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.

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.

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.

TERT Promoter Mutation and Extent of Thyroidectomy in Patients with 1-4 cm Intrathyroidal Papillary Carcinoma.

There are concerns regarding overtreatment in papillary thyroid carcinoma (PTC). BRAF V600E and TERT promoter mutations play important roles in the development of PTC. However, initial surgical approaches for PTC based on genetic characteristics remain unclear. The present study aimed to identify genetic mutations as predictors of prognosis and to establish proper indications for lobectomy (LT) in patients with 1-4 cm intrathyroidal PTC. Prospectively accumulated data from 685 consecutive patients with PTC who underwent primary thyroid surgery at the Cancer Institute Hospital, Tokyo, Japan, between 2001 and 2012 were retrospectively reviewed. Of the 685 patients examined, 538 (78.5%) had BRAF V600E mutation and 133 (19.4%) had TERT promoter mutations. Patients with TERT promoter mutations displayed significantly worse outcomes than those without mutations (10-year cause-specific survival (CSS): 73.7% vs. 98.1%, p < 0.001; 10-year disease-free survival (DFS): 53.7% vs. 93.3%, p < 0.001). As for extent of thyroidectomy among TERT mutation-negative patients with 1-4 cm intrathyroidal PTC, patients who underwent LT showed no significant differences in 10-year CSS and 10-year DFS compared to patients who had total thyroidectomy (TT) under propensity score-matching. Avoiding TT for those patients indicates a possible pathway to prevent overtreatment and reduce postoperative complications.

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.

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.

Stromal tiny black dots, like "sugar-coated", of von Kossa stain is a diagnostic clue to hyalinizing trabecular tumor of the thyroid gland.

Hyalinizing trabecular tumor (HTT) is a rare low-grade tumor, and a prominent feature is the basement membranous stroma. We assume that such characteristic stromal findings of HTT are related to calcium deposition, and examined HTT samples by von Kossa special staining. There has been no report describing von Kossa special staining for such stroma. We collected 12 cases of HTT and 30 cases of papillary thyroid carcinoma (PTC) that had matched age, gender, tumor size, and surgical procedure characteristics as a control group. We compared the staining pattern and degree of von Kossa positivity between HTT and PTC, and a grading system of von Kossa stain was adopted to highlight differences between them. On von Kossa staining, all HTT revealed many tiny black dots around vessels in the hyalinized stroma, like "sugar-coated", and a high degree of calcium deposition in most cases, whereas PTC showed sparse stromal calcification in some cases. The degree of von Kossa staining was significantly different between the two groups. This is the first report describing abundant tiny black dots, like a "sugar-coated" appearance, of von Kossa stain in HTT. Here, we propose this finding can be a useful diagnostic clue to HTT.

Molecular alterations of coexisting thyroid papillary carcinoma and anaplastic carcinoma: identification of TERT mutation as an independent risk factor for transformation.

Thyroid papillary carcinoma is the most common endocrine neoplasm and generally carries a favorable prognosis. However, a small subset of papillary carcinomas transforms into anaplastic carcinoma, an undifferentiated cancer with a dismal prognosis. Recent studies using next-generation sequencing revealed the genomic landscape of papillary carcinoma and anaplastic carcinoma. However, risk factors for anaplastic transformation in papillary carcinoma remain obscure. In the present study, we investigated molecular alterations of papillary carcinoma and anaplastic carcinoma components in 27 tumors in which anaplastic carcinoma coexisted with antecedent papillary carcinoma. We conducted direct sequencing for BRAF, TERT promoter and PIK3CA, and immunohistochemistry for p53, TTF-1 and subunits of the SWI/SNF complex (ARID1A, ARID1B, ATRX, SMARCA2, SMARCA4, SMARCB1, and PBRM1). BRAFV600E and TERT promoter mutated at the rate of 90% and 95%, respectively, and these mutational statuses were almost identical between the papillary carcinoma and anaplastic carcinoma components. PIK3CA mutation was positive in 33% of our samples with a heterogeneous mutation pattern of the papillary carcinoma and anaplastic carcinoma components. Aberrant expression of p53 and loss of TTF-1 were present in 63 and 59%, respectively, and these two alterations were confined to the anaplastic carcinoma components. There was a loss of the SWI/SNF complex in a subset of the tumors with a heterogeneous pattern of the papillary carcinoma and anaplastic carcinoma components: SMARCA4 in 4% and PBRM1 in 4%. In a multivariate comparison between the antecedent papillary carcinoma components and control papillary carcinomas without anaplastic transformation, TERT promoter mutation was independently associated with anaplastic transformation. Collectively, papillary carcinoma-derived anaplastic carcinomas are characterized by BRAF and TERT promoter mutations, and these mutations occur prior to anaplastic transformation. Alterations of PIK3CA and the SWI/SNF complex are relatively rare and temporally heterogeneous. Of note, a papillary carcinoma harboring TERT promoter mutation is at higher risk for anaplastic transformation.

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.

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.

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.

[Total Glossolaryngectomy of an Advanced Oropharyngeal and Tongue Squamous-Cell Carcinoma: A 29-Case Series Study].

We report herein on 29 patients with advanced oropharyngeal and tongue squamous-cell carcinoma who underwent a total glossolaryngectomy at the Cancer Institute Hospital of the JFCR between July 2005 and June 2013. In this study, we tried to evaluate associations between several variables of the primary tumor and prognosis in these 29 patients. The cause-specific 5-year survival rate with the Kaplan-Meier method was 45% in all patients. Tumor recurrence occurred in 15 patients. Four patients had recurrence in the primary site, 11 patients in neck lymph nodes or in the lungs or bone. The multivariate analysis revealed that the number of neck lymph node metastases, age and alcohol drinking were poor prognostic markers for patients undergoing a total glossolaryngectomy. Cause-specific survival was compared between patients with salvage surgery and initial surgery using Kaplan-Meier survival curves with log-rank tests. There was no significant association with survival (log-rank test: p = 0.13). The overall local control rate was 69% in all patients. Regarding salvage surgery, 9 of 16 patients had no recurrence in the primary site or neck lymph nodes. The limitations of this study include the small number of patients especially regarding the prognosis study and may have included a selection bias regarding undergoing a total glossolaryngectomy.

A Clinical Study of Pharyngolaryngectomy with Total Esophagectomy: Postoperative Complications, Countermeasures, and Prognoses.

OBJECTIVE: Patients with advanced hypopharyngeal or cervical esophageal cancer have a comparatively high risk of also developing thoracic esophageal cancer. Pharyngolaryngectomy with total esophagectomy is highly invasive, and few reports about it exist. We examined the postoperative complications and respective countermeasures and prognoses of patients who underwent pharyngolaryngectomy with total esophagectomy. STUDY DESIGN: Case series with chart review. SETTING: Department of Head and Neck Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Japan. SUBJECTS AND METHODS: We examined the postoperative complications and respective countermeasures and prognoses of 40 patients who underwent pharyngolaryngectomy with total esophagectomy in our hospital. RESULTS: Postoperative complications were observed in 23 patients (57.5%) and consisted of 8 groups: tracheal region necrosis in 5 patients; neck abscess formation/wound infection in 5; fistula in 4; tracheostomy suture leakage in 2; ileus in 2; lymphorrhea in 2; pulmonary complications in 2; and other complications, including hemothorax, tracheoinnominate artery fistula, temporary cardiac arrest due to intraoperative mediastinum operation, methicillin-resistant Staphylococcus aureus enteritis, and sepsis, in 1 patient each. A lethal complication-brachiocephalic vein hemorrhage due to tracheostomy suture leakage and hemorrhagic shock due to tracheoinnominate artery fistula-occurred in 2 (5%) patients. The crude 5-year survival rate was 48.6%. CONCLUSIONS: Serious postoperative complications were related to tracheostomaplasty. Although pharyngolaryngectomy with total esophagectomy is highly invasive, we believe that our outlined treatment method is the most appropriate for cases of advanced hypopharyngeal or cervical esophageal cancer that also requires concurrent surgery for esophageal cancer.

Risk-adapted management of papillary thyroid carcinoma according to our own risk group classification system: is thyroid lobectomy the treatment of choice for low-risk patients?

BACKGROUND: Our original system for risk group classification for predicting cause-specific death from papillary thyroid carcinoma (PTC) defined patients with distant metastasis and older patients (≥ 50 years) with either massive extrathyroidal extension or large (≥ 3 cm) lymph node metastasis as high risk; all others are low risk. For unilateral, low-risk PTC, the extent of thyroidectomy (less-than-total thyroidectomy vs total or near-total thyroidectomy) has been determined based on the choice of the patient since 2005. PATIENTS: Of 1,187 patients who underwent initial thyroidectomy for PTC (tumor size [T] >1 cm) between 1993 and 2010, 967 (82%) were classified as low risk. Among low-risk patients, 791 (82%) underwent less than total thyroidectomy. RESULTS: The 10-year cause-specific survival and disease-free survival rates did not differ between patients who underwent total thyroidectomy versus less than total thyroidectomy (cause-specific survival, 99% vs 99% [P = .61]; disease-free survival, 91% vs 87% [P = .90]). Age ≥ 60 years, T ≥ 3 cm, and lymph node metastases >3 cm represented significant risk factors for distant recurrence. CONCLUSION: The favorable overall survival of low-risk patients, regardless of the extent of thyroidectomy, supports patient autonomy in treatment-related decision making. Low-risk patients possessing risk factors for distant recurrence would be likely to benefit from total thyroidectomy followed by radioactive iodine.