(Secondary) solid tumors in thyroid cancer patients treated with the multi-kinase inhibitor sorafenib may present diagnostic challenges

A 67-year-old female was diagnosed with a well differentiated papillary thyroid carcinoma (PTC, BRAF c.1799 T > A; p.V600E mutation positive), stage T2N0M0, in 1989. She underwent a total thyroidectomy and RAI ablation therapy. Local recurrent disease was diagnosed ten years later and treated with a left-sided modified radical neck dissection, followed by RAI therapy. The post-therapy scintigraphy showed no RAI uptake. Six years later routine follow-up with computed tomography (CT) identified metastatic disease with multiple lung lesions, the largest measuring 5 mm (2005). A total body scintigraphy after RAI therapy showed no uptake of RAI despite elevated thyroglobulin levels (68 ug/l), indicating RAI refractory disease. Due to the progression of disease two years later (2007) the patient received sorafenib (2 x 400 mg/day initially, reduced to 1 x 200 mg/day after 6 months) in the context of a phase II study [2, 10]. Follow-up showed stable disease according to the Response Evaluation Criteria in Solid Tumours (RECIST) 1.0 [11]. Thirty-nine months after starting sorafenib, with ongoing stable disease, the patient stopped therapy mainly due to diarrhea.

After starting sorafenib treatment, the patient developed several skin lesions (for a summary see Table 1). Furthermore, within 2 months of beginning sorafenib therapy the patient developed left-sided tongue complaints, originally histologically diagnosed and treated as mucosal hyperplasia with Candida albicans infection. The symptoms persisted however and eventually led, 46 months after the initial complaints, to the diagnosis of a T2N2cM0 functional irresectable SCC of the tongue (thyroid transcription factor (TTF)-1 and thyroglobulin immunohistochemically negative; BRAF p.V600E negative) with ipsi-lateral lymph node metastasis (Fig. 1). Despite chemo-radiation therapy with 7 rounds of cisplatin, the patient died 5 months after diagnosis of the SSC.

The second (male) patient was diagnosed with a T4N1Mx PTC without squamous metaplasia (positive for the rare BRAF mutation c.1799-1801het_delTGA, Fig. 2) at the age 67 [12‐14]. He underwent a total thyroidectomy with a right-sided lymph node dissection, followed by RAI ablation therapy in 2001. In 2004 the patient had recurrent disease, and a bilateral para-tracheal lymph node dissection was performed. A year later he presented with local recurrent disease and the presence of multiple pulmonary metastases. A whole body scintigraphy after RAI therapy showed no RAI uptake, while thyroglobulin levels were 133 ug/l, thus demonstrating RAI refractory disease. In 2007, the patient was referred to our hospital for inclusion in a phase II trial and received sorafenib 400 mg twice daily [2, 10]. Despite initial stable disease, the patient became progressive under sorafenib after 19 months of therapy. The patient was subsequently enrolled in a clinical study (RAD001, www.​clinicaltrials.​gov CRAD001CNL08T) to determine the efficacy of everolimus in patients with progressive irresectable recurrent or metastatic differentiated, undifferentiated (anaplastic) and medullary thyroid carcinoma. The patient ceased everolimus therapy 18 months later due to progressive disease. A CT showed a new pulmonary lesion and a number of (non)target lesions according to RECIST 1.0 [11]. Since all conventional or study-based treatment options had been exhausted, the patient was referred back to his own hospital where he presented 2 months later with progressive dyspnea due to malignant pleural effusion. A CT showed multiple bilateral pulmonary metastases and a large right para-tracheal lesion. Surprisingly, right-sided pleural fluid cytology elsewhere revealed a primary adenocarcinoma of the lung. Immunohistochemistry of embedded cytological material showed TTF-1 and cytokeratin (CK) 7 positivity and absence of staining for thyroglobulin, cluster of differentiation (CD) 56 and CK20. Additional paired box (PAX) 8 and CK19 staining in our institute were however positive, indicative of metastatic PTC (Fig. 3). Molecular testing confirmed this diagnosis with the presence of the previous identified BRAF mutation. The patient died a month later due to disease progression.

A 60-year-old male was diagnosed with a T2N0M0 poorly differentiated PTC (BRAF c.1799 T > A; V600E mutation positive) in 2002. The patient was treated by total thyroidectomy with a left-sided lymph node dissection, followed by RAI ablation therapy. Three years later (2005) he presented with multiple pulmonary lesions, non-RAI avid on whole body scintigraphy after RAI therapy, and thyroglobulin levels of 127 ug/l. Due to disease progression in 2008 the patient was included in a phase II trial (and received 2 x 400 mg sorafenib daily) [2, 10]. In the first 6 months a partial response was achieved, which was ongoing until therapy discontinuation 32 months later due to complaints of diarrhea and hand-foot syndrome. A CT four months after therapy discontinuation still showed an ongoing partial response per RECIST 1.0 [11]. However, seven weeks later the patient presented with respiratory failure due to airway obstruction. A large tumor originating from the cricoid was visible on CT scan. Initial histological examination elsewhere concluded that the lesion was a SCC originating from the cricoid. Revision of the tumor showed a lesion with squamous differentiation (Fig. 4). Although P63 staining (indicative of squamous differentiation) was positive in a subset of cells, immunohistochemistry also showed TTF-1 and thyroglobulin to be focally positive, indicative of a PTC recurrence. Surprisingly, the BRAF mutation present in the primary tumor was not recovered from this tumor, possibly suggesting clonal divergence after sorafenib treatment. Given the fact that local treatment was not an option the patient received a tracheal stoma followed by radiotherapy. He died 8 months later due to tumor progression.