CASTLE tumors are rare malignant tumors occurring in the thyroid, but the prognosis and the concomitant long term survival rate is better than for other aggressive advanced thyroid neoplasms [1, 2, 5]. Among other things and according to the so far largest study of CASTLE-tumors comprising 25 cases [4, 6] a significant number may have been incorrectly classified, especially as squamous cell carcinoma of the thyroid. In this study Ito et al. showed a survival rate of 90% after 5 years and 82% after 10 years. Patients without lymph node metastasis had an overall survival rate of 100% after 5 years, those with lymph node metastasis 76% after 5 and 57% after 10 years. One of our patients with initial lymph node metastasis had recurrence after 2 months. No recurrence during an observation period of up to 73 months occurred in the other patients. Interestingly, the expression of Ki67 showed varying results between 2% and 85%, but could not be linked to the presence of lymph node metastases or advanced tumor stages, as the only case in which a tumor recurrence was observed showed a low proliferation rate (compared to e.g. striking 85% in case number 6 with no recurrence during an observation period of 22 months).
Because a diagnosis of CASTLE is difficult before resection of the tumor, patients are usually treated according to the standards of thyroid gland carcinoma with surgical removal of all or part of the thyroid gland with or without neck dissection. Depending on the tumor entity and stage postoperative therapy is often indicated. 5 of our patients underwent radiotherapy, 1 combined radiochemotherapy.
We have recently described chromosomal imbalances in CASTLE similar to those found in thymomas and thymic carcinomas . Given the morphological, immunohistochemical and genetic similarities with thymic carcinomas, it seems reasonable to assume that treatment of advanced CASTLE should follow the guidelines for thymic tumors and patients may benefit also from evolving therapeutic options for patients with thymic tumors [8–13].
CD117 is expressed in about 86% of thymic carcinomas , but KIT gene mutations are uncommon. So far, only few cases of metastasizing thymic carcinoma with an activating KIT mutation and a partial response to treatment with Imatinib have been described [15, 16]. In our analysis, all CASTLE tumors showed positive staining results for CD117, but no mutations of the KIT gene.
Membrane associated EGFR expression has been seen in thymomas as well as in thymic carcinomas. Girard summarized eight studies , which investigated EGFR expression levels in thymic malignancies [18–25] using immunohistochemistry. In this meta-analysis, EGFR was overexpressed in 70% of thymomas and 53% of thymic carcinomas, but there was no correlation between EGFR expression and thymic tumor type. Activating EGFR mutations seem to be exceptionally rare in thymic carcinomas with only few reported EGFR missense mutations in exon 21 (p.L858R in two cases and p.G863D in one case) [23, 26]. In the present series, five tumors showed weak to strong immunohistochemical staining results for EGFR. Two of the four cases, in which DNA-extraction was successful, showed a weak positivity for EGFR, the other two cases showed a strong signal. In three cases mutational analysis revealed a single nucleotide polymorphism (SNP) in the EGFR gene of Exon 20 (p.Q787Q), but no activating EGFR gene mutation could be found.
It has been shown that a therapeutic effect can be seen after the use of EGFR-inhibitors in non-small cell lung cancers, even if there is no activating mutation in the EGFR gene . In a small series of advanced thymic tumours only a slight therapeutic effect could be demonstrated with Gefitinib .
Randomised clinical trials have demonstrated the potential of COX-inhibitors in tumor prevention . Malka et al. showed that inhibition of COX-2 could play a possible therapeutic role in other tumor entities, for instance hepatocellular carcinoma . In particular, the combination of COX-2 inhibitors and EGFR-inhibitors seems to increase the therapeutic effect in colon or cervical carcinoma [31–34]. COX-2 is frequently upregulated in thymomas and thymic carcinomas [11, 12]. In our study all tumors expressed COX-2 raising the possibility to use COX-2 inhibitors in advanced cases.
Although in our investigation all four cases showed SNPs in the PDGFR-α gene of exon 12, no activating mutations in the PDGFR-α gene and no mutations in Codon 12 and 13 of the KRAS gene were detected.