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The prognosis for anaplastic thyroid cancer (ATC) is dismal, with survival usually but a few months, unlike that of differentiated thyroid cancers in which patients often live years even with distant metastases. The median overall survival for ATC is only 4.9 months, with a 1-year survival of 20 % [1–44]. All ATC patients are stage IV by American Joint Committee on Cancer (AJCC) criteria. Stage IVA encompasses patients with intrathyroidal ATC and carries the best prognosis but represents a minority of patients at presentation. Stage IVB patients have disease confined to the neck, while IVC requires distant metastases.

Table 100.1 illustrates the frequencies of stage IVA–C disease according to TNM classification. Stage IVA disease is, unfortunately, the least common presentation, with a median of only 10%. The median frequencies of stage IVB and IVC disease are similar, at 40.1 % and 45.8 %, respectively. As expected, the survival rates are highest for stage IVA patients (Table 100.2). Nevertheless, the 2-year survival for intrathyroidal disease is only 62 %. And no one with stage IVC disease lived 2 years [39]. Chen et al. [45] reported similar results when analyzing the Surveillance, Epidemiology, and End Results (SEER) database. They examined outcomes in 241 patients who had surgery performed or recommended and who survived a month or longer. If disease was confined to the thyroid, median survival was 50 % longer (9 vs. 6 months) than if adjacent tissues were involved and three times longer than if the tumor was more advanced (Table 100.3). However, even patients with stage IVA disease had only a 23 % 5-year survival. These findings emphasize that patients with disease seemingly confined to the thyroid also have a high mortality rate. Thus, microscopic metastases are present frequently, and aggressive systemic adjuvant therapy will be required to improve outcomes. The most favorable prognosis is seen when an incidental focus of ATC is identified in a thyroid specimen resected for goiter or differentiated cancer. Akaishi et al. [39] had six such cases; all were alive at 1 year, but one died 9 years later with pulmonary metastases. Pierie et al. [21] reported a 3-year survival of 90 % if ATC was discovered incidentally, while Sugino et al. [22] found 1- and 2-year survivals of 73 % and 46 %, respectively, with incidental ATC. Choi et al. [46] identified microscopic anaplastic foci (MAF) in 0.4 % of 3,587 PTC cases; 5-year cause-specific survival was 64 % in the MAF group and 98 % in the pure PTC cases.

Table 100.1 Staging distribution in anaplastic thyroid carcinoma
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Table 100.2 Survival according to TNM stage in anaplastic thyroid carcinoma [39]
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Table 100.3 Overall survival according to tumor extent in 241 patients with anaplastic thyroid cancer [45]
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Predictors of survival have been examined in many studies, using both univariate and multivariate analyses. The most obvious candidates would be size of the tumor, completeness of surgical resection, and lack of distant metastases, and this is borne out in Fig. 100.1 which illustrates the longest survival for patients with stage IVA cancer and shortest with IVC, as well as in Tables 100.2 and 100.3. What remains unexplained is why some patients are more fortunate and their cancer is detected at stage IVA, rather than IVB or IVC. It is recognized that all ATCs contain a plethora of genetic abnormalities responsible for the remarkable aggressiveness of the tumor [47–49]. It will be important to better understand the molecular derangements that contribute to the pathogenesis and progression at each stage of ATC, in order to develop more accurate predictive and therapeutic strategies.

Fig. 100.1
figure 1

Overall Kaplan-Meier survival in months. Data for historical 50-year Mayo Clinic outcomes for stage IVA, IVB, and IVC anaplastic thyroid cancer are compared to outcomes resulting from our recent practice change combining intensity-modulated radiation therapy with adjuvant and radiosensitizing chemotherapy. IMRT intensity-modulated radiation therapy (Reprinted with permission from Foote et al. [54])

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The prognostic factors most commonly evaluated are listed in Table 100.4. Younger patients (<70, 65, or 60 years) have longer survival times in some studies [4, 18, 21, 26, 28, 31, 33, 39, 43, 50], but not in all [13, 15, 24, 30, 32, 34, 35, 42]. Gender, on the other hand, did not influence survival in most studies [15, 24, 28, 31, 42, 43, 50, 51], but did in one [21]. Smaller primary tumors (<5, 6, or 7 cm) portend a more favorable outcome in eight reports [11, 13, 18, 21, 24, 31, 50, 51], but not in four others [28, 32, 39, 43]. The most striking, but not unexpected, predictor is extent of surgical resection, with longer survival observed in 81 % of studies [6, 8, 11, 13–15, 20–24, 27, 28, 30, 36, 39, 41, 50], but not in a minority [29, 31, 32, 43, 51]. Patients with a microscopic focus of ATC have the highest chance of survival, followed by patients with intrathyroidal stage IVA disease and R0 (negative margins) resections. Ito et al. [40] recently reported that stage IVB patients could be subdivided with IVB-a tumors involving the soft tissue, trachea, larynx, recurrent laryngeal nerve, or esophagus and IVB-b tumors which encased the carotid artery or mediastinal vessels or invaded the prevertebral fascia. Median survival was improved from 4.0 to 9.6 months in the IVB-a vs. IVB-b patients. Super-radical resection (trachea/larynx, esophagus/pharynx, major cervical arteries) in stage IVB patients improves survival compared to palliative but not restricted radical surgery [52].

Table 100.4 Predictors of survival in patients with anaplastic thyroid carcinoma (no. studies)
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Radiotherapy improved outcomes in 72 % of studies [10, 11, 13, 15, 21, 27–29, 34, 36, 39, 41, 43, 50], particularly in obtaining locoregional control of tumor and reducing death from airway and esophageal complications, but failed to improve survival in others [8, 24, 31, 35, 42]. Distant metastases, as one would predict, carried the worst prognosis in most [4, 6, 15, 26, 28–30, 33, 34, 39, 50, 51] but not all [24, 32] reports. Prior or concurrent differentiated thyroid cancer had an inconsistent effect on survival with a better prognosis in four reports [15, 19, 22, 23], but not in others [4, 14, 31, 51]. Leukocytosis carried a worse prognosis in several [39, 50, 53] but not all [24] studies, and dyspnea [8, 21, 42] and dysphagia [21] at presentation also are worrisome. FDG-PET uptake and intensity are inversely related to survival [44].

The causes of death are generally related to locoregional complications (asphyxia, pneumonia) or distant metastases. As radiotherapy techniques were modified to better accommodate the rapid doubling time of ATC, death rates from airway complications were reduced [3, 10, 13, 15, 27]. In one study, death was attributed to local complications in 37 %, distant metastases in 12 %, and both in 57 % of patients [38].

No single therapy has been optimal for ATC. While combination therapy has not improved survival in most studies [3, 8, 10, 21, 22, 24, 31–33, 41, 42] (Table 100.4), this reflects series spanning many decades during which the surgical, radiation, and chemotherapy approaches have evolved. Several studies of aggressive multimodal therapy [4, 17, 34, 40, 43, 50, 54] have shown some promise, at least in stage IVA and IVB ATC. Further experience and refinement of these strategies, and testing of newer agents with benefits demonstrated in preclinical studies [48, 49], will hopefully improve outcome in patients with all stages of ATC.