risk groups, PCR, next-generation sequencing and NGS methods can be considered; suspected FNMTC patients or high-risk groups can use NGS for extensive multi-gene screening; Families can use next-generation sequencing technology for verification.
Data quality control, gene variant classification and interpretation should be performed by clinical bioinformatics analysts with professional backgrounds and systematic training and qualifications.
The diagnosis strategy
1. Detection of HMTC
1.1 Ultrasound examination and ultrasound-guided fine needle aspiration biopsy
Ultrasonography is the imaging method of choice for the detection of MTC , which can assess the benign and malignant thyroid lesions and their relationship with surrounding tissues in real time, as well as evaluate cervical lymph nodes. The TI-RADS classification scores and classifies thyroid nodules based on ultrasonographic features, assesses malignancy risk, and guides nodule management. The vast majority of MTC TI-RADS were classified as category 4 or 5, indicating that ultrasonography has a high diagnostic value for MTC. Ultrasonography and ultrasound-guided fine needle aspiration (FNA) have an accuracy rate of about 50% in diagnosing MTC due to the diverse cytomorphological manifestations and lack of amyloid inImmunohistochemical staining can improve the diagnostic accuracy when there are sufficient tumor cells in FNA specimens. The diagnostic criteria include calcitonin, carcinoembryonic antigen, positive chromogranin staining, and thyroglobulin deficiency.
Expert group opinion: Ultrasonography and TI-RADS have high diagnostic value for MTC, and about 50% of MTC can be diagnosed by cytopathology through FNA. Ultrasonography combined with FNA is recommended for HMTC screening, ultrasound TI-RADS classification to assess malignancy risk, and immunohistochemical staining is recommended if necessary.
1.2 Serum Calcitonin Detection
Serum calcitonin is a tumor marker with high sensitivity and specificity in MTC. Serum calcitonin detection is earlier than other MTC diagnostic methods in clinical staging and has a better prognosis. Therefore, European scholars recommend routine detection of serum calcitonin in thyroid nodules for early diagnosis of MTC.
However, the low incidence of MTC has aroused concern about the cost-effectiveness of routine testing, and non-secretory MTC does not secrete calcitonin, so American scholars hold a neutral attitude toward routine serum calcitonin testing. At present, the threshold value of serum calcitonin for the diagnosis of MTC has not been unified.
Based on large sample studies, it is generally believed that MTC is basically excluded when serum calcitonin <10 pg/mL; MTC is highly suspected when serum calcitonin is ≥100 pg/mL; MTC is suspected when serum calcitonin is 10-100 pg/mL. Calcitonin testing in needle aspiration eluates ruled out non-MTC serum calcitonin elevations.
Expert group opinion: Serum calcitonin is a tumor marker with high specificity and sensitivity for MTC, and its increase suggests the possibility of MTC, but there is still controversy in the routine detection of serum calcitonin in thyroid nodules. Serum calcitonin detection is recommended for clinically suspected HMTC. When serum calcitonin is 10-100 pg/mL, combined calcitonin challenge test and fine needle aspiration eluate calcitonin detection are recommended.
1.3 Genetic testing and other testing
The genetic basis of HMTC is germline variation of the RET gene. For details, see “Risk Assessment and Genetic Testing” above. HMTC has a wide range of local invasion and a high rate of cervical lymph node metastasis and distant metastasis. In addition to neck ultrasound and serum calcitonin testing, preoperative evaluation should be combined with other tests. Serum CEA level reflects the extent of tumor invasion and differentiation, and can be used to assess tumor aggressiveness.
CT is better than ultrasound in evaluating metastatic lymph nodes in the central area, superior mediastinum and retropharyngeal space and their relationship with surrounding tissues, and CT has the highest sensitivity for lung metastases; enhanced CT and MRI are sensitive methods for detecting liver metastases; MRI and bone scintigraphy are more sensitive Sensitive method for the detection of bone metastases; PET/CT can be used for the evaluation of systemic metastatic lesions, but there is currently insufficient evidence to support the use of PET/CT for clinical staging of HMTC.
Expert group opinion: It is recommended to confirm the diagnosis of HMTC based on the diagnosis of MTC, combined with the detection of RET gene germline mutation and family history. Combined with neck ultrasonography, serum calcitonin and CEA detection in HMTC patients to comprehensively evaluate the degree of tumor invasion and clinical progress. When clinically suspected extensive neck invasion and distant metastasis, it is recommended to combine cervical and chest CT, liver-enhanced CT or MRI, bone MRI or bone scintigraphy, and PET-CT.
2. Detection of FMNTC
2.1 Ultrasound examination
The diagnostic value of ultrasonography in FNMTC is still controversial, given that there is little difference in ultrasound imaging features between FMNTC and SMNTC. PTEN germline mutation syndrome type FMNTC thyroid cancer has a higher risk, early onset, and high FTC ratio.
Therefore, it is recommended that patients with PTEN germline mutation should undergo thyroid ultrasonography at the time of diagnosis.
2.2 Genetic testing
The diagnosis of FMNTC mainly depends on family history. FMNTC should be consistent with the family with 2 or more NMTC patients among first-degree relatives and exclude the history of head and neck radiation exposure. No specific causative gene for FMNTC has been found. For details, see “Risk Assessment and Genetic Testing” above.
Expert group opinion: Syndromic FMNTC has a clear pathogenic gene, and patients with thyroid cancer with a typical syndromic phenotype should undergo targeted gene testing to confirm the diagnosis of FMNTC. Nonsyndromic FMNTC has no specific causative gene, and the diagnosis is mainly based on family history.
1. Treatment for HMTC
1.1 Treatment for operable HMTC
Surgery is the first choice for patients with HMTC, and traditional chemoradiotherapy is not effective.
At present, the opinions on the treatment of HMTC primary lesions are unified at home and abroad. Total thyroidectomy and central lymph node dissection are the most basic surgical methods.
Prophylactic upper mediastinal dissection is recommended for patients with a large central lymph node metastasis burden; for patients with upper mediastinal lymph node metastasis, therapeutic upper mediastinal lymph node dissection should be performed. For patients with cN1b, curative lateral neck dissection should be performed; while for cN0 patients, prophylactic lateral neck dissection remains controversial.
Studies have shown that the rate of lateral neck lymph node metastasis is closely related to the number of central lymph nodes. When 1 to 3 central lymph nodes metastasize, the ipsilateral lateral cervical lymph node metastasis rate is 77%. Lateral neck metastasis rate can reach 98%. The preoperative basal serum Ctn level can also reflect the degree of lymph node metastasis to a certain extent.
Panel opinion: Surgery is the preferred treatment for HMTC. For patients with cN0 HMTC, bilateral prophylactic central dissection is recommended on the basis of total thyroidectomy.
Therapeutic central lymph node dissection should be performed in all patients with cN1a HMTC. For patients with cN1b HMTC, therapeutic central and lateral neck dissection should be performed. Prophylactic lateral neck lymph node dissection was determined based on the primary tumor, central lymph node metastasis and serum Ctn level.
1.2 Treatment of locally advanced inoperable and distant metastatic HMTC
HMTC has a high degree of malignancy. Some HMTC patients are locally advanced and/or combined with distant metastasis at the first visit. The chance of R0 resection is extremely low, and the cost of loss of multiple organ functions is required.
For these patients, the overall treatment goals are to improve local control rates, relieve systemic and metastatic symptoms, and reduce disease-related deaths.
A variety of targeted drugs have been reported to be effective against advanced HMTC.
Small-molecule multi-target receptor tyrosine kinase inhibitors vandetanib and cabozantinib have been approved in Europe and the United States for the clinical treatment of locally advanced or distant metastatic MTC, and there are a variety of multi-target small molecule tyrosine kinase inhibitors.
Aminokinase inhibitors are in clinical trials. In addition to the above-mentioned multi-targeted tyrosine kinase inhibitors, there are also highly selective RET inhibitors, which have high affinity for RET and are effective for both fusion mutations and point mutations of RET.
There are currently two small molecule highly selective RET inhibitors (BLU-667 and LOXO-292) in clinical trials.
Expert group opinion: Targeted drug therapy can be considered for locally advanced or distant metastases in patients with HMTC who are not suitable for surgery. Doctors need to measure the relationship between tumor growth rate, quality of life and treatment toxicity, and choose a reasonable treatment plan.
1.3 Treatment for HMTC complications
Patients with MEN2A usually develop adrenal pheochromocytoma (PHEO) at the age of 30 to 40 years and are usually diagnosed at the same time as or after MTC. In patients in the ATA-H and ATA-HST categories, PHEO may have appeared by the age of 8 to 12 years, and in the patients in the ATA-MOD category, PHEO may have appeared by the age of 19 years.
Failure to diagnose PHEO at the time of thyroidectomy can lead to serious complications and even death in patients.
Therefore, for HMTC patients, PHEO should be carefully investigated before surgery, and PHEO should be removed first once the diagnosis is made.
After HMTC is diagnosed, MIBI imaging, ultrasound and CT screening should be used to locate hyperparathyroidism (HPTH). If all four glands are hyperplasia, subtotal parathyroidectomy or total parathyroidectomy can be selected for surgery surgery, autologous heterotopic transplantation.
Expert group opinion: It is recommended that HMTC patients be screened for PHEO as soon as possible, and PHEO should be removed first once diagnosed. After the diagnosis of HMTC, MIBI imaging, ultrasound and CT screening should be used to locate HPTH.
In patients with HPTH, significantly enlarged parathyroid glands should be removed, replacement therapy should be given after surgery, and thyroid function should be monitored.
2. Treatment for FNMTC
FNMTC has an autosomal dominant inheritance pattern, and the incidence of first-degree relatives of FNMTC is 5 to 8 times higher than that of the general population.
However, FNMTC cases have a high degree of genetic and molecular heterogeneity, and it is difficult to identify key genetic and molecular changes.
Since the clinical characteristics of patients with FMNTC and SMNTC are minimally different, the treatment strategies are basically the same.
However, compared with SMNTC, FMNTC has an earlier age of onset, more aggressiveness, higher multifocality and lymph node metastasis rate, and more frequent recurrence. Therefore, FMNTC requires routine dissection of central lymph nodes during surgical treatment.
More often, it may be necessary to add lateral cervical lymph node dissection.
FMNTC tends to be multifocal and bilateral, so the indications for bilateral total thyroidectomy may need to be appropriately relaxed when choosing surgical procedures for FMNTC patients.
Invasion of the capsule and surrounding soft tissue is considered to be one of the important indicators for evaluating tumor invasiveness.
FMNTC is more aggressive than SNMTC, and the scope of surgical resection may need to be increased for FNMTC.
Expert group opinion: At present, the treatment strategy of FMNTC is basically the same as that of SMNTC patients.
FMNTC is more prone to lymph node metastasis. Routine dissection of central lymph nodes is required during surgical treatment. When there are many central lymph node metastases, lateral neck lymph node dissection can be added.
Intervention for high-risk individuals
1. HMTC intervention
Early intervention in high-risk individuals should be managed according to different mutation sites and different risk stratification, and cannot be generalized. For patients with HST grade, thyroidectomy should be performed as soon as possible.
Infants with a high degree of suspicion of HST should undergo genetic testing immediately after birth. If HST is diagnosed, the recommended intervention time is thyroidectomy within the first year of life.
For H-grade patients, annual physical examination, neck ultrasound, and serum Ctn testing should be performed from age 3 years, and thyroidectomy should be performed before age 5 years, and the duration and extent of surgery should be guided according to Ctn levels.
For patients with MOD grade, annual physical examination, neck ultrasonography, and serum Ctn testing should be performed from the age of 5 years, and thyroidectomy should be performed in childhood or adulthood, and the duration of surgery is mainly determined by serum Ctn levels .
Because it is a preventive surgery, there are very few literatures, and there is also a lack of relevant legal provisions.
Expert group opinion: There is a significant correlation between HMTC and RET gene variation.
It is recommended that HMTC patients and their family members undergo RET gene testing as soon as possible, which is helpful to assess the genetic risk of thyroid cancer and carry out accurate risk stratification of the disease.
It is recommended to formulate a reasonable early intervention, treatment and follow-up plan through multidisciplinary consultation, and fully communicate with the patient or the guardian of the child to jointly decide the intervention method and timing.
Prophylactic thyroidectomy should be approved by the ethics committee of the hospital where it is located, and relevant laws should be consulted if necessary.
For RET germline mutation carriers who are in need of fertility, they should be informed of the risks that RET gene germline mutations may bring to family members, and pre-pregnancy or prenatal genetic counseling is recommended.
2. Intervention of FMNTC
There is also a phenomenon of “genetic early emergence” in the FMNTC family. Inherited early emergence refers to a genetic disease in successive generations, and its symptoms are found to be more severe than one generation, and the onset time is earlier than one generation.
Therefore, regular thyroid function serological testing and neck ultrasound screening are recommended for asymptomatic or no palpable nodules in FMNTC family members, in order to detect them in time and strive for better treatment effects.
All NMTC patients should be inquired about the family history in detail. If 2 or more NMTC patients are found in family members, all first- and second-degree relatives over 20 years old, especially women, should undergo 1/year examination.
Thyroid B-scan screening. In patients with adenomatous goiter and multiple NMTCs, familial screening is recommended even if there is no family history of thyroid cancer.
For FMNTC family members with asymptomatic or no palpable nodules, regular thyroid function serological testing and cervical ultrasound screening should be performed in order to timely detect and treat early, and strive for better therapeutic effect.
In addition, high-risk individuals such as FMMTC patients and their families are recommended to undergo comprehensive polygenic testing related to genetic susceptibility to thyroid cancer, which is helpful to assess the genetic risk of thyroid cancer and formulate reasonable treatment and follow-up plans.
Detailed information about Familial hereditary tumors: Thyroid cancer.
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