Thyroid cancer is the most common endocrine tumor, making up 3.8% of all new cancers in the USA (1), and in the last three decades its incidence has continuously increased all over the world (2). Most thyroid cancers are well differentiated and have an indolent evolution with a low mortality rate (approximately 0.5%), which has been relatively stable over the last decades but has been increasing in the recent years (3).

A specific thyroid cancer histotype, the anaplastic thyroid cancer (ATC) is the major contributor to thyroid cancer-related mortality. In spite of its rarity (1–2% of all thyroid cancers) ATC contributes to 15–50% to the annual mortality of thyroid cancer (4). ATC in fact is one of the most aggressive and deadly human cancers, with a disease-specific mortality close to 100% (5). ATC originates from the thyroid follicular epithelium but does not show any of the biological features typical of the differentiated follicular cells [response to TSH, iodine uptake, and thyroglobulin (Tg) synthesis]. ATC, therefore, is also different from the poorly differentiated thyroid cancers (DTCs) which maintain some of the immunohistochemical markers of the epithelial thyroid cell, such as Tg and thyroid transcription factor 1 (TTF1) (6, 7).

According to Surveillance Epidemiology and End Result (SEER), the ATC incidence is 1–2 cases/million inhabitants/year, and the trend, at variance with well-DTC, shows a progressive decrease (8). A dramatic reduction of ATC has been observed in the last three decades of the last century in Germany and Ireland and is attributed to the increase of dietary iodine and better treatment of DTC (9, 10). Nowadays ATCs represent 1.7% of all thyroid cancers in the United States (11). Based on either tumor registries or single center experience, the ATC frequency among all thyroid cancers is highly variable in different countries, being 1.3% in Australia, 1.9% in Luxembourg, 2.0% in Austria, 2.1% in Italy, 3.1% in Japan and Jordan, 4.2% in New Zealand, 4.7% in India, 7.5% in Israel, 7.9% in Netherlands, and 9.8% in Ireland (12).

Because of its aggressive behavior, ATC is classified as T4 and Stage IV cancer (IV A/B/C) by the latest American Joint Committee on Cancer Staging Manual (13). The median survival of ATC patients is 3–5 months after diagnosis with a survival rate of 20% at 1 year and less than 5% at 5 years (4).

Anaplastic thyroid cancer patients are generally older than patients with DTC with a peak of incidence in the sixth to seventh decade of life and less than 10% of cases younger than 50 years. The female to male ratio is lower than in DTC, between 2:1 and 3:1 (4, 14). ATC often occurs in patients with a pre-existing goiter (up to 80% of cases) or a DTC. More than 90% of ATC tumors are locally invasive (15, 16) and present a rapidly growing fixed neck mass, invading surrounding tissues with neck lymph node involvement (17). Therefore, local symptoms, including neck pain, tenderness, and compression (or invasion) of the upper aerodigestive tract, with dyspnea, dysphagia, hoarseness, and cough usually prevail on systemic symptoms (anorexia, weight loss, fatigue, shortness of breath, and fever of unknown origin) that appear only when the disease is more advanced (4). Fifty percent of patients present with distant metastases already at diagnosis: lung (80%), bone (6–16%), and brain (5–13%) are the most common metastasis sites (15).

Due to these characteristics at presentation ATC should be considered a systemic disease that requires multimodal therapy involving reductive surgical resection in addition to external beam radiation therapy and chemotherapy (doxorubicin and paclitaxel), either concurrently or sequentially (4). Hopefully, in the near future, a better understanding of the genomic and transcriptomic hallmarks of ATC (18) will allow for the development of new therapeutic strategies based on molecular approaches with single (19, 20) or multiple molecular target approaches (21–25).

The aim of this study was to analyze demographic and clinical characteristics of ATC relative to different environmental influences in individuals with a similar genetic background and lifestyle. ATC incidence was examined in rural vs urban areas of Sicily as well as in iodine-deficient areas and in industrialized areas and data compared to values in the rest of the island. Moreover, ATC was separately evaluated in the area of increased incidence of thyroid cancer identified around the Mt. Etna volcano (26). In that volcanic area, thyroid cancer incidence is doubled relative to the rest of Sicily and the increase is exclusively due to the papillary histotype (26). This increase of thyroid cancer in the volcanic area is associated with important non-anthropogenic environmental pollution. Analyzing 27 trace elements in drinking water, lichens, and in urines of residents in the volcanic area and in adjacent non-volcanic Sicilian areas, we found that values of many metals were significantly increased in water and atmosphere of the volcanic area with consequent biocontamination of the resident population (27, 28). In particular, average values of palladium (×9), vanadium (×8), manganese (×3), mercury (×2.6), tungsten (×2.4), and cadmium (×2.1) were the major biocontaminants identified (27–29).

Moreover, to evaluate the possible influence of the different genetic background, ATC data in Sicily were compared with those available from the SEER program in the USA. Survival rates and prognostic factors were also calculated. All these comparisons were aimed at evaluating the possible role of environmental characteristics on the incidence of ATC in populations living in adjacent areas and having a similar genetic background and lifestyle (Sicily) and also in two countries (Sicily and USA) with very different genetic background and lifestyle.

Our study on ATC in Sicily confirms that this cancer is a rare but extremely aggressive malignancy. In comparison with DTC, ATC in Sicily occurs at a more advanced age (mean age 71.6 vs 49.0 years for DTC) (33) and with a much lower female to male ratio (ATC = 1.4 vs 4.3 for DTC). Age, therefore, is a major risk factor and also significantly affects the prognosis: being less than 70 years old significantly improves survival at both univariate and multivariate analysis (Table 3). Furthermore, gender effect is different between ATC and DTC because the worse evolution of the thyroid cancer in males, which is typical of DTC (34–36), is not present in ATC (37–39). In our small series, the younger age and more prevalent IVA stage may have influenced the better survival in male patients relative to females.

In our ATC patients, the coexistence with DTC is associated with a better survival rate at the univariate analysis (p = 0.03, Table 3). Although these data are not confirmed at the multivariate analysis, a better prognosis in patients with coexistent DTC is possible because it is influenced by the more precocious ATC diagnosis, when only one or a few ATC foci are incidentally diagnosed at the pathological examination after total thyroidectomy for a DTC. Early diagnosed intrathyroidal ATCs, in fact, are expected to have a better prognosis because ATC foci are completely excised at surgery. When comparing long-term (>2 years) ATC survivors to the other ATC patients (Table 2) age was the only significant factor and the cancer stage was nearly significant.

The possibility of a thyroid hormone role on favoring cell proliferation and ATC via activation of the ERK 1/2 intracellular pathway (40) is not supported by our data since no ATC patient had a history of hyperthyroidism or l-thyroxine overreplacement after thyroidectomy.

Environmental factors such as iodine deficiency, living in industrial areas, and in either the rural or urban environment do not influence ATC incidence in Sicily. Moreover, the comparison of ATC data in Sicily with those obtained in the same period (2002–2009) from the SEER series in the USA shows very similar epidemiological characteristics in spite of the different genetic background, lifestyle, and access to medical healthcare. This similarity may suggest that the multistep oncogenic process leading from DTC to ATC (41–43) is driven by chance mutations occurring in an increased replicative situation (DTC) rather than by environmental influences (44). This hypothesis is supported by our observation that ATC incidence is higher in the provinces of Sicily closer to the Mt. Etna volcanic area. In that area, thyroid cancer incidence is doubled in comparison to the rest of Sicily (26, 27, 33, 45). This increase is associated with an important environmental pollution with metals and metalloids and consequent biocontamination of the residents (27). Other volcanic originated pollutants, such as sulfur, thiocyanate, sulfur dioxide, and other volcanic gases, have been hypothesized to influence molecular and cellular mechanisms of thyroid follicular cells favoring cancer (46). Although a cause–effect relationship between this biocontamination and increased cancer incidence is not demonstrated, environmental factors certainly influence the increase of thyroid cancer in volcanic areas (26, 47–49). Since many ATCs occur in long-term pre-existing DTCs by de-differentiation (11), the increased number of ATCs observed in a population having an increased DTC prevalence is in agreement with a minor role of environmental factors and the possibility of ATC incidence related to DTC incidence. This consideration, however, must be considered indirect evidence and does not exclude the possibility that one or more carcinogens in the volcanic areas can directly promote ATC.

One interesting difference between ATC data in Sicily and USA concerns the outcome in terms of overall survival: the percentage of patients surviving at 6 and 12 months after ATC diagnosis is higher in Sicily than in the USA although differences are not statistically significant (p = 0.09 and 0.08). This difference becomes significant when only younger (<70 years) patients are considered. Different causes may contribute to the longer survival of ATC patients in Sicily, including the smaller cancer size in Sicilian ATC patients with age <70 years and the less advanced stage at diagnosis (percent of patients with stage IV A 37.2 vs 10.1% in USA, p = 0.001). Treatment, of course, is also a factor determining survival (50) and precocious and aggressive multimodality therapy has been demonstrated to be beneficial in the absence of distant metastases (38). Different diagnostic and treatment procedures and different access to the medical system might be responsible for the differences observed between the two countries.

Our study provides no contribution in this regard because treatment of the 43 patients was not performed according to standardized protocols and the ATA guidelines for management of patients with ATC (not yet published when these patients were studied) (11). The heterogeneity of treatment procedures is a major limitation of our study since it may have affected survival. Other limitations, of course, include the small number of cases studied and the limitations common to any retrospective study.

In conclusion, ATC in Sicily was confirmed as a deadly disease with poor long-term survival favored mainly by young age, small tumor size, and a non-advanced stage. The influence of environmental factors in determining ATC incidence is probably minor and indirect: carcinogens might rather be effective at promoting DTC which, in turn, may favor progression to ATC.

MT, PM, PR, AM, MV, RV and GP gathered data and drafted the manuscript; MT and PM performed statistical analysis; MT, PM, RV and GP critically reviewed the manuscript. All authors contributed to the conception of the work and approved the final version of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.