Why does thyroid cancer occur?
Some experts believe that it is related to chronic thyroid stimulating hormone, and ionizing radiation can also lead to thyroid cancer.
What are the types of thyroid cancer? What is the degree of malignancy?
Different pathological types of thyroid cancer have different development and metastatic pathways, and the treatment varies, and can be divided into the following types.
Papillary carcinoma: It accounts for about 60% of thyroid carcinoma and is more common in young people, with low malignancy, slow growth and metastasis mostly in deep cervical lymph nodes, while some believe that papillary carcinoma is polycentric and can also metastasize to the opposite side.
Follicular carcinoma: It accounts for about 20% of thyroid carcinoma, more frequent in middle-aged people, with moderate malignancy and rapid development. However, it mainly metastasizes to bone and lung through blood.
Medullary carcinoma: It accounts for 5-10% of thyroid cancer and occurs in parafollicular cells (C cells) other than follicular epithelium. Familial cancer accounts for about 80% of cases, while sporadic cancer accounts for 20%. Microscopically, the cells are arranged in bands or bundles without papillae or follicular structures, and there are amyloid deposits in their interstitium. The interstitium has amyloid deposits. It secretes large amounts of calcitonin. Histologically undifferentiated, but its biological characteristics are different from undifferentiated carcinoma. It is moderately malignant, with early cervical lymph node metastasis and distant metastasis in advanced stages. Familial medullary carcinoma mostly involves bilateral lobes at the same time.
Undifferentiated carcinoma: It accounts for 10-15% of thyroid carcinoma, and can be classified into small cell and giant cell according to its cell morphology. It occurs mostly in the elderly, develops rapidly, is highly malignant, metastasizes to the cervical lymph nodes at an early stage, can invade the laryngeal nerve, trachea or esophagus, and can metastasize to bone and lung via blood.
5.Squamous cell carcinoma: It is rare, accounting for 0.8-2.2% of thyroid carcinoma, mostly seen in the elderly, and has no obvious relationship with gender, and may come from squamous metaplasia of thyroid follicular epithelium, or from embryonic residual squamous epithelial tissue. It is generally of unifocal origin, with strong infiltrative tumor cells, fast growth and short multiplication time, and lymph node metastasis.
What are the symptoms of thyroid cancer?
In the early stage of the disease, there are no obvious symptoms, but a hard and uneven nodule in the thyroid tissue. Patients may have pain in the ear, occipital and shoulder areas. Local metastases are often found in the neck, with hard, fixed lymph nodes. Distant metastases are usually found in the flat bones (e.g., skull, vertebrae, and pelvis) and lungs.
In some patients, the thyroid mass is not obvious, but metastatic cancer in the neck, lungs, and bones is the prominent symptom. Therefore, the thyroid should be carefully examined when metastatic carcinoma with unknown primary focus is present in the neck, lungs, and bones.
Medullary carcinoma is often familial and patients may have other endocrine gland diseases (pheochromocytoma and/or parathyroid hyperplasia or tumor) at the same time. As the carcinoma produces 5-hydroxytryptamine and calcitonin, clinical symptoms such as diarrhea, palpitations, flushing and decreased blood calcium may occur.
4. How to diagnose thyroid cancer?
Thyroid nodules found in children and men should be highly suspected to have cancer possibility. About 50% of thyroid nodules found in children are thyroid cancer, while adult men are two times more likely to have a single nodule in the thyroid gland as thyroid cancer than women. If a thyroid nodule grows rapidly, its surface is not smooth, its texture is hard, its mobility decreases when swallowing, or if a thyroid nodule that has existed for many years increases significantly in a short period of time, you should be alert to thyroid cancer. If the thyroid mass invades the surrounding tissues, corresponding symptoms may appear, such as hoarseness, dyspnea, Horner’s syndrome, etc. Sometimes, enlarged lymph nodes in the neck may appear.
Ultrasonography can distinguish whether a thyroid nodule is cystic or solid. If the ultrasound shows a solid nodule with microcalcifications, irregular margins of the hypoechoic nodule and an abundant blood supply in the nodule, it suggests that the nodule may be malignant.
Fine-needle aspiration cytology (FNA) is the most accurate and cost effective method for evaluating thyroid nodules. Traditionally, FNA biopsy results have been classified into four categories: inconclusive, malignant, indeterminate (or suspicious for new organisms), and benign. The sensitivity, specificity, and accuracy of FNA are influenced by many factors such as puncture technique, sampling site, staining method, and diagnostic experience, etc. Most of the literature reports of FNA accuracy above 80% are from cytopathologists at larger medical centers. Without skilled puncture technique and extensive experience in cytopathology diagnosis, the sensitivity, specificity and accuracy of FNA are difficult to meet clinical requirements.
The final diagnosis should be determined by pathological section examination. Therefore, pathological section examination should be routinely done for each resected thyroid nodule specimen, and if thyroid cancer is suspected before surgery, frozen section examination should be done intraoperatively in order to make a clear diagnosis and choose the appropriate surgical method.
V. How to treat thyroid cancer?
1.Surgical treatment: The malignant degree and metastatic pathways of thyroid cancer are different for each pathological type, so the treatment principles are also different.
Papillary carcinoma and follicular carcinoma are less malignant and belong to differentiated thyroid cancer. There is no unified opinion on the scope of thyroid surgery and whether to perform neck dissection.
There are three types of thyroid surgery suitable for differentiated thyroid cancer: lobectomy, subtotal thyroidectomy (removal of most of the visible thyroid tissue, leaving only a small amount of tissue (<1 g) attached to the recurrent laryngeal nerve into the cricothyroid muscle) and total thyroidectomy.
It is generally accepted that for papillary carcinoma with tumor diameter ≤ 1.0 cm, confined to the gland without extraperitoneal invasion, and without cervical lymph node metastasis on clinical and imaging examination and intraoperative visual examination, lobectomy of the affected thyroid gland is feasible.
Near-total thyroidectomy or total thyroidectomy should be performed if the following conditions exist.
①Tumor diameter ≥ 4.0 cm;
② localized extra-thyroidal invasion visible to the naked eye (cT4 stage);
③ Clinically significant lymph node metastasis (cN1 stage);
(iv) distant metastasis (cM1 stage). Patients with papillary carcinoma aged <15 years have a higher recurrence rate, and the above-mentioned procedures are also recommended.
If the size of the cancer is 1.0-4.0 cm, but still confined to one side of the glandular lobe gland, no extra-thyroidal invasion by the naked eye, and no cervical lymph nodes or distant metastases are found on physical examination and imaging, lobectomy of the affected side of the thyroid gland can be performed, as well as sub-total or total thyroidectomy. If the following conditions exist, more consideration can be given to subtotal thyroidectomy or total thyroidectomy.
①Thyroid nodules are present on the opposite side of the tumor;
②History of head and neck radiation treatment;
③History of differentiated thyroid cancer in first-degree relatives of the patient;
④Age >45 years old.
If the lesion is confined to the isthmus, total thyroidectomy is recommended. If the mass is less than 1.0 cm, confined to the gland without extra-thyroidal invasion, and no cervical lymph nodes or distant metastases are seen in clinical and imaging examinations, isthmus resection and major lobectomy on both sides of the gland can also be performed.
The rate of lymph node metastasis at the time of diagnosis of papillary carcinoma is 20% to 50%. The central area is the most common site of lymph node metastasis. If lymph node metastasis in the central region is detected by preoperative imaging and intraoperative visualization, therapeutic lymph node dissection in the central region is required. If lymph node metastasis in the central region is not detected by preoperative imaging and intraoperative visual examination, but the tumor is >4.0 cm or has extraperitoneal invasion (invasion of anterior cervical muscle, soft tissue around the thyroid gland, subcutaneous soft tissue, larynx, trachea, esophagus and laryngeal nerve), or is accompanied by lymph node metastasis in the lateral cervical region, lymph node dissection in the central region (region VI) during the first surgery can improve the survival rate, reduce the risk of lymph node recurrence and avoid recurrence. If the laryngeal nerve and parathyroid gland are easily damaged by reoperation, ipsilateral or bilateral preventive central zone dissection should be performed. Small (tumor <4.0 cm without extraperitoneal invasion, T1 or T2), non-invasive papillary carcinoma with negative clinical lymph nodes and most follicular carcinomas can be excluded from prophylactic debulking.
If lymph node metastasis in the lateral cervical region is detected by preoperative ultrasound or intraoperatively, lymph node dissection in the lateral cervical region is required. Scope of lymph node dissection: At present, for most differentiated thyroid cancers, it is mostly recommended to dissect lymph nodes in zones IIA, III, IV and most of zone VB adjacent to zone IV. If lymph nodes in zone IIA have obvious metastasis, zone IIB should be cleared at the same time. If there is involvement of lymph nodes in zone I and zone Va, they should also be cleared at the same time. If there is metastasis in the anterior superior mediastinal lymph nodes (zone VII), this zone should be cleared.
For local metastases or recurrent tumors limited to the neck, surgical resection should be performed; for tumors infiltrating into the esophagus and respiratory tract, surgery combined with radioiodine or radiotherapy should be used.
The scope of surgery for medullary carcinoma is total thyroidectomy. Since medullary carcinoma appears early with cervical lymph node metastasis, lymph node dissection should be performed in the central region bilaterally. If there is metastasis in the lymph nodes of the lateral cervical region, lymph node clearance of the affected side or bilateral lateral cervical region should be performed at the same time. If lymph nodes in the lateral cervical region have metastasis although no metastasis is found clinically, but there is lymph node metastasis visible to the naked eye in the central region, prophylactic ipsilateral lymph node clearance in the lateral cervical region is also recommended.
Undifferentiated carcinoma is a highly malignant tumor, and most of the lesions are already widely infiltrated or have distant metastases at the first visit, which are not suitable for surgical treatment or can only be biopsied for a definite diagnosis. Or tracheotomy may be performed to relieve airway compression. Occasionally, however, there are small lesions that are suitable for surgery, and radical surgery should be actively pursued. After surgery, radiation therapy should be added. In some cases, chemotherapy plus radiotherapy can be used to achieve certain effect.
Squamous cell carcinoma is also of fast development, high malignancy and early invasion of other important organs. The current treatment method is to excise the tumor as far as possible, followed by radical radiotherapy, or radical radiotherapy first and then surgery under clear diagnosis.
2.Endocrine therapy: differentiated thyroid cancer cells express TSH receptors on the surface and respond to TSH stimulation, which increases the expression of thyroid-specific proteins and cell growth rate. Giving thyroid cancer patients higher than physiological dose of L~T4 can inhibit pituitary TSH secretion and reduce the risk of thyroid cancer recurrence. There are side effects of TSH suppression therapy such as causing subclinical hyperthyroidism, exacerbating angina, developing atrial fibrillation and an increased risk of osteoporosis in menopausal women. It is recommended that the appropriate dose of thyroxine suppression therapy be determined according to a postoperative thyroid cancer recurrence risk stratification system.
Characteristics of patients in the low-risk group.
(i) No local or distant metastases;
(ii) All tumors visible to the naked eye have been removed;
③No tumor invasion in nearby tissue structures;
④The tumor is not of an aggressive histological type such as hypercellular, islet-like, or columnar cells;
⑤ If treated with 131 iodine, no uptake of 131 iodine outside the thyroid bed is detected during the first post-treatment whole body radioactive iodine scan (RxWBS);
(vi) No vascular invasion;
(vii) Negative clinical lymph nodes or ≤5 pathological lymph nodes with micrometastases (maximum diameter <0.2 cm);
(8) Follicular subtype of papillary thyroid carcinoma confined to the thyroid gland with envelope;
(9) Well-differentiated follicular carcinoma with envelope invasion but <4 lesions with vascular invasion confined to the thyroid gland.
Patients in the intermediate risk group.
①Tumor microscopic invasion of soft tissues surrounding the thyroid gland was found at the time of initial surgery;
(ii) 131 iodine uptake outside the cervical thyroid bed detected on whole body radioactive iodine scan after ablation of thyroid remnants;
(iii) Invasive histological type (hypercellular, columnar cell, diffuse sclerotic type, poorly differentiated component);
④Papillary carcinoma with vascular invasion;
⑤ clinical lymph node metastasis, or >5 pathological lymph node metastasis with metastatic lymph node maximum diameter <3.0 cm.
Patients in the high-risk group.
①Tumor invasion of soft tissues around the thyroid visible to the naked eye;
② Incomplete resection of tumor;
③Distant metastasis;
④Postoperative examination revealed that the Tg concentration exceeded the standard indicating distant metastasis;
⑤ Pathological confirmation of any metastatic lymph node with a maximum diameter ≥ 3.0 cm;
(6) Follicular thyroid cancer with extensive vascular invasion (>4 lesions with vascular invasion).
It is recommended that TSH should be suppressed to <0.1 mU/L for patients at high risk of thyroid cancer recurrence and to 0.1-0.5 mU/L for patients at intermediate risk, while maintaining T3 and T4 in normal range. For low-risk patients who undergo lobectomy, TSH can be suppressed to 0.5-2 mU/L levels. For patients who underwent total resection without ablation, or whose thyroglobulin is still detectable at low levels after total resection and ablation, TSH should be suppressed to 0.1-0.5 mU/L. For low-risk patients with undetectable thyroglobulin after total resection and ablation, TSH can be suppressed to a level of 0.5-2 mU/L. Low-risk patients who survive disease free after 5-10 years of treatment may be treated with replacement therapy only, with TSH controlled in the normal range. Patients receiving long-term TSH suppression therapy should take calcium and vitamin D.
3.Radiation therapy: Undifferentiated cancer is mainly treated with external radiation therapy. Well-differentiated papillary and follicular carcinoma are not sensitive to external radiation therapy. External radiation therapy is used only for small amount of residual lesions after surgery or for isolated distant metastases that cannot be removed by surgery.
The purpose of radioiodine 131 ablation after surgery to remove residual thyroid gland is to reduce local recurrence of cancer, facilitate whole body iodine scan and monitor thyroid cancer recurrence and metastasis by serum Tg measurement. Retrospective studies have found that this method reduces tumor recurrence and mortality in high-risk patients, but similar effects have not been found in studies of low-risk patients, and there is a lack of prospective findings.
All patients with extra-thyroidal invasion visible to the naked eye or distant metastases should be treated with radioiodine 131 therapy to remove residual thyroid and possible micro-metastases.
Iodine 131 therapy is not routinely recommended for patients with papillary carcinoma ≤1.0 cm, confined to the gland without extrathyroidal invasion, and without lymph nodes or distant metastases, regardless of whether the carcinoma is multiple.
If the cancer size is between 1.0 and 4.0 cm, without extra-thyroidal invasion and without lymph node metastasis, radioiodine therapy is not recommended. However, patients with invasive histological type or with vascular invasion can be considered for radioiodine therapy.
Other cases can be selectively treated with radioactive iodine 131. For cancer foci >4 cm, or cancer foci of any size with microscopic extrathyroidal cancer infiltration, or the presence of lymph node metastasis in the lateral cervical region/anterior superior mediastinum, or the presence of more severe lymph node metastasis in the central region (>5 metastatic lymph nodes in the central region, or metastatic lymph nodes >0.5 cm, especially metastatic lymph nodes >2 cm or with lymph node extravasation), non-stimulated thyroglobulin found during the follow-up of total thyroidectomy The treatment with radioactive iodine 131 may be beneficial if the thyroid is >5 to 10 ng/mL.
Follicular carcinoma and Hurthle cell carcinoma are generally considered high-risk tumors and should be treated with RAI. However, follicular thyroid carcinoma with only envelope invasion and no vascular invasion (also called “minimal invasive follicular carcinoma”) has a very good prognosis with surgical resection, and these patients do not require iodine 131 therapy.
Before treatment, levothyroxine should be stopped for 3 to 4 weeks to raise TSH level above 30 mU/L. For those who are on high iodine diet, they should change to low iodine diet for 1 to 2 weeks, and for those who cannot tolerate thyroxine discontinuation or whose TSH does not rise after thyroxine discontinuation, recombinant TSH can be used before treatment. 131 iodine therapy is not effective for undifferentiated carcinoma and medullary carcinoma because they do not absorb iodine.
4. Withholding treatment and active monitoring: For micro papillary thyroid carcinoma (<0.7cm) found by physical examination, if there is no tendency to invade surrounding organs, no lymph node metastasis and distant metastasis, no family history of thyroid cancer, no history of childhood radiation therapy and other high-risk factors, according to the patient's will, one can choose not to operate immediately and carry out close observation. According to long-term observation of bulk cases, about 90% of micro papillary thyroid carcinoma have no obvious progression, and about 10% of micro papillary thyroid carcinoma show signs of lymph node metastasis in the neck and require surgery, most of which have little effect on the outcome after timely surgical treatment. Especially for patients of advanced age, with serious heart and lung comorbidities and high risk of surgery, close observation instead of active treatment may be a better choice overall.
What should be the follow-up and review after thyroid cancer surgery?
The purpose of follow-up for patients with differentiated thyroid cancer is to monitor and manage the recurrence and metastasis of the tumor. The focus of long-term follow-up and treatment is different for patients with different risk levels. For low-risk patients (i.e., no local or distant metastases after initial surgery and radioiodine removal of the residual thyroid gland; all tumors visible to the naked eye have been removed; the tumors have not invaded local tissues and surrounding blood vessels; the tumor pathology is not aggressive such as high-cell carcinoma, insular carcinoma, or columnar carcinoma; no 131I uptake outside the thyroid bed on whole-body scans after initial 131I treatment), the purpose of long-term follow-up and management is is to monitor for tumor recurrence without the need for more aggressive therapy. For intermediate-risk patients (i.e., initial surgery with microscopic detection of tumor invasion into the soft tissues around the thyroid gland or into the blood vessels or aggressive type of pathology), a more aggressive strategy should be used in long-term follow-up and treatment to closely monitor for early detection of tumor recurrence and to take effective therapeutic measures. For high-risk patients (i.e. at the time of initial surgery. If the tumor is seen to have invaded into the surrounding tissues and not completely removed or if the tumor has distant metastasis or if 131I uptake is found in the extra-thyroidal area during radioiodine scan after removal of the residual thyroid gland), long-term follow-up and treatment should focus on treating or delaying tumor-related diseases and reducing the morbidity and mortality rate; or preventing tumor growth and reducing tumor size.
Role of serum Tg (thyroglobulin) assay: Serum Tg assay is highly specific and sensitive in monitoring residual and recurrent thyroid cancer. In particular, its sensitivity is highest after thyroidectomy and radioiodine removal of the residual thyroid, discontinuation of thyroxine or stimulation with recombinant TSH. It is recommended that serum Tg levels should be measured every 6 to 12 months during follow-up for total or subtotal thyroidectomy and radioiodine removal of the residual thyroid gland, and that serum thyroglobulin antibodies (TGAb) should be measured at the same time. When serum Tg>2ng/mL after TSH stimulation or Tg>1ng/mL in TSH suppressed state, it indicates possible tumor recurrence. Non-stimulated thyroglobulin >5 to 10 ng/mL is almost certain to recur. The sensitivity and specificity of Tg assays vary considerably from laboratory to laboratory by different methods, so patients are advised to have their assay performed by the same method in the same laboratory. As the sensitivity of commercially available Tg assays increases, the need to stimulate Tg assays will become less important.
Anti-thyroglobulin antibodies (TgAb) should be measured at the same time as thyroglobulin because TgAb is present in 25% of patients with thyroid cancer and its presence can interfere with the detection of thyroglobulin. Although the clinical importance of TgAb remains unclear, the persistence of TgAb more than 1 year after total thyroidectomy + iodine 131 ablation may indicate the presence of residual thyroid tissue or an increased risk of possible recurrence. Only 3% of the patients with Tg undetectable and TgAb below 100u/mL had recurrence. In patients with autoimmune thyroid disease at the time of surgery, TgAb may persist for a long time.1 A study of 116 patients with positive pre-thyroidectomy TgAb showed that some patients had detectable TgAb for more than 20 years without recurrence, and the median time to resolution of TgAb was 3 years.
Role of diagnostic whole-body scans, ultrasound and other imaging: In follow-up, diagnostic whole-body scans are most valuable when there is no or little surviving thyroid tissue. In follow-up, low-risk patients do not require routine diagnostic whole-body scans; in high- or intermediate-risk patients, low-dose 131I or 131I diagnostic whole-body scans are feasible at 6 to 12 months of follow-up. Ultrasound examination of the neck is highly sensitive to detect metastasis in the neck. Ultrasound examination of the neck should be performed at 6 and 12 months of follow-up to assess the condition of the thyroid gland and bilateral cervical lymph nodes, after which it can be reviewed annually for at least 3 to 5 years according to the patient’s serum level and risk of recurrence.
7. How long can thyroid cancer live after treatment? Can it be cured?
Most thyroid cancers are differentiated thyroid cancers with low malignancy and slow development, so it is generally believed that thyroid cancer has a good prognosis. In fact, the prognosis of different pathological types of thyroid cancer is significantly different. There are many factors affecting the prognosis of thyroid cancer, the main ones are pathological type, clinical stage, age, gender and whether the treatment is appropriate.
1.Pathological type
Well-differentiated papillary and follicular carcinomas are low-grade malignant carcinomas with good prognosis, and most of them can be cured if treated timely and reasonably. However, undifferentiated carcinoma is not, and it is highly malignant, develops quickly and has poor prognosis. Except for a few patients with early detection, timely treatment and thorough surgery, who may have a 10-year survival rate, most of them die within 1-2 years. The malignancy of medullary carcinoma is between the above two types of carcinomas, if the diagnosis and treatment are timely and the surgery is thorough, the 10-year survival rate can reach 82%, otherwise, the prognosis is not good.
2.Clinical stage
Once the primary foci infiltrate outward, the prognosis is obviously poor, which is basically consistent with the national and international data.
3.Gender and age
Most foreign scholars also believe that female patients have a better prognosis than males. Age is also an important factor, regardless of gender, as the age of patients, their survival rate gradually decreases; even in the same period of disease, the prognosis of young people is still better than that of older people.
4.The degree of eradication
Although most thyroid cancers have a good prognosis, the thoroughness of treatment is still an important factor in determining the prognosis.