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Thyroid Cancers

By

Laura Boucai

, MD, Weill Cornell Medical College

Reviewed/Revised Feb 2024
View PATIENT EDUCATION

Thyroid cancer can derive from follicular cells or parafollicular C-cells. Most thyroid cancers manifest as asymptomatic nodules. Diagnosis is often by fine-needle aspiration biopsy but may involve other tests. Treatment is surgical removal, sometimes followed by ablation of residual tissue with radioactive iodine.

Thyroid cancer can derive from

  • Follicular epithelial cells: Papillary, follicular, oncocytic, high-grade, poorly differentiated, and anaplastic thyroid cancer

  • Parafollicular C-cells: Medullary thyroid cancer

Most thyroid cancers are papillary (~84%) or follicular carcinomas (~4%) (1 General references Thyroid cancer can derive from follicular cells or parafollicular C-cells. Most thyroid cancers manifest as asymptomatic nodules. Diagnosis is often by fine-needle aspiration biopsy but may... read more ). Papillary and follicular carcinomas together are called differentiated thyroid cancer because of their histologic resemblance to normal thyroid tissue and because differentiated function (eg, secretion of thyroglobulin) is preserved. In contrast, high-grade, poorly differentiated, and anaplastic thyroid carcinomas are aggressive and secrete less thyroglobulin.

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (previously known as noninvasive encapsulated follicular variant of papillary thyroid carcinoma without capsular or vascular invasion) is now considered to be a benign lesion (1, 2 General references Thyroid cancer can derive from follicular cells or parafollicular C-cells. Most thyroid cancers manifest as asymptomatic nodules. Diagnosis is often by fine-needle aspiration biopsy but may... read more ).

Most thyroid cancers manifest as asymptomatic nodules that are found incidentally during imaging studies or on physical examination. It is rare to find metastases to lymph nodes, lung, or bone as the presenting signs of a thyroid cancer.

Diagnosis is often by fine-needle aspiration biopsy, but it may involve other tests on the biopsy specimen including immunostaining for thyroglobulin or BRAF V600E protein and molecular testing.

Treatment of well-differentiated thyroid cancers is surgical removal for lesions > 1.5 cm, with or without ablation of residual tissue with radioactive iodine. Smaller lesions are treated with surgery or active surveillance.

Papillary and follicular thyroid cancers are typically slow growing with an excellent overall survival at 5 years of 98.5% (3 General references Thyroid cancer can derive from follicular cells or parafollicular C-cells. Most thyroid cancers manifest as asymptomatic nodules. Diagnosis is often by fine-needle aspiration biopsy but may... read more ). However, mortality is high for high-grade, poorly differentiated, and anaplastic thyroid cancers. Patients with metastatic medullary carcinoma may live for many years but generally die of their cancer.

General references

  • 1. Fagin JA, Wells SA Jr. Biologic and Clinical Perspectives on Thyroid Cancer. N Engl J Med 2016;375(11):1054-1067. doi:10.1056/NEJMra1501993

  • 2. Nikiforov YE, Seethala RR, Tallini G, et al: Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: A paradigm shift to reduce overtreatment of indolent tumors. JAMA Oncol 2(8):1023–1029, 2016. doi:10.1001/jamaoncol.2016.0386

  • 3. SEER*Explorer: An interactive website for SEER cancer statistics [Internet]. Surveillance Research Program, National Cancer Institute; 2023 Apr 19. [updated: 2023 Nov 16; cited 2024 Jan 19]. Available from: https://seer.cancer.gov/statistics-network/explorer/. Data source(s): SEER Incidence Data, November 2022 Submission (1975-2020), SEER 22 registries.

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 3 to 9% of patients. Most patients present between ages 30 and 60 years. The tumor is often more aggressive in older patients (1 Papillary thyroid carcinoma references Thyroid cancer can derive from follicular cells or parafollicular C-cells. Most thyroid cancers manifest as asymptomatic nodules. Diagnosis is often by fine-needle aspiration biopsy but may... read more ).

The most common genetic mutation that gives rise to these tumors is BRAF V600E.

The incidence of papillary thyroid carcinoma has risen over the last several decades, primarily due to the incidental discovery of small cancers in patients undergoing neck ultrasonography, MRI, CT scans, or PET scans that include the neck in the imaging field.

Papillary thyroid cancer can spread via lymphatics to regional lymph nodes in one third of patients and may metastasize to the lungs. Patients < 55 years old with small tumors confined to the thyroid have an excellent prognosis.

Active surveillance for increasing size or appearance of cervical lymph nodes metastases using ultrasonography may be an alternative to surgery for appropriately selected patients with papillary carcinomas < 1.5 cm since only 15% enlarge by 3 mm at 10 years and only 3.4% develop cervical lymph node metastases at 10 years (2 Papillary thyroid carcinoma references Thyroid cancer can derive from follicular cells or parafollicular C-cells. Most thyroid cancers manifest as asymptomatic nodules. Diagnosis is often by fine-needle aspiration biopsy but may... read more ).

For small tumors (between 1.5 and 4 cm), hemithyroidectomy is an appropriate treatment option and almost always curative. Tumors > 4 cm or multifocal tumors require total or near-total thyroidectomy.

  • Low-risk: Intrathyroidal disease, unifocal or multifocal, and involvement of < 5 lymph nodes

  • Intermediate-risk: More extensive lymphadenopathy, extrathyroidal extension, and aggressive histologic characteristics or vascular invasion

  • High-risk: Large lymphadenopathy (> 3 cm), gross extrathyroidal extension, vascular invasion in follicular thyroid carcinomas, and distant metastases

Postoperative radioactive iodine is used to ablate residual thyroid tissue for one or more of the following reasons:

  • To enable interpretation of thyroglobulin levels during surveillance

  • As adjuvant therapy if residual thyroid cancer is suspected or the risk of recurrence is intermediate or high

  • To aid in cancer staging if distant metastatic disease is suspected in patients with high-risk thyroid cancer

In patients with intermediate or high-risk thyroid cancer, after initial treatment doses of levothyroxine sufficient to suppress thyroid-simulating hormone levels are given to suppress the growth of thyroid cancer, serum thyroglobulin and thyroglobulin antibody levels and neck ultrasonography are used to detect recurrent or persistent disease. Approximately 20 to 30% of patients with intermediate and high-risk thyroid cancer have recurrent or persistent disease. When radioiodine-refractory, structurally progressive metastases are documented, these patients require additional surgery or treatment with tyrosine kinase inhibitors.

Transition to a cancer survivorship program or follow-up by a primary care physician is typically recommended after 5 years of surveillance in patients without evidence of disease, since the risk of recurrence falls below 1%. A thyroid ultrasound and a thyroglobulin and thyroglobulin antibody panel every 5 years can detect late recurrences, which are infrequent.

Papillary thyroid carcinoma references

Follicular Thyroid Carcinoma

Follicular carcinoma accounts for approximately 4% of thyroid cancers. It is more common among older patients and in regions of iodine deficiency. It is more aggressive than papillary carcinoma Papillary Thyroid Carcinoma Thyroid cancer can derive from follicular cells or parafollicular C-cells. Most thyroid cancers manifest as asymptomatic nodules. Diagnosis is often by fine-needle aspiration biopsy but may... read more since it spreads hematogenously and carries a higher risk of distant metastases. The most common genetic mutation that gives rise to these tumors is a RAS mutation.

Treatment requires near-total thyroidectomy and postoperative radioactive iodine therapy. Metastases are more responsive to repeated doses of radioiodine therapy than are those of papillary carcinoma. Thyroid-stimulating hormone–suppressive doses of levothyroxine are given after treatment. Serum thyroglobulin measurements and neck ultrasongraphy should be done periodically to detect recurrent or persistent disease.

Oncocytic Thyroid Carcinoma (formerly Hurthle Cell Carcinoma)

Oncocytic thyroid carcinomas have been historically considered a subgroup of follicular thyroid carcinomas, but genomic data confirm that these tumors are a distinct entity. Loss of heterozygosity of most chromosomes and chromosomal duplications of chromosomes 5 and 7 as well as mitochondrial DNA mutations give these tumors a cytoplasm rich in mitochondria and their "oncocytic" designation.

These tumors can be encapsulated or widely invasive. Widely invasive oncocytic carcinomas respond less well to radioactive iodine, are FDG-avid on PET scans, and tend to metastasize hematogenously outside of the neck (1, 2 Oncotic thyroid carcinoma references Thyroid cancer can derive from follicular cells or parafollicular C-cells. Most thyroid cancers manifest as asymptomatic nodules. Diagnosis is often by fine-needle aspiration biopsy but may... read more ).

Oncotic thyroid carcinoma references

  • 1. Ganly I, Makarov V, Deraje S, et al. Integrated Genomic Analysis of Hurthle Cell Cancer Reveals Oncogenic Drivers, Recurrent Mitochondrial Mutations, and Unique Chromosomal Landscapes. Cancer Cell 2018;34(2):256-270.e5. doi:10.1016/j.ccell.2018.07.002

  • 2. Gopal RK, Kubler K, Calvo SE, et al. Widespread Chromosomal Losses and Mitochondrial DNA Alterations as Genetic Drivers in Hurthle Cell Carcinoma. Cancer Cell 2018;34(2):242-255.e5. doi:10.1016/j.ccell.2018.06.013

Anaplastic Thyroid Carcinoma

Anaplastic carcinoma is an undifferentiated cancer that accounts for approximately 1% of thyroid cancers, and it contributes to 20% of the annual thyroid cancer-related mortality (1 Anaplastic thyroid carcinoma references Thyroid cancer can derive from follicular cells or parafollicular C-cells. Most thyroid cancers manifest as asymptomatic nodules. Diagnosis is often by fine-needle aspiration biopsy but may... read more ). It occurs mostly in older patients and slightly more often in females. 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 Hashimoto Thyroiditis Hashimoto thyroiditis is chronic autoimmune inflammation of the thyroid with lymphocytic infiltration. Findings include painless thyroid enlargement and symptoms of hypothyroidism. Diagnosis... read more .

Approximately 45% of anaplastic tumors harbor a BRAF V600E mutation. In one study, patients who received targeted therapy with dabrafenib plus trametinib and, in most cases, an immune checkpoint inhibitor prior to surgery had a 1-year survival rate of 93%. Those undergoing surgery before receiving targeted therapy had a 1-year survival rate of 74%, and those who had targeted therapy but no surgery had a 1-year survival rate of 38% (2, 3 Anaplastic thyroid carcinoma references Thyroid cancer can derive from follicular cells or parafollicular C-cells. Most thyroid cancers manifest as asymptomatic nodules. Diagnosis is often by fine-needle aspiration biopsy but may... read more ).

Anaplastic thyroid carcinoma references

  • 1. Lim H, Devesa SS, Sosa JA, Check D, Kitahara CM: Trends in Thyroid Cancer Incidence and Mortality in the United States, 1974-2013. JAMA 2017;317(13):1338–1348. doi:10.1001/jama.2017.2719

  • 3. Bible KC, Kebebew E, Brierley J, et al: 2021 American Thyroid Association Guidelines for Management of Patients with Anaplastic Thyroid Cancer. Thyroid 31(3):337–386, 2021. doi: 10.1089/thy.2020.0944

  • 3. Zhao X, Wang JR, Dadu R, et al: Surgery After BRAF-Directed Therapy Is Associated with Improved Survival in BRAFV600E Mutant Anaplastic Thyroid Cancer: A Single-Center Retrospective Cohort Study. Thyroid 33(4):484–491, 2023. doi:10.1089/thy.2022.0504

Medullary Thyroid Carcinoma

Medullary carcinoma constitutes approximately 4% of thyroid cancers and arises from parafollicular C-cells that produce calcitonin. It may be sporadic (75%, usually unilateral); however, 25% of the cases are familial, caused by a mutation of the RET proto-oncogene. The familial form may occur in isolation (familial medullary thyroid carcinoma) or as a component of multiple endocrine neoplasia (MEN) syndrome type 2A Multiple Endocrine Neoplasia, Type 2A (MEN 2A) Multiple endocrine neoplasia, type 2A (MEN 2A) is an autosomal dominant syndrome characterized by medullary carcinoma of the thyroid, pheochromocytoma, parathyroid hyperplasia or adenomas (causing... read more Multiple Endocrine Neoplasia, Type 2A (MEN 2A) (medullary thyroid carcinoma, primary hyperparathyroidism, and pheochromocytoma) or MEN 2B Multiple Endocrine Neoplasia, Type 2B (MEN 2B) Multiple endocrine neoplasia, type 2B (MEN 2B) is an autosomal dominant syndrome characterized by medullary thyroid carcinoma, pheochromocytoma, multiple mucosal neuromas and intestinal ganglioneuromas... read more Multiple Endocrine Neoplasia, Type 2B (MEN 2B) (medullary thyroid carcinoma, pheochromocytoma, and gastrointestinal ganglioneuromas). 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 in the tumor.

Metastases spread is 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 before a palpable tumor develops during routine screening of affected kindreds with MEN 2A or MEN 2B.

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.

Radiography or ultrasonography may show a dense, homogenous, conglomerate calcification within the primary tumor.

All patients with medullary thyroid carcinoma should have genetic testing for mutations of the RET proto-oncogene; relatives of those with mutations should have genetic testing and measurement of basal and stimulated calcitonin levels. In hereditary forms, germline mutations of the RET proto-oncogene, which occur in 98% of cases, correlate with phenotype; that is, specific mutations in certain codons of the RET gene are associated with distinct syndromes or with more aggressive disease.

Pheochromocytoma Pheochromocytoma A pheochromocytoma is a catecholamine-secreting tumor of chromaffin cells typically located in the adrenals. It causes persistent or paroxysmal hypertension. Diagnosis is by measuring catecholamine... read more , if present, is usually bilateral. Pheochromocytomas should be ruled out by measuring plasma metanephrines and, if identified, removed before thyroidectomy because of the danger of provoking a hypertensive crisis during the operation.

Long-term survival is common in patients with sporadic medullary carcinoma and MEN 2A; more than two thirds of affected patients are alive at 10 years. Medullary carcinoma as part of 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 and a high-risk RET proto-oncogene codon mutation.

Medullary thyroid carcinoma reference

  • 1. Wells Jr SA, Asa SL, Henning D, et al: Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma prepared by the American Thyroid Association Guidelines Task Force on Medullary Thyroid Carcinoma. Thyroid 25(6): 567–610, 2015. doi: 10.1089/thy.2014.0335

Radiation-Induced Thyroid Cancer

Thyroid tumors develop in people whose thyroid is exposed to large amounts of environmental radiation, as occurs as a result of exposure to nuclear weapons, nuclear reactor accidents, or incidental thyroid irradiation due to external beam radiation therapy for adjacent malignancies. Tumors may be detected 10 years after exposure, but risk remains increased for 30 to 40 years. Such tumors are usually benign; however, approximately 10% are papillary thyroid carcinoma Papillary Thyroid Carcinoma Thyroid cancer can derive from follicular cells or parafollicular C-cells. Most thyroid cancers manifest as asymptomatic nodules. Diagnosis is often by fine-needle aspiration biopsy but may... read more . These thyroid cancers are frequently multicentric or diffuse, and the most common genetic mutations that occur in radiation-induced tumors are gene fusions.

Patients who had thyroid irradiation should undergo yearly thyroid palpation and selectively ultrasonography if a nodule if found on physical examination. A thyroid scan does not always reflect areas of involvement.

If ultrasonography reveals a nodule, fine-needle aspiration biopsy should be done.

Surgery is required if fine-needle aspiration biopsy suggests cancer. Near-total or total thyroidectomy is the treatment of choice with or without radioiodine ablation, depending on risk of recurrence (1 Radiation-induced thyroid cancer reference Thyroid cancer can derive from follicular cells or parafollicular C-cells. Most thyroid cancers manifest as asymptomatic nodules. Diagnosis is often by fine-needle aspiration biopsy but may... read more ).

Radiation-induced thyroid cancer reference

  • 1. Haugen BR, Alexander EK, Bible KC, et al: 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 26(1):1–133, 2016. doi: 10.1089/thy.2015.0020

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