Influencing factors and prediction model of ultrasound-based false-negative central lymph node metastasis in localized papillary thyroid carcinoma

Introduction

Thyroid cancer (TC) is the most common endocrine malignancy, accounting for approximately 3.4% of all newly diagnosed malignancies (1-3). The thyroid gland is located below the thyroid cartilage in the neck, adjacent to the trachea, and produces hormones that regulate human metabolism (3). According to different pathological types, TC can be divided into papillary carcinoma, follicular adenocarcinoma, medullary carcinoma, and undifferentiated carcinoma, among which papillary thyroid cancer (PTC) is the most common, accounting for approximately 85% of all TC (4-6). If differentiated TC is treated promptly, the overall prognosis is good, with a 5-year survival rate of approximately 94–98% (7,8). In recent years, incidence rate of TC have shown a significant upward trend, and its incidence growth rate ranks at the forefront of all malignant tumors. TC is one of the fastest-growing malignant tumors worldwide in terms of incidence rate (9-11). In China, TC ranks seventh among malignant tumors, with its incidence growth rate ranking first (12). Research has shown that radiation exposure, dietary habits, lifestyle, and genetic factors are all associated with an increased risk of TC (13,14).

The problem of false-negative central lymph node (CLN) refers to the inability to detect lymph nodes (LNs) metastasis during preoperative ultrasound examination but is confirmed by surgical and postoperative pathological examination (15). In the present study, nearly two-thirds of patients with PTC (68.88%) had occult CLN metastasis that was not identified by preoperative ultrasound. This finding suggests that ultrasound has limited capability in detecting metastatic disease within the central compartment, particularly when LNs or metastatic foci are small (16). The presence of false-negative CLN directly affects clinical practice. It may lead to insufficient selection of treatment strategies for patients with PTC, thereby affecting their prognosis. In this study, we investigated the preoperative factors associated with false-negative CLN findings and constructed a preliminary prediction model for risk assessment. We present this article in accordance with the TRIPOD reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2026-1-0129/rc).

Methods

Setting and population

A total of 5,614 consecutive patients with postoperative pathologically confirmed PTC who underwent surgical treatment at the Department of Breast and Thyroid Surgery, Shandong Provincial Hospital, between January 2013 and December 2023, were included in this study (Figure 1). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was reviewed and approved by the Ethics Committee of Shandong Provincial Hospital (approval No. SWYX2024-225; approved on April 15, 2024). Written informed consent was obtained from all participants before surgery. The work has been reported in line with the TRIPOD criteria (17). This research study was registered in https://www.clinicaltrials.gov/ and the registration ID is NCT06423105. According to the relevant literature, the criteria for identifying abnormal cervical LN under ultrasound were: disappearance of the LN hilum structure or abnormalities in the cortex and medulla, LN becoming round or having an increased aspect ratio, microcalcifications in the LN, cystic changes present in LN, and abnormal blood flow signals in LN (18,19). The inclusion and exclusion criteria were: all cases were newly diagnosed PTC cases; all cases underwent preoperative thyroid and neck LN examinations by the Ultrasound Department of the hospital; all cases underwent thyroid surgery and CLN dissection for the first time; all cases were diagnosed with PTC through postoperative pathological examination; excluding cases of other combined tumors or major diseases. This study used the postoperative paraffin pathology results as the gold standard for diagnostic testing.

Figure 1 The design flowchart of this study.

All ultrasound examinations were performed by two experienced senior sonographers with expertise in thyroid and LN imaging, strictly following a standardized institutional protocol and reporting system to minimize inter-operator variability. Ultrasound images and reports were interpreted based on uniform diagnostic criteria. When discrepancies occurred between the two sonographers, a third senior sonographer was consulted to reach a consensus, thereby improving diagnostic consistency. In addition, all included cases were retrospectively reviewed using standardized imaging interpretation criteria to further reduce potential inter-observer variability.

The extent of surgery was determined based on the patient’s clinical characteristics and preoperative evaluation. All patients underwent thyroid lobectomy, subtotal thyroidectomy, or total thyroidectomy combined with CLN dissection, which was performed either prophylactically or therapeutically according to preoperative and intraoperative risk assessment. Therapeutic CLN dissection was performed in patients with clinically or radiologically suspected CLN metastasis. Lateral lymph node (LLN) dissection was performed in patients with suspected LLN metastasis confirmed by preoperative fine-needle aspiration (FNA). The indications for prophylactic LN dissection were determined according to current clinical guidelines and after comprehensive preoperative counseling with informed consent. All patients were fully informed preoperatively about the potential benefits and risks of prophylactic dissection, including complications such as hypocalcemia and recurrent laryngeal nerve injury. Surgical decisions were made based on a comprehensive clinical risk assessment to balance potential benefits against the risk of overtreatment and to avoid unnecessary extensive surgery. All surgeries were performed by an experienced team of thyroid surgeons.

All pathological specimens were fixed in 10% neutral-buffered formalin, routinely embedded in paraffin, and sectioned at a thickness of approximately 4 µm, followed by hematoxylin and eosin staining. Immunohistochemical staining for TPO, CK19, Galectin-3, and HBME-1 was performed using the standard streptavidin-peroxidase (SP) method. Results were interpreted according to widely accepted international criteria. A positive result was defined as the presence of distinct brown-yellow staining in tumor cells with appropriate subcellular localization (membranous, cytoplasmic, or nuclear, depending on the antibody), with ≥10% of tumor cells showing staining and/or at least moderate to strong specific immunoreactivity. Cases showing no definite specific staining or only weak/background staining were considered negative. BRAF V600E mutation status was determined using tumor DNA extracted from formalin-fixed paraffin-embedded tissue (20,21). PCR amplification followed by Sanger sequencing was performed. A mutation was considered positive when a T>A substitution at nucleotide 1799 (c.1799T>A), resulting in the V600E amino acid change, was detected; otherwise, it was defined as wild-type. All slides were independently evaluated by two experienced pathologists, and discrepancies were resolved by consensus review.

Data collection and statistical analysis

Demographic and clinical information were prospectively recorded, and postoperative paraffin-embedded pathological findings were collected for subsequent analyses. Baseline characteristics of the study population were first summarized to describe the clinical profile of patients with PTC (Table S1). The diagnostic performance of ultrasound and FNA in evaluating cervical LN metastasis was then assessed (Table 1). Next, potential preoperative factors associated with false-negative CLN findings were systematically evaluated (Table S2). Variables showing statistical significance were further examined using multivariable logistic regression, and eight clinically relevant preoperative predictors were ultimately incorporated into a preliminary prediction model. A forest plot and nomogram were generated to illustrate the relative contributions of these predictors and facilitate risk estimation.

Statistical analyses were performed using IBM SPSS Statistics version 29.0. Continuous variables were summarized as the mean ± standard deviation (SD) when they satisfied the assumptions of normality and homogeneity of variance, with comparisons between groups performed using the independent-samples t test. Variables that did not meet these assumptions were presented as the median (interquartile range, IQR) and compared using the Mann-Whitney U test. Categorical variables were reported as frequencies and percentages, and differences between groups were assessed using the chi-square test or Fisher’s exact test, as appropriate. Variables with statistical significance in the univariate analysis and those professionally considered to have an impact on the outcome were included in the logistic regression model to explore the independent factors influencing the outcome. The test level P was set at 0.05. A forest map was drawn using Graphpad Prism 10.12 software, and a column chart and credibility analysis were drawn using R Studio 4.3 software. Missing data was eliminated.

Results

Patient characteristics

According to this study, the majority of patients with PTC were women, with men accounting for approximately 20.4% and women approximately 79.6%. The average age was 44.19±11.14 years, with the oldest patient being 80 years old and the youngest 9 years old. For age analysis, we segmented by 55 years of age using a consensus. Among the patients included in the study, approximately 18.7% had hypertension, diabetes, coronary heart disease, or hyperlipidemia. Gender [odds ratio (OR): 1.832, 95% confidence interval (CI): 1.570–2.137, P<0.001] and chronic disease (OR: 0.655, 95% CI: 0.552–0.778, P<0.001) are all risk factors for the occurrence of false-negative CLN of PTC (Table S1).

Ultrasound characteristics

We focused on analyzing the ultrasound features of the included patients, and the results showed that 65.4% of the patients had single thyroid nodule. Univariate analysis and multivariate logistic analysis suggested that diameter of malignant thyroid nodules under ultrasound (OR: 1.816, 95% CI: 1.511–2.182, P<0.001), diameter of CLNs under ultrasound (OR: 1.404, 95% CI: 1.074–1.836, P=0.01), enlargement of LLNs under ultrasound (OR: 1.550, 95% CI: 1.213–1.980, P<0.001) and diameter of LLN under ultrasound (OR: 0.645, 95% CI: 0.435–0.956, P=0.03) had statistical significance for false-negative CLN (Table S2, Table 2).

Testing effectiveness

We also analyzed the effectiveness of ultrasound in detecting cervical LN. For the ultrasound detection of CLN, postoperative pathology confirmed that the true negative rate was 96.05%, the false negative rate was 68.88%, the true positive rate was 31.12%, the false positive rate was 3.95%, the accuracy was 72.75%, the sensitivity was 31.12%, the specificity was 96.05%, the positive predictive value was 81.53%, the negative predictive value was 71.35%, the area under curve (AUC) was 0.622, and the 95% CI was 0.606–0.638 (Figure 2). For the ultrasound detection of LLN, postoperative pathology confirmed that the true negative rate was 34.44%, the false negative rate was 12.71%, the true positive rate was 87.29%, the false positive rate was 65.56%, the accuracy was 75.19%, the sensitivity was 87.29%, the specificity was 34.44%, the positive predictive value was 81.76%, the negative predictive value was 44.60%, the AUC was 0.609, and the 95% CI was 0.559–0.659. The AUC of FNA was 0.784, with 95% CI of 0.609 to 0.960. Ultrasound had a poor evaluation effect in CLN and LN, and was significantly less effective than FNA in evaluating LLN (Figure 2, Table 1).

Figure 2 ROC curves. (A) ROC curve of ultrasound detection efficiency in central lymph nodes. (B) ROC curve of ultrasound detection efficiency in lateral lymph nodes. (C) ROC curve of FNA detection efficiency in lateral lymph nodes. FNA, fine-needle aspiration; ROC, receiver operating characteristic.

Puncture characteristics

We conducted a differential analysis of factors influencing puncture. According to the statistical data, 2,286 (40.7%) patients underwent thyroid nodule puncture. 8 (0.1%) patients underwent CLN puncture. Considering that the sample size was too small and that this was not a conventional detection method, the analysis was meaningless; therefore, it will not be discussed here. Approximately 91 (1.6%) patients underwent LLN puncture, 431 (7.7%) patients had BRAF gene mutations, and 61 (1.1%) had no mutations. According to univariate and multivariate analyses, these factors were not statistically significant for the occurrence of false-negative results in the CLN of the thyroid gland (Table S1, Table 2).

Surgical pathological characteristics

We also analyzed the relevant surgical and pathological features. There was a strong correlation between the surgical methods and the number and location of thyroid nodules on ultrasound, which is consistent with the statistical data related to ultrasound features. For immunohistochemical features, we included the most common immunohistochemical items for univariate and multivariate analyses. The statistical results indicated that TPO, CK19, Galectin-3, and HBME-1 were not significantly associated with the occurrence of false-negative CLN (Table S2, Table 2).

Data display

Owing to the multiple influencing factors, we constructed a forest map to visually read the impact of each variable on the outcome (Figure 3). The forest map corresponds one-to-one to the data table on the left with a reference axis of X=1. To better predict the probability of false-negative CLN, we selected clinically significant preoperative factors for column chart analysis based on the relevant influencing factors detected in the multivariate analysis, as shown in the following figure (Figure 4). The ratio of the training and validation sets in the column chart was 6:4, and the training and validation sets were randomly divided using the random number method. The AUC of the training set was 0.675 (95% CI: 0.654–0.696), and AUC of the validation set was 0.665 (95% CI: 0.639–0.692) (Figure 5). This suggested that the column chart had poor performance for CLN false-negative predictive. In this study, we only provided a preliminary model, further exploration is needed in the future.

Figure 3 Forest diagram of related influencing factors. Due to the significant differences in OR values among different influencing factors, in order to accurately display the OR values and 95% confidence intervals of each group, it is divided into two parts for display. *, P<0.05. CL, confidence limits; CLN, central lymph node; LLN, lateral lymph node; OR, odds ratio; PR, pathological report; TN, thyroid nodules; US, ultrasound.

Figure 4 Nomogram. CLN, central lymph node; LLN, lateral lymph nodes; TN, thyroid nodules; US, ultrasound.

Figure 5 ROC curve, calibration curve and decision curve of training set and validation set. (A) ROC curve of training set and validation set. (B) Calibration curve of training set and validation set. (C) Decision curve of training set and validation set. AUC, area under the curve; CI, confidence interval; C.L., confidence limits; Eavg, average absolute error; Emax, maximum absolute error; ROC, receiver operating characteristic; S:p, Spiegelhalter’s P value; S:z, Spiegelhalter’s Z-statistic.

Discussion

Early diagnosis and treatment of PTC are crucial for patient prognosis (8). Related studies have shown a positive correlation between diagnostic surgery time and the 5-year survival rate of patients: delaying diagnostic surgery time to 91–180 days increases the risk by 30% (adjusted hazard ratio 1.30, 95% CI: 1.19–1.43), and delaying to 180 days or more increases the risk by 94% (adjusted hazard ratio 1.94, 95% CI: 1.68–2.24) (22) Compared with that in other types of malignant tumors, most patients with PTC have a better prognosis with early diagnosis and appropriate treatment. Only approximately 5–30% of patients with PTC have obvious extraglandular invasion, vascular invasion, distant metastasis, among other things (23,24). The diagnosis of PTC is a multi-step process that involves clinical evaluation, imaging examination, and cytological or histological analysis (25). By observing the size, shape, boundary, internal structure, and blood flow of the lesion under ultrasound, the properties of the thyroid and cervical LN can be preliminarily determined (26,27). Meanwhile, ultrasound also has high sensitivity and specificity for the diagnosis of small thyroid nodules (28).

Ultrasound is an important auxiliary method in FNA. Ultrasound-guided FNA can improve sample collection accuracy for deeper or smaller nodules (27,29). The combination of ultrasound and FNA greatly improves the accuracy of PTC diagnosis (29,30). Its non-invasive, accurate, and economical nature makes it an indispensable tool for diagnosing PTC (31,32).

Although ultrasound examination plays an important role in the diagnosis and evaluation of PTC, it has certain limitations in the evaluation of CLN metastasis, especially small metastases, particularly in relation to false-negative rates (33,34). After postoperative pathological confirmation, there is a high false-negative rate in ultrasound evaluation (34-36). The CLN are located around the thyroid gland and in front of the trachea, up to the hyoid bone, down to the upper edge of the sternum, and outside the common carotid arteries on both sides, including the cricothyroid, peritracheal, and retropharyngeal LN. These are the common sites of PTC metastasis (37,38). The reasons for false-negative CLN of ultrasound examination are multifaceted. Firstly, interference from the deep position of CLN and surrounding structures may affect the penetration and reflection of ultrasound, reducing imaging quality. Secondly, small LN metastases may not be easily identifiable on ultrasound images, especially when the metastatic nodules are smaller than the ultrasound resolution limit. In addition, LN with normal morphology and size on ultrasound cannot completely rule out small or early cancer cell metastasis (39). The research data in this study confirm this viewpoint.

In addition to ultrasonography and FNA, immunohistochemistry is a key diagnostic method. Immunohistochemical technology recognizes and binds antigens in pathological tissues using specific antibodies and is used to detect and quantify the expression of specific proteins, providing important information for the classification, staging, and treatment response evaluation of TC (40,41). The expression of these markers can help determine the origin, nature, and potential behavioral characteristics of the tumor (42,43). For example, the expression of thyroid transcription factor-1 (TTF-1) and thyroglobulin (TG) is usually associated with well-differentiated TC, while the expression of calcitonin suggests the presence of medullary TC, and the expression of carcinoembryonic antigen (CEA) may be associated with certain poorly differentiated TC (44-46). By quantitatively analyzing the expression levels of molecular markers in tumor tissues, it is possible to predict disease progression more accurately and guide subsequent treatment (47-49). Our study demonstrates that there is no statistically significant difference between the status of common immunohistochemical indicators and the occurrence of false-negative CLN in patients with PTC.

The prognosis of PTC varies depending on the type, stage, age, and other clinical characteristics of the tumor. LN metastasis in PTC is a key factor for evaluating disease prognosis and formulating treatment plans (28,50). Different studies and statistical data suggest that among all patients with PTC, 20–60% will experience varying degrees of LN metastasis (51). The fluctuation in this proportion can be attributed to various factors, including the type, size, and location of the tumor, as well as the age and sex of the patient (52). The evaluation of LN metastasis status in PTC has important clinical significance. Cervical LN metastasis is an important indicator of PTC progression. The spread of tumor cells through the lymphatic system may lead to the formation of new cancer foci, thereby increasing the difficulty and complexity of treatment. Therefore, the accurate assessment of neck LN status is extremely important for determining disease staging and predicting patient prognosis.

The management of CLN in the treatment of PTC has always been controversial, mainly because of the uncertainty of preoperative evaluation and the complexity of surgical decision-making. Currently, both domestic and foreign guidelines suggest that LN with metastases detected before surgery require therapeutic dissection. However, there is currently no consensus on whether preventive CLN dissection should be performed in patients with negative CLN on preoperative examination (31,53). Although preventive LN dissection can reduce the risk of recurrence, it also increases the risk of surgical complications, such as hypocalcemia and recurrent laryngeal nerve injury (54). The high false-negative rate of ultrasound examination suggests that not performing prophylactic LN dissection can reduce the risk of surgery-related complications; that is, it may miss LN that actually have metastasis, which can affect the patient’s prognosis. In this case, surgical decision-making needs to comprehensively consider the specific situation of the patient, including the classification and staging of cancer, as well as factors, such as the patient’s age and health status, to find a balance between reducing the risk of recurrence and reducing surgical complications. The issue of false-negative CLN suggests the need for more accurate preoperative evaluation and more comprehensive and personalized consideration in the development of treatment plans for patients with PTC.

The development of preoperative prediction models aimed to provide valuable references for surgeons and facilitate preoperative surgical planning. The extensive dataset in this study enhanced its credibility. However, this study has several limitations. First, this was a single-center retrospective study with a relatively limited sample size, which may introduce selection bias and potentially affect the generalizability of the findings. Second, the multivariable logistic regression model was primarily used to explore potential risk factors rather than to establish a fully validated predictive model; therefore, no external validation or cross-validation was performed, and model performance metrics (such as the AUC or calibration curve) were not systematically evaluated. As a result, the predictive ability of the model requires further validation in larger, multicenter cohorts. In addition, some potential confounding factors were not routinely assessed in all patients, which may have introduced residual confounding. Future prospective, multicenter studies are needed to further validate the stability and reliability of our findings.

Conclusions

For PTC patients, false-negative CLN are very common. This study suggests that preoperative model prediction evaluation can be performed on patients with negative CLN under ultrasound. For patients with high probability of false-negative, preventive CLN dissection can be performed and the scope of dissection should be appropriately expanded to maximize treatment effectiveness and improve prognosis. For patients with low probability of false-negative, we can skip preventive CLN dissection or perform small-scale preventive CLN dissection to minimize the surgical scope, minimize surgical complications, and avoid unnecessary dissection.

Acknowledgments

We would like to express our gratitude to our supervisors, participants, family, friends, and all the researchers and scholars whose work has contributed to this study, for their support, guidance, and unwavering belief in us.

Footnote

Reporting Checklist: The authors have completed the TRIPOD reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2026-1-0129/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-2026-1-0129/dss

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2026-1-0129/prf

Funding: This study was supported by Henan Provincial Medical Science and Technology Research Program, China (No. LHGJ20240293).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2026-1-0129/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Shandong Provincial Hospital (approval No. SWYX2024-225; approved on April 15, 2024). Written informed consent was obtained from all participants before surgery.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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