Since the Chernobyl nuclear power plant leak in the former Soviet Union in the mid-1980s, thyroid cancer has been the fastest growing solid malignancy in the last 20 years, with an average annual growth rate of 6.2%. Currently, it is the 5th most common malignant tumor in women.
The etiology of thyroid cancer is not very clear and may be related to dietary factors (high iodine or iodine deficiency diet), history of exposure to radiation, increased estrogen secretion, genetic factors, or other benign thyroid diseases such as nodular goiter, hyperthyroidism, thyroid adenoma and especially chronic lymphocytic thyroiditis.
Thyroid cancer is generally classified into differentiated thyroid cancer including papillary thyroid cancer and follicular thyroid cancer, low differentiated thyroid cancer such as medullary carcinoma and undifferentiated thyroid cancer, and some rare malignant tumors such as thyroid lymphoma, metastatic thyroid cancer and squamous thyroid cancer. Among them, the proportion of papillary thyroid cancer is about 90%, follicular thyroid cancer is about 5%, medullary thyroid cancer is about 4%, and the rest are other malignant tumors such as undifferentiated thyroid cancer. The following is a description of each of them.
Differentiated thyroid cancer
The incidence of differentiated thyroid cancer increases with age and is common between 30-60 years old. Differentiated thyroid cancer develops slowly. Patients may find a gradually increasing painless lump in the neck, which is discovered unintentionally by themselves or during physical examination, or during ultrasound and other examinations. In the advanced stage of the disease, different degrees of hoarseness, dysphonia, dysphagia and dyspnea may occur. On physical examination, cancer tumors are mostly hard, with smooth surface and clear boundary. If the cancer is confined to the thyroid gland, it can move up and down with swallowing; if it has invaded the trachea or adjacent tissues, it will be more fixed.
Most thyroid function tests are normal in patients with differentiated thyroid cancer, but if the cancer is transformed from other diseases such as hyperthyroidism or Hashimoto’s thyroiditis, there will be corresponding abnormal thyroid function.
Ultrasound is very helpful in the diagnosis of differentiated thyroid cancer. Most differentiated thyroid cancers are substantial masses on ultrasound, but some can be mixed masses with predominantly parenchymal components. Papillary thyroid carcinoma is mostly hypo- or very hypoechoic on ultrasound, with microcalcifications or gravelly calcifications in the parenchyma and no posterior acoustic shadowing; the morphology of the mass may be abnormal in a vertical or upright position, with abundant blood supply around the mass. Follicular carcinoma of the thyroid gland is usually a very homogeneous hyperechoic mass with rich blood supply in ultrasound. The size of the mass, whether the boundary is clear, whether the shape is regular, and whether there is an acoustic halo around the mass are not important indicators to determine whether the mass is malignant.
Currently, fine needle aspiration cytology (FNA) under ultrasound localization is preferred for masses suspected of malignancy by ultrasound. This method can further clarify the nature of the mass. However, because this test is best performed under ultrasound localization and requires a high level of physicians for cytologic diagnosis, it is not popular in China for the time being.
Generally differentiated thyroid cancer is mostly cold/nodular on isotope scan. However, nowadays, isotope examination is not very meaningful in determining the nature of thyroid masses.
If lymph node metastasis or invasion of surrounding organs and tissues, such as trachea, esophagus and nerves and blood vessels are suspected in differentiated thyroid cancer, it is better to perform additional CT or MRI to understand the extent of lymph node metastasis and the degree of invasion of the mass with trachea, esophagus or nerves and blood vessels, so as to facilitate the surgical planning and determine whether surgical resection is possible.
Papillary thyroid cancer is the most typical pro-lymphatic tumor. Whether unilateral or bilateral, the cancer will first and mainly metastasize to the cervical lymph nodes. According to the literature, 20%-90% of papillary (microscopic) cancer patients are found to have regional lymph node metastasis at the same time of diagnosis, and distant hematogenous metastasis occurs only at a later stage. In contrast, follicular thyroid carcinoma mainly metastasizes to lung, bone, brain and liver through hematologic distant metastasis, but its cervical lymph node metastasis pattern is similar to that of papillary carcinoma.
Cervical lymph nodes can be divided into zones I-VII. Zone I: includes lymph nodes in the subchin and submandibular regions; zone II: lymph nodes in the upper group of internal jugular vein; zone III: lymph nodes in the middle group of internal jugular vein; zone IV: lymph nodes in the lower group of internal jugular vein; zone V: includes supraclavicular lymph nodes and lymph nodes in the posterior region of the neck; zone VI: includes tracheoesophageal groove, pre-tracheal and anterior laryngeal lymph nodes; zone VII: is located in the upper mediastinum below the sternal incision. Zone VII: is the upper mediastinal lymph nodes located below the superior sternal incision. Generally, lymph nodes in zones II-VI are associated with metastasis of thyroid cancer. The lymph nodes in zones II-V are usually referred to as lateral cervical lymph nodes, while the lymph nodes in zone VI are also called central zone lymph nodes.
Lymph node metastasis of differentiated thyroid cancer has a certain pattern, and the central region is the first stop of lymph node metastasis. Generally, differentiated thyroid cancer metastasizes to the ipsilateral lymph nodes in the central region first, but it may also metastasize to the contralateral lymph nodes in the central region; then it metastasizes to the ipsilateral lymph nodes in the cervical region; however, some cancers, such as those located in the upper pole of the thyroid gland, may metastasize to the ipsilateral lymph nodes in the cervical region first. Here it is necessary to emphasize that differentiated thyroid cancer located in the isthmus of the thyroid gland, according to our clinical experience, it will first metastasize to the lymph nodes in the central region bilaterally.
Ultrasound is very convenient and sensitive to detect metastasis in the lymph nodes of the neck. However, if there are enlarged lymph nodes in the central region, we should consider the possibility of metastasis, except for Hashimoto’s thyroiditis. Lymph nodes in the lateral cervical region are relatively superficial and have a higher detection rate on ultrasound. If ultrasound reveals that the lymph gland structure of the lymph nodes in the neck is missing, and there is calcification or liquefaction, and the lymph nodes are rich in blood supply, metastasis should be highly suspected.
Since differentiated thyroid cancer has a good prognosis, complete surgical resection can achieve a curative effect. Even if metastasis occurs in other parts of the body, the thyroid gland can be removed and treated with iodine 131 to achieve remission of the disease.
Since papillary thyroid cancer has a metastasis rate of more than 50% in the central region, the latest guidelines for the treatment of differentiated thyroid cancer in China recommend lymph node dissection in the central region regardless of whether the lymph nodes in the central region are found preoperatively or not. The guidelines recommend that functional cervical lymph node dissection should be considered for those with lymph node metastasis in the central region detected by intraoperative freezing, and preferably functional cervical lymph node dissection with preservation of the cervical plexus. For the scope of thyroidectomy, the guidelines recommend total bilateral thyroidectomy for those who have a history of radiation exposure or metastasis to other parts of the body, or for those who have bilateral cancer or thyroid cancer invading to the outer envelope or tumor diameter greater than 4 cm, or for those who have papillary carcinoma with adverse pathological subtypes such as high cell type, columnar cell type, diffuse sclerosis type, insular cell type, or metastasis to bilateral cervical lymph nodes. For those who have no history of radiation exposure or metastasis to other parts of the body, or no invasion of the thyroid envelope or tumor diameter less than 1 cm, or no adverse pathological subtypes, we can perform lobectomy + isthmus resection on the cancerous side of the thyroid gland. For follicular thyroid cancer, the guidelines recommend bilateral total thyroidectomy if it is confirmed to be a widely invasive type with systemic metastasis, and lobectomy + isthmus on the cancerous side for the minimally invasive type.
In foreign countries, especially in Europe, America and Japan, bilateral total thyroidectomy is preferred for differentiated thyroid cancer. The advantage of this procedure is that it can avoid the risk of a second surgery for the recurrence of residual thyroid gland after surgery, and furthermore, it can be treated with iodine 131 after surgery, which is conducive to complete treatment. Also, after total thyroidectomy, it is possible to determine the level of serum thyroglobulin (Tg) at an early stage to know if there is a recurrence. Of course, total thyroidectomy increases the risk of damage to the recurrent laryngeal nerve and parathyroid glands, which may affect the patient’s life and work.
The fundamental reason why there is a difference in the scope of thyroidectomy for differentiated thyroid cancer between China and foreign countries is that the medical systems in China and foreign countries are different. Complications caused by thyroid surgery are not considered as medical malpractice in foreign countries, but not in China. As a result, foreign doctors can be more daring to perform more thorough surgeries for patients to achieve longer-term survival, while domestic doctors are more cautious and reluctant to take too much risk.
In my opinion, for papillary (microscopic) thyroid cancer, if there is a nodule on only one side of the thyroid gland and this nodule is confirmed to be a papillary (microscopic) cancer during surgery, a lobectomy of the thyroid gland + isthmus + lymph node dissection in the central region can be performed. If both thyroid glands have nodules and one side of the thyroid gland is confirmed to be papillary (microscopic) cancer during surgery, since there is a 20% to 40% chance that the nodule on the other side of the thyroid gland will develop into a malignant nodule, total excision of both thyroid glands + lymph node dissection of the central region on the cancerous side can be performed. If nodules are present in both thyroid glands and the intraoperative pathology is bilateral papillary thyroid carcinoma, total bilateral thyroidectomy + bilateral central lymph node dissection can be performed. For non-minor invasive follicular thyroid carcinoma, total bilateral thyroidectomy + lymph node dissection in the central region of the affected side can be performed.
Functional cervical lymph node dissection is mentioned here, which refers to cervical lymph node dissection with preservation of important tissues in the neck such as internal jugular vein, sternocleidomastoid muscle and paraneoplastic nerve. Functional cervical lymph node dissection with preservation of the cervical plexus is also advocated, which preserves the sensory function of the skin of the neck and prevents the occurrence of postoperative frostbite, especially in patients who live in cold areas. Since functional cervical lymph node dissection mostly adopts “L” shaped incision in the neck, which has a great impact on the aesthetics of patients, especially young women, some patients have concerns about performing functional cervical lymph node dissection. Now, we and Shanghai Cancer Hospital can perform functional cervical lymph node dissection with low collar and large curved incision in the neck to preserve the cervical plexus. With the premise of ensuring radical treatment, the function and appearance of the neck are preserved to the maximum extent, and the quality of life of patients is improved, which is in line with the modern concept of tumor treatment.
For patients with differentiated thyroid cancer who underwent total thyroidectomy, especially those with lymph node metastasis, postoperative iodine 131 therapy is recommended to consolidate the efficacy and prevent recurrence. However, for patients with more residual thyroid, since iodine 131 cannot directly kill the metastases and thyroxine preparation has to be stopped during iodine therapy, it increases the risk of tumor recurrence and dedifferentiation.
In addition to iodine therapy, thyroxine preparations (eugenol) are recommended for postoperative patients with differentiated thyroid cancer to prevent recurrence. According to the latest guidelines, patients with differentiated thyroid cancer are divided into two groups: high-risk and low-risk. The high-risk group includes: 1. age <15 years or >45 years, 2. male, 3. Nodule diameter >4 cm, 4. Extrathyroidal invasion, 5. History of radiation exposure, 6. Thyroid cancer-related disease, 7. Positive cut margins, 8. Distant metastasis, and 9. Extensive metastatic lymph node invasion in the cervical lymph nodes with lymph node envelope. The low-risk group includes: 1. 15 years < age < 45 years, 2. nodule diameter < 4 cm, 3. no history of radiation exposure, 4. no thyroid cancer-related disease, 5. negative cut margins, 6. no distant metastasis, 7. no metastasis to the lymph nodes in the neck, and 8. no other invasive variants. For the high-risk group, the guidelines recommend taking thyroxine preparations so that TSH is <0.1 mU/L; for the low-risk group, 0.1 < mU/L TSH <0.5 mU/L; and for the multi-year low-risk group, 0.3 mU/L < TSH <2.0 mU/L. Because suppression of TSH can cause certain toxic effects on the body, such as tachyarrhythmias (especially in the elderly), bone decalcification (especially in postmenopausal women), and thyrotoxicosis-related manifestations. Therefore, for each patient, the pros and cons of TSH suppression therapy need to be considered. In patients with long-term TSH suppression, a daily intake of calcium (1.2 mg/d) and vitamin D (1.0 U/d) should be ensured.
The overall 10-year survival rate of differentiated thyroid cancer is up to 85%. According to the aforementioned high- and low-risk staging, its 20-year survival rate: low-risk is about 90% and high-risk is about 61%. Even with metastases from other parts of the body, the 10-year survival rate of differentiated thyroid cancer can be 25% to 40%.
Post-operative iodine diet should be avoided for differentiated thyroid cancer, which includes consuming non-iodized salt and avoiding seafood. In addition, postoperative thyroid cancer patients should avoid fatigue and heavy physical work, and can take appropriate Chinese herbal medication.
Medullary thyroid cancer
Medullary thyroid cancer is a malignant tumor that occurs in the parathyroid cells (C cells) of the thyroid gland. Medullary thyroid cancer accounts for about 4% of thyroid cancer, of which 75% are sporadic cases and 25% are hereditary in families.
Patients with sporadic medullary carcinoma most often develop between the ages of 50 and 70 and are often seen with a lump in the anterior neck area or enlarged lymph nodes in the neck. If the tumor is huge, it may produce compression symptoms such as dyspnea and dysphagia; if the tumor invades the recurrent laryngeal nerve, hoarseness may occur. Currently, most patients are detected by thyroid ultrasound examination and thyroid function measurement before they have any conscious symptoms.
Patients with medullary carcinoma may show symptoms of carcinoid syndrome such as flushing, palpitation, diarrhea, and emaciation, but they are mostly not obvious under normal liver function, and are easily seen in patients with extensive intrahepatic metastases.
Medullary carcinoma can secrete many hormones, including calcitonin, calcitonin gene-related peptide, CEA, chromogranin A, serotonin, 5-hydroxytryptamine, ACTH, prostaglandins, growth inhibitory hormone and vasoactive intestinal peptide. When myeloid carcinoma occurs, these hormones may be elevated, especially calcitonin, which becomes a specific tumor indicator for myeloid carcinoma and can help in early clinical diagnosis and facilitate postoperative follow-up. If calcitonin exceeds 100ng/L, medullary carcinoma can be diagnosed.
Ultrasound is necessary for the diagnosis of medullary carcinoma and postoperative follow-up. ultrasound can not only observe the size, location and number of thyroid tumors, but also detect the condition of peripheral lymph nodes. In medullary carcinoma, ultrasound indicates that the masses are mostly located in the upper part of the thyroid gland, which can be single or multiple, hypoechoic, with calcification in the center of the masses, and the nodules have no acoustic corona and rich blood supply. Once medullary carcinoma is diagnosed, a CT scan of the chest and abdomen should be performed, because 10%-15% of patients have distant metastases at the time of initial diagnosis, and the preferred sites include mediastinum, liver, lung and bone.
Medullary thyroid carcinoma can develop lymphatic metastasis at an early stage and distant metastasis can occur through bloodstream, so the prognosis is worse than differentiated thyroid carcinoma. Since medullary carcinoma is ineffective with thyroxine suppression and iodine 131 therapy, surgery is the preferred and only possible cure for medullary carcinoma. The American Thyroid Association recommends total thyroidectomy and bilateral central group lymph node dissection as the basic procedure for medullary carcinoma. For clinically diagnosed medullary carcinoma, if the tumor is solitary and microfocal, calcitonin level is <400ng/L, and there is no sign of lymph node metastasis on imaging, total thyroidectomy and bilateral central group lymph node dissection is feasible. If the tumor diameter is >1cm or the lymph node metastasis in the lateral cervical region is suspected by ultrasound, lymph node dissection in the lateral cervical region on the affected side should be performed. For calcitonin level >400ng/L, lymph node dissection in the lateral cervical area should also be added if further examination clearly shows no distant metastasis. For patients with bilateral tumors or extensive lymph node metastasis in the cervical area on the side of the tumor, bilateral lymph node dissection in the cervical area should also be considered.
Prognosis: The malignancy of different medullary carcinoma cases varies greatly, some of them can be stable for many years or even insidious, while others are highly aggressive and have a high death rate. Overall, the 10-year survival rate associated with medullary thyroid carcinoma is 75%. Major prognostic factors include age at diagnosis, size of the primary lesion, presence of lymph node metastases and distant metastases. Survival rates according to TMN staging were 100%, 93%, 71%, and 21% for stages I, II, III, and IV, respectively.
For newborn offspring identified as MEN-2a family, blood should be drawn at 3-6 months for gene sequencing and calcitonin level measurement. If no mutation is found, no follow-up is necessary; if a mutation is found, calcitonin levels should be measured annually until 5 years of age. If calcitonin levels are found to be elevated during this period, surgery is indicated; if calcitonin levels remain stable at normal levels, prophylactic total thyroidectomy is recommended at age 5 years. In the newborn offspring of MEN-2b family, gene sequencing and calcitonin measurement are started at 1 to 3 months, and annual screening for medullary carcinoma is performed until the age of 3 to 5 years. For newborn offspring of the FMTC family, gene sequencing is performed from 6 months of age, and if mutations are present, calcitonin levels are monitored at 5, 7, and 9 years of age, and prophylactic total thyroidectomy is performed at 10 years of age.
Undifferentiated thyroid cancer
Undifferentiated thyroid cancer is a rare and highly malignant tumor, the incidence of which does not exceed 5% of thyroid cancer but accounts for 50% of thyroid cancer deaths.
The majority of patients present with a sudden onset of neck lump, which is hard, uneven, poorly defined and rapidly increasing in size. It may be associated with hoarseness, dyspnea and dysphagia, and localized lymph node enlargement, and may appear as a heterogeneous mass with unclear borders on ultrasound, often involving the entire lobe or gland. In most cases, necrotic areas may be present.
Because of the high malignancy of undifferentiated thyroid cancer, the disease develops very rapidly and easily invades the surrounding organs and tissues such as trachea, esophagus, nerves and blood vessels in the neck, therefore, it is often diagnosed at an advanced stage and cannot be removed surgically. In recent years, some people advocate that for early stage undifferentiated thyroid cancer, if the primary foci are small, lobectomy or total thyroidectomy can be performed, followed by external radiation and chemotherapy, which can also achieve very good results.
Prognosis: The death rate of undifferentiated thyroid cancer is about 50%, only very few patients can survive for a long time, and many patients die within a short time. Generally, the median survival period from diagnosis to death is only 4~8 months.