Int J Clin Exp Med 2019;12(4):3325-3332www.ijcem.com /ISSN:1940-5901/IJCEM0077032

Original Article Surgical approaches for follicular variant of papillary thyroid cancer: analysis of the surveillance, epidemiology, and end results database using propensity score matching

Zeming Liu1*, Qiuyang Zhao3*, Wen Zeng2, Shuntao Wang3, Pengfei Yi3, Xiangwang Zhao3, Tao Huang3, Chunping Liu3, Liang Guo1

Departments of 1Plastic Surgery, 2Ophthalmology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; 3Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Sci-ence and Technology, Wuhan 430022, China. *Equal contributors.

Received December 24, 2017; Accepted October 7, 2018; Epub April 15, 2019; Published April 30, 2019

Abstract: Currently, there exists no consensus on the appropriate surgical treatment of the follicular variant papil-lary thyroid carcinoma (FVPTC). Herein, we aimed to compare the prognosis of patients who underwent subtotal or near-total thyroidectomy and those who underwent lobectomy and total-thyroidectomy. The analysis included a large cohort of 26257 FVPTC patients using data obtained from the Surveillance, Epidemiology, and End Results data-base between 2004 and 2013. Survival was examined via a Kaplan-Meier analyses with log-rank tests, Cox propor-tional hazards regression analyses, and propensity score matching analyses. Multivariate Cox regression analyses showed that patients who underwent subtotal or near-total thyroidectomy had similar cancer-specific survival rates and all-cause survival rates when compared with patients who underwent lobectomy and total-thyroidectomy. After matching for influential factors using propensity scores, Kaplan-Meier analyses also showed that patients who un-derwent subtotal or near-total thyroidectomy had similar cancer-specific survival rates and all-cause survival rates in comparison with patients who underwent other surgical approaches. Our results provide helpful implications for the treatment of patients with FVPTC.

Keywords: Follicular variant papillary thyroid cancer, surgical approaches, SEER database, propensity score matching

Introduction

The incidence of thyroid cancer has increased dramatically over the past few decades [1-3]. The follicular variant of papillary thyroid cancer (FVPTC) accounted for approximately 30% of all cases of papillary thyroid cancer (PTC) [4, 5]. Studies show that FVPTC is the most common subtype of PTC and its incidence continues to grow at a rapid pace [6, 7].

The Surveillance, Epidemiology, and End Resu- lts (SEER) program of the National Cancer Ins- titute is an epidemiologic database that col-lects and publishes cancer incidence and survival data from population-based cancer registries in the United States; it covers approx-imately 28% of the population of the United States [1, 8].

FVPTC is a unique subtype that manifests special biologic behaviors. However, the surgi-cal approaches to treat FVPTC, which would have an impact on mortality and recurrence, remain poorly understood [5-7, 9-11]. There- fore, in this study, we aimed to investigate the correlation between different surgical approaches and prognosis of FVPTC based on the SEER database via propensity score match-ing (PSM).

Materials and methods

Ethical considerations, study population, and data collection

This study’s retrospective protocol was ap- proved by Union hospital’s ethical review bo- ard and complied with the ethical standards

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of the Declaration of Helsinki, as well as the rel-evant national and international guidelines. The SEER database contains information regarding cancer incidence, prevalence, and mortality, as well as population-based variables and primary tumor characteristics (i.e., histo-logical subtype) from multiple geographic regions.

The present population-based cohort analy- sis used data from the SEER program data- base (2004-2013) for patients with FVPTC using code C73.9 from the International Cl- assification of Diseases for Oncology (3rd edi-tion ICD-O-3: 8340/3, Papillary carcinoma, fol-licular variant). Cases without American Joint Committee on Cancer staging information (version 6) were excluded to ensure accurate analyses. Cases without information of follow up time were also excluded. The different surgi-cal approaches (lobectomy, subtotal or near-total thyroidectomy and total thyroidectomy) were compared according to age, sex, race, TNM stage, multifocality, extension, and radia-tion treatment (i.e., none or refused, external beam radiation therapy, or RAI).

Statistical analyses

All-cause mortality and cancer specific mortali-ty were two main outcomes in our study esti-mated. The quantitative variables were ex- pressed as mean ± standard deviation (SD), while the categorical ones were presented as percentages. Patient survival curves for thyroid cancer-specific mortality and all-cause mortali-ty were examined by Kaplan-Meier analyses with the log-rank test. Cox proportional ha- zard regression analyses were using to esti-mate hazard ratios and 95% CIs, in order to quantify the effects of the different histologi- cal subtypes on cancer-specific and all-cause mortality. The propensity score analysis gener-ally calculated using logistic regression with group as dependent, covariates as indepen-dent variables. PSM was also used to further adjust for potential baseline confounding fac-tors in this study. All p-values were 2-sided, and p-values < .05 were considered significant. Analyses were performed using SPSS version 23.0, Stata/SE version 12 (Stata Corp.), and GraphPad Prism version 6 (GraphPad Software Inc.).

Results

Demographic and clinical features

A total of 26257 patients who had FVPTC and who underwent treatment with various surgical approaches were included in this study. The patients were divided into groups according to the treatment that they received: Group A, subtotal or near-total thyroidectomy (n=1015); Group B, lobectomy, (n=4301); and Group C, total thyroidectomy (n=20941). The mean ages and follow-up periods stratified by surgical approach are shown in Table 1. The patients in Group A had significantly longer follow-up peri-ods than did patients who underwent other sur-gical approaches.

Cancer-specific and all-cause mortality rates for different surgical approaches

We investigated the cancer-specific mortality rate, which was defined as the mortality rate attributed to thyroid cancer. The cancer-specif-ic mortality rate per 1000 person-years was 0.81 (95% confidence interval [CI], 0.31-2.14), 0.67 (95% CI, 0.38-1.17), and 1.24 (95% CI, 1.02-1.51) in groups A, B and C, respectively (Table 2). Furthermore, the all-cause mortality rate per 1000 person years was 9.04 (95% CI, 6.75-12.11), 9.27 (95% CI, 7.96-10.79), and 9.03 (95% CI, 8.41-9.71) in groups A, B and C, respectively (Table 2).

Risk factors for thyroid cancer-specific and all-cause mortality rates

According to the univariate Cox regression anal-yses, age, sex, T/N/M stage, extension, and radiation treatment were significant risk factors for cancer-specific mortality. In the multivariate Cox regression model, cancer-specific mortality did not differ significantly between group A and groups B and C after adjusting for influential risk factors (Table 3). In the univariate Cox regression analyses of all-cause mortality, age, sex, race, T/N/M stage, extension and radiation were found to be significant risk factors. In the multivariate Cox regression analysis, all-cause mortality did not differ significantly between group A and groups B and C (Table 3).

Adjusting for patient characteristics using PSM

The cancer-specific mortality rate in group A was similar to that in groups B and C (P=0.065).

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Further, the all-cause mortality rate in group A and in groups B and C were also not significant-ly different (P=0.762; Figure 1A-D). To minimize selection bias, a PSM analysis was perform- ed, including age, sex, race, T/N/M stage, mul-tifocality, extension, and radiation treatment approaches.

After PSM for age, sex, and race, a cancer-spe-cific survival analysis showed that the progno-sis of patients in group A was similar to the prognoses of patients in groups B and C (P=0.186 and 0.201, respectively; Figure 2A, 2B). After PSM for age, sex, race, T/N/M stage, multifocality, and extension, there were still no significant differences in cancer-specific mor-tality between group A and groups B and C

(P=0.433 and 0.690, respectively; Figure 3A, 3B). Moreover, after matching for all influential factors (including radiation treatment), the prognosis of patients in group A remained simi-lar to the prognoses of patients in groups B and C (P=0.661 and 0.699, respectively; Figure 4A, 4B).

In an all-cause survival analysis, the prognosis in group A was similar to that in groups B and C after PSM for age, sex, and race (P=0.374 and 0.725, respectively; Figure 5A, 5B). Similar results were obtained after PSM for age, sex, race, T/N/M stage, multifocality, and extension (P=0.273 and 0.603, respectively; Figure 6A, 6B). After matching for all influential factors (including radiation treatment), patients in

Table 1. Characteristics for Patients with different surgery treatment

Covariate Level

Surgery treatmentSubtotal or near-total

thyroidectomy (n=1015)

Lobectomy (n=4301)

p-value (Lobec-tomy vs Subtotal

or near-total thyroidectomy)

Total thyroidectomy

(n=20941)

p-value (thyroidec-tomy vs Subtotal or near-total thyroid-

ectomy)Age (years) 50.66±14.81 51.41±14.98 0.151 50.01±14.78 0.218

Sex Female 799 (78.7%) 3419 (79.5%) 0.584 16486 (78.7%) 0.996

Male 216 (21.3%) 882 (20.5%) 4455 (21.3%)

Race White 788 (78.6%) 3506 (82.7%) < 0.001 17308 (83.5%) < 0.001

Black 136 (13.6%) 388 (9.2%) 1665 (8.0%)

Other 78 (7.8%) 344 (8.1%) 1765 (8.5%)

T-stage T1 631 (62.7%) 3106 (72.7%) < 0.001 12121 (58.3%) 0.001

T2 209 (20.8%) 716 (16.8%) 4248 (20.4%)

T3 136 (13.5%) 414 (9.7%) 3868 (18.6%)

T4 30 (3.0%) 37 (0.9%) 563 (2.7%)

N-stage N0 937 (93.6%) 4177 (98.1%) < 0.001 17845 (86.5%) < 0.001

N1 64 (6.4%) 81 (1.9%) 2794 (13.5%)

M-stage M0 1002 (98.7%) 4288 (99.7%) < 0.001 20711 (98.9%) 0.587

M1 13 (1.3%) 13 (0.3%) 230 (1.1%)

Multifocality No 594 (59.5%) 3115 (73.7%) < 0.001 10424 (50.3%) < 0.001

Yes 405 (40.5%) 1111 (26.3%) 10305 (49.7%)

Extension No 920 (90.7%) 4118 (95.9%) < 0.001 18177 (87.0%) 0.001

Yes 94 (9.3%) 177 (4.1%) 2708 (13.0%)

Radiation None or refused 582 (58.3%) 3309 (78.8%) < 0.001 8861 (43.2%) < 0.001

External beam radiation therapy 17 (1.7%) 38 (0.9%) 358 (1.7%)

Radioactive I-131 ablation 399 (40.0%) 851 (20.3%) 11297 (55.1%)

Survival (months) 58.87±35.91 50.24±34.93 < 0.001 47.58±33.74 < 0.001

Table 2. Hazard Ratios of different surgery for the thyroid cancer specific deaths and all-cause deaths

Surgery Cancer-Specific Deaths, No. %

Cancer-Specific Deaths per 1,000

Person-Years95% CI

All Cause Deaths,

No. %

All Cause Deaths per 1,000

Person-Years95% CI

Subtotal or near-total thyroidectomy 4 0.39 0.81 0.31-2.14 46 4.53 9.04 6.75-12.11

Lobectomy 12 0.28 0.67 0.38-1.17 176 4.09 9.27 7.96-10.79

Total thyroidectomy 106 0.51 1.24 1.02-1.51 757 3.61 9.03 8.41-9.71

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Table 3. Risk factors for survival: outcome is all-cause mortality and thyroid cancer specific mortality (n=26257)

Covariate Level

Thyroid Cancer specific mortality All-cause mortalityUnivariate Cox regression Multivariate Cox regression Univariate Cox regression Multivariate Cox regression

Hazard Ratio (95% CI) p-value Hazard Ratio

(95% CI) p-value Hazard Ratio (95% CI) p-value Hazard Ratio

(95% CI) p-value

Age 1.099 (1.083-1.114) < 0.001 1.089 (1.072-1.107) < 0.001 1.085 (1.080-1.090) < 0.001 1.080 (1.075-1.085) < 0.001

Sex Female Ref Ref Ref Ref

Male 4.443 (3.113-6.342) < 0.001 2.420 (1.621-3.614) < 0.001 2.490 (2.189-2.831) < 0.001 1.743 (1.522-1.997) < 0.001

Race White Ref Ref Ref Ref

Black 1.182 (0.633-2.206) 0.599 1.806 (0.924-3.531) 0.084 1.349 (1.102-1.652) 0.004 1.631 (1.320-2.016) < 0.001

Other 1.602 (0.930-2.760) 0.090 0.987 (0.524-1.857) 0.967 0.773 (0.596-1.002) 0.052 0.755 (0.574-0.994) 0.045

T-stage T1 Ref Ref Ref Ref

T2 1.629 (0.781-3.400) 0.193 1.462 (0.667-3.205) 0.343 0.918 (0.771-1.094) 0.339 1.056 (0.880-1.268) 0.555

T3 6.156 (3.543-10.694) < 0.001 4.032 (1.977-8.221) < 0.001 1.183 (0.996-1.405) 0.056 1.064 (0.832-1.360) 0.623

T4 59.544 (35.662-99.419) < 0.001 19.503 (8.356-45.521) < 0.001 4.388 (3.567-5.398) < 0.001 2.725 (1.866-3.980) < 0.001

N-stage N0 Ref Ref Ref Ref

N1 5.334 (3.658-7.779) < 0.001 1.889 (1.180-3.024) 0.008 1.495 (1.251-1.785) < 0.001 1.440 (1.168-1.775) 0.001

M-stage M0 Ref Ref Ref Ref

M1 50.143 (34.166-73.591) < 0.001 12.080 (7.580-19.252) < 0.001 8.449 (6.614-10.792) < 0.001 4.734 (3.537-6.335) < 0.001

Multifocality No Ref Ref Ref Ref

Yes 0.845 (0.583-1.226) 0.375 0.523 (0.346-0.789) 0.002 0.971 (0.854-1.103) 0.648 0.978 (0.853-1.120) 0.743

Extension No Ref Ref Ref Ref

Yes 12.534 (8.661-18.139) < 0.001 1.035 (0.523-2.048) 0.922 1.969 (1.687-2.298) < 0.001 0.926 (0.679-1.263) 0.627

Radiation None or refused Ref Ref Ref Ref

Radiation Beam or Rdioactive implants 13.523 (7.698-23.758) < 0.001 4.229 (2.231-8.016) < 0.001 1.666 (1.166-2.381) 0.005 1.196 (0.814-1.759) 0.363

Radioisotopes or Radiation beam+ isotopes/implants 1.614 (1.078-2.416) 0.020 0.960 (0.595-1.547) 0.866 0.687 (0.604-0.782) < 0.001 0.699 (0.603-0.809) < 0.001

Surgery Subtotal or near-total thyroidectomy Ref Ref Ref Ref

Lobectomy 0.840 (0.271-2.606) 0.763 2.049 (0.559-7.512) 0.279 1.079 (0.780-1.493) 0.646 1.052 (0.754-1.468) 0.767

Total thyroidectomy 1.619 (0.596-4.396) 0.345 1.889 (0.594-6.001) 0.281 1.017 (0.755-1.369) 0.914 1.099 (0.811-1.488) 0.543

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group A still showed a similar all-cause progno-sis when compared with patients in groups B and C (P=0.705 and 0.310, respectively; Figure 7A, 7B).

The age of patients who underwent subtotal or near-total thyroidectomy was not significantly different from those in the other two groups; however, the average follow-up duration for

Figure 1. Kaplan Meier curves among patients stratified by surgery for can-cer-specific mortality (A, B) and all-cause mortality (C, D). Group A (n=1015): subtotal or near-total thyroidectomy; group B (n=4301): Lobectomy; group C (n=20941): total thyroidectomy.

Figure 2. Kaplan Meier curves of cancer-specific mortality for matched sur-gery treatment pairs. Age, sex and race matching between subtotal or near-total thyroidectomy and Lobectomy (A), subtotal or near-total thyroidectomy and total thyroidectomy (B). Group A (n=1015): subtotal or near-total thyroid-ectomy; group B (n=4301): Lobectomy; group C (n=20941): total thyroidec-tomy.

Discussion

FVPTC patients are usually clinically categorized together with classic papillary thyroid cancer or follicular thyroid cancer patients [12]. The het-erogeneous nature of the dis-ease and the mutational pro-file of FVPTC strongly sugge- st that FVPTC is a mixture of diseases; however, the patho-logical appearance, such as follicular-patterned nucleus, of classic PTC suggests that FVPTC is a hybrid [13, 14]. Yu et al. have proved that the prognosis of the FVPTC falls between that of follicular thy-roid cancer and classic papil-lary thyroid cancer [13]. No- netheless, there exists no general agreement or unique recommendation for the sur-gical treatment of FVPTC based on their distinct behav-iors [5, 7, 15, 16]. Shi et al. have reported that FVPTC is the least aggressive com-pared to classic PTC and tall cell PTC [7]. However, clini-cians often face difficulties when attempting to select the most appropriate surgical approach for treatment of FVPTC.

For surgeons, optimizing the balance between treatment-associated benefits and the risk of adverse complications is important in the clinical management of thyroid can-cer [17-20]. The decision-mak-ing in terms of the surgical approach for FVPTC should take many factors into consid-eration, including tumor size, multifocality, and local inva-sion [4, 5, 21].

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Figure 3. Kaplan Meier curves of cancer-specific mortality for matched sur-gery treatment pairs. Age, sex, race, T/N/M stage, multifocality, extension matched between subtotal or near-total thyroidectomy and Lobectomy (A), subtotal or near-total thyroidectomy and total thyroidectomy (B). Group A (n=1015): subtotal or near-total thyroidectomy; group B (n=4301): Lobec-tomy; group C (n=20941): total thyroidectomy.

Figure 4. Kaplan Meier curves of cancer-specific mortality for matched Sub-type pairs. Age, sex, race, T/N/M stage, multifocality, extension, surgery and radiation treatment matched between subtotal or near-total thyroidectomy and Lobectomy (A), subtotal or near-total thyroidectomy and total thyroidec-tomy (B). Group A (n=1015): subtotal or near-total thyroidectomy; group B (n=4301): Lobectomy; group C (n=20941): total thyroidectomy.

those who underwent subto-tal or near-total thyroidecto- my was 58.87 years, which was longer than that observed in the lobectomy and total thy-roidectomy groups. This may be why the cancer-specific mortality and all-cause mor-tality showed no difference across the three groups.

Currently, the most frequent surgical approach for FVPTC is total or near total thyroi- dectomy [10]. Tang et al. dem-onstrated that total thyroi- dectomy may positively influ-ence the prognosis of FVPTC patients with tumor sizes > 2 cm combined with extrath- yroidal extension [6]. Similar results were obtained from David’s study, which found that a tumor size > 4 cm and local invasion were related to specific-cancer mortality in FVPTC [4]. In our study, pa- tients who underwent subto-tal or near-total thyroidec- tomy more frequently had a more advanced T stage and tumor extension than those who underwent lobectomy; however, these rates were lowest among patients who underwent thyroidectomy; th- erefore, the similar prognosis observed across the three groups may partly be ex- plained by these confound- ing factors. A recent study demonstrated that FVPTC with extrathyroid extension had a higher cancer-specific mortality rate than PTC [12]. In our study, patients who underwent subtotal or near-total thyroidectomy demon-strated a higher rate of exten-sion than those who under- went lobectomy and a lower rate of extension than those who underwent total thyroid-ectomy. Similar results for

Figure 5. Kaplan Meier curves of all-cause mortality for matched surgery treatment pairs. Age, sex and race matching between subtotal or near-total thyroidectomy and Lobectomy (A), subtotal or near-total thyroidectomy and total thyroidectomy (B). Group A (n=1015): subtotal or near-total thyroidecto-my; group B (n=4301): Lobectomy; group C (n=20941): total thyroidectomy.

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Figure 6. Kaplan Meier curves of all-cause mortality for matched surgery treatment pairs. Age, sex, race, T/N/M stage, multifocality, extension match-ing between subtotal or near-total thyroidectomy and Lobectomy (A), subtotal or near-total thyroidectomy and total thyroidectomy (B). Group A (n=1015): subtotal or near-total thyroidectomy; group B (n=4301): Lobectomy; group C (n=20941): total thyroidectomy.

Figure 7. Kaplan Meier curves of all-cause mortality for matched surgery treatment pairs. Age, sex, race, T/N/M stage, multifocality, extension, sur-gery and radiation treatment matching between subtotal or near-total thy-roidectomy and Lobectomy (A), subtotal or near-total thyroidectomy and total thyroidectomy (B). Group A (n=1015): subtotal or near-total thyroidectomy; group B (n=4301): Lobectomy; group C (n=20941): total thyroidectomy.

Furthermore, family history and molecular mutations were not investigated in our study or matched for analysis. In addition, data regarding recurrence information was not obtained from SEER data-base, which could have result-ed in an overestimation bias when evaluating the mortality rate.

In conclusion, we compared the prognoses after different surgical approaches for FV- PTC. Our findings could be beneficial for developing rea-sonable treatment strategies for FVPTC.

Disclosure of conflict of inter-est

None.

Address correspondence to: Liang Guo, Department of Plas- tic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China. E-mail: guoliang-whzn@163.com; Chunping Liu, Department of Breast and Th- yroid Surgery, Union Hospital, Tongji Medical College, Hua- zhong University of Science and Technology, Wuhan 430022, China. Tel: +8618065281998; Fax: (86) 027-67813591; E-mail: fac6myt@163.com

other risk clinicopathological factors such as lymph node metastasis, distant metastasis, and multifocality were observed. Therefore, clinicopathological features may be another factor that impacts prognosis due to different surgical approaches.

However, our study contains a few limita- tions. FVPTC consists of many specific sub-types with different genotypic and clinical ch- aracteristics: encapsulated FVPTC, nonencap-sulated FVPTC, and diffuse FVPTC. For exam-ple, diffuse FVPTC presents a higher rate of central lymph node metastasis, BRAFV600E mutation, and poor prognosis [21-23]. How- ever, in our study, we could not extract the accurate subtypes from the SEER database.

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