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.
Differentiated carcinoma (papillary and follicular): ♀ > ♂ (3:1)
Poorly-differentiated carcinoma (medullary and anaplastic): ♀ ≈ ♂
Incidence: ∼ 13.5 new cases per 100,000, per year.
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 TP53 mutations.
Subtypes and variants.
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
Metastatic (e.g., breast, renal, melanoma): rare
Papillary Thyroid Carcinoma
Papillary carcinoma accounts for 80 to 90% of all thyroid cancers. The female:male ratio is 3:1. It may be familial in up to 5% of patients. Most patients present between ages 30 and 60. The tumor is often more aggressive in older patients. Many papillary carcinomas contain follicular elements. One variant is called noninvasive follicular thyroid neoplasm with papillary-like nuclear features (previously known as noninvasive encapsulated follicular variant of papillary thyroid carcinoma .
The tumor spreads via lymphatics to regional lymph nodes in one third of patients and may metastasize to the lungs. Patients < 55 years with small tumors confined to the thyroid have an excellent prognosis.
Tumors > 4 cm or that are diffusely spreading require total or near-total thyroidectomy with postoperative radioiodine ablation of residual thyroid tissue with appropriately large doses of iodine-131 administered when the patient is hypothyroid or after recombinant thyroid-stimulating hormone (TSH) injections. Treatment may be repeated after 6 to 12 months to ablate any remaining thyroid tissue.
TSH-suppressive doses of l-thyroxine (levothyroxine) are given after treatment, and serum thyroglobulin levels are measured to help detect recurrent or persistent disease. Neck ultrasonography will detect recurrence in lymph nodes. About 20 to 30% of patients, mainly older patients, have recurrent or persistent disease.
Treatment for encapsulated tumors < 4 cm localized to one lobe is usually near-total thyroidectomy, although some experts recommend only lobectomy and isthmusectomy; surgery is almost always curative. Thyroid hormone in thyroid-stimulating hormone–suppressive doses is given to minimize chances of regrowth and cause regression of any microscopic remnants of papillary carcinoma. Active surveillance may be an alternative to surgery for papillary carcinomas < 1 cm with no evidence of lymph node or distant metastases.
Follicular Thyroid Carcinoma
Follicular carcinoma, including the Hürthle cell variant, accounts for about 10% of thyroid cancers. It is more common among older patients and in regions of iodine deficiency. It is more malignant than papillary carcinoma, spreading hematogenously with distant metastases.
Treatment requires near-total thyroidectomy with postoperative radioiodine ablation of residual thyroid tissue as in treatment for papillary carcinoma. Metastases are more responsive to radioiodine therapy than are those of papillary carcinoma. Thyroid-stimulating hormone-suppressive doses of l-thyroxine are given after treatment. Serum thyroglobulin measurements and neck ultrasonography should be done periodically to detect recurrent or persistent disease.
Medullary carcinoma constitutes about 4% of thyroid cancers and is composed of parafollicular cells (C cells) that produce calcitonin. It may be sporadic (usually unilateral); however, it is often familial, caused by a mutation of the ret proto-oncogene. The familial form may occur in isolation or as a component of multiple endocrine neoplasia (MEN) syndrome type 2A and MEN 2B. Although calcitonin can lower serum calcium and phosphate levels, serum calcium is normal because the high level of calcitonin ultimately down-regulates its receptors. Characteristic amyloid deposits that stain with Congo red are also present.
Metastases spread via the lymphatic system to cervical and mediastinal nodes and sometimes to liver, lungs, and bone.
Patients typically present with an asymptomatic thyroid nodule, although many cases are now diagnosed during routine screening of affected kindreds with MEN 2A or MEN 2B before a palpable tumor develops.
Medullary Thyroid Carcinoma
Medullary carcinoma may have a dramatic biochemical presentation when associated with ectopic production of other hormones or peptides (eg, adrenocorticotropic hormone [ACTH], vasoactive intestinal polypeptide, prostaglandins, kallikreins, serotonin).
The best test is measurement of serum calcitonin, which is greatly elevated. A challenge with calcium (15 mg/kg IV over 4 hours) provokes excessive secretion of calcitonin.
X-rays may show a dense, homogenous, conglomerate calcification.
All patients with medullary thyroid carcinoma should have genetic testing; relatives of those with mutations should have genetic testing and measurement of basal and stimulated calcitonin levels.
Total thyroidectomy is indicated even if bilateral involvement is not obvious. Lymph nodes are also dissected. If hyperparathyroidism is present, removal of hyperplastic or adenomatous parathyroids is required.
Pheochromocytoma, if present, is usually bilateral. Pheochromocytomas should be identified and removed before thyroidectomy because of the danger of provoking hypertensive crisis during the operation. Long-term survival is common in patients with medullary carcinoma and MEN 2A; more than two thirds of affected patients are alive at 10 years. Medullary carcinoma of the sporadic type and in MEN 2B has a worse prognosis.
Relatives with an elevated calcitonin level without a palpable thyroid abnormality should undergo thyroidectomy because there is a greater chance of cure at this stage. Some experts recommend surgery in relatives who have normal basal and stimulated serum calcitonin levels but who have the ret proto-oncogene mutation.
Anaplastic Thyroid Carcinoma
Anaplastic carcinoma is an undifferentiated cancer that accounts for about 1% of thyroid cancers. It occurs mostly in older patients and slightly more often in women. The tumor is characterized by rapid, painful enlargement. Rapid enlargement of the thyroid may also suggest thyroid lymphoma, particularly if found in association with Hashimoto thyroiditis.
No effective therapy exists, and the disease is generally fatal. About 80% of patients die within 1 year of diagnosis. In a few patients with smaller tumors, thyroidectomy followed by external beam radiation therapy has been curative. Chemotherapy is mainly experimental.
Thyroid tumors develop in people whose thyroid is exposed to large amounts of environmental radiation, as occurs as a result of atomic bomb blasts, nuclear reactor accidents, or incidental thyroid irradiation due to radiation therapy. Tumors may be detected 10 years after exposure, but risk remains increased for 30 to 40 years. Such tumors are usually benign; however, about 10% are papillary thyroid carcinoma. The tumors are frequently multicentric or diffuse.
Patients who had thyroid irradiation should undergo yearly thyroid palpation and ultrasonography. A thyroid scan does not always reflect areas of involvement.
If ultrasonography reveals a nodule, fine-needle aspiration biopsy should be done. In the absence of suspicious or malignant lesions, many physicians recommend lifelong TSH-lowering doses of thyroid hormone to suppress thyroid function and thyrotropin secretion and possibly decrease the chance of developing a thyroid tumor.
Surgery is required if fine-needle aspiration biopsy suggests cancer. Near-total or total thyroidectomy is the treatment of choice, to be followed by radioiodine ablation of any residual thyroid tissue if a cancer is found (depending on the size, histology, and invasiveness).
Firm, painless thyroid nodules may be palpated.
Hoarseness (vocal cord paresis)
Possible obstruction of the superior vena cava.
Thyroid function tests:
fT3 and fT4
Thyroglobulin (Tg): should be measured as a follow‑up to thyroidectomy in follicular or papillary thyroid carcinoma
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).
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 nodule with ↓ TSH level
Evaluation of ectopic thyroid tissue or retrosternal goiter
Findings: decreased tracer uptake suggests a malignant non-functioning (cold) nodule
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.
Bone scintigraphy or PET for detecting metastases
Thyroid Cancer Types and Incidence
Papillary and/or mixed papillary/follicular ~ 85%
Follicular thyroid cancer ~ 10%
Hurthle Cell thyroid cancer ~ 2%
Medullary Thyroid Cancer ~ 3%
Anaplastic < 1%
Lymphoma < 1%
What's the Prognosis of Thyroid Cancer?
We have very detailed prognosis information for all of the thyroid cancer types on different parts of the website. But as an introduction to thyroid cancer, you should know that most thyroid cancers are very curable. In fact, the most common types (papillary thyroid cancer and follicular thyroid cancer) are the most curable. In younger patients, both papillary and follicular cancers can be expected to have better than 97% cure rates when treated appropriately. What is critically important, is that the initial surgery for any thyroid cancer must be the most complete surgery as possible. What this means is that “incomplete” surgery (unfortunately this is very common) :
compromises the ability to control disease
causes the need for additional surgery
increases the risks of further surgery
potentially compromises survival.
Both papillary and follicular cancers are typically treated with complete removal of the lobe of the thyroid which harbors the cancer. If papillary thyroid cancer has extended outside of the confines of the thyroid gland or spread to lymph nodes of the neck, the entire thyroid gland is usually completely removed. Only expert thyroid cancer surgeons should perform total thyroidectomy. The bottom line, most thyroid cancers are papillary thyroid cancer, and this is one of the most curable cancers of all cancers that humans get, provided you are cared for by thyroid surgeons who have an expertise in treating thyroid cancer. As we often tell our patients, if you must choose a type of cancer to have, papillary cancer would be your choice. Have an expert doctor who treats it correctly and the cure rate is extremely high.
Follicular thyroid cancer frequently cannot be diagnosed until following surgery. The reason why this is so is because when you examine the cells under a microscope obtained by fine needle aspiration (FNA) of non-cancerous (benign) follicular thyroid nodules such as follicular adenomas, hurthle cell tumors, and follicular hyperplasia are indistinguishable from follicular thyroid cancers. Only upon removal of follicular thyroid cancers can pathologists determine whether the follicular cells are malignant since they have to visualize the follicular thyroid cancer cells microscopically growing into the capsule of the nodule or blood vessels surrounding the thyroid growth. Once again, you may possess a favorable thyroid cancer but you must also choose the right surgeon to perform the right and complete surgery required for your “at risk” disease.
Medullary thyroid cancer is significantly less common but has a worse prognosis. Medullary thyroid cancer can occur spontaneously in patients or be genetically inherited. Medullary cancers tend to spread to large numbers of lymph nodes very early on, and therefore requires a much more extensive operation than does the more localized cancers such as papillary and follicular. This cancer requires complete thyroid removal plus a dissection to remove the lymph nodes of the front and sometimes the sides of the neck.
The least common type of thyroid cancer is anaplastic which has a very poor prognosis. Anaplastic thyroid cancer tends to be found after it has spread and is not cured in most cases (it is very uncommon to survive anaplastic thyroid cancer). Rarely can a meaningful operation be performed unless all of the anaplastic thyroid cancer can be completely removed and there is no evidence of distant spread of the cancer. Anaplastic thyroid cancer is one of the deadliest of all cancers known to mankind. These patients often require a palliative symptom management during their treatment. Treatment of anaplastic thyroid cancer is much more aggressive than for other types of thyroid cancer and frequently includes chemotherapy, radiation therapy and targeted therapy--because this cancer is so much more aggressive.
Anechoic round mass
In many cases, dorsal acoustic enhancement
Relatively frequent and typically harmless
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
Radioiodine therapy : often conducted 4–6 weeks after surgery to destroy remaining thyroid tissue or metastases
Thyroid hormone therapy with L-thyroxine after thyroidectomy.
Reduces the risk of stimulating remaining malignant tissue
Administer the highest possible dose (according to the patient's tolerance)
Only administer after radioiodine therapy.
Total thyroidectomy with adjuvant radiochemotherapy if operable
Radiochemotherapy if locally advanced, inoperable
Accidental removal of parathyroid glands → hypocalcemia
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).