Thyroid Cancer

Spectrum of disease behaviour

• Encompasses malignancies arising from thyroid parenchymal cells, with clinical courses ranging from indolent, slow‑growing tumours to highly aggressive carcinomas.

Cell of origin

• Follicular cell–derived cancers (Differentiated Thyroid Carcinomas, DTC) – >90% of cases:
  • Papillary thyroid carcinoma: ~80% of all thyroid cancers; typically indolent.
  • Follicular thyroid carcinoma: defined by capsular and/or vascular invasion.
  • Oncocytic (Hürthle cell) carcinoma: tumour cells with abundant eosinophilic, granular cytoplasm.
• Parafollicular (C‑cell)–derived cancer (Medullary Thyroid Carcinoma, MTC) – ~1–2% of cases; arises from calcitonin‑secreting cells.
• Undifferentiated (Anaplastic) thyroid carcinoma – <1% of cases; characterised by rapid local invasion, early metastasis and very poor prognosis.

Functional characteristics

• Differentiated carcinomas generally retain thyroid‑specific functions (iodine uptake, thyroglobulin synthesis).
• Undifferentiated tumours lose these specialised features.

Further subclassification

• Follicular‑cell neoplasms may be stratified by architectural patterns and extent of invasion into:
  • Well‑differentiated forms
  • Poorly differentiated forms
  • Anaplastic forms

Genetic Predisposition

• Familial clustering occurs in around five per cent of papillary and follicular carcinomas and up to thirty per cent of medullary cases.
• Hereditary syndromes account for a minority of differentiated thyroid cancers through autosomal‑dominant inheritance.

Driver Mutations by Histological Type

Papillary thyroid carcinoma

• Activating point mutations in the BRAF gene (V600E) in approximately 30–70% of cases.
• RET/PTC rearrangements in a minority of tumours.
• RAS proto‑oncogene mutations in 10–20% of the follicular variant.

Follicular thyroid carcinoma

• RAS mutations in 40–50% of cases.
• PAX8–PPARγ fusion translocations in up to one third of tumours.

Anaplastic thyroid carcinoma

• Inactivating TP53 mutations in 50–80% of cases.
• CTNNB1 (β‑catenin) mutations in around two thirds.
• RAS mutations in 20–40%.
• Additional alterations affecting TERT, PI3K pathway components, chromatin‑remodelling complexes and cell‑cycle regulators.

Medullary thyroid carcinoma

• Germline RET proto‑oncogene mutations in hereditary forms (≈25% of cases).
• Somatic RET mutations and RAS mutations account for many sporadic tumours.

Environmental and Lifestyle Contributors

• Diagnostic intensity: increased use of imaging has led to detection of indolent papillary microcarcinomas.
• Ionising radiation: childhood exposures—therapeutic or accidental—significantly elevate risk, with a latency of 5–15 years.
• Obesity: higher body‐mass index is consistently linked to greater thyroid cancer risk.
• Smoking: paradoxically associated with reduced risk of differentiated thyroid malignancy.
• Reproductive factors: later age at first childbirth, later menopause and longer reproductive span increase risk; prolonged oral contraceptive use appears protective.
• Herbicide exposure: veterans exposed to Agent Orange demonstrate higher thyroid cancer rates.
• Iodine nutrition: low dietary iodine does not alter overall incidence but shifts subtype distribution towards follicular and anaplastic forms.

Inflammatory and Lymphoid Associations

• Chronic lymphocytic (Hashimoto’s) thyroiditis predisposes to primary thyroid lymphoma, most commonly diffuse large B‑cell or MALT lymphoma.

Genetic and Cellular Origins

• Arise from two principal cell types: follicular epithelial cells (differentiated, poorly differentiated, anaplastic) and parafollicular C‑cells (medullary).
• Follicular cells show variable growth capacity and TSH sensitivity; acquisition of somatic driver mutations alters proliferation and survival.
• Oncocytic (Hürthle) cells are a variant of follicular cells, with abundant granular eosinophilic cytoplasm and prominent nucleoli.

Key Signalling Pathways

•  90% of tumours harbour activating alterations in MAPK or PI3K/Akt cascades, conferring selective growth advantage.
• MAPK pathway alterations: RET/PTC and NTRK rearrangements; BRAF and RAS point mutations.
• PI3K/Akt pathway alterations: less common, involve genes such as PTEN and PIK3CA.

Continuum of Differentiation

• Tumours range from well‑differentiated (papillary, follicular, oncocytic) through poorly differentiated to undifferentiated (anaplastic).
• Poorly differentiated carcinomas exhibit partial loss of thyroid‑specific functions (radioiodine uptake, thyroglobulin synthesis).
• Tumour dedifferentiation occurs in up to two‑thirds of cases during progression.

Patterns of Spread

• Papillary carcinomas: lymphatic dissemination to cervical nodes.
• Follicular and oncocytic carcinomas: haematogenous metastases (lung, bone).
• Anaplastic carcinomas: aggressive local invasion and early distant spread.
• Primary thyroid lymphomas develop in chronic lymphocytic thyroiditis, showing B‑cell or MALT phenotypes.

Histological Features by Subtype

• Papillary carcinoma: papillae with fibrovascular cores; “Orphan Annie‑eyed” nuclei; nuclear grooves; psammoma bodies.
• Follicular carcinoma: neoplastic follicles with capsular/vascular invasion; lacks papillary nuclear features.
• Oncocytic carcinoma: sheets of granular, eosinophilic cells with invasive behaviour.
• Medullary carcinoma: spindle or polygonal cells; amyloid stroma; calcitonin positivity.
• Anaplastic carcinoma: pleomorphic giant cells, spindle‑cell or squamoid patterns; high mitotic rate; loss of thyroid markers.

Incidence

• Thyroid cancer is the most common endocrinological malignancy worldwide.
• It accounts for 1–4 per cent of all malignancies and is the fifth most common cancer in women in the United States.
• In the US, it represents 2.2 per cent of all new cancer diagnoses, with an estimated 44 020 new cases and 2 170 deaths in 2024.
• Age‑adjusted incidence rose from 5.0 to 13.5 per 100 000 persons between 1975 and 2021, driven mainly by papillary carcinoma.

Trends

• Global incidence of papillary thyroid carcinoma has increased by approximately 240 per cent over the past three decades, largely due to enhanced detection via imaging.
• True increases across all tumour sizes—not solely small, indolent lesions—have been documented.
• US incidence rates declined by about 2 per cent per year after 2014 following stricter diagnostic criteria .
• Incidence‑based mortality rose modestly, with an annual percent change of +0.61 per cent from 1987 to 2017.

Sex and Age

• Incidence is approximately three times higher in women than in men, with a lifetime risk of 1.8 per cent for females versus 0.7 per cent for males.
• Median age at diagnosis is 51 years, with peak incidence in the third and fourth decades of life.

Geographical Variation

• Highest incidence rates are recorded in North America and lowest in Africa, though this may reflect differences in surveillance and data quality [19].
• Rising incidence has been observed across both genders and multiple regions worldwide.

Mortality and Survival

• The five‑year relative survival rate in the US is 98.4 per cent
• Despite generally favourable outcomes, an estimated 2 170 deaths will occur in 2024 in the US, underscoring the importance of multidisciplinary care.

Overdiagnosis

• Overdiagnosis of asymptomatic papillary lesions is estimated to account for 70–80 per cent of US cases; clinically significant cancer incidence has remained stable over the past 80 years.

Risk Factors

Head and neck irradiation

• Therapeutic or accidental exposure—particularly during childhood—markedly increases lifetime risk of thyroid malignancy.

Female sex

• Women have an incidence roughly three times that of men; lifetime risk is about 1.8 per cent for females versus 0.7 per cent for males.

Family history

• Hereditary medullary thyroid carcinoma accounts for approximately 25 per cent of cases; rarely, non‑medullary forms also cluster in families.

Age extremes

• Nodules presenting before age 14 or after age 70 carry a higher probability of malignancy.

Thyroid Nodule History

Detection

• Most cases present as an asymptomatic nodule discovered either on neck palpation or incidentally via imaging, especially in women aged 30–40 years.

Growth pattern

• Rapid enlargement is suggestive of malignancy, whereas sudden onset of pain more often reflects benign events such as cyst haemorrhage or thyroiditis.

“Cold” nodules

• Hypofunctioning nodules on scintigraphy carry an estimated 5–8 per cent risk of malignancy, whether solitary or within a multinodular goitre.

Local Symptom History

Hoarseness

• New onset of voice changes indicates possible recurrent laryngeal nerve involvement by advanced disease.

Dysphagia & dyspnoea

• Symptoms of oesophageal or tracheal compression by the tumour.

Neck discomfort

• Painful nodules are uncommon in cancer and more often signal benign processes.

Systemic and Contextual History

Constitutional symptoms

• Weight loss and fatigue may occur in advanced disease but are nonspecific.

Syndromic features

• A personal history of pheochromocytoma or hyperparathyroidism suggests hereditary medullary carcinoma.

Herbicide exposure

• Veterans exposed to Agent Orange demonstrate an elevated incidence of thyroid cancer.

Thyroid nodule

• Presents as a painless, solitary lump; palpable in 4–7 per cent of the general population and detected by high‑resolution ultrasound in 19–67 per cent of screened individuals.
• Solitary nodules carry an estimated 5 per cent risk of malignancy; firm, fixed lesions are more suspicious than soft, mobile ones.

Cervical lymphadenopathy

• Lateral neck masses suggest regional nodal metastases and are particularly common in medullary carcinoma.
• Nerve involvement and compression
  • Hoarseness or vocal‑cord immobility on laryngoscopy indicates recurrent laryngeal nerve invasion.
  • Dysphagia and dyspnoea reflect oesophageal or tracheal compression by the lesion.

Tracheal deviation

• Displacement of the trachea on palpation denotes significant thyroid enlargement; may also occur with large benign goitres.
• Rapid neck enlargement
  • A sudden increase in size over days to weeks raises concern for anaplastic carcinoma, primary thyroid lymphoma or haemorrhage into a nodule.
• High‑risk demographic features
  • Nodules in patients aged under 14 or over 70, and in males, carry a higher pretest probability of malignancy.

Thyroid Function Tests

TSH

• First‑line assay in all patients with a thyroid nodule; most values are normal (0.4–4.0 mIU/L).
• Suppressed TSH suggests a hyperfunctioning (“hot”) nodule, where malignancy is very unlikely; normal or elevated TSH prompts imaging and cytology¹.

Free T4 & Free T3

• Measured when TSH is suppressed to confirm hyperthyroidism; elevated levels support an autonomous nodule.
• High‑dose biotin supplements can artefactually skew results and should be queried²

Neck Ultrasound

• Detects nodules in up to 67 per cent of adults, characterising size, solidity, cystic change and vascularity.
• ACR TI‑RADS risk categories guide FNA thresholds³:
  • TR1–2 (benign/not suspicious): no FNA;
  • TR3 (mildly suspicious): FNA if ≥ 2.5 cm;
  • TR4 (moderately suspicious): FNA if ≥ 1.5 cm;
  • TR5 (highly suspicious): FNA if ≥ 1 cm.
• Suspicious sonographic features: micro‑calcifications; taller‑than‑wide orientation; marked hypoechogenicity; irregular margins; extrathyroidal extension; abnormal lymph nodes³.

Fine‑Needle Aspiration (FNA)

• Indications: Nodules meeting TI‑RADS size/risk criteria or any nodule in high‑risk patients (prior irradiation, familial medullary carcinoma) when TSH is not suppressed³.
• Technique: Ultrasound‑guided sampling with a minimum of three passes to ensure adequacy and reduce false negatives.
• Bethesda classification assigns six categories with corresponding malignancy risks and management⁵:
  1. I (non‑diagnostic): repeat FNA
  2. II (benign, ~0–3 per cent): observe
  3. III (AUS/FLUS, ~5–15 per cent): repeat FNA or molecular testing
  4. IV (follicular neoplasm, ~15–30 per cent): consider lobectomy or molecular testing
  5. V (suspicious, ~60–75 per cent): surgical excision
  6. VI (malignant, ~97–99 per cent): definitive surgery
• Limitations: Cytology cannot distinguish follicular or oncocytic adenoma from carcinoma; detection of capsular/vascular invasion requires excision or molecular panels.

Molecular Testing

• Applied to indeterminate cytology (Bethesda III/IV).
• Multi‑gene panels (e.g., ThyroSeq, Afirma) detect driver mutations (BRAF V600E, RET/PTC, RAS, PAX8::PPARG), improving rule‑in specificity (> 90 per cent) and rule‑out negative predictive value (> 90 per cent).

Vocal‑Cord Evaluation

• Laryngoscopy (direct or indirect) assesses cord mobility in patients with hoarseness or suspected extrathyroidal spread; cord paralysis strongly indicates invasive disease.

Radioisotope Imaging

• I‑123 scan: Reserved for hyperthyroid patients; “hot” nodules are nearly always benign, whereas “cold” nodules require cytological assessment despite low overall malignancy rates.

Core Biopsy

• Indicated only when FNA suggests lymphoma, providing tissue architecture for immunophenotyping; not routine for carcinoma evaluation.

Cross‑Sectional Imaging

• CT/MRI of the neck: Used pre‑operatively in medullary carcinoma for nodal mapping and for large, substernal or rapidly growing masses to assess local invasion.

Serological Markers

• Serum calcitonin: Elevated in medullary carcinoma; used for diagnosis, staging and surveillance⁸.
• Thyroglobulin: Not diagnostic but vital for post‑treatment surveillance of differentiated thyroid cancer; rising levels indicate residual or recurrent disease.

Genetic Testing

• Germline RET analysis: Mandatory in familial medullary carcinoma or multiple endocrine neoplasia type 2; identifies at‑risk relatives and informs timing of prophylactic thyroidectomy.

Emerging Modalities

• Translaryngeal ultrasound: Non‑invasive, clinic‑based assessment of vocal‑cord movement.
• Sentinel lymph‑node biopsy: Investigational in clinically node‑negative patients to potentially refine staging.

Benign Thyroid Nodule

• Clinical features: Soft, mobile, non‑tender; no associated lymphadenopathy or vocal‑cord paralysis.
• Investigations:
  • Ultrasound: well‑circumscribed, homogenous echotexture without suspicious features.
  • FNA cytology: abundant colloid, uniform follicular cells without atypia.
  • Surgical pathology (adenomas only): no capsular or vascular invasion.

Toxic Nodular Goitre

• Clinical features: Signs of hyperthyroidism (palpitations, weight loss, heat intolerance); multinodular or solitary functioning nodules.
• Investigations:
  • TSH: suppressed; free T4 and free T3 elevated.
  • Radioiodine scan: “hot” nodule uptake with suppressed background thyroid; malignancy very unlikely.
  • FNA rarely indicated unless ultrasound reveals suspicious features.

Primary Thyroid Lymphoma

• Clinical features: Rapid enlargement of a firm gland in the setting of chronic lymphocytic (Hashimoto’s) thyroiditis; “B” symptoms (fever, weight loss, night sweats) may be present.
• Investigations:
  • Ultrasound: hypoechoic, diffuse gland involvement or focal mass.
  • FNA: atypical lymphoid population; flow cytometry and immunophenotyping confirm lymphoma.
  • Core biopsy: provides architectural detail to distinguish diffuse large B‑cell from MALT lymphoma.

Cervical Lymphadenopathy

• Clinical features: Enlarged, firm, non‑tender nodes in the lateral neck; may be unilateral or bilateral.
• Investigations:
  • Ultrasound: rounded nodes with loss of fatty hilum or micro‑calcifications.
  • FNA cytology: metastatic thyroid carcinoma cells (papillary features) or other malignancies; immunostaining for thyroglobulin or calcitonin as needed.

Preoperative Assessment

Cytology classification

• The Bethesda System guides pre‑operative FNA interpretation, assigning nodules to six categories with corresponding malignancy risks and management recommendations.

Multidisciplinary care

• Patients should be managed by a team including endocrinologists, surgeons, radiologists, nuclear medicine specialists and oncologists.

Differentiated Thyroid Cancer (Papillary, Follicular, Oncocytic)

Active surveillance

• Unifocal microcarcinomas (≤ 1 cm) without extrathyroidal extension or nodal metastases may be monitored with neck ultrasound every 6–12 months. This is especially suitable for older or high‑surgical‑risk patients.

Conversion criteria

• Switch to surgery if there is patient preference, tumour growth (> 3 mm or 50 % volume increase), new biopsy‑proven nodal or distant metastases, or invasion of adjacent structures.

Surgical strategy

• Total thyroidectomy is standard for tumours > 1 cm, multifocal disease, extrathyroidal extension or nodal involvement. Lobectomy may suffice for solitary tumours 1–4 cm without high‑risk features; completion thyroidectomy is indicated if pathology reveals widely invasive follicular/oncocytic carcinoma or ≥ 4 foci of vascular invasion.

Lymph node management

• Therapeutic central compartment neck dissection for clinically involved nodes; prophylactic dissection remains controversial due to increased complication rates.

TSH suppression

• High‑risk or residual disease: target TSH < 0.1 mIU/L. Intermediate‑risk: 0.1–0.5 mIU/L. Low‑risk: 0.5–2.0 mIU/L.

Radioactive iodine (RAI)

• Indicated after total thyroidectomy in high‑risk and selected intermediate‑risk patients. Not routine for low‑risk disease; dosage should be individualised and guided by staging and post‑operative thyroglobulin and ultrasound findings.

Surveillance & Recurrence

Biochemical monitoring

• Serial thyroglobulin (and anti‑thyroglobulin antibodies) and neck ultrasound; rising thyroglobulin prompts focused imaging.

Structural recurrence

• Lesions ≥ 8 mm (central) or ≥ 10 mm (lateral) on imaging merit surgical revision; smaller or surgically inaccessible recurrences may be treated with RAI, ablation or observation.

Distant metastases

• Occur in ~ 10 % of cases; management includes surgery for accessible disease, RAI for responsive metastases, external beam radiotherapy, thermal ablation and systemic kinase inhibitors guided by mutation profiling (e.g., BRAF, RET, NTRK).

Anaplastic Thyroid Cancer

Multimodal therapy

• Surgery if resectable, plus early radiotherapy and systemic therapy.

Targeted treatment

• Genetic testing for actionable mutations—BRAF V600E (dabrafenib + trametinib), NTRK fusions (larotrectinib/entrectinib), RET fusions (selpercatinib/pralsetinib), high TMB/MSI (pembrolizumab)—to guide personalised therapy.

Medullary Thyroid Cancer

Primary treatment

• Total thyroidectomy with central compartment (level VI) node dissection; extent guided by pre‑operative calcitonin levels and neck ultrasound.

Hormone replacement

• Levothyroxine to maintain euthyroidism; TSH suppression is not required.

Surveillance

• Serial calcitonin every 3 months (years 1–2), then every 6 months (years 3–5), then annually if undetectable; rising levels prompt ultrasound/CT and PET as needed.

Recurrent or metastatic disease

• Surgery and/or radiotherapy for locoregional recurrence; multikinase inhibitors (vandetanib, cabozantinib) for progressive metastatic disease; RET‑specific inhibitors for RET‑mutant tumours.

Primary Thyroid Lymphoma

Subtype‑guided therapy

• MALT lymphoma (stage I): surgery or radiotherapy alone. Advanced stages (IIE+): combined chemotherapy and radiotherapy.

Overall survival

• Thyroid cancers collectively have an excellent outlook
• Five‑year survival rates approaching 95 per cent in population‑based studies.

Papillary carcinoma

• Ten‑year survival exceeds 90 per cent
• Nodal metastases increase recurrence risk without affecting overall survival
• A positive PET scan indicates a poorer outcome.

Follicular carcinoma

• Localised disease carries near‑100 per cent five‑year survival
• Distant metastases reduce survival to approximately 63 per cent.

Oncocytic (Hürthle cell) carcinoma

• Minimally invasive tumours rarely recur
• Five‑year survival ranges from 85 to 95 per cent overall, though widely invasive forms have higher recurrence rates.

Medullary carcinoma

• Five‑year survival is nearly 100 per cent for localised disease and around 75 per cent when distant metastases are present.

Primary thyroid lymphoma

• Five‑year survival averages 66 per cent
• Varying by histological subtype and stage.

Anaplastic carcinoma

• Historically median survival measured in months
• Targeted therapies have improved median overall survival from around 0.63 years to approximately 1.31 years.

Favourable prognostic factors

• Female sex
• Age under 55 years
• Tumour size below 4 cm
• Absence of extrathyroidal extension or distant metastases
• Low‑grade histology

Local invasion and distant spread

• Untreated thyroid malignancies can infiltrate adjacent structures—airway, oesophagus and neurovascular bundles—potentially causing airway compromise requiring surgical relief.
• Distant metastases most often involve the lungs and bones.

Hypoparathyroidism

• Presents with peri‑oral numbness, carpopedal spasm or tetany.
• Transient hypocalcaemia typically resolves within a week with oral calcium and vitamin D; permanent hypoparathyroidism is uncommon.

Recurrent laryngeal nerve injury

• Manifests as hoarseness, usually resolving over 2–3 months.
• Persistent vocal‑cord palsy is rare and may be managed with speech therapy or vocal‑cord medialisation.

Haemorrhage

• Post‑operative bleeding can lead to neck swelling and respiratory distress.
• Urgent wound re‑opening, haematoma evacuation and vessel ligation are required.

Long‑term therapy‑related effects

TSH suppression

• Associated with increased risk of atrial fibrillation and potential bone mineral loss in post‑menopausal women, though its impact on fracture rates remains unclear.

Radioactive iodine

• Higher cumulative doses have been linked to secondary haematological malignancies (e.g., leukaemias) and salivary‑gland tumours.
• Doses above 200–300 mCi also risk chronic dry mouth.

Pathological fractures

• Rarely result from skeletal metastases of thyroid cancer.

Pregnancy

• Thyroidectomy performed during pregnancy has not been associated with increased maternal or foetal complications.

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