The Necessity of Prophylactic Central Lymph Node Dissection in Clinically N0 Papillary Thyroid Carcinoma: Perspective from the Endemic Region

doi:10.21203/rs.3.rs-4870592/v1

Background: Prophylactic central lymph node dissection (pCND) in papillary thyroid carcinoma (PTC) is still a matter of debate. Therefore, we aimed to identify the factors affecting central lymph node metastasis (CLNM) in patients with clinically node-negative (cN0) PTC.

Methods: This retrospective study included 248 patients with cN0 PTC who underwent total thyroidectomy (TT) or TT+pCND. Clinicopathological associations among CLNMs, complication rates and the effect of pCND on staging were assessed. Risk factors (RFs) and the pattern of lymph node metastasis (LNMs) in PTC patients were studied via multivariate analysis.

Results: A total of 216 patients underwent pCND, and 51.2% (127/216) had positive CLNMs. Male patients, aged <41 years, and those with lymphatic invasion were identified as RFs for CLNM, with odds ratios of 2.59, 2.26, and 4.09, respectively. Among the 216 patients, 65 (30%) had transient hypoparathyroidism (HPT) , and 20 (9.3%) had permanent HPT. Transient recurrent laryngeal nerve (RLN) palsy occurred in 15 (6.9%) patients, and permanent RLN palsy occurred in 3 (1.4%) patients. Over 55 years of age, 46.7% of patients were upstaged according to the American Joint Committee on Cancer (AJCC) TNM staging system, and 14.2% (n=18) of the 127 patients with CLNMs were upgraded according to the American Thyroid Association (ATA) risk stratification (RS) system.

Conclusion: Taken together, in terms of the high incidence rate of CLNM in cN0 PTC patients;

We believe that routine pCND, which can be performed with low morbidity rates, is optimal for cN0 PTC patients during their first treatment, especially for those with RFs for CLNM.

Papillary thyroid carcinoma

prophylactic central lymph node dissection

TNM staging

safety

lymph node metastasis

Thyroid carcinoma (TC), the most common endocrine malignancy, has been diagnosed worldwide with increasing frequency in recent decades, especially among women (1–3). PTC is the most common thyroid malignancy, accounting for approximately 90% of new cases of TC in iodine-sufficient areas of the world (4). PTC has become the second most prevalent carcinoma among women and eighth among men in Turkey (5). According to the 2018 cancer statistics data of the Ministry of Health, the prevalence of TC in women aged 25–49 in Turkey ranks 2nd after breast cancer.

The overall incidence of PTC is increasing; however, most PTC patients have excellent prognoses (6). Despite this favorable outcome, PTC has an average incidence of 60% of cervical lymph LNMs, which most commonly occur in the central neck compartment (7, 8). Clinically detectable macrometastatic lymph nodes (LNs) are found in up to 35% of patients; 80% of metastases present with microscopic LNs, resulting in a high locoregional recurrence (LRR) rate in the paratracheal region, which has been reported to be up to 30% (7, 9). Currently, there are no non or minimally invasive methods that are completely reliable for detecting all of the metastases. As many as half of the nodes found later in surgery can be missed during the initial ultrasound (US) examination (10).

There is no controversy about the operation of therapeutic central neck dissection (CND) when clinical LNMs exist in the central neck compartment, while pCND in clinically negative (cN0) LN PTCs remains controversial (11, 12). According to previous studies, the advantages of routine CND include a reduction in the LRR, a reduction in the risk for complications associated with reoperation at level VI, and a higher rate of patients with low serum levels of thyroglobulin (Tg) and antithyroglobulin antibodies (Anti-Tg), which facilitate tracking and potentially improve disease-specific survival (DSS) (13–15). In addition, pCND could also help in more precise staging of PTC, since nodal positivity could convert patients from cN0 to pN1a, leading many patients over 55 years of age from AJCC stage I to AJCC stage II, which in turn changes the therapeutic choices (16, 17). However, other studies have demonstrated that occult LNMs increase the LRR but do not affect DSS and that therapeutic CND in the event of central compartment recurrence can be performed with low morbidity, which is no greater than that after an initial pCND (18, 19). Considering that the risk of postoperative complications such as RLN injury and HPT following pCND outweighs the potential benefits, the routine use of pCND in PTC is not recommended (20, 21).

The recommendations of guidelines in different countries and regions are not the same. The 2015 ATA Guidelines and the 2019 European Society for Medical Oncology (ESMO) Clinical Practice Guidelines recommend pCND + TT only in advanced primary tumors or in the presence of certain RFs and lateral neck node involvement (22, 23). The 2020 Japan Associations of Endocrine Surgeons Clinical Practice Guidelines suggest that primary tumor surgery with pCND to T1B and above tumors is recommended with risk assessment (24).

The mortality rate of PTC patients is low and stable, and in the last decade, there has been a paradigm shift toward less aggressive surgical treatment of PTC. The main challenge still remains to identify patients at greater risk of recurrence who require more extensive surgical and postoperative radioactive iodine (RAI) treatment but also importantly, to avoid overtreatment of lower-risk patients. The aim of this study was to examine the incidence and RFs of LNMs in patients with cN0 PTC and the morbidity in patients with PTC treated with TT plus bilateral or ipsilateral CND compared with those in patients who underwent TT alone. The influence of CLNMs identified in the implementation of pCND, on the migration of AJCC TNM staging and ATA risk stratification (RS) in patients with cN0 PTC was also evaluated in our study. The data from this study may provide additional guidance for surgical and therapeutic decisions for cN0 PTC patients from endemic regions.

2.1 Study Design:

We conducted a prospectively planned study in which the data were collected and analyzed retrospectively. The study was conducted at the Department of General Surgery University of Health Sciences, Basaksehir Cam and Sakura Health Practices and Research Center. The study was approved by the local ethics committee of the Basaksehir Cam and Sakura Health Practices and Research Center (EK- 2021.03.10).

We performed a study between July 2020 and September 2023. A total of 367 patients underwent surgery for Bethesda 5 (B5)/Bethesda 6 (B6) thyroid nodules (25). Patients whose data are summarized in Table 1 were excluded. Among these 87 B5 and 174 B6 patients who had cN0 disease and who underwent surgery were included in the study. Among the 261 patients, 78 B5 nodules (90%) and 170 B6 nodules (98%) had histologically proven PTCs. Finally, 248 patients who underwent TT or TT + unilateral/bilateral pCND with cN0 histologically proven PTC were analyzed.

Table 1

Inclusion and exclusion criteria
Inclusion criteria	Exclusion criteria
Age > 18 years B5 and B6 nodules confirmed by fine needle aspiration (FNA) cytology (n = 367) No evidence of lymphadenopathy on clinical examination No evidence of lymphadenopathy on preoperative US	Subtotal or hemithyroidectomy as definitive procedure (n = 19) Evidence of nodal disease on preoperative US or clinical examination (n = 18) Benign final histology (n = 13) Lateral neck dissection performed at original surgery (n = 62) Distant metastatic disease (n = 3) Patients with prior thyroid surgery (n = 4)

First, the study group comprised patients who underwent TT without pCND (Group A). These patients were compared with patients who had TT + pCND (Group B). The Group B patients were subsequently divided into two groups on the basis of pathological analysis: those without CLNMs (Group pN0) and those with CLNMs (Group pN1).

The following parameters were prospectively registered in a specifically designed database (Microsoft Excel, Microsoft Corporation, Redmond, WA): patient demographics; preoperative data; surgical procedures; postoperative complications, including RLN palsy, HPT, neck hematoma and wound infection; histologic subtype; tumor laterality; focality; extrathyroidal extension (ETE); lymphovascular invasion; tumor size; central LN status; stage; number of removed and metastatic LNs; TNM staging; and the results of follow-up evaluations. Staging of PTCs was performed via the eighth edition of the AJCC staging system. Risk categories were defined on the basis of the 2015 ATA guidelines (22). A comparative analysis among the groups concerning the registered parameters was performed. All patients provided written informed consent for the study.

2.2 Preoperative assessment

All the patients included in the study had undergone a preoperative physical examination, neck US, FNA of suspicious nodules, and measurement of serum thyroid hormones, thyrotropin (TSH), Tg, and anti-Tg ; preoperative fiber nasopharyngolaryngoscopy was also routinely performed for vocal cord functions. The indication for surgery is based on suspicious nodules that demonstrate US characteristics typical for malignancy, are cold in thyroid scintigraphy and in which FNA determines B5 / B6. All US examinations and US-guided FNAs were performed in the Department of Radiology by a single experienced radiologist trained in neck ultrasonography. Every patient underwent an US examination of the thyroid gland, the central and lateral LNs. In addition, US-guided FNA of the “leading” thyroid nodule was conducted. Cytological and histopathological examinations were performed at the clinical institute of Pathology.

2.3 Surgical technique:

All surgical procedures were performed by experienced endocrine surgeons in our hospital (each having more than 100 thyroid operations per year) who followed a standard technique described by Barczynski et al. (26). Surgical procedures were accompanied by extended dissection of the RLN via intermittent intraoperative neuromonitoring. When feasible, all four parathyroid glands were visualized and carefully dissected from the thyroid capsule. If the blood supply of a parathyroid gland could not be maintained, the gland was removed and then immediately autotransplanted into the sternocleidomastoid muscle on the side opposite the tumor. Drainage was routinely used.

2.4 Definitions:

2.4.1: Postoperative disturbance of RLN function: Vocal cord movement was assessed routinely preoperatively and, in the case of suspected RLN injury, postoperatively with fiber nasopharyngolaryngoscopy. Temporary RLN palsy was defined as decreased or absent vocal cord mobility resolving within 6 months of surgery. Permanent RLN palsy was defined as vocal cord dysfunction persisting beyond 6 months after initial surgery. During the operations, adverse EMG parameters were defined as an amplitude decrease of 50% or more from the baseline value or a latency increase of 10% or more. Recovery was defined as amplitude recovery to > 50% of the initial baseline amplitude. Loss of signal (LOS) was defined as an amplitude of < 100 µV (27). In the case of LOS during TT, pCND was aborted if the amplitude did not recover to greater than 50% of the initial baseline amplitude within 20 minutes of the initial decline.

2.4.2: Postoperative HPT: Serum calcium levels and PTH levels were assayed on the first postoperative day and then on the basis of the evolution of clinical and biochemical parameters. Medication was started prophylactically, and no patient was allowed to develop symptoms of hypocalcemia. Calcium replacement (1·5–3·0 g calcium daily) was administered when the total serum calcium level was < 8 mg/dL, and calcium plus calcitriol (0·25–1·0 µg/day) was given when PTH was < 10 pg/ml (reference range: 15–65 pg/ml). A serum calcium level < 8 mg/dL (reference range: 8.6–10 mg/dl) with a subnormal serum PTH level (< 10 pg/ml) was defined as transient HPT if the level returned to a normal value within 12 months after the withdrawal of calcium therapy. Hypocalcemia with a serum PTH level < 10 ng/l for more than 12 months after surgery, requiring substitution with calcium with or without calcitriol, was regarded as permanent HPT (28).

2.5 Postoperative Follow-up:

Radioactive iodine remnant ablation was performed with iodine-131 (I131) after surgery, followed by thyroxine withdrawal in selected patients. Suppressive L-thyroxine therapy was routinely administered with the thyroxine dose adjusted to a risk TSH level below 0·1 uIU/ml for high-risk patients and 0·1–0·3 µIU/ml for low-risk patients. Routine follow-up (every 3 months in the first year and then yearly) included neck US, estimation of serum TSH and basal Tg levels, and measurement of anti-Tg. A basal serum Tg level < 0,2 ng/ml in any patient on levothyroxine suppressive therapy or TSH-stimulated Tg < 10 ng/ml was considered to indicate a low risk of recurrent disease (22).

2.6 Statistical analyses:

The normality assumption of continuous variables was tested with the Kolmogorov‒Smirnov test. Categorical variables are presented as frequencies (n, %); continuous variables are presented as the means and standard deviations. Comparisons between two groups in continuous variables were performed with the Mann‒Whitney U test. Comparisons between more than two groups were made with the Kruskal‒Wallis H test. Pearson’s chi-square test and Fisher's exact test were used to compare qualitative data. Multivariate logistic regression analysis was used to determine the independent variables associated with the dependent variables. Receiver operating characteristic (ROC) curve analysis and the Youden index were used to determine the most appropriate age group for pathologic LN involvement. The results were evaluated at the 95% confidence interval, and significance was evaluated at p < 0.05. All the statistical calculations were performed with SPSS software version 26 (IBM Corp., Armonk, NY, USA).

3.1 Comparison of TT vs TT + pCND:

The study included 198 women and 50 men with a mean age at diagnosis of 46.16 ± 12.49 years. Group A included 32 patients who underwent TT only, whereas Group B included 216 patients who underwent TT + pCND. Data were analyzed on the basis of the classification of patients into groups A and B. The two groups were similar in terms of sex distribution, pathological tumor size, and pathological prognostic features, such as the incidence of tumor multifocality, ETE, capsule invasion, and vascular invasion. However, the presence of aggressive histological subtypes, lymphatic invasion and multifocal tumor frequency were quite high in both groups. When the two groups were evaluated together, these rates were 31.8%, 74.6%, and 68%, respectively. The Group B patients with pCND were significantly younger (mean ± SD, 45.2 ± 12.1 vs 52.8 ± 13.4; p = 0.004) than the Group A patients were and had a higher rate of lymphatic invasion noted in the primary tumor (77% vs 59%; p = 0.034) Patient demographics and clinicopathologic characteristics are summarized in Table 2.

Table 2

Demographic and clinicopathologic characteristics by surgical type
Variables	All (n = 248)	Group A (n = 32)	Group B (n = 216)	P value
Age (year), mean ± SD	46.16 ± 12.49	52.84 ± 13.39	45.17 ± 12.07	0.004^a*
Sex, n(%)				0.094^b
Female	198(79.8)	22(68.8)	176(81.5)
Male	50(20.2)	10(31.3)	40(18.5)
pT Stage, n(%)				0.086^c
T1A (< 9 mm)	108(43.5)	11(34.4)	97(44.9)
T1B (10–19 mm)	93(37.5)	10(31.3)	83(38.4)
T2 (20–39 mm)	34(13.7)	7(21.9)	27(12.5)
T3 (≥ 40 mm or ETE regardless of tumor size)	13(5.2)	4(12.5)	9(4.2)
Histologic subtype, n(%)
Classic + Mixt type	141(56,9)	16(50)	125(59,7)	0.165^b
Follicular	28(11,3)	4(12,5)	24(11,1)
Tall cell/Hobnail	79 (31,8)	12(37,5)	67(29,2)
Multifocality	169(68,1)	18(56,3)	151(69,9)	0,122^b
Capsuler invasion	89(35,8)	15(46,9)	74(34,3)	0,381^b
Ekstrathyroidal extension	20(8)	3(9,4)	17(7,6)	0,471^b
Vasculer invasion	29(11,7)	5(15,6)	24(11,1)	0,509^b
Lymphatic invasion, n(%)	185(74.6)	19(59.4)	166(76.9)	0.034^b*
LNs removed, n(%)	217(87.5)	5(15.6)	216(100)	N/A
Number of LNs removed, mean ± SD	14.48 ± 8.91	2.00 ± N/A	14.54 ± 8.89	N/A
Lymph node metastasis, n(%)	128(59)	1(3.1)	127(58.8)	N/A
Number of metastatic LNs, mean ± SD	3.26 ± 2.88	1.00 ± N/A	3.28 ± 2.88	N/A

*p < 0.05, a: Mann‒Whitney U test, b: Pearson chi‒square test, c: Fisher's exact test, SD: standard deviation, N/A: not available.

As expected, group B patients had a significantly greater number of LNs harvested during the original operation. In group B, 127 patients (58.8%) had nodal metastatic disease proven at final histology. The mean number of LNs removed after pCND was 14.54 ± 8.89. Ipsilateral pCND was performed in 168 (78%) patients, and 48 (22%) had bilateral pCND. In group A, despite no formal CND, 5 patients had perithyroidal LNs found during pathological examination of the thyroid. One (3.1%) of these patients had LNM. RAI therapy was used in 199 (80%) of the 248 patients: 23 patients (71,9%) who had TT versus 176 (81,5%) who had TT + pCND (P = 0,203). The RAI dose in the TT + pCND patient group were higher (mean ± SD, 110.87 ± 39.04 vs 130.89 ± 30.19; p = 0.001).

In the study population as a whole, 27 (10,8%) patients and over 55 years of age 46.7% of patients were upstaged according to the AJCC staging system for differentiated thyroid cancer. In group A, 1 patient (3.12%) was upstaged to stage II. In group B, 26 patients (12%) were upstaged to stage II on the basis of LN involvement.

The operative complications are summarized in Table 3. Transient HPT was observed in 71 (28.6%) patients, and transient RLN palsy was observed in 23 (9.3%) patients. Permanent HPT was observed in 24 (9.7%) patients, and permanent RLN palsy was observed in 4 (1.6%) patients. However, there was no statistically significant difference in the incidence of transient-permanent HPT and permanent RLN palsy between groups A and B (p > 0.05). The rates of temporary RLN palsy were greater in Group A (25% vs. 6.9%; p = 0.004). Another notable finding is that only 2 of the cases of RLN injury occurred during pCND, and 1 of them became permanent.

Autografting of parathyroid glands was more common in Group B than in Group A, but this difference was not statistically significant (12.5% versus 3.1%, P = 0.143). The rates of wound infection and postoperative hemorrhage were equivalent between the 2 groups.

Table 3

Complications
Variables	All (n = 248)	Group A (n = 32)	Group B (n = 216)	P value
Hypoparathyroidism, n(%)
Transient	71(28.6)	6(18.8)	65(30.1)	0.185^a
Permanent	24(9.7)	4(12.5)	20(9.3)	0.527^b
RLN palsy, n(%)
Temporary	23(9.3)	8(25)	15(6.9)	0.004^b*
Permanent	4(1.6)	1(3.1)	3(1.4)	0.427
Parathyroid autotransplantation, n(%)	28(11.3)	1(3.1)	27(12.5)	0.143^b
Wound infection, n(%)	5(2)	1(3.1)	4(1.9)	0.502^b
Hemorrhage, n(%)	4(1.6)	1(3.1)	3(1.4)	0.427^b

*p < 0.05, a: Pearson chi-square test, b: Fisher's exact test.

3.2 Comparison of pN0 vs pN1:

3.2.1 Patient and tumor characteristics

We performed TT + pCND in 216 patients with PTC. There were 89 patients (41%) without and 127 patients (59%) with CLNMs. In the whole group of patients, the mean age was 45.17 ± 12.07; 163 patients (75.5%) were younger than 55 and 53 (24.5%) were 55 or older. There were 40 men (18.5%) and 176 women (81.5%). Classical variant PTC was the predominant histologic subtype, accounting for 57.9% (n:125) of all cases, followed by tall cell variant 31% (n:67) and follicular variant 6.5% (n:14). ETE was noted in 7.9% (n:17) of cases and lymphatic invasion in 76.9% (n:166). Average tumor size was 13.8 mm (median 13 mm, range 2 to 49 mm); 45.4% of tumors were < 10 mm in size and 54.6% were ≥ 10 mm. The majority of tumors was multifocal (69.9%). CND was performed in all patients. On average, 14.54 nodes were found per CND specimen, range 0–49 per specimen, median 13.

Table 4

Variables associated with lymph node involvement
Variables	All (n = 216)	pN0 (n = 89)	pN1 (n = 127)	P value
Age(year), mean ± SD	45.17 ± 12.07	47.28 ± 9.79	43.69 ± 13.27	0.032^a*
Sex, n(%)				0.003^b*
Female	176(81.5)	81(91.0)	95(74.8)
Male	40(18.5)	8(9)	32(25.2)
Tumor size group, n(%)				0.041^b*
< 10 mm	98(100)	48(49)	50(51)**
≥ 10 mm	118(100)	41(44.8)	77(65.2)**
Histologic subtype, n(%)				0.001^b*
Classic	125(57.9)	51(57.3)	74(58.3)
Follicular	14(6.5)	9(10.1)	5(3.9)
Tall cell	67(31)	20(22.5)	47(37)
Other	10(4.6)	9(10.1)	1(0.8)
Multifocal disease, n(%)	151(69.9)	58(65.2)	93(73.2)	0.204^b
Bilaterality, n(%)	112(51.9)	49(55.1)	63(49.6)	0.430^b
Capsule invasion, n(%)	74(34.3)	32(36)	42(33.1)	0.660^b
Extrathyroidal extension, n(%)	17(7.9)	3(3.4)	14(11)	0.040^b*
Vascular invasion, n(%)	24(11.1)	6(6.7)	18(14.2)	0.087^b
Lymphatic invasion, n(%)	166(76.9)	44(49.4)	122(96.1)	< 0.001^b*
TNM stage, n(%)				< 0.001^b*
I	184(85.2)	86(96.6)	98(77.2)
II	32(14.8)	3(3.4)	29(22.8)
pT stage, n(%)				0.276^b
T1A (< 10 mm)	98(100)	48(49)	50(51)**
T1B (10–19 mm)	82(100)	28(44.1)	54(65.9)**
T2 (20–39 mm)	27(100)	10(37)	17(63)**
T3 (≥ 40 mm)	9(100)	3(33.3)	6(66.7)**
ATA Risk Category, n(%)				< 0.001^b*
Low	89(41.2)	63(70.8)	26(20.5)
İntermediate	127(58.8)	26(29.2)	101(79.5)

*p < 0.05, a: Mann‒Whitney U test, b: Pearson chi‒square test, SD: standard deviation.

**Numerical values are given as row percentages

3.2.2 Clinicopathological Associations and RFs Predicting CLNMs

In univariate analysis the mean age of the patients in the pN1 group was lower and compared to the pN0 patient group, the male sex ratio was higher in the pN1 patient group (9% vs 25%).The most appropriate age limit for determining the presence of pN1 was determined as 41 years (AUC = 0.62). For 41 years of age, sensitivity, specificity and accuracy rates were 45%, 78% and 60%, respectively (Fig. 1). The difference was statistically significant for both age (p = 0.032) and sex (p = 0.003)(Table 3). In the group of patients with tumors < 1 cm in size we found metastases in 51% of the patients, whereas in the group of patients with tumors ≥1 cm metastases were found in almost 65% of patients. Compared to the pN0 patient group, the pN1 patient group had a presence of tumors over 10 mm (40% vs 75%; p = 0.041). It was also found tall cell tumor type (22.5% vs 37%; p = 0.001), ETE (3.4% vs 11%; p = 0.040) and presence of lymphatic invasion (49% vs 96%; p < 0.001) the factors affecting presence of CLNMs. The results of the analysis of variables associated with LN involvement are presented in detail in Table 3.

In addition, 14.2% (n:18) of the 127 patients with CLNMs were upgraded from the low-risk group to the intermediate-risk group according to the ATA RS system because the number of LNMs was ≥ 5. None of these 18 patients had T3 or T4 tumors. When pathology data were analyzed, 58 (36.1%) of 216 patients who underwent pCND received adjuvant treatment only for CLNMs, regardless of other poor prognostic factors such as vascular invasion, aggressive histological variant, ETE and tumor size. In patients with CLNMs, the micrometastasis rate was 38.5% (n:49), and when the micrometastasis rate was analyzed according to tumor size these rates were 20.4% (n:26), 12.6% (n:16), and 2.4% (n:3) in T1a, T1b, and T2-T3 tumors, respectively.

When we analyzed the clinicopathological RFs that could independently predict CLNMs in patients who underwent pCND. Multivariate logistic regression analysis revealed that < 41 years of age [OR = 2.59 (95% CI = 1.23–5.45); p = 0.013], male sex [OR = 2.26 (95% CI = 1.37–3.71); p = 0.001] and the presence of lymphatic invasion [4.09 (95% CI = 2.46–6.80); p < 0.001] were found to be independent factors affecting pathological LN involvement (Table 4).

Table 5

Independent variables associated with lymph node involvement (multivariate analysis)
Variables	OR(95% CI)	P value
Age (< 41 year vs ≥ 41yr)	2.59(1.23–5.45)	0.013*
Sex (male vs female)	2.26(1.37–3.71)	0.001*
Lymphatic invasion (yes vs no)	4.09(2.46–6.80)	0.001*
Tumor size (≥ 10 mm vs < 10 mm)	1.02(0.49–2.08)	0.964
Extrathyroidal extension (yes vs no)	2.19(0.55–8.69)	0.265
Histologic subtype
Follicular vs Classic**	1.61(0.32–8.15)	0.567
Tall cell vs Classic**	1.53(0.72–3.28)	0.270
Other vs Classic**	0.23(0.02–2.30)	0.212
Model summary	Model method = Enter
	Model, χ²=91.70; p < 0.001
	R²_N = 0.466
	AUC = 0.851

*p<0.05, OR: odds ratio, CI: confidence interval, **: reference value.

PTC is the most commonly diagnosed thyroid malignancy (29). Increased awareness of thyroid nodular disease, wide availability of US and FNA, and improved accuracy of histopathological examination of surgical samples have been suggested to be reasons for the increased incidence of detection (30). Fortunately, PTC is usually treatable and has a good prognosis if it is diagnosed early, although it is also accompanied by a high incidence of CLNMs (31). There is no consensus about the need to routinely perform pCND in patients with cN0 PTC. However, the optimal management for those patients is achieved by performing the most appropriate surgery at the time of diagnosis to achieve the best prognosis and minimize the risk to those patients and the need for unnecessary secondary procedures (32). Therefore, identifying RFs of CLNMs could guide surgeons in considering which cN0 PTC patients require pCND.

There are several studies in the literature to identify RFs that may predict CLNMs. Xue et al. (33) indicated that RFs for CLNMs including age < 45 years, male gender, tumor size of ≥ 1 cm, and ETE predicted CLNMs. Age is considered among the most important prognostic factors for TC (34,35). Yuan et al. (36) showed that the rate of CLNMs was higher in patients < 45 years than that ≥45 years. Multivariate analysis showed age < 45 years was independent predictor of CLNMs in patients with cN0 PTMC. Kim et al. also observed a trend to an inverse relationship between the incidence of CLNMs and age in patients with cN0 PTC (37).In a recent meta-analysis conducted by Hafez et al. (38) showed age <45 years, male sex, multifocality, bilaterality, capsular invasion, lymphovascular invasion and ETE are the factors significantly associated with CLNMs. Also as reported by Pontius et al. the presence of lymphovascular invasion among patients with PTC is associated with significantly decreased survival (39). In our study, univariate analysis shows that male gender, young age, the presence of ETE, a primary tumor size ≥10 mm , and lymphatic invasion were RFs of CLNMs. In multivariate logistic regression analysis we found; <41 years of age [OR=2.59 (95% CI=1.23-5.45); p=0.013], male gender status [OR=2.26 (95% CI=1.37-3.71); p=0.001] and presence of lymphatic invasion [4.09 (95% CI=2.46-6.80); p<0.001] were found to be independent factors affecting pathologic LN involvement. These results indicate that careful preoperative assessment of LN status must be followed in young and male patients.

In our study, the positive nodes were found in almost 59% of patients of PTC. Statistic analysis showed that the larger the tumor was, the more likely to find CLNMs, with the incidence of 51.5, 65.9, 63, and 66.7% in tumor size of; < 1, 1–2, 2–4 cm, and ≥ 4 cm, respectively. These results consist with most reports. Wang et al. (40) also showed a positive correlation between tumor size and the incidence of CLNMs, with the incidence of 35.1, 53.9, 47.1, and 100.0% in tumor size of; < 1, 1–2, 2–4 cm, and ≥4 cm, respectively. At the same time they found that, tumor size was also an independent predictive factor for CLNMs in cN0 PTC patients. Roh et al. (41) using multivariate analyses reported that tumor size > 1 cm was an independent factor for ipsilateral CLNMs. Park et al. (42) reported that tumor size > 0.7 cm was an independent variable predictive of CLNMs in patients with cN0 PTMC. However, other studies reported that there was no significant association between the presence of CLNMs and tumor size (43,44). In this study, multivariate analysis showed that tumor size ≥ 1 cm was not an independent predictor of CLNMs in patients with cN0 PTC. However, the incidence of CLNMs was much higher in tumors ≥1 cm (65.2% versus 44.8%). The difference in size cutoffs in each of those studies might affect the association between the incidence of CLNMs and tumor size. Further randomized controlled multicenter study will be helpful to draw the right conclusion.

Both TNM staging system (AJCC) and risk stratification system (ATA) have important prognostic values for TC. The former is used to predict disease-specific mortality, and the latter is mainly used to estimate the LRR. Several studies proposed that pCND did not help LRR and suggested RAI therapy to control the disease (45,46). This is in contrast to the findings of Moo et al. (47), who found a trend toward lower recurrence in TT+pCND, which could be due to increased control over local metastases or increased doses of RAI ablation in patients with recognized LNMs. Barczynski et al. (26) reported that pCND for more accurate N staging, followed by personalized adjuvant RAI treatment, and significantly improved both 10-year DSS improving from 92.5% to 98.0% and locoregional control, without increasing the risk of permanent morbidity in patients with PTC. Randolph et al. (48) showed that prognosis is negatively impacted if ≥5 LNMs are identified during neck dissections. In our study, CLNMs were found in 58.8% (127 of 216 cases) of patients with cN0 PTC. Because of the CLNMs detected after pCND, 46.7% of patients over 55 years of age were upstaged. Most of our patients had other RFs that also upgraded them to the ATA intermediate-risk group, however, in 18 patients (14.2%), the CLNMs data was the only factor that led to their stratification to the intermediate risk category. From patients with CLNMs 58 (26.8%) were recommended to receive the RAI therapy after initial surgery only for CLNMs, regardless of other poor prognostic factors. These patients would have been inappropriately down staged and possibly undertreated if pCND had been omitted. Similar to our results, Zhang et al.(8) reported that the percentage of upstaged patients with cN0 PTMC was 16% and Nylen et al. (49) reported that 23% of patients upgraded to intermediate-risk group. They also noted that 4% of these patients were upgraded only because of LN data. Recent studies have suggested that approximately one-third of patients who underwent pCND may have been upstaged.(48,50) The present studies results agree with this observation, as 58.8% of our cN0 PTC patients who underwent pCND had CLNMs , and 36.1% of pCND received RAI therapy for N1a ≥0.2 cm. Bonnet et al. reported data suggesting that pCND resulted in increased use of RAI and, ultimately, in more favorable outcomes (51).

Another important reason for pCND is that there is no other reliable method to verify CLNMs, whether preoperative or intraoperative US or other methods are far from sufficient sensitivity to verify CLNMs (52). Stulak et al. (53) reported that in a total of 511 patients with PTC, 476 patients were cN0; preoperative US detected CLNMs in 10 patients (2.1%), but CLNMs were confirmed in 179 patients (32.5%). Preoperative US for the detection of CLNMs has high specificity (92%) and positive predictive value (81%–92%) but low sensitivity (51%–61%) and negative predictive value, especially for central LNs (63%–76%) (54,55). Therefore, before other reliable authentication methods arise, there is no better way to assess CLNMs other than pCND. The detection of CLNMs is associated with the administration of higher doses of RAI for postoperative ablation, decreased recurrence in patients undergoing pCND, and the need for reoperation.

Studies have reported higher rates of HPT and RLN palsy with reoperative surgery because of tumor recurrence and local invasion (56,57), and LNM is strongly associated with recurrence after TT (58). In the literature, however, the rate of transient HPT has been reported to be between 9.7 and 56.5% after TT+pCND. A permanent HPT has been reported in up to 19.4% of patients after pCND, compared with 0.6–8.1% after simple TT (59). In this study, results consistent with the literature were obtained. According to the results of a recent meta-analysis published by Yang et al. (60), the TT+pCND group had a significantly higher rate of transient HPT than that of the TT alone group. This finding was consistent with that of Moo et al. (47), who reported that the number of patients with transient HPTs in the TT+pCND group was greater than that in the TT alone group at the beginning of the study. Some researchers have reached similar conclusions (8, 61-64). This study revealed that the rates of transient HPT were higher when a pCND was performed, but the difference was not statistically significant (30 vs 18.8; p = .185). Importantly, the rate of permanent HPT was not different between the 2 groups. We implemented the policy of liberal autografting of parathyroid glands where necessary, which may explain the lower rate of permanent HPT.

The other main complication related to pCND is RLN injury. Roh et al. (63) demonstrated an increased risk of transient RLN palsy after TT+pCND, which could be explained by increased RLN injury caused by dissection of the LNs. However, Wang et al. (65) reported that there were no significant differences in the incidence of other complications, such as transient HPT, permanent HPT, transient RLN palsy and permanent RLN palsy, between the TT and TT+pCND groups. Our data revealed that the rates of transient and permanent RLN palsy were 6.9% and 1.4%, respectively. These results are in accordance with those reported in the literature, which reported rates of transient RLN palsy ranging from 1% to 13% and rates of permanent RLN injury ranging from 0% to 3.6%. (66-69). The addition of CND to TT has been reported to increase neither the risk of transient nor permanent RLN palsy in prophylactic or therapeutic procedures (61,70-73). In this study, TT+pCND did not increase the incidence of transient or permanent RLN palsy, but the incidence of transient RLN palsy was lower in the TT+pCND group than in the TT alone group. This may be explained by the fact that we avoid performing pCND in patients with RLN injury or signal loss. On the basis of our data, we can conclude that pCND can be safely performed with comparable permanent morbidity by experienced surgeons.

The incidence of TC is increasing worldwide. In a large cohort study, an overall 23.3-fold increased risk of TC was observed following the diagnosis of any benign thyroid gland disorder (compared with no diagnosis) (74). For this reason, especially in our country, which is endemic for thyroid diseases, the treatment approach for PTC gains much more importance. Another striking finding in our study was the high rate of tall cell variants, one of the aggressive subtypes of PTC (31.8%). In the literature, the incidence of tall cell variant is reported to be between 1.3% and 13% (75,76), and as is well known, tall cell variant has a poorer prognosis with significantly higher rates of LN and distant metastases and lower 5-year DSS (77,78). Furthermore, Machens et al. reported that microscopic lymphatic invasion in PTC was associated with LNMs and multifocal tumor growth (79). In our study, the rate of lymphatic invasion was 74% in the whole group and 96% in the group of patients with CLNMs.

The first limitation of this study was that it was a retrospective study from a single center, and there might have been selection bias. The second limitation of this study was that we could not evaluate the effects of pCND on the cancer-specific survival and recurrence rates of patients with cN0 PTC because the follow-up time was relatively short.

In conclusion, the main reason stoping us performing pCND is potential complications, but as mentioned above, the incidence of complications could be reduced by careful and experienced teams. We argue that patients with RF for significant CLNMs that upgrade them to the intermediate-risk group would benefit the most from pCND even in the absence of clinically evident CLNMs. Taken together, given the high incidence rate of CLNMs in cN0 PTC patients in endemic areas such as our country, we believe that routine pCND is optimal for cN0 PTC patients during their initial treatment, especially for those with RFs for CLNMs.

Ethical Approval Statement: This is retrospective study. The study was approved by the local ethics committee of the Basaksehir Cam and Sakura Health Practices and Research Center (EK- 2021.03.10)

Clinical Trials Number: NCT05873283

DATA AVAILABILITY STATEMENT (p15)

ETHICS STATEMENT

Author Contribution

Conceptualization: T.M.O, S.S.Data curation: T.MO,S.A.Formal Analysis: A.C.,Y.S.Investigation: T.M.O,S.A.Methodology: S.S.Project administration: S.S.Resources: T.M.O., S.S.Software: A.C.H.K.Supervision: S.S.Validation: S.A., S.S.Visualization: G.Y., Y. S.Writing – original draft: T.M.All authors reviewed the manuscript.

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No competing interests reported.

The Necessity of Prophylactic Central Lymph Node Dissection in Clinically N0 Papillary Thyroid Carcinoma: Perspective from the Endemic Region

Status:

Version 1

Abstract

Figures

1. INTRODUCTION

2. MATERIALS AND METHODS

2.1 Study Design:

2.2 Preoperative assessment

2.3 Surgical technique:

2.4 Definitions:

2.5 Postoperative Follow-up:

2.6 Statistical analyses:

3. RESULTS

3.1 Comparison of TT vs TT + pCND:

3.2 Comparison of pN0 vs pN1:

3.2.1 Patient and tumor characteristics

3.2.2 Clinicopathological Associations and RFs Predicting CLNMs

4. DISCUSSION

CONCLUSION

Declarations

References

Additional Declarations

Status:

Version 1