Preoperative and Postoperative Risk Stratification of Thyroid Papillary Microcarcinoma: A Comparative Study Between Kuma Criteria and 2015 American Thyroid Association Guidelines Risk Stratification

Abstract

Background:

The incidence of micropapillary thyroid carcinoma (mPTC) has increased in the last decade. Active surveillance (AS) has been proposed as an alternative management for low-risk mPTC based on preoperative Kuma criteria. Controversy still exists on how to appropriately manage this group of patients, as some low-risk mPTC may harbor some postoperative features associated with disease recurrence as described in the 2015 American Thyroid Association (ATA) guidelines.

Methods:

We retrospectively reviewed 108 patients with histopathologic diagnosis of mPTC after surgery at a third level hospital in Mexico City from 2000 to 2018. Demographic and clinicopathologic data were analyzed as predictors for disease recurrence and/or metastatic disease (lymph node or distant). Comparison between group stratification based on preoperative Kuma criteria and postoperative 2015 ATA guidelines risk criteria for disease recurrence was performed. Measures of diagnostic accuracy were obtained for preoperative risk features according to the Kuma criteria.

Results:

Of 108 patients, 79 (73%) were classified as preoperative high-risk mPTC and 29 (27%) as low risk based on the Kuma criteria. Of these 79 high-risk patients, 38 (48%) were reclassified as low risk for disease recurrence, 12 (15%) as intermediate risk, and 29 (37%) remained as high risk based on the 2015 ATA risk criteria. Of the 29 preoperative low-risk patients, 19 (65.5%) remained as postoperative low risk for disease recurrence, 2 (7%) as intermediate risk, and 8 (27.5%) as high risk. Higher accuracy of preoperative risk features was obtained for lymph node and distant metastases, 84.2% and 97.2%, respectively. After multivariate analysis, age <40 years and microscopic extrathyroidal extension (ETE) were associated with higher risk for metastatic disease (lymph node or distant) in our cohort.

Conclusions:

Patients with mPTC under 40 years old and microscopic ETE are more prone to develop metastatic disease (lymph node or distant). One-third of our patients stratified as low-risk mPTC according to the Kuma criteria for AS had histopathologic features associated with a more aggressive clinical behavior or structural recurrence. In addition, lymph node and distant metastases are the preoperative risk features with the highest diagnostic accuracy for preoperative risk stratification.

Introduction

Papillary thyroid carcinoma (PTC) is the most common histological subtype of well-differentiated thyroid cancer, with an estimated frequency of ∼85% among all thyroid cancers (1). Generally, PTC tends to grow slowly, displaying an indolent clinical behavior in most patients with an excellent prognosis and survival. In the past decades, a rise in the incidence of PTC has been noticed in part due to the widespread use of imaging studies with greater diagnostic accuracy as well as increased routine screening protocols in some countries (2,3). This phenomenon has occurred at the expense of the detection of subcentimetric PTC, favoring its “overdiagnosis” as the main cause of the current low-risk PTC “epidemic” (4 –7). According to the World Health Organization, micropapillary thyroid carcinoma (mPTC) is defined as any PTC with a diameter ≤1.0 cm (8).

Based on the observation that mPTC is found to be a harmless occult carcinoma with a prevalence of ∼15% in autopsy studies (9,10), active surveillance (AS) has been proposed for low-risk mPTC with the pioneering work of our Japanese colleagues and more recently supported by a study from the United States of small PTC (<1.5 cm) (11,12). Low-risk mPTC refers to the absence of high-risk features such as lymph node or distant metastasis, extrathyroidal extension (ETE), high-grade cytology, growth progression, location close to the recurrent laryngeal nerve (RLN), or attachment to the trachea (13). Ito et al. (14) in 2014 published the results of AS in 1235 patients observed for 10 years, showing a limited progression rate of 8% with an additional 3.8% rate of new lymph node metastasis development, and a lower risk for disease progression in patients older than 40 years.

Preoperative factors associated with a predictive value for lymph node metastasis in mPTC have been described in recent studies. These include: multifocality or bilateral tumors, nodule size >5 mm, male sex, ETE, and age <55 years (15 –18). In addition, serum markers such as neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been proposed as prognostic factors associated with more aggressive forms of PTC. Moreover, some published studies have demonstrated that higher preoperative NLR does correlate with tumor size and ETE but is not associated with lymph node metastasis (19,20). However, risk stratification of PTC for disease recurrence is usually established in the postoperative period based on intraoperative findings, histopathologic data, serum thyroglobulin, and whole-body radioiodine (RAI) scan when indicated in accordance with the 2015 American Thyroid Association (ATA) guidelines for the management of differentiated thyroid cancer (21).

Controversy still exists on how to appropriately manage this group of patients, as some low-risk mPTC may harbor some postoperative risk factors associated with disease recurrence, entailing a more aggressive behavior.

The current study aimed to compare the preoperative risk classification of mPTC from the Kuma Hospital, originally described for AS, with the postoperative risk assessment for disease recurrence based on the 2015 ATA guidelines in a cohort of Mexican patients surgically treated for mPTC, and to determine measures of diagnostic test accuracy for each individual preoperative high-risk criterion. The secondary aim was to identify clinical, radiological, and histopathologic predictive factors associated with metastatic disease (locoregional lymph nodes or distant) and structural disease recurrence.

Materials and Methods

This is a retrospective analysis of a longitudinal cohort of consecutive patients who underwent thyroidectomy for mPTC from January 2000 to February 2018 at a national referral academic center in Mexico. Selection criteria included adult patients with PTC with a maximum diameter of ≤1.0 cm on histopathologic examination. Patients were excluded if the surgical procedure had been performed in a different institution or had incomplete medical records. Clinical, biochemical, radiological, and histopathologic data were collected. Our institutional review board approved the study (CIBH 3160).

For the analysis, we used the following operational definitions:

Recurrent laryngeal nerve proximity: Paratracheal thyroid nodule (TN) at the level of the cricoid cartilage located posteriorly according to the axial axis on preoperative ultrasound (US).

Strap muscles proximity: TN in the anterior aspect of the thyroid in contact with the strap muscles without a visible rim of normal thyroid tissue in between on the preoperative US.

Tracheal proximity: TN in direct contact with the trachea without a visible rim of normal thyroid tissue in between on the preoperative US.

Extrathyroidal extension (ETE): Loss of interface between the TN and the strap muscles, tracheal rings, or esophagus on US and/or computed tomography (CT) scan.

Neutrophil-to-lymphocyte ratio: The ratio obtained by dividing the absolute neutrophil count by the absolute lymphocyte count from a preoperative blood count.

Platelet-to-lymphocyte ratio: The ratio obtained by dividing the absolute platelet count over the absolute lymphocyte count from a preoperative blood count.

Preoperative low- and high-risk mPTC: Based on the Kuma Hospital criteria for AS (13).

Postoperative recurrence risk: low-, intermediate-, and high-risk PTC: Based on the 2015 ATA guidelines criteria for recurrent disease risk stratification.²¹

Structural disease recurrence: Histologically proven recurrence after initial surgery or elevated thyroglobulin levels in the fine needle aspiration (FNA) washout of a cervical lymph node 6 months after primary surgery or initial postoperative RAI administration (if given). Patients with pulmonary nodules or iodine-avid pulmonary lesions on CT scan or whole-body RAI scan more than 6 months after the initial treatment were also categorized in this group.

Distant metastatic disease: Unequivocal imaging evidence of distant metastasis by CT scan, whole-body RAI scan, or positron emission tomography (PET)/CT scan.

Imaging assessment

All, but one, cervical USs were performed at our institution. US imaging included evaluation of the thyroid gland, central and lateral neck compartments on both sides. Preoperative USs were read by a radiologist with more than 10-year experience in cervical US imaging. CT scan imaging was performed when there was suspicious of extrathyroidal invasion, either clinical or by imaging.

Statistical analysis

Descriptive and inferential statistics were performed in accordance with the variable's natural scaling using the IBM^® SPSS^© Statistics version 25 software (SPSS, Chicago, IL). Independent and nonpaired Student's t-test and Mann–Whitney U test were employed for continuous variables based on the data distribution, kurtosis, and skewness. For categorical variables, a Pearson's chi-square test or Fisher's exact test was performed. A multivariate statistical analysis was performed based on univariate analysis using a binary logistic regression through enter, conditional, Likelihood Ratio, and Wald stepwise methods to assess risk factors for metastatic disease (lymph node or distant) and recurrence. Any p-value <0.05 was considered statistically significant for a two-tailed test. Sensitivity, specificity, positive predictive value, negative predictive value (NPV), and diagnostic accuracy were determined for each preoperative risk features.

Receiver operating curve (ROC) analysis was also performed for some variables such as age with a predictive value determined in previous statistical comparisons.

Results

Three of 111 patients from our initial cohort were excluded due to incomplete medical records. One-hundred eight patients were included and analyzed in this study; 103 (95.4%) were female and 5 (4.6%) were male, with a mean ± standard deviation (SD) age of 47.2 ± 13.3 (range 21–80) years. The mean ± SD body mass index was 27.9 ± 5.6 (range 19.8–50.8) kg/m², with the mean ± SD maximum tumor diameter of 6.5 ± 3.2 (range 1–10) mm. In 52% of our patients, the suspicious TN was incidentally found on US or PET scan performed either for other thyroid or for nonthyroid conditions. In the remaining 48% of the cases, the tumor was identified by palpation during a physical examination or suspected due to local symptoms in the neck. CT scan was performed in eight patients (7.4%) before surgery.

According to the Kuma criteria, 79 (76.6%) of mPTCs were classified as high-risk tumors for an AS approach before surgery. Surgical indications were the diagnosis of cancer in the FNA in 89% of the patients, and the need for surgery was for other thyroid pathology in 11% of the cases. Total thyroidectomy was performed in 99 patients (91.7%), hemithyroidectomy in 4 (3.7%), subtotal thyroidectomy in 3 (2.8%), central thyroid resection (isthmusectomy) and near-total thyroidectomy in one patient each (1%). Therapeutic or prophylactic central neck dissection (CND) was performed in 60 (55.6%) patients and lateral lymph node dissection in 12 (11.1%) patients. Lung metastases were documented on CT scan and whole-body scan after RAI therapy in one patient (1%) and by F-18FDG PET scan in another (1%).

Based on the surgical findings and histological examination, and according to the 2015 ATA guidelines,²¹ from the 79 patients classified before surgery as high-risk mPTC for AS per Kuma criteria, 38 (48%) were reclassified as ATA low risk for recurrence after surgery, 12 (15%) as intermediate risk, and 29 (37%) remained as high risk for recurrence. Table 1 shows the comparative proportions of the features responsible for the high-risk category before and after surgery.

Table 1.

Features of Micropapillary Thyroid Carcinoma in the High-Risk Group According to the Kuma Criteria

	Before surgery, N (%)	After surgery, N (%)
High-risk mPTC	79 (73.1)	29 (26.8)
Lymph node metastasis (US suspicious)	23 (29.1)	11 (10.2)
Distant metastasis	2 (2.5)	2 (1.8)
Extrathyroidal extension	45 (56.9)	17 (15.74)
Proximity to RLN	37 (46.8)	—
Attached to trachea	42 (53.1)	7 (6.5)

RLN, recurrent laryngeal nerve; US, ultrasound; mPTC, micropapillary thyroid carcinoma.

Before surgery, 29 (26.8%) of our patients fulfilled the criteria of low-risk mPTC for AS per Kuma criteria. From these 29 patients, 2 (7%) had an intermediate risk for recurrence after surgery since 2 (7%) patients had microscopic ETE, with 1 (3.5%) having also multifocality. In addition, eight (27.5%) patients were reclassified as high risk for recurrence after surgery since five (17.2%) had macroscopic ETE and four (13.7%) had positive surgical margins (incomplete tumor resection) due to microscopic ETE. Considering the intraoperative findings and histological analysis as the gold standards, the diagnostic test accuracy of the preoperative findings is shown in Table 2.

Table 2.

Diagnostic Test Accuracy for Each Preoperative Risk Feature for Micropapillary Thyroid Carcinoma^a

	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)	Accuracy (%)
Lymph node metastasis	87.50	84	30.43	98.82	84.26
Distant metastasis^b	100	97.17	40	100	97.22
Extrathyroidal extension	56	62.65	31.11	82.54	61.11
High-grade cytology	33.33	99.08	50	98.18	97.32
Attached to trachea	50	62.77	16.67	89.39	61.11

Based on histology.

Detected by CT scan, whole-body scan after RAI therapy, or PET/scan.

PPV, positive predictive value; NPV, negative predictive value; CT, computed tomography; PET, positron emission tomography; RAI, radioiodine.

Structural disease recurrence was found in only seven cases (6.4%), with a mean follow-up of 11.2 ± 4.9 (range 6.1–19.5) years. Overall mean ± SD clinical follow-up was 6.6 ± 4.3 (0.2–19.5) years. Of the seven patients with recurrent disease, four (57%) were stratified as low-risk mPTC before surgery. Of these, two patients (28.5%) were reclassified as high risk after surgery and two (28.5%) remained as low risk. Three patients (43%) were categorized as high risk before surgery. Two patients (28.5%) remained as high risk for recurrence after surgery and one (14.2%) was considered as low risk.

After univariate analysis, we found statistically significant differences between groups with or without metastatic disease for the following variables: younger age (41.4 ± 14.8 vs. 49.8 ± 11.5, respectively; p = 0.019; t-test), histopathologic features such as multifocality (odds ratio [OR] 3.27, 95% confidence interval [CI 1.91–10.58], p = 0.021; chi-square test) and microscopic ETE (OR 5, [CI 1.27–19.8], p = 0.020; chi-square test). Other variables did not show any statistically significant difference as summarized in Table 3. In the comparative analysis using structural disease recurrence as the final outcome, no statistically significant differences were found in any of the variables analyzed. Demographic and operative variables are summarized in Table 4.

Table 3.

Univariate Analysis of Preoperative and Postoperative Risk Features for Metastatic Disease and Structural Recurrence as Outcomes

	Metastatic disease^a	No metastatic disease^a	p-Value	Structural recurrence	No structural recurrence	p-Value
	21	40		7	101
Preoperative
RLN proximity^b	7	16	0.45	3	34	0.65
Strap muscles proximity^b	7	16	0.37	1	44	0.19
Tracheal proximity^b	6	18	0.48	3	39	0.67
Neutrophil-to-lymphocyte ratio^c	2.1 ± 0.9	1.8 ± 0.7	0.19	1.9 ± 0.5	1.9 ± 0.9	0.90
Platelet-to-lymphocyte ratio^c	156.6 ± 56.0	132.4 ± 59.8	0.14	120.3 ± 36.6	138.2 ± 54.8	0.39
Postoperative
Macroscopic extrathyroidal invasion^b	7	9	0.23	3	20	0.17
Multifocality^b	15	17	0.02^*	4	51	1
Nodule diameter (mm)^c	7 ± 2.3	6.7 ± 2.57	0.74	7 ± 2.6	6.2 ± 263	0.44
Extrathyroidal extension^b	8	4	0.02^*	1	13	1
Lymphovascular invasion^b	5	3	0.08	1	10	0.38
Positive surgical borders^b	5	5	0.21	2	15	0.23

Asterisk indicates statistically significant p-value.

Patients with CND or distant metastasis.

Chi-square test.

Student's t-test.

CND, central neck dissection.

Table 4.

Demographic and Operative Variables in Patients With and Without Metastatic Disease

	Metastatic disease	No metastatic disease	p-Value
	21	40
Age (years)^a	41.4 ± 14.8	49.8 ± 11.5	0.02
Sex (M/F)^b	3/18	1/39	0.26
BMI (kg/m²)^a	26.9 ± 4.9	29.1 ± 4.9	0.13
Family history of thyroid cancer^b	1	2	0.75
Preoperative TSH (IU/mL)^a	2.9 ± 3	2.3 ± 3.2	0.43
Operative time (minutes)^a	154.4 ± 56.5	159.9 ± 60.2	0.74
Intraoperative blood loss (mL)^a	52.8 ± 47.2	78.8 ± 84.4	0.21
Length of stay (days)^a	2.6 ± 3.6	3.1 ± 4.4	0.63

Bold value is statistically significant.

Student's t-test.

Chi-square test.

BMI, body mass index; TSH, thyrotropin.

A ROC analysis was performed for age and the presence of metastatic disease to determine the cutoff value, which was 40 years for age. We compared this variable based on the status of metastatic disease or structural disease recurrence. Based on this analysis, we found that age >40 years was predictive value of metastatic disease but not structural disease recurrence (p = 0.044). Summarized in Table 5 are the individual or cumulative risks of statistically significant variables.

Table 5.

Variables Associated with Metastatic Disease

	OR	95% CI	p-Value
Age <40 years (A)	3.27	1.01–10.58	0.044
Multifocality (M)	3.88	1.18–12.8	0.021
Extrathyroidal invasion (ETI)	5	1.27–19.8	0.02
M + A	6.46	1.45–28.78	0.013
ETI + M	6.64	1.19–37.11	0.026
ETI + M + A	10	1.1–92.5	0.017
ETI + A	16.33	1.84–144.6	0.002

OR, odds ratio; CI, confidence interval.

In the multivariate analysis, microscopic ETE and age <40 years persisted as statistically significant predictors for metastatic disease (p = 0.02 and p = 0.05, respectively), but not multifocality (p = 0.09). Based on structural disease recurrence as an outcome, we were not able to find out any statistically significant predictors in the binary logistic regression model.

Discussion

The majority of patients with mPTC enjoy excellent prognosis (with low risk for recurrence and mortality) with a low progression rate if not surgically treated. Due to these excellent outcomes, some groups have advocated AS (or delayed surgical intervention) instead of upfront surgical treatment in an effort to discern clinically mPTC that will eventually progress (e.g., growth of at least 3 mm or a new lymph node metastasis during surveillance) to those that are not going to progress and have been for many years detected in autopsy studies for patients dying of nonthyroid-related illnesses with no clinical impact in the patient's outcomes such as survival. AS also seeks to avoid surgical complications in patients with indolent low-risk PTC, mainly hypoparathyroidism and RLN injury. Nevertheless, a subgroup of patients with mPTC might harbor histological features that increase their risk for structural disease recurrence or more aggressive behavior.

Imaging studies and FNA cytology findings may not raise the preoperative suspicion of these features and may lead to risk underestimation of low-risk mPTC cases. In addition, several studies have reported the presence of cervical lymph node metastasis in up to one-third (22) of mPTC patients and multifocality ranging from 20% to 46% (23), which have been traditionally described as risk factors for disease recurrence. Nonetheless, the microscopic lymph node metastases might not necessarily progress over time to clinical lymph node recurrences as documented by AS protocols, mainly performed in Japan (24,25).

In our cohort, we found a 33.3% of lymph node metastasis in patients treated with CND (n = 60), in addition to the thyroidectomy, consistent with the current published scientific literature. However, just seven (6.4%) of all our cohort patients had structural disease recurrence during long-term follow-up. Multifocality was reported in 51.9% of the thyroid specimens, but on our multivariate analyses, this feature was not associated with metastatic spread in our study cohort.

Recent studies on mPTC patients have demonstrated that male sex, age <45 years, tumor size, multifocality, and gross ETE are predictive risk factors for lymph node metastasis (26 –28). Our univariate analysis confirmed that age, multifocality, and microscopic ETE are risk factors for metastatic disease (lymph node or distant). The male sex, however, was not statistically significant. The high female prevalence in our cohort may explain the lack of statistical significance of sex as a risk factor.

Only seven patients (6.4%) developed structural disease recurrence during their follow-up. This low recurrence rate is consistent with the current published scientific literature in patients with mPTC (5%) (28). However, after univariate and multivariate analyses, no predictive risk factors for disease recurrence were identified in our study. These findings may be likely explained by the small number of patients with disease recurrence in our cohort. In addition, NLR or PLR did not show any predictive value for metastatic disease or structural disease recurrence, as previously reported by other investigators.

Postoperative recurrence risk classification of mPTC based on the 2015 ATA guidelines showed that ∼34.4% of preoperative low-risk mPTC patients were categorized as intermediate or high risk for structural disease recurrence. This risk reclassification was due to histopathologic features such as positive surgical margins, gross or microscopic ETE, lymphovascular invasion, or RAI-avid lymph nodes after therapy. Nonetheless, only seven of our patients had structural disease recurrence. Even excluding patients with positive surgical margins, three of those four patients had an additional histopathologic feature for recurrence risk. One-third of patients with mPTC, who maybe candidates for AS, may have histological features for a less-indolent behavior that would not be recognized in the initial clinical or radiological assessment, a risk acknowledged by some investigators advocating for AS in these patients (29).

In our cohort, preoperative risk features with the highest accuracy for lymph node and distant metastases had a sensitivity of 87.5% and 100%, respectively, and a specificity of 84% and 97.2%, respectively. Both ETE and attachment to the trachea had a diagnostic accuracy of 61.1%, with sensitivity/specificity of 56%/62.6% and 50%/62.8%, respectively. We only had one patient with high-grade PTC on histopathology, so we could not evaluate high-grade cytology.

According to our findings, the absence of preoperative findings such as ETE or attachment of mPTC to the trachea does not exclude these findings during the surgical procedure or on histopathology report since the NPV of these two findings was the lowest compared with lymph node and distant metastases. Some patients with preoperative low-risk mPTC may harbor these aforementioned features and most likely require more aggressive management instead of AS (delayed surgery). Preoperative molecular testing in the clinical setting of a biopsy-proven mPTC might better discern patients with increased aggressive features that would benefit from upfront surgery from those who clearly have indolent disease in which an AS can be a valid alternative. Improvement in image studies will be also extremely helpful. It is important also to highlight that the decision to perform AS should always be performed in a shared decision approach after a thorough and unbiased discussion with our patients.

Limitations of our study are the relatively small number of patients in our cohort, the retrospective nature of the study design, and the small number of patients who underwent CND. The lack of strict imaging criteria for ETE or tumor attachment to the trachea on US may render over- or under-interpretation of high-risk features. Despite these limitations and based on our results, we herein advocate the discretional use of AS in well-selected patients with mPTC taking into account some other relevant features a priori.

Based on our results, patients with mPTC under 40 years old with microscopic ETE are more prone to develop metastatic disease (lymph node or distant). One-third of our patients stratified as low-risk mPTC according to the Kuma criteria for AS could harbor histopathologic features associated with a more aggressive clinical behavior or structural recurrence. In addition, lymph node and distant metastases are the preoperative risk features with the highest diagnostic accuracy for preoperative risk stratification when compared with the histopathologic study report, followed by ETE and attachment to the trachea.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this study.

References

Limaiem

, Rehman

, Mazzoni

. 2019. Cancer, Papillary Thyroid Carcinoma (PTC). StatPearls (Internet). StatPearls Publishing, Treasure Island, FL.

Leenhardt

, Grosclaude

, Chérié-Challine

, Thyroid Cancer

Committee

. 2014. Increased incidence of thyroid carcinoma in France: a true epidemic or thyroid nodule management effects? Report from the French Thyroid Cancer Committee. Thyroid, 14:1056–1060.

Ward

, Jemal

, Chen

. 2010. Increasing incidence of thyroid cancer: is diagnostic scrutiny the sole explanation?. Future Oncol, 6:185–188.

Pacini

. 2012. Thyroid miocrocarcinoma. Best Pract Res Clin Endocrinol Metab, 26:381–389.

Ahn

, Kim

, Lee

, Han

, Kim

, Ko

, Brito

. 2016. Thyroid cancer screening in South Korea increases detection of papillary cancers with no impact on other subtypes or thyroid cancer mortality. Thyroid, 26:1535–1540.

Davies

, Welch

. 2014. Current thyroid cancer trends in the United States. JAMA Otolaryngol Head Neck Surg, 140:317–322.

O'Grady

, Gates

, Boscoe

. 2015. Thyroid cancer incidence attributable to overdiagnosis in the United States 1981–2011. Int J Cancer, 137:2664–2673.

World Health Organization. 2004. Classification of Tumors: Pathology and Genetics of Tumours of the Endocrine Organs. Third edition. IARC Press, Lyon, France.

Ito

, Kobayashi

, Tomoda

, Uruno

, Takamura

, Miya

, Matsuzuka

, Kuma

, Miyauchi

. 2005. Ill-defined edge on ultrasonographic examination can be a marker of aggressive characteristic of papillary thyroid microcarcinoma. World J Surg, 29:1007–1011.

10.

Lee

, Lim

, Chang

, Park

. 2014. Papillary thyroid microcarcinomas are different from latent papillary thyroid carcinomas at autopsy. J Korean Med Sci, 29:676–679.

11.

Tuttle

, Fagin

, Minkowitz

, Wong

, Roman

, Patel

, Untch

, Ganly

, Shaha

, Shah

, Pace

, Li

, Bach

, Lin

, Whiting

, Ghossein

, Landa

, Sabra

, Boucai

, Fish

, Morris

LGT

. 2017. Natural history and tumor volume kinetics of papillary thyroid cancers during active surveillance. JAMA Otolaryngol Head Neck Surg, 143:1015–1020.

12.

Ito

, Miyauchi

, Inoue

, Fukushima

, Kihara

, Higashiyama

, Tomoda

, Takamura

, Kobayashi

, Miya

. 2010. An observational trial for papillary thyroid microcarcinoma in Japanese patients. World J Surg, 34:28–35.

13.

Miyauchi

. 2016. Clinical trials of active surveillance of papillary microcarcinoma of the thyroid. World J Surg, 40:516–522.

14.

Ito

, Miyauchi

, Kihara

, Higashiyama

, Kobayashi

, Miya

. 2014. Patient age is significantly related to the progression of papillary microcarcinoma of the thyroid under observation. Thyroid, 24:27–34.

15.

Cheng

, Chen

, Zhu

, Zhou

, Xu

, Chen

, Wen

, Chen

. 2019. Risk factors for cervical lymph node metastasis of papillary thyroid microcarcinoma: a single-center retrospective study. Int J Endocrinol, 2019:8579828.

16.

Zheng

, Peng

, Gao

, Zhi

, Hou

, Zhao

, Wei

, Chi

, Li

, Qian

. 2019. Risk factors for cervical lymph node metastasis in papillary thyroid microcarcinoma: a study of 1,587 patients. Cancer Biol Med, 16:121–130.

17.

Zhou

, Gao

, Zhang

, Yang

, Guo

, Zhang

, Wang

. 2012. Factors predictive of papillary thyroid micro-carcinoma with bilateral involvements and central lymph node metastasis: a retrospective study. World J Surg Oncol, 10:67.

18.

Kaliszewski

, Diakowska

, Wojtczak

, Forkasiewicz

, Pupka

, Nowak

, Rudnicki

. 2019. Which papillary thyroid microcarcinoma should be treated as “true cancer” and which as “precancer”?. World J Surg Oncol, 17:91.

19.

Ceylan

, Kumanlioglu

, Oral

, Ertan

, Ozcan

. 2019. The correlation of clinicopathological findings and neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios in papillary thyroid carcinoma. Mol Imaging Radionucl Ther, 28:15–20.

20.

Lang

, Ng

, Au

, Wong

, Wan

. 2014. Does preoperative neutrophil lymphocyte ratio predict risk of recurrence and occult central nodal metastasis in papillary thyroid carcinoma?. World J Surg, 38:2605–2612.

21.

Haugen

, Alexander

, Bible

, Doherty

, Mandel

, Nikiforov

, Pacini

, Randolph

, Sawka

, Schlumberger

, Schuff

, Sherman

, Sosa

, Steward

, Tuttle

, Wartofsky

. 2016. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid, 26:1–133.

22.

Akin

, Yazgan-Aksoy

, Akin

, Kilic

, Yetisir

, Bayraktar

. 2017. Prediction of central lymph node metastasis in patients with thyroid papillary microcarcinoma. Turk J Med Sci, 47:1723–1727.

23.

Baloch

, LiVolsi

. 2006. Microcarcinoma of the thyroid. Adv Anat Pathol, 13:69–75.

24.

Ito

, Uruno

, Nakano

, Takamura

, Miya

, Kobayashi

, Yokozawa

, Matsuzuka

, Kuma

, Miyauchi

. 2003. An observational trial without surgical treatment in patients with papillary microcarcinoma of the thyroid. Thyroid, 13:381–387.

25.

Ito

, Tomoda

, Uruno

, Takamura

, Miya

, Kobayashi

, Matsuzuka

, Kuma

, Miyauchi

. 2004. Papillary microcarcinoma of the thyroid: how should it be treated?. World J Surg, 28:1115–1121.

26.

Gui

, Qiu

, Peng

, Wang

. 2018. Clinical and pathologic predictors of central lymph node metastasis in papillary thyroid microcarcinoma: a retrospective cohort study. J Endocrinol Invest, 41:403–409.

27.

, Xu

, Wang

. 2018. Clinical predictors of lymph node metastasis and survival rate in papillary thyroid microcarcinoma: analysis of 3607 patients at a single institution. J Surg Res, 221:128–134.

28.

Siddiqui

, White

, Antic

, Grogan

, Angelos

, Kaplan

, Cipriani

. 2016. Clinical and pathologic predictors of lymph node metastasis and recurrence in papillary thyroid microcarcinoma. Thyroid, 26:807–815.

29.

Qian

, Guo

, Zheng

, Sun

, Li

, Wu

, Ji

, Wang

. 2017. Contrastive study of two screening criteria for active surveillance in patients with low-risk papillary thyroid microcarcinoma: a retrospective analysis of 1001 patients. Oncotarget, 8:65836–65846.