Thyroid cancer is a malignant tumor that arises from either the thyrocytes or the parafollicular cells of the thyroid gland. It is more common in women, especially between 30–50 years of age. The predominant risk factors for thyroid cancer are a history of childhood irradiation to the head and neck and a family history of thyroid cancer. Thyroid cancer typically manifests as firm to hard thyroid nodule (or nodules). Initial evaluation of all patients includes TSH assay and thyroid ultrasound. Sonographic signs of thyroid cancer include a solid, hypoechoic nodule(s) with irregular margins, microcalcifications, and evidence of local infiltration into adjacent structures or cervical lymph nodes. On thyroid scintigraphy, which should be obtained in patients with low serum TSH, a malignant nodule is typically “cold” or hypofunctional. Cytopathological analysis with FNAB is required to confirm the diagnosis. Depending on the cell of origin, thyroid cancer can be classified as papillary, follicular, medullary, or anaplastic thyroid cancer. Most thyroid cancers are treated surgically with total thyroidectomy (in some cases with hemithyroidectomy), followed by adjuvant therapy, which may include RAIA and TSH suppression therapy with L-thyroxine, radiation therapy, and chemotherapy. In advanced anaplastic carcinoma, only palliative care may be feasible. The prognosis depends on the type of thyroid cancer.
- Genetic factors
- Medullary carcinoma: associated with MEN2 (RET gene mutations) or familial medullary carcinoma
- Papillary carcinoma: associated with RET/PTC rearrangements and BRAF mutations
- Follicular carcinoma: associated with PAX8-PPAR-γ rearrangement and RAS mutation
- Undifferentiated/anaplastic carcinoma: associated with TP53 mutation
- Ionizing radiation; (particularly during childhood): mostly associated with papillary carcinoma
|Characteristic features of thyroid cancer |
|Tissue of origin||Carcinoma||Differentiation||Characteristics|| |
|Thyrocytes||Papillary thyroid carcinoma|| |
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Follicular thyroid carcinoma
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Anaplastic thyroid carcinoma
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|Parafollicular cells (C cells)|| |
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Subtypes and variants
Hurthle cell carcinoma
- 3–10% of all well-differentiated thyroid cancers
- Often classified as subtype of follicular carcinoma
- Thyroid histopathology: hypercellularity with a predominance of Hurthle cells (large, polygonal epithelial cell with eosinophilic granular cytoplasm as a result of numerous altered mitochondria)
- B-cell lymphoma: usually develops from Hashimoto thyroiditis
- Sarcoma: rare
- Metastatic (e.g., breast, renal, melanoma): rare
Thyroid nodule 
- Firm to hard consistency
- Typically painless
- See also “Red flags for thyroid cancer.”
- Features of local infiltration or compression
- Painless cervical lymphadenopathy 
- Signs of distant metastasis 
- Paraneoplastic syndrome: diarrhea and facial flushing (typically seen in advanced medullary carcinoma) 
- For initial evaluation, follow the .
- Thyroid tumor markers help to estimate the prognosis and assess response to therapy.
- Staging of lymph node and distant metastases
- Patients with medullary carcinoma require further assessment.
- TSH: typically normal or mildly elevated 
Thyroid ultrasound: to assess for sonographic signs of thyroid malignancy ; 
- Solid or mostly solid hypoechoic nodule(s)
- Irregular margins
- Microcalcifications within nodules
- Nodules that are taller than wide
- Extrathyroidal growth
Thyroid scintigraphy 
- Contraindications: pregnant and breastfeeding women
- Supportive findings: decreased or no radiotracer uptake (i.e., hypofunctioning or nonfunctioning nodules, referred to as cold nodules) 
Confirmatory tests 
- Fine-needle aspiration cytology (FNAC)
- Intraoperative : Consider if FNAC cannot reliably rule out malignancy in high-risk patients.
Additional studies after confirmed diagnosis
Thyroid cancer tumor markers
The specific tumor markers depend on the histological type of the cancer.
- Follicular or papillary thyroid cancer
- Calcitonin: A hormone secreted by parafollicular cells, which is the tissue of origin of medullary carcinoma
- Carcinoembryonic antigen (CEA): nonspecific marker, used in combination with calcitonin to monitor response to therapy 
- Morphology: concentric lamellar calcifications
- Occurrence: seen in diseases associated with calcific degeneration
“Orphan Annie” eyes nuclei
- Morphology: empty-appearing large oval nuclei with central clearing
Nuclear grooves 
- Morphology: longitudinal invaginations of nuclear bilayer
- Occurrence: papillary thyroid carcinomas
- Uniform follicles
- Vascular and/or capsular invasion
- Ovoid cells of C cell origin and therefore without follicle development
- Amyloid in the stroma (stains with Congo red)
General principles 
Well-differentiated thyroid cancer 
- Standard management (regardless of nodal or distant metastases): total thyroidectomy (with neck dissection as needed) + RAIA + TSH suppression therapy
- Small cancers without nodal or distant metastases: Consider hemithyroidectomy + TSH suppression therapy.
- Papillary microcarcinoma in low-risk patients : Consider active surveillance.
- Poorly-differentiated thyroid cancer
- Total thyroidectomy should be combined with neck dissection as needed (e.g., in patients with regional lymph node spread).
- Thyroid hormone replacement is required in all patients who undergo total thyroidectomy.
- Small, well-differentiated thyroid carcinoma with all of the following characteristics:
- Preferred option in tumors < 1 cm in size with all of the above characteristics
- An alternative to total thyroidectomy in tumors 1–4 cm in size with all of the above characteristics
- Hypocalcemia: as a result of accidental removal of parathyroid glands 
Dysphonia (hoarseness) and/or dysphagia: as a result of transection of the superior and recurrent laryngeal nerve
- May occur during ligation of the superior laryngeal artery and inferior thyroid artery due to the proximity of the nerves to the arteries
- If only the external branch of the superior laryngeal nerve is damaged, complete loss of the voice is unlikely, but a loss of vocal range may occur (with potentially career-damaging consequences for, e.g., singers and actors).
- Vocal cord function should be assessed preoperatively with laryngoscopy.
Adjuvant therapy 
Well-differentiated thyroid cancer
- Radioactive iodine ablation (RAIA): conducted 4– 6 weeks after total thyroidectomy to destroy remaining thyroid tissue or metastases 
- TSH suppression therapy:
- Poorly differentiated thyroid cancer: adjuvant radiation therapy and/or chemotherapy as needed 
- Active surveillance 
- Palliative therapy: Palliative radiation therapy and/or chemotherapy may be considered for advanced anaplastic thyroid cancer.