Rate of occult neck nodal metastasis in primary and salvage laryngectomy

However, survival and outcome data have since been recorded for patients prospectively and form part of an ongoing prospective study.


| INTRODUCTION
The role of neck dissection (ND) in advanced laryngeal cancer remains controversial. 1 Cervical nodal metastases confer a worse prognosis with higher rates of local recurrence and reduced overall survival observed in this population. 2 Elective ND for clinically node negative (N0) patients during laryngectomy has been associated with reduced rates of regional recurrence 3 ; however, the addition of this surgical intervention introduces risk of complications including accessory nerve injury, wound healing issues and infection. 1 Select European society guidelines, such as the German guidelines for treatment of laryngeal cancer, recommend ipsilateral ND for lateralised laryngeal malignancy and bilateral ND for midline lesions, 4 while guidelines in the United Kingdom and the National Comprehensive Cancer Network (NCCN) in the United States offer more broad recommendations encompassing numerous surgical options. 5 In salvage laryngectomy, the role of N0 elective ND remains equally ambiguous. 1 The overall rate of occult metastasis following salvage laryngectomy with ND has been reported as 3%-19%. 3 Many studies pre-date the development of advanced radiological investigations and therapeutic techniques. Recent attempts at meta-analysis found only three papers suitable for inclusion in pooled analysis. 6

| Objective
To assess the rate of occult metastasis in ND specimens following both primary and salvage laryngectomy. We aim to correlate the preoperative radiological staging with final histological stage to determine the role of elective ND in the N0 setting in laryngectomy.

| METHODS
Following local ethical approval, a retrospective review of all patients who underwent laryngectomy at our institution between 2009 and 2019 was conducted. The study setting is a national, tertiary referral head and neck cancer centre. Patients were identified using the hospital electronic coding database (Hospital In-Patient Enquiry system [HIPE]) using search terms 'total laryngectomy', 'laryngectomy', 'partial laryngectomy', 'hemi-laryngectomy', 'laryngopharyngectomy', 'pharyngo-laryngo-oesophagectomy' and any relevant derivatives.
Patients met inclusion criteria if they underwent laryngectomy during the study period for laryngeal squamous cell carcinoma.
Patients who underwent laryngectomy for pathology outside the larynx (e.g., cervical oesophagus or hypopharynx) or with pathology other than SCC (e.g., sarcoma) were excluded. Patients designated as N0 on pre-operative radiological investigation but with N+ final histology were considered to have occult metastases, and patients with evidence of nodal disease on pre-operative investigation were excluded. Data collected included basic demographic data (age, sex), pre-operative radiological staging (CT, MRI or PET-CT), operative details, and final histological results. Staging for pathology and radiology was completed using the AJCC 8th edition.
All patients were discussed at the institutional multi-disciplinary

| Patient characteristics
A total of 124 patients were identified from the institutional database using the search criteria. Following case review, 8 patients were excluded due to non-larynx primary (n = 7) or non-SCC pathology (n = 1) and 48 patients were excluded for pre-operative node positive disease. Of the 68 patients included in the final analysis, the mean age at presentation was 62.1 years ±9.8, with 84% (n = 68) of patients being male.
No patients had undergone prior ND.
The mean depth of invasion was 12.9 ± 7 mm. Mean number of lymph nodes in ND was 36.1 ± 25 nodes. Amongst patients with N+ disease, the mean number of positive nodes was 0.6 ± 2 nodes.
In the primary laryngectomy cohort the most common final histological staging was T4 (83.3%) and N0 (73.3%). A full break-down can be found in Table 1.
• The risk of occult nodal disease is higher in the primary setting, when compared with the salvage setting (26.6% and 7.9%, respectively).
• Neck dissections at the time of laryngectomy can be considered in the N+ and primary laryngectomy setting, and can be avoided in the salvage setting.
• Where the decision has been made to perform a concomitant neck dissection at the time of laryngectomy, consideration could be given to performing a limited and unilateral neck dissection to reduce morbidity.
• No good prospective data exists to make strong recommendations for how to manage the neck in laryngeal malignancies.
site did not influence the risk of nodal disease (p = .168), whereas the size of the primary site did (p = .003). There was no correlation between T-stage and N-stage (p = .199).

| DISCUSSION
The present study aimed to assess the rate of occult metastases in patients undergoing total laryngectomy, both in the primary and salvage setting. We highlight a relatively low rate of overall occult metastases overall at 16.8%, however a high rate of occult disease in the primary laryngectomy setting (26.6%) signalling a role for further investigation to determine the optimal application of ND in laryngectomy for N0 patients.
Previously reported rates of occult metastasis in salvage laryngectomy range from 3% to 19%, in keeping with our results. 1,7 We found no association between tumour stage and rates of nodal metastasis or occult metastasis in our series. Similarly, there were no differences noted based on prior treatment protocols or imaging modality used. Three patients (7.9% of the salvage cohort) with pre-operative N0 radiological staging were subsequently found to be N+ on final histology.
An increased risk of treatment-related complications following ND is well-established, particularly in salvage laryngectomy. Serious complications have been shown to occur more frequently where concomitant ND is performed during salvage surgery, including pharyngocutaneous fistula formation. 7 We demonstrate a rate of occult metastasis of 16.8% overall but only 7.9% in the salvage laryngectomy cohort in our study. Given the very low rate of occult metastasis in this group, these data make a case for reserving ND only for patients with N+ pre-operative scan to reduce rates of surgical complication.
One recent, large systematic review and meta-analysis of 1353 patients from 19 series demonstrated an overall rate of occult metastasis of 14% following laryngectomy. 3 No statistically significant difference in disease-specific or overall survival was demonstrated when comparing ND to observation. A higher risk of surgical complications was observed when ND was performed (relative risk 1.29), however, risk of regional recurrence was reduced compared with observation (relative risk 0.62). 3 The authors of the study recommend a 'tailored, patient-specific approach' based upon 'patient factors, patient preference and tumour characteristics' to guide decision-making regarding ND. 3 Given ND did not alter DSS or OS and increased complications, however, we suggest that the role for ND in the N0 neck in the salvage setting should be examined more critically.
Where the decision has been made to perform a concomitant ND at the time of laryngectomy, consideration could be given to performing a limited and unilateral ND to reduce morbidity. 1  Spread to level IV has been described as occurring between 3.9% and 7.1%, 8 with some authors advocating for omission of level IV during ND for laryngeal malignancies. Our data support these reports which suggest a role to reduce patient exposure to the morbidity of ND on a selective basis.
The authors acknowledge that any attempt at surgery for nodal recurrence after salvage laryngectomy presents a major surgical challenge with potential for incomplete resection and complications.
Oncological outcomes for salvage surgery of neck recurrences is notably poor, reported previously as producing only a 9% control rate in salvage laryngectomy patients. 9 The present study has several limitations, including the lack of survival and outcome data. Survival data was only available for less than half of the patients in the dataset, so was excluded. Outcome data, specifically looking at complications relation to surgery was also incompletely recorded. Length of stay was available for all patients, however, had significant limitations, as it included waiting on step-down facilities, pre-operative investigations and did not accurately represent the risk for surgery-related complications.
However, survival and outcome data have since been recorded for patients prospectively and form part of an ongoing prospective study.

| CONCLUSION
We demonstrate a low risk of occult metastatic nodal disease in patients undergoing laryngectomy, particularly in the salvage setting.
It may be prudent, especially in the clinically N0 salvage setting, to forgo elective ND to reduce surgical complications. High rates of occult disease in the primary laryngectomy setting may still prompt an elective ND in this cohort. ACKNOWLEDGMENT Open access funding provided by IReL.

CONFLICT OF INTEREST
The authors have no conflicts of interest to disclose.

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1111/coa.14032.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.