Thyroid Cancer

Definition and pathogenesisTop

Most thyroid cancers originate from the follicular cells of the thyroid. This includes papillary thyroid carcinoma (most common) and follicular thyroid carcinoma, collectively referred to as well-differentiated thyroid cancer. These 2 cancers make up >85% of all thyroid cancers. Poorly differentiated and anaplastic carcinoma, as well as more aggressive cancers that also derive from follicular cells, are less common.

Medullary thyroid cancer arises from the parafollicular C cells. Primary lymphoma of the thyroid is rare but often presents as a B-cell lymphoma in a background of chronic Hashimoto thyroiditis. Distant metastases to the thyroid are also rare, but they may originate from primaries in the skin (melanoma), kidney (renal cell carcinomas), lung, and breast.

Microcarcinoma of the thyroid gland: A single papillary carcinoma tumor in postoperative examination sized ≤1 cm in diameter, with no lymph node or distant metastases; it may occur without a clinically manifest disease.

The postoperatively diagnosed noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a neoplasm that requires no further treatment but needs careful monitoring. In the 2017 classification of thyroid tumors according to the World Health Organization (WHO), Hürthle cell tumors (oxyphilic cells)—Hürthle cell carcinoma and Hürthle cell adenoma—were distinguished as a separate group.

Risk factors:

1) Exposure to ionizing radiation: The only proven risk factor for thyroid cancer (papillary carcinoma), especially if the exposure occurred in childhood (eg, radiotherapy for Hodgkin lymphoma).

2) Low availability of iodine in the environment (in areas poor in iodine the incidence of follicular cancer increases).

3) Hereditary factors (~25% of medullary carcinomas are hereditary and are caused by an activating germline mutation in the RET gene).

Several oncogenes have been identified in thyroid cancer. The BRAF gene mutation is the most common somatic mutation in papillary thyroid carcinoma and is associated with a slightly worse prognosis. Somatic mutations of the RET gene in medullary thyroid carcinoma and RAS mutations, most common in follicular carcinoma, have also been identified.

The observed increase in the incidence of thyroid cancer may result from the increasing use of diagnostic ultrasonography, which increasingly often detects small, nonsymptomatic disturbances in echostructure. It is not clear as to whether such cases of thyroid cancer pose a real mortality of morbidity threat to the patient or whether their diagnosis results in unnecessary procedures and treatment. Therefore, the American Thyroid Association (ATA) and European Thyroid Association (ETA) recommend that such foci should not be biopsied until their diameter is >10 mm (see Goiter, Nontoxic Multinodular).

CLINICAL FEATURES AND NATURAL historyTop

Most thyroid cancers are asymptomatic. Well-differentiated thyroid cancer can present as a nodule in the thyroid on physical examination or ultrasonography. Very frequently, it is an incidental finding on ultrasonography or other imaging modality. Fine-needle aspiration biopsy (FNAB) should be used for the diagnosis of cancer, although this method does not always differentiate between malignant and nonmalignant lesions. Regional metastases can also be biopsied with FNAB. The natural history depends on the histologic type of the cancer. Well-differentiated thyroid cancers usually grow slowly. Rapid growth of the nodule may indicate a more aggressive pathology (it may also occur in a benign hemorrhagic nodule). A very firm or immobile nodule, breathy hoarseness (due to immobility of the vocal cords), stridor, and regional lymphadenopathy all suggest a malignant diagnosis. In medullary thyroid cancer, a characteristic but rare symptom is diarrhea (caused by excessive secretion of calcitonin and other biologically active substances).

DIAGNOSISTop

Although thyroid cancer is definitively diagnosed based on postoperative histologic examinations, preliminary diagnosis is usually established based on FNAB. Often, FNAB is indeterminate and diagnostic thyroid lobectomy is necessary to reach the final diagnosis. Ultrasonography of the thyroid and neck is recommended to assess the nodule, look for other thyroid nodules, and examine for regional lymphadenopathy. Some centers may use computed tomography (CT) to assess for the possibility of regional or distant metastases. In thyroid cancer that is not the typical well-differentiated type, CT scan of the neck and chest is an essential part of the workup. The use of additional imaging such as positron emission tomography (PET)/CT is not widespread.

In medullary thyroid cancer, calcitonin levels are an important marker. Furthermore, genetic testing for the RET oncogene is important, as ~25% of cases are hereditary. Hereditary cases may have concomitant pheochromocytomas and hyperparathyroidism, and those should be excluded.

TREATMENTTop

Differences in the treatment of differentiated thyroid carcinomas, medullary carcinoma, and undifferentiated carcinoma are due to the different biology of these tumors and apply mostly to postoperative management. In the subsequent stages of the diagnosis and treatment of papillary and follicular thyroid cancer, the assessment of cancer stage is updated, which allows, to some extent, individual adjustment of the treatment intensity to the risk of recurrence.

Treatment of Papillary Cancer and Follicular Cancer (Well-Differentiated Thyroid Cancer)

Surgery

The mainstay of the management of well-differentiated thyroid cancer is surgery. For small thyroid cancers (<4 cm) confined to the thyroid, hemithyroidectomy alone is typically adequate treatment. Thyroid cancers that are larger or have regional metastases usually require total thyroidectomy with some form of lymphadenectomy. If thyroid cancer is found after a diagnostic lobectomy, completion thyroidectomy may be considered if there are adverse prognostic factors.

Treatment with Radioiodine

Radioactive iodine (radioiodine; 131I) ablation, which has become less common, involves the administration of a radioisotope of iodine, which is preferentially concentrated by malignant and benign thyroid cells. Typically it is reserved for more advanced thyroid cases or those with a high risk of recurrence.

Thyroid Suppressive Therapy

Following thyroidectomy, suppressive doses of levothyroxine can be considered. There is little evidence to support the use of thyroid suppression in the vast majority of cases; however, in advanced disease with distant metastases or unresectable areas, suppressive therapy can be considered.

Follow-Up of Well-Differentiated Thyroid Cancer

Patients with well-differentiated thyroid cancer are typically followed by a combination of ultrasonography and serum thyroglobulin level testing (used in this setting as a marker of local or distant residual or recurrent disease). In cases where antithyroglobulin antibodies are present, they may be used as a surrogate for thyroglobulin levels.

Treatment of Medullary Cancer

Surgery is the mainstay of therapy. Complete extirpation of disease is the primary goal of surgery. The presence of medullary thyroid cancer can be followed by measuring serum calcitonin levels. Normalization of calcitonin levels after surgery is an extremely good prognostic sign. In the treatment of aggressive and symptomatic, inoperable, locally advanced, or metastatic medullary thyroid cancer, tyrosine kinase inhibitors—vandetanib or cabozantinib—can be used.

Treatment of Poorly Differentiated and Undifferentiated (Anaplastic) Cancer

Treatment of poorly differentiated thyroid cancer is quite similar to that used in well-differentiated thyroid cancer, but the prognosis tends to be worse. Anaplastic thyroid cancer is an extremely aggressive malignancy that should be treated at a tertiary center by subspecialty experts. The use of targeted immunotherapy has recently shown great promise in improving the prognosis of this disease.

prognosisTop

The most common thyroid cancer, papillary thyroid cancer, has an excellent prognosis: an all-stage 5-year survival of 100%. Follicular thyroid cancer has an all-stage 5-year survival of 98%, and medullary thyroid cancer has an overall 5-year survival of 89%. Anaplastic thyroid cancer is extremely aggressive and has a 5-year survival rate of 7%.