Introduction to thyroid nodules and differentiated thyroid cancer
1. Prevalence of thyroid nodules
Thyroid nodules are a common thyroid disorder and are often overlooked in life because they may not have any clinical symptoms. The prevalence of thyroid nodules obtained by palpation (i.e., touch) is about 3% to 7%, and the prevalence of thyroid nodules obtained by ultrasound is about 20% to 76%; among thyroid nodules, about 5% to 15% are malignant, i.e., thyroid cancer.
2. Clinical manifestations of thyroid nodules
Most patients with thyroid nodules have no clinical symptoms. When combined with abnormal thyroid function, corresponding clinical manifestations may appear. For example, hyperthyroidism may include easy hunger, overeating, weight loss, change in temperament, rapid heartbeat, protruding eyes and other signs and symptoms, while hypothyroidism may include lazy speech, memory loss, mucinous edema of the skin and other signs and symptoms. In some patients, due to nodule compression of surrounding tissues, symptoms of compression such as hoarseness, feeling of pressure, difficulty in breathing, and difficulty in swallowing may occur.
The following medical history and physical examination findings are risk factors for thyroid cancer.
(1) history of head and neck radiation exposure or radioactive dust exposure in childhood; (2) history of systemic radiation therapy; (3) previous history or family history of thyroid cancer; (4) male; (5) rapid growth of nodules; (6) persistent hoarseness and dysphonia with exclusion of vocal cord lesions (inflammation, polyps, etc.); (7) dysphagia or dyspnea; (8) irregular shape of nodules with adhesion and fixation to surrounding tissues; (9) lymph nodes in the neck with pathological enlargement.
3. Changes in the incidence of thyroid cancer
The incidence of thyroid cancer has been increasing year by year according to domestic and international literature. In the United States, the expected number of new thyroid cancer cases in 2012 increased 4.99 times compared with 1982, with papillary thyroid cancer being the most common cancer. Domestic data show that the incidence of thyroid cancer is increasing at a rate similar to that of the United States; the fastest growing thyroid cancer and the one with the largest number of new cases is papillary thyroid cancer. In Shanghai, the number of new cases of thyroid cancer in women rose from the 10th in 2000 to the 5th in 2010, accounting for 6.02% of all malignant tumors in women; among all patients with existing malignant tumors, thyroid cancer accounted for the 3rd (7.74%) and the 10th (2.73%) in men. The incidence of thyroid cancer in women in Beijing has increased from the 10th place in 2001 to the 5th place in 2011, and is the most rapidly increasing female malignant tumor, with an annual increase of 14.2%, or 225.2% in 9 years. The incidence rate of TC in Xiaoshan District, Hangzhou City, showed a significant increase from 1988 to 2009, especially in women, and the incidence rate of TC in women reached 23.81/100,000 in 2009, accounting for 7.66% of the incidence of malignant tumors in women, ranking the third in the incidence rate of malignant tumors in women.
4. Etiology of thyroid cancer
To date, the cause of thyroid cancer is unknown and may be related to the following factors.
(1) Radiation injury
Radiological factors are the only clear risk factors for thyroid cancer so far. Irradiation of the thyroid gland of laboratory rats with x-rays can contribute to the development of thyroid cancer in animals. The epidemiological investigation of the Chernobyl nuclear leak confirmed that the incidence of thyroid cancer was significantly higher in areas exposed to radiation. The carcinogenic effect of radiation factors is age and dose-related, and the younger the age at the time of radiation exposure, the greater the risk of thyroid cancer development. Exposure to radiation during childhood will significantly increase the incidence of thyroid cancer, while the chance of thyroid cancer occurring after neck radiation therapy in adults is uncommon. It is generally believed that the latency period from the time a patient receives irradiation to the onset of thyroid cancer is at least 5-10 years.
(2) Iodine and thyroid cancer
Some studies have pointed out that the incidence of thyroid cancer is higher in iodine-deficient and high-iodine areas than in iodine-normal areas. Follicular carcinoma and undifferentiated carcinoma are more frequent in iodine-deficient areas, while papillary carcinoma is more frequent and undifferentiated carcinoma is less frequent in high-iodine areas. Iodine deficiency combined with radiation can lead to a higher incidence of thyroid cancer and a worse prognosis.
(3) TSH (thyroid stimulating hormone) stimulation
TSH acts on TSH receptors in thyroid follicular epithelial cells and causes follicular cell proliferation by activating the cAMP-dependent protein kinase signaling system. When normal thyroid follicular cells are damaged for various reasons, such as radiation and chronic lymphocytic thyroiditis, thyroid hormone secretion decreases and TSH secretion feedback increases at this time, increasing the risk of thyroid cancer.
(4) Endocrine factors
The incidence of thyroid cancer in women is three times higher than that in men, therefore, the relationship between female hormones and thyroid cancer is widely concerned. With the increase of endogenous estrogen secretion, the incidence of thyroid cancer in women over 10 years old gradually increases. Increased prevalence of thyroid cancer has also been clinically reported in patients with high estrogen concentrations such as those taking oral contraceptives and elderly primigraviders.
(5) Genetic factors
Studies have confirmed that the incidence of thyroid cancer among first-degree relatives of patients with sporadic papillary carcinoma is 4-6 times higher than that of the general population. About 5-10% of medullary thyroid cancers have a significant family history, and about 25% of medullary cancers have been found to be autosomal dominant disorders. In addition to this, thyroid cancer can also appear as part of certain familial syndromes, such as familial adenomatous polyposis, Gardner’s syndrome, Cowden’s disease, and Werner’s syndrome.
(6) Other factors
Some studies suggest that adult obesity may increase the risk of thyroid cancer by 40%. In recent years, there has been widespread concern about the hazards of PBDEs, which are brominated flame retardants that are widely added to plastic products and can easily escape from the products, and which have a chemical structure similar to that of thyroxine (T4) and can disrupt the thyroid system in adult and developing mammals, causing disruptions in T4 metabolism. Exposure to polycyclic aromatic hydrocarbons such as polybrominated diphenyl ethers (PBDEs) may lead to an increased risk of thyroid cancer development.
In conclusion, the etiology of thyroid cancer is more varied and individualized, and further research is needed.
5. Classification of thyroid cancer.
Thyroid cancer can be classified according to tissue origin and degree of differentiation as
(1) Papillary thyroid carcinoma (PTC), which is a low-grade malignant tumor, is the most common type of thyroid cancer, accounting for about 70%-85% of thyroid cancer and 85%-90% of differentiated thyroid cancer.
(2) Follicular thyroid carcinoma (FTC) is also a low-grade malignant tumor, but is slightly more malignant than PTC, accounting for 10%-15% of thyroid carcinoma.
Among them, PTC and FTC are more differentiated, also known as differentiated thyroid carcinoma (DTC), which accounts for about 90% of thyroid carcinoma and has good treatment effect.
(3) Medullary thyroid carcinoma (MTC) is moderately malignant. It originates from parafollicular C cells of the thyroid gland and accounts for 3%-8% of thyroid carcinoma. It can metastasize through cervical lymph nodes and blood circulation. Since it does not originate from thyroid follicular cells and has no iodine uptake function, 131I treatment is ineffective and also has poor effect on radiotherapy.
(4) Undifferentiated thyroid carcinoma (UDTC) is highly malignant and has the worst prognosis among TCs. It accounts for about 1.3%-9.8% of TC. The median survival time is usually 6 months-8 months. It is mostly seen in elderly patients. Progression is rapid, with rapid onset of pulmonary and systemic metastases. Some of them are derived from the dedifferentiation of DTC, also known as anaplastic thyroid cancer (ATC).
6. Key points in the treatment of thyroid nodules
All patients with thyroid nodules should be tested for serum thyroid stimulating hormone (TSH) levels and interventions should be made if necessary based on the results of the test. The literature reports that patients with thyroid nodules with lower than normal TSH levels have a lower percentage of nodules that are malignant than those with elevated TSH levels.
High-resolution ultrasonography is the preferred method for evaluating thyroid nodules, and ultrasonography of the thyroid and cervical lymph nodes should be performed in all patients with thyroid nodules. Ultrasound can assist in identifying benign and malignant thyroid nodules. The most common ultrasound signs of thyroid cancer are: hypoechoic, poorly defined, gravelly calcifications, abundant blood supply, etc.
Fine needle aspiration biopsy (FNAB) is the most sensitive and specific method for preoperative evaluation of benign and malignant thyroid nodules. Ultrasound-guided FNAB improves the success rate of sampling and diagnostic accuracy. However, FNAC cannot differentiate between follicular thyroid tumors and follicular thyroid carcinoma.
7. Treatment of papillary thyroid carcinoma
The current treatment of papillary thyroid cancer is mainly surgery, postoperative TSH suppression therapy and postoperative selective 131I therapy.
The surgical treatment includes thyroidectomy and cervical lymph node dissection, and the main surgical procedures for thyroidectomy in DTC include total/proximal thyroidectomy and lateral thyroid lobectomy (or isthmus).
Indications for total thyroidectomy.
(meeting any of the following)
(1) Age <15 or >45 years
(2) Tumor >100px
(3) Multiple carcinoma foci, especially bilateral carcinoma foci
(4) extra-thyroidal infiltration
(5) Known distant metastasis
(6) Lymph node metastasis in the neck
(7) Pathological staging is aggressive subtype
(8) With BRAF gene mutation.
Indications for lateral thyroid lobe (or plus isthmus) resection.
(all of the following conditions are met)
(1) Solitary PTC confined to one lobe of the gland
(2) Primary foci <25px< p="">
(3) No history of head and neck radiation during childhood
(4) No cervical lymph node metastasis or distant metastasis
(5) No nodules in the contralateral glandular lobe
(6) Non-invasive subtype
(7) Low risk of recurrence
There is still a controversy about lymph node dissection, especially whether to perform selective cervical lymph node dissection.
In China, the current treatment is to routinely perform lymph node dissection in the affected central region (affected paratracheal, pre-tracheal, and anterior laryngeal) at the same time, and decide whether to perform lymph node dissection in the contralateral central region according to the lymph node metastasis.
For the lymph nodes in the lateral cervical region, the current international and national views are consistent. If there are no clinically or pathologically positive lymph nodes, further cervical lymph node dissection will not be performed.
8. Papillary thyroid carcinoma (PTMC)
Micro papillary thyroid cancer refers to papillary thyroid cancer with tumor diameter less than 10mm. A significant proportion of PTMC is clinically quiescent and does not develop or disappear, especially lesions <5mm; however, a very small proportion of PTMC is found to grow in an invasive manner with local and distant metastases; some literature reports that patients with BRAF mutation-positive PTMC have a poorer prognosis than those with negative mutations. For micro papillary thyroid carcinoma, the current unified management is: if there is no distant metastasis, no extra-thyroidal infiltration, negative BRAF mutation test, and no high risk factors for thyroid cancer, the affected lobe can be resected and 131I treatment is not needed after surgery.
9. Surgical complications.
Complications of DTC surgery include bleeding, incisional infection, respiratory obstruction, parathyroid injury (transient or permanent hypocalcemia), recurrent laryngeal nerve injury, superior laryngeal nerve injury, and anesthesia-related complications. Foreign data show that the rate of postoperative injury to the recurrent laryngeal nerve after total thyroidectomy is 4.3%, the rate of bilateral recurrent laryngeal nerve injury is 0.6% (half of the patients underwent tracheotomy), the rate of symptomatic hypocalcemia is 14.0% (permanent hypocalcemia is 2.2%), the rate of postoperative bleeding is 8.0%, and the rate of incisional infection is 0.4%. The incidence of surgical complications was related to the operator’s experience.
9. Oral thyroxine after DTC
The main function of thyroid hormone synthesis after total thyroidectomy is reported to be completely replaced by oral levothyroxine, but whether there are other unpredictable effects is not clear. The effect is twofold. TSH suppression therapy is the first choice of levothyroxine (L-T4, trade name Euthyrox or Raltez), which should be taken early in the morning on an empty stomach. From overseas and domestic experience over the years, physiological doses of levothyroxine have almost no side effects and are safe and reliable.
10. 131I treatment after DTC surgery
Since DTC is not sensitive to radiotherapy, but effective to 131I treatment, 131I treatment includes two levels: firstly, 131I is used to remove the residual thyroid tissue after DTC surgery, referred to as 131I nail clearing; secondly, 131I is used to remove the metastatic foci of DTC that cannot be removed by surgery, referred to as 131I foci clearing. Overall, 131I nail clearing treatment can be considered for all DTCs except those with cancer foci <1 cm and no extra-glandular infiltration, lymph nodes or distant metastases. 131I nail clearance is contraindicated during pregnancy, lactation, planned short-term (6 months) pregnancy, and inability to follow radiation protection instructions. 131I therapy is one of the important tools for postoperative treatment of DTC, but not all DTC patients need 131I therapy. 131I nail clearance therapy is used selectively for DTC patients after surgery.
11. Prognosis of papillary thyroid cancer
The prognosis of papillary thyroid cancer is good, and the literature reports that the 5-year survival rate of PTC after standard treatment is 95%, 10-year survival rate is 93%, and 20-year survival rate is 90%. However, PTC has a high recurrence rate, and the literature reports that the cumulative recurrence rate of PTC 40 years after surgery is as high as 35%, and the chance of recurrence within the first 10 years after surgery is high, accounting for 2/3 of all recurrences, and about 1/3 of recurrent cases die from PTC. Therefore, for DTC, a malignancy with a high long-term survival rate, physicians should not only focus on the risk of death, but also stratify patients by the risk of recurrence.
Risk of recurrence stratification for differentiated thyroid cancer (DTC)
Risk of recurrence group
Eligible
Low risk group
Those who meet all of the following criteria.
-No local or distant metastases
-All tumors visible to the naked eye have been completely removed
-Tumor did not invade surrounding tissues
-Tumor is not an aggressive histologic subtype. and there is no vascular invasion
-If the patient is cleared and whole body iodine imaging is performed, no iodine uptake is found outside the thyroid bed
Intermediate risk group
Those who meet any of the following criteria.
-Pathologic examination after initial surgery reveals a tumor with peri-thyroidal soft tissue invasion on survival microscopy
-Abnormal radioactivity uptake is detected by cervical lymph node metastasis or whole body 131I imaging after nail clearance
-Invasive histological type of tumor or vascular invasion
High risk group
Those who meet any of the following criteria.
-Tumor invasion of surrounding tissues or organs is visible to the naked eye
-The tumor is not completely resected and there are intraoperative residuals
-with distant metastases
-High serum Tg level even after total thyroidectomy
-Family history of thyroid cancer