Abstract
Introduction
Surgery in the central compartment after previous thyroidectomy involves an increased risk of injury to critical organs, including the parathyroids and recurrent laryngeal nerve. Contrastingly, primary central neck dissection involves a relatively low operative risk.
Objective
This study aimed to compare the outcomes of central neck dissection in primary versus revision settings with respect to the lymph node yield and complication rates.
Methods
This single-center prospective study included patients who underwent primary or revision neck dissection surgery for histologically confirmed thyroid malignancy between January 2018 and January 2022.
Results
We included 30 patients who underwent total thyroidectomy with primary central neck dissection and 29 patients who underwent central neck dissection following remote thyroidectomy with or without previous central dissection. There was no significant between-group difference in postoperative complications, including permanent hypocalcemia and recurrent laryngeal nerve injury. However, both groups showed a significant postoperative decrease in calcium levels even though calcium and parathyroid hormone levels were within reference range.
Conclusion
Although many surgeons fear revision central neck dissection, it appears to have similar therapeutic outcomes and complication rates as primary neck dissection for papillary thyroid cancer. Specifically, there were no between-group differences in the lymph node yield, hypoparathyroidism, or recurrent laryngeal nerve paralysis. Patients with normocalcemia showed a significant postoperative reduction in calcium levels, suggesting subclinical parathyroid insufficiency.
Keywords: Central neck dissection, Thyroid malignancy, Primary neck dissection, Normocalcemia
Key points
The incidence of papillary thyroid cancer has increased by times 3-fold from 1975 to 2009 but this could be in part attributed to early detection of the disease and more frequent use of ultrasound imaging and other modalities of detection.
Central compartment neck dissection is indicated in cases that have clinically or radiologically significant metastatic lymph nodes usually from a primary thyroid tumor or in an elective setting in advanced thyroid and other high-risk tumors.
In a revision setting central or lateral lymph node dissection should be considered when suspecting persistent or recurrent disease, which is defined as central neck nodes sized more than 8 mm and lateral neck nodes are sized more than 10 mm on imaging studies.
Revision central neck dissection is associated with increased morbidity and lower lymph node yield however in this study there no significant difference in post-operative complications, such as permanent hypocalcemia, recurrent laryngeal nerve injury between the 2 groups.
Both groups in the study showed a significantly lower calcium level on the late postoperative tests when compared to preoperative tests, despite still having calcium and PTH levels within normal levels this may be due to parathyroid insufficiency.
Introduction
The central compartment is an area of the neck that is bounded by the two common carotid arteries laterally, and extends superiorly up to the prelaryngeal lymph nodes and down to the upper horn of the thymus. A central compartment neck dissection involves the complete resection of lymph-nodes in that area. it is indicated in cases that have clinically or radiologically significant metastatic lymph nodes usually from a primary thyroid tumor or in an elective setting in advanced thyroid and other high-risk tumors [1].
Over 40,000 cases of papillary thyroid cancer are diagnosed annually [2]. This has only been increasing at a rate of 4.4% per year in the US [3], a trend which is echoed in the Middle East [4]. Surgical treatment for papillary thyroid cancer involves total thyroidectomy with or without central neck dissection. Papillary thyroid cancer tends to spread to the central neck nodes before progressing to lateral cervical and mediastinal nodes. Nodal metastasis is associated with persistence and recurrence of disease, though it is unclear whether it is associated with increased mortality [5].
Primary central neck dissection is often associated with a low operative risk of recurrent laryngeal nerve (RLN) injury, hypoparathyroidism, infection or hematoma formation [6], whereas revision central neck dissection may be associated with increased morbidity and lower lymph node yield [7].
Operating on the central compartment after a previous thyroidectomy holds potentially a higher risk of injury to critical structures such as the parathyroids and recurrent laryngeal nerves. the therapeutic benefit of such a procedure might be compromised by fibrosis in the compartment which might limit the ability to clear pathologic lymph nodes.
The aim/objective of the study was to compare the outcomes of central neck dissections in primary vs. revision setting in terms of lymph node yield, post-operative complications such as permanent hypocalcemia, recurrent laryngeal nerve injury and other complications.
Materials and Methods
All patients with histologically confirmed papillary thyroid malignancy requiring thyroidectomy with at least central compartment lymph node dissection (CND), and patients undergoing central neck dissection after remote thyroidectomy with or without a previous central neck dissection (RCND) were collected. most of the revision cases were done primarily in another center then referred after discovering residual disease. Patients were recruited prospectively at a single tertiary care center, operated on by a single head and neck surgeon and diagnosed by the same pathology team, from January 2018 to January 2022.
Patients were consented for the anonymous use of their data for medical research purpose. Surgery was indicated by following the ATA guidelines: therapeutic CND was indicated in primary or revision setting when there was evidence of positive lymph nodes in the central neck. Prophylactic CND was indicated for advanced thyroid carcinoma (T3 and T4) in the primary setting only. Prophylactic central neck dissection was not performed in revision setting unless completion thyroidectomy was indicated.
The diagnosis of papillary thyroid carcinoma was performed using FNAC. Central neck involvement was defined by ultrasonography in the primary setting. CT neck was used to better localize lymph node disease.
Nuclear imaging was used in the revision setting when previous imaging modalities were not conclusive in the setting of a biologic indicator of a residual disease (such as high thyroglobulin).
Preoperatively, all patients were clinically assessed for vocal cord paralysis by indirect laryngoscopy, and their baseline calcium level was obtained. Calcium was reassessed 1 day postoperatively, and at 6 months follow up. Vocal cord paralysis was assessed clinically at one week post operatively and at 6 months post-operation. In cases of persistent hypocalcemia, parathyroid hormone was obtained 6 months post-operatively.
Outcomes analyzed included transient and permanent hypoparathyroidism, temporary and permanent recurrent laryngeal nerve injury. Hypoparathyroidism was defined as a calcium level below normal as per the institution reference range (8), or if calcium supplements or active vitamin D (one-alpha) replacement are required to maintain normocalcaemia (9) and the presence of a low PTH (10). Permanent hypoparathyroidism was defined as hypoparathyroidism persisting for ≥ 6 months. Permanent RLN injury was defined as the persistence of vocal cord paralysis on clinical exam for ≥ 6 months. recurrent laryngeal nerve injury was defined by laryngoscopy visualization, showing impaired vocal cord mobility.
Therapeutic potential benefit was measured by comparing the total number of lymph nodes and the number of positive nodes identified on histopathology between the 2 groups. All outcomes were compared between the CND and RCND groups. Chi-squared analysis was performed for categorical data, and student’s t-test for continuous data. Paired sample t-test was used whenever applicable. All statistical analyses were performed using the Statistical Package for Social Sciences (IBM SPSS Statistics Version 25).
Other collected data included age, sex and initial tumor stage.
Results
From 2018 to 2022, 30 patients underwent a total thyroidectomy with primary central neck dissection, and 29 patients underwent central neck dissection after a remote thyroidectomy. Table 1 shows the demographic data of both groups.
Table 1.
Demographic characteristics
| Characteristics | Revision Cases | Primary Cases | p value |
|---|---|---|---|
| Group 1 (n = 29) | Group 2 (n = 30) | ||
| Age, years | 39.10 ± 12.55 | 40.16 ± 15.31 | 0.958 |
| Distribution by sex | 0.283 | ||
| Male | 7 | 10 | |
| Female | 23 | 20 | |
| Tumor characteristics | |||
| T1 | 4 (13.7%) | 14 (46.6%) | 0.114 |
| T2 | 7 (24.1%) | 7 (23.3%) | |
| T3 | 12 (41.3%) | 7 (23.3%) | |
| T4 | 1 (3.3%) | ||
| N0 | 5 (17.2%) | 5 (16.6%) | 0.728 |
| N1 | 17 (58.6%) | 24 (80.0%) | |
| Nx | 3 (10.3%) | ||
| M0 | 5 (17.2%) | 4 (13.3%) | 0.458 |
| Mx | 11 (37.9%) | 17 (56.6%) | |
| # Hypocalcemia cases (latest) | 7 (24.1%) | 7 (23.3%) | 1 |
| Preoperative blood parameters | |||
| Ca level (units) | 2.23 ± 0.17 | 2.31 ± 0.18 | 0.297 |
| Phosphate (units) | 1.29 ± 0.29 | 1.53 ± 0.29 | 0.177 |
Data are presented as mean ± standard deviation or n (%)
In the revision cases the average age was 39.10 ± 12.55, predominantly female with M: F ratio of 1:3.8. In the primary case group, the mean age was 40.16 ± 15.31, and again women made the majority of the group with a M: F ratio 1:3.
In the revision’s cases group, 27 out of the 29 patients underwent central neck dissection for positive lymph nodes for papillary thyroid carcinoma. 2 patients underwent RCND for an advanced T stage while performing completion thyroidectomy and 2 patients underwent the RCND for a suspicious mass in the central neck rather then LN disease. The post operative histopathological in the revision group shows that 27 out of the 29 patient had a papillary lymph node metastasis with 2 patients having no histopathological significant lymph nodes.
While in the primary case group 29 out of the 30 patients underwent central neck dissection for clinically significant lymph nodes due to papillary thyroid carcinoma, and the last patient had an advanced T stage requiring prophylactic dissection.
Staging at the primary surgery was not available for all of the revision cases, as some were done at other institutions and records were not available. The stage distribution was not significantly different between the 2 groups.
Table 2 shows the post-operative outcomes of both groups.
Table 2.
Postoperative outcomes
| Characteristics | Revision Cases | Primary Cases | p value |
|---|---|---|---|
| Group 1 | Group 2 | ||
| Ca level (postoperative level – preoperative level) |
-0.13 ± 0.24, Paired sample p = 0.012 |
-0.13 ± 0.22, Paired sample p = 0.016 |
0.793 |
| Recent Ca levels | 2.12 ± 0.20 | 2.18 ± 0.12 | 0.511 |
| Recent Parathyroid hormone levels | 37.68 ± 24.4 | 37.68 ± 24.39 | 0.338 |
| Positive central compartment yield | 4.41 ± 4.64 | 5.13 ± 5.35 | 0.795 |
| Vocal cord paralysis | 0 (0%) | 3 (10.0%), later 0 (0%) | 1.00 |
Data are presented as mean ± standard deviation or n (%)
When comparing the preoperative to the late postoperative calcium level it was noticed that there was a consistent decrease in calcium levels in each group. The revision group had a difference of -0.13 ± 0.24 mmol/dl(p = 0.012) and primary group had a difference of -0.13 ± 0.22 mmol/dl (p = 0.016). There was no significant difference in the amount of calcium level reduction between the groups (p = 0.793).
The same analysis was repeated after excluding permanent hypo parathyroid patients, for both groups combined. it was found that post operatively, the calcium levels decreased significantly by -0.13 ± 0.23 mmol/dl (p = 0.00) for the whole group of normocalcemic patients as shown in Table 3.
Table 3.
Preoperative and postoperative calcium levels [r2] for the whole group
| Characteristics | Postoperative | Preoperative | MD, p value |
|---|---|---|---|
| Ca levels | 2.12 ± 0.20 | 2.26 ± 0.17 | -0.13 ± 0.23, 0.00 |
Data are presented as mean ± standard deviation
MD: Mean difference
In terms of other postoperative complications, there were no cases of permanent vocal cord paralysis in both groups. 3 patients in the primary group and none in the revision group developed transient vocal cord paralysis, all of whom recovered at latest follow up. One patient in each group developed a transient chyle leak that resolved with supportive measures. Chyle leak in both patients was a result of an associated lateral neck dissection and not central neck dissection. There were no postoperative mortality cases. (Table 2)
Table 4 shows the central compartment yield, the revision group yielded a mean of 11.16 ± 7.76 lymph nodes (LN) while the primary yielded a mean of 13.63. ± 7.80 LN. The number of LN was non-significantly less in the revision group.
Table 4.
Central compartment yield
| Characteristics | Revision Cases | Primary Cases | p value |
|---|---|---|---|
| Group 1 | Group 2 | ||
| Total Central compartment yield (whole group) | 11.16 ± 7.76 | 13.63 ± 7.80 | 0.216 |
| Total Central compartment yield (excluding second revision cases) | 12.47 ± 7.34 | 15.13 ± 8.37 | 0.706 |
To mention that 9 of the 29 revision cases were reported to have previous neck dissection during the primary surgery including the central compartment which would lower the LN yield as some lymph nodes were already removed.
When excluding those patients, the number of LN in revision group increased to 12.47 ± 7.34 (vs. 15.13 in the primary group).
The mean days from primary to revision surgery in revision group was calculated to be around 982.7 ± 1907.4 days (range 14- 8119 days).
Discussion
DTC accounts for more than 90% of all thyroid cancers, which includes most commonly the papillary thyroid carcinoma then followed by follicular carcinoma. PTC is mostly seen in women; it has a female to male ratio of approximately 2.5:1. The incidence of papillary thyroid cancer has increased by 3-fold from 1975 to 2009 but this could be in part attributed to early detection of the disease and more frequent use of ultrasound imaging and other modalities of detection. Even with a rising incidence mortality has not changed significantly [11, 12]. Recurrence in the cervical lymph nodes is most often the result of persistent disease after therapy and often leads to an increased mortality in high-risk patients.
Ultrasound to date remains the preferred modality for the evaluation of central and lateral neck lymph nodes for all patient with malignant finding on FNAC, however other imaging modalities such as CT and MRI may be considered when dealing with advanced disease as to identify the extent of locoregional structures. iodine scan is a highly specific test for differentiated thyroid cancer after total thyroidectomy. FDG PET scan however is not routinely recommended in the current guidelines but it may show neck involvement, mediastinal involvement and distant metastases in certain dedifferentiated cancer patients, when iodine avidity is believed to be lost [11].
In the setting of a primary thyroidectomy for differentiated thyroid cancers, the American thyroid association recommends central neck dissection for all patients with evidence of central neck lymph node disease and for patients with T3 and T4 disease in an elective setting. In a revision setting central or lateral lymph node dissection should be considered when suspecting persistent or recurrent disease, which is defined as central neck nodes sized 8 mm or more and lateral neck nodes are sized 10 mm or more, on imaging studies. RAI therapy for gross recurrent disease, identified on imaging, is not preferred for resectable disease [11].
In the matter of disease recurrence however, the surgeon must be more cautious when deciding whether or not to perform a secondary central neck dissection. In certain cases, there may be very minimal disease progression, yet in other cases initially well differentiated malignancies can progress into more aggressive disease with higher mortality (2, 7). A low risk of complications in reoperation may suggest that surgeons can be comfortable performing a revision central neck dissection. a curability benefit should as well be confirmed from revision surgery to advocate it.
Central compartment dissection is commonly done alongside the thyroidectomy in the treatment of papillary thyroid cancer. Historically its importance was emphasized by Hoie et al. where 730 patients underwent central neck dissection for papillary and medullary thyroid cancer between 1956 and 1978. They reported a low recurrence rate of differentiated thyroid cancer of around 15% [13]. Tissel et al. also highlighted that central lymph node dissection was able to keep recurrences and mortality to a minimum and that implementing it in their surgical strategy helped improve clinical outcomes [14].
A meta-analysis by Urken et al. explored the management of persistent or recurrent well differentiated thyroid cancer, the results showed that revision cases had a 1.2% incidence of permanent RLN paralysis, and a 3.5% incidence of permanent hypoparathyroidism, while the remission rates were between 20 and 61% [7].
In the retrospective review done by Hall et al., 30 prophylactics and 35 therapeutic interval central lymph node dissections were compared to 218 patients who underwent primary total thyroidectomy and central lymph node dissection. They measured the number of lymph nodes removed, the incidence of permanent hypoparathyroidism and the incidence of recurrent laryngeal nerve injury. The results showed that there were similar rates of cervical lymph node metastasis and post-operative complications in both groups [2].
Classically hypoparathyroidism is defined as hypocalcemia related to low PTH. In our study we defined 3 patients who fit such a definition. but after excluding those permanent hypoparathyroid cases of both groups, our study showed a significantly lower calcium level on the late postoperative tests when compared to preoperative tests, despite still having calcium and PTH levels within normal levels. In fact, the ATA defines a group of symptomatic hypo parathyroid patients with normal calcium levels, defined as parathyroid insufficiency [10]. such a category, shows us the limitation of the mere calcium and PTH level range to define hypoparathyroidism.
The significance of less functional parathyroid tissue while remaining asymptomatic and preserving a low normal calcium level, could reside in the long-term effect on bone metabolism, risk of osteoporosis and fracture risk. Lower calcium levels were previously documented after hemithyroidectomy. this was explained by the effect of a reduced thyroid hormone level on bone resorption and kidney reabsorption of calcium. this is unlikely in our group of patients as all of our patients are on a rather suppressive thyroxine dose for tumor control [15, 16]. We herein suggest that thyroidectomy patients should be more studied to understand the possible long-term effect of mild parathyroid insufficiency on the body physiology.
Our study results are similar to the current literature. There was no significant difference in post-operative complications, such as permanent hypocalcemia, recurrent laryngeal nerve injury between the 2 groups. Interestingly, there was a high rate of transient vocal cord paralysis (3 patients) in the primary group and none in the secondary groups. This shows the relative safety of reoperating on the central neck on the laryngeal nerves. recurrent laryngeal nerves are frequently injured at the berry’s ligament insertion of the thyroid gland during thyroidectomy and not necessarily during dissection of lymph nodes. This might explain those cases of transient weakness in the primary group but not the secondary group. Ultimately all of these cases recovered.
Current literature on the topic of central neck dissection in revision setting is still limited. Accurately defining the mean incidence of complications and therapeutic effect may require larger groups of patients. This may also allow a more statistically significant comparison between the two groups. Histological features were not analyzed in our study as pathological reports and specimen from the primary surgery in the revision group were frequently missing or incomplete when available.
Conclusion
Despite re-operative central neck dissection being approached with special care by many surgeons, therapeutic outcomes and complication rates appear to be similar to primary neck dissection for papillary thyroid cancer. In accordance with current literature, we found no difference between primary or revision central neck dissections in terms of lymph node yield, hypoparathyroidism or recurrent laryngeal nerve paralysis. patients within the range of normocalcemia had a significantly reduced calcium levels, suggesting a subclinical parathyroid insufficiency.
Acknowledgements
We would like to thank Editage (www.editage.com) for English language editing and journal submission support. The authors have authorized the submission of this manuscript through Editage.
Declarations
Ethical Approval
Ethical Approval was obtained from the institutional review board of King Hamad University Hospital (approval no. 20–353).
Footnotes
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References
- 1.Carty SE, Cooper DS, Doherty GM, Duh Q-Y, Kloos RT, Mandel SJ et al (2009) Consensus Statement on the Terminology and Classification of Central Neck Dissection for Thyroid Cancer [Internet]. Available from: www.liebertpub.com [DOI] [PubMed]
- 2.Hall CM, LaSeur DC, Snyder SK, Lairmore TC. Reoperative central lymph node dissection for incidental papillary thyroid cancer can be performed safely: a retrospective review. Int J Surg. 2018;56:102–107. doi: 10.1016/j.ijsu.2018.06.015. [DOI] [PubMed] [Google Scholar]
- 3.Lim H, Devesa SS, Sosa JA, Check D, Kitahara CM, JAMA - Journal of the American Medical Association (2017) Trends in thyroid cancer incidence and mortality in the United States, 1974–2013 [Internet]. Vol. 317,. American Medical Association; [cited 2021 Apr 19]. p. 1338–48. Available from: https://pubmed.ncbi.nlm.nih.gov/28362912/ [DOI] [PMC free article] [PubMed]
- 4.Aljabri KS, Bokhari SA, al Shareef MA, Khan PM An 18-year study of thyroid carcinoma in the western region of Saudi Arabia: A retrospective single-center study in a community hospital. Annals of Saudi Medicine [Internet]. 2018 Sep 1 [cited 2021 Apr 19];38(5):336–43. Available from: https://pubmed.ncbi.nlm.nih.gov/30284988/ [DOI] [PMC free article] [PubMed]
- 5.Hughes DT, Doherty GM. Central neck dissection for papillary thyroid cancer. Cancer Control. 2011;18(2):83–88. doi: 10.1177/107327481101800202. [DOI] [PubMed] [Google Scholar]
- 6.Kim MK, Mandel SH, Baloch Z, Livolsi VA, Langer JE, Didonato L et al (2004) Morbidity Following Central Compartment Reoperation for Recurrent or Persistent Thyroid Cancer [Internet]. Vol. 130, Arch Otolaryngol Head Neck Surg. Available from: http://archotol.jamanetwork.com/ [DOI] [PubMed]
- 7.Urken ML, Milas M, Randolph GW, Tufano R, Bergman D, Bernet V et al (2015) Management of recurrent and persistent metastatic lymph nodes in well-differentiated thyroid cancer: a multifactorial decision-making guide for the thyroid cancer care collaborative. Head and Neck, vol 37. John Wiley and Sons Inc., pp 605–614 [DOI] [PubMed]
- 8.Chisholm EJ, Kulinskaya E, Tolley NS. Systematic review and meta-analysis of the adverse effects of thyroidectomy combined with central neck dissection as compared with thyroidectomy alone. Laryngoscope. 2009;119(6):1135–1139. doi: 10.1002/lary.20236. [DOI] [PubMed] [Google Scholar]
- 9.Lamartina L, Borget I, Mirghani H, al Ghuzlan A, Berdelou A, Bidault F, et al. Surgery for neck recurrence of differentiated thyroid cancer: outcomes and risk factors. J Clin Endocrinol Metab. 2017;102(3):1020–1031. doi: 10.1210/jc.2016-3284. [DOI] [PubMed] [Google Scholar]
- 10.Orloff LA, Wiseman SM, Bernet VJ, Fahey TJ, 3rd, Shaha AR, Shindo ML, Snyder SK, Stack BC, Jr, Sunwoo JB, Wang MB. Thyroid. 2018;28(7):830–841. doi: 10.1089/thy.2017.0309. [DOI] [PubMed] [Google Scholar]
- 11.Haugen B, Alexander E, Bible K, Doherty G, Mandel S, Nikiforov Y, Pacini F, Randolph G, Sawka A, Schlumberger M, Schuff K, Sherman S, Sosa J, Steward D, Tuttle R, Wartofsky L. 2015 american thyroid Association Management Guidelines for adult patients with thyroid nodules and differentiated thyroid Cancer: the american thyroid Association Guidelines Task Force on thyroid nodules and differentiated thyroid Cancer. Thyroid. 2016;26(1):1–133. doi: 10.1089/thy.2015.0020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Uptodate.com. (2021) UpToDate. [online] Available at: <https://www.uptodate.com/contents/papillary-thyroid-cancer-clinical-features-and-prognosis? [Accessed 19 May 2021]
- 13.Hoie J, Stenwig AE, Brennhord IO Surgery in papillary thyroid carcinoma: a review of 730 patients. J Surg Oncol 1988 7 147–151. (10.1002/jso.2930370302) [DOI] [PubMed]
- 14.Tisell LE, Nilsson B, Mo¨lne J, Hansson G, Fja¨lling M, Jansson S, Wingren U. Improved survival of patients with papillary thyroid cancer after surgicalmicrodissection. World J Surg. 1996;20:854–859. doi: 10.1007/s002689900130). [DOI] [PubMed] [Google Scholar]
- 15.Lindblom P, Valdemarsson S, Lindergård B, Westerdahl J, Bergenfelz A. Decreased levels of Ionized Calcium One Year after Hemithyroidectomy: importance of reduced thyroid hormones. Hormone Res Paediatrics. 2001;55(2):81–87. doi: 10.1159/000049975. [DOI] [PubMed] [Google Scholar]
- 16.Bergenfelz A, Ahr, eacuten B. Calcium metabolism after Hemithyroidectomy. Horm Res. 1993;39(1–2):56–60. doi: 10.1159/000182696. [DOI] [PubMed] [Google Scholar]