Abstract
Importance
The extent of surgical resection for papillary thyroid carcinoma (PTCs) located in the isthmus has remained a matter of considerable debate.
Objective
To investigate the association between the extent of wide-field isthmusectomy and complications and recurrences.
Design
Clinicopathologic documents of patients who received total thyroidectomy and wide-field isthmusectomy were recorded.
Setting
A retrospective review study.
Participants
Patients with single tumor in the isthmus with no cervical lymph node metastasis were selected.
Intervention or Exposures
Patients received total thyroidectomy with neck dissection, or wide-field isthmusectomy with paratracheal and prelaryngeal lymph node dissection.
Main Outcome Measures
The locoregional results, complications, and rate of patients who were not required to receive thyroid-stimulating hormone suppression therapy were compared.
Results
A total of 389 patients were included in the study and divided into 3 groups. One hundred and nineteen (30.6%) patients were performed with wide-field isthmusectomy with a distance <0.5 cm (Group I), and 190 (48.8%) patients with a distance ≥0.5 cm (Group II). Eighty (20.6%) underwent total thyroidectomy (Group III). Eighty (67.2%) of 119 patients in Group I and 125 (65.8%) of 190 patients in Group II did not take medication at the mean follow-up of 37 months. Locoregional recurrence developed in 22 patients (18.5%) of Group I, 16 (8.4%) patients of Group II, and 5 (2.6%) patients of Group III. The overall morbidity was 6 (5.0%) in Group I, 14 (7.4%) in Group II, and 21 (26.5%) in Group III.
Conclusions
Wide-field isthmusectomy with a 0.5 cm distance may be a sufficient treatment for selected patients with PTC limited to the isthmus.
Relevance
Wild-field isthmusectomy and limited neck dissection may be a sufficient procedure for isthmic PTC. Further research is needed to determine whether prophylactic central compartment neck dissection can be omitted during isthmusectomy for these patients.
Key Messsage
Wide-field isthmusectomy with a 0.5 cm distance limits postoperative complications. This procedure may be a sufficient treatment for patients with papillary thyroid carcinoma limited to the isthmus.
Introduction
Although the majority of papillary thyroid carcinoma (PTC) is located in the thyroid lobes, a small minority of it arises from the thyroid isthmus. The reported incidence of PTC arising in the thyroid isthmus ranges from 1% to 9.2%. 1 PTC of the isthmus is reported to exhibit more aggressive behavior than PTC of the thyroid lobes, with a higher frequency of lymph node metastasis, multiple foci, and capsule invasion.2,3 Total thyroidectomy and prophylactic central compartment neck dissection (pCCND) are more frequently performed for the treatment of PTC located in the isthmus. As the cases of micro-PTC gradually increased and thyroid surgery become conservative, some authors have suggested that wide-field isthmusectomy alone or with limited neck dissection (including precricoid and pretracheal lymph node dissection) may be sufficient for treating patients with PTC confined to the thyroid isthmus.4-6
Wide-field isthmusectomy is a surgical procedure that involves removing the tumor along with a margin of surrounding normal thyroid tissue limited to the isthmus.
Most studies advocate for total thyroidectomy, while only a few suggest that isthmusectomy or wide-field isthmusectomy is a reasonable and appropriate surgical approach for this type of cancer.6-8 And the extent of the thyroid resection and the role of pCCND are controversial, especially for small PTC confined to the isthmus. This retrospective review study was performed to investigate the association between the extent of wide-field isthmusectomy and postoperative complications and recurrences. The second aim was to determine the optimal extent of wide-field isthmusectomy that balances locoregional recurrence and postoperative complications.
Methods
Patients
This retrospective review study was approved by the Medical Ethics Committee of Zhongnan Hospital of Wuhan University. Data from patients with thyroid carcinoma between April 2017 and December 2020 were reviewed at Zhongnan Hospital of Wuhan University. All operations were performed by the same senior surgeons (G.W. and J.H.) under general anesthesia, with the surgeons having an annual volume of 800 to 1000 thyroid surgeries.
The inclusion criteria were (1) patients aged 18 years or older; (2) patients with single tumor located in the isthmus; and (3) patients with no cervical lymph node metastasis. The exclusion criteria included (1) patients with multifocal cancer; (2) a family history of thyroid cancer; (3) previous radiation exposure; (4) postoperative radioactive iodine therapy; and (5) distant metastasis. A total of 389 patients were included in the study, all of whom showed Bethesda Category V (suspicious for malignancy) or VI (malignant) on preoperative ultrasonography-guided fine needle aspiration cytology (FNAC) for the solitary nodule located in the thyroid isthmus. Final histopathology results were used to confirm the diagnosis of thyroid cancer.
Thyroid Surgery
An isthmus tumor was defined as a tumor located within the isthmus of the thyroid gland (Figure 1). The lateral border of the isthmus was determined by drawing 2 perpendicular imaginary lines from the most lateral borders of the trachea, and the center point of the tumor was designated as the intersection of its longest and shortest diameters. If the center point of the tumor was located between the 2 virtual lines, the tumor was considered to be located in the isthmus.
Definition of an isthmus tumor.
The risk of thyroid cancer recurrence and the need for a second surgery impacted patients’ preference for treatment options. Patients who were afraid of encountering the completion total thyroidectomy preferred to receive total thyroidectomy and neck dissection. The patients were detailed about the treatment procedures before the commencement of the treatment. According to the patients’ disease characteristics and preferences, total thyroidectomy or isthmusectomy was recommended and performed randomly. Thyroidectomy was performed using a standard fine capsular en bloc dissection technique, starting from the inferior pole and proceeding to the superior pole. During the surgery, superior parathyroid glands were identified and preserved in situ, while inferior parathyroid glands were either protected in situ or autotransplanted in the sternocleidomastoid muscle, based on their location and blood supply. 9
Patients who underwent wide-field isthmusectomy also received paratracheal and prelaryngeal lymph node dissection that does not require full exploration of the tracheoesophageal groove and the ligament of Berry to identify the entire course of the recurrent laryngeal nerve. In contrast, patients who underwent total thyroidectomy had bilateral pCCND performed during the surgery to remove any cancerous or suspicious lymph nodes located in the central compartment of the neck. 10
Data Collection
Patient demographics and surgical details, including the extent of both thyroid and neck surgery, were recorded, as well as the presence of gross extrathyroid extension or residual disease upon the completion of surgery. Pathological details, such as tumor histology, size, presence of extrathyroid extension, and distance from the tumor to the resection margin, were also collected for analysis.
Complications
Following treatment, patients in Group III underwent thyroid-stimulating hormone (TSH) suppression therapy to maintain their TSH levels within the mid to lower reference range (0.5-2 mU/L). All of the patients were monitored for TSH at follow-up every 3 months after surgery in the first year, every 6 months in the second to fifth years, and annually thereafter at reexaminations. Transient or persistent hypoparathyroidism was confirmed by serum calcium levels below the lower limit at the examination center and symptoms of hypocalcemia. Every patient underwent a laryngoscopy after surgery. Postoperative vocal cord paralysis (VCP) was defined as fixed vocal cord mobility, as confirmed by a laryngofiberoscopic examination. All patients in both groups underwent laryngofiberoscopic examination on the second day after surgery. If VCP was detected, postoperative laryngofiberoscopic examination was repeated every 3 months in the first year, and then annually. Hypoparathyroidism or VCP lasting more than 6 months post-thyroidectomy was considered permanent.
The primary endpoint of the study was the occurrence of local or regional recurrence. Local recurrence was defined as the recurrence of cancer in the operative bed, including adjacent structures such as the trachea, strap muscle, or contralateral lobe. Regional recurrence was defined as the recurrence of cancer in the central or lateral cervical lymph nodes. The presence of locoregional recurrence was based on cytological or histopathological evidence of disease obtained via FNAC or surgical excisional biopsy.
Statistical Analysis
Continuous variables were compared between the groups using nonparametric tests. The positive rates of the 2 groups were compared by the chi-squared or Fisher’s exact test, if appropriate. Two-sided P < .05 was considered statistically significant. All statistical analyses were performed using SPSS17.0 for Windows (SPSS, Inc, Chicago, IL, USA).
Results
Patients
Of the 389 patients, 80 (20.6%) underwent total thyroidectomy and 309 patients underwent wide-field isthmusectomy. The distance from the tumor to the resection margin in 119 (30.6%) patients was <0.5 cm, while in 190 (48.8%) patients was ≥0.5 cm. The included 389 patients were divided into these 3 groups. Table 1 shows the demographic and pathologic characteristics of the 3 groups. The mean age at diagnosis in Groups I, II, and III was 43.50, 44.01, and 45.01 years, respectively, with an age range of 20 to 71 years. Tumor located in the isthmus was <4 cm, and the mean (±SD) tumor sizes were 0.971 (±0.640) cm, 0.915 (±0.577) cm, and 0.901 (±0715) cm in Groups I, II, III, respectively. There was no statistically-significant difference between groups regarding gender, tumor size, capsular invasion, microscopic extraglandular invasion, and lymphovascular invasion.
Baseline Characteristics of the Study Population.
Abbreviation: ETE, extraglandular invasion.
Clinicopathologic Characteristics
Median (lower quartile, upper quartile) retrieved lymph nodes were 9 (4, 14), 8 (4, 15), 11 (6, 18) in Groups I, II, and III, respectively. Bilateral pCCND identified unexpected positive lymph nodes in 29 (24.4%) of 119 patients who were performed with wide-field isthmusectomy with a distance <0.5 cm from the tumor to the section regional, and the mean metastatic lymph nodes were 3 ± 5. These lymph node metastases were microscopic with a mean size of 1.9 mm (range, 1-10 mm). Fifty-eight (30.5%) patients in Group II had microscopic central lymph node metastasis. The mean metastatic central lymph nodes were 2 ± 2, and the lymph node metastasis was microscopic with a mean size of 1.8 mm (range, 1-9 mm). Twenty-one (26.3%) patients were performed with total thyroidectomy presented with central lymph node metastasis. The mean metastatic central lymph nodes were 2.5 ± 2, and the mean size of lymph node metastasis was 2.0 mm (range, 2-11 mm).
Outcomes
The mean length of follow-up was 37 months (range: 24-60 months). TSH was maintained in the mid to lower reference range (0.5-2 mU/L), while surveillance for recurrence was continued. Thyroid hormone therapy was not needed if patients could maintain their serum TSH in this target range. If TSH rises, TSH treatment was continued. Fifty-two (43.7%) patients who were performed with wide-field isthmusectomy with a distance <0.5 cm received hormone replacement therapy. Four of these patients started thyroid hormone treatment due to hypothyroidism that developed respectively 1 and 2 years postoperatively. The remaining 48 patients started thyroid hormone medication for TSH suppression. One hundred and one (53.2) patients who performed wide-field isthmusectomy with a distance ≥0.5 cm started thyroid hormone treatment after surgery. Of the patients who underwent wide-field isthmusectomy, 28 in the distance <0.5 cm group and 36 in the distance ≥0.5 cm group stopped medication completely during the follow-up period. Therefore, 80 (67.2%) of 119 patients in Group I and 125 (65.8%) of 190 patients in Group II did not take medication at the end of their follow-up period.
In Group I, locoregional recurrence developed in 22 patients (18.5%): 9 regional (7.6%) and 13 local (10.9%) recurrences. Ipsilateral lateral neck lymph node recurred in 16 (8.4%) patients in Group II, and the residual thyroid in 5 (2.6%) patients. Four (5.0%) patients in Group III were found to have the recurrence of ipsilateral lateral neck lymph node. The disease-free survival (DFS) in Groups II and III were significantly higher than the DFS in the wide-field isthmusectomy with a distance <0.5 cm group (Figure 2).
Kaplan-Meier estimates of DFS. DFS, disease-free survival.
In the total thyroidectomy group, hypocalcemia with low serum calcium and PTH was observed in 16 patients (20.0%), whereas it was 6 (5.04%) in Group I and 12 (6.3%) in Group II. Three recurrent laryngeal nerve injuries were observed by laryngoscopy in the total thyroidectomy group, and no nerve injury occurred in the wide-field thyroidectomy groups. Postoperative drainage volume and length of postoperative hospital stay were similar in the 3 groups, and the operation time was significantly longer in the total thyroidectomy group. Neck hematoma, bleeding, and infection were not observed in the 3 groups. The overall morbidity was 6 (5.0%) in Group I, 14 (7.4%) in Group II, and 21 (26.5%) in Group III (P < .05). Table 2 shows that the number of postoperative complications and the recurrence of the participation in the 3 groups.
Postoperative Complications and Recurrence of the Participation in the 3 Groups.
Abbreviation: M (Q1, Q3), median (lower quartile, upper quartile).
Discussion
The extent of surgical resection for isthmic PTC remains a topic of considerable debate in the literature.7,11 Wide-field isthmusectomy involves the removal of normal thyroid tissue surrounding the malignant tumor with a negative resection margin. 12 This study retrospectively divided 389 patients with PTC originating from isthmus into 3 groups according to the distance from the tumor to the resection margin. Results revealed that wild-field isthmusectomy including a 0.5 cm edge of surrounding normal thyroid tissues of each lobe and modified or limited neck dissection is a sufficient primary surgical procedure for isthmus PTC. The distance could be measured with a ruler for wide-field isthmusectomy.
In healthy individuals, ~20% of T3 production is derived from the thyroid gland, while the remaining 80% is produced through the conversion of T4 to T3 outside of the thyroid. In hypothyroid patients receiving levothyroxine replacement therapy, increased extrathyroidal T3 production is compensated for the absence of thyroidal T3 secretion. 13 The long-term consequences of prolonged exposure to abnormal T3/T4 ratios are unknown. Patients who have had only 1 lobe removed can still produce some thyroid hormone from the remaining tissue, unlike those who have undergone total thyroidectomy and depend entirely on exogenous hormone replacement therapy. 14 In the study, 80 (67.2%) of the 119 patients in Group I and 125 (65.8%) of the 190 patients in Group II did not require levothyroxine replacement therapy at the end of the follow-up period. This may be a desirable feature for patients, as it allows for the possibility of avoiding hormone supplementation even after surgery. Preserving normal thyroid tissue can also reduce the risk of damage to the recurrent laryngeal nerves and parathyroid glands by avoiding exposure to the tracheoesophageal grooves.
PTC arising in the isthmus has been reported as more likely to be associated with multifocal lesions, lymph node metastasis, and capsular invasion. 15 Bilateral central neck dissection should be considered for isthmic PTC due to the high rate of bilateral central lymph node metastasis, particularly to pretracheal and bilateral paratracheal lymph nodes. 3 The lymph node dissection yield was similar among the 3 groups in this study, but the incidence of postoperative hypocalcemia was significantly lower in the 2 isthmusectomy groups than in the total thyroidectomy group. The rates of locoregional recurrence between patients who were performed with wide-field isthmusectomy with a distance <0.5 cm and patients with a distance ≥0.5 cm were 18.5% and 7.4%, respectively, while node recurrence was observed in 4 (5.0%) patients in the total thyroidectomy.
Preserving the superior and inferior thyroid arteries and parathyroid glands can reduce the occurrence of both transient and permanent hypocalcemia during pCCND. 16 Specifically, the rates of hypocalcemia in the wild-field isthmusectomy group were 5.04% and 6.3% (P < .05) for distances <0.5 and ≥0.5 cm, respectively, while the incidence of hypocalcemia in the total thyroidectomy group was 20.0% (P < .01). In contrast to total thyroidectomy, wild-field isthmusectomy does not require full exploration of the tracheoesophageal groove and the ligament of Berry to identify the entire course of the recurrent laryngeal nerve. Therefore, isthmusectomy significantly reduces the risk of recurrent laryngeal nerve injury.
This study has some limitations that should be noted. Firstly, it was conducted without any prospective randomizations, and only a limited number of patients from a single institution were included. Secondly, various international practice guidelines do not recommend pCCND for small cN0 PTC. Therefore, a larger scale multicenter study with a longer follow-up period is needed to thoroughly examine the oncologic outcomes of pCCND. Additionally, further research is required to determine whether pCCND can be omitted during isthmusectomy for patients with small cN0 isthmic PTC.
Conclusion
Wide-field isthmusectomy with a 0.5 cm distance may be a sufficient treatment for selected patients with PTC limited to the isthmus. This procedure has the benefit of avoiding dissection of the recurrent laryngeal nerve and parathyroid glands, thus limiting postoperative complications.
Footnotes
Acknowledgements
The authors thank the studied patients for their willingness to cooperate with our study.
Data Availability Statement
Not applicable.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethical Approval and Informed Consent Statements
This research was comprised of human participants and was approved by Medical Ethics Committee of Wuhan University Zhongnan Hospital. Informed consent was obtained from all individual participants included in the study.
