Association of BRAF or TERT Promoter Mutations and Advanced Papillary Thyroid Carcinoma.

BACKGROUND/AIM: BRAF and TERT promoter mutations are associated with the poor prognosis of papillary thyroid carcinoma. This single-center retrospective study investigated the influence of these genes on advanced cases. PATIENTS AND METHODS: Advanced cases who underwent gene panel testing and cases who underwent complete resection were classified as groups A and C, respectively. The gene mutations were determined using gene panel testing or Sanger sequencing using tumor DNA. RESULTS: The study included 51 cases in group A and 44 cases in group C. In group A, all cases had unresectable lesions or distant metastasis; 82.4% of cases showed no accumulation of radioactive iodine in metastasis and 47.1% of cases were administered drug therapy. Meanwhile, all cases of group C did not have distant metastasis. The prevalence of TERT promoter mutations was significantly higher in group A compared to group C (70.6% vs. 18.2%, p<0.001). However, there was no significant difference in the prevalence of BRAF mutations between the two groups (86.3% vs. 90.9%). In Group C, disease-free survival was significantly shorter in patients harboring the TERT promoter mutations (p<0.001), despite no significant difference in that according to the BRAF mutation status. In addition, there was no significant difference in overall survival in group A according to the TERT promoter mutation status. CONCLUSION: Advanced papillary thyroid carcinoma was associated with the TERT promoter mutations, but not with BRAF mutation. Meanwhile, TERT promoter mutations did not affect overall survival among the advanced cases.

Genomic landscape and clinical features of advanced thyroid carcinoma: a national database study in Japan.

CONTEXT: The relationship between genomic profile and prognosis of advanced thyroid carcinoma requiring drug therapy has not been reported. OBJECTIVE: To evaluate the treatment period and overall survival time for each genetic alteration in advanced thyroid carcinoma that requires drug therapy. METHODS: We conducted a retrospective observational study using a national database in Japan, which included 552 cases of thyroid carcinoma out of 53,543 patients in the database. RESULTS: The database included anaplastic thyroid carcinoma (23.6%), poorly differentiated thyroid carcinoma (10.0%), and differentiated thyroid carcinoma (66.4%). The most common genetic abnormalities were TERT promoter (66.3%), BRAF (56.7%), and TP53 (32.2%). The typical driver genes were BRAF V600E (55.0%), RAS (18.5%), RET fusion (4.7%), NTRK fusion (1.6%), and ALK fusion (0.4%). The most common regimen was lenvatinib, and the time to treatment failure was not different despite the presence of BRAF or RAS mutations. In differentiated thyroid carcinoma and poorly differentiated thyroid carcinoma, TP53 alterations independently predicted worse overall survival (hazard ratio = 2.205, 95% confidence interval: 1.135-4.283). In anaplastic thyroid carcinoma, no genetic alterations were associated with overall survival. CONCLUSION: Genetic abnormalities with treatment options were found in 62.7% of advanced thyroid carcinomas. TP53 abnormality was an independent poor prognostic factor for overall survival in differentiated thyroid carcinoma. The time to treatment failure for lenvatinib was not different based on genetic profile.

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.

Outcome of initial lenvatinib treatment in patients with unresectable anaplastic thyroid cancer.

Anaplastic thyroid cancer (ATC) is a very rare disease with a poor prognosis and with no established effective drug therapy. The present study aimed to report the outcomes of lenvatinib single-agent therapy as an initial drug treatment in ATC, and to investigate its safety and efficacy. This retrospective cohort study included 56 patients with unresectable primary ATC, of whom 36 were treated with lenvatinib and 12 with weekly paclitaxel, and 8 patients who refused any drug treatment who received palliative care. The average survival in the lenvatinib group was 5.8 months, which was significantly longer than 2.0 months in the paclitaxel group (P=0.005). The efficacy of lenvatinib in the 36 patients with ATC, whose primary tumors were unresectable, was evaluated. The response rate was 33% and the median overall survival time was 5.0 months. A safety review indicated that lenvatinib should be used under the careful observation of local findings. Two patients, who showed a reduction with lenvatinib, underwent conversion surgery, which prolonged the prognosis in terms of avoiding events, such as asphyxia, fistula and hemorrhage due to tumor growth; however, the surgical margins were positive, indicating that complete remission was impossible even if surgical resection was performed. Therefore, starting with lenvatinib treatment and identifying a therapeutic drug based on genomic analysis is an acceptable treatment strategy for ATC while halting the disease progression.

Migration of Risk Classification Between the JAES Versus ATA guidelines for Papillary Thyroid Carcinoma.

BACKGROUND: This study aimed to investigate outcomes in the same cohort of patients with papillary thyroid carcinoma (PTC) risk-stratified according to the Japan Association of Endocrine Surgery (JAES) and American Thyroid Association (ATA) guidelines. METHODS: A total of 1044 patients with PTC who underwent initial thyroidectomy at Yokohama City University Medical Center between January 2000 and June 2022 were included. RESULTS: According to the JAES guidelines, 480 (46%), 386 (37%), and 178 (17%) patients were classified as low, intermediate, or high risk, respectively. Furthermore, according to the ATA guidelines, 590 (57%), 261 (25%), and 193 (18%) patients were reclassified as low, intermediate, or high risk, respectively. Among 1044 patients with PTC, the 10-year cause-specific survival (CSS) rates of patients with JAES low and intermediate risk were 99.7 and 98.6%, respectively, and there was no statistically difference (p = 0.096). However, the 10-year CSS rates of patients with ATA low and intermediate risk were 100 and 99.5%, respectively (p = 0.007). Among 1001 patients with M0 PTC, the 10-year distant metastasis-free survival (DMFS) rates of patients with JAES intermediate and high risk were 94.2, and 76.7%, respectively (p < 0.001). However, the 10-year DMFS rates of patients with ATA intermediate and high risk were 88.1 and 86.6%, respectively (p = 0.233), and there was no statistically difference. CONCLUSIONS: Both JAES and ATA risk classifications properly stratified the PTC patients. Furthermore, the ATA risk classification more precisely extracted patients with better and worse prognoses.

Conversion surgery after lenvatinib treatment for anaplastic thyroid carcinoma: a case report.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid carcinoma. Lenvatinib, a multikinase inhibitor, is rarely used in preoperative settings due to adverse effects including delayed wound healing and fistula formation. Herein, we report the use of lenvatinib treatment prior to conversion surgery for the treatment of ATC. CASE PRESENTATION: A 71-year-old woman was referred to our hospital with suspected thyroid cancer with recurrent laryngeal nerve invasion and cervical lymph node metastasis based on the results of ultrasonography. Computed tomography demonstrated the presence of a thyroid tumor invading the trachea and esophagus with no evidence of distant metastasis. Fine needle aspiration of the left cervical lymph node indicated the lymph node metastasis of ATC. As the tumor had widely invaded the trachea and esophagus, unresectable ATC was diagnosed and treatment with lenvatinib was initiated at a dose of 24 mg/day. On day 13 of lenvatinib treatment, the primary tumor and lymph node metastases demonstrated a partial response to therapy. As the tumor was now considered resectable, the decision was made to perform conversion surgery. Total thyroidectomy and left lateral neck node dissection were performed 7 days after the withdrawal of lenvatinib. The patient was discharged on postoperative day 5 with no complications. Histopathological examination demonstrated that the tumor contained the component of papillary thyroid carcinoma, squamoid ATC cells, and granulation tissue. In areas of granulation tissue, atypical cells with spindle-shaped or polygonal morphology, pyknotic nuclei, and scant cytoplasm were observed. Immunohistochemically, these cells were positive for cytokeratin AE1/AE3, TTF-1, and p53 and negative for thyroglobulin and PAX8. Therefore, the areas of granulation tissue observed within tumor samples were also considered ATC that were affected by lenvatinib treatment. In total, approximately 50% of resected tumor comprised ATC, and 70% of them had been changed to granulation tissue. CONCLUSIONS: The findings in the present case indicate that lenvatinib may have significant antitumor effects in preoperative settings. Lenvatinib may represent a promising candidate therapy for unresectable ATC by increasing tumor resectability.

Validation of EZH2 Inhibitor Efficiency in Anaplastic Thyroid Carcinoma Cell Lines.

BACKGROUND/AIM: The prognosis of anaplastic thyroid carcinoma (ATC) is poor, and there is currently no established treatment to improve its outcome. We previously reported that enhancer of zeste homolog 2 (EZH2) was highly expressed in ATC, and may be a therapeutic target; however, the effects of EZH2 on ATC growth currently remain unknown. MATERIALS AND METHODS: We investigated the effects of an EZH2 inhibitor (DZNep) on four ATC cell lines (8305C, KTA1, TTA1 and TTA2). We performed a gene panel analysis of all ATC cell lines to identify differences in DZNep sensitivity between the cell lines. To investigate the effects of DZNep on the recovery of differentiation, we assessed changes in thyroid differentiation markers (TDMs) before and after the DZNep treatment using PCR. RESULTS: EZH2 was expressed in all ATC cell lines. The cell-reducing effects of DZNep were detected in all ATC cell lines, and were the strongest in KTA1 cells followed by TTA2 cells. The TTA1 and 8305C cell lines, which showed weak cell-reducing effects, had TP53 mutations. No changes in TDMs were observed in any ATC cell line. CONCLUSION: DZNep, an EZH2 inhibitor, exerted suppressive effects on the growth of ATC cell lines and has potential as a therapeutic strategy; however, its effects may be attenuated in ATC with TP53 mutations.

Prognostic significance of lung metastasis-related finding in lenvatinib treatment for differentiated thyroid cancer.

PURPOSE: This study aimed to analyze the clinical course of patients with differentiated thyroid cancer (DTC) who were treated by lenvatinib and investigate the specific criteria for the initiation of lenvatinib in lung metastasis. METHODS: A total of 111 patients with DTC treated by lenvatinib were included in the study. Patients were divided into two groups based on the target lesion for the initiation of lenvatinib: lung metastasis group and other metastases group. RESULTS: In the univariate analysis, the tumor size for the lung metastasis (p = 0.002) and the factor of lung metastasis group (p < 0.001) were significantly associated with overall survival (OS). Multivariate analysis revealed that the factor of lung metastasis group [hazard ratio, 0.408; 95% confidence interval (CI), 0.206-0.810; p = 0.010] was the only independent prognostic factor of OS. Of the 53 patients in the lung metastasis group, 12 (23%) had lung metastasis-related finding such as pleural effusion (n = 12), hemoptysis (n = 2), and dyspnea (n = 1) at the initiation of lenvatinib treatment. The median OS in patients with or without lung metastasis-related findings were 41.0 [95% CI, 10.4-not available (NA)] months and 62.9 (95% CI, 53.0-NA) months, respectively (p = 0.022). CONCLUSION: Patients with lung metastasis-related finding at the initiation of lenvatinib treatment had a poorer prognosis among the lung metastasis group. It is important to consider not only the tumor size but also the presence of lung metastasis-related findings when initiating lenvatinib treatment for DTC patients with lung metastasis.

Impact of Local Control on Clinical Course in Stage IVC Anaplastic Thyroid Carcinoma.

BACKGROUND: The present study investigated the association between local resection and cause of death in anaplastic thyroid carcinoma (ATC) patients with stage IVC disease. METHODS: A total of 54 ATC patients with stage IVC disease were included in the study. Information including patient characteristics, laboratory data including complete blood count, treatment, and death were collected for analysis. RESULTS: The median overall survival (OS) for patients with or without resection was 8.4 [95% confidence interval (CI) 5.9-14.4)] and 4.2 (95% CI 2.5-6.2) months, respectively (p < 0.001). No patients survived without resection at 1 year. Univariate analysis revealed that resection (p < 0.001) and radiotherapy (p = 0.018) were significantly associated with OS. Multivariate analysis revealed that resection (hazard ratio 0.257; 95% CI 0.115-0.575; p < 0.001) was the only independent prognostic factor of OS. In ATC patients with known resection status, the median OS for the patients with a resection status of R0/1 (n = 28) and R2 (n = 7) were 13.0 (95% CI 7.5-18.7) and 1.7 (95% CI 0.1-6.2) months, respectively (p < 0.001). The most common specific cause of death was respiratory insufficiency (35%), followed by airway obstruction (25%) and cerebral cardiovascular-related death (5%). The frequency of airway obstruction was significantly lower in patients with resection (p = 0.018). CONCLUSIONS: Resection probably impacts on clinical course in ATC patients despite the presence of distant metastasis. However, R2 resection is likely to be harmful and surgeons should carefully consider the resectability of thyroid tumors.

Pneumatosis intestinalis associated with lenvatinib during thyroid cancer treatment: a case report.

BACKGROUND: Pneumatosis intestinalis is a rare disease characterized by gas-filled cysts within the submucosa or serosa of the intestinal tract. In recent years, pneumatosis intestinalis was reported in patients undergoing cancer treatment, and some case reports exist that report that pneumatosis intestinalis occurs during administration of vascular endothelial growth factor inhibitors, such as bevacizumab and sunitinib. Here, we report the first case of pneumatosis intestinalis during lenvatinib treatment. CASE PRESENTATION: A 77-year-old Japanese man presented to our hospital with a chief complaint of numbness in the right leg and weakness of the lower limbs 9 years after right thyroid lobectomy. Computed tomography showed a tumor 90 mm in size from the lumbar spine to the sacrum, causing spinal cord compression. Blood tests showed that the patient's thyroglobulin level was increased to 11,600 ng/ml. We diagnosed him with thyroid cancer with bone metastases. External beam radiotherapy (39 Gy/13 Fr) was performed on the bone metastases, followed by total thyroidectomy and radioactive iodine therapy. Four months after radioactive iodine therapy, lenvatinib was introduced because the symptoms of numbness and weakness recurred. Lenvatinib was introduced at dose of 24 mg, and then it was reduced to 14 mg owing to Common Terminology Criteria for Adverse Event grade 3 paronychia of the right foot. Although no further significant adverse events occurred, a scheduled computed tomography image showed pneumatosis intestinalis of the ascending colon 14 weeks after the introduction of lenvatinib. No abdominal or digestive symptoms were observed; therefore, we selected conservative treatment. We discontinued lenvatinib for a week, but we were required to restart lenvatinib as the numbness in the right leg worsened after withdrawal. Since the introduction of lenvatinib, 3 years and 5 months passed; we continued lenvatinib treatment, and the therapeutic effect remains partial response. There has been no recurrence of pneumatosis intestinalis. CONCLUSIONS: Although rare, it is important to recognize that pneumatosis intestinalis can occur in association with lenvatinib and should be differentiated from intestinal perforation. Pneumatosis intestinalis association with lenvatinib can be improved by withdrawal.

Inflammatory biomarkers and dynamics of neutrophil-to-lymphocyte ratio in lenvatinib treatment for anaplastic thyroid carcinoma.

BACKGROUND: Inflammatory biomarkers have been reported to be associated with anticancer drug efficacy in various cancers. This study aimed to investigate the associations between baseline inflammatory biomarkers or dynamics of neutrophil-to-lymphocyte ratio (NLR) and treatment outcomes of lenvatinib in ATC. METHODS: Twenty ATC patients whose complete blood count were available were included in this study. Patients characteristics, overall survival (OS), and the associations between baseline inflammatory biomarkers or dynamics of NLR and treatment outcomes of lenvatinib were investigated. RESULTS: All 20 patients had a median baseline NLR of 4.5 (range, 1.4-19.7), a median platelet-to-lymphocyte ratio (PLR) of 169.9 (range, 66.8-671.1), and a median lymphocyte-to-monocyte ratio (LMR) of 2.6 (range, 0.5-5.5). The median OS was 4.2 (95% CI: 1.1-10.3) months in patients with baseline NLR ≤4.5 and 3.1 (95% CI: 1.1-8.3) months in patients with baseline NLR >4.5 (P=0.681). The median OS was 4.2 (95% CI: 1.1-7.8) months in patients with baseline PLR ≤169.9 and 3.9 (95% CI: 0.6-8.3) months in patients with baseline PLR >169.9 (P=0.822). The median OS was 3.7 (95% CI: 1.1-9.8) months in patients with baseline LMR ≤2.6 and 4.2 (95% CI: 0.6-5.4) months in patients with baseline LMR >2.6 (P=0.421). NLR was increased more than the standard deviation of the baseline NLR after lenvatinib initiation in two of 16 patients with follow-up NLR data available. The median OS was 2.0 (95% CI: 1.1- not estimable) months in the increased group but was 5.3 (95% CI: 3.1-9.8) months in the non-increased group (P=0.003). CONCLUSIONS: There was seemed to be no association between prognosis or treatment efficacy of lenvatinib and baseline inflammatory biomarker values in our cases with ATC. However, we possibly estimate prognosis for ATC during lenvatinib treatment by observing the dynamics of NLR.

Invasive procedures in patients undergoing treatment with lenvatinib for thyroid cancer.

Lenvatinib is a multi-tyrosine kinase inhibitor that inhibits angiogenesis and is currently in use for the treatment of refractory thyroid cancer. Therapy using this agent can be prolonged in patients, although serious complications may ensue among those who require surgical procedures. To the best of our knowledge, the safety of invasive surgical procedures in patients undergoing treatment with lenvatinib has not been fully evaluated. A total of 94 patients were treated with lenvatinib for thyroid cancer between June 2015 and August 2019 at the Kanagawa Cancer Center. Of this cohort, 14 invasive procedures were performed on 11 patients. A total of 8 of these procedures were performed under local anesthesia and 6 under general anesthesia; 3 belonging to the latter group were emergency procedures. No primary wound complications were observed among the patients in the cohort; however, one case of delayed healing secondary to placement of a thoracic drain for acute pneumothorax was reported in the present study. Lenvatinib was initially discontinued in this patient, but it was reintroduced 17 days later due to hypoxemia that may have been related to lung metastases. Hypoxemia improved, although wound healing spanned 14 weeks. Therapy was discontinued prior to percutaneous endoscopic gastrostomy in a patient with local progression; while no wound complications were observed, the patient ultimately died from exacerbation of neoplastic disease. In the current study, which focused on surgical interventions performed on patients undergoing lenvatinib treatment, 1 in 14 wound complications improved conservatively. However, it is critical to recognize that disease progression may occur if drugs are withdrawn prior to performing invasive procedures.

Membrane type 1 matrix metalloproteinase regulates anaplastic thyroid carcinoma cell growth and invasion into the collagen matrix.

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive cancer types; however, the molecular mechanism contributing to the aggressive characteristics remain unclear. Membrane type 1 matrix metalloproteinase (MT1-MMP) plays an important role in cancer invasion and has been associated with a poor prognosis in various malignant neoplasms. In this study, we investigated the relationship between MT1-MMP expression and the proliferation and invasion of ATC cells, along with the association with clinicopathologic factors in patients with ATC. Suppression of MT1-MMP reduced the proliferation and invasion of ATC cells, and suppressed ERK activity, indicating a role in cancer cell proliferation in collagen matrix culture conditions. The expression of MT1-MMP was detected in 29 of 34 (85.3%) surgical specimens from ATC patients. In addition, the expression of MT1-MMP in the tumor lesion was higher than that of normal and stromal tissues. Collectively, these results suggest that elevated MT1-MMP expression plays a role in the pathogenesis of ATC, which may promote its aggressive characteristics such as proliferation and invasion, highlighting a potential new therapeutic target.

Clinical outcomes and risk stratification for papillary thyroid carcinoma presenting with distant metastasis before the era of tyrosine kinase inhibitors.

Radioactive iodine (RAI) therapy has been the mainstay of treatment for papillary thyroid carcinoma (PTC) patients with distant metastasis (DM). Although tyrosine kinase inhibitors (TKIs) were introduced for the treatment of RAI refractory metastatic thyroid carcinoma several years ago, clinical outcomes for PTC patients with DM treated using RAI therapy remain unclear. We retrospectively examined 64 PTC patients (9 men, 55 women) with DM at diagnosis treated using RAI therapy without administration of any kind of chemotherapy or TKIs. Median age of patients was 58 years. Site of DM was the lungs (n = 59), bone (n = 3), and pleural dissemination (n = 2). No patients showed multiple-organ metastases at diagnosis. By the end of the study period, 21 patients had died of PTC. Cause-specific survival rates at 10, 15, and 20 years after initial surgery were 68.2%, 63.6% and 61.1%, respectively. Uni- and multivariate analyses identified age ≥55 years (HR 3.1, p = 0.023), site of DM other than the lungs (HR 13.4, p < 0.0001), and DM with no RAI avidity (HR 5.1, p = 0.0098) as factors independently associated with disease-related death. When analyses were restricted to patients with lung metastasis (n = 59), surgical non-curability was another independent risk factor (HR 5.2, p = 0.0047) in addition to age and RAI avidity. According to risk stratification analysis based on these risk factors, patients with site of DM other than the lungs or with lung metastasis showing ≥2 risk factors among age ≥55 years, DM with no RAI avidity, and surgical non-curability are expected to show higher mortality rates.

Occult Thyroid Carcinoma without Malignant Thyroid Gland Findings during Preoperative Examination: Report of Three Cases.

Occult thyroid carcinoma preceded by clinical manifestations and findings from extrathyroidal tumors is rare. The lack of malignant findings in the thyroid during the preoperative examination makes diagnosis difficult. We encountered a 71-year-old man with a primary ectopic thyroid carcinoma causing superior vena cava syndrome. Although no malignant findings were found in the thyroid gland, biopsy of bone metastases led to the diagnosis of thyroid cancer. HE staining of bone metastases revealed nuclear features of papillary carcinoma, and immunostaining was positive for thyroglobulin and PAX-8. The second case involved an 84-year-old man with a mediastinal tumor and suspected thyroid cancer because of high thyroglobulin levels in blood. The pathological tumor finding was papillary thyroid cancer. The last case was that of a 56-year-old woman lacking preoperative thyroid examination malignant findings, but with cervical lymph node metastasis. The thyroglobulin level of the lymph node puncture fluid was useful for preoperative diagnosis. We performed total thyroidectomy plus bilateral modified neck dissection. Pathology revealed a 1 mm papillary carcinoma in the left lobe. All of these cases were difficult to diagnose. However, we combined the results of various tests such as radiographic imaging, blood tests, and immunohistological tests to diagnose our patients.

Evaluation of the 8th Edition TNM Classification for Anaplastic Thyroid Carcinoma.

BACKGROUND: The tumor-node-metastasis (TNM) classification system to categorized anaplastic thyroid cancer (ATC) was revised. METHODS: The revised system was evaluated using a large database of ATC patients. RESULTS: A total of 757 patients were analyzed. The proportion and median overall survival values (OS: months) for each T category were T1 (n = 8, 1.1%, 12.5), T2 (n = 43, 5.7%, 10.9), T3a (n = 117, 15.5%, 5.7), T3b (n = 438, 57.9%, 3.9), and T4 (n = 151, 19.9%, 5.0). The OS of the N0 and N1 patients were 5.9 and 4.3, respectively (log-rank p < 0.01). Sixty-three (58.3%) patients migrated from stage IV A to IV B by revision based on the existence of nodal involvement and 422 patients (55.7%) were stratified into stage IV B, without a worsening of their OS (6.1), leaving 45 patients (5.9%) in stage IV A with fair OS (15.8). The hazard ratios for the survival of the patients of stage IV B compared to stage IV A increased from 1.1 to 2.1 by the revision. No change was made for stage IV C (n = 290, 38.8%, 2.8). CONCLUSION: The revised TNM system clearly indicated the prognoses of ATC patients by extracting rare patients with fair prognoses as having stage IV A disease and categorized many heterogeneous patients in stage IV B.

Expression of fibroblast growth factor receptor 4 and clinical response to lenvatinib in patients with anaplastic thyroid carcinoma: a pilot study.

PURPOSE: Fibroblast growth factor receptor 4 (FGFR4) expression has association with tumor malignancy. In thyroid cancers, FGFR4 has been reported to be characteristically expressed in aggressive thyroid tumors, such as anaplastic thyroid carcinoma (ATC). METHODS: We investigated FGFR4 expression in patients with ATC and analyzed their clinical responses to lenvatinib. Primary tumor samples were obtained from 12 patients with ATC who underwent surgery or core needle biopsy. FGFR4 protein expression in all ATC samples was analyzed via immunohistochemistry, and the treatment efficacy of lenvatinib was evaluated. RESULTS: The proportion of FGFR4-positive cells in the samples ranged from 0 to 50%. Four patients had partial responses, and three patients had stable diseases as a best clinical response to lenvatinib. The median PFS durations of patients with none, weak, and moderate intensity were 0.5, 3.2 (95% CI 1.1-not estimable [NE]), and 4.6 (95% CI 1.1-NE) months, respectively (p = 0.003). CONCLUSIONS: Because FGFR4 was expressed in ATC tissues, the FGFR4 expression might be associated with the treatment efficacy of lenvatinib in a part of ATC patients. To clarify whether FGFR4 can serve as a prognostic or predictive factor for lenvatinib therapy, more cases must be accumulated.