Thyroid Cancer — Types, Diagnosis, Surgery, Radioiodine & Targeted Therapy — Symptoms, Causes & Treatment | MyMedicPlus

Thyroid cancer is the most common endocrine malignancy and is increasing in incidence globally — largely driven by increased detection of small papillary thyroid microcarcinomas through widespread use of neck ultrasonography. Despite rising incidence, mortality from thyroid cancer remains relatively stable — reflecting the generally excellent prognosis of differentiated thyroid cancers and improved management. There are four main histological types, arising from distinct cell lineages and with very different biological behaviours and prognoses: Papillary thyroid cancer (PTC — approximately 80-85% of all thyroid cancers): arises from follicular epithelial cells; often contains characteristic nuclear features (Orphan Annie-eye nuclei, nuclear grooves, psammoma bodies) and BRAF V600E mutation (approximately 60% of PTC); typically slow-growing with excellent prognosis (10-year survival above 95%); spreads predominantly to regional cervical lymph nodes; distant metastases uncommon but can occur to lungs and bone. Follicular thyroid cancer (FTC — approximately 10-15%): arises from follicular epithelial cells; RAS mutations and PAX8-PPAR-gamma fusion common; cannot be distinguished from follicular adenoma on fine-needle aspiration cytology (FNAC) — requires histological capsular or vascular invasion assessment; spreads haematogenously to bone and lung (rather than lymph nodes — unlike PTC); Hürthle cell (oncocytic) carcinoma is a variant with worse prognosis and reduced radioiodine uptake. Medullary thyroid cancer (MTC — approximately 3-5%): arises from parafollicular C cells (calcitonin-secreting); sporadic (75%) or hereditary (25% — multiple endocrine neoplasia type 2, MEN2A and MEN2B — from germline RET proto-oncogene mutations); serum calcitonin is the primary tumour marker; does not respond to radioiodine; surgical cure the only option; targeted therapy (vandetanib, cabozantinib, selpercatinib) for systemic disease. Anaplastic thyroid cancer (ATC — below 1%): the most aggressive solid tumour in clinical oncology — median survival of 5 months from diagnosis; frequently presents as a rapidly enlarging neck mass; may arise from dedifferentiation of a pre-existing differentiated thyroid cancer.

Radiation exposure: the strongest established risk factor for papillary thyroid cancer — external beam radiation to the head and neck region during childhood (previously used for tinea capitis, thymic enlargement, acne, and tonsillitis — historical treatments now abandoned; and current therapeutic radiation for childhood cancers, particularly lymphoma, head and neck cancers); latency period 10-30 years after radiation exposure; the Chernobyl nuclear accident (1986) produced a dramatic increase in childhood PTC in Ukraine and Belarus — predominantly I-131 fallout; the atomic bomb survivors in Japan showed increased PTC incidence; iodine-131 from nuclear accidents primarily targets the thyroid gland. Iodine deficiency: associated with follicular thyroid cancer and toxic multinodular goitre; iodine-sufficient areas have a higher proportion of papillary cancer; iodine supplementation (iodised salt) reduces follicular thyroid cancer incidence. Hereditary and genetic factors: Familial medullary thyroid cancer (MTC): germline RET proto-oncogene mutations — MEN2A (RET codon 634 — MTC, phaeochromocytoma, primary hyperparathyroidism; 95% of MEN2A); MEN2B (RET codon 918 — MTC [more aggressive, earlier onset], phaeochromocytoma, marfanoid habitus, mucosal neuromas; highest-risk RET mutations associated with MTC by age 6 months). Cowden syndrome (PTEN hamartoma tumour syndrome — PTEN mutations): increased follicular thyroid cancer risk. Familial adenomatous polyposis (APC mutations): increased cribriform-morular variant PTC risk (particularly in young females). Non-medullary familial thyroid cancer: 5% of PTC cases occur in 2 or more first-degree relatives without a known germline mutation — HABP2, DICER1, FOXE1, NKX2-1 variants implicated. Female sex and hormonal factors: papillary and follicular thyroid cancer are 3-4 times more common in women — suggesting oestrogen influence; incidence peaks in reproductive years. Obesity: associated with thyroid cancer risk — possibly through insulin and IGF-1 pathway activation. Hashimoto's thyroiditis: associated with increased PTC risk through chronic lymphocytic thyroiditis — thyroid cancer is more common in background of autoimmune thyroid disease. BRAF V600E mutation: present in approximately 60% of PTC — associated with extrathyroidal extension, lymph node metastases, and slightly worse prognosis; diagnostic and potentially therapeutic target. RAS mutations (NRAS, HRAS, KRAS): present in follicular thyroid cancer (40-50%) and the follicular variant of PTC; associated with increased metastatic potential. RET/PTC rearrangements: inversions and translocations involving RET — present in 10-20% of classical PTC; more common in radiation-associated PTC.

Thyroid cancers — particularly small papillary microcarcinomas (below 10 mm) — are frequently asymptomatic and discovered incidentally on neck ultrasonography performed for other indications, or during thyroidectomy for benign thyroid disease (incidental carcinoma). Painless thyroid nodule or neck lump: the most common presenting feature — a palpable or visible thyroid nodule (solitary or within a multinodular goitre); cancer is found in approximately 5-10% of all clinically palpable thyroid nodules (and in 1-2% of incidentally detected sub-centimetre nodules on ultrasound). Features suggestive of malignancy in a thyroid nodule: rapid growth; firm, hard, or irregular consistency on palpation; fixation to surrounding structures (fixed, non-mobile nodule — indicates extra-thyroidal invasion); solitary rather than multiple nodules (though cancer can occur in any nodule in a multinodular goitre); age extremes (children and adolescents: any thyroid nodule has a 25-40% malignancy rate; adults above 65 similarly higher risk); male sex (nodules in men have higher malignancy rate — approximately 10-15% vs. 5% in women). Lymph node metastases: cervical lymphadenopathy (lateral neck or central compartment) — PTC commonly spreads to regional cervical lymph nodes; detected as multiple or large fixed lymph nodes in levels II-VI of the neck; approximately 30-50% of PTC patients have lymph node involvement at diagnosis. Symptoms of local invasion (advanced disease): hoarseness of voice (recurrent laryngeal nerve invasion or external pressure — urgent evaluation with laryngoscopy); dysphagia (oesophageal compression or invasion — particularly in large or anaplastic tumours); stridor (tracheal compression or invasion — respiratory emergency in rapidly growing ATC); Horner's syndrome (sympathetic chain invasion — partial ptosis, miosis, anhidrosis). Distant metastasis symptoms: bone pain (pathological fractures — follicular thyroid cancer and de-differentiated cancers); haemoptysis (pulmonary metastases — PTC and FTC). Medullary thyroid cancer-specific features: diarrhoea (calcitonin and prostaglandin E2 secretion — watery secretory diarrhoea in advanced MTC); facial flushing; ectopic ACTH secretion causing Cushing's syndrome (rare). MEN2-associated features: phaeochromocytoma (episodic hypertension, headache, sweating, palpitations — must be excluded BEFORE thyroid surgery); hyperparathyroidism (hypercalcaemia in MEN2A); mucosal neuromas (lips, tongue — MEN2B).

Thyroid ultrasound (the primary imaging investigation): essential for all palpable thyroid nodules and incidentally discovered nodules; characterises size, echogenicity, margins, vascularity, and microcalcifications; ACR TIRADS (Thyroid Imaging Reporting and Data System) or BTA/ATA Bethesda-correlated ultrasound risk stratification guides biopsy decisions: TIRADS 1 (benign — no biopsy); TIRADS 2 (not suspicious — no biopsy); TIRADS 3 (mildly suspicious — biopsy if above 2.5 cm); TIRADS 4 (moderately suspicious — biopsy if above 1.5 cm); TIRADS 5 (highly suspicious — biopsy if above 1 cm); suspicious features: microcalcifications, irregular margins, taller-than-wide shape, marked hypoechogenicity, solid composition. Fine-needle aspiration cytology (FNAC — ultrasound-guided): the key investigation for thyroid nodule risk stratification — Bethesda classification of cytological results: Bethesda I (non-diagnostic — repeat FNAC); Bethesda II (benign — 0-3% malignancy risk; clinical/US surveillance); Bethesda III (atypia of undetermined significance/follicular lesion of undetermined significance — 5-15% risk; repeat FNAC or molecular testing); Bethesda IV (follicular neoplasm — 15-30% risk; diagnostic hemithyroidectomy); Bethesda V (suspicious for malignancy — 60-75% risk); Bethesda VI (malignant — greater than 97% — total thyroidectomy). Molecular testing (ThyroSeq v3, Afirma Gene Sequencing Classifier): for Bethesda III-IV indeterminate nodules — improves benign or malignant classification, reducing unnecessary diagnostic surgery; detects BRAF, RAS, RET/PTC rearrangements, and gene expression signatures. Thyroid function tests: TSH (typically normal in thyroid cancer — a suppressed TSH suggests toxic adenoma which is almost never malignant); FT4; thyroglobulin (used as a tumour marker post-thyroidectomy — not useful pre-surgery due to interference from normal thyroid tissue). Calcitonin: elevated in medullary thyroid cancer (MTC) — the most sensitive and specific tumour marker for MTC; used for diagnosis, staging, and post-operative surveillance; carcinoembryonic antigen (CEA) also elevated in MTC. RET mutation testing: all MTC patients should have germline RET testing to identify hereditary MEN2 — triggers screening of at-risk family members. CT neck, chest, abdomen: staging in suspected lymph node disease or distant metastases; CT identifies tracheal or oesophageal invasion and paratracheal lymphadenopathy not visible on ultrasound. PET-CT (FDG-PET): used in de-differentiated (radioiodine-refractory) differentiated thyroid cancer and anaplastic thyroid cancer — FDG avidity correlates with tumour aggressiveness and dedifferentiation. Radioiodine scan (diagnostic I-123 or I-131 scan): whole-body scan performed after total thyroidectomy (with thyroid hormone withdrawal or recombinant TSH — Thyrogen stimulation) to detect residual thyroid tissue and iodine-avid metastases before radioiodine ablation. Post-operative thyroglobulin monitoring: thyroglobulin should be undetectable after total thyroidectomy and radioiodine ablation in disease-free patients; rising thyroglobulin indicates recurrence — thyroglobulin above 1 ng/mL on thyroid hormone suppression or above 10 ng/mL on TSH stimulation warrants imaging.

Differentiated thyroid cancer (papillary and follicular): Surgery: total thyroidectomy is the standard for most DTC (all tumours above 1 cm, bilateral disease, or high-risk features); hemithyroidectomy (lobectomy) may be adequate for low-risk papillary microcarcinomas (below 1 cm, unifocal, no extrathyroidal extension, no lymph node metastases) — avoids lifelong levothyroxine dependency; central neck dissection (levels VI-VII) for clinically or radiologically involved central compartment lymph nodes; lateral neck dissection for confirmed lateral lymph node metastases. Complications of thyroidectomy: recurrent laryngeal nerve injury (unilateral — hoarseness: 1-2% permanent; bilateral — bilateral cord paralysis, stridor, respiratory emergency requiring tracheostomy: 0.5%); hypoparathyroidism (the most common complication — from inadvertent parathyroid gland removal or devascularisation — temporary in 5-10%, permanent in 1-2% — permanent hypoparathyroidism requires lifelong calcium and calcitriol supplementation). Radioiodine ablation (I-131 RAI): for intermediate and high-risk DTC after total thyroidectomy — destroys residual thyroid tissue (reduces recurrence) and ablates iodine-avid metastases; preparation: either thyroid hormone withdrawal (achieving TSH above 30 mU/L for 2-4 weeks — hypothyroid symptoms) or recombinant human TSH injection (Thyrogen 0.9 mg IM for 2 days before — avoids hypothyroid side effects); low-iodine diet for 2 weeks before RAI; doses 30-100 mCi (1.1-3.7 GBq) for adjuvant ablation; higher doses (100-200 mCi) for metastatic disease. TSH suppression therapy: levothyroxine titrated to suppress TSH below 0.1 mU/L (subnormal TSH removes proliferative drive from TSH receptors on DTC cells) — for high-risk patients; relaxed to 0.1-0.5 mU/L for lower-risk patients after 1-2 years of disease-free status; TSH suppression increases AF risk and bone loss (osteoporosis) — requires cardiac and bone density monitoring. Targeted therapy for radioiodine-refractory DTC: lenvatinib (Lenvima — multi-kinase inhibitor targeting VEGFR1-3, FGFR1-4, PDGFR-alpha, RET, KIT — SELECT trial: PFS improved from 3.6 to 18.3 months — FDA approved 2015; NICE approved); sorafenib (DECISION trial — earlier, less potent alternative). RET fusion-positive DTC (RET/PTC rearrangements — approximately 15-20% of PTC): selpercatinib (Retevmo — highly selective RET inhibitor; LIBRETTO-001 trial response rate 79%; well-tolerated; approved FDA 2020/NICE 2022) or pralsetinib. Medullary thyroid cancer (MTC): total thyroidectomy with central neck dissection is the only curative treatment — performed at experienced thyroid surgery centres; adjuvant external beam radiotherapy for high-risk post-surgical residual disease; systemic targeted therapy for progressive/metastatic MTC: vandetanib (Caprelsa — RET/VEGFR/EGFR multikinase inhibitor; ZETA trial: PFS improved from 19.3 to 30.5 months); cabozantinib (Cometriq — RET/MET/VEGFR2; EXAM trial: PFS improved from 4.0 to 11.2 months). For RET M918T and other RET-mutated MTC: selpercatinib (response rate 70%; longer durability); pralsetinib (response rate 71% in MTC). Anaplastic thyroid cancer (ATC): the most aggressive treatment protocol — combination external beam radiotherapy (60-66 Gy) with concurrent chemotherapy (docetaxel or doxorubicin-based regimens); BRAF V600E-mutated ATC (approximately 30-45% of cases): dabrafenib (BRAF inhibitor) plus trametinib (MEK inhibitor) — FDA approved; response rate approximately 56%; median OS improved to approximately 43 weeks (vs. median weeks without targeted therapy); lenvatinib and immunotherapy (pembrolizumab) under investigation. Multidisciplinary management essential — all thyroid cancer cases should be reviewed at a designated thyroid cancer MDT.

Surgical complications: recurrent laryngeal nerve (RLN) injury (the most feared surgical complication — unilateral paralysis causes hoarseness, voice change, and aspiration; bilateral paralysis causes stridor and respiratory failure requiring tracheostomy; intraoperative neuromonitoring of the RLN reduces permanent injury rates to below 1%); hypoparathyroidism (the most common significant complication — temporary hypocalcaemia from parathyroid bruising occurs in 15-30%; permanent hypoparathyroidism in 1-2% after total thyroidectomy — requires lifelong calcium carbonate and activated vitamin D [calcitriol] supplementation; consequences include tetany, perioral tingling, Chvostek's and Trousseau's signs, prolonged QT interval [cardiac arrhythmia risk], and cataract formation); wound haematoma (post-thyroidectomy — neck haematoma causing tracheal compression is a life-threatening emergency requiring immediate wound re-opening at the bedside). Complications of radioiodine treatment: radiation thyroiditis (transient neck pain and swelling); radiation sialadenitis (salivary gland inflammation — the most common long-term complication — occurs in 10-30%; dry mouth, pain); lacrimal gland damage (dry eyes); temporary altered taste sensation; nausea; bone marrow suppression (at high cumulative doses); second primary malignancy risk (leukaemia — very small absolute risk; bladder and salivary gland cancers); teratogenicity — pregnancy must be avoided for 6 months after RAI; breastfeeding must be stopped before RAI. Complications of TSH suppression therapy: atrial fibrillation (risk increased 3-fold — lifelong low TSH; regular ECG monitoring and risk factor management); osteoporosis (particularly in post-menopausal women — DEXA monitoring every 2-3 years; calcium and vitamin D supplementation; bisphosphonates if indicated). Recurrence: local (remnant thyroid bed or cervical lymph nodes — approximately 10-30% of high-risk PTC over 10 years), regional (lymph node recurrence), or distant (lung — the most common site of distant metastases in PTC; bone — FTC); post-operative surveillance with thyroglobulin (stimulated and suppressed), neck ultrasound at 6-12 months and annually, and chest CT/FDG-PET for rising thyroglobulin without identified disease. Dedifferentiation: over time, some metastatic DTC loses radioiodine uptake and thyroglobulin expression — 'radioiodine-refractory' disease — a poor prognostic development indicating more aggressive tumour biology; FDG-PET demonstrates increasing metabolic activity (flip-flop phenomenon); requires systemic targeted therapy.

Radiation protection: avoidance of unnecessary radiation to the head and neck, particularly in children — modern radiation therapy uses more targeted techniques minimising scatter to the thyroid; after significant nuclear accidents or events with I-131 release, distribution and administration of stable potassium iodide tablets (KI) to children saturates the thyroid gland and prevents uptake of radioactive iodine-131 — highly effective if taken within a few hours before or immediately after exposure; public health stockpiling of KI is a standard component of national nuclear emergency preparedness plans. Genetic surveillance and prophylactic surgery in MEN2 and CDH1 families: all MTC patients should have germline RET testing; RET mutation carriers (family members identified through cascade testing) should undergo prophylactic thyroidectomy at an age determined by the specific RET mutation risk level (highest-risk mutations — MEN2B RET codon 918 — prophylactic thyroidectomy recommended within the first 6 months of life; high-risk — MEN2A codon 634 — by age 5; moderate-risk mutations — by age 5-10 or when calcitonin rises above normal); phaeochromocytoma must be excluded biochemically (24-hour urine catecholamines and metanephrines, or plasma metanephrines) BEFORE thyroid surgery — adrenal surgery first if phaeochromocytoma confirmed. Post-treatment surveillance for differentiated thyroid cancer: neck ultrasound at 6-12 months post-surgery and then annually for 5 years in high-risk, or 1-2 yearly in low-risk; suppressed thyroglobulin (on levothyroxine) annually — the most important surveillance marker; stimulated thyroglobulin (after thyroid hormone withdrawal or Thyrogen) at 6-12 months post-RAI for high-risk patients; rising thyroglobulin requires structural imaging (CT, MRI, FDG-PET) to localise recurrence. Active surveillance for low-risk papillary microcarcinoma: for unifocal papillary microcarcinomas (below 10 mm, no high-risk features) in older patients with significant surgical comorbidity — active surveillance (ultrasound every 6-12 months; surgery if growth above 3 mm or lymph node metastases develop) is an internationally accepted alternative to immediate surgery; supported by the ATA 2015 guidelines and Japanese long-term surveillance data. Patient education and support: Butterfly Thyroid Cancer Support (UK), ThyCa (US) — patient advocacy organisations providing support and information to patients and families.

See a GP urgently (within 2 weeks — 2WW referral) for: any new palpable thyroid nodule in an adult — particularly if firm, hard, or rapidly growing; a thyroid nodule associated with hoarseness of voice (possible recurrent laryngeal nerve compression — urgent ENT referral for laryngoscopy); a thyroid nodule with associated cervical lymphadenopathy; and any thyroid nodule in a child or adolescent (higher malignancy rate — 25-40% in children vs. 5-10% in adults). Go to A&E immediately for: stridor (noisy breathing from airway compression) or rapidly progressive difficulty breathing or swallowing associated with a thyroid mass — possible anaplastic thyroid cancer or haemorrhage into a thyroid nodule causing tracheal compression (rare but emergency); post-thyroidectomy: neck swelling, increasing pain, progressive breathing difficulty — possible haematoma requiring immediate re-exploration. For patients with MEN2 family history: all first-degree relatives of a patient with medullary thyroid cancer should have genetic counselling and germline RET testing — do not delay this process as prophylactic surgery timing is RET mutation-specific. For patients under thyroid cancer surveillance: contact your endocrinologist promptly for: unexplained rising thyroglobulin (possible recurrence); new neck lump or lymphadenopathy; hoarseness, dysphagia, or neck pain after thyroid cancer treatment. Do not miss post-operative thyroglobulin and neck ultrasound appointments — early detection of recurrence allows effective salvage treatment.