Anaplastic thyroid cancer (ATC) is a rare and lethal type of thyroid cancer. The survival rate of patients with ATC has not changed markedly over the past 20 years (1). Although clinical trials (randomized and non-randomized) have been conducted (2-4), including one with a large cohort of 205 patients, the considerable improvement in the understanding of the pathogenesis and genetics of ATC has not notably improved patient outcome (5). According to the American Thyroid Association guidelines, once a patient is diagnosed with stage IVC ATC, either systemic treatment and/or palliative treatment, including best supportive care (BSC), should be immediately implemented (6). Systemic therapy trials are time-consuming, and disease progression is quicker than the trial entry process prior to treatment initiation; therefore, the patient may not have sufficient time for treatment (7). In 2015, the Japanese Ministry of Health, Labor and Welfare approved the clinical use of lenvatinib for the treatment of patients with ATC and differentiated thyroid cancer (DTC). Therefore, lenvatinib may be used for the prompt systemic treatment of stage IVC ATC (8). Conversely, when patients treated with weekly paclitaxel (PTX), palliative radiation, or tracheostomy for local control manifest disease progression, BSC is administered to prolong survival. To the best of our knowledge, no studies to date have compared such cases and their prognoses, or have reported basic data of such cases. Although ATC is hypothesized to evolve from DTC, no report has yet proven that ATC originates from DTC (9,10). The aim of the present study was to examine whether the clinical course of ATC was different from that determined using the presence and the shape of calcifications observed on computed tomography (CT) scans at the time of diagnosis.

The genetic analysis of ATC (12) demonstrated that some ATCs evolve from PTCs, FTCs and aggressive DTCs; the remaining cases are de novo carcinomas. An interesting previous study demonstrated that PTC coexisted with ATC and harbored the same BRAF mutation (13). Moreover, previous reports hypothesized that DTC is a pre-existing condition in the majority of ATC cases (9,10). In fact, it is not uncommon to observe the coexistence of DTC in ATC pathological tissues (14,15). In the present study, a co-existing PTC in the biopsied specimen was detected in 3 patients, and their CT images displayed calcification. The co-existence of DTCs in ATC surgical specimens is occasionally observed, but it is difficult to prove pre-existing DTC. It is desirable to determine the presence of DTC prior to the development of ATC. In the present study, CT examination at the time of diagnosis revealed calcification in the primary lesion, which may have resulted from a thyroid disease, such as DTC or multinodular goiter. Few studies have reported image findings for ATC. Takashima et al reported that 58% of ATC patients had dense calcifications (16). Although this incidence was lower compared to the 67.9% in the present study, over half ATCs displayed calcifications. Thus, it may be hypothesized that pre-existing diseases may result in calcification in ATC. It was suggested that differentiation may affect lenvatinib efficacy, and the treatment results of lenvatinib were superior in patients who had calcifications in the primary lesion. In order to avoid treatment-related deaths due to fistula formation in all patients, discontinuation and dose reduction must be considered before the condition becomes life-threatening.

In a phase II study, the use of lenvatinib in 17 patients with ATC was reported (5,6). The median progression-free survival was 7.4 months and the median OS was 10.6 months. The majority of the patients had been pretreated prior to lenvatinib treatment: 14 patients underwent surgery, 7 patients underwent chemotherapy, and 9 patients received external irradiation. The present study only compared patients receiving lenvatinib with those receiving palliative treatment for stage IVC ATC. Following lenvatinib treatment, 13 patients exhibited a reduction in tumor size, of whom 5 (31.3%) achieved a cPR; 1 patient displayed an increase in tumor size after 1 month and 2 did not display any changes. Although this treatment response does not appear to be a bad result, we believe that extensive tumor necrosis, AE-related mortality and treatment discontinuation caused by formation of tumor-skin fistula may severely compromise treatment outcomes. It is crucial that a median 2.2-month survival benefit was obtained with lenvatinib compared with palliative therapy. In addition, it was reported that an initial low dose of lenvatinib (10, 14 and 20 mg) did not alter the results of DTC (17). Recently, ATC has been treated with low-dose lenvatinib, depending on the patient's condition. In ATC, as the tumor is close to the skin, treatment should be initiated as soon as possible after confirmation of diagnosis using core needle biopsy, as a fistula may form where the tumor is exposed at the biopsy site. As ATC progresses rapidly, prompt initiation of treatment is required; moreover, it is necessary to arrest tumor progression and administer a proper dose to avoid deterioration of the fistula. This is also to avoid treatment-related deaths due to profuse bleeding from large vessels located close to the fistula. In the present study, co-existing PTC was detected in 3 patients, who also displayed calcifications on the CT scan. It has been reported that DTC coexisted in 35% of patients with ATC (2) and that ATC coexists not only with DTC, but also with thyroid diseases, such as nodular goiter (3). The calcification patterns identified in our study displayed the typical characteristics of PTC, and 3 patients had coexisting PTC, which was detected by core needle biopsy; therefore, transformation of PTC to ATC was suggested.

In addition to than lenvatinib, BRAF inhibitors serve as effective therapeutic agents for type I ATC with BRAF mutation (18). Programmed death-1 checkpoint blockers may be also efficacious in patients with aggressive forms of thyroid cancer (19). However, these agents are not approved for use in Japan. The combination of PLX4720 and dasatinib induced apoptosis, increased immune cell infiltration and reduced tumor volume in a preclinical model of ATC, and may be expected to be approved as treatment for patients with ATC in the future (20). The results of the present study may serve as a basis for progress in ATC treatment, including combination treatment with lenvatinib.

In conclusion, the L group demonstrated a median survival benefit of 2.2 months compared with the P group in stage IVC ATC. Although cPR was confirmed in 5 patients who received lenvatinib, 2 patients died. These results suggest that an appropriate lenvatinib dose reduction is necessary.