Impact of Lymph Node Dissection on Postoperative Complications of Total Thyroidectomy in Patients with Thyroid Carcinoma

Round 1

Reviewer 1 Report

The authors aim to analyze the morbidity of lymph node dissection in patients with differentiated thyroid cancer and identify predictive risk factors of complications of lymph node dissection in these patients. The topic is highly relevant, but has been widely investigated and reported already. The main findings (central lymph node dissection leads to a higher rate of postoperative hypoparathyroidism and lateral lymph node dissection to a higher rate of recurrent laryngeal nerve palsy) are well known. The manuscript adds no new information to the field No risk factor analysis for complications of lymph node dissection has been performed (e.g. one- vs. two-stage-procedure, number of resected lymph nodes, enlarged vs. non-enlarged lymph nodes, invasion of the capsule, underlying disease (e.g. Grave´s disease), BMI, etc.). The results should be compared to patients with intraoperative neuromonitoring, which is the standard procedure nowadays. The conclusions are consistent with the evidence but do not address the main question. The references are relevant, but latest references date from 2018, please see https://pubmed.ncbi.nlm.nih.gov/34157088/ as an example for more recent literature.

Author Response

The authors aim to analyze the morbidity of lymph node dissection in patients with differentiated thyroid cancer and identify predictive risk factors of complications of lymph node dissection in these patients. The topic is highly relevant, but has been widely investigated and reported already. The main findings (central lymph node dissection leads to a higher rate of postoperative hypoparathyroidism and lateral lymph node dissection to a higher rate of recurrent laryngeal nerve palsy) are well known.

The manuscript adds no new information to the field No risk factor analysis for complications of lymph node dissection has been performed (e.g. one- vs. two-stage-procedure, number of resected lymph nodes, enlarged vs. non-enlarged lymph nodes, invasion of the capsule, underlying disease (e.g. Grave´s disease), BMI, etc.).

 

We thank the reviewer for his careful reading of our study and his constructive remarks. Indeed, the results of our study confirm those from the literature. However, the vast majority of studies have focused on the impact either of central lymph node dissection or central lymph node dissection associated with lateral lymph node dissection on postoperative complications without making a precise distinction between the different type of lymph node dissections.  Thus, the aim of our retrospective study was first to assess precisely the morbidity of the different type of lymph node dissection (ie cental, lateral, ipsi or bilateral lymph node dissection) and to analyse the risk factors of post-thyroidectomy complications in a cohort of 1547 patients with thyroid carcinoma. Thus, due to the large number of patients included and to uni and multivariate analyses, we were able to demonstrate the precise role of central neck dissection on the occurrence of postoperative hypocalcemia and of lateral lymph node dissection on post operative recurrent laryngeal nerve palsy. We are agreed with the reviewer that other factors could have been analyzed such as obesity or grave’s disease, but due to the retrospective design of this study those data have not been recorded and further prospective cohort study are needed to determine the role of those factors on postoperative complications.

 The results should be compared to patients with intraoperative neuromonitoring, which is the standard procedure nowadays.

We are fully agreed with the reviewer that intra operative neuromonitoring is the standard procedure nowadays. However, in our study, we concentrated on the impact of LND on postoperative RLN function. For that purpose, we chose to review an historical cohort before implementing intraoperative neuromonitoring, to avoid bias due to the utilization of this novel technique.

 The conclusions are consistent with the evidence but do not address the main question.

We are fully agreed with the reviewer that our study does not allow us to answer the main question which is the oncological interest of lymph node dissection. However, the morbidity of lymph node appears more and more to be an important consideration especially for small cancers less than 4 cm diameter due to the absence of high-level evidence for the carcinologic benefit of prophylactic central lymph node dissection (Viola D, JCEM, 2015; Sippel R, Ann Surg, 2020). While data from high-volume centers report low rates of postoperative complications (Barczynski M, Br J Surg, 2013), national database analyses report higher complication rates after prophylactic central neck dissection (Kim SK, J Am Coll Surg, 2016). Similarly, recent meta-analyses have confirmed a significant increase in the rate of transient and definite hypoparathyroidism and transient recurrent palsies after prophylactic central curage (Su H, Braz J Otorhinolaryngol, 2019; Chen L, World J Surg, 2018; Zhao WJ, Eur J Surg Oncol, 2017). Thus, prophylactic central lymph node for tumors smaller than 4 cm remains a feasible option for a surgeon regularly performing thyroid surgery, especially when there are risk factors for lymph node metastasis (age<45 years, male gender), to decrease the local recurrence rate, to improve tumor classification, and to allow for tailored individual management. However, these advantages should not be outweighed by excess morbidity due to insufficient expertise. Thus, this study highlights the importance of training, experience, and the need for prospective assessment of morbidity which should be considered when selecting the surgical team (Adam M, Ann Surg, 2017).

 The references are relevant, but latest references date from 2018, please see https://pubmed.ncbi.nlm.nih.gov/34157088/ as an example for more recent literature.

We thank this reviewer for his/her remark and more recent references have been added to the text. We have also added the reference quoted above in the discussion which confirms that CLND was a risk factor for permanent hypoparathyroidism.

Reviewer 2 Report

The authors addess a topic that is truly relevant in the field of thyroid malignancies and endocrine surgery. A retrospective single-center study has been performed in order to assess whether a more radical approach including lymph node dissection is associated with higher morbidity.

- The introduction is well written and briefly presents the need for this study

- Please provide a reference for the paragraph starting in line 47 ("Conversely, TT with LND is.....")

- line 75 "All operations were performed or supervised by an experienced surgeon" this sentence is not clear, please clarify whether all surgeries were performed by the same experienced surgeon or the levels of experience of the surgeons performing thyroidectomies did differ

- line 102: "under 80 mg/dl " should be less tham 8.0?

- please confirm the percentage of female gender is correct in table 1 (22.9%), it is unusual to have so many males in a thyroidectomy group ?

- also please discuss the important percentage of toxic goiter 9% in the group of thyroid cancers

- The results are relevant but could be greatly improved. Besides the experience of the surgeon and extent of surgery, maybe other factors such as a large volume of the goiters, preoperative compression symtoms could also impact complications, maybe some correlations colud be made, the statistics are very basic

- how many cases had a malignant cytology result before surgery? how many cases of microcarcinomas did have lymphadenomectomy? it is not clear how and when LN dissection was decided in these cases - maybe it should be discussed separately 

- The discussions are well-documented and well-written

- The font for refernces is not appropriate

Author Response

The authors addess a topic that is truly relevant in the field of thyroid malignancies and endocrine surgery. A retrospective single-center study has been performed in order to assess whether a more radical approach including lymph node dissection is associated with higher morbidity. The introduction is well written and briefly presents the need for this study

- Please provide a reference for the paragraph starting in line 47 ("Conversely, TT with LND is.....")

References from recent meta-analyses which have confirmed a significant increase in the rate of transient and definitive hypoparathyroidism and transient recurrent palsies after prophylactic central curing (Su H, Braz J Otorhinolaryngol, 2019; Chen L, World J Surg, 2018; Zhao WJ, Eur J Surg Oncol, 2017) have been provided for this paragraph.

- line 75 "All operations were performed or supervised by an experienced surgeon" this sentence is not clear, please clarify whether all surgeries were performed by the same experienced surgeon or the levels of experience of the surgeons performing thyroidectomies did differ

We thank this reviewer for having raised this important.  We rephrased the sentence as suggested to avoid any confusion: “All operations were performed by surgeons with different levels of experience.”

- line 102: "under 80 mg/dl " should be less tham 8.0

We apologized for this typo, which has been corrected 

- please confirm the percentage of female gender is correct in table 1 (22.9%), it is unusual to have so many males in a thyroidectomy group ?

We thank the reviewer for his/her careful reading. The percentage in Table 1 does correspond to male gender. The percentages have been changed in the table according to the female gender.

- also please discuss the important percentage of toxic goiter 9% in the group of thyroid cancers

We thank the reviewer for raising this important point. In our study we included 1547 patients who had a total thyroidectomy and whose definitive histology confirmed the presence of thyroid cancer. Among these patients, the indication for total thyroidectomy was a toxic goiter in 9% of cases. However, the definitive histological analysis revealed the presence of a micropapillary cancer in 78.1% (n=107) of cases, a papillary cancer in 18.2%, (n= 25) a follicular tumor in 3% (n=4), and a poorly differentiated contingent in 0.1% (n=1). These results are consistent with data from the literature. Indeed, recent studies suggested a higher risk of cancer in these patients with Graves’ disease, multinodular goiter and toxic nodular goiter (10-20%). Study from Smith JJ et al. (Smith JJ et al. Cancer after thyroidectomy: a multi-institutional experience with 1,523 patients. J Am Coll Surg 2013;216:571-9. Epub February 8, 2013.) found that the total risk of cancer was 16% with with 61 % of cancers inferior than 1 cm.

- The results are relevant but could be greatly improved. Besides the experience of the surgeon and extent of surgery, maybe other factors such as a large volume of the goiters, preoperative compression symtoms could also impact complications, maybe some correlations colud be made, the statistics are very basic

We fully agree with this reviewer that many of other factors could be study. However, due to the retrospective nature of this study, some variables such as suggested compressive signs could not be found for all patients and therefore were not studied. Nevertheless, the volume of the goiter estimated by the weight of the thyroid was studied (table 1) and did not emerge as a predictive factor of postoperative complications (Table 3 and 5).

- how many cases had a malignant cytology result before surgery? how many cases of microcarcinomas did have lymphadenomectomy? it is not clear how and when LN dissection was decided in these case. maybe it should be discussed separately 

We thank the reviewer for raising this important point. Indeed, this is an retrospective study of a historical cohort.  At that time, cytology and per operative ultrasound were much less efficient than today. Thus, only nodules with a positive cytology of malignancy were considered as a suspicious nodule (n=519 (33.5%)). Nodules whose preoperative cytology was in favor of benignity or non-contributive or nodules that did not have preoperative cytology were considered as benign nodule (n=891 (57.6%)). Among microcarcinomas (n=779), 33 (4.2%) underwent a central LND and 5 (0.6%) underwent a lateral LND. As described in the material and methods section, Prophylactic lymph node dissection for the central neck compartment was performed in patients for suspect malignant thyroid tumor with clinically node-negative disease, primarily in the ipsilateral compartment. Therapeutic central neck dissection was performed when abnormal lymphadenopathy was detected during the preoperative or intraoperative examination. In patients with suspect malignant thyroid tumor, lymph node sampling (LNS) for frozen section could be performed in ipsilateral central or lateral compartments. Lateral neck dissection was performed only in patients with cytology-proven metastatic lymph nodes in the lateral neck, including levels II-V

- The discussions are well-documented and well-written

- The font for refernces is not appropriate

The references have been changed follow the MDPI reference guide.

Reviewer 3 Report

The manuscript "Impact of lymph node dissection on postoperative complications of total thyroidectomy in patient with thyroid carcinoma" is an interesting manusript that aims to undersyabd the comorbilities and morbidity of lymph node dissection (LND) in patients with thyroid carcinoma. The manuscript is well structured and well written. With the presented results, the authors demonstrate that LND can increase postoperative morvidity demonstrating the importance of of the procedure in thyroid surgery and in personalized therapy. I believe that un the matherials and methods, the authors should include better the criretia of inclusion and exclusion. The patients selected have other prior malignancies (besides thyroid)? Or these patients were excluded?

Author Response

The manuscript "Impact of lymph node dissection on postoperative complications of total thyroidectomy in patient with thyroid carcinoma" is an interesting manusript that aims to undersyabd the comorbilities and morbidity of lymph node dissection (LND) in patients with thyroid carcinoma. The manuscript is well structured and well written. With the presented results, the authors demonstrate that LND can increase postoperative morvidity demonstrating the importance of of the procedure in thyroid surgery and in personalized therapy. I believe that un the matherials and methods, the authors should include better the criretia of inclusion and exclusion. The patients selected have other prior malignancies (besides thyroid)? Or these patients were excluded?

We thank the reviewer for his/her suggestions about criteria of inclusion and exclusion. As suggested those criteria were clarified in the materials and methods section. Patients with prior malignancy different from thyroid cancer such as esophageal cancer, breast cancer, skin cancer or prostate cancer were included in our study.

Reviewer 4 Report

I have read the paper with great interest which presents a large case series (above 1500 patients) analyzing risk factors following thyroidectomy.

The authors in this case series put benign and malignant lesions in the same paper: we would be happy to understand the rationale for benign lesions that underwent total thyroidectomy instead of near-total or lobectomies. Please explain in the manuscript.

We noticed that the population under study was divided in below and above 45 years old. It would be of interest more stratification of age parameter since we know that thyroid neoplams have a different behaviour especially in pediatric age (<18 years of age) when in comparison with adulthood, hence a different morbidity. Please argument better this aspect.

Please discuss better the option of parathyroid autotransplantation in the light of the statistical difference in the group with and without lymph node dissection. Please explain the potential reasons for this result.

In the discussion section the authors should insert a wider argumentation the risk of complications that are variable with age especially when taking into account <18 years old versus adulthood (please look at - Cervical lymph node metastases of PTC in the central and lateral compartments in children and adolescents: predictive factors -  World J Surgery, 2018 and  Factors associated with postoperative hypocalcemia following thyroidectomy in childhood, Ped Blood Cancer, 2022).

Author Response

I have read the paper with great interest which presents a large case series (above 1500 patients) analyzing risk factors following thyroidectomy.

The authors in this case series put benign and malignant lesions in the same paper: we would be happy to understand the rationale for benign lesions that underwent total thyroidectomy instead of near-total or lobectomies. Please explain in the manuscript.

We thank this reviewer for raising this important point. In our study, we included only patients who underwent total thyroidectomy for benign lesions or suspicious nodules and in whom thyroid cancer was proven by postoperative histological examination. Thus, near-total or lobectomies were excluded from this study. To further clarify the inclusion and exclusion criteria, the materials and methods were revised.

We noticed that the population under study was divided in below and above 45 years old. It would be of interest more stratification of age parameter since we know that thyroid neoplams have a different behaviour especially in pediatric age (<18 years of age) when in comparison with adulthood, hence a different morbidity. Please argument better this aspect.

We thank this reviewer for his/her suggestion. We choose to divided below and above 45 years old because several risk factors for node metastasis in the central compartment have been identified such as young age (<45 years), male gender, and tumor size (Suman P, Surgery, 2016). However as suggested by Tuttle et al. (Tuttle M, Thyroid, 2017) any single cut point for age is likely to perform less well than models that consider age as a continuous variable. Thus, we decided to withdraw the age cutoff and to consider age as a continuous variable to avoid any confusion and since age was not a predictive factor of postoperatives complications. The statistical analysis has been redone and confirms that younger the age increase the risk of permanent hypocalcemia. We also agreed that cancer thyroid carcinoma in pediatric age presents at a more advanced stage with larger primary tumour, more neck lymph node involvement and more distant metastases at diagnosis (Nikiforov et al, Cancer Res, 1997). In our series, 18 patients were less than 18 yo. Among those, 3 (17%) patients presented with transient hypocalcemia none of them had definitive hypocalcemia, and 1 (6%) patient had a transient RLN injury and 1 (6%) patient had a permanent RLN injury. Probably due to the low number of patients < 18 years old, no difference was observed between pediatric age and adulthood for transient hypocalcemia (13.5% vs 16.7%, P=0.725), definitive hypocalcemia (1.7% vs 0%, P=1.0), transient RLN injury (8.9% vs 5.6,; P=1.0) and permanent RLN injury (2.8% vs 5.6%, P=0.407).

Please discuss better the option of parathyroid autotransplantation in the light of the statistical difference in the group with and without lymph node dissection. Please explain the potential reasons for this result.

In our study, the number of parathyroid glands were more frequently auto transplanted in patients with central LND in comparison with those without central LND (46 % vs 9%, P<0.001).  These results are consistent with data from the literature where parathyroids were found in the pathology specimen of 34% of patients and 40% had parathyroids autotransplanted after central LND (Tracy-Ann, Ann Surg 2009). In Indeed, superior parathyroid glands are easier to identify and preserve in situ during central neck dissection because their anatomical location and superior vessels are relatively constant compared to inferior parathyroid glands. For inferior parathyroid glands, we pay particular attention to preserve their vascularization. However, when the inferior glands cannot be preserved at the risk of limiting the extent of the lymph node dissection, the inferior parathyroid glands are auto-transplanted which explain the high rate of parathyroid autotransplantation in the central LND group. However, as described in the literature, we also found that parathyroid autotransplantation increased the risk of post operative hypoparathyroidism but not the risk of permanent hypoparathyroidism (Lo CY et al., Surgery, 2001).

In the discussion section the authors should insert a wider argumentation the risk of complications that are variable with age especially when taking into account <18 years old versus adulthood (please look at - Cervical lymph node metastases of PTC in the central and lateral compartments in children and adolescents: predictive factors -  World J Surgery, 2018 and  Factors associated with postoperative hypocalcemia following thyroidectomy in childhood, Ped Blood Cancer, 2022).

We thank the reviewer for his sound advice and for alerting us to the fact that young age increase the risk of post operative hypoparathyroidism. As previously said, our study includes a very few numbers of patients <18 years old which represents a major limitation for the interpretation of age as a risk factor for postoperative complications.

Round 2

Reviewer 1 Report

Despite the description provided by the authors, I see no novelty in this work. Moreover, the authors concentrate on a dated surgical technique with no clinical significance. The statistical analyses, correlations and comparisons are confusing, not accurate (for example Table 4: main factor for transient hypoparathyroidism is gender and resection of the parathyroid glands) and partially dependent (for example table 4: Parathyroid glands on the specimen and autotranplantation). 

Author Response

We thank the reviewer for his comments. Indeed, we presented in this study a historical cohort of patients undergoing total thyroidectomy with histologically proven thyroid carcinoma. In this study, we deliberately chose to include patients who underwent total thyroidectomy before the introduction of intraoperative neuromonitoring to avoid any bias due to the use of this technique even though neuromonitoring is now routinely used during thyroidectomies in our department. However, no study has yet been able to demonstrate that its use reduces the rate of postoperative paralysis (Davey MG, Am J Surg. 2022). Similarly, we have recently started using indocyanine green to better identify parathyroid glands and their vasculature and avoid postoperative hypoparathyroidism (J Vidal Fortuny, BJS, 2018). However, no study has yet shown that its use can reduce the rate of hypocalcemia.  We agree with the reviewer that more recent studies on the use of these novel techniques are more than necessary to investigate their impact on postoperative complications, but we believe that this was not the purpose of our study.

The statistical analyses were validated by a statistician from our team and consisted first of a univariate analysis of the pre- and postoperative factors of the surgery. Then, predictive factors with a P value <0.2 were considered for the multivariate model using a top-down stepwise binary logistic regression analysis. Here, as the reviewer rightly pointed out, we indeed demonstrated that female gender was an independent risk factor for postoperative hypoparathyroidism. Several studies (Thomusch O, Surgery, 2003; JN Cho, International Journal of Surgery, 2016; A Su, Medicine, 2017; ) and a recent meta-analysis (Chen Z, J Int Med Res. 2021) have demonstrated that female gender has been identified as an independent risk factor for the development of post-thyroidectomy hypocalcemia (16,47,62). However, the mechanism of this phenomenon remains to be determined.

Round 3

Reviewer 1 Report

The arguments of the authors were unfortunately not convincing. Therefore, I could not change my opinion.