Clinical impact of proteinuria on renal function and treatment outcomes in patients with radioiodine-refractory thyroid cancer treated with lenvatinib.

Proteinuria has been described as a major on-target adverse event of lenvatinib, although its long-term impact on renal function and clinical outcomes remains unclear. We conducted a retrospective observational study to assess renal function and prognosis in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) receiving lenvatinib. Overall, 70 patients with RR-DTC treated with lenvatinib were enrolled. When proteinuria was observed, the dose and schedule of lenvatinib were adjusted to achieve a urine protein-to-creatinine ratio (UPCR) of less than 3.5 g/gCre according to the study protocols of recent pivotal trials. In total, 50 (71%) and 25 (36%) patients presented with any-grade and grade 3 proteinuria, respectively. Multivariate analysis revealed that age [>65; odds ratio (OR) 8.24, 95% confidence interval (CI) 1.74-39.00, p < 0.01], history of diabetes mellitus (OR 7.79, 95% CI 1.31-46.20, p = 0.02), and hypertension (OR 4.07, 95% CI 1.22-13.60, p = 0.02) were significantly associated with the development of grade 3 proteinuria. Overall, the median estimating glomerular filtration rate (eGFR) gradually decreased every 3 months during treatment. However, no significant deterioration in eGFR was observed in patients with grade 3 proteinuria compared with patients with grades 0-2 proteinuria until 48 months. Patients who developed proteinuria had better survival outcomes than those without proteinuria. In conclusion, the proteinuria grade was not significantly associated with decreased eGFR under UPCR monitoring in our study. Therefore, lenvatinib can carefully be continued targeting UPCR of less than 3.5 g/gCre.

Surgical strategy for patients with papillary thyroid carcinoma invading the trachea: a comparison of tracheal sleeve resection with end-to-end anastomosis and window resection with tracheocutaneous fistula.

Background: Sleeve resection with end-to-end anastomosis (Procedure A) and window resection with a tracheocutaneous fistula (Procedure B) are the major surgical procedures for patients with papillary thyroid carcinoma (PTC) exhibiting transluminal tracheal invasion. For each procedure, the indications, postoperative course, and treatment results were examined retrospectively. Methods: Of 1,456 patients with PTC (maximum tumor diameter >1 cm) who received initial treatment between 1993 and 2013, we reviewed 51 patients. Of these 51 cases, 45 showed full-layer tracheal invasion, and 6 did not reach the tracheal mucosa, but required full-layer tracheal resection. Twenty-four patients underwent Procedure A, and 27 patients underwent Procedure B. Results: Regarding surgical procedure selection, Procedure B was selected significantly more frequently than Procedure A for cases with preoperative recurrent laryngeal nerve (RLN) palsy, tumor invasion of the esophagus, clinical lymph node metastasis, or a large number of resected tracheal rings. Postoperative airway-related complications were not significantly different between the procedures, but decreased with the use of intraoperative neuromonitoring (IONM). The postoperative hospital stay was significantly longer for Procedure B than for Procedure A. In addition, the rate of a permanent postoperative tracheostoma was higher with Procedure B than with Procedure A. Local recurrence-free survival (LRFS) and cause-specific survival (CSS) did not differ significantly between the two procedures. Conclusions: Certain patients may benefit from Procedure A with IONM in terms of a shorter hospital stay and avoiding the need for a permanent tracheostoma. Although Procedure B was indicated for patients with more advanced disease than Procedure A, treatment outcomes were similar.

Patient-Reported Outcomes in Patients with Low-Risk Papillary Thyroid Carcinoma: Cross-Sectional Study to Compare Active Surveillance and Immediate Surgery.

BACKGROUND: This cross-sectional study compared patient-reported outcomes of low-risk papillary thyroid carcinoma (PTC, T1N0M0) between patients who underwent active surveillance (AS) and those who received immediate surgery, METHODS: Using the State-Trait Anxiety Inventory, Short-Form 36 version 2, and a visual analog scale for neck symptoms, 249 patients under AS and 32 patients underwent immediate surgery were compared. To match the difference in time from the onset of treatment to the survey, we conducted propensity score matching. We also investigated factors affecting anxiety in patients under AS in multiple linear regression analysis. RESULTS: In the entire group, patients under AS had significantly longer time from the onset to the survey than patients underwent immediate surgery (7.9 vs. 4.0 years). After matching, AS group showed significantly better trait anxiety and mental component summary (MCS) compared to surgery group, while surgery group showed better role-social component summary. AS group also had significantly better MCS than the Japanese norm-based score. Surgery group displayed worse neck symptoms than AS group. Among AS group, trait anxiety and time from the onset were significant predictors of state anxiety. Compared with the group with < 5 years since starting AS, the group with ≥ 5 years of follow-up showed a significantly better state anxiety only in patients with better trait anxiety. CONCLUSIONS: Low-risk PTC patients under AS showed better trait anxiety and mental health than surgery group. After a certain period, the anxiety of patients under AS seems to be improved, especially in patients with better trait anxiety.

Long-Term Outcomes After Lobectomy for Patients with High-Risk Papillary Thyroid Carcinoma.

BACKGROUND: Guidelines universally recommend total thyroidectomy for high-risk papillary thyroid carcinoma (PTC). However, in Japan, thyroid-conserving surgery had been widely applied for such patients until recently. We investigated long-term outcomes for this strategy. METHODS: A prospectively recorded database was retrospectively analyzed for 368 patients who had undergone curative surgery for high-risk PTC without distant metastasis between 1993 and 2013. High-risk PTC was defined for tumors showing tumor size > 4 cm, extrathyroidal extension, or large nodal metastasis ≥ 3 cm. RESULTS: Median age was 59 years and 243 patients were female. Mean duration of follow-up was 12.7 years. Lobectomy was conducted for 207 patients (LT group) and total or near-total thyroidectomy for 161 patients (TT group). The frequency of massive extrathyroidal invasion and large nodal metastasis was lower in the LT group than in the TT group. After propensity score matching, no significant differences were seen between groups for overall survival, cause-specific survival or distant recurrence-free survival. In the overall cohort, multivariate analysis identified age ≥ 55 years, large nodal metastasis, tumor size > 4 cm and massive extrathyroidal invasion as significantly associated with cause-specific survival, whereas extent of thyroidectomy was not. CONCLUSIONS: For patients with high-risk PTC without distant metastasis, curative surgery with lobectomy showed almost identical oncological outcomes compared to total thyroidectomy. The benefits of total thyroidectomy for high-risk PTC should be reevaluated in the future prospective studies.

A proposed clinical scoring system for initiation of lenvatinib treatment in radioiodine-refractory thyroid cancer patients.

PURPOSE: The optimal timing for starting lenvatinib treatment in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) has long been controversial because of the relatively slow-growing nature of differentiated thyroid cancer. The aim of this study was to establish a scoring system using known clinical factors to simplify decision-making in when to start lenvatinib in RR-DTC patients. METHODS: We retrospectively analyzed RR-DTC patients treated with lenvatinib. We developed the clinical indication scoring algorithm on the basis of age, tumor-related symptoms, histology, metastatic sites, neutrophil-to-lymphocyte ratio, size of lung metastases, baseline sum of tumor diameters, and tumor-volume doubling time that was used to categorize patients into low-, intermediate-, and high-risk groups. RESULTS: A total of 59 patients were analyzed; 13 low-risk, 36 intermediate-risk, and 10 high-risk. The respective median progression-free survival from the initiation of lenvatinib was 93.7 months in the low-risk group, 20.3 months in the intermediate-risk group, and 6.2 months in the high-risk group (p < 0.02). Patients in the high-risk group had significantly worse overall survival compared with those in the low-risk (hazard ratio [HR] 6.59, 95% confidence interval [CI] 1.25-34.90, p < 0.03) or intermediate-risk (HR 2.99, 95% CI 1.03-8.63, p < 0.05) group. Using our proposed algorithm, patients in the intermediate-risk group showed treatment outcomes similar to that were observed in the pivotal trial of lenvatinib, and were the optimal patients to start lenvatinib. CONCLUSION: Our proposed scoring system can separate treatment outcomes and prognosis of RR-DTC patients treated with lenvatinib. This simple algorithm can be helpful for oncologists in deciding whether to start lenvatinib treatment in patients with RR-DTC.

Correlation between low expression of protein disulfide isomerase A3 and lymph node metastasis in papillary thyroid carcinoma and poor prognosis: a clinicopathological study of 1,139 cases with long-term follow-up.

The incidence of papillary thyroid carcinoma (PTC) is increasing worldwide. The biomarkers to identify aggressive types of PTC are limited, illustrating the need to establish reliable novel biomarkers. Protein disulfide isomerase A3 (PDIA3) is a chaperone protein that modulates the folding of newly synthesized glycoproteins and stress-responsive proteins in the endoplasmic reticulum. Although the role of PDIA3 in various cancers such as breast, uterine cervix, head and neck, and gastrointestinal tract has been examined, its expression in thyroid cancer has not been reported. We retrospectively reviewed accumulated data with long-term follow-up of 1,139 PTC patients, and investigated the correlation between immunohistochemical expression of PDIA3 in PTC patients and clinicopathological features and prognosis. PDIA3 expression was significantly lower in PTCs compared to normal thyroid tissues (NTT; n = 80, p = 0.002). In PTCs, correlation between low PDIA3 expression and lymph node metastasis (p = 0.018) and the number of positive nodes (p = 0.004) was observed. Patients with low PDIA3 expression exhibited worse cause-specific survival compared to those with high PDIA3 expression (p = 0.013). Our findings indicate that low PDIA3 expression is related to poor clinical outcome in PTC patients, and that PDIA3 may potentially be a novel ancillary biomarker. Further clarification of the biological role of PDIA3 in PTC is warranted for the future clinical application.

Multifocality and Progression of Papillary Thyroid Microcarcinoma During Active Surveillance.

BACKGROUND: Prospective trials of active surveillance (AS) have shown low rates of progression in low-risk papillary thyroid microcarcinoma (PTMC; T1aN0M0). However, the significance of multifocality as a prognostic factor remains controversial. METHODS: Data from 571 patients (mean age, 53.1 years; 495 females) who underwent AS were reviewed. PTMC was unifocal in 457 patients (80.0%) and multifocal in 114 patients (20.0%), with 2-5 lesions each (261 tumors in total). Tumor progression was defined as tumor size enlargement ≥ 3 mm and/or development of clinically evident lymph node metastasis (LNM). RESULTS: After a mean duration of AS of 7.6 years, 53 patients (9.3%) showed tumor enlargement and 8 patients (1.4%) developed LNM. The 10-year progression rate was 13.1%. Age, sex, and calcification pattern did not differ significantly between uni- and multifocal diseases. However, anti-thyroglobulin antibody and/or anti-thyroid peroxidase antibody was more frequently positive with multifocal PTMCs (46.7%) than with unifocal disease (34.4%, p = 0.024). Patients with uni- and multifocal disease showed no significant differences in 10-year rate of tumor enlargement (11.4% vs. 14.8%), LNM development (1.1% vs. 2.4%), or progression (12.4% vs 15.9%). Multivariate analysis of predictors for progression showed multifocality was not a significant risk factor (odds ratio, 1.45; 95% confidence interval, 0.79-2.54; p = 0.22). Eventually, 9 patients (7.9%) with multifocal PTMCs underwent surgery and 7 needed total thyroidectomy, although 7 still showed T1N0M0 low-risk cancer. CONCLUSIONS: Even patients with multiple PTMCs (T1amN0M0) are good candidates for AS. Many patients can avoid total thyroidectomy and subsequent surgical complications.

Baseline Tumour Size as a Prognostic Factor for Radioiodine-refractory Differentiated Thyroid Cancer Treated With Lenvatinib.

BACKGROUND/AIM: Lenvatinib is standard therapy for radioiodine-refractory differentiated thyroid cancer (RR-DTC), although the optimal timing for starting treatment is still controversial. The aim of this study was to evaluate the prognostic impact of baseline tumour size (BTS) in patients with RR-DTC treated with lenvatinib. PATIENTS AND METHODS: Fifty-one RR-DTC patients who had at least one measurable lesion and treated with lenvatinib were retrospectively analysed. BTS was defined as the sum of the longest dimensions of all measurable target lesions. RESULTS: Median progression-free survival (PFS) and overall survival (OS) in the larger BTS (≥42 mm) group were shorter than those in the smaller (<42 mm) group. This result was more significant in patients with fast-growing tumours. BTS was an independent prognostic factor for both PFS and OS. CONCLUSION: Starting lenvatinib at BTS <42 mm should be recommended to achieve good treatment outcomes in patients with RR-DTC.

Prognostic significance of 8 weeks' relative dose intensity of lenvatinib in treatment of radioiodine-refractory differentiated thyroid cancer patients.

Lenvatinib is a standard therapy for radioiodine-refractory differentiated thyroid cancer (RR-DTC). However, because of the high incidence of adverse events resulting from this treatment, it is not easy to maintain the dose intensity of lenvatinib, especially in Japanese patients. Although the prognostic impact of lenvatinib dose interruption has been reported, the target dose intensity of lenvatinib to optimize survival benefits remains unknown. We therefore propose a target dose intensity of lenvatinib during the first 8 weeks of treatment. We retrospectively analyzed 42 RR-DTC patients who were treated with lenvatinib for more than 8 weeks. We performed receiver operating characteristic curve analysis to determine the cut-off value of 8 weeks' relative dose intensity (8w-RDI) to predict treatment response, and identified that the optimal cut-off value of 8w-RDI was 60% (sensitivity: 81.8%; specificity: 80.6%). Median progression-free survival (PFS) (not reached [NR] vs. 11.0 months; hazard ratio [HR] 0.29; 95% confidence interval [CI] 0.11-0.72; p < 0.01) and overall survival (NR vs. 27.6 months; HR 0.44; 95% CI 0.11-0.91; p = 0.03) were longer in the higher 8w-RDI (≥60%) patients than in the lower 8w-RDI (<60%) patients. Multivariate analysis revealed that 8w-RDI at ≥60% was an independent prognostic factor for PFS (HR 0.29; 95% CI 0.09-0.96; p = 0.04). Targeting for ≥60% of the relative dose intensity during the first 8 weeks of lenvatinib treatment can be sufficient to achieve significant tumor shrinkage and prolong PFS in RR-DTC patients.

Neutrophil-to-Lymphocyte Ratio as a Prognostic Marker for Anaplastic Thyroid Cancer Treated With Lenvatinib.

BACKGROUND/AIM: Lenvatinib is one of the few options for patients with anaplastic thyroid cancer (ATC). However, tumor markers for ATC treated with lenvatinib is lacking. The aim of this study was to explore whether the neutrophil-to-lymphocyte ratio (NLR) can be a tumor marker for ATC treated with lenvatinib. PATIENTS AND METHODS: We retrospectively analyzed the prognostic significance of the NLR in 13 ATC patients treated with lenvatinib. RESULTS: The disease control rate was better in patients with lower NLR (<8; 89%) than higher NLR (≥8; 25%) (p=0.05). Median progression-free survival and overall survival were longer in patients with lower NLR than higher NLR (4.0 vs. 1.6 months, p<0.05; and 10.2 vs. 3.8 months, p<0.05, respectively). Patients whose NLR on day 14 decreased compared to baseline had a slightly higher overall response rate than patients without NLR decrease (42.9% vs. 0%, p=0.19). CONCLUSION: The baseline NLR is a potential prognostic marker, and the change of NLR can be an early indicator of response for ATC patients treated with lenvatinib.

A Phase II study of the safety and efficacy of lenvatinib in patients with advanced thyroid cancer.

AIM: To investigate the safety and efficacy of lenvatinib in advanced thyroid cancer. PATIENTS/METHODS: In this Phase II study, 51 Japanese patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC), medullary thyroid cancer (MTC) or anaplastic thyroid cancer (ATC) received once-daily lenvatinib 24 mg. The primary end point was safety. RESULTS: All patients experienced ≥1 adverse event (AE); only one patient experienced an AE leading to discontinuation. The most common any-grade AEs were hypertension, decreased appetite, palmar-plantar erythrodysesthesia, fatigue and proteinuria. Response rates for RR-DTC: 68%; MTC: 22%; ATC: 24%. Median progression-free survival for RR-DTC: 25.8 months; MTC: 9.2 months; ATC: 7.4 months. CONCLUSION: Lenvatinib demonstrated a manageable safety profile, proven antitumor activity in RR-DTC and promising efficacy in MTC and ATC. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov NCT01728623.

Active Surveillance for T1bN0M0 Papillary Thyroid Carcinoma.

BACKGROUND: Prospective trials of active surveillance for asymptomatic papillary microcarcinoma (T1aN0M0) since the 1990s have shown progression rates of only 5-10%. Late rescue surgery after progression had no deleterious effects on mortality and morbidity. The 2015 American Thyroid Association guidelines approved active surveillance for very low-risk papillary thyroid carcinoma (PTC) as an alternative method to immediate surgery. However, there is no study that evaluates long-term active surveillance for T1b tumors. METHODS: A prospective trial of active surveillance with 360 very low-risk PTC (T1aN0M0) patients has been conducted since 1995. Of the 392 T1bN0M0 patients, 61 selected active surveillance over surgery and eventually participated in this trial, while the remaining 331 patients underwent surgery. To find an appropriate management strategy for patients with T1bN0M0 PTC, the outcomes of active surveillance for T1bN0M0 to T1aN0M0 PTC were investigated and compared, and the outcomes of surgery for T1bN0M0 PTC were studied. RESULTS: After a mean of 7.4 years of active surveillance, 29 (8%) T1aN0M0 tumors and four (7%) T1bN0M0 tumors had increased in size (p = 0.69). Development of lymph node metastasis was seen in three (0.8%) patients and two (3%) patients, respectively (p = 0.10). No significant difference in progression rate was seen between groups. Among T1bN0M0 tumors, weak calcification and rich vascularity were risk factors for tumor-size increase, and younger age was a predictor for the development of lymph node metastasis. Mean initial tumor size was significantly greater in T1bN0M0 patients who underwent immediate surgery (14.5 ± 2.8 mm) than it was in patients who chose observation (11.7 ± 1.1 mm; p < 0.0001). No postoperative recurrence was seen in patients with tumor <15 mm in diameter. CONCLUSIONS: Active surveillance is an option for selected patients with T1bN0M0 PTC.

Thick tumor capsule is a valuable risk factor for distant metastasis in follicular thyroid carcinoma.

OBJECTIVE: While the biological behavior of follicular thyroid carcinoma (FTC) has been studied in great detail using clinical experience, few studies have investigated pre- or intraoperative factors related to the risk of distant metastasis (DM) among patients with FTC. The aim of this study was to analyze the characteristics of FTC with DM. METHODS: This study retrospectively investigated 102 patients with FTC who underwent surgery between 1988 and 2013. We compared clinicopathological characteristics between FTC with and without DM. RESULTS: Univariate analysis revealed nodal metastasis (p=0.045), serum thyroglobulin (Tg) at initial operation (≥1000ng/ml; p<0.0001), widely invasive appearance according to macroscopic findings (p<0.0001), thick tumor capsule (≥1mm; p<0.0001), vascular invasion (p=0.0003), extrathyroidal invasion (p=0.047), and venous tumor embolism (p=0.045) as significant risk factors for DM. Multivariate analysis conducted using pre- and intraoperative factors identified thick tumor capsule (≥1mm), serum Tg at initial operation (≥1000ng/ml), and macroscopically widely invasive appearance as risk factors independently associated with development of DM. CONCLUSION: Patients with these risk factors should undergo total thyroidectomy and radioactive iodine ablation.

Lenvatinib for Anaplastic Thyroid Cancer.

BACKGROUND: Lenvatinib has been approved by regulatory agencies in Japan, the United States, and the European Union for treatment of radioiodine-refractory differentiated thyroid cancer (RR-DTC). Thyroid cancer, however, is a clinically diverse disease that includes anaplastic thyroid cancer (ATC), the subtype associated with the highest lethality. Effective therapy for ATC is an unmet need. PATIENTS AND METHODS: This phase 2, single-arm, open-label study in patients with thyroid cancer, including ATC, RR-DTC, and medullary thyroid cancer was conducted from 3 September 2012 to 9 July 2015. Patients received lenvatinib 24 mg daily until disease progression or development of unacceptable toxicity. The primary endpoint was safety, and the secondary endpoint was efficacy, as assessed by progression-free survival (PFS), overall survival (OS), and objective response rate. RESULTS: At data cutoff, 17 patients with ATC were enrolled. All experienced ≥1 treatment-emergent adverse event (TEAE). The most frequent TEAEs were decreased appetite (82%), hypertension (82%), fatigue (59%), nausea (59%), and proteinuria (59%). Of note, only one patient required lenvatinib withdrawal because of a TEAE, and this TEAE was considered unrelated to lenvatinib. The median PFS was 7.4 months [95% confidence interval (CI): 1.7-12.9], the median OS was 10.6 months (95% CI: 3.8-19.8), and the objective response rate was 24%. CONCLUSION: In this study, lenvatinib demonstrated manageable toxicities with dose adjustments and clinical activity in patients with ATC. This clinical activity of lenvatinib warrants further investigation in ATC. CLINICALTRIALSGOV: NCT01728623.

Impending Atypical Femoral Fracture in Patients With Medullary Thyroid Cancer With Skeletal Metastasis Treated With Long-term Bisphosphonate and Denosumab.

Atypical femoral fractures (AFFs) occur in osteoporosis patients receiving long-term bisphosphonate. Atypical femoral fractures also occur in cancer patients receiving long-term bisphosphonate or denosumab, but the prevalence is low. We describe a 53-year-old woman with a history of medullary thyroid cancer and skull metastasis who was prescribed bisphosphonate for 6 years and denosumab for 1.5 years, consecutively. Bone scintigraphy performed because of spontaneous groin pain showed uptake in the lateral aspect of the left femur, which was confirmed as impending AFF. In oncological patients receiving long-term bisphosphonate or denosumab, AFF should be included as a differential diagnosis with focal femoral findings.

The Safety and Efficacy of Weekly Paclitaxel Administration for Anaplastic Thyroid Cancer Patients: A Nationwide Prospective Study.

BACKGROUND: Anaplastic thyroid cancer (ATC) is a rare and extremely aggressive malignancy, with a median survival of less than 6 months due to rapid progression and resistance to multimodal therapies. Effective treatment strategies have not been identified. A prospective clinical study was performed to objectively evaluate outcomes of treatment with paclitaxel. METHODS: An investigator-initiated, multicenter, nonrandomized, open-label, single-arm study to evaluate the feasibility and efficacy of weekly paclitaxel (80 mg/m(2)) administration for patients with pathologically confirmed ATC was conducted in a nationwide organization. RESULTS: Feasibility was analyzed in 56 patients. More than one course of treatment was performed in 52 (93%) patients retaining sufficient dose intensity (>84%). No patient had to terminate the treatment because of an adverse event. The median overall survival was 6.7 months [confidence interval 4.4-9.0]. The 6-month survival was 54%. Among the 42 patients with an evaluable lesion, none demonstrated complete remission, 9 (21%) showed partial remission, 22 (52%) achieved stable disease, and 8 (19%) exhibited progressive disease; 3 did not complete the initial treatment course. The objective response rate was 21%, and the clinical benefit rate was 73%. The median time to progression was 1.6 months. Statistically, no additional effect of concomitant radiation was demonstrated in 6 patients receiving combined therapy. Eight patients, in whom a complete post-treatment surgical removal of the tumor was feasible, survived significantly longer (median 7.6 months [CI 8.1-23.0]) than the other 34 patients in whom the tumor could not be completely removed after chemotherapy (5.4 months [CI 3.0-7.8], p = 0.018). SUMMARY: The study demonstrates objective and accurate information concerning the feasibility and efficacy of a standardized treatment with weekly paclitaxel administration for ATC patients. CONCLUSIONS: Weekly paclitaxel administration for ATC patients can be of clinical benefit in a neo-adjuvant setting.

Histopathological analysis of anaplastic thyroid carcinoma cases with long-term survival: A report from the Anaplastic Thyroid Carcinoma Research Consortium of Japan.

The aim of this study was to clarify the histopathological features of anaplastic thyroid carcinoma in patients who achieved long-term survival. We reviewed 88 anaplastic thyroid carcinoma cases in which the patient survived less than 3 months (short-term survival), and 68 anaplastic thyroid carcinoma cases in which the patient survived more than one year (long-term survival) from the database of the Anaplastic Thyroid Carcinoma Research Consortium of Japan. We examined these cases both histologically and immunohistochemically. Six (6.8%) short-term survival cases and 27 (39.7%) long-term survival cases were considered not to be anaplastic thyroid carcinoma after central review. Of these, 12 were revised to papillary carcinoma with squamous cell carcinoma. In cases without chemotherapy, long-term survival was significantly more common if there was a pre-existing tumor, epithelial growth, or lymphocytic infiltration, and short-term survival was more common if neutrophilic infiltration was present. In cases with chemotherapy, long-term survival was significantly more common if epithelial growth or a squamous cell carcinoma component was present, whereas short-term survival was more common in cases with rhabdoid cells. Immunohistochemical results were not related to survival. Some long-term survival cases showed histological findings other than those typically associated with anaplastic thyroid carcinoma. The presence of a pre-existing tumor, epithelial growth, a squamous cell carcinoma component, no neutrophilic infiltration and lymphocytic infiltration may therefore be favorable prognostic factors in anaplastic thyroid carcinoma.

Common carotid artery rupture during treatment with lenvatinib for anaplastic thyroid cancer.

Anaplastic thyroid cancer is a fatal disease for which no effective therapeutic strategies exist. Lenvatinib, a tyrosine-kinase inhibitor that targets vascular endothelial growth factor receptor, has recently been approved in Japan for the treatment of patients with unresectable thyroid cancer including anaplastic thyroid cancer. Although lenvatinib, like the other tyrosine-kinase inhibitors, sunitinib and sorafenib, might also confer a risk of bleeding, fatal bleeding as a result of lenvatinib treatment for anaplastic thyroid cancer has not been described. A 61-year-old woman presented with a 7-cm mass in the right lobe of the thyroid, lymph node metastases to the neck and multiple lung metastases. Fine needle aspiration revealed that the tumor was anaplastic thyroid cancer. The TNM classification was T4aN1bM1, stage IVC. Shortly after local curative surgery, a tumor recurred in her neck that was treated with lenvatinib (24 mg/day). Nineteen days later, the common carotid artery ruptured and the lenvatinib was stopped. She received the best possible supportive care but died 40 days after stopping the lenvatinib. Autopsy findings showed that the tumor had invaded the adventitia of the common carotid artery at the region of the neck surgery, and an aneurysm had developed. However, the adventitia of the common carotid artery was preserved at the non-dissected area. Lenvatinib might confer risk for fatal bleeding in patients with recurrent anaplastic thyroid cancer after neck surgery, particularly with dissection around the common carotid artery.

Natural History of Asymptomatic Papillary Thyroid Microcarcinoma: Time-Dependent Changes in Calcification and Vascularity During Active Surveillance.

BACKGROUND: Prospective trials of non-surgical observation have shown progression rates of only 5-10% in patients with asymptomatic papillary microcarcinoma (PMC). This study investigated time-dependent changes in calcification patterns and tumor vascularity on ultrasonography (US) to clarify the natural course of PMC. METHODS: We examined calcification patterns and tumor vascularity for 480 lesions in 384 patients. Calcification patterns were classified as: (A) none; (B) micro; (C) macro; or (D) rim. Tumor vascularity was classified as rich or poor via color Doppler US. RESULTS: After a mean of 6.8 years of observation, 29 lesions (6.0%) had increased in size. Mean age for initial calcification pattern was 52.1 years for A (n = 135), 54.2 years for B (n = 235), 56.3 years for C (n = 96), and 60.1 years for D (n = 14), and the incidence rates of tumor enlargement were 9.6, 5.5, 3.2, and 0%, respectively. The cumulative rate of upgrade in calcification pattern was 51.8% at 10 years. Lesions with initially rich vascularity (n = 70) had significantly higher rate of tumor enlargement than those with poor vascularity (n = 410); however, the majority of tumor (61.4%) with initially rich vascularity had decreased their blood supply during the follow-up. Multivariate analysis showed that strong calcification (C or D) and poor vascularity at last examination correlated significantly with non-progressive disease. CONCLUSIONS: PMCs in older patients showed significantly stronger calcification patterns and poorer vascularity. Both consolidation of calcification and loss of vascularity occurred in a time-dependent manner during observation and were significant indicators for non-progressive disease.

Ultrasonographic and non-enhanced CT features of acute transient thyroid swelling following fine-needle aspiration biopsy: report of four cases.

We report four cases of acute transient thyroid swelling following fine-needle aspiration biopsy, a rare complication of still unknown origin. The ultrasonographic pattern was fairly similar to that in previous reports: swelling of the thyroid with a patchy and heterogeneous appearance and diffusely scattered hypoechoic "cracks" that showed no blood flow signals with color Doppler ultrasound. There were also some features that differed from those in previous reports. Though thyroid swelling is typically diffuse and bilateral, it was unilateral or asymmetrical in some of our cases. While thyroid swelling is said to resolve spontaneously within 1-20 h, abnormal ultrasonographic findings persisted for more than 48 h in one case. Unlike previous reports, we have experienced cases with ultrasonographic findings of concomitant minor subcapsular hematomas. In one case, CT demonstrated not only thyroid swelling but also abnormal attenuation in perithyroid tissue extending to the retro-hypopharyngeal space and to the paraesophageal mediastinum. Although vasodilatation and diffuse vascular leakage are speculated to be the underlying mechanisms, our ultrasonograms at the time of the complication failed to demonstrate enlarged intrathyroidal vessels or hypervascularity with color Doppler ultrasound. More awareness and a description of the cases may help to clarify the pathogenesis of this self-limited complication.