Comparison of parathyroid hormone kinetics in endoscopic thyroidectomy via bilateral areola with open thyroidectomy

Patients who had undergone total thyroidectomy and CND for thyroid cancer with postoperative iPTH evaluation were prospectively observed between October 2013 and April 2018. All participants gave informed consent before research commenced. The study was conducted in accordance with the Declaration of Helsinki, while the protocol was approved by the ethics committee of China-Japan Union Hospital of Jilin University (see protocol n. 2012-wjw-004).

Research took place at the Academic Hospital, which is a single institutional, tertiary referral center.

Patients who had undergone thyroidectomy without CND, concomitant parathyroid disease, renal failure, unilateral lobectomy, ‘berry picking’ dissection, re-done central neck dissections, high or low basal iPTH values (normal range 15-65 pg/ml) were excluded from analysis. Patients with vitamin D deficiency or preoperative calcium supplementation were also excluded. Inclusion and exclusion criteria for ETBAA can be seen in Table 1. The study only included patients with a malignant thyroid disease. Cancer patients were placed into three groups: (A) patients who were eligible for endoscopic treatment and who accepted ETBAA (ETBAA); (B) patients eligible for ETBAA yet who opted for OTA (OTA-L); (C) those cancer patients who were ineligible for endoscopic intervention who had undergone OTA (OTA-H). The inclusion criterion was cN0 on clinical and US examination for the ETBAA and OTA-L group, while those from the OTA-H group were ineligible for endoscopic intervention, including cN1. See Fig. 1 for a grouping flow chart. Patients could be included if they had PTC, been diagnosed preoperatively using cytological diagnosis, were diagnosed with N0 neck either clinically or following ultrasonography (US), and those whose diagnosis had been confirmed following intraoperative inspection.

All participants were subjected to preoperative high-resolution US [12]. The 2009 Bethesda classification system of thyroid cytopathology was utilized [12]. Non-contrast slides from CT scans were frequently utilized during the initial evaluation of a solitary thyroid cancer.

The ETBAA technique has been previously described (Additional file 1: Video S1) [13]. The third and fourth intercostal incisions of male ETBAA patients are conventionally used for the endoscopic access. The middle incision is 12 mm, and the bilateral incisions are approximately 5–6 mm. The central neck dissection (level VI) is then performed similarly to that of women patients. Standardized neural monitoring was implemented in all groups [13]. All surgeries were performed by the same endocrine surgeon (DZ). Dissection and hemostasis were achieved in OTA with a Focus Plus device, and were achieved in ETBAA by means of an ACE plus device (Johnson & Johnson Company, Cincinnati, OH, USA). Drainage tubes were attached from the chest incision.

Preservation of the parathyroid glands as well as their blood supply was attempted in all cases. Efforts to identify all four glands also took place in all cases. However, an extensive neck exploration to search for one or two missing glands was not carried out. A classification scheme for parathyroid glands location was utilized (see Fig. 2). Type A: the gland is firmly fixed to thyroid gland. Type A can be grouped into three subtypes. A1: the parathyroid gland is attached to the inherent thyroid capsule. A2: the gland is partially embedded in thyroid gland. A3: the gland is located in thyroid tissue and is discovered after thyroid gland excision. Type B can be defined as a gland which is separate from the thyroid gland [14].

In cases where the parathyroid glands had been damaged, auto-transplantation was undertaken. Prior to auto-transplantation, a section of a fragment of the parathyroid gland was frozen. Parathyroid tissue was stored in a saline solution after excision. Sliced parathyroid tissue and 1 ml of saline was withdrawn into a syringe and injected into the monolateral sternocleidomastoid muscle (Additional file 1: Video S1).

The techniques for CND applied have been described previously [8, 15‐17].

iPTH measurements were assessed by chemiluminescence (STAT-Intraoperative-Intact-PTH, Future Diagnostics, Wijchen, Netherlands). Venous samples were obtained before surgery and at skin closure. According to our protocol, if iPTH was < 15 pg/mL, then the subject received oral calcium and vitamin D substitution [15‐17]. Serum calcium (range 2.2 to 2.6 mmol/L) was monitored at 24, 48, 72 h and + 15 days postoperatively. On follow-up visits at + 1, 3 and 6 months, both the serum calcium and the iPTH level were verified [15‐17]. If two consecutive serum calcium determinations were within or above the normal value, then firstly calcium and secondly vitamin D were no longer given [15‐17].

Pre- and postoperative follow-up included laryngoscopy [15‐17]. Measurement of serum Thyroglobulin, stimulated thyroglobulin hormone (TSH) and thyroglobulin antibodies were monitored in all patients after surgery in the follow up period [15‐17]. After surgery, patients were given TSH-suppressive L-thyroxine therapy [12]. The seventh edition of the AJCC/TNM cancer staging system was used [12]. Papillary thyroid cancer indications for RAI treatment (4–5 weeks after surgery) include: > 45 years or < 18 years; tumor > 2 cm; thyroid capsule, soft tissue, adjacent organ tumor extension; LN+ (in any area of the neck); non-classical variants of PTC; M+; remnant ablation; BRAF+.

Neither profiles of thyroglobulin, TSH and thyroglobulin antibodies nor prevalence/dose of RAI analysis are the purpose of this preliminary report.

iPTH kinetics in ETBAA versus open surgery were considered as the primary end-point.

PTH < 15 pg/ml was utilized for statistical testing [15‐17]. The cut-off value for the serum calcium level was 2.0 mmol/L [7, 15‐17]. Analysis of the data was calculated using SPSS version 19.0 (SPSS Inc., Chicago, USA) and SAS version 9.4 (SAS Inc., North Carolina, USA). Data were presented as mean ± standard deviation. The differences between parathyroid gland outcomes, changes of PTH perioperative or serum calcium and calcium supplementation in the ETBAA, OTA-L and OTA-H groups were analyzed using Cochran’s and Mantel-Haenszel Chi-square test. The level of statistical significant was 0.05.

Over the six-year period of the study, 315 patients underwent total thyroidectomy and CND as a one-stage procedure. Figure 3 depicts a flow chart with the number of patients eligible and not eligible for the study. Based on the selection and exclusion criteria, 300 patients were eligible for the study. These were 44 men and 256 women, aged 16–54 years (median 37.7). Demographic, clinical, laboratory, operative, morbidity and histology data can been seen in Table 2. Mean length of follow-up was 20 ± 6 months (range five to 52 months). No instances of instrument malfunction (neuromonitoring, endoscopy, ultrasound scalpel and so on) were recorded in this study.

There were 100 patients in each group. In the ETBAA group, mean age was 31.2 ± 9.31, and there were 11 male and 89 female participants. In the OTA-L group, mean age was 36.2 ± 10.5, and there were 16 male and 84 female patients. In the OTA-H group, mean age was 47.9 ± 15.7, while there were 17 male and 83 female participants. The only significant difference between the ETBAA and OTA-L groups was the mean operating time and drainage (Table 2). The preoperative TSH (P = 0.17) and tireoglobulin levels (P = 0.26) were seen to be within the normal range for both groups. None of the patients in the study population had a preoperative recurrent laryngeal nerve (RLN) palsy. There was no significant difference found between the incidence of hypoparathyroidism (permanent 0% versus 1%; transient 7% versus 5%) and hypocalcemia (permanent 0% versus 1%; transient 9% versus 10%) (Table 2). A comparison of the ETBAA and OTA-H groups and of the OTA-L and OTA-H groups found that the mean tumor diameter, rate of extracapsular invasion and number of lymph node metastases were significantly different and were positively correlated with both hypoparathyroidism and hypocalcemia following surgery (Table 2). The endoscopic group were treated during an earlier stage of thyroid cancer. Regarding RLN injury, both transient and permanent unilateral palsy were found in the ETBAA group at 7% versus 0%, the OTA-H group at 4% versus 2% and the OTA-L group at 2% versus 0% (p > 0.05) (Table 2). No cases of bilateral palsy were found.

A significant difference was found between the ETBAA and OTA-H groups in parathyroid type A2, as well as a loss of parathyroid glands and a number of parathyroid transplantation procedures (P < 0.05). Details are described in Table 3 and Fig. 4.

No significant difference was found in preoperative iPTH values between the OTA-L, OTA-H and ETBAA groups (Table 4, Fig. 5). Fifteen minutes following surgery, the iPTH profile of each group decreased, although this was most consistent in the OTA-H group (Fig. 5). No significant difference was found in iPTH between the ETBAA and OTA-L groups. There was a significant difference found between the OTA-H and ETBAA groups, and between the OTA-H and OTA-L groups (Table 4). When comparing the ETBAA with OTA-L, the iPTH level change is similar.

No significant difference was found in basal serum Ca values for the OTA-L, OTA-H and ETBAA groups (Fig. 6, Table 5). On the first day following surgery, there was no significant difference found in serum Ca values between the OTA-L, OTA-H and ETBAA groups. No significant difference was found in calcium supplementation between the OTA-L and ETBAA groups.

On day two after surgery, no difference was found in the serum Ca values of the OTA-L and ETBAA groups. However, a significant difference was discovered in serum Ca values between the OTA-H and ETBAA groups, as well as the OTA-H and OTA-L groups. There was also a difference in calcium supplementation between OTA-H and ETBAA groups as well as the OTA-H and OTA-L groups.

On the third day after surgery, no significant difference was found in the serum Ca values between the OTA-L, OTA-H and ETBAA groups. Statistical analysis found a positive correlation in calcium supplementation between the OTA-H and ETBAA groups as well as between the OTA-H and OTA-L groups (Table 5, Fig. 6).

Histopathology confirmed that all participants had suffered from PTC. There was a significant difference found in thyroid volume, mean diameter of tumor, extracapsular invasion, coexistence thyroiditis and level VI metastasis between the OTA-H and ETBAA groups as well as between the OTA-H and OTA-L groups (Table 2). A significant difference was found in the mean number of lymph nodes dissected between the OTA-L and ETBAA groups as well as the OTA-L and OTA-H groups (Table 2). Statistics found a positive correlation in the mean number of metastasis between the OTA-L and ETBAA groups as well as the OTA-L and OTA-H groups.