Understanding Thyroid and Parathyroid Cancers

Endocrine malignancies, although relatively uncommon, are often difficult to diagnose and treat effectively. According to American Cancer Society (ACS) estimates, more than 48,020 new cases of endocrine neoplasms will be diagnosed in the United States in 2011, and approximately 1,740 deaths will result from these cancers. This chapter will focus on thyroid and parathyroid cancers.
Thyroid cancer is the most common endocrine cancer. The number of deaths from thyroid cancer estimated for 2011 is 1,740, or 3.6% of all new thyroid cancer cases.

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.

The prevalence of thyroid nodules in the general population is 4% to 7%, with nodules more common in females than 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. Differentiated (papillary and follicular) thyroid cancers account for > 90% of thyroid malignancies and constitute approximately 0.8% of all human malignancies. Medullary thyroid cancers represent 3% to 5% of all thyroid neoplasms. About 75% of patients with medullary cancer have a sporadic form of the disease; the remaining 25% have inherited disease. Anaplastic carcinoma represents < 3% of all thyroid carcinomas.

Papillary thyroid carcinoma

Papillary thyroid carcinoma is the most common subtype and has an excellent prognosis. Most papillary carcinomas contain varying amounts of follicular tissue. 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 tumors arise from thyroid follicular cells, are unilateral in most cases, and are often multifocal within a single thyroid lobe. They vary in size from microscopic to large cancers that may invade the thyroid capsule and infiltrate into contiguous structures. Papillary tumors tend to invade the lymphatics, but vascular invasion (and hematogeneous 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 for 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 radioactive iodine (which can be used for therapy). Metastases may be appreciated many years after the initial diagnosis.

Follicular tumors, although frequently encapsulated, commonly exhibit 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).

Thyroglobulin, normally synthesized in the follicular epithelium of the thyroid, is present in well-differentiated papillary and follicular carcinomas, infrequently in anaplastic carcinomas, but not in medullary carcinomas. Therefore, thyroglobulin immunoreactivity is considered to be indicative of a follicular epithelial origin.

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 apt to concentrate radioactive iodine.

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 calcitonin secretion, can be clinical features of advanced medullary thyroid carcinoma. On gross examination, most tumors are firm, grayish, and gritty.

Sporadic medullary thyroid carcinoma usually presents as a solitary thyroid mass; 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.

Hereditary medullary thyroid carcinoma typically presents as a bilateral, multifocal process. Histologically, hereditary medullary carcinoma of the thyroid does not differ from the sporadic form. However, the hereditary form is frequently multifocal, and it is common to find areas of C-cell hyperplasia in areas distant from the primary carcinoma. Another characteristic feature of hereditary medullary carcinoma is the presence of amyloid deposits.

There are three hereditary forms: familial medullary thyroid carcinoma; 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 neuromas. These syndromes are associated with germ-line mutations of the RET proto-oncogene, which codes for a receptor tyrosine kinase (RTK). Hereditary medullary thyroid carcinoma is inherited as an autosomal-dominant trait with high penetrance and variable expression. In addition, approximately 40% of sporadic medullary thyroid carcinomas contain somatic RET mutations, which may represent potential therapeutic targets. (For a discussion of genetic testing to screen for RET mutations in MEN kindreds, see section on "Diagnostic workup.")

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 preexisting differentiated thyroid carcinoma or in a preexisting goiter.

Other tumor types

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

EPIDEMIOLOGY

Age and gender

Most patients are between the ages of 25 and 65 years at the time of diagnosis of thyroid carcinoma. Women are affected more often than men (2:1 ratio for the development of both naturally occurring and radiation-induced thyroid cancer).

ETIOLOGY AND RISK FACTORS

Differentiated thyroid cancer

Therapeutic irradiation

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 developing 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 sporadic thyroid cancer.

Non therapeutic radiation exposure

Other factors

Besides radiation-induced thyroid cancer, there are only 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. BRAFmutations so far have only been documented in papillary thyroid carcinoma (45%) and papillary thyroid carcinoma derived anaplastic thyroid carcinoma (25%). Patients with BRAF mutations have higher rates of mortality and are typically less responsive to radioactive iodine therapy. Because of this, BRAF mutations have been implicated as potential prognostic factors and therapeutic targets. In addition, as angiogenesis is critical for survival of tumors, vascular endothelial growth factor (VEGF) expression in PTC correlates with decreased disease-free survival, and presence of BRAF mutation is associated with a higher risk of metastasis and recurrence.

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.

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 of a nodule for specific mutations (BRAF, RAS, RET/PTC, and PAC8/PPAR-gamma) can be useful in the analysis of an indeterminate FNA cytology. Standard molecular testing is not yet recommended.

History

The history is important in the evaluation of thyroid nodules. If there is a history of irradiation to the head and neck, the risk of there being cancer in the nodule is higher (as great as 50%) than in nonirradiated patients (10% to 20% risk).

Age

Age also is important in the evaluation of thyroid nodules. Nodules that occur in either the very young or the very old are more likely to be cancerous, particularly in men.

A new nodule or a nodule that suddenly begins to grow is worrisome as well.

FNA

FNA has become the initial diagnostic test for the evaluation of thyroid nodules. Ultrasound guided FNA can determine whether the lesion is cystic or solid. 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.

In a series of 98 "suspicious" FNAs, 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. Core needle biopsy has been used as an alternative method for diagnosis. Some studies have shown the adequacy of sample may be greater with core biopsy than FNA. However, there are conflicting reports as to whether a core biopsy offers greater accuracy in the diagnosis of a thyroid nodule. Thus, the 2009 guidelines by the American Thyroid Association recommend ultrasound-guided FNA for evaluating thyroid nodules. 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.

Imaging modalities

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

Ultrasonography is now widely considered an essential tool in the assessment of thyroid nodules. The presence of certain features is associated with malignancy and can guide physicians in deciding which nodules should be biopsied. 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, as the likelihood of cancer has been shown to be the same regardless of nodule size.

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 more tall than wide dimensions. No single feature has both high sensitivity and specificity; however, the combination of more than one factor can increase the likelihood of cancer. Other than characterization of thyroid nodules, ultrasonography can guide the FNA biopsy, which increases the diagnostic efficacy of the procedure. Additionally, ultrasonography can identify abnormal cervical lymph nodes, which should prompt a biopsy of the lymph node and possibly an ipsilateral thyroid nodule.

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. "Hot" thyroid nodules (ie, those that concentrate radioiodine) represent functioning nodules, whereas "cold" nodules are nonfunctioning lesions that do not concentrate the isotope. Most thyroid carcinomas occur in cold nodules, but only 10% of cold nodules are carcinomas. It is not necessary to operate on all cold thyroid nodules. Computed tomography (CT) or magnetic resonance imaging (MRI) scans of the neck may be appropriate in some cases.

Calcitonin level

Medullary thyroid carcinomas secrete calcitonin, which is a specific product of the thyroid C cells (parafollicular cells). 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.

Ruling out pheochromocytoma

Medullary thyroid carcinoma can be associated with MEN-2A, MEN-2B, or familial non-MEN. Both the MEN-2A and MEN-2B syndromes are characterized by medullary thyroid cancer and pheochromocytoma. Thus, in any patient with hereditary medullary thyroid carcinoma, 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.

Genetic testing

Germ-line mutations in the RET proto-oncogene are responsible for familial non-MEN medullary thyroid carcinoma, 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 a RET mutation. The 2009 Management Guidelines for the American Thyroid Association regarding MTC recommend that all patients with FNA or calcitonin diagnostic or suspicious for MTC undergo RETmutation analysis, ideally performed with genetics counseling and completed preoperatively. Approximately 95% of patients with a RET mutation will eventually develop medullary carcinoma of the thyroid; 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 recent report of 50 patients (ages 19 years and younger) treated surgically after positive RET mutational analysis, 33 patients 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 to establish the early diagnosis of medullary thyroid carcinoma in those who do not undergo surgery but will not always prevent the development of metastatic medullary thyroid carcinoma.

SCREENING

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

STAGING AND PROGNOSIS

Differentiated thyroid cancers 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  

Recurrence and death following initial treatment of differentiated thyroid cancer can be predicted using a number of risk-classification schemes. The most commonly used systems are the AMES (age, metastases, extent, and size) and AGES (age, grade, extent, and size) classifications.

Low-risk patients are generally those < 45 years of age with low-grade nonmetastatic tumors that are confined to the thyroid gland and are < 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 old with a high-grade, metastatic, locally invasive tumor in the neck or with a large tumor. Large size is defined by some authors as > 1 cm and by others as > 2 or > 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 ~85%.

Medullary thyroid carcinoma

Medullary thyroid carcinoma is associated with an overall 10-year survival rate of 40% to 60%. When medullary carcinoma is discovered prior to becoming 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 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), the long-term survival rate 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 of patients with MTC by Barbet et al, those with a calcitonin doubling time of < 6 months had a survival of 25% at 5 years and 8% at 10 years vs 100% survival among patients with a calcitonin doubling time of > 2 years. The 2009 American Thyroid Association (ATA) management guidelines for MTC recommend monitoring of doubling time of CEA and calcitonin. Frequency of surveillance has been recommended based on the doubling time calculation for CT and CEA. Patients with calcitonin or CEA doubling times of greater than 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 with doubling time of less than 2 years should be considered for treatment.

source:- cancernetwork