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Background: The question of how to manage patients with low-risk papillary thyroid microcarcinoma (PTMC; T1aN0M0) has recently become an important clinical issue. Two Japanese centers have conducted prospective clinical trials of active surveillance (AS) for low-risk PTMC since the 1990s, reporting favorable outcomes. This policy has thus seen gradual adoption worldwide to avoid overtreatment. Not all PTMCs are suitable for AS, however, and many physicians still hesitate to apply the management policy in daily clinical practice. A task force on management for PTMC created by the Japan Association of Endocrine Surgery collected and analyzed bibliographic evidence and has produced the present consensus statements regarding indications and concrete strategies for AS to facilitate the management of adult patients diagnosed with low-risk PTMC. Summary: These statements provide indications for AS in adult patients with T1aN0M0 low-risk PTMC. PTMCs with clinical lymph node metastasis, distant metastasis, recurrent laryngeal nerve (RLN) paralysis due to carcinoma invasion, or protrusion into the tracheal lumen warrant immediate surgery. Tumors suspected of aggressive subtypes on cytology are recommended for immediate surgery. Immediate surgery is also recommended for tumors adherent to the trachea or located along the course of the RLN. Practical strategies include diagnosis, decision-making, follow-up, and monitoring related to the implementation of AS. The rate of low-risk PTMC progression is lower in older patients. However, we recommend continuing AS as long as circumstances permit. Future tasks in optimizing management for low-risk PTMC are also described, including molecular markers and patient-reported outcomes. Conclusions: An appropriate multidisciplinary team is necessary to accurately evaluate primary tumors and lymph nodes at the beginning of and during AS, and to adequately reach a shared-decision with individual patients. If appropriately applied, AS of low-risk PTMC is a safe management strategy offering favorable outcomes and preserves quality of life at low cost.

Background: Active surveillance is accepted as a first-line management for patients with low-risk papillary thyroid microcarcinoma (PTMC) without metastasis or extrathyroid extension. While the lung is the most frequent site of distant metastasis of papillary thyroid carcinomas (PTCs), it is unclear if chest computed tomography (CT) is necessary at the initiation of active surveillance. In our institution, we usually did not perform chest CT for candidates identified for active surveillance. However, routine preoperative chest CT for patients with thyroid cancers, including PTMCs, was standard practice. The present study aimed to evaluate the clinical value of chest CT for patients with PTMCs. Methods: We retrospectively reviewed preoperative chest CT images from 1000 consecutive patients (88.5% women; median age, 55 years) with cT1aN0 PTC who underwent surgery between January 2006 and May 2012 in our hospital. The median maximum size of PTMCs was 8 mm. Results: Abnormal findings were detected in 326 (32.6%) of the 1000 patients. Of these, 290 patients had presumed benign or inflammatory lesions of no clinical importance. In total, 36 patients (3.6%) were referred to specialized departments for further evaluation of the lesions, and 9 patients (0.9%) received invasive tests and/or treatments. Five patients (0.5%) benefited from the chest CT (lung cancer was detected in four, and a cardiac lesion was detected and treated in one), while the lesions in the other four patients were benign, not necessarily requiring treatment. The remaining 27 patents were followed for presumed benign or inflammatory lesions. Thus, none of the present 1000 patients was found with distant metastasis of thyroid cancer. Conclusions: Routine chest CT did not detect thyroid cancer lung metastasis in patients with PTMC. Thus, routine chest CT at the time of presentation is not required for patients with cT1aN0 PTCs.

Background: Two Japanese prospective trials of active surveillance (AS) for adult patients with low-risk papillary thyroid carcinoma (PTC) ≤1 cm (cT1aN0M0 PTMC) have verified the safety of AS in oncological control and its superiority over immediate surgery with respect to unfavorable outcomes. Thus, AS has been accepted as an alternative to immediate surgery for asymptomatic papillary thyroid microcarcinomas (PTMCs). However, the real-world clinical approach for PTMC is unknown. Thus, this study aimed to investigate the current state of management of asymptomatic PTMCs in Japan. Methods: We conducted a questionnaire survey on the actual treatment patterns for adult patients with low-risk PTMCs. The subjects were member institutions of the Japan Association of Endocrine Surgery (JAES) or Japanese Society of Thyroid Surgery (JSTS), including the departments of surgery and head and neck surgery (HNS). Results: Responses were obtained from 134 institutes, where 72.4% of Japanese thyroid cancer cases operated by surgeons were treated. For suspicious tumors on ultrasound, 18 responders (13.4%) conducted cytological examination routinely, while 69 (51.5%) and 40 (27.8%) conducted it only for tumors >5 and >10 mm, respectively. After the diagnosis, 42 responders (31.3%) recommend AS, 35 (26.1%) recommend immediate surgery as the management, and 52 (38.8%) allowed patients to decide the treatment course. The present responders tended to recommend surgery for PTMCs that were located adjacent to the dorsal surface of the thyroid, were multiple, or measured almost 10 mm in size. At these institutions, 1176 patients with PTMC underwent surgery in 2017, accounting for 18.1% of surgeries for PTC. During the succeeding three months, 310 of 576 (53.8%) PTMC patients underwent AS. The treatment strategies did not differ between the departments (Surgery or HNS). The institutions that have six or more surgeons, that were located in metropolitan areas, or that were certified by JAES or JSTS performed AS more actively. Conclusion: More than 50% of low-risk PTMCs are on AS in Japan. However, the indication and recommendation for AS vary significantly between institutions. To improve the implementation of this management modality, physicians and patients should be further educated, and the sociomedical environment should be improved.

Background: The cribriform-morular variant (CMV) is a rare subtype of papillary thyroid carcinoma (PTC), and is often associated with familial adenomatous polyposis (FAP). This variant is generally...

Background: Therapeutic options for treating advanced or metastatic medullary thyroid carcinoma (MTC) and anaplastic thyroid carcinoma (ATC) are still limited in Japan, even though vandetanib for MTC and lenvatinib for MTC and ATC have been approved. Sorafenib is an oral multikinase inhibitor approved for the treatment of patients with radioactive iodine-refractory differentiated thyroid cancer (DTC). An uncontrolled, open-label, multicenter, single-arm, Phase 2 clinical study was conducted to evaluate the safety and efficacy of sorafenib in Japanese patients with MTC and ATC. Methods: Japanese patients with histologically confirmed ATC and locally advanced or metastatic MTC were enrolled from April to September 2014. The primary endpoint was to evaluate the safety of sorafenib. Treatment efficacy variables including progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and maximum reduction in tumor size were evaluated as secondary endpoints. Patients received sorafenib 400 mg orally twice daily on a continuous basis and then continued treatment until the occurrence of disease progression, unacceptable toxicity, or withdrawal of consent. Results: A total of 20 patients were screened, and 18 (8 with MTC and 10 with ATC) were enrolled. The most common drug-related adverse events were palmar-plantar erythrodysesthesia (72%), alopecia (56%), hypertension (56%), and diarrhea (44%). In the ATC patients, median PFS was 2.8 months [confidence interval 0.7–5.6], and median OS was 5.0 months [confidence interval 0.7–5.7]; ORR and DCR were 0% and 40%, respectively. In the MTC population, neither median PFS nor OS had been reached at the time of this analysis; ORR was 25% and DCR was 75%. Conclusions: The toxicities reported in this study were consistent with the known safety profile of sorafenib. Sorafenib seems to be effective in the treatment of advanced MTC but not ATC, and could be a new treatment option for locally advanced or metastatic MTC and radioactive iodine-refractory DTC.

The incidence of papillary microcarcinoma (PMC) of the thyroid is rapidly increasing globally, making the management of PMC an important clinical issue. Excellent oncological outcomes of active surveillance for low-risk PMC have been reported previously. Here, unfavorable events following active surveillance and surgical treatment for PMC were studied.From February 2005 to August 2013, 2153 patients were diagnosed with low-risk PMC. Of these, 1179 patients chose active surveillance and 974 patients chose immediate surgery. The oncological outcomes and the incidences of unfavorable events of these groups were analyzed.In the active surveillance group, 94 patients underwent surgery for various reasons; tumor enlargement and the appearance of novel lymph node metastases were the reasons in 27 (2.3%) and six patients (0.5%), respectively. One of the patients with conversion to surgery had nodal recurrence, and five patients in the immediate surgery group had a recurrence in a cervical node or unresected thyroid lobe. All of these recurrences were successfully treated. None of the patients had distant metastases, and none died of the disease. The immediate surgery group had significantly higher incidences of transient vocal cord paralysis (VCP), transient hypoparathyroidism, and permanent hypoparathyroidism than the active-surveillance group did (4.1% vs. 0.6%, p 0.0001; 16.7% vs. 2.8%, p 0.0001; and 1.6% vs. 0.08%, p 0.0001, respectively). Permanent VCP occurred only in two patients (0.2%) in the immediate surgery group. The proportion of patients on L-thyroxine for supplemental or thyrotropin (TSH)-suppressive purposes was significantly larger in the immediate surgery group than in the active surveillance group (66.1% vs. 20.7%, p 0.0001). The immediate surgery group had significantly higher incidences of postsurgical hematoma and surgical scar in the neck compared with the active surveillance group (0.5% vs. 0%, p 0.05; and 8.0% vs. 100%, p 0.0001, respectively).The oncological outcomes of the immediate surgery and active surveillance groups were similarly excellent, but the incidences of unfavorable events were definitely higher in the immediate surgery group. Thus, active surveillance is now recommended as the best choice for patients with low-risk PMC.

Background: An active-surveillance clinical trial of low-risk papillary microcarcinoma (PMC) patients has been performed at the authors' institution, Kuma Hospital, since 1993. Favorable oncological results have been reported. During the trial, a few patients were encountered with PMC that showed enlargement during pregnancy, and these cases have been reported. During pregnancy, a large amount of human chorionic gonadotropin (hCG) having weak thyrotropin (TSH) activity is produced, possibly affecting the progression of PMC. This study investigated how pregnancy and delivery influenced the progression of PMC in the entire active surveillance PMC patient series. Methods: From 1993 to 2013, 1841 patients with low-risk PMC chose the active surveillance program. Fifty of the 1549 female PMC patients experienced 51 pregnancies/deliveries. To minimize observer variation, a single specialist sonographer re-evaluated the changes in the size of these 50 patients' PMCs before and after the pregnancies/deliveries. Results: Four patients (8%) showed enlargement of PMC by ≥3 mm; one patient (2%) showed a decrease by ≥3 mm, and the remaining 44 patients (45 events, 90%) showed stable disease. None of the patients had a novel appearance of lymph node metastases during pregnancy. Of the four patients with enlargement, two underwent surgery after delivery, and the other two continued the active surveillance, since their tumors did not grow after the delivery. After delivery, the PMC of one of these four patients remained stable, and another showed a decrease in PMC size. To date, six more PMC patients underwent surgery after delivery for reasons other than disease progression due to pregnancy and delivery: two opted out of active surveillance, two were identified with a nodal metastasis during active surveillance after delivery, one had Graves' disease, and one showed enlargement of nodules of the contralateral lobe. Conclusions: Pregnancy and delivery was associated with an increase in size of PMCs in only 8% of the 51 pregnancies/delivery cases. None of the patients developed nodal metastasis during pregnancy. Thus, a possible future pregnancy does not prevent such patients from undergoing active surveillance, although watchful observation during pregnancy is recommended.

The 2015 American Thyroid Association thyroid cancer management guidelines endorse an active surveillance management approach as an alternative to immediate biopsy and surgery in subcentimeter thyroid nodules with highly suspicious ultrasonographic characteristics and in cytologically confirmed very low risk papillary thyroid cancer (PTC). However, the guidelines provide no specific recommendations with regard to the optimal selection of patients for an active surveillance management approach. This article describes a risk-stratified clinical decision-making framework that was developed by the thyroid cancer disease management team at Memorial Sloan Kettering Cancer Center as the lessons learned from Kuma Hospital in Japan were applied to a cohort of patients with probable or proven papillary microcarcinoma (PMC) who were being evaluated for an active surveillance management approach in the United States.A risk-stratified approach to the evaluation of patients with probable or proven PMC being considered for an active surveillance management approach requires an evaluation of three interrelated but distinct domains: (i) tumor/neck ultrasound characteristics (e.g., size of the primary tumor, the location of the tumor within the thyroid gland); (ii) patient characteristics (e.g., age, comorbidities, willingness to accept observation); and (iii) medical team characteristics (e.g., availability and experience of the multidisciplinary team). Based on an analysis of the critical factors within each of these domains, patients with probable or proven PTC can then be classified as ideal, appropriate, or inappropriate candidates for active surveillance.Risk stratification utilizing the proposed decision-making framework will improve the ability of clinicians to recognize individual patients with proven or probable PMC who are most likely to benefit from an active surveillance management option while at the same time identifying patients with proven or probable PMC that would be better served with an upfront biopsy and surgical management approach.

Background: Several single nucleotide polymorphisms (SNP) have been identified to be associated with the risk for differentiated thyroid cancer in populations of distinct ethnic background. The relationship of these genetic markers to a benign tumor of the thyroid, follicular adenoma (FA), is not well established. Methods: In a multicenter retrospective case-control study, five thyroid cancer-related SNPs - rs966513 (9q22.33, FOXE1), rs944289 (14q13.3, PTCSC3), rs2439302 (8p12, NRG1), rs1867277 (9q22.23, FOXE1), and rs6983267 (8q24, POU5F1B) - were genotyped in 959 cases of histologically verified FA, 535 papillary thyroid carcinomas (PTC), and 2766 population controls. Results: A significant association was found between FA and rs944289 (p=0.002; OR 1.176 [CI 1.064-1.316]), and suggestively with rs2439302 (p=0.033; OR 1.149 [CI 1.010-1.315]). In PTC, significant associations were confirmed for rs965513 (p=4.21E-04; OR 1.587 [CI 1.235-2.000]) and rs944289 (p=0.003; OR 1.234 [CI 1.075-1.408]), newly found for rs2439302 (p=0.003; OR 1.266 [CI 1.087-1.493]) and rs1867277 (p=1.17E-04; OR 1.492 [CI 1.235-1.818]), and was not replicated for rs6983267 (p=0.082; OR 1.136 [CI 0.980-1.316]) in this series. A significant correlation between rs2439302 genotype and relative expression of NRG1 was detected in normal and tumor counterparts of PTC (about 10% decrease per each risk allele). NRG1 expression also significantly correlated with that of PTCSC3. Conclusions: Association of rs944289, which was previously known to confer risk for thyroid cancer, with FA, and the correlation between PTCSC3 and NRG1 expression demonstrates that predisposing genetic factors are partly common for benign and malignant thyroid tumors, and imply broader roles of the pathways they underlie in thyroid tumorigenesis, not limited to carcinogenesis., Thyroid, 25(3), pp.333-340; 2015

Detectable serum thyroglobulin (Tg) in patients with papillary thyroid carcinoma (PTC) after total thyroidectomy implies unsuccessful surgery, indicating a high risk of recurrence. Serum Tg kinetics in such patients have not been extensively studied. We studied serum Tg kinetics in patients with suppressed serum thyrotropin levels and undetectable anti-Tg antibody to minimize the effects of these factors on Tg values, and evaluated the relationship of prognosis to the serum Tg doubling-time.Between January 1998 and December 2004, 1515 patients with PTC underwent total thyroidectomy in Kuma Hospital. After excluding patients with other thyroid cancers and those positive tests for anti-Tg antibody, there were 426 patients with 4 or more serum Tg measurements at a time that serum thyrotropin concentrations were0.1 mIU/L. These patients were selected for the present retrospective study. Tg doubling-time was computed using Tg values measured during routine follow-up. Patients were followed for a mean of 88.1 months and a median of 86.7 months.Of the 426 patients, 137 patients had 4 or more measurements that revealed detectable Tg in serum Tg. The Tg doubling-time (DT), calculated using all available data, varied widely, and were grouped into those that were1 year (17 patients), those that were 1-3 years (21 patients), and those that were ≥ 3 years (30 patients), as well as those with a negative value due to decrease in serum Tg (69 patients). There were also 88 patients who had three or fewer serum Tg measurements that showed detectable Tg levels, as well as 201 patients in whom serum Tg measurements were below the lower limit of detection. In the group of patients with a Tg-DT of1 year the cause specific survival at 10 years was 50%, and in the group with a Tg-DT of 1-3 years it was 95%. In all other groups it was 100%. Many classical prognostic factors (TNM stage, age, and gender) as well as the Tg-DT were significant indicators of survival by univariate analysis, but Tg-DT remained the only independent predictor by multivariate analysis. Tg-DT was also the only independent predictor of distant metastases and loco-regional recurrence on multivariate analysis. Tg-DT calculated using only the first four data [Tg-DT (first four data)] was also the only independent predictor of survival, distant metastases, and loco-regional recurrence on multivariate analysis.Tg-DT (all data or first four data) is a very strong prognostic predictor superior to the classical prognostic factors in patients with PTC.

Tumor thrombus in the thyroid vein or the internal jugular vein may be caused by thyroid malignancies. Therefore, a tumor thrombus is very suspicious for malignancy. Total thyroidectomy should be performed in such patients if there is a primary thyroid tumor, and a high probability of pulmonary metastasis seems likely as there is direct exposure of malignant cells to the circulation. Our study was performed to determine whether ultrasonography is an effective preoperative modality to detect tumor thrombi of thyroid malignancies and whether tumor thrombi are associated with pulmonary metastases.Between 2004 and 2009, all thyroid surgery patients at Kuma Hospital had preoperative neck ultrasonography to look for tumor thrombi in the thyroid veins and the internal jugular veins as well as thyroid masses and abnormal lymph nodes. We looked for solid masses with an echogenic "tongue" in the internal jugular vein and masses with a projection from thyroid tumor to the thyroid vein on grayscale ultrasonography. We also used Doppler ultrasonography to look for the absence of blood flow.Among 7754 patients who had thyroid surgery, there were 9 patients with tumor thrombi. In seven of the patients, tumor thrombi were detected by preoperative ultrasound, and in the remaining two patients, tumor thrombi were detected during surgery. Tumor thrombi were identified in the internal jugular vein in six patients and in the thyroid vein in three patients. Pulmonary metastases were present in three patients (50% of the patients with thyroid carcinoma). The patients with tumor thrombi were more likely (33.3%) to have pulmonary metastasis than those without (0.9%) tumor thrombi (p 0.0001). In four patients with papillary carcinoma, projection-like lesions of irregularly shaped tumors were misdiagnosed to be tumor thrombi in the thyroid veins on preoperative ultrasound. These four patients did not have pulmonary metastases.The preoperative detection of a tumor thrombus on ultrasonography has important clinical significance. Therefore, preoperative neck ultrasound in patients with thyroid masses should attempt to determine whether there are signs of tumor thrombi as well as to characterize the nature and location of abnormal thyroid and extrathyroid masses.

Ultrasonography is the most useful tool for detection and evaluation of thyroid nodules. In this study, we present our classification system for ultrasonographic evaluation, which has been routinely performed since 1995. Of 1244 nodules identified by ultrasonography in 900 patients, 1145 nodules demonstrating adequate specimens on fine-needle aspiration biopsy were enrolled in the study. We stratified these nodules into classes 1 to 5 with intermediate steps of 0.5 for classes 2 to 5. Nodules classified as 3.5 or greater were evaluated as malignant, those classified as 3 were evaluated as borderline, and those classified as 2.5 or lower were evaluated as benign. Of 233 nodules evaluated as malignant, 179 (76.8%) were cytologically confirmed as malignant. Furthermore, 145 of 159 nodules (91.2%) classified as 4 or greater were cytologically diagnosed as carcinoma. Of 710 nodules evaluated as benign, 683 (96.1%) were cytologically confirmed as benign. Two hundred fifty-five nodules of 210 patients were surgically resected and pathologically examined. In this series, the positive predictive value of ultrasonographic evaluation of malignancy was 97.2%. These findings suggest that our classification system is simple and useful to facilitate ultrasonographic evaluation of thyroid nodules.

Medullary thyroid carcinoma (MTC) is a thyroid malignancy originating from C cells. To date, serum calcitonin measurement and fine-needle aspiration biopsy (FNAB) have been prominent diagnostic approaches to these lesions. Although an elevated serum calcitonin level strongly suggests the presence of MTC, this examination cannot identify the origin of the calcitonin overexpression, especially in patients demonstrating multiple thyroid nodules. For the treatment planning, it is important to know which nodule is MTC, especially in nonhereditary MTC. In this study, we propose calcitonin measurement in the washout of FNAB needles after sampling each tumor (FNAB-CT) as a new approach to diagnosis of MTC. We performed FNAB-CT for five MTC cases. Although only one of these cases was definitively diagnosed as having MTC by FNAB cytology, FNAB-CT values ranged from 17,000 to 560,000 pg/mL, which were exceedingly higher than those of 11 controls (seven papillary carcinomas, two adenomatous nodules, one chronic thyroiditis, and one normal thyroid), which showed values ranging from

We herein report a 28-year-old woman with a follicular neoplasm showing subcutaneous needle tract implantation. One month after fine-needle aspiration biopsy (FNAB) for a tumor measuring 2.5 cm, the patient became aware of a subcutaneous nodule measuring about 1 cm at the needle insertion site. FNAB smear of this nodule showed poorly cohesive clusters of follicular cells with nuclear crowding, overlapping and resetting with some microfollicular architecture. Total thyroidectomy and resection of the subcutaneous nodule were performed. Although there was no capsular or vascular invasion of the nodule, the lesion was diagnosed as follicular carcinoma because of the subcutaneous seeding. Ki-67 labeling indices of the thyroid nodule and implanted tumor were higher than 5%. Furthermore, although galectin-3 was completely negative in the thyroid nodule, it was heterogeneously positive in the implanted tumor. It is therefore suggested that high cell proliferating activity as a characteristic of the original nodule and the subsequently obtained invasive characteristic of the implanted tumor contributed to this event. To date, there has not been any recurrence of the implanted lesion. Because implanted follicular carcinoma can be surgically removed, this complication should not impair the usefulness of FNAB.

Complications of thyroid fine-needle aspiration biopsy (FNAB) are exceedingly rare. Hematoma formation is the most commonly encountered complication. Infection and seeding of carcinoma cells in the needle track has also been reported in a rare case. Here we describe patients diagnosed as having transient vocal cord paralysis after FNAB of benign thyroid tumor.Retrospective review of patients with concurrent diagnosis of vocal cord paralysis after FNAB.Among 10,974 patients who underwent FNAB, 4 patients showed vocal cord paralysis on laryngoscopy. These patients had solid and/or cystic lesion in the thyroid. Routine FNAB of the nodule was performed using a 23-gauge needle. Cytologic findings were benign tumor. Change of voice in the patients occurred 1 or 2 days after FNAB and vocal cord paralysis ipsilateral to FNAB was determined by flexible laryngoscopy. Vocal cord paralysis of all patients resolved spontaneously within 6 months (average, 4 months).Although the incidence of vocal cord paralysis in patients with thyroid tumor after FNAB is reported to be 0.036%, the true incidence is unknown because asymptomatic subjects are not screened. This report should alert the examiner to the possibility of vocal cord palsy after FNAB.