Association of sonographic features and clinicopathologic factors of papillary thyroid microcarcinoma for prevalence of lymph node metastasis: a retrospective analysis

ABSTRACT Objective: The objective of the study was to develop an association between clinicopathologic and sonographic features of patients with papillary thyroid microcarcinoma and the prevalence of lymph node metastasis. Subjects and methods: Clinicopathologic and sonographic features of 415 patients of papillary thyroid microcarcinoma with (n = 102) or without (n = 313) lymph node metastasis were retrospectively reviewed. The thickness of the lymph node ≥ 6 mm with intra-lymph nodal occupying lesions considered lymph node metastasis. Also, it was considered metastasis if lymph node perfusion or blood flow defect was found with any thickness size. Univariate following multivariate analysis was performed for the prediction of sonographic features and clinicopathologic factors for the prevalence of lymph node metastasis. Results: Male gender ( p = 0.041), age < 45 years ( p = 0.042), preoperative calcitonin > 65 pg/ mL ( p = 0.039), nodule size > 5 mm in diameter ( p = 0.038), bilaterality ( p = 0.038), tumor capsular invasion ( p = 0.048), cystic change ( p = 0.047), and hyper vascularity ( p = 0.049) of thyroid nodules were associated with lymph node metastasis. Also, thyroid nodules 5 mm and more in diameter may have high aggressiveness. Conclusion: These data helped the surgeon for individualized treatment in thyroid carcinoma and avoid unnecessary prophylactic surgery of the lymph node.


INTRODUCTION
T hyroid carcinoma measuring 1 cm or less in its greatest dimension is considered as thyroid microcarcinoma (1).Papillary thyroid microcarcinoma is the most common form of thyroid microcarcinoma (2).It is associated with the risk of lymph node metastasis (1,3) and exhibits aggressive behavior (2).However, low-risk papillary microcarcinomas have excellent oncological outcomes of active surveillance (4).Papillary thyroid microcarcinoma is a subset of tumors with an indolent course and an even less aggressive treatment now proposed for these patients.However, some of these tumors may have higher rates of recurrent and persistent disease.Therefore, it is important to identify initial clinical and pathological characteristics that can predict a higher risk of progressive disease, avoiding undertreatment in this scenario.This is especially important for surgeons and clinical endocrinologists who face an increase in the incidence of papillary thyroid microcarcinoma today and must make accurate and economical treatment decisions in their routine.
Ultrasound imaging and fine-needle aspiration cytopathology are generally used for the diagnosis of papillary thyroid microcarcinoma (5).Ultrasound evaluates half of the lymph nodes due to the presence of thyroid (1).A retrospective chart review reported only 38% sensitivity of high-resolution ultrasound for predicting lymph node metastasis in papillary thyroid carcinoma (6).Japanese Society of Thyroid Surgeons Metastasis for papillary thyroid microcarcinoma Arch Endocrinol Metab.2020;64/6 (JSTS) (7) and Chinese Society of Clinical Oncology (CSCO) (8) guidelines suggested prophylactic lymph node resection to overcome complications regarding reoperations (8,9) but it is controversial in patients with papillary thyroid microcarcinoma (10) because of no evidence that rates of recurrence are decreased with this prophylactic lymph node resection (11).A retrospectively studies reported that lymph node metastasis frequency is higher in multifocal papillary thyroid microcarcinoma with higher sized nodules (1,5,10).The other retrospective study reported that clinicopathologic factors of papillary thyroid microcarcinoma of 5 or less mm diameter (Ø) nodules were less aggressive than more than 5 mm Ø nodules (2).A retrospectively studies reported that preoperative more than 65 pg/mL serum levels of calcitonin, subcapsular locations and the size of nodules are associated with lymph node metastasis (6,10).While retrospective studies reported that preoperative locations and the size of nodules are not associated with lymph node metastasis (2,5).Moreover, papillary thyroid microcarcinoma patients with clinically negative lymph node cancer have reported 3 % lymph node metastasis in the follow-up period after surgeries (12).Therefore, it is advisable to predict the association of clinicopathologic factors and preoperative sonographic features for papillary thyroid microcarcinoma for improvement of the diagnostic value of ultrasonography (2).
The aim of the retrospective study was to develop an association between clinicopathologic and sonographic features of patients with papillary thyroid microcarcinoma and the prevalence of lymph node metastasis.

Ethics approval and consent to participate
The first hospital of Lanzhou University, China approved the retrospective study (No.L-296) and waived the requirements of written informed consent form from the enrolled patients.Electronic medical records of patients have studied anonymously.

Study population
From 15 January 2016 to 28 November 2019, a total of 2,830 patients underwent thyroid surgery (total thyroidectomy, lobectomy, or central compartment lymph node resection) at the first hospital of Lanzhou University, Lanzhou, China.Patients age ≥ 18 years, surgical pathological diagnosis reported papillary thyroid microcarcinoma (10 mm or less than in its maximum Ø) (9) with or without lymph node metastasis were retrospectively reviewed.2,407 patients had other diagnosis than papillary thyroid microcarcinoma, two patients had incomplete data, one patient had age less than 18 years, two patients had a history of radiation exposure, three patients had a family history of thyroid carcinoma.Therefore, these patients were excluded from the study.In the case of multifocality, the largest nodule was used for analysis (5).Sonographic and clinicopathological data of 415 patients were used for analysis (Figure 1).

Ultrasonography
Grayscale and power Doppler ultrasound performed using ultrasound equipment (iU22, Philips Medical Systems, Amsterdam, Netherlands) with 7 MHz linear transducers.Cervical and thyroid sonography was performed in the longitudinal, transverse, and oblique planes.Ultrasound was performed by radiologists (minimum 3-years' experience) of the institute.All ultrasound images were analyzed by ultrasound technologists (had 5-years of experience in thyroid imaging).

Histopathology
It was performed for fresh surgically resected nodules of all patients by the pathologists (minimum 3-years' experience) of the institute as per the 2004 World Health Organization (WHO) criteria.If two foci were found on at least one lobe it was considered bilaterality.Ø was calculated as the average of maximal diameter of all sides of nodules (1).The accompanying disease was considered Hashimoto's thyroiditis (2).Clinicopathologic parameters were collected by authors.

Lymph node metastasis
After surgeries in follow-up, in grayscale or color Doppler ultrasound, the thickness of the lymph node ≥ 6 mm with intra-lymph nodal occupying lesions considered lymph node metastasis.Also, it was considered metastasis if lymph node perfusion or blood flow defect was found with any thickness size.If perfusion or blood flow defect found with any size thickness of the lymph node considered as metastasis (13).The suspected lymph nodes been submitted to fine needle aspiration for cytopathological confirmation.The decision of lymph node metastasis was reached by ultrasound technologists.

Metastasis for papillary thyroid microcarcinoma
Arch Endocrinol Metab.2020;64/6 parameters are reported in Table 1.A total of 102 patients were developed lymph node metastasis in the follow-up time (the thickness of the lymph node ≥ 6 mm with intra-lymph nodal occupying lesions: 57 patients, lymph node perfusion: 37 patients, and blood flow defect: 8 patients).

Clinicopathologic factors
Among 415 patients 299 patients were female and 116 patients were male.The other demographical and clinicopathologic factors of patients are reported in Table 2.

Association of features for the prevalence of lymph node metastasis
Univariate analysis reported that tumor capsular invasion (p < 0.0001), cystic change (p = 0.001), and hypervascularity (p = 0.015) of thyroid nodules were associated with lymph node metastasis (Table 3).Statistical analysis SPSS v25.0IBM Incorporation, Armonk, NY, United States was used for statistical analysis purposes.Constant data demonstrate frequency (percentage) and continuous data demonstrate mean ± SD.Fischer exact test for constant data and twotailed unpaired t-test for continuous data performed for statistical analysis (1).Univariate following multivariate analysis was performed for the prediction of sonographic features and clinicopathologic factors for the prevalence of lymph node metastasis (3).All the results were considered significant at a 95% confidence level.

DISCUSSION
The study reported that tumor capsular invasion, cystic change, and hypervascularity of thyroid nodules were independent ultrasound features for the predictor of lymph node metastasis.The results of the study were agreed with the results of retrospective studies (2,3,6,10).Extra thyroidal extension of nodules (5) and multifocal lesions (1) have chances of lymph node metastasis.Calcification and vascularity increased as size increased (2).Preoperative ultrasound plays an important role in the prediction and management of lymph node metastasis in patients with papillary thyroid microcarcinoma.
The study reported that the male gender, age < 45 years, preoperative calcitonin > 65 pg/ mL, nodule size > 5 mm Ø, and bilaterality of nodules were independent clinicopathological parameters for the predictor of lymph node metastasis.The results of the study were agreed with the results of retrospective studies (1-3,5,9,10).Thyroid nodules > 5 mm Ø have

Table 1 .
The preoperative ultrasound features of the enrolled patients

Table 2 .
The demographical and clinicopathologic factors of the enrolled patients Constant data demonstrate frequency (number) and continuous data demonstrate mean ± SD.