Thyroid cancer (Thyroid carcinoma)

The majority of thyroid cancers are well-differentiated carcinomas. The principal risk factors are exposure to ionizing radiation and genetic predisposition; thyroid cancers also disproportionately affect women. A distinction is made between well-differentiated thyroid carcinomas (papillary or follicular carcinoma) and poorly differentiated carcinomas (medullary or anaplastic carcinoma); the two groups vary considerably with regard to treatment options, metastatic pathways, and prognosis. Papillary thyroid carcinomas are the most common type of thyroid cancer. Early detection is crucial for improving the prognosis but challenging because symptoms often appear late in the course of the disease. Imaging plays a central role in detection: nodules that appear hypoechoic on ultrasound and cold on scintigraphy should raise suspicion of malignancy. Additional testing is needed to determine the type of thyroid cancer, including measuring hormone levels, tumor markers, and/or biopsy via fine-needle aspiration. Most thyroid cancers are treated surgically (hemithyroidectomy or thyroidectomy), followed by thyroid hormone therapy to replace physiological hormone production and to limit the growth stimulus for any remaining metastases. Further therapeutic measures depend on the type of thyroid cancer involved and include radioiodine therapy and possibly chemotherapy.

• Genetic factors:
  • Medullary carcinoma: associated with MEN2 (RET gene mutations) or familial medullary carcinoma.
  • Papillary carcinoma: associated with RET/PTC rearrangements and BRAF mutations
  • Follicular carcinoma: associated with PAX8-PPAR-γ rearrangement and RAS mutation
  • Undifferentiated/anaplastic carcinoma: associated with TP53 mutation
• Ionizing radiation; (particularly during childhood): mostly associated with papillary carcinoma

References:^[1][3][4]

Tissue of origin	Carcinoma	Differentiation	Characteristics	Distribution	Peak incidence
Thyrocytes	Papillary thyroid carcinoma	Well-differentiated	Most common type of thyroid cancer Palpable lymph nodes due to metastatic spread (often detected before primary tumor) May be multifocal Very good prognosis	∼ 80% of cases	30–50 years of age
	Follicular thyroid carcinoma		Hematogenous metastasis especially to Lungs Bone (lytic lesions) Rarely multifocal Vascular and capsular invasion Good prognosis	∼ 10% of cases	40–60 years of age
	Anaplastic thyroid carcinoma	Poorly-differentiated	Rapid local growth Symptoms of compression of the structures of the neck (e.g. dysphagia, dyspnea) Lymphatic and hematogenous metastasis Very poor prognosis	∼ 1–2% of cases	After 60 years of age
Parafollicular cells (C cells)	Medullary carcinoma		Sometimes a genetic predisposition → multiple endocrine neoplasia type 2 (MEN2) (25% of medullary carcinomas) Sporadic (75% of medullary carcinomas) Produces calcitonin	< 10%of cases	50–60 years of age

Remember that Papillary carcinoma is the most Prevalent type of thyroid cancer, that it features Palpable lymph nodes, and that it has the best Prognosis compared to all other types of thyroid cancer.

References:^{[1][4][5][6][7]}

• Early stages:
  • Often asymptomatic
  • Firm, painless thyroid nodules may be palpated.
• Late stages: ^[1]
  • Dyspnea
  • Dysphagia
  • Hoarseness (vocal cord paresis)
  • Horner syndrome
  • Possible obstruction of the superior vena cava

Only 25% of thyroid carcinomas detected on ultrasound had previously manifested with clinical signs or symptoms!

References:^[1][9]

Laboratory tests

• Thyroid function tests:
  • Basal TSH
  • fT3 and fT4
• Tumor markers
  • Thyroglobulin (Tg): should be measured as a follow‑up to thyroidectomy in follicular or papillary thyroid carcinoma
  • Calcitonin
    • For supporting diagnosis of medullary thyroid carcinoma and follow‑up
  • Patients with medullary thyroid carcinoma often also have elevated levels of carcinoembryonic antigen (CEA) and chromogranin A (which serve to support diagnosis in unclear cases).

Imaging

Ultrasound ^[10][11][12]

• Hypoechoic thyroid lesions with irregular margins > 1 cm are potentially malignant although normal echogenicity does not rule out carcinoma!
• Malignancies often show microcalcifications; (typical for papillary thyroid carcinomas)

Thyroid scintigraphy

• Indications:
  • Thyroid nodule with ↓ TSH level
  • Evaluation of ectopic thyroid tissue or retrosternal goiter
• Findings: decreased tracer uptake suggests a malignant non-functioning (cold) nodule.

Nodules that appear hypoechoic on ultrasound and cold in scintigraphy are highly suspicious for malignancy!

Fine-needle aspiration (FNA)

• Indicated if malignancy is suspected based on ultrasound or scintigraphy
  • If biopsy results are unclear or in any way suspicious, surgery is usually recommended.

Staging

• Chest x-ray
• Abdominal ultrasound
• Neck CT/MRT
• Bone scintigraphy or PET for detecting metastases
• Family screening

References:^{[1][13][14][15][10][11][12][16][17]}

Papillary carcinoma

Psammoma bodies ^[18]

• Morphology: concentric lamellar calcifications
• Occurrence: seen in diseases associated with calcific degeneration
  • Papillary thyroid carcinomas (evidence of psammoma bodies in thyroid tissue should always raise suspicion of malignancy) ^[4]
  • Serous papillary cystadenocarcinoma of ovary and endometrium
  • Meningiomas
  • Mesotheliomas

“Orphan Annie” eyes nuclei

• Morphology: empty-appearing large oval nuclei with central clearing
• Occurrence
  • Papillary thyroid carcinomas
  • Autoimmune thyroiditis (e.g., Hashimoto disease, Grave disease)

Nuclear grooves ^[19]

• Morphology: longitudinal invaginations of nuclear bilayer
• Occurrence: papillary thyroid carcinomas

To memorize that papillary thyroid cancer is histologically characterized by psammoma bodies and Orphan Annie-eye nuclei, imagine that “Papi and Moma adopted Orphan Annie.”

Follicular carcinoma ^[20]

• Uniform follicles
• Vascular and/or capsular invasion

Medullary carcinoma ^[21]

• Ovoid cells of C cell origin and therefore without follicle development
• Amyloid in the stroma (stains with Congo red)

Remember that medullary carcinoma is composed of C-cells producing Calcitonin and is characterized by amyloid aCCumulation staining with Congo red.

Anaplastic thyroid carcinoma ^[22]

• Undifferentiated giant cell (i.e., osteoclast-like cell)
• Areas of necrosis and hemorrhage

References:^{[23][23][4][18][21][20][22]}

References: ^[24]

Well-differentiated cancers

• Surgical management: primary treatment of choice (see thyroid surgery)
  • Intrathyroidal tumor < 1 cm: hemithyroidectomy
  • Intrathyroidal tumor 1–4 cm: hemithyroidectomy or total thyroidectomy
  • Intrathyroidal tumor > 4 cm, extrathyroidal spread, or metastasis: total thyroidectomy with neck dissection
  • Evidence of regional lymph node spread: therapeutic neck dissection
• Postoperative management
  • Radioiodine therapy : often conducted 4–6 weeks after surgery to destroy remaining thyroid tissue or metastases
  • Thyroid hormone therapy with L-thyroxine after thyroidectomy
    • TSH suppression
      • Reduces the risk of stimulating remaining malignant tissue
      • Administer the highest possible dose (according to the patient's tolerance)
    • Only administer after radioiodine therapy!

Poorly-differentiated cancers

• Total thyroidectomy with adjuvant radiochemotherapy if operable
• Radiochemotherapy if locally advanced, inoperable

Complications

• Accidental removal of parathyroid glands → hypocalcemia ^[25]
• Transection of superior and recurrent laryngeal nerve → dysphonia (hoarseness), dysphagia
  • May occur during ligation of the superior laryngeal artery and inferior thyroid artery due to the proximity of the nerves to the arteries.
  • If only the external branch of the superior laryngeal nerve is damaged, complete loss of voice is unlikely, but a loss of vocal range may occur (with potentially career-damaging consequences for occupational voice users, e.g., singers).

References:^{[26][10][1][6]}