Anaplastic thyroid carcinoma

INTRODUCTION — Anaplastic thyroid carcinomas are undifferentiated tumors of the thyroid follicular epithelium. In marked contrast to differentiated thyroid carcinomas, anaplastic carcinomas are extremely aggressive, with a disease-specific mortality approaching 100 percent. Early recognition of the disease is essential to allow prompt initiation of therapy.

The major clinical issues related to anaplastic thyroid carcinoma will be reviewed here. The molecular pathogenesis of this disorder, and detailed information on chemotherapy are discussed separately.

EPIDEMIOLOGY — The age-adjusted annual incidence of anaplastic carcinoma is about two per million persons], and accounts for only 2 to 5 percent of all thyroid cancers. Patients with anaplastic carcinoma are older than those with differentiated carcinoma; the mean age at diagnosis is 65 years, and fewer than 10 percent are younger than 50 years. Sixty to 70 percent of tumors occur in women

ANTECEDENT THYROID DISEASE — Approximately 20 percent of patients with anaplastic thyroid cancer have a history of differentiated thyroid carcinoma, and 20 to 30 percent have a coexisting differentiated carcinoma; the percentage may be even higher with extensive sectioning of the thyroid gland. The majority of synchronous thyroid tumors are papillary carcinomas, but coexisting follicular carcinomas have also been reported. Nearly 10 percent of patients with Hürthle-cell carcinomas have foci of anaplastic carcinoma within the Hürthle-cell carcinoma.  In addition, transformation from differentiated to anaplastic carcinoma has been described in a patient who was followed with serial biopsies.

These findings lend support to the hypothesis that anaplastic carcinoma develops from more differentiated tumors as a result of one or more dedifferentiating events, possibly loss of the p53 tumor suppressor protein, 16p loss   or BRAF activating mutations

Up to one-half of patients have a history of multinodular goiter, and some have a history of partial thyroidectomy for goiter.

DISEASE PRESENTATION — Nearly all patients with anaplastic carcinoma present with a thyroid mass. However, regional or distant spread is apparent at the time of initial diagnosis in 90 percent of cases . Sites of regional involvement can include the perithyroidal fat and muscle, lymph nodes, larynx, trachea, esophagus, tonsil, and great vessels of the neck and mediastinum. Distant metastases are found at initial disease presentation in 15 to 50 percent of patients

  • The lungs are the most common site of distant metastases, being involved in up to 90 percent of patients with distant disease. These metastases are usually intrapulmonary mass lesions, but pleural involvement can occur.
  • Approximately 5 to 15 percent of patients have bone metastases.
  • Five percent have brain metastases, and a few have metastases to the skin, liver, kidneys, pancreas, heart, and adrenal glands
  • Rare patients have no detectable thyroid tumor at the time of diagnosis, presenting with metastatic disease

CLINICAL MANIFESTATIONS — The primary symptom of anaplastic carcinoma is a rapidly enlarging neck mass, occurring in about 85 percent of patients. The enlarging thyroid tumor may cause neck pain and tenderness, and compression (or invasion) of the upper aerodigestive tract, resulting in dyspnea (about 35 percent of patients), dysphagia (30 percent), hoarseness (25 percent), cough (and sometimes hemoptysis) (25 percent). Less common symptoms are chest pain, bone pain, headache, confusion, or abdominal pain from metastases

Constitutional symptoms can occur, including anorexia, weight loss, fatigue and fever of unknown origin]. Rarely, rapid growth of the tumor within the thyroid causes thyroiditis, with symptoms of hyperthyroidism and more severe neck pain and tenderness

Signs — On physical examination, most patients have bilateral but asymmetric thyroid enlargement. The goiter is typically hard and nodular, and may be tender. A dominant nodule is often present. Some nodules may be softer and fluctuant, indicating focal tumor necrosis

A few patients have a solitary nodule or a diffuse non-nodular goiter. The goiter is often fixed to the surrounding structures and does not move with swallowing. By the time of presentation, the primary tumor is usually greater than 5 cm in diameter, but exact measurements are often difficult because the borders of the tumor are indistinct.

Approximately 50 percent of patients have enlarged cervical lymph nodes. Other findings of local extension of the disease include stridor, tracheal deviation, and vocal cord paralysis due to compression or invasion of the trachea; and venous dilatation and superior vena cava syndrome due to retrosternal tumor growth.

The skin overlying the tumor may be erythematous, or even ulcerated, and there may be metastases in the skin of the chest and abdomen. Focal neurologic symptoms or signs suggesting brain metastases may also be present.

DIAGNOSIS — The diagnosis of anaplastic carcinoma is usually established by cytologic examination of cells obtained by fine-needle aspiration biopsy or of tissue obtained by large-needle or surgical biopsy.

Most patients have normal serum thyroid hormone and thyrotropin (TSH) concentrations, except for those few patients with tumor-related thyroiditis and hyperthyroidism from presumed rapid tumor growth and concomitant tissue destruction. Serum thyroglobulin concentrations may be high, most often due to secretion from a coexisting differentiated carcinoma rather than the anaplastic carcinoma.

Imaging — Diagnostic imaging is useful for defining the extent of disease, planning therapy, and monitoring the response to treatment:

  • Computed tomography (CT) of the neck and mediastinum can accurately delineate the extent of the thyroid tumor and identify tumor invasion of the great vessels and upper aerodigestive tract. Typical findings include masses that are isodense or slightly hyperdense relative to skeletal muscle, dense calcifications, and areas of necrosis.
  • Ultrasonography of the neck also can accurately identify involvement of local and regional nodes. Although ultrasonography cannot distinguish benign from malignant intrathyroidal tumors (both tend to be hypoechoic), detection of extrathyroidal invasion can provide support for the diagnosis of carcinoma. In addition, both ultrasonography and CT can help to guide fine needle aspiration of solid, non-necrotic tumor for diagnosis
  • Most thoracic metastases are parenchymal nodules that can be detected by routine chest radiographs
  • In patients with bony metastases, skeletal radiographs typically show lytic lesions.
  • Radionuclide imaging with iodine or pertechnetate usually reveals hypofunctioning foci corresponding to areas of palpable tumor. More than 75 percent of anaplastic carcinomas take up gallium, but this radionuclide is also taken up by lymphomas and areas of chronic thyroiditis .

Prognostic factors — Several important prognostic characteristics have been identified. Patients with disease either confined to the thyroid or with only local and regional metastases survive longer than those with distant metastases]. Tumor size also appears to be important. In one study, as an example, the two-year survival was 25 versus 3 to 15 percent in patients with tumors less than 6 cm versus larger than 6 cm in maximum dimension

Other variables that may predict a worse prognosis include older age at diagnosis, male sex, and dyspnea as a presenting symptom. Patients who were previously treated for differentiated carcinoma and subsequently developed anaplastic carcinoma have outcomes similar to those without an antecedent cancer

TREATMENT

Tumor localized to the thyroid

Surgery — Surgery is often not indicated because in most patients, the disease is advanced at the time of diagnosis]. However, if the tumor appears localized to the thyroid, complete resection should be attempted since some patients have prolonged survival, often in conjunction with postoperative adjuvant therapy (see below). Relatively favorable prognostic factors include unilateral tumor, diameter of less than 5 cm, and the absence of extrathyroidal invasion or cervical lymph node involvement.

For resectable tumors, thyroid lobectomy with wide margins of adjacent soft tissue on the side of the tumor is an appropriately aggressive surgical approach. As long as the tumor is small and confined entirely to the thyroid, total thyroidectomy with complete tumor resection does not prolong survival compared with ipsilateral thyroid lobectomy, and is associated with a higher complication rate

Impact of adjuvant therapy — Although widely applied after surgical resection, the efficacy of adjuvant radiotherapy after surgery is supported only by uncontrolled observations]. Multiple reports support a possible survival advantage for combined modality therapy combining radiation and chemotherapy, although selection bias is a major confounding factor in determining the effect of treatment on outcome. Patients who undergo resection followed by adjuvant therapy often have less extensive disease. The optimal timing of the individual components and the selection of chemotherapy regimen are uncertain. This topic is discussed in detail elsewhere.

Advanced or metastatic disease — There is no effective therapy for advanced or metastatic anaplastic thyroid carcinoma, and the disease is uniformly fatal. The median survival from diagnosis ranges from three to seven months, and the one- and five-year survival rates are 20 to 35 percent and 5 to 14 percent, respectively. Death is usually attributable to upper airway obstruction and suffocation (often despite tracheostomy) in 50 to 60 percent of patients, and to a combination of complications of local and distant disease in the remainder

Radiation therapy — External beam radiotherapy, administered in conventional doses, does not prolong survival when administered for advanced disease. Although up to 80 percent of patients may initially respond to radiation, most have local recurrences

For patients with locally advanced disease hyperfractionated radiotherapy, combined with radiosensitizing doses of doxorubicin, may increase the local response rate to about 80 percent, with subsequent median survival of one year; distant metastases then become the leading cause of death. Similar improvement in local disease control has been reported with the combination of preoperative or neoadjuvant hyperfractionated radiotherapy and doxorubicin, followed by debulking surgery in responsive patients. However, the addition of larger doses of other chemotherapeutic drugs has not been associated with improved control of distant disease or increased survival. The topic of combined modality therapy for anaplastic thyroid cancer is discussed in detail elsewhere.

Chemotherapy — The most effective drug for anaplastic thyroid cancer is paclitaxel. Response rates as high as 50 percent are reported in distant metastatic sites, although response duration is generally short, and long-term survival (as well as local control in the neck) probably unaffected.

For patients who present with locally advanced inoperable disease, we suggest combined radiotherapy and chemotherapy for local control of disease. Surgical resection for residual tumor could be considered if the disease is responsive. Given the overall poor prognosis of current treatment modalities, consideration should always be given to referring a patient with anaplastic carcinoma for participation in a clinical trial.

SUMMARY AND RECOMMENDATIONS — Anaplastic thyroid carcinoma is almost always rapidly fatal, the few exceptions being patients whose tumors are small and who are treated very aggressively.

Presentation and diagnosis

  • Approximately 20 percent of patients have a history of differentiated thyroid carcinoma, and 20 to 30 percent have a coexisting differentiated carcinoma
  • The primary symptom of anaplastic carcinoma is a rapidly enlarging neck mass, occurring in about 85 percent of patients
  • The diagnosis of anaplastic carcinoma is usually established by cytologic examination of cells obtained by fine-needle aspiration biopsy or of tissue obtained by large-needle or surgical biopsy. Imaging, in particular, CT and ultrasound, are used to determine the extent of disease

Treatment

  • We suggest ipsilateral thyroid lobectomy rather than total thyroidectomy for patients who are surgical candidates (no evidence of extrathyroidal disease)
  • We suggest postoperative combined modality therapy with radiation and chemotherapy for those patients whose tumors are resected completely. In most patients, however, this is not possible, and treatment should be directed toward securing the airway and ensuring access for nutritional support.
  • For patients who present with locally advanced inoperable disease, we suggest combined radiotherapy and chemotherapy for local control of disease