Rate of occult neck nodal metastasis in primary and salvage laryngectomy.

Abstract

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 recurrence3; 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 To assess the rate of occult metastasis in ND specimens following both primary and salvage laryngectomy. We aim to correlate the pre-operative radiological staging with final histological stage to determine the role of elective ND in the N0 setting in laryngectomy. 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 meeting (MDT) prior to undergoing surgery. Radiology and pathology results were verified by a board-certified specialist with subspecialist interest in head and neck oncology. Typical institutional practice is to complete a level II–IV and level VI ND in laryngectomy cases, with dissection of level I and V reserved for cases where pathological nodes are apparent in these areas. Statistical analysis was performed using IBM® SPSS® version 26 (IBM, SPSS Inc., New York). Pearson's chi-squared test was used to compare two categorical variables, with Bonferroni correction used to compare column proportions. Analysis of variance (ANOVA) was used to compare means amongst several groups, with Bonferroni correction used for post hoc analysis. Correlation between categorical and continuous variables was performed using Point-Biserial correlation. All results are reported as mean ± standard deviation (SD), unless otherwise specified. Statistical significance was assumed when p ≤ .05. 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. Primary laryngectomy was completed in 44.1% (n = 30) while salvage surgery was completed in 55.9% (n = 38). In the salvage laryngectomy group, prior treatment included radiotherapy alone in 55.3% (n = 21), with 44.7% (n = 17) receiving chemoradiotherapy. No patients had undergone prior ND. Pre-operative radiological investigations included PET-CT in 86.8% (n = 59), separate CT neck with contrast in 67.6% (n = 46), and MRI in 52.9% (n = 36). The mean size of the primary laryngeal tumour was 13.3 ± 17 mm. Pre-operative staging was recorded as T4 in 52.9% (n = 36), T3 in 13.2% (n = 9), T2 in 19.1% (n = 13) and T1 in 14.7% (n = 10). Only salvage laryngectomy patients were staged T1 or T2 pre-operatively. Nodal staging was N0 in all patients, according to exclusion criteria (Table 1). All patients (n = 68) underwent total laryngectomy. Of those patients, 61 patients (89.7%) underwent unilateral ND. A bilateral ND was performed in 75.0% (n = 51) of cases. A total of 112 ND were included for final analysis. Of the patients that did not have a ND at the time of their laryngectomy (n = 7), one patient underwent subsequent ND for possible nodal recurrence, but remained N0 on final histology following ND. Histological staging for the overall group (n = 68) was T4 in 57.4% (n = 39), T3 in 17.6% (n = 12), T2 in 14.7% (n = 10), and T1 in 10.3% (n = 7). Nodal staging was N0 in 83.8% (n = 57), N1 in 5.9% (n = 4), N2 in 8.8% (n = 6) and N3 in 1.5% (n = 1) (Table 1). The mean size of the primary laryngeal tumour on final histology was 28.1 ± 11 mm. 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. In the salvage laryngectomy cohort the most common final histological staging was T4 (36.8%) and N0 (92.1%) (Table 1). The risk for occult nodal metastases was 16.2% (n = 11/68) of total cases, a rate of 26.6% (n = 8/30) for the primary group and 7.9% (n = 3/38) for the salvage group. Within this cohort, all patients had undergone pre-operative radiological investigation, which included PET-CT in 86.8% (n = 59), separate CT neck with contrast in 67.6% (n = 46), and MRI in 52.9% (n = 36). Depth of invasion the primary 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). 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 Risk of contralateral nodal involvement for lateral laryngeal lesions is as low as 4%.8 A very low rate of level IIB metastasis (1.7%) has been established in earlier studies, with recent randomised data supporting omission of level IIB to reduce impairment of shoulder function.8 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. 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. Justin M. Hintze, Conall W. R. Fitzgerald, Bronagh Lang and Amy Hannigan devised the project, collected the data, interpreted the data, drafted and approved the final version of the manuscript. John Kinsella, Paul Lennon and Conrad Timon interpreted the data, revised and approved the final version of the manuscript. Open access funding provided by IReL. The authors have no conflicts of interest to disclose. Ethics from St James' - Tallaght University Hospital Joint Ethics Board. The peer review history for this article is available at https://publons.com/publon/10.1111/coa.14032. The data that support the findings of this study are available from the corresponding author upon reasonable request.