Anaplastic thyroid carcinomas are aggressive undifferentiated tumors, with a disease-specific mortality approaching 100%. Patients with anaplastic carcinoma are older than those with differentiated carcinomas, with a mean age at diagnosis of approximately 65 years. Fewer than 10% of patients are younger than age 50 years, and 60% to 70% of patients are women.35 Approximately 50% of patients with anaplastic carcinoma have either a prior or coexistent differentiated carcinoma. Anaplastic carcinoma develops from more differentiated tumors as a result of one or more dedifferentiating steps, particularly loss of the p53 tumor suppressor protein. No precipitating events have been identified, and the mechanisms leading to anaplastic transformation of differentiated carcinomas are uncertain.

Patients with anaplastic carcinoma present with extensive local invasion, and distant metastases are found at initial disease presentation in 15% to 50% of patients.189 The lungs and pleura are the most common site of distant metastases, being present in up to 90% of patients with distant disease. About 5% to 15% of patients have bone metastases; 5% have brain metastases; and a few have metastases to the skin, liver, kidneys, pancreas, heart, and adrenal glands. All anaplastic carcinomas are considered stage IV (A, B, or C) The T4 category includes: (1) T4a tumors which are intrathyroidal and surgically resectable; (2) T4b tumors which are extrathyroidal and not surgically resectable.

The diagnosis of anaplastic carcinoma is usually established by FNA or surgical biopsy. Diagnostic procedures include a complete blood count, serum calcium, and TSH level. CT scans of the neck and mediastinum can accurately determine the extent of the thyroid tumor and can identify tumor invasion of the great vessels and upper aero-digestive tract structures.190 Most pulmonary metastases are nodules that can be detected by routine chest radiographs. Bone lesions are usually lytic.

No effective therapy exists for anaplastic carcinoma, and the disease is uniformly fatal. The median survival from diagnosis ranges from 3 to 7 months. The 1- and 5-year survival rates are about 25% and 5%, respectively.Death is attributable to upper airway obstruction and suffocation (often despite tracheostomy) in 50% of these patients, and to a combination of complications of local and distant disease and/or therapy in the remaining patients. Patients with disease confined to the neck at diagnosis have a mean survival of 8 months compared with 3 months if the disease extends beyond the neck. Other variables that may predict a worse prognosis include older age at diagnosis, male sex, and dyspnea as a presenting symptom. Except for patients whose tumors are small and confined entirely to the thyroid or readily excised structures, total thyroidectomy with complete tumor resection has not been shown to prolong survival. External beam RT, administered in conventional doses, also does not prolong survival. Although up to 40% of patients may respond initially to RT, most have local recurrence. Treatment with single-drug chemotherapy also does not improve survival or control of disease in the neck, although perhaps 20% of patients have some response in distant metastases. The introduction of hyperfractionated RT, combined with radiosensitizing doses of doxorubicin, may increase the local response rate to about 80%, with subsequent median survival of 1 year. Distant metastases then become the leading cause of death.193 Similar improvement in local disease control has been reported with a combination of hyperfractionated RT 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 with improved survival. Paclitaxel has been tested in newly diagnosed patients and may provide some palliative benefit.A patient with anaplastic thyroid cancer had a durable complete response in a phase I trial of the agent combretastatin A4 phosphate (CA4P), and he has been disease free for more than 3 years.CA4P is now being examined in phase II studies both as (1) single-agent treatment for patients with metastatic or unresponsive anaplastic carcinoma, and (2) in combination with doxorubicin, cisplatin, and radiotherapy for newly diagnosed patients with locally advanced disease. A vascular targeting agent, CA4P causes a rapid and selective shutdown of tumor blood vessels leading to massive necrosis. CA4P may be efficacious when combined with conventional chemotherapeutic drugs or radiation.196 However, CA4P is associated with some cardiovascular toxicity; thus, patients will have to be carefully selected.Once the diagnosis of anaplastic carcinoma is identified pathologically, the panel recognizes the importance of rapidly determining the potential for local resection, because 50% of all patients die of uncontrollable disease in the neck. Patients should undergo a neck CT scan and a chest x-ray. If the disease is deemed likely to be resectable, an attempt at total or near-total thyroidectomy should be made, with selective resection of all involved local or regional structures and nodes. The guidelines also recommend that patients with tumors that cannot be completely removed should, instead, receive efforts to protect their airway, including the possibility of a prophylactic tracheostomy. All patients, regardless of surgical resection, should then undergo multimodality therapy. Although optimal results have been reported with hyperfractionated RT combined with chemotherapy, the panel acknowledged that considerable toxicity is associated with such treatment and that prolonged remission is uncommonly reported. The guidelines do not recommend particular chemotherapeutic agents, either for radiosensitization or full-dose therapy, because of a lack of clear evidence of efficacy for any particular regimen. Considering alternative approaches to RT and chemotherapy, particularly in clinical trials, is therefore recommended.