Selpercatinib for treating recurrent mixed medullary and follicular cell-derived thyroid carcinoma: a case report.

BACKGROUND: Mixed medullary and follicular cell-derived thyroid carcinoma (MMFCC) is characterized by the coexistence of follicular and C cell-derived tumour cell populations within the same lesion. Due to its rarity, its etiology and clinical course remain unclear, and treatment for advanced or recurrent cases has not been established. CASE PRESENTATION: We report a case of MMFCC treated with selpercatinib. The patient was a 69-year-old male presenting with tumors in the right thyroid lobe and in the upper mediastinum. Fine-needle aspiration (FNA) cytology of the right thyroid lobe tumor revealed a medullary carcinoma; germline RET mutations were not detected. After resection of the right thyroid lobe with central node dissection, rapid intraoperative diagnosis of the mediastinal mass confirmed malignancy, leading to total thyroidectomy with excision of the upper mediastinal tumor. Histologically, the tumor in the right thyroid lobe and the pretracheal lymph node revealed a mixture of medullary and follicular carcinoma components, diagnosed as MMFCC. The mediastinal lymph node exhibited only medullary carcinoma components. At 11 months postoperatively, computed tomography scans showed enlargement of the right supraclavicular and upper mediastinal lymph nodes. FNA cytology of the right supraclavicular lymph node suggested the recurrence of medullary thyroid carcinoma. The gene panel testing (The Oncomine Dx Target Test Multi-CDx system®, Thermo Fisher SCIENTIFIC) of metastatic lymph node revealed RET somatic mutation (M918T). Treatment with selpercatinib was initiated, and both the cervical and mediastinal lymph nodes showed a reduction in size. CONCLUSIONS: We report a rare case of selpercatinib use for MMFCC. Since RET mutations may occur frequently in MMFCC, selpercatinib could be effective in treating MMFCC.

Clinicopathological analysis of thyroid carcinomas with the RET and NTRK fusion genes: characterization for genetic analysis.

Thyroid carcinomas exhibit various genetic alterations, including the RET and NTRK fusion genes that are targets for molecular therapies. Thus, detecting fusion genes is crucial for devising effective treatment plans. This study characterized the pathological findings associated with these genes to identify the specimens suitable for genetic analysis. Thyroid carcinoma cases positive for the fusion genes were analyzed using the Oncomine Dx Target Test. Clinicopathological data were collected and assessed. Among the 74 patients tested, 8 had RET and 1 had NTRK3 fusion gene. Specifically, of the RET fusion gene cases, 6 exhibited "BRAF-like" atypia and 2 showed "RAS-like" atypia, while the single case with an NTRK3 fusion gene presented "RAS-like" atypia. Apart from one poorly differentiated thyroid carcinoma, most cases involved papillary thyroid carcinomas (PTCs). Primary tumors showed varied structural patterns and exhibited a high proportion of non-papillary structures. Dysmorphic clear cells were frequently observed. BRAF V600E immunoreactivity was negative in all cases. Interestingly, some cases exhibited similarities to diffuse sclerosing variant of PTC characteristics. While calcification in lymph node metastases was mild, primary tumors typically required hydrochloric acid-based decalcification for tissue preparation. This study highlights the benefits of combining morphological and immunohistochemical analyses for gene detection and posits that lymph node metastases are more suitable for genetic analysis owing to their mild calcification. Our results emphasize the importance of accurate sample processing in diagnosing and treating thyroid carcinomas.

The frequency of mutations in advanced thyroid cancer in Japan: a single-center study.

We analyzed the outcomes of genetic testing to study the frequency of mutations in advanced thyroid cancer in Japan. Patients (n = 96) with unresectable or metastatic thyroid carcinoma were included for retrospective chart review. Results of gene panel testing, which was performed between May 2020 and April 2023, were analyzed. The median age of the patients was 73.5 years (range, 17-88); 59 were women, and 39 were men. Overall, 17 patients had anaplastic thyroid carcinoma (ATC), 68 had papillary thyroid carcinoma (PTC), 7 had follicular thyroid carcinoma, and 6 had poorly differentiated thyroid carcinoma (PDTC). Of the 81 patients with differentiated thyroid carcinoma (DTC) and PDTC, 88.9% were radioactive iodine-refractory, and 32.7% of all cases had previously been treated with multiple kinase inhibitors. Of ATC cases, 52.9% had BRAF mutations, and 5.9% had RET fusion. Of PTC cases, 83.1% had BRAF mutations, 9.2% had RET fusion, and 1.5% had NTRK fusion. One case each of ATC and PTC had a tumor mutation burden of ≥10. ATC cases had a significantly higher prevalence of TP53 alterations than the other cases (82.3% vs. 11.8%), whereas the frequencies of TERT promoter mutations were 88.2% in ATC cases and 64.7% in the other cases, albeit without a significant difference. In conclusion, 58.8% of ATC, 93.8% of PTC, and 42.9% of PDTC had genetic alterations linked to therapeutic agents. Active gene panel testing is required to increase treatment options.

Lenvatinib and selpercatinib successfully treated RET fusion gene-positive papillary thyroid carcinoma cardiac metastases: a case report.

Background: Cardiac metastasis from thyroid cancer is rare and has an extremely poor prognosis. Although some patients who undergo heart surgery survive, the therapeutic effectiveness of systemic therapy is limited. Case Description: A 53-year-old woman with a history of papillary thyroid carcinoma (PTC) presented with cough and right chest discomfort. She underwent total thyroidectomy, followed by three rounds of radioactive iodine therapy, to treat pulmonary metastasis. Metastases to the lung, chest wall, liver, heart, and lymph nodes were observed on computed tomography. Core needle biopsy of the tumor in the right chest wall revealed the recurrence of PTC. Cardiac metastasis was discovered by echocardiography and cardiac magnetic resonance imaging, and blood test indicated a thyroglobulin level of 851 ng/mL. Based on the presence of cardiac metastasis and strong clinical symptoms, the condition was assumed to be fatal, and lenvatinib was started right away. Three weeks after starting lenvatinib, every metastatic lesion shrank. Once the ERC1-RET fusion gene was identified, we switched to selpercatinib therapy. Ten weeks after starting selpercatinib, every tumor shrank and blood thyroglobulin dropped to 68.1 ng/mL. Initial symptoms such as cough and right chest pain improved. Lenvatinib- and selpercatinib-related adverse effects can be managed with supportive care. Conclusions: To the best of our knowledge, this is the first case of successful systemic therapy for cardiac metastasis from PTC. Conventionally, cardiac surgery is the main treatment for cardiac metastasis, but now systemic therapy is also an important alternative.

Hyperthyroidism due to thyrotropin receptor antibody stimulation of metastatic thyroid carcinoma during lenvatinib treatment: a case report.

BACKGROUND: Hyperthyroidism after total thyroidectomy is extremely rare. No studies have investigated hyperthyroidism during multiple kinase inhibitor treatment for advanced thyroid carcinoma. CASE DESCRIPTION: A 57-year-old man with a history of radioactive iodine refracted thyroid follicular carcinoma presented to our hospital with back pain. Computed tomography (CT) showed a huge tumor at the left ilium and multiple metastases in the lung, liver, and bone. His serum thyroglobulin was 322,000 ng/mL and bone biopsy revealed thyroid carcinoma metastasis. After left iliac tumor decompression surgery, lenvatinib and denosumab treatment were initiated. Serum thyroglobulin decreased to 88,600 ng/mL, and no progression was observed on CT. Although thyrotropin (TSH) was suppressed at 125 µg of levothyroxine sodium, serum free T3 started to increase at 70 weeks after lenvatinib initiation. Levothyroxine sodium was gradually reduced to 25 µg. At 83 weeks after initiation, the patient was hospitalized due to nausea, diarrhea, and anorexia. Serum free T3 increased to 13.98 pg/mL, whereas CT showed progression of lung and liver metastasis. Given the patient's positivity for anti-thyrotropin receptor antibody (TRAb), levothyroxine sodium and lenvatinib were discontinued and methimazole was administered at the dose of 15 mg/day. Lenvatinib was restarted after 2 weeks withdrawal. Methimazole was gradually reduced to 5 mg/day as thyroid function normalized. However, CT showed pleural effusion and enlargement of the lung, liver, and adrenal metastases. The patient died at 100 weeks after lenvatinib initiation due to disease progression. CONCLUSIONS: The patient developed Graves' disease after lenvatinib treatment for radioactive iodine refracted thyroid follicular carcinoma. Persistent TSH stimulation caused by TRAb can be involved in tumor growth and thyroid hormone secretion from metastases.