Residency · Residency · General Surgery

Thyroid Nodules and Thyroid Cancer

Thyroid Anatomy

The thyroid is a bilobed gland connected by an isthmus, located anterior to the trachea at the level of C5 to T1. Its blood supply comes from the superior thyroid artery (a branch of the external carotid artery), the inferior thyroid artery (from the thyrocervical trunk), and the thyroid ima artery (a variable vessel arising from the aorta or innominate artery). Venous drainage is via the superior and middle thyroid veins to the internal jugular vein, and the inferior thyroid veins to the brachiocephalic veins.

The recurrent laryngeal nerve courses in the tracheoesophageal groove and innervates all intrinsic laryngeal muscles except the cricothyroid. The right RLN loops around the subclavian artery, while the left RLN loops around the aortic arch. A non-recurrent laryngeal nerve occurs on the right side in 0.5-1% of patients and is associated with an aberrant right subclavian artery (arteria lusoria). The external branch of the superior laryngeal nerve innervates the cricothyroid muscle, which is important for high-pitched voice, and runs with the superior thyroid artery. The parathyroid glands are typically four in number. The superior glands, derived from the fourth pharyngeal pouch, have a more constant position, while the inferior glands, derived from the third pharyngeal pouch, are more variable in location.

Thyroid Nodules

Epidemiology

Palpable thyroid nodules are found in 4-7% of adults, while incidental nodules on ultrasound are identified in 20-67% of adults. The malignancy rate is 5-15% of all thyroid nodules.

Workup

The workup begins with a history and physical examination, focusing on voice changes, dysphagia, family history of thyroid cancer or MEN2, radiation exposure, rapid growth, a fixed nodule, and cervical lymphadenopathy. TSH is the first-line laboratory test. A low TSH prompts a radioiodine scan to evaluate for an autonomous ("hot") nodule, which is rarely malignant and does not require FNA. A normal or elevated TSH leads to thyroid ultrasound and FNA. On ultrasound, suspicious features include a solid and hypoechoic nodule, taller-than-wide shape, irregular margins, microcalcifications, and extrathyroidal extension. The ACR TI-RADS scoring system guides FNA recommendations based on size and ultrasound features.

ACR TI-RADS (Thyroid Imaging Reporting and Data System)

The TI-RADS system categorizes nodules by point score. TR1 (benign, 0 points) and TR2 (not suspicious, 2 points) do not require FNA. TR3 (mildly suspicious, 3 points) warrants FNA if the nodule is 2.5 cm or larger, with follow-up if 1.5 cm or larger. TR4 (moderately suspicious, 4-6 points) warrants FNA if 1.5 cm or larger, with follow-up if 1 cm or larger. TR5 (highly suspicious, 7 or more points) warrants FNA if 1 cm or larger, with follow-up if 0.5 cm or larger.

<image>Thyroid ultrasound images showing benign (isoechoic, well-defined, spongiform) versus malignant (hypoechoic, microcalcifications, irregular margins, taller-than-wide) features of thyroid nodules</image>

Fine Needle Aspiration (FNA) -- Bethesda Classification

The Bethesda system classifies FNA results into six categories:

Bethesda I is non-diagnostic or unsatisfactory, requiring repeat FNA in 4-6 weeks. Bethesda II is benign, with a 2-4% malignancy risk, and is followed with ultrasound. Bethesda III is atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS), carrying a 10-30% malignancy risk. Bethesda IV is follicular neoplasm or suspicious for follicular neoplasm, with a 25-40% malignancy risk. Bethesda V is suspicious for malignancy, with a 50-75% malignancy risk. Bethesda VI is malignant, with a 97-99% malignancy risk.

Molecular Testing

Molecular testing is used for Bethesda III and IV results to refine malignancy risk and guide management. ThyroSeq is a next-generation sequencing panel with high sensitivity and negative predictive value. Afirma GSC is a gene expression classifier whose "benign" result allows surveillance. Rule-out tests with high negative predictive value allow safe surveillance if negative, avoiding diagnostic surgery. Rule-in tests with high positive predictive value support surgical management when positive.

Management by Bethesda Category

Bethesda I requires repeat FNA. Bethesda II is managed with surveillance using serial ultrasound. Bethesda III is managed with molecular testing or diagnostic lobectomy, with repeat FNA as an option. Bethesda IV is managed with molecular testing or diagnostic lobectomy. Bethesda V is treated with lobectomy (or total thyroidectomy if the tumor is large, disease is bilateral, or per patient preference). Bethesda VI is treated with surgery, either lobectomy or total thyroidectomy, based on tumor characteristics.

Thyroid Cancer

Types

Differentiated thyroid cancer accounts for 90% of thyroid cancers. Papillary carcinoma (85%) is the most common, spreads via lymphatics, and carries an excellent prognosis. Follicular carcinoma (10%) spreads hematogenously to lung and bone, and requires tissue diagnosis because it cannot be diagnosed on FNA since capsular or vascular invasion must be demonstrated. Hurthle cell carcinoma is a variant of follicular carcinoma that is more aggressive and less iodine-avid.

Medullary thyroid cancer comprises 5-10% of thyroid cancers and arises from parafollicular C cells that produce calcitonin. It is sporadic in 75% of cases and hereditary in 25%, occurring in the setting of MEN2A, MEN2B, or familial MTC, with RET proto-oncogene mutations identified.

Anaplastic thyroid cancer accounts for less than 2% of thyroid cancers. It is rapidly progressive, undifferentiated, and historically uniformly lethal. It often arises from dedifferentiation of differentiated thyroid cancer. BRAF V600E mutation is common, and targeted therapy with dabrafenib plus trametinib may improve outcomes.

Primary thyroid lymphoma is rare, is associated with Hashimoto's thyroiditis, and diffuse large B-cell lymphoma is the most common subtype.

<image>Histologic images comparing papillary thyroid carcinoma (nuclear features: Orphan Annie eyes, nuclear grooves, pseudoinclusions), follicular thyroid carcinoma (capsular invasion), and medullary thyroid carcinoma (amyloid stroma)</image>

Papillary Thyroid Cancer -- Surgical Management

Extent of Surgery

Lobectomy is appropriate for unifocal tumors less than 4 cm that are intrathyroidal without extrathyroidal extension, with no clinical evidence of lymph node metastases, no prior head or neck radiation, and no aggressive histologic subtypes (such as tall cell, hobnail, or diffuse sclerosing variants). The ATA 2015 guidelines support lobectomy as sufficient for low-risk differentiated thyroid cancer measuring 1-4 cm.

Total thyroidectomy is indicated for tumors larger than 4 cm, bilateral disease, extrathyroidal extension, clinically apparent lymph node metastases (cN1), planned radioactive iodine therapy, aggressive histologic subtypes, or patient preference to avoid potential completion thyroidectomy. Completion thyroidectomy is performed when lobectomy reveals cancer with high-risk features on final pathology that warrant total thyroidectomy.

Lymph Node Dissection

Central neck dissection (level VI) is performed therapeutically for clinically involved nodes (cN1a). Prophylactic central neck dissection is controversial; the ATA recommends therapeutic dissection for cN1a, and prophylactic dissection may be considered for T3-T4 tumors to increase staging accuracy, though it adds the risk of hypoparathyroidism. Lateral neck dissection (levels II-V) is performed therapeutically only, for biopsy-proven lateral neck metastases (cN1b), as a modified radical neck dissection that preserves the internal jugular vein, sternocleidomastoid, and spinal accessory nerve. It is never performed prophylactically.

Follicular Thyroid Cancer

Follicular thyroid cancer cannot be diagnosed on FNA because capsular or vascular invasion must be demonstrated on final pathology. A diagnostic lobectomy is performed, followed by completion thyroidectomy if high-risk features are found, such as widely invasive disease or vascular invasion. Minimally invasive follicular carcinoma with limited capsular invasion only may be adequately treated with lobectomy alone.

Medullary Thyroid Cancer

The preoperative workup includes serum calcitonin, CEA, calcium and PTH levels, exclusion of pheochromocytoma (24-hour urine catecholamines and metanephrines), and RET mutation testing. The surgical treatment is total thyroidectomy with bilateral central neck dissection at minimum. Lateral neck dissection is performed for clinically involved nodes or when calcitonin exceeds 200 pg/mL. If a pheochromocytoma is present, it must be addressed first with adrenalectomy before thyroidectomy. Radioactive iodine has no role in medullary thyroid cancer. Adjuvant external beam radiation is considered for locally advanced disease. Targeted therapies including vandetanib, cabozantinib, and RET inhibitors (selpercatinib and pralsetinib) are used for advanced disease.

Anaplastic Thyroid Cancer

Anaplastic thyroid cancer presents as a rapidly enlarging neck mass, often with compressive symptoms. Staging includes CT of the neck and chest, and PET-CT. If resectable, treatment is surgery followed by chemoradiation. The identification of BRAF V600E mutation has been a paradigm shift, with treatment using dabrafenib, trametinib, and immunotherapy (pembrolizumab). Tracheostomy may be needed for airway compromise. Prognosis has historically been poor with a median survival of 5-6 months, though this is improving with targeted therapy.

<image>Surgical anatomy during thyroidectomy showing identification and preservation of the recurrent laryngeal nerve in the tracheoesophageal groove and the parathyroid glands</image>

Complications of Thyroidectomy

Recurrent Laryngeal Nerve Injury

Temporary injury occurs in 5-10% of cases, with permanent injury in 1-2%. Unilateral injury causes hoarseness and a breathy voice. Bilateral injury causes airway compromise with stridor and may require intubation or tracheostomy. Intraoperative nerve monitoring is widely used and helps identify the nerve and predict function but does not prevent injury. Visual identification of the nerve remains the gold standard for preservation.

Hypoparathyroidism

Temporary hypoparathyroidism occurs in 10-30% of cases, while permanent hypoparathyroidism occurs in 1-4%. Calcium and PTH levels should be monitored postoperatively at 6-12 hours after surgery. Symptoms include perioral numbness, tingling, Chvostek sign, Trousseau sign, and tetany. Treatment involves oral calcium carbonate and calcitriol, with intravenous calcium gluconate for severe or symptomatic cases. Risk factors include total thyroidectomy, central neck dissection, re-operative surgery, and a low-volume surgeon. Autotransplantation of a devascularized parathyroid gland, performed by mincing the tissue and implanting it into the sternocleidomastoid muscle, should be performed when a gland appears compromised.

Postoperative Hematoma

Postoperative hematoma is rare (less than 1%) but potentially life-threatening due to airway compromise. It typically presents within the first 6-24 hours with neck swelling, pain, dyspnea, and stridor. Management requires immediate return to the operating room for evacuation. If airway compromise is imminent, the wound should be opened at the bedside -- opening the skin, separating the strap muscles, and evacuating the clot. Most surgeons observe patients overnight after total thyroidectomy.

Radioactive Iodine (RAI) Therapy

Radioactive iodine is an adjuvant treatment for differentiated thyroid cancer after total thyroidectomy. It is indicated for high-risk disease (T3-T4, N1, M1, aggressive histology, or incomplete resection) and is not indicated for low-risk unifocal papillary carcinoma less than 1 cm, minimally invasive follicular carcinoma, or lobectomy patients. RAI requires TSH stimulation through either thyroid hormone withdrawal or recombinant TSH (Thyrogen). A diagnostic whole-body scan assesses iodine avidity. Common side effects include sialadenitis, xerostomia, and nausea, with secondary malignancies as a rare long-term risk.

Clinical Pearls

TSH is the first lab test for any thyroid nodule, as a suppressed TSH suggests a hot nodule that rarely harbors malignancy. Bethesda III/IV represents the "gray zone," and molecular testing helps avoid diagnostic surgery in 50-60% of these patients. Lobectomy is increasingly accepted for low-risk differentiated thyroid cancer measuring 1-4 cm, avoiding the complications of unnecessary total thyroidectomy. Pheochromocytoma must always be ruled out before thyroidectomy in MTC patients with MEN2 syndrome, as operating without adrenalectomy first can precipitate a pheochromocytoma crisis. The recurrent laryngeal nerve must be identified and preserved in every thyroid operation, with visual identification being the gold standard. Postoperative hematoma is a surgical emergency, and every surgeon and ward nurse must know to open the wound immediately if airway compromise develops. Any devascularized parathyroid gland should be autotransplanted into the sternocleidomastoid during thyroidectomy.

References

• Haugen BR, et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2016;26(1):1-133.
• Cibas ES, Ali SZ. The 2017 Bethesda System for Reporting Thyroid Cytopathology. Thyroid. 2017;27(11):1341-1346.
• Wells SA Jr, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25(6):567-610.
• Tessler FN, et al. ACR Thyroid Imaging, Reporting and Data System (TI-RADS). J Am Coll Radiol. 2017;14(5):587-595.
• Subbiah V, et al. Dabrafenib plus trametinib in patients with BRAF V600E-mutated anaplastic thyroid cancer. J Clin Oncol. 2022;40(5):542-548.

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