Thyroid Cancer

Overview

Definition

Thyroid cancer is a malignancy arising from the cells of the thyroid gland, including thyroid follicular cells (thyrocytes), calcitonin-producing C cells, lymphocytes, and/or stromal and vascular elements.

Epidemiology

• In the United States:
  • Thyroid cancer accounts for 1% of new cancer diagnoses annually.
  • Incidence has increased over 30 years, but mortality has not changed.
• Peak incidence dependent on type of cancer
• Slight female predominance

Etiology

• Genetic factors:
  • Driver mutations:
    • Set of genetic mutations found in different types of thyroid cancer (e.g., papillary thyroid carcinoma (PTC): BRAF and RET mutations)
    • Most are involved in the receptor tyrosine kinase (RTK) pathway.
  • Family history:
    • Family history of thyroid cancer (in 1st-degree relative)
    • Family history of thyroid cancer syndrome (familial polyposis, Cowden syndrome, MEN2)
• Environmental factors:
  • Ionizing radiation:
    • Leads to DNA mutations, especially during first 2 decades of life
    • Noted in people exposed to radiation from the atomic bombs in Hiroshima and Nagasaki and from the nuclear plant accident in Chernobyl
  • Iodine deficiency: higher frequency of follicular carcinoma

Pathophysiology

Origins and precursor lesions

• Most thyroid cancers are derived from:
  •  Thyroid follicular cells (papillary, follicular, anaplastic carcinomas)
  •  Parafollicular C cells (medullary carcinoma)
• Rare types arise from:
  • Lymphoid tissue (lymphoma)
  • Stroma or connective tissue (sarcoma)
• Recognized precursor lesions:
  • Papillary microcarcinoma → PTC
  • Noninvasive thyroid neoplasm with papillary-like nuclear features → invasive encapsulated follicular variant PTC
  • Nonfunctioning follicular adenoma → follicular carcinoma

Pathogenesis

• Papillary thyroid carcinoma:
  • Rearrangements involving RET and NTRK1 (seen in approximately 5%):
    • Form fusion genes encoding constitutively active RTK
    • Lead to development of malignancy
  • Gain-of-function mutations in BRAF:
    • BRAF encodes a serine–threonine kinase
    • BRAF V600E: most common mutation
    • Noted in PTCs with recurrence, invasive growth, and extrathyroidal extension
    • Not found in follicular thyroid carcinoma
    • Also found in other cancers (e.g., melanoma, colon cancer)
• Follicular thyroid carcinoma:
  • Gain-of-function mutations in RAS:
    • Thyroid differentiation markers (such as thyroglobulin and thyroid peroxidase) are expressed, leading to follicular growth.
    •  Found in up to 40% of follicular adenomas and up to 50% of follicular carcinomas
  • Fusion gene PAX8–PPARG:
    • Translocation results in fusion of PAX8 (a thyroid transcription factor) and peroxisome proliferator–activated receptor gamma 1 (PPARG).
    • Effect: inhibition of cell differentiation and ↑ cell growth
  • Gain-of-function mutations of PIK3CA 
• Anaplastic (undifferentiated) and poorly differentiated carcinoma:
  • Can arise from dedifferentiation of papillary or follicular thyroid carcinoma (more mutational burden)
  • TP53 mutation → reduced apoptosis of cells
  • TERT (encodes telomerase) and CTNNB1 mutations appear to have aggressive cancer behavior.
• Medullary thyroid carcinoma:
  • Most are sporadic
  • 25% are familial (associated with MEN2 syndrome: autosomal dominant inheritance) involving the RET proto-oncogene

Clinical Presentation

General features

• Initially presents asymptomatically or as a painless thyroid nodule in the neck:
  • May be on the thyroid or a cervical lymph node
  • Progresses to a tender or painful lesion as disease advances
• Usually euthyroid, but hypothyroidism/hyperthyroidism symptoms can occur.
• Symptoms associated with local invasion: 
  • Trachea fixation
  • Recurrent laryngeal nerve damage → hoarseness
  • Cervical sympathetic nerve invasion → Horner’s syndrome
  • Esophageal compression → dysphagia and odynophagia
• Metastasis:
  • Pulmonary metastasis → cough, dyspnea
  • Brain metastasis → neurologic deficits, seizures
  • Bone metastasis → bone pain, pathologic fractures
  • Liver → abnormal liver enzymes

Rare malignancies

• Hürthle cell carcinoma: 
  • Presentation similar that of follicular carcinoma (thyroid nodule) but also differs in its tendency for lymph node spread
  • Histology: + oncocytes (eosinophilic cells with abundant cytoplasm)
• Lymphoma: 
  • Most are B-cell lymphomas.
  • Associated with Hashimoto’s thyroiditis
• Sarcoma: aggressive tumor, with poor chemotherapy response
• Metastases from renal, breast, melanoma, and colon cancers

Diagnosis

Initial workup

• Tests are directed by the presenting signs and symptoms.
• Generally, the diagnostic approach follows the detailed workup for thyroid nodules.
• Thyroid-stimulating hormone (TSH): normal/↑ TSH or ↓ TSH
  • ↓ TSH: Evaluate for hyperthyroidism and determine if functioning (hot), nonfunctioning (cold), or indeterminate nodule on thyroid scan.
  • In both normal/↑ TSH and ↓ TSH: correlate with ultrasound
• Thyroid ultrasound (US):
  • Suspicious nodule findings:
    • Composition: solid nodule
    • Echogenicity: hypoechoic
    • Shape: more tall than wide
    • Echogenic foci: microcalcifications or rim calcifications with extrusion of soft tissue
    • Margin: irregular borders and/or with extrathyroidal extension
  • Other suspicious US findings:
    • Subcapsular location adjacent to recurrent laryngeal nerve or trachea
    • Abnormal cervical lymph nodes
    • Central vascularity
    • Documented growth

Fine-needle aspiration biopsy

• ≥ 1 cm nodules and:
  • Elevated/normal TSH + suspicious US findings
  • Low TSH + suspicious US findings + cold or indeterminate nodules
• Large nodules, ≥ 1.5 cm
• Thyroid nodule of any size with risk factors:
  • Young age
  • Family history of thyroid cancer
  • Familial adenomatous polyposis (FAP) or other associated syndromes
  • History of radiation
• Suspicious lymph nodes on biopsy

Postdiagnosis tests

Further tests should be obtained after diagnosis:

• Laboratory tests:
  • Serum thyroglobulin (differentiated thyroid carcinoma)
  • Calcitonin and carcinoembryonic antigen (CEA) (medullary thyroid carcinoma)
• DNA analysis for RET germline mutation:
  • For medullary thyroid carcinoma
  • RET + or unknown:
    • Serum calcium: workup for hyperparathyroidism (component of MEN2A)
    • Plasma fractionated metanephrines: workup for pheochromocytoma (component of MEN2A and B)
  • If index patient is positive, family screening and testing should be offered.
• Imaging:
  • Neck US: 
    • Search for involvement of cervical lymph nodes
    • Directs necessity and extent of neck dissection
  • Assessment of other symptoms and distant metastasis:
    • Chest X-ray
    • MRI
    • CT
    • Bone scintigraphy

Management and Prognosis

Differentiated thyroid carcinoma

• Include papillary and follicular thyroid carcinomas
• Surgery:
  • Thyroid lobectomy: 
    • Tumor < 1 cm with no lymph nodes or extrathyroidal extension
    • An option for tumor 1–4 cm with no lymph nodes or extrathyroidal extension (no other risk factors and/or patient decision)
    • Multifocal papillary microcarcinoma (< 5 foci)
    • No prior history of head and neck radiation
    • No family history of thyroid cancer
    • No abnormalities in contralateral lobe
  • Total thyroidectomy (neck dissection as indicated):
    • Tumor 1–4 cm with no lymph nodes or extrathyroidal extension
    • Tumor ≥ 4 cm with metastasis or extrathyroidal extension
    • Multifocal papillary microcarcinoma (> 5 foci)
    • Any tumor size, with history of head and neck radiation, strong family history of thyroid cancer
    • Abnormal US findings on the contralateral lobe
• Surgical complications:
  • Hypoparathyroidism (parathyroid gland removal) → ↓ calcium
  • Recurrent laryngeal nerve injury
  • Bleeding
• Postsurgery assessment:
  • Factors with intermediate to high risk of cancer persistence and recurrence:
    • Microscopic or macroscopic invasion
    • Cervical lymph node or distant metastasis
    • Aggressive histology or vascular invasion
    • Incomplete resection with evidence of residual disease
    • Multifocal papillary microcarcinoma with extension and BRAF V600E mutation
    • Elevated postoperative thyroglobulin (Tg)
  • Serum Tg:
    • Obtain ≥ 4 weeks later (expected to be very low after thyroidectomy +/– radioiodine ablation)
    • Low risk of recurrence if Tg levels are undetectable
    • Elevated values: Evaluate with neck US to determine if surgery was complete.
    • ↑ Level: Also consider metastasis and recurrence.
• Radioactive iodine therapy:
  • Ablation of remaining thyroid tissue (residual and metastatic)
  • Given to patients with intermediate to high risk of persistent and recurrent disease
• Levothyroxine:
  • Thyroid replacement and thyroid hormone–suppressive therapy
  • Suppression of TSH:
    • Needed because TSH is a growth factor for thyroid cells
    • TSH goal depends on disease extent and risk of recurrence.
    • If high-risk disease: TSH goal < 0.1 mU/L
• Other treatments:
  • External radiotherapy: for inoperable tumors or painful bone metastases
  • Kinase inhibitor therapy
  • Chemotherapy (e.g., doxorubicin)
• Surveillance (frequency dependent on findings/results):
  • Physical examination
  • Serum Tg
  • Serum TSH and thyroid function tests
  • Neck US and other radiologic tests (whole-body thyroid scan, CT as indicated)

Anaplastic thyroid carcinoma

• Surgery:
  • Often not performed, as disease is advanced at time of diagnosis
  • If with localized or locally advanced operable tumor: total thyroidectomy with neck dissection and combine with other methods
• Radiotherapy: adjuvant (postsurgery) or primary treatment for inoperable disease
• Kinase inhibitors and/or chemotherapy
• Palliative care: important component, as disease progression is rapid
• No role for radioactive iodine therapy
• Levothyroxine:
  • For thyroid replacement (in those who have undergone thyroidectomy)
  • TSH suppression not required.
• Surveillance:
  • Monitor with CT (neck, chest, abdomen, and pelvis) every 3 months for the first 2 years (if there is initial response to treatment).
  • PET detects disease not evident on CT.

Medullary thyroid carcinoma

• Surgery:
  • Total thyroidectomy (with neck dissection)
  • In MEN2 (hyperparathyroidism and/or pheochromocytoma): Perform additional surgery (e.g., adrenalectomy) as indicated.
• Kinase inhibitors and/or chemotherapy: for progressive, metastatic medullary thyroid cancer
• No role for radioactive iodine therapy
• Levothyroxine:
  • Thyroid replacement therapy (TSH suppression not required, as C cells are not TSH responsive)
  • Does not reduce risk of recurrence
• Postsurgery assessment:
  • Serum calcitonin and CEA: Normal results after surgery indicate very good prognosis.
  • ↑ Levels: marker of residual or recurrent disease
• Surveillance (frequency dependent on findings/results):
  • Physical examination
  • Serum calcitonin and CEA 
  • US of the neck (other radiologic tests as indicated)

Prognosis

• Dependent on type of cancer and extent of disease
• From 2010 to 2016 in the United States (5-year survival rate):
  • Papillary: 
    • Overall: near 100%
    • Distant metastasis: 76%
  • Follicular: 
    • Overall: 98%
    • Distant metastasis: 64%
  • Medullary: 
    • Overall: 89%
    • Distant metastasis: 38%
  • Anaplastic:
    • Overall: 7%
    • Distant metastasis: 3%

Clinical Relevance

• Thyroid nodules: disordered growth of thyroid cells, producing a mass in the thyroid gland: Nodules, the majority of which are benign, are detected on examination or found incidentally in radiologic images. Workup includes TSH and US, followed by a radioactive iodine uptake (RAIU)/thyroid scan if hyperthyroidism is present. Biopsy is recommended in those with suspicious US findings, cold nodules on thyroid scan, large-sized nodules (generally, > 1.5 cm) and risk factors for malignancy. Treatment is dictated by pathology findings.
• Hashimoto’s thyroiditis: also called chronic lymphocytic thyroiditis: Hashimoto’s thyroiditis is the most common cause of hypothyroidism in iodine-sufficient regions. It is an autoimmune disorder leading to destruction of the thyroid cells and thyroid failure. Presentation can be a painless goiter (in later stages, the gland is atrophic). Lab tests show elevated TSH, low free thyroxine (T₄), and positive antibodies against thyroglobulin and thyroid peroxidase. Treatment is lifelong thyroid replacement therapy.
• Hypothyroidism: a condition characterized by a deficiency of thyroid hormones: Iodine deficiency and Hashimoto’s thyroiditis are the 2 leading etiologies. Clinical features reflect the effects of slowed organ function/decreased metabolic rate. Lab tests show elevated TSH and a low free T₄. Treatment is with levothyroxine.
• Hyperthyroidism: condition caused by sustained overproduction and release of the thyroid hormones T₃ and T₄. Graves’ disease is the most common cause of hyperthyroidism. Manifestations are mostly due to the increased metabolic rate and overactivity of the sympathetic nervous system. Lab tests show low TSH and elevated free T₄. Treatment depends on the underlying condition.
• Goiter: abnormal enlargement of the thyroid gland that occurs in settings of hypothyroidism, hyperthyroidism, or euthyroidism: The presentation of goiter can be a diffusely enlarged or multinodular thyroid gland. Diagnostic tests include thyroid function tests and thyroid antibodies. Radiologic imaging helps if worrisome features are present. Treatment options are observation, medication, surgery, and radioiodine ablation, depending on findings.
• MEN2 syndrome: MEN2 is an autosomal dominant condition involving the RET proto-oncogene. There are 2 syndromes: MEN2A consists of medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism; MEN2B consists of medullary thyroid carcinoma, pheochromocytoma, Marfanoid body habitus, mucosal neuromas, and ganglioneuromatosis of the bowel.