STEPTRACKERENDOCRINE + ONCOLOGY | PATHOLOGY + GENETICS | HIGH-YIELD REVIEW

Thyroid Neoplasms

Working up a nodule, and the four carcinomas — each with its own nucleus, invasion pattern, gene and route of spread.

FOCUS ON
Papillary (most common, radiation, BRAF/RET-PTC): Orphan Annie nuclei, grooves, psammoma bodies, lymph spread, excellent prognosis. Follicular: diagnosis needs capsular/vascular invasion (FNA can't), blood spread. Medullary: C cells, calcitonin, amyloid, RET, MEN2. Anaplastic: older, rapid, invasive, TP53, fatal. Nodule: TSH first — low → scan; normal → ultrasound + FNA.
TUMOR · TOPIC
MECHANISM · GENETICS
FEATURES
CLUE
Thyroid nodule workup
Most nodules are benign
TSH first: low → radioiodine scan (hot nodules rarely malignant) · normal/high → ultrasound → FNA
Cold nodules carry more cancer risk
Red flags for malignancy
Clinical risk features
Childhood neck radiation, male, extremes of age, rapid growth, hard fixed nodule, hoarseness, cervical nodes
Microcalcifications on US
Follicular adenoma
Benign encapsulated follicular tumor; RAS
Solitary, encapsulated, no capsular or vascular invasion
Usually cold, euthyroid
Papillary carcinoma
~80%
Ionizing radiation in childhood; BRAF V600E, RET/PTC rearrangements
Papillae; Orphan Annie (empty, ground-glass) nuclei, nuclear grooves, pseudo-inclusions; psammoma bodies
Spreads to cervical nodes · excellent prognosis
Follicular carcinoma
RAS mutations, PAX8-PPARγ fusion; iodine deficiency
Uniform follicles; malignancy = capsular or vascular invasion (needs excision, not FNA)
Hematogenous → bone, lung
Medullary carcinoma
Parafollicular C cells (neural crest); RET gain-of-function; sporadic or MEN2A/2B
Sheets of polygonal/spindle cells in amyloid stroma (calcitonin-derived, Congo red ⁺)
↑ calcitonin, CEA · prophylactic thyroidectomy in RET carriers
Anaplastic carcinoma
Dedifferentiated; TP53; often from prior papillary/follicular
Older patients; rapidly enlarging, hard, invasive neck mass → dysphagia, dyspnea, hoarseness
Very poor prognosis
Thyroid lymphoma
B-cell lymphoma (marginal zone, DLBCL) arising in Hashimoto
Older woman, rapidly enlarging goiter
Responds to chemo/radiation
Treatment & follow-up
Thyroidectomy → radioiodine ablation for differentiated cancer → TSH suppression with levothyroxine
Thyroglobulin = tumor marker after total thyroidectomy
Medullary: no radioiodine (C cells don't take up iodine)
Thyroidectomy complications
Nearby structures
Recurrent laryngeal nerve → hoarseness · parathyroid removal → hypocalcemia, tetany · external branch of superior laryngeal nerve → weak high-pitched voice
RLN runs with inferior thyroid artery

Mechanism — four carcinomas, four drivers

Follicular cell
→
BRAF / RET-PTCPapillary
RAS / PAX8-PPARγFollicular
+ TP53 lossAnaplastic
C cell (neural crest)
→
RET activation
→
Medullary carcinomaCalcitonin, amyloid

Papillary spreads by lymph; follicular by blood — the only common carcinoma pair where this split is a rule.

Carcinomas compared

TYPE
KEY HISTOLOGY
SPREAD
MARKER
Papillary
Orphan Annie nuclei, psammoma
Lymph nodes
Thyroglobulin
Follicular
Capsular/vascular invasion
Blood (bone, lung)
Thyroglobulin
Medullary
Amyloid stroma
Nodes, blood
Calcitonin, CEA
Anaplastic
Pleomorphic, giant cells
Local invasion
—

How it's tested

COMMON CONFUSIONFollicular adenoma vs follicular carcinoma can't be separated by FNA cytology — the cells look the same. Only the excised capsule shows invasion.
THE TRAPBefore thyroidectomy for medullary carcinoma, screen for pheochromocytoma (MEN2) — operating on an unknown pheo can cause a hypertensive crisis.
YOUR APPROACHTSH → scan or US → FNA → histology clue (nuclei, invasion, amyloid, pleomorphism) → gene → spread → marker for follow-up.

If you see… think…

Childhood neck radiation, now a thyroid nodule with cervical nodes → papillary carcinoma
Empty-looking nuclei with grooves and psammoma bodies → papillary carcinoma
Thyroid cancer with bone metastasis and capsular invasion → follicular carcinoma
Thyroid tumor with amyloid stroma and ↑ calcitonin → medullary carcinoma
Medullary thyroid cancer + pheochromocytoma + hyperparathyroidism → MEN2A (RET)
Elderly patient with rapidly growing hard neck mass and stridor → anaplastic carcinoma
Low TSH with a nodule → radioiodine scan — hot nodule likely benign
Rising thyroglobulin after total thyroidectomy → recurrent differentiated carcinoma
Hoarseness after thyroidectomy → recurrent laryngeal nerve injury
Perioral tingling and carpal spasm the day after thyroidectomy → hypoparathyroidism