Utilization of artificial intelligence in minimally invasive right adrenalectomy: recognition of anatomical landmarks with deep learning.

BACKGROUND: The primary surgical approach for removing adrenal masses is minimally invasive adrenalectomy. Recognition of anatomical landmarks during surgery is critical for minimizing complications. Artificial intelligence-based tools can be utilized to create real-time navigation systems during laparoscopic and robotic right adrenalectomy. In this study, we aimed to develop deep learning models that can identify critical anatomical structures during minimally invasive right adrenalectomy. METHODS: In this experimental feasibility study, intraoperative videos of 20 patients who underwent minimally invasive right adrenalectomy in a tertiary care center between 2011 and 2023 were analyzed and used to develop an artificial intelligence-based anatomical landmark recognition system. Semantic segmentation of the liver, the inferior vena cava (IVC), and the right adrenal gland were performed. Fifty random images per patient during the dissection phase were extracted from videos. The experiments on the annotated images were performed on two state-of-the-art segmentation models named SwinUNETR and MedNeXt, which are transformer and convolutional neural network (CNN)-based segmentation architectures, respectively. Two loss function combinations, Dice-Cross Entropy and Dice-Focal Loss were experimented with for both of the models. The dataset was split into training and validation subsets with an 80:20 distribution on a patient basis in a 5-fold cross-validation approach. To introduce a sample variability to the dataset, strong-augmentation techniques were performed using intensity modifications and perspective transformations to represent different surgery environment scenarios. The models were evaluated by Dice Similarity Coefficient (DSC) and Intersection over Union (IoU) which are widely used segmentation metrics. For pixelwise classification performance, accuracy, sensitivity and specificity metrics were calculated on the validation subset. RESULTS: Out of 20 videos, 1000 images were extracted, and the anatomical landmarks (liver, IVC, and right adrenal gland) were annotated. Randomly distributed 800 images and 200 images were selected for the training and validation subsets, respectively. Our benchmark results show that the utilization of Dice-Cross Entropy Loss with the transformer-based SwinUNETR model achieved 78.37%, whereas the CNN-based MedNeXt model reached a 77.09% mDSC score. Conversely, MedNeXt reaches a higher mIoU score of 63.71% than SwinUNETR by 62.10% on a three-region prediction task. CONCLUSION: Artificial intelligence-based systems can predict anatomical landmarks with high performance in minimally invasive right adrenalectomy. Such tools can later be used to create real-time navigation systems during surgery in the near future.

The impact of intraoperative neural monitoring during papillary thyroid cancer surgery on completeness of thyroidectomy and thyroglobulin response: a propensity-score matched study.

BACKGROUND: Intraoperative neural monitoring (IONM) has been utilized for a variety of thyroid pathologies, including papillary thyroid carcinoma (PTC). Remnant thyroid tissue following total thyroidectomy (TT) in patients with PTC is associated with increased recurrence. The aim of this study is to investigate whether the use of IONM in PTC surgery has an impact on the completeness of thyroidectomy. METHODS: Retrospectively, patients with preoperative diagnosis of PTC, who underwent TT in a tertiary center were reviewed. They were grouped based on the IONM usage, and 1:1 propensity-score match was performed. Primary outcome was the completeness of thyroidectomy, determined by measuring postoperative stimulated thyroglobulin levels (sTg). RESULTS: Among 274 clinically node-negative PTC patients who underwent TT and ipsilateral prophylactic central lymph-node dissection, a total of 170 patients (85:85) were matched. Postoperative sTg levels were significantly lower in the IONM group (1 ng/dL vs. 0.4 ng/dL; p < 0.01) with higher percentage of the patients with sTg levels <1 ng/ml (50.6% vs. 69.4%; p = 0.01). More patients in the no-IONM group received RAI ablation with significantly higher doses (mean mci: 120 vs. 102; p = 0.02). CONCLUSION: The use of IONM during thyroidectomy provides improvement in the completeness of thyroidectomy and reduction in postoperative sTg levels which can be used as a guide by clinicians to avoid RAI ablation in selected PTC patients and to adjust low ablative doses in patients who are scheduled for remnant ablation.

Transoral endoscopic parathyroidectomy vestibular approach (TOEPVA) for primary hyperparathyroidism: Turkey's experience.

AIM: Parathyroid surgery has witnessed a significant evolution with the introduction of more efficacious preoperative localization imaging techniques and the use of rapid intraoperative parathormone assays. Parathyroid surgery can now be performed with the minimum of invasion. Through the adaptation of the transoral endoscopic thyroidectomy vestibular approach (TOETVA), the technique has now been adopted for parathyroid surgery, known as the transoral endoscopic parathyroidectomy vestibular approach (TOEPVA). We present here the initial experiences of 11 centers carrying out TOEPVA surgery in Turkey. MATERIALS AND METHODS: Participating in the study were 11 centers, all of which were tertiary care institutions carrying out endocrine surgery. A retrospective review was made of 35 primary hyperparathyroidism patients who underwent the TOEPVA procedure between July 2017 and January 2020. RESULTS: Of the total 35 patients, 32 patients underwent the TOEPVA procedure successfully. All patients but one were female, and the mean age was 47.2 (20-73) years. According to localization studies, 18 of the lesions were lower left, 12 were lower right, 3 were upper right and 2 were upper left. The mean operative time was 116 (30-225) min, and three cases were converted to an open procedure. Simultaneous thyroidectomy was performed in seven cases. The average PTH level dropped to normal within 20 min. after the resection in all cases. The complication rate was 19% (ecchymosis, subcutaneous emphysema, nasal bleeding, surgical site infection and seroma). There were neither recurrent nerve palsies, nor mental nerve root or branch injuries. The average hospital stay was 1 day. No persistence was documented on follow up. CONCLUSION: TOEPVA is a "hidden scar" parathyroidectomy procedure that can be safely performed on parathyroid adenomas, in cases that have scar-related concerns. Having its own procedure-related complications, the procedure provides satisfactory objective results, particularly in centers experienced in endoscopic and endocrine surgery.

Electrophysiological monitoring of the nonrecurrent inferior laryngeal nerve and radiological evaluation of concurrent vascular anomalies.

Purpose: The objective of this study was to characterize the electrophysiological characteristics of nonrecurrent inferior laryngeal nerves (NRILNs) that were dissected via intraoperative neuromonitoring (IONM) and concomitant vascular anomalies in patients with NRILNs. Methods: A retrospective analysis was conducted on 7865 patients who underwent thyroidectomy with IONM at three tertiary referral centers. The study included 42 patients in whom an NRILN was detected. IONM data and postoperative vocal cord (VC) examinations were recorded for all patients. The absence of an initial vagal EMG response and/or a short (<3.5 ms) latency period during the initial vagal stimulation or the inability to identify the RLN within the Beahrs triangle was considered highly suspicious for the presence of an NRILN. Postoperative cross-sectional imaging was performed in 36 out of 42 patients to assess any concurrent vascular anomalies. Results: The prevalence of NRILN was 0.53%. An NRILN was suspected due to EMG findings in 32 (76%) patients and the inability to identify the RLN within the Beahrs triangle in the remaining 10 (24%) patients. The mean right VN latency period was 3.05 ± 0.15 ms. The V1 latency period of the right VN was shorter than 3.5 ms in 39 (93%) and longer than 3.5 ms in 3 (7%) patients. One of these three patients with latency>3.5ms had a large mediastinal goiter. Transient VC paralysis occurred in one (2.4%) patient. Of the 36 patients with postoperative imaging data, 33 (91.4%) had vascular anomalies. All 33 patients had aberrant right subclavian arteries, and 13 (39.4%) also had accompanying additional vascular anomalies. Conclusion: The NRILN is an anatomical variation that increases the risk of nerve injury. Observation of an absent EMG response and/or a short latency period during the initial vagal stimulation facilitates the detection of an NRILN at an early stage of thyroidectomy in the majority of patients.

An unusual finding after adrenal surgery: a case series of adrenal schwannomas.

Adrenal schwannomas are rare benign tumors with no specific imaging and laboratory findings to diagnose preoperatively. Due to the limited number of cases in the literature, clinical, imaging, and pathological findings are presented in this study. Case 1 is a 61-year-old woman patient who has a 31-mm mass in the right adrenal gland. This mass was nonfunctional; in imaging studies, this mass had a cystic necrotic component, and high 18-fluorodeoxyglucose (FDG) uptake was seen. There was no metaiodobenzylguanidine (MIBG) uptake. Laparoscopic transabdominal right adrenalectomy was performed, and the pathology result was consistent with adrenal schwannomas. Case 2 is a 63-year-old man patient who presented with a 38-mm mass in the left adrenal gland. This mass was nonfunctional and similar to that in Case 1; this mass had a cystic component. Laparoscopic transabdominal left adrenalectomy was performed. The diagnosis of adrenal schwannoma with degeneration was revealed. Case 3 was a 72-year-old woman patient admitted to the hospital for a 125-mm left adrenal mass. Similar to Case 1, this mass also had a cystic necrotic component in imaging studies. High FDG uptake was seen, and the patient underwent conventional adrenalectomy due to the suspicion of malignancy. After pathological evaluation, a diagnosis of adrenal schwannoma was made. A main diagnostic challenge in adrenal schwannomas is the preoperative diagnosis. These masses have no pathognomonic finding or specific hormonal function. Imaging findings of these masses may increase the suspicion of malignancy, which may affect decisions for surgery and the surgical technique.

Artificial Intelligence in Minimally Invasive Adrenalectomy: Using Deep Learning to Identify the Left Adrenal Vein.

BACKGROUND: Minimally invasive adrenalectomy is the main surgical treatment option for the resection of adrenal masses. Recognition and ligation of adrenal veins are critical parts of adrenal surgery. The utilization of artificial intelligence and deep learning algorithms to identify anatomic structures during laparoscopic and robot-assisted surgery can be used to provide real-time guidance. METHODS: In this experimental feasibility study, intraoperative videos of patients who underwent minimally invasive transabdominal left adrenalectomy procedures between 2011 and 2022 in a tertiary endocrine referral center were retrospectively analyzed and used to develop an artificial intelligence model. Semantic segmentation of the left adrenal vein with deep learning was performed. To train a model, 50 random images per patient were captured during the identification and dissection of the left adrenal vein. A randomly selected 70% of data was used to train models while 15% for testing and 15% for validation with 3 efficient stage-wise feature pyramid networks (ESFPNet). Dice similarity coefficient (DSC) and intersection over union scores were used to evaluate segmentation accuracy. RESULTS: A total of 40 videos were analyzed. Annotation of the left adrenal vein was performed in 2000 images. The segmentation network training on 1400 images was used to identify the left adrenal vein in 300 test images. The mean DSC and sensitivity for the highest scoring efficient stage-wise feature pyramid network B-2 network were 0.77 (±0.16 SD) and 0.82 (±0.15 SD), respectively, while the maximum DSC was 0.93, suggesting a successful prediction of anatomy. CONCLUSIONS: Deep learning algorithms can predict the left adrenal vein anatomy with high performance and can potentially be utilized to identify critical anatomy during adrenal surgery and provide real-time guidance in the near future.

The Role of American Thyroid Association Pediatric Thyroid Cancer Risk Stratification and BRAFV600E Mutation in Predicting the Response to Treatment in Papillary Thyroid Cancer Patients ≤18 Years Old

Objective: This study aimed to evaluate the role of risk stratification by the American Thyroid Association (ATA) pediatric thyroid cancer risk levels and BRAFV600E mutation to predict the response to treatment in papillary thyroid cancer (PTC) patients ≤18 years old. Methods: Clinical outcomes during a median period of 6 (2-21.8) years were assessed in 70 patients, according to ATA pediatric risk stratification, BRAFV600E mutation status, and dynamic risk stratification (DRS) at final follow-up. Results: Of 70 patients, 44 (63%), 14 (20%), and 12 (17%) were classified initially as low-, intermediate-, and high-risk, respectively. BRAFV600E mutation analysis data was available in 55 (78.6%) patients, of whom 18 (32.7%) had the BRAFV600E mutation. According to the final DRS, 61 (87%), two (3%), six (9%), and one (1%) patients were classified as an excellent, incomplete biochemical, incomplete structural, and indeterminate response, respectively. All ATA low-risk patients showed excellent response to treatment, whereas the rate of excellent response was 65.4% in intermediate- and high-risk levels (p<0.001). The rates of excellent response in BRAFV600E positive and negative patients were 83% and 92%, respectively (p=0.339). The rate of locoregional recurrence was significantly higher in BRAFV600E positive vs negative patients (33.3% vs 2.7% respectively, p=0.001). Conclusion: ATA pediatric risk stratification is effective in predicting response to treatment in PTC patients ≤18 years old. The presence of BRAFV600E mutation was highly predictive for recurrence but had no significant impact on the rate of excellent response to treatment at final follow-up.

Varied Recurrent Laryngeal Nerve Course Is Associated with Increased Risk of Nerve Dysfunction During Thyroidectomy: Results of the Surgical Anatomy of the Recurrent Laryngeal Nerve in Thyroid Surgery Study, an International Multicenter Prospective Anatomic and Electrophysiologic Study of 1000 Monitored Nerves at Risk from the International Neural Monitoring Study Group.

Background: The recurrent laryngeal nerve (RLN) can be injured during thyroid surgery, which can negatively affect a patient's quality of life. The impact of intraoperative anatomic variations of the RLN on nerve injury remains unclear. Objectives of this study were to (1) better understand the detailed surgical anatomic variability of the RLN with a worldwide perspective; (2) establish potential correlates between intraoperative RLN anatomy and electrophysiologic responses; and (3) use the information to minimize complications and assure accurate and safe intraoperative neuromonitoring (IONM). Methods: A large international registry database study with prospectively collected data was conducted through the International Neural Monitoring Study Group (INMSG) evaluating 1000 RLNs at risk during thyroid surgery using a specially designed online data repository. Monitored thyroid surgeries following standardized IONM guidelines were included. Cases with bulky lymphadenopathy, IONM failure, and failed RLN visualization were excluded. Systematic evaluation of the surgical anatomy of the RLN was performed using the International RLN Anatomic Classification System. In cases of loss of signal (LOS), the mechanism of neural injury was identified, and functional evaluation of the vocal cord was performed. Results: A total of 1000 nerves at risk (NARs) were evaluated from 574 patients undergoing thyroid surgery at 17 centers from 12 countries and 5 continents. A higher than expected percentage of nerves followed an abnormal intraoperative trajectory (23%). LOS was identified in 3.5% of NARs, with 34% of LOS nerves following an abnormal intraoperative trajectory. LOS was more likely in cases of abnormal nerve trajectory, fixed splayed or entrapped nerves (including at the ligament of Berry), extensive neural dissection, cases of cancer invasion, or when lateral lymph node dissection was needed. Traction injury was found to be the most common form of RLN injury and to be less recoverable than previous reports. Conclusions: Multicenter international studies enrolling diverse patient populations can help reshape our understanding of surgical anatomy during thyroid surgery. There can be significant variability in the anatomic and intraoperative characteristics of the RLN, which can impact the risk of neural injury.

Pure transoral robotic thyroidectomy; institutional adaptation and early results from a tertiary endocrine surgery centre.

PURPOSE: Novel thyroidectomy techniques have been described to minimize the visible scar. Hereby, we aim to present our experience with transoral robotic thyroidectomy (TORT) without axillary access. MATERIAL AND METHODS: Between August 2018 and March 2019, six eligible patients were enrolled to undergo TORT. Procedures were performed by using the Da Vinci Xi platform under intermittent intraoperative nerve monitoring. RESULTS: All patients were female, and the mean age was 40.0 ± 14.4 years. Three patients underwent total thyroidectomy, and lobectomy was performed for the remaining three patients. In one patient, the procedure was converted to conventional open thyroidectomy due to bleeding. The mean docking time, console time and total operative time were 22.8 ± 5.2 min, 118.5 ± 48.7 min and 218.29 ± 50.6 min for total thyroidectomy and 21.8 ± 4.1 min, 68.6 ± 6.1 min and 177.6 ± 15.1 min for lobectomy, respectively. All patients were discharged uneventfully. CONCLUSIONS: Pure TORT is a safe procedure, when performed in carefully selected patients by experienced surgeons, but further prospective studies with larger number of patients are required.

Multicentricity Is More Common in Thyroid Papillary Microcancer with a Preoperative Diagnosis Compared to Incidental Microcancer.

OBJECTIVE: Although multicentricity is a common feature of thyroid papillary microcancer, it might be difficult to predict this histopathological feature preoperatively. METHODS: The records of 306 papillary microcancer patients who underwent thyroidectomy were evaluated. Papillary microcancer was diagnosed as an incidental histopathological finding in 242 (group 1), and by preoperative fine-needle aspiration biopsy in 64 (group 2). Demographic data and histopathological features were compared between the two groups. RESULTS: Age (44 ± 11.4 vs. 43 ± 14 years) and male/female ratio (44/193 vs. 12/52) showed no significant difference between groups 1 and 2 (p > 0.05). Mean tumor size was significantly larger in group 2 (5.2 ± 2.8 mm) compared to group 1 (3.7 ± 2.4 mm) (p = 0.004). The frequency of thyroid capsule invasion (44 vs. 19%, p = 0.0001), microscopic extrathyroidal invasion (25 vs. 10%, p = 0.004) and multicentricity (44 vs. 29%, p = 0.04), and bilateral lobar involvement (22 vs. 10%, p = 0.0001) was significantly higher in group 2 compared to group 1. CONCLUSION: Multicentricity with bilateral lobar involvement and aggressive histopathological features are more frequent in papillary microcancer patients diagnosed with preoperative fine-needle aspiration biopsy compared to papillary microcancer diagnosed as postoperative incidental histopathological finding.

Association of Pro-apoptotic Bad Gene Expression Changes with Benign Thyroid Nodules.

BACKGROUND/AIM: This study aimed to investigate the role of the mitochondrial apoptotic pathway in benign thyroid nodules. MATERIALS AND METHODS: Paired samples of nodular and normal tissues were collected from 26 patients with nodular goiters undergoing thyroidectomy. Variable expression of Bcl-2, Bax and Bad genes were evaluated by quantitative PCR. RESULTS: Expression level of Bad gene in nodules was found to be significantly decreased compared to normal tissues (p=0.049). A positive correlation was observed between nodule size and Bad expression levels (correlation coefficient=0.563, p=0.004); and this correlation was stronger in hot nodules (n=18, correlation coefficient=0.689, p=0.003). No significant difference was observed between nodular and normal tissue expressions of Bax and Bcl-2. CONCLUSION: These results suggest that Bad expression correlates with the size of benign thyroid nodules and also its relatively lower expression in nodules, warrant further investigation.

The impact of combined interpretation of localization studies on image-guided surgical approaches for primary hyperparathyroidism.

BACKGROUND: The impact of single and combined interpretations of ultrasonography and sestamibi scintigraphy to select the appropriate surgical approach in patients with primary hyperparathyroidism were evaluated retrospectively. METHODS: A total of 183 patients with primary hyperparathyroidism who were evaluated preoperatively using both ultrasonography and sestamibi scintigraphy were included in the study. The results of preoperative localization studies were correlated with intraoperative findings and postoperative histopathological results. The localization rates of individual and combined interpretations of ultrasonography and sestamibi scintigraphy were evaluated. RESULTS: The overall sensitivity and the positive predictive value of ultrasonography and sestamibi scintigraphy were 76% and 90%, and 81% and 91%, respectively. Both imaging studies were concordant for the same localization(s) in 121 (66%) of 183 patients. The prevalence rates of single-gland and multiglandular disease were 90% (N.=109) and 10% (N.=12), respectively, in patients with concordant results (P=0.0001). The overall rate of localization was 91% (N.=110) in these patients. In these patients with concordant results, the sensitivity and the positive predictive value of imaging were 91% and 100%, respectively. The localization rates were 96% and 42% for single-gland and multiglandular disease, respectively (P=0.0001). Of the remaining 62 patients, 50 had negative imaging with either ultrasonography (N.=29) or MIBI (N.=21). Of the 29 patients with negative ultrasonography results, sestamibi scintigraphy was positive in 23. Of the 21 patients with negative sestamibi scintigraphy imaging, ultrasonography was positive in 15. Thus, 38 patients had a single positive imaging result. The majority (95%) of these 38 patients had single-gland disease, and the rate of multiglandular disease was 5% (P=0.0001). The rate of localization was 95% (36/38) in patients with a single positive imaging study. Eighteen patients had discordant imaging results. CONCLUSIONS: The overall rate of localization in primary hyperparathyroidism is greater than 90% if ultrasonography and sestamibi scintigraphy are concordantly positive for the same localization, and the prevalence of multiglandular disease is low in patients with concordant imaging. An image-guided surgical approach and selective parathyroidectomy exhibit high cure rates in the setting of concordantly positive sestamibi and ultrasonography results, even if intraoperative parathormone monitoring is not used.

Classic Architecture with Multicentricity and Local Recurrence, and Absence of TERT Promoter Mutations are Correlates of BRAF (V600E) Harboring Pediatric Papillary Thyroid Carcinomas.

This study is aimed to investigate the BRAF (V600E) and TERT promoter mutation profile of 50 pediatric papillary thyroid carcinomas (PTCs) to refine their clinicopathological correlates. The median age at the time of surgery was 16 years (range, 6-18). No TERT promoter mutations were identified in this series. The BRAF (V600E) mutation was present in 15 (30 %) tumors. From genotype-histologic variant correlation perspective, 13 of 24 classic variant PTCs and 2 of 7 diffuse sclerosing variant PTCs were found to harbor BRAF (V600E) mutation. One cribriform-morular variant, 3 solid variant, and 15 follicular variant PTCs were BRAF wild type. While tumors with distant metastasis were BRAF wild type, two of five tumors with extrathyroidal extension (ETE) harbored BRAF (V600E) mutation. Nine of 15 BRAF (V600E) harboring tumors had central lymph node metastases. There was no significant correlation with BRAF (V600E) mutation and age, gender, tumor size, ETE, central lymph node metastasis, the status of pT, pN1a-b, and distant metastasis. An adverse correlation between BRAF (V600E) mutation and disease-free survival (DFS) was noted in the entire cohort; however, the predictive value of BRAF (V600E) mutation disappeared within the group of tumors displaying classic architecture as well as classic variant PTCs. The present cohort identifies that the classic architecture with multicentricity and local recurrence are correlates of BRAF (V600E) harboring pediatric PTCs. While the small size of this cohort is one of the limitations, neither the BRAF mutation status nor the classic tumor architecture does seem to be an independent prognosticator of DFS in this series. Evidence also suggests that TERT promoter mutations do not seem to play a major role in the pathogenesis of pediatric PTCs.

The long term outcome of papillary thyroid carcinoma patients without primary central lymph node dissection: expected improvement of routine dissection.

BACKGROUND: We investigated central compartment recurrence (CCR) and mortality rate in patients with papillary thyroid carcinoma (PTC) who had no central lymph node dissection (CLND) at the time of primary operation. METHODS: The medical records of 343 patients who underwent operations for PTC between January 1988 and December 2002 with a mean postoperative follow-up period of 9 +/- 4 years, were reviewed. RESULTS: Twenty-two patients (6%) had locoregional recurrence. The lateral, central, or both compartments were involved in 16, 2, and 4 of 22 patients, respectively. The rate of CCR was 2% (6/343). Five (2%) patients died from PTC due to locoregional invasion (tracheal and esophageal invasion) in 3 patients and distant metastasis in 2 patients. Older age (>or=60), initial metastatic lateral cervical lymph nodes, size of primary tumor size >or=3 cm, microscopic extrathyroidial extension, and aggressive histologic subtypes (diffuse sclerosing, tall-cell, poorly differentiated) of PTC were risk factors for CCR and mortality (P = .0001). CONCLUSION: Initial CLND might be of value to prevent CCR and mortality in PTC patients with initial metastatic cervical lateral lymph nodes, older age (age >or=60), primary tumor size >or=3 cm, and agressive histopathologic features of PTC.

The risk factors for malignancy in surgically treated patients for Graves' disease, toxic multinodular goiter, and toxic adenoma.

BACKGROUND: The impact of age, gender, and coexisting cold nodules on the frequency of thyroid carcinoma in hyperthyroid patients in an endemic iodine-deficient region was investigated. METHODS: The medical records of 817 patients who underwent operations for Graves' disease (GD) (n= 342), toxic multinodular goiter (TMG) (n = 299), and toxic adenoma (TA) (n = 176) between January 1988 and April 2006 were reviewed. RESULTS: Cold nodules were found in 293 (36%) of the patients, and 524 (64%) patients had no cold nodules. The incidence of thyroid carcinoma was 6.5% (53/817).The frequency of carcinoma was 3.8% in GD, 6.4% in TMG, and 12% in TA. The frequency of carcinoma in older patients (>/=50 years) was significantly higher than in younger patients (10.2% vs 4.3%, P = .001). The presence of cold nodules significantly increased the frequency of carcinoma (13% vs 2.9%, P = .001). A tumor was discovered within a cold nodule in 45% of the patients with thyroid carcinoma. CONCLUSION: Cold nodules are frequent in hyperthyroid patients in endemic iodine-deficient regions. Older patients (>/=50 years) and cold nodules are significant risk factors for malignancy in patients with hyperthyroidism. Surgical treatment may be suitable for those particular patients if malignancy can not be excluded.