Thyroid and Parathyroid Cancers

, , ,

This management guide of endocrine malignancies covers the risk factors, diagnosis, screening, and treatment of both thyroid and parathyroid cancers.


Endocrine malignancies, although relatively uncommon, are often difficult to diagnose and treat effectively. This chapter will focus on thyroid and parathyroid cancers. (A discussion of carcinoid tumors, insulinomas, gastrinomas, and other gastrointestinal neuroendocrine tumors, as well as adrenocortical cancer, can be found in the “Pancreatic, Neuroendocrine GI, and Adrenal Cancers” chapter.)

Thyroid Cancer


Thyroid cancer is the most common endocrine cancer and the ninth most common cancer overall. The American Cancer Society estimates that about 64,300 new cases of thyroid cancer will be diagnosed in the United States in 2016 (49,350 in women and 14,950 in men). Thyroid cancer represents 3.8% of the new cancer cases. Although most cancers are either stable or declining in incidence, the incidence of thyroid cancer continues to increase. Rates for new thyroid cancer cases have been rising on average 5.5% each year over the last 10 years. Death rates have been rising on average by 0.8% each year from 2002 through 2011. Despite standard treatment, an estimated 1,980 deaths from thyroid cancer (1,070 women, 910 men) will occur in 2016. The prevalence rate for occult thyroid cancers found at autopsy is 5% to 10%, except in Japan and Hawaii, where the rate can be as high as 28%. Autopsy rates do not correlate with clinical incidence.

Most patients are between the ages of 45 and 64 years at the time of thyroid carcinoma diagnosis. Median age at diagnosis is 50 years. About 2% of thyroid cancers occur in children and teenagers. Women are affected more often than men (3:1 ratio) and are usually diagnosed at a younger age. The most common stage at diagnosis is localized disease (confined to the thyroid) in 68% of cases, followed by regional disease (spread to regional lymph nodes) in 26% of cases, distant metastases in 4%, and unknown in 2% of patients. The 5-year survival for patients with localized thyroid cancer is 99.9%. The overall survival depends on stage; age; and in patients with differentiated thyroid cancer, the ability of the tumor to take up radioactive iodine (RAI). The 10-year overall survival is significantly reduced to < 10% in patients who are older, have distant metastases (macronodular lung metastases or bone metastases), and are RAI non-avid.

The prevalence of thyroid nodules in the general population is 4% to 7%, with nodules more common in females than in males. The prevalence of thyroid cancer in a solitary nodule or in multinodular thyroid glands is 10% to 20%; this increases with irradiation of the neck in children and older men (see section on “Etiology and risk factors“).

Tumor Types

Thyroid cancer is classified into four main types according to its morphology and biologic characteristics. Papillary and follicular carcinomas, also known as differentiated thyroid cancers, account for more than 90% of thyroid malignancies and constitute approximately 0.8% of all human malignancies. Medullary thyroid cancers represent < 4% of all thyroid carcinomas. About 75% of patients with medullary cancer have a sporadic form of the disease; the remaining 25% have inherited disease. Anaplastic carcinoma represents less than 2% of all thyroid carcinomas.

Papillary thyroid carcinoma

Papillary thyroid carcinoma is the most common subtype, and it typically has an excellent prognosis. Most papillary carcinomas contain varying amounts of follicular tissue, since they derive from thyroid follicular cells. When the predominant histology is papillary, the tumor is considered to be a papillary carcinoma. Because the mixed papillary-follicular variant tends to behave like a pure papillary cancer, it is treated in the same manner and has a similar prognosis.

Papillary thyroid carcinomas are unilateral in most cases, but they also can be multifocal. They vary in size from microscopic to large cancers that may invade beyond the thyroid tissue and infiltrate into contiguous structures. Papillary tumors tend to invade the lymphatics, but vascular invasion (and hematogenous spread) is uncommon. Up to 40% of adults with papillary thyroid cancer may present with regional lymph node metastases, usually ipsilateral. Distant metastases occur, in decreasing order of frequency, in the lungs, bones, and other soft tissues. Older patients have a higher risk of locally invasive tumors and of distant metastases. Children may present with a solitary thyroid nodule, but cervical node involvement is common in this age group; up to 10% of children and adolescents may have lung involvement at the time of diagnosis.

Follicular thyroid carcinoma

Follicular thyroid carcinoma is less common than papillary thyroid cancer, occurs in older age groups, and has a slightly worse prognosis. Follicular thyroid cancer can metastasize to the lungs and bones, often retaining the ability to accumulate RAI (which can be used for therapy). Metastases may be appreciated many years after the initial diagnosis. Follicular thyroid carcinoma, although frequently encapsulated, commonly exhibits microscopic vascular and capsular invasion. Microscopically, the nuclei tend to be large and have atypical mitotic figures. There is usually no lymph node involvement.

Follicular carcinoma can be difficult to distinguish from its benign counterpart, follicular adenoma. This distinction is based on the presence or absence of capsular or vascular invasion, which can be evaluated after surgical excision but not by fine-needle aspiration (FNA).

Hürthle cell, or oxyphil cell, carcinoma is a variant of follicular carcinoma. Hürthle cell carcinoma is composed of sheets of Hürthle cells and has the same criteria for malignancy as does follicular carcinoma. Hürthle cell carcinoma is thought to have a worse outcome than follicular carcinoma and is less likely to concentrate RAI.

Medullary thyroid carcinoma

Medullary thyroid carcinoma originates from the C cells (parafollicular cells) of the thyroid and secretes calcitonin. Secretory diarrhea and flushing, related to secretion of neuroendocrine peptides, are clinical features of advanced medullary thyroid carcinoma in 30% of cases. On gross examination, most tumors are often found in the upper two-thirds of the thyroid gland and are firm, grayish, and gritty.

Hereditary medullary thyroid carcinoma, which accounts for 25% of all cases, typically presents as a bilateral, multifocal process. Histologically, hereditary medullary carcinoma of the thyroid does not differ from the sporadic form, which usually presents as a solitary thyroid mass. However, the hereditary form is frequently associated with a background of C-cell hyperplasia. Another characteristic feature of hereditary medullary carcinoma is the presence of amyloid deposits.

There are two hereditary forms: multiple endocrine neoplasia type 2A (MEN-2A), characterized by medullary thyroid cancer, pheochromocytomas, and hyperparathyroidism; and multiple endocrine neoplasia type 2B (MEN-2B), characterized by medullary thyroid cancer, marfanoid habitus, pheochromocytomas, and mucosal neuromas and gastrointestinal ganglioneuromas. Familial medullary thyroid carcinoma is now considered a variant of MEN-2A in which family members do not demonstrate any of the other endocrine tumors. These syndromes are associated with germ-line mutations of the RET proto-oncogene, which codes for a receptor tyrosine kinase, called RET. Hereditary medullary thyroid cancer is inherited as an autosomal dominant pattern with high penetrance and variable phenotypic expression. (For a discussion of genetic testing to screen for RET mutations in MEN kindreds, see section on “Diagnostic workup.”)

Approximately 40% of sporadic (ie, nonhereditary) medullary thyroid carcinomas contain somatic RET mutations and 13% will have a RAS somatic mutation (predominantly the HRAS type), which may represent potential therapeutic targets.

Metastases to cervical and mediastinal lymph nodes are found in half of patients and may be present at the time of initial presentation. Distant metastases to the lungs, liver, bones, and adrenal glands most commonly occur late in the course of the disease.

Anaplastic carcinoma

Anaplastic tumors are high-grade neoplasms characterized histologically by a high mitotic rate and lymphovascular invasion. Aggressive invasion of local structures is common, as are lymph node metastases. Distant metastases tend to occur in patients who do not succumb early to regional disease. Occasional cases of anaplastic carcinoma have been shown to arise from pre-existing differentiated thyroid carcinoma or in a pre-existing goiter.

Other tumor types

Lymphomas of the thyroid account for less than 5% of primary thyroid carcinomas. Other tumor types, such as teratomas, squamous cell carcinomas, and sarcomas, may also rarely cause primary thyroid cancers.

Renal cell carcinoma is the most common extra-thyroidal tumor to metastasize to the thyroid. It accounts for almost half (42%) of patients with this condition. Colorectal cancer, lung cancer, breast cancer, and sarcomas account for 26%, 19%, 11%, and 6%, respectively, of metastases to the thyroid. Females show a slight predilection for metastases to the thyroid from nonthyroidal tumors. Of metastases to the thyroid gland, 44.2% occur in glands with abnormalities, such as primary thyroid neoplasms and benign thyroid conditions. The interval between diagnosing the primary tumors and their metastases to the thyroid gland is 4.5 months to 75 months.

Etiology and Risk Factors

Differentiated thyroid cancer

Radiation–induced thyroid cancer. Radiation exposure of the thyroid during childhood is the most clearly defined environmental factor associated with benign and malignant thyroid tumors. The predominant types of radiation are therapeutic external radiation for the treatment of cancer, historical use of external radiation to treat a wide variety of nonmalignant conditions, and exposure to nuclear fallout (from testing or accidents or in Japanese survivors of atomic bombing and children living in the area of Chernobyl). External low-dose radiation therapy to the head and neck during infancy and childhood, frequently used between the 1940s and 1960s for the treatment of a variety of benign diseases, has been shown to predispose an individual to thyroid cancer. The younger a patient is at the time of radiation exposure, the higher is the subsequent risk of developing thyroid carcinoma. Also, as mentioned previously, women are at increased risk of radiation-induced thyroid cancer. There is a latency period ranging from 10 to 30 years from the time of low-dose irradiation to the development of thyroid cancer.

As little as 11 cGy and as much as 2,000 cGy of external radiation to the head and neck have been associated with a number of benign and malignant diseases. It was once thought that high-dose irradiation (> 2,000 cGy) to the head and neck did not increase the risk of neoplasia. However, it has been shown that patients treated with mantle-field irradiation for Hodgkin lymphoma are at increased risk of thyroid carcinoma compared with the general population, although they are more likely to develop hypothyroidism than thyroid cancer.

Radiation-associated thyroid cancer has a natural history and prognosis identical to those of sporadic thyroid cancer.

Family history. A first-degree relative with history of thyroid cancer also increases the risk of being diagnosed with thyroid cancer, although the genetic basis is unclear.

Hereditary cancer syndromes. Individuals with certain familial cancer syndromes can develop differentiated thyroid cancer. Familial adenomatous polyposis (FAP), caused by a mutation in the APC gene, can predispose affected persons to development of papillary thyroid cancers. Cowden disease is associated with thyroid cancer of the papillary or follicular type. This syndrome is most often caused by defects in PTEN. Carney complex, type I is associated with an increased risk for papillary and follicular thyroid cancers. This syndrome is caused by defects in the PRKAR1A gene.

Besides radiation-induced thyroid cancer, there are sparse data on the etiology of differentiated thyroid cancer. There has been intensive research on distinguishing molecular factors important for cell differentiation, growth, and motility. Considerable attention has focused on BRAF, a member of the RAF family of serine/threonine kinases that mediates cellular responses to growth-promoting signals via the RAS-RAF-MEK-MAPK signaling pathway. BRAF mutations so far have only been documented in papillary thyroid carcinoma (45%) and papillary thyroid carcinoma–derived anaplastic thyroid carcinoma (25%). Presence of the somatic BRAF V600E mutation in papillary thyroid carcinoma has been reported to correlate with aggressive tumor characteristics (extrathyroidal extension, advanced tumor stage at presentation, lymph node or distant metastases). Patients with BRAF mutations have higher rates of mortality and are typically less responsive to radioiodine therapy. Because of this, BRAF mutations have been implicated as potential prognostic factors and therapeutic targets. In addition, because angiogenesis is critical for survival of tumors, vascular endothelial growth factor (VEGF) expression in papillary thyroid carcinoma correlates with decreased disease-free survival, and presence of BRAF mutation is associated with a higher risk of metastasis and recurrence.

Sidebar: Liu et al have reported on the relevance of mutations of the telomerase reverse transcriptase (TERT) in thyroid cancer, which, in association with BRAF V600E mutation, seem to portend a worse outcome. They found the transcriptional activity of the mutated TERT promoter was several-fold higher than that of the wild-type TERT promoter in thyroid cancer cells. BRAF V600E promotes the expression of the mutated TERT promoter. BRAF and TERT knockouts have decreased cellular migration and proliferation. This may explain the additive effect of these two mutations in aggressive cellular thyroid cancer and tumor behaviors of the disease (Liu X et al: Endocr Relat Cancer 20:603–610, 2013).

Medullary thyroid cancer

The notable risk factor for medullary thyroid cancer is having a germ-line mutation of the RET proto-oncogene (see information in this chapter on genetic testing). Approximately 25% of cases of medullary thyroid cancer are associated with heritable syndromes due to a RET mutation, multiple endocrine neoplasia types 2A (MEN-2A) and 2B (MEN-2B). Exome sequencing of sporadic medullary thyroid cancer showed mutations in RET, HRAS, and KRAS genes, suggesting that these mutations are the principal drivers of oncogenesis.

Follicular thyroid cancer

RAS gene mutations are identified in 20% to 35% of follicular thyroid carcinomas, and may represent a potential drive to development of this type of thyroid cancer.

Anaplastic thyroid cancer

Approximately 20% of patients with anaplastic thyroid cancer have a history of differentiated thyroid cancer. The majority of synchronous thyroid tumors are papillary cancers, but coexisting follicular cancers have also been reported. Anaplastic thyroid cancer develops from more differentiated tumors as a result of one or more dedifferentiating events. Since activating mutations in BRAF and RAS are seen in both well-differentiated thyroid malignancies and anaplastic thyroid cancer, these are presumed to be early events in the progression pathway. Late events that are seen more commonly in the anaplastic tumor, rather than the precursor well-differentiated tumor, include mutations in TP53, 16p, CTNNB1, and PIK3CA.

Signs and Symptoms

Most thyroid cancers present as asymptomatic thyroid nodules. Patients may feel pressure symptoms from nodules as they begin to increase in size. A change in the voice can be caused by a thyroid cancer or benign goiter. The voice change usually occurs when there is compression of the larynx or invasion of the recurrent laryngeal nerve. Secretory diarrhea and flushing can be symptoms suggestive of advanced medullary thyroid cancer.

On physical examination, a thyroid nodule that is hard or firm and fixed may represent a cancer. The presence of palpable enlarged nodes in the lateral neck, even in the absence of a palpable nodule in the thyroid gland, could represent metastases to the lymph nodes.

Diagnostic Workup

As mentioned previously, thyroid nodules are present in 4% to 7% of the general population and in a higher percentage of individuals who have had irradiation to the head and neck region. Most thyroid nodules are benign (colloid nodules or adenomas); therefore, it is important for the workup to lead to surgical resection for malignant nodules and to avoid unnecessary surgery for benign lesions. Although most solid nodules are benign, thyroid carcinomas usually present as solid nodules. A cystic nodule or a “mixed” (cystic-solid) lesion is less likely to represent a carcinoma and more likely to be a degenerated colloid nodule. Molecular testing can be performed on nodules with an indeterminate FNA cytology to help with therapeutic decisions.

History and physical examination. With the discovery of a thyroid nodule, a complete patient history should be taken and physical examination focusing on the thyroid gland and adjacent cervical lymph nodes should be performed. Pertinent historical factors include a history of childhood head and neck irradiation, total body irradiation for bone marrow transplant, family history of thyroid carcinoma or thyroid cancer syndrome in a first-degree relative, exposure to ionizing radiation from fallout in childhood or adolescence, rapid growth of the nodule, and hoarseness. In patients with a history of irradiation to the head and neck, the risk of cancer is higher (by as much as 50%) than in non-irradiated patients (10% to 20%). Nodules that occur in either the very young or the very old are likely to be cancerous, particularly in men. Also, a new nodule or a nodule that suddenly begins to grow is worrisome. Pertinent physical findings suggesting possible malignancy include vocal cord paralysis, lateral cervical lymphadenopathy, and fixation of the nodule to surrounding tissues.

Imaging modalities. Ultrasonographic and radionuclide (radioiodine and technetium) scans are also used in the evaluation of thyroid nodules.

• Ultrasonography-Ultrasonography is now widely considered an essential tool in the assessment of thyroid nodules. Thyroid ultrasonography should be performed in all patients with known or suspected thyroid nodules. Certain features are associated with malignancy and can guide physicians in deciding which nodules should be biopsied. A consensus statement from the Society of Radiologists in Ultrasound outlined various features of solitary nodules associated with thyroid cancer: microcalcifications, hypoechogenicity, irregular margins or no halo, solid composition, intranodule vascularity, and nodules that are taller than they are wider on a transverse plane. No single feature has both high sensitivity and specificity; however, the combination of two or more factors can increase the likelihood of cancer. Certain ultrasonographic appearances may also be highly predictive of a benign nodule-a pure cystic nodule is highly unlikely to be malignant. A spongiform appearance, defined as an aggregation of multiple microcystic components in more than 50% of the nodule volume, is 99.7% specific for identification of a benign thyroid nodule. Although there is a decrease in cancer rate per nodule in patients with multiple nodules, the overall rate of thyroid cancer per patient is similar to that seen in patients with a solitary nodule.

Thyroid cancer is most often found in the dominant, or largest, nodule in multinodular glands; however, approximately one-third of the cases of cancer are found in nondominant nodules. Nodule size is a poor predictor of malignancy, because the likelihood of cancer has been shown to be the same regardless of nodule size. Multiple ultrasonographic features other than size need to be considered in determining which nodules are more likely to be malignant and thus should be biopsied, including increased intranodular vascularity, hypoechogenicity of a solid nodule, microcalcifications, or presence of abnormal cervical lymph nodes. Patients with multiple thyroid nodules have the same risk of malignancy as those with solitary nodules, and selective FNA biopsy based on suspicious ultrasonographic findings is performed for further diagnosis.

• Radioactive iodine uptake and scan-If the serum thyroid stimulating hormone (TSH) level is subnormal, a radioiodine thyroid scan should be obtained to document whether the nodule is hyperfunctioning, or “hot” (ie, tracer uptake is greater than the surrounding normal thyroid); isofunctioning, or “warm” (ie, tracer uptake in the nodule is equal to that of the surrounding thyroid); or nonfunctioning, or “cold” (ie, tracer uptake is less than in the surrounding thyroid tissue). Thyroid isotope scans cannot differentiate absolutely a benign from a malignant nodule but can, based on the functional status of the nodule, assign a probability of malignancy. Most thyroid carcinomas occur in cold nodules, but only 10% of cold nodules are carcinomas. If the cytology reading reports a follicular neoplasm, an I-123 thyroid scan may be considered if it has not already been done, especially if the serum TSH level is in the low-normal range. If a concordant autonomously functioning nodule is absent on the radionuclide scan, lobectomy should be considered.

Computed tomography (CT) or magnetic resonance imaging (MRI) scans of the neck may be appropriate in some cases.

A fluorodeoxyglucose positron emission tomography (FDG-PET) scan is shown to improve diagnostic accuracy of indeterminate thyroid nodules, but results vary among studies. A meta-analysis by Bertagna et al found that the incidence of thyroid “incidentalomas” on FDG-PET or PET/CT was 2.46%. For solitary nodules with FDG-avidity, a malignancy ratio was found to be 34.6%. Diffuse uptake in the thyroid is commonly due to benign disease, such as thyroiditis.

FNA. FNA has become the most accurate and cost-effective initial diagnostic test for the evaluation of thyroid nodules, and it is the procedure of choice. The 2009 guidelines by the American Thyroid Association (ATA) recommend ultrasound-guided FNA for evaluating thyroid nodules; this can determine whether the lesion is cystic or solid. Ultrasound guidance is preferred over palpation to localized nodules and leads to a higher likelihood of diagnostic cytology (> 25% to 50% cystic component) or sampling error (difficult to palpate or posteriorly located nodules). A prospective study showed that ultrasound-guided FNA was more cost-effective than FNA by palpation. For solid lesions, cytology can yield one of three results: benign, malignant, or indeterminate. The accuracy of cytologic diagnosis from FNA is 70% to 80%, depending on the experience of the person performing the aspiration and the pathologist interpreting the cytologic specimen. FNA biopsy results are divided into four categories: nondiagnostic, malignant, indeterminate or suspicious for neoplasm, and benign. In a series of 98 “suspicious” FNA biopsies, findings of cellular atypia (pleomorphism, enlarged nuclei, nuclear grooves, coarse or irregular chromatin, prominent or multiple nucleoli, or atypical or numerous mitotic figures) or follicular lesions with atypia were associated with malignancy 20% and 44% of the time, respectively. Follicular lesions without atypia have a 6.7% risk of malignancy. Use of the Bethesda System recommended by the National Cancer Institute for reporting thyroid cytopathology allows for more systematic assessment of risk of malignancy and helps in determining follow-up and a further course of management.

Core needle biopsy has been used as an alternative method for diagnosis. Some studies have shown that the adequacy of sample may be greater with core needle biopsy than with FNA. However, there are conflicting reports as to whether a core needle biopsy offers greater accuracy in the diagnosis of a thyroid nodule.

Lymph nodes may also be sampled. Thyroglobulin washout performed on cystic lymph nodes can help detect the presence of metastatic disease.

Molecular markers. Approximately 5% to 30% of aspirations yield indeterminate cytologic findings, which include three subtypes: atypia (or follicular lesion) of undetermined significance, follicular neoplasm or suspicious for follicular neoplasm, and suspicious for malignancy. Improvement in the assessment of indeterminate FNA biopsy results may allow better risk stratification. Certain clinical features can improve the diagnostic accuracy for malignancy in patients with indeterminate cytology, but overall predictive values are still low. These include male sex, nodule size (> 4 cm), older patient age, and cytologic features such as presence of atypia.

In the United States, there are two commercially available approaches to the molecular characterization of FNA aspirates: molecular markers of malignancy and high-density genomic data for molecular classification.

The use of molecular markers (either for mutations or gene rearrangements of BRAF, RAS, RET/PTC, and PAX8-PPARγ) may be considered for patients with indeterminate cytology on FNA, to help guide management. These genetic markers have high specificity and a high positive predictive value; therefore, they can be used to identify which indeterminate nodules are malignant. However, they fail to rule out cancer with sufficient certainty to avoid surgery in most patients with indeterminate nodules.

Recent studies have described the development of gene-expression classifiers that better distinguish benign from malignant thyroid nodules. With the use of the gene-expression classifier, the negative predictive value was 95% for aspirates classified as atypia (or follicular lesions) of undetermined significance and 94% for aspirates classified as follicular neoplasms or lesions suspicious for follicular neoplasm. These data suggest consideration of a more conservative approach (observation or ultrasound) for most patients with thyroid nodules that are cytologically indeterminate on FNA and benign according to gene-expression classifier results.

Laboratory evaluation

Thyroglobulin. Thyroglobulin (Tg), normally synthesized in the follicular epithelium of the thyroid, is present in well-differentiated papillary and follicular carcinomas, and is noted infrequently in anaplastic carcinomas, but is not observed in medullary carcinomas. Therefore, thyroglobulin immunoreactivity is considered to be indicative of a follicular epithelial origin. Routine measurement of serum Tg for initial evaluation of thyroid nodules is not recommended by the 2009 ATA guidelines. Measurements of serum Tg provide important information about the presence or absence of residual, recurrent, or metastatic disease in patients with differentiated thyroid cancer. Limitations of serum Tg assays include interassay variability and the high prevalence of anti-Tg antibodies, which may interfere with Tg assay results. Testing should be done using a sensitive assay, ideally using the same assay for each sample. Thyroglobulin antibodies should be measured with each sample. Anti-Tg antibodies are present in 25% to 30% of patients with differentiated thyoid cancer. Due to their superior sensitivity, immunometric assays are becoming the standard of care. However, antibody interference can cause underestimation of Tg levels. In contrast, the radioimmunoassay and liquid chromatography–tandem mass spectrometry (LC-MS/MS) methods resist antibody interference but have lower sensitivity. Laboratories often reflex Tg measurement to radioimmunoassay or LC-MS/MS when the serum Tg antibody is positive.

In the absence of antibody interference, serum Tg has a high degree of sensitivity and specifcity to detect thyroid cancer, especially after total thyroidectomy and remnant ablation, with the highest degrees of sensitivity noted following thyroid hormone withdrawal or stimulation using recombinant human TSH (rhTSH). A single rhTSH-stimulated serum Tg level < 0.5 ng/mL in the absence of anti-Tg antibody has an approximately 98% to 99.5% likelihood of identifying patients who are completely free of tumor on follow-up.

Calcitonin level. Calcitonin is a specific product of thyroid C cells (parafollicular cells). The routine measurement of serum calcitonin in patients with thyroid nodules is controversial and is not currently recommended in the United States, given the rarity of the disease. However, if obtained, a basal or stimulated serum calcitonin level of 100 pg/mL or greater should be interpreted as suspicious for medullary thyroid carcinoma, and further evaluation and treatment should ensue.

The serum calcitonin concentration should be measured preoperatively in patients with medullary thyroid cancer and in carriers of a RET mutation for comparison with postoperative values. It is a sensitive marker of residual medullary thyroid carcinoma. When the postoperative basal serum calcitonin is undetectable, the risk of persistent or recurrent residual disease is low. In patients who have clinically palpable medullary carcinoma, the basal calcitonin level is almost always elevated. In patients with smaller tumors or C-cell hyperplasia, the basal calcitonin level may be normal, but administration of synthetic gastrin (pentagastrin) or calcium results in marked elevation of calcitonin levels. The use of calcitonin levels as a tumor marker and stimulation screening in hereditary forms of medullary cancers has been largely replaced by genetic testing (see below).

Carcinoembryonic antigen (CEA). Serum CEA levels may be elevated in patients with medullary thyroid cancer. The serum markers (calcitonin and CEA) are important in the follow-up of patients with medullary thyroid cancer, and they should be measured 2 to 3 months postoperatively.

Ruling out pheochromocytoma and hyperparathyroidism. Medullary thyroid carcinoma can be associated with MEN-2A or MEN-2B. Both the MEN-2A and MEN-2B syndromes are characterized by medullary thyroid cancer and pheochromocytoma. Thus, in any patient with hereditary medullary thyroid cancer, it is imperative that the preoperative workup include a determination of 24-hour urinary catecholamine and metanephrine levels to rule out the presence of a pheochromocytoma. Fractionated plasma metanephrine levels have been demonstrated to have a high sensitivity and may be included in the initial assessment. According to the ATA 2009 guidelines, exclusion of a pheochromocytoma may include any of the following tests: (1) negative RET proto-oncogene analysis and family history; (2) negative plasma free metanephrines and normetanephrines, or negative 24-hour urinary metanephrines and normetanephrines; (3) negative findings on adrenal CT or MRI scans. Given the possibility that any patient with medullary thyroid cancer may have MEN-2, preoperative testing must also include measurement of serum calcium to rule out primary hyperparathyroidism, which requires concomitant surgical intervention.

Genetic testing. Germ-line mutations in the RET proto-oncogene are responsible for familial non-MEN medullary thyroid cancer, in addition to MEN-2A and MEN-2B. DNA analysis performed on a peripheral blood sample is a highly reliable method for identifying the presence of an RET mutation. The 2009 management guidelines of the ATA regarding medullary thyroid cancer recommend that all patients with FNA or calcitonin diagnostic or suspicious for medullary thyroid cancer undergo RET mutation analysis, ideally performed with genetics counseling and completed preoperatively. Approximately 95% of patients with an RET mutation will eventually develop medullary thyroid cancer; thus, prophylactic surgical treatment is recommended. The specific mutated codon of RET may correlate with the aggressiveness of medullary carcinoma of the thyroid. This should be considered when counseling affected individuals and their families regarding prophylactic thyroidectomy and the age at which to perform such surgery. Long-term data regarding the effectiveness of prophylactic thyroidectomy based on RET testing are scarce at this time. In a report of 50 patients (19 years of age and younger) treated surgically after positive RET mutation analysis, 33 had carcinoma identified in the surgical specimen. At the time of the publication, 44 patients were found to be free of disease more than 5 years after surgery.

Recommended ages for prophylactic surgery range from within the first 6 months of life to 10 years of age, depending on the mutation. The prophylactic surgical procedure of choice is total thyroidectomy with or without central lymph node dissection.

Periodic determinations of stimulated calcitonin levels may help establish the early diagnosis of medullary thyroid cancer in those who do not undergo surgery, but they will not always prevent development of metastatic medullary thyroid carcinoma.


At this time, no organization recommends periodic screening for thyroid cancer using neck palpation or ultrasonography in average-risk, asymptomatic adults. However, the American Cancer Society recommends examination of the thyroid during a routine checkup, since this surveillance can result in case findings.

Staging and Prognosis

TABLE 1: AJCC/UICC staging of thyroid cancer

Unlike most other cancers, in which staging is based on the anatomic extent of disease, the American Joint Committee on Cancer (AJCC) and International Union Against Cancer (UICC) staging of thyroid cancer also takes into consideration patient age at the time of diagnosis and tumor histology (Table 1).

Differentiated thyroid cancers

Recurrence and death following initial treatment of differentiated thyroid cancer can be predicted using a number of risk-classification schemes. Some commonly used systems are Tumor Node Metastasis (TNM) or Metastases, Age, Completeness of Resection, Invasion, Size (MACIS); the AMES (age, metastases, extent, and size) and AGES (age, grade, extent, and size) classifications; and then an additional clinicopathologic staging system, such as the American Thyroid Association (ATA) system, to estimate the risk of recurrence.

Low-risk patients are generally those younger than 45 years with low-grade nonmetastatic tumors that are confined to the thyroid gland and are less than 1 to 5 cm. Low-risk patients enjoy a 20-year survival rate of 97% to 100% after surgery alone.

High-risk patients are those 45 years and older with a high-grade, metastatic, locally invasive tumor in the neck or with a large tumor. Large size is defined by some authors as more than 1 cm and by others as more than 2 or more than 5 cm. The 20-year survival rate in the high-risk group drops to between 54% and 57%.

Intermediate-risk patients include young patients with a high-risk tumor (metastatic, large, locally invasive, or high grade) or older patients with a low-risk tumor. The 20-year survival rate in this group of patients is approximately 85%. Increasing age and tumor size, male sex, poorly differentiated carcinoma, lymph node involvement, and regional and metastatic disease were associated with increased cumulative incidence of death resulting from thyroid cancer.

Medullary thyroid carcinoma

Medullary thyroid carcinoma is associated with an overall 10-year survival rate of 40% to 60%. When medullary carcinoma is discovered before it becomes palpable, the prognosis is much better: patients with stage I medullary tumors (ie, tumors ≤ 2 cm or nonpalpable lesions detected by screening and provocative testing) have a 10-year survival rate of 95%.

Stage II medullary cancers (tumors > 2 cm but < 4 cm) are associated with a survival rate of 50% to 90% at 10 years. Patients who have lymph node involvement (stages III and IVA disease) have a 10-year survival rate of 15% to 50%. Unfortunately, approximately 50% of patients have lymph node involvement at the time of diagnosis.

When there are distant metastases (stages IVB and IVC), long-term survival is compromised. In patients with metastatic medullary thyroid cancer, the disease often progresses at a very slow rate, and patients may remain alive with disease for many years. Doubling time of calcitonin and CEA are predictive of prognosis. In a 2005 study by Barbet et al of patients with medullary thyroid cancer, those with a calcitonin doubling time of < 6 months had a survival of 25% at 5 years and 8% at 10 years versus 100% survival among patients with a calcitonin doubling time of > 2 years. The 2009 ATA management guidelines for medullary thyroid cancer recommend monitoring of doubling time of CEA and calcitonin. Frequency of surveillance has been recommended on the basis of the doubling time calculation for calcitonin and CEA. Patients with calcitonin or CEA doubling times of > 2 years typically do not require systemic therapy, and such treatment should only be initiated after thorough discussion with the patient. Patients with rapidly progressing disease (doubling times of < 2 years) should be considered for treatment.

The ATA website has a calculator for CEA and calcitonin doubling time.

Sidebar: Ho et al recently reported on a postoperative nomogram for predicting cancer-specific mortality in medullary thyroid cancer. The authors identified a total of 249 patients with medullary thyroid cancer managed entirely at one institution between 1986 and 2010. Patient, tumor, and treatment characteristics were recorded from patient charts. A risk model was then built to predict the 10-year cumulative incidence of medullary thyroid cancer. All predictors of interest were added in the starting full model before selection, including age, gender, preoperative and postoperative serum calcitonin, preoperative and postoperative CEA, RET mutation, perivascular invasion, margin status, M status, pathologic N status, and pathologic T status. Of 249 patients, 22.5% (56 of 249) died from medullary thyroid cancer, while 6.4% (16 of 249) died secondary to other causes. The mean follow-up period was 87 ± 67 months. The seven variables with the highest predictive accuracy included age, gender, postoperative calcitonin level, perivascular invasion, pathologic T status, pathologic N status, and M status.

Anaplastic thyroid cancer

Anaplastic thyroid cancer does not have a generally accepted staging system, and all patients are classified as having stage IV disease. Anaplastic carcinoma is highly malignant and has a poor 5-year survival rate (0% to 25%). Most patients die of uncontrolled local disease within several months of diagnosis.

Treatment of Thyroid Cancer

Because most thyroid nodules are not malignant, it is important to differentiate malignant from benign lesions to determine which patients should undergo surgery. If the cytologic result from FNA biopsy indicates that the nodule is benign, which is the case most of the time, then the nodule can be safely monitored.


Malignant or indeterminate cytologic features are the primary indications for surgery.

Malignant nodule

Differentiated thyroid cancer. If the cytologic result shows a malignant lesion, a total thyroidectomy is recommended if any of the following are present: a primary lesion > 1 cm, contralateral thyroid nodules, regional or distant metastases, personal history of radiation therapy to the head or neck, or a first-degree family history of differentiated thyroid cancer. There is significant debate in the literature regarding the extent of thyroid surgery for primary tumors confined to one lobe and for tumors that are small and of low-risk potential for recurrence. The surgical options include total lobectomy, total lobectomy with contralateral subtotal lobectomy (subtotal thyroidectomy), or total thyroidectomy. The decision about which procedure to perform should be based on the risk of local recurrence and the anticipated use of radioactive iodine (see section on “Radioactive I-131”).

Most authorities agree that a low-risk patient (age < 45 years) with a 1-cm or smaller papillary thyroid cancer should undergo ipsilateral lobectomy alone. Most experts also agree that total thyroidectomy (or at least subtotal thyroidectomy) is appropriate for high-risk patients with high-risk tumors. Intermediate-risk patients are treated with total lobectomy alone or total (or subtotal) thyroidectomy plus postoperative radioactive iodine. Preoperative neck imaging may be helpful in planning the surgery. Patients with radiation-induced thyroid malignancies can be treated similarly, because their cancers have a similar prognosis; however, a total thyroidectomy may be preferable in these patients because of the increased risk of multicentric tumors.

For multinodular glands with a single nodule positive for differentiated thyroid cancer, the surgical approach would include total thyroidectomy. A lobectomy may be considered in some instances if other nodules are benign or if it is the patient’s preference.

The neck should be palpated intraoperatively. If positive nodes are found, a regional lymph node dissection should be performed.

Medullary carcinoma. Patients with medullary thyroid cancer should be treated with total thyroidectomy and central neck dissection. If there is involvement of the lateral neck nodes found on imaging or on clinical examination, a modified neck dissection should be performed (see section on “Lymph node dissection”). If the cancer is confined to the thyroid gland, the patient is usually cured. Postoperative adjuvant external irradiation may be used in certain circumstances (see section on “External radiation therapy”).

Anaplastic carcinoma. A tracheostomy often is required in patients with anaplastic thyroid cancer because of compression of the trachea. If the tumor is confined to the local area, total thyroidectomy may be indicated to reduce local symptoms produced by the tumor mass. Radiation therapy is used to improve locoregional tumor control, often together with radiosensitizing chemotherapy.

Indeterminate or suspicious nodule

Indeterminate and suspicious FNA samples should be treated as possible cancers and should be histologically evaluated. The initial operation performed in most patients should be total lobectomy, which entails removal of the suspicious nodule, hemithyroid, and isthmus. There is no role for nodulectomy or enucleation of thyroid nodules. The specimen can be sent for frozen-section analysis during surgery. If the frozen section is clearly benign, no further resection is required.

Follicular lesion. If frozen-section biopsy results indicate a follicular lesion in a patient who is a candidate for total thyroidectomy and a decision cannot be made as to whether the lesion is benign or malignant, two options are available: (1) stop and wait for final confirmation of the diagnosis, which may require a future operation; or (2) proceed with subtotal or total thyroidectomy, which obviates the need for a later operation. The diagnosis of follicular carcinoma requires identification of vascular or capsular invasion, which may not be evident on frozen-section biopsy.

Hürthle cell carcinoma. If the nodule is diagnosed as a Hürthle cell carcinoma, total thyroidectomy is generally recommended for all large (> 4 cm) invasive lesions. Small lesions can be managed with total lobectomy. However, controversy remains over the optimal treatment approach for this cancer.

Lymph node dissection

Therapeutic dissection. Therapeutic central neck node dissection should be performed for medullary carcinomas and other thyroid neoplasms with nodal involvement by palpation or preoperative imaging. The dissection should include all the lymphatic tissue in the pretracheal area and along the recurrent laryngeal nerve and anterior mediastinum. If there are clinically palpable nodes in the lateral neck, a modified neck dissection is performed.

Prophylactic dissection. There is no evidence that performing prophylactic neck dissection improves survival. Therefore, aside from patients with medullary thyroid cancer, who have a high incidence of involved nodes, only therapeutic neck dissection is indicated.

Removal of individual abnormal nodes. “Berry picking” is not advised when lateral neck nodes are palpable, because of the likelihood of missing involved nodes and disrupting involved lymphatic channels.

Metastatic or recurrent disease

Survival rates from the time of the discovery of metastases (lung and bone) from differentiated thyroid cancer are less favorable than those associated with local recurrence (5-year survival rates of 38% and 50%, respectively). Survival also depends on whether the metastatic lesions take up I-131.

Surgery, with or without I-131 ablation (discussed below), can be useful for controlling localized sites of recurrence. Approximately half of patients who undergo surgery for recurrent disease can be rendered free of disease with a second operation.

Radioactive I-131

Uses in papillary or follicular thyroid carcinoma

There are two basic uses for I-131 in patients with papillary or follicular thyroid carcinoma: ablation of normal residual thyroid tissue after thyroid surgery and treatment of thyroid cancer, either residual disease in the neck or metastasis to other sites in the body. It should be emphasized that patients with medullary (in the absence of a concomitant epithelial cell-derived differentiated thyroid cancer), anaplastic, and most Hürthle cell cancers do not benefit from I-131 therapy.

Postoperative ablation. Postoperative ablation of residual thyroid tissue should be considered in high-risk patients and patients with high-risk tumors. Ablation of residual normal thyroid tissue allows for the use of I-131 scans to monitor for future recurrence, possibly destroys microscopic foci of metastatic cancer within the remnant, and improves the accuracy of thyroglobulin monitoring. Studies show that radioactive iodine conveys no benefit for patients who have a low risk for recurrent disease, and therefore it should not be used empirically.

Complete thyroidectomy must also be accomplished in patients with regional or metastatic disease before the use of I-131 for treatment, because the normal thyroid tissue will preferentially take up iodine compared with the cancer. Some states permit the use of I-131 for ablation and treatment on an outpatient basis, but administration is strictly governed by national guidelines, which minimize the risk of radiation exposure to the public.

Patients determined to benefit from radioiodine treatment following surgery can be treated with liothyronine for 2–4 weeks, with discontinuation 2 weeks prior to radioiodine scan and treatment. The TSH level should be determined approximately 4 to 6 weeks after surgery; in patients who undergo total or subtotal thyroidectomy, TSH levels will generally be greater than 50 μU/mL. A postoperative, diagnostic iodine scan can then be performed. If this scan documents residual thyroid tissue, then an ablative dose of I-131 should be given. The patient should be advised not to undergo any radiographic studies with iodine within 2 to 3 months of ablation therapy. Patients are prepared with a specific, low-iodine diet before the I-131 therapy and instructed to avoid seafood and vitamins or cough syrups containing iodine. Iodine-123 may also be used in the postoperative setting for the diagnostic scan. It may produce better-quality images than I-131 scans.

For patients who have contraindications for thyroid hormone withdrawal, administration of rhTSH is an alternative for preparation for radioiodine ablation of a postsurgical thyroid remnant.

In general, I-131 will ablate residual thyroid tissue within 6 months following ingestion. In some patients, it may take up to 1 year for complete ablation to occur. A large, multicenter, 2-by-2, randomized, noninferiority trial by Mallick et al compared low-dose RAI (30 mCi, 1.1 GBq) and high-dose RAI (100 mCi, 3.7 GBq) plus thyrotropin alfa administration versus thyroid hormone withdrawal for patients with differentiated thyroid cancer (excluding extracervical metastatic disease). Noninferiority with successful ablation, as defined by a negative scan and thyrotropin level, was found, demonstrating less toxicity with the lower doses of RAI. At the same time, another randomized, 2-by-2 phase III trial reported by Schlumberger et al in a similar group of patients with differentiated thyroid cancer showed comparable results. This also raises the issue of whether any RAI therapy is required for low-risk patients. Patients should be monitored following ablation, and when they become hypothyroid, hormone replacement therapy should be given until they are clinically euthyroid and TSH is suppressed.

Follow-up I-131 scans 12 months or longer after initial treatment could be considered based on clinical findings of progression or residual disease.

Treatment of residual cancer. For disease in the tumor bed or lymph nodes that is not surgically resectable, an I-131 dose of 100 to 150 mCi is given. For disease in the lungs or bone, the I-131 dose is 200 to 250 mCi. Following this therapy, the patient is again given thyroid hormone replacement, and adequate suppression is maintained by monitoring TSH levels.

Some clinicians advocate obtaining a repeat scan in 1 year, along with a chest x-ray film, and repeating this procedure yearly until a normal scan is obtained. However, the frequency of repeated scans and the dose of I-131 are rather controversial and should be guided by the individual patient’s risk profile.

Following thyroid remnant ablation, serum Tg measurements are useful in monitoring for recurrence. Given that Tg in a patient receiving thyroid hormone replacement may be suppressed, a normal test result may be incorrect about 10% of the time. In general, the presence of disease is accurately predicted by a Tg value of > 5 ng/mL while the patient is in the suppressed state and by a value of > 10 ng/mL in the hypothyroid state. However, measurable disease may not be identified in many patients. Whether or not they should be treated on the basis of the Tg value if the I-131 scan is normal is a subject of current debate. Any rise in the Tg level from the previous value should increase the suspicion of recurrent disease.

Neck ultrasonography is useful to evaluate locoregional tumor recurrence and should be performed at yearly intervals for 5 to 10 years after initial therapy, depending on the stage of disease. Continued monitoring is necessary, because late recurrence can occur. It should be pointed out that certain aggressive tumors may neither be RAI-avid nor synthesize Tg. PET scanning may contribute to localization of disease in some cases and may even carry prognostic value. PET/CT may be more useful than other imaging techniques; in a recent study, additional information was obtained with PET/CT in up to 67% of cases.

Side effects and complications

Acute effects. The acute side effects of I-131 therapy include painful swelling of the salivary glands and nausea. Ibuprofen or other pain relievers are usually used to decrease salivary gland discomfort. Nausea may be treated with standard antiemetics.

Rarely, in patients with significant residual thyroid tissue, radioactive iodine may cause acute thyroiditis, with a rapid release of thyroid hormone. This problem can be treated with steroids and beta-blockers.

Patients must also be cautioned not to wear contact lenses for at least 3 weeks following ingestion of I-131, because the tears are radioactive and will contaminate the lenses and possibly lead to corneal ulceration.

Long-term complications. Long-term risks of radioactive iodine are not well understood. They can include effects on the salivary glands consisting of sialadenitis and xerostomia, and possible increased risk of bladder tumors and colon cancers with repeated administration. Bone marrow suppression and leukemia are potential long-term complications of I-131 therapy but are poorly documented and appear to be extremely rare. Patients should have a complete blood cell count performed prior to ingestion of an I-131 dose, to ensure adequate bone marrow reserve. They should also have blood counts measured yearly. Leukemia occurs rarely with doses of I-131 < 1,000 mCi.

Pulmonary fibrosis. Pulmonary fibrosis may be seen in patients with pulmonary metastases from papillary or follicular thyroid cancer who are treated with I-131. Those with a miliary or micronodular pattern are at greater risk, because a portion of normal lung around each lesion may receive radiation, leading to diffuse fibrosis.

Effects on fertility. Data have documented an increase in follicle-stimulating hormone (FSH) levels in one-third of male patients treated with I-131. Changes in FSH levels after one or two doses of I-131 are generally transitory, but repeated doses may lead to lasting damage to the germinal epithelium. Sperm banking should be considered in male patients likely to receive cumulative doses of I-131 > 500 mCi.

The effects of I-131 on female fertility have been investigated. A published article showed no significant difference in the fertility rate in women receiving RAI. Exposure to > 100 mCi of I-131 was also not associated with increased miscarriages, congenital malformations, or thyroid disease or cancer in offspring. However, it is generally recommended to avoid pregnancy for 1 year after therapeutic I-131 administration.

External Radiation Therapy

Papillary or follicular thyroid cancer

There are a number of indications for external irradiation of papillary or follicular thyroid carcinoma. Surgery followed by RAI may be used for disease that extends beyond the capsule. However, if all gross disease cannot be resected, or if residual disease is not RAI-avid, external irradiation is used as part of the initial approach for locally advanced disease in older patients. The benefit of adjuvant external irradiation for cause-specific survival is inferred from institutional series. Intensity-modulated radiation therapy is associated with decreased severe late toxicities in an institutional series and provides the best target coverage in dosimetric studies.

Unresectable disease. External irradiation is useful for unresectable disease extending into the connective tissue, trachea, esophagus, great vessels, and anterior mediastinum. For unresected disease, doses of 6,000 to 6,500 cGy are recommended. The patient should then undergo I-131 scanning, and if uptake is detected, a dose of I-131 should be administered.

Recurrence after resection. External irradiation may also be used after resection of recurrent papillary or follicular thyroid carcinoma that no longer shows uptake of I-131, or for gross unresectable disease. In this situation, doses of 5,000 cGy to 6,600 cGy are delivered to the tumor bed to prevent local recurrence. Multiple-field techniques and extensive treatment planning are necessary to deliver high doses to the target volume to minimize the risk of significant complications.

Recurrences to regional lymph nodes that are not resectable can be salvaged with regional external radiation therapy. In either situation, the radiation fields extend from cervical lymph node stations to the superior mediastinum, with esophageal stricture reported as a common long-term morbidity of treatment.

Palliation of bone metastases. External radiation therapy is useful in relieving pain from bone metastasis. If the metastasis shows evidence of I-131 uptake, the patient should be given a therapeutic dose of I-131 followed by local external radiation therapy to the lesion of up to 4,000 to 5,000 cGy. The use of intravenous bisphosphonate therapy has been shown to decrease the pain of bone metastasis and improve reported quality of life.

Anaplastic thyroid carcinoma

Anaplastic carcinoma of the thyroid is an exceptionally aggressive disease, with few long-term survivors. It often presents as a rapidly expanding mass in the neck and may not be completely resected. External irradiation to full dose (6,000 cGy to 6,500 cGy) may slow the progress of this disease but rarely controls it.

Chemoradiation therapy. There are reports of the use of accelerated fractionation regimens of external irradiation (160 cGy twice daily to 5,700 cGy) with weekly doxorubicin in patients with anaplastic thyroid cancer, as well as reports of the combination of doxorubicin and cisplatin with external irradiation. These regimens have improved local tumor control but at the expense of increased toxicity. Unfortunately, the majority of patients die of local and/or distant recurrence.

Medullary thyroid carcinoma

External irradiation has been used for medullary thyroid cancer in the postoperative setting, but only data from retrospective series are available. Therefore, this technique is controversial. However, much of the available literature has indicated that indications would include positive surgical margins, gross residual disease, or extensive lymph node metastasis. Further controversy exists in the setting of elevated postoperative calcitonin levels in patients who have undergone macroscopically complete resection, without radiographic evidence of distant disease. The recommended dose is 5,000 cGy to 7,000 cGy over a period of 5 to 7 weeks. Radiation is also used for palliation of different sites of metastatic disease. However, given the availability of tyrosine kinase inhibitors for the treatment of advanced, progressive medullary thyroid carcinoma and the risk of fistula formation or gastrointestinal perforation, decisions regarding adjuvant external beam radiation therapy to the neck after surgery should be made very carefully and deferred if there is no clear need.

Role of Medical Therapy

Differentiated thyroid cancer

Thyroid hormone suppression. As mentioned previously, thyroid hormone is used to suppress TSH in most patients with differentiated thyroid cancer after surgery and I-131 (as appropriate) treatment. Greater TSH suppression has been associated with improved progression-free survival in patients with high-risk papillary thyroid carcinoma. Modest TSH suppression in patients with stage II disease yields similar results. Patients with stage I disease do not appear to have any change in outcomes based on the degree of TSH suppression. ATA and National Comprehensive Cancer Network (NCCN) guidelines recommend that initial TSH suppression should be below 0.1 mU/L for high-risk and intermediate-risk thyroid cancer patients, while maintenance of the TSH at or slightly below the lower limit of normal (0.1 to 0.5 mU/L) is appropriate for low-risk patients. Patients who remain disease-free for several years can probably have their TSH levels maintained within the reference range.

Long-term management. Dynamic risk stratification is important. While initial staging systems can be used to guide initial therapeutic and diagnostic follow-up strategy decisions, it is important to recognize that initial risk estimates may need to change as new data are accumulated during follow-up examinations and testing. A restratification at each follow-up visit using a system that emphasizes the response to therapy is advocated by many thyroid cancer specialists.

A proposed nomenclature for response to initial therapy includes: (1) excellent response-no clinical, structural, or biochemical evidence of disease; (2) biochemical incomplete response-for example, an elevated thyroglobulin level with absent structural disease; (3) structural incomplete response-structural persistent or recurrent disease; and (4) indeterminate response-nonspecific biochemical or structural findings that do not clearly indicate a benign or malignant condition.

A proposed reclassification strategy at each follow-up visit will also guide additional treatment and follow-up needed for an individual patient.

• An excellent response to therapy should lead to a decrease in the intensity and frequency of follow-up. Patients who demonstrate an excellent response to therapy can have their TSH goal raised to 0.5–2 mU/L and be seen for physical examination and nonstimulated thyroglobulin values yearly, with surveillance neck ultrasound at 3- to 5-year intervals. ATA-classified indeterminate- and high-risk patients who achieve an excellent response to therapy may benefit from closer follow-up and more intense TSH suppression for a few more years.

• Patients who demonstrate a biochemical incomplete response to therapy (abnormal Tg in the absence of structurally identifiable disease) should continue to be monitored at 6- to 12-month intervals with ongoing TSH suppression and yearly neck ultrasound for several more years. Patients with stable or declining Tg values should have continued observation with ongoing TSH suppression, while rising Tg values should prompt additional imaging and, potentially, additional therapies.

• Patients with a structural incomplete response to therapy may require additional imaging or therapy depending on many factors, including the location, rate of growth, RAI avidity, FDG avidity, and specific pathology of the structural lesions.

Patients with an indeterminate response to therapy (nonspecific biochemical or structural imaging) continue on mild TSH suppression (TSH 0.1–0.5 mU/L) with follow-up visits at 6-months intervals for 2 to 3 years and annual neck ultrasound (US). After 2 to 3 years, these patients can usually be reclassified as having an excellent, biochemical incomplete, or structural incomplete response to therapy, for longer-term management. As an example, nonspecific findings that become suspicious over time or rising Tg or Tg antibody levels can be further evaluated with additional imaging or biopsy.

A similar restratification strategy is not clearly defined for medullary thyroid cancer.

Sidebar: The National Thyroid Cancer Treatment Cooperative Study Group published an updated analysis of multi-institution prospectively collected data related to clinical outcomes in patients with differentiated thyroid cancer after initial treatment. Moderate (TSH maintained subnormal-normal) but not aggressive (TSH maintained undetectable-subnormal) thyroid hormone suppression therapy (THST) was associated with significantly improved overall survival in all stages (risk ratio [RR] in stage I was 0.13, in stage II was 0.09, in stage III was 0.13, and in stage IV was 0.33). Disease-free survival was evident in all stages (RR in stage I was 0.52, in stage II was 0.40, and in stage III was 0.18). Only moderate THST was associated with significantly improved overall survival when distant metastatic disease was diagnosed during long-term follow-up. Both lower initial disease stage and moderate THST were independently predictive of improved overall survival. Further, moderate THST was independently predictive of improved disease-free survival for at least the first 3 years of follow-up in patients rendered disease free after initial therapy. In contrast to earlier reports, only moderate THST is associated with better outcomes in all stages (including low-risk stage I patients), and aggressive THST may not be warranted even in patients diagnosed with distant metastatic disease during follow up. Moderate THST continued at least 3 years after diagnosis may be indicated in higher-risk patients (Carhill A et al: Thyroid 24[suppl 1]: abstract 11, 2014).

Management of metastatic disease

Patients who present with distant metastases at the time of diagnosis should be treated with first-line, standard therapy, which consists of surgery, subsequent RAI, and thyroid hormone therapy to suppress the TSH.

RAI-refractory disease is defined as the presence of any of the following: (1) no radioiodine uptake at known sites of metastatic disease; (2) continued growth of disease despite RAI treatment and confirmed uptake; (3) distant disease growing over a 1-year period after RAI; and (4) a total cumulative dose of RAI ≥ 600 mCi

The management of metastatic thyroid cancer can be divided into three major categories: (1) active surveillance, (2) local therapy, and (3) systemic therapy.

Active surveillance. Active surveillance, or the “watch and wait” approach, is appropriate in patients with either differentiated or medullary thyroid cancer who are asymptomatic, have a low tumor burden, and/or have a slow pace of disease progression. Most patients with widely metastatic, RAI-refractory differentiated thyroid cancer or residual medullary thyroid cancer have a long indolent phase during which the tumor is stable or slowly progressive and asymptomatic. These patients can enjoy a good quality of life for many years before requiring systemic therapy. In such patients, the benefits of novel therapies may be outweighed by drug toxicities, and active surveillance is a valid strategy. Routine visits that include disease site–specific imaging should be maintained to monitor for change in the pace of growth or to evaluate the patient for potential new sites of disease if the Tg is increasing in the setting of stable areas of known disease. The imaging modalities used to detect disease include: ultrasound of the neck; thin-section spiral CT of the chest; and, when indicated by a given clinical scenario, MRI of the brain, spine, and pelvis; bone scan; and FDG-PET/CT scan.

Local therapy. In selected patients with RAI-refractory differentiated or recurrent medullary thyroid cancer with isolated or localized metastases, surgical resection and radiotherapy can be considered.

For patients with bone metastases, local therapy with external beam radiation therapy (EBRT) is often considered in two scenarios: to palliate painful metastases and to provide local control of disease. Embolization of a site of bony metastatic disease is useful in some cases and can lead to tumor shrinkage and palliation of pain. Agents that inhibit osteoclast activity, such as bisphosphonates (zoledronic acid [Zometa]) and the RANK ligand inhibitor denosumab, are used in patients with solid tumor and bone metastases. Based on favorable experience in other cancers with bone metastases, use of these drugs has become an encouraging treatment option for pain and disease in thyroid cancer.

Systemic therapy. Eighty-five percent of patients with differentiated thyroid cancer are cured with surgery, RAI, and TSH suppression. A small percentage of patients will develop or present with metastases and are more difficult to treat. When metastases have RAI avidity, prognosis is better and further RAI may be used. However, when multiple doses of have been tried or the patient has non-RAI–avid disease, other options need to be considered. Although it is the most effective medical treatment for differentiated thyroid cancer, only about 50% to 80% of primary tumors and their metastases take up RAI.

Once differentiated thyroid cancer is found to be refractory to RAI or recurrent medullary thyroid cancer is deemed inoperable or widely progressive, patients should have full staging examinations to determine the extent of disease and rate of progression. The progression rate is assessed using response evaluation criteria in solid tumors (RECIST). Patients with measurable lesions and documented progression should be considered candidates for systemic treatment.

Systemic cytotoxic chemotherapy. The more frequently used agent in thyroid cancer studies was doxorubicin, either alone or in combination with cisplatin. Responses to treatment were limited and only lasted a few months. Use of newer cytotoxic drugs (eg, taxanes, gemcitabine, and irinotecan) has not been reported in a significant number of patients with differentiated thyroid cancer. Because of toxic side effects, short duration of responses, and low response rates, cytotoxic chemotherapy agents are not recommended.

Newer molecular-targeted therapy. Within the past decade, molecularly targeted treatments have been studied in patients with locally recurrent unresectable and metastatic medullary thyroid cancer and advanced differentiated thyroid carcinoma no longer responsive to RAI. The understanding that RET mutations (germline and somatic), upregulation of VEGF, and VEGF receptor (VEGFR) expression are found in medullary thyroid cancer led to clinical trials of tyrosine kinase inhibitors (TKIs) in this setting, since they inhibit receptors of both VEGF and RET. The recognition of the presence of oncogenic mutations such as BRAF, RAS, and RET/PTC in differentiated thyroid carcinoma has prognostic implications and guides therapeutic effect in patients with advanced cancer. Because VEGFR is also upregulated in patients with differentiated thyroid cancer, clinical trials of drugs targeting VEGFR have also been undertaken.

According to the ATA and NCCN guidelines, patients with metastatic differentiated thyroid cancer that is not amenable to surgery or RAI therapy, or patients with progressive and/or symptomatic medullary thyroid cancer not amenable to surgery or localized therapy should be considered for treatment with TKIs or referred to a clinical trial investigating targeted therapies.

Several factors should be taken into account when considering therapy with TKIs. The use of TKIs can be associated with progression-free survival but is not curative. Also the natural histories of both MTC and differentiated thyroid cancer have variable progression rates, ranging from a few months to many years. Therefore, the pace of disease progression should be a determining factor in treatment decisions. Careful patient selection is essential, since this drug therapy is associated with side effects that have an impact on quality of life. Common side effects of TKIs include skin rash, diarrhea, nausea, fatigue, anorexia, hypertension, mucositis, and cytopenias. More significant but less common problems can arise from heart failure, cardiac arrhythmias, enteric fistulas and perforations, abnormal hepatic function, bleeding, proteinuria, neurological dysfunction, and squamous malignancies.

Sorafenib was approved in November 2013 as treatment for progressive RAI-refractory differentiated thyroid cancer. It has activity against VEGFR, PDGF, and RET. In phase II trials patients treated with sorafenib had a progression-free survival ranging from 15 months to more than 19 months, compared with historical progression-free survival of 6 to 9 months. Partial response to sorafenib therapy was observed in 40% of patients, but no complete response to treatment was observed. Two major limitations of these studies were lack of a direct comparison control group and the inclusion of patients with stable disease. Many patients experienced adverse effects from the drug (eg, diarrhea, skin rash, hypertension, fatigue, plantar-palmar erythrodysesthesia) requiring dose reduction in more than 50% of the patients, and over 10% of patients discontinued the drug due to adverse events.

DECISION, a multicenter, randomized, double-blind, placebo-controlled, phase III trial reported by Brose et al, investigated sorafenib (at 400 mg orally twice daily) in patients with radioactive iodine–refractory locally advanced or metastatic differentiated thyroid cancer that had progressed within the past 14 months. The primary endpoint was progression-free survival. Patients in the placebo group could cross over to open-label sorafenib upon disease progression. The intention-to-treat population comprised 417 patients (207 in the sorafenib group and 210 in the placebo group). Median progression-free survival was significantly longer in the sorafenib group (10.8 months) than in the placebo group (5.8 months) (HR, 0.59; 95% CI, 0.45–0.76; P < .0001). Progression-free survival improved in all prespecified clinical and genetic biomarker subgroups, irrespective of mutation status. Adverse events occurred in 204 of 207 (98.6%) patients receiving sorafenib during the double-blind period and in 183 of 209 (87.6%) patients receiving placebo. Most adverse events were grade 1 or 2 with the following frequent adverse events in the sorafenib group: hand-foot skin reaction (76.3%), diarrhea (68.6%), alopecia (67.1%), and rash or desquamation (50.2%).

Dadu et al performed a retrospective review to determine the efficacy of salvage therapy after first-line sorafenib failure. This review included patients with metastatic differentiated thyroid cancer who received first-line sorafenib only (group 1) and those who went on to salvage therapy after initial sorafenib failure (group 2). Sixty patients with metastatic, RAI-refractory differentiated thyroid cancer were included (group 1 = 35, group 2 = 25), with the groups being well balanced. Median overall survival time for the 60 patients was 41 months; median overall survival was significantly longer with salvage therapy than with sorafenib alone (63 months vs 24 months, P = .013). In group 2, there were 17 patients evaluable for best response. Best responses with first-line sorafenib were partial response in 2 of 15 (13%), stable disease in 10 of 15 (67%), and progressive disease in 3 of 15 (20%) patients. With salvage therapy, partial responses were seen in 7 of 17 (41%) and stable disease in 10 of 17 (59%) patients. Median progression-free survival was 7.4 months with first-line sorafenib only and 11.4 months with salvage therapy. Salvage therapy included sunitinib (4 patients), pazopanib (3 patients), cabozantinib (4 patients), lenvatinib (3 patients), and vemurafenib (3 patients).

In a phase I study of thyroid cancer treatment with the BRAF protein inhibitor dabrafenib, Falchook et al enrolled 14 patients with BRAF V600E-mutant thyroid carcinoma were enrolled. The results in non-melanoma patients were reported in a supplementary appendix. Dabrafenib showed promising clinical activity; it was well tolerated and resulted in durable responses in patients with BRAF V600E-mutant thyroid carcinoma. In a small group of patients with RAI-resistant BRAF-mutant papillary thyroid carcinoma evaluated by Rothenberg et al, new iodine uptake following treatment was demonstrated. Five of nine patients demonstrated new I-131 uptake after 28 days of treatment with dabrafenib. Three patients received a therapeutic dose of RAI; one of the three had a complete response and the remaining two patients had stable disease. Clinical trials are currently underway to evaluate the response to dabrafenib with or without trametinib.

Sidebar: In February 2015, the US Food and Drug Administration (FDA) approved lenvatinib for patients with locally recurrent or metastatic progressive, RAI-refractory differentiated thyroid cancer. The approval was based on the results of SELECT, a phase III, multicenter, double-blind, placebo-controlled trial of lenvatinib in patients with I-131 refractory differentiated thyroid cancer. The study, reported by Schlumberger et al, enrolled 392 patients who had RAI-refractory differentiated thyroid cancer with documented disease progression within 13 months. Patients were randomized 2:1 to drug or placebo (at 24 mg daily on a 28-day cycle). Upon progression, patients receiving placebo could cross over to open-label treatment with lenvatinib. The primary endpoint was progression-free survvial, and secondary endpoints included overall response rate (complete response + partial response), overall survival, and safety. Patients on lenvatinib had a significantly prolonged progression-free survival time (18.3 months) compared with those randomized to placebo (3.6 months; HR, 0.21; 95% CI, 0.14–0.31; P < .001). A progression-free survival benefit of lenvatinib was observed in all predefined subgroups; median progression-free survival for patients on lenvatinib with prior versus no prior VEGF-therapy was 15.1 months (n = 66) and 18.7 months (n = 195), respectively. Rates (n) of responses are as follows: The rate of complete responses with lenvatinib was 1.5% (4 patients) versus 0% in the placebo group. The rate of partial responses with lenvatinib was 63.2% (165 patients) versus 1.5% with placebo (2 patients). The most common adverse events related to treatment with lenvatinib (occurring in >30% of patients, any grade) were hypertension (69.3%), diarrhea (59.4%), fatigue (59%),decreased appetite (50.2%), weight loss (46.4%), nausea (41%), stomatitis (35.6%), palmar-plantar erythrodysesthesia syndrome (31.8%), and proteinuria (31%). Lenvatinib-associated AEs of grade ≥ 3 were hypertension (41.8%), proteinuria (10%), weight loss (9.6%), fatigue (9.2%), diarrhea (8%), and decreased appetite (5.4%). The dose was reduced in 82.4% of patients treated with lenvatinib and discontinued due to adverse events in 14.2% .

There are two FDA-approved molecular targeted agents for medullary thyroid cancer: vandetanib (a TKI inhibitor of a variety of cell receptors, mainly VEGFR2, EGFR, and RET tyrosine kinases) and cabozantinib (a TKI inhibitor of c-Met, and VEGFR2).

In April 2011, under a restricted prescription program, Risk Evaluation and Mitigation Strategies (REMS), the FDA approved vandetanib for treatment of medullary thyroid carcinoma in patients with progressive locoregional and metastatic disease. Approval was based on two pivotal trials of vandetanib. An open-label phase II trial of vandetanib in locally advanced or metastatic hereditary medullary thyroid carcinoma showed partial response in 20% of patients, stable disease at 24 weeks or more in 53%, calcitonin levels decreased by 50% in 80%, and CEA levels decreased by 50% in 53%. In addition, vandetanib exhibited a significant objective response rate compared with placebo. Safety and efficacy results were established in an international phase III randomized, double-blind, placebo-controlled study that showed median progression-free survival of 19.3 months in the placebo group versus 30.5 (estimated) months in the vandetanib arm (HR, 0.46; 95% CI, 0.31–0.69; P < .001). In clinical trials of vandetanib, QT interval prolongation, torsade de pointes, and sudden death have been reported; thus, prescribers must be properly educated about these risks and should participate in the REMS program. An ongoing randomized trial is now evaluating the relative efficacy and tolerability of starting with the either the lower 100-mg daily dose or the approved 300-mg dose to clarify efficacy and toxicity profiles at each dosing.

In November 2012, cabozantinib was also approved for this rare disease. In a randomized trial, 330 patients with progressive, metastatic or unresectable locally advanced medullary thyroid cancer were randomly assigned to receive either cabozantinib (140 mg) or placebo once daily. A significant prolongation in progression-free survival was observed for cabozantinib treatment compared with placebo (11.2 months vs 4 months; HR, 0.28; 95% CI, 0.19–0.40; P < .001). Partial responses were observed in 27% of the cabozantinib-treated versus 0% of placebo-treated patients. The most common side effects, occurring in ≥25% of patients, were diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, hypertension, and abdominal pain. Although uncommon, clinically significant adverse events included fistula formation and osteonecrosis of the jaw, but a REMS program was not required. Significant electrocardiographic abnormalities were not observed.

TABLE 2: Trials that led to FDA approval of vandetanib and cabozantinib for medullary thyroid cancer

At this time, there are no data to indicate which agent is more effective in patients with medullary thyroid carcinoma. Thus, when systemic therapy is indicated due to evidence of progression by RECIST that is not amenable to further surgery or localized treatment, it is very important to take into account patient characteristics and potential side effects with treatment when deciding which drug to choose first. A summary of both drugs is shown in Table 2.

Sidebar: In 2014, Cabanillas et al published a comprehensive analysis of cabozantinib and vandetanib in the context of patients with advanced or symptomatic medullary thyroid carcinoma, which included recommendations on when to initiate treatment and how to use a patient-centered approach toward selecting the most-appropriate TKI for treatment.

Anaplastic thyroid carcinoma

As mentioned previously, the usual treatment for patients with resectable or localized anaplastic thyroid cancer is surgery. Like radiotherapy, chemotherapy is an important alternative approach, but further evaluation is needed to optimize its effectiveness. Patients with unresectable local tumors should be referred to clinical trials, treated with radiotherapy and chemotherapy, or maintained with best supportive care. Imatinib (Gleevec, an inhibitor of Bcr-Abl and PDGF) and sorafenib are being studied in phase II trials in patients with anaplastic thyroid carcinoma, with preliminary data showing partial response in 13% to 25%, and stable disease in 27% to 50% of patients. Further investigation is needed to identify better therapeutic options for patients with this aggressive form of thyroid carcinoma.

Parathyroid Carcinoma

Parathyroid carcinoma accounts for < 1% of the parathyroid gland tumors and almost always presents as primary hyperparathyroidism. The serum calcium level is very high in up to 65% of patients; however, there are cases when the calcium level is only mildly elevated or even normal.

Epidemiology and Etiology

In Europe, the United States, and Japan, parathyroid carcinoma has been estimated to cause hyperparathyroidism up to 5% of cases. The median age of patients is between 45 and 51 years. It affects both sexes equally, in contrast to primary hyperparathyroidism, in which there is a significant female predominance.

The etiology of parathyroid carcinoma is largely unknown. A causal relationship with prior neckirradiation is not apparent, as only 1.4% of patients have a history of neck irradiation. Parathyroid carcinoma can be associated with the hereditary hyperparathyroidism–jaw tumor syndrome with an incidence of 10% to 15%, which is due to an inactivating mutation of the CDC73 gene (formerly HRPT2) that encodes the parafibromin protein. In addition, somatic mutations of the HRPT2 gene have been demonstrated in sporadic parathyroid carcinomas (66% to 100%) but have not been seen with sporadic adenomas.

Parathyroid cancer has been occasionally reported in familial isolated hyperparathyroidism, MEN type 1 and MEN-2A syndromes.

Signs and Symptoms

Most patients with parathyroid cancer have symptomatic moderate to severe hypercalcemia (mean serum calcium level, 15 mg/dL) and high parathyroid hormone levels (5 to 10 times greater than the upper limits of normal). They often present with a palpable neck mass with possible recurrent laryngeal nerve palsy. Unlike benign hyperparathyroidism, renal and bone abnormalities are more common in patients with parathyroid cancer.

In hyperparathyroidism–jaw tumor syndrome, patients present in late adolescence or early adulthood with multigland cystic parathyroid adenomas that carry a high risk for carcinoma. Patients with this syndrome will have maxillary or mandibular ossifying fibromas (30% to 40%) or renal cysts or hamartomas (20%).

Rarely, nonfunctioning tumors may present as neck masses; their clinical course is similar to that of functioning tumors. Clinical concern about parathyroid cancer should be raised in the presence of a palpable neck mass and severe hypercalcemia, recurrent hyperparathyroidism, or associated vocal cord paralysis.

Parathyroid cancer usually has an indolent course because the tumor has a rather low malignant potential. At initial presentation, very few patients with parathyroid carcinoma have metastases either to regional lymph nodes (< 5%) or distant sites (< 2%).


The principal features of parathyroid cancer include a trabecular pattern, mitotic figures, thick fibrous bands, and capsular or vascular invasion of disease. Other important features include lymphatic or hematogenous metastases and histologic evidence of tumor infiltration into the surrounding tissues (including macroscopic adherence or vocal cord paralysis).

Although cytologic evidence of mitoses is necessary to establish the diagnosis of carcinoma, mitotic activity alone is an unreliable indicator of malignancy. The loss of parafibromin staining on immunohistochemistry is 94.4% specific for parathyroid carcinoma.The only reliable microscopic finding of malignancy is invasion of surrounding structures or metastasis to lymph nodes or other organs.


Surgical treatment of primary hyperparathyroidism

The diagnosis of parathyroid carcinoma is sometimes made during surgical exploration for primary hyperparathyroidism. Most surgeons advocate identification of all four parathyroid glands. In most cases, the upper glands can be found on the posterior aspect of the upper third of the thyroid lobe, just cephalad to the inferior thyroid artery and adjacent to the recurrent laryngeal nerve as it enters the larynx.

The inferior parathyroid glands are more variable in location. Most are found on the posterior or lateral aspect of the lower pole of the thyroid gland, but the inferior parathyroid glands may be ectopically placed in the superior or true mediastinum, often within the thymus. The inferior and, less commonly, superior glands can be found in an ectopic location in the upper or lateral neck, adjacent to the esophagus, or within the carotid sheath. Parathyroid carcinoma usually arises from the inferior glands.

Surgical exploration for primary hyperparathyroidism. Most cases of primary hyperparathyroidism are caused by a single hyperfunctioning parathyroid adenoma. If the surgeon finds one (or occasionally two) enlarged abnormal gland(s) and the remaining glands are normal, the enlarged gland should be removed.

If four enlarged glands are found, indicating the rare case of primary parathyroid hyperplasia, subtotal parathyroidectomy including 3.5 glands should be performed. Consideration should be given to transplanting the remaining gland remnant to an ectopic location that would be easily accessible to the surgeon if hyperparathyroidism recurs.

If only normal glands are found at exploration, a missed adenoma in an ectopic location should be suspected. Thorough intraoperative neck and superior mediastinal exploration should be performed, and if the missing gland cannot be found, thymectomy and hemithyroidectomy should be performed to exclude an intrathymic or intrathyroidal adenoma. Localization studies, including CT/MRI or radionuclide imaging, should precede re-exploration for a missed adenoma.

Intraoperative parathyroid hormone (ioPTH) levels are increasingly used to guide surgery for primary hyperparathyroidism. A 50% or greater decrease in the ioPTH level from the pre-excision value to the 10-minute postexcision value is used as a predictor of successful surgery. The advent of ioPTH monitoring, coupled with preoperative localization studies (sestamibi scanning), has facilitated less invasive surgical techniques, such as minimally invasive parathyroidectomy. This has resulted in shorter average hospitalization stays and reduced postoperative recovery times. Loss of parafibromin and Rb expression and overexpression of galectin-3 can be distinguishing features of parathyroid carcinoma versus other parathyroid tumors.

The use of ioPTH with parathyroid hyperplasia requires more strict evaluation of ioPTH levels. Siperstein et al performed a prospective evaluation of ioPTH and bilateral neck exploration and found that up to 15% of cases will have additional “abnormal” glands that were not predicted by ioPTH or preoperative imaging. This study demonstrates the need for long-term follow-up of patients undergoing focused parathyroid surgery.

If parathyroid carcinoma is suspected, based on the severity of hyperparathyroidism or invasion of surrounding tissues by a firm parathyroid tumor, aggressive wide excision is indicated. This procedure should include ipsilateral thyroidectomy and en bloc excision of surrounding tissues as necessary.

Patterns of recurrence of cancer. Parathyroid carcinoma is typically extremely indolent but progressive over time. After surgical resection, the recurrence rate is between 40% and 60%. The average time from initial surgery to the first recurrence of cancer is usually 2 to 5 years but may be as long as 10 years. In most cases, hypercalcemia precedes physical evidence of recurrent disease. The thyroid gland is the usual site of involvement, with disease “seeding” in the neck a common pattern. Other sites of involvement include the recurrent nerve, strap muscles, esophagus, and trachea.

Distant metastases can be present at the time of initial surgery, or local spread to contiguous structures in the neck may be followed by distant metastases to the lungs (40%), liver (10%), and bone (rare).

In a recent analysis, 85% of patients with parathyroid carcinoma were alive 5 years after diagnosis; death usually results from complications of the hypercalcemia rather than from the tumor burden. When advanced metastatic disease is found at the initial presentation, the mortality approaches 85% at 10 years.

Treatment of isolated metastases. Isolated metastases should be aggressively resected to enhance survival and control hypercalcemia. Liver-directed therapies can be considered to reduce tumor/hormonal burden.

Medical therapy

Morbidity and mortality are generally caused by the effects of unremitting hypercalcemia rather than tumor growth. Medical treatment provides temporary palliation of hypercalcemia, which includes aggressive hydration, cardiac function permitting, with normal saline to correct the hypotension and volume depletion due to hypercalciuria. Drugs used include bisphosphonates, such as pamidronate (at 60 to 80 mg every 4 to 6 days) or zoledronic acid (4 mg); and calcitonin, at 4 to 8 IU/kg every 6 to 12 hours. Cinacalcet, a calcimimetic that targets the calcium-sensing receptor on parathyroid cells and reduces parathyroid hormone secretion, is an FDA-approved oral treatment of hypercalcemia associated with parathyroid carcinoma (up to 90 mg bid) in patients who do not respond to surgery or other medical treatments. Recent investigation into denosumab in hypercalcemia of malignancy may show promise for management of hypercalcemia in patients with hypercalcemia of malignancy and parathyroid carcinoma.

In December 2014, the FDA approved denosumab for treatment of hypercalcemia of malignancy refractory to bisphosphonates. The approval was based on positive results from an open-label, single-arm study by Hu et al, which enrolled 33 patients with advanced cancer and persistent hypercalcemia after recent bisphosphonate treatment. The primary endpoint was the proportion of patients with a response, defined as albumin-corrected serum calcium (CSC) ≤ 11.5 mg/dL within 10 days after the first dose of denosumab. Secondary endpoints included the proportion of patients who experienced a complete response (defined as CSC ≤ 10.8 mg/dL) by day 10, time to response, and response duration. The study reported a response rate at day 10 of 64% and an overall complete response rate of 33%. The estimated median time to response (CSC ≤ 11.5 mg/dL) was 9 days, and the median duration of response was 104 days.

In two separate, unique case reports, Vellanki et al and Karuppiah et al described patients with recurrent metastatic parathyroid carcinoma in whom refractory hypercalcemia was successfully managed by the addition of denosumab.

Radiation therapy

There is little evidence for an effect of adjuvant radiation therapy in achieving locoregional control. Some institutions have used surgical margin status to determine whether patients receive adjuvant radiation therapy including elective nodal irradiation.

In general, nonsurgical therapies for parathyroid carcinoma tend to have poor outcomes. Patients should undergo lifelong surveillance as they can potentially be susceptible to relapses over prolonged periods of time. Patients rarely die from the tumor itself; rather, they die from the metabolic complications of uncontrolled hyperparathyroidism.

Suggested Reading

On Thyroid Carcinoma

Agrawal N, Jiao Y, Sausen M, et al: Exomic sequencing of medullary thyroid cancer reveals dominant and mutually exclusive oncogenic mutations in RET and RAS. J Clin Endocrinol Metab 98:E364–E369, 2013.

Algeciras-Schimnich A, Netzel B, Castro M, et al: Greater understanding of anti-thyroglobulin (Tg) antibody interference in Tg immunoassays: a systematic evaluation of six tg immunoassays against a tg mass spectrometry assay. Thyroid 24(suppl 1): poster 40, 2014.

Ali SZ: Thyroid cytopathology: Bethesda and beyond. Acta Cytol 55:41 2, 2011.

Barbet J, Campion L, Kraeber-Bodere F, et al: Prognostic impact of serum calcitonin and carcinoembryonic antigen doubling times in patients with medullary thyroid carcinoma. J Clin Endocrinol Metab 90:6077–6084, 2005.

Bertagna F, Treglia G, Piccardo A, et al: Diagnostic and clinical significance of F-18-FDG-PET/CT thyroid incidentalomas. J Clin Endocrinol Metab 97:3866–3875, 2012.

Boone D, Suman P, Prinz R, et al: Impact of radioactive iodine on survival in papillary thyroid carcinoma. Thyroid 24(suppl 1): abstract 15, 2014.

Brose MS, Cabanillas ME, Cohen EEW, et al: An open-label, multi-center phase 2 study of the BRAF inhibitor vemurafenib in patients with metastatic or unresectable papillary thyroid cancer (ptc) positive for the BRAF V600 mutation and resistant to radioactive iodine. Presented at the European Cancer Congress 2013 (ECCO-ESMO-ESTRO), Amsterdam, the Netherlands, Sept. 27–Oct. 1, 2013. Abstract 28.

Brose M, Nutting C, Jarzab B et al: Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: A randomised, double-blind, phase 3 trial. Lancet 384:319328, 2014.

Brown RL, De Sousa J, Cohen EE: Thyroid cancer: Burden of illness and management of disease. J Cancer 2:193–199, 2011.

Cabanillas ME, Patel A, Danysh BP, et al: BRAF inhibitors: Experience in thyroid cancer and general review of toxicity. Horm Cancer. 6:21–36, 2015.

Cabanillas ME, Hu MI, Durand JB, et al: Challenges associated with tyrosine kinase inhibitor therapy for metastatic thyroid cancer. J Thyroid Res 2011:985780, 2011.

Cabanillas ME, Hu MI, Jimenez C: Medullary thyroid cancer in era of tyrosine kinase inhibitors: to treat or not to treat--and with which drug--those are the questions. J Clin Endocrinol Metab 99: 43904396, 2014.

Can AS, Peker K: Comparison of palpation-versus ultrasound-guided fine-needle aspiration biopsies in the evaluation of thyroid nodules. BMC Res Notes 1:12, 2008.

Carhill A, Litofsky DR, Ain K, et al: Long-term moderate thyroid hormone suppression therapy is associated with improved outcomes in differentiated thyroid carcinoma: National Thyroid Cancer Treatment Cooperative Study Group registry analysis 1987–2012. Thyroid 24(suppl 1): abstract 11, 2014.

Cooper DS, Doherty GM, Haugen BR, et al: Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 19:11671214, 2009.

Dadu R, Devine C, Hernandez M, et al: Survival and efficacy of tyrosine kinase inhibitors after first line sorafenib failure in patients with advanced differentiated thyroid cancer. Oral presentation at the American Thyroid Association 83rd Annual Meeting. San Juan, Puerto Rico, October 2013.

Elisei R, Schlumberger MJ, Muller SP, et al: Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol 31:36393646, 2013.

Falchook GS, Long GV, Kurzrock R, et al: Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: A phase 1 dose-escalation trial. Lancet 379:1893–1901, 2012.

Garsi JP, Schlumberger M, Rubino C, et al: Therapeutic administration of 131-I for differentiated thyroid cancer: Radiation dose to ovaries and outcome of pregnancies. J Nucl Med 49:845–852, 2008.

Gómez K, Varghese J, Jiménez C: Medullary thyroid carcinoma: Molecular signaling pathways and emerging therapies. J Thyroid Res 2011:815826, 2011.

Hall NC, Kloos RT: PET imaging in differentiated thyroid cancer: Where does it fit and how do we use it? Arq Bras Endocrinol Metab 51:793805, 2007.

Ho AL, Grewal RK, Leboeuf R, et al: Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med 368:623632, 2013.

Ho AS, Wang L, Palmer FL, et al: Postoperative nomogram for predicting cancer-specific mortality in medullary thyroid cancer. Ann Surg Oncol 22:2700–2706, 2015.

Jasim S, Ozsari L, Habra MA: Multikinase inhibitors use in differentiated thyroid carcinoma. Biologics 8:281291, 2014.

Kim KB, Cabanillas ME, Lazar AJ, et al: Clinical responses to vemurafenib in patients with metastatic papillary thyroid cancer harboring BRAF mutation. Thyroid 23:12771283, 2013.

Klein Hesselink EN, Klein Hesselink MS, de Bock GH, et al: Long-term cardiovascular mortality in patients with differentiated thyroid carcinoma: An observational study. J Clin Oncol 31:40464053, 2013.

Kloos RT, Eng C, Evans DB, et al: Medullary thyroid cancer: Management guidelines of the American Thyroid Association. Thyroid 19:565612, 2009.

Lassmann M, Reiners C, Luster M: Dosimetry and thyroid cancer: The individual dosage of radioiodine. Endocr Relat Cancer 17:R161–R172, 2010.

Lee JW, Koo BS: The prognostic implication and potential role of BRAF mutation in the decision to perform elective neck dissection for thyroid cancer. Gland Surg 2:206-211, 2013.

Mallick U, Harmer C, Yap B, et al: Ablation with low-dose radioiodine and thyrotropin alfa in thyroid cancer. N Engl J Med 366:16741685, 2012.

Mayson SE, Yoo DC, Gopalakrishnan G: The evolving use of radioiodine therapy in differentiated thyroid cancer. Oncology 88:247256, 2015.

Meadows KM, Amdur RJ, Morris CG, et al: External beam radiotherapy for differentiated thyroid cancer. Am J Otolaryngol 27:2428, 2006.

Pacini F, DeGroot LJ: Thyroid cancer. Published by Endocrine Education, Inc. South Dartmouth, Massachusetts. Last updated March 27, 2013.

Pathak KA, Mazurat A, Lambert P, et al: Prognostic nomograms to predict oncological outcome of thyroid cancers. J Clin Endocrinol Metab 98:4768–4775, 2013.

Rothenberg SM, McFadden DG, Palmer E, et al: Re-differentiation of radioiodine-refractory BRAF V600E-mutant thyroid carcinoma with dabrafenib: A pilot study. J Clin Oncol 31(suppl): abstract 6025, 2013.

Tuttle M: Risk adapted management for thyroid cancer. Endocr Pract 16:764774, 2008.

Schlumberger M, Catargi B, Borget I, et al: Tumeurs de la Thyroïde Refractaires Network for the Essai Stimulation Ablation Equivalence Trial. Strategies of radioiodine ablation in patients with low-risk thyroid cancer. N Engl J Med 366:1663–1673, 2012.

Sawka AM, Lea J, Alshehri B, et al: A systematic review of the gonadal effects of therapeutic radioactive iodine in male thyroid cancer survivors. Clin Endocrinol (Oxf) 68:610–617, 2008.

Schlumberger M, Catargi B, Borget I, et al: Strategies of radioiodine ablation in patients with low-risk thyroid cancer. N Engl J Med 366:1663–1673, 2012.

Schlumberger M, Tahara M, Wirth LJ, et al: Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 372:621–630, 2015.

Sherman SI: Advances in chemotherapy of differentiated epithelial and medullary thyroid cancers. J Clin Endocrinol Metab 94:1493–1499, 2009.

Sherman SI: Targeted therapies for thyroid tumores. Mod Pathol 24(suppl)S44–S52, 2011.

Sherman SI: Tyrosine kinase inhibitors and the thyroid. Best Pract Res Clin Endocrinol Metab 23:713–722, 2009.

Sherman SI, Angelos P, Ball DW, et al: Thyroid carcinoma. J Natl Compr Canc Netw 5:568–621, 2007.

Siegel R, Naishadham D, Jemal A: Cancer statistics, 2014. CA Cancer J Clin 62:10–29, 2012.

Silverberg SJ, Rubin MR, Faiman C, et al: Cincalet hydrochloride reduces the serum calcium concentration in inoperable parathyroid carcinoma. J Clin Endocrinol Metab 92:3803–3808, 2007.

United States Nuclear Regulatory Commission: Medical, industrial, and academic uses of nuclear materials: Regulations, guidance, and communications. Available from:

Urhan M, Dadparvar S, Mavi A, et al: Iodine-123 as a diagnostic imaging agent in differentiated thyroid carcinoma: A comparison with iodine-131 post-treatment scanning and serum thyroglobulin measurement. Eur J Nucl Med Mol Imaging 34:1012–1017, 2007.

Verburg FA, de Keizer B, Lips CJ, et al: Prognostic significance of successful ablation with radioiodine of differentiated thyroid cancer patients. Eur J Endocrinol 152:33–37, 2005.

Vianello F, Mazzarotto R, Mian C, et al: Clinical outcome of low-risk differentiated thyroid cancer patients after radioiodine remnant ablation and recombinant human thyroid-stimulating hormone preparation. Clin Oncol (R Coll Radiol) 24:162168, 2012.

Wells SA Jr, Robinson BG, Gagel RF, et al: Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: A randomized, double-blind phase III trial. J Clin Oncol 30:134141, 2012.

Xing M, Alzahrani AS, Carson KA, et al: Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. JAMA 309:14931501, 2013.

Xing M, Liu R, Bishop J: TERT promoter and BRAF mutations cooperatively promote papillary thyroid cancer-related mortality. Thyroid 24(suppl 1): Short call abstract 1, 2014.

Yang L, Shen W, Sakamoto N: Population-based study evaluating and predicting the probability of death resulting from thyroid cancer and other causes among patients with thyroid cancer. J Clin Oncol 31:468–474, 2013.

Ying AK, Huh W, Bottomley S, et al: Thyroid cancer in young adults. Semin Oncol 36:258–274, 2009.

On Parathyroid Carcinoma

Fang SH, Lal G: Parathyroid cancer. Endocr Pract 17(suppl 1):36–43, 2011.

Karuppiah D, Thanabalasingham G, Shine B, et al: Refractory hypercalcaemia secondary to parathyroid carcinoma: Response to high-dose denosumab. Eur J Endocrinol 171:K1–K5, 2014.

Hu MI, Glezerman I, Leboulleux S, et al: Denosumab for patients with persistent or relapsed hypercalcemia of malignancy despite recent bisphosphonate treatment. J Natl Cancer Inst 105:1417–1420, 2013.

Hu MI, Glezerman I, Leboulleux S, et al: Densosumab for treatment of hypercalcemia of malignancy. J Clin Endocrinol Metab 99:3144–3152, 2014.

Marcocci C, Cetani F, Rubin MR, et al: Parathyroid carcinoma. J Bone Miner Res 23:1869–1880, 2008.

Munson ND, Foote RL, Northcutt RC, et al: Parathyroid carcinoma: Is there a role for adjuvant radiation therapy? Cancer 98:2378–2384, 2003.

Silverberg SJ, Rubin MR, Faiman C, et al: Cinacalcet hydrochloride reduces the serum calcium concentration in inoperable parathyroid carcinoma. J Clin Endocrinol Metab 92:3803–3808, 2007.

Siperstein A, Berber E, Mackey R, et al: Prospective evaluation of sestamibi scan, ultrasonography, and rapid PTH to predict the success of limited exploration of sporadic primary hyperparathyroidism. Surgery 136:872–880, 2004.

Vellanki P, Lange K, Elaraj D, et al: Denosumab for management of parathyroid carcinoma-mediated hypercalcemia. J Clin Endocrinol Metab 99:387–390, 2014.