Thyroid cancer

Thyroid cancer is a malignant tumor that arises from either the thyrocytes or the parafollicular cells of the thyroid gland. It is more common in women, especially between 30–50 years of age. The predominant risk factors for thyroid cancer are a history of childhood irradiation to the head and neck and a family history of thyroid cancer. Thyroid cancer typically manifests as firm to hard thyroid nodule (or nodules). Initial evaluation of all patients includes TSH assay and thyroid ultrasound. Sonographic signs of thyroid cancer include a solid, hypoechoic nodule(s) with irregular margins, microcalcifications, and evidence of local infiltration into adjacent structures or cervical lymph nodes. On thyroid scintigraphy, which should be obtained in patients with low serum TSH, a malignant nodule is typically “cold” or hypofunctional. Cytopathological analysis with FNAB is required to confirm the diagnosis. Depending on the cell of origin, thyroid cancer can be classified as papillary, follicular, medullary, or anaplastic thyroid cancer. Most thyroid cancers are treated surgically with total thyroidectomy (in some cases with hemithyroidectomy), followed by adjuvant therapy, which may include RAIA and TSH suppression therapy with L-thyroxine, radiation therapy, and chemotherapy. In advanced anaplastic carcinoma, only palliative care may be feasible. The prognosis depends on the type of thyroid cancer.

• Incidence: ∼ 13.5 new cases per 100,000 per year ^[1]
• Sex ^[2]
  • Differentiated carcinoma (papillary and follicular): ♀ > ♂ (3:1)
  • Poorly-differentiated carcinoma (medullary and anaplastic): ♀ ≈ ♂
• Age: See “Overview” below.

Epidemiological data refers to the US, unless otherwise specified.

• 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:^[3]

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

• Hurthle cell carcinoma
  • 3–10% of all well-differentiated thyroid cancers
  • Often classified as subtype of follicular carcinoma
  • Thyroid histopathology: hypercellularity with a predominance of Hurthle cells (large, polygonal epithelial cell with eosinophilic granular cytoplasm as a result of numerous altered mitochondria)
    • Hurthle cells are nonspecific and also observed in Hashimoto thyroiditis, Graves disease, previously-irradiated thyroid glands, and in Hurthle cell adenoma (no vascular or capsular invasion; no metastasis)
    • They are also found in the parathyroid glands, salivary glands, and kidneys
• B-cell lymphoma: usually develops from Hashimoto thyroiditis
• Sarcoma: rare
• Metastatic (e.g., breast, renal, melanoma): rare

Thyroid carcinoma may be asymptomatic (e.g., thyroid incidentaloma) or manifest with any or all of the following clinical features: ^[10]

• Thyroid nodule ^[11][12]
  • Firm to hard consistency
  • Typically painless
  • See also “Red flags for thyroid cancer.”
• Features of local infiltration or compression
  • Fixed thyroid nodule ^[13][14]
  • Recent onset of any of the following: ^[12]
    • Hoarseness of voice (vocal cord paresis)
    • Dyspnea
    • Dysphagia
    • Horner syndrome (rare) ^[15][16]
    • Venous obstruction (very rare): IJV thrombosis, SVC syndrome ^[17][18]
• Painless cervical lymphadenopathy ^[14]
  • More common in papillary thyroid cancer and anaplastic thyroid cancer
  • Less common in follicular thyroid cancer
• Signs of distant metastasis ^[19]
  • More common in follicular thyroid cancer and anaplastic thyroid cancer
  • Less common in papillary thyroid cancer
  • Examples include:
    • Pulmonary metastases: coughing, hemoptysis, dyspnea
    • Bone metastases: bone pain, pathologic fractures
    • Brain metastases: focal neurologic deficit, seizures
• Paraneoplastic syndrome: diarrhea and facial flushing (typically seen in advanced medullary carcinoma) ^[8]

Approach ^[11][14]

• For initial evaluation, follow the diagnostic approach to thyroid nodules.
  • TSH, ultrasound, potentially scintigraphy
  • Confirmation: fine-needle aspiration cytology (FNAC) or intraoperative frozen-section
• Thyroid tumor markers help to estimate the prognosis and assess response to therapy.
  • Differentiated thyroid cancer: serum thyroglobulin (Tg)
  • Medullary carcinoma: serum calcitonin and carcinoembryonic antigen (CEA)
• Staging of lymph node and distant metastases
• Patients with medullary carcinoma require further assessment.
  • Genetic testing for RET germline mutations ^[8]
  • Screening of family members
  • Screening for associated conditions (e.g., MEN2)

Initial evaluation

Laboratory studies and ultrasound

Serum TSH and ultrasound should be obtained in all patients with thyroid nodules.

• TSH: typically normal or mildly elevated ^[14]
• Thyroid ultrasound: to assess for sonographic signs of thyroid malignancy ; ^[11][14]
  • Solid or mostly solid hypoechoic nodule(s)
  • Irregular margins
  • Microcalcifications within nodules
  • Nodules that are taller than wide
  • Extrathyroidal growth

Thyroid scintigraphy ^[11]

• Indications
  • Thyroid nodule(s) with ↓ TSH levels
  • Multinodular thyroids (to identify nodules that require FNAC)
  • Prior to RAIA to evaluate eligibility for adjuvant treatment of well-differentiated thyroid cancer
• Contraindications: pregnant and breastfeeding women
• Supportive findings: decreased or no radiotracer uptake (i.e., hypofunctioning or nonfunctioning nodules, referred to as cold nodules) ^[20]

Nodules that appear hypoechoic on thyroid ultrasound and cold on thyroid scintigraphy should increase suspicion for malignancy.

Hyperfunctioning nodules (hot nodules) are rarely malignant and typically do not require further evaluation for malignancy. ^[11][21]

Confirmatory tests ^[11][14]

• Fine-needle aspiration cytology (FNAC)
  • Indications: sonographic signs of thyroid cancer detected on thyroid ultrasound (see “Indications for FNAC of thyroid nodules”)
  • Supportive findings: typically reported as “malignant” or “suspicious for malignancy” according to the Bethesda system for thyroid cytopathology
• Intraoperative frozen-section: Consider if FNAC cannot reliably rule out malignancy in high-risk patients.

Additional studies after confirmed diagnosis

Thyroid cancer tumor markers

The specific tumor markers depend on the histological type of the cancer.

• Follicular or papillary thyroid cancer
  • Thyroglobulin (Tg): precursor of thyroid hormones; produced exclusively by the thyroid gland ^[14]
    • Indicated after total thyroidectomy or RAIA therapy
    • Baseline (pretreatment) levels are not routinely indicated.
• Medullary carcinoma
  • Calcitonin: A hormone secreted by parafollicular cells, which is the tissue of origin of medullary carcinoma
    • Indicated preoperatively if FNAC is suspicious for medullary carcinoma (supportive diagnostic marker) ^[8][11])
    • Used to monitor response to therapy
  • Carcinoembryonic antigen (CEA): nonspecific marker, used in combination with calcitonin to monitor response to therapy ^[8]

Elevation of tumor markers after total thyroidectomy or RAIA indicates persistent disease, recurrence, or metastasis.

Staging ^[14]

Staging includes evaluation for cervical lymph node metastases in all patients and of distant metastases as needed.

• Preoperative assessment of cervical lymph nodes
  • Neck ultrasound in all patients with confirmed diagnosis
  • FNAC of lymph nodes with signs of metastases ^[14]
• Assessment of distant metastases: based on clinical suspicion ^[22]
  • Chest x-ray or CT
  • Bone scintigraphy
  • CT or MRI head ^[23]

Papillary thyroid cancer

Psammoma bodies

• 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)
  • 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 ^[24]

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

“Papi and Moma adopted Orphan Annie:” papillary thyroid cancer is histologically characterized by psammoma bodies and Orphan Annie-eye nuclei.

Follicular carcinoma

• Uniform follicles
• Vascular and/or capsular invasion

Medullary carcinoma

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

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

Anaplastic thyroid carcinoma

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

• See the article “Thyroid nodules.”
• Thyroid cyst
  • Ultrasound findings
    • Anechoic round mass
    • In many cases, dorsal acoustic enhancement
  • Relatively frequent and typically harmless

The differential diagnoses listed here are not exhaustive.

General principles ^[8][14][23]

• Well-differentiated thyroid cancer ^[8][14]
  • Standard management (regardless of nodal or distant metastases): total thyroidectomy (with neck dissection as needed) + RAIA + TSH suppression therapy
  • Small cancers without nodal or distant metastases: Consider hemithyroidectomy + TSH suppression therapy.
  • Papillary microcarcinoma in low-risk patients : Consider active surveillance.
• Poorly-differentiated thyroid cancer
  • Medullary carcinoma: total thyroidectomy + neck dissection ± radiation therapy and/or systemic chemotherapy as needed. ^[8]
  • Anaplastic carcinoma ^[23]
    • Resectable cancer: total thyroidectomy + neck dissection + radiochemotherapy
    • Unresectable or metastatic cancer: palliative care

RAIA and TSH suppression therapy are not useful in the management of medullary carcinoma or anaplastic thyroid cancer. ^[8][23]

Surgery ^[14]

Surgical resection is the primary treatment for thyroid cancer. For further information on preoperative testing and complications see “Thyroid surgery.”

Total thyroidectomy

• Indications
  • Well-differentiated thyroid carcinoma
    • Tumor size ≥ 4 cm
    • Tumor size 1–4 cm (individual decision)
    • With/without extrathyroidal extension
    • With/without nodal or distant metastases ^[14]
  • Medullary carcinoma ^[8]
  • Resectable anaplastic thyroid cancer ^[23]
• Important considerations
  • Total thyroidectomy should be combined with neck dissection as needed (e.g., in patients with regional lymph node spread).
  • Thyroid hormone replacement is required in all patients who undergo total thyroidectomy.
    • Maintain TSH within the physiological range for poorly-differentiated thyroid cancer. ^[8]
    • TSH-suppressive therapy is required for well-differentiated thyroid cancer. ^[14]

Hemithyroidectomy ^[14]

• Indications
  • Small, well-differentiated thyroid carcinoma with all of the following characteristics:
    • Intrathyroidal tumors (i.e., no evidence of extrathyroidal extension)
    • No nodal or distant metastasis
    • No high-risk patient factors such as age > 45 years, history of head and neck radiation, or family history of cancer
  • Preferred option in tumors < 1 cm in size with all of the above characteristics
  • An alternative to total thyroidectomy in tumors 1–4 cm in size with all of the above characteristics
• Contraindications
  • Intrathyroidal tumor ≥ 4 cm
  • Extrathyroidal spread
  • Distant or nodal metastasis
  • High-risk patient factors

Complications ^[25]

• Hypocalcemia: as a result of accidental removal of parathyroid glands ^[26]
• Dysphonia (hoarseness) and/or dysphagia: as a result of transection of the superior and recurrent laryngeal nerve
  • 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 the voice is unlikely, but a loss of vocal range may occur (with potentially career-damaging consequences for, e.g., singers and actors).
  • Vocal cord function should be assessed preoperatively with laryngoscopy.

Adjuvant therapy ^[14]

• Well-differentiated thyroid cancer
  • Radioactive iodine ablation (RAIA): conducted 4– 6 weeks after total thyroidectomy to destroy remaining thyroid tissue or metastases ^[11]
  • TSH suppression therapy:
    • Administration of L-thyroxine to suppress serum TSH to subnormal levels to minimize the risk of tumor recurrence
    • Administered after completion of RAIA in patients who have undergone total thyroidectomy
    • L-thyroxine also serves as hormone replacement therapy after surgery and RAIA.
• Poorly differentiated thyroid cancer: adjuvant radiation therapy and/or chemotherapy as needed ^[8][23]

Nonoperative management

• Active surveillance ^[14]
  • Papillary microcarcinoma (i.e., a tumor < 1 cm in diameter) with no nodal or distant metastasis in low-risk patients ^[27]
  • Multimorbid patients with high surgical risk or short life expectancy
• Palliative therapy: Palliative radiation therapy and/or chemotherapy may be considered for advanced anaplastic thyroid cancer. ^[23]

• Physical examination
• Biochemical tests
• Neck ultrasound
• Further imaging, if a relapse is suspected

References:^[14]