32. Thyroid carcinoma

1. Definition

• Thyroid carcinoma → malignant tumour of the thyroid gland
• Arises from follicular cells → differentiated (papillary, follicular, oncocytic), poorly differentiated, anaplastic
• Arises from parafollicular C cells → medullary carcinoma

2. Epidemiology

• Most common endocrine malignancy
• Female predominance → about 3:1
• Thyroid nodules → palpable in 5%; on ultrasound in up to 50% by age 50 years
• Malignant nodules → rare, about 4 per 100 000 per year
• Solitary thyroid nodule → most common thyroid disorder; colloid nodule most often

3. Aetiology and risk factors

• Ionising radiation in childhood → papillary carcinoma (Chernobyl, Hiroshima, head and neck radiotherapy)
• Family history of differentiated thyroid cancer
• Hereditary syndromes:
  • Familial adenomatous polyposis, Gardner's syndrome → papillary
  • Cowden syndrome → follicular
  • Carney complex → papillary, follicular
  • Multiple endocrine neoplasia type 2 (MEN2) → medullary (RET mutation)
• Iodine deficiency → follicular
• Long-standing goitre → anaplastic
• Hashimoto's thyroiditis → thyroid lymphoma

4. Pathogenesis

• Papillary → BRAF V600E mutation, RET/PTC rearrangement
• Follicular → RAS mutation, PAX8-PPARγ rearrangement
• Medullary → RET proto-oncogene mutation; sporadic 75%, hereditary 25%
• Anaplastic → dedifferentiation of a differentiated tumour, TP53 mutation

5. Classification

A. Papillary carcinoma (PTC)

• Most common → about 80–85%
• Young adults, women
• Spread → lymphatic to central and lateral neck nodes; microscopic nodal disease in up to 80%
• Distant metastases → 3–5%, lung and bone
• Papillary microcarcinoma → ≤ 1 cm
• Histology → papillae, Orphan Annie (clear) nuclei, nuclear grooves, pseudoinclusions, psammoma bodies
• Multifocal, often bilateral
• Aggressive variants (< 1%) → tall cell, hobnail, diffuse sclerosing, columnar

B. Follicular carcinoma (FTC)

• Second most common
• Older adults, female to male 3:1, iodine-deficient areas
• Spread → haematogenous to lung and bone; nodes in < 10%
• Diagnosis → capsular or vascular invasion on histology; cannot be made on FNA
• Minimally invasive → capsular invasion only; excellent prognosis
• Widely invasive → through the capsule into the gland and vessels; haematogenous metastases

C. Oncocytic carcinoma

• Formerly Hürthle cell carcinoma
• ≥ 75% oncocytic cells
• Less radioiodine-avid

D. Medullary carcinoma (MTC)

• From parafollicular C cells → secretes calcitonin and carcinoembryonic antigen (CEA)
• Sporadic → unifocal, age 40–60 years
• Hereditary → bilateral, multifocal; MEN2A, MEN2B, familial medullary carcinoma
• MEN2A → MTC, phaeochromocytoma, hyperparathyroidism
• MEN2B → MTC, phaeochromocytoma, mucosal neuromas, marfanoid habitus
• Does not take up iodine → no role for RAI

E. Anaplastic carcinoma (ATC)

• Older women, rapidly growing hard mass over weeks
• Hoarseness, dysphagia, stridor
• Most aggressive → median survival about 5 months
• All are stage IV

F. Others

• Thyroid lymphoma → diffuse B-cell non-Hodgkin's or mucosa-associated lymphoid tissue (MALT) lymphoma; background of Hashimoto's thyroiditis; rapid growth; core biopsy; chemotherapy and radiotherapy
• Metastases to the thyroid → kidney, lung, breast, melanoma

Staging

• Tumour, node, metastasis (TNM) system, American Joint Committee on Cancer (AJCC) 8th edition
• Differentiated cancer → age 55 years is the cut-off
• Under 55 years → stage I without distant metastases, stage II with them

6. Clinical picture

Symptoms

• Painless thyroid nodule → most common presentation
• Rapid growth
• Hoarseness → recurrent laryngeal nerve invasion
• Dysphagia, dyspnoea, cough, haemoptysis
• Diarrhoea, flushing → medullary carcinoma (calcitonin)
• Bone pain → metastases

Signs

• Hard, irregular, fixed nodule
• Solitary nodule in a man, a child or an elderly patient → higher cancer risk
• Rapid growth of a long-standing nodule
• Cervical lymphadenopathy
• Vocal cord palsy
• Horner's syndrome → extensive spread

7. Diagnosis

Laboratory

• TSH → usually normal
• Calcitonin and CEA → medullary carcinoma
• RET mutation testing → all medullary carcinomas and their families
• Plasma metanephrines before surgery in medullary carcinoma → exclude phaeochromocytoma
• Thyroglobulin → tumour marker after total thyroidectomy, not for diagnosis

Imaging

• Ultrasound of the thyroid and neck nodes:
  • Suspicious → hypoechoic, solid, taller than wide, irregular margins, microcalcifications, extrathyroidal extension
  • United Kingdom → British Thyroid Association U1–U5 grading: U1 normal, U2 benign, U3 equivocal, U4 suspicious, U5 malignant
  • United States → thyroid imaging reporting and data system (TI-RADS)
  • FNA for U3–U5
• FNA cytology, United Kingdom Thy system (risk of malignancy):
  1. Thy1 → non-diagnostic; repeat
  2. Thy2 → benign colloid nodule; 0–3%
  3. Thy3a → atypia; 5–15%
  4. Thy3f → follicular lesion; 15–30%; diagnostic lobectomy
  5. Thy4 → suspicious of malignancy; 60–75%
  6. Thy5 → malignant; 97–100%
• Bethesda system (6 categories) → used outside the United Kingdom; same steps from non-diagnostic to malignant
• Follicular adenoma or carcinoma → separated only on histology after excision
• Molecular testing → indeterminate cytology (Bethesda 3 and 4)
• CT of neck and chest → locally advanced disease, retrosternal extension
• Laryngoscopy → vocal cord function before surgery
• Core biopsy → lymphoma, anaplastic carcinoma

8. Differential diagnosis

• Benign colloid nodule, multinodular goitre
• Follicular adenoma
• Thyroid cyst
• Thyroiditis → Hashimoto's, Riedel's
• Parathyroid tumour
• Lymphadenopathy of other origin

9. Treatment

Surgical

• Differentiated carcinoma:
  • Lobectomy with isthmus → minimum operation; diagnostic for Thy3f; curative for papillary < 1 cm and minimally invasive follicular carcinoma
  • Lobectomy also acceptable → low-risk papillary 1–4 cm, no nodes, no extrathyroidal extension (current guidelines)
  • Total thyroidectomy → > 4 cm, extrathyroidal extension, nodal or distant metastases, previous neck radiation, familial disease, bilateral tumours
  • Completion thyroidectomy → after lobectomy shows high-risk papillary or widely invasive follicular carcinoma
  • Microcarcinoma < 1 cm, low risk → lobectomy or active surveillance
• Neck nodes:
  • Clinically involved central nodes → central compartment (level VI) dissection
  • Involved lateral nodes → central and lateral (levels II–V) neck dissection
  • Prophylactic central dissection → selected high-risk tumours (T3, T4)
• Medullary carcinoma → total thyroidectomy with central neck dissection; lateral dissection for involved nodes
• Prophylactic thyroidectomy in RET carriers → timing set by the mutation; in the first year of life in MEN2B
• Anaplastic carcinoma → resection if localised; tracheostomy for the airway only if needed

Conservative and adjuvant

• Radioactive iodine (RAI) → ablation of remnant and metastases after total thyroidectomy in intermediate and high-risk differentiated cancer
• Uptake needs a high TSH → stop liothyronine (T3) for 2 weeks, or give recombinant human TSH (rhTSH) without stopping hormone
• TSH suppression with levothyroxine:
  • Low to intermediate risk → TSH 0.1–0.5 mU/L
  • High risk → TSH < 0.1 mU/L
• External beam radiotherapy → unresectable or anaplastic disease
• Targeted therapy → tyrosine kinase inhibitors for RAI-refractory and medullary disease; dabrafenib + trametinib for BRAF V600E anaplastic carcinoma
• Follow-up → thyroglobulin, anti-thyroglobulin antibodies, neck ultrasound

10. Complications

• Recurrent laryngeal nerve injury
• Hypoparathyroidism → hypocalcaemia
• Haematoma, airway compression
• Superior laryngeal nerve injury → voice fatigue, loss of high pitch
• Local recurrence, distant metastases
• RAI → sialadenitis, dry mouth, secondary malignancy

11. Prognosis

• Papillary → 10-year survival > 90%
• Follicular → slightly worse than papillary
• Medullary → depends on stage and calcitonin doubling time
• Anaplastic → very poor