Proposed Risk Stratification and Patterns of Radioactive Iodine Therapy in Malignant Struma Ovarii

Abstract

Introduction:

Malignant struma ovarii (MSO) is a rare thyroid cancer arising within an ovarian teratoma. While surgical excision of the primary tumor is widely accepted as standard of care, recommendations for adjuvant treatment of MSO—whether or not to administer radioactive iodine (RAI)—are based largely on case reports and remain debated. In this study, we aimed to propose a risk stratification and analyze RAI utilization patterns in MSO cases.

Methods:

The National Cancer Database (NCDB) was queried for patients with MSO between 2004 and 2016. Demographic, oncological, and clinicopathologic data were compared between groups using Fisher's exact test. Kaplan–Meier curves were used to estimate overall survival (OS), and variables associated with OS were assessed via univariate Cox regression. We adapted the 2015 American Thyroid Association risk guidelines for MSO patients. We stratified patients into low-, intermediate-, and high-risk groups using metastasis, extraovarian extension, lymphovascular invasion, lymph node status, surgical margins, tumor size, and grade. Risk stratification, demographic, oncological, and clinicopathologic data were compared between the groups receiving and not receiving RAI therapy. We then queried the Surveillance, Epidemiology, and End Results (SEER) 18 registry for patients with MSO between 2000 and 2018 to confirm our risk stratification analysis.

Results:

In the NCDB analysis, a total of 158 patients were identified, and 19 received RAI. RAI therapy was associated with distant metastasis (p = 0.005) and lymph node status (p = 0.012). Twenty-one NCDB patients were stratified as high risk, and 30% of high-risk patients received RAI. High-risk stratification was associated with decreased OS via univariate Cox regression (hazard ratio = 4.0 [95% confidence interval 1.11–14.26], p = 0.034). In our subsequent analysis using the SEER registry, there were 95 MSO patients, and 18 received RAI. Again, the majority of high-risk patients did not receive RAI, with only 41% of high-risk patients receiving RAI.

Conclusions:

MSO is a rare malignancy with apparently variable and inconsistent patterns of postoperative RAI administration. The risk stratification described here provides a framework to identify patients potentially at risk for mortality, and utilization of RAI in this group should be studied further.

Introduction

Struma ovarii is an ovarian teratoma containing >50% thyroid tissue,^1,2 while malignant struma ovarii (MSO) is defined by the histology or behavior of the tumor. MSO containing well-differentiated thyroid cancer is diagnosed histologically using thyroid carcinoma criteria, including nuclear appearance, mitotic figures, and the presence of vascular invasion,^3,4 while a “biologically malignant” MSO is defined by recurrence or metastasis.^5,6 MSO can contain papillary or follicular carcinomas and have been characterized with common thyroid carcinoma gene mutations, such as RAS and BRAF.^7
–9 Moreover, there have been cases of benign struma ovarii that recur as malignant well-differentiated thyroid tumors.¹⁰ Given the extreme rarity of MSO, with <200 reported cases in a 2010 review of the literature,¹¹ there is no consensus on optimal management and recommendations are based on case reports and small series.^4,12

–15

Surgical treatment options for MSO include ovarian cystectomy, unilateral or bilateral salpingo-oophorectomy with or without hysterectomy, lymphadenectomy, and omentectomy. Adjuvant treatments include chemotherapy, hormonal therapy, external beam radiation (EBRT), and radioactive iodine (RAI) after total thyroidectomy. RAI therapy recommendations range from ubiquitous administration to all patients with MSO¹⁵ to selective administration based on clinicopathologic features such as extraovarian extension (EOE) or metastasis.¹³ Although the majority of MSO literature is composed of case reports and series, more recent population-based studies have been published. A 2015 analysis using the Surveillance, Epidemiology, and End Results (SEER) database of 68 patients diagnosed with MSO showed excellent survival despite these variations in management and concluded that MSO may be overtreated.¹⁶ However, this analysis did not stratify patients based on risk and only six patients received RAI.

For cervical thyroid carcinoma, the American Thyroid Association (ATA) 2015 guidelines provide a risk stratification schema for recurrence.¹⁷ RAI is recommended for intermediate- and high-risk differentiated thyroid cancers, which have been associated with decreased recurrence rates and improved overall survival (OS).^17

–20 Given the similarities between cervical thyroid cancer and MSO, the goal of our study was to utilize the National Cancer Database (NCDB) to use pathological variables to stratify risk of MSO cases similar to the ATA stratification for cervical thyroid cancer. Our secondary aim was to analyze RAI treatment patterns in MSO with consideration to the risk stratification schematic. We then confirmed our analysis using an updated cohort of MSO patients in the SEER database.

Materials and Methods

Institutional review board approval

This study used publicly available, de-identified data and was designated exempt by the Weill Cornell Medicine Institutional Review Board.

NCDB query, study definitions, and variables

The NCDB was queried for all patients with the histology code for MSO as per the International Classification of Diseases for Oncology, third edition (ICD-O-3), between 2004 and 2016. The NCDB data are collected from more than 1500 Commission on Cancer-accredited cancer programs, including 70% of newly diagnosed cancer cases and 34 million historical records from the United States.²¹ The NCDB is sponsored by both the American College of Surgeons and the National Cancer Society.²¹

Demographics included age at diagnosis, race, and Hispanic ethnicity. Clinical data included Charlson–Deyo Score (CDS), history of malignancy, tumor laterality, presence of distant metastasis at diagnosis, CA-125 levels, type of surgery, surgery at other sites, chemotherapy, hormonal therapy, and radiation treatment, including EBRT, RAI, or implanted radiation seeds. The CDS accounts for comorbidities, not including the cancer diagnosis of MSO in these cases, and is a validated prognostic score for survival analysis.^22,23 Scores were coded as 0, 1, 2, or ≥3. Surgical treatment variables included no surgery, unilateral oophorectomy, bilateral oophorectomy, oophorectomy with omentectomy, debulking surgery, and unknown.

Pathological data included stage, tumor size, lymph node status, lymphovascular invasion (LVI), EOE, tumor extension, and surgical margins. Pathological staging was coded as I, II, III, IV, or unknown. Tumor size was coded as <1, 1–2, 2–4, >4 cm, and unknown. Lymph node status was positive, negative, or not examined. Tumor extension was defined as confined to ovary, local capsule rupture, positive peritoneal washings, pelvic invasion, and unknown. Surgical margins included no residual tumor, residual tumor, and unknown.

NCDB risk stratification

Using the 2015 ATA risk stratification as a guide, we stratified MSO pathological variables as closely as possible to the thyroid cancer variables to develop our proposed MSO risk stratification schema—this was largely based on analogous ATA high-risk variables such as gross extrathyroidal extension, incomplete tumor resection, lymph node metastases, and distant metastases. Moreover, more conservative RAI recommendations suggest that patients with EOE and distant metastases should be receiving RAI.¹³ As such, patients in the NCDB cohort were risk-stratified based on EOE, lymph node status, distant metastasis, surgical margins, LVI, and tumor size (Fig. 1).

FIG. 1.

Pathological variables used for risk stratification of MSO cases. ^aNCDB data only, ^bSEER data only. EOE, extraovarian extension; LVI, lymphovascular invasion; MSO, malignant struma ovarii; NCDB, National Cancer Database; SEER, Surveillance, Epidemiology, and End Results.

Tumor extension was classified into EOE 1–4 based on the degree of tumor extension beyond the ovary at time of surgery. EOE 1 tumors were confined to the ovary, while EOE 2 tumors experienced local capsule rupture during surgery. EOE 3 tumors had positive pelvic washing, and EOE 4 tumors had definitive pelvic invasion. Patients were stratified as high risk if they had EOE 3 or 4, positive lymph nodes, distant metastasis, or positive surgical margins. Patients were stratified as intermediate risk if they had EOE 2, positive LVI, or tumor size >4 cm. Likewise, patients were stratified as low-risk if the tumor was EOE 1, no metastasis, tumor <4 cm, and negative margins.

SEER query and risk stratification

The National Cancer Institute's SEER 18 Research Plus database, containing cases from 2000 to 2018, was queried using the same ICD-O-3 histology code for MSO. The SEER 18 database is made up of 18 cancer registries and accrues data from ∼30% of the United States' population.²⁴ Clinicodemographic variables were extracted as well as subsequent diagnoses of thyroid cancer, as the SEER registry allows patients' cancer cases to be linked. Variables were extracted for validation of risk stratification, survival data, and RAI status, which included radiation status, tumor size, EOE, metastasis, lymph node status, and tumor grade. Risk stratification variables used for the SEER cohort were the same as the NCDB cohort with exceptions.

For example, surgical margin status and LVI were not recorded in the SEER data set and thus were exempt from this subset analysis. Additionally, tumor grade is recorded in the SEER data set, and thus, well-differentiated tumors were stratified as low risk, moderately differentiated as intermediate risk, and poorly differentiated as high risk (Fig. 1). Survival data in the SEER database included survival in months and cause of death if applicable.

Statistical analyses

Continuous parametric variables are presented as mean ± standard deviation (SD), and nonparametric variables are presented as the median and interquartile range. Patients were dichotomized between those who received RAI and those who did not. Demographic, oncological, and clinicopathologic data including risk status were compared between RAI treatment groups using Fisher's exact test or Pearson's chi-squared test, as appropriate. Kaplan–Meier curves were generated to estimate the OS. Given the limited size of each cohort and the small number of events per database, 14 (NCDB) and 10 (SEER), only univariate Cox regression analyses were performed to assess for significant factors influencing the OS. Hazard ratios (HRs) with 95% confidence intervals [CIs] are reported for all univariate Cox regression analyses. A p-value of <0.05 was considered statistically significant. Statistical analyses were performed using Stata, version 16.1 (Stata Corp., College Station, TX) and Prism, version 8.0 (GraphPad, San Diego, CA).

Results

NCDB cohort characteristics

A total of 158 MSO patients were identified from the NCDB from 2004 to 2016, with a mean age of 49 years (SD ±13.9) (Table 1). Regarding pathological data, most lymph nodes were not examined (67.7%), and of those who had examined lymph nodes (n = 51), 4 (7.8%) contained metastatic disease. Approximately 35% of tumors were >4 cm in diameter. The tumors were commonly unilateral (95.6%), confined to the ovary (69.4%), and resected without residual tumor (72.8%) (Table 1). Most patients had Stage I disease (67.7%), and 7 (4.4%) had Stage IV disease. A limited number of patients received RAI (12.0%) or hormonal therapy (7.0%) (Table 1).

Table 1.

Demographic, Clinical, and Pathological Characteristics of Patients with Malignant Struma Ovarii in the National Cancer Database

Patient characteristics	n (%)
Demographic
Female sex	158 (100)
Age at diagnosis ± SD, years	49.4 ± 13.9
Race
White	122 (77.2)
Black	19 (12.0)
Asian	13 (8.2)
Other/unknown	4 (2.5)
Hispanic	20 (12.7)
Clinical
Charlson–Deyo Score
0	136 (86.1)
1	17 (10.8)
2	4 (2.5)
≥3	1 (0.6)
First malignant neoplasm	121 (76.6)
Distant metastases at diagnosis	6 (3.8)
Elevated CA-125 (n = 76)	34 (44.7)
Surgery at primary site
No surgery	5 (3.2)
Unilateral oophorectomy	43 (27.2)
Bilateral oophorectomy	63 (39.9)
Oophorectomy with omentectomy	36 (33.8)
Debulking surgery	8 (5.1)
Unknown	3 (1.9)
Surgery at other sites (n = 156)	29 (18.6)
Surgery at other site and other cancer (n = 37)	7
Surgery at other site and first cancer (n = 119)	22
Radiation
None	131 (82.9)
Beam	1 (0.6)
Implants	1 (0.6)
RAI	19 (12.0)
Unknown	6 (3.8)
Chemotherapy agents	4 (2.5)
Hormonal therapy	11 (7.0)
Vital status, deaths	14 (9.4)
Pathological
Stage
I	107 (67.7)
II	4 (2.5)
III	6 (3.8)
IV	7 (4.4)
Unknown	34 (21.5)
Tumor size (cm)
<1	31 (19.6)
1–2	12 (7.6)
2–4	14 (8.9)
>4	56 (35.4)
Unknown	45 (28.5)
Laterality
Right	81 (51.3)
Left	70 (44.3)
Bilateral	3 (1.9)
Unknown	4 (2.5)
Lymph node status
Not examined	107 (67.7)
Negative	47 (29.8)
Positive	4 (2.5)
LVI (n = 51)	4 (7.8)
Extraovarian extension	25 (18.7)
Tumor extension
Confined to ovary	109 (69.4)
Local capsule rupture	10 (6.4)
Positive peritoneal washings	4 (2.6)
Pelvic invasion	11 (7.0)
Unknown	23 (14.6)
Surgical margins
No residual tumor	115 (72.8)
Residual tumor	2 (1.3)
Unknown	36 (22.8)
No primary site surgery	5 (3.2)
Median follow-up (IQR), months	44 (16–83)

LVI, lymphovascular invasion; RAI, radioactive iodine; SD, standard deviation.

Survival analysis and RAI patterns in NCDB

The 5-year OS was 91.0%, with a median follow-up of 44.4 months. Variables associated with decreased OS on univariate Cox analyses were increasing age and receiving chemotherapy (HR = 1.04 [CI 1.01–1.08], p = 0.017, and HR = 19.9 [CI 5.11–77.6], p < 0.001, respectively). Patients who received RAI therapy were more likely to have distant metastases, undergo surgery at other sites, and receive hormonal therapy (Supplementary Table S1). However, only 62.2% of patients receiving RAI had surgery at other sites. Tumor stage, tumor size, EOE, surgical margins, and extent of surgery did not differ with RAI therapy.

Risk stratification and OS in NCDB

We next stratified patients into risk levels analogous to the ATA guidelines (Fig. 1). For risk stratification, 74.1% (117/158) patients had enough data to be stratified (Fig. 2). The majority, 44.4% (52/117), of patients were intermediate risk, while 18.0% (21/117) and 37.6% (44/117) were high and low risk, respectively. Only 30% of high-risk patients received RAI therapy (Table 3). Although limited by small cohort size, high-risk stratification appears to be associated with worse OS compared with low- and intermediate-risk patients (Fig. 3A) on univariate Cox regression (HR = 4.0 [CI 1.11–14.26], p = 0.034).

FIG. 2.

NCDB and SEER program cohorts. Patients without adequate pathological data were excluded from risk stratification and overall survival analysis. Patients without follow-up were excluded from overall survival analysis. *There were 14 deaths in the NCDB cohort; however, only 10 patients had adequate pathological and follow-up data to be included in the overall survival analysis. RAI, radioactive iodine.

FIG. 3.

Kaplan–Meier estimates of overall survival based on high-risk stratification compared with all other MSO patients in (A) the NCDB and (B) the SEER cohorts.

Table 3.

Risk Stratification for High-Risk Malignant Struma Ovarii Patients in the National Cancer Database and Surveillance, Epidemiology, and End Results Cohorts

Risk stratification	No RAI, n (%)	Received RAI, n (%)	p
NCDB			0.044
High	14 (70.0)	6 (30.0)
Low or intermediate	80 (87.9)	11 (12.1)
SEER			0.014
High	10 (58.8)	7 (41.2)
Low or intermediate	54 (85.7)	9 (14.3)

NCDB, National Cancer Database; SEER, Surveillance, Epidemiology, and End Results.

SEER cohort characteristics and OS

To confirm our NCDB findings that most high-risk patients were not receiving RAI, we analyzed an additional MSO cohort in the SEER database. A total of 95 patients were identified in the SEER 18 registry from 2000 to 2018, and 18.9% (18/95) received RAI (Table 2). Nine patients had subsequent thyroid cancer after their MSO diagnosis—8 with papillary thyroid cancer (PTC) and 1 with follicular carcinoma. Of the PTC patients, 2 were follicular variant and 1 was diffuse sclerosing variant. For the MSO SEER patients, the 5-year disease-specific survival was 98.9% and the OS was 93.2%, with a median follow-up of 107 months.

Table 2.

Demographic, Clinical, and Pathological Characteristics of Patients with Malignant Struma Ovarii in the Surveillance, Epidemiology, and End Results

Patient characteristics	n (%)
Demographic
Female sex	95 (100)
Age at diagnosis (years)
<30	8 (8.5)
30–39	24 (25.4)
40–49	27 (28.4)
50–59	14 (14.7)
60–69	17 (17.9)
70–79	4 (4.2)
>80	1 (1.1)
Race
White	68 (71.6)
Black	11 (11.6)
Asian	14 (14.7)
Other/unknown	2 (2.1)
Hispanic	17 (17.9)
Clinical
Distant metastases at diagnosis	6 (6.3)
Surgery at primary site
No surgery	4 (4.2)
Unilateral oophorectomy	27 (28.4)
Bilateral oophorectomy	35 (36.8)
Oophorectomy with omentectomy	22 (23.2)
Debulking surgery	5 (5.3)
Unknown	2 (2.1)
Thyroid cancer after MSO	9 (9.5)
8 papillary thyroid carcinoma
2 follicular variant
1 diffuse sclerosing variant
1 follicular carcinoma
Radiation
None	76 (80.0)
Beam	1 (1.1)
Implants and RAI	1^a (1.1)
RAI	17 (17.8)
Vital status, deaths	10 (10.5)
Vital status, deaths due to MSO	2 (2.1)
Pathological
Tumor size (cm)
<1	17 (17.9)
1–2	9 (9.5)
2–4	10 (10.5)
>4	33 (34.7)
Unknown	26 (27.3)
Laterality
Right	46 (48.4)
Left	42 (44.2)
Bilateral	1 (1.1)
Unknown	6 (6.3)
Lymph node status
Unknown	19 (20.0)
Negative	74 (77.9)
Positive	2 (2.1)
Extraovarian extension	16 (16.8)
Tumor extension
Confined to ovary	67 (70.5)
Local capsule rupture	5 (5.3)
Positive peritoneal washings	0 (0)
Pelvic invasion	12 (12.6)
Unknown	11 (11.6)
Grade
Unknown	73 (76.8)
Well differentiated	14 (14.7)
Moderately differentiated	6 (6.3)
Poorly differentiated/anaplastic	2 (2.1)
No primary site surgery	4 (4.2)
Median follow-up (IQR), months	107 (41–155)

One patient was treated with RAI and implants.

IQR, interquartile range; MSO, malignant struma ovarii.

When stratified by RAI treatment, patients receiving RAI had increased rates of thyroid cancer after MSO diagnosis (9 [50%] vs. 0 [0%], p < 0.001) and distant metastases at diagnosis of MSO (3 [16.7%] vs. 2 [2.6%], p = 0.017). Patients who received RAI also had increased pelvic invasion (6 [33.3%] vs. 6 [7.9%], p = 0.008) (Supplementary Table S2). The rate of patients receiving RAI appeared to fluctuate with the incidence of cases over time (Fig. 4).

FIG. 4.

The number of cases of MSO compared with the rate of radioactive iodine treatment from 2000 to 2018 in the SEER 18 registry.

Risk stratification in SEER

The same risk stratification used in the NCDB cohort was applied to the SEER cohort, with the exception that the MSO SEER data do not include surgical margin status or LVI status but does include tumor grade. As with the NCDB, not all SEER MSO patients were able to be risk stratified due to incomplete data—only 84.2% (80/95) of patients had known variables to be stratified (Fig. 2). Most SEER MSO patients were classified as intermediate risk, 40.0% (32/80), while 21.3% (17/80) were high risk and 38.8% (31/80) were low risk. Similar to the NCDB analysis, only 7 (41.2%) patients in the SEER high-risk cohort received RAI (Table 3). High-risk stratification was not associated with the OS in the SEER database (HR = 1.31 [CI 0.34–5.11], p = 0.699) (Fig. 3B).

Discussion

MSO is a rare malignancy, with variable treatment algorithms based largely on case series. Recent analyses have concluded that MSO has excellent disease-specific survival despite the nonstandardized management utilized.^6,13,16 Moreover, the role of RAI therapy is unclear, and its use in MSO is associated with mostly positive outcomes in the literature.^10,15 In this large hospital-based study confirmed with a population-based cohort of MSO patients, we demonstrated that MSO cases can be stratified by pathological features similar to the ATA guidelines for thyroid cancer. RAI was only administered to ∼30–40% of patients stratified as high risk, namely those with overt EOE, positive margins or lymph nodes, or distant metastasis.

The utility of RAI in the MSO treatment algorithm remains controversial. As the number of patients receiving RAI and the number of deaths were small in our cohorts, we were underpowered to adequately draw conclusions regarding RAI therapy's association with survival. Thyroid cancer literature, not limited by rarity such as MSO, supports the use of RAI,^18,20 while MSO case reports have also correlated RAI utilization with decreased recurrence in MSO.^15,25 A 2003 series found that MSO patients who received adjuvant RAI did not suffer recurrence, and in the seven patients who received RAI after recurrence, the majority had a complete response to RAI.¹⁵

The rarity of MSO and the limited use of RAI use in our study, which is mostly descriptive in nature, as well as others preclude definitive conclusions on any potential benefits of RAI therapy. However, our analysis based on risk stratification showed that the majority of patients stratified as high risk were not receiving RAI, as recommended by expert opinion in the MSO literature.¹³ We hypothesize that the variations in RAI administration are due in part to the extreme rarity of MSO as well as the variety of clinicians who may care for MSO patients, including gynecologic oncologists, medical oncologists, endocrinologists, and endocrine surgeons.

In our NCDB cohort analysis, treatment strategies for MSO were variable, which included surgery, chemotherapy, hormonal therapy, and radiation, as previously described in prior MSO analyses.^13,16 Since RAI therapy has been shown to decrease recurrence and improve the OS in certain PTC,^18,20 increased RAI utilization in MSO designated as high risk may be beneficial for OS. In a recent randomized phase 3 clinical trial with low-risk differentiated thyroid cancer, RAI after thyroidectomy had similar outcomes as surgery alone²⁶ and highlights the importance of risk level for RAI benefit. Our NCDB analysis found that high-risk stratification was associated with worse OS in MSO—this finding was not statistically replicated in the SEER dataset, although the sample size was smaller and SEER does not include surgical margin status.

Taken together, our data suggest that this risk stratification schema could identify patients who are potentially at increased risk for mortality. Just as the ATA risk stratification guides treatment in PTC,¹⁷ we anticipate that our proposed MSO stratification can ultimately serve as a guide for RAI utilization in MSO cases after additional prospective validation. Finally, as PTC cases benefit from RAI treatment guided by discussion at multidisciplinary thyroid conference,²⁷ MSO cases may benefit from similar risk stratification and multidisciplinary discussion for RAI utilization based on risk.

Limitations to our study include the confines of retrospective databases as well as the nature and rarity of MSO. The NCDB and SEER databases are both retrospective databases reliant on accurate coding, with unknown and missing variables among cases. This is highlighted by the fact that only 62% of patients receiving RAI in the NCDB had “surgery at other sites,” when presumably all RAI patients had a subsequent thyroidectomy. It is possible that this discrepancy is due to thyroidectomy being performed at another institution and not reported. As MSO is extremely rare, even these large national databases have a limited number of cases and events. Thus, we were also not able to adjust for confounders in our analyses and our data are mostly descriptive of RAI patterns.

Neither database includes recurrence data, which is relevant as the ATA risk stratification guidelines are based on¹⁷ and validated²⁸ using recurrence of thyroid cancer. Additionally, there may be some overlap of patients between our NCDB and SEER cohorts, although the two databases have been used concurrently²⁹ and to validate findings,³⁰ as they are two separately maintained entities. Additional limitations include that MSO is not directly comparable to cervical thyroid cancer, and MSO is usually diagnosed incidentally after surgery for an ovarian tumor, precluding preoperative staging.

The previous ATA risk stratification guidelines have been validated using large-scale retrospective data from a single institution,²⁸ which is not possible for MSO cases given the extreme rarity. Large database studies such as ours provide additional insight to help shape guidelines for potential risk stratification, as others have called for a risk stratification system for MSO.^31,32 Moreover, total thyroidectomy with RAI treatment could definitively diagnose concurrent cervical PTC, as a previous study noted an increased incidence in MSO patients¹⁶ and thyrotropin levels could be titrated by hormone replacement, as has been recommended.³²

In conclusion, MSO is a rare malignancy, and the treatment of MSO with RAI is not standardized. Our study, like most of the MSO literature, is underpowered to make definitive conclusions on potential benefits of RAI utilization. However, the risk stratification described here provides a framework to identify MSO patients potentially at risk for mortality, and RAI utilization in this group should be further studied.

Footnotes

Authors' Contributions

C.E.: Acquisition, analysis, or interpretation of data for the work, article writing and revision, final approval of the version to be published, agreement to be 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. D.S.: Acquisition, analysis, or interpretation of data for the work, article revision, final approval of the version to be published, agreement to be 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. J.W.T., Y.J.L., and J.G.: Analysis or interpretation of data for the work, article revision, final approval of the version to be published, agreement to be 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.

T.B. and R.Z.: Interpretation of data for the work, article revision, final approval of the version to be published, agreement to be 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. P.J.C.: Substantial contributions to the analysis, or interpretation of the data for work, article revision, final approval of the version to be published, agreement to be 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. I.L.K. and T.J.F.III.: Substantial contributions to the conception or design of work, analysis, or interpretation of the data for work, article revision, final approval of the version to be published, agreement to be 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.

B.M.F.: Substantial contributions to the conception or design of work, analysis, or interpretation of the data for work, article writing and revision, final approval of the version to be published, agreement to be 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.

Acknowledgments

Part of this project was accepted as a poster presentation at the American Association of Endocrine Surgeons annual meeting April 2020 in Birmingham, AL, that was canceled due to the COVID-19 pandemic.

Author Disclosure Statement

All authors declare no conflicts of interest.

Funding Information

No funding was received for this project.

Supplementary Material

Supplementary Table S1

Supplementary Table S2

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