Thyroid Neoplasms — Papillary, Follicular, Medullary and Anaplastic Carcinoma, WHO 2022 and Bethesda

The simplest way to classify thyroid tumours is by the cell of origin. Most arise from the follicular epithelial cells that make thyroglobulin and take up iodine — papillary, follicular, oncocytic and anaplastic carcinoma. A minority arise from the parafollicular C cells that make calcitonin — medullary thyroid carcinoma. That single split explains most exam facts: follicular-cell cancers can be followed with thyroglobulin and treated with radioiodine; C-cell cancers are followed with calcitonin and CEA and do not take up iodine.

Papillary thyroid carcinoma (PTC) is the most frequent thyroid cancer — 80 to 85% of cases — and carries the best overall prognosis. The best-established risk factor is ionising radiation, especially low-dose head and neck irradiation in childhood; the average interval from irradiation to tumour is about 10 years but can exceed 30 years. About 5% of cases are familial. At the molecular level, RET rearrangements, NTRK1 and the BRAF V600E mutation are the key events; BRAF V600E is linked with prognosis.

The diagnosis is made on nuclear features, not on the papillae. StatPearls lists the diagnostic nuclear constellation: enlarged, elongated, crowded and overlapping nuclei; irregular contours; chromatin clearing with peripheral margination — the Orphan Annie eye nuclei; nuclear grooves; and intranuclear cytoplasmic pseudo-inclusions. Psammoma bodies (laminated calcifications) complete the picture. The papillae themselves have a central fibrovascular core.

• Presentation: a painless, hard thyroid nodule, usually under 5 cm, with or without cervical nodes. Thyroid function is usually normal.
• Spread: a key feature is invasion of lymphatics; lateral neck nodes are involved in about 27% at presentation. Distant metastases (mainly lung and bone) are uncommon.
• Imaging: ultrasound is the imaging of choice — hypoechoic solid nodule, irregular margins, microcalcifications (highly specific), taller-than-wide shape. On a thyroid scan PTC is usually a cold nodule.
• FNA is often the first diagnostic test because the nuclear features are visible on cytology.

Follicular thyroid carcinoma (FTC) is the second commonest type, about 10 to 15% of thyroid cancers, and is relatively more frequent in iodine-deficient areas (around 25–40% there versus about 10% in iodine-sufficient areas). Its cells do not show the nuclear atypia of papillary carcinoma. Instead, it is defined by capsular and/or vascular invasion on histology. Up to half carry RAS point mutations and about a third a PAX8–PPARγ rearrangement.

Because the cytology of a follicular adenoma and a follicular carcinoma looks the same, the decision depends on examining the whole capsule after excision. That is why an aspirate showing a follicular pattern is reported as a follicular neoplasm (Bethesda IV) rather than a definite cancer label; molecular testing, repeat sampling or excision of the nodule decides the next step.

Prognosis tracks the degree of invasion: StatPearls quotes about 98% 10-year survival for minimally invasive and about 80% for widely invasive follicular cancer. In one series quoted there, metastases went to bone in 42%, lung in 33% and lymph nodes in 8% — the 'bone and lung' pattern exams like.

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumour of the parafollicular C cells, which make calcitonin. It forms about 1 to 5% of thyroid cancers. About 75% are sporadic and 25% hereditary — most often MEN 2A, then MEN 2B and familial MTC. Germline RET proto-oncogene mutations underlie all hereditary cases and about half of sporadic tumours also carry RET mutations.

• Histology: tumours may show amyloid derived from calcitonin and coarse calcifications.
• Markers: baseline serum calcitonin and CEA are the essential tumour markers; both are repeated about 3 months after surgery to look for residual disease.
• Hormonal symptoms: advanced disease causes diarrhoea and flushing from calcitonin and other peptides; ectopic ACTH can cause Cushing syndrome.
• MEN 2A: MTC + phaeochromocytoma + primary hyperparathyroidism (95% of MEN 2 cases). Screen for phaeochromocytoma before thyroid surgery when MEN is suspected.
• Treatment: total thyroidectomy with central neck dissection (bilateral central neck dissection for tumours of 1 cm or more). Carriers of germline RET mutations are offered prophylactic thyroidectomy, timed by mutation risk and calcitonin.
• No radioiodine: C cells do not concentrate iodine, so radioactive iodine is ineffective and TSH suppression is not indicated — levothyroxine is given only as replacement.

Anaplastic (undifferentiated) thyroid carcinoma is rare — about 2 to 3% of thyroid neoplasms in StatPearls (1–10% across series) — but causes up to half of all thyroid cancer deaths. It mostly affects people over 65, women more than men, and about 20% have a history of differentiated thyroid cancer or long-standing multinodular goitre, reflecting dedifferentiation. TP53 and TERT promoter mutations are common; some carry BRAF V600E.

• Presents almost invariably as a rapidly growing anterior neck mass with early compressive or invasive symptoms (airway, oesophagus, recurrent laryngeal nerve). Cervical nodes are involved in up to 40%.
• Thyroid lineage markers such as thyroglobulin and TTF-1 are usually absent; PAX8 is retained in about half.
• All anaplastic carcinomas are staged as stage IV (IVA intrathyroidal, IVB extrathyroidal, IVC distant metastasis).
• Historic SEER data put median survival at only a few months. Airway involvement may need a tracheostomy; BRAF V600E–mutant tumours can be treated with dabrafenib plus trametinib.

The 5th edition WHO classification (2022) reorganised thyroid tumours by cell of origin, pathology, molecular profile and behaviour. Follicular-cell–derived tumours are now split into benign, low-risk and malignant neoplasms.

The Bethesda System for Reporting Thyroid Cytopathology standardises FNA reports into six categories, each with an implied risk of malignancy and a management step. The third edition (2023) gave each category a single name, updated the risks (adding an average risk to the range), simplified the AUS subgroups and aligned the wording with WHO 2022.

1. TSH first. Most cancers are euthyroid. A normal-to-high TSH, prior neck irradiation or a MEN history raises suspicion.
2. Ultrasound. Suspicious features: microcalcifications, irregular margins, hypoechogenicity, taller-than-wide shape and internal vascularity.
3. FNA of suspicious nodules, reported with the Bethesda categories above.
4. Surgery by risk. For papillary carcinoma, lobectomy is an option for unifocal tumours under 4 cm without extrathyroidal extension or node metastasis; tumours over 4 cm, gross extrathyroidal extension (cT4), clinical nodes (cN1) or distant metastasis (cM1) need near-total or total thyroidectomy.
5. Radioiodine after thyroidectomy ablates remnant tissue in differentiated (follicular-cell) cancers — not in medullary carcinoma.
6. Lifelong levothyroxine after thyroidectomy; in differentiated cancers the dose initially suppresses TSH, since TSH can stimulate residual tumour cells.

For the physiology behind thyroglobulin, iodide trapping and TSH drive — the reason radioiodine works for follicular-cell cancers but not for C-cell cancers — see thyroid hormone synthesis.