Management of paratracheal lymph nodes in laryngeal cancer with ...

Received: 7 October 2016

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Revised: 7 March 2017

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Accepted: 28 June 2017

DOI: 10.1002/hed.24905

ORIGINAL ARTICLE

Management of paratracheal lymph nodes in laryngeal cancer with subglottic involvement Marco Lucioni, MD1 | Luca D’Ascanio, MD2 Marco Lionello, MD1

| Elena De Nardi, MD1 |

| Andy Bertolin, MD1 | Giuseppe Rizzotto, MD1

Department of Otolaryngology – Head and Neck Surgery, Vittorio Veneto Civil Hospital, Vittorio Veneto, Italy 1

Department of Otolaryngology – Head and Neck Surgery, “Carlo Poma” Civil Hospital, Mantova, Italy 2

Correspondence Luca D’Ascanio, Department of Otolaryngology – Head and Neck Surgery, “Carlo Poma” Civil Hospital, Strada Lago Paiolo, 10 - 46100 Mantova, Italy. Email: [email protected]

Abstract Background: The purpose of this study was to present our findings on the involvement of paratracheal lymph nodes in laryngeal squamous cell carcinoma (SCC) with subglottis extension, which is controversial. Methods: We assessed 196 patients with laryngeal SCC involving the subglottis, treated with open laryngeal surgery with or without paratracheal neck dissection (PTND). The relationship of the paratracheal lymph node metastatic pattern with laterocervical nodal status and tumor location within different subglottic subsites was analyzed. The influence of PTND on regional disease control was assessed. Results: Paratracheal lymph nodes were affected in 12.2% of cases. An increased frequency (P 5 .064) of paratracheal metastasis was noticed in case of anterior subglottis extension with respect to other subsites. A correlation (P < .001) between paratracheal lymph node and laterocervical node involvement was found among subjects with posterior subglottic extension. Conclusions: Prophylactic PTND is indicated in laryngeal SCC with anterior subglottic extension and/or posterior subglottis involvement with clinically apparent laterocervical node metastases. KEYWORDS laryngeal cancer, neck dissection, paratracheal node metastasis, subglottis, surgical indications

1 | INTRODUCTION Head and neck cancers have a proclivity to metastasize to the lymph nodes in the neck rather than spread hematogenously. The prevalence and distribution of lymph node involvement depends mainly on the site and size of the primary tumor.1 As with other head and neck neoplasms, metastatic nodal disease is the most important prognostic factor for laryngeal cancer.2 Accepted surgical treatment of macroscopic node metastatic disease usually involves radical or modified radical neck dissection, whereas in the clinically negative (cN0) neck, selective neck dissection is recommended if the risk of microscopic disease exceeds 20%.2 Head & Neck. 2017;1–10.

Even though several studies have been carried out to assess the frequency and pattern of microscopic node metastasis in the lateral cervical lymph nodes, controversies still exist about the involvement of paratracheal lymph nodes in head and neck cancers. The paratracheal lymph nodes are part of the central compartment, also referred to as the anterior compartment of the neck or cervical lymph node level VI. The anatomic borders of paratracheal lymph nodes are represented by the medial edge of the common carotid artery (lateral border), the tracheal wall (medial border), the inferior cricoid edge (cranial border), and the suprasternal notch, which is considered to be the caudal border.3,4 Despite such boundaries, the anatomic conformation of the thoracic inlet in different

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patients varies. Therefore, the paratracheal lymph nodes and the superior mediastinal lymph nodes are not separated by a constant anatomic landmark that can be consistently identified radiologically or during surgery, which makes the comparison of different studies extremely difficult.1 Furthermore, paratracheal lymph nodes are not included in radical, modified radical, or selective dissection of the lateral neck (levels I-V). Therefore, the results on paratracheal lymph nodes’ oncologic involvement in various studies should be compared with some caution. Because the status of the cervical lymph nodes is the single most important tumor-related prognostic factor, it is of great importance for an optimal treatment plan to know the exact involvement rate of all the cervical nodes (also considering paratracheal lymph nodes’ metastases may develop independently from lymph node metastases in other levels).1,5 If node metastases are present, it is obvious that treatment, usually lymph node dissection or irradiation, is required. However, management of clinically negative lymph nodes is controversial: in case of probable occult (clinically undetectable) node metastases or when the patient will be unavailable for regular/adequate follow-up, a choice must be made between elective treatment and watchful waiting. These policies harbor the risk of undertreatment or overtreatment, which may affect survival and morbidity.1 The reported prevalence of paratracheal lymph node metastasis in laryngeal cancer ranges between 9% and 27%.1 Even though several studies have been published on paratracheal lymph node involvement in cancer of the hypopharynx, cervical esophagus, and larynx, controversies still exist about the involvement of paratracheal lymph nodes in laryngeal cancer with subglottis extension.6 Primary cancers arising in the subglottic region are anecdotal. Kleinsasser7 even doubted the existence of primary subglottic carcinomas. Almost invariably, the subglottis is reached by tumors arising in the glottis or supraglottis through a caudal transglottic growth or paraglottic space invasion.6 Involvement of the subglottis seems to be associated with a relatively high frequency of lymphatic spread to the paratracheal lymph nodes and stomal recurrences, which significantly affect patients’ survival.6,8 Despite such findings, the risk of paratracheal metastasis is often underestimated before laryngeal surgery because paratracheal lymph nodes are difficult to be detected by palpation and preoperative imaging, such as ultrasound, CT, MRI, and fluorodeoxyglucose-positron emission tomography. Clarifying the frequency of paratracheal lymph node involvement in those cases has a crucial importance to determine the need of paratracheal neck dissection (PTND) for the most appropriate surgical treatment of tumors affecting the subglottis. The necessity to define some indications for PTND has increased in our experience after the development by our group of supratracheal laryngectomies for the treatment of laryngeal

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tumors with subglottis extension as an alternative to total laryngectomy.9–12 In the attempt to clarify these issues, we carried out a retrospective study on a cohort of patients with laryngeal squamous cell carcinoma (SCC) involving the subglottis treated with laryngeal surgery (supratracheal horizontal laryngectomy, total laryngectomy, and glottic-subglottic laryngectomy) with or without PTND. We analyzed the paratracheal nodal yield, metastatic rate, and the relationship with laterocervical nodal status in the different surgical subgroups to assess the possible relationship between tumor location within the different subglottic subsites and paratracheal lymph nodes metastatic pattern (primary outcome). We also evaluated the effects of PTND on paratracheal disease control in the different surgical subgroups (secondary outcome) in the attempt to draw some conclusions on the indications to PTND in laryngeal cancers with subglottic extension.

2 | PATIENTS AND METHODS 2.1 | Patients Between 1999 and 2011, 196 patients were submitted to laryngeal surgery for laryngeal SCC affecting the subglottis at the Department of Otolaryngology-Head and Neck Surgery of Vittorio Veneto Laryngeal Cancer Center, Italy (Table 1). Patients were included on the basis of postoperative histological examination demonstrating the involvement of the subglottic area. We considered the subglottis as the region extending from an ideal horizontal line running along the doubling of the fibroelastic membrane, about 10 mm caudally to the medial edge of the true vocal folds (superior boundary), to the lower border of the cricoid cartilage (inferior boundary; Figure 1).13,14 Tumor involvement of the cricoarytenoid unit was considered as an extension to the subglottis because the cricoarytenoid unit is composed of the arytenoid, the cricoarytenoid joint, and the underlying hemicricoid plate (Figure 1).10–12 Preoperative assessment included videolaryngoscopy, biopsy, and neck and chest CT scan with contrast. Additional examinations (larynx and neck MRI with contrast or positron emission tomography) were carried out in selected cases. According to an accepted diagnostic algorithm,15 our radiological evaluation included the assessment of: (a) the minimal and maximal axial diameters of all paratracheal lymph nodes; (b) the capsular contour irregularity and/or infiltration; (c) the presence of central necrosis and/or heterogeneity on T2-weighted MRIs. The preoperative records, radiologic images, as well as all surgical specimens were retrospectively reviewed to allow the reclassification of all cases according to the Union for

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T A BL E 1

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Characteristics, T classification, and treatment history of the study population

Variables

OPHL type IIIa, group A (n 5 76)

OPHL type IIIa, group B (n 5 24)

Total laryngectomy (n 5 84)

Glottic-subglottic laryngectomy (n 5 12)

Total (n 5 196)

69 (90.79%) 7 (9.21%)

23 (95.83%) 1 (4.17%)

78 (92.86%) 6 (7.14%)

11 (91.67%) 1 (8.33%)

181 (92.35%) 15 (7.65%)

10 (13.16%) 15 (19.73%) 35 (46.05%) 13 (17.11%) 3 (3.95%)

2 (8.33%) 7 (29.17%) 12 (50.00%) 3 (12.50%) 0 (0%)

5 (5.95%) 13 (15.48%) 25 (29.76%) 28 (33.33%) 13 (15.48%)

1 2 6 2 1

18 37 78 46 17

0 (0%) 24 (31.58%) 39 (51.31%) 13 (17.11%)

0 (0%) 5 (20.83%) 17 (70.84%) 2 (8.33%)

2 (2.38%) 2 (2.38%) 32 (38.09%) 48 (57.15%)

1 (8.33%) 10 (83.34%) 0 (0%) 1 (8.33%)

3 (1.53%) 41 (20.92%) 88 (44.90%) 64 (32.65%)

0 (0%) 5 (6.58%) 39 (51.31%) 32 (42.11%)

0 (0%) 3 (12.50%) 13 (54.17%) 8 (33.33%)

1 (1.19%) 1 (1.19%) 17 (20.24%) 65 (77.38%)

1 2 4 5

(8.33%) (16.67%) (33.33%) (41.67%)

2 (1.02%) 11 (5.61%) 73 (37.25%) 110 (56.12%)

57 (75.00%)

20 (83.33%)

54 (64.29%)

12 (100%)

143 (72.96%)

7 (9.21%) 12 (15.79%)

2 (8.33%) 2 (8.33%)

12 (14.28%) 18 (21.43)

0 (0%) 0 (0%)

21 (10.71%) 32 (16.33%)

10 (13.16%)

4 (16.67%)

24 (28.57%)

2 (16.67%)

40 (20.41%)

Sex Male Female Age, years 45 46-55 56-65 66-75 76

(8.33%) (16.67%) (50.00%) (16.67%) (1.33%)

(9.18%) (18.88%) (39.80%) (23.47%) (8.67%)

cT classification T1 T2 T3 T4a pT classification T1 T2 T3 T4a Treatment history Primary surgery Salvage surgery Previous RT Previous surgery Postoperative RT

Abbreviations: group A, extension to the anterior subglottis; group B, extension to the posterior subglottis; OPHL, open partial horizontal laryngectomy; RT, radiotherapy.

International Cancer Control/American Joint Committee on Cancer classification.16

2.2 | Surgery: Management of the larynx Laryngeal surgical treatment included supratracheal horizontal laryngectomy or total laryngectomy or glottic-subglottic laryngectomy, based on tumor extension. In particular, supratracheal horizontal laryngectomy with tracheohyoidoepiglottopexy (type IIIa open partial horizontal laryngectomy according to the “OPHL” classification proposed by the European Laryngological Society)10 was carried out in glottic cT2 with subglottic extension, selected cT3 glottic/transglottic (ie, anterior subglottic extension or cricoarytenoid joint invasion) and selected cT4 (minimal anterior extralaryngeal extension) tumors. Depending on tumor location with respect to an imaginary horizontal line running between the

anterior edges of the arytenoids vocal process (Figure 2), the patients submitted to the OPHL type IIIa procedure were divided into 2 groups: (1) OPHL type IIIa for anterior tumor location (OPHL group A), in case of extension to the anterior subglottis, without cricoarytenoid unit involvement; and (2) OPHL type IIIa for posterior tumor location (OPHL group B), in case of extension to the posterolateral subglottis, or with fixation of the cricoarytenoid joint (in this case, a type IIIa 1 cricoarytenoid unit procedure was carried out).9 A total laryngectomy was performed in more locally extended cases (ie, glottic-subglottic cT3 tumors with massive invasion of the inferior paraglottic space reaching the posterior cricoarytenoid muscle and the pyriform sinus submucosa or gross glottic-subglottic cT4a tumors with massive cricoid invasion or tumors with posterior extension involving both arytenoids) or in case of contraindications to conservative laryngeal surgery (ie, severe chronic bronchopulmonary

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was electively performed for suspected microscopic nodal disease (cN0) or, with curative intent, for clinically/radiologically limited node metastasis.3,4 As for lateral neck dissection, in case of supraglottic extension or transglottic cancer involving the midline, a bilateral SND (levels II, III, and IV) was carried out, whereas in case of unilateral laryngeal involvement, a unilateral neck dissection was performed.3,4,6 As for PTND, it was not routinely performed in case of subglottis involvement before 2006, if there was no clinical/radiological suspect of paratracheal lymph node metastasis (“no PTND patients” subgroup). Since 2006, we have carried out routine PTND (“PTND patients” subgroup) in patients with subglottis extension as follows: in case of midline involvement, a bilateral dissection was performed, whereas in case of unilateral extension, a monolateral dissection was carried out (Table 2). Paratracheal dissection included dissection of all nodes between the carotid artery laterally and the trachea medially, as far inferior as the suprasternal notch.1,2,6,8 The majority of paratracheal nodes were distributed along the recurrent laryngeal nerve and the tracheoesophageal groove.

2.4 | Pathological assessment FIGURE 1

Laryngeal coronal macrosection. The cranial and caudal boundaries of the subglottis (S) are defined by the horizontal lines (see text for details). The cricoarytenoid joint (J) belongs to the subglottis; a 5 arytenoid cartilage; c 5 cricoid cartilage; pc 5 posterior commissure; t 5 thyroid cartilage [Color figure can be viewed at wileyonlinelibrary. com]

In “PTND patients,” the status of paratracheal lymph nodes was directly evaluated by the pathological examination of the surgical specimen. Routine pathological examination was performed on 4-lm thick formalin-fixed and paraffinembedded sections from each tissue sample. Sections were then counterstained with hematoxylin-eosin. As for subjects not submitted to PTND (“no PTND patients”), the status of

obstructive disease and neurological problems impairing the ability to expectorate and/or swallow).9 A glottic-subglottic laryngectomy was carried out in cT1 and selected cT2 primary anterior subglottic tumors up to 200817,18; afterward, an OPHL type IIIa was preferred because of better functional outcomes obtained in our experience with this approach (unpublished data). A subglottic extension was considered a contraindication to transoral laser microsurgery.6,11 The patients with tumor extension to the trachea and/or hypopharynx were excluded from the study. Those subjects submitted to preoperative tracheostomy were excluded from the study to avoid the bias related to potential paratracheal tumor seeding during the tracheostomy procedure.6 Before surgery, all patients signed an accurate informed consent. All surgical procedures were performed by the same surgical team.10–12

2.3 | Surgery: Management of the neck Radical neck dissection or modified radical neck dissection was carried out if clinically/radiologically proven bulky node metastases were evident. A selective neck dissection (SND)

F I G U R E 2 Laryngeal axial glottic macrosection. The horizontal line, running between the anterior edges of the vocal process of the arytenoid cartilages, divides the anterior and posterior glottic-subglottic regions; a 5 arytenoid cartilage; ac 5 anterior commissure; pc 5 posterior commissure; t 5 thyroid cartilage [Color figure can be viewed at wileyonlinelibrary.com]

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T A BL E 2

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Nodal classification and stomal/local recurrence rate among all the patients enrolled OPHL type IIIa group A (n 5 76)

OPHL type IIIa group B (n 5 24)



Total (n 5 196)

75 (98.69%) 1 (1.31%) 0 (0%) 0 (0%)

21 (87.50%) 3 (12.50%) 0 (0%) 0 (0%)

71 (84.52%) 11 (13.10%) 1 (1.19%) 1 (1.19%)

11 (91.67%) 1 (8.33%) 0 (0%) 0 (0%)

178 (90.82%) 16 (8.16%) 1 (0.51%) 1 (0.51%)

66 (86.84%) 6 (7.90%) 4 (5.26%) 0 (0%)

19 (79.17%) 2 (8.33%) 3 (12.50%) 0 (0%)

61 (72.62%) 8 (9.52%) 15 (17.86%) 0 (0%)

9 2 1 0

155 (79.09%) 18 (9.18%) 23 (11.73%) 0 (0%)

3 (3.94%) 7 (9.21%)

2 (8.33%) 4 (16.67%)

3 (3.57%) 16 (19.05%)

1 (8.33%) 0 (0%)

9 (4.59%) 27 (13.77%)

7 (9.21%) 11 (14.47%) 3 (3.95%)

3 (12.50%) 1 (4.16%) 0 (0%)

7 (8.33%) 4 (4.76%) 4 (4.76%)

1 (8.33%) 3 (25%) 0 (0%)

18 (9.18%) 19 (9.69%) 7 (3.57%)

cN classification N0 N1 N2 N3 pN classification N0 N1 N2 N3

(75.00%) (16.67%) (8.33%) (0%)

pN 1 classification Paratracheal lymph nodes Lateral cervical lymph nodes, levels II-V Stomal recurrence True stomal recurrence Peristomal recurrence Parastomal recurrence

Abbreviations: group A, extension to the anterior subglottis; group B, extension to the posterior subglottis; OPHL, open partial horizontal laryngectomy.

paratracheal lymph nodes was indirectly determined on the basis of peristomal recurrence onset recorded during the follow-up period, as suggested by Chiesa et al.6 In particular, based on the experience of the European Institute of Oncology (Milan, Italy), recurrences in the stomal area were subdivided into 3 categories, according to their exact location and relationship with tracheal mucosa and putative pathogenesis: (1) true stomal recurrence: early superficial ulceration involving the inner wall of the stoma or both mucosa and skin; (2) peristomal recurrence: a subcutaneous node adherent to the tracheal wall, secondarily involving the skin (it should be considered a metastasis in the paratracheal lymph nodes or thyroid tissue); and (3) parastomal recurrence: a suprastomal nodule deep in soft tissue (it should be considered the consequence of intraoperative seeding or insufficient removal of paralaryngeal muscles containing cancer foci or extension through submucosal lymphatic channels).6

2.5 | Adjuvant treatments On the basis of pathological findings (advanced-stage disease with extralaryngeal extent, positive margins, perineural/vascular/lymphatic invasion, and pN >0), 40 patients (20.4%) were submitted to adjuvant radiotherapy (RT; Table 2). Even though 110 patients had pT4a tumors, the majority displayed only a limited extralaryngeal spread, which was manageable with strap muscles and thyroid resection (isthmus/ipsilateral

lobe). For this reason, adjuvant RT was added only in those cases with more extensive extralaryngeal extent. A large volume encompassing the primary site and all draining lymph nodes was irradiated with a dose of up to 54 Gy/2 Gy. Regions at higher risk for malignant dissemination received a 12-Gy boost (total 66 Gy/2 Gy; range 62-68 Gy). Furthermore, concomitant chemotherapy was also scheduled in selected patients because of a higher risk of regional recurrence (advanced-stage disease with histologic evidence of invasion of 2 or more regional lymph nodes, extracapsular extension of nodal disease, and microscopically involved mucosal margins of resection): those subjects received 100 mg/m2 cisplatin on days 1, 22, and 43 of the course of RT.12,19,20

2.6 | Data collection and statistical analysis Data relating to tumor lesion, including site, size, stage, and surgery performed, were documented and reviewed retrospectively with additional information on histopathological findings and follow-up. Patients’ characteristics were represented as frequencies and percentages. The comparison between different variables among patient groups was assessed using the Student’s t test for unpaired data and Kaplan-Meier analysis. Pearson’s correlation coefficient (r) was used to measure the possible association between different variables. Regional disease-free survival was calculated

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T A BL E 3 Sites of neck nodal metastasis and clinical (cN)/pathological (pN) nodal classification in relation to lymph node location among the patients submitted to paratracheal neck dissection Surgical subgroups

Nodal status

OPHL type IIIa Group A (n 5 44)

OPHL type IIIa Group B (n 5 13)



cN0

cN1

pN0

pN1

Paratracheal lymph nodes

3 (6.82%)

2 (15.38%)

3 (12.50%)

1 (20%)

85 (98.84%)

1 (1.16%)

77 (89.53%)

9 (10.46%)

Lateral cervical lymph nodes

4 (9.09%)

2 (15.38%)

5 (20.83%)

0 (0%)

79 (91.86%)

7 (8.14%)

75 (87.21%)

11 (12.79%)

Abbreviations: OPHL 5 open partial horizontal laryngectomy; Group A 5 extension to the anterior subglottis; Group B 5 extension to the posterior subglottis.

on the basis of time interval between surgery and recurrence or last follow-up assessment. A paratracheal recurrence was defined as a carcinoma occurring in the paratracheal region after completion of primary treatment independent of its localization in the subglottis area (anterior or posterior, ipsilateral or contralateral). In disease-free subjects, the followup was carried out for a minimum of 5 years (range 5-16 years). Statistical analysis was performed using SPSS version 10.0 for Windows (SPSS, Chicago, IL). A value of P < .05 was considered as statistically significant.

3 | RESULTS The main characteristics of the patients included in the study are reported in Table 1. Most subjects were men (92.3%) and the mean age was 62.7 years. Current or former smokers made up 89% of the cohort. One hundred eighty-three patients (93.3%) had advanced (pT3-T4a) laryngeal SCC involving the subglottis. Among our patients, 76 (38.7%) were submitted to OPHL type IIIa for anterior tumor location (OPHL group A), 24 (12.2%) to OPHL type IIIa for posterior tumor location (OPHL group B), 84 (42.8%) to total laryngectomy, and 12 (6.1%) to glottic-subglottic laryngectomy. Primary laryngeal surgery was carried out in 143 patients (72.9%), whereas salvage surgery was performed in 53 patients (27.0%) because of disease recurrence/persistence after RT or previous surgery (Table 1). A unilateral/bilateral SND, including levels II-IV, was carried out in 66.8% of cases. A PTND (unilateral or bilateral) was performed in 86 patients (43.8%; “PTND patients”), whereas no PTND was carried out in the remaining 110 patients (56.1%; “no PTND patients”). No significant difference in terms of postoperative complications was noticed between the 2 groups. When PTND was performed, the mean number of paratracheal nodes dissected per side was 3 (range 1-6 nodes). Among 178 patients with cN0 disease (paratracheal, prelaryngeal, and laterocervical nodes),

23 (12.9%) turned out to be N 1 on pathological examination (Table 2).

3.1 | Primary outcomes In the analysis of the nodal metastasis sites, lateral cervical lymph nodes (levels II-V) were the most affected ones (13.7%). In particular, the higher rate of lateral cervical lymph node involvement was found in the OPHL group B patients (16.6%) and among patients submitted to total laryngectomy (19.0%). Paratracheal lymph nodes were involved in 4.5% of the cases (Table 2). As for the stomal relapse rate, 44 of 196 patients (22.4%) showed a local recurrence. In particular, 18 patients (9.1%) had a true stomal (endoluminal mucosa) relapse, 19 (9.6%) had a peristomal/paratracheal (paratracheal lymph nodes), and 7 (3.5%) had a parastomal/submucosal (deep wall) recurrence (Table 2). The higher peristomal relapse rate (Table 2) was noticed in the OPHL group A (14.4%) and the glottissubglottic laryngectomy group (25%). When considering paratracheal lymph node involvement in “PTND patients,” paratracheal nodes were involved in 9 of 86 cases (10.4%; Table 3). Among all “PTND patients,” only 1 of 86 (1.1%) showed clinically positive paratracheal lymph nodes on preoperative imaging. Among the remaining 85 patients with cN0 disease, 8 turned out to be N 1 on pathological examination (Table 3). Therefore, preoperative imaging showed a sensitivity of 1 of 9 (11.1%) in the diagnosis of paratracheal lymph node involvement among those patients. When a bilateral PTND was carried out, only 1 case (in a patient with midline anterior subglottis involvement) of bilateral paratracheal lymph node metastasis was recorded. Among “no PTND patients,” paratracheal nodes (peristomal recurrence) were involved in 15 of 110 cases (13.6%), with the higher rate among subjects submitted to OPHL type IIIa for anterior tumor location (group A; 28.1%; Table 4). When analyzing paratracheal involvement in both groups together (paratracheal lymph nodes in “PTND patients” plus peristomal/paratracheal recurrence in “no PTND patients”), 24

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T A BL E 4

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Different sites of stomal recurrence in patients not submitted to paratracheal neck dissection OPHL type IIIa Group A (n 5 32)




Total (n 5 110)

True stomal/local recurrence (endoluminal mucosal)

1 (3.12%)

1 (9.09%)

5 (8.33%)

0 (0%)

8 (7.27%)

Peristomal/paratracheal recurrence (paratracheal lymph nodes)

9 (28.12%)

1 (9.09%)

3 (5.00%)

2 (0%)

15 (13.63%)

Parastomal/submucosal recurrence (deep tracheal wall)

1 (3.12%)

0 (0%)

3 (5.00%)

0 (0%)

4 (3.63%)

Stomal/local recurrence

Abbreviations: group A, extension to the anterior subglottis; group B, extension to the posterior subglottis; OPHL, open partial horizontal laryngectomy.

of 196 patients (12.2%) showed paratracheal involvement, with the higher rate among patients submitted to the OPHL group A (15.7%) and glottic-subglottic (25%) laryngectomy (Table 5). An increased frequency (P 5 .064) of paratracheal metastasis was noticed in case of tumors with anterior subglottic extension (OPHL group A and glottic-subglottic laryngectomy) with respect to carcinomas affecting the posterolateral subglottis (OPHL group B and total laryngectomy). Furthermore, when comparing paratracheal lymph node and lateral cervical lymph node status in the different surgical subgroups, a statistically significant (P < .001) correlation between paratracheal lymph node and lateral cervical lymph node involvement was noticed among “PTND patients” submitted to OPHL for posterior tumor location (group B): all subjects showing paratracheal lymph node involvement had homolateral affected lateral cervical lymph nodes. No significant correlation between paratracheal lymph node and lateral cervical lymph node involvement was noticed in the other surgical subgroups. No significant difference in paratracheal lymph node involvement was found between patients treated with primary laryngeal surgery and those submitted to salvage treatment.

3.2 | Secondary outcomes In order to assess the effect of prophylactic PTND on regional disease control, we compared paratracheal recurrence rates among “PTND patients” versus “no PTND patients” in the different surgical subgroups (Figure 3A-D). A statistically significant (P 5 .021) reduction of paratracheal recurrence was noticed in “PTND patients” with respect to “no PTND patients” only in the OPHL group A. In the other surgical subgroups, an improvement of regional control was found in “PTND patients” with respect to “no PTND patients,” although the difference was not statistically significant. Among those patients who developed a paratracheal relapse, no one survived beyond 36 months.

4 | DISCUSSION Our study on 196 patients submitted to surgery for laryngeal SCC with subglottic involvement in a tertiary referral cancer center, shows an overall frequency of 12.2% for paratracheal involvement in such tumors. This rate is slightly inferior to

T A BL E 5 Involvement of paratracheal node assessed by adding the rate of positive nodes, pN(PT)1, in patients submitted to paratracheal neck dissection to the rate of peristomal/paratracheal recurrence in subjects not submitted to paratracheal neck dissection OPHL type IIIa Group A (n 5 76)




Total (n 5 196)

3 (3.94%)

2 (8.33%)

3 (3.57%)

1 (8.33%)

9 (4.59%)

(“no PTND patients”)

9 (11.84%)

1 (4.17%)

3 (3.57%)

2 (16.67%)

15 (7.65%)

Total

12 (15.78%)

3 (12.50%)

6 (7.14%)

3 (25.00%)

24 (12.24%)

pN(PT)1 (“PTND patients”) Peristomal/paratracheal recurrence

Abbreviations: group A, extension to the anterior subglottis; group B, extension to the posterior subglottis; OPHL, open partial horizontal laryngectomy; PTND, paratracheal neck dissection.

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F I G U R E 3 Paratracheal disease-free survival in patients submitted (PTND) and not submitted (no paratracheal neck dissection [PTND]) to paratracheal neck dissection in the different surgical subgroups: A, open partial horizontal laryngectomy (OPHL) type IIIa for anterior tumor location (76 patients; P 5 .021); B, OPHL type IIIa for posterior tumor location (24 patients; P 5 .277); C, total laryngectomy (84 patients; P 5 .853); D, glottic-subglottic laryngectomy (12 patients; P 5 .751) [Color figure can be viewed at wileyonlinelibrary.com]

the frequency reported by some other authors. In particular, Weber et al,21 in their study on 91 patients submitted to total laryngectomy, hemithyroidectomy/total thyroidectomy, and PTND for laryngeal SCC, found an overall paratracheal metastases rate of 17.6%. However, this difference may be due to potential bias related to different sample’s numerosity and selection criteria. Our study also shows the importance of paratracheal lymph node involvement as a major prognostic factor for laryngeal cancer with subglottic extension, which is confirmed by the fact that among those subjects who developed a paratracheal relapse, no one survived beyond 36 months. Among 22 patients submitted to bilateral PTND, only 1 case (4.5%; in a patient with midline anterior subglottis involvement) of bilateral paratracheal lymph node metastasis was recorded. Such result may be explained by the anatomic findings of Welsh,22 who studied the lymphatic drainage of the larynx by injecting colloidal gold-198 and measuring uptake in the regional nodes. He noted that when the tracer was injected in one side of the subglottic region, almost all tracer uptake (96%) was detected in the ipsilateral paratracheal nodes. The differences in paratracheal lymph node metastasis rate we noticed in the different surgical subgroups of our

study can be explained by the different tumor extension associated with the various surgical procedures. Among our patients, the higher rate of paratracheal involvement was recorded for subjects submitted to OPHL for anterior tumor location (group A; 15.7%) and glotticsubglottic laryngectomy (25%). These results are comparable with those reported by Garas and McGuirt,23 who found a paratracheal lymph node metastasis rate of 26.6% in their study of 15 patients with SCC originating in the subglottic region. In our study, we noticed a trend (P 5 .064) showing a higher rate of paratracheal metastasis in cases of tumors with anterolateral subglottic extension, which may be explained by the numerous efferent lymphatics draining from the anterolateral subglottis into paratracheal lymph nodes.24,25 On the contrary, the patients with posterolateral subglottic extension showed the higher rates of lateral cervical lymph node involvement, which may suggest a prominent lymphatic drainage from such posterior subglottic areas to the homolateral lateral cervical lymph nodes. The prominent lymphatic drainage from the anterolateral subglottis to the paratracheal lymph nodes is confirmed by the significant reduction of paratracheal recurrence rate we noticed among patients submitted to PTND in the OPHL group A (Figure

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3A). In the other surgical subgroups, we noticed a trend (although not statistically significant) toward an improved paratracheal control among the patients submitted to PTND with respect to those who were not. Such findings may confirm the prophylactic/therapeutic role of PTND in laryngeal SCC with subglottis extension, especially in case of an anteroinferior subglottic involvement. The lower prevalence of paratracheal lymph node involvement in the total laryngectomy subgroup (7.1%) may be related to: (a) the higher percentage of patients submitted to adjuvant RT in the “total laryngectomy” subgroup with respect to the other subjects (Table 1); and/or (b) the fact that total laryngectomy was carried out also in patients with minimal subglottic extension (and a consequently low risk of paratracheal lymph node involvement) who showed contraindications to conservative laryngeal surgery (ie, severe bronchopulmonary chronic disease and neurological problems).9 Based on our experience, elective PTND is indicated in advanced (T3-T4) laryngeal carcinomas with anterior subglottic extension (in tumors confined to one side of the larynx, treatment/dissection should include the ipsilateral paratracheal nodes, whereas in tumors involving both sides of the larynx, a bilateral PTND should be performed) or in case of subglottis involvement with clinically apparent node metastases in the lateral compartment of the neck. In patients candidate to total laryngectomy for tumors with subglottic extension, elective PTND may be omitted in case of scheduled postoperative RT. According to our experience, the importance of such indications for elective PTND is enhanced by the low sensitivity (11.1%) of preoperative imaging in the diagnosis of paratracheal lymph node involvement, potentially leading to an understaging/undertreatment of these tumors.5,6 When a bilateral PTND is performed in association with conservative laryngeal surgery, special care should be taken not to damage the inferior laryngeal nerve during the PTND in order to preserve subglottis sensitivity and cricoarytenoid unit (or cricoarytenoid units if both of them are preserved) function on the side where the arytenoid will be maintained.9 In case of inferior laryngeal nerve injury, the residual cricoarytenoid unit motility will be impaired and, consequently, the neolaryngeal function will be compromised. In our study, no significant difference, in terms of complications, was found between “PTND patients” and “no PTND patients.” These findings are in contrast with the ones reported by van der Putten et al.26 Such difference may be due to the higher rate of patients submitted to salvage surgery after RT failure in their study (95%), with respect to our cohort (27%). In conclusion, even though in our study the frequency of paratracheal lymph node metastasis in paratracheal cN0 exceeds 20% (recommended prevalence limit for PTND)2 only in the glottic-subglottic laryngectomy subgroup, the limited morbidity of PTND, the rate of paratracheal

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lymph node metastasis in laryngeal SCC with subglottic involvement in the other subgroups, and most important, the severe impact of paratracheal metastasis on patients’ survival argue in favor of elective paratracheal lymph node treatment according to the abovementioned principles. Large prospective studies are needed to better identify the subgroups of patients at higher risk of paratracheal metastasis. Based on future studies, it is hoped that clinical guidelines can be developed and undertreatment or overtreatment may be avoided. O R CI D Marco Lionello MD 9618 Luca D’Ascanio MD 326X

http://orcid.org/0000-0002-2454http://orcid.org/0000-0002-5351-

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How to cite this article: Lucioni M, D’Ascanio L, Nardi E, Lionello M, Bertolin A, Rizzotto G. Management of paratracheal lymph nodes in laryngeal cancer with subglottic involvement. Head & Neck. 2017;00:1–10. https://doi.org/10.1002/hed.24905