Thyroid cancer is the most common malignancy of the endocrine system and also the most prevalent malignant tumor in the head and neck region, accounting for approximately 1–2% of all cancers. The disease predominantly affects women and has shown a rising incidence in recent years. Most thyroid cancers, with the exception of medullary thyroid carcinoma, originate from follicular epithelial cells.

Pathology

Thyroid cancer is classified into four types: papillary carcinoma, follicular carcinoma, anaplastic thyroid carcinoma, and medullary thyroid carcinoma. Papillary carcinoma and follicular carcinoma are collectively referred to as differentiated thyroid carcinoma, comprising more than 90% of all thyroid cancers.

Papillary Carcinoma

Papillary carcinoma occurs most commonly in young and middle-aged women, especially those aged 21–40 years. It accounts for about 70% of adult thyroid cancers and is the predominant type in pediatric thyroid cancer. This type is well-differentiated, slow-growing, and has low malignancy. It often presents with multicentric lesions and early cervical lymph node metastasis, but the prognosis remains favorable.

Follicular Carcinoma

Follicular carcinoma accounts for approximately 15% of thyroid cancers and is more frequently observed in women around the age of 50. It is moderately malignant and tends to invade blood vessels. Cervical lymph node metastasis occurs in about 10% of cases, and its prognosis is less favorable compared to papillary carcinoma.

Anaplastic Thyroid Carcinoma

Anaplastic thyroid carcinoma constitutes 5–10% of thyroid cancers and frequently occurs in the elderly. It is highly aggressive and rapidly progresses, with about 50% of cases showing early lymph node metastasis or local invasion of the recurrent laryngeal nerve, trachea, or esophagus. Hematogenous metastasis to distant sites is common. The prognosis is extremely poor, with an average survival of 3–6 months and a 1-year survival rate of only 5–15%.

Medullary Thyroid Carcinoma

Medullary thyroid carcinoma, which is rare, arises from parafollicular cells (C cells) capable of secreting calcitonin. Microscopically, the tumor shows a nest-like or bundle arrangement of the cells, lacking papillary or follicular structure, and demonstrating amyloid deposits in the stroma. Although it appears poorly differentiated, its biological behavior differs from anaplastic carcinoma, with moderate malignancy. Cervical lymph node and hematogenous metastases can occur.

Clinical Manifestations

The primary clinical presentation of thyroid cancer is a neck mass or thyroid nodule, often discovered incidentally or during physical examinations. The condition lacks specific symptoms, and its nonspecific clinical features and complex histopathology result in a generally low rate of preoperative diagnosis.

Papillary and follicular carcinomas are often asymptomatic in the early stages. In some cases, cervical lymphadenopathy prompts medical attention, particularly in papillary carcinoma. As the disease progresses, the mass gradually enlarges, becomes firm, and shows reduced mobility during swallowing.

Anaplastic thyroid carcinoma progresses rapidly and invades surrounding tissues. Advanced stages may lead to hoarseness, difficulty swallowing, dyspnea, and Horner's syndrome due to compression of the cervical sympathetic nerve. Pain in the ear, occiput, or shoulders may occur due to involvement of the superficial branches of the cervical plexus. Cervical, upper mediastinal lymph node metastases and distant organ metastases are common.

Medullary thyroid carcinoma presents with a neck mass and systemic symptoms resulting from the secretion of serotonin and calcitonin by the tumor. These symptoms may include diarrhea, palpitations, facial flushing, and hypocalcemia. A family history of the disease may suggest multiple endocrine neoplasia type II (MEN-II).

Diagnosis

Thyroid cancer should be suspected in cases of firm, fixed thyroid masses, cervical lymphadenopathy, compressive symptoms, or long-standing thyroid nodules that rapidly enlarge over a short period. Several diagnostic methods can provide further clarification.

Ultrasound Examination

Ultrasound findings indicative of malignancy include hypoechoic or markedly hypoechoic lesions, solid nodules, ill-defined and irregular borders (aspect ratio ≥1), increased central vascularity, and multiple echogenic foci resembling microcalcifications. Calcification is a relatively specific marker for thyroid cancer because malignant cells are large, overlapping, and poorly differentiated, resulting in an echogenic tumor that lacks strong reflective interfaces. However, as the disease progresses, nodules may exhibit mixed solid-cystic echotexture, hyper-echogenicity, or pseudocapsule appearance.

Radionuclide Scanning

Thyroid cancer typically appears as cold or cool nodules on radionuclide scans, while warm nodules are uncommon, and hot nodules are rare. Thyroid scans can provide information on thyroid functional activity; however, the limitations of this modality must be considered. A cold nodule does not necessarily indicate malignancy, as most cold nodules are benign. Functional activity is generally not a definitive criterion for distinguishing thyroid cancer.

Cytological Examination and Biopsy

Fine-needle aspiration cytology (FNAC) is useful in diagnosing thyroid cancer. FNAC is warranted for solid nodules larger than 1 cm, mixed cystic-solid nodules larger than 1.5 cm, or nodules suspected of malignancy on ultrasound. The presence of cancer cells in the aspirate often indicates thyroid cancer, but a negative result does not exclude malignancy. For lesions smaller than 1 cm, ultrasound-guided fine-needle biopsy may be performed. This is currently the most effective method for diagnosing nodular thyroid disease and differentiating between benign and malignant thyroid nodules. It is safe, cost-effective, reliable, and has a diagnostic accuracy exceeding 80%.

CT Examination

Thyroid cancer appears as hypodense or isodense lesions within the gland, sometimes accompanied by hyperdense calcifications. Non-contrast imaging shows uneven or homogeneous density, while contrast enhancement reveals inhomogeneous enhancement, occasionally homogeneous but less intense than normal thyroid parenchyma. The lesion margins are irregular and poorly defined, and continuity may be disrupted. Psammoma body calcifications are a characteristic feature of thyroid cancer. CT scanning can also identify cervical lymph node metastasis.

MRI Examination

Thyroid cancer typically presents as abnormal masses within the gland showing high signal intensity on both T₁-weighted and T₂-weighted images, with heterogeneous signal intensity, unclear borders, and irregular morphology. Contrast enhancement shows heterogeneous enhancement, while areas of cystic degeneration or necrosis demonstrate even higher signal intensities on both T₁- and T₂-weighted images. Calcifications appear as low-signal areas on both T₁- and T₂-weighted images. MRI may also reveal blurred distinctions between the thyroid and nearby muscles or blood vessels, along with features indicative of cervical lymph node metastasis.

Serological Examination

Levels of total T₃ and total T₄ in serum generally remain unchanged. Measurement of serum calcitonin can assist in diagnosing medullary thyroid carcinoma.

Intraoperative Frozen Section and Histopathological Examination

Due to the lack of specific clinical manifestations unique to thyroid cancer, intraoperative frozen section analysis has become an important diagnostic method. This enables rapid determination of the pathological type and nature of a thyroid mass during surgery, helping to decide the extent of thyroidectomy. Postoperative evaluation of tissue using paraffin embedding and routine histopathology remains necessary for definitive diagnosis.

Differential Diagnosis

Thyroid Adenoma

The clinical presentation often includes a solitary, smooth-surfaced, slowly growing mass with notable mobility during swallowing. Ultrasound typically shows a solid, mixed, or cystic nodule with clear boundaries and homogeneous internal echogenicity, with solitary nodules being the most common. CT imaging reveals a inhomogeneous, hypodense, round nodule with clear demarcation from the surrounding normal hyperdense thyroid tissue. MRI findings show a solitary nodule within the thyroid gland appearing as a high-signal, homogeneous lesion on T₁- and T₂-weighted images, with a clear round or oval boundary and no significant abnormalities in the surrounding thyroid parenchyma. Contrast-enhanced scans reveal homogeneous or slightly inhomogeneous enhancement of the lesion, with enhancement intensity lower than that of normal thyroid tissue. Tumor borders appear clearer than on plain CT or MRI scans. Some thyroid adenomas may undergo malignant transformation, with a transformation rate of 10–20%. Suspicion of malignancy arises in cases of rapid tumor growth, restricted or fixed tumor mobility, compressive symptoms such as hoarseness or dyspnea, a firm and irregular tumor surface, or cervical lymphadenopathy. Definitive diagnosis requires pathological examination.

Nodular Goiter

This condition is often characterized by multiple nodules. Ultrasound shows nodules with smooth surfaces, intact capsules, and hypo- or isoechoic patterns. In contrast, solitary nodules are the most significant indicator of thyroid cancer, as approximately 80% of differentiated thyroid carcinomas and 2/3 of undifferentiated thyroid carcinomas present as solitary nodules. Nevertheless, some thyroid cancers also manifest as multiple nodules. Additionally, thyroid cancer is often associated with large, hard lymph nodes palpable in the lower third of the neck, particularly in pediatric and young adult patients with papillary carcinoma. A previously stable thyroid nodule that suddenly enlarges rapidly and painlessly should raise suspicion of malignancy.

Chronic Thyroiditis

This includes chronic lymphocytic thyroiditis and chronic fibrous thyroiditis. Chronic lymphocytic thyroiditis, also known as Hashimoto’s thyroiditis, progresses slowly with diffuse thyroid enlargement that is firm, elastic, and rubber-like, presenting a smooth surface without adhesion to surrounding tissues. The thyroid gland moves with swallowing and may be accompanied by mild hypothyroidism. Advanced stages may lead to significant compression symptoms. Erythrocyte sedimentation rate (ESR) is often elevated. On ultrasound, the thyroid appears irregularly enlarged with a generally smooth outline and areas of inhomogeneous hypoechogenicity within the lesions. In cases where differentiation is challenging, fine-needle aspiration cytology aids in diagnosis.

Treatment

Surgical resection serves as the primary treatment method for all types of thyroid cancer except anaplastic carcinoma. Additional treatments, including radioactive isotopes, thyroid hormones, and external radiation, are also used as adjunct therapies.

Surgical Treatment

This approach includes thyroidectomy and cervical lymph node dissection.

Thyroidectomy

The completeness of tumor resection is an independent prognostic factor. Studies indicate that near-total or total thyroidectomy is associated with lower recurrence rates. Among low-risk cases, the 30-year recurrence rate is 14% following lobectomy but only 4% after total thyroidectomy. In high-risk cases, the local recurrence rate is 26% after lobectomy compared to 10% after bilateral total thyroidectomy. Although total thyroidectomy can significantly reduce local recurrence, it increases the risk of both short- and long-term complications, such as recurrent laryngeal nerve injury and severe hypoparathyroidism. Treatment decisions should be based on risk stratification. For low-risk cases, thyroid lobe and isthmus resection may suffice if the surgical margins are tumor-free. Low-risk cases include solitary, well-differentiated thyroid carcinomas confined to one lobe with a diameter ≤4 cm, no lymph node metastasis, low recurrence risk, no nodules in the contralateral lobe, and minimal stromal invasion.

High-risk cases warrant near-total or total thyroidectomy of the contralateral lobe. High-risk factors include prior neck radiation therapy, tumor diameter exceeding 4 cm, extracapsular invasion, bilateral multifocal tumors, highly aggressive histological subtypes, local or distant metastasis, non-microscopic papillary carcinoma in patients under 15 years of age, and poorly differentiated carcinoma.

Cervical Lymph Node Dissection

Thyroid cancer typically spreads sequentially along lymphatic drainage pathways, initially affecting the paratracheal lymph nodes (level VI), followed by the jugular chain nodes (levels II–IV), posterior cervical nodes (level V), or the mediastinum. Level VI remains the most common site of metastasis, while "skip metastasis" (absence of central neck lymph node metastasis with involvement of other cervical regions) is rare. Preoperative assessment of lymph node status is crucial for determining treatment strategy and prognostic evaluation. Preoperative evaluation includes neck palpation, ultrasound, CT, MRI, and, if necessary, fine-needle aspiration biopsy to assess the size, location, number, and extracapsular invasion of lymph nodes.

Although occult lymph node metastases are common in differentiated thyroid carcinoma, they do not significantly affect survival rates. Routine prophylactic lymph node dissection is not generally recommended due to the increased risk of complications such as recurrent laryngeal nerve and parathyroid injury, which may be harder to manage than cancer recurrence. Most experts advocate for therapeutic lymph node dissection instead of prophylactic dissection. In low-risk patients with microcarcinomas, cervical lymph node dissection may not be necessary if preoperative imaging and intraoperative exploration reveal no lymphadenopathy. For cases with preoperative or intraoperative evidence of metastasis or cN0 cases with high-risk factors (e.g., T₃–T₄ lesions, multifocal cancers, childhood exposure to ionizing radiation), central neck lymph node dissection is advised. This involves removing lymphatic tissue adjacent to the common carotid artery, around the thyroid, in the tracheoesophageal groove, and in the upper mediastinum. Functional lateral neck dissection should be performed only when clinical evidence of metastasis exists, while prophylactic lateral neck dissection is not recommended. Cases with advanced disease—where tumors invade the internal jugular vein, sternocleidomastoid muscle, or accessory nerve—may necessitate radical or modified radical neck dissection.

Endocrine Therapy

Patients who undergo near-total or total thyroidectomy require lifelong thyroid hormone replacement therapy to prevent hypothyroidism and suppress TSH levels. Both papillary and follicular carcinoma cells express TSH receptors, and TSH stimulation promotes thyroid cancer cell growth. Optimal thyroid hormone dosages and treatment durations lack definitive evidence from randomized clinical trials. Generally, therapy aims to maintain low TSH levels (below 0.1 mU/L for high-risk patients and between 0.1–0.5 mU/L for low-risk patients) without inducing hyperthyroidism. Common regimens include levothyroxine at doses of 100 µg/day or thyroid hormone tablets at 80–120 mg/day, with regular monitoring of plasma T4 and TSH levels to adjust dosage. Patients receiving long-term TSH suppression should be monitored for symptoms of thyrotoxicosis, such as anxiety, insomnia, palpitations, atrial fibrillation, and osteoporosis. Adequate daily calcium and vitamin D intake is essential to minimize adverse effects.

Radioactive Isotope Therapy

The therapeutic goals of radioactive iodine (¹³¹I) include the ablation of occult residual thyroid cancer or micrometastases, facilitating the detection of recurrence or metastasis via radionuclide imaging, enhancing the value of thyroglobulin (Tg) as a tumor marker during postoperative follow-up, and reducing recurrence and mortality in high-risk cases. ¹³¹I therapy is suitable for papillary and follicular carcinoma patients with tumor diameters exceeding 4 cm, local or distant metastasis, multifocal lesions, extracapsular invasion, residual disease, or Tg levels >10 ng/mL following surgery.

External Radiotherapy

The sensitivity of thyroid cancers to radiation varies depending on the degree of differentiation, with poorly differentiated tumors displaying greater sensitivity. Anaplastic thyroid carcinoma responds most effectively to radiotherapy and is the primary target of this treatment modality. While external radiotherapy does not cure the disease or extend life expectancy in cases of anaplastic carcinoma, it can palliate symptoms, alleviate pain, and improve quality of life. In addition, external radiotherapy can provide regional control for high-risk, persistent, recurrent, or metastatic differentiated thyroid cancer after surgery.