Thyroid cancer

— Evaluation and Management of the Solitary Thyroid Nodule

— Anaplastic Carcinoma and Other Thyroid Carcinomas

The key to the workup of the solitary thyroid nodule is to differentiate malignant from benign disease and, thus, to determine which patients require intervention and which patients may be monitored serially. History taking, physical examination, laboratory evaluation, and fine-needle aspiration biopsy (FNAB) are the mainstays in the evaluation of thyroid nodules. Imaging studies can be adjuncts in select cases.

Fine-needle aspiration biopsy

FNAB is the most important diagnostic tool in evaluating thyroid nodules and should be the first intervention. The technique is inexpensive and easy to perform, and it causes few complications.

To perform FNAB, comfortably position both the patient and the physician. Extend the patient’s neck slightly and palpate the nodule with the nondominant hand. Clean the skin with alcohol and infiltrate the area with local anesthesia. Place a 21- to 25-gauge needle on the end of a syringe. Many physicians use trigger-style aspirating handles on the syringe. Introduce 2 mL of air into the syringe, and place the needle into the skin. Apply negative pressure to the syringe, and pass the needle through the nodule, which is identified by using the nondominant hand. After several passes, release the negative pressure, and withdraw the needle. Use the air remaining in the syringe to expel the specimen from the hub and needle onto a glass slide or into cytologic solution for a cell block. Fix the slide in alcohol for Papanicolaou and hematoxylin-eosin staining. Some slides can be air dried and stained with Romanowsky stain (Diff-Quick).

Successful diagnosis by the cytologist depends on accurate sampling of the nodule and specimen cellularity. For this reason, several authors recommend performing at least 3 aspirations to ensure adequacy of the specimen and to minimize false-negative results. Ultrasonographic guidance can help to increase the accuracy of FNAB. Danese et al report increased false-negative rates with palpation FNAB compared with ultrasonography-guided FNAB.

The 4 results from FNAB are benign disease, malignant disease, indeterminate for diagnosis, and nondiagnostic. In their review of several large series, Gharib and Goellner (1993) found that 69% of FNAB results were benign, 4% were malignant, 10% were indeterminate, and 17% were nondiagnostic. Their false-positive rate was 2.9%, and their false-negative rate was 5.2%. Sensitivity and specificity were 83% and 92%, respectively.

Results of FNAB determine the next step in managing the thyroid nodule. A definitive diagnosis is obtained in as many as 50% of repeated biopsies. Patients whose findings are nondiagnostic despite repeat biopsy can undergo surgery for lobectomy for tissue diagnosis, or they can be monitored clinically. In these circumstances, radioiodine scans can be useful for determining the functional status of the nodule, as most hyperfunctioning nodules are benign.

Indeterminate biopsy findings are labeled suspicious at some institutions. When cellular material is adequate for evaluation but when malignant and benign disease cannot be differentiated, biopsy results can be labeled suspicious. Patients with a suspicious diagnosis should undergo lobectomy for definitive diagnosis.

Malignant diagnoses require surgical intervention. Papillary thyroid carcinoma and MTC are often positively identified on the basis of FNAB results alone. In patients with these carcinomas, definitive surgical planning can be undertaken at the outset. However, it is nearly impossible to distinguish a follicular adenoma from a follicular carcinoma on the basis of FNAB findings. Patients with follicular neoplasm, as determined with FNAB results, should undergo surgery for thyroid lobectomy for tissue diagnosis. These patients require complete thyroidectomy if a malignancy is discovered on review of the pathology. Some controversy exists regarding the extent of thyroidectomy (total thyroidectomy, subtotal thyroidectomy, or lobectomy) for a particular pathologic diagnosis. Each pathologic diagnosis and its corresponding extent of thyroidectomy are discussed below.

Complications of FNAB are few and generally minor. The most common complications are minor hematoma, ecchymosis, and local discomfort. Clinically significant hematoma and swelling is exceedingly rare. Inadvertent puncture of the trachea, carotid artery, or jugular vein usually does not cause clinically significant problems and is managed with the application of local pressure.

Laboratory evaluation

The serum thyroid-stimulating hormone (TSH) concentration is a highly sensitive measure for hyperthyroidism or hypothyroidism. A sensitive TSH assay is useful in the evaluation of solitary thyroid nodules. A low serum TSH value suggests an autonomously functioning nodule, which typically is benign. However, malignant disease cannot be ruled out on the basis of low or high TSH levels.

Other thyroid function tests are usually not necessary in the initial workup. Serum thyroglobulin measurements are not helpful diagnostically because they are elevated in most benign thyroid conditions.

Elevated serum calcitonin levels are highly suggestive of MTC. Serum calcitonin measurement, which was once the mainstay in the diagnosis of FMTC, has been replaced by sensitive polymerase chain reaction (PCR) assays for germline mutations in the RET proto-oncogene. These mutations are present in patients with MEN 2A, MEN 2B, and FMTC (see Genetic testing for MEN and FMTC in the Medullary Thyroid Carcinoma section). However, calcitonin and the more sensitive pentagastrin-stimulated calcitonin are used as tumor markers to monitor patients who have been treated for MTC. Because of the low incidence of MTC overall, testing of serum calcitonin is not a cost-effective screening tool in the primary workup of thyroid nodules.

Imaging procedures

Ultrasonography is the imaging modality most commonly used to evaluate thyroid disease. This noninvasive study enables accurate evaluation of the thyroid gland. However, the usefulness of ultrasonography for distinguish between malignant and benign nodules is limited. Simple cysts found on sonograms are benign, but simple cysts are rarely found. Cysts are most commonly complex, with at least some solid component that could potentially harbor malignancy. Microcalcifications noted on sonograms are associated with thyroid malignancy. Ultrasonography is highly sensitive for thyroid nodules and can depict nodules only a few millimeters in size.

A sonogram ordered to evaluate a solitary nodule often reveals additional nodules of questionable clinical significance. The accuracy of FNAB results increases when sonographic guidance is used. Use of ultrasonography-guided FNAB can be useful for biopsy of small or difficult-to-palpate thyroid nodules as well as for FNAB of nodules in children. Ultrasonography can also be useful for accurate measurement of thyroid nodules that are being monitored serially.

Radioiodine imaging can help in determining the functional status of a nodule. Nonfunctional nodules do not take up radiolabeled iodine-123 and appear as cold spots in the thyroid (cold nodules). Hyperfunctioning nodules take up radioiodine and appear as hot spots (hot nodules). Warm nodules appear similar to the surrounding normal thyroid tissue. Hot or warm nodules were historically thought to be benign; therefore, they did not require further evaluation for malignancy. However, in a review of 5000 patients undergoing thyroidectomy regardless of radioimaging findings, Ashcraft and Van Herle (1981) found that 4% of hot nodules harbored malignancy.

Carcinoma cannot be excluded on the basis of radioiodine scans. Therefore, radioiodine scans are usually not helpful for the routine evaluation of thyroid nodules. In select situations, radioiodine studies can be diagnostic adjuncts. When results of repeated FNAB of a nodule are nondiagnostic, a radioiodine imaging can help in directing management if a hot nodule is to be monitored clinically.

CT scanning and MRI can be used to evaluate soft-tissue extension of large or suspicious thyroid masses into the neck, trachea, or esophagus and to assess metastases to the cervical lymph nodes. These studies do not have a role in the routine management of solitary thyroid nodules. The use of iodinated contrast agents should be avoided in patients with possible thyroid carcinoma because they interfere with the postoperative use of radioactive iodine.

WELL-DIFFERENTIATED THYROID CARCINOMA

— Evaluation and Management of the Solitary Thyroid Nodule

— Anaplastic Carcinoma and Other Thyroid Carcinomas

Papillary carcinoma

Clinical features

Papillary carcinoma is the most common thyroid malignancy, representing approximately 80%. Papillary carcinoma and follicular carcinoma make up the well-differentiated thyroid carcinomas. Women develop papillary cancer 3 times more frequently than men do, and the mean age at presentation is 34-40 years.

Cases can occur familially, either alone or in association with Gardner syndrome (familial adenomatous polyposis). As noted above, radiation exposure, especially during childhood, is associated with the development of papillary thyroid carcinoma. Tumors typically appear after a latency period of about 10-20 years. In addition, an increased incidence of papillary cancer is hypothesized among patients with Hashimoto thyroiditis (chronic lymphocytic thyroiditis). Despite this possibility, the rate of malignancy for a given nodule in people with Hashimoto thyroiditis is similar to that of individuals with a normal gland.

Papillary carcinoma is a slow-growing tumor that arises from the thyroxine (T4)- and thyroglobulin-producing follicular cells of the thyroid. The cells are TSH sensitive and take up iodine. They produce thyroglobulin in response to TSH stimulation. This feature has both diagnostic and therapeutic value for managing residual disease and recurrences after surgical excision (see Treatment and Prognosis below).

Pathology

On gross pathologic examination, papillary carcinomas are whitish invasive neoplasms with ill-defined margins. Under microscopy, the tumors are unencapsulated neoplasms that characteristically grow with papillae consisting of neoplastic epithelium overlying fibrovascular stalks. Very differentiated tumors can have a complex arborizing pattern. Nuclei have an empty ground-glass appearance with characteristic nuclear grooves and pseudoinclusions. Mitoses are rare.

Another histologic feature is the presence of psammoma bodies, which occur in 50% of papillary carcinomas. Psammoma bodies are calcific concretions that have a circular laminated appearance. They are found in the stroma of the tumor. In addition, many papillary carcinomas contain areas that show a follicular growth pattern. However, when the nuclear features in follicular areas are the same as those in papillary areas, the tumor behaves like a classic papillary carcinoma and should be designated as such. Papillary carcinoma may be multicentric, with foci present in both the ipsilateral and contralateral lobes.

Local invasion

Tumors can grow directly through the thyroid capsule to invade surrounding structures. Growth into the trachea can occur, producing hemoptysis. Extensive involvement can cause airway obstruction. The recurrent laryngeal nerves can become involved because of their proximity in the tracheoesophageal groove. Patients present with a hoarse, breathy voice and, occasionally, dysphagia.

Regional and metastatic disease

Another common feature of papillary carcinoma is its propensity to spread to the cervical lymph nodes. Clinically evident lymph node metastases are present in approximately one third of patients at presentation. Microscopic metastases are present in one half. The most common site of lymph node involvement is in the central compartment (level 6) located medial to the carotid sheaths on both sides, with extension from the hyoid bone superiorly to the sternal notch inferiorly. The jugular lymph node chains (levels 2-4) are the next most common sites of cervical node involvement. Lymph nodes in the posterior triangle of the neck (level 5) may also develop metastases. This finding has important implications on the treatment algorithm for patients in this situation (see Treatment and Prognosis below and Images 1-2).

Approximately 5-10% of patients develop distant metastases. Distant spread of papillary carcinoma typically affects the lungs and bone.

Follicular carcinoma

Clinical features

Follicular carcinoma is the second most common thyroid malignancy and represents about 10% of thyroid cancers. Follicular carcinoma represents an increased portion of thyroid cancers in regions where dietary intake of iodine is low. Similar to papillary carcinoma, follicular carcinoma occurs 3 times more frequently in women than in men. Patients with follicular carcinoma are typically older than those with papillary carcinoma at presents. The mean age range at diagnosis is late in the fourth to sixth decades.

Like papillary carcinomas, follicular carcinomas arise from the follicular cells of the thyroid. The neoplastic cells are TSH sensitive as well, taking up iodine and producing thyroglobulin—a feature that is exploited diagnostically and therapeutically (see Postoperative radioiodine scanning and ablation below).

Pathology

On gross pathology, the tumors appear as round, encapsulated, light brown neoplasms. Fibrosis, hemorrhage, and cystic changes are found in the lesions. Under microscopy, the tumors contain neoplastic follicular cells, which overall can have a solid, trabecular, or follicular growth pattern (that usually produces microfollicles). The follicular cells in these tumors do not have characteristic features like papillary carcinoma cells.

Follicular carcinomas are differentiated from benign follicular adenomas by tumor capsule invasion and/or vascular invasion. For this reason, differentiating follicular adenomas from follicular carcinomas is extremely difficult with FNAB cytology and frozen section analysis. The tumors are divided into minimally invasive and widely invasive lesions depending on the histologic evidence of capsule and vascular invasion. Immunohistochemical staining for thyroglobulin and cytokeratins is nearly always positive.

Local invasion

Local invasion can occur as it does with papillary carcinoma, with the same presenting features (see Local invasion for Papillary Carcinoma, above).

Cervical and distant metastases

Unlike papillary carcinoma, cervical metastases from follicular carcinomas are uncommon. However, the rate of distant metastasis is significantly increased (approximately 20%). Lung and bone are the most common sites.

Treatment and prognosis

Surgical treatment

The extent of surgical therapy for well-differentiated neoplasms is controversial. Primary treatment for papillary and follicular carcinoma is surgical excision whenever possible. Total thyroidectomy has been the mainstay for treating well-differentiated thyroid carcinoma. In this procedure, all apparent thyroid tissue is surgically removed. Major complications in this procedure are recurrent laryngeal nerve injury and hypoparathyroidism from inadvertent damage or removal of the parathyroid glands. Complications associated with total thyroidectomy are discussed in the Technique of Thyroidectomy section below.

After total thyroidectomy, patients undergo radioiodine scanning to detect regional or distant metastatic disease (see Postoperative radioiodine scanning and ablation below), followed by radioablation of any residual disease found.

Over the years, modifications to total thyroidectomy have been proposed in an effort to reduce recurrent laryngeal nerve injury and hypoparathyroidism associated with total thyroidectomy. Subtotal thyroidectomy has been proffered as an alternative to total thyroidectomy. With subtotal thyroidectomy, a small portion of gross thyroid tissue opposite the side of malignancy is left in place to minimize the risk of injuring the recurrent laryngeal nerve and of inadvertently removing the parathyroid glands on that side. Patients usually receive postoperative radioiodine treatment in an attempt to ablate the remaining thyroid tissue.

With improved stratification of patients into prognostic groups (see Prognostic factors below), some surgeons have proposed thyroid lobectomy with isthmectomy alone as definitive treatment for patients at low risk for recurrent or metastatic disease. This approach remains to be substantiated as a feasible alternative to total thyroidectomy.

Management of the neck

The neck must be thoroughly examined for lymphatic metastases. Ultrasonography of the neck with particular attention to the central compartment (level 6) is an effective diagnostic approach. FNAB of suspicious lymph nodes can be performed. Cervical metastases discovered preoperatively or intraoperatively should be removed by means of en bloc lymphatic dissection of the respective cervical compartment (selective neck dissection) while sparing the nonlymphatic structures. Excision of single nodes, known as berry picking, is inadequate therapy for metastatic disease. Elective neck dissection (removal of clinically benign neck lymphatic tissue) in a well-differentiated carcinoma is not indicated because postoperative radioiodine treatment effectively treats microscopic lymphatic metastases.

Postoperative radioiodine scanning and ablation

Because differentiated thyroid tissue and well-differentiated thyroid carcinomas are TSH sensitive and because they take up iodine, radioiodine preferentially targets residual normal or malignant tissue after thyroidectomy. Therefore, radioiodine can be given in diagnostic doses to detect residual normal or neoplastic tissue in the body and in therapeutic doses to ablate this tissue. After thyroidectomy, use of radioiodine scanning and ablation has become commonplace for diagnosing and treating residual thyroid tissue, as well as regional and distant metastases from well-differentiated thyroid carcinomas. Pretherapeutic iodine-uptake scanning is controversial because of its cost and because of concerns about ¹³¹I-induced tumor stunning, which may decrease the effectiveness of radioiodine treatment.

After thyroidectomy, patients are given thyroid replacement therapy with T4 (Synthroid) or triiodothyronine (T3, Cytomel). ¹³¹I or ¹²³I scanning is performed when the patient is in a hypothyroid state (TSH >30-50). Approximately 4-6 weeks after thyroidectomy, hypothyroid can be induced by discontinuing replacement (T4 for 4 weeks or T3 for 2 weeks) to obtain high serum TSH levels. A diagnostic dose of ¹³¹I or ¹²³I is given initially. Whole-body scanning is performed to detect any tissue taking up radioiodine. If any normal thyroid remnant or metastatic disease is detected, a therapeutic dose of ¹³¹I is administered to ablate the tissue. Posttreatment scanning should also be performed because it may reveal metastatic disease not otherwise noted.

The role of recombinant human TSH (Thyrogen) in remnant ablation continues to evolve. Thyrogen is approved for postsurgical remnant ablation in Europe but not the United States. Barbaro et al found equivalent results in postsurgical remnant ablation when they compared traditional T4 withdrawal with the discontinuation of T4 1 day before TSH stimulation. Thyrogen stimulation avoids the discomfort of patients having to discontinue thyroid replacement and is especially useful in those unable to tolerate hypothyroidism or to generate a high TSH level.

If a treatment dose of ¹³¹I is required, diagnostic thyroid scanning is repeated while the patient is in the hypothyroid state about 6 months after initial treatment. Again, if the diagnostic scan is positive, an additional therapeutic dose is given. This process is repeated until the diagnostic scan is negative.

A promising new development for follow-up thyroid scanning is the use of recombinant human TSH as opposed to withdrawing T4 to increase autogenous TSH levels. This approach avoids the discomfort of having to discontinue thyroid replacement therapy for these scans.

Thyroid suppression

After thyroidectomy and radioiodine ablation, patients with well-differentiated thyroid carcinoma are maintained on thyroid-suppression suppression. Patients take T4 in daily doses sufficient to suppress TSH production by the pituitary. Low TSH levels in the bloodstream reduce tumoral growth rates and reduce recurrence rates of well-differentiated thyroid carcinomas. The extent to which TSH should be suppressed is controversial. Most authors recommend reducing TSH levels to 0.1 mU/L. This level provides adequate thyroid suppression while avoiding deleterious cardiac and bone effects of profound thyroid suppression.

Follow-up care

Patients are regularly monitored every 6-12 months with serial radioiodine scanning and serum thyroglobulin measurements after surgery and radioiodine therapy. Thyroglobulin is a useful marker of tumor recurrence because well-differentiated thyroid cancers synthesize thyroglobulin. However, it is useful only after total thyroid ablation. Serum thyroglobulin is measured at the time of follow-up thyroid scanning, during the withdrawal of thyroid hormone or the administration of recombinant TSH. Serum antithyroglobulin antibodies are measured in addition to thyroglobulin because their presence invalidates the assay. Thyroglobulin antibody levels should be obtained with each thyroglobulin measurement. Rising thyroglobulin level after thyroid ablation suggests recurrence. Ultrasonography of the neck can also be used to detect regional recurrences.

Management of recurrence

Recurrences are best treated with surgical excision if the disease is clinically evident and surgically accessible. Nonlocalized recurrences detected on the basis of elevated thyroglobulin levels are treated with ¹³¹I. On occasion, recurrent tumors do not concentrate iodine. Positron emission tomography (PET) may be helpful in localizing disease in such circumstances. When surgical excision of recurrent disease is not feasible, external-beam radiation therapy may be useful. Chemotherapy, usually with doxorubicin, is reserved for tumors that do no respond to other treatments and for palliative care. Response rates of 35-40% are reported, though complete responses to chemotherapy are rare.

Prognostic factors

The long-term disease-free survival with aggressive treatment and management is nearly 90% overall. A variety of factors are associated with prognosis, as listed below.

— Age: The patient’s age at diagnosis is one of the most important prognostic features of well-differentiated thyroid carcinoma. Cancer-related death is most likely to occur if the patient is >40 years at the time of diagnosis. Recurrences are most common in patients whose disease is diagnosed when they were <20 years or >60 years.

— Sex: Men are twice as likely as women to die from thyroid cancer.

— Size: The size of the primary tumor is related to survival. Patients with primary tumors >4 cm have increased recurrence and cancer-related mortality rates.

— Histology: Overall, papillary carcinoma is associated a 30-year cancer-related death rate of 6%. Follicular carcinoma has a 30-year cancer-related death rate of 15%.

— Local invasion: Invasion of surrounding tissues outside of thyroid indicates biologic aggressiveness and significantly worsens the patient’s prognosis.

— Lymph node metastasis: Lymph node metastasis does not appear to be as important in the outcome of well-differentiated thyroid carcinomas as in the outcome of most other solid tumors.

— Distant metastasis: Distant metastasis at initial examination is associated with a 68.1-fold increase in the rate of disease-specific death.

H&UUML;RTHLE CELL CARCINOMAS

— Evaluation and Management of the Solitary Thyroid Nodule

— Anaplastic Carcinoma and Other Thyroid Carcinomas

Clinical features

Hürthle cell carcinoma is a rare thyroid malignancy that is often considered a variant of follicular carcinoma. Also known as oncocytic carcinoma, Hürthle cell carcinoma has unique biologic features. About 75-100% of the tumor is composed of Hürthle cells, which are also known as oxyphilic, oncocytic, Askanazy, or large cells. These are large, polygonal follicular cells that contain abundant granular acidophilic cytoplasm. Hürthle cells can be found in a variety of benign thyroid conditions, such as Hashimoto thyroiditis, Graves disease, and multinodular goiter. Benign neoplasms, called Hürthle cell adenomas, that contain more than 75% Hürthle cells can also occur.

Hürthle cell carcinomas account for 2-3% of all thyroid malignancies. They occur more commonly in women than in men and typically manifest in the fifth decade of life. The clinical presentation is similar to that of other thyroid malignancies.

Pathology

On pathologic examination, Hürthle cell carcinoma, like follicular carcinoma, is differentiated from Hürthle cell adenoma by the presence of capsular invasion, vascular invasion, or both. On gross evaluation, Hürthle cell carcinomas appear brown and solid. Most have an appreciable capsule. Under microscopy, the tumors have a solid or trabecular growth pattern of large, granular, polygonal Hürthle cells.

Because malignant tumors are difficult to identify on the basis of cellular elements alone, Hürthle cell tumors identified on FNAB findings cannot be categorized as malignant or benign. Therefore, when FNAB results suggest a Hürthle cell neoplasm, a surgically obtained specimen is required.

Management

Hürthle cell carcinomas behave aggressively. Patients with these lesions are at high risk for recurrent and metastatic disease. These tumors most often do not take up radioactive iodine, thereby removing the diagnostic and therapeutic benefits that papillary and follicular carcinomas have. Most surgeons advocate an aggressive approach to treating these tumors. Patients with a diagnosis of Hürthle cell neoplasm based on FNAB findings undergo lobectomy and isthmectomy. If, the final pathologic result confirm Hürthle cell carcinoma, patients return to surgery for completion thyroidectomy. For tumors >5 cm or for palpable lymphatic metastases, total thyroidectomy (including neck dissection for palpable lymph nodes) is often performed during the initial operation.

Prognosis

Patients with Hürthle cell carcinoma should be monitored closely for recurrent and metastatic disease. The overall 5-year survival rate is 50-60%. Because tumors do not take up iodine and are not TSH sensitive, thyroid suppression and radioiodine therapy have little value. External-beam radiation therapy can used to treat metastatic disease. Surgery is the mainstay of treatment.

MEDULLARY THYROID CARCINOMA

— Evaluation and Management of the Solitary Thyroid Nodule

— Anaplastic Carcinoma and Other Thyroid Carcinomas

Clinical features

MTCs represent approximately 5% of all thyroid malignancies. A slight female preponderance is observed. Tumors arise from the parafollicular C cells of the thyroid gland. C cells are neural-crest derivatives and produce calcitonin. About 75% of MTCs occur sporadically, and 25% occur familially. Familial cases are commonly multifocal throughout the thyroid gland, whereas sporadic cases are usually not multifocal.

Patients may present with clinical evidence of MTC, or they may present before MTCs develop if they are from a family with known FMTC syndrome. New germline mutations can also occur. Patients with new germline mutations present with MTCs without a positive family history, but they are at risk for passing on the syndrome.

The FMTC syndromes consist of MEN 2A, MEN 2B, and FMTC. They are inherited in an autosomal dominant fashion. Children inheriting an FMTC syndrome have a 100% risk of developing MTC.

MEN 2A (Sipple syndrome) consists of MTC, pheochromocytoma (in 50% of patients), and hyperparathyroidism (10-20% of patients). MEN 2B consists of MTC, pheochromocytoma (in 50% of patients), marfanoid habitus, and ganglioneuromatosis. FMTC consists of MTC alone. MTC in MEN 2B has the most aggressive biologic features. In this situation, MTC usually develops by the age of 10 years, and it has a high propensity for rapid growth and metastasis. MTC in MEN 2A can appear in the first decade of life, and it almost always develops by the second decade. MTC in FMTC usually develops during adulthood.

Diagnosis of sporadic cases

Sporadic cases typically manifest with painless solitary thyroid nodules, like other thyroid malignancies do. Likewise, symptoms of pain, dysphagia, and hoarseness can develop with local invasion.

Genetic testing for MEN and FMTC

Genetic testing is now the mainstay in the diagnosis of the FMTC syndromes. RET proto-oncogene mutations (on chromosome arm 10q) have been discovered in each of the MTC syndromes. The RET proto-oncogene is a receptor tyrosine kinase whose exact function and role in these syndromes has not been elucidated. Patients with MEN 2A have germline RET mutations resulting in substitutions of conserved cysteine residues in exons 10 and 11. All patients with MEN 2B have a germline mutation resulting in a threonine-for-methionine substitution in codon 918 of exon 16. Mutations are described in exons 13 and 14 in patients with FMTC.

Genetic screening with sensitive PCR assays for germline RET mutations is routinely performed in at-risk patients. Children of parents known to have MEN or FMTC are tested for RET mutations to guide therapy and future genetic counseling. In addition, patients presenting with sporadic MTC should undergo RET mutational analysis to rule out new spontaneous germline mutations, which should prompt the testing of offspring for similar mutations.

Biochemical testing for MTC

Because MTC cells produce calcitonin, elevated serum calcitonin levels are diagnostic of MTC. Although routine measurement of serum calcitonin has low yield in managing the solitary thyroid nodule because of the uncommon nature of MTCs, it is useful in the surveillance of patients with a history of MTC and in managing familial forms. Stimulating calcitonin release by using intravenous pentagastrin increases the sensitivity of the test. For pentagastrin-stimulated calcitonin evaluation, a baseline plasma calcitonin level is measured, followed by the intravenous administration of pentagastrin 0.5 mg/kg and serial measurements of calcitonin 1.5 and 5 minutes after injection. Elevated basal or stimulated calcitonin levels above the normal range for the laboratory strongly suggest MTC.

Plasma calcitonin levels are commonly increased before clinical evidence of MTC appears. Although this finding was once the mainstay in diagnosing familial forms of MTC, results of genetic testing have largely supplanted it. Plasma calcitonin testing is now used for the early detection of MTC in patients already known to be at risk for MTC because of their family history and genetic results. This level is most commonly used as a tumor marker to identify residual and metastatic disease after thyroidectomy to treat MTC.

Pathology

On gross examination, MTCs are fairly well circumscribed, though they are unencapsulated. They are typically tannish pink and often contain yellow granular regions, which represent focal calcification. Most tumors arise in the middle and upper third of the thyroid lobes, commensurate with the location of the parafollicular C cells in the thyroid gland. Sporadic tumors are unilateral, and inherited forms usually involve both thyroid lobes.

MTCs can have a varied microscopic appearance. The tumors typically have a lobular, trabecular, insular, or sheetlike growth pattern. Some tumors have a fibrotic character. Malignant cells may appear round, polygonal, or spindle shaped. The cytoplasm is eosinophilic and finely granular. In the stroma, characteristic deposits of amyloid are commonly observed. This amyloid has typical green birefringence on Congo red staining, and this is a feature unique to MTC among thyroid malignancies. Immunohistochemical stains for calcitonin and carcinoembryonic antigen are microscopically useful for differentiating MTC from other tumors.

A unique feature to the familial cases of MTC is the finding of C-cell hyperplasia, which can help in distinguishing familial cases from sporadic ones. C-cell hyperplasia is considered a precursor to MTC and is usually adjacent to foci of MTC. The finding of C-cell hyperplasia with MTC should raise the suspicion for familial disease.

Treatment

Both sporadic MTCs and FMTCs are treated with total thyroidectomy and lymphatic dissection of the anterior compartment of the neck (level VI). If the vasculature of the parathyroid gland is disrupted, autotransplantation of the parathyroid gland into the sternocleidomastoid muscle or the nondominant forearm is performed.

Metastasis to the cervical lymph nodes is common in patients with MTC, particularly those with familial forms with multicentricity and bilaterality of the primary tumor. Lymph node metastases can occur in more than 50% of patients. Both before and at the time of surgery, the lateral jugular lymphatics should carefully be palpated for evidence of metastatic disease. Selective neck dissection (sparing nonlymphatic structures when possible) of levels II, III, IV, and V is performed when metastases are clinically evident.

Prophylactic thyroidectomy in patients with MEN 2A and MEN 2B

MTC is the most common cause of mortality in patients with MEN 2A and MEN 2B, and many patients who inherit these syndromes develop MTC in the first decade of life. Therefore, prophylactic thyroidectomy and central-compartment lymph-node dissection is being performed in children with these syndromes. Surgery is offered to patients when the diagnosis is made on the basis of RET mutational analysis. Children with RET mutations whose parents decline surgery should be monitored with annual measurement of calcitonin levels. Thyroidectomy is performed when results are abnormal.

Follow-up care

After receiving treatment for MTC, patients are monitored with annual measurement of serum calcitonin levels for surveillance. Pentagastrin-stimulated calcitonin testing is no longer widely available. Carcinoembryonic antigen is another tumoral marker associated with the recurrence of MTC, and it may also be used for surveillance. Patients with elevated levels of calcitonin or carcinoembryonic antigen are evaluated for recurrent disease. Neck, abdominal, and pelvic CT or MRI may used to detect disease if metastasis or recurrence is suspected. Ultrasonography may be useful to localize cervical disease. In addition, radionuclide studies and selective venous catheterization with sampling of calcitonin levels can be performed to localize recurrences. The role of PET is evolving.

Radiation therapy is used in an adjuvant setting at some centers, and it can be used to treat patients with surgically inoperable recurrences and metastases. Because MTC does not concentrate iodine, radioiodine therapy has no role in follow-up care or treatment.

A variety of chemotherapeutic regimens have been used to treat metastatic disease. MTC is relatively insensitive to chemotherapy, though partial responses have been obtained. To date, the most effective combination is dacarbazine, vincristine, and cyclophosphamide. Adding doxorubicin to this regimen, some investigators have gained a partial response rate of about 35%.

Prognosis

The overall prognosis for patients with MTC is worse than that of patients with well-differentiated carcinoma. The reported 10-year survival rate is 65% overall. Young age, small primary tumor, low stage of disease, and completeness of initial resection improve survival. Patients with MEN 2B have a prognosis substantially worse than that of patients with MEN 2A, though the prognosis for both groups has improved with early diagnosis and intervention.

ANAPLASTIC CARCINOMA AND OTHER THYROID CARCINOMAS

— Evaluation and Management of the Solitary Thyroid Nodule

— Anaplastic Carcinoma and Other Thyroid Carcinomas