Predictors of Nodal Metastasis in Pediatric Differentiated Thyroid Cancer

Jina Kim, Zhifei Sun, Mohamed A. Adam, Obinna O. Adibe, Henry E.

Rice, Sanziana A. Roman, Elisabeth T. Tracy

PII: S0022-3468(16)30494-8
DOI: doi: 10.1016/j.jpedsurg.2016.10.033
Reference: YJPSU 57877

To appear in: Journal of Pediatric Surgery

Received date: 8 October 2016

Accepted date: 20 October 2016

Please cite this article as: Kim Jina, Sun Zhifei, Adam Mohamed A., Adibe Obinna O.,
Rice Henry E., Roman Sanziana A., Tracy Elisabeth T., Predictors of Nodal Metasta-
sis in Pediatric Differentiated Thyroid Cancer, Journal of Pediatric Surgery (2016), doi:
10.1016/j.jpedsurg.2016.10.033

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Title Page

Title: Predictors of Nodal Metastasis in Pediatric Differentiated Thyroid Cancer

Author Names/Affiliations:

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Jina Kim, M.D., Duke University Department of Surgery

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Zhifei Sun, M.D., Duke University Department of Surgery

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Mohamed A. Adam, M.D., Duke University Department of Surgery
Obinna O. Adibe, M.D., MHS, Duke University Division of Pediatric Surgery
Henry E. Rice, M.D., Duke University Division of Pediatric Surgery

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Sanziana A. Roman, M.D., Duke University Division of Advanced Oncologic and GI Surgery
Elisabeth T. Tracy, M.D., Duke University Division of Pediatric Surgery

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Corresponding Author:
Jina Kim, M.D.
Duke University Medical Center
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Box 3443
Durham, NC 27710
E-Mail: jina.kim1@dm.duke.edu
Tel: 919-681-3816
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Fax: 919-681-7934

Level of Evidence: Level III

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Type of Study: Treatment study, retrospective comparative

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Author Contributions:
 Study conception and design: Jina Kim, Elisabeth Tracy
 Data acquisition: Jina Kim, Zhifei Sun, Henry Rice
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 Analysis and data interpretation: Jina Kim, Zhifei Sun, Mohamed Adam, Sanziana
Roman, Elisabeth Tracy
 Drafting of the manuscript: Jina Kim
 Critical revision: Obinna Adibe, Henry Rice

Conflict of Interest: The authors have no conflicts of interest to declare.

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Abstract:

Background/Purpose: There are limited data identifying risk factors for nodal metastasis in

children with differentiated thyroid cancer.

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Methods: The 1998-2011 Surveillance, Epidemiology, and End Results Program database was

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queried for patients ≤ 18 years of age diagnosed with differentiated thyroid cancer who

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underwent nodal examination. Patients were grouped by absence or presence of nodal metastasis.

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Multivariable logistic regression methods were used to identify independent risk factors for

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nodal metastasis.

Results: In total, 1,075 children met study criteria: 734 (68%) had nodal metastases, while 341
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(32%) did not. After adjustment, risk factors for nodal metastasis included larger tumor size (1.1

– 2 cm: odds ratio [OR] 2.02, 95% confidence interval [CI] 1.22 – 3.34, p = 0.006; 2.1 – 4 cm:
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OR 3.37, 95% CI 2.03 – 5.60, p < 0.001; > 4 cm: OR 3.39, 95% CI 1.69 – 6.81, p = 0.001),
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extrathyroidal extension (OR 7.28, 95% CI 4.07 – 13.01, p < 0.001), and multifocal disease (OR

1.94, 95% CI 1.33 – 2.84, p = 0.001).

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Conclusions: Increasing tumor size, extrathyroidal extension, and multifocal disease are
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independent factors associated with nodal metastases in pediatric differentiated thyroid cancer. If

these risk factors are present, children with differentiated thyroid cancer should undergo careful

preoperative evaluation for evidence of lateral cervical lymph node metastases, and the central

compartment should be evaluated intraoperatively, with consideration of central

lymphadenectomy.

Key Words: thyroid neoplasms, lymph node metastasis, pediatric thyroid cancer

Abbreviations: ATA: American Thyroid Association; DTC: differentiated thyroid cancer; LN:

lymph node; SEER: Surveillance, Epidemiology and End Results Program

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1. Introduction

Differentiated thyroid cancer (DTC) is the most common pediatric endocrine malignancy,

with incidence rising over the past decade [1-3]. Compared to adult DTC, pediatric DTC has

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unique pathological and clinical characteristics, especially in children under 10 years of age [4,

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5]. Although children with DTC often present with multicentric disease—more than 70%

presenting with lymph node metastases at time of diagnosis—the prognosis is generally

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favorable [6-8]. Currently, attention has been focused on strategies to risk-stratify children with

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DTC in order to minimize the intensity of treatment for low-risk disease while more

appropriately directing treatment for those with highest risk disease [4, 8].
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In order to minimize the morbidity of surgical management of pediatric DTC, the role of

lymph node dissection in pediatric DTC has been debated in the literature. Currently, the 2015
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American Thyroid Association (ATA) guidelines for pediatric DTC recommend a thorough
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central neck dissection for clinically detectable nodes, malignant cytology on preoperative fine

needle aspiration of lymph nodes, extrathyroidal extension of the primary tumor, or evidence of
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locoregional metastasis either on preoperative or intraoperative evaluation (therapeutic

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lymphadenectomy) [4]. Less clear is the role of central lymph node dissection in the absence of

clinical nodal disease on preoperative work-up (prophylactic central lymphadenectomy). Given

the known high incidence of nodal disease in children with DTC and the challenges of managing

patients with residual or recurrent disease after initial resection, prophylactic central neck

dissection has been considered. However, due to concerns about the higher rates of recurrent

laryngeal nerve injury and hypocalcemia, which ranges from 1-4% even in experienced hands [7,

9-11], the ATA does not recommend prophylactic neck dissection in children.

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Recognizing the need to balance the potential morbidity of a non-therapeutic central neck

dissection with appropriate risk stratification of children with pediatric DTC, we sought to better

define risk factors for nodal metastasis that could guide clinicians in determining optimal

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surgical management and adjuvant treatment. Therefore, we utilized a national dataset to identify

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clinical and pathologic factors associated with lymph node metastasis in pediatric DTC.

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2. Methods

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2.1 Data Source

The Surveillance, Epidemiology and End Results Program (SEER) Program of the
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National Cancer Institute is a population-based cancer registry that collects cancer outcomes

from 30% of the U.S. population. The SEER database is representative of the U.S. in regards to
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patient socioeconomic status and education, although sampled areas tend to have more foreign-
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born inhabitants [12]. The study period included data for cases diagnosed between 1998 and

2012, which was determined based on availability of data regarding lymph node status and
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treatment.
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2.2 Study Design

This study was considered exempt from review by the Duke University Institutional

Review Board. All patients ≤ 18 years of age with differentiated thyroid cancer were identified

within SEER, using the International Classification of Diseases for Oncology histology codes for

papillary thyroid carcinoma (8050, 8260, 8340, 8341, 8342, 8343, 8344, 8350), follicular thyroid

carcinoma (8330-8332, 8335), and Hürthle cell carcinoma (8290). Any patients with missing

lymph node harvest data, non-malignant pathology, or history of any other malignancy were

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excluded.

2.3 Statistical Analysis

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The cohort was stratified by the presence or absence of pathologically proven nodal

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metastasis. Baseline characteristics were compared using the Kruskal-Wallis test for continuous

variables and χ2 test for categorical variables. Multivariable logistic regression modeling was

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used to assess patient demographic and clinical characteristics that were predictive of nodal

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metastasis. A p-value of less than 0.05 was considered statistically significant. Statistical analysis

was performed using R version 3.1.2 (R Foundation for Statistical Computing, Vienna, Austria).
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3. Results
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In total, 1,075 children met study criteria: 734 (68%) had nodal metastases, while 341
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Table 1 (32%) did not, with a median age of 16 years in both groups (Table 1). The overall cohort was

predominantly female (81.1%) and Caucasian (86.5%). Papillary thyroid carcinoma occurred in
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95.4% of the cohort. Children with nodal metastasis were more likely to have extrathyroidal
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extension (44.0% vs. 7.9%, p < 0.001), distant metastasis (15.1% vs. 0.3%, p < 0.001), and

multifocal disease (53.8% vs. 27.0%, p < 0.001).

After adjustment for patient and tumor characteristics, three independent, tumor-related

risk factors associated with nodal metastasis were identified: larger tumor size (1.1 – 2 cm: odds

ratio [OR] 2.02, 95% confidence interval [CI] 1.22 – 3.34, p = 0.006; 2.1 – 4 cm: OR 3.37, 95%

CI 2.03 – 5.60, p < 0.001; > 4 cm: OR 3.39, 95% CI 1.69 – 6.81, p = 0.001), extrathyroidal

extension (OR 7.28, 95% CI 4.07 – 13.01, p < 0.001), and multifocal disease (OR 1.94, 95% CI

Figure 1 1.33 – 2.84, p = 0.001) (Figure 1). Follicular thyroid carcinoma and Hürthle cell carcinoma were

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associated with lower risk of nodal metastasis, compared to papillary thyroid carcinoma (OR

0.05, 95% CI 0.02 – 0.19, p < 0.001). Age, sex, and race did not increase risk of nodal metastasis

in pediatric differentiated thyroid cancer (all p > 0.05).

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4. Discussion

In this population-level study, we identified three tumor characteristics associated with

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increased risk of nodal metastasis in pediatric DTC: larger tumor size, extrathyroidal extension,

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and multifocal disease. Of these, extrathyroidal extension was the most important risk factor for

nodal metastasis in pediatric DTC.

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Recognition of these risk factors may help identify children with differentiated thyroid

cancer who are at higher risk for harboring metastatic lymph nodes. All patients with a diagnosis
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of DTC should undergo careful sonographic interrogation of the central and lateral cervical
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lymph node compartments to potentially identify clinical metastases. Extrathyroidal tumor

extension should be specifically evaluated on preoperative sonography. Those patients who have
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no evidence of radiographic or clinical lymph node metastases should undergo careful evaluation
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at the time of surgery. Gross extrathyroidal extension, very large tumor size and known

multifocal disease should be weighed in the decision to proceed with a prophylactic ipsilateral

central lymph node dissection.

Previous studies have found tumor size and extrathyroidal extension to predict nodal

disease or disease recurrence. A previous SEER study of pediatric papillary thyroid carcinoma

found tumors ≥ 1 cm more likely to have nodal metastases (OR 39.4, p < 0.001), concurring with

our results [13]. In a retrospective, institutional review of 56 children with papillary and

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follicular cancer, thyroid capsule invasion, soft tissue invasion, and positive margins (all p <

0.05) were significant risk factors for recurrent disease [14].

Multifocal disease has also been identified as a risk factor for disease recurrence in

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pediatric DTC, which may act as a surrogate for nodal metastasis, since regional nodes are the

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most likely location for recurrence [1, 15]. In a study of 740 children from Belarus, multifocality

(OR 1.74, p = 0.0460) and known N1 status (OR 2.32, p = 0.0147) were risk factors for recurrent

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nodal disease, while older age (OR 0.87, p = 0.0071) and ipsilateral or bilateral neck dissection

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(OR 0.25 and 0.01, respectively, both p < 0.05) were protective [1]. Smaller, single-center

studies have consistently found multifocal disease to be a risk factor for disease recurrence, in
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both children and adults [16-18].

We recognize that our study has limitations that are inherent to any study that uses a
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national, secondary dataset, such as coding errors and lack of data granularity. However, SEER
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is a rigorous dataset that has been well validated. There are several variables missing in the

dataset and could not be analyzed, such as radiographic imaging, surgical intent of resection,
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lymph node size or extranodal disease. Current databases also do not contain information on
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genetic mutations, which may be associated with higher risk of nodal metastases in DTC. Studies

have identified the BRAF V600E mutation as a possible marker of nodal metastasis in adult

papillary thyroid cancer; however, this mutation is less frequent in pediatric DTC [19-21]. In a

recent prospective study of 148 patients with papillary thyroid carcinoma with clinically negative

regional nodes, the BRAF V600E mutation was present in 53.4% of cases and predicted presence

of occult central lymph node metastasis (OR 2.727, p = 0.029) [20]. As pediatric thyroid cancer

care continues to evolve, mutation profiling will become increasingly important in

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individualizing care. Few mutational analyses have been conducted in children with DTC, and

due to small cohort sizes, it is difficult to draw definitive conclusions [22-24].

Despite these limitations, our study provides useful, population-level evidence to better

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risk stratify children with DTC. Since pediatric DTC is uncommon compared to adult DTC,

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single-center studies have been limited by sample size. The paucity of evidence in pediatric DTC

has led to the extrapolation of adult guidelines for lymph node management in these patients.

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Although this is a reasonable approach, the differences in tumor biology and surgical morbidity

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between children and adults indicate a need for more age-specific studies to guide care of

children with DTC.

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5. Conclusions
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We propose that children with DTC who have risk factors for nodal metastasis receive a
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thorough preoperative evaluation for evidence of lateral cervical lymph node metastases as well

as intraoperative examination of the central compartment with consideration of ipsilateral central

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lymph node dissection. By understanding the age-specific molecular alterations and clinical
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differences between pediatric and adult DTC, clinicians will be able to provide more

personalized cancer care based on specific tumor and patient characteristics.

Acknowledgements: None

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Table/Figure Legends:

Table 1. Baseline characteristics of patients ≤ 18 years of age with differentiated thyroid cancer,
stratified by absence or presence of nodal metastases. Footnote: Categorical variables are
represented as percent (number) and continuous variables are represented as median
(interquartile range). LN: lymph node.

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Figure 1. Demographic and pathologic factors associated with lymph node metastasis among
patients ≤ 18 years of age with differentiated thyroid cancer. Footnote: Black circles represent

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odds ratios for the independent association of each factor with nodal metastasis; 95% confidence
interval bounds are represented by the corresponding horizontal lines. Factors to the right of the

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dashed vertical line at 1.0 are independently associated with lymph node metastasis in pediatric
differentiated thyroid cancer.

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Figure 1.

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Table 1.

Variable Negative LN (N=341) Positive LN (N=734) P-value

Age (years) 16 (14, 17) 16 (13, 17) 0.007

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Sex 0.038
Male 15.2% (52) 20.6% (151)

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Female 84.8% (289) 79.4% (583)

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Race 0.178
White 89.7% (306) 85.0% (624)

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Black 2.3% (8) 2.6% (19)
Asian 6.2% (21) 9.7% (71)
Other 1.8% (6) 2.7% (20)

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Histology Type <0.001
Papillary 86.8% (296) 99.5% (730)
Follicular/Hürthle 13.2% (45) 0.5% (4)
Tumor Size <0.001
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≤ 1 cm 25.2% (82) 10.0% (66)
1.1 – 2 cm 32.0% (104) 29.2% (193)
2.1 – 4 cm 31.4% (102) 41.1% (271)
> 4 cm 11.4% (37) 19.7% (130)
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Extrathyroidal Extension 7.9% (27) 44.0% (312) <0.001

Multifocal Disease 27.0% (69) 53.8% (264) <0.001
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Extent of Disease <0.001

Localized 82.1% (279) 0.0% (0)
Regional 17.6% (60) 84.9% (623)
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Distant 0.3% (1) 15.1% (111)

Extent of Surgery <0.001
Lobectomy 11.1% (38) 2.0% (15)
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Sub/Total Thyroidectomy 87.7% (299) 97.5% (716)

Unspecified 1.2% (4) 0.4% (3)
Radioactive Iodine Therapy Used 55.7% (190) 78.1% (573) <0.001

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