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Salvage neck dissection for isolated neck recurrence in head and neck tumors: intra and postoperative complications


Academic year: 2021

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Tesi di Specializzazione in


Salvage neck dissection for

isolated neck recurrence in head

and neck tumours: intra and

postoperative complications

Relatore: Dott.ssa Giuditta Mannelli

Candidato: Dott.ssa Lara Valentina Comini


2 1. Introduction

1.1 Surgical anatomy of the neck Pag. 3

1.2 Definition and type of neck dissection Pag. 18

1.3 Complication of neck dissection Pag. 19

2. Salvage neck dissection for regional recurrence of head and neck tumours

2.1 Epidemiology Pag. 23

2.2 Diagnosis of regional recurrence Pag. 25

2.3 Therapeutic options in regional recurrences Pag. 29 3. Clinical study

3.1 Objective Pag. 38

3.2 Material and methods Pag. 39

3.3 Results Pag. 40

3.4 Discussion Pag. 53

3.5 Conclusion Pag. 57


3 1. Introduction

1.1 Surgical anatomy of the neck

The neck is the part of the trunk that joins the head and the chest. Its upper limits run along the inferior and posterior borders of the mandible, the extreme posterior of the zygomatic arches, the anteroinferior borders of the external auditory canals, the profiles of the mastoid apophyses, the superior nuchal line, and the external occipital protuberance. Its lower boundaries lie along the superior border of the sternum and clavicles, the acromioclavicular joints, and an imaginary line joining the acromioclavicular joints to the spinous process of the seventh cervical vertebra.

On transverse section, the neck appears to be roughly divided into two parts, a posterior or nuchal part and an anterior or tracheal part. The conventional dividing line extends from the transverse vertebral processes to the anterior edges of the trapezius muscles (Fig.1).[1] The posterior region has a function of static and movement support and contains cervical vertebrae, posterior muscles (scalene group, levator of the scapula, splenius and semispinal of the head, rhomboids and prevertebral group), cervical and brachial plexus and phrenic nerve. In contrast, the anterior compartment is thus located anteriorly to prevertebral fascia and mainly includes viscera and glands (pharynx/larynx/trachea, cervical oesophagus, thyroid, parathyroid, submandibular gland and inferior edge of parotid gland), carotid artery and its arterial system, jugular vein and its tributaries, muscles (platysma, sternocleidomastoid, supra and infrahyoid muscles), X, XI, XII cranial nerve and inferior branch of facial nerve and cervical lymphatic system.[2]


4 The cervical lymphatic system forms a three-dimensional network into whose nodal points the lymph nodes are intercalated. Lymph nodes are grouped into lymph gland stations that are anatomically divided in:

1. A superficial, subfascial lymph node system (occipital, mastoid, parotid, submandibular, and submental lymph nodes and along the course of the external jugular vein).

2. A deep lymph node system (peri-jugular, spinal and supraclavicular node).

3. A perivisceral lymph node system close to the median viscera (prethyroidean, pretracheal, retropharyngeal, recurrent and final prelaryngeal lymph nodes).[1]

Although this categorization remains conceptually valid, the neck is topographically divided in triangles, based on anatomical boundaries and the structures they contain.

1 = trachea 2 = esophagus

3 = vertebral body of seventh cervical vertebra

4 = interapophyseal articulation 5 = anterior jugular vein 6 = platysma muscle

7 = sternocleidomastoid muscle 8 = external jugular vein 9 = sternohyoid muscle 10 = sternothyroid muscle 11 = omohyoid muscle 12 = thyroid gland 13 = recurrent nerve 14 = inferior thyroid vein 15 = internal jugular vein 16 = common carotid artery 17 = vagus nerve

18 = prevertebral muscles 19 = vertebral artery and vein 20 = anterior scalene muscle 21 = brachial plexus 22 = medial scalene muscle 23 = posterior scalene muscle 24 = trapezius muscle


5 Sternocleidomastoid muscle (SCM) divides the cervical region in two triangles: the anterior cervical triangle (located anterior to SCM, inferior to the mandibular border and with medial limit to the midline) and the posterior cervical triangle (located between SCM, anterior border of trapezius and upper border of the clavicle). The

first contains the submaxillary (digastric) triangle, carotid triangle, muscular triangle and submental (suprahyoid) triangle; the second is instead

divided into occipital and subclavian triangle by omohyoid muscle.[1,3] Figure 2 shows this subdivision and the anatomical boundaries of each area (Fig. 2).

In 1991, K. Thomas Robbins et al.[4] introduced a classification, subsequently modified in 2002 [5], which is still universally accepted and commonly used in routine oncological practice. Its aim was to achieve uniformity in the nomenclature of cervical lymph node levels, with reference to the anatomical structures encountered intraoperatively and involved in the excision. The neck is therefore divided into a total of 6 six levels; sublevels are identified for defining selected lymph node groups within levels I, II, and V (Fig.3). The anatomical boundaries of each level are described in Table 1.



Figure 3: The six sublevels of the neck used to describe the location of lymph nodes within level I, II and V. Level IA, submental group; level IB, submandibular group; level IIA, upper jugular nodes along the carotid sheath, including the subdigastric group; level IIB, upper jugular nodes in the submuscular recess; level VA, spinal accessory nodes; and level VB, the supraclavicular and transverse cervical nodes; level VI, anterior compartment of the neck. (Cummings cap 119, pag 1839)


7 Submental and submandibular region (Level IA and IB)

Two important lymph node groups are found within level I: these are the submental group (level IA) and the submandibular group (level IB). The first group is

T ab le 1 : A na to m ic al s tr uc tu re s de fi ni ng th e bo un da ri es o f th e ne ck le ve ls a nd s ub le ve ls .[ 5]


8 uneven and median and it is contained within the boundaries of the submental triangle (the anterior belly of the digastric muscles and the hyoid bone). In contrast, there is one level IB for each side of the neck and its boundaries are represented by the anterior and posterior bellies of the digastric muscle and the body of the mandible. [5,6]

The submandibular triangle includes submandibular gland and surrounding lymph nodes, which are divided in four group: preglandular (anterior to the anterior surface of the gland), prevascular (anterior to the facial artery up to the anterior surface of the gland), postvascular (posterior to the facial artery up to the posterior surface of the gland), and postglandular (posterior to the posterior aspect of the gland). [7] During neck dissection, the submandibular gland is usually removed to ensure thorough exenteration of all of the lymph nodes within this triangle. [6,7]

Some significant anatomical structures are contained or in close proximity to submandibular region and their knowledge is mandatory in surgical practice. They are mainly represented by: marginal branch of the facial nerve, facial artery, lingual artery, lingual nerve, Wharton’s duct and hypoglossal nerve. (Fig.4)



Figure 4: submandibular region (ablation of the submandibular glad)

Lucini pag36 cap5

The marginal nerve, the inferior branch of facial nerve, runs 1 cm above the inferior margin of the corpus mandibulae; it can be identified below the platysma, in the thickness of the superficial cervical fascia, which envelope the submandibular branch. Traumatization of the marginal nerve causes temporary paresis of the depressor labii inferioris. For this reason, Hayes Martin maneuver can be used to protect the nerve: after identification of facial pedicle straddling the inferior margin of

p = parotid; m = mandible; i = hyoid bone 1 = posterior belly of digastric muscle 2 = stylohyoid muscle

3 = internal jugular vein 4 = external carotid artery 5 = internal carotid artery 6 = occipital artery

7 = posterior auricular artery 8 = hypoglossal nerve

9 = descending branch of hypoglossal nerve 10 = thyrolinguofacial venous trunk 11 = superior thyroid artery and vein 12 = superior laryngeal artery and vein 13 = lingual vein

14 = lingual artery

15 = facial vein 16 = facial artery 17 = retromandibular vein 18 = external jugular vein

19 = platysma branch (facial nerve) 20 = marginal branch (facial nerve) 21 = submental artery

22 = submental vein 23 = mylohyoid muscle

24 = anterior belly of digastric muscle 25 = thyrohyoid muscle

26 = omohyoid muscle 27 = sternohyoid muscle 28 = hyoglossus muscle

29 = anterior process of submandibular gland


10 the mandible, by the anterior border of the masseter muscle, the facial vein is ligated and lifted to protect the nerve, which crosses it at the top.[1,6] However, some authors disagree on the oncological validity of this maneuver and a careful dissection of perifacial lymph node is advisable when the primary site involved is the lip, buccal mucosa, anterior nasal cavity, or soft tissue of the cheek. [8]

The facial artery, branch of the external carotid artery, emerges behind the posterior belly of the digastric muscle, posteriorly skimming the submandibular gland; running backward and forward, and upward and downward, it surfaces to surround the inferior margin of the mandible, immediately anterior to the facial vein.[1] Lesion of this artery can lead to important intra or post-surgical haemorrhage and must be avoid. Furthermore, preservation of the facial artery is advisable when a free flap reconstruction is planned, due to its usefulness as recipient vessel.

Deep to the submandibular gland, on the plane of the hyoglossus, some important anatomical structures can be identify by moving the posterior margin of the mylohyoid muscle forward: the lingual nerve (a sensory nerve arising in the posterior trunk of the mandibular branch of the trigeminal nerve; it provides sensory and taste innervation of the mucosa in front of the lingual “V”) connected to the submandibular ganglion (parasympathetic, with afferent impulses from the chorda tympani of the facial nerve, and efferent impulses to the lingual nerve with a submandibular and sublingual secretory function); Wharton’s duct, oriented anteriorly toward the sublingual gland; the hypoglossal nerve (motor nerve of the tongue and, in concert with the descending branch of the cervical plexus, the subhyoid muscles, save the thyrohyoid muscle, which it

innervates separately).[1]

The lingual artery, which is the second branch of the external carotid artery, instead runs on the posterior margin of the hyoglossal muscle, throght Beclard’s (bounded by posterior belly of the digastric muscle, the greater cornu of the hyoid bone, and the posterior margin of the hyoglossal muscle) and Pirogoff’s triangle (located between the intermediate tendon of the digastric muscle, the hypoglossal nerve, and the posterior margin of the mylohyoid muscle) (Fig. 5). [9]


11 Laterocervical/Sternocleidomastoid Region (Levels II, III, and IV)

The sternocleidomastoid region comprises roughly the sternocleidomastoid muscle and all that lies below it, considering the head in a normal position. It corresponds approximately to Robbins levels II, III, and IV and its margins are represented by the base of the skull (superior limit), the clavicle (inferior limit), the posterior margin of the sternocleidomastoid muscle (posterior limit), and, anteriorly, the lateral border of the sternohyoid muscle; the carotid bifurcation (surgical landmark) or hyoid bone and the junction of the omohyoid muscle with the IJV (surgical landmark) or the lower border of the cricoid arch (clinical and radiologic landmark) marks the boundaries between level II-III and level III-IV, respectively. [1,2,5,6] The level II is furthermore divided in two sublevel by accessory nerve.[5]

The cervical vasculonervous bundle, formed laterally by the internal jugular vein, medially by the common carotid artery, and posteriorly, in the dihedral angle formed by the two vessels, by the vagus nerve, runs through all the sternocleidomastoid region. Figure below shows an overview of level II-III-IV and main structures encountered during surgery.



Figure 6: Robbins Levels II-III-IV. Lucioni cap 7 pag 62

The most cranial anatomical structure to identify and preserve in level II is the common trunk of the spinal accessory nerve (SAN). After passing through the jugular foramen, this nerve progresses onward and travels past the internal jugular vein (IJV) laterally, although there is a degree of variation in this part of its route.[10,11] SAN then descends medially to the styloid process and travels past the stylohyoid and digastric muscles; it runs alongside

Figure 7: Photograph demonstrating a triangle bordered by SBOA medially (A), superior sternocleidomastoid tendon laterally (T), and the posterior belly of the digastric superiorly (D). SNA (yellow) runs in this triangle. (A Novel Approach to Identifying the Spinal Accessory Nerve in Surgical Neck Dissection)

c = clavicle

1 = spinal accessory nerve 2 = levator scapulae muscle 3 = lesser occipital nerve 4 = cervical plexus 5 = internal jugular vein 6 = internal carotid artery 7 = superior laryngeal nerve 8 = external carotid artery 9 = occipital artery 10 = thyrolinguofacial trunk 11 = superior thyroid vein 12 = superior thyroid artery 13 = hypoglossal nerve 14 = facial vein 15 = lingual vein

16 = intermediate tendon of digastric muscle

17 = common carotid artery 18 = vagus nerve

19 = omohyoid muscle 20 = sternothyroid muscle 21 = sternohyoid muscle 22 = inferior thyroid artery 23 = phrenic nerve

24 = anterior scalene muscle 25 = transverse cervical artery 26 = thyrocervical trunk 27 = transverse scapular artery 28 = brachial plexus

29 = anterior scalene muscle 30 = dorsal scapulae nerve 31 = posterior scalene muscle


13 the superior SCM branch of the occipital artery and enters the deep surface of the upper portion of the SCM muscle.[11] Some important anatomical landmarks have been described to find the nerve in the level II and the most commonly used in clinical practice are the transverse process of C1 (SAN lays anteriorly to the transverse process of the atlas in 77% of cases), SCM branch of the occipital artery (SBOA), and superior SCM tendon. In particular, Eastwood et al.[12] recently demonstrate that SAN is contained in 95.8% of cases in a triangle bordered by the superior SMC tendon laterally, SBOA medially and digastric muscle superiorly; so, careful dissection of this area is recommended to avoid nerve injuries.

Caudally to spinal accessory nerve runs the cervical plexus. It is composed of three anastomosing loops formed by the anterior branches of the upper four cervical nerves (C1–C4). It gives rise to sensory nerves (lesser occipital, great auricular, supraclavicular, and cutaneous nerves of the neck) and to motor nerves (nerves serving the sternocleidomastoid and trapezius muscles, phrenic, and descending cervical nerves). The descending cervical nerve, lying laterally to the cervical vasculonervous bundle, joins the descending branch of the hypoglossal nerve and forms the hypoglossal loop.[1]

A major landmark within this region is represented by the greater cornu of the hyoid bone, in view of its close proximity to lingual artery, hypoglossal nerve, superior laryngeal pedicle and external carotid artery. Figure 4 shows the relationship between all these structures.

Furthermore, in order to identify the external carotid artery at its origin, anatomists describe a “triangular window” bounded by the medial wall of

the internal jugular vein, the lateral wall of Figure 8: Farabeuf's triangle. (Lucioni cap 7 pag


14 the thyrolinguofacial trunk, and, at the top, the hypoglossal nerve; this space is referred to as Farabeuf ’s triangle (Figure 7).[1,2]

Describing the lower portion of the sternocleidomastoid region, one of the most important structure to recognise is represented by the thoracic duct, particularly in the left side. It is located in the laterally open dihedral angle formed by the internal jugular and subclavian veins.[1] Anatomists do not recognise a precise landmark for the cervical portion of thoracic duct; however, it can be approximatively located in an area beginning approximately 2.0 cm lateral to the midline and 3.5 cm superior to the sternal notch, extending superiorly to a point roughly 3.5 cm from the midline and 2.5 cm inferior to the cricoid cartilage, and terminating within the venous system at a point approximately 4.5 cm lateral to the midline and 3.0 cm superior to the sternal notch.[13]

In relation to the medial margin of the anterior scalene muscle, it is easy to find the thyrocervical trunk, which arises in the subclavian artery and branches out at this point into secondary arteries, namely: the transverse scapular artery, transverse cervical artery, the ascending cervical artery, and the inferior thyroid artery. (Fig.9)

Supraclavicular Region (Level V)

The supraclavicular region corresponds to Robbins level V. It is bounded superiorly by the apex formed by the convergence of the trapezius and sternocleidomastoid muscles, inferiorly by the clavicle, anteriorly by the posterior

Figure 9: Thyrocervical trunk. Lucioni cap 7 pag 64

c = clavicle

1 = medial scalene muscle 2 = brachial plexus 3 = anterior scalene muscle 4 = phrenic nerve

5 = transverse cervical artery 6 = transverse scapular artery 7 = ascending cervical artery 8 = inferior thyroid artery 9 = thyrocervical trunk 10 = subclavian artery 11 = internal thoracic artery 12 = vertebral artery 13 = vagus nerve 14 = internal jugular vein 15 = common carotid artery 16 = recurrent nerve 17 = innominate artery (brachiocephalic trunk)


15 margin of the sternocleidomastoid muscle, and posteriorly by the anterior margin of the trapezius.[1] Using the horizontal plane that corresponds to the inferior border of the cricoid cartilage, level V is divided into two sublevels, VA and VB.[6] In depth, the emerging of the cervical and brachial plexi separates level V from levels II, III, and IV.[1]

Knowledge of the distal course of SAN after exiting the posterior border of SCM is mandatory in surgical practice. It can be detected mainly by two anatomical landmarks: 1. 1 cm superiorly to Erb’s point (located approximately at the junction of the upper and middle thirds of SCM, where the great auricular nerve emerges from behind the muscle); 2. On entry to the trapezius, about 2 cm above the point where this muscle and the inferior belly of the omohyoid muscle cross (Fig 10).[1,11]

A second keypoint located below the spinal accessory nerve (level VB) is the brachial plexus. It is formed by the anterior branches of the fifth through eighth cervical nerves and of the first thoracic nerve. Three primary nerve trunks exit between the anterior scalene muscle and the median scalene muscle. One branch of the brachial plexus, the dorsal scapular nerve, exits between the median scalene and the posterior scalene muscles. The transverse cervical vessels and transverse scapular vessels cross the plexus in mediolateral direction.[1] In neck surgery, lesions of the brachial plexus are very rare: it is readily identifiable by blunt dissection of the fatty tissue in the lower neck and it is well protected by a dense layer of deep cervical fascia surrounding the scalene muscles (Fig 11).[14] The phrenic nerve is a ramus muscularis of the four of the cervical plexus. It rests on the surface of the anterior scalene muscle, taking a slightly diverging lateromedial course with respect to the brachial plexus (as a memory


16 aid, the phrenic nerve can be thought of as the thumb of a hand, while the other four fingers represent the branches of the brachial plexus).[1]

Figure 11: Brachial plexus. Lucioni cap 6 pag 48

The subclavian artery crosses posteriorly to the phrenic nerve and the anterior scalene muscle and continues its course inferomedially to the brachial plexus; after climbing over the first rib, it becomes the axillary artery. An excellent landmark for ligating the interscalene portion of the subclavian artery is represented by the Lisfranc’s tubercle, which is a bony prominence where the anterior scalene muscle is attached to the first rib and which can be easily palpated during dissection.[1]

Anterior Region (Level VI)

Level VI encompasses the lymph nodes of the anterior compartment of the neck. This group comprises nodes that surround the midline visceral structures of the neck, extending from the level of the hyoid bone superiorly to the sternal notch or the innominate (brachiocephalic) artery (use of the latter as the lower border implies inclusion of the anterior superior mediastinum above the innominate artery, sometimes referred to as level VII). On each side, the lateral boundary is formed by the medial border of the carotid sheath. Located within this

1 = posterior scalene muscle 2 = medial scalene muscle 3 = anterior scalene muscle 4 = phrenic nerve

5 = internal jugular vein 6 = anthracotic lymph node

7 = transverse cervical artery and vein 8 = deep cervical fascia

9 = dorsal scapular nerve 10 = brachial plexus

11 = transverse artery of the scapula

Figure 12: Lymph nodes of central compartment. Consensus Statement on the Terminology and Classification of Central Neck Dissection for Thyroid Cancer


17 compartment are the perithyroidal lymph nodes, the paratracheal lymph nodes, and the precricoid (Delphian) lymph node (Fig. 12).[6,15]

Precricoid and anterior paratracheal node are located deep to strap muscles and they lie on the laryngotracheal axis, resulting easily accessible to the surgeon. Conversely, dissection of perithyroidal ones is challenging because of proximity to recurrent laryngeal nerve (RLN) and parathyroids.

The recurrent laryngeal nerves are asymmetric. The nerve on the left arises from the vagus nerve where it crosses the arch of aorta; at contrast, it crosses anterior to the subclavian artery on the right side. After this turn, they ascend in the tracheoesophageal groove posterior to the thyroid gland and finally enter the larynx behind the cricothyroid articulation and the inferior cornu of the thyroid cartilage. Thus, the left recurrent nerve is generally more closely applied to the trachea in the lower part of its ascending course than is the right nerve.[16]

Some useful landmarks can be used to identify recurrent nerve during thyroidectomy or central compartment dissection. Classically, the recurrent laryngeal nerve is found intraoperatively in the Simon triangle, formed by the common carotid artery laterally, the oesophagus medially, and the inferior thyroid artery (ITA) superiorly.[16] Considering the relation between the RLN and ITA, the first runs posterior to the artery in 35.8% of cases, anterior to it in 32.9%, and between its branches in 30.1%; in 1.2% of cases the artery is surrounded by the nerve. [17] Other anatomical landmarks for SLN identification are tracheoesophageal sulcus (the RLN is mostly anterior to the sulcus on the right side and it runs into it on the left side), the Berry’s ligament (the nerve is lateral to the ligament in 88,1% of cases), inferior constrictor muscle of the pharynx (the RLN is found below the inferior rim of the muscle in 90.4% of cases) and Zuckerkandl’s tuberculum (the nerve lies in front when the tuberculum is a very small lateral projection or only a thickening of the lateral edge of thyroid lobes; more frequently the nerve runs in a tunnel deep behind the tubercle).[17,18]

It is equally of primary importance to consider that, even if more often the recurrent nerve enters the larynx as a single trunk, in about 40% of cases it splits into 2 or more


18 branches. This event is most common on the right side and the distance of RLN extralaryngeal division from the cricothyroid joint is frequently <2 cm.[17]

1.2 Definition and type of neck dissection

The terms neck dissection and cervical lymphadenectomy are synonymous, and both refer to the systematic removal of lymph nodes, along with their surrounding fibrofatty tissue, from the various compartments of the neck.[6]

Depending on purpose and timing of this procedure, we can divide:

- therapeutic neck dissection: performed for clinical or radiologically detectable metastatic disease in a patient with previously untreated cancer;

- elective neck dissection: performed when the likelihood of microscopic lymphatic metastasis is significantly high, even in absence of clinical or radiological sign of disease;

- planned neck dissection: performed as a second step of treatment in patient with advanced stage tumour previously undergone to (chemo)radiotherapy;

- salvage neck dissection: treatment of recurrent cervical nodal disease.[6,19,20]

The modern classification of neck dissection based to Robbin’s lymph node level removed was historically proposed by the Committee for Head and Neck Surgery and Oncology of the American Academy of Otolaryngology–Head and Neck Surgery, in conjunction with the Education Committee of the American Society for Head and Neck Surgery (ASHNS) in 1991. After a first revision (2002), in 2008, ASHNS published an update that include four type of neck dissection:

- Radical neck dissection is the standard basic procedure for cervical lymphadenectomy which includes removal of lymph nodes from levels I to V, with removal of the sternocleidomastoid muscle, the spinal accessory nerve, and the internal jugular vein.

- Modified radical neck dissection involves removal of lymph nodes from levels I to V with the preservation of at least 1 of the nonlymphatic structures (ie,


19 sternocleidomastoid muscle, spinal accessory nerve, and/ or internal jugular vein).

- Extended neck dissection refers to removal of additional lymph node levels or groups, and/or nonlymphatic structures (eg, muscle, blood vessel, nerve) not normally removed with a radical neck dissection.

- Selective neck dissection refers to preservation of 1 or more lymph node levels. There are several variations of the selective neck dissection, some of which have traditionally been given specific names (eg, lateral, supraomohyoid, extended supraomohyoid, posterior or central, in addition to others).[19]

Simultaneously, in 2005, the Japan Neck Dissection Study Group proposed a different classification system, based on division of cervical node in three regions: S (submental-submandibular), J (jugular), and P (posterior triangle). In addition to lymph node group, nonlymphatic tissue resected was listed as follow: N in case of spinal accessory nerve sacrifice, V for internal jugular vein, and M for sternocleidomastoid muscle.[19,20]

Considering the strengths of the previous system, such as the use of conventional terminology for the first method and abbreviated and tabular nature for the latter, in 2010 Ferlito et al.[19] finally proposed the current in use classification:

- The first symbol ‘‘ND’’ represent the term neck dissection (A prefix should be included to denote the side of the neck upon which the dissection has been performed using the abbreviation L for left, and R for right. If bilateral, both sides must be classified independently);

- The second component of the description should be the neck levels and/or sublevels removed, each designated by the Roman numerals I through VII, in ascending order and according to Robbin’s classification;

- The third component of the description should be the non-lymphatic structures removed, each identified through the use of specified acronyms, similarly to the Japan Neck Dissection Study Group method.


20 Due to the complex anatomy of the neck and the importance of the structures it contains, neck dissection can lead to potentially serious or even fatal complications.[21] While a careful knowledge of surgical anatomy can limit its onset, the increasingly advanced age of patients and their important comorbidities, previous treatments, prolonged operative time and advanced stage at diagnosis could determine an increased risk of adverse events.[22–24] On the other hand, a careful preoperative evaluation of the patient, the prevention of complications, a scrupulous surgical technique and an adequate postoperative management are essential to improve the outcomes of patients with head and neck cancer.[22,25,26]

The range of possible local complications of neck dissection is wide; Table 2 summarizes the most important by frequency and severity.[6]

Complication Incidence Risk factors Wound Dehiscence and flap


0-11% Type of incision (trifurcate); previous RT; nutritional status

Seroma 3-20% Type of ND (RND)

Infection 3.2-10% -

Scar/keloid formation - -

Lymphedema 17-36% Previous RT

Vascular Carotid blowout 3-4% Wound complications, salivary fistula, previous RT, tumour involvement of arterial wall, nutritional status, tobacco use IJV occlusion 5.8-29% Surgical technique, presence of

central venous catheters, wound complications, postoperative RT IJV hemorrhage 1.3% Salivary fistula, nutritional status,

tobacco use

Hematoma 4% -

Nerve Marginalis branch of facial nerve

1-6% Type of ND (level I) Vagus nerve (main


<1% Type of ND (level III-IV) Recurrent nerve 1-1.5% Type of ND (level VI),

thyroidectomy Spinal accessory nerve


5-60% Type of ND (level IIb and V) Hypoglossal nerve 0.42% Type of ND (level I-II) Phrenic nerve 8% Type of ND (level IV)


21 Lingual nerve 3% Type of ND (level I)

Sympathetic chain (Horner syndrome)

0.56% -

Chyle Chylous fistula 1-2% Left side, Type of ND (level IV)

Although frequent, wound complications are potentially preventable through adequate prophylactic antibiotic therapy and adherence to asepsis during surgery, such as a meticulous planning of skin incision.[25] Nevertheless, they should not be underestimated, since in a not negligible percentage of cases they can lead to a prolongation of hospitalization and related costs, the onset of major complications (such as carotid blowout) and the need for reoperation with or without flap reconstruction.[6,25,27,28] In a recent study, Pellini et al.[27] analysed postoperative wound complication in 119 patients underwent to neck dissection without concomitant primary exeresis. They reported a wound complication in 20% of cases; of which 14/24 patients (11% of the total) required a surgical revision and 10/24 were managed conservatively. In this study, preoperative chemoradiation therapy (CRT) and the type of neck dissection were associated with a higher risk of major complications; even if this conclusion is not fully confirmed by previous reports[25,29,30].

Unlike wound complications, vascular complications are uncommon but more serious on average. In particular, the carotid blowout is highly lethal, with a mortality of 63%. This complication, often delayed (about 2 years after tumour diagnosis), occurs more frequently in the case of previous RT, wound complication after neck dissection and the presence of mucocutaneous fistulas, especially in the case of simultaneous excision of the primary tumour [28]; the same risks factors are advocate in case of postoperative internal jugular vein rupture[31]. Bleeding from smaller vessels can lead to the development of hematomas and, in case of acute onset in the postoperative period, to surgical revision, even if a specific bleeding site is not identified in most cases. Factors predictive of postoperative wound bleeding are currently unknown[32,33].

Within the scope of nervous lesion, spinal accessory nerve is the most frequently involved. Despite this, according to a study conducted by Prim et al.[34] out of 442 patients underwent neck dissection, accidental nerve injury occurs in only


22 1.68% of cases. The term “Shoulder syndrome” describes a clinical picture linked to denervation of the upper trapezius muscle due to spinal accessory nerve lesion and consisting of pain and limited abduction of the shoulder, full passive range of motion, and anatomic deformities such as scapular flaring, droop and protraction.[35] Despite the rarity of intraoperative accidental nerve injury, severe upper extremity impairment can be found in up to 60% of patients treated by RND and around 5-25% in nerve-sparing neck dissections; this event could be mainly ascribed to traction and devascularization during surgery.[35–37]


23 2. Salvage neck dissection for isolated regional recurrences of head and neck tumours

2.1 Epidemiology

Despite improvement in prompt diagnosis and tailored treatment of patients affected by head and neck tumours, a great amount of them still experience treatment failure. Recurrence rate, type of recurrence, such as risk factors of relapse, could be lightly different depending on localization of the tumour and its histology.

Squamous cell carcinoma (SCC) is the most frequent head and neck tumour, accounting more or less 80% of all malignancies in this area. SCC recurrences mainly occur within 3 years after initial treatment either as local, regional and/or distant metastases, local being the most common. Depending on site and primary treatment, recurrence rate in patients with advanced stage disease can reach 50% of cases.[38– 40]

Despite high SCC tendency to spread to lymph nodes, isolated regional recurrences (IRR) are extremely rare. Lindegaard et al.[41], in a large series of 1811 patients with HNSCC treated with (chemo)radiotherapy, recently reported IRR only in 5.2% of cases. Moreover, regional recurrences show improved survival compared to local, loco-regional or distant metastases.[41,42]

The risk factors for development of IRR in HNSCC are actually not well defined: some authors advocate the role of initial advanced local and regional stage, p16 status and presence of node with extranodal extension (ENE) in neck dissection carried out as primary treatment to be linked to a higher IRR rate but strong evidences are still lacking.[41–44] Similarly, isolated neck recurrences seem to be located in previous treated neck side in about 80% of cases but further studies are needed to confirm this data.[41,43] There are no difference in the IRR rate based on tumour location.[42]

The occurrence of isolated neck recurrence is likewise uncommon in the other head and neck malignancies and a great variety of predictive and prognostic factors are under investigation for each different histological subtype; nevertheless, the rarity


24 of this condition makes the enrolment of large court of patients challenging and evidence in this field are consequently weak.

According to 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer[45] the risk of neck recurrence in thyroid cancer is closely related to the initial lymph node status: most lymph node recurrences occur in already involved compartments; the risk increases with a higher number of N1 and a higher number of N1 with extracapsular extension and with macroscopic rather than microscopic lymph node metastases. In low- and intermediate-risk patients, the risk of lymph node recurrence is low (<2%) in patients with undetectable serum thyroglobulin (Tg) and is much higher in those with detectable/elevated serum Tg.

Literature about neck metastases in medullary carcinoma is poor; however, it is well known that they mainly affect central compartment/mediastinal node and ipsilateral latero-cervical levels. A recent study by Machens et al.[46] reported recurrences in the dissected central, ipsilateral lateral and contralateral lateral neck in 4.4%, 6.3% and 2.1% of cases, respectively. This author identifies tumour size > 20 mm and extranodal growth as predictive factor of overall and node recurrence in the central neck and the ipsilateral lateral neck, respectively.

Considering sinonasal malignancies, IRR are 7.3% of all recurrences, being the most frequent local or loco-regional relapse. Primary tumour location, histology, stage, or local extension are sometimes identify as risk factor of recurrence but no conclusive evidences are actually available due to the rarity of the pathology, the limited number of patients enrolled in each study and the low rate of neck relapses.[47] In addition, it is important to remember that recurrence can occur many years after definitive treatment for particular histological varieties, such as esthesioneuroblastoma, adenoid cystic carcinoma or malignant melanoma, and long-term follow-up is consequently recommended.[48–50]

Melanoma differ from other tumours for pattern of recurrence: in a large study regarding 168 patients affected by stage I and II melanoma, Namin et al.[51], reported occurrence of local, regional, distant and simultaneous recurrences in 18%, 18%, 49%


25 and 15% of cases, respectively, being distant metastases the most frequent. For stage IIIB disease, clinically evident relapse in cervical lymph nodes are instead reported in 28 % of patients and ENE could be consider an important risk factor associated with recurrence and a poor prognosis.[52] Careful attention must be paid to recognise a suspect relapse in the parotid gland, which could represent the first drainage station for most head melanomas; furthermore, a recent study by Den Hondt et al.[53] demonstrate that patients with clinically apparent metastatic melanoma involving the parotid lymph nodes had a 20% risk of occult neck disease, with the disease most commonly found in levels II, III and V.

2.2 Diagnosis of regional recurrence

In general, after definitive treatment for head and neck tumour, patients enter a period of observation and surveillance. The main aim is to attempt to identify neck recurrence at an early stage and, therefore, to institute salvage treatment where possible.[54–56]

The important of clinical examination remains straightforward in follow-up of HNSCC patients; however, palpation alone is not accurate in recognizing metastatic lymph nodes both before and after primary treatment and it is not useful to assess deep space of the neck.[57] For this reason, imaging studies are essential in surveillance of HNSCC.[58]

As the post-treatment neck can be difficult to evaluate on imaging because of the distortion of anatomy and postradiation/postsurgical changes, it is critical to obtain high-quality baseline posttreatment imaging, especially for areas that are difficult to evaluate clinically, in order to have comparison images available for follow-up studies. [54,55].

Several imaging modalities, including contrast-enhanced computed tomography (CT), contrast-enhanced magnetic resonance imaging (MRI), and fluorodeoxyglucose (FDG) positron emission tomography (PET) or PET-CT are


26 commonly used during follow-up for detection of residual/recurrent nodal disease in HNSCC[54,55,58,59].

CT and MRI suspect criteria for neck metastases include rounded shape (maximum longitudinal length to transaxial width ratio of less than 2), maximum lymph node axial diameter (>8 mm for the parapharyngeal and retropharyngeal spaces, >15 mm for levels I–II, or >10 mm for other cervical regions) and presence of central necrosis (a central area of low attenuation on CT or a core of T2 hyperintensity and central non-enhancement on T1-weighted postcontrast images). Lymph nodes are considered suspect on PET/PET-CT if a focus activity is significantly above expected background and could not be explained by a normal structure; standardized uptake values (SUV) is secondary indicators for malignancy[59,60].

Contrast-enhanced MRI and CT are routinely used in follow-up in HNSCC patients and they are useful to detect synchronous local recurrence and to evaluate high-resolution node detail that may be essential to exclude or otherwise indicate salvage surgery, such as for example the presence of extracapsular spread, vascular infiltration, muscle, cartilage or bony invasion, infiltration to other organ (thyroid, oesophagus, brain or dural invasion), extension to cranial base or superior thoracic outlet. However, CT and MRI show important limitations in detect recurrent head and neck cancer after radiotherapy mainly due to radiation-induced tissue distortions.[56,61] For example, CT is reported to have a negative predictive values of 94–97%, with a good sensitivity (75–97%) but with a specificity ranging from 24% to 93%.[56] Similarly, MRI has been found to have a slightly disappointing sensitivity and specificity in detecting metastatic nonenlarged lymph nodes as it shows a sensitivity of 72% and a specificity of 88% in cervical recurrent disease.[62]

The current generation of PET and CT/PET, with 5 to 6 mm resolution, may be more sensitive and specific than cross-sectional anatomic imaging for the diagnosis of head and neck cancer when neck recurrence is suspected and its use is recommended alone or in addiction to CT/MRI in HNSCC surveillance[59,60,63–65]. In a recent review of 27 studies, Isles et al. reported a sensibility, specificity, positive predictive value and negative predictive value of PET/CT for detecting residual or recurrent


27 HNSCC of 94%, 82%, 75% and 95%, respectively. In addition, Kim et al.[59] recently developed a comparative study between CT, MRI and PET-CT for the detection of nodal recurrence and demonstrated the highest accuracy of the latter than the other methods in this field: the sensitivity/specificity/accuracy of CT, MRI, and PET-CT results 66.3/99.4/92.4%, 74.7/99.4/94.2%, and 85.5/94.9/93.0%, respectively.

The most significant disadvantage of PET or PET/CT in follow-up of HNSCC patients is linked to the hight rate of false-negative result when performed close to the end of radio(chemo)therapy. It could be due to radiation-induced changes in FDG uptake, the transient decrease the number of viable cancer cells or extended necrosis development.[66] For this reason, many authors recommended not to perform PET or PET/CT within 3 month of CT/RT. [58–60,63–66]

Another important tool to confirm the presence of neck recurrences is fine needle aspiration cytology (FNAC). Previous data suggest that FNAC is a highly accurate, safe, and inexpensive method of assessing lymph node metastasis in untreated HNSCC.[67,68] A review by Tandon et al.[67] on 30 studies and 3459 FNAC total sample, detect a sensibility, specificity, positive and negative predictive value for lymph nodes evaluation of 94.2%, 96.9%, 98.9% and 84.6%, respectively. However, limited data are available to evaluate the efficacy of this technique in the setting of prior CRT and uncertainty still exists to possible role of post-treatment necrosis and fibrosis to misdiagnosis. A recent study by Fleischman et al.[69] proves the usefulness of FNAC to confirm suspect neck recurrence on CT in previously treated HNSCC patients, detecting a sensitivity of 80%; specificity, 100%; positive predictive value, 100%; and negative predictive value, 92.3%. However, a Kotowski et al.[70] subsequently demonstrated a high number of non-diagnostic samples in irradiated field, equal to 33%. Both these studies enrol less than twelve patients and are not enough to validate the accuracy of FNAC in detection of neck recurrences.

In this panorama, some modern imaging techniques promise important advantage to detect recurrent neck disease in HNSCC patients.

Diffusion-weighted MRI uses strong magnetic field gradients to make the MRI signal sensitive to the molecular motion of water and is able to characterize tissue and


28 generate imaging contrast based on differences in diffusion motion of water protons in the tissues. The molecular motion can be determined by calculating the apparent diffusion coefficient (ADC) with diffusion-weighted MRI. ADC values are expected to vary according to microstructures or pathophysiologic states of the tissues: residual or recurrent lesions appear as areas of low signal intensity on the ADC map, whereas, post-treatment changes appear as areas of high intensity on the ADC map.[56] A recent study of Mundada et al.[71] recently shows that DWIMRI could be considered a useful tool in post-treatment follow-up of HNSCC patients and it may aid the surgeon to confidently perform or defer selective salvage neck dissection in the treated neck: sensitivity, specificity, positive (PPV) and negative (NPV) predictive values of this method result 100%, 44.4% (15.3;77.3), 86.1%, and 100%, respectively. However, literature in this field is actually poor and the limited availability of this tools in various centers limits its routine use in clinical practice.

Finally, PET/MRI could very helpful in overcome the limit of MRI alone in identifying micrometastatic disease in nonenlarged lymph nodes. However, the evidence in this field are largely insufficient and its potential needs to be investigated further.[62]

The diagnostic iter to assess neck recurrence for other malignancies is almost the same as described above for HNSCC, such as cutaneous melanoma, salivary gland tumour and most of paranasal sinus cancers;[58,72] however some important variations are sometimes needed for other histological entity. For example, ATA guidelines[45] clearly indicate the best diagnostical tools in follow-up after curative treatment for thyroid cancer in order to achieve an early detection of neck recurrences. In thyroid cancer, serum markers represent important tool in early detection of recurrence: serum levels of Calcitonin (Ctn) and carcino-embryonic antigen levels (CEA), should be measured 3 months after primary treatment of medullary carcinoma and, if level exceeds 150 pg/mL further investigations are needed. Similarly, serum thyroglobulin (Tg) could be used in follow up of differentiated thyroid carcinoma.


29 Another important and not-invasive tool is ultrasonography; it is highly sensitive in the detection of cervical metastases in patients with differentiated thyroid carcinoma (DTC) and medullary thyroid cancer. All the suspicious lymph nodes >8– 10 mm in the smallest diameter should be biopsied for cytology with thyroglobulin (Tg) or calcitonin (Ctn) measurement in the needle washout fluid.

The last peculiarity in recurrence diagnosis in thyroid cancer is represented by whole-body scintigraphy (WBS) with Iodine 123: it allows detection of iodine-secerning tissue whether it is local or lymph node recurrence or distant spread. It can be useful, mainly in combination to CT scan (SPET/CT), in three primary clinical settings for a better characterization of suspicious regional metastases: (i) patients with abnormal uptake outside the thyroid bed on posttherapy WBS, (ii) patients with poorly informative postablation WBS because of large thyroid remnants that may hamper the visualization of lower uptake in neck lymph nodes, and (iii) patients with Tg antibodies, at risk of false-negative Tg measurement, even when neck US does not show any suspicious findings.

2.3 Therapeutic options in regional recurrences.

Salvage neck dissection

According to NCCN guidelines and current literature, salvage neck dissection offers the best curative chance for patients with resectable isolated neck recurrences of head and neck cancer.[41,44,45,47,51,52,58,72–74] The major criteria of unresectable disease include lymph node metastases involving prevertebral fascia, skull base or encasing carotid artery.[73]

Although indication to salvage surgery is straightforward for neck recurrence of HNSCC in previous untreated neck and surgical treated neck, the approach in case of primary radiotherapy is deeply changed in the next ten years. It is generally accepted that patients with documented recurrence or residual regional disease after RT require an additional neck dissection; as opposite, in case of initial N1 disease with a complete response after radiotherapy no treatment are needed. In case of N2–N3 disease, a


30 planned neck dissection (PND) 8 weeks after radiation was considered the gold standard in many institutions; however, the results of modern radiation techniques associated with chemotherapy in achieving long-lasting loco-regional control and improvements in diagnostic technology have led to abandon the indication of PND.[43,75,76] Moreover, viable tumour cells are recorded in only 30-50% of routinely performed neck dissection specimens after chemoradiation; so surgical indication still exists only in case of proved residual or recurrent disease on clinical and radiological evaluation +/-FNAC.[56]

The extent of neck dissection after CTRT is actually under discussion: the early literature supported the use of the modified radical neck dissection in all patients regardless of whether there was a complete response in the neck or not; however, subsequent studies demonstrated that it is feasible to perform a conservative salvage neck dissection that is limited to 2 contiguous neck levels, particularly when disease is limited to 1 or 2 level.[29,77–80] However, there is an emerging body of evidence to suggest that occult additional metastases can be detected in salvage neck dissection specimen in 25% of patients with IRR, mainly located in level IV and V; on the other hand, the real prognostic significance of these metastases is still unknown.[73] In summary, the discussion regarding the extent of neck dissection in IRR is still open and further study are needed to solve the matter.

Over the past three decades, several studies have focused their attention on the outcome of salvage neck dissection in IRR, looking for prognostic factors to select patients who might primarily benefit from this treatment. This type of surgery could indeed be challenging due to the patients' overall poor health at the time of relapse and the increased risks of short-term adverse events and related complications reported by previous authors after chemoradiotherapy or in case of second neck surgery.[29,73]

The literature relating to SCC is particularly extensive and recent studies confirm the indication of salvage therapy in about 80% of cases with an overall 5-year survival between 20% and up to 70%.[41,44,73,74,81–85] Although there is no agreement on prognostic factors, the most investigated and which seem to correlate best with the outcome of these patients are the presence of ENE[41,44,73,74,85],


31 margins[41,74] and the ground-breaking role of HPV status[41]. Table 3 summarises the main and most recent evidence in this field.


32 Author Year Number of


Localizatio n

Primary treatment Time to recurrenc e


Salvage treatment Oncologic outcome after salvage treatment Prognostic factor Lindegaar d A.M. et al.[41] 2007-2017 95 IRR/1811 tot (5.2%) HNSCC RT 36.8% CHT-RT 54.7% Surg+RT 8.4% 7 Palliation 14% Surgery 84% RT 2% 2-years OS 40% 5-years OS 25% (-) ENErec and R+ (+) p16+ Giger R. et al.[73] 2003-2017 76 IRR/498re c (15.2%) HNSCC RT 22.4% CHT-RT or Surg+RT 46% Surg 31.6% 18.1 Palliation 14.5% Surgery 76.3% RT 7.8% 5-years OS 56.89% 5-years RFS 37.5% (-) initial stage IVA-B, ENErec, higher LNR, soft-tissue infiltration Liu Y. et al.[74] 1984-2014 294 IRR Only nasophary nx

CHT-RT 100% 20 Surgery 100% 3-years OS, LRFS, RRFS, DMFS of 67%, 51.4%, 64.3%, 65% 5-years OS, LRFS, RRFS, DMFS of 40.5%, 29.6%, 38.4%, 39.8% (-) ENErec, rN, R+ Leòn X. et al.[44] 1985-2012 123 IRR HNSCC CHT-RT or RT 68.3% Surg+RT 31.7%

- Surgery 100% 5-years salvage specific survival in ENE+ 32%


33 5-years salvage specific survival in ENE- 77.2% Lim j. et al.[81] 1991-2006 61 IRR /236rec (26%) HNSCC Surg+RT 100% 7 Palliation 19.7% Surgery 57% CHT-RT or RT 23% 3-years OS surgical salvage ND 36% 3-years non-surgical salvage 12% (+) surgery alone as primary treatment, rN1 Krol B. et al.[82] 1981-1988 77 IRR in treated field HNSCC RT 31.2% Surg 14.3% Surg+RT 50.6%

- Surgery 100% 3-years DFS 33% (+) not surgery as primary treatment, R0 in primary treatment, no prio recurrence, ipsilateral recurrence, surgery as salvage treatment Chung E. et al.[83] 1993-2012 55 IRR HNSCC CHT-RT 25.5% Surg 29.0% Surg+RT 45.5% <6 months (52.4%) >=6 months (67.6%) Surgery 100% 5-years OS 55% 5-years DFS 60% (-) ENE and advanced N in primary tumour, in field recurrence


34 (+) Time to recurrence >6 months van den Bovenka mp K. et al.[84] 2003-2015 87 IRR HNSCC RT 35% CT-RT 65% 6.4 Surgery 100% 5-years OS 55% 5-years DFS in RT alone 42% 5-years DFS in CHT-RT 62% None Jeong W. et al.[85] 1988-2004 25 rec/463 tot (5.4%) 76% IRR 24% loco-regional rec Only laryngeal cancer RT 24% CHT-RT 12% Surg 64% 13 Surgery 100% (ND+/-laryngectomy) 5-years OS 61.2% 5-years DFS 39.5% (-) Contralateral recurrence (history of local recurrence, recurrence in previous ND, recurrent node>3cm) Table 3: Recent literature regarding surgical treatment of isolated neck recurrence (IRR) in head and neck squamous cell carcinoma (HNSCC).


35 Surgery is the best treatment option in isolated cervical recurrence not only for SCC patients but also in other hystological varieties of head and neck tumours.

According to 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer[45], malignant central neck nodes >=8 mm and lateral neck nodes >=10 mm in the smallest dimension that have undergone FNAB and can be localized on anatomic imaging (US with or without axial CT) can be considered surgical targets. However, given the risks of revision nodal surgery, multiple factors in addition to size should be taken into account when considering surgical options, including proximity of given malignant nodes to adjacent vital structures and the functional status of the vocal cords. Revision lateral neck dissection should involve levels II, III, and IV, while revision central neck dissection includes at least one paratracheal region with prelaryngeal and pretracheal subcompartments.

Despite uncertainty linked to high rate of distant metastases in cutaneous melanoma, NCCN guidelines[72] recommend surgical treatment for in-transit and regional recurrences, followed by adjuvant systemic or locoregional (RT or re-RT) therapy. A recent study by Barbour et al.[52] recorded a head and neck regional 5-year recurrence rate (combining in-basin nodal and in-transit) of 23 %. All patient underwent to salvage therapy (surgery in 89% and radiotherapy in 11% of cases) but distant disease progression occurred in 63 % of patients and mainly within 12 months; thus, the authors concluded that nodal recurrence is often the precursor of distant disease and emphasize the need of an aggressive treatment with a keyrole of adjuvant treatment.

Non-surgical treatment

Treatment of surgically non-salvageable recurrent HNSCC remains a therapeutic problem with reirradiation with a tumouricidal dose as being one of the few available curative options. The improvement of technology and the introduction of new tools, such as proton therapy, has changed the old assumption of a too high incidence of radiation-related toxicities in previous treated neck; thus, irradiation or re-irradiation can actually be considered an option for these patients.[42] In our


36 knowledge, papers focused only to the outcomes of radiotherapy in IRR are not available; nevertheless, studies including both surgery than IMRT as treatment option in these patients do not show significant difference in overall survival, despite of a trend toward a better results in surgical group.[41,73,81] For example, Lim et al.[81] reported 3-years OS of 12% in nonsurgical salvage group compared to 36% in patients underwent neck dissection (p = 00.101). According to Ward et el.[86], the group most suitable group of recurrent HNSCC to benefit the re-irradiation are patients that relapse after > 2 year from the index treatment with unresectable recurrence or ≤2 year from the index treatment but without organ dysfunction.

Literature regarding proton and carbon-ion therapy is increasing in the last few years. Romesser et al.[87] reported on the outcome of 92 patients with recurrent HNSCC treated with proton reirradiation and recorded a 1-year OS and loco-regional control rates of 65% and 75%, respectively, despite therapy-related toxicity in about 7% of patients. Similarly, Gao et al.[88] analysed 141 patients treated with carbon-ion therapy for locoregional recurrence of head and neck cancer and reported 1-year overall survival rate, local, regional, and distant progression free survival rates of 95.9%, 84.9%, 97.7%, and 96%, respectively. However, both these studies do not separately show the outcomes regarding neck disease and long-time results and further studies are needed to confirm the indication of proton and cabon-ion therapy in this field; moreover, an important limit is that these techniques are not actually available worldwide.

In case of differentiate thyroid cancer, percutaneous ethanol injection (PEI) and radiofrequency ablation (RFA) could represent an alternative option to salvage surgery. Even if the studies regarding PEI are limited, recent researches show ablation of recurrent lymph nodes in 46-84% of cases with no major complications; on the other hand, disadvantages include the need of multiple session (one to five) and the inability to treat lymph node >2cm. RFA shows similar limitations and results with a complete disappearance of the metastatic foci in 40%–60% of the cases. In conclusion, these techniques should be mainly considered as in patients who are poor surgical candidates.[45]


37 Systemic therapy and immunotherapy are indicated in patients with non-salvageable isolated cervical recurrence to control the disease. The major development of the past decade in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck was the introduction of cetuximab in combination with platinum plus 5-fluorouracil chemotherapy (CT), followed by maintenance cetuximab (the “EXTREME” regimen).[89] In platinum-refractory patients, Nivolumab represented the second-line treatment.[90]

However, a randomised study done at 200 medical centres in 37 countries and including 882 participants (KEYNOTE-048) recently indicate pembrolizumab plus platinum and 5-fluorouracil as first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy for PD-L1-positive recurrent or metastatic HNSCC: OS in pembrolizumab alone versus cetuximab with chemotherapy in PD-L1 positive patients are 14·9 months and 10.7 months, respectively; Pembrolizumab with chemotherapy improved overall survival versus cetuximab with chemotherapy in the total population (13.0 months vs 10.7 months).[91]


38 3. Clinical study

3.1 Objective

Neck dissection (ND) certainly represents one of the highly complex and potentially life-threatening procedures in head and neck surgery; however, careful and thorough anatomical knowledge, as well as surgical experience and expertise, ensure complications to remain reasonably low.[25,27,29,33,34]

In recent years, radiotherapy (RT), whether or not associated with chemotherapy (CHT), is finding more and more indications as primary treatment of head and neck tumours, guaranteeing survival rates comparable or even higher than surgery alone, together with a better functional outcome[58,92–96]. On the other hand, in case of regional or locoregional recurrence, previous RT/CHT treatments might increase salvage treatment related complications[75,97,98]. In fact, previous studies[99–101] have largely demonstrated that radiotherapy and chemotherapy induce tissue reworking and increase local fibrosis which could make surgery particularly complex, by affecting the vascularization and healing capacity of the tissues.

Although complications of salvage surgery after primary conservative laryngeal and pharyngeal cancer treatment have been largely studied in literature[102– 104], evidences regarding the adverse events of salvage neck dissection (ND) alone are currently poor. In our opinion, considering patients with both regional and locoregional recurrence could lead to an overestimation of the complication rate of ND after RT/CHT, since the adverse events are more attributable to surgery on tumour site, rather than on cervical node recurrence.

In this setting, herein we propose a multicentric retrospective study to analyse isolated regional recurrence (IRR) salvage treatment’s outcomes in head and neck cancer patients. Our primary aim was to assess differences, if any, between the incidence of complications of salvage neck procedure after primary surgery +/- adjuvant treatment vs. primary single modality RT or concurrent RT-CHT. Our secondary endpoint, was to identify factors affecting re-recurrence incidence and survivals.


39 3.2 Material and methods

We retrospectively analysed all the patients who underwent salvage neck dissection for isolated neck recurrences in three different second-level Italian Institutions (Careggi University Hospital in Florence; University Hospital in Verona and University Hospital in Modena) between 2008 and May 2020.

This study was conducted in accordance with the current revision of the Declaration of Helsinki and with the approval by the local Ethical Committee (registration number: 17798_oss).

The indications for salvage neck dissection included the presence of IRR at preoperative evaluation without other concomitant site of relapse, regardless of primary treatment performed (surgery and/or RT/CHT). Patients had been informed of the risks, alternatives, and goals of treatment, and they had provided informed consent before initiation of treatment.

Preoperative management included magnetic resonance imaging (MRI) and/or computed tomography (CT), followed by positron-emission tomography (PET) and/or fine needle aspiration. The decision regarding the best suitable therapy was made by the multidisciplinary tumour board of each institute.

Amendable patients received salvage neck (with or without postoperative re-irradiation) with curative intent for isolated neck recurrence of head and neck malignant tumour. All primary tumour subsites and histological types were included. Neck recurrences were confirmed at the final histological report. Exclusion criteria encompassed: any concomitant loco-regional or isolated local or distant recurrences; patients who received extra-boost salvage RT; incomplete reports on recurrence stage and surgical salvage strategy, such as post-operative complication time onset and type; absence of histologically confirmed relapse; absence of consent to join to the study.

Specific tumor and treatment characteristics were stated, including: 1) patient preoperative assessment; 2) type and stage of primary and recurrent tumour; 3) surgical data (type of treatment, type of neck dissection performed, surgical time and intraoperative details, such as: extension to other structures, need of free flap


40 reconstruction, presence of difficult dissection, accidental vascular and nervous injury); 4) hospital stay and postoperative complications (surgical and systemic complications, need to revision surgery, drainage tube volume and removal, nasogastric tube and tracheal cannula removal, hospital stay); 5) adjuvant postoperative treatments. In particular, comorbidity was recorded and classified according to Charlson Comorbidity Index version validated for head and neck[105].

Statistical analysis

The following endpoints were considered: complication rate of salvage neck dissection, including both surgical and systemic ones; post-recurrence overall survival (OS), defined as the time between the date of salvage surgery and the date of death/last visit; post-recurrence disease-free survival (DFS), defined as the time between the date of salvage surgery and the date of any recurrence/last visit.

Lymph node ratio (LNR) was calculated as the ratio of positive lymph nodes out of the total number of lymph nodes removed. Based on the median LNR value of 10.3, a LNR cut-off value of 10% was selected to stratify patients into roughly equal-sized groups[106].

The influence of type of primary and recurrence treatment was estimated through the computation of OS and DFS curves using the Kaplan–Meier method and comparison by the χ2 test. Univariate analysis regarding most clinically relevant factors for re-recurrence and death risk and complication development was performed using the regression Probit test with 95% confidence intervals (CI).

All the tests were 2 tailed, and p values <.05 were considered to be statistically significant. Data were analysed using Stata 14.0 software.

3.3 Results

Study population

A total number of seventy-three patients underwent salvage neck dissection for suspected isolated neck recurrence at our Institutes during the study period. 64 out of them met our inclusion criteria, while the remaining nine were excluded because they had no histologically proven disease at the final histological report.


41 Our study population included 51 male and 13 female (M:F=3.9:1) and the mean age at the diagnosis of single neck recurrent disease was 65.6 years (SD 11.89 ± 1.49; range 29-87 years); most of the patients reported current or previous smoking habits (almost 70% of total cases). Table 4 summarizes demographic, clinical and treatment characteristics.

Regarding the primary tumour, the oral cavity was the most frequently affected site (20.31%), followed by pharynx and skin (18.75% each respectively). Clinical stages reported a high percentage of T1 and T2 (34.38% and 25.00%, respectively); whereas, advanced stages were unusual (T3 and T4 in 12.50% and 15.63% of the cases, respectively). In more than half of the cases (53.13%) there was no evidence of lymph node metastasis at primary diagnosis.

n° patients % Epidemiology and risk factor


M 51 79.69 F 13 20.31 Age 69 (median); 65.6 (mean) (SD 11.89 ± 1.49) Charlson Comorbidity Index

0 3 4.69 1-2 15 23.44 3-4 22 34.38 >=5 24 37.50 Smoke No smoker 17 26.56 Ex smoker 12 18.75 Current smoker 31 48.44 Not available 4 6.25 Primary tumour Location Oral cavity 13 20.31 Pharynx p16- 12 18.75 Pharynx p16+ 5 7.81 Larynx 8 12.50 Thyroid 2 3.13 Paranasal sinus 2 3.13 Nasopharynx 5 7.81 Melanoma 3 4.69 Skin cancer (not melanoma) 12 18.75

Other 2 3.13 cT


42 cT2 16 25.00 cT3 8 12.50 cT4 10 15.63 Not available 8 12.50 cN cN0 34 53.13 cN1 7 10.94 cN2a 2 3.13 cN2b 4 6.25 cN2c 4 6.25 cN3a 4 6.26 cN3b 1 1.56 Primary treatment Surgery 24 37.50 RT or RT/CHT 22 34.38 Surgery + adj RT/CHT 18 28.13 Type of neck dissection

No neck dissection 44 68.75 Ipsilateral ND 11/20 55.00 Bilateral ND 9/20 45.00 pT (42 patients) pT1 18 41.86 pT2 8 19.05 pT3 6 14.28 pT4 6 14.28 Not available 5 11.90 pN (20 patients) pN0 9 45.00 pN+ 9 45.00 Not available 2 10.00 ENE ENE- 19 95.00 ENE+ 1 5.00

Primary treatment included surgery, single modality RT or concurrent RT/CHT or surgery followed by adjuvant treatment in 37.50%, 34.38% and 28.13% of the cases, respectively. Primary neck dissection was performed in 55% of the cases; all but one patient underwent selective neck dissection, both ipsilateral than bilateral. Both post-operative RT and single modality RT treatments included prophylactic neck irradiation.

Salvage neck dissection

Table 4: Demographic, clinical and treatment characteristics of primaru tumour. ND: neck dissection; ENE: extranodal extension.


43 Ipsilateral regional recurrence was detected in 76.56% of the cases; whereas, contralateral or bilateral relapse affected 18.75% of the patients. Preoperative staging showed single (51.56%) and multiple (45.31%) suspected cervical nodes detection, respectively. Even if 33 out of 64 patients had only one metastatic lymphadenopathy (rcN1), 11 out of them (33.3%) were classified clinically extra-nodal extension (ENE) positive (rcN3), showing an advanced nodal stage despite single cervical recurrence. Overall, clinical staging of recurrent disease was recorded as follow: rcN1 (25.00%), rcN2 (42.19%) and rcN3 (28.12%).

A mean interval of 26.79 months (range 3-264 months) for isolated regional recurrence (IRR) disease onset was observed in our study population; the 45.31% of the cases experienced IRR within the first 2 years of follow-up (Figure 13). In particular, a mean time to relapse for rcN1, rcN2 and rcN3 stage was 35.36 months (SD 61.10 ± 15.78), 35.08 months (56.40 ± 10.85) and 9.11 months (SD 9.21 ± 2.17), respectively. As show in Figure 14, 61.11% of rcN3 recurrence was observed within 6 months, compared to 33.33% and 1.56% at 6-24 and 24-60 months; no rcN3 recurrences occurred after 5 years.

0 5 10 15 20 25 30

<6 months 6-24 months 24-60 months > 60 months

Time distribution of recurrences

rcN1 rcN2 rcN3 All rcN

Figure 13: Time distribution of IRR. Coloured lines distinguish clinical stage of neck recurrence.


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We know from animals studies that fermentable fiber and prebiotics reduce the risk of metabolic disease and obesity (Arora et al., 2012), and similarly, that the type and quantity

An open biopsy in the neck always is done by a surgeon familiar with the plan- ning for possible neck dissection, because a diagnosis of squamous cell cancer in a node mandates

Since fewer than 3% of cysts are found in pa- tients older than 50 years, the pathologist must be care- ful in making this diagnosis in this age group; a met- astatic cystic

One reason for assembling all these different organs under the title “Pathology of the Head and Neck” is that the proximity of the organs of the head and neck region makes

Axial T2-weighted image demonstrates high het- erogeneous signal from the mass lesion in the right parotid gland

Intense soft palate and right greater than left posterior tongue activity, probably physiologic.. Negative for metastatic disease on

A complete sinusogram (as opposed to an incomplete or absent sinusogram) diagnoses total opacity of the sinus (if opposed to partial opacity, i.e., the air–fluid level, hypertrophy

(1984) Dental and maxillofacial abnormalities in long-term survivors of childhood cancer: effects of treatment with chemotherapy and radiation to the head and neck. Kaste SC

Angiogram shows tumoral blush arising from the internal maxillary artery, the facial artery and the ascending pharyngeal artery (c–f). Preoperative embolization with particles

Proven regional dif- ferences concerning the density and also the orientation of the lymphatics of the upper aerodigestive tract are not only important regarding the direction

It is the staining of the tumor cells that establishes the correct diagnosis because aspirates from medullary and metastatic carcinomas in the thyroid may also show


Functional imaging with FDG PET has been shown to be useful in the detection of the primary tumor site in patients with metastatic cervical adenopathy, initial staging of