Undifferentiated thyroid cancer Undifferentiated thyroid cancer is an aggressive undifferentiated tumor with a 100% disease-related mortality rate. Patients with undifferentiated thyroid cancer are older than those with differentiated thyroid cancer, with an average age at diagnosis of approximately 65 years. Less than 10% of patients are younger than 50 years of age, and 60-70% of patients are women.37 Nearly 50% of patients with undifferentiated thyroid cancer have prior or concurrent differentiated thyroid cancer. Undifferentiated thyroid cancer often develops from differentiated thyroid cancer through one or more steps of dedifferentiation, particularly loss of the tumor suppressor protein P53.188 Key events have not been identified and the mechanisms leading to the undifferentiated transformation of differentiated thyroid cancer are unknown. Differentiated thyroid cancers can polyiodinate, express TSH receptors and produce thyroglobulin, but poorly differentiated or undifferentiated tumors do not have these functions. Therefore, radioiodine scanning is not recommended and radioiodine therapy is ineffective in patients with poorly differentiated or undifferentiated thyroid cancer. Fifteen to 50% of patients with undifferentiated thyroid cancer have extensive local infiltration or distant metastases at the time of initial diagnosis.189 The lungs and pleura are the most common sites of distant metastases, accounting for 90% of distant metastases. About 5-15% of patients have bone metastases; 5% have brain metastases; and other rare metastatic sites include skin, liver, kidney, pancreas, heart, and adrenal glands. All undifferentiated thyroid cancers are stage IV (A, B or C). (See Table 1) T4 classification includes: (1) T4a tumor: located within the thyroid gland and can be surgically removed; (2) T4b tumor: invades outside the thyroid gland and is not surgically resectable. Undifferentiated thyroid cancer usually presents clinically as inoperable. Undifferentiated thyroid cancer is usually diagnosed by FNA or surgical biopsy. However, sometimes it is difficult to differentiate undifferentiated thyroid cancer from other primary malignant thyroid diseases (e.g., MTC, thyroid lymphoma) or from poorly differentiated carcinoma that has metastasized to the thyroid gland.190 Diagnostic steps include: routine blood tests, blood calcium and TSH levels. CT scans of the neck and mediastinum can determine the extent of thyroid tumor invasion and can identify whether the tumor has invaded large blood vessels and structures in the upper airway and gastrointestinal tract.191 Most pulmonary metastases are multinodular and can be detected by routine chest radiography. Bone metastases are usually osteolytic changes. Treatment and prognosis There is no effective treatment for undifferentiated thyroid cancer, and the disease is fatal. The median survival from diagnosis is 3-7 months. 1-year and 5-year survival rates are 25% and 5%, respectively.189 Fifty percent of patients die from upper airway obstruction and asphyxia (although tracheostomy is often available), and the remainder die due to other local or distant metastatic complications. Patients with lesions confined to the neck have a median survival of 8 months, and a median survival of only 3 months if the tumor invades outside the neck.192 Other factors predictive of a poor prognosis include older age at first diagnosis, male gender, and complaints of dyspnea. Total thyroidectomy generally does not prolong survival except in patients with small tumors that are confined to the thyroid or easily resectable structures.192,193 External RT therapy given at conventional doses also generally does not prolong survival. Although nearly 40% of patients initially respond to RT, local recurrence occurs in most patients. Although distant metastases respond to single-agent chemotherapy in approximately 20% of patients. Generally this treatment does not improve survival or control the progression of neck disease. Hyper-segmented RT in combination with the radiosensitizer adriamycin increases local response rates by up to 80%, with a subsequent median survival of 1 year. In contrast, distant metastases are a major cause of death.194 The combination of hypersplit RT and adriamycin, followed by chipping in responsive patients, also improves local disease control.195 However, the addition of high doses of other chemotherapeutic agents does not improve control of distant metastases or improve survival. One study applying paclitaxel to newly diagnosed patients showed a palliative benefit.196 In phase I clinical trials, undifferentiated thyroid cancer had some complete response time to cobutamine A4 phosphate (CA4P) and achieved disease-free survival of more than 3 years.197 Phase II clinical trials of CA4P are now underway with studies that include: (1) single agent use for the treatment of metastatic or non-responsive undifferentiated thyroid cancer; and (2) in combination with adriamycin, cisplatin and radiotherapy for the treatment of patients with newly diagnosed and locally progressive disease. As a vascular targeting agent, CA4P rapidly and selectively inhibits tumor vasculature and causes massive necrosis.CA4P may be effective in combination with conventional chemotherapeutic agents or radiotherapy.198 However, CA4P has some cardiovascular toxicity, and therefore, patients receiving this treatment need to be carefully selected. Once the pathologic diagnosis of undifferentiated thyroid cancer is established, the panel considers it most important to rapidly determine the possibility of local excision, since 50% of patients die from uncontrolled neck disease. Patients require a CT scan of the neck and a chest radiograph. If tumor resection is possible, total or near-total thyroidectomy combined with elective resection of all invaded local or regional structures and lymph nodes is an option. This guideline recommends that measures to protect the airway are needed for patients whose tumors cannot be completely resected, including: prophylactic tracheostomy. In addition to surgical treatment, all patients should receive multidisciplinary treatment. Although optimal efficacy is achieved with hyper-segmented RT in combination with chemotherapy, the panel concluded that this treatment is relatively toxic and that prolonged remission is rarely reported. Due to the lack of evidence for the effectiveness of specific agents, this guideline does not recommend any specific chemotherapeutic agent for radiotherapy sensitization or full-dose therapy. Therapeutic measures other than RT and chemotherapy may be considered, particularly in clinical trials.