Thyroid carcinoma (TC) is the most common malignant tumor of the endocrine system. Based on histological characteristics, malignant tumors originating from thyroid follicular epithelium are primarily categorized into differentiated thyroid carcinoma (DTC), poorly differentiated thyroid carcinoma (PDTC), and anaplastic thyroid carcinoma (ATC). DTC mainly includes papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), and oncocytic carcinoma of the thyroid, accounting for over 90% of all thyroid cancers. Patients with early-stage DTC generally have a good prognosis, whereas ATC is highly aggressive with poor treatment response and prognosis. Malignant tumors originating from thyroid C-cells are classified as medullary thyroid carcinoma (MTC). This section focuses primarily on DTC.
Pathology
Papillary Thyroid Carcinoma (PTC)
PTC is the most common pathological type of thyroid cancer, comprising 65% to 93% of all cases. Its characteristic histopathological features include papillary structures in the cancer tissue, invasive growth, and the distinctive PTC nuclear features (nuclear enlargement, overlap, crowding; ground-glass nuclei; nuclear grooves and pseudoinclusions). PTC often has multifocality and a propensity to invade intraglandular and extrathyroidal tissues. It typically spreads via the lymphatic system but can also metastasize hematogenously, with distant metastases most commonly occurring in the lungs and bones.
Follicular Thyroid Carcinoma (FTC)
FTC accounts for approximately 6% to 10% of thyroid cancers and is more common in iodine-deficient regions. Histologically, FTC exhibits varying degrees of differentiation with mostly intact follicular structures and lacks the nuclear features of PTC. Poorly differentiated FTC shows solid growth patterns, incomplete follicular structures, or trabecular arrangements, with marked cellular atypia. FTC resembles follicular adenoma under microscopic examination, and diagnosis often requires postoperative pathological evaluation to assess for capsular, vascular, or adjacent tissue invasion. FTC primarily metastasizes hematogenously to the bones, lungs, and central nervous system.
Oncocytic Carcinoma
Oncocytic carcinoma accounts for about 5% of thyroid cancers. The tumor typically contains approximately 75% oncocytic cells with solid or solid/trabecular arrangements, though follicular arrangements may also be observed. It lacks the nuclear features of PTC and does not exhibit high-grade features such as tumor necrosis and ≥3 mitoses per 2 mm2. Oncocytic carcinoma metastasizes via both hematogenous and lymphatic routes and is more aggressive compared to the previous two pathological types.
Pathogenesis
A history of childhood head and neck radiation exposure is an important risk factor for thyroid cancer. Genetic mutations such as BRAF V600E and RAS, as well as RET/PTC gene rearrangements, lead to abnormal activation of signaling pathways like MAPK and PI3K, which play a key role in the development of thyroid cancer. Mutations in the TERT promoter and TP53 are associated with increased tumor invasiveness.
Clinical Features
Clinically, DTC most commonly presents as a thyroid nodule. Most patients are asymptomatic, and thyroid cancer is often detected incidentally during physical examination or imaging studies. In some cases, DTC may first present as pathological enlargement of cervical lymph nodes or distant metastases. Tracheal compression may cause cough and shortness of breath, recurrent laryngeal nerve involvement may lead to hoarseness, and esophageal compression can result in dysphagia or pain. Distant metastases may produce symptoms related to the affected organs.
Diagnosis
Ultrasound-guided FNA is the international standard for the preoperative diagnosis of DTC. Molecular testing can assist in diagnosing cytologically indeterminate nodules and in assessing the prognosis of DTC. A combination of BRAF V600E mutation with TERT promoter or TP53 mutations is indicative of poor prognosis.
Cervical ultrasound is effective for evaluating lymph node metastases, and suspicious lymph nodes can undergo biopsy for confirmation. Cervical CT, MRI, and 18F-FDG PET imaging are useful for assessing the involvement of extrathyroidal tissues and organs.
Treatment
The treatment of differentiated thyroid carcinoma (DTC) primarily includes surgical treatment, postoperative radioactive iodine (RAI) therapy, and thyroid-stimulating hormone (TSH) suppression therapy.
Surgical Treatment
Surgery is the preferred treatment method for DTC and involves removing the primary tumor and clearing affected lymph nodes. Common surgical procedures include total/near-total thyroidectomy and unilateral thyroid lobectomy (with isthmus resection). Total/near-total thyroidectomy allows for the removal of potential microscopic residual lesions, reduces postoperative recurrence rates, and facilitates postoperative monitoring for residual disease or recurrence. Unilateral thyroid lobectomy (with isthmus resection) can be selected for cases where the primary tumor is confined to a single thyroid lobe, measures ≤4 cm, has no extrathyroidal extension, no lymph node or distant metastasis, non-aggressive pathological subtypes, and no history of head and neck radiation exposure during childhood.
Therapeutic lymph node dissection is recommended for patients with preoperative evidence of cervical central or lateral lymph node metastases. Prophylactic central lymph node dissection may be performed for high-risk features, such as tumors >4 cm, extrathyroidal extension, or lateral neck lymph node metastasis, even without evidence of cervical central lymph node involvement.
Active surveillance is an option for non-aggressive PTC subtypes with tumor diameter ≤1 cm, no extrathyroidal extension, and no lymph node metastasis. In such cases, thyroid ultrasounds are conducted every six months. If the tumor increases in size by more than 3 mm or new lymph node metastases emerge during surveillance, surgery is recommended.
Common surgical complications include postoperative bleeding, lymphatic leakage, hypoparathyroidism, and recurrent laryngeal nerve injury. In elderly patients, additional attention is required for complications such as cardiopulmonary diseases and infections.
Postoperative pathological diagnosis, TNM staging, and recurrence risk stratification (see TSH suppression therapy) play a crucial role in determining the need for postoperative radioactive iodine therapy and guiding TSH suppression therapy.
Radioactive Iodine Therapy (131I Therapy)
Residual thyroid tissue in the thyroid bed and surrounding areas may remain after total thyroidectomy, affecting postoperative follow-up and monitoring. 131I therapy serves as an essential method to ablate residual thyroid tissue, as well as any residual or metastatic lesions. The uptake of 131I depends primarily on the expression level of sodium-iodide symporters (NIS) and is stimulated by TSH. Residual thyroid tissue and DTC cells express NIS and respond to TSH stimulation, which is the basis for effective 131I therapy.
131I therapy is indicated for patients with moderate-to-high recurrence risk, including extrathyroidal extension, vascular invasion, lymph node metastases, or aggressive pathological subtypes. The therapy is typically administered 6–12 weeks after surgery. To increase the therapeutic efficacy by enhancing iodine uptake, a low-iodine diet (iodine intake <50 µg/day) is followed for 2–4 weeks before therapy. TSH levels above 30 mU/L are achieved through two methods: (1) discontinuing levothyroxine (L-T4) for 3–4 weeks, or (2) intramuscular injection of recombinant human TSH (rhTSH) at 0.9 mg/day for two days, followed by 131I therapy on the third day.
131I therapy can be categorized based on its purposes:
- Ablative therapy (dose: 1.1–3.7 GBq): Removes residual thyroid tissue post-surgery, facilitating monitoring for residual disease, recurrence, or metastasis through serum thyroglobulin (Tg) levels and whole-body scanning (WBS).
- Adjuvant therapy (dose: 3.7–5.5 GBq): Removes suspected microscopic cancerous foci, improving disease-specific and disease-free survival.
- Therapeutic intervention (dose: 5.5–7.4 GBq): Targets unresectable local or distant metastatic lesions.
TSH Suppression Therapy
Postoperative TSH suppression therapy using L-T4 provides significant clinical benefits for DTC patients. The therapy aims to (1) meet the physiological need for thyroid hormone, and (2) suppress serum TSH levels using supraphysiological doses of L-T4. Reducing TSH stimulation of TSH receptors on DTC cells inhibits tumor growth and decreases the risk of recurrence. However, prolonged supraphysiological doses of L-T4 may lead to subclinical hyperthyroidism, increasing the risk of cardiovascular diseases and osteoporosis.
TSH suppression therapy requires balancing recurrence risk, treatment response efficacy, and the risk of adverse effects. Individualized TSH suppression targets are determined based on this comprehensive evaluation. For patients with low recurrence risk and good treatment response, partial suppression of TSH is sufficient. For patients with high recurrence risk or poor treatment response, strict TSH suppression is necessary. In high-risk patients with potential adverse effects, TSH levels may be set at a more relaxed target.
Initial recurrence risk within the first year after surgery may be stratified based on pathological subtype, tumor invasion extent, and lymph node metastases, as follows:
- Low risk: Intrathyroidal non-aggressive subtype with ≤5 involved lymph nodes (metastatic foci diameter <0.2 cm).
- Intermediate risk: Aggressive pathological subtype, microscopic extrathyroidal extension, vascular invasion, or >5 involved lymph nodes (metastatic foci diameter <3 cm).
- High risk: Extensive extrathyroidal extension, incomplete tumor resection, distant metastases, lymph nodes >3 cm in size, or high-risk mutation combinations (e.g., BRAF V600E with TERT promoter mutation or TP53 mutation).
Target TSH levels for low-risk patients are 0.5–2 mU/L, 0.1–0.5 mU/L for intermediate risk, and <0.1 mU/L for high-risk patients. The average L-T4 dose is 1.5–2.5 µg/kg/day.
Targeted Therapy
For advanced radioiodine-refractory DTC, multi-target tyrosine kinase inhibitors (TKIs), such as sorafenib and lenvatinib, show potential clinical application. Side effects of these drugs and the requirement for maintenance therapy necessitate careful management.