Optimal Surgical Approaches for Thyroid Cancer: A Comparative Analysis of Efficacy and Complications

Introduction

Thyroid cancer is the most common endocrine malignancy and its incidence rates have been increasing worldwide over the past few decades, which has been associated with better diagnostics [2]. However, the death rate from thyroid cancer has remained stable in comparison to the increase in the number of diagnoses [2]. Therefore, the threshold for surgical interventions (and the exact approach) in uncertain situations has become an issue [1,3].

Differentiated thyroid cancer (DTC), which includes papillary (80%) and follicular (10–15%) carcinomas, and, less frequently, Hurthle cell and poorly-differentiated histologies (5–10%), accounts for 90–95% of newly diagnosed thyroid cancers [4,5]. Treatment of DTC requires a risk-adaptive multimodal approach including active surveillance, surgery, and radioiodine therapy [6]. Although the prognosis is relatively good in most patients with DTC, approximately 15% of patients develop radioiodine-resistant metastatic disease and their prognosis is poor [4,7]. Total thyroidectomy (TTx) is the most common endocrine surgical procedure for treatment of both benign and malignant lesions of the thyroid [2,8]. However, Vaccarella et al estimated that more than half a million people were over-diagnosed with thyroid cancer between 1988 and 2007 [3]. One of the most important reasons for overtreatment is indeterminate outcomes from fine-needle aspiration cytology (FNAC), which can affect surgery decisions, particularly since definitive results can only be obtained with final histopathological examination [9–12].

Nonetheless, due to the mostly good prognosis of thyroid cancers [8] and the complications of thyroid surgery, conservative surgical procedures are being performed more frequently in patients without definitive FNAC results [1,13]. This situation ultimately increases the number of patients undergoing completion thyroidectomy (CTx) [9]. However, the percentage of patients with benign pathology in CTx specimens seems to be considerably higher than that of malignant results [9,14]. For instance, it has been reported that only 24.2% of patients undergoing CTx after hemithyroidectomy (HTx) were found to have malignancy in the contralateral lobe [9]. Indicating that more than 75% of patients undergo unnecessary CTx and have to use hormone replacement therapy for the rest of their lives. There is no consensus on which patients should be administered CTx after HTx [14,15]. Studies on the subject offer contradictory results [14,16–19] and the current guidelines [6,20,21] do not seem to meet the needs of clinical practice.

Due to the high frequency of thyroid cancer, the difficulties in preoperative definitive diagnosis, and the unclear boundaries of the surgical procedures that should be performed, the present study sought to determine the optimal margin of thyroid surgery. We postulated that there may be malignancy predictors that can prevent unnecessary surgery in patients who are planned to undergo completion thyroidectomy, total thyroidectomy, or recurrent thyroid surgery due to suspicion of malignancy. Therefore, we aimed to present the frequency of malignancy in the CTx specimens of patients initially treated with HTx, in the opposite lobe in patients who underwent TTx, and in revision thyroidectomy material in patients who underwent revision thyroid surgery after TTx, to investigate variables that may predict malignancy in these specimens, especially in the CTx specimens, and to compare complications of cases treated with CTx after HTx, TTx, or revision surgery after TTx to emphasize the importance of limited surgery.

Material and Methods

STUDY DESIGN AND ETHICAL ISSUES:

This was a retrospective study conducted at the Department of General Surgery, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey. The study was approved by the Ethics Committee of Yüzüncü Yıl University Faculty of Medicine (Decision date: 20.11.2019, decision no. 09). The principles outlined in the Declaration of Helsinki and its later amendments were followed. The requirement for informed consent was waived due to the retrospective study design.

PARTICIPANTS:

The data of 1619 patients undergoing conventional open thyroidectomy in our center between January 2014 and October 2019 were reviewed and 3 different groups were formed (Figure 1).

The first group included patients who underwent HTx based on the BETHESDA 2007 cytopathologic classification, [22] in accordance with the American Thyroid Association (ATA) 2009 [23] guideline and whose HTx material resulted as DTC and therefore CTx was performed. This group was named the CTx-HTx group. A total of 321 patients underwent HTx during the study period. We excluded patients who had undergone another surgery in addition to hemithyroidectomy in the first surgery, cases with undifferentiated thyroid cancer as a result of HTx pathology, cases requiring neck dissection as a result of pathological examination, cases with surgical intervention to the neck area for other reasons, and those with central or lateral neck dissection. A final total of 60 patients with CTx-HTx were found to meet these criteria and were included in this group. The first surgery (HTx) of 7 patients in this group had been performed in another center. The patients in this group were divided into 2 subgroups: malignant patients (CTx-M) and benign patients (CTx-B), according to the final pathology results of CTx.

The second group, named the TTx group, was formed as follows. First, 1191 patients who had undergone TTx in accordance with the ATA 2009 guideline were identified. We excluded those who had a previous history of thyroid surgery, patients undergoing TTx for any reason other than malignancy suspicion, patients with conclusive FNAC result for malignancy (BETHESDA-6), cases with thyroid malignancies with adjacent tissue invasion, and those with central or lateral neck dissection. The second group was formed with 60 age-matched participants randomly selected from the remaining patients.

The third group was formed with 47 patients undergoing reoperation due to recurrence or residual tissue in the thyroid lodge after initial TTx. Patients with toxic or retrosternal (substernal) goiter, Graves’ or other thyrotoxicosis and subjects with an FNAC conclusive for malignancy (BETHESDA-6) were excluded. This group was defined as the revision thyroidectomy after TTx (RTx-TTx) group.

In all 3 groups, any patients who had simultaneously undergone parathyroidectomy were excluded.

DATA COLLECTION:

Patient data on demographic features (age and sex), thyroid cancer history in family, radiation to the neck history, tumor side (for CTx-HTx group), pathology results after first and second surgeries–if any (tumor type, tumor size and side, capsular invasion, vascular invasion, extrathyroidal invasion, multifocality, lymph node metastasis), laboratory results (thyroglobulin levels before CTx), preoperative and postoperative calcium levels, postoperative transient or permanent hypocalcemia status, time between surgeries (for the CTx-HTx group), postoperative recurrent laryngeal nerve (RLN) injury, and length of stay in hospital were obtained from hospital database records, patient charts, and by calling patients (for missing information). Since the number of patients who were determined to have received chemotherapy was very small (n=8) and the patients’ chemotherapy-related data could not be accessed in detail, this parameter was not included in the study.

CLINICAL PRACTICES, LABORATORY ASSESSMENTS, AND DEFINITIONS:

Diagnosis and treatment management of thyroid cancer patients were made according to the 2009 ATA guidelines [23], 2007 BETHESDA cytopathological classification [22], and 2015 Turkey Endocrinology and Metabolism Association (TEMD) guidelines [24].

A detailed physical examination and laboratory examinations, including thyroid function tests and thyroglobulin and serum calcium levels, were performed in all patients with a suspicious or obvious thyroid nodule on thyroid examination. After detecting a nodule on thyroid ultrasonography (USG), FNAC was performed under USG guidance. The results of FNAC were classified according to the BETHESDA 2007 system [21]. Vocal cord examination with fibrolaryngoscopy was performed in all patients before the initial and secondary surgery and in patients with suspicious RLN injury findings after surgery. New-onset RLN injury was defined as RLN paralysis that did not exist before the operations and appeared after the operation and whose grade increased compared to before surgery.

CTx-HTx was applied to 5 patients with a tumor size of <1 cm in the HTx specimen, according to patient decision after providing detailed information. Intraoperative RLN monitoring was performed and the RLN and the parathyroid glands were systematically sought and identified. We did not use frozen sections during surgery for guidance when deciding on the extent of the surgery.

Serum calcium levels were measured 24 and 72 h after each surgery in all patients. While hypocalcemia (<8 mg/dL) that improved with treatment up to the postoperative first year was considered to be transient hypocalcemia, hypocalcemia requiring exogenous calcium and vitamin D supplementation after the first year was considered to be permanent hypocalcemia [25]. All laboratory measurements were performed in the Biochemistry Department of the Health Research and Application Hospital of Yüzüncü Yıl University, using calibrated standard measuring devices and according to the manufacturer’s recommendations.

All pathological assessments and diagnoses were made in the Pathology Department of the same center, according to relevant international guidelines.

OUTCOMES:

The primary objectives of this study were to determine the malignancy rates in CTx specimens from patients undergoing CTx after HTx and to determine the factors that could predict these malignancies. The secondary outcome was to compare CTx-HTx, TTx, and RTx-TTx surgeries in terms of pathological results and postoperative complications.

STATISTICAL ANALYSIS:

All analyses were performed on IBM SPSS Statistics for Windows, Version 25.0 (IBM Corp., Armonk, NY, USA), with a significance threshold set at P<0.05. In the determination of distribution characteristics for continuous variables, we employed the evaluation of histograms and Q-Q plots. Data are given as mean±standard deviation or median (minimum-maximum) for continuous variables according to normality of distribution, and as frequency (percentage) for categorical variables. Age was analyzed with the independent samples t test or one-way analysis of variances (ANOVA), depending on the number of groups being compared. Time between surgeries was analyzed with the Mann-Whitney U test. Preoperative and postoperative measurements of calcium were analyzed with the two-way repeated measures ANOVA. Categorical variables were analyzed with the chi-square test or Fisher’s exact test. Pairwise comparisons were adjusted with the Bonferroni correction method. Unadjusted and adjusted odds ratios were calculated using logistic regression analysis.

Results

Of the CTx-HTx group, 76.7% (n=46) were CTx-B and 23.3% (n=14) were CTx-M. The mean age of the patients in the CTx-HTx group was 39.38±13.12 years (CTx-B subgroup: 38.96±11.85, CTx-M subgroup: 40.79±17.10; P=0.652). Forty-six (76.7%) of the patients in the CTx-HTx group, 36 (78.3%) of the patients in the CTx-B subgroup, and 10 (71.4%) of the patients in the CTx-M subgroup were female (P=0.720). According to univariate analysis results, no significant difference was found between the CTx-B and CTx-M subgroups in terms of any of the variables investigated (Table 1). Potential risk factors for malignancy in CTx were investigated by logistic regression. It was determined that none of the variables were associated with malignancy (including age >45, male sex, familial thyroid cancer history, tumor size, capsular, vascular or extrathyroidal invasion, multicentricity, lymph node metastasis, and thyroglobulin ≥30) (Table 2).

The mean age of the TTx group was 41.60±14.14 years, while the RTx-TTx group had a mean age of 44.00±12.98 years. Females represented 76.7% (n=46) of the TTx group and 80.9% (n=38) of the RTx-TTx group. When the CTx-HTx, TTx, and RTx-TTx groups were compared, there was no significant difference among them in terms of age (P=0.214) or sex (P=0.842). The main side malignancy rate was 100.0% in the CTx-HTx group, 75.0% in the TTx group, and 51.3% in the RTx-TTx group, and these differences were statistically significant (P <0.001). What is meant by main side pathology result is pathology results of hemithyroidectomy specimens for CTx-HTx, postoperative pathology results of the FNAC performed side for TTx and postoperative pathology result of the side that had FNAC before the first surgery for RTx-TTx. The opposite side malignancy rate was 23.3% in the CTx-HTx group, 13.3% in the TTx group, and 23.4% in the RTx-TTx group, and these differences were not statistically significant (P<0.295). Opposite site pathology result means pathology results of complementary thyroidectomy specimen for CTx-HTx, postoperative pathology result of the contralateral lobe for TTx and pathology results after revision surgery for RTx-TTx. Mean postoperative calcium levels of the TTx, CTx-HTx, and RTx-TTx groups (after second surgery in the latter 2) were significantly lower than before the surgeries (P<0.001 for all). However, postoperative calcium levels of the TTx group were significantly lower than the CTx-HTx group (P=0.006). Furthermore, the decrease in calcium levels in TTx was significantly higher than CTx-HTx (P<0.001). The percentage of patients with postoperative hospital stay of 2 or more days in the TTx group was significantly higher than that of the CTx-HTx group (P=0.025) (Table 3). Of note, none of the participants had a history of radiation to the head and neck.

Multivariable logistic regression revealed that older patients (age >45) had 2.417-fold higher risk for hypocalcemia than younger patients after adjusting for sex (OR: 2.417, 95% CI: 1.106–5.278, P=0.027). TTx caused 2.223-fold higher risk for hypocalcemia than other surgeries after adjusting for age and sex (OR: 2.223, 95% CI: 1.005–4.913, P=0.048) (Table 4).

Discussion

LIMITATIONS OF THE STUDY:

The CTx-HTx group created for the primary purpose of the study had a small sample size with respect to the frequency of the disease, which prevents generalization of results. Also, the single-centered nature of the study may have contributed to this limitation. Since the study was retrospective, there were important parameters that could not be included due to loss of data or lack of investigation during diagnosis or surgery, such as details of surgical complications, TIRADS scores (preoperative USG findings), thyroid cancer histologic types, cancer grade and stage, radiotherapy or adjuvant chemoradiotherapy data, PTC high-risk variants, and parathyroid hormone results. Moreover, comorbidity data could not be included, and this may have affected the length of hospital stay. The difference in the number of patients between benign and malignant groups weakened the statistical power. Lastly, there were missing data in some pathological results, which must be accounted for in future research.

Conclusions

In conclusion, the malignancy rate in CTx specimens performed after HTx was 23.3%, in the opposite lobe of TTx specimens it was 13.3%, and in revision thyroid surgery specimens performed after TTXx it was 23.4%, indicating an alarmingly high frequency of unnecessary CTx, TTx, and revision thyroid surgery. None of the clinical, demographic, and pathological parameters included in the study were associated with malignancy likelihood in patients who underwent CTx following HTx. TTx was found to cause a greater reduction in postoperative calcium levels and longer hospital stay than the CTx-HTx and RTx-TTx approaches. The number of patients being overtreated can be reduced by choosing more conservative surgeries as an initial surgery, especially if there is no clear indication for TTx, and also by narrowing down the indications that necessitate CTx after HTx, TTx, and revision thyroid surgery.