Edited by: Ali Yadollahpour, The University of Sheffield, United Kingdom
Reviewed by: Shengye Wang, Zhejiang Cancer Hospital, China; Yukun Li, Hebei Medical University, China
This article was submitted to Precision Medicine, a section of the journal Frontiers in Medicine
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Low-risk papillary thyroid microcarcinoma (PTMC) without clinically evident lymph nodes, extrathyroidal expansions, and distant metastases may be candidates for active monitoring.
The purpose of this research is to identify risk factors for papillary thyroid microcarcinoma (PTMC) metastasis to central cervical lymph nodes (CLNM) and to discuss the viability of an active surveillance strategy to minimize unnecessary therapy for patients.
This single-center retrospective study was conducted on the data and medical records of the patients who were diagnosed with PTMC and underwent surgery at the Baotou Cancer Hospital, China, between January 1, 2018, and December 31, 2019. Both lobectomy and complete thyroid resections were performed, and central lymph node dissections (CLND) were used in all patients. Comparisons and analyses were conducted on the preoperative ultrasound (US) characteristics, the post-operation pathological results, and lymph node metastasis.
We analyzed 172 patients with PTMC with average age 48.32 ± 10.59 years old, with 31 males and 142 females. US testing showed 74 (43.0%) patients had suspicious lymph nodes; 31 (41.9%) had capsular invasion and 52 (30.2%) patients were confirmed to have CLNM. Based on logistic regression analysis, central lymph node metastasis was shown to be more common in individuals with PTMC who were older than 45 years old, male, and had tumors that lacked micro-calcification on US imaging. Postoperative pathology assessments suggested that 58 cases (33.7%) were more suitable candidates for active surveillance cohorts.
While active surveillance might benefit many PTMC patients, treatments for the patients should also encompass occult lymph node metastasis, especially in patients with over 45 years old, male, tumor without micro-calcification in the US imaging. Furthermore, the prediction of lymph nodes in the central cervical
Thyroid cancer prevalence has increased substantially over the last several decades, but mortality from the disease have stayed essentially stable (
Active surveillance has been found to be a viable first-line therapy strategy for low-risk PTMC in recent trials (
For low-risk PTMC, active monitoring was originally evaluated as a therapy option in Japan. Japan introduced active monitoring into standards in 2010, and the United States followed suit 5 years later in 2015. The Japan Association of Endocrine Surgeons (JAES) and the Japanese Society of Thyroid Surgeons (JSTS) issued the first guidelines for differentiated thyroid carcinomas, which included active monitoring as a therapy option for low-risk PTMC (
However, occult lymph node metastasis (LNM) is still a possibility for clinical node-negative (CN0) PTMC. Therefore, the necessity and extent of surgical treatment option for low PTMC patients remain a controversial subject (
This was a single-center retrospective study conducted on the data and medical records of the patients who were diagnosed with PTMC and underwent surgery at the Baotou Cancer Hospital, China, between January 1, 2018, and December 31, 2019. Data and medical records of the patients with PTMC who underwent monitoring and therapeutic procedures at the otolaryngology (ear, nose, and throat) division of Baotou Cancer Hospital, China between January 1, 2018, and December 31, 2019, were analyzed retrospectively for this research. The patients were all candidates for thyroid surgery, either lobectomy or complete thyroid removal. Prophylactic central lymph node dissection (CLND) was also done on the same side as the lesion, as recommended by the Chinese guidelines for the diagnosis and treatment of thyroid nodule and differentiated thyroid carcinoma. Comparisons and analyses were conducted on the preoperative ultrasound characteristics of PTMC, the pathological results post-operation, and lymph node metastasis.
SPSS (IBM SPSS Inc., Chicago, IL, Windows version 22.0.0) was used to conduct statistical analyses on the study's data, including the
After applying inclusion and exclusion criteria, of 1,586 patients hospitalized for thyroid disease, 172 PTMC patients were included in this study [age: 48.32 ± 10.59 (SD) years old, and male/female ratio 31/142]. Ninety-eight cases of suspected lymph nodes were not detected
Clinical characteristics and results of US imaging and pathologic assessments of the patients.
All | 172 | 74 (43.0%) |
Female | 142 (82.0%) | 56 (75.7) |
Male | 31 (18.0%) | 18 (24.3) |
Age (mean ± SD) (year) | 48.32 ± 10.59 | 47.62 ± 12.06 |
Group 1 age <45 | 57 (33.1) | 26 (35.1) |
Group 2 45 ≥ age > 55 | 63 (36.6) | 28 (37.8) |
Group 3 age ≥ 55 | 52 (30.2) | 20 (27.0) |
3 | 10 (5.8%) | 3 (4.1) |
4a | 42 (24.4%) | 18 (24.3) |
4b | 77 (44.8%) | 33 (44.6) |
4c | 1 (0.6%) | 0 |
5 | 41 (23.8%) | 19 (25.7) |
6 | 1 (0.6%) | 1 (1.4) |
Unifocal | 121 (70.3%) | 49 (66.2) |
Double or multifocal | 51 (29.7%) | 25 (33.8) |
The max diameter (mean ± SD) | 5.68 ± 2.48 mm | 5.95 ± 2.32 mm |
US capsular invasion | 50 (29.1%) | 31 (41.9) |
US microcalcification | 101 (58.7%) | 48 (64.9) |
Unifocal | 121 (70.3) | 49 (66.2) |
Double or multifocal | 51 (29.7) | 25 (33.8) |
Capsule invasion | 74 (43.0) | 31 (41.9) |
Nerve invasion | 5 (2.9) | 4 (5.4) |
Fewer than 5 CLNM | 164 (95.3) | – |
Co-exist thyroid goiter | 73 (42.4) | 23 (31.1) |
Co-exist Hashimoto thyroiditis | 55 (32.0) | 28 (37.8) |
Recurrent nerve palsy | 0 | |
Temporary hypoparathyroidism | 9 (5.2) | |
Permanent hypoparathyroidism | 2 (1.2) |
Patients with lymph node metastases were found to be less common in the Group 2 (45 ≤ age <55 years old), compared to the Group 1 (<45 years old) and the Group 3 (≥55 years old) (
Statistical data of the patients with central cervical lymph nodes metastasis (CLNM).
57 (33.1) | 63 (36.6) | 52 (30.2) | 172 | |
CLNM patients (%) | 24 (42.1) | 14 (26.9) | 14 (26.9) | 52 |
CLNM lymph nodes (%) | 85 (64.4) | 24 (18.2) | 23 (17.4) | 132 |
CLN dissected (%) | 322 (35.2) | 343 (37.4) | 251 (27.4) | 916 |
Using US imaging to identify CLNM has a sensitivity of 0.62, specificity of 0.35, and an area under the curve (AUC) of 0.63. For PTMC patients, the probability of central lymph node metastasis was highest among those who were male, over the age of 45, and whose tumors lacked micro-calcification on US imaging. The remaining parameters did not show any statistically significant link (
Statistical data of the logistics regression analysis.
Male | 1.00 | |
Female | 2.09 (0.18–0.96) | |
Age <45 | 1.00 | |
Age ≥ 45 | 2.09 (1.01–4.30) | |
None | 1.00 | |
Sandy | 0.48 (0.23–0.99) |
According to active surveillance exclusion criteria as per reported by Ito et al. (
The over-treatment of indolent lesions with mostly low malignant potential is not uncommon, but it may be caused by the lack of evidence and comprehensive understanding regarding the disease at that time. The progression of diagnosis technology has caused a rapid increase in PTMC cases. However, lack of accurate and precise classification and prediction still exists for the disease, which may increase the amount of unnecessary invasive treatments.
AS partially slowed down the PTMC over-treatment trend safely and prudently. Emerging evidences from active surveillance studies have demonstrated that many low-risk PTMC patients can benefit from active surveillance and their morbidity probability is reduced. This is caused by operations and follow-up radioiodine therapies with increased risk stratification
It remains unknown whether or not PTMC is associated with occult central lymph node metastasis, or whether or not risk stratification is upgraded. Moreover, It remains uncertain whether or not it is safe and controllable to wait until these hidden lymph nodes can be detected clinically. Likewise, it is unknown whether or not this will increase the local recurrence rate or the probability of secondary operations and side injuries. Lastly, how to accurately select these patients and conduct more detailed risk stratifications remains unknown.
PTC has a relatively high rate of lymph node metastasis so that lymph node metastasis derived from PTC first involves the central compartment (
However, there is a lack of simple and reliable methods for conducting accurate preoperative judgments of occult lymph node metastasis and the biological characteristics of PTMC. Ultrasound accuracy when diagnosing central lymph nodes remains low. A meta-analysis concluded that for detecting central CLNM with ultrasound the pooled sensitivity was 0.33 [95% confidence interval (95% CI): 0.31–0.35], the specificity was 0.93 (95% CI: 0.92–0.94), the DOR was 5.63 (95% CI: 3.50–9.04), and the area under curve (AUC) was 0.69. In this study, we used pre-operative US imaging for detection of CLNM and the sensitivity was 0.62, the specificity was 0.35, and the area under curve (AUC) was 0.63. If the US imaging does not find a suspicious lymph node, then the lymph node FNAB target cannot be determined. There is not enough evidence to show that such PTMCs with CLNM are indolent and could be safely monitored. Moreover, this must be conducted preoperatively or at the latest intraoperatively to evaluate the central compartment LN status precisely. However, this study found that even if suspected lymph nodes were noted, it is hard identifying the suspicious LN found preoperatively
Not all patients are comfortable with observational treatment when presented with a cancer diagnosis, and many refuse active surveillance as a treatment option (
Lymph node metastasis (LNM) is a major recurrence predictor and affects PTMC patients' survival rate, although it does not seem to alter PTMC patients' 10-year disease-free survival rate (
This study had some limitations that should be considered in generalizing the findings into the general population. The study's single-center retrospective design was a weakness, and even after removing potentially relevant data, it remained gaps that may introduce bias. There is not a single accepted method for quantitatively assessing mental health. Long-term surveillance and follow-up of patients in this research is still necessary to determine their prognosis.
Despite a meteoric rise in the number of cases identified, mortality from intrathyroidal papillary microcarcinomas has been about the same. Active monitoring has arisen as an alternative to surgical resection with the purpose of identifying the subset of individuals who will develop clinically and would benefit from rescue operations. These tumors (particularly those between 1 and 2 cm) show no development during follow-up, grow at very slow rates, and can even shrink in size. Since papillary microcarcinomas are so common and observational results are so good, active monitoring may be a viable option for carefully chosen individuals. Active surveillance might benefit many PTMC patients and reduce damages caused by surgical therapies and related treatments, but PTMC treatments should also focus on the existence of occult lymph node metastasis, especially in patients with over 45 years old, male, tumor without micro-calcification in US. While accuracy of preoperative US imaging in the prediction of lymph nodes in the central cervical regions needs improvement, CLNM potential should be kept track of vigilantly in PTMC patients with microcalcification or suspected lymph nodes. Further studies should be conducted to improve the PTMC risk stratification accuracy. In this study, about 30% of the patients with PTMC had no active surveillance high-risk factors but required surgical treatment. Although informed of the details, PTMC patients' fear of cancer is still the main reason for choosing surgical treatment for active surveillance.
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.
The studies involving human participants were reviewed and approved by the Baotou Cancer Hospital, China. The patients/participants provided their written informed consent to participate in this study.
BH, JW, and JF contributed to conception and design of the study. SH organized the database. ZH performed the statistical analysis. BH wrote the first draft of the manuscript. SH, JW, JF, and ZH wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.